UA80250C2 - Inhibitors of cruzipain and other cysteine proteases - Google Patents

Abstract

Compounds of general formula (I) or general formula (II) wherein R1, P1, P2, Q, Y, (X)o, (W)n, (V)m, Z and U are as defined in the specification, are inhibitors of cruzipain and other cysteine protease inhibitors and are useful as therapeutic agents, for example in Chagas' disease, or for validatingtherapeutic target compounds. (I) (II)

Description

M(Co-7-alkyl)2, M(C3-6-cycloalkyl)" or M(Ag-Co-7-He)1 alkyl)";

M - СВИ2ВИЗ-СО, where B!2, VIZ is selected from Со-- Ры Ры в У alkyl, C3-cycloalkyl or Ag-Co-7-alkyl; i | TV in | That in the group (X)o X x SE"B, where B!" and B? M. ro E r. is chosen independently from Co-alkyl, C3-e-cycloalkyl and Ag-Co-7-y, ; alkyl, and o is a number from zero to three; in the group (M/n MM - 0, 5, С(О), 5(0) or 5(0)2 or both

MA!5, where B'E is selected from Co-alkyl, C3-6-M o cycloalkyl and Ag-Co-7-alkyl, and n is zero or two with E 2-4 in the group (Mt M - C( О), С(8), 5(0), (0) в(О»МН where В" is:

ОСС), Mne), MO), Neo)», ОС(OMN, Sol-alkyl, Cse-cycloalkyl, Ag-Co-chalkyl, O-Co--

С(О)МН or СВ», where В" and В' are independently chosen- 0 aLKL. О Cze-cycloalkyl O-AgSoalkyl, 5-Sot- are used from Co--alkyl, C3-e-cycloalkyl, Ag-Co- - alkyl, C-Cze-cycloalkyl, C-AgSoalkyl, MH Co: alkyl, and t is a number from zero to three, for alkyl, MH-Cze-cycloalkyl, MH-AgCo--alkyl, M(Co- conditions, that when t is greater than one, (M)t contains alkyl)", H(C3-cycloalkyl)" or M(Ag Co -alkyl)"; at most one carbonyl or sulfonyl group - or, as part of a CH" or CE group, EC " can be a halogen;

C is a stable 5-7-membered monocyclic or 8-11- membered bicyclic ring selected from: sna, CH, o, and MA; where K" is as defined above; and K- is chosen by stitches 3: Co-alkyl, C3-e-cycloalkyl, and Ar-Co-7-alkyl; vya 5 V A B, Or and C independently choose from:

Ak | р с СВ", where В!: is as defined above, M or M- h - oxide (M--0О); E is chosen from: " у " СННе, СНБА"У, О, 5 and МЕ2О, where В": and 229 are as defined above; // Х Ю У, С, М, В, Т, Т", Тз and Та are independently chosen from: o. M Mod СВ!З и M or M-oxide (M--0O), where B"? is such that , ; defined above;

T5 is chosen from: ry) ry with CH or mm; m ah r x 4 is a number from one to three, determine

M r d M r - Learning in this way a 5-, 6- or 7-membered ring. "dv E "d E and all its salts, hydrates, solvates, complexes and prodrugs. " ! 2. Compound according to item 1, where independently or in combination:

In part B o) and (a) 7 represents 0; r t | r yo Her (5) Ri and R" represent SN"; and

E zd dy, (c) O represents CH" or MH; , , (9) In! is Co-7-alkyl or Ag-Co-alkyl; in У (is) М is SE!2ВЗ-СО, where 2, В" is eliminated

B and C are selected from Co-7-alkyl, C3-6-cycloalkyl or Ag-Co-7- and TI x M alkyl; o, schi ME ()) in the group (X)o X represents SE""B?, where each of

E in A and B! chosen from Co-alkyl or Ag-Co-- ! ! alkyl; and (9) in the group (M/)n UM represents O, 5, 50» 50, C(O) p - p ZT or ME!E, where E!Z represents Co--alkyl, and n doriv-

It is | | IZ is 0 or 1;

M, and"? M. 1" (n) in the group (M)t M is C(0), C(O)MH or

А , А Ц , СНВ"У, where ВZ is Co-4-alkyl, and t is 0 or 1; in that r to () О is a 5- or 6b-membered saturated or // M CI unsaturated heterocycle or saturated or unsaturated. | Mod | saturated 9-10 membered heterocycle selected from

E 7 and the structures listed in point 1. " o " 3. The compound according to paragraphs 1 or 2, where B! is H, C-

Z is 4"-alkyl or Ag-Ci-"-alkyl. tr ry ra 4. A compound according to any of paragraphs 1-3, where (Х)о-Ж knock out 5 Е and Те from one of the following fragments:

Em

E a a , 5 5 o. at,

(Fin! where BZ, B2O and Ag are as defined in clause 1. 5. A compound according to any of clauses 1-4, where U is SNREZSO, where B!Z is Ag-SNe -, where the aromatic ring is a phenyl or monocyclic heterocycle, optionally substituted groups are B", where B" is as defined in point 1; or , , B !Z is cyclohexylmethyl. 6. The compound according to any of clauses 1-5, where (X)o-Z is selected from the following groups:

With o with o with "AH o with c) with

G VI s N de t c) (c) o, 5

MAgovgo yah 005

C 1-3 o (6) ra ra ! ! (Ho | (Ho o z o z soOvgo SOoMAgodgo

Г 1-3 ГГ 1-3 (Хо | (0, ра в) в) (Хо | (Хо | ' ' o z o z dya 5 o

C 1-3 C 13 iv; ; where VZ and Ag are as defined in clause 1. (хо | 006 | 7. The compound according to any of clauses 1-6, where (ММ)н-(Х)в-У о о is one of the following fragments: to ! "ХХ

A (muru (mu U

GP I on o Z i p S (x 53 (M/up U (Mu U she o on

Ag (mu (in u

Pe o sp, ve (ho | (Mp U (UM up U iv) z

MAgodgo Soovgo reshcha h y iz m theo u v i (ud (Mu U 9 19 tp-i po -1

A mo M - 8 m - SN, U - SN(SNU)

SUMMAGOGO t ti -1

G 1-3 SG z (my Sm (mupo TU o 9 z z |B) 5O, ra ra vya u (X)5 p

To the Czech Republic

M - 50, p-b

У - СН(СН»СН») У - СО) c) c) "t -1 t -1 dv ! (Мп У | (Мп У | o ry Hv de В!" and 220 are as defined earlier. (5) Н 8. A compound according to any of clauses 1-7, where in the group (Х)о Х D bo represents SV/ЯВ!5, D!" represents hydrogen, B/5 u bal" СО 20 is C-1-alkyl, and o-: 0 or 1. n 1 '9. The compound according to any of items 1-8, where in the group (Mn: l-1 M- MAV

MU is О, 5, 50", С(О) or МН; and n is equal to 0 or 1. М - (0) М С(О) 10. A compound according to any of clauses. 1-9, where the group (M/p t t 1 represents МН. о 11. The compound according to any of paragraphs 1-10, where the compound Y

SHO-(M)t-(UM)p-(X)0-M or О-(M)t-(UM)a-(X)yu is one of the following fragments in battle: (c) H 6) ra PO y (Xo (Yu6- (X) p-1 t Sh mu - MAE c - 1 die- H lo 0 M - IF) M - CO) t -0 tey t 1 12. A compound for any - which of the items 1-11, where the connection

O-(M)t-(UM)p-(X)o-X is one of the following fragments:

So 5 dv Od what (mu-o (mu-o 000 Mu-V De (Mi, - chn

We - (OU - snu -"sNi p: M), - (0 "here (We - (OO) (Ma- SN, (Mi - SN M -sni M y ) (M - СО)

13. A compound according to any of paragraphs 1-12, where y includes the appearance or development of a disease state, which is one of the following fragments: includes: (a) evaluation of the binding properties of the compound described in 7 of the "Sono" in any of paragraphs. 1-16 with isolated known she 'm' 5 or putative cysteine protease by

measuring the activity and, optionally, one or more of the following steps: (b) evaluating the binding of the compound described in (b) to any of .1-16 with a closely related homologous target protease and common proteases

Kk of the digestive tract (for example, by trypsin), by

CO ee «co g measurement of selectivity; o " 5 ; and (c) determining the activity of a specific cysteine protease using a functional cellular epi, v, er (cell-based) marker in the presence of a compound described in any of items 1-16; where !" is as defined in clause 1. (4) determination of the activity of a specific cysteine pro- 14. A compound according to any of clauses. 1-13, where О represents theses with the help of a functional marker on a group: based on an animal model in the presence of a compound not described in any of paragraphs. 1-16. wai ui chich I in M re DI 18. The compound of the general formula (I) or (Iii) for any of the following: Om o sho yakim from pp. 1-16 or its pharmaceutically or veterinarily acceptable salt as an active agent in the method 6 in-9 in the determination of the effect of the biochemical function of a known or known cysteine protease on the appearance or

ModeT reduces the development of the disease state. 19. The compound of the general formula (I) or (II) according to any and which of paragraphs 1-16 or its pharmaceutical or veterinary. : o rya 0- Fe vh i narnally acceptable salt for use in medicine

Iii iii z Ci r d My E tedy M NO. b Modyai pn a ' | 20. The compound of the general formula (I) or (Ii) for any- you as I what With pp. 1-6 or its pharmaceutical or veterinary powder and its tonally acceptable salt for use in the profession of CATS Mevyav, lactation or the treatment of infections caused by I Rpesthosuvii saiipia, Gurzapota sgygi, Turzapota de k", 0O,E, but G, M, K, T, Te, Tz Y Ta are such as rgisei, U" iarpuyusosste acgetsv, Goivptapia tv Sponm In p. b 1-14 in tehisapa, Siovilait Pisiouiysit, foot-and-mouth virus, a group : according to any of paragraphs 171, where o represents Stilidia bivisciaia; osteoporosis, autoimmune diseases, schistosomiasis, malaria, metastases, etc. and from tumors, the target of chromatic leukodystrophy, and in the elbow veins of muscular dystrophy or atrophy of muscle tissue. пн н у ей ше 21. The compound of the general formula (I) or (II) for any

And in-is / which With pp. 1-16 or its pharmaceutical or veterinary

I t gu gur: a, normally acceptable salt for use in treatment

IA zu sha and Ii vk sha of an autoimmune disease. бужяу я Aж, 22. The compound of the general formula (I) or (II) according to any of paragraphs 1-16 or its pharmaceutical or veterinary acceptable salt for use in the treatment of osteoporosis. AND

Мне" и, и 23. The compound of the general formula (I) or (II) according to any of items 1-16 or its pharmaceutical or veteride KU, O, E, o, U, I, M, K and T are as defined narly acceptable salt for use in the pro- 1, lactation or treatment of Chagas disease. ) or (II) for any group: which of items 1-16 or its pharmaceutically or veterially acceptable salt as an active medicinal ingredient

Y po onov, the Russian remedy for the treatment of infections caused by ms (A A ey A, s Rpeshitosuviiv saiipii, Turzapota sgilgi, Tgurzapota s-9 | rgisei, Zarpuiosossiv atsygetsv, I eivptapia shcha yiU-a - pe scho tehisapa, Siovigidisht Ppivioiuysit, foot-and-mouth disease, with the disease Spipidia tizisshatsa; osteoporosis, autoimmune disease, schistosomiasis, malaria, metastases, where VU, O, E, o, "5 and I. are such as tumors, the target of chromatic leukodystrophy, 17. The method of determining the effect of the biochemical function of a compound of the general formula (about or tissue, known or suspected cysteine protease on the I U p. rm in any of paragraphs 1-16 or its pharmaceutical or veteri-

orally acceptable salt as the active principle of a medicinal product for the prevention or treatment of a medicinal product for the treatment of autoimmune Chagas disease. roaring 28. Pharmaceutical or veterinary composition, 26. A compound of the general formula (I) or (II) for any containing one or more compounds common to which of items 1-16 or its pharmaceutical or veterinary formula (I) or (II), specified in any of paragraphs 1- a narally acceptable salt as an active principle of drugs 16, or their pharmaceutical or veterinary preparations for the treatment of osteoporosis. distinct salts and pharmaceutical or veterinary 27. A compound of the general formula (I) or (II) in any acceptable carrier. which of the paragraphs 1-16 or its pharmaceutical or veterinary 29. The method of obtaining a pharmaceutical or veterinary acceptable salt as an active principle of a medicinal composition according to item 28, which includes mixing the active compound (compounds) with a carrier.

This invention relates to compounds that are a means for chemotherapeutic treatment with protease inhibitors of cruzipain, a gene product of Tturapozota sgy?i. parasite Tturapozota sgygi. In particular, the invention relates to Classically, the identification of enzymes for which compounds that can be used have been found to be responsible for the therapeutic treatment of an infection or the spread of an infectious disease,

Tgturapozota sgili, before the use of these compounds, was an effective tool for the development of pharmaceutical compositions that include them. successful drugs, such as antivirals

In addition, the present invention relates to compounds, drugs (for example, HIV aspartyl inhibitors, which are inhibitors of a wide range of cysteine proteases, theases) and antibacterial agents (for example, for the use of these compounds and pharmaceutical lactam antibiotics). When searching for similar compositions that include them. Such compounds of the Achilles heel in parasitic infections could be used for therapeutic treatment - many enzymes have been studied (for example, parasitism of diseases in which cytic dihydrofolate reductase is involved in the development, see Spomapigu stein proteases. 5. E. viai., U. Med. Spec., 42(21), 4300-4312, 1999;

The trypanosome family of parasites affects trypanothione reductase, see 7. ei ai., human and animal health throughout the world (MeKetgtomu, Visogd. Med. Spet. Gay, 11(2), 251-254, 2001; pa-

U.N., eig a, App. Chem. Misgobio!. 47, 821-853, 19931. rhizic glyceraldehyde-3-phosphate dehydrogenase,

One of the parasites of this family, Turapozota see Agapom A. M. ei ai., U. Med. Spet., 41(24), sgygi, is the cause of Chagas disease, affecting 4790-4799,1998). In a particularly promising region, research has established the role of cysteine proca- more than twenty million people annually in Latin and South America, is the leading cause of certase encoded by the parasite, which play a central role in diseases in these regions and leads to during the life cycle of the parasite more than 45,000 deaths annually (data from the website of IMeKeitom, .). N., ei ai., Vioogu. Honey. Spet., 7, 639 of the Center for Disease Control and Prevention 644, 1999|. Proteases form an important group (Oiizease Sopigoi and rhemepiyop). In addition, from the increase of biological molecules, which to date constitute the migration of the infected population from rural approximately 295 all gene products, identified areas to cities and movement from South and Valuable in the course of several programs to establish post-literal America to North America, the infection of the length of the genome And, for example, see Zotsiapap S... is spread through blood transfusions and during childbirth. 5si, 6, 453-458, 2000). It was found that Jenny. The predominant proteases currently used are involved in a wide range of biological drugs for the treatment of infection. , a huge number of proteins found in nature.

Tygep5, UR, ei aiI., Moi Viospet Ragazyo!., 82 (1), Such a hydrolytic action is carried out with the help of 125-9, 1996) is at best moderately initial recognition, then binding, reaching 6095 treatment for acute rheumatic fever, with three-dimensional (spatial) electron phase of infection (see Juosatro, EK. Sy. RPpagt. them surfaces that are present in proteins that sum-

Oezidp, 7, 1157-1164, 2001 for general reports a bond that is cleaved, exactly from rennia|, despite the fact that they are not at all designated as a catalytic site of a protease. Then begins tea in the chronic phase, in which catalytic hydrolysis often occurs with the help of nucleophilic cardiomyopathy, associated with heart failure, an attack on the amide bond, which is split,

IKitsppoi, GO. M. Mem Epoi. 9. Med., 329, 639-644, or through the amino acid side chain of the same 19931. In addition, these two drugs possess proteases, or through the action of water molecules, which have a serious adverse toxic effect, bound to the protease and activated by her. Proteases that require direct medical obser- in which the attacking nucleophile is a thiol-reduction during treatment and have been shown to ny side chain of a cysteine residue are known to induce chromosomal damage in children with cysteine protease. Classified as general Chagas' disease Sogia, M. V. ei a!I., Mshai. The term "cysteine protease" contains many members,

Nez. 206, 217-220, 1988|. Therefore, there is a clear me- discovered in a wide range of organisms from viruses, there is an urgent need for new effective medicinal bacteria, the simplest unicellular organisms, models of disease associated with infecting plants and fungi to mammals. yum Tgurapozota sgyi. So, there is a clear medical

Biological studies of Tguraposh infection, the need for the development of such studies "evidences7i revealed a number of specific enzymes that are the principle" in terms of clinical candidates, which are crucial for the development of the life cycle of the para- are suitable for use in humans with the help of zita. One such enzyme, cruzipain, cathepsin I - the creation of more effective inhibitors of cruzipain, a similar cysteine protease, represents an obvious thera- that have the desired combination of efficacy, sele- therapeutic target for the treatment of Chagas disease activity, low toxicity, and optimized fa-

Ma) Sagasho 4. 9. ei ai., Sy. Rpapt. Oev. 7.1143- rmakokinetic parameters. 1156, 2001; (c) Siteu S K. ei aiI., Sigtg. Ogad Tagdeev, Kruzipain and indeed many other key parasita- 1, 155-162, 20001. Although the exact biological role of cruzy proteases belong to the papain-like CA zipain in the life cycle of the parasite remains C1 of the family and have close structural homologues in unclear, increased levels of messenger RNA of crustaceans. Cysteine proteases are classified by "rosypain in the epimastigote stage of development indicate the roof" on the basis of their similarity in the spatial structure of the role in food cleavage of molecules or the preserved location of catalytic hosts in liposome-like vesicles (Epodei 9. them residues in the primary sequence of the protease.

S. ei ai., 9. SeiI. Axis, 111, 597-606, 1998). Acknowledgments In addition, the "genera" are further divided into cruzipain families as viable therapeutic targets, in which each protease has been statistically associated with levels of complexity that will increase relatedness to other members when compared. Addition of the general |inhibitor cysteine- parts of the amino acid sequence, which

Tnproteases, 2-Rpe-AIia-EMK to mammalian cell cultures are the parts responsible for proteases infected with Tgurapozota sgyi, blocked the activity (see Vaigtei, A. Uei aI., in "Naparook replication and differentiation of the parasite, stopping in oi Rgoieouis Eplute5 (Handbook of proteolytic such a way of the life cycle of the parasite INagii o., ei enzymes)", Eaz. Vagtey, A. 9., Kaulipd5, M. O., and a!., Moi. Viospet. Ragavziyu!. 58, 17-24, 1993). Vve- Mu/oezzpeg, u. B. Rybri. Asadetis Rgez5, 1998, for the use of an inhibitor based on vinylsulfone in animals - a comprehensive discussion. Until now, a model of a mouse infected with Tgurapozota sgyli, not cysteine proteases classified into five genera, SA, only saved the mouse from a lethal outcome, SV, SS, SO and SE | Vagtey A. U. ei aI., 1998) . Protease but also led to the complete recovery of the tropical papaya fruit, "papain", forms the main

IEpoeyi, 9. S. eyi ai., 9). Ex. Med., 188 (4), 725-734, in the genus SA, which currently contains more than 80 19981. Other numerous studies, including confirmed and complete records in various databases, showed that infections with alternative parasites, sequences, with more with a greater number, expected from attempts to establish the genome sequence

Rgos. May Asai. si. Sh.5.A., 96, 11015-11022, which are currently being held. Proteases of the genus 1999|, Zspiziobzota tapzopi and Riaztoaiit CA/family C1 are involved in many inflammatory processes

TaIsirapyt (Oesop.). E. eyi ai., Visogd. Honey. Spet., 7, ryuvan, for example, human proteases, such as ca- 633-638, 1999| can be stopped or cured - thepsin K (osteoporosis), cathepsin 5 (autoimmune diseases during treatment with cysteine protease inhibitors. disease), cathepsin | (metastases) or

To create cruzipain inhibitors, parasitic proteases such as falcipain (a small number of synthetic approaches have been described. However, although the plow parasite Riaztodisht TaIsiragit), cruzipain provides biological “proof of principle (Tgurapozota sgili infection). Recently, the bacterial "treatment" of Tgurapozota sgyli infection, protease inhibitors, staphylopain (infection 5. aiygetsv), and those that exist now, have a number of biochemicals that have been experimentally attributed to their genus and physical properties that can prevent - SA. X-ray crystallographic structures to test their clinical distribution. For example, they are unique for a number of the above-mentioned proteases in a complex with sia (a) Vgipep, G.. 5. ei ai., Zihysiige, 8, 831-840, 2000, a number of inhibitors, for example ) Tatsch4, ak,

Mekke!tomu U. N. and Epdei 9., unpublished results - Itet, Irdo, Iaumu, Iauts), cathepsin G. (Is58), cathepsin ty, cited in Zspeiya K. A. ei ai!., Viosogu Mea. 5 |incomplete, but published data Meosgaiy, M.

Speth, 6, 2477-2494, 1998); (c) ry, H. eyi aI., Spet. B. ei ai., Rgoivip Zsiepse, 7, 1294-1302, 19981, kru-

Vio!., 7, 733-742, 2000, arylureas, usually from zipain (recombinant form of cruzipain, characterized by low indicators of activity and high values). ) (Temur, Chen Siod and, therefore, by low solubility in water and, 1ait, 2ait, 1629, 1E2A, 1628, 1E2C), staphylopain probably by low oral bioavailability; (c) (Ism8). Each of the structures has a common topology

Warriors of the MU. VA her AI., Temaneadhop, 56, 9747-9762, of the active site, as could be expected from their 2000, peptidylepoxysuccinates, irreversible inhibition- classifications of "genus" and "family" and such a structural tory with strong activity against grass proteases- the similarity illustrates one aspect of digestive tract difficulties such as cathepsin B; (a) Her, K. ei ai., appear during the creation of a selective inhibitor

Visogd. Honey. Spet., 4 (9), 1421-1427, 1996; of bis-cruzipain, which is suitable for the use of lyudyl hydrazides and chalcones, polyhydroxylated with arone. However, subtle differences in depth and matrix connections are evident; (e) US Patent 6143931, M/O complex form of deepening of the active site co-9846559, non-peptide o-ketoamides|. Among the multitude of CA C1 proteases, which can be used in different approaches to the inhibition of the enzyme, for the design of a selective inhibitor. In addition to today, only cruzipain protease inhibitors and many currently existing complexes have confirmed the effectiveness of animal-based treatment of the inhibitor substrate and proteases of the CA family

C1 show a number of hydrogen bonds between the inhibitor tetrahydrofuran carbonyl and the active cy- and main chain of the protease, which are well conserved by the cysteine residue (M/yKpegdiop, 4., 19991.), which make a significant contribution to the effectiveness. In addition, the same the compounds themselves are cyclic ketones, a description of the inhibitor. First of all, bidentatsan is observed in (M/O-A-9953039I| as part of a widely described hydrogen bond between the protease and cysteine protease inhibitors associated with the parasitic (СхО )/inhibitor M-H and protease /SiIubb diseases, with a specific mention of (MNO/inhibitor (C-O), where the inhibitor (C-0) and (MH) treatment of malaria by inhibiting fal- is provided due to the amino acid residue However, later the literature describes these MnenNKsSO compounds, which make up Zagpidsite- bows - cyclic ketones described in (ММО-А-98505331, the binding element inside the inhibitor I (see) as unsuitable for further development or for the description nomenclature of protease sai the method of binding pharmacokinetic assessment through physics Vegdeg A., apa 5speesieg I., Rpyo5. Thapv5. K. chemical properties of inhibitors, weak chiral os. And oops. (|VioI.), 257, 249-264, 1970). Often, the stability of the α-aminoketone chiral center is protected by an additional hydrogen bond between as- IMagodniv, A. MU. Yei ai., U. Mei. Spet., 44 (5), 725- paraginic or aspartic acid (158 to 736, 20011). In MUO-A-0069855| described compounds that 163, the residue number varies depending on can also be attributed to cyclic ketones, proteases) main chain of the protease (C-O) and with specific mention of the possibility of inhibition by an inhibitor (M-H), where the inhibitor (MH) is provided by cathepsin 5. Compounds according to (ММО-А-00698551 | review

With the subsite-binding element inside are given as successful in comparison with the compounds, opi- inhibitor. Thus, at the known level of development, sleds in (MUO-A9U850533), since they have a p-substituent in the cyclic ketone system of this area among substrate-based inhibitors, which provides

CA C1 protease has a widely observed motif X- ensures chiral stability for the α-carbon of the cyclic

MNSNASO-MN-U. of the (ring) ketone system.

In the known state of the art prior to this However, for the compounds described in (ММО-А-00698551|, of the invention, recently intense activity was observed for the compounds described in (|МО-А-) for the development of cysteine pro-inhibitors 9850533, the presence of a potential votase is required for use in humans. Turning to the day-containing fragment ХМНОНКСО-МН-М, which is a member of the CA C1 family, special attention is paid to the development of inhibitors of human cathepsins, widely observed in known substrates, in pe-based inhibitors CA C1 protease, cathepsin K (osteoporosis), cathepsin 5. Currently, it has been established that some compounds (autoimmune diseases) and cathepsin GI (metastasis, which are defined by the general formulas (I) and (II), are due to the use of peptides and pepti-strong and selective inhibitors of cruzipain domimetic nitriles (for example, see UMO-A- proteases that can be used for the treatment of infection Tg urapozota sgyi. Other compounds, 9924460, M/OA-0049008, M/O-A-0048992, UM/O-A - defined by general formulas (1) and (I), are 0049007, UMO-A-0130772, UMO-A-0055125 . , which are caused by cysteine protease peptidomimetics (for example, see Mebeg 0. R. and we. Compounds defined by the general formulas (1)

Tpotrzop, 5.K., Syt. Orip. Disgust Oizsomegu Nemkh., Z and (I), do not contain the X-AUNSNASO-MN-U fragment, which (4), 362-369, 2000, UMO-A-0170232, MO-AO178734, is widely observed in CA C1 protein inhibitors

M/O-A-0009653, UMO-A-0069855, UUO-A-0029408, az based on a substrate of a known level in this area

M/O-A-0134153 to M/O-A-0134160, ММО-А-0029408, common, but unexpected compounds, defined in general

M/O-A-9964399, UMO-A-9805336, UMO-A9U8505331, with formulas (I) and (I), retain good ketoheterocycles | (for example, see /UMO-A- activity. This invention relates to substitu- 0055144 . -b|pyrrole-Z-one, hexahydropyrrolo|3,2-

A-01091691|. At the known level of development of this obla- bipyrrole-3-one, hexahydrocyclopenta|(p|pyrrole-b-one, effective inhibitors of ip migo are described, but also tetrahydrofuroi3,2-c|Ipyrazol-b-one, tetrahydrothione- attention is drawn to there are many difficulties in the separation of 3,2-s|Ipyrazol-b-one, hexahydropyrrolo!|3,2- bsi of medicines for humans. For example, in Cpyrazol-b-one, hexahydrocyclopentapyrazol-b-

IMO-A-9850533 and UMO-A0029408). described compounds, one, hexahydrofuro|3,2-5|Ipyridin-3-one, hexahyd- which can be called cyclic ketones, and are rotienoY3,2-b|Ipyridin-3-one, octahydropyrroloi3,2- inhibitors of cysteine proteases, especially of the BIpyridin-3-one family, octahydrocyclopenta|b|pyridin-7-papain protease and, as the most preferred variant of it, hexahydrofuroi3,2-c|Ipyridazin-7-one, hexahydrocycline, cathepsin K. U (M/IO-A -9850533| described drotienoiY3,2-c|Ipyridazin-7-one, octahydropyro-compounds, later characterized in detail in lilo|C3,2-|pyridazin-7-one or octahydrocyclopenteratura as effective cathepsin K inhibitors with ho- and I(sipyridazin-7-one) - bicyclic compounds with high oral bioavailability (MMypegipoiop, defined by general formulas (1) and (II).

U., "Teigapudgotigap5 az Beyesime Saiyperzip. К Accordingly, in the first aspect, the invention is

Ippiryoge", KEZS teeiipo, ViVIipdiop Noize, I opdop, is connected to the compound corresponding to the general form 19991). It was reported that the compounds described in (MMO-mule (I) or general formula (10):

A-9850533| bind to cathepsin K due to the formation of a reversible covalent bond between

R where R? represents: l Co-7-alkyl, C3-e-cycloalkyl, Ag-Co-7-alkyl, O-Co-7-v alkyl, O-C3--cycloalkyl, O-Ag-Co--alisil, 5-Co-- heyl alkyl, 5-C3-e-cycloalkyl, 5-Ag-Co-;-alkyl, MH-Co-7-g Ho, alkyl, MH-C3-e-cycloalkyl, MH-Ag-Co --alkyl, M(Co-7-alkyl)", M(C3-e-cycloalkyl)" or M(Al-Co-7-alkyl)"2; where: B'Co--alkyl (when c-0, E! is either, as part of the SNE" or SV! group, B!Z can be simply hydrogen), C3-is-cycloalkyl or Ag-Co--alkyl be a halogen; (when C-O, B! is simply aromatic, A is chosen from: Ag fragment); Sneg, SNA"U, O, 5 and ME2O; where KZ is such as v-7 - 0, 5, СВ2ВЗ or ME", where B: is selected from the above values; and K?2? is selected from: Co--alkyl, C3-6-

Co-7-alkyl, C3-6-cycloalkyl or Ar-Co-7-alkyl; cycloalkyl and Ag-Co-7-alkyl;

Р'АСВ5ВЕ, В, О and С are independently selected from: SVU, where VZ is р2-СВ'ВУ, such as defined above, or M;

O - SVRV!O or ME", where V"! selected from Co-7-E selected from: alkyl, Czv-cycloalkyl or Ag-Co--alkyl; sne, SNAU, 0, 5 and MAO, where KZ and Ko are such as

Each of 2, BZ, B", B.B", VU, BZ and 2!O is independently defined above; is selected from C0--alkyl, C3-cycloalkyl, Ag-U, 1, M, B, T, T", Tz and Ta are independently chosen from:

C0--alkyl, O-C0--alkyl, O-C6-cycloalkyl, O-Ag- SV M, where EE" is as defined above;

Co-alkyl, 5-Co-7-alkyl, 5-C3-e-cycloalkyl, 5-Ag-T5 is selected from:

Co-alkyl, MH-Co-alkyl, MH-C3-6-cycloalkyl, CH or M;

MH-Ag-Co?-alkyl, MI((Co-7-alkyl)", M(C3-v- is a number from one to three, cycloalkyl)"2 or M (Ag-Co-7- alkyl)2; thus meaning a 5-, 6- or 7-membered ring.

UESVI2VIZ-CO, where B/2, VIZ is chosen from Co-z- B,0, 6,9, |, M, KE, T, T», Tz and Ta additionally mo-alkyl, C3-cycloalkyl or Ag-Co -7-alkyl; to be M-oxide (M-»0). (Yu0-SV'YAV", where B1Y and B15 are independently selected. This invention includes all salts, hydrates, salts of Co-; -alkyl, C3-E-cycloalkyl and Ar-Co-7-alkyl , and vats, complexes and prodrugs of compounds according to this o is a number from zero to three; invention. It is meant that the term "compound" (MU)n - O, 5, C(O), B(O) or 5(0)2 or ME", which includes all such salts, hydrates, solvates, complexes

VE is selected from Co-7-alkyl, C3-6-cycloalkyl and Ag- and prodrugs, unless the context suggests

Co-7-alkyl, and n is zero or one; another (Mt i- С(0), С(5), 5(0), 5(0О)2, 5(О2МН, Suitable for pharmaceutical and veterinary use

ОС(О), МНС(ОО), МНО(О), МНе(О)г, ОС(ОМН, distinct salts of compounds of the general formulas (I) and (II) incl.

C(ОМН or СЕ"B'Z, where EE!" are independently selected as salts of organic acids, especially carbono- from Co---alkyl, C3-e--cycloalkyl, Ar-Co-7-alkyl, etc. of acids, including but not limited to, is a number between zero and three, provided that acetate, trifluoroacetate, lactate, gluconate, citrate, when t is greater than one, (M)t contains a maximum of tartrate, maleate, malate, pantothenate, adipate, algi- one carbonyl or sulfonyl group; nat, aspartate, benzoate, butyrate, digluconate, cyclo-

O-stable 5-7 membered monocyclic or lopentanate, glucoheptanate, glycerophosphate, oxa-stable 8-11 membered bicyclic ring that is either lat, heptanoate, hexanoate, fumarate, nicotinate, saturated or unsaturated, and which includes from palmitate , pectinate, 3-phenylpropionate, picrate, pivalate - zero to four heteroatoms (as in detail vilate, propionate, tartrate, lactobionate, pivalate, as detailed below): mphorate, undecanoate and succinate, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphor, their GC C sulfonate, 2-naphthalene sulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisul-

Calcium phosphate, thiocyanate, persulfate, phosphoric and sodium salts 2 | lphonic acid. Salts that are not pharmaceutically or veterinary acceptable may also be of value as intermediate compounds. 9. vve SS Prodrugs can be any cov-

Med e 2 tape-linked compounds that release the active starting drug in accordance with the general formulas (I) or (II) and more. Prodrugs, for example, may consist of a ketal or semi-ketal derivative of гА-В, ва|. exocyclic ketone function, which is present in the main framework of tetrahydrofuro-3,2-5|pyrrol-3-one, tetrahydrothieno-3,2-b|Ipyrrole-3-one, hexahydropyrrolo|3,2-B|pyrrole-3- onu, hexahydrocyclopenta|p|pyrrole- (4 t «bu SS is: b-one, tetrahydrofuroi3,2-D|pyrazol-b-one, tetrahy-

Me M. Se drotienoiY3,2-c|Ipyrazol-b-one, hexahydropyrroloi3,2-

Cpyrazol-b-one, hexahydrocyclopentapyrazol-b-one, hexahydrofuro|3,2-b|Ipyridin-3-one, hexahydro-

rotieno|Z3,2-b|Ipyridin-3-one, octahydropyrrolo!|3,2- C-o in the substituent Ag-So--alkyl, the substituent is simply yav-

B|Ipyridin-3-one, octahydrocyclopenta|b|pyridin-7- is an aromatic ring fragment Ag. one, hexahydrofuro3,2-Dpyridazin-7-one, hexahyd- It is intended that other expressions containing rotienoiY3,2-c|Ipyrvdazin-7-one, octahydropyrrolo!|3,2- terms such as alkyl and cycloalkyl are interpreted

Cypyridazin-7-one or octahydrocyclopene - according to the above definitions. Napryta-isopyridazin-7-one. If a chiral center or clade, "Ci-4 alkyl" represents the same as Co-7- another form of isomeric center is present in the alkyl compound, except that it contains from one according to the present invention, it is meant, that all up to four carbon atoms. forms of such an isomer or isomers, including If different structural isomers are present and/or there are enantiomers and diastereoisomers included in the volume of one or more chiral centers, then the invention is present. Compounds according to the present invention, meaning that all isomeric forms are covered, contain a chiral center, can be used by the invention. Enantiomers are characterized absolutely in the form of a racemic mixture, by the enantiomerically stable configuration of their chiral centers and an arbitrated mixture or a racemic mixture can be sled using the K and 5 sequence rules and separated using the well-known methods of Kahn, Ingold, and Prelog. Such conditional marks were, and it is possible to use separately individual well-known ones in this area (for example, see enantiomers. "Aduapsei Ogdapis SPpetivigu", Z eayop, ed.

It is understood that the term "halogen", as it Mageny, 9., khonpp UMieu apa bopv, Mem Moik, 19851. is used in this description, includes BK, SI, Preferred compounds having the general for-

VG, I. mules (I) and (I), include, but are not limited to

It is understood that the term "heteroatom" as we, those in which, independently or in combination: it is used in this description, includes 0, 5 7 represents 0, 5, MH or CH";

THEM. Ri and Rg represent Si"; and

It is understood that the term "Co-7-alkyl", as it O represents CH" or MH. used in this description, includes stable Also preferred compounds having the general linear and branched aliphatic carbon la- formulas (I) and (I) include, but are not limited to nts containing from zero (i.e., just hydrogen) them, those in which, independently or in combination: 7 and up to seven carbon atoms, such as methyl, ethyl, is ME, where B? represents Ag-Ci-4-alkyl propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or a substituted carbonyl or sulfonyl group; pentyl, isopentyl, hexyl, heptyl and any Ri and Rg thereof are Si"; and the simple isomer. Additionally, any Co-7-alkyl O is CH»e or MH. may optionally be substituted in any In this manner, examples of preferred compounds position with one, two, or three halo atoms include those containing a bicyclic frag- logene (as defined above), for example, giving ment selected from tetrahydrofuro |Z,2-b|pyrrole-3-trifluoromethyl substituent. In addition, Co-7-alkyl one, tetrahydrothieno|3,2-b|Ipyrrole-Z-one, hexahydro- can contain one or more heteroatoms (like pyrrolo|3,2-b|pyrrole-Z-one, hexahydrocyclopen- defined above), for example, giving simple ethers, and , hexahydrones, amidines, guanidines, carboxylic acids, carboxypyrrolo|3,2-c|Ipyrazol-b-one, hexahydrosamides. If the heteroatom is located at the end of the cyclopentapyrazol-b-one, hexahydrofuro3,2- chain, then it is suitably substituted by one B|Ipyridin-3-one, hexahydrothieno|3,2-b|pyridin-3-one or two hydrogen atoms.Heteroatom or one, octahydropyrrolo|3,2-b|Ipyridin-3-one, octahyd-halogen are present only when Co-7-alkyl contains rocyclopenta|b|pyridin-7-one, hexahydrofuro3,2- as at least one carbon atom. c|Ipyridazin-7-one, hexahydrothienoi3,2-c|Ipyridazin-

The term "C3-e-cycloalkyl", 7-one, octahydropyrrolo|13,2-c|pyridazin-7-one or as used herein is intended to include octahydrocyclopenta|c|pyridazin-7-one, as shown - any variants of Co-7-alkyl, which additionally contain but below. carbocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The carbocyclic and A ring may be optionally substituted with one or more halogens (as defined above) or heteroatoms (as defined above), for example, giving tetrahydrofuran, pyrrolidine, tetrahydrofuran8,2- tetrahydrothieno(3,2- hexahydropyrrolo32, piperidine, piperazine or morpholine Vipyrrol-z-on BIpyrrol-z-on Bipyrrolez-on substitute. A

The term "Ag-C0-7-alkyl" as used herein is intended to include any variants of C0-7-alkyl that additionally contain an aromatic ring moiety "Ag". Aromatic - Tetrahydrofuroiv»choY Tetrahydrothieno(3»»e) / Hexahydropyrroloi wine) sho. - pyrazol-6-one pyrazol-6-one pyrazol-b-one ring fragment Ag can be a stable 5- or 6-membered monocyclic or stable 9- or 10-membered bicyclic ring, which is not saturated, as previously defined for Ш in the general formulas (I) and (I). The aromatic ring fragment Ag can be replaced by P" (as defined above for Hexahydrocyclo- Hexahydrocyclo- above) in the general formulas (1) and (I)). When pentaHb)pyrrole-b-one pentapyrazol-b-one de B" , B2O and Ag are as defined above. ; and More preferred B'"Z groups include C-4 alkyl, which may be substituted by OH, MeE2OB2O,

СООВ2, or СОМПРЕ-, or cycloalkylmethyl, or Ag-

Teusuhydraf teo» Hexahygdutisnor Z» Systuti drotarokov Za» Ci-4-alkyl, where the aryl group can be substituted

Vitiridny-3-by Vmirnakn-zcheh vipiryadanizchu VZ: where is each of B? and 220 is independently as defined above. х Even more preferred groups of VZ include Ag-

SnHe-, where the aromatic ring is an optionally substituted phenyl or monocyclic hetero- and cycle. Additionally, B'Z groups are even more preferred

Hekotidnafuroi Z si Hexagiirokisnaya 5, ache| Hydrocarbons include simple branched alkyl groups, such as pyridine substituents such as isobutyl or linear heteroalkyl chains, such

And as benzylsulfanylmethyl or benzylsulfonylmethyl. In addition, even more predominant groups V'Z same. " include cyclohexylmethyl. Examples of even more preferred substituents on Y include the following:

Okhzhydrotsikhl Smgtagiduyupnhla» pentyaleitrnlinstom 0 pentare)pyridaznky and ve g | about; K. Be

In the compounds of the general formulas (1) and (II) there are re- ; it is important that B' includes Co-alkyl or Ag-Co-C in alkyl. Thus, for example, the preferred fragments of B! include hydrogen or a linear or branched alkyl chain, or a linear or branched heteroaryl chain, or an unpaired os in the group (where des ZA is a necessarily substituted arylalkyl chain, or is substituted with soalkyl or ligoioalkyl, an optionally substituted arylheteroalkyl example, hydrogen, a linear or branched alkyl chain, a linear or branched hetelic chain,

It is especially preferable that R! was a boroalkyl chain optionally substituted with C 1 -C 1 alkyl or C 1 -C 1 -alkyl, and examples of an arylalkyl chain or optionally substituted B' substituents include, but are not limited to, an arylheteroalkyl chain. 14, More preferred groups (X)o include K'"", which are represented by: K!? represents Si-"-alkyl, which can be replaced by OH, Movo SOOV?O or nyshin I - - peku SOM; or Ac-Ci-alkyl, wherein the aryl group may be substituted with EC, wherein each of E!3 and 220 is independently as defined above. wherein B? is as defined above. Examples of preferred groups (X)o include na-

In the preferred compounds of the general formulas (1) and step: (I), M represents SNEZSO, where B" is selected from

Co-alkyl or Ag-Co-alkyl, for example, hydrogen, Х С Ж linear or branched alkyl chain, ХА linear or branched heteroalkyl lap of the same chain, optionally substituted arylalkyl chain or optionally substituted arylhetone is a type of rhoalkyl chain. In addition, in the preferred compounds of the general formulas (I) and (I), C is selected from C3-e-cycloalkyl, for example, cyclohexylmethyl.

