UA77180C2 - Hiv protease inhibitors - Google Patents

Abstract

Compounds of formula (I) where the formula variables are as defined herein, are disclosed that advantageously inhibit or block the biological activity of the HIV protease. Theses compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with the HIV virus. Intermediates and synthetic methods for preparing such compounds are also described. I

Description

Description of the invention

This invention relates to novel compounds useful as HIV protease inhibitors and to the use of such compounds 2 as antiviral agents for the treatment of HIV-infected individuals. This invention also relates to methods of obtaining these compounds and intermediates useful in their preparation.

Acquired immunodeficiency syndrome (AIDS) causes gradual destruction of the body's immune system, as well as progressive deterioration of the central and peripheral nervous systems. Since its initial detection in the early 1980s, AIDS has spread rapidly and has now reached epidemic proportions in a relatively limited 70 sector of the population. Intensive research led to the identification of the responsible agent, human T-lymphotropic retrovirus II (HTIM-III), now more commonly known as human immunodeficiency virus or HIV.

HIV is a member of a class of viruses known as retroviruses. The retroviral genome consists of RNA, which is converted into DNA by reverse transcription. This retroviral DNA is then stably integrated into the chromosome of the host cell and, using the replicative mechanisms of the host cell, produces new retroviral particles and 12 transmits the infection to other cells. HIV has been found to have a specific affinity for human T-4 lymphocyte cells, which play a vital role in the body's immune system. HIV infection of these white blood cells dramatically reduces the population of these white blood cells. Ultimately, the immune system becomes inoperative and ineffective against various opportunistic diseases such as pneumocystis pneumonia, sarcoma, among others.

Kaposi, and cancer of the lymphatic system.

Although the exact mechanism by which the HIV virus is formed and functions is not understood, the identification of the virus has led to some progress in the fight against the disease. For example, the drug azidothymidine (AT) has been found to be effective in inhibiting the reverse transcription of the retroviral genome of the HIV virus, providing a treatment option, although not a cure, for patients affected by AIDS. The search for drugs that can cure or at least improve ways to fight the deadly HIV virus continues. with

Retroviral replication is usually characterized by post-translational processing of poly proteins. This Ge) processing is accompanied by the HIV-protease enzyme coded by the virus. This gives fully developed polypeptides, which will further contribute to the formation and functioning of the infectious virus. If this molecular processing is inhibited, then normal HIV production is limited. Therefore, HIV protease inhibitors may function as agents against the HIV virus. at

HIV protease is one of the translated products of the HIV structural protein gene. This retroviral protease specifically cleaves other structural polypeptides at discrete sites to release these newly activated structural proteins and enzymes, thus resulting in virion replication efficiency. As such, inhibition of HIV protease by effective compounds may prevent proviral integration of infected cells

T-lymphocytes during the early phase of the HIV-1 development cycle, as well as to inhibit viral proteolytic 3o processing during its late stage. In addition, protease inhibitors may have the advantages of being more suitable, longer acting in the virus, and less toxic than currently available drugs, possibly due to their specificity for the retroviral protease.

Related HIV protease inhibitors are described, for example, in US patent Mo5962640, US patent Mo5932550, Australian patent Mo705193, Canadian patent application Mo2179935, European patent application Mo0751145 and Japanese patent application Mo100867489. Other related inhibitors of HIV protease are described |K. Mozpitiga, ei ai., Rgosi Maid. Asai Zsi. OBA, 96, 8675-8680 (1999) and T. Mitokyu, et al., U. Meda. Spet., 42, 1789-1802 (1999)).

Existing treatment of HIV-infected individuals with HIV protease-inhibiting compounds has resulted in the development of mutant viruses having proteases that are resistant to the inhibitory action of these compounds. Therefore, in order to be effective, new HIV protease inhibitors must be effective not only against natural strains of HIV, but must also show efficacy against new mutant strains that have emerged and are resistant to and commercially available suitable protease inhibitors. Accordingly, the development of new inhibitors targeting the HIV protease in natural and mutant HIV strains is needed. The invention relates to compounds useful in inhibiting the activity of HIV-protease, of the formula I:

B represents a 5- or b-membered mono-cyclic carbocyclic or heterocyclic group, where said carbocyclic or heterocyclic group is saturated, partially unsaturated or fully unsaturated and is unsubstituted or substituted by one or more suitable substituents;

IN? represents substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, b5 zSubstituted phenyl, substituted phenylalkyl, substituted or unsubstituted phenylalkenyl or substituted or unsubstituted phenylalkynyl,

22? represents H or substituted or unsubstituted S.--Slalkyl;

X represents STILL I ; where Ku represents H or one or more suitable substituents of Aeneas and its lead 7 represents 5, О, 50, 505, СН» or СЕН;

K represents H or substituted or unsubstituted C.-C, alkyl 70 B", 25, 25 and KE" independently selected from the group: H or C.-Svalkyl; and 28 and EB are independently selected from the group: H halogen C-Saliphatic group or C.4-Shalogen substituted aliphatic group; where any of the indicated substituted alkyl, alkenyl, or alkynyl is substituted by one or more suitable substituents, provided that the indicated 5- or 6-membered monocyclic heterocycloalkyl, heterocycloalkenyl, or heteroaryl contain at least two hetero atoms, when B? represents substituted phenyl, substituted phenylalkyl, substituted or unsubstituted phenylalkenyl, or substituted or unsubstituted phenylalkynyl; or provided that said alkyl, alkenyl or alkynyl part of said substituted phenylalkyl, phenylalkenyl or phenylalkynyl is substituted with one or more substituents selected from the group: halogen or keto; or provided that said substituted phenyl or the phenyl portion of said substituted phenylalkyl, phenylalkenyl or phenylalkynyl is substituted with one or more suitable substituents other than halogen or methyl.

The present invention relates to compounds of the following formula I and their prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts and solvates that inhibit the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2), and as well as their mutant strains. These compounds are useful in the treatment of HIV infection and the treatment of acquired immunodeficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions of the present invention may be used alone or in combination with other antiviral agents, immunomodulators, antibiotics, or vaccines.

Compounds of the present invention can also be converted into prodrugs by derivatization by conventional methods. at

Methods of treatment of AIDS, methods of treatment of HIV infection and methods of inhibition of HIV protease are revealed. ee)

According to the convention used in the prior art, сх is used here in structural formulas to denote a bond that is the point of attachment of a group or substituent to the core or framework structure. uh-

As used herein, the term "aliphatic" represents a saturated or unsaturated straight-chain or branched-chain hydrocarbon containing from 1 to 10 carbon atoms, which may be unsubstituted or substituted with one or more suitable substituents as described below. The term "aliphatic" includes alkyl, alkenyl and alkynyl.

As used herein, the term "alkyl" represents a straight or branched chain saturated or unsaturated hydrocarbon containing from 1 to 10 carbon atoms, which may be unsubstituted or substituted with one or more suitable substituents as described below. Typical alkyl substituents include, but are not limited to, methyl (Me), ethyl (Eu, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.) The term "lower alkyl" refers to an alkyl containing from 1 to 6 carbon atoms." The term "alkenyl" represents a saturated or unsaturated hydrocarbon with a straight or branched chain containing one or more carbon-carbon double bonds, and having 2-10 carbon atoms, which may be unsubstituted or substituted by one or more by suitable substituents described below.Typical alkenyl substituents include, but are not limited to, ethenyl, propenyl, butenyl, allyl, pentenyl, etc. -I The term "alkynyl" represents a saturated or unsaturated hydrocarbon with a straight or branched chain containing one or more triple carbon-carbon bonds, and has 2-10 carbon atoms, which may be unsubstituted or substituted with one or more suitable substituents described below.

Go! The 20 moiety may also have one or more carbon-carbon double bonds. Typical alkynyl substituents include, but are not limited to, ethynyl, butynyl, propynyl (proparpl), isopropynyl, pentynyl, hexynyl, and the like. me, The term "carbocyclic" represents a saturated, partially saturated, or fully unsaturated (aromatic) cyclic hydrocarbon group containing from 3 to 14 carbon atoms, which may be unsubstituted or substituted with one or more of the substituents described hereinbelow. The term "carbocyclic" includes mono-, di- and tri-cyclic saturated, partially saturated or fully unsaturated hydrocarbon groups such as cycloalkyl,

HF) cycloalkenyl and aryl. The term "carbocyclic" also encompasses di- and tri-cyclic hydrocarbon groups that contain any combination of ring moieties that are saturated, partially saturated, or fully unsaturated where (aromatic). Partially saturated carbocycles include, for example, dihydro-arenes (eg, indanyl) or tetrahydro-arenes (eg, tetrahydronaphthalene), where any one or more of the saturation sites can exist in any ring part of the carbocycle.

In addition, it is understood that the bond between any di- or tricyclic carbocyclic group and any other substituent or variable constituent group may be at any suitable position of the carbocycle. The term "carbocyclic-aliphatic" group covers aliphatic groups having a carbocyclic substituent (eg, phenylmethyl-(benzyl), phenylethyl-, cyclopropylmethyl-, etc.) where the carbocyclic part and the aliphatic part may be independently substituted with one or more suitable substituents

"Cycloalkyl" represents a group containing non-aromatic monocyclic, dicyclic or tricyclic hydrocarbons containing from 3 to 14 carbon atoms, which may be unsubstituted or substituted with one or more suitable substituents described below. Typical cycloalkyls include monocyclic rings having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

Illustrative examples of cycloalkyls include the following:

Son's horse oh hundred Kvt pehe shi ku sh uh ut dna ME: SHE yi U ? Y SCHE B change you SHA SHYMY I

En still Day day then gg essays MN si EE re pav M sr aa lezi

TYNY ho NE m TO another 70 ris y sg t I re I V as in

The term "Cycloalkenyl" represents a group containing non-aromatic monocyclic, dicyclic, or tricyclic hydrocarbons containing from 4 to 14 carbon atoms, which may be unsubstituted or substituted by one or more suitable substituents described below and contain at least one double bond carbon-carbon bond. Typical monocyclic cycloalkenyls include groups having 4-8, preferably 5-6 carbon atoms, such as cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and the like. Illustrative examples of cycloalkenyls include the following:

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Eh Ya ek ka zho TE i z Bern and still swi yasii until hek z ve plo shi se Z ryh DRINK and

Y x h mn rda and s di, Mn NE eta ti

Bi He) "Aryl" represents a group containing an aromatic, monovalent monocyclic, dicyclic, or tricyclic radical containing from b to 18 ring carbon atoms, which may be unsubstituted or substituted with one or more suitable substituents described below. Illustrative examples of aryls include the following: (av)

Galen

I still have ZE c

She rey slya "nnlau: znshh shchi i it i E y : Met ney NE dvkesoya a pe so ZV -k --oEYA she ii y i i: "-- gg r zan: mya Yak ah t: I p sn Mo 1 ' I ma U zh I slya BE zli rt Melon

IS; I. sk so B E U! from Z

I what ZK and She: s Y Her V I E -

Masses 0 sa an soya En Te ; 5

U rn o N as v pe i, B i n t i" in t. V y Aleya m zh inanna M ee o Be a do -

TE 7 Ez more

The term "carbocyclic" also includes mixed di- and tri-cyclic cycloalkyl/cycloalkenyl/aryl, which may be unsubstituted or substituted with one or more suitable substituents described below.

Illustrative examples of such mixed di- and tricyclic groups include the following:

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ЧА lev so Ne я ik Z iv pk: OK V nki y

SYA sm ze za y ; From the 2nd y s i: od cheazhlh Not a I you or s SHE ha y M ss feny On How B garden that tv sha Native and

What are we; ' vk Give me Teh S ef - g; DE 3 V and Koch B and r - | RIZI S NeEV sZDh from n

Ш р кв хг С Асвый

It is understood that the attachment or substitution of any di-cyclic or tri-cyclic carbocyclic or (ee) heterocyclic group described herein can be in any suitable position on any ring. o Illustrative examples of such bonding in mixed di- and tri-cyclic carbocyclic groups include the following: име) 60 b5

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I PUN EN her zani hms VyBkiYa zh g tyschi deya ayu ee and A ii ver igoya and zhkeruie r ya ANI multiple p: I g Ni sn TE do snast de: ii i ut tv oh: hayet ped naa ey dance Di ne she t Y s yu y shi zhk. heh heh heh I'm so

Zesh: windows and Zhe rayko ey o and shby be and U s

EV ke i o Tikh t ON lomy an i ХВАТ silo p Kaya VTK vnshe pe i Y Kehy nan sho ren hm

More. te ko SCHE ACT drink z a g. Y She i "y sny EKBoy sodi yan de or des s s yiv o ryi not I Ж kikh is 4 I sho ist v m myah z i osonyyy st oda sodi EV o u sia S s - t Xia and no

Sho t more As with E R. she x SHI More

Shov Ye el And also Yi and and her KE. MORE

OM SM Y Pl, khan uni. RAIN more

Hey TE still x SYA drink Ua zore Noya sho shi ami S zozhstnY How nni nklsleen EE eh I ze. in the spring: ha (SHHI I dk

Kk ss K i 5 in sn

ZY shk (o) de VE! represents any suitable substituent.

The term "heterocyclic" represents a saturated, partially saturated, or fully unsaturated (aromatic) cyclic group containing from 3 to 18 ring atoms and including from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur and may be unsubstituted or substituted by one or more substitutes that are described here below. The term "heterocyclic" includes mono-, di- and tri-cyclic saturated, partially saturated, o or fully unsaturated heteroatom-containing cyclic groups; for example, heterocycloalkyl, heterocycloalkenyl, and heteroaryl. The term "heterocyclic" also encompasses di- and tri-cyclic groups that contain any combination of ring moieties that are saturated, partially saturated, or fully unsaturated (aromatic). rya

Partially saturated heterocycles include, for example, dihydroheteroarenes (eg, dihydroindole) or

From tetrahydro-heteroarenes (for example, tetrahydroquinoline), where any one or more saturation sites can exist in any ring part of the heterocycle. In addition, it is understood that the linkage between any di- or tricyclic heterocyclic group and any other substituent or variable component may occur at any suitable position of the heterocycle (ie, there is no restriction that the substituent or variable component " must be connected to a heteroatom-containing component of a di- or tricyclic heterocyclic group). The term - 70 "heterocyclic-aliphatic" group covers aliphatic groups having a heterocyclic substituent (eg, with pyridylmethyl-, thiazolylmethyl-, tetrahydrofuranylmethyl-, etc.) where their heterocyclic component and aliphatic "" component may be independently substituted with one or more suitable substituents "Heterocycloalkyl" represents a group containing a saturated monovalent monocyclic, dicyclic, or tricyclic radical containing 3-18 ring atoms and including 1-5 heteroatoms selected from nitrogen, - 45 oxygen and sulfur, and may be unsubstituted or substituted with one or more suitable substituents described below. Illustrative examples of heterocycloalkyl include, but are not limited to, azetidinyl, -I pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl , with tetrahydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azadicyclo!3,2,octyl, azadicyclo! With,3,1|no nil, azadicyclo!|4,3,F|nonyl,

Ge | 20 oxadicyclo|2,2,1)heptyl, 1,5,9-triazacyclododecyl, etc. Illustrative examples of heterocycloalkyl include the following: (42) ime) 60 b5 pk sah her 7; zviv ha yi 1 tsa SE :odivniyniynk: y i hai Y

KT -i Z kiy i sa za E y ve se hekhii kr B Y

I still have a different window z: SHE ON A s z Y M lyny Y t. i ko dit k.e ZY N v y i. si v-e all U, M 1. -- s EK ey neck ko dn Sn ; go TYA Z ne TE se give JE I r: ZE nya tova sshkei sich i tni direnty ve B: z iz MA Shk,

Sh- i: I am even more shreh s: ih ptn and i siy Y Z Y. Kit y gskukvkne r Ne A B zh ZE, EE i g wn Bi Tya Kai: srt prov zzvedyatik zvor re i i sha yi M Duka Kt, KE dndnm 7 h ban sess "NISCHINY

SHK and Se tYsh I SHE. zna s ; ia ke VE: And ke jo still ; with. sa SHE same re A I - -I sa si. B nai ZY, E her. in syasei Bere s i Z shchi, DYN NOT Z : A sa Gi a TK a ro t y I i t s SHE NE sna shi ov Men Shk i

Mykh: OM Bo kety yah THEY same WE x Z still M, i and their ak Ii vlak ak that E Z khz roya that SHE, Tl, I LSH x " te tv pdv gyi Yar sv shtnrh v i i, sia I s iy t sk . uh s deno zn NK, still Zhe tity che "i yi İ E g syak re ne - Ai ne EE chl ia be "ie set: zridr Z I p shchy S de iya sl gene o

Shev SHE Z same, and B; These: T o

I Polem Zhsk NI odeE i V s y, 1 zn Ed v 25 I PO OM be syh s neo y ta yo sa Gle ey 29 y re eV o eto ey - Z h r od te DE, set 00 VO with Zhe i sy shi

Sem ve V B, z sv E x so d 7 Sr gra:x What is the meaning of: and how M Z where K represents H, alkyl, hydroxyl or represents the compound of formula I, and the bond marked as yfudenya , represents binding to any surface of the dicyclic group (ie, endo or exo). Cha

The term "heterocycloalkenyl" represents a non-aromatic, monovalent monocyclic, dicyclic, or tricyclic radical containing 4-18 ring atoms and may include 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur and may be unsubstituted or substituted with one or more suitable "substituents" , described below, and contains at least one carbon-carbon double bond or one carbon-heteroatom double bond. Typical monocyclic heterocycloalkenyls include groups having 4-8, preferably 5-6 ring atoms. Illustrative examples of heterocycloalkenyls include, but are not limited to, dihydrofuryl, dihydropyranyl, isoxazolinyl, dihydropyridyl, tetrahydropyridyl, and the like. Illustrative examples of "heterocycloalkenyls" include the following: -i -i - (ee) (42) ime) 60 b5

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DK: . ZE s I y i - as z5Y I - y u va r re y s y 1 ih As : E This is where s KN tv : t, t bhoy y odni y zh ki And as m)

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As N.Ya ee sv y sei KU t t; from Gola etc. SIYA: Siy ori Y

I: ze et a SHE lek TEN st y : skh, s ne z Y sce I schi Bu h y same g SVK. s ke piv i lyy

Jan kr re E GY Oh what a etKr chiY X viit E.

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Ya cha ya! ух с ЧИ , Nesy where K represents H, alkyl, hydroxyl or represents a compound of formula I. co "Heteroaryl" represents a group containing an aromatic monovalent monocyclic, dicyclic, or tricyclic radical containing 5-18 ring atoms, including from 1 to 5 heteroatoms selected from 87 nitrogen, oxygen and sulfur and may be unsubstituted or substituted with one or more suitable M substituents described below. As used herein, the term "heteroaryl" also encompasses the M-oxide derivative 32 (or M-oxide derivatives if the heteroaryl contains more than one nitrogen so that more than one M-oxide derivative can be formed) of the nitrogen-containing heteroaryls described here. Illustrative examples of heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo|B|hyenyl, "naphthoic|2,3- b) gianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, - indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, c benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinolinyl, pterylidinyl, betazolinyl, carba- carbolinyl, "» phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl. " Illustrative examples of heteroaryl M-oxide derivatives include, but are not limited to, pyridyl-M-oxide, pyrazinyl-M-oxide, pyrimidinyl-M -oxide, pyridazinyl-M-oxide, triazinyl-M-oxide, isoquinolyl-M-oxide, and quinolyl-M-oxide. The following examples of heteroaryls include the following groupings: - and - and - (ee) «2 ko bo b5 zazhav ke y yye Ilya, NK 4 . with IN

EE s kietens Y zh g ee V khnshvneh ron s) m t E: ШЭ more deektitnyah a se t - sya prah id z v v y sech, And also these shiy eh Zhe de ila y Bu Zh I I i Sp: i and I ze What. MK: Z. Not yet Z TSE not yet gal ZD se n yaakya Vis i nam i Te M Na I -- Niz ee

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SZhoya is not there. How | I: y and I her: I same "GE b; di: 0 0 BM or She kr i o V 75 y ke o i same NK Be x'; ve : Al dai pl u ME What kind of poet y UT rev 5: still more with pi and: BY and two to her She 7 xx with same Ж 5 zone Muvltya m (sniff no with : and ey Dt W TU Ye sten y y

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U a KVK MELON even sht ad: y ii» p KA TI ist kuryu s pl I "HOW a I, because ve: ALREADY IE with DE: ayu When -k

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ZE: Tl I in! Yan Yak - ZY r» svya sho - Z EK

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Kg iy on; UKV s: VEN, yad bo pek: y z ozhner sta black kiy te sii

SI: "tinv UoY t NI NV g "lyh i r: z i dk. stele Sai i where K represents H, alkyl, hydroxyl or represents a compound of formula I.

The term "heterocyclic" also includes di- and tri-cyclic heterocycloalkyl/heterocycloalkenyl/heteroaryl, which may be unsubstituted or substituted with one or more suitable substituents described below. Illustrative examples of such mixed di- and tri-cyclic heterocyclic groups include the following:

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Chek MN s I hv ZE vi de I NN Yan. tuya noya Pk pa nsyu oyu "BE o sa UA sa s LOKIV so ZNYAV av: elephants ka peschi SN i z Ved V Sche koney hy : Kv TEKA seni and MEN. YAN o she Ex o ie VROYA i s PRIY py Bo li sh Her In all her her

NOT Mr. "uva sy a NK ey EV Ya loh t. U NYA s Es V suk ny g. і Z ve Z V den iy "i pe ti NM s

Kan sE t Ba SCHE not kl Y yary p g. vyshka tive "proe mn: і still Eh Z i: | v I s ze: A o)

Eh av tol now in. V I IY gu EE eh

Shch o rez: ZB Z At os Ot VK Z I IY idei R a Ne: pen ti BC Byk pora ruta: V NI v. shop and I Not 7 same and Yes "go she NI seni ss ee Hey I pl. k Shni" Ieshchya and zey tt ionna In KD 2 av)

Illustrative examples of such bonding in mixed di- and tri-cyclic heterocyclic groups include the following: pet, and ШЭ What shshk;: ty "- pt Shchenya 00 Eva z y chi ly y dn A -khivre - a A DY ron kry history ns

A I chi Na ov a ie: rn he A a I ks PI, gi Ki, ik -: TV acti Mon MN SEC a No Puppy ne y - s? sia a VE me NE I zt re. ANA va V i:

S ks ov, AND NOT SHY She shi SHY shik: SHY she sir I STILL: In: Ne SHE sizhke:: СХ rt tku

Eh wai a tem t. 7 as uki SK privn rr with Me Ser de la m ee

DE: ee ki gyyrtya M we "z Kayatni: tios ns re pi "VOK sevizh nechir dtseschu ze vanni c) vyk u ron lina t nan MK ny shlach s z syak Zv A eV NN THEY: sb on Ni tinu

SHI t. PN ov shk SAT NE sides Z Ze: i YN : ih Shh SN 1 i I ek YAM: which: Still in kznyoVya i. ; t "Zhe iya NI Se. ore: i y n Ne z Y g zhen v:

KN YN vn: ev p. 00 SN No Sai! And I'm in kg I'm what KD POINT of them SEN, Mf you NVK. i t. DI

The same, "The same: Drink Op and ME eti She stodi and:

I Be: и: AGE se s spon SND: w

Y Sate BYA t ly di ie yy set nn - ge pk teet y toni oschyeV she "syn gendekenyu - tey V i ND Pe zh sh g deno Shche sya 1: v so y te dekm z: i Kl s zv y tn kv sya and I te BAD i Na: ie o nia

She ovllya KK r istsa "BYY pay, ON AV me, Iii UYU: OV si. Y pope: in AYA u Cena. MORE

On td Ese» rai de K represents any suitable substitute. o In the compounds of the present invention, alkyls, alkenyls and alkynyls may optionally be substituted with one or more suitable substituents independently selected from the group: phenyl, nitro, amino, cyano, halogen, hydroxyl, im) alkoxy, haloalkyloxy, aryloxy, cycloalkyloxy , циклоалкілалкілокси, циклоалкенілокси, циклоалкенілалкілокси, гетероциклоалкокси, гетероциклоалкілалкілокси, гетероциклоалкенілокси, 6о гетероциклоалкенілалкілокси, гетероарилокси, алкіл карбоніл, алкенілкарбоніл, алкінілкарбоніл, алкілоксикарбоніл, алкенілоксикарбоніл, алкінілоксикарбоніл, алкілкарбонілокси, алкенілкарбонілокси, алкінілкарбонілокси, арилкарбоніл, арилкарбонілокси, арилоксикарбоніл, циклоалкілкарбоніл, циклоалкілкарбонілокси, циклоалкілоксикарбоніл, гетероарилкарбоніл , heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, 65 heterocycloalkyloxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, alkenylamino, alkynylamino, cyclo oalkylamino, cycloalkenylamino, arylamino, heterocycloalkylamino,

гетероциклоалкеніламіно, гетероариламіно, діалкіламіно, алкіламінокарбоніл, алкеніламінокарбоніл, алкініламінокарбоніл, циклоалкіламінокарбоніп, циклоалкеніламіно, ариламінокарбоніл, гетероциклоалкіламінокарбоніл, гетероциклоалкенілкарбоніл, гетероариламінокарбоніл, діалкіламінокарбоніл, алкілам і ноті окарбоніл, циклоалкіламінотіокарбоніл, ариламінотіокарбоніл, гетероциклоалкіламінотіокарбоніл, гетероариламінотіокарбоніл, діалкіламінотіокарбоніл, алкілсульфоніл, арилсульфоніл, алкілсульфеніл, арилсульфеніл, алкілкарбоніламіно , циклоалкілкарбоніламіно, арилкарбоніламіно, гетероциклоалкілкарбоніламіно, гетероарилкарбоніламіно, алкілтіокарбоніламіно, циклоалкілтіокарбоніламіно, арилтіокарбоніламіно, гетероциклоалкілтіокарбоніламіно, гетероарилтіокарбоніламіно, алкілсульфонілокси, /о арилсульфонілокси, алкілсульфоніламіно, арилсульфоніламіно, меркапто, алкілтіо, галогеналкілтіо, арилтіо та гетероарилтіо, де будь-які алкільні, алкенільні, алкінільні, арильні , cycloalkyl, cycloalkenyl , heterocycloalkyl, heterocycloalkenyl, heteroaryl moieties represented in the above substituents may themselves be substituted. The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl portions of any of the above /5 substituents may optionally be substituted with one or more substituents independently selected from the group: alkyl (except alkyl), halogen alkyl , aryl, nitro, amino, alkylamino, dialkylamino, halogen, "hydroxyl, alkoxy, haloalkyloxy, aryloxy, mercapto, alkylthio, haloalkylthio or arylthio.

In the compounds of the present invention, the substituted carbocyclic or heterocyclic groups may be substituted, as an option, with one or more suitable substituents independently selected from the group: alkyl, halogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, nitro amino cyano halogen halogen ch cycloalkylcarbonyl, cycloalkyl, carbonyloxy, cycloalkyloxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, i) heterocycloalkyloxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, c ульфо, алкіламіно, циклоалкіламіно, ариламіно, гетероциклоалкіламіно, гетероариламіно, діалкіламіно, алкіламінокарбоніл, циклоалкіламінокарбоніл, ариламінокарбоніл, гетероциклоалкіламінокарбоніл, гетероариламінокарбоніл, о зо діалкіламінокарбоніл, алкіламінотюкарбоніл, циклоалкіламінотіокарбоніл, ариламінотіокарбоніл, гетероциклоалкіламінотіокарбоніл, гетероариламінотіокарбоніл, діалкіламінотіокарбоніл, алкілсульфоніл, со арилсульфоніл, алкілсульфеніл, арилсульфеніл, алкілкарбоніламіно , циклоалкіл, карбоніламіно, - пе арилкарбоніламіно, гетероциклоалкілкарбоніламіно, гетероарилкарбоніл, аміно, алкілтіокарбоніламіно циклоалкілтіокарбоніламіно, арилтіокарбоніламіно, гетероциклоалкілтіокарбоніламіно, ї- гетероарилтіокарбоніламіно, алкілсульфонілокси, арилсульфонілокси, алкілсульфоніламіно, ї- арилсульфоніламіно, меркапто, алкілтіо, галогеналкілтіо, арилтіо та гетероарилтіо, де будь-які alkyl alkylene and aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl and, the heteroaryl moieties represented by the above substituents may themselves be substituted. Preferred "suitable substituents" include alkyl alkene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, "Halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkyloxy, heteroaryloxy, alkylthio, haloalkylthio et"), and carboxyl. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl portions of any of the above substituents may be optionally substituted with one or more substituents independently selected from the groups: alkyl, haloalkyl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkylthio, mercapto, alkylthio, haloalkylthio or arylthio.

For example, are phenyl or the phenyl part of CC substituted in the compounds of the present invention? may include -And at least one substituent (not halogen or methyl) selected from the group of haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkylcarbonylalkyl, haloalkylalkyl, aryloxyalkyl, alkylthialkyl,

Haloalkylthioalkyl, arylthioalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, aryl, - cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, nitro, amino, cyano, hydroxyl alkoxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkylenedioxy, aryloxy, cycloalkyloxy, co циклоалкілалкілокси, циклоалкенілокси, циклоалкенілалкілокси, гетероциклоалкокси, гетероциклоалкілалкілокси, о гетероциклоалкенілокси, гетероциклоалкенілалкілокси, гетероарилокси, алкілкарбоніл, алкілокси, карбоніл, алкілкарбонілокси, арилкарбоніл, арилкарбонілокси, арилоксикарбоніл, циклоалкілкарбоніл, циклоалкілкарбонілокси, циклоалкілоксикарбоніл, гетероарилкарбоніл, гетероарилкарбонілокси, гетероарилоксикарбоніл, гетероциклоалкілкарбоніл, гетероциклоалкілкарбонілокси, гетероциклоалкілоксикарбоніл, карбоксил , carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, iF) cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cocyc лоалкіламінокарбоніл, ариламінокарбоніл, гетероциклоалкіламінокарбоніл, гетероариламінокарбоніл, діалкіламінокарбоніл, алкіламінотіокарбоніл циклоалкіламінотіокарбоніл, ариламінотіокарбоніл, бо гетероциклоалкіламінотіокарбоніл, гетероариламінотюкарбоніл, діалкіламінотюкарбоніл, алкілсульфоніл, арилсульфоніл, алкілсульфеніл, арилсульфеніл, алкілкарбоніламіно, циклоалкілкарбоніламіно, арилкарбоніламіно, гетероциклоалкілкарбоніламіно, гетероарилкарбоніламіно, алкілтюкарбоніламіно, циклоалкілтіокарбоніламіно, арилтюкарбоніламіно, гетероциклоалкілтюкарбоніламіно, гетероарилтіокарбоніламіно, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, 65 arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio and heteroarylthio, where any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties represented in the above substituents may be themselves substituted. Preferred "suitable substituents" include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, halogen, hydroxyl, alkoxy, alkylenedioxy aryloxy, cycloalkyloxy, heteroaryloxy, alkylthio, haloalkylthio, and carboxyl. Alkyl, alkylene aryl, cycloalkyl, heterocycloalkyl, heteroaryl parts of any of the above substituents may be optionally substituted with one or more substituents independently selected from the group: alkyl, haloalkyl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkylthio, mercapto, alkylthio, haloalkylthio or arylthio.

If the substituents themselves are not compatible with the methods of synthesis of the present invention, the substituent may be protected 7/0 by a suitable protecting group that is stable under the conditions of the reaction used in these methods. The protecting group can be removed at an appropriate time in the reaction sequence of the method to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known in the art; examples can be found in |T. sgeepe and R.

Mutsiv, Rgoiesiipud Sioiirz ip Spetisa! Zupipeviv (39 units), addendum Umieu 5: Zopz, MU (1999)), which is introduced here by reference 75 In its entirety. In some cases, the substituent may be specifically chosen to be reactive under the conditions of the reaction used in the methods of the present invention. In these cases, the reaction conditions convert the selected substituent into another substituent that is useful in an intermediate in the methods of the present invention or is a desired substituent in the target compound.