Examples of preferred substituents include the following: - Е «а г «з и Л where ВЗ and 229 are as previously defined. d Even more preferred compounds having the general formulas (I) and (I) include groups (X)o, which are simple alkyl groups, such as methylene, ideo - 0 or 1. and In the (M/)n group, MU is mostly 0.5,

It is Pe ZO", 5 (0), C(O) or ME", where VE is Co-4-alkyl; and n is 0 or 1.

Gr. re More She ge More pe and and . Reversible compounds having general c formulas (I) and (II) include groups (UM)a, defined

And as О, 5, 50", С(О)Й МН, where пп - 0 or 1.

Even more preferred compounds having the general formulas (1) and (I) include groups (UMup, "higher" "r" denoted as МН where p.-1. » ;

In the group (M)t, M is mostly C(O), .

C(O)MH or SNR", where B"Z is Co-"-alkyl; i ) t is equal to 0 or 1. i

Preferred combinations of M and MU substituents not covered by the general formulas (1) and (II) include, but are not limited to, where ВZ is as previously defined.

More preferred compounds having the general properties of formulas (I) and (I) contain a group Y, which has a bulky alkyl or aryl group in the paraposition of the aryl and 2 Ag. Also, more preferred compounds contain a metacyclic group (UN) or a parabiaryl Ag-Ag, where Ag is as previously defined. Additionally, more preferred compounds contain 6,6- or 6,5- or 5,6-fused aromatic

C | I | not a ring Examples of more predominant groups are: her schtvo, 00 zbo Же an ke re І і і ; plen) che chai r te y a Mao) - or zh1 /

In addition, the preferred combination of the substituents Мр and МУ, covered by the general formulas (І) |и (ІІ), includes, but is not limited to: and also со. ev sa 0 0 pi ; вn with inn hair dryer where V? O, E, C, U, I, M, B, T, T", Tz and Ta are as defined earlier.

More preferred combinations of substituents M, UM and X. Even more preferred compounds having the following are covered by general formulas (I) and (II), including formulas (I) and (I), especially for inhibition of tea, but not limited to by this: cruzipain, contain an OO group that includes a b-member

Ag ring containing bulky alkyl or aryl

And well, the group in the paraposition, where Ag is such as defined

YAH, rya 4 AH, cheno earlier pre duet sitya Gai their same Al with U Ж шка ше Жж schu so no peyava; p ii B,

In the preferred compounds of the general formulas (1) and -e io (I), O includes an optionally substituted 5- or 6- / U-membered saturated or unsaturated heterocycle of salo and Ya or Ag group, or an optionally substituted saturated Ka d. A saturated or unsaturated 9- or 10-membered hetero-, cycle or Ag group. Examples of such preferred O rings include the following: dev" O, E, C, 9,1, M, B, and T are as previously defined. Even more preferred compounds having the general formulas (1) and (I) contain the group | , c, U and I. are as defined earlier.

Abbreviations and symbols, usually used in the field of peptides and in the field of chemistry, are used. not in this description for the description of the compounds according to the present invention in accordance with the general guidelines presented by the Joint Commission on Biochemical Nomenclature IUPAC (ISHRAS-|ISHV), as described in (Eig. y.: i

Viospet., 158, 9-, 1984). Compounds of formulas (1) and (II) and - o; intermediate compounds and starting substances used | ! for their receipt, named according to the pra- . y, vill of the IUPAC nomenclature, in which the characteristic / groups have a decreasing priority for mention as a principle group. An example of a compound of the formula (I), compound (1), in which B' represents H, Ri represents methylene, OO represents methylene, 7 (ZaB,bavb) 1-(25-Benzyloxy-4- is oxygen, M is 4A-methylpentanoyl)hexahydrocyclopenta|(p|pyrrole-b-one methylpentyl, (X)o is zero, (M/)n is co- The fourth example of a compound of formula (I), a combination of oxygen, (M)t is methylene, and О is an arc (4), in which B' is H, Ri is phenyl, is called as follows: methylene, OO is methylene, 7 is

MH, M is 4-methylpentyl, (X)o is zero, (M/)p is oxygen, (M)t is methylene, and SHUSh is phenyl, called as follows:

Fo o h o i m ! ee m a / da 1 . is a) (Za5,bac)4-(25-Benzyloxy-4-methylpentanoyl)tetrahydrofuro|3,2-5|pyrrol-3-one

The second example of a compound of formula (I), compound Fo (2), in which E! represents H, Ri represents methylene, O represents methylene, 7 represents sulfur, (Za5,bav) 1--25-Benzyloxy-4-

U represents 4-methylpentyl, (X)o is equal to zero, methylpentanoyl)hexahydropyrrolo!|3,2-B|pyrrol-3-one (UU)n represents oxygen, (M)m represents methyl- Fifth example compounds of the formula (I), the compound lene, and 0 is phenyl, is called such (5), in which K' is H, Ri is methyl: lene, OO is MH, 7 is oxygen, U represents 4-methylpentyl, (X)o is equal to zero, (MM)n represents oxygen, (M)m represents methylene, and 0 represents phenyl, is called in the following way: ! and I I y В, : I | and 1 et c) 8 ) and her (zac, bak) 4-(25-Benzyloxy-4- methylpentanoyl)tetrahydrothienoiY3,2-b|pyrrol-3-one 9

The third example of a compound of formula (I), compound (3), in which B! represents H, Ri represents methi- (zac, base). | 4-(25-Benzyloxy-4-lene, O is methylene, 7 is methylpentanoyl)tetrahydrofuro|3,2-I|pyrazol-b-one ethylene, Y is 4-methylpentyl, (Kho doriv- Shostiy an example of a compound of formula (I), the compound is zero, (M) represents oxygen, (M)m represents (6), in which K' represents H, Ri represents methyl, methylene, and ) represents phenyl, is called - lene, 0 is MH, 2 is sulfur, U is as follows: is 4-methylpentyl, (X)o is zero, (MM)p is oxygen, (M)t is methyl

len, and 0 is phenyl, is called the following Example of a compound of formula (II), compound (9), in the manner: which B! is H, Ri is methylene,

Pg is methylene, O is methylene, 7 is oxygen, M is 4-methylpentyl, (X)o is zero, (M/)l is oxygen, (M)m is methylene, and U represents

And by itself phenyl, it is called in the following way: - stu (3 |

F "a: "Me ley y y (zac,baz) 4-(-25-Benzyloxy-4-F' y methylpentanoyl)tetrahydrothienoi|3,2-Ygrazol-6b-one y Gaia

The seventh example of a compound of formula (I), compound (7), in which Ki is H, Ri is methyl, OO is MH, 7 is methylene, Y is 4-methylpentyl, (X)o is equal to zero, (Za5,7ab) 4-(-25-Benzyloxy-4- (M/)g represents oxygen, (M)t represents methyl-methylpentanoyl)hexahydrofuroyl3,2-b|pyridin-3-one, and 0 represents phenyl, called in such a Second example of a compound of formula (I), compound method: (10), in which B! represents H, Ri represents methylene, Po represents methylene, 0 represents methylene, 7 represents sulfur, Y represents 4-; methylpentyl, (X)o is equal to zero, (M/)l is an oxygen atom, (M)t is methylene, and U is: i 2 is phenyl, it is called as follows: 1 where

In U nosin

In M la and F | | | Ai

AND

. (Zan,bavb) 1-(25-Benzyloxy-4-Me/I methyspentanoyl)hexahydrocyclopentapyrazol-b-one E

The eighth example of the compound of formula (I), compound (8), in which B' represents H, Ri represents methylene, O represents MH, 2 represents MH, U (Zav,7av) 4--25 -Benzyloxy-4- is 4-methylpentyl, (X)o is zero, methylpentanoyl)hexahydrothieno|3,2-b|pyridin-3-one (UM)n is oxygen, (M)t is methyl an example of a compound of formula (II), a lene compound, and Sh is phenyl, is called such (17), in which B! is H, Pi is methylene, Po is methylene, 0 is methylene, 7 is methylene, Y is 4-methylpentyl, (X)o is zero, (M/)l. is oxygen, (M)t is methylene, and O is phenyl is called as follows:

І Chia zhu and dob that shk I dv dk di Vch i in F «2 ) o (ZaB,bav) 1--25-Benzyloxy-4- and E methylpentanoyl)hexahydropyrrolo!|3,2-s|pyrazole-6- he n)

(4а5,7ав) 1--25-Benzyloxy-4-methylpentanoyl)octahydrocyclopenta(|p|pyridin-7- i on !

The fourth example of a compound of formula (II), compound (12), in which B! represents H, Ri represents pyl) fdunnia methylene, P» represents methylene, O represents o | is methylene, 7 is MH, M is 4-B methylpentyl, (X)o is zero, (M/)n is oxygen, (M)t is methylene, and U is phenyl, is called as follows: a" (dak,7ak) 4-(25-Benzyloxy-4-methylpentanoyl)hexahydrofuroyl|Z3,2-c|Ipyridazin-7-one

The seventh example of a compound of formula (II), compound 4 of item (15) in which E! represents H, Pi represents 1 methylene, Po represents methylene, 0 represents h MH, 7 represents methylene, M represents 4-methylpentyl, (X)o is zero, (M/)l represents so- of oxygen, (M)t is methylene, and O is . itself is phenyl, is called as follows: a" (Zab5,7ak) 4-(25-Benzyloxy-4-methylpentanoyl)octahydropyrroloyi3,2-p|Ipyridin-3-one p cant

The fifth example of a compound of formula (II), a compound with x (13), in which E! is H, Ri is methylene, P" is methylene, O is i and z4a

MH, 7 represents oxygen, U represents the 4th. and what in ; with zi, methylpentyl, (X)o equals zero, (M/)n represents co- and | o, oxygen, (M)t is methylene, and U is phenyl, it is named as follows: su I y y a chas (4ав,7ав5) 4-(25-Benzyloxy-4- : methylpentanoyl) octahydrocyclopenta|c|pyridazin- ia sa ia a 5 7-on

Fo o | B) The eighth example of a compound of formula (II), compound (16), in which E! is H, Pi is methylene, P" is methylene, OO is o MH, 7 is MH, M is 4-az methuypentyl, (X)o is zero, (MM)n is so- of oxygen, (M)t is methylene, and U is (4α,7α) 4-(28-Benzyloxy-4-isophenyl) is called as follows: methylpentanoyl)hexahydrofuroyl|3,2-s|Ipyridazin-7-one

The sixth example of a compound of formula (II), compound (14), in which E! represents H, Ri represents methylene, P» represents methylene, O represents

MH, 7 is sulfur, M is 4-methylpentyl, (X)o is zero, (M/)n is so- and B is oxygen, (M)t is methylene, and Y is phenyl, is called as follows: . (4α8,7αβ) 4-(-25-Benzyloxy-4-methylpentanoyl)octahydropyrrolo!|3,2-c|Ipyridazin-7-one

Compounds according to the present invention include, but are not limited to, the following examples, which are the (Za5,bac) isomer of the general formula (I), where 220 and B!-"H', and also include equi-

valence analogues included in the full definition of 7 and M-P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-

B". hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl/|-4-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-1,2,3Hyadiazol-5-ylbenzamide hexahydrofuro3,2-5|pyrrol-4-yl/ethyl)benzamide M-(1 -(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4-tert-butyl-M-|1-(4-hydroxybenzyl)-2-oxo-2-hexahydrofuroi3,2-b|pyrrole-4 -yl)ethyl-4-pyrazol-1-(3-oxo-hexahydrofuroyl3,2-b|pyrrol-4-ylbenzamide yl)ethyl|benzamide M-(1-(4-hydroxybenzyl)-2-oxo-2-( 3-oxo-

M-(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo- hexahydrofuroi|3,2-b|pyrrole-4-iluethyl|-5-thiophene-2-hexahydrofuroi3,2-b|pyrrole -4-iluethyl/|-4-ylnicotinamide trifluoromethoxybenzamide M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4-dimethylamino-IM-|1-(4-hydroxybenzyl)-2- hexahydrofuroi|3,2-b|pyrrole-4-iluethyl|-6-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-phenylnicotinamide yl)ethyl|benzamide P1-(4-hydroxybenzyl)- 2-oxo-2-(3-oxo-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuro(3,2-b|pyrrol-4-yl)ethyl|amide 2-hexahydrofuroi3,2-b|pyrrole-4 -yl)uethyl/|-4-phenylthiazole-4-carboxylic acid isopropylbenzamide I1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4-difluoromethoxy-M-|1-(4-hydroxybenzyl)- 2-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-pyridine-3-ylthiazole-4-carboxylic acid yl) ethyl|benzamide P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuro/3,2-b|pyrrol-4-yl)ethyl|amide 5-hexahydrofuro3,2-b|pyrrole-4 -yl)uethyl/|-4-phenylthiophene-2-carboxylic acid trifluoromethylbenzamide P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4-bromo-M-(1-(4-hydroxybenzyl)- 2-oxo-2-(3-hexahydrofuro/3,2-b|pyrrol-4-yl)ethyl|amide 5-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|benzamide pyridine-Z-ylthiophene -2-carboxylic acid

3-bromo-M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-I1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-oxo-hexahydrofuroi3,2-b) |pyrrol-4-yl)ethyl|benzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide 2-methyl-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-5-phenylfuran-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)uethyl/|-4- P1- (4-hydroxybenzyl)-2-oxo-2-(3-oxo-vinylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4- (1-(4-hydroxybenzyl)-2-oxo-2- (3-oxo-phenylthiophene-2-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|iIamide naphtha-P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxolin-2 -carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-pyridine-3-ylthiophene-2-carboxylic acid) hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|iamide naphtha-P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxoline-1-carboxylic acid hexahydrofuro!|3,2-b |pyrrole-4-yl)ethyl|amide 2- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-thiophen-2-ylthiazole-4-carboxylic acid hexahydrofuro3,2-b)|Ipyrrole- 4-yl)ethyl|amide quinoline-P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-b-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)uethylamide. 2-methyl- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-5-(pyrrolidine-1-sulf onyl)furan-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide benzo(bithiophene-2-carboxylic acid P1-(4-hydroxybenzyl)-2-oxo-2-( 3-oxo- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 3-hexahydrofuro3,2-b|pyrrole-4 -yl)ethyl|amide ben-phenylpyrrole-1-carboxylic acid zo(bithiophene-3-carboxylic acid M-13-methyl-1-(3-oxo-hexahydrofuroyl)3,2- (1-(4-hydroxybenzyl)-2- oxo-2-(3-oxo-b|Ipyrrole-4-carbonyl)butyl|benzamide hexahydrofuro|Z,2-5|pyrrol-4-yl)ethyl|amide benzoty-4-tert-butyl-M-|Z- methyl-1-(3-oxo-azole-5-carboxylic acid hexahydrofuro3,2-b|pyrrole-4-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-carbonyl)butyl)|benzamide hexahydrofuroi|3,2-B5|pyrrol-4-yl)ethyl|iamide biphenyl-M-3-methyl-1-(3-oxo-hexahydrofuroiY3,2-4-carboxylic acid BIpyrrole-4-carbonyl)butyl-4-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-trifluoromethoxybenzamide hexahydrofuro3,2-b|pyrrol-4-yl)uethyl/|-4-4-dimethylamino-M-|IZ- methyl-1-(3-oxo-phenoxybenzamide hexahydrofuroi3,2-b|pyrrole-4-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-carbonyl)butyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-3-4-isopropyl-M- (Z-methyl-1-(3-oxo-phenoxybenzamide hexahydrofuroi3,2-b|pyrrole-4-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-carbonyl)butyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-imidazol-1-4- difluoromethoxy-M-|3-methyl-1-(3-oxo-ylbenzamide hexahydrofuroi|3,2-B5|pyrrole-4-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-carbonyl)butyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-thiophen-2-M- 13-methyl-1-(3-oxo-hexahydrofuroi3,2-ylbenzamide bipyrrole-4-carbonyl)butyl-4-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-trifluoromethylbenzamide hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|-4-oxazol-5-4-bromo-M- |3-methyl-1-(3-oxoylbenzamide hexahydrofuro|3,2-B5|pyrrole-4-carbonyl)butyl|benzamide

3-bromo-M-|3-methyl-1-(3-oxo-3-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-hexahydrofuroi3,2-b|pyrrole-4-4-carbonyl) )butyl|amide 4-pyridine-3-ylthiophene-2-carbonyl)butyl|benzamide carboxylic acid

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-3-methyl-1-(3-oxo-hexahydrofuroyl3,2-b)pyrrole-

BIpyrrole-4-carbonyl)butyl|-4-vinylbenzamide 4-carbonyl)butyl|amide 2-thiophen-2-ylthiazole-4-

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-carboxylic acid 4-carbonyl)butyl|naphthalene-2-carboxylic acid 13-methyl-1-(3-oxo-hexahydrofuroi3,2- b|pyrrolotes 4-carbonyl)butyl| amide 2-methyl-5-(pyrrolidine-1-

I3-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-sulfonyl) furan-3-carboxylic acid 4-carbonyl)butyl|iamid naphthalene-1-carboxylic acid I3-methyl-1-(3- Oxo-hexahydrofuroyl 3-phenylpyrrole-1-carboxylic acid

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrolic acid 4-carbonyl)butyl|amide quinoline-b-carboxylic acid- M-(1-(3-hydroxybenzyl)-2-oxo-2 -(3-oxo- hexahydrofuroyl|3,2-5|pyrrol-4-yl)ethyl|benzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-tert-butyl-M-|1-(3-hydroxybenzyl)-2-oxo-2-4-carbonyl)butyl|amide benzoHb |thiophene-2-carboxylic acid (Z-oxo-hexahydrofuroyl3,2-b|pyrrole-4-acid yl)ethyl|benzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-4-carbonyl)butyl|amide benzoHb| hyophene-3-carbonic hexahydrofuro|3,2-b|pyrrol-4-yl)uethyl|/|-4- acid trifluoromethoxybenzamide

Benzothiazole-5-carbon oxo-2 -(3-oxo-hexahydrofuroic3,2-b|pyrrole-4- acid yl)ethyl|benzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-4-carbonyl)butylamide biphenyl-4- carboxylic acid-hexahydrofuro|3,2-b|pyrrol-4-yl) ethyl-4-thy isopropylbenzamide

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-4 difluoromethoxy-M-|1-(3-pdroxybenzyl)-2-p|Ipyrrole-4-carbonyl)butyl|-4-phenoxybenzamide oxo- 2-(3-oxo-hexadrofuroi|3,2-b|pyrrole-4-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-yl)ethyl|benzamide p|Ipyrrole-4-carbonyl)butyl|-3-phenoxybenzamide M-(1-(3-hydroxybenzyl)-2- oxo-2-(3-oxo-4-imidazol-1-yl-M-(3-methyl-1-(3-oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)uethyl|/|- 4-hexahydrofuro3,2-b|pyrrole-4-trifluoromethylbenzamide carbonyl)butyl|benzamide 4-Bromo-M-|1-(3-hydroxybenzyl)-2-oxo-2-(3-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-oxo-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|benzamide

B|Ipyrrole-4-carbonyl)butyl|-4-thiophen-2-ylbenzamide Z-bromo-M-I|1-(Z-hydroxybenzyl)-2-oxo-2-(3-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-oxo-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|benzamide

B|pyrrole-4-carbonyl)butyl|-4-oxazol-5-ylbenzamide M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl/|-4-

BIpyrrole-4-carbonyl)butyl-4-(11,2,3|hiadiazole-4-vinylbenzamide ylbenzamide I1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|ylamide naphtha-

lin-2-carboxylic acid bipyrrole-4-carbonyl)butyl|-4-pyrazol-1-ylbenzamide

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-P1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-p|Ipyrrole-4-carbonyl)butyl|-5- Thiophen-2-ylnicotinamide hexahydrofuroi|3,2-b|pyrrol-4-yl)ethyl| amide naphtha-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-lin-1-carboxylic acid

B|Ipyrrole-4-carbonyl)butyl|-6-phenylnicotinamide P1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl| amide quinoline-4-carbonyl)butyl|iamide 2-phenylthiazole-4-carboxylic b-carboxylic acid acid I1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

13-methyl-1-(3-oxo-hexahydrofuroi|3,2-b|pyrrole-hexahydrofuroi|3,2-b|pyrrol-4-yl)ethyl| amide benzo-4-carbonyl)butyl|amide 2-pyridin-3-ylthiazol-4- iso(bithiophene-2-carboxylic acid carboxylic acid I1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-hexahydrofuroi|3,2-5|pyrrol-4-yl)uethyl| amide ben-4-carbonyl)butyl|iamide 5-phenylthiophene-2-carboxylic acid zo(bithiophene-3-carboxylic acid acid I1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-hexahydrofuro|3,2-b|pyrrol-4-yl)ethyl amide benzoty-4-carbonyl)butyl|amide 5-pyridine-3- ilthiophene-2-azole-5-carboxylic acid carboxylic acid I1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrol-hexahydrofuro|3,2-b|pyrrol-4-yl)ethyl amide biphenyl-4-carbonyl)butyl|amide 2-methyl-5- phenylfuran-3-4-carboxylic acid carboxylic acid M-P1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4-4-carbonyl)butyl Iiamide 4-phenylthiophene-2-carbon phenoxybenzamide acid M-P1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- hexahydrofuroic|3,2-b|pyrrole-4-iluethyl|-3-phenoxybenzamide

M-(P1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-4 difluoromethoxy-M-|2-oxo-2-(3-oxo-hexahydrofuroyl)-2-oxo-4-yl) )ethyl|-4-imidazol-1-hexahydrofuroyl3,2-b|pyrrol-4-yl)-1-pyridin-4-ylbenzamide ylmethylethylI|benzamide

M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-hexahydrofuro3,2-b) pyrrole-4-yl)ethyl|-4-thiophen-2-4-yl)-1-pyridin-4-ylmethylethyl|-4-ylbenzamide trifluoromethylbenzamide

M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-4-bromo-M-|2-oxo-2-(3-oxo-hexahydrofuroi3,2-hexahydrofuroi3,2-b) pyrrole-4-yl)ethyl|-4-oxazol-5-B|pyrrol-4-yl)-1-pyridin-4-ylmethylethyl|benzamide ylbenzamide Z-bromo-M-|2-oxo-2-(3- oxo-hexahydrofurois3,2-

M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-B|pyrrol-4-yl)-1-pyridin-4-ylmethylethyl|benzamide hexahydrofuroiZ3,2-b|pyrrol-4- yl)ethyl|-4-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-

1,2,3-Hyadiazol-5-ylbenzamide 4-yl)-1-pyridin-4-ylmethylethyl|-4-vinylbenzamide

M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-b) pyrrol-4-yl)ethyl|-4-pyrazol-1-yl)-1-pyridin-4-ylmethylethylamide naphthalene-2-ylbenzamide of carboxylic acid

M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-b) pyrrol-4-yl)ethyl|-5-thiophen-2-yl)-1-pyridin-4-ylmethylethyl|amide naphthalene-1-ylnicotinamide carboxylic acid

M-(1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-b| pyrrol-4-yl)ethyl|-6-yl)-1-pyridin-4-ylmethylethyl|amide quinoline-6b-phenylnicotinamide carboxylic acid (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyridin-4-ylmethylethylamide benzo (rigiophene-2-phenylthiazole-4-carboxylic acid carboxylic acid (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b |pyrrole-4-hexahydrofuro[2-b]pyrrole-4-yl)ethyl|amide 2-yl)-1-pyridin-4-ylmethylethylamide benzo|p|thiophene-3-pyridine-3-ylthiazole-4-carboxylic acid carboxylic acid (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-b| Pyrrol-4-yl)ethyl|amide 5-yl)-1-pyridin-4-ylmethylethyl|amide benzothiazole-5-phenylthiophene-2-carboxylic acid carboxylic acid (1-(3-hydroxybenzyl)-2-oxo-2- (3-oxo- (2-oxo-2-(3-oxo-hexahydrof uroy3,2-b|pyrrole-4-hexahydrofuro[2-b|pyrrole-4-yl)ethyl|amide 5-yl)-1-pyridin-4-ylmethylethylamide biphenyl-4-pyridine-3-ylthiophene-2-carbono carboxylic acid (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-hexahydrofuro3,2-b |pyrrol-4-yl)ethylamide 2-methyl-4-yl)-1-pyridin-4-ylmethylethyl|-4-phenoxybenzamide of 5-phenylfuran-3-carboxylic acid M-(2-oxo-2-(3-oxo) -hexahydrofuroi3,2-b|pyrrole- (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-4-yl)-1-pyridin-4-ylmethylethyl|-3-phenoxybenzamide hexahydrofuroi3,2- b|pyrrole-4-yl)ethyl|amide 4-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-phenylthiophene-2-carboxylic acid 4-yl)-1-pyridine- 4-ylmethylethyl)-4-imidazol-1- (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4-M -(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-pyridine-3-ylthiophene-2-carboxylic acid 4-yl)-1-pyridin-4-ylmethylethyl|-4-thiophene-2 - (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuro|3,2-b|pyro 1-4-yl)ethyl|amide 2-M-(2-oxo-2-(3-oxo-hexahydrofuroyl3,2-b|pyrrol-thiophen-2-ylthiazole-4-carboxylic acid 4-yl)-1- pyridin-4-ylmethylethyl|-4-oxazol-5- (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|iamide 2 -methyl- M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-5-(pyrrolidine-1-sulfonyl)furan-3-carboxyl-4-yl)-1-pyridin- 4-ylmethylethyl|-4-1H1,2,3|hiadiazol-5-ylbenzamide (1-(3-hydroxybenzyl)-2-oxo-2-(3-oxo-M-(2-oxo-2-(3 -oxo-hexahydrofuroi3,2-b|pyrrole-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|amide 3-4-yl)-1-pyridin-4-ylmethylethyl|)-4-pyrazol-1-phenylpyrrole -1-carboxylic acid ilbenzamide

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)-1 -pyridin-4-ylmethylethyl|benzamide 4-yl)-1-pyridin-4-ylmethyl|-5-thiophen-2-ylnicotinamide 4-tert-butyl-M-|(2-oxo-2-(3-oxo- M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-hexahydrofuro3,2-b|pyrrol-4-yl)-1-pyridin-4-4-yl)-1 - pyridin- 4-ylmethylethyl|-6-phenylnicotinamide ylmethylethyl|benzamide (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-

M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-yl)-1-pyridin-4-ylmethylethyl|iamide and 2-phenylthiazol-4-4-yl)-1-pyridin- 4-ylmethyl/-4-carboxylic acid trifluoromethoxybenzamide (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-4-dimethylamino-M-(2-oxo-2-(3-oxo- yl)-1-pyridin-4-ylmethylethylamide 2-pyridin-3-hexahydrofuroyl3,2-b|pyrrol-4-yl)-1-pyridin-4-ylthiazole-4-carboxylic acid ylmethylethyl|benzamide (2-oxo-2 -(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-

M-(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyridin-4-ylmethylethyl]iamide 5-phenylthiophen-2-4-yl)-1-pyridin-4 -ylmethylethyl|-4-isopropylbenzamide carboxylic acid

(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)-1-pyridine -4-ylmethylethyl|amide 5-pyridin-3-yl)-1-pyridin-3-ylmethylethyl|amide biphenyl-4-ylthiophene-2-carboxylic acid carboxylic acid (2-oxo-2-(3-oxo-hexahydrofuroyl) 2-b|pyrrole-4-M-(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyridin-4-ylmethylethyl)amide 2-methyl-5-4- yl)-1-pyridin-3-ylmethylethyl|-4-phenoxybenzamide phenylfuran-3-carboxylic acid M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole- (2-oxo-2- (3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1-pyridin-3-ylmethylethyl|-3-phenoxybenzamidyl)-1-pyridin-4-ylmethylethyliamide 4-phenylthiophene-2-M- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-carboxylic acid 4-yl)-1-pyridin-3-ylmethylethyl|-4-imidazol-1-(2-oxo-2-( 3-oxo-hexahydrofuro3,2-b|pyrrol-4-ylbenzamidyl)-1-pyridin-4-ylmethylethyl|amide 4-pyridin-3-M-(2-oxo-2-(3-oxo-hexahydrofuro3,2 -b|pyrrole-ylthiophene-2-carboxylic acid 4-yl)-1-pyridin-3-ylmethylethyl|-4-thiophene-2-(2-ox o-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-ylbenzamidyl)-1-pyridin-4-ylmethylethyl|amide 2-thiophen-2-M-(2-oxo-2-(3- oxo-hexahydrofuro3,2-b|pyrrolylthiazole-4-carboxylic acid 4-yl)-1-pyridin-3-ylmethylethyl|-4-oxazol-5- (2-oxo-2-(3-oxo-hexahydrofuro3, 2-b|pyrrol-4-ylbenzamidyl)-1-pyridin-4-ylmethylethyl|amide 2-methyl-5-M-(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyridin-4-ylmethylethyl|amide pyrrolidine-1-sulfonyl/furan-3-carboxylic acid-4-yl)-1-pyridin-3-ylmethylethyl|-4-1H1,2,3|hiadiazol-5-thiylbenzamide (2-oxo-2-(3 -oxo-hexahydrofuro3,2-b|pyrrole-4-M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-yl)-1-pyridin-4-ylmethylethyliamide Z-phenylpyrrole-1 - 4-yl)-1-pyridin-3-ylmethylethyl|-4-pyrazole-1-carboxylic acid ylbenzamide

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)-1 -pyridin-3-ylmethylethyl|benzamide 4-yl)-1-pyridin-3-ylmethylethyl|-5-thiophen-2-4-tert-butyl-N-(2-oxo-2-(3-oxo-ylnicotinamide hexahydrofuroyl) ,2-b|pyrrol-4-yl)-1-pyridin-3-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-ylmethylethyl|benzamide 4-yl)-1- pyridin-3-ylmethylethyl|-6-phenylnicotinamide

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1 -pyridin-3-ylmethylethyl|-4-yl)-1-pyridin-3-ylmethylethyl Iiamide 2-phenylthiazole-4-trifluoromethoxybenzamide carboxylic acid 4-dimethylamino-M-(2-oxo-2-(3-oxo- (2- oxo-2-(3-oxo-hexahydrofuroyl)-1-pyridin-3-ylmethylethylamide 2-pyridin-3-ylmethylethylbenzamide ylthiazole-4-carboxylic acid

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1 -pyridin-3-ylmethylethyl|)-4-isopropylbenzamidyl)-1-pyridin-3-ylmethylethyl Iiamide 5-phenylthiophene-2-4-difluoromethoxy-M-|(2-oxo-2-(3-oxo-carboxylic acid hexahydrofuroyl) . ylmethuethyl|amide 5-pyridine-3-

M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-ylthiophene-2-carboxylic acid 4-yl)-1-pyridin-3-ylmethyl/-4-(2-oxo-2 -(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-trifluoromethylbenzamidyl)-1-pyridin-3-ylmethylethyl|amide 2-methyl-5-4-bromo-M-|(2-oxo-2-( 3-oxo-hexahydrofuroi3,2-phenylfuran-3-carboxylic acid

B|pyrrol-4-yl)-1-pyridin-3-ylmethylethyl|benzamide (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-

Z-bromo-M-|(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyridin-3-ylmethylethyliamide 4-phenylthiophene-2-

B|pyrrol-4-yl)-1-pyridin-3-ylmethylethyl|carboxylic acid benzamide

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1 -pyridin-3-ylmethyl)|-4-vinylbenzamidyl)-1-pyridin-3-ylmethylethyl|amide 4-pyridin-3- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole- 4-ylthiophene-2-carboxylic acid yl)-1-pyridin-3-ylmethylethyl|amide naphthalene-2-(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyrrole-4-carboxylic acid yl) -1-pyridin-3-ylmethylethyl|amide 2-thiophen-2-(2-oxo-2-(3-oxo-hexahydrofuroyl3,2-b|pyrrole-4-ylthiazole-4-carboxylic acid yl)-1-pyridine -3-ylmethylethyl|amide naphthalene-1-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-carboxylic acid yl)-1-pyridin-3-ylmethylethyl|amide 2-methyl- 5- (2-oxo-2-(3-oxo-hexahydrofuroyl)3,2-b|pyrrole-4-(pyrrolidine-1-sulfonyl/furan-3-carboxylic acid-yl)-1-pyridin-3-ylmethylethyl|amide quinoline-b- carboxylic acid (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4 - yl)-1-pyridin-3-ylmethylethylamide 3-phenylpyrrol-1-yl)-1-pyridin-3-ylmethylethylamide benzo(rigiophene-2- carboxylic acid carboxylic acid M-P1-(4-bromobenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole -4- hexahydrofuroi|3,2-5|pyrrol-4-yl)uethyl|benzamidyl)-1-pyridin-3-ylmethylethylamide benzo(rigiophene-3- 4-tert-butyl-M-(1-(4- bromobenzyl)-2-oxo-2-(3-carboxylic acid oxo-hexahydrofuro3,2-pyrrole-4- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl |benzamidyl)-1-pyridin-3-ylmethylethyl|amide benzothiazol-5-M-(1-(4-Bromobenzyl)-2-oxo-2-(3-oxo-carboxylic acid hexahydrofuro3,2-b|pyrrole- 4-yl)ethyl/|-4-trifluoromethoxybenzamide

4 dimethylamino-IM-|1-(4-bromobenzyl)-2-oxo-2- M-P1-(4-bromobenzyl)-2-oxo-2-(3-oxo- (3-oxo-hexahydrofuroi3,2- B|pyrrole-4-hexahydrofuroyl3,2-b|pyrrole-4-iluethyl|-6-yl)ethyl|benzamide phenylnicotinamide

M-(1-(4-Bromobenzyl)-2-oxo-2-(3-oxo-I1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4 -yl)uethyl/|-4-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|amide 2-isopropylbenzamide of phenylthiazole-4-carboxylic acid 4-difluoromethoxy-M-|1-(4-bromobenzyl)-2- oxo-11-(4-bromobenzyl)-2-oxo-2-(3-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro3,2-b|pyrrol-4-yl) pyridine-3-ylthiazole-4-carboxylic acid ethyl|amide 2-yl)ethyl|benzamide

M-P1-(4-bromobenzyl)-2-oxo-2-(3-oxo-I1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4- yl)uethyl/|-4-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|amide 5-trifluoromethyl benzamide of phenylthiophene-2-carboxylic acid 4-Bromo-M-(1-(4-bromobenzyl)-2- oxo-2-(3-oxo-I1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrol-4-yl/ethyl|benzamide hexahydrofuro3,2-b|pyrrole -4-yl)ethyl|amide 5-

3-bromo-M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-pyridine-3-ylthiophene-2-carboxylic acid) hexahydrofuroic acid3,2-5|pyrrol-4-yl/ethyl| benzamide I1-(4-bromobenzyl)-2-oxo-2-(3-oxo-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)ethyl|iamide 2-methyl-hexahydrofuroi3,2-b|pyrrole -4-yl)ethyl|-4-5-phenylfuran-3-carboxylic acid vinylbenzamide I1-(4-bromobenzyl)-2-oxo-2-(3-oxo- (1-(4-bromobenzyl)-2-oxo -2-(3-oxo-hexahydrofuro/3,2-b|pyrrol-4-yl)ethyl|amide 4-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|iIamide of naphtho-phenylthiophene-2-carboxylic acid lin-2-carboxylic acid I1-(4-bromobenzyl)-2-oxo-2-(3-oxo-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro)/3,2 -b|pyrrol-4-yl)uethyl|amide 4-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|iIamide naphtha-pyridine-3-ylthiophene-2-carboxylic acid lin-1-carboxylic acid I1-( 4-bromobenzyl)-2-oxo-2-(3-oxo- (1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro/3,2-b|pyrrol-4-yl) uethyl|amide of 2-hexahydrofuroi3,2-b|Ipyrrol-4-yl)ethyl|Iamide of quinoline-thiophen-2-ylthiazole-4-carboxylic acid b-carboxylic acid I1-(4-bromobenzyl)-2-oxo-2- (3-oxo-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|iamide 2-meth yl-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide ben-5-(pyrrolidine-1-sulfonyl)furan-3-carboxylic acid kis- (bithiophene-2-carboxylic acid lota (1-(4- bromobenzyl)-2-oxo-2-(3-oxo-11-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide ben- phenylpyrrole-1-carboxylic acid (1-(4-bromobenzyl)-2-oxo-2-(3-oxo) - M-P1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrol-4-ylethyliamide benzothi-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl benzamide azole -5-carboxylic acid 4-tert-butyl-M-I|1-(4-fluorobenzyl)-2-oxo-2-(3- (1-(4-bromobenzyl)-2-oxo-2-(3- oxo-oxo-hexahydrofuroi3,2-B| pyrrole-4-hexahydrofuro3,2-5|pyrrole-4-ylethyliamide biphenyl-yl)ethyl|benzamide of 4-carboxylic acid M-(1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)uethyl|/|-4-hexahydrofuroi3,2-b|pyrrole -4-yl)uethyl/|-4-trifluoromethoxybenzamide phenoxybenzamide 4-dimethylamino-M-|1-(4-fluorobenzyl)-2-oxo-2-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-(3-oxo-hexahydrofuroI3,2-b|pyrrole-4-hexahydrofuroI3,2-b|pyrrol-4-yl)ethyl |-3-yl)ethyl|benzamide phenoxybenzamide M-(1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)ethyl|/|-4-hexahydrofuro3,2-b|pyrrole -4-yl)ethyl|-4-imidazol-1- isopropylbenzamide ylbenzamide 4-difluoromethoxy-M-|1-(4-fluorobenzyl)-2-oxo-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro3,2-b|pyrrol-4-yl) )ethyl-4-thiophen-2-yl)ethyl|benzamide ylbenzamide M-P1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)ethyl|/|-4-hexahydrofuroIZ3,2-b|pyrrole -4-yl)ethyl|-4-oxazol-5-trifluoromethylbenzamide ylbenzamide 4-Bromo-M-I|1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-