In the compounds of the present invention, B? and B, independently or taken together, may be a suitable nitrogen-protecting group. As shown above, nitrogen-protecting groups are well known in the art and any nitrogen-protecting group that is useful in the methods of making a compound of the present invention or may be useful in the HIV protease inhibitor compounds of the present invention can be used. Typical nitrogen protecting groups include alkyl, substituted alkyl, carbamate, urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl, phosphoryl, silyl, organometallic, and boric acid and boronic acid groups. Examples of each of these groups, methods of protecting the nitrogen group using these groups, and methods of removing these groups from the nitrogen group are disclosed in T. Sgeepe and R. Mutsiv, supra. Mostly when B 2? and/or B independently represent suitable nitrogen-protecting groups, suitable substituents of B? and B? include, but are not limited to, carbamate protecting groups such as alkyloxycarbonyl (e.g. Boc: tert-butyloxycarbonyl) and aryloxycarbonyl (e.g. Cb: benzyloxycarbonyl or EMOS: fluorene-9-methyloxycarbonyl), o 30 alkyloxycarbonyl (e.g. methyloxycarbonyl), alkyl or arylcarbonyl, substituted alkyl especially co arylalkyl (eg, trityl (triphenylmethyl), benzyl and substituted benzyl), etc. When? and B taken together are a suitable nitrogen-protecting group, suitable 2/2 substituents include phthalimido and stabaz -- (1,2-bis(dialkylsilyl))ethylene). uh-

The terms "halogen" represent chlorine, fluorine, bromine or iodine. "Heterocycle" means heteroaryl or heterocycloalkyl. "Acyl" means the radical -C(0)-K where K represents substituted or unsubstituted alkyl, - cycloalkyl, aryl, heterocycloalkyl or heteroaryl. "Acyloxy" means the radical -OC(O)-K, where K is substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl. "Thiosacyl" means the radical -C(5)-K, where K represents a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl, or di-heteroaryl. "Sulfonyl" means the diradical -505-. "Sulfenyl" means the diradical -50-. "Sulfo" means the radical -505Н. "Hydroxy" means the -OH radical. "Amine" or "amino" means the radical -MH". "Alkylamino" means the radical -MNK.a, where Ka represents alkyl. "Dialkylamino" means the radical -MKaK, where Ka and Ku, each independently :z» represent an alkyl, and means heterocycloalkyl, where Ka and K, taken together form a heterocyclic ring that includes an amine nitrogen. "Alkoxy" means the radical -OK., where Ka represents alkyl. Typical alkoxy groups include methoxy, ethoxy, propoxy, and the like. "Lower alkoxy" groups have an alkyl part having from 1 to 4 carbon atoms. "Alkoxycarbonyl" means the radical -C(O)OK., where Ka represents alkyl. "Alkylsulfonyl" means the radical -502Ka, where Ka represents alkyl. "Alkylenedioxy" means a divalent radical -OKAO-, which is bonded to neighboring atoms (for example, neighboring atoms on a phenyl or naphthyl ring), where K a - represents a lower alkyl. "Alkylaminocarbonyl" means the radical -С(О)МНЕ 4, where КА. represents alkyl. "Dialkylaminocarbonyl" means a radical. "C(O)MKaR", where Ka and Ku each independently represent an alkyl. (ee) "Mercapto" means the radical -ZN. "Alkylthio" means the radical -ZKa, where Ka represents alkyl. "Carboxy" means the radical -C(O)OH. "Keto" or "oxo" means the diradical -O. "Thioketo" means -5 diradical. "Carbamoyl" means the radical -С(О)МН». "Cycloalkylalkyl" means the radical -alkyl-dicycloalkyl, where alkyl and cycloalkyl are defined above and are represented by a linking arrangement represented by the groups -CH o-cyclohexane or -CHno-cyclohexane. "Arylalkyl" means the radical -alkylaryl, wherein alkyl and aryl are as defined above, and are represented by the linking arrangement represented by benzyl. "Aminocarbonylalkyl" means a radical

HF) -alkylC(O)MH. and represented by the binding arrangement represented in the group -"СН "СНоС(О)МН". 7 "Alkylaminocarbonylalkyl" means the radical -alkylС(О)МНЕ., where Ka represents alkyl, and is represented by the binding configuration represented by the group -СН 6СНоС(О)МНСН». "Alkylcarbonylaminoalkyl" means the radical -alkylLMNOS(O)-alkyl and is represented by the binding arrangement represented by the group 60 -СНоМНес)снН». "Dialkylaminocarbonylalkyl" represents the radical -alkylC(O)MK aK, where Ka and Ku each independently represent alkyl. "Aryloxy" means the radical -OXx, where Co is aryl. "Heteroaryloxy" means the radical -OKu, where Ku is heteroaryl. "Arylthio" means the radical -ZK c, where Ks represents aryl. "Heteroarylthio" means the radical -ZCu, where Ku is heteroaryl. If the compound of the invention is a base, the desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid such as hydrochloric acid,

hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid acid,

A pyranosidic acid such as glucuronic acid or galacturonic acid an alpha-hydroxy acid such as citric acid or tartaric acid an amino acid such as aspartic acid or glutamic acid an aromatic acid such as benzoic acid or cinnamic acid a sulfonic acid, something like p-toluenesulfonic acid or ethanesulfonic acid or similar.

If the compound of the invention is an acid, the desired salt may be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary); alkali metal or alkaline earth metal hydroxide; or similar.

Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum, and lithium.

Specific embodiments of the compounds of the present invention, containing the compounds denoted by the formula | can also be described. For example, this invention relates to compounds useful for inhibiting HIV protease activity of the above formula I, wherein:

B represents 5- or b-membered mono-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, where said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group: alkyl, haloalkyl, amino, cyano, halogen, hydroxyl, alkoxy, haloalkyloxy, alkylenedioxy, di-haloalkylenedioxy, aryloxy, cycloalkoxy, cycloalkylalkoxy, cycloalkenyloxy, cycloalkenylalkoxy, heterocycloalkoxy, heterocycloalkylalkoxy heterocycloalkenyloxy, su heterocycloalkenylalkoxy, heteroaryloxy, alkylcarbonyloxy, arylalkylcarbonyloxy, alaaryloxy dialkylamino, keto, alkylsulfonyl, arylsulfonyl, alkylcarbonylamino, alkylthio, haloalkylthio, and arylthio, wherein any alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl represented by the above substituents may themselves be substituted with one or more substituents, whether selected from the group: alkyl, haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, av! haloalkyloxy, aryloxy, mercapto, alkylthio, haloalkylthio and arylthio;

IN? represents substituted alkyl, substituted or unsubstituted alkeny, or substituted or unsubstituted co-alkynyl, wherein said alkyl, alkenyl, or alkynyl is a straight or branched chain group, and -- wherein said substituted alkyl, alkenyl, or alkynyl is substituted by one or more substituents, independently selected from the group: amino, cyano, halogen, hydroxyl, alkyloxy, haloalkyloxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkenyloxy, cycloalkenylalkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, heterocycloalkenyloxy, heterocycloalkenylalkyloxy, heteroaryloxy, alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, aryl , alkylthio, haloalkylthio, arylthio and heteroarylthio, wherein any alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, "heteroaryl represented by the above substituents may themselves be substituted with one or more substituents independently selected from : alkyl, haloalkyl, halogen, hydroxy l, alkoxy, haloalkyl, - alkylthio and haloalkylthio. h» c represents H, methyl, ethyl or propyl, where the specified methyl, ethyl or propyl is unsubstituted or substituted by halogen or hydroxyl;

X represents fs, where Ku represents H or one or more substituents independently selected from the group: halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxyl, alkylenedioxy,

Go! 20 dihaloalkylenedioxy, alkylamino, dialkylamino, alkylthio and haloalkylthio; 7 represents 5, O, 50, 505, CH" or SEN; c VZ represents H; 27, 25, 25 and K" are independently selected from the group H or methyl; a

VZ and CC? independently selected from the group: H, halogen, methyl, monohalogen-methyl, dihalogen-methyl and tri-halogenmethyl; (F) or its prodrug, a pharmaceutically active metabolite, or a pharmaceutically active salt or solvate.

GI In more specific embodiments, this invention relates to compounds of formula I, above, wherein:

B represents phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, uranyl, b thienyl or tetrahydropyridazinyl, where the indicated phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl is unsubstituted or substituted by one or more more substituents independently selected from the group: alkyl, haloalkyl, halogen, and hydroxyl;

IN? represents substituted alkyl, substituted or unsubstituted C.-Svalkenyl, or substituted or unsubstituted

C.-Alkynyl, wherein said alkyl, alkenyl, or alkynyl is a straight or branched chain group, and wherein said substituted alkyl, alkenyl, or alkynyl is substituted with one or more substituents independently selected from the group consisting of cyano, halogen, and alkylamino

2 represents H, methyl or ethyl;

X represents o, where K represents H, halogen or alkoxy,

And tro tanya from "ec

A SHHI a 7 represents 5, OSN" or SEN; 23, 7, E5 8 and KU each represent H; and B? and B" are independently selected from the group: H or methyl; or a prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically active salt or solvate.

In preferred specific embodiments, this invention relates to compounds of the above formula I, where: in! represents phenyl, wherein said phenyl is substituted by one or more substituents independently selected from /5 Groups: alkyl, halogen or hydroxyl;

IN? represents C --Svalkenyl or C.-Svalkynyl, where said alkenyl or alkynyl is a group with a linear or branched chain, and where said alkenyl or alkynyl is unsubstituted or substituted by one or more halogen substituents;

IN? represents H;

X represents MORE. yes: ; where Ku represents H; t pdknivn ik gu v tan s s 7 represents 5, o

VZ, 7, ve", 8 and EU represent, each H; and 25 and KE" each represent a methyl; or a prodrug, a pharmaceutically active metabolite, or a pharmaceutically active salt or solvate thereof.

More specifically, this invention relates to compounds useful in inhibiting the activity of ViIL-protease of the above formula I, where: ee)

B represents 5- or b-membered mono-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, where indicated cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, -- heterocycloalkenyl or heteroaryl is unsubstituted or substituted by one or more substituents, regardless of /- Them" selected from the group: alkyl, haloalkyl, amino, cyano, halogen, hydroxyl, alkoxy, haloalkyloxy, alkylenedioxy, dihalogenalkylenedioxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkenyloxy, he cycloalkenylalkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, heterocycloalkenyloxy, heterocycloalkenylalkyloxy, heteroaryloxy, alkylcarbonyloxy, aryl , heteroarylcarbonyloxy, alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, alkylcarbonylamino, alkylthio, haloalkylthio and " du arylthio, where any alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl part, c represented by the above substituents, is substituted by one or more substituents we, independently selected from the group: alkyl, haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkyloxy, aryloxy, mercapto, alkylthio, haloalkylthio, and arylthio; 415 V? represents substituted phenyl, substituted phenylalkyl, substituted or unsubstituted phenylalkenyl or -1 substituted or unsubstituted phenylalkynyl; where the indicated alkyl, alkenyl or alkynyl part of the indicated phenylalkyl, phenylalkenyl or - phenylalkynyl has a linear or branched chain; - 2 represents H, methyl, ethyl or propyl, where the specified methyl, ethyl or propyl is unsubstituted or substituted with halogen or hydroxyl; and because X represents V. where Ku is represented by H or one or more substituents, regardless of whether

HF) selected from the group: halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxyl, alkylenedioxy, dihaloalkylenedioxy, alkylamino, dialkylamino, alkylthio and haloalkylthio; o 7 represents 5, O, 50, 505, CH" or SEN;

VZ represents H; 60 B", 85, C and E" are independently selected from the group: H or methyl; and

ВZ and вк are independently selected from the group: H, halogen, methyl, monohalogen-methyl, dihalogen-methyl and tri-halogenmethyl; provided that the indicated 5- or 6-membered mono-cyclic heterocycloalkyl, heterocycloalkenyl or heteroaryl 65 Contain at least two heteroatoms: or provided that the alkyl, alkenyl or alkynyl part of the indicated substituted phenyl alkyl is indicated,

phenylalkenyl or phenylalkynyl substituted with one or more substituents selected from the group: halogen or keto; or provided that said substituted phenyl or the phenyl portion of said substituted phenylalkyl, phenylalkenyl, or phenylalkynyl is substituted with one or more substituents other than halogen or methyl, wherein said one or more substituents are independently selected from the group consisting of: haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl . 70 alkynyloxy, alkylenedioxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkenyloxy, cycloalkenylalkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, heterocycloalkenoxy, heterocycloalkenylalkyloxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkyl арбонілокси, циклоалкілоксикарбоніл, гетероарилкарбоніл, гетероарилкарбонілокси, гетероарилоксикарбоніл, гетероциклоалкілкарбоніл, гетероциклоалкілкарбонілокси, гетероциклоалкілоксикарбоніл, карбоксил, карбамоїл, форміл, кето, тіокето, сульфо, алкіламіно, циклоалкіламіно, ариламіно, гетероциклоалкіламіно, гетероариламіно, діалкіламіно, алкіламінокарбоніл, циклоалкіламінокарбоніл, ариламінокарбоніл, гетероциклоалкіламінокарбоніл, гетероариламінокарбоніл, діалкіламінокарбоніл, алкіламінотіокарбоніл, циклоалкіламінотіокарбоніл, ариламінотіокарбоніл, гетероциклоалкіламінотіокарбоніл, гетероариламінотіокарбоніл, діалкіламінотіокарбоніл, алкілсульфоніл, 2о арилсульфоніл, алкілсульфеніл, алілсульфеніл, алкілкарбоніламіно, циклоалкілкарбоніламіно, арилкарбоніламіно, гетероциклоалкілкарбоніламіно, гетероарилкарбоніламіно, алкілтіокарбоніламіно, циклоалкілтіокарбоніламіно, арилтіокарбоніламіно, гетероциклоалкілтіокарбоніламіно, гетероарилтіокарбоніламіно, алкілсульфонілокси, арилсульфонілокси, а alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio, and heteroarylthio, wherein any alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl represented by the above substituents is unsubstituted or substituted with one or more substituents independently selected from the groups : alkyl, haloalkyl, i) halogen, hydroxyl, alkoxy, haloalkyl, alkylthio and haloalkylthio; or prodrugs, a pharmaceutically active metabolite, or a pharmaceutically active salt or solvate thereof. If the phenyl or phenyl portion of B2 contains more than one substituent, the substituents may be the same or different and may be independently selected from the above-described substituents.

More specifically, this invention relates to compounds useful in inhibiting the activity of HIV-protease c of the above formula I, where: "h-

B represents phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, uranyl, thienyl or tetrahydropyridazinyl, where the indicated phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, - tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl are unsubstituted or substituted by one or more than substituents independently selected from the group: alkyl, haloalkyl, halogen, and hydroxyl;

IN? represents a substituted phenylalkyl, where the indicated alkyl part of the indicated phenylalkyl has a linear or branched chain; " 2 represents H, methyl ethyl or propyl, where said methyl, ethyl or propyl is unsubstituted or substituted by hydroxyl; o) c x represents phi, where Ku represents H, halogen, or alkoxy,

And" ich I re "

Kay

B. 7 represents 5, O, CH" or SEN; - 23, c, 5, 8 and EU each represent N; a - 25 and B" are independently selected from the group: H or methyl; for 50, provided that B" is selected from the group: isoxazolyl, pyrazolyl, thiazolyl or tetrahydropyridazinyl, where the specified isoxazolyl, pyrazolyl, thiazolyl or tetrahydropyridazinyl is unsubstituted or substituted by one or more m) substituents independently selected from the group: alkyl, haloalkyl, halogen and hydroxyl, when K? represents substituted or unsubstituted phenylalkyl or provided that K' is selected from the group: phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl, when B? represents substituted phenyl alkyl, and

HF) the specified phenyl part of the specified substituted phenylalkyl includes one or more substituents that are not halogen or methyl, where the specified one or more substituents are independently selected from the group: haloalkyl, amino, o-hydroxyl, alkoxy, haloalkyloxy, alkylenedioxy, di-haloalkylenedioxy, cycloalkylalkyloxy, dialkylamino, alkylsulfonyl and alkylthio; 60 or their prodrugs, a pharmaceutically active metabolite, or a pharmaceutically active salt or solvate.

In preferred embodiments, this invention relates to compounds of the above formula I, wherein:

Ge represents phenyl, where said phenyl is substituted by one or more substituents independently selected from the group: methyl, halogen, or hydroxyl; 65 V? represents a substituted phenylalkyl, where the indicated alkyl part of the indicated phenylalkyl represents an alkyl with a linear or branched chain;

where the indicated phenyl part of the indicated substituted phenylalkyl includes one or more substituents that are not halogen or methyl, where the indicated one or more substituents are independently selected from the group: trifluoromethyl, amino, hydroxyl, C-C, alkoxy, alkylenedioxy, di-fluoro -alkylenedioxy, cyclopropylmethoxy, dimethylamino, methanesulfonyl and methylthio; 22 represents H, methyl or ethyl;

X represents fs, where Ku represents H; i the C "and tn and 7 represents 5 or O; and 23, 27, ve", 5, in", BB and VU represent each, H; or prodrugs, a pharmaceutically active metabolite, or a pharmaceutically active salt or solvate thereof.

All compounds of the present invention contain at least one chiral center and can exist as single stereoisomers (eg, single enantiomers or single diastereomers), any mixture of stereoisomers (eg, any mixture of enantiomers or diastereomers), or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are encompassed within the broad scope of the present invention. Compounds identified herein as single stereoisomers refer to compounds presented in a form containing at least 9095 single stereoisomers of each chiral center represented in the compounds. Where the stereostructure of the chiral carbon atoms represented in the chemical structures illustrated herein is not defined, the chemical structure encompasses compounds containing a stereoisomer of each chiral center represented in the compound. Preferably, however, the compounds of the invention are used in an optically pure form, which is a stereoisomerically pure form, or an essentially optically pure (essentially stereoisomerically pure) form. As used herein, the term "stereoisomeric" purity (or "optical" purity) refers to the "enantiomeric" purity and/or (o) "diastereomeric" purity of a compound. Compounds that are essentially enantiomerically pure contain at least 9090 unit isomers and preferably contain at least 9595 unit isomers of each chiral center present in the enantiomer. Compounds that are essentially diastereomerically pure contain at least 9090 units of each chiral center diastereomer and preferably contain at least 9595 units of each chiral center. More preferably, the substantially enantiomerically and diastereomerically pure compounds of this invention contain at least 97,595 unit isomers and most preferably contain at least 9995 unit isomers of each chiral center in the compound. The term "racemic" or "racemic mixture" refers to a mixture of equal amounts of enantiomeric compounds, which includes both a mixture of enantiomers and a mixture of enantiomeric diastereomers. The compounds of the present invention can be obtained in either stereoisomerically pure (ie, enantiomerically and/or diastereomerically pure) or essentially stereoisomerically pure (ie, essentially enantiomerically and/or diastereomerically pure) form. Such compounds can be prepared synthetically by methods described herein using optically pure or substantially optically pure materials. Alternatively, these compounds can be obtained by separating/separating a mixture of stereoisomers, including racemic mixtures, by conventional methods. Typical methods that may be useful for the separation/separation of stereoisomeric mixtures include chromatography and crystallization/recrystallization. Other useful methods can be found in |"Epapitegv5, Kaseta(ez, apia Kezoiishiope" 9). dasdtsev ei aiYi.,, 1981, doip UMyeu and :z" Zopv, Mem/ HogK, MU, which is introduced here by reference. Preferred stereoisomers of the compounds of the present invention are described herein.

Particularly preferred embodiments of the present invention include compounds where the stereogenic centers (chiral 415 carbon atoms) have the following defined stereostructure: va re , E Shchi i

ShK ko khz wai s

More preferably, at least two stereogenic centers have the following defined stereostructure: име) 60 b5 lsh with the same Bo o0yu. O.IE, V

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Be Kiss:

Even more preferably, at least three stereogenic centers have the following defined stereostructure: ex. Place ех: и , хе прия, in Я and one zone of ЦЯ ac. iy

Il, Vanni Burs, Z lyh and A

EVIL "X yan Shita You

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No: t a; in: E. a.

ME se y: ZB BD dela V Kv NE KK i sel DN ka i: S envnleeih TE slia nya o vo tese i ogs isis En y

Typical compounds of the present invention include: o (av) (ee) «- y and - - a -i -i - (ee) 62 ko bo b5

GRANDFATHER: and the cake and she got it from the ninety-nine-year-old girl

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Z Ve Z pr s ee shen: zbe a i,

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TE I Ne en Y AUD and their prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates.

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NO ee U ne ОН Ж VNY edervyih pt: KN Ж-. HIV protease inhibitor compounds of the present invention include their prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates. In preferred embodiments, the compounds of formula I!, their prodrugs, c pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates exhibit activity:c» of an HIV-protease inhibitor corresponding to Ki; at least 100nM ЕКво at least 10mMM or IR;о at least 10mMM. Preferably, the compounds of the present invention show the activity of an HIV protease inhibitor, which corresponds to K; 15 at least 1OnNM, EKeo at least 1mM or IR;o at least 1mM. More preferably, the compounds of the present invention exhibit HIV protease inhibitor activity against mutant strains of HIV, corresponding to K; at least 100nM, EK;o at least 10mM or IKeo, at least 10mM. Even more preferably, compounds -i of the present invention show protease inhibitor activity against mutant strains corresponding to Ki at least - 1onM, ECo at least 1mM ICeo at least 1mM. "Prodrug" means a compound that is converted under physiological conditions by solvolysis or metabolically to (ee) a defined compound that is pharmaceutically active. Prodrugs can be derivatives of one compound of the present invention containing a group, such as -СО ok, -РО(ОК)» or -С-МК, which can be split under physiological conditions or by solvolysis. Any suitable substituent K can be used which provides pharmaceutically acceptable solvolysis or cleavage of the product. Prodrugs containing such a group can be obtained by conventional methods by treating the compounds of the present invention containing, for example, an amido, a carboxyl group, or a hydroxyl with a suitable reagent. "Pharmaceutically active metabolite" means

GF) a pharmacologically active compound produced during the metabolism of a certain compound in the body. Prodrugs and active 7 metabolites of the compounds of the present invention of the above-described formulas can be determined using methods known in the art, for example, through metabolic studies. See, for example, "Oezidp oi Rgodgydv" (Vypddaaga, in ed.) 1985, Eivzemieg Rybiizpege V.M., Atviegaat Tpe MeTeriapaz). The following is an example of a prodrug that can be converted into a compound of the present invention under physiological conditions, by solvolysis or metabolically:

EE, dey 3 and I and I are not like this. more at yay o "SHE ee set Y shii MAKHY Ot; "Pharmaceutically acceptable salt" means a salt that retains the biological effectiveness of the free acids and bases of the specified compound and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrosulfates, sulfites, hydrosulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanosates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates ) phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates (mesylates), propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. "Solvate" means a pharmaceutically acceptable solvate of a defined compound that retains the biological efficacy of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO ethyl acetate, acetic acid or ethanol amine. In the case of compounds, salts, or solvates that are solids, as will be understood by those skilled in the art, the compounds of the invention, salts, and solvates may exist in distinct crystalline forms, all of which are within the scope of the present invention and the defined formulas.

The present invention also relates to a method of inhibiting the activity of HIV protease, which includes directly contacting the protease with an effective amount of a compound of formula I!, or its pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate. For example, the activity of HIV protease can be (o) inhibited in mammalian tissue using a compound of formula I! or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the presented method concerns the inhibition of HIV protease activity. "Treating" or "curing" means at least ameliorating a disease in a mammal, such as a human, that is alleviated by inhibiting HIV protease activity. Methods of treatment to alleviate the disease include the use of the compound of the present invention in any conventionally acceptable manner, for example, prophylactically. The activity of the compounds of the invention as inhibitors of HIV protease activity can be measured by any suitable method known to those skilled in the art, including IP mimo and IP migo assays. Examples of suitable assays for activity measurements are described here. The use of compounds of the formula | and their pharmaceutically acceptable - from prodrugs, salts, active metabolites and solvates can be carried out by any general methods of use suitable for specialists. Illustrative examples of suitable routes of administration include oral, nasal, parenteral, topical, transdermal and rectal.

The compound of the invention of formula I or its pharmaceutically acceptable salt, prodrug, active metabolite, or solvate can be used as a pharmaceutical composition in any pharmaceutical form known to those skilled in the art as suitable. Suitable pharmaceutical forms include solid, semi-solid, liquid or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. The pharmaceutical compositions of the invention may also include suitable excipients, diluents, fillers, and carriers, as well as other pharmaceutically active agents, depending on the intended use or method of use. Acceptable methods of obtaining suitable pharmaceutical forms of pharmaceutical compositions can be readily determined by those skilled in the art.

For example, pharmaceutical preparations may be prepared by conventional methods of pharmaceutical chemistry, which -1 include steps such as mixing, granulating and pressing, when necessary, into tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to obtain the desired products for - and oral, parenteral, topical, intraapical, intranasal, intrabronchial, intraocular, intraaural and/or rectal use.

The present invention includes pharmaceutical compositions useful in inhibiting HIV protease, containing (ee) an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating HIV infection, or treating AIDS or ACS are also encompassed by the present invention, as is a method of inhibiting HIV protease, and a method of treating HIV infection, or treating AIDS or ACS. In addition, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an agent for the treatment of HIV infection/AIDS selected from the group: (F) 1) an antiviral agent against HIV/AIDS, d) 2) anti-infective agent, and

C) immunomodulator. The present invention also includes the use of a compound of the present invention described above in the preparation of a medicament for (a) inhibition of HIV protease, (b) prevention or treatment of HIV infection, or (c) treatment of AIDS or ACS.

The present invention further includes the use for HIV protease inhibition of any compound of the present invention described above in combination with one or more agents for the treatment

HIV infection/AIDS selected from an HIV/AIDS antiviral agent, an anti-infective agent, and a b5 immunomodulator for the manufacture of a medicament for (a) inhibiting HIV protease, (b) preventing or treating HIV infection, or (c) treating AIDS or ACS, said medicament contains an effective amount of an HIV protease inhibitor compound and an effective amount of one or more therapeutic agents.

Solid or liquid pharmaceutically acceptable carriers, diluents, excipients, or excipients may

Use in pharmaceutical compositions. Illustrative solid noses include the following: starch, lactose, calcium sulfate dihydrate, white clay, sucrose, talc, gelatin, pectin, gum acacia, magnesium stearate, and stearic acid. Illustrative liquid noses include syrup, peanut oil, olive oil, salt solution, and water. The carrier or diluent may include a suitable sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, an elixir emulsion, a soft gelatin capsule, a sterile injectable liquid (eg, a solution), or a non-aqueous or aqueous liquid suspension. A dose of a pharmaceutical composition contains at least a therapeutically effective amount of an active compound (ie, a compound of formula I or its pharmaceutically acceptable salt, prodrug, active metabolite or solvate), and preferably consists of one or more pharmaceutically dosed units. The selected dose can be administered to a mammal, e.g., a human, in need of treatment, 7/5 mediated inhibition of HIV protease activity, by any known or suitable route of administration of the dose, including: topical (e.g., as an ointment or cream), oral, rectal (e.g. as a suppository), parenterally (by injection) or continuously by intravaginal, intranasal, intrabronchial, intradural, or intraocular infusion. "Therapeutically effective amount" means an amount of an agent of the invention which, when administered to a mammal in need thereof, is sufficient to effectively treat disease by inhibiting the activity of one or more variants of the HIV protease. The amount of administered compound of the invention that will be therapeutically effective will depend on factors such as the particular compound, the disease and its severity, the individual mammal in need, and this amount can be readily determined by a physician.

The compounds of the present invention are also useful in obtaining and conducting tests for antiviral compounds.

For example, the compounds of the present invention are useful for isolating mutant enzymes that are excellent screening tools for more potent antiviral compounds. In addition, the compounds of the present invention are useful in establishing or determining the binding sites of other antiviral agents with HIV protease, for example, i) competitive inhibition. Therefore, the compounds of the present invention are commercial products for sale for this purpose.

General methods of synthesis

Preferably, the compounds of the invention are prepared by the methods of the present invention, including the general methods shown below. When the stereostructure is not defined in the chemical structure, any stereocenter can be used. The following abbreviations are also used: Bos (tert-butoxycarbonyl), Ac ( acetyl), СБ72 со (benzyloxycarbonyl), рмв (2,4-dimethoxybenzyl), твз (tert-butyldimethylsilyl), TVORZ dr (tert-butyldiphenylsilyl), Me (methanesulfonate), Te (toluenesulfonate), Bp (benzyl), and Tg (triphenylmethyl).

All reactions were carried out in sealed flasks with a membrane under a slight overpressure of argon, unless otherwise specified. All commercially purchased reagents and solvents were used as obtained from the supplier, with the exception of: Tetrahydrofuran (THF) was distilled from sodium benzophenoneketyl before use.

Dichloromethane (DCM) was distilled from calcium hydride before use. Flash chromatography was performed using silica gel 60 (Megsk AG 9385). "YAN NMR spectra were recorded at 300 MHz using a Mapap SHMITURiz 300 spectrometer. Chemical shifts are presented in parts per million (5) relative to the internal tetramethylsilane, and coupling constants were obtained in Hz. Infrared absorption spectra were recorded using a Regkt-EIteg 1600 zeg spectrometer ETIK . Elemental analyzes were performed by Ayapius Misgoyar, MD, Mogsgov, CA. Melting points were uncorrected. All variants of amines P mentioned in General Methods A-E described herein below were purchased and used directly or were synthesized as follows .

Method A: A representative method for the reduction of ketones to alcohols.

V. and and and and and. "T | spshe Ya Y - la Teyah Me n ik yin so y. food c2 6,7-Dihydro-4-(5H)-benzofuranone (1) (100 g 7.34 mmol) was dissolved in methanol (55 ml). The mixture was cooled to 02C and added portions of Mavn (0.31g, 8.0v8mmol). The reaction mixture was stirred for 2 hours at 02C while the methanol evaporated. The residue was dissolved in EtOAc and poured into Manso (saturated aq.) and extracted with EtOAc (3x1Oml). The combined organic extracts were washed with brine (1 Oml), passed through

F! a thin layer of sodium sulfate and concentrated in vacuo to give 2 (1.01 g, 9995 as a mixture of isomers) as a pale yellow, thick oil that was of sufficient quality to be used in the next step without further purification. CGI (5095 EUAs/hexanes): 0.53.

Method B: Representative method of reduction of acids to alcohols. yu V pav. ssshe VE NK, s re me. also: b5. and

Tiglinic acid (1) (20.0g, O0.200mol) was dissolved in ether (8Oml) and added dropwise over 30 minutes to a suspension of HYAIN (15.0g, 0.417mol) in ether (8Oml) at 02C and the reaction mixture was allowed to warm to room temperature. After 3 hours, the mixture was again cooled to 02C and quenched slowly by adding H2O (15 ml), 1590

Mmaon (15 ml) and water (15 ml). The reaction mixture was filtered to remove granular sediment and washed with ether. The filtrate was washed successively with 1N HCl, MansSoO (saturated aq.), and brine. The combined organic layers were dried over MAO and concentrated in vacuo to give (E)-2-methyl-but-2-en-1-ol (2) as a clear oil (12.8g, 7496).

Method C: Representative method of alkylation of phenolic alcohols. ili l 4 x zn -- i SN, Yasna Mia E: pov i i Ye Be ho hna i Zhtey insh i ves i SA z Bei

3-Hydroxybenzyl alcohol (1) (0.500g, 4.03mmol) was dissolved in DMF (2ml) at external temperature.

Ethyl bromide (0.90 mL, 12.1 mmol) and finely ground CO2 (2.78 g, 20.1 mmol) were added and the reaction mixture was stirred for 5 hours. The DMF was further removed in vacuo and the residue was partitioned between EtOAc and H 20 and extracted with E(Ac (3x10 mL). The organic layers were washed with brine (10 mL) and passed through a thin layer of sodium sulfate. The solvents were removed in vacuo to give alcohol 2 (0.55 g, 9095) as a pale yellow, thick oil that was of sufficient quality to be used in the next step without further purification.

EtOAc/hexanes): 0.69.

Method O: A representative method of converting alcohols into amines.

EN v i gyi sya kij tcher y p: warming my shk v y Y what I vyli yY i What s with a rod. 3-Ethoxy-phenyl-methanol (1) (123g, 8.08mmol) was dissolved in CH 25SiI (1Oml) at external temperature, and diphenylphosphorylazide (2.67g, 9.7Omol) and 1,8-diazadicyclo |5,4,F0)undec-7-ene (145ml, 9.7Ommol).