M-(1-(4-bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrol-4-yl)ethyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl -4- 3-bromo-M-|1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-

1,2,3-Hyadiazol-5-ylbenzamide hexahydrofuro|C,2-b|pyrrol-4-yl)ethyl|benzamide

M-P1-(4-bromobenzyl)-2-oxo-2-(3-oxo- 4-yl)ethyl|-4-pyrazol-1-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl/|-4-ylbenzamide vinylbenzamide

M-P1-(4-bromobenzyl)-2-oxo-2-(3-oxo-I1-(4-fluorobenzyl)-2-oxo-2-(3-oxo- hexahydrofuroiZ3,2-b|pyrrole-4- yl)ethyl|-5-thiophene-2-hexahydrofuroi|3,2-5|pyrrole-4-iluethyl|Iamide naphtha-ylnicotinamide lin-2-carboxylic acid

(1-(4-fluorobutyl)-2-oxo-2-(3-oxo-1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)-2-ylpyrrol-4-yl) )ethyl|iIamide naphtha-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|amide of 2-lin-1-carboxylic acid thiophen-2-ylthiazole-4-carboxylic acid (1-(4-fluorobenzyl)-2- oxo-2-(3-oxo-1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyrrol-4-yl)ethyl|Iamide quinoline-hexahydrofuro3,2-b |pyrrol-4-yl)uethylamide 2-methyl-b-carboxylic acid 5-(pyrrolidine-1-sulfonyl)furan-3-carboxylic acid- (1-(4-fluorobenzyl)-2-oxo-2-(3 Hexahydrofuro3,2-oxo- lutes -b|pyrrol-4-yl)ethyl|amide 3- (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-phenylpyrrole-1-carboxylic acid hexahydrofuro3,2-b|pyrrole-4- yl)ethyl|amide ben-M-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- (bithiophene-3-carboxylic acid hexahydrofuro3,2-5|pyrrol-4-yl)uethyl |benzamide (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-4-tert-butyl-M-|1-(4-chlorobenzyl)-2-oxo-2-(3- hec sahydrofuroi3,2-5|pyrrol-4-ylethyliamide benzothi-oxo-hexahydrofuroi3,2-pyrrole-4-azole-5-carboxylic acid yl)ethyl|benzamide (1-(4-fluorobenzyl)-2-oxo-2- (3-oxo-M-P1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrol-4-ylethyl)iamide biphenyl-hexahydrofuro3,2-b|pyrrol-4-yl )ethyl/|-4- 4-carboxylic acid trifluoromethoxybenzamide

M-P1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-4-dimethylamino-M-(1-(4-chlorobenzyl)-2-oxo-2-hexahydrofuroyl)3,2-b|pyrrole- 4-yl)ethyl|-4- (Z-oxo-hexahydrofuroi3,2-B| pyrrole-4-phenoxybenzamide yl)ethyl|benzamide

М-П1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-М-П1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- hexahydrofuroiZ3,2-b|pyrrole- 4-yl)ethyl|-3-hexahydrofuroi|3,2-b|pyrrol-4-yl)uethyl|/|-4-phenoxybenzamide isopropylbenzamide

M-(1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-4-difluoromethoxy-M-|1-(4-chlorobenzyl)-2-oxo- hexahydrofuroiZ3,2-b|pyrrole-4- yl)ethyl|-4-imidazol-1 - 2-(3-oxo-hexahydrofuroyl3,2-B| pyrrole-4-ylbenzamide yl)ethyl|benzamide

М-П1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-М-П1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole- 4-yl)ethyl|-4-thiophene-2-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl/|-4-ylbenzamide trifluoromethylbenzamide

M-P1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-4-bromo-M-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)3,2 -b|pyrrol-4-yl)ethyl|-4-oxazol-5-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|benzamide ylbenzamide 3-bromo-M-(1-(4-chlorobenzyl)-2 -oxo-2-(3-oxo-

M-(1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)uethyl /|-4- M-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-

1,2,3-Hyadiazol-5-ylbenzamide hexahydrofuroyl 3,2-b|pyrrol-4-yl)ethyl|/|-4-

M-P1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-vinylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-pyrazol-1-(1-(4-chlorobenzyl )-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|ylamide naphtha-

M-(1-(4-fluorobenzyl)-2-oxo-2-(3-oxoline-2-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-5-thiophen-2- ( 1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-ylnicotinamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|ylamide naphtha-

M-(1-(4-fluorobenzyl)-2-oxo-2-(3-oxoline-1-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-6- (1-(4 -chlorobenzyl)-2-oxo-2-(3-oxo-phenylnicotinamide hexahydrofuroi3,2-b|Ipyrrol-4-yl)ethylamide quinoline- (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo - b-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 2-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-phenylthiazole-4-carboxylic acid hexahydrofuro3), 2-b|pyrrol-4-yl)ethyl|amide ben- (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo- (bigiophene-2-carboxylic acid) hexahydrofuroic acid) -4-yl)ethyl|amide 2-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-pyridine-3-ylthiazole-4-carboxylic acid hexahydrofuro3,2-b|pyrrole-4- yl)ethyl|amide ben- (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo- (bithiophene-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 5- (1-(4-Chlorobenzyl)-2-oxo-2-(3-oxo-phenylthiophene-2-carboxylic acid hexahydrofuroic|3,2-5|pyrrole-4-iluethylIiamide benzothi- (1-(4-fluorobenzyl )-2-oxo-2-(3-oxo-azole-5-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)eth L|amide 5-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-pyridine-3-ylthiophene-2-carboxylic acid hexahydrofuro|3,2-5|pyrrole-4-ylethyl)iamide biphenyl- (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-4-carboxylic acid hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|iamide 2-methyl-M-(1-(4 -chlorobenzyl)-2-oxo-2-(3-oxo-5-phenylfuran-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4-(1-(4-fluorobutyl)- 2-oxo-2-(3-oxo-phenoxybenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4-M-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo - phenylthiophene-2-carboxylic acid hexahydrofuroi|3,2-b|pyrrole-4-iluethyl|-3- (1-(4-fluorobenzyl)-2-oxo-2-(3-oxo-phenoxybenzamide hexahydrofuroi3,2-b) |pyrrole-4-yl)ethyl|amide of 4-pyridine-3-ylthiophene-2-carboxylic acid

M-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-4 difluoromethoxy-M-|1-(3,4-dichlorobenzyl)-2-hexahydrofuroic3,2-b|pyrrole-4- yl)ethyl|-4-imidazol-1-oxo-2-(3-oxo-hexahydrofuroyl,2-b|pyrrol-4-ylbenzamide yl)ethyl|benzamide

M-(P1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- M-(P1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2- b|pyrrol-4-yl)ethyl|-4-thiophen-2-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl/|-4-ylbenzamide trifluoromethylbenzamide

M-(P1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-4-bromo-M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-hexahydrofuroyl)3, 2-b|pyrrol-4-yl)ethyl|-4-oxazol-5-oxo-hexahydrofuroi3,2-5|pyrrol-4-yl)ethyl|benzamide ylbenzamide Z-bromo-M-|1-(3,4 -dichlorobenzyl)-2-oxo-2-(3-

M-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-oxo-hexahydrofuro3,2-5|pyrrol-4-yl)ethyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl )ethyl|-4- M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-

I1,2,3Hiadiazol-5-ylbenzamide hexahydrofuro|3,2-b|pyrrol-4-yl) ethyl)-4-

M-(P1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-vinylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-pyrazol-1- I1-(3,4 -dichlorobenzyl)-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|ylamide naphtha-

M-(P1-(4-chlorobenzyl)-2-oxo-2-(3-oxoline-2-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-5-thiophen-2-I1 -(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-ylnicotinamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|ylamide naphtha-

M-(P1-(4-chlorobenzyl)-2-oxo-2-(3-oxoline-1-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-6- I1-(3, 4-dichlorobenzyl)-2-oxo-2-(3-oxo-phenylnicotinamide hexahydrofuro3,2-b|Ipyrrol-4-yl)ethylamide quinoline- (1-(4-chlorobenzyl)-2-oxo-2-(3- Oxo-b-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 2-I1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-phenylthiazole-4-carboxylic acid) hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide ben- (1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- (bHiophene-2-carboxylic acid) hexahydrofuro3,2-b |pyrrole-4-yl)ethyl|amide 2-11-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-pyridine-3-ylthiazole-4-carboxylic acid hexahydrofuro3,2-b|pyrrole -4-yl)ethyl|amide ben-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- (bithiophene-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl) ethyl|amide 5- I1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-phenylthiophene-2-carboxylic acid hexahydrofuroic|3,2-5|pyrrole-4-iluethylIiamide benzothi- (1- (4-chlorobenzyl)-2-oxo-2-(3-oxo-azole-5-carboxylic acid hexahydrofuroic3,2- b|pyrrol-4-yl)ethyl|amide 5-11-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-pyridine-3-ylthiophene-2-carboxylic acid hexahydrofuroic|3,2- 5|pyrrol-4-ylethyliamide biphenyl- (1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-4-carboxylic acid hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|iamide 2- methyl-M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-5-phenylfuran-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|- 4- (1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-phenoxybenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4-M-(1-(3,4- dichlorobenzyl)-2-oxo-2-(3-oxo-phenylthiophene-2-carboxylic acid hexahydrofuroic|3,2-b|pyrrole-4-iluethyl|-3- (1-(4-chlorobenzyl)-2-oxo- 2-(3-oxo-phenoxybenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4-M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-pyridine) -3-ylthiophene-2-carboxylic acid hexahydrofuroyl 3,2-b|pyrrol-4-yl)ethyl|-4-imidazole-1-(1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- ylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 2-M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-thiophen-2-ylthiazol-4- carbon fiber Slots of hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-thiophen-2- (1-(4-chlorobenzyl)-2-oxo-2-(3-oxo-ylbenzamide) hexahydrofuro3,2-b|pyrrole -4-yl)ethyl|iamide 2-methyl-N-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-5-(pyrrolidine-1-sulfonyl)furan-3-carbon oxy-hexahydrofuroic|3,2-b|pyrrole-4-iluethyl|-4-oxazol-5-lotylbenzamide (1-(4-chlorobenzyl)-2-oxo-2-(3-oxo- M-(P1- (3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 3-hexahydrofuro|3,2-b|pyrrol-4-yl) uethyl|/|-4-phenylpyrrole-1-carboxylic acid I1,2,3Hiadiazol-5-ylbenzamide

IM-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-M-(P1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)3, 2-5|pyrrol-4-yl/ethyl|benzamide hexahydrofuroi3,2-b|pyrrol-4-yl)uethyl|-4-pyrazol-1- 4-tert-butyl-M-|1-(3,4- dichlorobenzyl)-2-oxo-2-ylbenzamide (3-oxo-hexahydrofuroyl3,2-b|pyrrole-4-M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-yl) )ethyl|hexahydrofuroic benzamide|3,2-b|pyrrole-4-iluethyl|-5-thiophene-2-

M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-ylnicotinamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4- M-(1-(3, 4-dichlorobenzyl)-2-oxo-2-(3-oxo-trifluoromethoxybenzamide hexahydrofuroi|3,2-b|pyrrole-4-iluethyl|-6-4 dimethylamino-M-|1-(3,4-dichlorobenzyl)- 2- phenylnicotinamide oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-I1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxoyl)ethyl|benzamide hexahydrofuro3, 2-b|pyrrol-4-yl)uethyl|amide2-

M-(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo-phenylthiazole-4-carboxylic acid hexahydrofuro3,2-bI|pyrrol-4-yl) ethyl/-4- isopropylbenzamide

(1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-b| Pyrrol-4-yl)ethyl|amide 2-yl)-1-thiophen-2-ylmethylethyl|amide benzo(thiophene-3-pyridine-3-ylthiazole-4-carboxylic acid carboxylic acid (1-(3,4-dichlorobenzyl )-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroyl) -1-thiophen-2-ylmethylethylamide benzothiazole-5-phenylthiophene-2-carboxylic acid carboxylic acid (1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo- (2-oxo-2-( 3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 5-yl)-1-thiophen-2-ylmethylethylamide biphenyl-4-pyridine-3-ylthiophene -2-carboxylic acid carboxylic acid (1-(3,4-dichlorobenzyl)-2-oxo-2-(3-oxo- M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole) - hexahydrofuro3,2-b|pyrrol-4-yl)ethylamide 2-methyl-4-yl)-1-thiophen-2-ylmethylethyl|-4-phenoxybenzamide 5-phenylfuran-3-carboxylic acid M-(2-oxo 2-(3-oxo-hexahydrofuroi3,2-b|pyrrole- (1-(3,4-dichlorobenzyl) -2-oxo-2-(3-oxo-4-yl)-1-thiophen-2-ylmethylethyl|-3-phenoxybenzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|amide 4-M-(2 -oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-phenylthiophene-2-carboxylic acid 4-yl)-1-thiophen-2-ylmethylethyl|-4-imidazol-1-(1-(3, 4-Dichlorobenzyl)-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 4-M-(2-oxo-2-(3-oxo-hexahydrofuro3, 2-b|pyrrole-pyridine-3-ylthiophene-2-carboxylic acid 4-yl)-1-thiophen-2-ylmethylethyl|-4-thiophene-2-(1-(3,4-dichlorobenzyl)-2-oxo -2-(3-oxo-ylbenzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|amide 2-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-thiophene- 2-ylthiazole-4-carboxylic acid 4-yl)-1-thiophen-2-ylmethylethyl)|-4-oxazol-5-

I(1-(3,4-dichlorobenzyl)2-oxo-2-(3-oxo-ylbenzamide hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|iamide 2-methyl-M-(2-oxo-2 -(3-oxo-hexahydrofuroi3,2-b|pyrrol-5-(pyrrolidine-1-sulfonyl)furan-3-carboxylic acid-4-yl)-1-thiophen-2-ylmethylethyl)-4-I(1, 2,3|hiadiazol-5-lotylbenzamide (1-(3,4-dichlorobenzyl)-2-oxo-2-(3-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b) pyrrole-oxohexahydrofuro3,2-b|pyrrol-4-yl)ethylamide /3-4-yl)-1-thiophen-2-ylmethylethyl|-4-pyrazole-1-phenylpyrrole-1-carboxylic acid ylbenzamide

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)-1 -thiophen-2-ylmethylethyl|benzamide 4-yl)-1-thiophen-2-ylmethylethyl|-5-thiophen-2- 4-tert-butyl-N-(2-oxo-2-(3-oxo-ylnicotinamide) hexahydrofuroiZ3 ,2-b|pyrrol-4-yl)-1-thiophen-2-M-(2-oxo-2-(3-oxo-hexahydrofuroyl3,2-b|pyrrol-ylmethylethyl)benzamide 4-yl)-1-thiophen- 2-ylmethylethyl)|-6-phenylnicotinamide

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1 -thiophen-2-ylmethylethyl|-4-yl)-1-thiophen-2-ylmethylethyl|iamide 2-phenylthiazol-4-trifluoromethoxybenzamide carboxylic acid 4-dimethylamino-M-(2-oxo-2-(3-oxo- ( 2-oxo-2-(3-oxo-hexahydrofuroyl)-1-thiophen-2-ylmethylethylamide 2-pyridin-3-ylmethylethylbenzamide ylthiazole-4-carboxylic acid

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1 -thiophen-2-ylmethylethyl|-4-isopropylbenzamidyl)-1-thiophen-2-ylmethylethyl|iamide 5-phenylthiophene-2-4-difluoromethoxy-M-|(2-oxo-2-(3-oxo-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)-1-thiophen-2- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-ylmethylethyl)-1-thiophene-2 -ylmethylethylamide 5-pyridin-3-

M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-ylthiophene-2-carboxylic acid 4-yl)-1-thiophen-2-ylmethylethyl|-4- (2-oxo-2 -(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-trifluoromethylbenzamidyl)-1-thiophen-2-ylmethylethylamide 2-methyl-5-4-bromo-M-|(2-oxo-2-(3- oxo-hexahydrofuroi3,2-phenylfuran-3-carboxylic acid

B|pyrrol-4-yl)-1-thiophen-2-ylmethylethyl|benzamide (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-

Z-bromo-M-|(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-thiophen-2-ylmethylethyl|iamide and 4-phenylthiophene-2-

Bipyrrol-4-yl)-1-thiophen-2-ylmethylethylbenzamide carboxylic acid

M-(2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-4-yl)-1 -thiophen-2-ylmethylethyl/|-4-vinylbenzamidyl)-1-thiophen-2-ylmethylethylamide 4-pyridin-3- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4- ylthiophene-2-carboxylic acid yl)-1-thiophen-2-ylmethylethylamide naphthalene-2-(2-oxo-2-(3-oxo-hexahydrofuroyl)-1-pyrrole-4-carboxylic acid yl)-1-thiophene -2-ylmethylethylamide 2-thiophen-2- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-ylthiazole-4-carboxylic acid yl)-1-thiophen-2-ylmethylethylamide naphthalene- 1- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-carboxylic acid yl)-1-thiophen-2-ylmethylethyl|amide 2-methyl-5-(2-oxo-2 -(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-(pyrrolidine-1-sulfonyl/furan-3-carboxylic acid-yl)-1-thiophen-2-ylmethylethylamide chiinoline-6-thicarboxylic acid (2- oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)-1-thiophen-2- ylmethylethylamide 3-phenylpyrrol-1-yl)-1-thiophen-2-ylmethylethylamide benz o(bithiophene-2-carboxylic acid carboxylic acid M-P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroic|3,2-5|pyrrol-4-yl)ethyl|benzamide

4-tert-butyl-M-(1-(4-aminobenzyl)-2-oxo-2-(3-M-P1-(4-Aminobenzyl)-2-oxo-2-(3-oxo-oxo-hexahydrofuro) |3,2-b|pyrrol-4-yl)ethyl|benzamide hexahydrofuroyl,2-b|pyrrole-4-yl)ethyl|-5-thiophene-2-

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-ylnicotinamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl/|-4- M-(1-(4-Aminobenzyl) )-2-oxo-2-(3-oxo-trifluoromethoxybenzamide hexahydrofuro|3,2-b|pyrrole-4-iluethyl|-6- 4 dimethylamino-IM-|1-(4-aminobenzyl)-2-oxo-2 - phenylnicotinamide (Z-oxo-hexahydrofuro3,2-b|pyrrole-4- (1-(4-Aminobenzyl)-2-oxo-2-(3-oxoyl)ethyl)benzamide hexahydrofuro3,2-b|pyrrole- 4-yl)ethyl|amide 2-

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-phenylthiazole-4-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4- I1-(4 -aminobenzyl)-2-oxo-2-(3-oxo-isopropylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 2-4-difluoromethoxy-M-|1-(4-aminobenzyl)-2- Oxopyridine-3-ylthiazole-4-carboxylic acid 2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-1-(4-aminobenzyl)-2-oxo-2-(3-oxoyl) ethyl|benzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|amide 5-

M-(1-(4-aminobenzyl)-2-oxo-2-(3-oxo-phenylthiophene-2-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4- I1-(4 -aminobenzyl)-2-oxo-2-(3-oxo-trifluoromethylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 5-4-bromo-M-(1-(4-aminobenzyl)-2- oxo-2-(3-oxo-pyridine-3-ylthiophene-2-carboxylic acid hexahydrofuro3,2-5|pyrrol-4-yl/ethyl|benzamide I1-(4-aminobenzyl)-2-oxo-2-(3 -oxo-

3-bromo-M-(1-(4-aminobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)uethyl|iamide 2-methyl-hexahydrofuroi|Z ,2-5|pyrrol-4-yl)ethyl|benzamide of 5-phenylfuran-3-carboxylic acid

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-I1-(4-aminobenzyl)-2-oxo-2-(3-oxo- hexahydrofuro3,2-b|pyrrole-4 -yl)uethyl/|-4-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|amide 4-vinylbenzamide of phenylthiophene-2-carboxylic acid (1-(4-aminobenzyl)-2-oxo-2-(3 -oxo-1-(4-aminobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|iIamide naphtha-hexahydrofuro3,2-b|pyrrol-4-yl )ethyl|amide of 4-lin-2-carboxylic acid pyridine-3-ylthiophene-2-carboxylic acid (1-(4-aminobenzyl)-2-oxo-2-(3-oxo-11-(4-aminobenzyl)- 2-oxo-2-(3-oxo-hexahydrofuroiZ3,2-b|pyrrol-4-yl)ethyl|iIamide naphtha-hexahydrofuro!|Z,2-b|pyrrol-4-yl)uethyl|amide 2-lin- 1-carboxylic acid thiophene-2-ylthiazole-4-carboxylic acid (1-(4-aminobutyl)-2-oxo-2-(3-oxo- I1-(4-aminobenzyl)-2-oxo-2-(3 -oxo-hexahydrofuroi3,2-b|Ipyrrol-4-yl)ethyl|Iamide quinoline-hexahydrofuroi3,2-b|pyrrol-4-yl)uethylamide 2-methyl-b-carboxylic acid 5-(pyrrolidine-1-sulfonyl )furan-3-carboxylic acid- (1-(4-aminobenzyl)-2-oxo-2-(3-oxo- hexahydrofuro3,2-b|pyro 1-4-yl)ethylamide ben-I1-(4-aminobenzyl)-2-oxo-2-(3-oxo- (bigiophen-2-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl) ethyl|amide 3-(1-(4-aminobenzyl)-2-oxo-2-(3-oxo-phenylpyrrole-1-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide ben- M- (1-benzyl-2-oxo-2-(3-oxo- (bithiophene-3-carboxylic acid hexahydrofuro3,2-5|pyrrol-4-yl)ethyl)benzamide (1-(4-aminobenzyl)-2- oxo-2-(3-oxo-4-tert-butyl-M-|P1-benzyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrole-4-ylethyl]iamide benzothi-hexahydrofuroi|3, 2-5|pyrrol-4-yl)ethyl|benzamide azole-5-carboxylic acid M-P1-benzyl-2-oxo-2-(3-oxo- (1-(4-aminobenzyl)-2-oxo-2 -(3-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)uethyl|/|-4-hexahydrofuroi3,2-5|pyrrol-4-ylethyliamide biphenyl-trifluoromethoxybenzamide of 4-carboxylic acid 4-dimethylamino-M -(1-benzyl-2-oxo-2-(3-oxo-

M-(1-(4-aminobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrol-4-yl)uethyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)uethyl /|-4- M-(1-benzyl-2-oxo-2-(3-oxo-phenoxybenzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl/|-4-

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo- isopropylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-3-4 difluoromethoxy-M-|1-benzyl- 2-oxo-2-(3-phenoxybenzamide oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|benzamide

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-M-P1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroyl)-2-b|pyrrol-4-yl )ethyl|-4-imidazol-1-hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl/|-4-ylbenzamide trifluoromethylbenzamide

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-4-bromo-M-HP1-benzyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole) -4-yl)ethyl|-4-thiophene-2-hexahydrofuroyl|3,2-5|pyrrol-4-yl)uethyl|benzamide ylbenzamide 3-bromo-M-H1-benzyl-2-oxo-2-(3 -oxo-

M-(1-(4-aminobenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-5|pyrrol-4-yl)ethyl|benzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl |-4-oxazol-5-M-(1-benzyl-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4-

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo-vinylbenzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-P-benzyl-2-oxo-2- (3-oxo-hexahydrofuroi|3,2-

1,2,3-Hyadiazol-5-ylbenzamide p|Ipyrrol-4-yl)ethyl|iamide of naphthalene-2-carboxylic acid

M-(P1-(4-aminobenzyl)-2-oxo-2-(3-oxo- hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-pyrazol-1-ylbenzamide

(1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2- P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-

Bipyrrol-4-yl)ethylamide of naphthalene-1-carboxylic acid bipyrrol-4-yl)ethylamide of 2-thiophen-2-ylthiazol-4-carboxylic acid (1-benzyl-2-oxo-2-(3- oxo-hexahydrofuroi|3,2- P-beuyl-2-oxo-2-(3-oxo-hexahydrofuroi3,2- p|pyrrol-4-yl)ethylamide of quinoline-b-carboxylic acid BIpyrrol-4-yl)ethyl| Amide 2-methyl-5-(pyrrolidin-1-(1-benzyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-sulfonyl)furan-3-carboxylic acid p|pyrrol-4-yl) ethylamide benzo(b|thiophene-2-carboxylic acid P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroic|3,2- bipyrrol-4-yl)ethylamide 3-phenylpyrrole-1-carboxylic acid (1-benzyl -2-oxo-2-(3-oxo-hexahydrofuroic|3,2- p|pyrrol-4-yl)ethylamide benzo(b|thiophene-3-carboxylic acid 4-(2-(4-tert-butyl-benzylsulfanyl) )-4- methylpentanoyltetrahydrofuroic acid3,2-BI|pyrrol-3-one (1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroic|3,2- 4-(2-(4-tert-butyl- benzylsulfanyl)-3-(4-

BIpyrrol-4-yl)ethyl|amide benzothiazole-5-carbonic hydroxyphenyl)propionyl)| tetrahydrofuroic3,2- acids B|pyrrol-3-one (1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroic|3,2- 2-isobutyl-1-(3-oxo-hexahydrofuroic3,2- p Pyrrol-4-yl)ethylamide biphenyl-4-carboxylic acid B|pyrrol-4-yl)-4-(3-phenylpyrrol-1-yl)butane-1,4-dione and 2-isobutyl-1-( 3-oxo-hexahydrofurois!3,2-

M-(1-benzyl-2-oxo-2-(3-oxo-B|pyrrol-4-yl)-4-(3-phenylpyrrolidin-1-yl)butan-1,4-hexahydrofuroyl3,2-b| pyrrole-4-yl)uethyl/|-4-dione phenoxybenzamide 2-(4-hydroxybenzyl)-1-(3-oxo-

M-(1-benzyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)-4-(3-phenylpyrrole-1- hexahydrofuro)3,2-b|pyrrole- 4-yl)ethyl|-3-yl)butan-1,4-dione phenoxybenzamide 2-(4-hydroxybenzyl)-1-(3-oxo-

M-(1-benzyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)-4-(3-hexahydrofuro3,2-b|pyrrol-4-yl) ethyl|-4-imidazol-1-phenylpyrrolidin-1-yl)butan-1,4-dione ylbenzamide 4-(1,3-dihydroisoindol-2-yl)-2-isobutyl-1-(3-

M-(1-benzyl-2-oxo-2-(3-oxo-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)butane-1,4-dione hexahydrofuroiZ3,2-b|pyrrole-4 -yl)ethyl|-4-thiophen-2- 4-(1,3-dihydroisoindol-2-yl)-2-(4- ylbenzamide hydroxybenzyl)-1-(3-oxo-hexahydrofuroi3,2-

M-(1-benzyl-2-oxo-2-(3-oxo-B|pyrrol-4-yl)butan-1,4-dione hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|-4- oxazol-5-4-(3,4-dihydro-1H-isoquinolin-2-yl)-2-isobutyl-1-ylbenzamide (3-oxo-hexahydrofuro3,2-5|pyrrol-4-yl)butan-1 ,4-

M-P1-benzyl-2-oxo-2-(3-oxodione hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|-4- 4-(3,4-dihydro-1H-isoquinoline-2- yl)-2-(4-

I1,2,3hiadiazol-5-ylbenzamide hydroxybenzyl)-1-(3-oxo-hexahydrofuroi3,2-

M-(1-benzyl-2-oxo-2-(3-oxo-B|pyrrol-4-yl)butan-1,4-dione hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4- pyrazole-1- In addition, compounds of the present invention ilbenzamide include, but are not limited to, the following

M-(1-benzyl-2-oxo-2-(3-oxo) examples, which are (Zab5, so) or (Zak, hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-5-thiophene -2- taz) isomer of the general formula (I), where 2-0 and ilnicotinamide VEN', and also include equivalent analogs,

M-P1-benzyl-2-oxo-2-(3-oxo- are included in the full definition of 72 and K!. hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-6- M-(1-(4 -hydroxybenzyl)-2-oxo-2-(3-oxo-phenylnicotinamide hexahydrofuroi|3,2-b|pyridin-4-yl)ethyl|benzamide (1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi |3,2- 4-tert-butyl-M-|1-(4-hydroxybenzyl)-2-oxo-2-

B|pyrrole-4-yl)ethyl|iamide 2-phenylthiazole-4-carboxylic (3-oxo-hexahydrofuroi|3,2- M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-

BIpyrrole-4-yl)ethyl|amide 2-pyridin-3-ylthiazol-4-hexahydrofuroi|3,2-b|pyridin-4-yl)ethyl)-4-carboxylic acid trifluoromethoxybenzamide (1-benzyl-2-oxo- 2-(3-oxo-hexahydrofuroic|3,2-4 dimethylamino-M-|1-(4-hydroxybenzyl)-2- p|Ipyrrol-4-yl)ethylamide 5-phenylthiophene-2-carbonic oxo-2-( 3-oxo-hexahydrofuroi3,2-b|pyridine-4-acid yl)ethyl|benzamide (1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2- M-(1-(4- hydroxybenzyl)-2-oxo-2-(3-oxo-

BIpyrrole-4-yl)ethyl|amide 5-pyridin-3-ylthiophene-2-hexahydrofuroi|3,2-b|pyridin-4-yl)ethyl)-4-carboxylic acid isopropylbenzamide (1-benzyl-2-oxo- 2-(3-oxo-hexahydrofuroic|3,2-4 difluoromethoxy-M-|1-(4-hydroxybenzyl)-2-

BIpyrrol-4-yl)ethyl|amide 2-methyl-5-phenylfuran-3-oxo-2-(3-oxo-hexahydrofuroic3,2-b|pyridin-4-carboxylic acid yl)ethyl|benzamide (1-benzyl- 2-oxo-2-(3-oxo-hexahydrofuroi|3,2- M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-

BIpyrrole-4-yl)ethylamide. 4-phenylthiophene-2-carbonic hexahydrofuroic3,2-b|Ipyridin-4-yl)ethyl/|-4- acid trifluoromethylbenzamide (1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroic|3,2- 4 -Bromo-M-|1-(4-hydroxybenzyl)-2-oxo-2-(3-

BIpyrrole-4-yl)ethyl|amide of 4-pyridine-3-ylthiophene-2-oxo-hexahydrofuro3,2-b|pyridine-4-carboxylic acid yl)ethyl|benzamide

3-bromo-M-(1-(4-hydroxybenz)-2-oxo-2-(3-1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-oxo-hexahydrofuroyl)3,2-p pyridine-4-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide 2-yl)ethyl|benzamide of methyl-5-phenylfuran-33-carboxylic acid

M-(P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-I1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo- hexahydrofuroiZ,2-b|Ipyridine-4 -yl)ethyl/|-4-hexahydrofuroyl(2-b|Ipyridin-4-yl)ethyl|amide 4-vinylbenzamide of phenylthiophene-2-carboxylic acid (1-(4-hydroxybenzyl)-2-oxo-2-(3 -oxo- I1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|iamide naphth-hexahydrofuroi3,2-b|Ipyridin-4-yl )ethyl|amide of 4-talin-2-carboxylic acid pyridine-3-ylthiophene-2-carboxylic acid (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-11-(4-hydroxybenzyl)- 2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|iamide naphth-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide 2-talin-1-carbon thiophene-2-ylthiazole-4-carboxylic acid

I(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo- I1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|Ipyridine-4- yl)ethyl|iamide quino-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|amide of 2-lin-b6-carboxylic acid methyl-5-(pyrrolidine-1-sulfonyl)furan-3-

I(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-carboxylic acid hexahydrofuro3,2-b|pyridin-4-yl)lethylamide ben- P1-(4-hydroxybenzyl)-2-oxo- 2-(3-oxo- (bithiophene-2-carboxylic acid hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide 3- (1-(4-Hydroxybenzyl)-2-oxo-2-(3- oxo-phenylpyrrole-1-carboxylic acid hexahydrofuroi|Z,2-5|Ipyridin-4-yl)ethyl|amide ben-M-13-methyl-1-(3-oxo-hexahydrofuroi3,2-zo(bHiophen-Z- carboxylic acid BIpyridine-4-carbonyl)butyl benzamide (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4-tert-butyl-N-III-methyl-1-(3-oxo-hexahydrofuroyl)3 ,2-b|pyridin-4-yl)lethylamide benzo-hexahydrofuro3,2-b|pyridin-4-thiazole-5-carboxylic acid carbonyl)butyl|benzamide (1-(4-hydroxybenzyl)-2-oxo-2- (3-oxo-M-3-methyl-1-(3-oxo-hexahydrofuro3,2-hexahydrofuro3,2-b|pyridin-4-yl)lethylamide biphenyl-BIpyridin-4-carbonyl)butyl|-4-nyl- 4-carboxylic acid trifluoromethoxybenzamide

M-(P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4 dimethylamino-M-|3-methyl-1-(3-oxo-hexahydrofuroi3,2-b|garidin-4-yl) )ethyl|-4- hexahydrofuroi3,2-b|pyridine-4-phenoxybenzamide carbonyl)butyl|benzamide

M-(P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4-isopropyl-M-(3-methyl-1-(3-oxo-hexahydrofuroyl)-2-oxo-2-pyridine-4- yl)ethyl|-3-hexahydrofuroi|3,2-5|pyridine-4-phenoxybenzamide carbonyl)butyl|benzamide

M-(P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-4 difluoromethoxy-M-|3-methyl-1-(3-oxo-hexahydrofuroyl)-3,2-b|Ipyridin-4-yl )ethyl|-4-imidazole-hexahydrofuroyl3,2-b|pyridine-4-1-ylbenzamide carbonyl)butyl|benzamide

M-(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-M-3-methyl-1-(3-oxo-hexahydrofuro3,2-hexahydrofuro3,2-b|Ipyridin-4-yl) )ethyl-4-thiophene-2-bipyridine-4-carbonyl)butyl|-4-ylbenzamide trifluoromethylbenzamide

M-P1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-4-bromo-M-(3-methyl-1-(3-oxo-hexahydrofuroyl)-2-oxo-2-yl) )ethyl|-4-oxazol-hexahydrofuroi|3,2-b|pyridine-4-M-(3-methyl-1-(3-5-ylbenzamide oxo-hexahydrofuroi)3,2-5|-pyridine-4-carbo-

M-(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxonyl)butyl|-4-oxazol-5-ylbenzamide hexahydrofuroyl)3,2-b|pyridin-4-yl)ethyl|-4 - M-III-methyl-1-(3-oxo-hexahydrofuroi3,2-

1,2,3-Hyadiazol-5-ylbenzamide p|Ipyridine-4-carbonyl)butyl|-4-(1,2,3|Hyadiazole-4-

M-(P1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-ylbenzamide hexahydrofuro3,2-b|pyridin-4-yl)ethyl|-4-pyrazol-M-3-methyl-1- (3-oxo-hexahydrofuro3,2-1-ylbenzamide BIpyridine-4-carbonyl)butyl|-4-pyrazole-1-ylbenzamide

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-M-13-methyl-1-(3-oxo-hexahydrofuroyl)-3,2-hexahydrofuroyl)3,2-b|pyridin-4-yl )ethyl|-5-thiophene-b|Ipyridine-4-carbonyl)butyl|-5-thiophene 2- 2-ylnicotinamide ylnicotinamide

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-M-13-methyl-1-(3-oxo-hexahydrofuro3,2-hexahydrofuro13,2-b|pyridin-4-yl) )ethyl|-6- b|Ipyridine-4-carbonyl)butyl|-6-phenylnicotinamide phenylnicotinamide 13-methyl-1-(3-oxo-hexahydrofuroi3,2- (1-(4-hydroxybenzyl)-2-oxo-2 -(3-oxo- p|Ipyridine-4-carbonyl)butyl|amide 2-phenylthiazole-4-hexahydrofuro3,2-in|Ipyridin-4-yl)ethyl|amide 2-carboxylic acid phenylthiazole-4-carboxylic acid IZ- methyl-1-(3-oxo-hexahydrofuroi3,2- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-b|Ipyridine-4-carbonyl)butyl|amide 2-pyridine-3- hexahydrofuro3,2-in|Ipyridin-4-yl)ethyl|amide of 2-ylthiazole-4-carboxylic acid pyridine-3-ylthiazole-4-carboxylic acid I3-methyl-1-(3-oxo-hexahydrofuro3,2- (1 -(4-hydroxybenzyl)-2-oxo-2-(3-oxo- p|Ipyridine-4-carbonyl)butyl|iamide 5-phenylthiophene-2- hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide 5-carboxylic acid phenylthiophene-2-carboxylic acid 3-methyl-1-(3-oxo-hexahydrofuroic acid3,2- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-b|Ipyridine-4 -carbonyl) to be Pyridine-3-ylthiophene-2-carboxylic acid 5-pyridine-3-hexahydrofuroyl)ethylamide 5-ylthiophene-2-carboxylic acid

13-methyl-1-(3-oxo-hexahydrofuro3,2-4-tert-butyl-N-|1-cyclopropylmethyl-2-oxo-2-p|Ipyridine-4-carbonyl)butyl|amide 2-methyl-5 - (Z-oxo-hexahydrofuro3,2-b|pyrrole-4-phenylfuran-3-carboxylic acid yl)ethyl|benzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-

Bipyridine-4-carbonyl)butyliamide 4-phenylthiophene-2-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4-carboxylic acid trifluoromethoxybenzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-4-dimethylamino-M-|1-cyclopropylmethyl-2- p|Ipyridine-4-carbonyl)butyl|amide 4-pyridine-3-oxo-2-( 3-oxo-hexahydrofuro3,2-b|pyrrole-4-ylthiophene-2-carboxylic acid yl)ethyl|benzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-4-isopropyl-M-/1-cyclopropylmethyl-2-oxo-2-(3-

BIpyridine-4-carbonyl)butyl|amide 2-thiophene-2-oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|benzamide ylthiazole-4-carboxylic acid 4-difluoromethoxy-M-|1-cyclopropylmethyl-2 -

13-methyl-1-(3-oxo-hexahydrofuroi3,2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-

B|Ipyridine-4-M-|13-methyl-1-(3-oxo-yl)ethyl|benzamide hexahydrofuro3,2-b|Ipyridine-4-carbonyl)butyl|-4-M-(1-cyclopropylmethyl-2 -oxo-2-(3-oxo-oxazol-b5-ylbenzamide hexahydrofuroi|3,2-b|pyrrol-4-yl) ethyl)-4-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-trifluoromethylbenzamide

BIpyridine-4-carbonyl)butyl|/-4-1Н1,2,3|hyadiazol-4-4-Bromo-M-P1-cyclopropylmethyl-2-oxo-2-(3-ylbenzamide oxo-hexahydrofuroi3,2-b| pyrrole-4-yl)ethyl|benzamide

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-3-bromo-M-|1-cyclopropylmethyl-2-oxo-2-(3-

BIpyridine-4-carbonyl)butyl|-4-pyrazol-1-ylbenzamide oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|benzamide