The mixture was stirred for 5 hours during which time the dichloromethane was removed in vacuo and the crude residue was partitioned between EtOAc and water and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL), passed through a thin layer of sodium sulfate, and concentrated in vacuum, obtaining a yellow oil, which was loaded directly onto a flash column with silica gel and quickly eluted with a mixture of 1095 E(OAc/hexanes. -

35 Solvents were removed in vacuo to give azide 2 (1.43 g, 8495) as a colorless oil. MG (3095 E(OAc/hexanes): η- 0.79. 1-Azidomethyl-3-ethoxy-benzene (2) (119 g, 6.71 mmol) was dissolved in MeonN (15 ml) and 1095 palladium on activated carbon, wet ( 20 wt) was added. The reaction mixture was hydrogenated for 30 minutes at 40 psi in a Parr apparatus. The black suspension was then filtered through brownmillerite and the methanol was removed at 470° vacuum to give amine sxc C (0.88g, 8890) as a pale yellow a thick oil which was of sufficient quality to be used in the coupling reactions without further purification. Method E: A representative method for the conversion of alcohols into bromides. ol (1) (1.00g, 11.6 mol) and carbon tetrabromide (3.85g, 139mmol) were dissolved in CH 25Si» SO 50 (75ml). The mixture was cooled to 02C and triphenylphosphine (3.65ml, 13, 9 mmol), dissolved in

СНоСИ" (5 Oml). The mixtures were allowed to warm to room temperature and stirred overnight. Dichloromethane m) was removed in vacuo and the crude residue was loaded directly onto a flash silica gel column and rapidly eluted with a mixture of 2095 E(Ac/hexanes. The solvents were removed in vacuo to give bromide 2 (1.53 g, 8895) as a colorless volatile oil. CI (3095 E(Ac/hexanes): 0.89.

Method P: A representative method for converting bromides into amines. mixture of I. bromide (3.00 g, 20.1 mmol), di-tert-butyl iminodicarboxylate (4.8 g, 22 mmol), and K»CO»z (3.10 g, 80.4 mmol) in DMF ( ZOml) was stirred at external temperature overnight. The mixture was distributed between 1H NSI and Es. The organic layer was washed with water and brine, then dried over sodium sulfate. Concentration in vacuo gave a yellow oil which, after purification by flash column chromatography (hexane gradient to 596 E(OAc/Hex)) gave the protected amine 2 as a clear oil (2.0 g, 3590). 65 A mixture of di-BOC-amine 2 (2 .0g, 7.0mmol) of trifluoroacetic acid (2.7ml, Zbmmol) and СНоSiO (40ml) were stirred at external temperature overnight. The reaction mixture was concentrated in vacuo to give the TRA (E)-2-methyl-but-2- enylamine (3).

Method c: Representative method of reduction of aromatic nitro groups by hydrogenation. t WHAT 5 she schey s gave y Z Y yVkuto -- I ey x Well and, their t 7- TE dao

Compound 1 (2.04, 5.79 mmol) was dissolved in EtOAc (20 mL) and 1095 palladium on activated carbon / wet (20 masob) was added. The reaction mixture was hydrogenated for 4 hours at 45 psi in a Parr apparatus. The black suspension was further filtered through compact brownmillerite and the methanol removed in vacuo to give aniline 2 (1.65g, 8895) as a pale yellow, thick oil of sufficient quality to be used in the acetylation reaction without further purification.

Method H: Representative method of acetylation of anilines. I am correcting A M again se IY this ke for MNN o Y: z zaan ME AN Z y

ШХН х вия Коста МУ ше с ко . and and

Aniline 1 (1.65 g, 5.12 mmol) was dissolved in dichloromethane (25 ml) at external temperature. Acetyl chloride (0.48g, 6b, 14mmol) and N,M-Diisopropylethylamine (0.79g, 6.14mmol) were added and the reaction mixture was stirred overnight. The dichloromethane was removed in vacuo and the crude residue was partitioned between EtOAc and 595 KNB 5 O , and extracted with EtOAc (3x10 mL). The combined organic extracts were washed with MnH2SO4 (saturated aq., 10 mL), brine (100 mL), and dried over sodium sulfate. The solvents were removed in vacuo to give an orange oil of sufficient quality to be used in the next step without further purification. KG (5090 p

EtOAc/hexanes): 0.42. Go)

Method I: Representative method of reducing aldehydes to amines. d They ah svi un svi A, ! ("in")

SHK tuya teh o l I Ve U Pen min all de: "zhk tt "slit di NI Tsi "t; zast V, KN: хх и ее: и ная что Же i i ХЧО orotevv tih va ' Z; Bey v ntiv Met s "PEV ZHEO press be ynyatiai: SNU o Yak Shk; sy t y: She) 7 th I th -

Hydroxyl amine hydrochloride (758 mg, 10.7 mmol) and pyridine (2.1 bml) were added to a solution of 2,2-difluoro-5-formyl benzodioxol (1) (2.00 g, 10.7 mmol) in Meon (1Oml). After 18 hours MeonN was removed in vacuo. The reaction mixture was diluted with EIAs and washed successively with water, 1095 wt/v of SizO, and brine and then dried with magnesium sulfate. The solution was concentrated under vacuum. Hydroximine was purified by column chromatography using a mixture of 20956 EtOAc/Hexanes to give 1.37g (6495 yield) of a white C solid product. The imine was further subjected to the reduction of GH AN as described above to obtain amine 3. c The following amines were synthesized for the corresponding numbers of examples "» Example A26 p s roya A also B -I i t sti II II II I

The amine was formed by alkylating 3-hydroxybenzyl alcohol with ethyl bromide, as described in Method C above, and then converting the alcohol to an amine, as described in Method O above, to obtain the desired amine. so to I o Example A4Z3

The amine was formed as described above in Example A43 using propyl bromide as an alkylating agent.

An example of AZZ and dinsche ze: Where is I?

The amine was formed by replacing the bromide in 3-nitrobenzylboromid with di-BOC-amine as described in Method E above. bo Reduction of the nitro group to aniline (method C above) followed by acetylation (method H above) and removal

BOC (Method E above) gave the desired amine.

Example АЗб, Example АЗ7 and Example A40 about zvi. p :: S g Ky xx Va t nyak, dn u MNN U pa Sho pre. Is. I'm talking about it and not from the school. s fisvnyu nlyek pi EN i b5 san COMI OM PI: pact:

Amines were formed by conversion of the corresponding primary alcohols as described in Method E above. Replacement of the bromide with di-BOCS-amine and deprotection of TEA (Method E above) afforded the desired amines.

An example of AZO. 2 o rya ma sov Z Ki he MYH and h che

STILL Not Me

The amine was formed from 3-dimethylaminobenzyl alcohol as described in Method OO above.

Example AZ4 at ve

The amine was formed by reduction of the corresponding methyl ester to the primary alcohol Г(MMiri 9. Ogd. Spet. 1994, 59, 4875-86). Conversion to the bromide (Method E above) followed by substitution with di-IVOS-amine and deprotection (Method E above) afforded the desired amine.

Example of AZ5 g B

The amine was formed from the corresponding carboxylic acid. Reduction of the acid as described in method B above, followed by replacement with bromide as described in method E above gave the primary bromide. The conversion of the bromide to the primary amine is described in Method E above.

Example A42 Gee!

Z loshe s ss pa ssvfszy ZK tn SV (5) vka g. Ye Kk Ei

IS; and co

The amine was formed from 3-benzyloxybenzyl alcohol. Conversion to azide and reduction of the azide and benzyl protecting group was performed using method 0 described above with a longer hydrogenation time. at

Example A44. so zha and NK

My

The amine was formed by the reduction of GiAIN, 2-cyanophenol | sdetap, 5.M., ei a). IN). Honey. Spent 1975, 18 1252-3). -

Example OR za shchi ch zo eV - s Gah y sk ne ch Bezh z re

Sleep

AND

In | | shi and -I Amine was formed by condensation of oo-tolualdehyde with 2-aminoethanol, followed by reduction with sodium borohydride |Teigapedhop Azzut. 1997, 8, 2367-74. - Example A48 - : pu ves oIY ni i

Pen oi tribute I o y

The amine was formed from the corresponding aldehyde by reductive amination, as described in method | above.

Example A7 52 sdo still o y les nya -i rya M o

Oh, and the deadline

The amine was formed by reductive amination from the corresponding aldehyde (Ago!. RNnagt. 1987, 320, 647-54|.

Example A49 bo ME A se

In la Ted sody Ve what is the twist?

The amine was formed on the thiazolidine core as follows:

Diphenylchlorophosphate (1.0ml, 4.2mmol) and then triethylamine (0.59ml, 4.2mmol) were added to a cooled to 02 solution of BOC-UOMTA 1 (1.0g, 33.dmol) in EtOAc (10ml). The mixture was stirred for 1 hour during which triethylamine (0.59 mL, 4.2 mmol) and ethanolamine (0.25 mL, 4.2 mmol) were added. The reaction mixture was stirred overnight at ambient temperature and then partitioned between 1N HCl and EtOAc. The organic layer was washed

Manso" (saturated water) and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to a pale yellow oil 2. The oil was stirred with thionyl chloride (2 mL) for 45 minutes at room temperature. The mixture was concentrated in vacuo and the residual oil was partitioned between 1N NaOH and EtOAc.

The organic layer was extracted with 1N NOI (2x20ml). The combined aqueous layers were made alkaline with 1H Mahon and further extracted

EUAs (3xbOml). The organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give (K)-5,5-Dimethyl-thiazolidine-4-carboxylic acid (2-chloro-ethyl)-amsh C as a clear oil (0.39g, 5590).

The following amines were prepared as described:

SHE: 12 The above-mentioned amines were obtained according to (Sagizep N. ., U. Ne(egosusie Spet. 1997, 34, 797-806). - BD.

Example A41

The above amine was obtained according to O'Vgiep, R.M., U. Med. Spent 1994, 37, 1810-18221.

I am 25007 SUK

Example A7 Fr

The above amine was obtained in accordance with (MUeiipNeit, (3. Agsp. RNagt. 1987, 320, 647-6541.

General method A What and in and I Ж ooo

Y dis deky Shadows ek dnih shi so tk i zh Go Ne Gbke vi I tia pd h o: t Ko os : poh Ж іквттевт r SE svi N і і ші i Шыні і і і і broken - "k і х і

And Petenn V shk Bumelkn re m , and TK.

What else - I and. ! ssh She and s more sHE that - s YOU tya seni zhen. y: B sne NV oon certain p Penn they still NOT r t" a: s ZD Е TO i dream of evil: MIC spra sv V i; і » Bacon -I s s s re lys s v ME ty kush i SIK.

S bar BO EY Tys still OO, MO NK

On the whole, Z and 5 lack Y

Still hehe same vh z and s

The synthesis of compounds of the general structure 5 is given below. Bos-protected thiazolidinecarboxylic acid 1 -I is combined with the required amines 2 to obtain aminoamides 3, using a two-step process. The two-step -3z process involves treatment of 1 of 2 in the presence of diphenylchlorophosphate or NATI, followed by the action of methanesulfonic acid. The final compounds 5 are obtained by the SUCC-mediated coupling of C and 4 followed by deprotection of (oo) 20 P2-phenol. The final compounds were purified by flash chromatography or preparative HPLC. (42)

Ф) име) 60 b5 yishke SHU same y: sp: vk. DAY 5: zhu Zhe and BE zu p. VVA VU EF; ie B sbinann rsov ves svi: Still Ko ove fs TNK Ya ov Es pn tpiekh ee NA eV pes "Nodnikh 7 Ж shotsi i a zh B 7 i v v ey

ALREADY Ese YOU NOT: ZY VEN Well "pk i pa to g ve y how i

I.

She BO 15 certain inv. slo y i x shchy M

How: zi syu fe I to what and what I in o i i ON a r, v pav vn NK NK NK pli i rya ZAY ta chi y Ku I svy N- ziys-euvnh KIV vant ee INK 5 ZAY. I'm burning, Ex

She NE ks ke KP is pn fa sa IV UM u ah le HYd stitched 0 В cha Ж

An alternative approach to general structures 5 is as follows. Thiazolidine ester b is combined with acid 7 b. SU 25 under the conditions of the carbodamide reaction, leading to product 8, which is converted into acid 9 by mild basic o hydrolysis. Acid 9 was coupled with various amines using diphenylphosphorylazide followed by cleavage of Po2-acetate to give the final compounds 5. The products were purified by flash chromatography or preparative HPLC.

Specific Method A. shk and "c) 30 I ee: FOR what I what and she Y Sha (ge)

UBy, THIS: and: svsheh shi KOP oso ". SHY 35 same siy "she ANOTHER SCHE. Sh What sha: ZK re I Ey 40 zh v - h o-vy More

B; ; STILL an o res in NE eza pe paz chas. pnh -I constant lan vn a t I pov nn in other m KD "KN -i in A B ev I: ai zna es liy 50 Example A1: (ee) 3-(2-Hydroxy-3-(3-hydroxy -2-methyl-benzoylamino)-4-phenyl-butyryl|-5-dimethyl-thiazolidine-4-carboxylic acid o (1,4-tetrahydro-naphthalen-1-yl)-amide

The named compound was obtained as follows. (K)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1 (01g, 1.15mmol) was dissolved in EtOAc (3ml) and cooled to 092С. Diphenyl chlorophosphate (0.2bml, 1.2bmmol) was added followed by TEA (0.18ml, 1.2bmmol). The reaction mixture was stirred at O2 for 1 hour and treated with (5)-1,2,3,4-Tetrahydro-1-naphthylamine (0.19g, 1.2bmmol). The reaction mixture was stirred (F) at room temperature overnight, then partitioned between 1N HCl (ml) and EtOAc (10ml). Organic layer

The GI was washed with saturated sodium chloride, brine, dried over sodium sulfate, and concentrated to a light yellow oil.

The resulting crude oil was dissolved in EtOAc (bml) and cooled to 09C. Methanesulfonic acid (0.3bml, 60 5.32mmol) was added and the solution was stirred at 09 for 15 minutes, then at room temperature for 1 hour. The mixture was again cooled to 09C and quenched with 596 Ma»CO»z (ml) and then extracted with EtOAc (1Oml). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give

For how yellow oil. Yellow oil Za (0.34g, 1.15mmol) was dissolved in EtOAc (12ml). AMV-ANRVA 4 (0.40 g, 1.09 mmol) was added, followed by NEW (0.15 g, 1.09 mmol). The mixture was stirred overnight. The mixture was filtered at 65 °C and the filtrate was washed with 1N HCl (10 ml). saturated with MansSO" (1Oml), brine (1Oml), dried with sodium sulfate and concentrated, obtaining a crude white solid product (contaminated with OSI). The wasps were removed by flash chromatography (3095 to 5095 EAs in hexanes) to give a white solid as dissolved in MeOH (2 mL) and treated with 4H HCl in 1,4-dioxane (0.2 bmL, 1.1 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between 1N HCl (10 mL) and EtOAc (10 mL). The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a residue which was purified by flash chromatography (6095 EOAc in hexanes) to give the title compound as a white solid, mp -125-1262C. IR (cm") 3320. 2932, 1704 1644, 1530, 1454, 1361. 1284; "NMR (DMSO-IV): 5 9.36 (c, 1H), 8.28 (a, 2-86, 1H), 8.21 (a, 9-8.8, 1H), 7.35- 6.91 (t, 10OH), 6.76 (a, 9-8.0, 1H) 6.54 (a, 9-7.5, 1H), 5.34 (a, 9-6.0, 1), 5.13 (a, 2-9.0, 1H), 5.02 (a, 92-9.0, 1H) 4.60-4.30 (t, 4H), 2.81-2 ... 34NazoMaO5 1.5, C, 64.95, H, 6.73, M, 6.68.

Found C, 64.88; H, 6.31; M 6.18.

Example Ag: (k)-3-(25 3K)-2-Hydroxy-3-11-73-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5- Dimethyl-thiazolidine-4-carboxylic acid Z-methoxy-benzylamide

На: ях зе ше и что Кока see 200 иж ех шаны ян ие у кли и Уапа: и Uк я т щей ше r жк ж шы

White solid product temp.pl. 108-1102C, IR (pure cm") 3310, 2965, 1644, 1586, 1531, 1455, 2359, 1284; "NMR (DMSO-iv): 5 9.37 (in, 1H), 8.40 (i, 9-6.0, 1H), 8.09 (4, 9-81, 1H), 7.31-6.52 (t, 12H), 5.49 s 29 (4, 9-6.0, 1H ) 5.12 (y 2-93, 1H), 5 00 (4, 9-9.3, 1H), 4.44-4.35 (t, ЗН), 4.42 (v, 1H), 4 ... .49 (in, ZN), 1.34 (8, ZN); Calculated for

Cz2NaMzO65.0.75H20: C, 63.50; H, 6.41; M, 6.94. Found C, 63.60; H, 6.23; M, 6.80.

The following examples were obtained by the above-mentioned specific method using the desired amine 2. o

Example of AZ: (k)-3-(2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5-dimethyl-thiazolidine- 4-k (ee) arboxic acid 2-methoxy-benzylamide - iy. : and She Shk. y ge : shk write ak ZK Me YAN YASCHIE 70 White solid product temp.pl.-123-1259C, IR (cm") 3318, 2965, 1644, 1525, 1495, 1464, 1286, 1246, 1120, 8 s 1030; NMR (DMSO-iv): 5 9.36 (c, 1), 8.26 (5 9-59, 1H), 8.14 (a, 9-80), 7.39-7.13 (t , bH), with 6.95-6.76 (t, 5H), 6.53 (a, 9-7.5, 1H), 5.49 (a, 9-6.0, 1H), 5, 13 (a, 20-90, 1), 5.01 (a, 9U-9.0, 1H), 447 (85, 1H), 4.41-4.16 (t, 4H), 3.78 ( in, ЗН), 2.90-2.62 (t, 2Н), 1.81 (in, ЗН), 1.49 (in, ЗН), 1.32 (in ЗН); Calculated for 415 Cz2Na»MzO65-0.75H20: C, 63.50; H, 6.41; M, 6.94; Found C, 63.68; H, 6.20; M, 6.54. - Example A4: 3-(2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4 -carbonic acid 3-trifluoromethyl-benzylamide "ZM: (ee) 50 shades" Wounds and skin and wounds in (F) White solid product: temp.pl.-108-1102С; IR (cm") 3308, 3065 , 1646, 1540, 1456, 1362, 1329, 1284, 1165, ko 1125, 1074; NMR (DMSO-iv): 5 9.38 (in, 1H), 8.56 (in -6.0, 1), 8.12 (a, 9-82, MN), 7.65 (in, МН), 7.60-7.47 (t, ЗН), 7.28-7.13 (t, 5Н), 6.96-6.92 (t, 71Н) 6.77 (а, 9-8 ... .00 (a, 9-9.2, 1H), 4.53-4.41 (t, 4H), 4.22 (aa, .-16.0, 6.0.1H), 2.86- 2.66 (t, 2H), 1.81 (5, ЗН), 149 (v, ЗН), 1.31 (5, ЗН); Calculated for C z32NaaEzMa3OB5Be: C, 61.04; H, 5.44 M, 6.67.

Found: C, 61.03; H, 5.56; M, 6.51.

Example AB: 3-(2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methianoyl|amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-car 65 bonic acid fluorine trifluoromethyl-benzylamide with SHE ZSh. A: "aa 95 TZ Y r g Ya re y t Kk p E g her

Key vti ion of each skeleton and "NMR (DMSO-yv): 5 9.33 (v, 1H), 8.69 (f 9-5.6, 1H), 8.12-6.56 (t, 11H) , 5.50 (a, 9-6.0, 1H), 5.22 (a, -9.3, 1H), 5.06 (a, 9U-9.3, 1H), 4.60-4 .36 (t, 5H), 4.50 (85, 1H), 2.89-2.67 (t, 2H), 1.83 (85, ЗН), 1.55 (in,

ZN), 1.39 (in, ZN); Calculated for C 32NazzMaOB5ZE;: C 59.34; H, 5.14; M, 6.49 5, 4.95. Found: C, 59.06; H, 5.31; M, 6.22; 5, 4.66.

Example Ab: t (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid 4-methoxy-benzylamide

Be t-- OV « 7 a and 5 o

IR (cm-"7) 3335, 2920, 1641, 1516, 1463, 1374, 1285, 1249, 1172, 1118; "NMR (DMSO-div): 5 9.38 (in, 1H), 8.37 (o ) (6 9-5,5,1Н), 8,12 (a, 9-82, 1), 7,33-7,13 (t, 7Н), 6,94 (B 0-7,7, 1Н ), 6.84-6.79 (t, ZN), 6.54 (a,

U-7.0, 71), 5.48 (а, 9-6.6, 1), 5.12 (а, 9-92, 1Н), 500 (а, 0-92, 1Н), 449- 442 (t, ZN), 4.32 (aa, 5-6.2, 14.8, 6, 1H), 4.09 (ad, 9O-14.8, 5.3, 1H), 3.67 (in, ZN), 2.87-2.68 (t, 2H), 1.82 (in, ZN), 1.48 (in, ZN), o z 1.32 (in, ZN); MO-VR (ЕР - electron sputtering) t/7, calculated for C zo2NazMzOvzMa (MeMa)n614.2301, found 614.2305; Calculated for С5з2На7МаО65.0.75Н2О: С, 63.50; H, 6.41; M, 6.94. d)

Found: C, 63.65; H, 6.43; M, 6.74. "-

Example A?7: 3-(2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl|-

Same - same rn

De VE ХЖЕ ге те бек ос? o a a this t s | as well as 5,5-dimethyl-thiazolidine-4-carboxylic acid methyl-(2-methyl-benzyl)-amide;" TN NMR (DMSO-yv): 5 9.36 (in, 1H), 8.44 (i 9-7.98, 1H), 8.13-8.07 (t, 2H), 7.34-7 ,13 (t, OH), 6.93 (i,

U-7.9, 1), 6.78 (a, 0-7.7, 1H), 6.53 (a, 9-71, 1H), 5.58 (4, 9-68, 1), 545 (a, 9-7.0, 1H), 5.12 (aa, 97.8, 8.2, 1H), 4.51-4.31(t, 6H), 2.86-2.67 (t, 2H), 2.19 (in, ЗН), 1.81 (85, ЗН), 1.51 (in, ЗН), 1.34 (in, ЗН); -I Calculated for SzzNaeMaOv5-0.37N.O: C, 66.45; H, 6.72; M, 7.15. Found C, 66.34; H, 728; M, 7.45.

Example AB: - 3-(2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl/|-5,5-dimethyl-thiazolidine-4-carboxylic acid) methyl-(Z -methyl-thiophen-2-ylmethyl)-amide - BVE in 1 z and schi Pak. in t Where and on 2 i is clear oo i; ko IR (pure or KVg cm") 3150, 3000, 2942, 2187, 3712, 1600, 1567, 1505; "NMR (DMSO-div): 5 9.36 (in, 1H), 8.44 (, 9-7.98, 1H), 8.13-8.07 (t, 2H) , 7.34-7.13 (t, 5H), 6.93 (Her, -7.9, 1H), 6.78 (a, 9-7.7, 1H), 6.53 bo (a, 0-71, 1), 545 (a, 9-7.0, 1H), 5.12 (aa, 0-7.8, 8.2, 1H), 4.51-4.31 (t, 4H ), 2.86-2.67 (t, 2Н), 2.19 (8, ЗН), 1.81 (8, ЗН), 1.51 (в, ЗН), 1.34 (в, ЗН) ; Calculated for C39Na5Ma3O552: calculated C, 61.94; H, 6.06; M, 7.22. Found C, 62.38; H, 6.23; M, 7.17.

Example A9: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-ethyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thia 65 zolidine-4-carboxylic acid 4-trifluoromethyl-benzylamide m.

LK tn will throw ost, siy. Mr. and Mrs

IR (pure cm") 3343, 2931, 1543, 1530, 1454, 1326, 1122: "H NMR (DMSO-iv): 5 9.38 (in, 1H), 8.57 (i, 3-5.0 , 1), 8.15 (a, 9-8.4, 1H), 7.59 (a, 9-82, 2H), 7.50 (a, 9-8.2, 2H) 7.28- 7.13 (t, 5H), 6.93 (5 9-75, 13, 6.77 (a, 9-7.7, 1H), 6.54 (a, 9-7.3, 1H), 5.50 (in p, 71) 5.15 (a, yu-9.2, 1H), 5.02 (a, 2-92, 1H), 4.47-4.21 (t, 5H), 2.85-2.67 (t, 2H), 1.81 (in, ZN), 1.51 (in, ZN), 1.34 (in, ZN); MO-VR (ERE) t/2, calculated for

Cz"NaRzMzO5ZMa (MMa)" 652.2063, found 652.2044; Calculated for C 32Na(ERzMa3O55-0.25H20: C, 60.60; 75 NN, 5.48; M, 6.63. Found: C, 60.50, H, 5.29, M, 6.48.

Example A10: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide

In ok it is Yu under Zk: "and NO." NMR (DMSO-iv): 5 9.39 (z, 1H), 8.36 (9-4.8, 1H), 8.15 (y, 9-81, 71H ), 7.98 (a, 9-74, 1H), 7.65 (t, 71), 7.52 (t, 2H), 7.32-7.11 (t, 6H), 6.93 ( B -7.9, 1H), 6.76 (a, 9-7.9, 1H), 6.54 (0, 9-7.5, 1H), 542 (4, 9-6.4, tn ), 5.08 (a, 9-93, 1H), 5.02 (a, 2-9.0, 1H), 4.78-4.30 (t, 5H), 2.84-2.66 (t, 2Н), 1.81 (in, ZN), F 1.57 (in, ZN), 1.45 (in, ZN); MO-VR (ЕР) t/y, calculated for C 32Но5МаО65Ма (MeMa )" 612.2139, found with 612.2141.

Example A11: 3-(2-Hydroxy-3111-(3-hydroxy-2-methyl-phenyl)-methanol-amino)-4-phenyl-butanoyl-5,5-dimethyl-thiazolidine-4-carboxylic acid C-fluoro-4-trifluoromethyl-benzylamide

As Fr. I - o yash zak yav oh so u y di y i EE ze ogoi - un "

Kikvostten who "from which ah and you in: and her on pen stey se NK v s Kos -Y Я Я I I: and EE " so t Pi is" TN NMR (DMSO-yv): 5 9.34 (z, 1H ), 8.62 (5 9-5.9.1H), 8.09-6.54 (t, 11H), 545 (with B, 1H), 5.18 (4, 5-92, 1H), 5.03 (a, 9-9.2, 1H), 4.55-4.00 (t, 5H), 4.45 (c, 1H), 2.86-2.49 (t, 2H), 1.82 (8, ЗН), 1.53 (в, ЗН) 1.36 (в, ЗН); Calculated for C z32NazMz3OB55E,;; C, 59.34; H, 5.14; M, 6.49 ; 5, 4.95. Found: C, 59.14; H, and 5.29; M, 6.21; 5, 4.67. -1 Example A12: 3-(2-Hydroxy-3-(1 -(3-Hydroxy-2-methyl-phenyl)-methianoyl-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carbonic acid-2-trifluoromethyl-4-fluoro-benzylamide

Mass about St. Sah sha and EK Ob eh

GF) oh pok Set. still tt Ge ze snserne sh kyu ' a y Zh

TN NMR (DMSO-yv): 5 9.33 (in, 1H), 8.65 (B, 9-5.9, 1H), 8.12-6.54 (t, 11), 5.45 ( a, 9-6.9, 1H) 5.18 (49, in 5-9.2, 1H), 5.05 (a, 9-9.2, 1H), 4.59-4.34 (t , 5H), 4.50 (85, 1H), 2.85-2.67 (t, 2H) 1.82 (in, ЗН) 1.53 (in,

ZN), 1.37 (8, ZN); Calculated for C 32NazzMa3OB5ZE; C, 59.34; H, 5.14; M, 6.49; 5, 4.95. Found: C, 59.26;

H, 5.35; M, 6.23; 5, 4.69.

Example A13: 3-(2-Hydroxy-3-/3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl/|-5,5-dimethyl-thiazolidine-4-carboxylic acid 4-methanesulfonyl-benzamide rt Kan sei y ke Vedy i.) piky po Od te Y aoshsyzy to "YAN NMR (DMSO-yv): 5 9.38 (v, 1H), 8.37 (, 9-5.5, 1H), 8.12 (9, 1H, y. 8.2, 1H), 7.33-7.13 (t, 7H), 6.94 (B OH, 0-7.7, 1H), 6.84- 6.79 (t, ZN), 6.54 (a, 1nH,)-7.3, 1), 5.48 (a, 0-66, 1H), 5.12 (a, 9-92, 1H ), 5.00 (Ya, yin 0-92, 1), 4.49-4.42 (t, ZN), 4 32 (aa, 0-14.8, 6.2, 1H), 4.09 (aa, YAN, -14.8, 5.3, 1H) 3.47 (5,

ЗН), 2.87-2.68 (t, 2Н), 1.82 (8, ЗН), 1.48 (8, ЗН), 1.32 (v, ЗН); Calculated for С doNa; MaО 5»: С, 60.07; H, 5.83; 755. M, 6.57. Found C, 60.25; H, 6.13; M, 6.74.

Example AT14: (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-nphenyl-butanoyl)-5,5-dimethyl -thiazolidine-4-carboxylic acid allylamide on. How gy IN v, I dna ak zda: ee Ne Zo DE SHE pd" zhh v:

IR (pure cm") 3342, 2966, 1637, 1531, 1460, 1366, 1284, 1108; "H NMR (DMSO-iv): 5 9.36 (in, 1H), 8.13-8.07 (t , 2H), 7.34-7.13 (t, 5H), 6.93 (i, -7.9.5 1), 6.78 (a, 0-7.7, MH), 6.53 (a, 9-.0, NN), 5.82-5.70 (t, 7H), 5.46 (a, 9-6.6, 1H), 5.23-4.97 (t, 4H ), 4.40 (t, ЗН), 3.81-3.59 (t, 2Н), 2.86-2.67 (t, «Ф 2Н), 1.81 (v, ЗН), 1, 50 (in, ZN), 1.35 (in, ZN); MO-VR (ERE) t/y. calculated for C 27 NazM3O55 Ma (MaMa)" so 534.2039, found 534.2062; Calculated for 5: C, 63.38; H, 6.50; M, 8.21. Found: C, 63.68; H , 6.57; M, 8.29.

Example A15: (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazo part of lidin-4-carboxylic acid 4-dimethylamino-benzylamide; in. и- и Най с МИ игЯ и о кзнючойню сеПклййнсляй им

And" Sho and

IR (pure cm") 3331, 2931, 1643, 1519, 1455, 1349, 1284; "NMR (DMSO-dv): δ 9.37 (in, 1H). 8.26 (t, 1H), 8.12 (a, 0-7,1,1H), 7.38-6.92 (t, 8H), 6.78 (I, 9-7.9, 1), 66O (a, 9U-8.6, 1), 6.55 (a, 9-7.3, 1H), 6.42 (a, 9-8.2, 1), 5.46 (a , 9-6.0, 1), 5.11 (a, 2-93, 1), 5.00 (y 2-9.3, 1Н), 4.45 (t, ЗН), 4.25 ( t, 1H), -1 4.03 (t, ЗН), 2.80 (85, ЗН), 2.87-2.73 (t, 2Н), 1.82 (5, ЗН), 1.48 (5, ZN), 1.32 (in, ZN); MO-VR (ERE) t/". calculated for Czz3NaoMaO5ZMa (MeMa)" 627.2612, found 6272607. - Example A16: o 20 ()-3-((25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl) )-methanoyl-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid 4-amino-benzylamide with "PDK,

Vk S t water write mi g'shyah,. dekle In what and and and and and

SN geo otoy; Z Z TE! .