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-p|Ipyridine-4-carbonyl)butyl|-5-thiophene 2-hexahydrofuroyl,2-b|pyrrol-4-yl)ethyl-4-ylnicotinamide vinylbenzamide

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-P1-cyclopropylmethyl-2-oxo-2-(3-p|Ipyridine-4-carbonyl)butyl|-6-phenylnicotinamide oxohexahydrofuro!|Z, 2-b|pyrrol-4-yl)lethyl|amide na-

3-methyl-1-(3-oxo-hexahydrofuro-3,2-phthalene-2-carboxylic acid)

BIpyridine-4-carboshl)butyl|Iiamide 2-phenylthiazol-4-P1-cyclopropylmethyl-2-oxo-2-(3- carboxylic acid oxohexahydrofuro|3,2-b|pyrrol-4-yl)ethylIiamide na-

13-methyl-1-(3-oxo-hexahydrofuro3,2-phthalene-1-carboxylic acid p|Ipyridine-4-carbonyl)butyl|amide 2-pyridine-3-P1-cyclopropylmethyl-2-oxo-2-(3 -oxo-ylthiazole-4-carboxylic acid hexahydrofuro3,2-b|Ipyrrole-4-yl)ethylamide quinoline-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b-carboxylic acid

Bipyridine-4-carbonyl)butyliamide 5-phenylthiophene-2-P1-cyclopropylmethyl-2-oxo-2-(3- carboxylic acid oxohexahydrofuroic|Z,2-b|pyrrol-4-yl)lethyl|amide ben-

13-methyl-1-(3-oxo-hexahydrofuro3,2-iso(bithiophene-2-carboxylic acid p|Ipyridine-4-carbonyl)butyl|amide 5-pyridin-3-P1-cyclopropylmethyl-2-oxo-2- (3-ylthiophene-2-carboxylic acid oxohexahydrofuroic|Z,2-b|pyrrol-4-yl)lethyl|amide ben-

13-methyl-1-(3-oxo-hexahydrofuroyl3,2-iso(bithiophene-3-carboxylic acid p|Ipyridine-4-carbonyl)butyl|amide 2-methyl-5-P1-cycloisopropylmethyl-2-oxo-2- (3-oxo-phenylfuran-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide benzothi-

13-methyl-1-(3-oxo-hexahydrofuro-3,2-azole-5-carboxylic acid)

Bipyridine-4-carbonyl)butyliamide 4-phenylthiophene-2-P1-cyclopropylmethyl-2-oxo-2-(3-oxo-carboxylic acid hexahydrofuro|3,2-5|pyrrol-4-ylethyliamide biphenyl-

13-methyl-1-(3-oxo-hexahydrofuro3,2-4-carboxylic acid p|Ipyridine-4-carbonyl)butyl|amide 4-pyridine-3-M-(1-cyclopropylmethyl-2-oxo-2-( 3-oxo-ylthiophene-2-carboxylic acid hexahydrofuro3,2-bI|pyrrol-4-yl) ethyl-4-

13-methyl-1-(3-oxo-hexahydrofuro3,2-phenoxybenzamide bigaridine-4-carbonyl)butyl amide 2-thiophene-2-M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-ylthiazole-4 -carboxylic acid hexahydrofuroic|3,2-b|pyrrol-4-yl) ethyl|-3-

13-methyl-1-(3-oxo-hexahydrofuro3,2-phenoxybenzamide p|Ipyridine-4-carbonyl)butyl|amide 2-methyl-5-4-imidazol-1-yl-m-P1-cyclopropylmethyl-2-oxo - (pyrrolidine-1-sulfonyl/furan-3-carboxylic acid-2-(3-oxohexahydrofuro3,2-p|pyrrol-4-thyl)ethyl|benzamide

13-methyl-1-(3-oxo-hexahydrofuroi3,2-M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-

Bipyridine-4-carbonyl)butylamide 3-phenylpyrrole-1-hexahydrofuroyl 3,2-b|pyrrol-4-yl)ethyl|-4-thiophene-2-carboxylic acid ylbenzamide

Additional compounds according to the present invention M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-) include, but are not limited to, the following hexahydrofuro|3,2-b|pyrrole-4-iluethyl|-4-oxazole -5- examples representing (Zab5, bak) isomer ylbenzamide of the general formula (I), where 2720 and BH, and also M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-) include equivalent analogs, are included in the complete definition of hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-4- 7 and B. I,2,3Hiadiazol-4-ylbenzamide

M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-M-(1-cyclopropylmethyl-2-oxo-2-(3-oxo-hexahydrofuro)3,2-5|pyrrol-4-yl/ethyl) benzamide hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-4-pyrazol-1-ylbenzamide

M-P-cyclopropylmethyl-2-oxo-2-(3-oxo- (1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|- 5-thiophene-2-carbonyl)butylamide of quinoline-b-carboxylic acid and nicotinamide (1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-

М-P-cyclopropylmethyl-2-oxo-2-(3-oxo-carbonyl)butyl|amide benzo(bBithiophene-2-carbonic hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-6- acid phenylnicotinamide (1 -(Z-oxo-hexahydrofuroi3,2-b|pyrrole-4-

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-carbonyl)butyl|amide acid (1-(3-oxo-hexahydrofuroic3,2-b|pyrrole-4-

1-Cyclopropylmethyl-2-oxo-2-(3-carbonyl)butyl|amide benzothiazole-5-carboxylic acid- oxohexahydrofuroic3,2-b|pyrrol-4-yl)ethylamide -:2- lots pyridine-3-ylthiazole-4 -carboxylic acid (1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-carbonyl)butylamide of biphenyl-4-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide 5-M-(1-(3-oxo) -hexahydrofuroiZ3,2-5|pyrrole-4-phenylthiophene-2-carboxylic acid carbonyl)butyl|-4-phenoxybenzamide

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-M-(1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl)amide 5-carbonyl)butyl|-3-phenoxybenzamide pyridine-3-ylthiophene-2-carboxylic acid 4-imidazol-1-yl-Mm-P-(3-oxo-

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-b|pyrrole-4-hexahydrofuro3,2-5|pyrrole-4-ylethyl]iamide 2-methyl-carbonyl)butyl|benzamide 5-phenylfuran -3-carboxylic acid M-(1-(Z-oxo-hexahydrofuroiZ3,2-b|pyrrole-4-

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-carbonyl)butyl|-4-thiophen-2-ylbenzamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|amide 4-M-(1-( Z-oxo-hexahydrofuroiZ3,2-b|pyrrole-4-phenylthiophene-2-carboxylic acid carbonyl)butyl|-4-oxazol-5-ylbenzamide

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-M-(1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl)amide 4-carbonyl)butyl|/-4-(1,2,31 thiadiazol-4-ylbenzamide pyridine-3-ylthiophene-2-carboxylic acid M-(1-(3-oxo-hexahydrofuro)3,2-b|pyrrole-4 -

P1-cyclopropylmethyl-2-oxo-2-(3-carbonyl)butyl|-4-pyrazol-1-ylbenzamide oxohexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|iamide :2-M-(1-(3 -Oxo-hexahydrofuroC3,2-B|pyrrole-4-thiophene-2-ylthiazole-4-carboxylic acid carbonyl)butyl|-5-thiophene-2-ylnicotinamide

P1-cyclopropylmethyl-2-oxo-2-(3-oxo-M-(1-(3-Oxo-hexahydrofuroyl)3,2-b|pyrrole-4-hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|iamide 2-methyl-carbonyl)butyl|-6-phenylnicotinamide 5-(pyrrolidine-1-sulfonyl)furan-3-carboxylic acid- (1-(3-Oxo-hexahydrofuroyl)3,2-b|pyrrole-4-lot carbonyl)butyliamide2 -phenylthiazole-4-carboxylic acid (P1-cyclopropylmethyl-2-oxo-2-(3-oxohexahydrofuroyl)ethyl)amide 3- (1-(3-oxo-hexahydrofuroyl)3,2- b|pyrrole-4-phenylpyrrole-1-carboxylic acid carbonyl)butyl|amide 2-pyridine-3-ylthiazole-4-

M-P1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-carboxylic acid carbonyl)butyl|benzamide (1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-4-tert-butyl- M-|1-(3-oxo-hexahydrofuroiZv2-carbonyl)butyl|iamide of 5-phenylthiophene-2-carbon

BIpyrrole-4-carbonyl)butyl|benzamide acids

M-P1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4- (1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-carbonyl)butyl|-4-trifluoromethoxybenzamide carbonyl)butyl|amide 5-pyridine-3-ylthiophene-2-4-dimethylamino-Ich-|1-(3-oxo-carboxylic acid hexahydrofuro3,2-b|pyrrole-4- (1-(3-oxo-hexahydrofuro3,2-b| pyrrole-4-carbonyl)butyl|benzamide carbonyl)butyl|amide 2-methyl-5-phenylfuran-3-4-isopropyl-M-HP1-(3-oxo-hexahydrofuroic3,2-carboxylic acid p|pyrrole-4-carbonyl )butyl|benzamide (1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-4-difluoromethoxy-M-|1-(3-oxo-carbonyl)butyl|iamide of 4-phenylthiophene-2-carbon hexahydrofuro3, 2-b|pyrrole-4- acid carbonyl)butyl|benzamide (1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-

M-P1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-carbonyl)butyl|amide 4-pyridine-3-ylthiophene-2-carbonyl)butyl|-4-trifluoromethylbenzamide carboxylic acid 4-bromo-M- |/1-(Z-oxo-hexahydrofuro|3,2- (1-(Z-oxo-hexahydrofuroi3,2-b|pyrrole-4-

BIpyrrole-4-carbonyl)butyl|benzamide carbonyl)butyl|amide2-thiophene-2-ylthiazole-4-

Z-bromo-M-|1-(Z-oxo-hexahydrofuro|3,2- carboxylic acid p|pyrrole-4-carbonyl)butyl|benzamide (1-(Z-oxo-hexahydrofuroi3,2-b|pyrrole-4 -

M-P1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-carbonyl)butyl|amide 2-methyl-5-(pyrrolidine-1-carbonyl)butyl|-4-vinylbenzamide sulfonyl)furan-3-carbonyl acid

I1-(3-oxo-hexahydrofuroyl3,2-b|pyrrole-4- (1-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-carbonyl)butylamide naphthalene-2-carboxylic acid carbonyl)butyl|amide Z-phenylpyrrole-1-carboxylic acid

I1-(3-oxo-hexahydrofuroic acid,2-b|pyrrole-4-4-methyl-M-3-methyl-1-(3-oxo-carbonyl)butylamide of naphthalene-1-carboxylic acid-hexahydrofuroic acid|3,2- B5|pyrrole-4-thy carbonyl)butyl|benzamide

4-methoxy-M-3-methyl-1-(3-oxo-P1-cyclohexylmethyl-2-oxo-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro|3,2-b|pyrrole- 4-iluethyliamide furan-3-carbonyl)butyl|benzamide carboxylic acid

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-P1-cyclohexylmethyl-2-oxo-(3-oxo-

BIpyrrole-4-carbonyl)butyl|-4-morpholin-4-ylbenzamide hexahydrofuroi|3,2-5|pyrrole-4-ylethylIiamide thiophene-4-tert-butyl-M-|1-(4-methoxybenzyl)-2- oxo-2-2-carboxylic acid (Z-oxo-hexahydrofuro3,2-b|pyrrole-4-P1-cyclohexylmethyl-2-oxo-(3-oxoyl)ethyl|benzamide hexahydrofuro3,2-b|Ipyrrole-4 -yl)ethylamide thiophene-

I(1-(4-methoxybenzyl)-2-oxo-2-(3-oxo-3-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|iIamide naphtha-P1-cyclohexylmethyl-2-oxo- (3-oxolin-2-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyliamide morpho-

I(1-(4-Methoxybenzyl)-2-oxo-2-(3-oxoline-4-carboxylic acid hexahydrofuro3,2-5|pyrrole-4-ylethyl)iamide biphenyl-M-|/1-cyclohexylmethyl-2- oxo-(3-oxo-4-carboxylic acid hexahydrofuro3,2-b|pyrrol-4-yl)ethyl/|-2- 4-tert-butyl-M-|1-(4-hydroxymethylbenzyl)-2-phenylacetamide oxo -2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-M-|/1-cyclohexylmethyl-2-oxo-(3-oxo-yl)ethyl|benzamide hexahydrofuroi|3,2-b|pyrrole- 4-iluethyl|-3-(1-(4-hydroxymethylbenzyl)-2-oxo-2-(3- phenylpropionamide oxohexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide na-M-|/1-cyclohexylmethyl-2 -oxo-2-(3-oxophthalene-2-carboxylic acid hexahydrofuro|3,2-5|pyrrol-4-yl)uethyl|benzamide (1-(4-hydroxymethylbenzyl)-2-oxo-2-(3 -oxo- P1-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuroi3,2-5|pyrrol-4-ylethyliamide biphenyl-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|iamide naphtha-4- carboxylic acid lin-1-carboxylic acid (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo- P1-cyclohexylmethyl-2-oxo-2-(3-oxo- hexahydrofuroi3,2-b|Ipyrrole -4-yl)ethylamide. furan-2- hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|amide ben-carboxylic acid zo(bithiophene-2-carboxylic acid (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo - 3,3-Dimethyl-1-(3-oxo-hexahydrofuro3,2-hexahydrofuro3,2-b|pyrrol-4-yl)ethylamide furan-3-p|pyrrole-4-carbonyl)butylamide furan-2-carbonic acid acid (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-3,3-dimethyl-1-(3-oxo-hexahydrofuro3,2-hexahydrofuro3,2-5|pyrrole-4-ylethyl)iamide) Thiophene-p|Ipyrrole-4-carbonyl)butylamide furan-3-carboxylic acid 2-carboxylic acid acid (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo- 3,3-dimethyl-1-( 3-oxo-hexahydrofuro3,2-hexahydrofuro3,2-5|pyrrole-4-ylethyliamide thiophene-BIpyrrole-4-carbonyl)butyliamide thiophene-2-carbon

3-carboxylic acid acid (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo- 3,3-dimethyl-1-(3-oxo-hexahydrofuroi3,2- hexahydrofuroi3,2-b|pyrrole- 4-illuethylamide morpho- p|Ipyrrole-4-carbonyl)butyl|amide thiophene-3-carboxylic acid lin-4-carboxylic acid

M-(1-(4-hydroxybenzene)-2-oxo-2-(3-oxo-3,3-dimethyl-1-(3-oxo-hexahydrofuro3,2-hexahydrofuro3,2-b|pyrrol-4-yl) )ethyl|-2-bipyrrole-4-carbonyl)butyl|amide morpholine-4-phenylacetamide carboxylic acid

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-M-3,3-Dimethyl-1-(3-oxo-hexahydrofuroi3,2-hexahydrofuroi3,2-b|pyrrole-4 -yl)ethyl-3- p|Ipyrrole-4-carbonyl)butyl|-2-phenylacetamide phenylpropionamide -3,3-dimethyl-1-(3-oxo-hexahydrofuroi3,2-

13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|pyrrole-p|ipyrrole-4-carbonyl)butyl|-3-phenylpropionamide 4-carbonyl)butyl|iamide furan-2-carboxylic acid I3,3- dimethyl-1-(3-oxo-hexahydrofuroi3,2-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-b|Ipyrrole-4-carbonyl)butyl|amide benzo(b|thiophene-2-4-carbonyl)butyl|iamide furan-3-carbon carboxylic acids

3-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-3,3-dimethyl-1-(3-oxo-hexahydrofuro3,2-4-carbonyl)butyl|Iamide thiophene-2- carboxylic acid- bipyrrole-4-carbonyl)butyl benzamide and P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroic|3,2-

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrol-BIpyrrol-4-yl)ethylamide furan-2-carboxylic acid 4-carbonyl)butyl|iamide thiophene-3-carboxylic acid-P-benzyl- Furan-3-carboxylic acid 2-oxo-2-(3-oxo-hexahydrofuroic|3,2-thy b|Ipyrrol-4-yl)ethyl|iamide

13-methyl-1-(3-oxo-hexahydrofuro3,2-b|pyrrole-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-4carbonyl)butylamide of morpholine-4-carboxylic acid Bipyrrol-4-yl)ethylamide of thiophene-2-carboxylic acid lota P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-

Thiophene-3-carboxylic acid M-(3-methyl-1-(3-oxo-hexahydrofuroyl3,2-p|pyrrol-4-yl)ethylamide

BIpyrrole-4-carbonyl)butyl|-2-phenylacetamide P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroiZ52-

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-bipyrrol-4-yl)ethylamide morpholine-4-carboxylic acid p|pyrrole-4-carbonyl)butyl|-3-phenylpropionamide lot 1-cyclohexylmethyl -2-oxo-(3-oxo-M-P1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|Ipyrrol-4-yl)ethylamidofuran-2-hexahydrofuroi3,2-b |pyrrole-4-yl)ethyl/|-2-carboxylic acid phenylacetamide

M-(1-benzyl-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4-hexahydrofuro3,2-b|pyrrole-4- yl)ethyl|-3-yl)-1-(phenylmethanesulfonylmethyl)ethyl|iamide /- fu-phenylpropionamide ran-2-carboxylic acid (1-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2 - (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-

Bipyrrole-4-yl)ethylamide benzo[rithiophene-2-carboxyl]-1-phenylmethanesulfonylmethyl)ethylamide -: fu- acid ran-33-carboxylic acid

M-(1-benzyl-2-oxo-2-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-hexahydrofuroi3,2-5|pyrrole-4- yl/ethyl|benzamide yl)-1--phenylmethanesulfonylmethyl)ethylIiamide / thio-

P1-cyclopentylmethyl-2-oxo-(3-oxo-phen-2-carboxylic acid hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl amide furan-2-(2-oxo-2-(3-oxo-hexahydrofuroyl)3, 2-b|pyrrole-4-carboxylic acid yl)-1-phenylmethanesulfonylmethyl)ethyliamide / thio-

P1-cyclopentylmethyl-2-oxo-(3-oxo-phen-3-carboxylic acid hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyliamide furan-3-(2-oxo-2-(3-oxo-hexahydrofuroyl) 2-b|pyrrole-4-carboxylic acid yl)U-1--phenylmethanesulfonylmethyl)ethyl|Iamide mor-

P1-cyclopentylmethyl-2-oxo-(3-oxofolin-4-carboxylic acid hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl| amide thiophene-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-2-carboxylic acid 4-yl)-1--phenylmethanesulfonylmethyl)ethyl|-2-

P1-cyclopentylmethyl-2-oxo-(3-oxo-phenylacetamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|iamide thiophen-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-b) |pyrrole-

3-carboxylic acid 4-yl)-1-phenylmethanesulfonylmethyl)ethyl|-3-

P1-cyclopentylmethyl-2-oxo-(3-oxo-phenylpropionamide hexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide morpho- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4 - lin-4-carboxylic acid yl)-1-(phenylmethanesulfonylmethyl)ethyliamide ben-

M-P-cyclopentylmethyl-2-oxo-(3-oxo- (bithiophene-2-carboxylic acid hexahydrofuroyl)ethyl|-2-M-(2-oxo-2-( 3-oxo-hexahydrofuro3,2-b|pyrrole-phenylacetamide 4-yl)-1--(phenylmethanesulfonylmethyl)ethylbenzamide

M-P-cyclopentylmethyl-2-oxo-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrole-4- hexahydrofuro3,2-b|pyrrol-4-yl)ethyl |-3-yl)-1-(phenylmethanesulfonylmethyl)ethyl|iamide naph-phenylpropionamide talin-1-carboxylic acid

M-(1-cyclopentylmethyl-2-oxo-2-(3-oxo-4-(2-benzyloxy-3-hexahydrofuroi3,2-5|pyrrol-4-yl/ethyl|benzamide cyclohexylpropionyl)tetrahydrofuroi3,2-b| pyrrole-1-cyclopentylmethyl-2-oxo-2-(3-oxo-3-one hexahydrofuroyl)ethylamide naphtha-4-(2-(4-tert-butylbenzyloxy)- 4-lin-1-carboxylic acid methyspentanoyltetrahydrofuro|C3,2-b|pyrrole-3-one

P1-cyclopentylmethyl-2-oxo-2-(3-oxo-4-(2-(naphthalen-1-ylmethoxy)-3-phenylpropionyl|- hexahydrofuroyl),2-b|pyrrol-4-yl)ethyl|amide ben- tetrahydrofuro3,2-b|pyrrole-3-one zo(bithiophene-2-carboxylic acid 4-13-cyclohexyl-2-(furan-2-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-ylmethanesulfanyl)propionoyl|tetrahydrofuro!y3,2-hexahydrofuroyl]3,2-b|pyrrol-4-yl)uethylamide furan-2-B|pyrrol-3-one carboxylic acid acid 4-13-cyclohexyl-2-(furan-3-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxoylmethanesulfanyl)propionoyl|tetrahydrofuroi3,2-hexahydrofuroi3,2-b|pyrrol-4-yl)uethyliamide furan-3-B|pyrrol-3-one carboxylic acid 4 -III-cyclohexyl-2-(furan-2-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-ylmethanesulfonyl)propionoyl|tetrahydrofuroi3,2-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|iamide thiophen-B|pyrrol-3-one 2-carbon acid 4-13-cyclohexyl-2-(furan-3-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxoylmethanesulfonyl)propionoyl tetrahydrofuro!3,2-hexahydrofuroI3,2-b|pyrrol-4-yl)ethyl|iamid thiophene-B|pyrrol-3-one

3-carboxylic acid 1-cyclohexylmethyl-2-oxo-2-(3-oxo-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)ethyl hexahydrofuroi3,2-b|pyrrol-4-yl)ethyliamide morphomorpholin-4- carboxylic acid lin-4-carboxylic acid З-methyl-1-(3-oxo-hexahydrofuro!З 2-5|pyrrole-

M-(1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-4-carbonyl)butyl ether of morpholine-4-carbon hexahydrofuro3,2-b|pyrrol-4-yl)ethyl-2-acid phenylacetamide Z,Z -dimethyl-1-(3-oxo-hexahydrofuroi3,2-

M-(1-benzylsulfanylmethyl-2-oxo-2-(3-oxo- p|Ipyrrole-4-carbonyl)butyl ether of morpholine-4-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-3-carbon acid phenylpropionamide 2-cyclohexylmethyl-4-morpholin-4-yl-1-(3-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)butane-1,4-dione hexahydrofuroi3,2-b|pyrrol-4-yl) ethyl|amide ben-2-isobutyl-4-morpholin-4-yl-1-(3-oxo- (bithiophene-2-carboxylic acid hexahydrofuro|3,2-b|pyrrol-4-yl)butan-1, 4-dione

M-(1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-2-(2,2-Dimethylpropyl)-4-morpholin-4-yl-1-(3-hexahydrofuroi3,2-5|pyrrole-4 -yl/ethyl|benzamide oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)butane-1,4-dione (1-benzylsulfanylmethyl-2-oxo-2-(3-oxo- 4-(2-Biphenyl- 3-yl-4-hexahydrofuro-3,2-b|pyrrol-4-yl)ethyl|iamide naphtha-methylpentanoyl)tetrahydrofuro|3,2-b|pyrrol-3-one lin-1-carboxylic acid

Further, additional compounds according to this invention - M-|/1-cyclohexylmethyl-2-oxo-(3-oxo) include, but are not limited to, nastu-hexahydrofuroi|3,2-b|pyridin-4-yl)ethyl |-3- pne examples, which are (Za5,7ak) or phenylpropionamide (Zak,7azx) isomer of the general formula (II), where 2-0 and M-|/1-cyclohexylmethyl-2-oxo-2-(3 -oxo-

B'!- CH, and also include equivalent analogues, hexahydrofuro|3,2-b|pyridin-4-yl)ethyl|benzamide are included in the full definition of 7 and B. P1-cyclohexylmethyl-2-oxo-2-(3- oxo- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-b|pyridin-4-yl)ethylamide naphth-hexahydrofuroi3,2-in|Ipyridin-4-yl )ethyl|amide of futalin-1-carboxylic acid ran-2-carboxylic acid (1-cyclohexylmethyl-2-oxo-2-(3-oxo- (1-(4-hydroxybenzyl)-2-oxo-2-( 3-oxo-hexahydrofuroi3,2-5B|pyridin-4-yl)ethyl|iamide of ben-hexahydrofuroi3,2-in|Ipyridin-4-yl)ethyl|amide of fuso(bHiophene-2-carboxylic acid ran-Z- carboxylic acid 3,3-dimethyl-1-(3-oxo-hexahydrofuroyl)3,2- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-b|Ipyridine-4-carbonyl)butyl|amide furan-2-hexahydrofuro3,2-in|Ipyridin-4-yl)ethyl|amide of thio-carboxylic acid of phen-2-carboxylic acid I3,3-dimethyl-1-(3-oxo-hexahydrofuro3,2- (1-( 4-hydroxybenzyl)-2-oxo-2-(3-oxo-b|Ipyridine-4-carbonyl)butyl|amide furan-3-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide thio-carbons of phen-3-carboxylic acid 3,3-dimethyl-1-(3-oxo-hexahydrofuroi3,2- (1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo- b|Ipyridine-4 -carbonyl)butyl|amide thiophene-2-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|iamide mor-carboxylic acid folin-4-carboxylic acid 3,3-dimethyl-1-(3-oxo-hexahydrofuroi3, 2-

M-(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-b|Ipyridin-4-carbonyl)butyl|thiophene-3-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl |-2- carboxylic acid phenylacetamide IZ,Z-dimethyl-1-(3-oxo-hexahydrofuroi3,2-

M-(1-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-b|Ipyridine-4-carbonyl)butyl|amide morpholine-4-hexahydrofuroyl)3,2-b|pyridin-4-yl)ethyl |-3- carboxylic acid phenylpropionamide -IZ,Z-dimethyl-(3-oxo-hexahydrofuroi|3,2-

M-(1-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-B|Ipyridine-4-carbonyl)butyl|-2-phenylacetamide hexahydrofuro|3,2-5|pyridin-4-yl) ethyl|benzamide -3,3-dimethyl-1-(3-oxo-hexahydrofuroyl3,2-

I3-methyl-1-(3-oxo-hexahydrofuro3,2-b|Ipyridine-4-carbonyl)butyl|-3-phenylpropionamide p|Ipyridine-4-carbonyl)butyl|amide furan-2- I3,3-Dimethyl- 1-(3-oxo-hexahydrofuro3,2-carboxylic acid bipyridine-4-carbonyl)butyliamide benzo(rhithiophene-2-

13-methyl-1-(3-oxo-hexahydrofuro3,2-carboxylic acid p|Ipyridine-4-carbonyl)butyl|amide furan-3- -3,3-dimethyl-1-(3-oxo-hexahydrofuro3,2- carboxylic acid BIpyridine-4-carbonyl)butyl|benzamide

3-Methyl-1-(3-oxo-hexahydrofuroi3,2-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-

Bipyridine-4-carbonyl)butyl|amide thiophene-2-bipyridin-4-yl/oethylamide furan-2-carboxylic acid lota

13-methyl-1-(3-oxo-hexahydrofuro3,2-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2- p|Ipyridine-4-carbonyl)butyl|amide thiophene-3 - p|Ipyridin-4-yl)ethylamide furan-3-carboxylic acid lota

3-Methyl-1-(3-oxo-hexahydrofuroi3,2-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-

Bipyridine-4-carbonyl)butyl|amide morpholine-4-bipyridine-4-ylethylamide thiophene-2-carboxylic acid lota

M-(3-Methyl-1-(3-oxo-hexahydrofuroi3,2-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2- b|Ipyridine-4-carbonyl)butyl|- Thiophene-3-carboxylic acid 2-phenylacetamide p|pyrrol-4-yl/ethylamide

M-(3-methyl-1-(3-oxo-hexahydrofuroyl)3,2-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroyl|3,2-b|Ipyridine-4-carbonyl)butyl|- 3-phenylpropionamide B|Ipyridin-4-yl)ethyl|amide morpholine-4-carboxylic acid 1-cyclohexylmethyl-2-oxo-(3-oxo-acid hexahydrofuro3,2-in|Ipyridin-4-yl)ethyl|amide fu- M-(1-benzyl-2-oxo-2-(3-oxorane-2-carboxylic acid hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl/|-2-

P1-cyclohexylmethyl-2-oxo-(3-oxo-phenylacetamide hexahydrofuroyl3,2-b|pyridin-4-yl)ethyl|amide fu-M-(1-benzyl-2-oxo-(3-oxo-hexahydrofuroyl3,2 - ran-Z-carboxylic acid B|Ipyridin-4-yl)ethyl|-3-phenylpropionamide

P1-cyclohexylmethyl-2-oxo-(3-oxo-P-benzyl-2-oxo-2-(3-oxo-hexahydrofuroi|3,2-hexahydrofuroi3,2-in|Ipyridin-4-yl)ethyl|amide thio - BIpyridin-4-yl)ethyl|amide benzo|b|thiophene-2-phen-2-carboxylic acid carboxylic acid 1-cyclohexylmethyl-2-oxo-(3-oxo-M-P1-benzyl-2-oxo-2 -(3-oxo-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|amide thio-hexahydrofuroi|3,2-b|pyridin-4-yl)ethyl|benzamide of phen-3-carboxylic acid P1-cyclopentylmethyl- 2-oxo-(3-oxo-

P1-cyclohexylmethyl-2-oxo-(3-oxo-hexahydrofuroi3,2-b|pyridin-4-yl)ethyl|amide fu-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|iamide moran-2 -carboxylic acid folin-4-carboxylic acid P1-cyclopentylmethyl-2-oxo-(3-oxo-

M-P1-cyclohexylmethyl-2-oxo-(3-oxo-hexahydrofuroyl3,2-b|pyridin-4-yl)ethyl|amide fu-hexahydrofuroyl3,2-b|pyridin-4-yl)ethyl|-2- ran -3Z-carboxylic acid phenylacetamide

P1-cyclopentylmethyl-2-oxo-(3-oxo- (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyridine-hexahydrofuroi3,2-v|Ipyridin-4-yl)ethyl|amide thio- Phen-2-carboxylic acid morpholine-4-carboxylic acid 4-yl)-1-phenylmethanesulfonylmethyl)ethylamide

P1-cyclopentylmethyl-2-oxo-(3-oxo-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2- hexahydrofuroi3,2-in|Ipyridin-4-yl)ethyl|amide thio- BIpyridin- 4-yl)-1-phen-3-carboxylic acid (phenylmethanesulfonylmethyl)ethyl|-2-

P1-cyclopentylmethyl-2-oxo-(3-oxo-phenylacetamide hexahydrofuroi3,2-b|pyridin-4-yl)ethyl|iamide mor-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-foline) -4-carboxylic acid BIpyridin-4-yl)-1-

M-P-cyclopentylmethyl-2-oxo-(3-oxo-(phenylmethanesulfonylmethyl)ethyl|-3-hexahydrofuroyl3,2-b|Ipyridin-4-yl)ethyl|-2-phenylhydropionamide phenylacetamide (2-oxo-2-( 3-oxo-hexahydrofurois3,2-

M-P-cyclopentylmethyl-2-oxo-(3-oxo-B|Ipyridin-yl)-1-hexahydrofuroyl)3,2-b|pyridin-4-yl)ethyl|-3-(phenylmethanesulfonylmethyl)ethyl|amide ben-phenylpropionamide zo(bigiophene-2-carboxylic acid

M-P-cyclopentylmethyl-2-oxo-2-(3-oxo-M-(2-oxo-2-(3-oxo-hexahydrofuroi3,2-hexahydrofuroi3,2-b|pyridin-4-yl)/ethyl| benzamide BIpyridin-4-yl)-1-

P1-cyclopentylmethyl-2-oxo-2-(3-oxo- (phenylmethanesulfonylmethyl)ethyl|benzamide hexahydrofuroi3,2-b|pyridin-4-yl)ethyl|iamide naphth- (2-oxo-2-(3-oxo- Hexahydrofuroyl,2-b|pyridin-talin-1-carboxylic acid 4-yl)-1-phenylmethanesulfonylmethyl)ethyl|amide na-

P1-cyclopentylmethyl-2-oxo-2-(3-oxo-phthalene-1-carboxylic acid hexahydrofuro3,2-b|pyridin-4-yl)lethylamide benzyl-1-cyclohexylmethyl-2-oxo-2-(3-oxo - zo(bithiophene-2-carboxylic acid hexahydrofuro3,2-b|Ipyridin-4-yl)dethyl ether

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-morpholine-4-carboxylic acid hexahydrofuroyl3,2-b|pyridin-4-yl)ethyl|amide fu-4-13-cyclohexyl-2-(furan-2 - ran-2-carboxylic acid ilmethanesulfanyl)propionylIhexahydrofuroi3,2-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-B|Ipyridin-3-one hexahydrofuroyl)ethyl|amide fu- 4-13-cyclohexyl-2-(furan- 2- ran-Z-carboxylic acid ylmethanesulfonyl)propionylIhexahydrofuroi3,2-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-B|Ipyridin-3-one hexahydrofuroyl3,2-b|pyridin-4-yl)ethyl|amide thio-4-13-cyclohexyl-2-(furan- 3-phen-2-carboxylic acid ylmethanesulfanyl)propionyl|Ihexahydrofuroi3,2-01

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-pyridin-3-one hexahydrofuroyl)ethylamide thio-4-13-cyclohexyl-2-(furan-3- phen-3-carboxylic acid ylmethanesulfonyl)propionylIhexahydrofuroi3,2-

P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-B|Ipyridin-3-one hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|iamide mor-2-cyclohexylmethyl-4-morpholin-4-yl -1-(3- folin-4-carboxylic acid oxo-hexahydrofuro3Z,2-b|Ipyridin-4-yl)butan-1,4-

M-P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-dione hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|-2- Considering all the above examples, also phenylacetamide it is meant that they include oxidized

M-(1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-analogues of kep(end)-groups containing light oxide-hexahydrofuroyl)3,2-b|pyridin-4-yl)ethyl|-3-luated nitrogen, with the formation of M-oxide, or light-phenylpropionamide acidified sulfur, giving a sulfone. The following structures

P1-benzylsulfanylmethyl-2-oxo-2-(3-) are illustrative examples. oxohexahydrofuro3,2-b|pyridin-4-yl)ethylamide benzo|b|thiophene-2-carboxylic acid

M-P1-benzylsulfanylmethyl-2-oxo-2-(3-oxo- and hexahydrofuro3,2-b|pyridin-4-yl)/ethyl|benzamide (1-benzylsulfanylmethyl-2-oxo-2-(3-oxo- hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|iamide naphth-5 1 talin-1-carboxylic acid (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyridin-4-yl)- 1-(phenylmethanesulfonylmethyl)ethyl|Iamide of furan-2-carboxylic acid and che (2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyridin-4-yl)-1-(phenylmethanesulfonylmethyl)ethyl| Iamide of furan-3-carboxylic acid (2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyridin-4-yl)-1-(phenylmethanesulfonylmethyl)ethylamide) 2-carboxylic acid chemistry, compounds of the general formulas (I) and (II) can easily be synthesized using numerous 4-yl)- 1--«phenylmethanesulfonylmethyl)ethylamide of chemical strategies carried out either in solution or of phen-3-carboxylic acid in the solid phase | see Afepop, E. and Zperraga, K.S.

In "Zoiii Rpaze Reriide BZupipe5ib: A Rgasiisai

Arrgoasp", Ohioga Opimegeiu Rgez5, Ohoga, Central Committee.

1989, for a general overview of the principles of solid state-Sagau, 9U., 9 Ogd. Speth, 54, 3260-3264, 1989, (c) new synthesis). The solid-phase strategy is attractive - Neineg V. 9., Uoshe M. M., Gays. Hek, 30, 7021-7024, left, as it makes it possible to obtain baga- 1989, (4) Em'ipud UM. K., Uotiye M.M., Neyegosusiev, those thousands of analogues, usually on a scale of 5-100 mg, 27, 2843-2850, 1988, (e) KoiIoagiv| 5.A., Maizpai! and. due to the use of methodologies in parallel - A., Ipi. in. Rary. Rogoi Vev., 48, 274-280, 1996, (i) th synthesis, for example, see (a) Vazio5, M.; Maeii, Emapz 0. A., UMereg, A, E., U At. Spent boss, 109,

M. u. Areyev, A.- N. Rgos. May Asai. from OBA, 92, 7151-7157, 1987, (9) IGapdioi M., NaKoipagadapu 6738-6742, 1995). Thus, one of the strategies of E., Teganeagop, 56, 2437-2448, 2000, (p) Z!ydizaki, C synthesis of compounds of general formulas (I) and (II) includes: N.,eai!., Tei. Gay, 39, 3413-3416, 1998, (i) Steek S, (a) Obtaining in a suitable (suitable) manner ei ai., Tei. I ey., 37, 2031-, 1996, ()) Adati S, ey ey., functionalized and protected building blocks of Tei. Hey, 37, 4001-, 19961). of bicyclic ketones in solution. Activation of a suitably protected p- (B) Addition of the building block (a) to solid hydroxyproline (17) using a mixed anhiphase with the help of a linker that is stable in the dry with isobutyl chloroformate with subsequent con- conditions of synthesis, but is easily cleaved at - densation with diazomethane gives intermediate compounds for the synthesis of divya datev, I. MU., Teigapeadgop, 55 of diazomethylketone (18). Treatment of intermediate compounds (Verop MO 489), 4855-4946, 1999, examples of "lindiazomethylketone (18) with lithium chloride in aqueous core" function when applied to solid-phase acetic acid leads to protected tetrahy- synthesis). drofuroi3,2-b|Ipyrrole-Z-one (19). The introduction of simple (c) Solid-phase organic chemistry (see Vhom/p of KE substituents) can be carried out by condensation

A. 0., 9. Spet. boss, Reizhkip Tgapv. 1,19, 3293-3320, activated (17) with alternatives to diazomethane 19981 for the construction of another molecular structure, compounds such as diazoethane (B'-CHvz), or 1-ly. phenyloxydiazoethane (E'-CHhORN). (4) Cleavage of the compound from the solid phase into Protected building blocks (the synthesis is illustrated by the example of tetrahydrofuro|3,2-5|pyrrol-3-one (ie) Cleavage treatment and analysis of the compound. (19)), in detail described in scheme 1, you can use

The first stage of the synthesis of common compounds in the solid-phase synthesis of inhibitor molecules of formulas (I) and (II) is the preparation of functionalizers in solution (stages (5)-(e)). For stage (B), binding from a lysed and protected building block. A typical solid phase of an aldehyde or ketone, the described scheme of the approach to tetrahydrofuroyl3,2-b|pyrrole-Z-one, a set of methods and, for example, see (a) datez I. (19) is presented in detail in scheme 1. Next MU., 1999, (p ) Gee A., Nyapa G.., EPtap .. A., 9. At. descriptions, presented in detail in diagrams 1-13, from Spet. bos, 121 (43), 9907-9914, 1999, (c) Mygrpa A. can be easily used when using M., ei ai., U. At. Spent boss, 114, 3156-3157, 19921). of alternative elements of the frame of general fo- A suitable method, capable of reversible connection (I) and (1). The formation of a functional group of an alkyl ketone, such as (19), consists in a combination of the previously described chemical reactions. You can use semicarbazid,

The formation of 1(hydrazinocarbonyl)iamino|methylcyclohexanecarboxylic acid with pe po (20) Mygrpu, A. M., ei a!., U. At. Spent 5osk 114, and about 3156-3157, 19921, as shown in diagram 2, which illustrates

Scheme 1. (a) IVNOSOSI, MMM, DHM, -157С, 10 minutes, in an argon atmosphere. (B) Diazomethane in dihydrofuro|3,2-bipyrrole-Z-one ethyl ether, from -157C to room temperature for 1 hour, (c) Acetic acid (4) HisCl (1 Equiv. ) in 807% aqueous acetic acid, from 57"С e (in "КК" to room temperature for 1 hour. I С soju

EtOSi(O) means the well-known protecting group of amine -9-fluorenylmethoxycarbonyl (EGtos, see a" in

AshShepop E. and Zperraga K.S., 19891, and "Rd" means n or a free hydroxyl or a hydroxyl protecting group such as tert-butyl ether. In the considered case, condensation with diazomethane leads to: "vu (c) compounds with B/-H. Although the formation of diazoketone is clearly observed in U C deddadyu when the reaction proceeds for 1 hour, a general improvement in the yield of the product isolated from I is obtained by leaving the reaction mixture with an ethereal solution of diazomethane for 24 hours. General formula (1)

As for stage (a), the synthesis can be started- Scheme 2. (a) (19) in 9095 EYUN/NgO/I, 5 eq. starting from suitably protected p-MaodAc/trifluoroacetate 4-hydroxyproline (17) (or protected /D-IShydrazinocarbo-hydroxypipecolic acid), which can be obtained from nyl)iamino|methylIcyclohexanecarboxylic acid according to the set of methods described in (20 ), 2 hours, boiling with reverse cooling- literature, for example (a) Neitpeg V. .), e!i a!., In At. com. (r) Zeq. designs (21)/Zeq. NGO/Zeq.

Spent boss, 114, 10181-10189, 1992; (c) Nidnez, R., NOVuvekv. MMM, NN2-SOLID PHASE, DME, room-

tne temperature overnight, (c) 2095 pipe- cases may prove to be a winning temporary dyn/DMF, 30 minutes, (4) A series of chemical reactions to protect the carboxylic acid in the form of methyl insertion Sh-M-M/-X-X (e) TFOC/NgO (95:5, v/v), of an ester (e.g., compound (32), scheme room temperature, 2 hours. 6) before interaction with the alkyl halide. Intermediate

Construction (21) is obtained by the reaction of a molecule- ester compound, then simply hydrolyze the li-linker (20) and tetrahydrofuro3,2-b|pyrrol-3-one to acid (26). Analogues (27), using (19), heating at reflux with a wide range of (M)t and ОО in the general formula by a divider in a mixture of aqueous ethanol/acetate na- (I), can be obtained according to the general three conditions detailed for scheme 4. Since

Standard methods of solid-phase synthesis, the final stage of synthesis includes cleavage of

Go to AfshShepop E. and Zperraga Kk. C, 19891 of the compound used with the solid phase, is indirectly used to attach the structure (21) to the functionalized trifluoroacetic acid (TFOC), analogs, in the solid phase functionalized with amino groups, for which a simple ether is labile to the action is substituted with the help of the free functionality of the carboxylic TFOC , can be obtained by alternative acids, obtaining the charged structure (22). by the solution route (see scheme 11).

The loaded structure (22) can interact with a wide range of commercially available or previously described carboxylic acids to introduce the left-hand side part "O-M-M/-X-Y" into the quenched formula ( AND). In the simplest example, the complete left-hand part of the inhibitor of the general formula (I) includes a capped amino acid (Scheme 3), which leads, for example, to analogs of the general formula: " (), where VEN (X)v--, (M)p- MN V'Z-H, p-it, av a» se (M)t- SO", t-1, Okharyl.

Scheme 4. (a) MaOg/NgzO, 070 -» room temperature and temperature, 2 hours (b) 2.3 equiv. Ma, 1:11 DMF/DHM, nok tverdafatya -YAOKOMVYU su, 1.4 eq. benzyl bromide, overnight (c) 20,905 pip ik 9 ridin/DMF, 30 minutes, (4) 1Eq. (26)/1О0eq. с с» NvVtTO/LOekv. NEW/2 Equiv. MMM, DMF, room

General formula (1), where K"-'H, temperature, during the night (e) TFOK/NgO (955,

OO, 0 SUMIMNU sp, vol./06.), room temperature, 2 hours. (In CO, te, O-phenia, 2-70" Alternatively, binding of structure (22) (after removal of Ripos) with c-hydroxy acid (25)

Scheme 3. (a) 2095 piperidine/DMF, 30 min leads to universal solid-bound (B) 20 equiv. Ptos-amino acid/20 equiv. NVTISH/2Eq. phase of the intermediate substituent "y" in the general form

NOVIaOeq. MMM, DMF, during the night (c) 5 equiv. mud (I), which can interact with many reagents - carboxylic acid/5 equiv. NVTO/5eq.. NEW/1Oeq. over there For example, o-hydroxyl can interact in

MMM, DMF, room temperature, during the night Minunobu conditions (Nidpez 0. 1. Ogud. Veasi. (M. M), (4) TFOK/NgO (95:5, vol./o06.), room temperature- 42, 335-656, 19921, giving simple ethers (ie X--, ra, 2 h. ut, in the general formula (I)) (see sgaromuvKka

Alternatively, carboxylic acids can be U. ei aiI., A. Sotbr. Spet., 2 (5), 475-490, 2000, substances obtained in solution by traditional methods (for example, the Minunobu reaction in the solid phase). Alternatively, o-hydroxyl can interact with car- solid phase (schemes 4-8). For example (Scheme 4), bamoyl chloride, giving a carbamate (i.e., X--, treatment in an amino acid solution, illustrated by umo", Me"MNO(O), in the general formula (3). (24), sodium nitrite/H25O: leads to co- Alternatively, (Scheme 5), treatment in a hydroxy acid solution illustrated in (25) (Oedegoesc of the amino acid presented in example (24), nit-

E. ei ai., U. SNnet. boss, Reykip Tgapv. 1, 11-14, 1993). rhythm of sodium/He5Olg/potassium bromide leads to

Treatment of c-hydroxy acid (25) with sodium hydride into o-bromoacid represented by formula (28) of a dimethylformamide/dichloromethane mixture with the following - ISOCE!z A. .). ei ai., Zupipeviv, 4, 583-585, 19991, with it the addition of benzyl bromide leads to preservation of the configuration. Treatment of a- to 2k5-benzyloxy-3-cyclohexylpropionic acid bromide (28) with an alkylthiol represented by 4-lot (26). Cross-linking (26) with solid-phase const-tert-butylphenylmethanethiol (29), in a mixture with dimerization (22) followed by cleavage gives (27), tylformamide/triethylamine leads to 25-(4- an example of a compound of the general formula (I), where KH, tert-butylbenzylsulfanyl)-4-methylpropionic (X)o--, (MM)y-O, n-1, (M)t-CH" i.e. B", AN, acid (30), with inversion of configuration. Cross-linking т-т1, ии O-phenyl. For specialists in the field of practical (30) with a solid-phase structure (22) from the following organic synthesis, a wide range of amino cleavage leads to (31), an example slot, such as ( 24), can be transformed into compounds of the general formula (I), where B'Z-H", (Xo-corresponding oo-hydroxy acid, such as (25) , n-1, (M)te CH", i.e. B/7, VAN", t-1, following the general conditions described in detail.

Additionally, benzyl bromide can be substituted in organic synthesis, a wide range of amino acids, any suitable Ag-CV'"B'B-halide, such as (24), can be converted into according to the general conditions described in detail, many o-bromoacid, such as (28), when using a variant of the carboxylic acid (26). Under some general conditions described in detail. In addition, ex-

proceeding from the 5-isomer (24), an analogue of the 5-isomer under the general conditions is obtained. Thus, acid bromide (28) and K-thioester analog (30) can. In addition to obtaining analogues (34), using this method, (4-tert-butylphenyl)methanethiol (29) can be of the range (M)m and 0 in the general formula (1) replaced by any suitable Ag-SV !"В!8-5Н, when using general conditions, describing in detail many variants of carboxylic acid in scheme 6. (30) according to the general conditions described in detail. Thus, analogues of g and can be obtained (31), with the use of a wide range of В solid veil З дя (М)т и О in the general formula (I) when using the general conditions described in detail in scheme 5. The general formula (1), where г smae, - i in (Ho CO, solid phase pe, (My CO, te, in" c" 0" 2" O-morpholino, 25 0

During the day Scheme 6. (a) Mezb5isiI, Meon, room temperature, during the night. (r) and. SOSIg/DHM/during "kr tru Tue, (litsnya, thu Kk, nights. i. Morpholine/DHM OS, 2 hours, iii. SLEEP at in vv in BOUN, mon, Obbtrom NgO/dioxane, 02S. (c) 2095 piperidine/DMF, 30 min- butylphenyl, DO lin, (4) iEq.(33)/LOeq.NVTY/1Eq.o and NOVU2gEq.MMM, DMF, room temperature,

Scheme 5. (a) MaOg/Ne5O", KVg OS -" room overnight, (e) TFOC/NgO (95:5, vol./vol.), room temperature, 2 hours (B) Alkylthiol (299/ DMF/MEIz, at temp., 2 h. overnight (s) 2095 piperidine/DMF, 30 min. Alternatively, (Scheme 7), a wide range of alkyl- (4) 1TOeq (30)/10eq nNwtTYLOeq Newgoeq succinate complex esters, represented by

MMM, DMF, room temperature, during the night with a layer of 1-methyl ether 2v- (6) TFOK/Н2гО (95:5, vol./vol.), room temperature- cyclohexylmethylbutanedioic acid (35) bark, 2 hours. . commercially available or can be easily obtained

Alternatively, linking construction (22) is done in known ways (see (a) Agat eyi a. .). (after removal of Htos) with o-bromic acid, e.g. Zos. Reykip Tgapv. 1, 621-, 1996; (p) Emapz her class (28), leads to the universal connected a!., U. Spet. boss. Regkip Tgapv. 1, 103, 2127, 1981; with the solid phase of the intermediate substituent "7 in the general (c) Oikama et al., Tei. Gay, 37, 6169, 19961. Active formula (I), which can interact with many carboxyl cations in the alkylsuccinate complex reagents. For example , o-bromide can be replaced by ethers (35) followed by the addition of morpholine to the chain with nucleophiles, for example, alcohols, thi-dimethylformamide, and subsequent hydrolysis of the compound, carbanions, etc., leading to simple ethers leading to 2Р-cyclohexylmethyl- 4-ethers (i.e. X--, UU-O, in the general formula (13), morpholin-4-yl-4-oxo-butanoic acid (36). Cross-linked thioesters (i.e. X--, Uu-5, in of the general formulation (36) with the solid-phase structure (22) from (I). Thioesters can optionally be oxidized by subsequent cleavage leading to (37), addition of sulfone (see Scheme 9, i.e. X-"-, M/- 50О», I put the compounds of the general formula () where B'2-H., in the general formula (I)) (see SgaromuzKa, TSO. ei (Ho-CH» i.e. B, B'5-H, 0-1, ( MM)n- SO", p-1, ai., U. Sotr. Spet., 2 (5), 475-490, 2 000, example (Mut--, and Yuemorpholino. For specialists in the field of bromide substitution and thioether oxidation in practical organic synthesis, a wide range of red phases). alkyl succinate esters, such as (35),

Alternatively, (Scheme 6), treatment with os- can be obtained and converted into the corresponding hydroxy acid, represented by example (25), a substituted alkylbutanedioic acid, such as (36). trimethylsilyl chloride and methanol leads to In addition, morpholine can be replaced by any complex methyl ether (32). Activation with a suitable amine, leading to numerous free hydroxyls to chloroformate from the use of carboxylic acid (36) according to the melting of phosgene in dichloromethane with the general conditions described in detail below. Thus, by giving morpholine and then hydrolysis, analogs of (37) can be obtained, which can be used in a wide range of (X)o, (M)m and 0 in general ether morpholine-4-carboxylic acid (33). Cross-linking of formula (I) using the general conditions, giving (33) with the solid-phase structure (22) with those clearly described in scheme 7. The following cleavage leads to (34), an example of a compound of the general formula (I) where K" -H, , to, (Mn-O, pei, (MiyebO, te, vapvn pn sur,

Oxmorpholino. For specialists in the field of practical organic synthesis, a wide range of complex esters of a» o-hydroxy acids, such as (32), could be converted into activated chloroformate, following the general conditions clearly described. In addition, it has been shown that SUS, morpholine can be replaced by any suitable amine, leading to numerous variants of all Msmorpholino, TO carboxylic acid (33), following the detailed description

Scheme 7. (a) and EOSL using m-perchlorobenzoic acid in dichloro-hydroxybenzotriazole/DMF, 0"C, 30 minutes, ii. rmethane before cleavage to obtain analog

Morpholine, room temperature, overnight ha sulfone (42). Based on the variant of carboxylic (B) SHON in NegO/dioxane, 0"С (c) 20905 piperic acid (30), 3-cyclohexyl-25-(furan-2-dyne/DMF, 30 minutes, (j) 1Oeq. (36)/10 equiv. (methylsulfanyl)propionic acid (41), or

NGO/LOeq. NEW/2O0eq. MMM, DMF, room chewing sulfone (42), an example of the general formula, temperature, during the night (is) TFOK/HgO (95:5, () where B'H', (X)o---, (M)n- 50»2, p-1, (M)t- CH», vol./vol.), room temperature, 2 hours. that is, B", VZN", t1 and Ox2-furanyl. As described

Alternatively, (Scheme 8), a large number of bis- for Scheme 5, according to the detailed described rylalkylacetic acids, presented exemplary conditions, a variety of 25-biphenyl-3-yl-4-methylpentanoic acid nts of carboxylic acids can be obtained ( 30), for example (41). Such (39), which is easily accessible when used in a known way, can be obtained analogs of (42) using methods (see (a) OezdavViai", V. I. ei ai.,". t and 0 in general

Spent boss, 120, 9114-9115, 1998; (c) Obayia, V. M. formula (I) when using general conditions, do-ei aiI.,, MO 0149288). Cross-linking of the bisarylalkylacetic acid (39) clearly described in schemes 5 and 9 with the solid-phase structure (22) followed by cleavage leads to compound C (40), an example of the general formula (I) where K"Z-"H, C"kak (X )at--. (MM)p-y--, (M) I OHm-biphenyl. For fahi-th ХК den zkayufa. in the field of practical organic synthesis, a wide range of bisarylalkylacetic acids, such as Sho - (39) can be obtained by alkylation of the c-anion Zkgavon fovtv Chede ver, an analogue of the free acid (38), which, in turn, ru obbetyuuv ev are obtained by the Suzuki (Zygiki) condensation of phenyl-Se svr in KU VOSUN, t boronic acid and methyl ether 3-Bofur VU of bromophenylacetic acid. The phenylboronic acid in the Suzuki condensation can be replaced by a large number of arylboronic acids, providing (B) eq. (41)/5 eq. NVTO/5eq. NEW Eq. MMM, many variants of carboxylic acid (39) answer- DMF, room temperature overnight (s) 5eq. but to the general conditions described in detail. Analogues (40) of m-chloroperbenzoic acid/DCM, room temperature, can be obtained in such a way, at room temperature, 5 hours, (4) TFOC/HgO (95:5, vol./vol.) And in general, room temperature, 2 hours. rmules (I) using general conditions, details. As a result, compounds having the general forms described in scheme 8. stepwise steaming, lyophilization, etc. by obtaining standard analytical characteristics - vapuvnya zve, osud, TIC. c» The second strategy for the synthesis of compounds having general formulas (I) and (I) includes:

Ж General formula (I), where (a) Obtaining in a solution in a suitable manner fu-

Оуух 2, Оу в", b, Оуех, nctionalized and protected building-block tet-

OM O-m-biphenyl, 2-70" rahydrofuroi3,2-b|pyrrole-3-one, tetrahydrothienoi3,2- o" ev B|Ipyrrole-Z-one, hexahydropyrrolo!|Z3,2-b|pyrrole-Z -onu

I I I hexahydrocyclopenta(b|pyrrole-b-one, tetrahydrofu-

Scheme 8. (a) CHON in NgO/dioxane, 07С (B) I. IOA, roi3,2-c|Ipyrazol-b-one, tetrahydrothieno|3,2-

THF, 2-methylpropenyl bromide. her. Ra/C, EUN, Not (c) c|pyrazole-b-one, hexahydropyrrolo|3,2-c|pyrazole-b- 2096 piperidine/DMF, 30 minutes, (49) TOeq. one, hexahydrocyclopentapyrazol-b-one, hexahyd- (39)/LOeq. NGO/LOeq. NEW/2 Equiv. MMM, DMF, rofuroi3,2-5|pyridin-3-one, hexahydrothieno|3,2- room temperature, overnight (is) TFOK/NgO rIpyridin-Z-one, octahydropyrrolo|3,2-bIpyridin-3- ( 95:5, vol./vol.), room temperature, 2 hours. one, octahydrocyclopenta(b|Ipyridin-7-one, hexagi-

To obtain derivatives of the structure (22) for dropfuro|3,2-s|Ipyridazin-7-one, hexahydrothieno|3,2- the following preparation of compounds of the general formula c|Ipyridazin-7-one, octahydropyrrolo|3,2-s|Ipyridazine - () many other possible 7-one or octahydrocyclopenta|c|Ipyridazin-7-one can be used. of solid-phase organic chemistry and, for example, Preferable protective groups for chemicals, see Vhomlp, K. 0. U. Spet. 5os, Regkip Tgapv. 1, reactions in the solution phase are Ma-tret- 19, 3293-3320, 1998, review of recent publications in the butoxycarbonyl group and Me- area of ROS (solid-phase organic synthe- benzyloxycarbonyl group. zu)| (and similarly, with the help of suitable navan- (5) Standard methods of organic chemistry for peteated derivatives, compounds of the general formula (III)). transformation of the building block (a) into compounds having

For example, the left-hand part of 0-M-M-X-Y in the general formulas (I) and (I). In the simplest example, the general formulas () can be partially collected, the left-hand part of the inhibitor of the general background in the solution, connected with the construction (22) and added (I) and (I) can be completely obtained in the solution modified on the solid phase. For example, by conventional methods of organic chemistry in (scheme 9), a simple extension of scheme 5 is in solution and cross-linked with the building block (a) (see the oxidation scheme of intermediate solid-phase samples in 10, which illustrates the preparation and application of third-

butyl ether 3,2-oxo-hexahydrofuro. The third strategy for the synthesis of compounds of general pho-

of bipyrrole-4-carboxylic acid (45)). rmul (I) and (I), where the connection of О-М-М/-Х-МХ to the protected building block includes multi-stage organic

Ra ovo nocturnal reactions, includes: "Me vk "rya a. Shk (a) Preparation in solution of a suitably functionalized and protected building block of tetrahydrofuro3,2-b|pyrrol-3-one, tetrahydrothieno3,2-pz «a o B|ipyrrole-Z-one . b-one, hexahydropyrrolo|3,2-c|pyrazol-6-one, hexahydrocyclopentapyrazol-b-one, hexahydro-

Shu NN rofuro|3,2-b|Ipyridin-3-one, hexahydrothienoi|3,2- sho B|Ipyridine-Z-one, octahydropyrrolo|3,2-b|pyridin-3-one, octahydrocyclopenta(|b| pyridin-7-one, hexa-

General formula (1) dropuro|3,2-s|pyridazin-7-one, hexahydrothieno|3,2-

Scheme 10. (a) '!VCHOSOSI, MMM, DXM, -152С, 10 Ipyridazin-7-one, octahydropyrrolo|(3,2-s|pyridazine- minutes, under argon. (b) Diazomethane in diethyl 7-one or octahydrocyclopenta|sipyridazin-7-one. ether, from -157C to room temperature for 24 hours, (c) Acetic acid (4) TSI (10 eq.). in reactions in the solution phase is / Mostret- 8095- in aqueous acetic acid, from 52C to room temperature for 1 hour, (e) 4M NCI in benzyloxycarbonyl group.d (about dioxane, 02C, 2 hours, () Preliminary preparation (c) Protection of the ketone function in building blocks tet-

C-U-Mu-X-u-COOH/activation, e.g. rahydrofuro|3,2-B|pyrrole-Z-one, tetrahydrothieno|3,2-

NATI/NOAUMMM, DMF, room temperature, B|pyrrole-Z-one, hexahydropyrrolo|3,2-B|pyrrole-Z-one, overnight. hexahydrocyclopenta|p|Ipyrrol-b-one, tetrahydrofu-

The general strategy detailed in Scheme 10 for c|pyrazol-b-one, hexahydropyrrolo|3,2-s |pyrazole-b- a compound of the general formula (I) contains a substituent, one, hexahydrocyclopentapyrazole-b-one, hexahyde- which is labile under the action of trifluoroacetic acid, which rofuro|(3,2-p|Ipyridine-Z-one, hexahydrothieno|3 ,2- is the last reagent used in the solid-phase synthesis of bipyridine-Z-one, octahydropyrrolo|3,2-b|pyridin-3-one in schemes 4-9. Naprione, octahydrocyclopenta|rIpyridin-7-one, hexahyclad, (Scheme 11) treatment in a solution of hydroxy acid of dropuro|3,2-s|pyridazin-7-one, hexahydrothieno|3,2- (47) with sodium thydride in a mixture of dimethylfor-s|pyridazin-7-one, octahydropyrrolo |(3,2-s|pyridazin-mamide/dichloromethane followed by addition of 4-7-one or octahydrocyclopenta|s|Ipyridazin-7-one, tert-butylbenzyl bromide leads to 285-(4- for example, in the form of dimethyl acetal. Alternate- tert-butylbenzyloxy)-4-methylpe tively to nthanoic acid, the ketone can be reduced to achiral forms (48). Cross-linking (48) with the hydrogen chloride salt of secondary alcohols and re-oxidation to the last (46) gives (49), an example of a compound of the general formula at the synthetic stage. pi () where B2--H, (X)o--, (M/)n-O, n-1, (M)te"CH", (c) Standard methods of organic chemistry for pe- i.e. B!7 , B8-H, t, ii Sh-4-tert-butylphenyl transformation of the building block (B) into compounds of general

For specialists in practical organic synthesis, formulas () (1). , 4-tert-butylbenzyl bromide can be replaced (4) Intermediate compounds can be obtained in any suitable АгСВ/"Б'8-halide, in solution followed by their binding to the building- ensuring the preparation of numerous variants of - by block (5) and subsequent derivatization for oderbonic acid (48) under the conditions presented. Obtaining compounds having the general formulas (1) and (I) this way under the conditions detailed in (see scheme 12, illustrating preparation and application of scheme 11, analogues (49) can be obtained, substitution of tert-butyl ether //3- expressed in a wide range of (M)t and SHO in the general hydroxyhexahydrofuro|3,2-B|pyrrole-4-carbon formula (1). acids (50)).

The general formula (I), where vii-n, |.

OO, (Kto, pe, (Ue SN", i.e. VAN, te, and Tsechi-tret- Be; butylphenyl, 7-0" --- sha what. ;

Scheme 11. (a) 22 eq. Man, 171 DMF/DHM, per 1.25 equiv. 4-tert-benzyl bromide, 2 hours (B) Current (48), Current |IVYOSOSI, 2 sq. MMM, DXM, -152С, 1 General formula (1) hour, in a nitrogen atmosphere, then Te eq. (46), kim- Scheme 12. (a) Recovery, for example Mavna nate temperature during the night. (o) 4M HCl in dioxane, 02C, 2 hours, (c) Stepwise interaction with intermediate compounds U, then X, cells) activity of a specific cysteine protease in that M/, etc., to stepwise create a compound of the presence of a compound; and (52). (4). marker on an animal model of activity

Alternatively, depending on the chemical nature of the particular cysteine protease in the presence of the compound. of the reactions used to create the left-hand side. Therefore, the invention relates to the method of the sub-chain of Ш-М-М/-Х compounds of the general structure of the known or predicted cysteine protein of formulas (I) and (I), it may be necessary to protect the ketone, as as a therapeutic goal (target). Different approaches and, for example, in the form of dimethyl acetal. Such different levels of complexity are suitable for the effective inhibition and "confirmation" of a specific mescheme 13 is explained in detail and illustrated on the example of obtaining and using it. In the first case, the method includes the evaluation of the binding of benzyl ether 3,3- and migo compounds having the general formulas dimethoxyhexahydrofuro3,2-b|pyrrole-4-carbonate (I) or (II), with an isolated known or predicted - acids (54). by cysteine protease, providing a measurement of "activity". Additional assessment of binding of compounds of the general formula (I) or (II) with closely related ns - io; homologous target proteases and general

I ome with proteases of the digestive tract (for example, trypsivo (vv) nom) provides measurement of "selectivity".

And |. The second level of complexity can be assessed by monitoring the activity of a specific cyst using a functional cellular marker. va, 4 Tnproteases in the presence of a compound of general formula (I) or (II). For example, the "human osteoclast resorption assay" was used as a secondary test system based on a migo cell to monitor the activity of cathepsin K and biochemical formula (1), the potent effects of protease inhibitors (for example, see

Scheme 13. (a) Triethylorthoformate/l-U d-9850533), Analysis of "MNO-Y/- process"A/MeOH. (0) Na, Ra-S. o g final treatment-activation of T-cell" was used- with intermediate compounds g, then X, then etc. as a secondary testing system based on stepwise compound design (56). (j) i.p. migo cells to control the activity of

Trifluoroacetic acid/SNeSi/Nho. . thepsin 5 and the biochemical action of protease inhibitors (ZP,

This invention extends to the above-described S-R., ei ai., Ittipyu, 10, 197-206, 1999). When experiencing intermediate compounds! methods of obtaining compounds, the detection of viral and bacterial infections, such that have general formulas (1) or (P), from each of the markers could simply be a functional assessment of immediate precursor compounds. In turn, viral (for example, the number of mRNA copies) or methods of obtaining intermediate compounds from their bacterial load and evaluation of the biochemical invention. precursors are also part of the action of protease inhibitors. The third level of difficulty

Compounds of general formulas (I) and (I) can be evaluated by monitoring with the help of

In hu, . the use of a functional marker in an animal model to be used as a laboratory tool as the activity of a specific cysteine protease in the presence of therapeutic agents. In the laboratory, some compounds are compounds of the general formula (I) or (1). For example, according to the present invention, it is possible to use a clade, a mouse model of Ieiptapia infection, R. to establish the fact whether a biochemical Mipekei infection, malaria (inhibition of falcipain) and on the function of a known or newly discovered cysteine pro-T.sgigi infection (cruzipain) indicates that the inhibition of thease is a decisive or at least a significant contribution of cysteine proteases, which play a key role in the widespread appearance or development of a disease state, a process caused by a pathogen, is effective in stopping the symp- mentioned usually as "justification of the goal". volumes of the disease, "confirming" the specified

According to the second aspect of the invention, it is an object. developed a method of confirmation of a known or Therefore, the invention extends to the use of a pre-banned cysteine protease as a therapeutic compound of the general formula (I) or (II) for the confirmation (target), which includes! . (a) evaluation of the binding of the enzyme described above as a therapeutic target of the compound from the isolated known or suspected Compounds of the general formula () and (I) can be cysteine protease, providing a measure of activity to be used for immunotherapy or treatment pro- (effectiveness) and, optionally, one or more lactics of diseases in which cystes and 'b Tnproteases participate. (5). assessment of binding. According to the third aspect of the invention, a compound of the general formula (I) or (I) for general proteases of the digestive tract (for example, for use in medicine, especially for prophylactics, trypsin) is made by soluble homologous target proteases, ensuring measurement networks or treatment of diseases in which the pathology of lectivity, I of the disease can be modified by (c) controlling (monitoring) with the help of inhibition of cysteine prosthesis. functional cell marker (based on According to the fourth aspect of the invention, the application of a compound of the general form was developed

mules (I) or (II) in the preparation of a medicinal product for the inhibition of cysteine protease. Compounds can be used for the prevention or treatment of diseases, which must be administered from one to four times at which the pathology of the disease can be modified at the level necessary to achieve the drug by inhibiting cysteine protease. daily dose from about 0.4 to about

Some cysteine proteases play a role in pork 40Omg/kg/day. The exact amount of compound according to the tea physiological process of protein breakdown of this invention that is therapeutically effective- in animals, including humans, for example, in den- and the route by which such compound is best administered, gradations of connective tissue. However, elevated levels of these enzymes in the body can be easily determined by an ordinary expert in the body by comparing the level of the agent in the blood with pathological conditions that lead to diseases. concentration necessary to provide therapy

Thus, cysteine proteases may be involved in tic action. A suitable method can be ode- in various disease states, including, but not limited to, prodrugs of the compounds of the present invention. limited to this, infections of Rpesthosuvia5 sagipi, For those compounds in which the proline fragment represents

Tgurzapota sgili, Tgurzapota rgisei Bgisei and its ketone function, in particular ketal and/or

Stivpidia tTizisciava; as well as osteoporosis, autoimmune vketals, transformation can be performed according to the disease, schistosomiasis, malaria, metastases among the generally accepted methods. tumors, metachromatic leukodystrophy, muscular. See (M/O-A-9404172 and EP-A-0603873 and so that the concentration of the drug will be sufficient, cited in both of them). In addition, the bacterial cysteine protease secreted to inhibit bone resorption or to achieve any other therapeutic effect, called staphylopain, is bacterial as indicated in this description. Usually a virulence factor (Roietra .., ei ai. 9. Vioi. a pharmaceutical composition containing a compound,

Speth, 262 (6), 2664-2667, 19981I. administered orally in a dose of about 0.1 to

The invention can be used for the profile of approximately 50 mg/kg in a way that corresponds to the condition of the tics and/or treatment of each of the indicated patients. Preferably, the oral dose will be for the developing conditions, or disease states, to be from about 0.5 to about 20 mg/kg. referred to above. The present invention can also be used in methods of treatment or profi- when introducing the compounds according to the present invention lactic diseases caused by pathological according to the present invention. Compounds according to the given levels of cysteine proteases, especially the cysteine proteases of the invention, which can have good biocompatibility of the papain subfamily, the specified methods include footing, can be tested in one of the introduction to an animal, in particular, a mammal, even more specific biological analyzes to determine specifically a human , compounds according to the present invention. concentration of the compound that is required to provide the data

In particular, this invention provides methods of drug-pharmacological action. diseases in which cysts are involved. According to the fifth aspect of the invention, the development of

Tnproteases, including infections of Rpesthosuvia5 blena pharmaceutical or veterinary composi- sagipi, Tturzapota spili, Tturzapota Bhysei, tion, which includes one or more compounds of general

Eizptapia tehisapa, Siovigdisht Nisyuusit, formulas (I) or (I) and pharmaceutics or veterinary-ziarpuyusossy5z acygei5, foot-and-mouth virus and Stypiaia narno acceptable carrier. There can also be pritisiaesg, as well as osteoporosis, autoimmune diseases, other active substances that can be considered, schistosomiasis, malaria, tumor metastases, you are suitable or appropriate for the disease or metachromatic leukodystrophy, muscle dystonia, that is amenable to treatment or for its protrophy and atrophy of muscle tissue. Inhibitors of cru- prophylaxis. The carrier, or, if more zipain, in particular cruzipain-specific compounds, is present, one, each of the carriers, must be acceptable for the treatment of the disease in terms of compatibility with the other ingredients

Chagas compositions and not harmful to the recipient. The compo-

According to the present invention, the effective kizizis include those that are suitable for the rectality of the compound of the general formula (I) or (Ii) possible, nasal, local (including buccal) to enter to inhibit the protease involved in the ny and sublingual ), vaginal or a specific condition or disease. Of course, parenteral (including subcutaneous, intra- such a quantitative dosage will be further modified, intramuscular, intravenous and intradermal) in accordance with the method of administration of the compound. introduction, but mainly the composition is

For example, to achieve an "effective amount" of a composition for oral administration. Compositions - in emergency therapy, parenteral treatment is preferred; it can be conveniently presented in the form of single-dose administration of a compound of the general formula (I) or in the form of a single preparation dosage form, (I). Intravenous infusion of the compound in the 595th example, in the form of tablets and capsules with slow dextrose solution in water or normal physiological release, and can be obtained in any solution, or a similar formulation with methods well known in the field far-date excipients is the most effective, mation. Such methods include a step of combining, although the internal active agent defined above with a carrier may also be used. Intramuscular bolus injection. Of course, parenterally, the compositions are obtained by homogeneous per dose will be from approximately 0.01 to close and close association of the active agent with liquid approximately 100mg/kg; preferably between 0.1 and 20 mg/kg, such carriers and finely divided solid carriers in a way to maintain the concentration of the drug or both, and then, if necessary, the formation of the agent in the plasma at the concentration of the effective product. The invention extends to methods of obtaining

according to the sixth aspect of the invention, a solution or combination of compounds of the general formula is made, a method of obtaining a pharmaceutical or (I) or (II) from a pharmaceutical or veterinary composition, as described above, given by a distinct carrier or diluent. method includes combining an active joint

Compositions for oral administration in dacs (compounds) with a carrier, for example, by mixing the invention can be present in the form of: discrete units, such as capsules, wafers Predominant distinguishing features of each aspect of the wine- or pill, each of which contains in advance moves are the same as for every other aspect, with a defined (given) amount of active agent; in the corresponding changes. in the form of powder or granules; in the form of a solution or Further, the invention will be illustrated by the following suspensions of the active agent in an aqueous liquid or non-examples: aqueous liquid; or in the form of a liquid emulsion oil-in-Chemistry in the solution phase - general methods in water or a liquid emulsion water-in-oil; or in the form of All solvents were obtained from EOMIS tsa bolus, etc. (Uuategreasi, Satbgidde, OK) and had high purity

In the case of compositions for oral administration (5p) or were absolute (Ni-Ogu quality), daily (for example, tablets and capsules), the term is not specified otherwise. Reagents for general "acceptable carrier" includes carriers such as zagal- peptide synthesis obtained from Speth-Itrekh pi). accepted excipients, for example, binders Ips. (M/o Vaie Ii 60191, OBA). Thin-layer chro-agents, for example, syrup, gum arabic, gelatin, matography (TLC) was carried out on pre-coated sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), etched plates (MegsK aluminum sheets, coated with methyl cellulose, ethyl cellulose, sodium carboxy-silica gel 60 B254, catalog number 5554). methylcellulose, hydroxypropylmethylcellulose, The manifestation of compounds was carried out in ultraviolet-sucrose and starch; fillers and carriers, in direct light (254 nm) or with the use of additives, corn starch, gelatin, lactose, no dye reagent. Column flash sucrose, microcrystalline cellulose, kaolin, mass chromatography was performed on silica gel 60 (Megsk nit, dicalcium phosphate, sodium chloride and alginine 9385). All analytical HPLC results were performed with acid; and lubricants, such as magnesium stearate - using a column of Rpepotepeh OUyrieg C4, sodium stearate and stearates of other metals, stea- 5μm, ZO0A, 250x4 bmm, using mixtures of arate of glycerin, stearic acid, liquid strength - solvent A-0.195 aqueous trifluoroacetic acid con, talc waxes, oils and colloidal dioxide (TFOC) and solvent B-9095 acetonitrile/1095 silicon. It is also possible to use solvent A flavorings on an automated Addiepy system with agents such as peppermint, wintergreen oil, UV detection at 215 and/or 254 nm. If not cherry perfume and the like. In order to indicate otherwise, for complete analytical HPLC the preparative dosage form was easier to analyze used a gradient of 10-9095 V in A identified, it may be desirable to add over 25 minutes at a rate of 1.5 ml/min. HPLC dye. Tablets can also be coated. MS analysis was performed on an Adiiepi 1100 Series instrument by methods well known to LC/MOD specialists using automated systems in this field. Adiiepi HPLC at a gradient of 10-9095 V in A during

The tablet can be obtained by pressing for 10 minutes on a Rpepotepeh Soishtryv C8 column, or by molding, optionally using 5μm, ZO0A, 50x2.0mm and a speed of 0.4ml/min. Spect - one or more additional agents. Pressors of nuclear magnetic resonance (NMR) obtained tablets can be obtained by pressing on the Vgykeg ORKHA0OO device (frequency of 400 MHz of movement in a suitable tableting machine active for 1H; ОХІ probe) in the specified solvents and with the agent in free-flowing form (such as at the specified temperature. Chemical shifts are expressed powder or granules), optionally mixed with in parts per million (5) and attributed to the residual binding agent, lubricating agent, iner- solvent signals. The constants of spin-spin interaction with the diluent, preservative, surface interaction are expressed in Hz. active substance and dispersing agent. Solid-phase chemistry - general methods. Formed tablets can be formed. Examples of inhibitors (1-156) were obtained by preparation in a suitable mixing device using a combination of chemical reactions carried out in a powdery compound moistened with an inert solution and a solid phase with Ethos- base |see liquid thinner. Tablets are not necessarily "Boii Rpaze Reriide bupipeziv, Agfshepop, E. apa can be covered with a shell or equipped Zperragi, E. S, IV. Rgezz tsa, Okhtoga, OK, 1989, as notches, and their formulation can be made up of a general description. so as to ensure a slow or controlled release of the active agent in a suitably protected and functionalized manner. building block was obtained in solution (for example

Other compounds suitable for oral administration include the general compound (19, scheme 1), followed by circulation, which include cakes, which include actively attached it to the solid phase for a tive agent in an aromatized base, usually with the help of a suitable linker. Then sucrose and gum arabic or gum tragacanth were used; cycles of cross-linking/deprotection/chemical modifica- lozenges including the active agent in an inert tion, for example, oxidation, until it is solid- base, such as gelatin and glycerin, or sucrose and started to obtain a full-length gum arabic molecule; and mouthwashes including (scheme 2). Inhibitor samples were then released (reactive agent in a suitable liquid carrier. inoculated) from the solid phase, analyzed, purified

Parenteral compounds will usually be prepared and analyzed for their inhibition of a number of proteases. boring

Of course, for the solid-phase synthesis of correlatives), condensed in DMF with the addition of stovaval multipins (polyamide 1,2 -» 10 μmol MMM (10 molar equivalents). load, see m/mlmu.titoiore5.sot), although the cycle of acidolytic cleavage can be any suitable surface is selected Mixture 95956 TFOK/595 water pre-dispersed solid phase. Usually, 1.2 μmol of carriers were specialized in two polystyrene 96-well planar shapes in the form of gears used in sheets (WesKtap, one ml of wells, bbO0 μl of solution per well for obtaining crude samples in the experimental well for crowns and ZO0 μl of solution per well for tahs in on a small scale for pre-carriers in the form of gears) according to the scheme corresponding to the screening, while the crown micromol uses the synthesis scheme. Residual multil was added to scale up the synthesis and clean up the prefoamed assembly product to the first plate of important samples. Standard sp- (mother tablet) was used, the block was covered with tin-stitching and removal of the protective group with Ethos foil and cleavage was carried out during

Idivys SgaromuzKa, M. ei ai., U. Sotbr. Spent 2 (5), 2 hours. The cleaved multipin product was beaten 475-490,2000, for a detailed description of the solid-phase wound, it was then removed from the first tablet and added to the second tablet (washing tablet) for 15

Obtaining the original product of the collection of minutes. Used multi-pin product

The carboxyl group in the building-assembly structures was then discarded and the mother/wash block-linker (for example (21), usually from 100mg to the tablet was evaporated using NT-4 Sepe 2g) is activated with hexafluorophosphate /--2-(1H-Mas of the tablet evaporator). benzotriazol-1-yl)-1,1,3,3-tetramethyluronium Analysis and purification of cleaved samples (NVTO, 1 molar equivalent), hydrate 1- (a) Example 1.2 μmol carrier in the form of hexa-hydroxybenzotriazole (NOVT, 1 molar equiv. to each product after cleavage and lent) and M-methylmorpholine (MMM, 2 molar equiv- drying in the well of the washing tablet add valences) in dimethylformamide (DMF, usually from 10 ml) for 5 minutes. Functionally mixed and transferred to the appropriate amine-analyzed CA/MOA crown or NO carrier well after cleavage and drying of the mother- special form (10 μmol per crown/1.2 μmol tablet and thoroughly mixed again. on a carrier in the form of a gear, 0, 33 molar equivalents (10 μl of this DMSO solution) were diluted to the total functionalization surface with amine every 100 μl using a mixture of 9095 acetonitride (to the activated structure), followed by the addition of 0.190 aqueous trifluoroacetic acid/109o. with the addition of DMF to cover the surface Aliquots of 20 μl were analyzed using the solid phase. The loading reaction was left for HPLC MS and full analytical HPLC. Every night. After loading the crown/case carrier overnight, the crude sample of molecules gave the expected ion (Ma-NO" and the peak in HPLC was 28095 (when washing, removal of the Ethos protective group and quantitative UV analysis at 215nm) in the form of a gear was subjected to standard cycles). Such a technique provided an estimate of the loading (see SgaromuzKa, O.) of approximately 10 mm of the initial solution in crude DMSO for obtaining loaded constructions of white samples of good quality for preliminary screening-block-linker (for example, (22) ). The analysis indicated inhibition of proteases on the visually quantitative load in all samples (b) Example 1 µmole crown. 500 µl of a mixture of cal. 9095 acetonitrile/109o 0.190 aqueous TFOK to

Condensation cycles were given to each well of the washing tablet, re-

Condensation of standard Ritos-amino acids was thoroughly mixed, transferred to the appropriate (10 or 20 molar equivalents) well of the mother tablet and thoroughly mixed again by activating the carboxyl using. 5 μl of this solution was diluted with 2-(1H-benzotriazol-1-yl)-hexafluorophosphate to 100 μl with a mixture of 9095 acetonitrile/1095 0.19v-1,1,3,3-tetramethyluronium (NVTI, 10 or 20 mol aqueous TFOK. Aliquots of 20 μl were analyzed from them (equivalents), 1-hydroxybenzotriazole hydrate using HPLC MS and full analytical (NOVT, 10 or 20 molar equivalents) and M-HPLC. In each case, an unpurified sample of methylmorpholine (MMM, 20 or 40 molar equivalents gave the expected ion (MANI and peak in HPLC bands) in dimethylformamide, with previous acti- was 280905 (in UV analysis at 215 nm). 5 minutes. Activated samples, distyrol blocks containing crude samples were then perfused in suitable wells of a polypropylene 96-well plate (WesKtap, iml wells, 500 μl (c) Individual samples (example (p)) repeatedly solution per well in case crowns or 250 μl were dissolved in a mixture of 11 0.190 water level in the case of carriers in the form of gears) in the necessary TFOC/acetonitrile (1 ml) and purified using the scheme suitable for synthesis. Loaded semi-preparative HPLC (Rpepotepeh Uirieg C4, building-block design) was added - linker of free amines (at 5μm, ZO0A, 250x10mm, 25-90905 V in A with gradient example (22)) and the condensation reaction was left for 25 minutes, 4.Oml/min., 215nm UV detect overnight At the end of the condensation of water). Fractions were lyophilized in pre-hanging gear-shaped crowns/carriers in the form of glass ampoules for samples to be obtained by standard cycles of washing and removal of purified samples (usually from 2 to 4 mg, yield

The ethos of the protective group |see SgaromuzKa, Ts. ei ai|. 40-80).