GF) shk TEDE wept and SENNE ZHUH tre R pev ekshitiketnsyai vo

From the mouth o en Kk x NNYA used in KN

Pale yellow solid product temp.pl.-107-10992: IR (cm") 3378, 2919, 1631, 1518, 1453, 1382, 1281, 1121: "NMR (DMSO-iv): 5 9.36 (in , 1H), 8.21 (5 9-6.0. 1H), 7.40-7.10 (t, 6H), 8.12 (9, 9-81, 1H), 6.92 (a, 9-84, 2H), 6.77 (a, 9-7.2, 1H), 6.54 (y, 9-7.2, 1H), 644 (a, 0-84, 2H), 5, 44 (а, 9-6.0, 1), 5.10 (а, 35-92, 1Н), 4.99 (а, ю0-9.2, 1Н), 4.90 (в, 2Н), 4.50-4.532 (t, ЗН), 4.22-3.93 (t, 2Н), 2.90-2.60 (t, 2Н), 1.81 65 (8, ЗН), 1.47 , (85, ZN), 1.31 (5, ZN); Calculated for C3)Hz6MaO55-0.25H20: C, 64.06; H, 6.33; M, 9.64. Found:

C, 64.17; H, 6.38; M, 9.60.

Example A17: 3-2-Hydroxy-3-(1-13-hydroxy-2-methyl-phenyl)-methanol)|-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-car prop-2-inylamide of bonic acid

And what?

KN syatateya dak rah mah zhveni v

TN NMR (DMSO-iv): 5 9.33 (zM IN), 8.38 (B, 9-5.5, 1H), 8.08 (4, U-8.3, 1H), 7.35 -6.53 (t, 8H), 5.46 (a,

У-6.6, 1Н), 5.10 (а, ю9-9.2, ИЕ), 5.02 (0, 9-9.2, 1Н), 4.44-4.40 (t, 1Н ), 4.40 (in, 1H), 3.85 (t, ЗН), 3.08 (i, 75 42.5, 1H), 2 88-2.68 (t, 2H), 1.82 ( 8, ZN), 1.51 (in, ZN), 1.37 (85, ZN). Calculated Co7Na1M3O55: C, 63.63; H, 6.13; M, 8.24; 5, 6, 29. Found: C, 63.50; H, 6.33; M, 7.81; 5, 5.68.

Example A18: 3-(2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanoylamino)-4-phenyl-butanoyl)|-5,5-dimethyl-thiazolidine-4-carbone acid (2-methylsulfanyl-phenyl)-amide and SHIELD. imagine -ta hv o agel in de rai t t chi kn ta, A VEN o VO p Kiya dk y y dya: Ж I doki pat

It is me. whether TSO FOR OH FRI. square with Ve 7- Zdes She

TN NMR (DMSO-iv): 5 9.33 (z, 1H), 8.41 (B 9-5.7, 1H), 8.10 (4, U-8.3, 1H), 8.09 -6.54 (t, 12H), 5.46 (4. 9-66, 1H), 5.14 (a, 9U-9.2, 1H), 5.04 (ai, 9-92, 1H) , 4.50-4.02 (t, 4H), 4.50 (in, 1H), 2.89-2.69 (t, 23), Ф 2.51 (in, ЗН), 1.84 ( in, ZN), 1.53 (8, ZN), 1.39 (in, ZN); Calculated for Cz32Na7M3O5Zo: C, 63.24; H, 6.14; M, 6.91. co

Found: C, 63.01; H, 6.30; M, 6.53.

Example A19: (k)-3-(2535)-2-Hydroxy-3-(1-13-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazo part of lidin-4-carboxylic acid phenethyl-amide

PE - i- ih s v SHY SHE SHE SHE SCHE: « and eye AK A Ky t VV ky odv vie NK Va ne s ; but Beh vyy ze y

Eh i play ey 7 i t r ZK o " » la. Na " "YAN NMR (DMSO-yv): 5 9.41 (in, 1H), 8.38 ( 9-48, 1H), 8.16 ( a, 9-81, 1), 8.01 (a, 9-74, 1H), 7.64 (t, 71), 7.52 (t, 2H), 7.32-7.11 (t, 6H), 6.93 (B -7.9, 1H), 6.76 (a, 9-7.9, 1H), 6.54 (0, 9-7.5, 1H), 542 (04, 9-6A, 1H), 5.10 (y, y0-9.3, 1H), 5.05 (0, 9-9.0, 1H), 4.80-4.532 (t, 5H), 2, 84-2.66 (t, 4H), 1.80 (in, ZN), 7 1.56 (in, ZN), 1.45 (in, ZN); Calculated for C 32NazMzOBZ: C, 66.76; H, 6.48; M, 7.30. Found C, 66.50; H, -i 6.56; M, 7.23.

Example A20O: - (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazo o 20 lidin-4-carboxylic acid ((Z)-1-phenyl-ethyl)-amide o i. scha IY siya her I shu ka o KE tina wounds and sia tan ko ZHE! podo 7 and ours and: in White solid product temp.pl. 114-11590: IR (pure cm") 3306, 2971, 1643, 1531, 1451, 1372, 1284, 1211, 1107; "NMR (DMSO-iv): 5 9.36 (c, 1), 845 (a, 9-8.2, 1), 819 (a, 9-8.2, 1), 7.32-7.18 (t, 1OH), 6.96-6.91 (t, 7), 6, 76 (a, 9-8.1, 1), 6.54 (a, 0-7.5, 1), 5.36 (y, 0-72, 1), 5.08 (y, 9-9 .7, 1H), 5.01 (0, y-9.7, 1H), 4.95-4.85 (t, 2H), 4.48 (v, 1H) 4.45-4.30 ( t, 1H), 2.80-2.60 (t, 2H), 1.79 (in, ЗН), 1.47 (in,

ZN), 1.36 (a, 9-72, ZN), 1.30 (a, 9-7.0, ZN); Calculated for Cz2Na7MzO55.0.25H20: C, 66.24; H, 6.51; M, 7.24. 65 Found C, 66.30; H, 6.56, M, 6.89.

Example A21:

(k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5-dimethyl- thiazolidine-4-carboxylic acid ((K)-1-phenyl-ethyl)-amide o

M. pezhgod I ve in E even GE sn pivnyh" what zvi TEN Ge ti re I I in, their se

WHAT A HELL

White solid product: temp.pl. 1114-1159; IR (pure cm") 3299, 1643, 1583, 1520, 14541377, 1284, 1104; "NMR (DMSO-iv): 5 9.35 (in, 1H), 8.36 (4, 9U-8.21H) , 8.15 (a, 9-8.2, MH) 7.44-7.13 (t, 1OH), 6.96-6.91 (t, 1), 6.75 (a, 9U-8 ... 4.99 (a, 72.)-9.7, 1H), 5.28-4.74 (t, 1H), 4.52 (c, 1H), 4.49-4.35 (t, 2H ) 2.80-2.60 (t, 2H), 1.79 (in, ЗН), 1.50 (in, ЗН), 1.38 (in, ЗН), 1.34 (а, 9-7 ,0, ZN); Calculated for Cz2Na7MzO5Z-0.25H20: C, 66.24; H, 6.51; M, 7.24. Found:

C, 66.38; H, 6.52; M, 7.30.

Example A22: 3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5-dimethyl- thiazolide of in-4-carboxylic acid (benzo|1,3)dioxol-5-ylmethyl)-amide and the same.

AND; zu I J s «ik i she for I not ; ebdnknt and wai KK ancient dyan tia piny ven vu and Bono eh m. yin

IR (pure or KVg cm") 3302, 2922, 2351, 2333, 1768, 1750, 1646, 1537; "H NMR (DMSO-IV): 5 9.36 (8, 1H), o 8.44 (in, 1H), 8.13 (a, 9-7.9 1H), 7.34-7.13 (t, 5H), 6.99-6.77 (t, 4H), 6.78 (4, 9 -7.7, 1H), 5.93 (a, 9-71, Fo 2), 5.15 (4, yu-7.0, 1), 5.08 (a, 0-78, 1H), 4.43 (y, 2-9.32, 2H), 4.34 (t, 2H), 4.12 (ai, 9-6.18, 1H), 4.08 - (4, 9-6, 08, 1H), 2.86-2.67 (t, 2H), 2.55 (8, 1H), 1.81 (5, ЗН), 1.51 (in, ЗН), 1.39 (in , ZN); Calculated

Cz2Na5Ma3075.0.65TEA.1.0H20: C, 57.31; H, 5.44; M, 6.02. Found: С, 57,58; H, 5.47; M, 5.85. and -

Example A23: im (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5 ,5-dimethyl-thiazolidine-4-carboxylic acid allyl-methyl-amide and " py

So - In DV with

E. se U tk -IN IT v vysh sho i dih. - and IR (pure, cm") 3380, 2943, 1637, 1460, 1284, "H NMR (DMSO-div): 5 9.37 (in, 1H), 8.24 (a, 9-84, 1H) , 7.34-7.15 (t, 5H), 6.94 (B 9-7.5, 1H), 6.77 (a, -7.7, 1H), 6.53 (a, 9- 7.5, 1H), 5.99 (t, 1H), 5.70-5.65 (t, and 1H), 5.49-5.00 (t, 5H), 4.30-3.85 (t, 4H), 3.08 (in, ЗН), 2.78-2.65 (t, 2Н), 1.80 (85, ЗН), 1.58 (in, ЗН), 1.38 - (in, ZN); MO-VR (ERE) t/2, calculated for SobNaz5MaO5ZMa (MeMa)" 548.2190, found 548.2178. so 50 Example Aha: (k)-3-(2535)-2-Hydroxy-3-(11- (3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazo 62 lidine-4-carboxylic acid fluoro-trifluoromethyl-benzylamide scha and sei Z io

GF) I K. ANOTHER 5th B in and Shi a vo and 1st sc veto ZV,

TN NMR (DMSO-iv): 5 9.34 (z, 1H) 8 32 (, 9-6.0, 1), 8.20 (a, 9-84, 1), 7.70-7 56 ( t, ZN), 7.37 (49,

U-6.9, 2H), 7.27 (5 9U-7.5, 2), 7.18 (B 9-74, 1), 6.97 (5 -7.0, 1H) 6.79 (a, yu-7.0, yin) 6.58 (a, 9-66, v5 13, 5.15 (a, 2-9.0, 1H), 5.02 (y, 9-9.0 , 1H), 4.60-4.48 (t, ЗН), 4.48-4.32 (t, 2Н), 2.88-2.65 (t, 2Н), 1.83 (5, ЗН ), 1.48 (in, ZN), 1.34 (in, ZN); MO-VR (ERE) t/2 calculated for C 52Naz3Mz3O55EMa (MaMa)" 670, 1969,

found 670,1999; Calculated for C 32NazzMaOB5ZE,.1H20, 0.3 TEA: C, 55.94; H, 5.08; M, 6.00. Found: C, 55.74; N, 4.98; M, 5.94.

Example A25: 85 (K)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid -3-trifluoromethoxy-benzylamide eco a ME

White solid product, temp.pl.-102-1052С, IR (cm) 3306, 2966, 1644, 1586 1520, 1216, 1166; "H NMR (DMSO-4b): 5 9.38 (in 1H), 8.53 (9-6.0, 1), 8.12 (a, 9-8.1, 1H), 7.40- 7.13 (t, 9H), 6.96-6.91 (t, 1H), 6.77 (a, yu-8.2, 1), 6.54 (y, yu-7.7, 1H ) 548 (y, 0-64, 1), 513 (90, y-9.2, 1), 5.00 (a, 0-9.2, 1H), 4.46-3.97 (t, 5H), 2.87-2.67 (t, 2H), 1.81 (85, ЗН), 1.50 (85, ЗН), 1.30 (в, ЗН); Calculated for

Cz2NaaEM3O65-0.25H20: C, 5911; H, 5.35; M, 6.46. Found: C, 58.91; H, 5.40; M, 6.30.

Example A2b: (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazol lidin-4-carboxylic acid 3-ethoxy-benzylamide

From setniny st M MY; Uk MNSH PIMNDDY N I red o vna hi I act it ik tuya yi veni

Tai v ke Ka o

Shk t BC sho so so

White solid product temp.pl.-105-1072С, IR (cm") 3322, 3063, 2978, 1643, 1585 1538, 1454, 1354, 1265. 1159, 1050; "H NMR (DMSO-iv): 5 9, 38 (in, 1H), 8.40 (y, 9U-5.6, 1), 8.11 (9, 9-82, 1H), 7.30-6.70 (t, 11), 7 6 53 (a, 9-7.5, 1H), 5.48 (9, 9-5.9, 1H), 5.11 (a, 9-8.9, 1H), 5.00 (y, 9 -8.9, 1H), 4.50-4.20 (t, 4H), 407 Kc (da, 9-15.0, 5.3, 1H), 3.94 (ad, 9-14.0 , 6, 2H), 2 90-2.62 (t, 2H), 1.81 (in, ЗН), 1.49 (in, ЗН), 1.34 (in, 325 ЗН), 1.25 ( 5 9U-6,9, ZN); Calculated for С 53Нз9М3О65-0.75Н20; C, 64.01; H, 6 59; M, 6.79. Found: С, - 63.89; H, 6.27; M, 6.44.

Example A27: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiase of olidine-4-carboxylic acid methyl-prop-2-ynyl-amide 0 cc 7 s in priv -1 Shossky ME sly in pe -z IR (pure, cm") 3378, 1643, 1461, 1279 , 1108, "H NMR (DMSO-yv): δ 9.37 (c, 1H), 8.21 (a, 94-92, 1H), 7.33-7.13 (t, 5H), 6, 94 (B -7.7, 1), 6.78 (а, 9-81, 1), 6.52 (а, 9-7.0, 1), 545 (а, 9-6.8, 1Н ), 5.16 (og) 50 (04, 2-92, 1), 5.02 (y, 20-9.2, 1H), 4.98 (8, 1H), 4.47-4.13 (in, Н), 4.03-3.92 (t, 1Н), 3.17 (in, Н), 2.88 o (8, 1Н), 2.79-2.50 (t, 2Н) , 1.80 (in, ZN), 1.57 (in, ZN), 1.36 (in, ZN); Calculated for SovNazMa3O55.0.6Nyu: C, 62.95;

H, 6.45; M, 7.86. Found: C, 62.95; H, 6.39; M, 7.69.

Example A28: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-Dimethyl-thiazolidine-4-carboxylic acid (2-methyl-allyl)-amide: c. - hey and I 60 vyti it m GE Z a -

L so ke; ES: Where am I? re; ke tai 65 TN NMR (DMSO-yv): 5 9.33, (z, 1H), 8.18-7.79 (t, 2H), 7.39-7.12 (t, 5H), 6, 92 (5 9-81, 1H), 6.75 (49, 9-81, 7), 6.53 (a, y-7.01H), 5.09 (y, 0-92, 1H), 4 .96 (a, 9-92, 1H), 4.70 (8, 1H), 4.43 (c, 1H), 4.40

(bho8, 2H) 3.81-3.49 (t, 4H), 2.85-2.65 (t, 2H), 1.82 (8, ЗН), 1.63 (8, ЗН), 1 .49 (in, ZN), 1.35 (in, ZN);

Calculated for SobNa5MaOva: C, 63.97; H, 6.71; M, 7.99. Found: C, 63.85; N, 6.92; M, 7.65.

Example A29: (k)-3-(25,35)-2-Hydroxy-3-111-3-hydroxy-2-methyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiase of olidine-4-carboxylic acid. Z-amino-benzylamide "y; and

Koh

H sv 70 I about them xx: attention of A. m E Z Shche. cash registers: 0 No

I and a y we and V I lk SHE!

IR (pure, cm") 3401, 2943, 1643, 1525, 1461, 1373; "H NMR (DMSO-iv): 5 9.36 (in, 1H), 8.28 (i, 9-80, 1) , 8.12 (a, 9-8.91H), 7.33-6.37 (t, 12H), 5.45 (4, 9-7.0, 1n), 510 (a, 9-89, 1H) 4.99 (a, 0-8.9, МН), 4.50-435 (t, ЗН), 4.30-3.90 (t, 2H), 2.90-2.70 (t , 2H), 2.06 (in, 2H), 1.81 (in, ЗН), 1.48 (in, ЗН), 1.33 (in,

ZN); Calculated for С34Нзв6МАО55.НоО: С, 63 57; H, 6.37; M, 9.57. Found: C, 63.59; H, 6.38; M, 9.58.

Example of AZO: 20. (c)-3-((2538)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanoyl-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid cyanomethylamide 7 m a shk (6) gast SOURCE: Z Y. UNE

Na nia kt; IN ste IY Ge: V AN ro SV sy: Ku ve u:

TN NMR (DMSO-in): 5 9.34 (z, 1H), 8.65 (in, 1H), 8 15 (t, 1), 7.42-7.19 (t, 5H), 6, 94 (i 9-7,9,1H), so 6,81 (a, 9U-7,9, 1), 6,62 (a, 9-7,9, 1), 5,22 (9, у0 -9.7, 1Н) 5.5 (9, ю-9.7, 1Н), 461-4.36 (t, 4Н), «- 3.01-2.71 (t, 4Н), 1, 84 (in, ZN), 1.47 (in, ZN), 1.34 (5, ZN). Calculated for Co6NzoMAOBe: C, 61.16; H, 5.92; M, 10.97. Found C, 61.24; H, 6.14; M, 10.62. -

Example AZ1: cha (k)-3-(25,35)-2-Hydroxy-3-/H-(3-hydroxy-2-methyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)- 5,5-dimethyl-thiazopodin-k of carbolic acid (2)-but-2-enylamide " and en : Z - aeo Do and ZK "Code in

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TN nMR (DMSO-in): 5 9.37 (in, 1H), 8.35 (t, 1H), 8.12 (t, 1H), 7.15-6.98 (t, 6H), 6 .77 (a, 9U-7.7, 1H), i 6.68 (y, 9-7.5, 1H), 5.60-5.33 (t, ЗН), 5.18 (y, 9 -92, 1), 5.2 (ai, 9-92, 1H), 4.52-4.39 (t, ЗН), - 3.79-3.68 (t, 2H), 2.92- 2.62 (t, 2Н), 1.80 (v, ЗН), 1.61 (а, 9У-6.9, ЗН), 1.51 (в, ЗН), 1.38 (85, ЗН) ; Calculated for so 50 SovNzBMzOBa: С, 63.97; H, 6.71; M, 7.99. Found: C, 63.73; H, 6.75: M, 7.83.

Example AZ2: 2 (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5- dimethyl-thiazolidine-4-carboxylic acid (3-methyl-but-2-enyl)-amide with ОВ str: mn bo "ny y a She;

Men NU yar She "'NYMR (DMSO-yv): 5 9.33 (5, 1), 8.19 (а, 9-8.6, МН), 7.96 (in B, 1Н), 7, 39-7.13 (t, 5H), 6.91 (y, -7.6, 1), 6.79 (a, y-7.9, 1H), 6.55 (a, 9-7, 1, 1), 541 (t g, 1H), 5.21 (t, 2H), 5.02 (a, 9-91, МН), 4.57-4.37 (t, ЗН), 3, 79-3.61 (t, 2H), 2.90-2.71 (t, 2H), 1.81 (in, ЗН), 1.63 (z, 6Н) 1.52 (in, ЗН), 1.40 (c, b5 ZN); Calculated for SooiNz7MzOB5e: C, 64.54; H, 6.91; M, 7.79. Found: C, 64.75; H, 6.82; M, 7, 43.

Example of AZZ:

(k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanoyl-amino)-4-phenyl-butanoyl)-5,5-dimethyl- thiazo lidin-4-carboxylic acid. Z-acetylamino-benzylamide

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White solid product temperature pl.-145-1472C; IR (pure, cm") 3373, 2919, 1637, 1514, 1461, 1361; "NN NMR (DMSO-4v): 5 9.87 (v, 1H), 9.36 (v, 1H), 8.45 -8.40 (t, 1H), 8.12 (0, 9-7.9, 1H), 7.49-6.91 (t, 7OH), 6.77 (a, 9-7.9, 1), 6.55 (a, 9-7.9, 1H), 549 (a, 0-7.0, 1H), 5.10 (9, 9-9.3, 1H), 5.00 ( a, 2-9.3, 1H), 4.44-3.95 75 (t, 5H), 2.90-2.62 (t, 2H), 2.00 (85, ЗН) 1.80 ( in, ZN), 1.48 (in, ZN), 1.32 (in, ZN); Calculated for

Cz2NovMaO65-1.5H20: C, 61.38; H, 6.40; M, 8.68. Found: C, 61.49; H, 6.14; M, 8.35.

Example of AZAa: (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazolidine-4-carboxylic acid ((27)-2-methyl-but-2-enyl)-amide

I

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No No

TN NMR (DMSO-iv): 5 9.36 (c, 1H), 8.16 (a, 9-84, 1H), 8.00 (f 9-5.3, 1H), 7.36-7 ,13 (t, 5H) 6,94 (i,

U-7.7, 1H), 6.77 (a, 9-8.1, 1H), 6.53 (a, 9-7.3, 1H), 5.37 (a, 9-5.7 , 1H), 5 24 (t, 1H), 5.12 (a, 9-9.0, yin), F 5.00 (y, 90-90, 1H), 4.48-4.39 (t , ЗН), 3.71 (a, 9-3.7, 2Н), 2.82-2.65 (t, 2Н), 1.80 (85, ЗН), 1.61 (t, 6Н), so 1.49 (in, ZN), 1.35 (in, ZN); MO-VR (ЕР) t/2 calculated for C »29Na7MzO55ZMa (Mae-Ma)" 562.2346, found 562.2360; Calculated for SooNaz7MaOBvBa: C, 64.54; H, 6.91; M, 7.79 . Found C, 64.33; H, 6.92; M, 7.60. "-

Example AZ5B: im (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)-5 -dimethyl-thiazolidine-4-carboxylic acid "E)-2-methyl-but-2-enyl)-amide c. sho i-y iya, ih " still: pyky I STILL Pa her and: Y y E shi ish j yavy g

TN NMR (DMSO-iv): 5 9.37(5, 1H), 8.11 (94, 9U-8.2, 1), 7.96 (5 9-5.5, 1H), 7.34 -7.13 (t, 5H), 6.94 (i, -I -7.7, 1), 6.77 (a, 0-81, 1), 6.53 (a, 9-7.3 , 1Н), 544 (а, 0-66, 1), (а, 9-6,6, 1), 510 (а, 9-90, - 1), 4.98 (0, 9-91, МН ), 4.47-4.36 (t, ZN), 3.71 (aa, -14.7, 66, 1H), 3.46 (aa, -14.5, 4.8, 1H), 2 .85-2.67 (t, 2H), 1.81 (v, ЗН), 1.50 (t, 9Н), (5, ЗН); MO-VR (ЕР) t/2 calculated for C»29Na7MzO5ZMa (MaMa)" - 562.2346, found 562.2220. so 50 Example of AZb: (k)-3-(25,35)-2-Hydroxy-3 -11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiase 62 olidine-4-carboxylic acid (E)-pent-2- enilamid peso y t a 5 o Nesy "Vu soni s s y sta kouty NK pek oon o o ne nka

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White solid product temperature pl.-113-1159C; IR (pure, cm") 3315, 2964, 1643, 1584, 1530, 1454, 1371, 1283, 1104, 969; "H NMR (DMSO-iv): 5 9.35 (z, 1H), 8.11 ( 4, 9-8.2, 1H), 8.02 (B 9-5.6, 1H), 7.33-7.13 (t, 5H), 6.96-6.90 (t, 1H) , 6.76 (a, 9-82, 1H), 6.52 (y, 9-7.5, 1H), 5.66-5.56 (t, 1H), 5.43 (a, 9- 68, 1H), 5.38-5.31 (t, 71H), 5.10 (a, 9-8.9, 1H), 4.99 (y, 9-8.9, 1H), 4, 47-4.39 (t, 2H), 4.38 (8.1), 3.72-3.53 (t, bo 2H), 2.84-2.66 (t, 2H) 1.98- 1.83 (t, 2H), 1.80 (with ZN), 1.48 (in, ZN), 1.34 (in, ZN), 0.87 (5 9-73, ZN);

Calculated for SooNaUMaO»5.0,5Н.0: C, 63 48; N, 6.98; M, 7.66. Found: C, 63.30; H, 7.00; M, 7.28.

Example AZ7: (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazolidine-4-carboxylic acid (7)-pent-2-enylamide 70

Z hai BE Yavni ek Ya

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White solid product temperature pl.-112-11392C; IR (pure, cm") 3320, 2965, 1659, 1643, 1538, 1455, 1372, 1285, 75. 1210, 1105, 1048; "H NMR (DMSO-y5): 5 9.35 (in, 1H), 8.11 (9, 9-7.9, 1H), 8.03 (5 9-5.3, 1H) 7.35-7.13 (t 5H), 6.96-6.90 (t, 1H), 6.76 (a, 9-81, 1), 6.53 (a, 9-7.3, 1), 5.42 (a, 9-6.7, 1H), 5.37- 5.35 (t, 1H), 5.29-5.23 (t, 71H), 5.09 (y, 9-9.2, 1H), 4.99 (a, y9-9.2, 1H ), 4.45-4.38 (t, 2H), 4.36 (v, 1H), 3.80-3.62 (t, 2H), 2.84-2.70 (t, 2H), 2.07-1.97 (t, 2H), 1.80 (in, ZN), 1.48 (in, ZN), 1.34 (in, ZN), 0.90 (5 9-7.5 , ZN);

Calculated for SooNaUMaO»5.0,5Н.0: C, 63.48; N, 6.98; M, 7.66. Found: C, 63.60; N, 6.92; M, 7.48.

Example of AZV: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid (E)-but-2-enylamide

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TN NMR (DMSO-iv): δ 9.39 (in, 1H), 8.19 (t g, 1H), 8.03 (t g, 1), 7.40-7.16 (t, 5H) , 6.94 (i, 9-71, 13, 6.79 (a, 0-7.7, 1H), 6.55 (a, 9-7.5, 1H), 5.64-5.31 (t, ЗН), 5.19 (а, 9-92, 1), 5.02 (а, ю0-9.2 1Н), - 4.55-4.38 (t, ЗН), 3.80 -3.69 (t 2H), 2.84-2.70 (t, 2H), 1.80 (8, ЗН), 1.61 (in B, ЗН), 1.51 (5, ЗН) 1 ,39 (8, |h-

ZN); Calculated for SovNz5MaOBa: C, 63.73; H, 7.07; M, 7.96. Found: C, 63.41; H, 7.23; M, 7.71.

From Example AZO: - (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)- 5,5-dimethyl-thiazolidine-4-carboxylic acid 3-dimethylamino-benzylamide

KO. - et E i i - "p I syzy od Bach neo sh. Shchi i: TO U sov Be laiy im White solid product: temp.pl.-105-1062C; IR (pure, cm") 2219, 2966, 1732, 1644, 1585, 1531, 1494, - 1454, 1373, 1264, 1047; "H NMR (DMSO-yv): 5 9.37 (z, 71Н), 8.33 (5 9-61, 71), 8.08 (а, 9-81, МН), - 7.32-6 .52 (t, 12Н), 5.54 (а, 9-6.0, 1), 510 (y, ю0-9.2, 1Н), 4.99 (а, ю9-9.2, 1Н) , 4.43-4.31 (t, 4H), 4.03 (aa, 9-15.3, 5.3, 1H), 2.84 (c, 6H), 2.84-2.67 ( t, 2Н), 1.81 (8, ЗН), 1.49 (5, ЗН), 1.935 (8, ЗН). Calculated for со СzzNaоМаО55.0.1Н20: С, 65.35; Н, 6.68 ; M, 9.24. Found: C, 65.49; H, 6.67; M, 9.30. o Example A40: (k)-3-(25,35)-2-Hydroxy-3-11 -(3-Hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid (E)-4,4,4-trifluoro -but-2-enyl)-amide and GK yu shi: shi She skh sagliek, it is s Жy r Я le

NY tsa Mi zh TV same vro, for pe thudi ru v vo Y and vd: still b Yakso Y and sin ke SE st i tsk ee i i

White foam; IR (pure, cm") 3332, 1661, 1641, 1584, 1531, 1443, 1280, 1119; "NMR (DMSO-aiv): 5 9.36 (in, 1H), 8.32 (B 9-5, 6, 1H), 8.15 (ai, 9-8.4, 1), 7.35-7.12 (t, 5H), 7.00-6.90 (t, 1), 677 (a, 9-7.3, 1H), 6.52 65 (a, 9-7.3, 1H), 6.49-640 (t, 1H), 6.08-6.00 (t, 1), 549 (a, 9-64, 1H), 5.15 (y, 9-92, 1H), 5.01 (a, 4-9.2, 1H), 4.50-4.40 (t, 2H) , 4.38 (in, 1H), 4.10-3.90 (t, 7H), 3.80-3.70 (t, 1H), 2.90-2.60 (t, 2H), 1 ,80

(85, ZN), 1.51 (in, ZN),. 1.34 (5. ZN), Calculated for Со8НазоРзМзОБ5: С, 58.02; H, 5.56; M, 7.25. Found: C, 58.37; H, 5.70; M, 6.91.

Example A41: (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazolidine-4-carboxylic acid (1-cyano-1,1-dimethyl-methyl)-amide 70 Z Ж 5 Ж: Сх с ши си он в

I ZE Y g and si

Mor not Zh kn s kn which for et

TN NMR (DMSO-iv): 5 9.39 (z, 1H), 8.31-8.12 (t, 2H), 7.38-7.17 (t, 5H), 6.97 (5 9 -7.3 1H), 6.79 (4, 9-7.7, 1), 6.59 (a, 9-7.4, 1), 5.41 (t B, 71), 5.21 (9, 2-9.2, 1), 5.00 (а, ю0-9.2, 1Н), 4.58-4.35 (t,

ЗН), 2.85-2.62 (t, 2Н), 1.81 (85, ЗН), 1.62 (в, 6Н), 1.47 (в, ЗН), 1.39 (в, ЗН ). Calculated for SovNzaM.OB55: C, 62.43; H, 6.36, M, 10.40. Found: C, 62.12; H, 6.55; M, 10,13.

Example A42: 20. (K)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)- 5-Dimethyl-thiazolidine-4-carboxylic acid 3-hydroxy-benzylamide as Y še sch 29 vd: shre re; Z Shchi S y (o) elk and syh Ge SY jays" KN

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TNMR (DMSO-iv): 5 0.37 (8, 1H), 9.30 (c, 2), 8.35 (9-5.9, 1), 8.11 (a, 9-81, 1H ), 7.33-7.15 (t, 5), 7.04 (B 9-7.7, 1H), 6.94 (i, 0-7.9, 1H), 6.77 (a, 9-8.1, 1H), 6.70-6.54 (t, 4H), 5.49 (in B, 1H), 5.11 -- (a, 9-92, 1H), 5.00 (9, 9-9.3, 1H), 4.43 (t, ZN), 4.27 (aa, 9-15.2, 6.0, 1H), 4.07 (aa, 9U-15, 0, 5.5, 1), 2.88-2.67 (t, 2H), 1.82 (in, ЗН), 1.49 (in, ЗН), 1.33(5, ЗН): Calculated for C 34Na35M3O85-NYO: C, 62.50; H, 6.26;

M, 7.05. Found: C, 62.66; H, 6.19; M, 6.83. -

Example A43: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid 3-propoxy-benzylamide

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White foam; IR (cm") 3319, 2966, 1644, 1585, 1531, 1454, 1373, 1264, 1047; "H NMR (DMSO-α): 5 9.37 (v. 1H), - 8.40 (Her, 9-5.8, 1), 8.10 (a, 9-84, 1), 7, 31-6.71 (t, 11H), 6.53 (a, 0-7.3, 1H), 5.46 (a, 2-64, 1H), 512 - (4, 24-9.2, 1H), 5.00 (y, 9Yu-9.2, 1H), 4.50-4.20 (t, 4H), 4.11-3.83 (t, ЗН), 2.90-2, 62 (t, 2H), 151 (in, ЗН), 1.72-1.60 (t, 2Н), 1.49 (in, ЗН), 1.34 (in, ЗН), 0.92 (i , 9-7.3 ZN). Calculated for С 54НМ3О655.0.25Н20: С, 65.42; со Н, 6.70; M, 6.73. Found: С, 65.49; Н, 6.67 ; M, 6.70. o Example A44: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4 -phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid 2-hydroxy-benzylamide etc. as well

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TN NMR (DMSO-iv): δ 9.50 (z, 1H), 9.36 (b, 1H), 8.33 ( 9-55, B), 8.14 (4, 9U-8.2, 1H), 7.32-7.12 (t, 65 6H), 7.04-6.91 (t, 2H), 6.76 (t, 2H), 6.68 (i, 9-7.5 , 1), 6.54 (a, "9-7.5, 1H), 5.46 (a, 9-6.6, 1H), 5.13 (a, 90-92, 1H), 5, 01 (a, 9-9.3, 1H), 4.47 (t, ЗН), 4.28-4.19 (t, 2H), 2.86-2.67 (t, 2H), 1, 82 (in, ZN), 1.49

(8, ZN), 1.32 (in, ZN); MO-VR (ERE) t/lh. calculated for С3з1НзеМаО65 (МН) 578.2325, found 578.2325.

Example A45: (k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5, 5-Dimethyl-thiaz opidine-4-carboxylic acid (3,3,3-trifluoro-propyl)-amide also I

VZ her t 7 zim SE

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TN NMR (DMSO-yv): 5 9.36 (in, 1H), 8.20 (5 9-5.5, 1H), 8.13 (y, 9U-8.2, 1H), 7.34 -7.13 (t, 5H), 6.93 75 (O-7.7, 1), 6.76 (a, 9-81, 1), 6.08 (a, 9-7.5, 1H ), 5.44 (a, 9-68, 1H), 5.10 (9, 0-92, 1H), 5.05 (a, 4-9.2, 1H), 4.48-4.38 (t, 2H), 4.35 (v, 1H), 3.32-3.25 (t, 2H), 2.75-2.70 (t, 2H), 2.44-2.35 (t , 2H), 1.80 (in, ZN), 1.49 (in, ZN), 1.34 (z, ZN); MO-VR (ERE) t/:. calculated for C27NazMz3O55Ez (MAN) 568.2093, found 568.2118.

Example A46: (K)-3-3425,35)-2-Hydroxy-3-31-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazolidine-4-carboxylic acid methyl-propyl-amide

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White solid product: temperature pl.-108-11092; IR (cm") 3325, 2964, 1637, 1522, 1456, 1372, 1284; "H NMR He) (DMSO-4v): δ 9.35 (v, 1), 8.22 (y, 9-86, 1H), 7.34-7.12 (t, 5H), 6.96-6.90 (t, 1H), 6.77-6.75 (t, 1H), 6.53-6.50 ( t, 1H), 5.46 (a, 9-64, 1H), 5.18-4.70 (t, ЗН), 4.48-4.20 (t, 2H), 3.31 (85, 3H), 2.90-2.50 (t, 2H), -- 1.80 (in, ЗН), 1.80-1.77 (t, 2Н), 1.56 (in, ЗН), 1 .56-1.36 (t, 2H), 1.37 (in, ЗН), 0.79 (i, 9-7.5, ЗН). Calculated for rch-

SoviNz7MzO55-1.0H20: C, 61.63; H, 7.20; M, 7.60. Found: C, 62.03; N, 6.93; M, 7.33. 3o Example A47: c (k)-3-(125,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)- 5,5-dimethyl-thiazolidine-4-carboxylic acid 4-trifluoromethoxy-benzylamide and « NOT yet

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White solid product: NMR (DMSO): 5 9.37 (in, 1H), 8.51 (i, 9-5.9, 1H), 8.13 (4, 9-7.3, 1H), 7.39 (4, 7 9-86, 1), 7.32-7.10 (t, 5H), 7.00-6.90 (t, 1H), 6.76 (a, 9-8, 2, 1H), 6.53 (y, 90- 7.3, 1H), 549 (a, 9-66, - 13, 5.14 (9, 2-9.3, 1), 5.00 ( a, 2-9.3, 1H), 4.49-4.537 (t, 4H), 4.17 (da, 0-15.0, 5.7, 1H), 2.90-2.64 (t , со 50 2Н), 1.81 (5, ЗН), 1.49 (в, ЗН), 1.32 (з, ЗН); MO-VR (ЕР)t/7. calculated for Сз2На5М3О55Ез (MAN) 646 .2199, found 646.2184. "2 Example A48: (k)-3-(25,35)-2-Hydroxy-3-111-(3-hydroxy-2-methyl-Phenyl)-methanol|-amino) -4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid (2-difluoro-benzo|1,3|dioxol-5-ylmethyl)-amide and:

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Essay 07 still OO peky men U nen i b5 AN: UM; ia "'NMR (DMSO-iv): 5 9.36 (c, 1H), 8.55 (B 9-5.8, 1H), 8.14 (a, 9-84 1H), 7.29- 7.11 (t, 8H), 6.94 (i,

У-7.8, 1), 6.77 (а, ю-7.9, 1Н), 6.54 (4, 0-74, тн), 5.58 (а, 9-82, 1), 5.17 (a, 9-92, 1H), 5.02 (a, 4-9.2, 1H), 4.49-4.39 (a, ЗН), 4.43 (c, 1), 4.21 (da, 0-54, 15.3, 1H), 2.83 (t, 1), 2.71 (aa, 9-13.5, 10.7, 1H), 2.20 (in , ZN), 1.51 (in, ZN), 1.34 (in, ZN); MO-BP (ЕР) t/y, calculated for С 32Нз4Б»М3075 (MEN)" 642.2086. found 642.2099: Calculated for С 32НззРоМ3О.5: С. 59.90; H, 5.18; M, 6.55 Found: C, 60.01, H, 5.27, M, 6.29.

Example A49: (k)-3-(25,35)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl|-5,5-dimethyl-thiazolidine-4- carboxylic acid (2-chloro-ethyl)-amide and

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For 7 days of NNMR (DMSO-yv): 5 9.40 (in, 1H), 8.31 (B MN, 9-5.5), 8.17 (9, YAN, 9-84), 7 .37-7.16 (t, 5H), 6.96 (i, 1H, 9-7.93, 6.79 (a, yin, 2-81), 6.55 (a, yin, 9-7 .5), 547 (a, yin, 9-68), 5.11 (a, tn, 9-9.3), 5.03 (a, tn, 4-9.3), 4.50-4 .45 (t, 2H), 4.41 (5, 1H), 3.64-3.58 (t, 2H), 3.46-3.34 (t, 2H), 2.86-2.69 (t, 2H), 1.82 (in,

ZN), 1.53 (5, ZN), 1.40 (in, ZN). The exact mass calculated for SobNazM3O55S1 (МН) is 534.1829, found 534.1841.

Example OR: sc re (k)-3-(2535)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5 ,5-dimethyl-thiazolidine-4-carboxylic acid (2-hydroxyethyl)-(2-methyl-benzyl)-amide (o) ditto, o

Zo set Y schey so yaoyar sny: M Ж SD і- і ях С: a ik Ef

Ne Beh es "YAN NMR (DMSO-yv): 5 9.38 (v, 1H), 8.29 (9, 9-84, 1H), 7.42-6.87 (t, TON), 6, 78 (4, 9-71, 1H), 6.55 (4, « -6.8, 1H), 5544 (a, 9-68, 1H), 5.26 (y, 9-10.0, 1H ), 5.08 (in, 1H), 5.04 (y, 9-92, 1H), 4.82-4.67 (t, 2H), З s 4.55-4.24 (t, ЗН ), 3.67 (t, 2H), 3.47 (t, 2H), 2.78 (t, 2H), 2.24 (8, ЗН), 1.82 (в, ЗН), 1.61 (in, ZN), 1.45 t (in, ZN); MO-BP (ЕР) ti/g, calculated for С34Н41Ма3О65Ез (МН) 620.2794, found 620.2798; Calculated "» for Сз4НАМзОв65-1Н20: C, 64.03; H, 6.80; M, 6.59. Found: C, 63.66; H, 6.40; M, 6.59.

Example AB: 3-(2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl|-5,5-dimethyl-thiazolidine-4-carboxylic acid methyl-(2- ethyl-benzyl)-amide ev with i - I shki

Bema i Se ee U OBO vo s MY 29 White solid product: "H NMR (DMSO-dv): 5 9.40 (in, 1H), 8.45 (5 9-7.99, 1), 8.10 (4, 9-81, 1H),

HF) 7.41-6.91 (t, 12H), 6.62 (a, 9-7.8, 1), 5.41 (a, 9-6.8, 1H), 5.12 (da , 9-8.1, 7.8, 1H), 4.44-4.35 (t, ЗН), 4.42 (8, 1H), 2.91-2.67 (t, 2H), 2 .54-2.21 (a, 9-6.89, 2H), 2.1 (in, ЗН), 1.88 (in, ЗН), 1.56 (Her, 2-6.90, ЗН) , about 1.49 (in, ЗН), 1.34 (5, ЗН): calculated for С з34НАиМ3О55,0.75Н20: С (62.34), Н (6.43), M (6.23), C (62.72), H (6.52), M (5.97) were found. MO-VR (ЕР) t/2, calculated for С34Н«М3О65 604.2845, found 604.2845. 6o Example AB2: 3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanoyl|-amino|-4-phenyl-butanoyl-5,5-dimethyl- thiazolides of n-carboxylic acid (2-methylamino-ethyl)-amide b5 and.

B V ke EE them I I shcha

Kovi KU Re NI and is. hey shit Ai drink ee

Clear: S A K I t 70 White solid product: "H NMR (DMSO-yv): 6 9.40 (in, 1H), 8.45-8.01 (t, 1H), 7.41-7.13 (t, 12H), 6.98 (i, -7.8, 1H), 6.78 (a, 0-6.85, 1H), 6.55 (a, 9U-6.99, 1H), 5.41 (t, 1H), 5.12-4.98 (t, 2H), 4.44-4.35 (t, 2H), 3.15 (t, 2H), 2.91-2, It was calculated C (60.31), H (6.94), M (10.42), found C (60.59), H (6.50), M (8.08) MO-VR (ЕР) t/ g, calculated 556.2771, found 556.2770.

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Amides of the general structure C (synthesized as in the methods of section A) are combined with Boc-protected acid 15 and subjected to the action of methanesulfonic acid, obtaining amines 16. Exposure of amines 16 to the conditions indicated

Sh- reactions, gave a series of amides 17 and ureas 19. - and "Synthesis of amines of the general type 16. with No

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The named compound was obtained as follows. (K)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1 (1.95 g, 7.47 mmol) was dissolved in EtOAc (25 ml) and cooled to 09C. Diphenylchlorophosphate (1.71 mL, 8.23 mmol) was added followed by TEA (1.14 mL, 8.2 mmol). The reaction mixture was stirred at 09C for 1 hour and treated with (5)-Cyclohex-2-enylamine (0.8g, 8.23mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between 1N HCl (25ml) and EtOAc (30ml). The organic layer was washed with saturated MansSoO» brine, dried over sodium sulfate and concentrated to a yellow oil. The resulting oil v5 (2.54 g, 7.47 mmol) was dissolved in EtOAc (3 mL) and further cooled to 02C. Methanesulfonic acid (2.27mL, 33.62mmol) was added and the solution was stirred at 02C for 15 minutes then at room temperature for 4 hours. The mixture was again cooled to 09C and quenched with 1095 Ma»gSO»z (30ml) and then extracted with EtOAc (30ml). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a yellow oil 3. The resulting yellow oil (1.86g, 7.74mmol) was dissolved in EtOAc (77ml). BOC-ANRVA 4 85 (2.29g, 7, 7A4mmol), followed by NEW (1.03g, 7.74mmol). The mixture was stirred at room temperature for 1 hour and then cooled to 020. OCC (1.60g, 7.74mmol) was added slowly as a solution in EtOAc (30ml). The mixture was allowed to gradually warm to room temperature and stirred overnight. OSI was removed by flash chromatography (3095 to 5095 EA in hexanes) to give a white solid (4 g, 7.73 mmol), which was dissolved in EtOAc (30 mL) and further cooled to 0 2 C. Methanesulfonic acid (2.35 mL, 34.7 mmol) ) was added and the solution was stirred at 09 for 15 minutes further at room temperature uri within 3 hours. The mixture was again cooled to 02C and quenched with 1095 Ma»CO3 (Zb5Bml) and then extracted with EtOAc (30ml).

The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo to give 75 material, which was recrystallized from a mixture of 6095 E(UAs) in hexanes to give the named compound (2.4 I g, 80965) as a white solid. : 5 8.21 (a, 9-81, M1H), 7.31-7.17 (t, 5H), 5.80 (a, 9-56, 1H), 5.52-5.48 (t , 2H), 5.30-525 (t, 2H), 4.89 (in, 2H), 4.26 (in, 1H), 4.21-4.00 (t, ЗН), 3.15- 2.70 (t, 2H), 2.50-2.00 (t, 2H), 2.00-1.00 (t, 4H), 1.49 (in, ZN), 1.31 (in, ЗН); Calculated for Со22Наз4Маозе: C, 63.28; H, 7.48;

M, 10.06. Found: C, 63.40; H, 7.20; M, 9.98.

The following amines a-p were synthesized by the above specific methods, using the required amines. tn s sini goes -oYa dika skhyan ke pah sek s o NV j dae.

EK LNN Y trace: ped s in "YAN yNMR (DMSO-yv): 5 8.36 ( 9-6.0, 1H), 7.36-7.14 (t, 5H), 5.70 (t, IN), 5.34 (with Bg, 1), 5.12 (4, so 3-17.0, 1H), 4.96-4.88 (t, ЗН), 4.34 (in, 1H) , 4.10 (a, 9-7.0, 1H), 3.80-3.55 (t, 2H), 3.06 (a, 9U-13.01H), - 2.87 (i, U -9.0, 1H), 2.38 (ad, U-13.0, 10.0, 1H), 1.52 (8, ZN), 1.33 (8, ZN).

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TN NMR (DMSO-iv): 5 8.69 (B, 9-5.3, 1H), 7.34-7.14 (t, 5H), 5.34 (in B, 1H), 4.90 (in, 2H), 4.29 (in, 1H), in 4.08 (a, 9-7.0, 1H), 3.90-3.70 (t, 2H), 3.07 (9, 9-13.4, 2.5, ZN), 2.96 (5 -2.6, 1H), 2.88, (aa, 9-98, 8.0, 2.8, 1H), 2, 37 (ad, 9U-13.2, 9.9, 1H), 1.50 (5, ZN), 1.32 (in, ZN). b5

M. I

70 Ma and NMR (DMSO-iv): 5 8.13 (5 9-5.4, 1H), 7.35-7.15 (t, 5H), 5.28 (4, 9-81, 1H ) 4.79 (t, 2H), 4.27 (v, 1), 4.07 (5 9-7.1, 1H), 3.10-2.71 (t, 4H), 2.37 ( ad, 9-132 9.9, 1H), 1.49(5, ЗН), 1.34 (t, 2H), 1.33 (in,

ZN), 0.77 (6 9-74, ZN). with the same /

El Y exit: 8495; MO (ARSI, p/z): 461, 463 (MAN) o "Y wai where are they 2 so what and I: PM NO -

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Output: 9390; MO (ARSI, pt/2): 464 (M.N). 1694... this is the same and "

I Zn vuh za: shi c zir ZByY KE, shchi shchi, puh t TI i ik miie yayi p sol SCHE NK uh ZHE, Iza i still pt rn s nya -I Output: 8670; MO (ARSI, vol. 2): 496 (M'nN).

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I and ek Here we are: VT o tishe and sho and le. and output: 8796 MO-ARSI (t/gt): 458. o Synthesis of final products of general type 17 from 1ba-y,

General methods: for Formation of amide - To a solution of amine acid 16 and NOVT in dichloromethane was added ЕХОС and the solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and a small portion of water. The solution was washed with saturated MNACI or 0.5N NS! (2x), saturated MansSoz (2x), brine (1x), dried with magnesium sulfate and concentrated in a vacuum. The resulting residue was subjected to flash chromatography on silica gel or preparative HPLC, obtaining the desired product. bo Formation of urea My - The corresponding amine and isocyanate (1.1-1.2 equiv.) were dissolved in dichloromethane and stirred at room temperature under nitrogen (1.5 hours - overnight). The solvent was further removed in -BO0-

vacuum and the resulting residue was subjected to flash chromatography on silica gel or preparative HPLC to give the desired product.

Formation of urea Me2 - The corresponding amine was dissolved in dichloromethane and treated with dmisopropylethylamine (1.5 eq.) and phosgene (Teq. 2095 solution in toluene) at -782C. The resulting solution was warmed to room temperature and treated with an amine of general structure 16. The resulting residue was subjected to flash chromatography on silica gel or preparative HPLC, obtaining the desired product.

Specific Urea Synthesis

Example B1: 70... 3-(2-hydroxy-3-(1-(3-hydroxy-pyrrolidinyl)-methanol|-amino)-4-phenyl-butanoyl)-5-dimethyl-thiazolidine-4-carbon acid 2-methyl-benzylamide

(K)-Pyrrolidin-3-ol (0.21 g, 2.40 mmol) was dissolved in dried CH»-Si» (15 ml) and cooled to -7892С under argon with magnetic stirring. To this solution was added d-isopropylethylamine (0.633ml, 3.bZmmol) followed by phosgene as a 2095 solution in toluene (1.2ml, 2.40mmol). The resulting yellow solution was stirred for 20 minutes at -782C, then allowed to warm to room temperature. The solution was concentrated and redissolved in dried CH2Cl2 (ml) and THF (bml). Diisopropylethylamine (0.3 ml, 1.8 mmol) was added to this, and then. CM 16 p. The result was stirred for 16 hours at 232C, then diluted with EtOAc (5 Oml). The mixture was washed successively at 1095 with citric acid (1x5Oml) saturated with MansSoO»z (11x5Oml), HO (1x5Oml). The organics were dried with sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (595 meon in EtOAc) to give the title compound (0.12g, 1895) as a white foam.

TN NMR (DMSO-yv): 5 8.38 (B 9-5.7, 1H), 7.34-7.09 (t, TON), 5.99 (y, 9-8.3, 1H) . 4.22-3.83 (t, 4H), 3.29-3.04 (t, ZN), 2.77-2.70 (t, He) 2H), 2.28 (8, ZN), 1.52 (8, ZN), 1.32 (in, ZN), 1.82-1.69 (t, 2H); MO-VR (ЕР) t/2, designed for SooNzaM.O5ZMa (Mama)! 577.2455, found 577.2440. Calculated for С 29НзвМаО55.2НЭО; C, 58.96; H, 7.17; M, 9.48; 5, -- 5.43. Found: C, 58.90; H, 6.40; M, 9.23; 5, 5,24. uh-

The following examples were obtained by the above-mentioned appropriate specific method, using the desired PI fragment.

Example b2: isoxazole-5-carboxylic acid

C15,25)-1-benzyl-3-(K)-5,5-dimethyl-4-42-methyl-benzylcarbamoyl)-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl)-amide pra in s ve vi Ya tu le uk y" BE Mk nnni ke schi one neoe orda sya i shrrke M tn y se s sm sh I skh sh 45 ho Mo VI s a:

White solid product, mp -82-842С, IR (pure, cm") 3313, 2967, 1656, 1538, 1454, 1372, 1283, 1211, c. 1108, 916. "H NMR (DMSO-iv): 5 8.91 (4, 9-86, 1H), 8.67 (а, 9-2.0, 1), 8.35 (ф 9-5.0, 1H), 7.31-7.08 (t, - on), 7.03 (a, 9-2.0, 1H), 5.63 (a, 9U-6.9, 1H), 5.02 (90, 2-86, 1H), 4.97 (a, 2-8.6, 1H), 4.60-4.30 (t, 4H), so 50 4.14-4.00 (t, 1H), 2.90-2.75 (t, 2H), 2.23 (in, ЗН), 1.49 (in, ЗН), 1.28 (5, ЗН); MO-VR (ЕР) t/2, calculated for

SovNz2MaO5ZMa (MeMa)" 559.1986, found 559.1994; Calculated for Со8Нз2М4О55.0.5Н.О; С, 61.63; Н, «2 6.10; M, 10.27. Found: С, 61 ,40; H, 5.91; M, 9.97.

Example c: isoxazole-3-carboxylic acid 415,25)-1-benzyl-3-Y(K)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl|-2- hydroxy-3-oxo-propyl)-amide

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White solid product: IR (pure, cm") 3436, 1643, 1537, 1425, 1378; "H NMR (DMSO-α): 5 9.03 (in, 1H), 8.66 (a, 9-8, 7, 1H), 8.32 (B 9-5,3,1H), 7.30-7.11 (t, 9H), 6.79 (c, 1H), 5.67 (a, 9-6 ... 84 (t, 2H), 2.24 (in, ЗН), 1.49 (in, ЗН), 1.34 (t, ЗН); MO-VR

(ЕРЕ) t/2, calculated for SozNaz»2МаО5ЗМа (М--Ма)" 559.1986, found 559.1980.

Example: 5-Chloro-isoxazole-3-carboxylic acid

C15,25)-1-benzyl-3-((K)-5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl)|-2-hydroxy-3-oxo-propyl)-amide

PD. - Hey b "EE sh ura pikeneya oche M se Che

White solid: IR (neat, cm") 3320, 2969, 1657, 1547, 1434, 1372, 1266: "H NMR (DMSO-yv): 6 8.74 (04, 9-8.2, 1), 8.29 (B 9-5.5, 1H), 7.28-7.08 (t, 9H), 6.90 (c, 1H), 5.72 (y, 9-71, 1H), 4 ... .6, 1H), 2.85 (t, 2H), 2.83 (in, ЗН), 1.49 (in, ЗН), 1.33 (in, ЗН); MO-VR (ERE) t/2, calculated for SovNziMO55SIM (MaMa)" 593.1596, found 593.1569.

Example B5: (k)-3-(25,35)-2-Hydroxy-4-phenyl-3-((1-thiophen-2-yl-methanoyl)-amino|-butanoyl)-5,5-dimethyl- thiazolidine-4-carboxylic acid 2-methyl-benzylamide

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White solid product: temperature pl.-98-1012C; IR (pure, cm") 3416, 1644, 1538, 1455, 1372, 1291, 1107; "H NMR o (DMSO-4v): 5 8.56 (a, 9-8.0, 1), 8.38 (i 0-48, МН), 7.85 (а, 9-3.5.1Н), 7.69 (а, 0-48, 1Н), 7.36-7.08 (t, TON), 5.38 (y, 9-72, 1H), 510 (94, 9-8.8, M1H), 4.98 (y, 9-8.8, 1H), 4.54-4.20 (t , 5H), 2.90-2.70 (t, 00 2H), 2.25 (in, ЗН), 1.49 (in, ЗН), 1.34 (in, ЗН); MO-VR (ЕР) t/2, calculated for C 259NaziM3O4ZoMa (MeMa) "pe 574.1805, found 574.1818; Calculated for C 29Na33M5O452-0.75Н20: C, 61.62; H, 6.15; M , 7.43 Found:

C, 61.31; H, 5.97; M 7.28. -

Example B6: h-(k)-3-(25,35)-2-Hydroxy-4-phenyl-3-|(1-thiophen-3-yl-methanol)-amino)-butanoyl)-5-dimethylthiazolidine- 4-carboxylic acids 2-methyl-benzylamide - IN sha -

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М AV с: и -И White solid product: temperature pl.-98-10092; IR (pure, cm") 3312, 3086, 2966, 1644, 1538, 1455, 1372, - 1286, 1109; "NMR (DMSO-iv): 5 8.42-8.34 (a, 2H), 8, 14 (t, 1H), 7.54-7.06 (t, 11H), 5.74 (4, 9-93, 1H), 5.35 (a, 9-68, 1H), 4.99 ( y, 2-9.3, 1), 4.53 (y, 9-3.0, 1), 4.50 (5, 1H), 4.42 (da, 0-15.0, 7.0 , 1H), - 4.40-4.30 (t, 1), 4.15 (yes, 90-15.0, 5.0, 1H), 2.90-2.70 (t, 2H), 2.26 (in, ZN), 1.50 (in, ZN), 1.35 (in, ZN); at 20 MOo-BP (ERE) t/2, calculated for C 29NazzM3O0452Ma (Mema)u" 574.1805, found 574.1789; Calculated for SooNazzM3O452-1H20: C, 61.14; H, 6.19; M, 7.38. Found: C, 60.74; H, 5.90; M, 7.15. "2 Example B7: (k)-3-(25,35)-2-Hydroxy-4-phenyl-3 -4(5)-1-tetrahydro-furan-2-yl-methanoyl)-amino|-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid 2-methyl-benzylamide 29 ex Yaya and sy iF) tu kyu What I I i-y ve "vk si na nia Y dey bo with S tv She what for and NO: ze o Z) NO No ni SCHE tia I 5 one sk Set VD

White solid product: temp.pl.-82-842C, IR (pure, cm") 3314, 2969, 3651, 1531, 1456, 1372, 1109, 1071; "N

NMR (DMSO-α): δ 8.35 (f 9-6.0, 1H), 7.60 (α, 9-9.2, 1H), 7.31-7.09 (t, 9H), 5.45 (a, 9-6.8, 1H), 4.97 (a, bo 3-9.5, 1H), 4.93 (a, 9-9.5, 1H), 4.46 ( c, 1H), 4.41-4.07 (t, 4H), 3.77-3.65 (t, ЗН), 2.78-2.64 (t, 2H), 2.26

(5, ЗН), 2.00-1.80 (t, 1Н), 1.60 (t, 71Н), 1.49 (в, ЗН), 1.44-1.38 (t, 2Н), 1.34 (in, ZN); MO-VR (ERE) those/". calculated for С2оНаз7МаОБОЗМа (МаеМа)" 562.2346, found 562.2345; Calculated for С»29На7МаО55.0.1Н20:

C, 63.48; H, 6.98; M, 7.66. Found: P. 63,61; H, 6.85; M, 7.58.

Example B8: 3-(2-hydroxy-3-11-(3-hydroxy-pyrrolidinyl)-methanol|-amino)-4-phenyl-butanoyl)-5-dimethyl-thiazolidine-4-carboxylic acid 2-methyl- benzylamide 2 lk ko Ya 70 show uki u syavay STILL OO ih o: Z still Kene sny Y VYN ze. s W SCHE SCHE ev i y

Y en t CHE

TN NMR (DMSO-yv): 5 8.38 (B 9-5.5, 1H), 7.34-7.09 (t, TON), 5.99 (y, 9-82, 1H), 5 .04 (9, 9-95, 1H), 4.96 (a, 9-9.5, 1H), 4.49 (c, 1H), 4.48-4.38 (t, ЗН), 4 ,35-4.16 (t, ЗН), 4.00 (t, 1), 3.29-3.04 (t, ЗН), 2.718-2.70 (t, 2Н), 2.28 (8 , ZN), 1.83-1.65 (t, 2Н), 1.52 (in, ZN), 1.36 (in, ZN); MO-VR (ERE) t/". calculated for

SooNazvMaO5ZMa (MaMa)" 577.2455, found 577.2473; Calculated for C »29NzvMaO55-2H20: C, 58.96; M, 9.48.

IN

Found: C, 58.68; M, 9,11.

Example 89: (k)-3-(2535)-2-Hydroxy-4-phenyl-3-((K)-3-tetrahydro-furan-2-yl-methanol)-amino|-butanoyl)-5,5 -dimethyl-thiazolidine-4-carboxylic acid 2-methyl-benzylamide 2 M: o

I; "-

White solid: IR (neat, cm") 3324, 2959, 2873. 1724, 1651, 1526, 1455, 1372, 1289, 1073; "H NMR (DMSO-α): 5 8.35 (5 9-4, 9, 1H), 7.77 (a, 9-8.9, 1H), 7.52-7.09 (t, OUN), 5.51 (9, 9-6.6, 1H), 4, 97-4.89 (t, i- 2H), 4.52-3.66 (t, 8H), 2.90-2.60 (t, 2H), 2.25 (v, ЗН), 1, 99-1.63 (t, 4H), 1.48 (in, ZN), 1.33 (in, ZN); MO-VR im- (ERE) t/2, calculated for C 29NaMz3O5ZMa (MaMa)" 562.2346, found 562.2366. Calculated for

SooNa; MaO5z-0.25H20: C, 64.01; H, 6.95; M, 7.72. Found: C, 64.20; H, 6.90; M, 7.82.

Example of Tue: 3,5-Dimethyl-isoxazole-4-carboxylic acid "

C15,25)-1-benzyl-3-((K)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl|-2-hydroxy-3-oxo-propyl)- amidrya v) nd wine lecture ХЭ Х.

Sh- Output: 9296. 1LH-NMR (400 MHz, DMSO-ydv): 6 8.38 (i, 1H), 8.13 (i, 1H), 7.04-7.35 (t, TON), 5 .52 (a, 1H), - 5.09 (0, 1), 5.0 (9, 1H), 4.53 (t, 1H), 4.5 (c, 1H), 448 15 (t, 2H), 4.17 (aa, tn) 2.87 (aa, tn), 2.7 (a, so 50 LN), 2.26 (c, 6H), 2.09 (c, ЗН), 1 .52 (in, ZN), 1.35 (with, ZN); IR (KVg in cm): 3313, 1643, 1521, 743; MS (ARSI, t/g). 565 (MAN), 519.265; 53; M, 9.71, Found: C, 63.81; H, "2 6.43; M, 9.92; TOP: CI (min.) 20.167; Purity: 9890.

Example B11: 2,4-Dimethyl-thiazole-5-carboxylic acid (1-benzyl-3-(5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl)-2-hydroxy- 3-oxo-propyl)-amide dk a i o yah I Y 0 so "same not yet ren V trya Z TOZ: stv

Yield 8095, 1H-NMR (400MHz, DMSO-av): 5 8.35 (B 1H), 3.14 (a, 1H), 7.0-7.35 (t, 10H), 5.48 (a , 1nH) 5.04 (d, 1), 5.0 (a, 1H), 4.52 (t, 1H), 4.4 (c, 1H), 4.35 (t, 2H) 4.14 (аа, ИЕ), 2.78 (8, 2Н), 2.57 (в, ЗН), 2.30 65 (в, ЗН), 2.26 (в, ЗН), 1.48 (в, ЗН ), 1.35 (in, ZN); IR (KVg in cm"): 3310, 1641, 1534, 743; MS (ARSI t/lg): 531 (Mann), 317, 265.259; SzoNzvMAaO452.0.39 NhO. Calculated C, 61.30; H, 6 ,31; M, 9.53. C, 62.04; H, 6.25; M,

9.65; TOP OF KI (min.) 19,613; Purity: 98905.

Example B12: (k)-3-(2535)-2-Hydroxy-3-(1-methyl-1H-pyrrole-2-carbonyl)-amino|-4-phenyl-butyryl)-5,5-dimethyl-thiazolidine -4-carbonic acid 2-methyl-benzylamide is responsible for it

Z ZE a z 0 kno ki nya, 2 it KH ee zhk Ni zer ra che s Z Bk K r rt

Output 8295; "H-NMR (400MHz, DMSO-av): 8.35 (i, 1), 7.91 (9, 1), 7.35-7.04 (t, 7OH), 6.78 (z, 2H ), 75 5.96 (c, 1H), 5.35 (a, 1), 5.13 (c, 1H), 5.0 (y, 1H), 4.48 (c, 2H), 4, 38 (ad, 1), 4.30 (t, 1H), 4.13 (aa, 1H), 3.7 (c, ЗН) 2.8 (t, 2H), 2.26 (c, ЗН) , 1.52 (in, ZN), 1.35 (in, ZN); IR (E"- 1): 3324, 1639, 1538, 735;

MS (ARSI, t/g2): 549 (MH), 503, 382, 285, SzoNzeMaO,51 2.44H2O. Calculated C, 60.80; H, 6.95; M, 9.45.

It was found C, 65.67; H, 6.61; M, 10.21; TOP OF KI (min.) 20.745; Purity: 100905.

Example B13: 20. (K)-3-C425,35)-3-(1,5-Dimethyl-1H-pyrazole-4-carbonyl-amino|-2-hydroxy-4-phenyl-butyryl)-5,5 -dimethyl-thiazolides of n-4-carboxylic acid 2-methyl-benzylamide se tk: g ShK SHE kare shchi z shcha TSH Z she J ore (8)

Without the secret of SUK kv n beast ee AS Her. "Br OO sonne ST Noty y sey Z ich y, KY A M shki

KE This cha Z av)

Output 6895, "H-NMR (400 MHz, DMSO-dv): 5 8.30 (B MH) 7.83 (9, 1), 7.31-7.04 (t, TON), 6.30 (in , 1H), so 5.48 (y, 1H), 4.92 (in, 2H), 4.30-4.48 (t, 4H), 4.17 (da, 1), 3.7 (in , ZN), 2.74 (t, 2Н), 2.26 (v, ZN), 2.18 (5, ZN), 1.48 (5, ZN), 1.30 (8.3Н), IR (KVh in cm") 3313, 1645 1532, 744; MS (ARSI, vol. 2): 564 (Man), 300272; 7

SaonNa; М5О451-0.5Н20. Calculated: C, 62.86; H, 6.69; M, 12,22. Found: C, 63.92; H, 6.62; M, 12.42: HEV to them-

EI (minutes) 19,724; Purity: 100905.