Analogous conditions of activation and condensation were used (4) Purified samples were dissolved in a suitable solvent for the condensation of a number of carboxylic acids in the volume of DMSO, obtaining 10 mm of the original solution (А-СООН). Alternatively, chloroformates, e.g., for precise screening of protease inhibitors. clade morpholine-4-carbonyl chloride (10 molar ex-

Example 1. (Example of general formula (1)). C-9), 67.04/67.33 (d, Ethos CH"), 68.24/68.51 (odi- (Zab5, bow) M-(15-(4hydroxybenzyl)-2-oxo-2- (3-Nychniyl, Co), 73.12/74.23 (single, Cr), oxo-hexahydrofuroyl3,2-B|pyrrol-4-yl)ethyl|benzamide 120.49/120.52 (single, Ethos 0 -4 and c-5), 125.49/125.58 (single, Ptos C-1 and 0-8), 127.50 n (single, EGtos 0-2 and C-7), 128.04 (single , svi Etos 0-3 and C-6), 140.99/141.09 (sq., Rtos 0-4 and c-

F. c), 144.02/144.16 (sq., Etos S-1 and 0OS-8), sh ; 154.33/154.54 (qv, OSOM), 172.10/172.39 (COOH). (2) Preparation of 2-allyl ether of 1-(9H-g fluoren-9-ylmethyl) ether (25,35) (3-hydroxy)pyrrolidine-1,2-dicarboxylic acid. with and and ! . 1--"9H-Fluoren-9-ylmethyl) ether (25.35) (3-

In 4 hydroxy)pyrrolidine-1,2-dicarboxylic acid (10.9 g, 30.mmol) was dissolved in toluene (75 ml) in a 1 - 4 unit with a Dean-Stark trap. Allyl-4-yl alcohol (20 ml) was added, followed by the addition of p-toluenesulfonic acid hydrate (6.05 g, 31.4 mmol).

According to the general details, the mixture was heated at boiling with reverse holon in scheme 1, the necessary bicyclic building block with a dilator for 1 hour, cooled and added - 9H-fluoren-9-ylmethyl ether (Za5, vav) 3- SNeiz (300 ml) was given. The organic layer was washed with oxo-hexahydrofuro|3,2-b|Ipyrrole-4-carboxylic acid MansSoOz (300ml), 0.in HCl (300ml) and saturated lot (19), obtained in 8 stages in this way with a salt solution (30Oml ), then dried (Ma»5zO»). (1) Preparation of 1-(9H-fluoren-9-ylmethyl) Ether (25.35) (3-hydroxy)pyrrolidin-1,2- by filtration and evaporation in a vacuum gave a pale yellow foam (13.5g). The crude foam was purified on dicarboxylic acid silica gel (150 g) by gradient elution with

Trans-3-hydroxy-bo-proline (10.0g, 76.mmol) in a mixture of heptane.ethyl acetate 3:1 -» 1:11. The target fractions were added to intensively stirred cooling, combined and evaporated under vacuum, obtaining ice-chewed sodium carbonate solution colorless resin, yield 10.34g (26.3mmol, 85.495). (16.90 g, 160 2 mmol) in water (100 ml). 1,4- TLC was added (single spot in UV, -0.30, hep-dioxane (75ml), obtaining an opaque (cloudy), tan-ethyl acetate 1:1), analytical HPLC РЧ-18,849 but mobile solution. Minutes were added over 1 hour, HPLC-MS (single major peak in UV from 9-fluorenylmethylchloroformate (20.31g, 8Ommol) -8.354 minutes, 394.2 (Me, 416.2 |Me-Mmag). in 1,4- dioxane (75 ml), then ice-cold ba- Analysis using "H and 3 NMR showed that the mixture was stirred at room temperature- the essence of the cis and trans geometric water (3300 ml), the reaction mixture was washed with "NN (SOCI3 at 298K); 2.00-2.21 (2H5, m), chloroform (2x250 ml) and the combined organic layers 2.10/2, 85 (OH, width), 3.72-3.81 (2H5, m), 4.12-4.67 were discarded. The aqueous phase was acidified with Mn NOSI to pH 2, (He, Nv, Ethos H-9 and Sng . ,33 (2H aromatic- (2x500ml) and now discarded the clear aqueous phase. ny, Ethos H-2 and H-7), 7.34-7.41 (2H aromatic,

The cloudy combined layers of chloroform were dried Etos H-3 Her H-6), 7.53-7.66 (2H aromatic, Etos (Mag2504), filtered and evaporated in a vacuum, H-1 and H-8), 7, 77-7.81 (2H aromatic, Etos H-4 and receiving portion 1 (5.70g). The obtained precipitate (su- H-5). mish of the product and dried) was triturated with hot "C (SOCI3 at 298K); 32.28/33.04 (d, SU, with methanol (2x250 ml) and combined solutions in meta- 44.98/45.32 (d, Sv), 47.56/47.63 (single, Ethos zeros in vacuum, obtaining portion 2 С-9), 66.44 (d, СООСНоСНАСН»), 68.01/68.11 (d, (10.25 g). Portions 1 and 2 were analyzed separately using Ethos CHn), 68.32/68.72 (single, Ca), melting of TH (a single spot in UV, K-O,15, 2096 74 49/75.67 (single, Wed), 119.20/119.48 (d, CO-

MeOH in SNSIs) and HPLC-MS (the only main peak of /O/OsSNoSneCH"), 120.34/120.37 (single, Ptos C-

UV with KI-1.069 minutes, 354.2 IMENI, 376.2 |MUMaM) 04 o-5), 125.36/125.60 (single, Rtos C-1 and C-8), and found that they are identical, giving a total of 127 At (single, Etos C-2 and C-7), 128.06/128.12 r yield 15.95g (45.2mmMole, 59.25). Analysis 3 (single, Ethos C-3 and C-8), 131.79/131.94 (single - using IN and Zb NMR showed the presence of a chemical, СООСНСНАСН»), 141.65/141.71 (KV, Ethos cis and trans geometric isomers relative to 3" amis and C-5), 144.12/144 34 (KV, Ethos C-i and C-8), bottom bond, 155.13/155.59 (KV , OSOM), 170.53/170.55 (SOO-"H (DMSO-ie at 298K); 1.80-2.02 (2H,, m), cHnesNesn"). 3.49-3.62 ( 2H5, m), 4.12-4.38 (He, Hv, Ethos H-9 and (3) Preparation of 2-allyl ether 1-(9H-

SnHe", m), 5.55/5.62 (OH), 7.30-7.31 (2H aromatic, fluoren-9-ylmethyl) ether (25.38) (3-

Ethos H-2 and H-7), 7.35-7.37 (2H aromatic, Hthos formyloxy) pyrrolidine-1,2-dicarboxylic acid.

H-Z and H-6), 7.43-7.45 (2H aromatic, Gtos H-1 and Triphenylphosphine (2.76g, 10.5mmol, TPP) dis-

H-8), 7.63-7.65 (2H aromatic, Htos H-4 and H 5), was dissolved in dry tetrahydrofuran (75 ml) in an atmosphere of 12.8-13.0 (СООН). sphere of nitrogen during stirring and cooling "b (DMSO-yb at 298K); 31.70/32.70 (d, Su), with ice. During 15 minutes, 44.68/45.32 (d, Sv), 46.94/46.97 (single, Etos diisopropylazodicarboxylate (2.12g, 2.07ml,

10.5 mmol, OIAO), obtaining a white mixture with osa- СнНгНна:снН»), 120.39 (single, Etos С-4 and С-5), dom that precipitates. 2-allyl ether 1-125.32/125.46/125.56 (single, Ptos C-1 and C-8), (9H-fluoren-9-ylmethyl) ether (25.35) (3- 127 ,46 (single, ERtos C-2 and C-7), 128.12 (single hydroxy)pyrrolidine-1,2-dicarboxylic acid, Etos C-3 and C-6), 132.03/132.14 (single, (4.15g, 10.5mmol) and formic acid (0.97g, СсООСнНгНАСсН»), 141.65/141.69 (KW, Ptos 0-4 and 0.79ml, 21.0mmol) in dry tetrahydrofuran C-53, 144.00/144.16/144.43/144.48 (KV, EGtos C-1 and (ZOml) and added within 15 minutes to the mixture C-83, 154.88/155.25 (KV , EIGHT), 169.94/169.99

TRR/PIAO. The reaction mixture was stirred by adding heated for 1 hour at 0"C, then during (5) Preparation of 2-allyl ether 1-(9H-) overnight at room temperature. in vacuum, obtaining a viscous pale yellow oil of butoxy)pyrrolidine-1,2-dicarboxylic acid. (11,17). The crude oil was purified on silica gel. 2-Allyl ether 1-"9n-fluorene-9- (250g), using gradient elution, ylmethyl) ether (1.75 g, 4.45 mmol) (25.3 K) (3- with a mixture of heptane:ethyl acetate 4:1 -» 1:1. Fractions of hydroxy)pyrrolidine-1,2-dicarboxylic acid dissolved of the product was identified and evaporated in a vacuum, dissolved in dry dichloromethane (20 ml) in 50 ml, obtaining 2-allyl ether 1-(9H-fluorene-9- glass container for working under pressure and cooling methyl) ether (25.3K)-(3 -formyloxy) were pyrolyzed to -78"С. Gasopodidine-1,2-dicarboxylic acid/bis-hydrazide OIAO, isobutylene ("1Oml") were condensed into the solution, and conc. H2bOx4 is a white solid, yield 4.0 g. TLC (single spot (100 μl). A magnet was added for stirring, UV, KI-0.50, heptane-ethyl acetate 11), the analytical container (tube) was sealed, cooling removed HPLC KI-19.064 minutes, HPLC- MS (the only one and stirred at room temperature pro- the main peak in the UV with P-9.721 minutes, 422.2 draft 72 hours. The soldered tube was cooled to -

Imeni", 444.1 |M-Ma)" and the peak with 7t8"С is not detected in the UV, M-methylmorpholine (200 μl,

CI -5.057 min, 205.1 (MANI 7, 431.2 |2M--Mmag). 1 wt. eq. at room temperature, which corresponds to (4) Preparation of 2-allyl ether 1-(9H-conc. - of hydroxy)pyrrolidine-1,2-dicarboxylic acid in a bath for 2 hours. Dichloromethane was added

A mixture of 2-allyl ether 1-(9H-fluorene-9- (75 ml) and the organic layer was washed with Mmansozylmethyl) ether (25.3K)-(3- (75 ml), then with a saturated salt solution (75 ml) and formyloxy)pyrrolidine- 1,2-dicarboxylic acid was dried (Mag2504). Solvents were removed under vacuum, VIAO thi/bis-hydrazide (4.0 g) was dissolved in allylic alcohol to obtain mobile pale brownish-golden alcohol (18 ml), concentrated H25OX4 (75 μl) and oil (2.41 g) were added. Crude oil was purified on silica gel (150 g) was heated under reflux with gradient elution for 90 minutes. The mixture was cooled, adding a mixture of heptane:ethyl acetate 4:1 -» 3:11. EIAs (200 ml) were added and Mansoz (200 ml) was washed, the left fractions were combined and evaporated in a vacuum, saturated with salt solution (200 ml) and dried to obtain a thick transparent oil, yield 1.66 bg (Mag2504). Solvents were removed in vacuo, yielding (3.69 mmol, 83.095). TLC (single spot in UV, chewing a viscous golden-brown oil (4.2g). Ne- 0.45, heptane-ethyl acetate 2:11), analytical HPLC purified oil was purified on silica gel (150g), with - 22.811 minutes, HPLC-MS (the only main peak using gradient elution with a mixture of UF with K-1 1.193 minutes, 450.2 (MANI 472.2 heptane:"ethyl acetate 2:1 -" 1:11. Target fractions combined IM -Ma/", 921.4 (2M-Mag). nuved and evaporated in a vacuum, obtaining a bar-free (6) Preparation of 1-(9H-fluoren-9-ylmethyl) oil, yield 1.75 g (4.44 mmol, 42.4965). 17.795 minutes, HPLC- 2-Allyl ether 1-"9n-fluorene-9-

MS (the only main peak in UV with EI-8.574 minutes, ylmethyl) ether (25.3E) (Z-tert- 394.2 (MaNi", 416.2 |M-MgH). Analysis using butoxy)pyrrolidine- of 1,2-dicarboxylic acid (1.60 g, N and C NMR showed the presence of cis and trans 3.5 mmol) was dissolved in dry dichloromethane geometric isomers relative to the 3" amide bond (20 ml) with stirring. .phenylphosphine palladium (0) (8Zmg, 0.071mmol, "H (SOCI3 at 298K); 2.09-2.19 (2H,, m), 2.52 O0.02eq.) followed by the addition of phenyltrihydro- (OH, dd, 4 1.0, 6.0), 3.54-3.65/3.70-3.82 (2H5, m), silane (0.77g, 0.674ml, 7.12mmol, 2eq.). After 2 4.14-4.20/4.22-4.30 (Ethos H-9, dm), 4.30-4.39 (1 hour, dichloromethane (150 ml) and organic

Ethos SnNe, m), 4.43-4.58 (not 1 x Ethos CH", m), the first layer was washed with 0.01N HCl (150 ml), saturated 4.60-4.65 (Nv, m) 4 .65 4.76 (2 x СООСНоСНеСН», salt solution (150 ml) and dried (Ma590). Solution - m), 5.23-5.36 (2 x СООСНоСНАСН», m), 5.81-6.00 (1) was removed in vacuo to give a dark gray solid, 7.28-7.38 (2H aromatic, solid (2.147).

Ethos H-2 and H-7), 7.39-7.46 (2H aromatic, Ethos wine was purified on silica gel (75g) using

H-Z and H-6), 7.53-7.69 (2H aromatic, Rtos H-1 and gradient elution with a mixture //hep-

H-8), 7.73-7.81 (2H aromatic, Ethos H-4 and H-5). tan:'ethyl acetate 2:11 - 1:6. The target fractions are combined (SOS1z at 298K); 32.34/33.22 (d, Su), collected and evaporated in vacuum, obtaining a white crystal 44.65/44.90 (d, Sv), 47.57/47.63 (single, Ethos talic substance, yield 0.89m (2.17mmol, 61.1965).

C-9), 63.89/64.22 (single, So), 66.38/66.41 (d, LH (single spot in UV, MHO, З0, tep

СООСНХСН-СНЕ), 68.02 (d, Ethos СНе), 71.84/72.80 Tanethyl acetate 1-2), analytical HPLC RIST 9.135 (single, Ce), 119.08/119.31 (d.соО - minutes, HPLC-MS (the only main peak in UV with

E-9.386 minutes, 354.1 |(MAN-Vy-Ts", 410.2 MANI,

432.1 Me-Ma!", 841.1 (2M--Ma/"). Analysis using (8) Cyclization in 9H-fluoren-9-ylmethyl by melting "H and 30 NMR showed the presence of cis and ether (Zab5, bak) 3-oxo-hexahydrofuroi3,2-b|pyrrole-trans geometric isomers relative to 3" amide 4-carboxylic acid (19). connection A solution of lithium chloride (205mg, 4.8mmol) in sodium chloride water (SOCI3 at 298K); 1.23 (9H, 5), 1.98-2.28 (1.25 ml) and acetic acid (5.Oml) were added to 9H- (2H,, m), 3.40-3.50 (1H5, m), 3.68-3.81 (1H5, m), 4,10-fluoren-9-ylmethyl ether (25.32) (Z-tert- 4.50 x Ethos CH", m), 7,29-butoxy)-2-(2-diazoacetyl)pyrrolidine-1-carbonate 7,40 (2H aromatic, Ethos H-2 and H-7), 7,42-7, 47 acids (209mg, 0.48Zmmol). Gas was released, and yellow (2H aromatic, Ethos H-3 and H-6), 7.55-7.70 (2H and an oily substance dissolved during 1 aromatic, Ethos H-1 and H-8), 7.73 -7.85 (2H aro- hours, giving a visually colorless solution. Chematic, Ethos H-4 and H-5), 6.30-8.30 (СООН, res 90 minutes added chloroform (150 ml) and or- width.). the ganic layer was washed with ManNsoz (2 x 150 ml), saturated (SOSIz at 298U); 28.285 (unit, measured with salt solution (150 ml) and dried (Ma25O"). (CH3)C), 31.47/32.29 (d, C), 44.13/44.38 (d, St), Solvents removed in vacuo to give a thick 47.51/47.80 (single, Rtos C-9), 62.73/02.95 yellow resin (200mg). The crude resin was purified (single, Co), 67.96/68.13 (d, Ethos CH"), on silica gel (400, using a gradient of 7177/1267 (single, Sv), 120.33 (single, elution with a mixture of heptane ethyl acetate 32 - 11

Ethos C-4 and C-5), 125.39/125.50/125.55/125.61 (single target fractions were combined and evaporated in vacuum, night, Ethos C-1 and C-8), 127, 46 (single, Rtos obtaining a white crystalline substance, yield 133 mg

С-2 and С-7), 128.01/128.07 (single, Ethos С-3 and С- (0.38 mmol, 18.65 based on the starting acid-6), 141.58/141.66 (qv, Etos С-4и0ОС-5), tu). TLC (single spot in UV, 0.25, hep- 144.04/144.23/144, A6 (q, Etos C-1 and 0 C-8), tan-ethyl acetate 111), analytical HPLC, extended 154 ,95/155.32 (square, eight), 175.19/175.65 (COOH). nth peak P15.2-17.6 minutes, HPLC-MS (single (7) Preparation of 9H-fluoren-9-ylmethyl broad peak in UV from RI2745-8.56 minutes, 350, ether (25.38) (3- tert-butoxy)-2-(2- IMENI, 372.1 IM-ma) «721.2 (g2mM-Mar). Analysis of C 1 13, diazoacetyl)pyrrolidine-1-carboxylic acid. using Ni 7 NMR showed the presence of 1-(9H-Fluoren-9-ylmethyl) ether (25,38) (3- cis and trans geometric isomers relative to 3" ami-tert-butoxy) pyrrolidine-1,2-dicarboxylic acid of the first compound (615mg, 1.5mmol) was dissolved with stirring in "H (SOCI3 at 298U); 1.61-1.97 (2NU, m), 3.32- dry dichloromethane (15ml). The reaction mixture of 3, 45 (1Н»5, m), 3.66-3.75/3,853.95 (1/2Н5 хз 1/2Н5, dm), blown with nitrogen and cooled to -152С. Added 3.95/4.10 (1 x SOSN»» i 1 x SOSN»v, dm), 4,154,30 simultaneously in aliquots of 0.5 ml for 15 min- (Htos H-9 and 2 x Rtos CH", m), 4,40-4,60/ 4.80-4.92 lin isobutyl chloroformate (225mg, 1.6bmmol in su- (Na same Hv, total), 7.20-7.30 (2H aromatic, homo dichloromethane (2.5ml) and M-methylmorpholine Ethos H -2 and H-7), 7.931-7.42 (2H aromatic, Htos (30 mg, 3.0 mmol in dry dichloromethane (2.5 ml). H-Z Her nH-A6), 7.50-7.57/ 7.60-7.66 (2H aromatic,

To the activated amino acid solution was added Etos H-1 and H-8), 7.68-7.76 (2H aromatic, Htos diazomethane in ether (generated from dialdehyde H-4 and H-5). (4.77, "15 mmol in diethyl ether (/75ml) over "b (SOCl3 at 298K); 31.76/32.28 (d, C), sodium hydroxide (5.25g) in a mixture of water 45.59/45.95 (d, St ), 47.64 (single, Ethos C-9), (7.5ml)u/ethanol (15ml) at 60"C) and stirred 62.26/62.77 (single, Co), 68.03/68 ,65 (d, Htos at room temperature for 24 hours. For CHg), 71.28 (d, COCH2), 82.17/83.11 (single, quenching reaction was added acetic acid (h2ml), Sv), 120, 38 (single, Etos (0-4 and os-5), then tert-butyl methyl ether 125.41/125.59/125.88 (single, Etos C-1 and C-8) was added (150 ml), organic the layer was washed with water 127.45/127.49 (single, Ethos C-2 and C-1), 128.13 (x2g0Oml), then dried (Mag50"). Solvents (single, Ethos C-3 and C-6) . 8 90 mg). Crude oil was purified on silica gel 155.33 (KV, OSOM), 209.32 (OSNZ). (757), using gradient elution Following the general details of Scheme 2, with a mixture of heptaneethyl acetate 3:11 -» 271, Target bypass bicyclic building-block 9H-fluorene-9- fractions were combined and evaporated in vacuum, oderyl methyl ether ( Za5, bav) 3-oxo- 9H-fluoren-9-ylmethyl ether (25.3K) (3-hexahydrofuro|3,2-B|Ipyrrole-4-carboxylic acid tert-butoxy)-2-(2-diazoacetyl )pyrrolidine-1- (19) was converted into the building block carboxylic acid structure, pale yellow solid, linker (21) as follows: yield 270 mg (0.624 mmol, 41/690). TLC (single 9H-fluoren-9-ylmethyl ether (Za5, tank) 3-spot in UV, KI-0.55, heptane-ethyl acetate 1:1), ana- oxo-hexahydrofuroi|3,2-5|pyrrole- 4-carboxylic acid HPLC i-20.085 minutes, HPLC-MS (2 lots (19) (100 mg, 0.286 mmol) was dissolved in a mixture of the main peaks in UV with RI-7.48 minutes, 350.1 ethanol (5.Oml ) and water (0.75 ml) containing trihydric

IMANI, 372.1 |Me-Ma, 721.0 (2M-Marg and mki-9.949 rat sodium acetate (59mg, 0.428mmol, 1.5eq). minutes, 406.2 (Ma-H-M2!", 456.2 |M-АМа|", 889.3 Trifluoroacetate 4- (2 gM--Ма)| 7) was added. I(hydrazinocarbo-

Note that in the HPLC-MS analysis of t/2 nil)amino|methyl|cyclohexanecarboxylic acid 350.1 corresponds to the target bicyclic product (95mg, 0.286mmol, 1.00eq., |Mygrpu, A.M. ei ai.,». 9H-fluoren-9-ylmethyl ether (Za5, tank) 3- At. Spect. bos, 114, 3156-3157, 19921) and a mixture of oxo-hexahydrofuro|3,2-b|Ipyrrole-4-carboxylic acid heated by refluxing lots (19). within 90 minutes. Chloroform (500 ml) was added, and the organic layer was washed with HCl (50 ml, UrH3Z), concentrated and evaporated in vacuo. , obtaining hydroxybenzyl)-2-oxo-2-(3-oxo-unrefined building-block-linker construction (21) in hexahydrofuro|3,2-5|pyrrol-4-yl)ethyl|benzamide in the form of a colorless resin. Yield 172mg , analytical

TOP: 2 peaks CI-16.477 and 18.512 minutes (cis/trans geometric isomers). HPLC-MS (2 x UV peaks with

K-7.75 and 8.2 minutes, 547.3 |MeNI", 569.3

IM-Ma|). Unrefined (21) was used directly for the loaded structure. According to the general details given for scheme 2, the required building-block-linker structure (21) was attached to the solid phase, obtaining the loaded building-block-linker structure (22) in the following way:

Building-block-linker construction (21) (0.26bmmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (NVTI, 98.6bmg, 0.26mmol), hydrate 1- - I o I of hydroxybenzotriazole and (NOVT, 39, vmg, Me i 15.89 minutes (2909), HPLC 0, 26bmmol) was dissolved in dimethylformamide (Zml) and Example 4. (za5, vav) M-18-( 4- added M-methylmorpholine (MMM, 58 μl, Hydroxybenzyl)-2-oxo-2-(3-oxo-0.52 mmol). After preliminary activation during hexahydrofuro|3,2-b|pyrrol-4-yl)ethyl| -5-thiophene-2- minutes, a carrier in the form of a gear with free nicotinamide amine (72Xx1.2 μmol) was added, followed by the addition of dimethylformamide (5.5 ml) and left overnight.

The spent condensation solution was then added to the crowns with free amine (10x1O0μmol) and left overnight. Standard washing and analysis indicated quantitative loading. According to the general details given for scheme 2, the necessary loaded building-block-linker structure (22) was processed in the solid phase as follows:

The loaded construction (22) was transformed into the sample of example 1 - (Zam, ba) Mm-(15-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)3,2-5|pyrrol-4-yl )u ethyl|benzamide using the standard removal of Etos protective HPLC hCh-11.12 minutes (29090), HPLC-MS group and subsequent crosslinking with Etos-TuU(OVy)-OH, 478.2 |IMMUNI and then with benzoic acid. Crude sample Example 5, (Za5, tank) (15-(4-Hydroxybenzyl)- was cleaved and analyzed (see general 2-oxo-2-(3-oxo-hexahydrofuro|3,2-b|pyrrole-4- methods) HPLC RI-10.15 minutes (29595), HPLC-yl)ethylamide of 2-pyridine-3-ylthiazole-4-carboxylic acid

MS 395.1 (MANI. slots

The following examples (2-82) were prepared as described in example 1, condensing with the necessary reagents to give the full-length molecule.

Example 2. (Za5, tank) (15-(4-Hydroxybenzyl)-2-oxo2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide of biphenyl-4-carboxylic acid

HPLC RI-8.58 minutes (29095), HPLC-MS 479.2

IMZhNg

Example 6. (Za5, tank) M-(15-(4-

Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethyl|-4-thiophen-2-. ilbenzamide

HPLC R -14, 94-15.46 minutes (29095), HPLC-

MS 471.2 (MANI!

VERH VI-17.45-18.62 minutes (» 9095), VERH-

MS 401.2 (MANI:

Example 10, (Za5, tank) Mm-13-methyl-1-(3-oxo-hexahydrofuroyl|3,2-5|pyrrole-4-carbonyl)butyl|-4-phenoxybenzamide

HPLC -14.77-15.31 minutes (29095), HPLC

MS 477,2 (MANI: I | y . ! y.

Example 7. (Zav, tank) M-I15-(4- vo i dh ' y

Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuro|3,2-p|pyrrol-4-yl)ethyl|-4- HPLC Vi-17.26-18.38 minutes (290965), HPLC- trifluoromethoxybenzamide MS 437.2 (MANI

Example 11. (Za5, tank) M-13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|Ipyrrole-4-carbonyl)butyl|-3-phenoxybenzamide is your sound?

HPLC (-14.68 minutes (29095), HPLC-MS 479.2 (MANI: HPLC in-17.34-18.52 minutes (79095), HPLC-

Example 8. (Zab5, tank) (Za5, tank ) of 4-Bromo-Mm-|3-methyl-1-biphenyl-4-carboxylic acid (3-oxo-hexahydrofuro3,2-B|pyrrole-4-carbonyl)butyl|benzamide under these conditions.

HPLC v1-16.90-18.04 minutes (79095), HPLC- HPLC (-14.81 minutes (29095), HPLC-MS

MS 421.3 (MANI: 423.2/А425.2 (MANI

Example 9. (Za5, tank) 4-tert-butyl-M-I(3- Example 13. (Zab5, tank) 3-bromo-M-|3-methyl-1-methyl-1-(3-oxo- hexahydrofuro|Z3,2-b|pyrrole-4- (Z-oxo-hexahydrofuroI3,2-b|pyrrole-4-carbonyl)butyl|benzamide carbonyl)butyl|benzamide Om 9,

HPLC v-14.85-16.20 minutes (79095), HPLC-

MS 423.2/425.2 MANI"

Example 14. (Za5, tank) 4-isopropyl-M-13-methyl-. 1-(Z-oxo-hexahydrofuro3,2-5|pyrrole-4-carbonyl)butyl|benzamide and U

HPLC v-16.49-18.34 minutes (79095), HPLC-

Me 4272 (MANI:

Example 18. (Za5, tank) Mm-13-methyl-1-(3-oxo-hexahydrofuroyl|3,2-5|pyrrole-4-carbonyl)butyl|-4-oxazol-5-ylbenzamide

HPLC v-16.41-17.65 minutes (79095), HPLC-

Me 387.2 (MANI:

Example 15. (Za5, tank) mM-|13-methyl-1-(3-oxo-hexahydrofuroi3,2-5|pyrrole-4-carbonyl)butyl|-4-vinylbenzamide - F nt (Y n C

HPLC (-12.79 minutes (29095), HPLC-MS 412.2 MANI"

Example 19. (Za5, tank) (|3-methyl-1-(3-oxo-

HPLC hCh-14.63 minutes (29095), HPLC-MS of hexahydrofuro3,2-b|pyrrole-4-carbonyl)butyl|amide 3711 (MH of 2-phenylthiazole-4-carboxylic acid

Example 16. (Za5, tank) 4-imidazol-1-yl-M-|3-methyl-1-(3-oxo-hexahydrofuro|3,2-b|pyrrole-4-carbonyl)butyl|benzamide

HPLC v-16.41-17.80 minutes (79095), HPLC- - o Y MS 428.2 (MANI. m VI-9.20 minutes (29095), HPLC-MS 411.2 Example 20. (for 5, bab) (3-methyl-1-(3-oxo-

Example 17. (Za5, vav). M-13-methyl-1-(3-oxo-pyrrole-t-carbonyl)butylamide hexahydrofuro-3,2-5|pyrrole-4-carbonyl)butyl|-4-phenylthiophene-2-carboxylic acid Sho Sud Yu»

HPR Ri-16.9 minutes (29095), HPR-MS 4272 (MANI

Example 21. (Zab5, bak) (|3-methyl-1-(3-oxo-hexahydrofuroi3,2-5|pyrrole-4-carbonyl)butyl|amide of quinoline-b-carboxylic acid and !che and Fu HPLC-10 , 22 minutes (29095), HPLC-MS. I 429.2 (MANI se; m - Example 25. (Za5, tank) Mm-13-methyl-1-(3-oxo-s hexahydrofuroyl|3,2-5 |pyrrole-4-carbonyl)butyl|-4-trifluoromethoxybenzamide

HPLC RF-9.08 minutes (29095), HPLC-MS 396.2

MN"

Example 22. (Za5, tank) mM-|13-methyl-1-(3-oxo-hexahydrofuroi3,2-5|pyrrole-4-carbonyl)butyl|-4-

I1,2,3Hiadiazol-4-ylbenzamide; F and : what

From n g

F 4 and t I i i z (I GI | F VERH R-16.90-18.534 minutes (29095), VERH- i y: Me 429.2 (MANI r. Yua g. Example 26. (Za5, tank) 4-tert-butyl-M-(P1 5-(3-

Fe hydroxybenzyl)-2-oxo-2-(3-oxo-

And hexahydrofuroi|3,2-5|pyrrol-4-yl)uethyl|benzamide

HPLC Ri-13.1 minutes (29095), HPLC-MS 429.2 (MANI

Example 23. (Zab5, ban) M-13-methyl-1-(3-oxo-hexahydrofuroyl|3,2-5|pyrrole-4-carbonyl)butyl|-5-thiophen-2-ylnicotinamide

With HPLC -16.14-17.02 minutes (29095), HPLC- . p : / MS 451.2 (MANI 4 ' Example 21. (Za5, tank) M-I15-(3-

Hydroxybenzyl)-2-oxo-2-(3-oxo-

HPLC P-13.24 minutes (29090), HPLC-MS hexahydrofuroyl3,2-b|pyrrol-4-yl)ethyl|-4-thiophen-2- 428.2 MANI" ylbenzamide

Example 24. (Zab5, tank) 2-pyridin-3-ylthiazole-4-carboxylic acid

HPLC I-7.38 minutes (29595), HPLC-MS 404.2

HPLC -15.31-16.07 minutes (29095), HPLC- (Main

MO 477.2 (MANI Example 31. (Za5, tank) (3-methyl-1-(3-oxo-

Example 28. (Zaz, tank) 4-tert-butyl-M-P 5-(4-hexahydrofuro|(3,2-5|pyrrole-4-carbonyl)butylamide fluorobenzyl)-2-oxo-2-(3- oxo-hexahydrofuroi3,2-morpholine-4-carboxylic acid

BIpyrrol-4-yl)ethyl|benzamide

M

VERH-MS 354.2 MANI.

HPLC v-18.37-19.63 minutes (29095), HPLC-Example 32. (Zav, tank) and 3-cyclohexylmethyl-

MS 453.1 (MANI: 2-oxo-2-(3-oxo-hexahydrofuro|3,2-B|pyrrole-4-

Example 29. (Za5, vav) 2-oxo-2-(3-oxo-hexahydrofuroyl)M-115-(4-Fluorobenzyl)-yl)ethylamide of morpholine-4-carboxylic acid 3,2-b|pyrrol-4-yl) ethyl I-4-thiophen-2-ylbenzamide region

HPLC-MS 394 2 (MANI. o Example 33. (Za5, tank) | 15-benzyl-2-oxo-2-(3-

HPLC hche17.45-18.59 minutes (59095), HPLC-oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)ethyl|amide

MO 479.2 (MANI | morpholine-4-carboxylic acid

Example 30. (Zav, ban) (1 5-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethylamide of morpholine-4-carboxylic acid

HPLC (-10.07 minutes (29595), HPLC-MS with dichloromethane (5ml, then 10ml), which was discarded. 3881 (MANI. The aqueous layer was acidified with 1M hydrochloric acid

Example 34. (245, Za5, tank) 4-(2-benzyloxy- (1Oml), then extracted with dichloromethane

C-(cyclohexyl|protonoyl)tetrahydrofuroi|3,2- (2x10 ml). The layer containing dichloromethane was dried

B|pyrrole-3-one. (Ma505) and the solvent was removed in vacuo. The residue (0.55g) was dissolved in dimethylformamide (3ml), then cooled to 00°C, after which sodium hydride (190mg of 6095 dispersion in oil, 4.75mMmol) was added.

The mixture was stirred for 30 minutes, then polymer-bound isocyanate (380 mg, 2 mmol Mg) was added. The mixture was stirred for 2 hours at ambient temperature, then poured into water (15 ml). 1 M hydrochloric acid (100 ml) was added ), then the product was extracted with dichloromethane (2 x 10 ml), dried (Mg5Oy) and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel using gradient elution with a mixture of meta-

HPLC VI-17.5-19.7 minutes (9095), HPLC-MS zero: dichloromethane 01 - with 1:20. Suitable fractions 372.4 Me NO", 390.3 (MEN 18G. were combined and the solvents were removed in vacuo, yielding ) scheme acid in the form of a colorless oil, yield. 41 mg 4) ze 70).

A solution of sodium nitrite (12.1 g, 175 mmol) in VEK water (the main drug in te Z and (40 ml) was added dropwise to the hydrate suspension, IRMeMai) 2 MANI, 2852 | Memar, 547.3 which is mixed, (5) - a- and , aminocyclohexanepropionic acid (5g, "H (400MHz, SO3 at 298K); 0.72-1.03 (2H, 26.5mmol) in 0.5M sulfuric acid (120ML, cyclohexane, m), 1, 08-1.38 (ZH, cyclohexane, m), bomole) at 02C for 1.5 hours. The mixture is 1.45-1.93 (6H-2 Hr, cyclohexane, m), 3.93-4.18 (1H r, allowed to warm to ambient temperature - OSNO), 4.354.53 (TA, CHO, d , U-11.52Hz), 4.68-th medium for 20 hours. The extracted product is 4.88 (1N CHO, D, 9-11.54 GSH), 7.20-7.47 (ZN, AN, washed with diethyl ether (2x25ml), then ether m), 9.36 (1N, OH , width, c), the layers were washed with a saturated aqueous solution. Compound (26) was cross-linked under standard conditions with sodium chloride (2x25 ml), dried (Mag2504) and with an unloaded building-block-linker structure, the factors were removed in a vacuum. The residue (5.3 g) of compound 34 was cleaved, yielding a compound that was crystallized from a mixture of diethyl ether (10 ml) and heptane (25 ml), obtaining 33-cyclohexyl Example 35. (Zav, tank) PA 25-hydroxypropionic acid in in the form of a white benzypsulfanylmethyl-2-oxo-2-(3-oxo) solid, yield 2.4 g, (5396). hexahydrofuro|3,2-p|pyrrol-4-yl)ethyl|amide morpho-5Zn (400 MG SOCI3 at 298K), 0.89-1.35 (5H, m) lin-4-carboxylic acid and 1.51-1.86 (7H, m) (ОСНеCH» and cyclohexyl), 4.32 (IN, OSНОН ;", m). (5) Preparation of 2k5-Benzyloxy-3-cyclohexylpropionic acid (Compound (26) Scheme 4)

Sodium hydride (265 mg of 6095 dispersion in oil, 6 mmol) was added in two portions to a stirred mixture of 3-cyclohexyl-25-hydroxypropionic acid (0.52 g, 3 mmol), dimethylformamide (5 mL), and dichloromethane ( 5ml) at 0"C for 5 minutes. The mixture was stirred at 0"C for 5 minutes, then at ambient temperature for 45 minutes.