Example B14: - 3-C1)-3-(5-Chloro-13-dimethyl-1H-pyrazole-4-carbonyl)-amino|-2-hydroxy-4-funyl-butyryl)-5,5-dimethyl-thiazolidine -4-carboxylic acid 2-methyl-benzylamid g « she y 2 2-3 KE I as y krach x poridi ak M kit NI V t i t gu i Sak i t "I nya EE I da ikh iy y Be

Bo I I OVNA In keshe and Output 9295 1H-NMR (400 MHz, DMSO-iv): 5 8.35, (B 1), 7.74 (a, 1H), 7.30-7.0 (t, TON), 5.44 (a, tn), -I 4.96 (a, 2H), 448 (t, 1H), 4.35 (t, 2H), 4.13 (da, 1), 2 74 (t, 2H), 2.22 (in, ZN), 2.09 (in, ZN), 1.48 (in, - ZN), 1.26 (in, ZN), IR (KVh in cm") : 3438, 3313, 1693, 1649, 1513, 1372, 754; MS (ARSI, t/2): 598 (M.N) 334276, 174; СЗ3ОНЗбМ50451С11.0.17 NoО. Calculated: С, 59.93; H , 6.09; MI 1.65. Found: C, 60.24; H, 6.07; M, (ee) 11.71. TOP: CI (min.) 19.829; Purity: 10905. o Example B15: 2-Amino-4-methyl-thiazole-5-carboxylic acid

C5)-1-benzyl-3-(5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl|-2-hydroxy-3-oxo-propyl)-amide and

GF) Ku. in i and; i y p ste a NE ii ka Yasne de Me i r DY; these with I in ant oi before I them hall i 60 days and She tyka and tla i

Yield: 4296 "H-NMR (400 MHz, DMSO-av): δ 8.48 (he, 1H), 8.35 (bis, 1H), 7.44 (j, 1H), 7.35-7.04 (t, 9H), 6.91 (c, 1H), 5.37 (j, 1), 4.96 (ad, 2H), 4.48-4.0 (t, 5H), 2.96 ( t, 2H), 2.22 (2, ZN), 2.13 (in, ZN), 1.48 bo (in, ZN), 1.30 (in, ZN); IR (KVh in cm"): 3307, 1625, 1495; MS (ARSI, vol. 2): 582 (M.N), 442, 318; С29Н35М50452С11. -B4-

Calculated: C, 60.13; H, 6.5; M, 10.82. Found: C, 59.87; H, 6.06; M, 12.04; TOP: CI (minutes) 17.981;

Purity: 98905.

Example B16; 3-(2-Hydroxy-3--2-methyl-benzoylamino)-4-phenyl-butyryl/|-5,5-dimethyl-thiazolidine-4-carbon

ACIDS 2-methyl-benzylamide and oneea

KE Ш ше Z: SYA: IY: M; I tyu Ducks REK In color B si KK

MK that GE t

Output: 7696; "H-NMR (400 MHz, DMSO-iv): 5 8.31 (5 1), 8.22 (a, 1), 7.32-7.04 (t, 13H), 5.48 (a, 1H ), 75: 5.13 (a, 1), 5.0 (y, OH), 4.48 (z, 2H), 4.38 (aa, 2H), 4.09 (da, tn), 2 .83 (y, 1), 2.70 (5 1), 2.26 (in,

ZN), 2.01 (in, ZN), 1.48 (in, ZN), 1.33 (in, ZN); IR (KVg in cm"): 3309, 3641, 1520, 742: MS (ARSI, t/lx): 560 (MH), 514.296, 265: С32Н37М30451.0.64Н5О Calculated: С, 67.40; Н, 6 ,59; M, 7.37, Found: C, 68.79; H, 6.49;

M, 7.52; TOP: CI (min.) 21.024; Purity: 98905.

Example B17: 3-I3--23-Dimethyl-benzoylamino)-2-hydroxy-4-phenyl-butyryl|-5-dimethyl-thiazolidine-4-carboxylic acid 2-methyl-benzylamide

Well, SHE STILL I and I "M 7 I os bo nn and yashnnyN 1an MEEYA o

OV What about Sady SHE

BE Ee 7

Output: 7296; "H-NMR (400 MHz, DMSO-IV): 5 8.33 (, 1), 8.22 (a, 1), 7.35-6.83 (t, 128), 5.48 (a, 1 ), F 5.713 (a, 1), 5.04 (a, yin), 4.48-4.30 (t, 4H), 4.09 (aa, 1n), 2.84 (y, 1), 2.70 (6 tons), 2.26 (in, ZN), 2.17 so (in, ZN), 1.87 (in, ZN), 1.48 (in, ZN), 1.30 (in , ZN); IR (KVh, cm"): 3307, 1640, 1515, 743; MS (ARSI, t/y): 574 (MN), 528, 310, 265; SZ3Z3NZOM30451. 0.54Н2О Calculated: C, 68.05; H, 6.76; M, 7.21. Found: C, 69.20; H, 6.76; --

M, 7.34; TOP: CI (min.) 21.449; Purity: 99905. M

Example b18: 6-Oxo-1,4,5,6-tetrahydro-pyridazine-3-carboxylic acid

Zo (1-benzyl-3-|5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl|-2-hydroxy-3-oxo-propyl)-amide - ze Z. ex « with is yav ev i

NOT g - a Ah t ee "z YOU gnlii m zhi son: she di and or, and Kanny an How vyt luk vv y v

Yield: 6795, "H-NMR (400MHz, DMSO-av): 5 8.35 (i 1), 8.09 (9, 1), 7.30-7.0 (t, TON), 5.6 (4, 1H), -I 4.91 (a, tn), 4.83 (y, 1H), 4.44 (5, 1H) 4.30 (t, ЗН), 4.17 (aa, yin ), 2.78 (а, 2), 2.61 (5 2Н), 2.30 (6 - 2Н), 2.22 (в, ЗН) 1.48 (в, ЗН), 1.30 (в , ZN); IR (KVh in cm"): 3306, 1650, 1521, 742; MS (ARSI, t/g2): 566 (M.N), 520.265, С29Н35М450551.0.7Н5О. Calculated: C, 60.23; H, 6.34; M, 12,11. Found: C, 61.57; H, 6.24; M, th 12.38. TOP: CI (min.) 18.455; Purity: 97905. o 20 Example B19: 2,4-Dimethyl-5-oxo-2-dihydro-isoxazole-3-carboxylic acid (1-benzyl-3-(5,5-dimethyl-4-i2-methyl-benzylcarbamo !l)-thiazolidin-3-yl|-2-hydroxy-3-oxo-propyl)-amide "2 sy tek Me r at sa "De Go. Z pet X (F) rya svo g VE B t x x Sunday NO

A otit si SHY Be; Ker ein es Yavy g tiy t. DU. Goethe 60 Output: 7390; 1H-NMR (400 MHz, DMOSO-av): 65 8.91 (a, 1H), 8.35 (B 1), 7.30-7.04 (t, 9H), 5.70 (a, tn) . 2.65 (B 1H), 2.22 (8, ZN), 1.52 (5, ZN), 1.48 (in, ZN), 1.30 (in, ZN); IR (KVg in cm"): 3325, 2932, 1729, 1649, 1527, 742; MS (ARSI, t/g): 581 (MN), 539, 493, 225; SZONZbM40O651. Calculated: С, 62.29; H, 5.61; M, 9.19. Found: C, 62.05; H, 6.25; M, 9.65;

TOP: KI (min.) 19.638. Purity: 10090. b5

Example 820:

(k)-3-(25,35)-2-Hydroxy-3-11-(3-hydroxy-2,4-dimethyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)-5,5 -dimethyl-thiazolidine-4-carboxylic acid allylamide

KE A i yo zhov

D ND, I. gtary derev" still kah: MO I 7 a uo0 ezhlnianie t ZDDN ka

B ts es aYa pe tgt ne "zhNo

VV h

TN NMR (DMSO-yv): 5 8.23 (in, 1H), 8.10-3.03 (t, 2H), 7.33-7.12 (t, 5H), 6.85 (9, 9-7.7, 1H), 6.51 (4, 9-7.7, 1H), 5.82-5.70 (t, 1H), 5.44 (a, 9-68, 1H), 5.22-4.97 (t, 4H), 4.50-4.30 (t ЗН), 3.84-3.60 (t, 2H), 2.84-2.66 (t, 2H) , 2.13 (8, ZN), 1.85 (in, ZN), 1.49 (in, ZN), 1.35 (in, ZN); MO-VR (ЕР) t/7, calculated for 75 SovNazvMaО55 (МН) 526.2376; found 526.2380; Calculated for Со8НзеМаО55.0.2TEA: С, 62.19; H, 6.47;

M, 7.66. Found: C, 62.27; H, 6.78; M, 7.26.

Example B21: 3-(2-Hydroxy-3-(1-(3-hydroxy-2,4-dimethyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine- 4-carboxylic acid prop-2-inilamide

Z and V

ZE: ех Б NOT З в; As B Ge pe Leo and M. 29! More "More" in VE fra.

TN nMR (DMSO-in): δ 8.40 (9-54, 1H), 8.22 (in, 1H), 8.02 (98, 9-82, 1H), 7.35-6.52 ( t, 7H), 5.44 (4, o 20 U-6.8, 1H), 5.10 (a, 9-9.1, 1H), 5.02 (y, 9-91, 1H), 4.46-4.40 (t, 2H), 4.40 (5, 1H), 3.86 (in BG, 2H), 3.08 (5 91.8, 1), 2.82-2, 72 (t, 2H), 2.15 (in, ЗН), 1.88 (8, ЗН), 1.51 (in, ЗН), 1.37 (in, ЗН); MO-VR (ЕР) t/2, 00 calculated for SovNavMa3O55 (MaN)" 524.2219, found 524.2219; Calculated for C ovNaveM3O55-0.5Н»0: С, "- 63.13; H, 6, 43; 7.89; 5, 6.02. Found: C, 62.80; H, 6.64; M, 7.71; 5, 5.69.

Example 822: c. 3-2-Hydroxy-3-K1-methyl-1H-pyrrole-2-carbonyl)-amino|-4-phenyl-butyryl)-5,5-dimethyl-thiazolidine-4-carboxylic acid

Acids 2-chloro-benzylamide and Ш і і і і Pa

What if he was a woman?

Output 5095: LN-NMR (400 MHz, DMSO-a9): 5 6.40-7.40 (t, 11H), 6.00 (t, 1H), 4.20-5.20 (t, 7H), 3.71. -2.1 Hz, ZN), MO (ARSI, t/z2): 570 (M.N). -I Example v23: 3,5-Dimethyl-isoxazole-4-carboxylic acid from 11-benzyl-3-14-(2-chloro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl|-2-hydroxy -3-oxo-propyl)-amid vla Her still ona ee don te TSI Y BA still Z shchi ce x Z h oh vv Жыssau Zhe LYA» Z B

From F:

HF) Yield: 5595, "H-NMR (400 MHz, DMSO-aE): 7.00-7.40 (t, 9H), 4.36-5.08 (t, 7H), 2.70-2, 90 (t, 2H), 2.34, 2.25 (in, ЗН), 2.18, 2.12 (in, ЗН), 1.56 (y, 9-8.5Hz, ЗН), 1, 35 (a, 9-6.2 Hz, ZN), MS (ARSI, t/2): 586 (MNN), about SgoNzaSIMz3O55.0.42H20. Calculated: C, 58.77; H, 5.75; M, 9.45. Found: C, 58.37; H, 5.73; M, 9.19.

Example B24: 60 3-(2-Hydroxy-3-((1-methyl-1H-pyrrole-2-carbonyl)-amino|-4-phenyl-butyryl)-5,5-dimethyl-thiazolidine-4-carboxylic acid2 ,6-difluoro-benzylamide b5 -58v-

IN

Not ZHEO MN t: wounds

Output 7595; "H-NMR (400MHz, DMSO-a5): 6.40-7.40 (t, TON), 6.00 (t, 1H), 4.20-5.20 (t, 7H), 3.64 3.61 70. (8, ZN), 2.70-2.90 (t, 2H), 1.52, 1.49 (in, ZN), 1.33 1.29 (in, ZN); MS (ARSI, t/2): 571 (MAN), SgoNzoB2 IM. 045

Calculated: C, 61.04; H, 5.65; M, 9.82. Found: C, 60.86; H, 5.94; M, 9.71.

Example c25: 3,5-Dimethyl-isoxazole-4-carboxylic acid (1-benzyl-3-I(4-(2,6-difluoro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl)-2 -hydroxy-3-oxo-propyl)-amide; to the Chief Executive Officer of the VC,

KOH Хих осив Ян so я Ня vne і і

Not about juice NI about VAN NN

Output 7596; "H-NMR (400 MHz, DMSO-aZ): 6.60-7.40 (t, 8H), 4.26-5.08 (t, 7H), 2.70-2 90 (t, 2H), 2.32-2.28 (in, ZN), 2.16, 2.13 (in, ZN), 1.56 1.53 (85, ZN), 1.37, 1.34(5, ZN) MS (ARSI, vol. 2): 587 (MN);

SgoNzoB2YMaOB55. Calculated: C, 59.37; H, 5.50; M, 9.55. Revealed: C, 59.12; H, 5.88; M, 9.50.

Example 826: Gee! 3Z-2-Hydroxy-3-(1-methyl-1H-pyrrole-2-carbonyl)-phenyl-butyryl)-5,5-dimethyl-thiazolidine-4-carboxylic acid o 2-trifluorobenzylamide

V shk v Sche CHE What shOf oo .m, y, o p: SCHE I u z: o ay z ONY so be 007 OM ot a -

Output 83956; TN-NMR (400MHz, DMSO-aU): 6.40-7.60 (t, 11H), 6.00 (t, 1H), 4.20-5.20 (t, 7H), 3.70, 3.54 (in, ZN), 2.70-2.90 (t, 2H), 1.52 (in, ZN), 1.36, 1.29 (in, ZN). MS (ARSI, vol. 2): 619 (MAN): SzoNazzEz3MaOA5. Calculated: /ich-

C, 59.79; H, 5.52; M, 9.30. Found: C, 59.42; H, 5.55; M, 9.06.

Example b27: 3,5-Dimethyl-isoxazole-4-carboxylic acid (1-benzyl-3-(5,5-dimethyl-4-(2-trifluoromethyl-benzylcarbamoyl)-thiazolidin-3-yl|-2-hydroxy- 3-oxo-propyl)-amide « pes asya

I hv Z s Shchy le zh zh ory zh chny - Z zh shchi rizh on sha z Vs SHE s - Output: 9396; "H-NMR (400 MHz, DMSO-ab): 7.05-7.60 (t, 9H), 4.36-5.08 (t, 7H), 2.70-2.90 (t, 2H) , 2.30, -I 2.21 (8, ZN), 2.15, 2.05 (8, ZN), 1.54, 1.52 (in, ZN), 1.39, 1.32 ( in, ZN); MO (ARSI, t/lg): 619 (MAN); SovNzaMAO/5.Н2О.

Calculated: C, 58.24; H, 5.38; M, 9.06, Found: C, 57.87; H, 5.68; M, 9.02. -

Example B28: about 20 M-K15,25)-3-(4-allylcarbamoyl-5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl|-nicotinamide

Z. 2 SHE. g with She: sl i shk Sha NA .

NE jerks of sao vala

White solid product: "H NMR (DMSO-4) 5 8.81 (a, 9-86, 1), 8.77 (9, 9-6.2, 1H), 8.12 (t, 1H), 7.99 bo (t, 1), 7.63 (t, 1H), 7.32-7.12 (t, 7H), 5.78 (t, 71H), 5.18 (t, 2H), Analysis (SooNaz»2M405-0.5H20-0.5TEA) calculated C (57.65), H (6.36), M (10.19), found C (57.73), H (5.91), M ( 10.15). MO-VR (ЕР) t/2, calculated for 483.2075, found 497.2066.

Example 829: in 3-(2-Hydroxy-3-t4-methoxy-2-methyl-benzoylamino)-4-phenyl-butyryl|-5-dimethyl-thiazolidine-4-carboxylic acid 2-methyl-benzylamide She She: with

Ves aka: VD: VINYK S I ms Z

Kiya dvy ke

Ех ц B ЖЖ ОБ т сн still I, still

HO o nese Koty koint T I pt and u ve, and re Nidaynh i

Yield: 5695. "YAN NMR (400 MHz, DMSO-av): 5 8.32 (B 1), 8.09 (a, 1), 7.33-7.27 (t, ZN), 7.23- 7.19 (t, 2H), 7.15-7.08 (t, 5H), 6.69 (a, 2H), 5.46 (a, 1), 5.13 (a, 1H), 4 .99 (d, tn), 4.49 (v, 2H), 4.41-4.36 (t, 70 2H), 4.10 (da, 71), 3.71 (v, ЗН), 284 -2.81 (t, 1H), 2.72 (B 1), 2.24 (in, ЗН), 2.07 (in, ЗН), 1.48 (in, ЗН), 1.933 (in, ЗН ); MO-ARSI (t/ha): 326, 590 (MN). TOP: K (min.) 21.26, Purity: 10095; SzzNazoMaO55-0.4H20: calculated: C, 66.40; H, 6 ,72; M, 7.04, found: C, 66.38; H, 6.71; M, 6.94.

Example 830: (k)-3-(25,35)-2-Hydroxy-4-phenyl-3-((1-o-tolyl-methanol)-amino|-butanoyl)-5,5-dimethyl-thiazolidine- 4-Carboxylic /5 Acids Propyl amide etc

Ye My ryh Kesh nan: THE ONE with the same SM B drank ZE THIS uko tat g bu I

IR (pure cm") 3318, 2964, 1642, 1530, 1445, 1372, "H NMR (DMSO) 5 8.21 (4, 9-84, 1H), 7.90 (i, 9-56, ch 1H )U, 7.35-7.07 (t, 9H), 545 (a, 2-6,, 1), 5.09 (a, 2-92, 1H), 5.00 (a, 9Yu-9 ,2, 1H), 4.50-4.38 (t, 2H), 4.37 (v, 1H), 3.01 (a, 9U-6.9, 2H), 2.90-2.60 (t, 2H), 2.02 (in, ЗН), 1.49 (in, ЗН), 1.44-1.35 (t, 2Н), 1.34 (in, (o)

ZN), 0.82 (Her, 9-7.5, ZN); MO-VR (ЕР) t/2, calculated for C27NzeMa3045 (МН) 498.2424, found 498.2427.

Example 831. (k)-3-(25,35)-3-C1-(3-Fluoro-methyl-phenylmethanoyl|-amino)-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine - about 4-carboxylic acid propyl amide and. what did you do -

SNY sa V - eh zho BO o

Io Ne INY. KT: Chnyshchykv: pe and I and Sai z. S. and ke I h-

White solid product: "H NMR (DMSO) 5 8.34 (a, 9U-8.1.1H), 7.91 (5 9-5.9, 1H), 7.40-7.10 (t, 7H), 6.93 " (a, 9-6.9, 1H), 5.51 (a, 9U-6.2, 1H), 5.008 (a, 9U-8.8, ЗН), 5.00 (a, 9-8.8, 1H), 4.50-4.39 (t, 2H), 4.38 (c, U c 1), 3.00 (da, 9-12.3, 5, 9, 2H), 2.90-2.60 (t, 2H), 1.89 (in, ЗН), 1.49 (in, ЗН), 1.40-1.34 (t, 2Н) 1, 34 (in, and ZN), 0.82 (Her, 9-7.7, ZN); MO-VR (ERE) t/2, calculated for С27Нз5М4504Е5 (МН) 516 2332, found 516.2339. и"? Example 832: (kO)-3-(25,35)-3-11-(3-Fluoro-2-methyl-phenyl)-methanoyl|-amino)-2-hydroxy-4-phenyl-butanoyl)-5, 5-dimethyl-thiazolidine-4-carboxylic acid 3-methoxy-benzylamide

In NN shi and Pe -' re you vi and Stand, and OB What sl

Te V pa YAN s VE o s syu Vsya KUN (ee) pe y. z "y o: Sho s mya ps losa v

I: ace beach tk I tey

Ok aphid

White solid product: "H NMR (DMSO) 5 8.43 (i, 9-5.9, 1H), 8.34 (9, 9-81, 1), 7.31-6.72 (t, 12H ), 5.57 (a, 9-6.8, 1), 5.12 (90, u0-9.3, 1H), 5.01 (a, 9U-9.3, 1H), 4.50 -4.30 (t, 4H), 4.12 (aa, o0-15.7, 5.9, 1H), o 3.69 (v, ЗН), 2.95-2.62 (t, 2H ), 1.90 (in, ZN), 1.49 (in, ZN), 1.34 (in, ZN); MO-VR (ЕР) t/7, calculated for

Сз2На7Ма3О55Е (МН) 594.2434, found 594.2438. Example 833: (k)-3-(25,35)-3-C11-(3-Fluoro-2-methyl-phenyl)-methanoyl|-amino)-2-hydroxy-4-phenyl-butanoyl)-5 ,5-dimethyl-thiazole 60 dyne-4-carboxylic acid allylamide b5 ve . - 5th more

KE. SCHE y En Y ok ih sk su Yan, "Eh s sami, zay

White solid product: "H NMR (DMSO) 5 8.34 (y, 9-8.3, 1H), 8.10 (B 9-5.7, 1H), 7.40-6.90 (t, 8H), 5.81-5.69 (t, 1H), 5.54 (a, 9-6.6, 1H), 5.30-4.90 (t, 4H), 4.50-4, 35 (t, ЗН), 3.80-3.65 (t, 2Н), 2.90-2.60 (t, 2Н), 1.89 (в, ЗН), 1.49 (в, ЗН) 1.35 (in, ZN); MO-VR (ЕР) t/g, calculated for С 27Нз33МаОЕ5 (МН) 514.2182, found 514.2176.

Example BZ4: 75. 3-(25,35)-2-Hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl|-5,5-dimethyl-thiazolidine-4- carboxylic acid allylamide c tata -

EE Z and IA, | SVK ay s tA, t I'm the same word - roses ee like me too (8)

TN NMR (DMSO-yv) 5 9.23 (in, 1H), 8.09 (t, 2H), 7.35-7.17 (t, 5H), 6.60 (5, 1H), 6, 37 (in, 1H) 5.74 (t, 1H), 5.41 (rgv, 71H), 5.20 (da, 2-17.2, 1.6, 1H), 5.11 (а, у0 -9.2, 1H), 5.02 (aa, 9-10.2, 1.5, 1H), 5.00 (a, o 4-91, 1H), 4.46-4.37 (t , ZN), 3.79 (adaa, o-15.9, 5.5, 5.3, 1H), 3.63 (adcha, 9-15.9, 5.4, 5.3, 1H), 2.82 (ав, 4-13.9, 0.3, 1Н), 2.71 (ад, 9-13.6, 10.7, 1Н), 2.16 (в, ЗН), 1.76 (in, ZN), 1.51 (5, ZN), 1.36 (5, ZN); Calculated for S

SovNz5;MaO55-0.3H2O: C, 63.32; H, 6.76; M, 7.91. Found: C, 63.35 N, 6.70; M, 7.71. -

Example 835: 3-C25,35)-3-(5-fluoro-3-hydroxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyryl/|-5,5-dimethyl-thiazolidine-4- ka - b y . y rbic acid allylamii nm z x Х M VZY h to НЯ I NE х НЯ poz Jak) y pdr And 2 more ba Zo on net uter ru ee і jako z: NI v ikon i TN NMR (DMSO-yv) 5 9.94 (z, 1H), 8.23 (y, 9-8.2, 1), 8.10 (B 9-56, 1H), 7.33-7.17 (t, 5H), 6.58 (ad, -I U-10.6, 2.5, 1H), 6.32 (da, 0-88, 2.5, 1H), 5.78 (t, 1H), 5.54 (riv, 1), 5.21 (aa, 9-17.2, 1.7, 1H), 510 (4, 90-91, 71H), 5.03 (aa, 2-10.2, 1, 5, 1H), 5.01 (a, 9-91, 1H), 4.50-4.42 (t, ZN), 3.78 (aa, 9-15.9, 54, - 5.4, 1), 3.63 (ada, o-15.9, 5.4, 5.3, 1H), 2.84 (aa, 2O-14.5, 3.3, 1H), 2.70 (aa , 9-13.5, 10.3, 1H), 1.75 (in, about 20 Н), 1.50 (in, Н), 1.36 (5.3Н); The analysis was calculated for C 27H32EM3O55-0.3H20: C, 60.61; H, 6.14; M, 7.85,

Found: C, 60.63; H, 6.08; M, 8.7. "2 Example 836: (k)-3-(25,35)-3-C11-3-fluoro-2-methyl-phenyl)-methanoyl|-amino)-2-Hydroxy-4-phenyl-butanoyl)-5 ,5-dimethyl-thiazolidine-4-carboxylic acid 2-methyl-benzylamide

PEN PE. NMR (DMSO-yv) 5 8.85-8.35 (t, 2H), 7.38-6.90 (t, 12H), 5.55 (0, 9-5.9 , 1H), 5.12 (9, 9-92, 1H), 5.01 (90, 9-9.2, 1H), 4.58-4.32 (t, 4H), 4.10 (aa , 0-15.0, 4.6, 1H), 2.92-2.62 (t, 2H), 2.24 (8, ЗН), 1.90 (in, bo ЗН), 1.49 ( in, ZN), 1.34 (5, ZNI); MO-VR (ERE) t/h, calculated for С 32На7М3О4Е5 (МН) 57.2489, found

578.2486. The analysis was calculated for C 52Na6Ma3O,5.0.2EAs: C, 66.17; H, 6.37; M, 7.06, found C, 66.30; H, 6.54; M, 6.74.

Example 837: 85 (K)-3-(25,35)-3-(1-(4-Fluoro-2-methyl-phenyl)-methanoyl)-amino)-2-hydroxy-4-phenyl-butanoyl)- 5,5-dimethyl-thiazolidine-4-carboxylic acid 2-methyl-benzylamide 70 g Zh g also i i Z

White solid product: "H NMR (DMSO) 5 8.40-8.30 (t, 2H), 7.35-6.90 (t, 12H), 5.53 (a, U-6.8, 1H ), 5.13 75 (9, 9-9.0, 1H), 5.00 (a, 9U-9.0, 1H), 4.48 (85, 1H), 447-445 (t, 2H) , 4.38 (da, 0-15.0, 5.9, 1H), 4.10 (aa, 3-15.0, 4.8, 1H), 2.90-2.62 (t, 2H ), 2.24 (in, ZN), 2.04 (8, ZN), 1.48 (in, ZN), 1.33 (in, ZN); MO-VR (ЕР) t/2 calculated Co2Na7Ma30, 5E (MN) 578.2463, found 578.2489.

Example: Nicotinic acid 3-(15,25)-3-(K)-4-allylcarbamoyl-5,5-dimethyl-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl|-2-methyl-phenyl zac . 4. r» ma: - Bo-eh 2 dk

Still Me ze eh i y SCHE y un odiestt g pane so ne : rek, sskd shchi ze Ge

EE S "V ee. where ZI syo (5) and payi schi JHE cht sly et y p dl sia "Schi

White solid: "H NMR (DMSO) 5 9.26 (yes, 9-2.0, 0.9, 1H), 8.90 (yes, 9-5.6, 2.0, 1H), 8 .47 (4, 9-7.9, 2.0, 1H), 8.40 (a, 9-8.2, 1), 8.1 (6 9-5.7, 1H), 7.65 (ada, o-7.9, 5.6, 0.9, 1H), 7.40-7.10 (t, 8H), o 5 82-5.658 (t, 1), 5.6 (a, 9-6, 1H), 5.30-4.90 (t, 4H), 4.540 (t, 2H), 440 (in, 3.80-3.70 (t, ), oso 3.00-2 .60 (t, 2H), 1.85 (5, ZN), MO (in, ZN), 1.34 (ZN).

Example 839: -- (k)-3-(25,35)-2-Hydroxy-3-(4-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl|-5,5-dimethyl-thiazolidine- 4-carbon of tannic acid 2-methyl-benzylamide enyene - g EV Z ns vaye EV y vane: I i d i ih r I i i i a: Od, o z isoAdN vh ni J ys Ex " White solid product: TN nMR (DMSO) 5 9.55 (8, 71H), 8.32 (i 9-49, 1H), 8.00 (a, 0-84, 1H), 7.36-7.00 (t, OH) , 6.54-648 (t, 2H), 5.44 (a, 9-66, 1), 513 (a, 2-92, 1H), 4.99 (y, yu-9.2, 1H) , 450-432 (t, 4H), 4.11 (da, 9-15.0, 4.8, 1H), 3.50-2.80 (t, 2H), 2.25 (in, ЗН) . ; M, 7.24. Found: C, 66.25; H, 6.55; and M, 7.35.

Example b40: 6-Amino-pyridine-2-carboxylic acid - 415.25)-1-benzyl-3-((K)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidine-3- yl|-2-hydroxy-3-oxo-propyl)-amide shk Yaosoglya so data She

НЙ sny Ж -definog" and yes dvyaln and KZ N slya siva i OO un

I NED es Same pk y and y. gg zvi i BO DK Nm. ek san She: she "NYMR (DMSO-av) 5 8.44 (y, t, 9-5.6), 8.36 (9, t, 9-9.3), 7.69-7.49 (B t, 9-7.7), 7.34-7.06 (t, TON), 6bo 6.61 (a, yin, 2-84), 6.27 (rg 8, 2H), 547 ( a, tn, 9-71), 5.00 (t, 2H), 4.54-4.43 (t, 2H), 4.50 (c, 1H), 4.38 (aa, yin, 2- 64, 15.2), 4.19 (da, yin, 2-46, 14.7), 2.87-2.65 (t, 2H), 2.28 (v, ЗН), 1.53 ( в, ЗН), 1.38 (в, ЗН). The exact mass calculated for СзоНовМ5О45 (МН) is 562.2488, found 562.2493.

Example BA1: 415,25)-1-Benzyl-3-(K)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-ylI-2-hydroxy-3-oxo-propyl) -23 b5 -dichloro-isonicotinamide dn Uev i DE ve tdanya koh E ly . NMR (DMSO-ab6) 5 8.89 (4, yin, U-8.42), 8.40 (B MH, 9-55), 8.38 (a, 1H, 9-48) , 7.30-7.08 (t, TON), 5.58 (4, 1H, 0-7.3), 5.07 (a, yan, 2-88), 5.00 (a, 1H, 9U-8.8), 4.54-4.50 (t, 1H) 4.51 (in, 1H), 4.43-4.36 (t, 2H), 4.16 (da, YAN, 9 -5.1, 15.0), 2.89-2.85 (t, 1H), 2.71-2.63 (t, 1H), 2.26 (8, ЗН), 1.50 (in .

С3оНз»МАОу5СИ»: С, 58.54; H, 5.24; M, 9,10. Found: C, 58.48; H, 5.10; M, 8.80.

Example B42: 415,25)-1-Benzyl-3-(K)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl-2-hydroxy-3-oxo-propyl) -3- chlor-isonicotinamid nyases that g zt i chek are thrown into them nn KN KUSH. heh)

Ve nn sa; i se s es

TN nMR (DMSO-yv) 5 8.82 (a, MH, 9U-8.6), 8.62 (c, 1H), 8.52 (4, MH, -4.93, 8.39 (y , MN, 9-51), o 7.29-7.09 (t, 71OH), 5.54 (a, tn, 9-7.1), 5.09 (y, YAN, 2-9.0 ), 4.99 (d, 1H, 2-9.0), 4.5-6.49 (t, 1H), 4.51 (v, 00 1H), 4.44-4.37 (t, 2H), 4.15 (yes, 1H, 92-51, 15.0), 2.88-2.83 (t, 1H), 2.74-2.65 (t, 1H), 2.26 ( in, ZN), 1.50 - (in, ZN), 1.35 (in, ZN). The exact mass was calculated for SzoNaziM,O,5SI (M) 581.1989, found 581.1983.

Example B43: - (k)-3-(2535)-2-Hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl|-5-dimethyl-thiazolidine-4-carbo The composition of the new acid 2-methyl-benzylamide was added. vn Sonnets

M o i « 2 fe VK 2

KOL I Jhe ee i t: sah o KN » j zd BE: p i s Y Shi i - 35 "'NYMR (DMSO-yv) 5 9.24 (v, 1H), 8.31 (5 9-5, 6, 1H), 8.10 (4, 9U-8.2, 1H), 7.34-7.09 (t, OH), 6.60 (z, 1H), 6.38 (8, 1H) , 5.42 (riv, 1H), 5.14 (a, 90-9.1, 1H), 5.01 (a, 92-91, 1H), 4.50 (c, 1H), 4.50 -4.37 (t, ЗН), - 4.11 (аа4, 90-15.1, 4.7, 1Н), 2.76 (t, 2Н), 2.26 (в, ЗН), 2, 16 (85, ЗН), 1.77 (8, ЗН), 1.50 (8, ЗН), 1.35 (in, - ЗН); MO-VR (ЕР) t/2, calculated for C z3NaoMzO55 ( MN) 590.2689, found 590.2676; Calculated for

SzzNazoMzO55-0.3H20: C, 66.60; H, 6.71; M, 7.06. Found: C, 66.65; H, 6.69; M, 7.05. (ee) Example B44: o M-(15,25)-1-Benzyl-3-I5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-ylI-2-hydroxy-3-oxo -propyl)-2-methyl-nicotinamide c, y. p

F, B in E and E m Z E

Tez t shik sl Be li fan sera Z ha play i ee y y. with. II 60 i Also: Not 7 Z

White solid product: "H NMR (DMSO-yv) 5 8.53-8.33 (t, 2H), 7.47 (9.9-7.82, 1H), 7.38-7.10 (t , 12H), 5.62 (4, 9-7.94, 1H), 5.118 (aa, 2-96, 7.6, 2H), 4.43-4.37 (t, ЗН), 4.17 (yes, 0-7.81, 6.99, 1H), 2.87-2.67 (t, 2H), 2.28 (in, ЗН), 2.2 (in, ЗН), 1.49 (in ZN), 1.34 (in, ZN); Analysis (Cz4Hz6MaO45-1.0H20-1.0-.MesSmM) calculated C 65 (63.95), H (6.67), M (11.30 ), found C (63.94), H (6.75), M (11.26). MO-VR (ЕР) t/2, calculated for 561.2544, found 561.2556.

Example c45: Pyridine-2-carboxylic acid ((15,25)-1-benzyl-3--5-dimethyl-4-(2-methyl-benzyl carbamoyl)-thiazolidin-3-yl)-2-hydroxy-3 -oxo-propyl)-amide.

M. and NK; stey kg zna a I NYA t KE ol vriety i

White solid product: "H NMR (DMSO-ydv) 5 8.89 (a, 9U-7.86), 8.66 (9, 9-42, 1H) 8.39 (j, 9-6.54, 1H), 7.89 (t, 2H), 7.32-7.12 (t, 9H), 5.68 (a, 9-7.28, 1H), 5.03 (aa, yu-9, 7, 8.3, 2H), 4.56 (t, ЗН), 4.40 (a, y-7.5, 1H), 4.35 (a, 9-7.5, 1H), 4, 21 (a, 9-6.7, 1H) 2.87-2.67 (t, 2H), 2.25 (in, ЗН), 1.49 (8, ЗН), 1.34 (in, ЗН ); Analysis 15... (SzoNzaM.O,5.H2O.0.1EOAc) calculated C (65.52), H (6.33), M (10.05), found C (65.78), H (6.69), M (9.66).MO-VR (ЕР) t/2, calculated for 547.2380, found 547.2373.

Example c46: Pyridine-2-5-hydroxy-carboxylic acid 415,25)-1-benzyl-3-15,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl|-2-hydroxy -3-oxo-propyl)-amide

SHE fee ren shcha o ya hi ek y (5)

White solid product: "H NMR (DMSO-45) 5 8.89 (4, 9-7,9, 1), 8.66 (9, 9-42, 1H), 8.39 (B 9U-6, 54, 1H), 7.89 (t, 2H), 7.32-7.12 (t, 9H), 5.68 (y, 0-7.2, 1H), 5.03 (ad, 9- 9.7, 8.3, 2H), 4.56 (t, ЗН), 4.40 (a, y-7.5, 1H), 4.35 (a, 9-7.5, 1H), 4.21 (а, 9-6.7, 1Н), 2.87-2.67 (t, 2Н), 2.25 (в, ЗН) 1.49 (в, ЗН), 1.34 (в , ЗН); Analysis of 3о (СзоНзаМ4О55.0.5Н20.0.5EOАс) calculated C (62.29), H (6.42), M (9.91), found C (62.53), H ( 6,4), M os (10,10). MO-VR (ЕР) t/7, calculated for 563.2325, found 563.2328. -

Example B47:

M-(15,25)-1-Benzyl-3-(5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl|-2-hydroxy-3-oxo-propyl)-nico - tinamid early m

MORE of her. still g « s BA and By I Ko I

White solid product: "H NMR (DMSO-4dv) 5 8.89 (y, 9-7.9, 1H), 8.66 (a, 9-4.2, 1H), 8.39 (B 9- 6.54, 450 1H), 7.89 (t, 2H), 7.32-7.12 (t, 9H), 5.68 (y, 9-7.3, 1H), 5.03 (aa, 9 -9.7, 8.3, 2H), 4.56 (t, ZN), 4.40 (a, -I 9-7.5, 1H), 4.35 (a, 9-7.5, 1H), 4.21 (a, 90-6.7, 1H), 2.87-2.67 (t, 2H), 2.25 (in, ЗН), 1.49 (in, ЗН), 1 ,34 (in, ZN); Analysis (SzoNzaM,O,5-0.5H20-0.5Mesm) calculated C (64.61), H (6.39), M (10.94), found C (65, 02), H (6.58), M - (10.90). MO-VR (ЕР) t/7, calculated for 547.2372, found 547.2379. - Example B48:

M-(15,25)-1-Benzyl-3-15,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl1-2-hydroxy-3-oxo-propyl)-nicotinamide about Z

F. What's wrong with the gray hole: 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year, 1 year. , 8.66 (a, 9-4.2, 1H), 8.39 (B 9-6.54, 1H), 7.89 (t, 2H), 7.32-7.12 (t, 9H ), 5.68 (y, 9-7.28, 1H), 5.03 (ad, 9-9.7, 8.3, 2H), 4.56 (t, ЗН), 4.40 (a , 9-7.5, 1H), 4.35 (a, 9-7.5, 1H), 4.21 (a, 90-6.7, 1H), 2.87-2.67 (t, 2H), 2.25 (in, ZN), 1.49 (in, ZN), 1.34 (in, ZN); Analysis (SzoNzaMaO55.HO) calculated C (61.42), H (6.32) , M (9.49). Found C (61.64), H (6.17), M (9.12). MO-VR (ЕР) t/7, calculated for 563.2326, found 563.2328 65 Example B49:

M-К15,25)-3-(4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)|-benzyl-2-hydroxy-3-oxo-propyl|-2-methyl-nicotinamide and with 5. and td shko I ZE and Z also ka si with kg; t: Si hvy KE STOLAH

White solid product: "H NMR (DMSO-yv) 5 8.58 (t, 1H), 8.29 (y, 9-7.54, 1H), 7.78 (a, 9-7.88, 2H ), 7.32-7.12 (t, 7H), 5.78 (t, 1H), 5.18 (da, 2U-9.7, 8.3, 2H), 4.56 (t, ЗН ), 4.40 (t, 4H), 2.87-2.67 (t, 2H), 2.25 (in ZN), 1.49 (in, ZN), 1.34 (in, ZN): Analysis (SobNz»MAaO45.0.5H20.0.5TEA) calculated C (57.68), H (6.66), M (8.31), found C (57.66), H (6.18) , M (8.77). MSO-VR (ЕР) t/. calculated for 497.2232, found 497.2223.

General ways of C that J

And EE V - ren Not me ny g. . M as; Yana

NAME of trouble B: s Z . a and a middle leg; SCHI What: ped - ha « -yai I and what rn la s 25 V dya 5 y ! V. o se she y shk NO In ny zh kih shk she She y she y- J esh . "-

HOW THEM 35 The synthesis of compounds from the general structure 24 is as follows. Bos-protected carboxylic acids 20a are coupled with the required amines 2, obtaining amino amides 23, using a two-step process. The two-stage process includes treatment of 20 2 in the presence of diphenyl chlorophosphate or EOSI, and then exposure to NS! or methanesulfonic acid. Final compounds 24 are obtained by OCC-mediated coupling of 23 and 4, followed by deprotection of phenol P2. The final compounds were purified by flash chromatography or preparative HPLC. « and Z Y IB SI

Additional General possi son with Fr. that Vr Bk IV;" Fe: NO; ZE pe OB - y en in sk j KO ! sho: VN r VVE : Me: Za de, y siv, NE KN SY -i y i-- r la ee wn ; li ny Ps TEN sht be 72 shk sit y o y, I kv V

S sheh Vsh ZY i ke pk: i

ГФ) and in; i zhk Y I sk ED nki TSI i kv NV

NK E Ge

The synthesis of the compound of general structure 31 (where P2 is not 2-methyl-3-hydroxybenzamide) is as follows. The amines of the general structure 23 were coupled with the Boc-acidic intermediate 15, using the OSS coupling conditions.

The resulting intermediate 29 was deprotected under acidic conditions to give the amine of the general structure 30. 65 The final compounds were obtained by modifying the amine 30 by the methods described in the general methods of section B to give P2 amides and ureas.

Methods of synthesis of compounds with RI variants.

EOSI-combination - EOSI was added to a solution of acid, amine and NO in CH.-SI" and the solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and a small portion of water. The solution was washed with saturated MNACI (2x), saturated MnSOOz (2x), brine (15), dried with magnesium sulfate and concentrated in vacuo. The crude product was used without further purification, unless otherwise specified. reCs-combination - A solution of acid, amine and NOVT was obtained in ethyl acetate. To the solution was added OSS in EUDAs at 02C and the mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated MH C (2x), saturated Manso (1x), brine (1x), dried with sodium sulfate and concentrated in vacuo. The crude product was used without further purification unless otherwise specified.

Removal of Bos-protection by 4N HCI - A 4H solution of HCI in dioxane was added to the solution of Bos-amine in dioxane and the solution was stirred overnight at room temperature. The solution was poured into saturated Manso with and the product 7/5 was extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was used without further purification unless otherwise specified.

Removal of Bos-protection Meso 2H - Methanesulfonic acid was added to a solution of Bos-amine in ethyl acetate at 090 and the solution was stirred for 3-6 hours at room temperature. The solution was cooled to 02C and sufficiently saturated MnSO 2 was added to quench the acid. The solution was diluted with ethyl acetate, washed with saturated Manso's and brine. dried over sodium sulfate and concentrated in vacuo. The crude product was used without further purification unless otherwise specified.

Removal of protection by phenol acetate KSM - A solution of phenol acetate and KSM in ethanol was heated at 50 C overnight. The solution was concentrated under vacuum. The residue was purified by flash chromatography, eluting with a mixture of 0-590 methanol in СНоСи», unless otherwise specified. Ge

Removal of protection with Phenol acetate MaOMe/MeonN - Removal of protection with Phenol acetate 0.5N (5)

Mmaosn/Meon - A solution of phenol acetate in E(Ac) and methanol was cooled to 02C in an ice bath. 0.5N Mmaosn/Meon was then added dropwise and further stirred at 02C for 1.5-2 hours after addition.

Additional EtOAc was added further, 15H HCl (4.eq.) was added dropwise. The phases were separated and the organic phase was washed with 2.596 aqueous solution of Ma»CO3, then with O01H Nei/brine (2:1), and then the brine was dried with magnesium sulfate and concentrated in a vacuum. The resulting residue was flash chromatographed on silica gel to afford the desired product, unless otherwise specified.

Removal of protection with phenolic acetate NCI/Meon - 4H was added to a solution of phenolic acetate in methanol --

NOI in dioxane and the solution were stirred at room temperature for approximately 4 hours. The solution was concentrated in a vacuum. The residue was purified by flash chromatography eluting with 0-596 methanol in dichloromethane unless otherwise specified. -

Fragments of the general structure 20. more «

Ha schey zom N. sk Be se gai r z) pr ody snai yaya ot a kn y I ya shi s i vu y y "Y yak "y y myav Ne: z5 BK EK she she she she 5 V te 0 BU: ИЯ ---: И : И ! y eh cha di ve DZ Ж - and zh shi so You beat her 2. va ekv still in I Arenas i as EI -I BO I Й Ks NK I zh ШЙ Ko x Enea y g ko Bo ns y Eh - y: zh : t so 20 zve vk pyt omeae s Source of Vos-carboxylic acids 20a-i

Vos-acids 20a and 206 were obtained by the method Oetapoe, I.; Mepe?g, A.; Oidame, S. Tei. And hey. 1998, 39, 1169.

Vos-acids 20c, 204, 20e and 207 were obtained by the method of KagapemuzkKu. O., ey aI. U. Med. Spent 1990, 33, 1459. 59 Specific Method S

HF) Example SI: t (5)-4,4-Difluoro-1-(25,35)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyrylI-pyrrolidine- 2-carboxylic acid 2-methyl-benzylamide 60 b5 zhve Z Zh i i

КК вех, не я г Ес я рядк В и ее s 2 vyr vy shiv

Eerii SUK plei, OO lyrkya nya Same th The named compound was obtained in accordance with the general methods using the corresponding Bos-protected pyrrolidine acid (0.96g, 3.dmmol), o-methylbenzylamine (0.57ml 4.bmmol), NOVT (0.62g . . Vos was removed using general deprotection of 4H NSI Vos. 4H NOI in 1,4-dioxane (ml), 1,4-dioxane (5ml).

The result was an aminoamide of general structure 23, yield: 0.79g (71965, 2 steps). "H NMR (400 MHz, DMSO-IV): 5 9.02 (B 1H), 7.24-7.14 (t, 4H), 4.55 (i, 1), 4.35 (ad, tn) , 4.30 (aa, tn), 3.73 (t, 2H), 2.94 (t, 2H), 2.52 (t, 1H), 2.27 (in ZN), "E NMR (376 MHz , DMSO-): 5 -95.3 (ad, 9U-235.15Hz, IF), -96.5 (ad, 9U-235, 12Hz, 1B),

MO-ARSI (t/ght): 255.

Aminoamide 23 (100 mg, O0.34 mmol) was combined with carboxylic acid 4 (140 mg, 0.3 mmol). using the above general method of combining OSS. NOVT (51mg 0.3vmmol), OSS (78mg, 0.3vmmol), TEA (5Omkl,

O, Zbmmol), CHNosSiI" (10 ml). The crude product was purified by chromatography, eluting with 1095 acetone in dichloromethane.

Yield: 0.13g (6395) MOS-ARSI (t/28): 608. This material was subjected to KSM conditions for general deprotection with phenol acetate (1300mg, 0.21mmol), KSM (mg, 100mmol), ethanol (100ml). The crude product was precipitated from diethyl ether and ethyl acetate with hexanes at -782C, yield: 0.10 g (84965). "H NMR (400 MHz, DMSO-dv) 5 9.37 s (8, 1H), 8 36 (Hi, 1H), 8.16 (y, 1H), 7.32-7.09 (t, 9H) , 6.93 (B 1), 6.76 (a, 1), 6.54 (a, tn), 5.49 (a, o 1H), 4.66 (ai, 1H), 4.34- " NMR (376 MHz,

DMSO-): 5 -98.7 (t, 2P), MOS-ARSI (pt/2k): 566; TOP Purity: 10095, Ki (min.) 19.01; Analysis

Cz4NazzMzOB2-0.3H20O C, H, M calculated C, 6521; H, 5.93; M, 7.36; found: C, 65.11; N, 5.90; M, 7.17.

Example C2: ("c") (25,4K)-4-Fluoro-1-(25,35)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl/ |-pyrrolidine-2-carboxylic acids 2-methyl-benzylamide - у: че:

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The isolated material was subjected to flash chromatography on silica gel, eluting with a mixture of Е(dAc/hexanes (50/50) "» and then with a mixture of ЕХАс ЭХАс/hexanes (4:11), obtaining the named compound. "H NMR (400 MHz, DMSO-av): 5 9.37 (in, " 1), 8.46 (5 tn), 8.21 (a, yn), 7.34 (a, 2), 7, 26 (a, 2H), 7.21 (5 2H), 7.15-7.07 (t, 3H), 6.94 (i, 1H), 6.76 (a, tn), 6.56 ( a, 1H), 5.51-5.38 (rejr5, 1H), 5.06 (a, 1H) 4.58 (f 1H), 4.45 (da, 1H), 4.35-4.27 (t, 2H), 4.21-4.09 (t, ZH), 3.94-3.91 i- 3.84-3.81 (t zh-t, 1H), 2.69 (y, 2H), 2.23 (v, ZN), 2.19-2.01 (t, 1H), 1.83 (8, ZN); MO-ARSI (t/2k): 548; HPLC: K (minutes .) 18.72; Purity: 96905. Analysis of Cz4Hz4aM3O5E-0.3H2O calculated: -I 67.33, 6.31, 7.60, found: 67.37, 6.25, 7.35. with Example SSZ: (25,45)-4-Fluoro-1-(2535)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl|-pyrrolidine-2-carbonov

Ge | 20 acid 2-methyl-benzylamide

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Nosov sne ko Myty eh SCHE? The separated material was subjected to flash chromatography on silica gel, eluting with EAs/hexanes (50/50) and further with

EAs to give the title compound. "H NMR (400MHz, DMSO-44): δ 9.37 (c, 1H), 8.21 (a, 1), 7.96 (i, 1H), 7.29 (a, 2H), 7, 23 (5 2H), 7.18-7.13 (t, 2H), 7.10-7.04 (t, ZN), 6.90 (i, 1), 6.75 (a, 1), 6.52 (y, tn), 5.55 (y, 1H), 5.45n5.32 (rv-re, 1H), 4.54 (0, 1H), 4.42-4.36 (t, 1H), 4.29-4.40 (t, 5H), 2.98 (i, 1H), 2.73 b (6 1), 2.32-2.21 (t, 2H), 2.19 (in, ZN), 1.78 (in, ZN); MO-ARSI (t/2k): 548; HEV: Kphvilin.) 18.21;

Purity: 9995; Analysis of C34NazaM3O5E-0.5H2O calculated: 66.89, 6.34, 7.55, found: 66.85, 6.22, 7.41.

Example CA: (5)-3-((25,35)-2-Hydroxy-3-C9-(3-hydroxy-2-methyl-phenyl)-methanol)|-amino)-4-phenyl-butanoyl)- Oxazolidine-4-carboxylic acid 2-methyl-benzylamide is still . rya: 2N Byy KI: eco NT, sk ko pane she: MN ZY eh BYK ve oy r Shut ve

White solid product: "H NMR (DMSO-yv) 5 9.36 (in, 1H), 8.80 (44, 9-8.8, 4.8, 1H) 8.30 (i, 9-55, 1H), 8.12 (a, 9-86, 1H), 7.30-7.13 (t, 9H), 6.96 (i U-7.9, 1H), 6.76 (a, 9 -7.9, 1H), 6.55 (а, 9-7.2, 1), 5.74 75 (а, 9-88, 1), 5.31 (а, 0-38, 1), 523 (y, 9-42, 1), 4.49 (aa, 2-66, 6.5, IE), 4.33-4.11 (t, 5H), 2.94-2.68 (t .

Example C5: (45.5K)-3-(25.35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanoyl|-amino)-4-phenyl-butanoyl)- 5-methylnzxa zolidine-4-carboxylic acid 2-methyl-benzylamide

I ey po ho che v: GUILTY OF ZE no she: y di: za EE y rya y Py Cha kr o y ay sy da o s sny o sleep and Ie" salts

White solid product: TN nMR (DMSO-α) 5 9.38 (in, 1H), 8.51 (5 9-60, 1), 8.15 (a, 9-84, 1H), o 7.33 -7.13 (t, 9H), 6.96 (5 9-7.7, 1), 6.79 (a, 9-8.2, 1H), 6.58 (a, 9-73, 1H ), 5.69 (0, 9U-5.7, 1H), 5.50 so (0, 9-46, 1H), 5.10 (y, 9-48, 1H), 4.39-4, 22 (t, 4H), 4.11-4.01 (t, 2H), 2.90 (t, 1H), 2.74 (t, 1H), 2.27 (8, ЗН), 1.82 (in, ZN), 1.37 (9, 9-5,9,5 18); МСО-ВР (ЕР) t/2, calculated for С з4Нз6еМз3Ов (МН) 546.2604, 077 found 546.2595. M

Example St: (5)-3-(25,35)-2-Hydroxy-3-C1-(3-hydroxy-2-

Zo methyl-phenyl)-methanoyl-amino)-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylic acid - 2-methyl-benzylamide

E "vka still che By ; - s ey still lak syichya s yar I Er, I oi their g" they and i ly vh u Vus U UR By" a sl i sen SEBE p a a - 35 White solid product: "NYMR (DMSO-iv) 5 9 .34 (in, 1H), 8.32 (5 9-5.8, 1H), 8.11 (9U-9.0, 1H), 7.31-7.10 (t, 9H), 6, 93 (B 9-7.9, 1H), 6.76 (y, 9-81, 1H), 6.55 (a, 9-6.5, 1H), 5.73 (0, 9-40, 1), 546 (a, 9-41, -i 1H), 5.23 (y, 9-3.9, 1H), 4.39-4.532 (t, 2H), 4.18 (t, ЗН) , 2.92 (t, 1H) 2.69 (t, 1H), 2.27 (in, ЗН), 1.81 (in, - ЗН), 1.28 (8, ЗН), 1.18 ( in, ZN); MO-BP (ERE) t/g, calculated for C 32NavMazO6 (MAN) 560.2761, found 560.2759; Calculated for Cz2Naz7MaOv.-0.5Н»О: C, 67.59; H, 6.74; M, 7.39. Found: C, 67.74; H, 6.75; M, 7.16. (ee) Example C7: o (5)-3-((25,35)- 2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-phenyl-butanoyl)-5,5-dimethyl-oxazo lidine-4-carboxylic acid propyl amide - c, t As "YAN NMR (DMSO-yv) 5 9.37 (z, 1H), 8.12 (y, 9-93, 1H), 7.93 (5 9-5.6, 1H), 7.34 -7.18 (t, 5H), 6.96 (Her 9-81, 71), 6.79 (a, yu0-8.1, 71H), 6.56 (a, 90-71, 1), 5.73 (a, 9-62, 1H), 5.44 (a, 0-40, 1H), 5.24 (a, 9U-3.8, 1H), 4.36 (t, 71H), 4.18 (t, 71H), 4.11 (5, 1H), 3 ,10-2.92 (t, ЗН), 2.75-2.66 (t, 7Н), 1.80 (v, ЗН), 65 1.46-1.39 (t, 2Н), 1, 31 (in, ZN), 1.22 (in, ZN), 0.86 (Y, 9-7.2, ZN); MO-VR (ЕР) t/2, calculated for С27НзвМз3Об (М-н)" 498.2604, found 498.2590.

Example C8: (45,55)-3-((25,35)-2-Hydroxy-3-11-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl) -5-methyl-oxazolidin-4-carboxylic acid 2-methyl-benzylamide and ve r

White solid product: TN nMR (DMSO-α) 5 9.36 (c, 1), 8.26 (B -5.5, 1H), 8.09 (a, 9-88, 1H), 7.30 -7.08 (IN, 9H), 6.93 (5 9-7.7, 1), 6.76 (a, -7.9, 1H), 6.56 (a, 9-7.5 1H ), 5.72 (90, 9-64, 1H), 5.55 75 (0, 9-3.7, 1H), 5.08 (4, 9-3.8, 1H), 4.40- 4.33 (t, ZN), 4.26-4.12 (t, ZN), 3.10-2.89 (t, 1H), 2.78-2.67 (t, 1H), 2, 26 (in, ZN), 1.78 (in, ZN), 1.15 (a, 9-6.2, ZN); MO-VR (ЕР) t/h, calculated for С 34Наз6Мз3Ов (МН) 546.2604, found 546.2592.

Example CO: (5)-3-((25,35)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)- 5,5-dimethyl-oxa zolidine-4-carboxylic acid 5-fluoro-2-methyl-benzylamide

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White solid product: TN nMR (DMSO-α) 6 9.35 (c, 1), 8.41 (5 9-56, 1H), 8.12 (a, 9-8.9, 1H), 7, 28-7.08 (t, 8H), 6.95-6.90 (t, 1H), 6.76 (a, 9-8.1, 1H), 6.55 (a, 0-7.2 , 1), 5.78 (0, 9-61, 1), 547 (y, 0- 93.8, 1H), 5.24 (a, 9-3.8, 1H), 4.40-4 .25 (t, 2H), 15 4.20-4.10 (t, ZH), 3.00-2.60 (t, 2H), 2.22 (in, ZN), m 1.77 (in , ZN), 1.30 (in, ZN), 1.19 (in, ZN); Calculated for C z32Na7MzOvE: C, 66.54; H, 6.28; M, 7.27. Found: C, 66.37; H, 6.20; M, 7.21. -

Example C10: (5)-3-((25,35)-2-Hydroxy-3-(1-(3-hydroxy-2-methyl-phenyl)-methanol|-amino)-4-phenyl-butanoyl)- 5,5-dimethyl-oxa zolidine-4-carboxylic acid cyanomethyl-amide "

Ladle KI and 8 ri and Y n B. : dk - and Y Ok - White solid product: TN nNMR (DMSO-av) 65 9.36 (8, 1H), 8.72 (B 9-5.3, 1H ), 8.11 (a, 9-9.0, 1H), 7.29-7.16 (t, 5H), 6.94 (1, 9-7.7, 1H), 6.76 (a , 0-8.1, 1H), 6.50 (a, 0-7.5, 1H), 5.85 (90, 9-6.0, 1H), 549 - (4, 9-4.0 , 1), 5.23 (9, 9-3.9, 1H) 4.35 (t, 1H), 4.18-4.12 (t, ЗН), 4.11 (85, 1H), 2 .92 (t, 1H), 2.70 (t, so 50 1H), 1.76 (in, ЗН) 1.29 (in, ЗН), 1.19 (in, ЗН); MO-VR (ERE) t/y, calculated for C 26Na«MaO6 (MN) 4952244, found 495.2239. i) Example C11: (5)-3-((2535)-3-11-(3-Fluoro-2-methyl-phenyl)-methanol|-amino)-2-hydroxy-4-phenyl-butanoyl)-5 ,5-dimethyl-oxazolidine-4-carboxylic acid 2-methyl-benzylamide

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TN nMR (DMSO-yv) 5 8.34 (t, 2H), 7.30-7.13 (t, 11), 6.95 (y, 9-71, 1H), 5.82 (9, 7 -64, 1H), 545(9, 93.9, 1H), 5.23 (a, 9-4.0, 1H), 4.38-4.31 (t, 2H), 4.18-4 ... , ZN), 1.18 (in, ZN); MO-VR (ЕР) t/h, calculated for C 32На7МоОБЕ (МН) 5622717,

found 562.2713.

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The synthesis of compounds from the general structure of 27 is as follows. Bos-protected thiazolidine carboxylic acids 1 are converted into amino ketones 26 with the necessary Grignard reagents 25 in the presence of oxalyl chloride. Final compounds 27 are obtained by OCC-mediated coupling of 26 and 4, followed by deprotection of phenol P2. The final compounds were purified by flash chromatography or preparative HPLC. d)

The specific method of Yu

Example p: A

I(15,25)-1-Benzyl-3-(K)-5,5-dimethyl-4-pent-4-enoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl|-Z -hydroxy-2-methyl-benzamide

The named compound was obtained as follows: (K)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1 (1.0 g, 3.8 mol) was dissolved in benzene (1 ml) and cooled to 02C with magnetic stirring. Two drops of DMF were added and then oxalyl chloride (0.3 mL, 3.8 mmol) was added dropwise. When gas evolution stopped, the solution was concentrated to a yellow-purple residue. The material was dissolved in dried THF with" (1 Oml) and cooled to -782C with magnetic stirring. Grignard reagent, 3Z-butenylmagnesium bromide (7.7 ml,

C.8O0mmol) was added dropwise over 10 minutes. The result was stirred at -78 °C for 1 hour, then at -55 °C for 30 minutes. The reaction was quenched at -5592C with a saturated MHC solution (3ml) and then poured into -1 but HO (5Oml). The mixture was extracted with EtOAc (2 x 50 ml). The combined organics were washed with brine (1x100 ml), dried with sodium sulfate, filtered and concentrated. The result was aminoketone 26, which was pure enough to be used in the next step. Clear oil 26 (0.24g, 1.15mmol) was dissolved in EtOAc (10ml) AMV-ANRVA - 4 (0.40g, 1.09mmol) was added, and then NEW (0.15g, 1.09mmol). The mixture was stirred at room temperature for 1 hour, then cooled to 062 ОСС (0.24g, 1.15mmol) was added slowly as a solution in EtOAc (bml). The mixture was warmed to room temperature and stirred overnight. The mixture was filtered and the filtrate was washed with 1N HCl (100ml), sat. Tpe OSI was removed by flash chromatography (3095 to 50956 E in hexanes) to give a white solid, which was dissolved in MeOH (2 mL) and treated with 4H HCl in 1,4-dioxane (0.2 b mL 1.1 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between 1H HCl (1Oml) and EtOAc (1Oml). The organic layer was washed with sat. -aiv) 5 9.36 (in, 71), 8.23 (0, 9-81, 1H), 7.35-7.14 (t, 5H), 6.96 (5 -7.5, 1H ) 6.78 (a, 9-8.2, 1H), 6.52 (a, bo 9-7.5, 1H), 5.81-5.69 (t, 2H), 5.32 (0 , 9-9.7, 1Н), 5.11-5.91 (t, ЗН) 4.40 (t, ЗН) 2.89-2.61 (t 4Н), 2.37-2.14 ( t, 2Н), 1.81 (5 ЗН), 1.55 (5 ЗН), 1.30 (в, ЗН); Calculated for Со8НазаМоОБ5е: С, 65.86; Н, 6.71; M, 5 , 49. Found: C, 65.52; H, 6.55; M, 5.81.

The following examples were synthesized using the above specific method. using an acceptable Grignard reagent for the desired compound. 65 Example 02:

M-11-Benzyl-3-15,5-dimethyl-4-(4,4,4-trifluoro-butanoyl)-thiazolidin-3-yl|-2-hydroxy-3-oxo-propyl)-3-hydroxy- 2

-methyl-benzamide. y ke v, g nn y si em tn pah I pig og, st i IEE. g EE KU. in still Gedya-eya TK tk - EE. naci Do not let with. sf foam puree not: NI I in I V zlstit no in C 70 eye

TN NMR (DMSO-yv) 5 9.34 (b, 1H), 8.16 (a, 1H, 9-86), 7.29-6.49 (t, 8H), 5.88 (a, 1H , 4-61), 5.33 (4, 1H, 2-9.53, 5.10 (a, 1H, Yu-9.5), 4.56 (in rg, ЗН), 2.98-2 ,57 (t, 6H), 1.74 (in, ЗН), 1 55 (in, ЗН), 1.30 (in,

ZN); MO-VR (ЕР) t/2, calculated for С 27На2М2О5ЗЕз (MEN) 553.1984, found 553.1984; Calculated for C27Naz1MoOB5ZE5-0.5Н20: C, 58.59; H, 5.66; M, 5.06; 5, 5.79. Found: C, 58.96; H, 6.02; M, 5.58; 5, 5.33.