Benzyl bromide (0.45 mL, 3.9 mmol) was added, then the mixture was stirred for 1 hour, after which dimethylformamide (5 mL) was added. After HPLC K(e12.15 minutes (29595), HPLC-MS stirring for 4 hours, potassium iodide 434 1 (MANI. potassium (50mg, 0, Zmmol) was added). The mixture was stirred pro- Example 36. (Za5, tank) Mm-IZ -methyl-1-(3-oxo) for 20 hours, then heated at 557C for hexahydrofuro3,2-b|pyrrole-4- 1 hour, then left to cool to ambient temperature and poured into water (15ml) A saturated aqueous solution of sodium chloride (5ml) was added, then the mixture was extracted

- ? shu

HPLC -12.43 minutes (29595), HPLC-MS " 345.2 (MANI. - about .

Example 37. (Zav, bak) M-G v- 379 Me. 12.85 Minutes (9036), VERZH-MO benzypsulfanipmethyl-2-oxo-2-(3-0Xo- Example 40. (Zab5, tank) (15-cyclopentylmethyl-hexahydrofuroi3,2-5|pyrrol-4-yl/ethyl Furan-3-carboxylic acid 2-oxo-2-(3-oxo-hexahydrofuro)-3,2-bipyrrole-4-yl/ethylamide benzamide

F; and HPLC (-13.23 minutes (29595), HPLC-MS

HPLC -15.09 minutes (29575), HPLC-MS example 41. (ab, tank) /Mch1544- 12 example 38 (forgotten) M-18- Hydroxybenzyl)-2-oxo-2-(3-oxo- cyclohexylmethyl -2-oxo-2-(3-oxo- hecohydrofuro3,2-pyrrole-yl)ethyl i:hexahydrofuro3,2-5|pyrrol-4-yl/ethyl|benzamide phenylacetamide

F and and n '

HPLC (-15.63 minutes (29095), HPLC-MS 385.3 (MENI, 791.3 (gM.-Mar). HPLC -10.71 minutes (29595), HPLC-MS

Example 39. (Za5, tank) M-P15-benzyl-2-oxo-2- 4091 I MANI. (Z-oxo-hexadrofuro|3,2-B|pyrrole-4- Example 42. (Zab5, bag) M-13-methyl-1-(3-oxo-yl)ethyl|benzamide hexahydrofuroi3,2-B|pyrrole -4-carbonyl)butyl|-2-phenylacetamide Я Ф 4 их

OD in g: For; Щ я |: ' 8 n y

HPLC Ch-13.00 minutes (29595), HPLC-MSO 359.2 in

NAMES - oh -

Example 13. (open, open) Mchv-mk E-13.2 minutes (29095), HPLC-MSO 393.2 benzypsulfanyl et la oxo a (VOK: Example 46. (Za5, bak) (15-(4-Hydroxybenzyl )- hexahydrofuro|3,2-BIpyrrol-4-yl)ethyl 2-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrole-4-phenylacetamidyl)ethylamide furan-3-carboxylic acid (Ж ,

EC o, - 439 ME. 15.53 minutes (29090), HPLC-MO HPLC VI-8.65 minutes (29596), HPLC-MS 385.2 " " me. NAMES Cyclohexy methyl dok oko Shk Example 47. (Zaz5, bak) C metal okoo: hexahydrofuroi/3,2-b|pyrrol-4-yl)ethyl|-2- uran ot onyl)butylamide phenylacetamide ur p

HPLC K(-10.95 minutes (29095), HPLC-MS 335.1 (MANI, 357.1 |MAMag.

HPLC Me-18.5 minutes (29095), HPLC-MSO 399.2 Example AB. (Zav, vav) M 1v-

NAMES benzylsulfanylmethyl-2oxo-2-(3-oxo-

Example 45. (Za5, tank) M-/15-benzyl-2-oxo-2-hexahydrofuro|3,2-b|pyrrol-4-yl)ethylamide furan-3- (3-oxo-hexahydrofuro|3,2 -b|pyrrol-4-yl)ethyl|-2-carboxylic acid phenylacetamide

HPLC -14.07 minutes (29595), HPLC-MS 377.3 (MANI.

Example 52. (Zaz5, tank) (15-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide of thiophene-3-carboxylic acid i

HPLC Ri-13.68 minutes (29095), HPLC-MS 415.1 (MANI.

Example 49. (Zaz5, tank) (15-cyclohexylmethyl-2-oxo-2(3-oxo-hexahydrofuroi3,2-BI pyrrole-4-yl)ethyl|amide of furan-3-carboxylic acid HPLC - 11.75 minutes (29595), HPLC-MS 401.3 (MANI.

Example 53. (Za5, tank) (13-methyl-15-(3-oxo-hexahydrofuro|3,2-5|pyrrole-4-carbonyl)butylamide of thiophene-3-carboxylic acid and

HPLC Ri-14.39 minutes (29095), HPLC-MS 375.2 (MANI, 771.3 (2gM-Mmag.

Example 50. (Za5, tank) (15-benzyl-2-oxo-2-(3- - o Y oxo-hexahydrofuro|3,2-b|pyrrol-4-yl)ethylIiamid. Fuschu timeni zum (29095 ), HPLC-MS of ran-3-carboxylic acid Example BA, (zav, wav) in-

Shk benzylsulfanylmethyl-2-oxo-2-(3-oxo-yt hexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide thiophene-y. C-carboxylic acid

F

HPLC Ri-11.51 minutes (29095), HPLC-MS 369.1 (MANI.

Example 51. (Za5, tank) (15-cyclopentalmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyl Iiamidethiophene-3-carboxylic acid

HPLC P-14.51 minutes (? 9595), HPLC-MS 431.1 (MANI).

Example 55. (Zav, tank) | 15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|pyrrol-4-yl)ethylamide of thiophene-3-carboxylic acid

HPLC P-15.11 minutes (29095), HPLC-MS 391.1 (MANI), 803.3 (2M-Mmag. HPLC -11.72 minutes (29095), HPLC-MS

Example 56. (Za5, tank) (15-benzyl-2-oxo-2-(3-423.2 MANI". oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)ethylamide thi- Example 59. (Zab5, tank) M-13-methyl-1-(3-oxo-phen-3-carboxylic acid hexahydrofuro3,2-5|pyrrole-4-carbonyl)butyl|-3-phenylpropunamide

HPLC h-12.27 minutes (29595), HPLC-MS HPLC i-13.46 minutes (29095), HPLC-MS 385.1 (MaANI", 407.1 |(Me-Ma)", 791.2 ( 2M-Mag". 3731 IMANG, 767.3 (2M--Ma/".

Example 57. (Za5, tank) 3,3-dimethyl-1-(3-oxo- Example bo. (Za5, bav) M-(tB-hexahydrofuro3,2-5|pyrrole-4-carbonyl)butyl|amide benzylsulfanylmethyl -2-oxo-2-(3-oxo-furan-3-carboxylic acid hexahydrofuro3,2-B|pyrrol-4-yl)ethyl/|-3-phenylpropionamide

For",

HPLC -12.50 minutes (29595), HPLC-MS 349.2 (MANI.

Example 58. (Za5, tank) M-(15-(4-

Hydroxybenzyl)-2-oxo-2-(3-oxo-HPLC K(-16.22 minutes (29090), HPLC-MS hexahydrofuro3,2-b|pyrrol-4-yl)ethyl|-3- 453.2 ( MANI, 475.0 |MA-Ma/|". phenylpropionamide Example 61. (Za5, tank) M-(15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuroyl|3,2-b|pyrrole- 4-iluethyl|-3-phenylpropionamide

HPLC -13.10 minutes (28595), HPLC-MS 451.1 MANI", 923.2 |(2M-Mai".

Example 65. (Za5, tank) (|3-methyl-15-(3-oxo-hexahydrofuro|3,2-5|pyrrole-4-carbonyl)butylamide and F benzo(bithiophene-2-carboxylic acid ": (U (WITH

VERH-MS 413, 2 MANI". y : h Rv oi

Example 62. (Zab5, tank) M-(15-benzyl-2-oxo-2-y;y: (3-oxo-hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethyl|-3-x. ; and phenylpropionamide - in the i th HPLC -15.62 minutes (29095), HPLC-MS

In 401.1 (MANI", 823.2 |(2M-Mai".

M y Example 66. (Zav, tank) M v h benzylsulfanylmethyl-2-oxo-2-(3-oxo- acids and | and

HPLC R-16.68 minutes (29095), HPLC-MS 407.2 (MANI, 835.2 |(2M-Mai).

Example 63. (Za5, tank) |3,3-dimethyl-1-(3-"oxohexahydrofuroyl3,2-5|pyrrole-4-! | , carbonyl)butyl|thiophene-3-carboxylic acid amide

HPLC -17.47 minutes (29095), HPLC-MS 481.1 (MANI", 983.2 |(2M--Mai").

Example 67. (Zaz5, tank) (15-cyclohexylmethyl-g 2-oxo-2-(3-oxo-hexahydrofuroyl)3,2-b|pyrrol-4-yl)ethylamidobenzo|bithiophene-2-carboxylic acid

HPLC Ri-13.24 minutes (29595), HPLC-MS 365.2 (MANI. .

Example 64. (Zaz5, tank) (15-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)2-b|pyrrol-4-»yl)ethylamidobenzo((b|thiophen-2- carboxylic acid ! F in HPLC - 18.15 minutes (29095), HPLC-MS - 441.2 MANI", 903.2 |(2M--Mai". ! | h Example 68. (Za5, tank) (15- benzyl-2-oxo-2-(3-u. i oxo-hexahydrofuroi|3,2-b|pyrrol-4-yl)ethyl|amide c | i | benzo|b|hiophene-2-carboxylic acid

F

7 c) in c oil,

HPLC -15.58 minutes (28595), HPLC-MS Sh 435.1 (Man, 891.2 |(2MmA-Mag. two minutes (906), HPLC-MO

Example 69. (Zaz, bak) P5-(4-Hydroxybenzyl)- Example 72. (Zaz5, vav) (15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-BIpyrrole-4- 2-oxo-2-(3-oxo-hexahydrofuroiZ 2-O-Ipyrrol-4-yl)ethylamide of naphthalene-1-carboxylic acid yl)ethyl amide of naphthalene-1-carboxylic acid (1 F: ( K Kk

HPLC (-17.45 minutes (29095), HPLC-MS

UL K(-12.42 minutes (28595), UL-MS 435.2 MANI", 891.4 |2MAMar". 445.1 (MENI, 911.3 (gM.-Ma)". Example 73. (Note5 , wt) (13-benzyl-2-oxo-2-(3-

Example 70. (Zaz, bak) (|3-methyl-1-(3-oxo-oxo-hexahydrofuro3,2-b|pyrrol-4-yl)ethyliamide na-hexahydrofuro3,2-b|pyrrole-4-carbonyl) butyl|amide of phthalene-1-carboxylic acid of naphthalene-1-carboxylic acid . and Y ( and F o ( So and (Z Fe you z

And and ; and w o, -

HPLC B-14.81 minutes (58596), HPLC-MS HPLC -15.17 minutes (29095), HPLC-MS

Y Y 429.1 (MANI, 879.3 (2M-Mag. 395.2 (MeANI), 811.3 (g M-Mmag. Example 74. (8 parts) 1- benzypsulfanylmethyl-o-skso 2-( 3-oxo. Pe cyclohexylmethyl-2-oxo-2-(3-oxo-psu. y y y I hexahydrofuroi3,2-b|pyrrol-4-yl) ethyl hexahydrofuroi3,2-b|Ipyrrol-4-yl) ethylamide naphthalene-morpholine-4-carboxylic acid 1-carboxylic acid with an aqueous solution of sodium chloride (100 ml), dried

HPLC-MS 395.2 (MANI), 811.4 (2M-A-Mai". (Mo9505) and the solvent was removed in vacuo, obtaining ester of mor-cyclohexyl-25-hydroxypropionic acid. Folin-4-carboxylic acid in the form of a white solid (Compound (32), Scheme 6).

Trimethylsilyl chloride (1.73 ml, 14.00 mmol) ether). TLC (single spot, K-0.20, meta- was added dropwise to the stirring solution, nol:dichloromethane 1:9), HPLC-MS (single basic sia, 3-cyclohexyl-25-hydroxypropionic acid peak with -7.614 minutes, 286.2 (Me, 287.2 (compound (25), 1.31g, 7.bmol) in methanol (35ml). IMZh2NI, 593.3 |(2M--Mai").

The mixture was stirred at room temperature (400MHz, SOSIz at 298K); 0.75-1.00 (2Н, during 20 hours, the solvents were removed in vacuo - CH» (cyclohexane), m), 1.02-1.28 (4Н, CH» (cyclogeum, obtaining in the residue a pale -yellow oil xane), m), 1.33-1.46 (1H, CH (cyclohexane), m), 1.50- (1.38g). The crude oil was purified by chromatography 1.79 (6Н, СНег (cyclohexane), m), 3.28-3.73 (8Н, on silica gel using a gradient eluent - СснНгОосН» and СНгМСН», m), 4.92-5, 02 (1Nes, m), 5.99 ml of a mixture of n-heptane:ethyl acetate (4:1). Attachment- (IN, ОН, width s). the fractions were combined and the solvents were removed to Compound (33) was cross-linked under standard conditions in a vacuum to obtain the methyl ether /3- loaded construction of the building-block-linker (22), cyclohexyl-25-hydroxypropionic acid was then cleaved, obtaining the compound of looks like colorless oil, output 1.26m (8995). HPLC-MS du 74. (The only main peak from KI-7.43 minutes, 187.14 Example 75. (Za5, bug) 4-(2-(4-third-

IMENI, 395.2 (gM--Ma)). butylbenzylsulfanyl)-4-zH (400MHz, SOCI3 at 298K); 0.84-1.04 (2H, methylpentanoyl|tetrahydrofuroi3,2-b|pyrrol-3-one

CH» (cyclohexane), m), 1.09-1.36 (ЗН, СН» (cyclohexane), CH (cyclohexane), m), 1.45-1.77 (7Н, CH» (cy - clohexane), CH (cyclohexane), m), 1.80-1.90 (1Нр,

M), 2.72 (1H, OH, d, 9U-5.99 Gu), 3.80 (ZN, SNZO, s), 4.20-4.31 (INo., m). (5) Preparation of i-carboxy-2-cyclohexylethyl ether of morpholine-4-carboxylic acid (Compound (33), Scheme 6)

A solution of phosgene (33.bml, 2095 in toluene) was added to the methyl ether of 3-cyclohexyl-25-hydroxypropionic acid (compound (32), 0.7g, 4.03mmol) followed by the addition of 6 drops of dimethylformamide. The mixture was stirred at ambient temperature for HPLC KI-21.3-23.4 minutes (28095), HPLC-MS 16 hours, then the solvents were removed under vacuum. 404.4 (MANI.

The residue was subjected to azeotropic distillation from toluene (3x20ml) and dissolved in anhydrous dichloroacetic acid (Compound (28), Scheme 5) (1ml). The solution was cooled to 0"C, then Morpholine (0.86 mg, 9.85 mmol) was added to a solution of sodium nitrite (5.1 g, 7 mmol) in water. -leucine, which is mixed between dichloromethane (30ml) and 0.5M hydrochloric acid (8.75g, b7mmol), potassium bromide (29.75g, 0.25mol) and that (30ml). The dichloromethane-retaining layer is washed with concentrated sulfuric acid (8.bml) in water was added to a saturated aqueous solution of hydrogen carbonate (100ml). The mixture was stirred for 30 minutes with a saturated aqueous solution of sodium chloride (30ml) at 0"C, then for 20 hours at the temperature of sodium chloride (30ml), dried (Mag5O4) and ambient solvent. The product was extracted and removed under vacuum. The residue was purified by chromatography with diethyl ether (2 x 150 ml), then combined with raffia on silica gel, eluting with an ethylacetate mixture, the ether layers were washed with saturated aqueous tritateptane 1:1. Suitable fractions were combined with various sodium chloride (2 x 100 ml), dried (Mazo"), and the factors were removed under vacuum, the solvent obtained in the residue was removed under vacuum. The residue was purified from 2-cyclohexyl-1-methoxycarbonylethyl ether by flash chromatography on silica gel using morpholine-4-carboxylic acid (0.13 g, 10905) under gradient elution with a meta-oil mixture. To cooled with ice water nol:dichloromethane 1:50 -» 1:20. Suitable fractions of the 2-cyclohexyl-1- solution were combined and the solvents were removed in vacuo, morpholine-4-demethoxycarbonylethyl ether was oxidized in the residue of 2P-bromo-4-methylpentanoic carboxylic acid (110 mg, 0.367 mmol) to dioxanic acid (28) in the form colorless oil, yield 1.60 g, (1.5 ml) was added solution of hydroxide monohydrate (12.395). TLC (single spot, 0.2, metallithium (17.5mg, 0.418mmol) in water (0.7bml). Nol:dichloromethane-1:20 mixture). Additionally, a second portion (5.2 g, 4095) of slightly contaminated medium was stirred at ambient temperature for 1 hour, then the mixture was diluted. with water (1 Oml). The aqueous layer was extracted with diethyl-ZN (400 MHz, SOCI3 at 298K); . 6M hydrochloric acid. Pro- CHZCH, m), 1.93 (2HB, m), 4.31 (No, t, 9U-7.7Hz), 9.3 The product was extracted with diethyl ether (2x10ml), (IN, SON , width c). then the combined ether layers were washed with sat

(5) Preparation of 25-(4-tert- The mixture was stirred for 5 hours at 0"С, butylbenzylsulfanyl)-4-methylpentanoic acid - then for 16 hours at the temperature of the excess medium (Compound (30, scheme 5)). The product was extracted with die-

A solution of 2K-bromo-4-methylpentanoic acid with ethyl ether (4x20 ml), then the combined ether (compound (28), 1.1 g, 5 mmol) and (4-(tert) layers were washed with a saturated aqueous solution of butyl)phenyl)methanethiol ( 1.0g, 5.bmmol) in sodium dimethyl chloride (2x50ml), dried (Ma5O»4) and dissolved in ethylformamide (15ml) was purged with a stream of nitrogen, the factor was removed under vacuum. The residue was purified for 5 minutes, then cooled to 0"C by chromatography on silica gel using

It was added dropwise during 1 minute triethyl gradient elution with a mixture of methalamine (0.79 ml, 5.7 mmol), then a mixture of mixed ethanol: dichloromethane 1:50 -» 1:20. The suitable fractions were stored for two days at the above temperature, combined and the solvents were removed in a vacuum, a separate medium. Solvents were removed under reduced vacuum and the residue was purified by flash chromatography (B)-o-bromocyclohexanepropionic acid on silica gel using a gradient elution- pale yellow oil, 0.374g, (2795). TLC (etching with a mixture of methanol:dichloromethane 0:1 -» 1:20. per spot, K-0.45, 1095 methanol in dichloromethane),

The suitable fractions were combined and the solvents extracted by HPLC-MS (the only main peak with CI-8.88 minutes, poured in a vacuum, obtaining a residue that was purified 2341/2361 (MANI, 2572/2592 |Ma-Ma|) by flash chromatography. on silica gel, eluting with 5H (400 MHz, SOCI3 at 298K); 0.83-1.88 (11H, with a mixture of ethyl acetate and teptane 2:5. Suitable fractions CH (cyclohexane), СНо (cyclohexane), m), 1.89- 2.05 were combined and the solvents were removed in vacuo, yielding (2HB, m), 4.32-4.44 (1Hex, m). rusting 25-(4-tert-butylbenzylsulfanyl)-4- (b) Preparation of 3- cyclohexyl-23-(furan-2-methylpentanoic acid (30) in the form of colorless ylmethylsulfanyl)propionic acid (Oil compound, yield 150mg, (995). TLC (single spot, K-0.2, (41), scheme 9) heptane:ethyl acetate 5:2), analytical HPLC with base- (B)-o-bromocyclohexanepropionic acid with a CI peak of 22.117 minutes, HPLC-MS (base (0.37g, 1.58mmol) and furan-2-ylmethanethiol ( 0.18Hg, peak in UV with KI-11.072 minutes, 317.2 |MaMa|"). 1.58mmol) was dissolved in dimethylformamide (10ml) with H (400MGu, SOCIz at 298K); 0.70 and 0.85 (both and purged with a stream of nitrogen for 10 minutes. va ЗН, СНИСН, d, 9-6.3), 1.29 (9Н, (СН3)зсС, с), 1.44- The solution was cooled to 02С, then 1.51 (IN, СНИСН, m) was added . ", d, 1.58 mmol). The mixture was stirred at 0"C for 13.2 Hz), 7.25-7.35 (AN, aromatic) for 30 minutes, then for 16 hours at room

Compound (30) was condensed at standard ambient temperatures. The solvent of the conditions with the loaded construction of the building block was removed under vacuum and the residue was purified by chromatoglinker (22), then cleaved by sporaphia on silica gel using a mixture of powder of example 75. ethanol:dichloromethane 1:100 as an eluent. Suitable

Example 76. (Za5, tank) 4-I(3-cyclohexyl-23- fractions were combined and the solvents were removed in vacuo -(furan-2-um, obtaining //3-cyclohexyl-25-(furan-2-ylmethanesulfonyl)propionylIttetrahydrofuro3 ,2-ylmethylsulfanyl)propionic acid (41) in

Bipyrrole-3-one looks like a light brown oil, yield 142mg, (3390).

Analytical HPLC peak with MKI-18.68 minutes. TLC (single spot, CI-0.45, 1095 methanol in dichloromethane), HPLC-MS (single main peak with I-9.53 minutes, 291.0 (Ma-Ma/"). zH (400MHz, SOSIz at 298K); 0.68-0.89 (2Н,

SnNeg (cyclohexane), m), 0.97-1.77 (11H, CH (cyclohexane), CHg (cyclohexane), m), 3.21-3.32 (1No., t, i . i y7 ... ; 3.94 (1Н, СНе5, d, 9У-14.8Hz), 6.15-6.28 (2Н, furan

M as 'H-3 and H-4, d, 9U-27.34 Hz), 7.30 (1H, furan H-5, c). and. And gi with . and Compound (41) was condensed under standard and conditions with a loaded construction of the building block and linker (22). Intermediate loaded thioether

Sh (1.2 μmol of a carrier in the form of gears) was oxidized with molene V RM (29095), HPLC-MO with chloroperbenzoic acid (Bekviv., 6595 reagent, 1.6 mg) in dichloromethane (200 μl) for 5 brotcyclohexanepropisnic acid (K)-o- hours, followed by standard washing and

A solution of sodium nitrite (0.45g, 6.5mmol) in water was then cleaved to give the title compound (1.2ml) was added dropwise at 07C over 4 hours. Example 77. (Za5, vacuum) 2b-cyclohexylmethyl- , (RK)-o-4-morpholin-4-yl-I-(3-oxo-hexahydrofuro-3,2- aminocyclohexanepropionic acid (g, pyrrol-4-yl)butan-1,4-dione 5.8 mmol), bromide potassium (2.3g, 19.2mmol) and concentrated sulfuric acid (0.bbml) in water (7ml).

zn (400MHz, SOSIz at 298K); 0.77-0.90 (2H,

CH» (cyclohexane), m), 1.05-1.40 (4Н, CH» (cyclohexane), m), 1.50-14.90 (7Н, CH (cyclohexane),

СНа(cyclohexane), m), 2.30-2.44 (2НБ, m), 2.64-2.77 (Не, m), 2.96-3.10 (1Н, ОН, width, с) , 3.40-3.78 (8H,

СнНГОосН»5» and СН2МСН», m).

Compound (36) was condensed under standard conditions with a loaded building-block-linker structure (22), then cleaved, obtaining the compound of example 77.

Example 78. (Zab5, tank) 4-(2-Biphenyl-3-yl-4-metalpentanoyl) tetrahydrofuroyl3,2-5|pyrrol-3-one.

HPLC-MS 393.1 (M.e-NI", 807.3 (2M--Ma)".

To a stirred solution of 1-methyl ether, 22-(cyclohexylmethyl)butanedioic acid (compound (35), 1.0g, 4.38mmol) in dimethylformamide (110ml) was added 1-(3-dimethylaminopropyl) -

3-ethylcarbodiimide-HCI (1.12g, 5.69mmol), then 1-hydroxybenzotriazole monohydrate (0.87g, 5.69mmol) at 0"C in an argon atmosphere. The mixture was stirred for 25 minutes, then added dropwise during 71 minutes morpholine HPLC gche-19.09-20.76 minutes (79095), HPLC- (0.7ml, 8.7bmmol) and stirring continued MO 378.4 (ME! I I I I at ambient temperature pro- ( a) Preparation of biphenyl-Z-yl methyl ether for 16 hours. The product was extracted with ethylacetoacetic acid (Compound (38), scheme 8) volume (200ml), then washed with 1.0M hydrochloric acid and concentrated sulfuric acid (588μl) until - lota (3x100ml), a saturated aqueous solution was added to a solution of 3-bromophenylacetic acid, sodium bicarbonate (3x100ml), water (100ml), (1 g, 46.5mmol) in methanol (100ml). The mixture was then heated with a saturated aqueous solution of sodium chloride under reflux (100 ml), dried (Mo50O5) and the solvent was removed within 1.5 hours and then cooled to room temperature tyl-4-morpholin-4-yl-4-oxol under reduced pressure, obtaining a residue. Zabutanoic acid in the form of a not quite white solid residue was re-dissolved in diethyl ether, yield 1.22 g, (9495). HPLC-MS (single peak (500 ml), washed with water (2 x 100 ml), saturated with VI-7.91 minutes, 298.1 (MeNi), 617.3 (2IMaMar). salt solution (100 ml), dried (MozO»4 ) and then (5) Preparation of 2B-cyclohexylmethyl-4- was evaporated under reduced pressure to give memorpholin-4-yl-4-oxo-butanoic acid (Compound 3-bromophenylacetic acid ethyl ester (36), Scheme 7). ( 10.65g). Methyl ether of 3-bromophenylacetic acid

A solution of lithium hydroxide monohydrate (0.51 g, dissolved in toluene (117 ml), then 12.18 mmol) was added in water (27 ml), phenylboronic acid (6.8 g, 55.69 mmol) was added to the solution, with cyclohexylmethyl-4-morpholine -4-yl-4-oxo-sodium (93ml, 2M) and tetrabutanoic acid (1.21g, 4.0bmmol) in tetrahydkis(triphenylphosphine)palladium (1.6g, 1.41mmol). rofuran (55ml) and methanol (27ml) at 02С. The mixture was stirred overnight, then cooled, stirred at ambient temperature, chewed to ambient temperature for 1 hour, then diluted higher and a saturated aqueous chloride solution (100 ml) was added. The aqueous layer was extracted with ammonium diethylide (100 ml). The mixture was extracted with ether (2 x 50 ml), which was discarded, then the layer with ethyl acetate (2 x 200 ml), dried (Mag 5 O 4 ) and acidified to pH-1-2 with 1M hydrochloric acid. It was stirred under reduced pressure, obtaining a residue. the extract was extracted with dichloromethane (3x50ml), then flash chromatography of the residue on silica gel (200g), the combined ether layers were washed with water (2x50ml), using a mixture of ethyl acetate and heptane (3:48) as a saturated aqueous solution of sodium chloride as an eluent gave biphenyl-3 methyl ether - vacuum, obtaining a residue. The residue was purified by spotting in UV, MCEO, 24, 1090 ethyl acetate in heptane), chromatography on silica gel using analytical HPLC -19.55 minutes, HPLC-MS gradient elution with a mixture of methanol and dich- (the only main peak in UV with RF-9.35 minutes , lormethane 1:100 -» 3:100. Suitable fractions are combined - 221.1 MEN). solids and solvents were removed in vacuo, obtaining zn (400mMHz, SOCI3 at 298K) 3.76 (2Н, с, 2В-cyclohexylmethyl-4-morpholin-4-yl-4-СНеСО»СН»), 3.77 (ЗН, c, OSH3), 7.34-7.66 (9H, m, oxobutanoic acid (36) in the form of a white solid biphenyl-3-yl). of substance, yield 0.82g, (7195), HPLC-MS (single peak (B) Preparation of biphenyl-Z-yl-acetic acid from VI-6.769 minutes, 284.2 |(MaNi), 589.2 (2M-Mar) To a solution of methyl ester of biphenyl-3-ylacetic acid (11.43 g, 50.57 mmol) in methanol

(265ml) water (39ml) was added, and then monohydrate main peak in UV with CI-10.15 minutes, 269.1 lithium hydroxide (4.2g, 101.5mmol). A mixture of alternating IMANI", 291.1 |M-Makr). shunted at ambient temperature (400MHz, SOSIz at 298K); 0.93 (6Н, d, higher for 2 hours, then the organic layer is В6.6ГЦ, 2 x СН3), 1.52-1.57 (1Н, m, 4-NI), 1.71-1, 76 was added under reduced pressure. The mixture was acidified (IN, m, 3-NI), 1.97-2.05 (1N, m, 3-Ni), 3.66 (1N, t, diluted hydrochloric acid (1M, 8Oml), extra- uE7, 8Hz, 2H)), 7.32-7.60 (9H, m, biphenyl-3-yl). was washed with chloroform (2x100 ml), dried (Md5oa) and the compound (39) was condensed in standard conditions and evaporated under reduced pressure, obtaining bi-conditions with a loaded structure of the building-block-phenyl-3-ylacetic acid in the form of a white solid linker (22), then cleaved, obtaining compounds, yield 10.6 g, (9995), analytical HPLC of onion of example 78.

MKI-I6.565 minutes, HPLC-MS (single main peak Example 79. (Za5, tank) 4-methyl-M-|3-methyl-1- in UV with ET-7.91 minutes, 213.1 MANI. (Z-oxo-hexahydrofuroiZ,2-B|pyrrole-4-zn (400MHz, SOCI3 at 298K) 3.77 (2H, c, carbonyl)butyl|benzamide

СНСОССН»), 7.28-7.52 (9H, m, biphenyl-3-yl). (c) Preparation of 2K5-Biphenyl-3-yl-4-methylpent-4-enoic acid

A solution of biphenyl-3-ylacetic acid (7.0 g,

ZZmmol) in anhydrous tetrahydrofuran (84 ml) was added dropwise to the isopropylamide solution. F lithium (36.4 ml, 2 M solution in hexanes) in anhydrous C; It was added to tetrahydrofuran (84 ml) at -78°C. The mixture was allowed to warm to 0°C and stirred for ! ), minutes. The mixture was then cooled to -78°C and 3-bromo-2-methylpropene (4.97 ml) was quickly added.

The mixture was stirred for 1 hour at -787C, HPLC RI-13.74-14.85 minutes (29096), then water (28 ml) and organic layer were added. , , were added under reduced pressure. Then the mixture is acidified- ' ! was poured with hydrochloric acid (EM, 14 ml), extracted with ethyl acetate (3 x 100 ml), dried (Ma5O) and evaporated under reduced pressure with carbonyl)butylbenzamide to give a residue.

Flash chromatography of the residue on silica gel (400 g) using methanol:dichloromethane (3:97) as eluent gave impure 2-biphenyl-3-yl-4-methylpent-4-enoic acid (8.3 g). Flash- ; chromatography on silica gel (400g) using F: a mixture of methanol: dichloromethane (1.5:98.5) gives | ; gave pure 2-biphenyl-3-yl-4-methylpent-4-enoic acid (YH in lot, yield 5.27g, (6095), TLC (single spot in UV, and Y , 0.28, 595 of methanol in dichloromethane), analytical Zh and gy

HPLC Ch-19.99 minutes, HPLC-MS (the only main peak in UV with KiI-9.57 minutes, 2671 (MANI). o "H (400MHz, SOSIz at 298K); 1.765 (ZN, s , Metric minutes (29096), HPLC- two t Zno probe viv h Example 81. (Za5, bai) 4-tert-butyl-M-15-(4- , , Hu, 1), 3.92 (1Н , dd, U-6.61 and 8.9 Hz, in 2-H), 4.79 (2H, d, 9-10.7Hz, 5-H2), 7.30-7.62 (9H, g, bromobenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-biphenyl-3-yl).BIpyrrol-4-yl)ethyl|benzamide (a) Preparation of 215-biphenyl-3-yl-4-methylpentanoic acid (Compound (39), scheme 8) is.

Palladium on carbon (1095, 300 mg) was added in portions to a solution of 215-biphenyl-3-yl-4-7 methylpent-4-enoic acid (1 g, 3.6 mmol) in ethanol (40 ml) at 0"C. Then hydrogen gas was introduced and the mixture was left to warm to the ambient temperature. The mixture was stirred for 18 hours, then the wax was removed in a day, the mixture was filtered through celite and a catalyst and from - I s washed with ethanol (40 ml). The combined organic filtrate was concentrated under reduced pressure to give a residue, which was subjected to flash chromatography on silica gel (150 g) using a mixture of methanol: dichloromethane (1: 99) as an eluent, obtaining 2K5-biphenyl-3-yl-4-methylpentane HPLC in 18.40-19.10 minutes (29095), HPLC-acid, yield 980mg, (98905), TLC (single spot in MS 513.2/515.2.

UV, MK-0.45, 595 methanol in dichloromethane), analytical Example 82. (Za5, bag) 4-tert-butyl-M-|195-(4- tic HPLC MI-20.92 minutes, HPLC-MS (single methoxybenzyl)-2-oxo-2-(3-oxohexahydrofuro3,2-b|pyrrol-4-yl)lethyl|benzamide

30.2m (82.2mmol, 79.5905). TLC (minor spot in h UV, MKIt 0.58, main spot in UV KI-0.25, meta-yacnol:chloroform 1:4), analytical HPLC main

I peak K-16.990 minutes, HPLC-MS (the only main and Y peak in the UV with B-7.976 minutes, 368.0 IMeNI", 390.0

With lm IMe-Mag. Analysis using H and C NMR revealed the presence of cis and trans geometric isomers relative to the 3-amide bond. and in "C" (DMSO-iv at 298K); 23.29/23.57 (d, St), y r "a ' 28.89 (d, Su), 40.19 (d, Se), 47.59 (single, Ethos p ' S-9), 59.11/59.43 (singular, So), 67.34 (singular and with chny, Ethos C-4 and C-5), 126.90/127.02 (single,

Etos 0-1 and C-8), 128.11 (single, Etos C-2 and C-7), 128.68 (single, Etos C-3 and C-6), 141.73 (KV,

HPLC gche17.50-18.31 minutes (29095), HPLC-Etos C-4 and C-5), 144.58/144.76 (KV, Etos C-1 and C-

Me 465.2 (MINI". 8), 155.71/156.23 (square, EIGHT), 172.37/172.63

Example 83 (Example of general formula (II)). (UNSC). (Zab5, 7an) (1 A-benzylsulfanylmethyl-2-oxo-2-(3- (2) Preparation of 2-allyl ether 1-(9H-oxo-hexahydrofuro|3,2-b|pyridin-4-yl)ethylamide fluoren-9-ylmethyl) ether // cis-rac-(3-morpholin-4-carboxylic acid. hydroxy)piperidine-1,2-dicarboxylic acid. 1-"9H-Fluoren-9-ylmethyl) ether cis-rac- (3-Hydroxy)piperidine-1,2-dicarboxylic acid (28.2 g, 76.7 mmol) was dissolved in toluene (200 mL) in an apparatus with a Dean-Stark nozzle. Alylic alcohol (5 mL) was added ) followed by the addition of p-toluenesulfonic acid hydrate (15.1 g,

E 78.2 mmol). The mixture was heated to boiling with a rotary refrigerator for 1 hour, cooled and stirred, and SNCI3 (500 ml) was added. Organic; and the layer was washed with MansSOz (2 x 250 ml), On Nei vych Ba CHI i yan "a (250 ml) and saturated salt solution (250 ml), then those x ; and dried (Mag25054). Filtration and evaporation in

A pale yellow mobile oil (35Hg) was given to it and the vacuum. The crude oil was purified on silica gel (240 g) using gradient elution with a mixture

Necessary bicyclic building block 9H- nuvaly and vaporized; With uk oder they are Meringue. Fluoren-9-ylmethyl ether (Zab5, 7ag) was 3-oxonated and evaporated in a vacuum, obtaining 7 hexahydrofuro3,2-b|pyridine-4-carboxylic acid in resin, yield 20.4m (50 mmol, 65.89) , TLC was obtained in 8 stages in the following manner. (single spot in UV, MO, 20, heptane-ethyl acetate (1) Preparation of 1-(9H-fluoren-9-ylmethyl) 27), analytical HPLC P-20.003 minutes, HPLC- ester of cis-rac-(3-hydroxy) piperidine-1,2-de; (the only main peak in UV with RF-9.473 minutes, dicarboxylic acid. 081 IMNI with 430.1 |IMAMa|"). Analysis of Kk! used-

Cis-rac-(3-hydroxy)piperidine-2-carbon quinyam Nilo Yam showed the presence of cis ! trans slot (obtained by hydrogenation of commercially available isomers relative to the 3" amide-linked 3-hydroxypicolinic acid vys I

Ogittopa U. s ai., u. Honey. Spet., 32, 2118-2128, zn (400MHz, COSiz at 298K); 1.55 (2Nu or 19891 (15.0g, 103.4mmol) was added to intensively 2He, d, .) 9.3), 1.81 (1Nu or 1H5, d, U 3.2), 2.06 ( Well, a stirred, ice-cooled solution or 1H5, d, 4) 3.2), 2.78/2.92 (No, d. width, t), 3.55 of sodium carbonate (22.90g, 217.1mmol) in in water (No dd, U 12.6, 9.2), 3.78 (OH, width), 3.95/4.11 (200 ml). 1,4-dioxane (100 ml) was added, obtaining (He, d, U 13), 4.91 (Htos H-9, m), 4.49 (Htos CH), a transparent pale yellow solution. Within 1 hour m ), 4.71 (2 x COOSHSNACH", m), 4.99/5.17 (Na, d, 9-fluorenyl methyl chloroformate (27.52 g, U 4.8) was added), 5.91 (2 x COOSHSNACH", m), 5.87 (1 x CO- 108.4 mmol) in 1,4-dioxane (100 ml), then OoSNeSNASN, m), 7.37 (2H aromatic, Htos H-2) were cooled with ice and the mixture was stirred at Y H-7), 7.47 (2H aromatic, Htos H-Z and H-6), 7.62 at room temperature additionally for 1 hour - (2H aromatic, Htos H-1 and H-8), 7.83 (2H aromas. Additionally, water (150 ml), reaction mixture, Htos H-4 and H-5 were added). the mixture was washed with chloroform (2 x 250 ml) and separated (SOCI3 at 298K); 23.87/24.11 (d, Sat), 30.59 nani organic layers were discarded. The aqueous phase was acidified (d, Su), 41.26/41.56 (d, Ce), 47.62 (single, Htos was diluted with Mn HCl to pH 2, obtaining thick opaque C-9), 58.29/59 .54 (single, Со), 66.44/66.54 (d, mixture. The acidified aqueous mixture was extracted with chloro-СОоОоСНоСН:СН»), 68.28 (d, Гтос СН»), 69.14/69.42 roform (2x500ml) and now discarded the clear (single, SD), 119.67/119.90 (d, COO- aqueous phase. Cloudy combined layers of chloroform SNeSNISN"), 120.43 (single, Ethos C-4 and С-5), dried (Ma»zO»), filtered and evaporated in vacuo 125.22/125.35 (single, Ethos С-1 and С-8), 127.48 kum, obtaining a white foamy substance, yield (single, Ethos C-2 and C-7), 128.15 (single,