Example 03:

M-11-Benzyl-2-hydroxy-3-I4-(4-methoxy-butanoyl)-5-dimethyl-thiazolidin-3-yl|-3-oxo-propyl)-3-hydroxy-2-methyl-benzamide What "is like she. 0. In sh

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TN NMR (DMSO-yv) 5 9.34 (c, 1H), 8.18 (a, 1H, 9-82), 7.32-6.51 (t, 8H), 5.56 (a, 1H , -7.8), 5.26 (4, 1H, 2-9.5), 5.08 (y, YAN, 2-9.5), 4.45-4.38 (t, 2H), 4.36 (85, 71Н), 3.15 (in, ZN), 2.93-2.61 (t, 2Н), 1.87-1.00 (t, EN), 1.80 (z, ZN), 1.55 (in, ZN), 1.36 (in, ZN); MO-VR (ERE) t/". calculated for SovNa; MoO65 (МН) 529.2165, found 529.2372; Calculated for Со8На6М2Ов65.0.5Н20: С, 62.55; H, 6.94; M, 5.21; 5, 5.96. Found: C, at 62.89; N. 7,32; M, 5.96; 5, 5.59. co

Example 04: (k)-3-(25,35)-2-Hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl/|-5,5-dimethyl-thiazolidine -4-ka -- carboxylic acid allylamide I cha

White solid product: H NMR (DMSO-dv) 5 9.23 (v, 1H), 8.09 (t, 2H) 7.35- 7.17 (t, 5H) 6.60 (v, 1H), 15 6.37 (8, 1), 5.82-5.68 (t, 71H), 541 (rg 5, 1), 5, 20 (aa, tn, 0-1.6, 25 17.23, 5.11 (a, yin, Yu-9.2) 5.02 -1 (a94, yin, 0-1.5, 10.23 ), 5 00 (a, yin, 2-91), 4.46-4.37 (t, ZN), C 79 (ada, yin, y-5.3 5.5, 15.9), 3, 63 (aaa, 1H, 9-5.4, 5.3, 159), 82 (aa, YAN, 2-0.3, 13.93, 2.71 (9, YAN, 9Yu-10.7, 13 ,6), 2.16 (in, ZN), 1.76 (in, ZN), 1.51 - (in, ZN), 1.36 (in, ZN); MO-VR (ERE) t/» g, calculated for Со8НабМаО55 (М 4-Н)" 526.6670, found 526.2376; - Analysis calculated for СовНзБМз3О55.0.3Н»О: С, 63.32; Н, 6.76; M, 7, 91; Found: C, 63.35; H, 6.70; M, 7.71.

Combinatorial chemical approach to P2-inhibitors of HIV protease so General method

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The combinatorial constructed block 8 is obtained using the following method: Bos-protected thiazolidinecarboxylic acid 1 is treated with allyl bromide in the presence of Manso with, obtaining Bos-protected thiazolidine-allyl ester 2. Deprotection of Bos-protected allyl ester, 2, CARRIER (g) In EUAcS gives salt

NOI of thiazolidine allylic ester-amine, 3, which is treated with TEA and combined with 4 in the presence of NOVT and "ros, obtaining the precursor of the constructed block, 5. Deprotection of the constructed block, 5. 4H HCI gives phenol, 6. Loading of the constructed block, b , on activated balls of polystyrene cross-linked with trityl chloride, 7, was carried out in this way. Polystyrene cross-linked with TNT was activated to trityl chloride, 7, by treatment with 2095 acetyl chloride in anhydrous dichloromethane at room temperature. Trityl chloride beads were combined with phenol 6 in the presence of Hunig's base in anhydrous dichloromethane to give substrate-loaded polystyrene beads 8. Intermediates were purified by flash chromatography or preparative HPLC. their v. a yddya E SHE i ii - y sl zh shk zh. "IV y ka ih yasne" shii ay ke R dere nn sia Ben MNK id ny de en, MY MK

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The synthesis of the HIV protease combinatorial library was carried out as follows. The allyl ester was removed by treatment

Ra (RRIz). and MMM in anhydrous THF to give the carboxylate 9, which was treated with pentafluorophenol, pentafluorophenoltrifluoromethylacetate, and pyridine in DMF to give the pentafluoroester, 10. o

Pentafluoroester 10 was treated with various primary amines in a 96-well plate format to give amides 12. The final products were denatured from polystyrene by TEA to give products 13.

Each product was analyzed by LC-MS and HPLC. The following table shows the compounds synthesized by this . "- in a combinatorial way. in and - - . and? -i -i - (ee) (42) ime) 60 b5 resets

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F) Scheme 3: Solid-phase synthesis of HIV protease inhibitors (analogues of AC 1776) 60 65

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Solid-phase combinatorial synthesis of HIV-protease inhibitors was carried out using the IKOKI direct sorting technology. Commercially purchased 4-formyl-3-methoxyphenoxymethyl polystyrene resin Ia (PE-MV-SHO, Ardopatsi Tesppoiodiev) or 4-formyl-3,5-dimethoxyphenoxymethyl polystyrene resin o 3o Iv (RI-OMR resins, Royiteg I Arogyugies) were loaded into separate minicans (mipikapv). (uh)

Stage A. Reductive amination with amines P2'

DCM (Zml/Mipicap) was added to separate flasks containing distributed MipiCaps. Acceptable primary amine P (Zeq), sodium triacetoxyborohydride (Zeq), and acetic acid (Zeq) were added, and the mixture was placed under argon with periodic purging at room temperature for 1-2 hours and allowed to react overnight. For resin Ia, the filtrates were poured out and Mipikapz was washed with DCM, MeOnH (2x) DCM (2x), -

EBM/DXM (1:3.3x), DXM (2x), MeOnH (ZX), and DXM (4x). For resin IB, the washing sequence dDxHM, meon (2x), DXM (2x), EBM/DXM (1:3,3x), DXM (2x), DMF, 1M Masnu/udmFf (1:5, 3x), DMF was used (Zh), Meon (Zh) and

DCM (ЗХ). Mipicapse was dried in a vacuum and transferred to Step B. "du Step B. Peptide conjugation with amino acids P!" with

DMF (Zml/ Mipikap) was added to separate flasks containing distributed MipiCaps. Acceptable EMOS-protected amino acid (2.5 eq) and 1-hydroxy-7-azabenzotriazole (NOAT) (Zeq) were added and mixed until dissolved, and 1,3-diisopropylcarbodiimide (CI H) (Zeq) was added. The flasks were placed under argon and stirred at room temperature overnight. The filtrates were decanted and the MipiCaps were washed with DMF (3x), MeOHN (3x), DCM (2x) and DMF (2x). MipiKape was transferred directly to Stage C. - Stage C. Removal of EMOS protection

A container of MipiKaps in DMF and piperidine (2595) with a total reaction volume of Zml/MipiCaps was stirred under argon at room temperature for 45 minutes. The filtrate was removed, and the reaction was repeated. - Mipicapse was filtered and washed with DMF (3x), MeOHN (2x), DCM (ZX) and DMF, and transferred directly to

Stage 0. (ee) 50 Stage O. Peptide coupling with EMOS-ARM5

EMOS-Allophenylnorstatin (ARMZ) (Zeq) was added to a flask with MipiCap in DMF (Zml/MipiCap). After (42) . : . and NOAT (3.5 eq) and IS (3.1 eq) were added without dissolution. The mixture was placed under argon and stirred at room temperature overnight. The reaction mixture was filtered and MipiCaps was washed with DMF (3x), MeOH (3xX), DCM (3x), and DMF. EMOS deprotection was carried out as in Stage C, and MipiCaps was washed with DMF (3x), MeOH (2x), DCM (3x), dried in a vacuum and transferred to Stages E or RE.

GF) Step E. Peptide conjugation with Ро 7 acids In separate flasks containing distributed Mipikapz (Zml/Mipikap), acceptable P 25 acid (Zeq), NOVT hydrate (4 eq), and (3Z--(dimethylamino)propyl)ethylcarbodiimide were added hydrochloride (EVAS) (3.5 eq). The reaction mixture was stirred under argon at room temperature for 3 hours. After filtration, MipiCaps was washed with 60 DdMF (3x), MeOnN (3x), and DCM (3x), dried in vacuum, and transferred to Stage 0.

Stage R. Cleavage and processing of HIV analogs

Individual MipCaps were distributed on supports for cleavage and a solution of 2595 TPA in DCM (Zml/MipCap) was added.

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Scheme 3. Two-phase synthesis of HIV protease inhibitors

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Acknowledgment of the background: sli gi vs y Shcheney, AS g El, t. ime) Kto Pi: phen ii la 60 Solid-phase combinatorial synthesis of HIV-protease inhibitors was carried out using the IKOKI direct sorting technology. Commercially purchased 4-, formyl-3-methoxyphenoxymethylpolystyrene resin Ia (RZ-MV-SHO, Agdopatsi Tesppoiodiev) or 4-formyl-3,5-dimethoxyphenoxymethylpolystyrene resin Ir (RI-OMR resins, Roiiteg I arogayugiev) were loaded into separate Mipikapv.

Step A. Reductive Amination with Amines Pg" 65 DCM (Zml/ MipiCap) was added to separate flasks containing distributed MipiCaps. Acceptable primary amine ( ), sodium triacetoxyborohydride (beq), and acetic acid (Zeq) were added, and the mixtures were placed under with argon, stirring with periodic purging at room temperature for 1-2 hours and allowed to react overnight. For Resin Ia, the filtrates were decanted and Mipicapz was washed with DCM, MeOnH (2x). DCM (25),

EBM/DXM (1:3.3x), DXM (2x), MeOnH (ZX), and DXM (4x). For resin IB, the sequence of washing DCM, MeOnN (2X), DCM (2x), EVM/DXM (1:3,3x), DCM (2x), DMF, 1M Maon/DMF (1:5, 3x), DMF was used (Х), MeOH (Х), and

DXM (ZX), Mipikapz were dried in vacuum and transferred to Stage B.

Stage B. Peptide Conjugation with Amino Acids P!"

DMF (Zml/ Mipikap) was added to separate flasks containing distributed MipiCaps. Acceptable EMOS-protected amino acid (2.beq) and 1-hydroxy-7-azabenzotriazole (NOAT) (Zeq) were added and mixed until dissolved and/or 1,3-disopropylcarbodiimide (IS) (Zeq) was added. The flasks were placed under argon and stirred at room temperature overnight. The filtrates were decanted and the MipiCaps were washed with DMF (3x), MeOH (3x), DCM (2X), and DMF (2x). MipiCape was transferred directly to Stage C.

Stage C. Removal of EMOS protection

A container of MipiKcaps in DMF and piperidine (2595) with a total reaction volume of Zml/MipiCaps was stirred 7/5 under argon at room temperature for 45 minutes. The filtrate was removed and the reaction was repeated. MipiCaps was filtered and washed with DMF (3x), MeOH (2xX), DCM (3X), and DMF and transferred directly to Step Y.

Stage O. Peptide conjugation with EMOS-ARM5

EMOS-Allophenylnorstatin (ARM) (Zeq) was added to a flask with MipiCaps in DMF (Zml/MipiCap). After dissolution, NOAT (Z3, beq) and Bis (Z, beq) were added. The mixture was placed under argon and stirred at room temperature overnight. The reaction mixture was filtered and MipiCaps was washed with DMF (3x), MeOH (3x),

DCM (ЗХ) and DMF. Deprotection of EMOS was carried out as in Stage C, and MipiCaps were washed with DMF (3x), MON (2x),

DCM (ZX), dried in vacuum and transferred to Stages E or RK.

Stage E. Peptide Combination with Po acids

In separate flasks containing distributed MipiKape DMF (Zml/MipiKcap) was added an acceptable acid P » (Zeq) scho ov hydrate NOVT (4eq) and (3--dimethylamino)propyl)-ethylcarbodinium hydrochloride (EBAS) (3.5eq). The reaction mixture was stirred under argon at room temperature for 3 hours. After filtering, MipiCaps was washed and)

DdMF (Zx), MeOnN (ZX), and DCM (ZX) were dried under vacuum and transferred to Stage 0.

Stage R. Cleavage and processing of HIV analogs

Individual Mipicaps were distributed on supports for cleavage and a solution of 2595 TEA in DCM (Zml/MipiCap) was added. o z0 The supports were stirred for 1.5 hours. Individual DCM filtrates and washings were collected, concentrated, and purified by HPLC to yield the final compounds. co

Table C "- cha i - shi s ;" -And -And - at 50 (42)

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Nixon and Cohen

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FOR PI JACK I and -

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Ken J

Biological evaluation

Cells and Viruses

T cell lines, SEM-55 and MT-2, and HIV-1 KE and HIV-1 MI 4-3 (rMI 4-3) viruses were obtained from the National

Institute of Health (AIYUO5 Kezeagsp ap Keiegepse Keadepi Rgodgat, Ve(Pezda, MO). HIV-1 MI 4-(154M/ ZOM) CAME FROM a clinical isolate that showed resistance to the protease inhibitor associated with I8a4M and I 90M substitutions, cloning fragment amplified by reverse transcriptase-polymerase chain reaction into unique cleavage sites of Ade | and re I pMIi 4-3.

Assays of inhibition of cytopathic action (CPE)

The ability of compounds to protect cells against HIV infection was measured by the method of reducing the dye MTT, 70, which is essentially described | Dyvys Rashmzhmeiv, K. VaiYigagti, U. Vara, M. Zpoesk, K. Zspoev, O.Yu. Negdemi|p, R. Oeztu(eg,

U. and JuOe Siegsd. E. 1988, "Kariy apa ashotaiyieai (eigagopyt-razei soiopteips azzau yog She deyesiop oi apii-NIM sotrotspav" 9 MigoY. Meiyoadz, 20: 309-321 and MUeviomU, 0.5. Kiveg, K. Ripe, O.Y. Vadeg, U. Zpoetakeg

K.N. and Voui, M.K. 1989. "Mem zvoISHBie-toghtalap azzau og NIM-1 suyuraiiis ePesiv: arriisayop (o pidn-Nikh zsgeepipd oi vupipeis apa paishga! rgodisiv yTog A!Yu5-apiimigai asimyu" 9. May. Sapseg Ipvi 81:577-586). 75 Cells were infected with the test virus at 0.025-0.819 or only medium was added | 2x107 cells per cell were added to 96-well plates containing half-log dilutions of the test compounds. After 6 days, 5Omkl

CTT (mg/ml CTT-tetrazolium, 0.02 nM phenazine methosulfate) was added to the cells and the plate was again incubated for 4 hours. Viability was determined by the amount of produced CTT formazan, which was determined spectrophotometrically by absorption at 45 Ohm. Data from CPE analyzes were expressed as 956 formazan. produced in compound-treated cells compared to formazan produced in cells with uninfected, compound-free cells. The effective 5095 concentration (EC0) was calculated as the concentration of compound causing an increase in the percentage of formazan production in infected, compound-treated cells by 5095 over that produced by uninfected, compound-free cells. The cytotoxic 5095 concentration (CC) was calculated as the concentration of compound that reduced the percentage of formazan produced by uninfected, compound-treated cells by 5095 of that produced by uninfected, compound-free cells. The therapeutic index was calculated by dividing the cytotoxicity (CCeo) by the antiviral activity (i9) (ECbo).

Sensitivity analyses

The compounds were tested in phenotypic sensitivity assays in Migoiodis, Ips., See Reihorotsios C 3. Ragkip "3

M.T., Mtoii K.S. Se M.5., MUpp T., Nyapod MU., Tiap N., Ztiy O., MMipviom S.A., Sarop 0, MUpysotr OM. 2000 "A pome!

SpetoiNeg 44(4):920-928), or using the assay described here. MT-2 cells were infected with HIV-1 MI4-3 or -/- ee

HIV-1 MI 4A-3(IV4AM/ 90OM) and incubated in the presence of serial semi-logarithmic dilutions of the test compounds. By

From day one, culture supernatants were collected and virus production, which was determined using p24 EP I5A, was analyzed. Percent inhibition was calculated as the concentration of p24 in compound-treated samples, which were compared with an infected, compound-free control. Inhibition of viral replication is determined by measuring the reduction of HIV p24 present in the culture supernatant, using the Vesktap-SoshNeg p24 HIV-1 Ad EIA kit and according to the attached protocol. Absorbance is read on a MEH microplate reader (Oupech

Thespoiodiesis) EC was calculated as the concentration of a compound causing a change in p24 production by infected compound-treated cells by 5095 of that produced by infected, compound-free cells. HIV-1 Protease KET Assay K values for HIV-1 protease inhibitors were determined using a resonance energy transfer (RET) assay. A mutant form of this enzyme (075) is used for this assay because it is more stable against auto -proteolysis than the native protein. This enzyme is first partially purified as -I inclusion bodies from the cell lysate. It is then solubilized in 8M urea and passed through an O-Zerpagose - (Rpagtasia) column for further purification. To fold this protein, samples containing 275 dialyzed in 5 mM sodium phosphate with pH 7.0, 5 mM Mass, 10 mM OT, and 1095 glycerol.- Commercially available peptide substrate (MoiiIesshag Rgorez Sai. MonH-2930) 5o RE(EOAM5Z)5OMURIMOK(BAVSTHI)K is used to analyze the activity and K. This peptide is quantitatively cleaved by HIV-1 Rg through the Tug-Rgo bond. The fluorophore ESAM5 absorbs at 34 Ohm and emits at 49 Ohm. o The reaction is carried out in a 96-cell plate in a total volume of 100 μl for 12 minutes at 37 C in strictly constant conditions with 5 µM substrate and 2 µM concentration of active enzyme dimer. The literature values of Kt for this substrate and enzyme are 103 -8 µM. 0.1 M sodium acetate pH 4.8, 1 M Mass, mM EOTA, 5 mM dithiothreitol, 1090 dimethyl sulfoxide, and 1 mg/ml bovine serum albumin. Inhibition curves were fitted using the Morrison compact binding equation.

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You were born in EK ts and sk ni Nelya Nancy ped i s she i i - V g ss: ШЭ Va i ! і її -Е s Ne t ї s ІІ і kN io shcha і | and / And with "B ; І ИЗ h

Жези З я р: ле и Кв и ше 0 В БЕ о Ж шчи se І з t s PD и ne еV "ЙЙ. sisters without: zezyo oyani I spe ZE " The following compounds were obtained by the methods described here, they showed the indicated activity: p

Although the invention is described in terms of preferred embodiments and specific examples, it will be understood by those skilled in the art that various changes and modifications can be made experimentally without departing from the scope of the invention. Therefore, the invention should -1 be understood as not limited by the above detailed description, but as defined by the appended claims and their equivalents. - and - th

Claims (1)

Formula of the invention (ee) 1. A compound having the formula (42): ntiv i V ' her still Ei 5B a moi tot ih i i tyap hi El, von Ya g in. ko dva yah i She ya en: PNKknen sv: MAYA Yenyath zey EY kan Mu deno yi OB i yah zh x KR v bo ila i sh--O 7. tota that I'm in something that give me you I I I Bey and. pi 65 ! ! ! ! but which includes all possible stereoisomers and in which: B is phenyl, and said phenyl is substituted with one or more substituents independently selected from alkyl, halogen, or hydroxyl; IN? means a Co-Cb alkenyl group or a Co-Ce alkynyl group, wherein said alkenyl or alkynyl group is a linear or branched group, and wherein said alkenyl or alkynyl group is unsubstituted or substituted by one or more halogen substituents; B2 means H; X also means dog dr pre I; with 3! ek also pt where ЭХ means H; 7 means 5, 30 or 50"; З, в, 85, 8 each ate independently, mean H; and Her 7, each independently, mean methyl; or a prodrug thereof, a pharmaceutically acceptable salt or solvate thereof. 2. Compound, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate according to claim 1, having the formula: formula | pk sch z» what else is behind MU and vya Go) ha RASI o ta: and Ba gave SCHE V ovoshi. Z she o ide A Le Ya still Men Pn ya In she Ei so B Se her Me yn i sot Vay t: o yah zh t KD ih y sk-e - still ee M y. pi 3. Compound, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate according to claim 1, which has the formula: "g shEfon y NE". 2 of them. sa i with her and ha RASI about them;" y IF I would give "In words -I zh still Zhe ee s i Still nannia to her I zh zh zh: zh t ho zh -I Kl E pen ih t hya saden Sen, -y koe sl 5 ZD YOU O Zh, o VK Zktyaet EE alu o shk 4. Compound, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate according to claim 1, having the formula: име) 60 b5 ; rya i sha y y ih zYa te g still de y y za she 2 o -E tk I I Vroklp: s o hu Se her Mu ee I dah I ho de vezh J TE Todldnya peynkh TE k i V i - I Mt: Dychko ee ZNU RO i t tone EE pd, Mep atgy 5. The compound according to claim 1, in which KE? means Co-Ce alkenyl group. 6. The compound according to claim 1, in which K? means Co-Cv alkynyl group. 7. A compound selected from: i -E. and cha ZHE ke ve. sho ich still: rem sv YAN zh she o ShTE: 1 as: su 0 sh I and l: koe sch Y I Still Y i shi o EE 3 EK se se JHE tyk ZHK she ZE Vtrkennnn Mr SHAMYKHYNinksh zhu y NE Byk obje z Shy Yaryane; at; still CHE» nii s tat and i schi And. I don't know what I know; BALI te Kk y Kista EY six y, sah z Y , ch- o: NEO SHY ena, Zo Ek s SHE che "Zhe KZ Yan yau s: Her sho sshdan pe I . ; SU CHE sk ns Y Ba SOYA Y gru I and d -i -o Bo ah SE 00 DEIEENE THEY, OTIT r NE nya Z sk kt REVE shi : became them EN in what. oven dae z 4 sne saYe and wa some shi h s s s MI koh ». . Zh sha oi Sena pl V YA E -I y re ZV ' pl selu - I і-E вх жа яе шк і і і ko zhe skor (ee) shaduniya OV t zak z g Es scheche shu "2 Be "rak Sat MAfreesoyukoya A I sko ee Mo Z yin zh dae n vho ee che seh PC srazhtinkykh pat end Knrt Sen ks dyakhya Y 5 nn - o sen eh i J y den mia o rya sya h ley ey - sh- in poh yin I 60 b5 patsa s .. Z den, yi Yake SHE salo I Tl ko dony kyi yi se A I JI Y I ' t y vk : s ze ikh yi CHE de x - : u she ia BE so Sl em KA to zi x | se ni ES VI and PKLKy pl de 53 i ; I sh day; towers Mokh EE AK Y vk y Ya r ya ! how ; I and KE, I sya s Here's what and Battle I tn M saju 7. oka z ee skyan vyd zuzuh CE-t5 Y pe t ih a TE. in. - ny Still entourage or K-T en lak sr day r. ka Ta aKu Te S her 4 B tk ah svi i Es. 5 VIEW i Still and shshsh lashny in zor so i E i ss: V: But EKINYAnnv VK, sh Kern, za o B Te menya pk so BI vk 5 SY I and I ren S Kk SHY o mashe Bi in yam Ya ery Even if you didn't know that. te firdunsya, Sh rey to ' ost neti i o st se. with the village ak ie v r. a g dnya nya - Jacques kavy sh vt rani s soda shii lasyy Zhi I Her. oh how TK zh ah tep, she m SE her he her KNU and I) Ksenia o let yours: SE s Ге жк lovy eЯ zi Zhe" ee Eh -- і s і і. She has rya r nksya I ше кр хоку к by her, KE call V sia " "in Ser I row KAT PA y. with. ; ryu I shZ end I Reya kn. y -I shi sere - I ha chani vo Ya Nana. with how! - va TYNY pev yar srn-- pe mk sti y. what I said about her. y izh ta ME y o Y EV with pairs Zhs y Y IY td, I genes pe Be. SHE: . same in. tser) and YOU! he ram F) Zhe oeyte bulls and : y Ben dae Kv nanya ven y g km ty B tan ele tod shchi sore tya te SN kozhe Z tet Pe ev pet v : "sh bo shcha So her sei zhk vda: bah y : Be eV chi v y b5 he deya shere y, pe Kn and stzhene sg Ne oti i. All the same, that is, I am confused today. ore char Mt ne z ey - Ege TE i de x znane y I pnia zo be (y in oshch y Yaku p. y DEC Z ssh Ky ge sce Yakszeya Brysteya ks so sN dk Ko. sht ia i. 5 sch nie y E KE kak pe Te! ) tin ny ze "- prdnychi er TI yi- i - NA ssya v se ha I still and no s se sya 50 still oi sii at don dy I dey ch snah - U Tk ny i z E IY Sho keshtv m xx de ih t s nt rot so in KN te p kh r: tcho x Kosha zr|І І Ko Mi Semen 0 porzhnaya Alya a rez ZD cho r Sh- V y vky Tk KI KEN vyav Yasya zhk Be ; se 4 Y Ann ZHE be mm still (ee) sideya TEH I ; o Ko -oah t vE- Ya rea I she Shah v o esh : y OV y shcha y sh y yy ben VN 60 stati Y xx Y Z I her s Ne paz: gai 15. si v shk he sta PEIKO same: hells Yeniso reko oh LE I day M s YAN uh NY ky Eh Their pre pera I; zah EN: HM kA HLEMUyat ge firs, yiv rsanu I Ya ke Btya "ya 3 ee an KN Posoeolstt pAtLyaUNy a cha pen lyukSU YUL t U U vm u sh b5 still shcha she Kai didke re, shchih nya and t i still. ze is i VE i I . i still -- she and their shcha her I in t. nya palanya KE i I "Sk: what with ma Shchi KU Sho her Not yet - given nine s i Z ke EE de zim I; bad inve she ke, z ZNA Be: od and ZU still H. Eh ta she and Bery s s ty KA stv ny EKYADENETTTY "hvy Shi sa zero ro 2: M Mb two SONS et I that OO be Mem UK s: Y Hz i in; reiv dallak M zh: , For le and their regions; in z Kesh p s i o i I sign y ha i... ok more yy Z y ich . mir svya y gy: I shchi sya s. Zv rot PE, ze CE and Bi ANe /: skh i zhd o u S u, ZHANNY beri porodev la z Ka red pe pkt Te ih M SA, Z CHE v u izhe I yi y yi shi zh she. What is it? " B ; ZE Ya ras, s Her: tu kat, essay of the day Keyalnoh : NI zhh Kt 2 i a kole oi eh shari -y den claim 2 mya dych plen , ee KE I zh genu poet Y ; V t gr 5 v ryn CHI x le sen is still to her as a poor person; me: And M in some se:. towers of the year Se ee tk -. don; BeeaENiya and tey gr Kos yau lek Sh-m go Pen; - и, ках и ла petaeni 2 Sonia de pan y Ve vs sska I sya still che I I with s shk YEAR 5 more to her ' and E im 7 lie "IN ZHE7y y E g S (F) eh I her I OV. Ponitene foot soldiers 0 ZBEOAYA r lesi SCHE; shi ke ET so sort yah CHE Eey what de yah kegel j pon giya i: : i yah NK ZHAVI Z Z this ash tree sa same 60 tower rschi VN VEK SHK pkt jako an iya ? SEN b5 in 1 p Ks KO s and also I ve: J 5. NI tA vuh yii: o shk: zm U Esh that ar. ne y g scheche E I vs KENE "Ж g M z Ek I I "I ško I So pl VE stand chel ee huya DEC E Pora zhár What KO be and I s-zoY dah AB still I No. h. KB "SHE I sshcky pasan: well I Me ar le ZE UK still ros-teD povnskerv I in koi Yak, the weaver of wounds is and x Hey She" Maya - Ta GU Ah. Schi Yi siy t ia I se: 5 more SHY Bl To SIK S t g: ZD tk, she - ! GK o onyn Zhit ks sia zh KN IN s, yi Kae y Be IC Te SK vi gi re sia : pi re | noi MEZH ZHY shenu shi nineeyunh uky SHK I s Ko Beka o iya ko z I en t 29 Btetya her --8 NAseek Mn ey biky J J vir BV DN len: rah rah a ay Ek za ah se alu I he "v) same I shki vk m Ku, |. Re B: SCHE m. sub; sv GOD ke sne zi: y ih taya zhi Iz te i re I che RE V 5 Be Myh zhk « sly s zh Zah y: And B her i kw Z POEM zneik umbilical cords removed n s Bezh Dos Aksi tsa |kt a o rela KU and. How, where are they: . and there is" that BA och: MNK in nai AN K t KEN: M tsyu sh ve rn j Her z. I am B de -I its 7 or its prodrugs, a pharmaceutically acceptable salt or solvate. - 8. The compound of the formula: r (ee) t also: How; re still kon she Ya ana. y ka mne IA oi (3 From the Son and ge I: Z Za SN kn, ZYM: y pory I vek Kk 33 Э Mo y ШЙ she zhen ser u nene emnlaenya: in S. Kz ok znsekete oi R. She still - pyt I ZE SCHI: Be I ME aga 50 | pe i I I ze i pn NYA gfoshzh taI on, zeni di sia I veka KL NNYA Ki x I or its pharmaceutically acceptable salt or solvate. 65 9. Compound of the formula: pe SE Em she still BE soy s ka de schy Shock s zna ikh zak S. | ShK. I'll tell you how to pass, I'm going to cross the currents from V T E Te i re Tsi re EE i She era of the same day. with the last as st KIN gne a KNEE an ven OO. shi dela rye Ba Me or a pharmaceutically acceptable salt or solvate thereof. 10. The compound of the formula: id: ny o TYPES of them Ben :anYy shE denenyut s g. Vu. Же рай и зотт I s яй zvani v SYA - S Ж гы я 0 жо Pra kw toy dey t Kaya Yar Ne a ay ze uyy nina sah i Z y s sch proEyu. I : d -eikh ЖХ зежтеш зденные щу: бовіже я а о SPЕ РІ жїВ "Kr sishchee ЖЕ ve me Ж Zoesvnh saden Y lenny sir: s i EV sy td schey sny oon ytnkrh N Zo so or its pharmaceutically acceptable salt or solvate. 11. The compound of the formula: -- cuts reatannyh kore o; ul Veh t m KO on - ke vij peki BE - ben ti km skh di she « te y a yi, U Hek tet sn. ik she - She o : B E Zhe so Me EE shchi s Eh b B.Yu io MEN I TSI I | I am and . and o and Y si and ZHE ХакЯ 3 я реня ШК их шеююе оте вия Mndymy вкс Борти still sh ve tety. sho r TI same "o t She I and in still ZAY - ; о ох х - or a pharmaceutically acceptable salt or solvate thereof. 12. The compound of the formula: Hn sia (ee) a y EE o tetshe 05 1 y i kh pakh s s rezh a t TA dazhnya still new zanm ia el miy tel ila YA TAZ. with se ime) and Bi be shi . E that zhh NV Ann drank M. in zychu and NN NN y ve ke BE : E s ke I zh y: I SN iz shcha NE Osn ek z veni BE y Z No, 65 or its pharmaceutically acceptable salt or solvate. 13. The compound of the formula: ke swi still schi in soksei i and that e i aa i ne "Hn y ser vh "i i DN Uk 70 : SHY. Z yiv Zhov S g I them and . Зв Е Пн В: и хв И poх ТЕЖ сай Шы tan shmeitke szhntnetnoynttni zkneteukyu v sya s m K teo ve Tse vah "v Shchy do i Zk But JHE s i tla roya siv y Na: ve Eh vd: 7 r te ste Besp ud ee Y Yandny se y kota M ih rani pry or a pharmaceutically acceptable salt or solvate thereof. 14. Compound of the formula: eV YAN ryn - skh Kun tan ze si sya, pek ke Od o A be tk Vts SYA sho chevryamikh zt Kv sk b. - VD o Me I dya To seienna zome 1 t lya te s dec isnu en y Y y sne Y ER (ee) for ay gts i zna eh ring p chen, KE se ak Still you t En Y de kak vane Y y E S. - Sh i shi shi rr sa Ky BE Zyae ya ve y - Vity yah rya kr or its pharmaceutically acceptable salt or solvate. 15. The compound of the formula: M sna "I in m: Such a lu zu s y s t. E. rve; ch nei nki Banya shvi. - Z where B; | Ku p - I and E Щ s - I ХЧ, payte MeYEDUTVY MNVK oj se Armor; Porerkayaetaney and "Er podsta EE ZHE a DUM is Tvoya sah IN sEratty syak y y spol ny it Z i : in V B io 5 I eta ry E " ze s - ZHE K, sany tlia z Y sia y as x i Z dk e n y Can be used with petri Ž še ee MUKY B Eh Y o che or its pharmaceutically acceptable salt or solvate. 16. Compound according to claim 4, in which 7 means 5. 0. и и и 0. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated F) microcircuits", 2006, M 11, 15.11.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 60 b5