Ethos 0-3 and 0-6), 131.43/131.57 (single, COO- Product 2. 2-allyl ether 1-(9H-fluorene-9-

СНаСНИсСНН»), 141.73 (sq., ERtos 0-47 0-5), ylmethyl) ether (2K.35) (3-hydroxy)piperidine- 144.19/144.38 (sq., Rtos C-1'ii 0-8), 155.67/156.27 of 1,2-dicarboxylic acid. (sq., EIGHT), 171.56 (SOOSNoSNASN"). White crystalline substance, yield 9.05m (3) Enzymatic cleavage of 2-allyl ether 1- (22.2 mmol, 46.1 95). TLC (single spot in UV, (9H-fluoren-9-ylmethyl) cis-rac-(3-KO,20, heptane: ethyl acetate 2:1), analytical HPLC of hydroxy)piperidine-1,2-dicarboxylic acid on 2 - KE- 19.970 minutes, HPLC-MS (single basic allyl ether 1-"9H-fluoren-9-ylmethyl) ether peak in UV with M-9.450 minutes, 408.1 (MaNI), 430.1 (28.93 5 ) (3-hydroxy)piperidine-1,2-dicarbonate IM-Mar). Analysis using "H and Zb NMR of acids and 2-allyl ether 1-(9H-fluorene-9-) showed the presence of cis and trans geometric iso-ylmethyl) ether (25.3K) (3-acetoxy)piperidine-mers relative to 3" amide bond. 1,2-dicarboxylic acid. zH (400MHz, SOSIz at 298K); 1.47-1.61 2-Allyl ether 1-49n-fluorene-9- (TNANNH, m), 1.71-1.81 (1H5, ext.), 2.02-2.11 (1H,, ylmethyl) ether cis-rac-(3-hydroxy)pyrrolidine-ext.), 2.71-2.81/2.84-2.94 (1He, dt), 3.54-3.59 (Hb, 1 ,2-dicarboxylic acid (19.6g, 48.1mmol), lipa-m), 3.70-3.82 (OH, ext.), 3.93-3.96/4.10-4.16/ 4.11 from RBZ (25g, ex Atapo Epgute Ips.), vinyl acetate (He, d, U 10), 4.24-4.31 (Ethos H-9, m), 4.40-4.56 (30Oml ) and isopropyl ether (200 ml) were mixed (Etos CH", m), 4.61-4.78 (2 x СООСНоСНАСН", m), at 38"С. After 5 days, HPLC showed equal to 4.98/ 5.18 (Na, d, U 5.0), 5.25-5.37 (2 x SOO-weight between 2 peaks (52956:4876, indicating 9576-Nu 00 сНЬСнНеСН», m), 5.86 -5.96 (1 x СООСНСНеСН", conversion) and the reaction mixture was filtered through m), 7.30-7.34 (2Н aromatic, Ethos H-2 and H-7), celite (3cm x 1Osm layer). Layer celite was washed with 7.41 7.AB (2H aromatic, Ethos H-Z and H-6), 7.53- chloroform (Z x 250ml) and combined organic 7.62 (2H aromatic, Ethos H-1 and H -8), 7.79-7.81 filtrate was evaporated in akuumi to viscous golden- (2H aromatic, Etosn-4 and H-5). brown oil (23.0 g). Crude oil was purified "C" (SOCIv at 298K); 23.87/24.12 (d, Cx), 30.60 on silica gel (300g) Using gradient (d, SU), 41.27/41.57 (d, Se), 47.82 (single, Ethos eluting with a mixture of heptane: ethyl acetate 31 - This is C-9), 58.29/59.54 (single, C), 66.44/66.54. (d, (identified TWO main fractions and evaporated them with CoOosCHnesHn-cH"), 68.28 (d, Ptos CH?2g), 69.15/69.42 vacuum. adduct 1, 1,2-allyl ether 1-( 9H- and pluoron oleic) ether of, (3- (Single, St), 119.67/119.91 (to CO. acetoxy) piperidine-1,2-dicarboxylic acid spesNesH"), 120.42 (single , Rtos CM 75),

Viscous very pale yellow oil, yield 9 BM 125.22/125.35 (single, Etos C-1 and C-8), 127.48 (21 tmol 43996), TLC (yes ' UV (single, EGtos 0-2 and 0-7), 128.15 (single, y; byu), a single spot in U, Ethos C-3 and C-6), 131.42/131.57 (single, SOO- 0.40 , heptane-ethyl acetate 2:11), analytical HPLC СНеСНеСН»), 141.73 (sq, Ethos C-4 and C-5)

I-22.633 minutes, HPLC-MS (single main peak 144 12/144 37 (q Etos s-g and C-8)), 155.67/156 26 in UV with EC-10.714 minutes, 450.1 (MaN| I", 472.1 (sq. som) 171 57 (СООСНСНеСН») " "

IM-Ma/"). Analysis using "H and 3C NMR showed (4) Preparation of 2-adyl ether 1-(9n- in the presence of cis and trans geometric isomers of fluoren-9-ylmethyl) ether (25, 3) (3- relative to the 3" amide bond. : and A "H (400 MHz, SOCIz at 298); 1.25-1.32/1.52- /Lrokomutperodin OH fluorene-o- 1.70/1.72 -2.00 (2Nu2Nh, width, m), 2.05-2.15 (OSO-ylmethyl) ether (25, ZE) (3-acetoxy)piperidine-

CH3, width, s), 3.35-3.58 (1He, m), 3.98-4.10/4.18- 1,2-dicarboxylic acid (4.5g, 1Omol) solution- 4.22 (He, dd), 4.24-4.31 (Htos H-9, m), 4.32-4.52 were dissolved in allyl alcohol (50 ml), conc. (Htos SnNa, m), 4.60-4.82 (2 x СОСНСНАСН, m), Hg5О»x (200 μl) and heated at reflux - 4.92-4.99 (Nv, m) , 5.22-5.32 (Na, m), 5.28-5.32/5.34- in the refrigerator for 24 hours. The mixture 5.41 (2 x СООСНоСНАСН», dd, at 17.2), 5.89-6.00 (1 was cooled, added EIUAs (250 ml) and washed СООССННесСН», m), 7.30-7, 37 (2H aromatic, filled with MansoO»z (250 ml), saturated salt solution

Ethos H-2 and H-7), 7,387.46 (2H aromatic, Htos (250 ml) and dried (Mag25054). Solvents were removed in

H-Z and H-6), 7.59-7.76 (2H aromatic, Htos H-1 and vacuum, obtaining a golden-brown oil

H-8), 7.78-7.80 (2H aromatic, Rtos H-4 and H-5, d, (4.27). The crude oil was purified on silica gel

In 7.5). (170g) with the use of gradient elution "C" (SOCIz at 298K); 21.22 (single, OSO- with a mixture of heptane:ethyl acetate 3:1 -» 1:11. Target

CH"), 23.01 (d, Sv), 25.54 (d, C), 40.51/40.88 (d, Ce), the fractions were combined and evaporated in a vacuum, obtaining 47.44 (single, ERtos C-9), 55.55 (single, chewing white crystalline substance, yield 3.0g

С», 66.08 (d, SOOSNoSNASN?:g), 68.30/68.65 (d, (7.37mmol, 73.790). TLC (single spot in UV,

Ethos CH"), 69.21/69.59 (single, Sv, EO,20, heptane: ethyl acetate 2:1), analytical HPLC 118.94/119.22 (d, СООСНоСНАСН»), 120.31 (odi - -19.474 minutes, HPLC-MS (single main peak nocturnal, Ethos C-4 and C-5), 125.34/125.49 (single, in UV from -9.507 minutes, 408.2 |MANI", 430, 2

Ethos 0-1 and 0-8), 127.43 (single, Ethos S-2 and S- IM-Mar). Analysis using "H and Zb NMR 7), 128.04 (single, Ptos C-3 and 0-6), 131.93 showed the presence of cis and trans geometric iso- (single, СООСНоСНАСН»), 141.61 (q , Rtos S-mers relative to the 3" amide bond.

A and C-5), 144.15 (kv, Rtos C-1'i C-8), 155.50/156.36 "NN (400MHz, SOSIz at 298K); 1.46-1.59 (sq., OSOM), 169.42/169.91/170.37 (cOo- (1NunH", m), 1.74-1.81 (1H5, width), 2, 01-2.10 (1H,,

SsnsnNesSNn" - OSOSN"). width), 2.70-2.82/2.88-2.99 (1He, dt), 3.49-3.62 (1Nv, m), 3.70-3.80 (OH, width. ), 3.90-3.94/4.09-4.14 (1H»e, dd), 4.26-4.32 (Ethos H-9, m), 4.41-4.58 (Ethos SN",

m), 4.60-4.80 (2 x SOOSNoSNASN", m), 4.96-"b (SOSIz at 298K); 23.69/23.99 (d, S»y), 4.98/5.17-5.18 (Neo, dd, y 4.8), 5.25-5.42 (2 x SOO- 28 ,38/28.65 (single, C(SNZz)z), 28.75 (d, Su),

СНаСНеСН», m), 5.82-5.97 (1 x СООСНеСНАСН», 40.40/40.72 (d, Ce), 47.61 (single, Ethos С-9), m), 7.30 -7.38 (2H aromatic, Rtos H-2 Her H-7), 58.36/58.47 (single, C"), 65.67 (d, СОО- 1.42 7.48 (2H aromatic, Yetos H -Z i H-6), 7.55- СНеСНеСН»g), 67.82 (single, Sv), 67.99/68.13 7.83 (2Н aromatic, Ethos H-1 and H-8), 7.79-7.84 (d, Ethos CH"), 74.97 (sq., С(СНЗ)з), 118.44/118.57 (d, (2H aromatic, Htos H-4 and H-5 ). SOOSsNoSNesN"), 120.40 (single, Ethos C-4 and "C (SOSIiz at 298K); 23.86/24.12 (d, St), 30.62 C-5), 125.39/ 125.48 (single, Ethos C-1 and C-8), (d, Su), 41.28/41.57 (d, Se), 47.62 (single, Htos 127.46 (single, Ethos C -2 and C-7), 128.10 (units

C-9), 58.29/59.54 (single, So) 66.43/66.54 (d, male, Etos 0-3 and C-6), 132.49 (single, SOO-

SOOSnNoSnNASNg), 68.27 (d, Ethos SNg), 69.- SNoSNASNg"), 141.71 (sq., Etos (0-47 Her S-5), 15/69.43 (single, St), 119, 69/119.91 (d, SOO- 144.14/144.30 (sq., Rtos S-1' and 0-8), 155.44/157.00

SNSNASN"), 120.42 (single, ERTOS C-4 and C-5), (square, OSOM), 170.43/171.05 (СООСНоСНА СН"). 125.22/125.35 (single, Ethos C-1 and C-8), 127.47 (6) Preparation of 1-"9H-fluoren-9-ylmethyl) (single, Ptos C-2 and C-7) , 128.14 (single, ether (25, ZE) (3-tert-butoxy)piperidine-1,2-

Ethos 0-3 and 0-6), 131.43/131.57 (single, COO- dicarboxylic acid.

СНоСНАСНг»), 141.73 (sq, ERtos (C-47 Her C-5), 2-allyl ether 1--9nH-fluorene-9- 144.12/144.37 (sq, Rtos C-1" her 0-8), 155.67/156.26 ylmethyl) ether (25, ZE) (3-tert- (q, OSOM), 171.57 (СООСНоСНАСН»). butoxy)piperidine-1,2-dicarboxylic acid ( 5) Preparation of allyl ether 2 1-(9H- (1.52 g, 3.29 mmol) was dissolved in dry dichloromethyl-fluoren-9-ylmethyl) ether (25, ZE) (3-tertane (25 ml) with stirring. Add tetrakis-butoxy)piperidine-1,2-dicarboxylic acid triphenylphosphine palladium(0) (7bmg, 0.06bmmol, 2-Allyl ether 1--9H-fluorene-9- 0.02eq.) followed by the addition of phenyltrihydroylmethyl) ether (25, ZK) (3-hydroxy)piperidin- silane (0.71g, 0.622ml, 6.58mmol, 2eq.). After 1 1,2-dicarboxylic acid (1.75g, 4.30mmol) for an hour dichloromethane (150 ml) was added and the organic layer was dissolved in dry dichloromethane (20 ml) in 50 ml. The first layer was washed with 0.01 N HCl (150 ml), saturated with a glass container (ampoule) for working under pressure and salt solution (1500 ml) and dried (Mag5O4). The solution was cooled and up to -78"C. Gaseous isobutylene was removed under vacuum, obtaining dark gray (UtOml), condensed into a solution, and conc. solid (2.05g). Unrefined solid

On 5 BO»h (100 μl). A magnet was added for the mixture, the mixture was purified on silica gel (75 g) using water, the ampoule was sealed, the cooling was removed by gradient elution with a mixture of heptanetyl- and mixed at room temperature with acetate 2:11 -» 1:2. The target fractions were combined for a period of 72 hours. The sealed ampoule was cooled and dried in a vacuum, obtaining a white crystalline 787 C, M-methylmorpholine (200 μl, substance, yield 0.97 m (2.29 mmol, 69.695) was added. TLC 1 wt. eq. at room temperature, which corresponds to (a single spot in UV, KI-0.25, heptane, ethyl acetate conc.Na5O»X) and left to warm to room temperature 171), analytical HPLC KI-21.310 minutes, HPLC- temperature in de-soldered form with stirring - MS (the only main peak in UV with CH-10,254 stirring for 2 hours.Dichloromethane was added, 368.2 (|MaAN-Vy-C, 446.2 |M-Mar, 869.3 (/75ml) and the organic layer was washed with MansoOz (g mMeMag). "H and C NMR analysis showed the presence of (75 ml), then saturated salt solution (75 ml) and cis and trans geometric isomers relative to 3" was dried (Ma250O4). Solvents were removed in vacuo, bottom connection. obtaining a pale golden oil (1.91g). Unpurified - zH (400MHz, SOSIz at 298K); 1.32/1.40 (9 x well oil was purified on silica gel (100g) with used - С(СНЗ)»z, dos), 1, 42-1.58 (NU H»5, m), 1.72-1.80 (NU yum gra of dient elution with a mixture of heptanieti- width, m), 1.82-1.96 (1Н5, width, m), 2.76-2.82/2.90-lacetate 5:11 -» 3:11. The target fractions were combined and 2.97 (1He, dt), 3.70-3.84 (Nv, wid.), 3.90-4.07 (1He, evaporated in a vacuum, obtaining a thick transparent dd), 4.22 -4.32 (Etos H-9), 4.40-4.58 (Etos CH", oil, yield 1.59g (3.43mmol, 79.890). TLC (single width, m), 4.59-4 ,61/5.02-5.04 (not, dd, in 5.7), 7.29- spot in UV, MK-0.50, heptane-ethyl acetate 2:1), ana- 7.36 (2Н aromatic, Ethos H-2 and H-7), 7.39-7.43 lytic HPLC I-24.123 minutes, HPLC-MS (single- (2H aromatic, Ethos H-3 and H-6), 7.53- 7.67 (2H main peak in UV with MI-11.91 minutes, 408.2 aromatic, Ethos H-1 and H-8), 7.76-7.81 (2H aro- (men-Vit, 486.3 Me Ma)", 949.5 (2 gMMa). Matric analysis, Ethos H-4 AND H 5), 10.90-1110 (COOH, using "H and Zb NMR showed the presence of existence of cis and trans geometric isomers relative to 3" "С (СОСИ3 at 298Ю); 23.71/24.23 (d, Св), amide bond. | 28.21/28.28 (single, С(СН33) z), 30.58/30.72. (d, "H (400 MGu, SOSIz at 298Y); 1.23 (9 x C(SNZ)5, SU), 40.49/40.79 (d, Ce ), 47.58/47.63 (single, c), 1.46-1.98 (2Nu - 2Nv m), 3.37 3.45/3.46-3.57 (1 No, Ethos 0-9), 5820/5843 (single, So), dt), 3.61-3.72 (No , width), 3.90-3.99/4.02-4.10 (1He, 67.78/68.32 (single, Se), 68.69/68.88 (d, Ethos dd), 4.20-4.72 (Htos H-9 and Ptos SNe and 2 x COO0-CH2g), 78.48/78.67 (sq, С(СНЗ3)з), 120.31 (single,

СНеСнНе-СН», width, m), 4.89/5.01 (Не, дд, - 6.3), Ethos С-4 and С-5), 125.16/125.27/125.50/ 125.53 (unit-524 (1 x SOOSTSNeSN", D, U 10.5), 5.38 (1 x night, Etos C-1 and C-8), 127.42/127, A6/127.59

СООСНоСН-СН:, од), 5.88-5.99 (1 x СО0- (single, Ethos С-2 and С-7), 128.03/128.10 (single-

СНеСНеСН», m), 7.29-7.36 (2Н aromatic, Htosic, Ethos С-3 and С-6), 141.55/141.69/141.79 (КВ,

H-2 and H-7), 7.38-7.47 (2H aromatic, Rtos H-Z and Etos C-4 and 0-5), 144.06/144.12/144.38/144 48 ( KV,

H-6), 7.56-7.69 (2 aromatic, Ethos H-1 and N-8), Ethos S-T and C-83, 155.73/156.49 (KV, OSOM), 7, 76-7.81 (2H aromatic, Ritos H-4 and H-5). 169.26/169.52 (UNSC).

(7) Preparation of 1-(9H-fluoren-9-ylmethyl) (INe, ext.), 3.97 (СОсСНазга, d, У 16.3), 4.15 (Htos ether (25, Zv) (З- tert-butoxy)-2-(2-H-9, width, t), 4.25-4.34 (He, width), 4.36-4.60 diazoacetyl)piperidine-1,2-dicarboxylic acid . (HtosCHg 4 СОСН»gv, width, m), 4.75-4.82/5.11-5.19 1-(9H-Fluoren-9-ylmethyl) ether (25, ZE) (He, width, d ), 7.30-7.36 (2H aromatic, Ethos H- (3-tert-butoxy) piperidine-1,2-dicarboxylic acid-2 and H-7), 7.41-7.49 (2H aromatic, Ethos H-3 and H-lots (830 mg, 1.96 mmol) were dissolved with stirring - 6), 7.52-7.68 (28 aromatic, Ethos H-1 and H-8), a bath in dry dichloromethane (20 ml) . Reactive 7.75-1.85 (2H aromatic, Ethos H-4 and H-5). the mixture was purged with a stream of nitrogen and cooled to "С" (СОСИ3 at 298K); 21.75/22.04 (d, Sv), 26.60 -15"6. Isobutyl chloroformate (d, SU), 41.40/41.66 (d, Ce), 47.59 (single, Etos) was added simultaneously (296 mg, 2.16 mmol) in dry dichloromethane (2.5 mL) C-9), 80.42 (single, Ce), 67.54 (d, Ethos CH), and M-methylmorpholine (397 mg, 3.92 mmol) in dry 68 21/68 39 (d cOsnyo) 72.61 (single, Sv) dichloromethane (2.5 ml) in aliquots of 0.5 ml throughout 120 39 (single Ethos sa and c-5) 125 43 (single 15 minutes. Diazomethane in ether (generated from 21 c-7) 12814 (single Ethos C-3 and St) 141.73 of dialdehyde was added to the solution of activated amino acid, Ethos C-1 and C-8) 127 51 (unit Ethos S- (2.5 g, "vmmol in diethyl ether (q. Etos c-g and c-53, 144 30 (q. Etos c-g c-8) (40 ml)) over sodium hydroxide (2.757) in a mixture of 155.79/ 156.35 (q, OSOM), 211.10/211.4 (q, CO- water (4.3ml)/ethanol (8.bml) at 60"C) and the mixture - CHO) ' ' ' ' ' ' walls at room temperature for 24 hours.According to the general details of Scheme 2,

To quench the reaction, the necessary bicyclic building block 9H-fluorene- (2 ml) was added to acetic acid, then tert-butyl methyl ether 9-ylmethyl ether (zav, tav) 3-oxo- (100 ml) was added, the organic layer was washed with water, hexahydrofuro 3.2 -b|Ipyridine-4-carboxylic acid (x150ml), then dried (Mag250). The solvents were converted into the building-block-linker structure and removed in vacuo to give a thick yellow oil as follows: (1.027). Crude oil was used in the next 9H-fluoren-9-ylmethyl ether (Zab5, Tact) 3-stage without purification. TLC (single major oxo-hexahydrofuro|3,2-0| pyridine-4-carbon spot in UV, th.40, Heptaneethyl acetate 21), ana: acid (250mg, 0.689mmol) was dissolved in a mixture of lytic HPLC me18.887 minutes ( 50.895) plus ethanol (12.0ml) and water (1.75ml) containing three minor peaks, HPLC-MS (2 major peaks in sodium acetate wire (141mg, 1.03mmol, 1.5eq).

UV from -9.095 minutes, 364.2 |MyaNI, 7492 Added trifluoroacetate d- (2Ma-Ma| and -10.856 minutes, 420.2 |MAN-MegH, ((hydrazinocarbo- 470.2 |My ma, 917.3 | (gM»Mmag) not nil)iamino|methylIcyclohexanecarboxylic acid

Note that during HPLC-MS analysis, t/x (227mg, 0.689mmol, 1, Equiv., (Mygrpu A.M. ei a)., 4). 364.2 corresponds to the desired bicyclic product dl, Spet.bos, 114, 3156-3157, 19921) and a mixture of

ZN-fluoren-Z-ylmethyl ether (zaz, Yes) 3- was heated at reflux with oxo-hexahydrofuro3Z,2-b|pyridine-4-carbonate for 4 hours. Chloroform (150 ml) and kispogi were added. pOsh I - the organic layer was washed with HCl (150 ml, -pH 3), (8) Cyclization in 9H-fluoren-9-ylmethyl was dried (Mag505) and evaporated in a vacuum, obtaining ether (Za5, Yes) Z'oxo-texahydrofuro| 3,2- or crude building-block-linker construction. in

Bipyridine-4-carboxylic acid. . in the form of a transparent viscous oil. Output of Z5Omg, analytes

A solution of lithium chloride (in 44 mg, 20 mmol) in water was used for HPLC; 2 peaks of Ri-17.101 (74795) and 18.547 wave- (bml) and acetic acid (20ml) were added to 1-(9H-ny (25.396) (cis/trans geometric isomers), HPLC-fluorene-Zylmethyl) ether (25, ZMK) (Z-tert: Mo (2 peaks in Uf with B-8.037 and 8.972 minutes, 561.2 butoxy)-2-(2.diazoacetyl)piperidine-1,2- IMANE). The crude structure directly of dicarboxylic acid (1000 mg, "2 mmol). The isolated gas and a yellow oily solid were dissolved in accordance with the general details of Scheme 2 for 1 hour, giving a visually free building-block structure. After 90 minutes, nuvals were added to the solid phase, obtaining loaded chloroform (150 ml) and the organic layer was washed with the building-block-linker structure as follows:

MansSoz (2x150 ml), saturated salt solution Building-block-linker construction. (0.595 mmol), (15 Oml) and dried (Ma»5O4). Solvents were removed in 2-(1H-benzotriazol-1-yl)-hexafluorophosphate in vacuo to give a pale yellow resin (920mgHg). 171,3,3-tetramethyluronium (nvty 226 OMg

The crude resin was purified on silica gel (1355) with 0.596 mmol) of 1-dihydroxybenzotriazole hydrate and using gradient elution with a mixture (NOVT, om, 0.596 mmol) was dissolved in dimeheptane-ethyl acetate 31 317. The target fractions were diluted with ethylformamide (Zml) and M -methylmorpholine was concentrated and evaporated in vacuo to give white (MMM, 131 μl, 1.197 mmol). After the previous crystalline substance, the yield of 370mg (1.02mmol, activation for 5 minutes, the carrier was added to fo- 51.976 based on the starting acid). TLC (single gear with free amine (160 x 1.2 μmol) with a spot in UV, 0.25, heptane-ethyl acetate 21), followed by the addition of dimethylformamide analytical HPLC LC-18.734 minutes, HPLC-MS (17.5 ml) and left for night. Then added solution (a single peak in the UV from -9.051 minutes, 3642 MH, worked solution for condensation to crowns with 386.2 IMeMma|). analysis using Nis free amine (18x10μmol) and left overnight. nMR showed the presence of cis and trans geometric Standard washing and analysis indicated isomers relative to the 3" amide bond. quantitative loading in both cases. "H (400MHz, SOCIz at 298K); 1.29-1.49 According to general details for schemes (1Нy Nv, m), 1.61-1.80 (1Н5, width, m), 2.06-2.19 2, the necessary loaded structure of the building (INu, width, m), 2.50-2 ,62/2.63-2.80 (1He, m), 3.96 block-linker was processed in the solid phase as follows:

The loaded construction (22) was transformed into the sample of example 83 - (Za5, 7anv) (b- benzylsulfanylmethyl-2-oxo-2-(3-oxohexahydrofuro3,2-b|pyridin-4-yl)ethylamide of morpholine-4-carboxylic acid according to by standard ERThos deprotection and subsequent cross-linking with EGtos-Suv(5B21)-OH and then with morpholine-4-carbonyl chloride. The crude sample was cleaved and analyzed (see general methods). -15.59 minutes (28095), HPLC-MS 409 MH minutes (28095), HPLC-MS 449.2 (MANI. ' and

The following examples (84-130) were obtained as in Example 87. (Zaz, 7ak) (3-methyl-1-(3-oxo) is described in detail in example 83, condensing from hexapdrofuro ar pyridinium b. with the necessary reagents to obtain a molecule with that full-length onyl)butylamide of naphthalene-2-carboxylic acid.

Example 84. (Zab5, so) (15-(4-Hydroxybenzyl)-2oxo-2-(3-oxo-hexahydrofuro3,2-b|pyridin-4-yl)ethylamide of naphthalene-2-carboxylic acid

Ф Ф 1 louse in me and we : / and ! F HPLC -18.28 minutes (28095), HPLC-MS ze ! p; and 409.2 MANI".

M " Shchi Example 88. (Za5, yes) M-I15-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-

HPLC v-15.79 minutes (28095), HPLC-MS hexahydrofuroyl3,2-p|Ipyridin-4-yl)ethyl/|-5-thiophene- 459.3 MANI". 2-ylnicotinamide

Example 85. (Za5, 7ak) 4-dimethylamino-N-(/15-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-) and hexahydrofuroyl3,2-b|pyridin-4-yl )/ethyl|benzamide Fo

AND

HPLC -13.16 minutes (28095), HPLC-MS 492.2 (MANI.

Example 89. (Za, 7ak) (15-(4-Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl)3,2-5|pyridin-4-yl)ethyl|iamide 2-pyridin-3-ylthiazole -4-carbon ky-

HPLC Ri-10.98 minutes (28095), HPLC-MS slots 452.2 (MANI.

Example 86. (Za5, 7ak) (Z-methyl-1-(3-oxohexahydrofuroyl3,2-bi|carbonyl"-pyridine-4-carbonyl)butylamide of naphthalene-1-carboxylic acid dev. om"

HPLC K-17.00 minutes (28095), HPLC-MS 491.2

HPLC vi-10.45 minutes (28095), HPLC-MS Mn". 493.2 ME". Example 93. (Za5, yes) M-(15-(4-

Example 90. (Za5, tav) (15-(4-Hydroxybenzyl)-Hydroxybenzyl)-2-oxo-2-(3-oxo-2-oxo-2-(3-oxo-hexahydrofuro|3,2-b| pyridine-4-hexahydrofuro|3,2-p|pyridin-4-yl)ethyl|-4-yl)ethylamide of biphenyl-4-carboxylic acid trifluoromethoxybenzamide

HPLC K(-17.07 minutes (28095), HPLC-MS

HPLC K(-17.38 minutes (28095), HPLC-MS 493.2 (MANI. 485.2 MANI". Example 94. (Za5, 7ag) mM-13-methyl-1-(3-oxo-o) Example 91. (Zaz, Tak) 4-tert-butyl-M-/15-(4-hexahydrofuro3,2-5|-pyridine-4-carbonyl)butyl|-5- hydroxybenzyl)-2-oxo-2-(3 -oxo-thiophen-2-ylnicotinamide hexahydrofuro|C,2-5|pyridin-4-yl)ethyl|benzamide

VERH KI-15.82 minutes (? 8095), VERH-MS 442.2 MANI".

Щ Example 95. (Za5, 7ak) (|3-methyl-1-(3-oxo- av min (28095), HPLC-MS hexahydrofuro3,2-b| pyridine-4- sh

Example 92. (adv., 7av) M-18-4-carbonyl)butylamide 2-pyridine-3-ylthiazole-4-. carboxylic acid

Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl1-4-thiophen-2-ylbenzamide

HPLC -12.55 minutes (28095), HPLC-MS. 443.2 (MANI.

Example 96. (Zab5, 7an) (|3-methyl-1-(3-oxohexahydrofuroi3,2-0|-pyridine-4-, carbonyl)butyl amide of biphenyl-4-carboxylic acid: ; (А | F nach u - HPLC -19.66 minutes (28095), HPLC-MS (A and 443.2 g hexahydrofuro3,2-5|-pyridine-4-

2-methyl-5-phenylfuran-3- carbonyl)butyl|amide; and carboxylic acid

HPLC Ri-19.88 minutes (28095), HPLC-MS 435.2 (MANI.

Example 97. (Za5, 7ak) 4-tert-butyl-M-I(3- i m methyl-1-(3-oxohexahydrofuroi3,2-5|-pyridine-4-:!carbonyl)butyl|benzamide I i azad ?

HPLC -20.48 minutes (28095), HPLC-MS 439.2 (MANI.

Example 101. (Za5, so) (15-(4-hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroyl3,2-b|pyridine-4-

HPLC RI-20.2 minutes (28095), HPLC-MS of yl)ethylamidemorpholine-4-carboxylic acid 415.2 (MANI.

Example 98. (Za5, 7ak) Mm-I3-Methyl-15-(3-oxo-hexahydrofuro|3,2-5|-pyridine-4-carbonyl)butyl|-4-thiophen-2-ylbenzamide and

VERH-MS 418, 2 (MANI.

Example 102. (Za5, yes) M-(13-(4-hydroxybenzyl-2-oxo-2-(3-oxo-

HPLC Vi-1960 minutes (78096), HPLC-MS hexahydrofuroi|3,2-b|pyridin-4-yl)ethyl|benzamide 441.2 (MANI. .

Example 99. (Za5, 7ak) mM-|13-methyl-1-(3-oxo- and hexahydrofuro|3,2-5|-pyridine-4-carbonyl)butyl|-4- and trifluoromethoxybenzamide. 9; thank you

HPLC-12.71 minutes (28595), HPLC-MS and 409.2 (MANI. o.

Example 103. (Zav, tav) (15-(4- t

Hydroxybenzyl)-2-oxo-2-(3-oxo-.hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|iamide naphtha. tallin-1-carboxylic acid va and ,

F | and y ' a che HPLC (-15.58 minutes (28595), HPLC-MS ' che : 465.2 (MAANI", 951.3 (2M-Mai". : ! and Example 107. (Za5, 7ak) ( 15-benzyl-2-oxo-2- (Z-oxo-hexahydrofuroiZ,2-b|pyridine-4-; syl)ethylamide of furan-3-carboxylic acid! and

HPLC (-14.88 minutes (28595), HPLC-MS and 459.2 (I

Example 104. (Zav, tav) (15-(4-I; hydroxybenzyl)-2-oxo-2-(3-oxo-!Y hexahydrofuroi3,2-b|Ipyridin-4-yl)ethylIamide: fu- with I of ran-Z-carboxylic acid in : i i ! HPLC (-14.44 minutes (28595), HPLC-MS ! 383.2 MANI. - ; Example 108. (Za5, 7ak) (15-benzyl-2-oxo- 2-

M (Z-oxo-hexahydrofuro3,2-b|Ipyridine-4-yl)ethylamide of thiophene-Z-carboxylic acid

HPLC-11.14 minutes (28595), HPLC-MS 399.2 (MANI.

Example 105. (Zav, tav) (15-(4-

Hydroxybenzyl)-2-oxo-2-(3-oxo- hexahydrofuro3,2-b|Ipyridin-4-yl)ethylamidobenzo((b|thiophene-2-carboxylic acid) I HPLC (-15.34 minutes (28095), HPLC - MS rya 399.2 MANI.

Example 109. (Za5, 7ak) (3-methyl-1-(3-oxo-3-hexahydrofuro-3,2-0|-pyridine-4-iocarbonyl)butylamide of morpholine-4-carboxylic acid)

HPLC (-15.99 minutes (28595), HPLC-MS n 465.2 (MANI.

Example 106. (Zav, tav) (15-(4-

Hydroxybenzyl)-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethylIiamidebenzo|rigiophene-3-carboxylic acid HPLC-MO 368.2 (MENI.

Example 110. (Za5, 7an) mM-|13-methyl-1-(3-oxo-hexahydrofuroyl-3,2-b|-pyridine-4-carbonyl)butyl|benzamide) n

HPLC (-13.55 minutes (28595), HPLC-MS 402.2 MANI".

HPLC B-15.42 minutes (28595), HPLC-MS Example 114. (Za5, 7ak) (Z-methyl-1-(3-oxo- 359.2 MEI". hexahydrofuro!|Z,2-B|- pyridine-4-

Example 111. (Zab5, 7av) (3-methyl-1-(3-oxo-carbonyl)butyl|iamide benzo (Bithiophene-3-carbonic hexahydrofuro3,2-5|-pyridine-4-acid carbonyl)butylIiamide furan-Z -carboxylic acid

Bob,

HPLC (-18.26 minutes (28595), HPLC-MS

HPLC-13.74 minutes (28595), HPLC-MS 415.2 (MA-NI". 349.2 (MANI. Example 115. (Zab5, 7ak) (|3-methyl-1-(3-oxo-

Example 112. (Za5, 7ak) (Z-methyl-1-(Zoxo-hexahydrofuro3,2-5|-pyridine-4-hexahydrofuro3,2-5|-pyridine-4-carbonyl)butylIamide of thiophene-3-carboxylic acid carbonyl )butyl|iamide of benzo|bithiophene-2-carboxylic acid g ii)

HPLC (-14.80 minutes (28595), HPLC-MS 365.2 MANI.

HPLC -18.52 minutes (28595), HPLC-MS Example 116. (Zav, yes) M-(t H- 415.2 (MANI, 851.3 |(2M--Ma)). benzylsulfanylmethyl-2-oxo -2-|IZ-oxo-

Example 113. (Za5, 7ak) 4-dimethylamino-K-|3-hexahydrofuro|3,2-b|pyridin-4-yl)ethyl|benzamide methyl-1-(3-oxo-hexahydrofuro|Z3,2-5 |-pyridine-4-carbonyl)butyl|benzamide and

HPLC-17.78 minutes (29095), HPLC-MS 439.2 (MANI", 899.3 (2M--Ma)".

Example 117. (Za5, tav) 1-benzylsulfanylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide of furan-3-carboxylic acid kn

HPLC -18.47 minutes (28595), HPLC-MS 399.2 (MeANI), 819.2 (2M--Mag.

Example 121. (Za5, yes) 15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide of furan-33-carboxylic acid

HPLC P-16.1 minutes (28595), HPLC-MS 429.2 (MANI, 451.2 |MA-Ma|".

Example 118. (Za5, tav) 1b- benzylsulfanylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyridin-4-yl)ethylamidthiophen-

C-carboxylic acid

HPLC -17.12 minutes (28595), HPLC-MS 389.2 (MaeNI), 411.2 (2M-mag.

Example 122. (Za5, yes) 15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyridin-4-yl)ethyl|amide of thio-phen-3-carboxylic acid

HPLC Ri-17.23 minutes (28595), HPLC-MS 445.2 (MANI, 911.2 (2M-Mai).

Example 119. (Za5, so) N5-cyclohexylmethyl-2oxo-2-(3-oxo-hexahydrofuroyl3,2-b|-pyridine-4-carbonyl)ethylamide of morpholine-4-carboxylic acid

HPLC -17.95 minutes (28595), HPLC-MS 405.2 (MANI", 831.2 (2M--Mai").

Example 123. (Za5, so) 15-cyclopentylmethyl-2-oxo-2-(3-oxo-hexahydrofuroyl)ethylamide furan-33-carboxylic acid and

HPLC-MS 408.3 MANI", 430.3 |M--Ma/|".

Example 120. (Za5, so) M-(15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|pyridin-4-yl)/ethyl|benzamide

HPLC -15.75 minutes (28595), HPLC-MS 379.2 (MeANI), 779.3 (2M-Mmag.

Example 127. (Za5, so) 15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuroyl33,2-0 pyridin-4-yl) ethyl ether of morpholine-4-carboxylic acid

HPLC Ri-15.0 minutes (28095), HPLC-MS 375.2 (MANI, 771.3 (2gM-mag.

Example 124. (Za5, yes) 15-cyclopentylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-b|Ipyridin-4-yl)ethylamidthiophen-

C-carboxylic acid

VERH-MS 409.2 (MANI, 839.5 (2M--Mar".

As described in detail for example 74, compound (33) was condensed under standard conditions (after removal of the tos group) with an equivalent of 9n-fluoren-9-ylmethyl ether (Za5, 7ak) of 3-oxo-hexahydrofuro|3,2-b| of pyridine-4-carboxylic acid loaded structure (22) building-block-linker, and then cleaved, obtaining the compound of example 127.

Example 128. (25, Zab5, 7ak) 4-(3-cyclohexyl-2-(furan-2-ylmethanesulfanyl) propio-

HPLC at 16.72 minutes (28595), HPLC-MS nyl)hexahydrofuro[3,2-bipyridin-3-one 3911 (MeANI", 803.3 (2M--Ma|").

Example 125. (Za5, 7ak) (|3,3-dimethyl-1-(3-oxo-hexahydrofuroi3,2-5|-pyridine-4-carbonyl)butyl|iamide of furan-3-carboxylic acid

Bob;

VERH-MS 392.1 (M.-NI", 805.2 |2M--Mai".

As described in detail for example 76, combined

HPLC P-15.06 minutes (29095), HPLC-MS ku (41) was condensed under standard conditions (after 363.2 (MANI, 747.4 (2M--Mag. removal of the tos group) with an equivalent of 9Nn-

Example 126. (Za5, 7ak) (|3,3-dimethyl-1-(3-fluoren-9-ylmethyl ether (Za5, 7ak) 3-oxo-oxohexahydrofuro3,2-0|-pyridin-4-hexahydrofuro|3 ,2-b|pyridine-4-carboxylic acid carbonyl)butyl|amide thiophene-3-carboxylic acid loaded structure (22) building-block-linker, and then cleaved, obtaining the compound of example 128.

Example 129. (25, Zab5, 7ak) 4-(3-cyclohexyl-2-(furan-2-ylmethanesulfonyl)propionylhexahydrofuroyl3,2-b|pyridin-3-one"

HPLC -19.015 minutes (295), HPLC-MS 424 1

IMaANI", 869.2 |2M--Ma|".

As described in detail for example 76, the compound Necessary bicyclic building block - 9Ннку (41) was condensed under standard conditions (after fluoren-9-ylmethyl ether (Заб5, 7ав) 3-oxo- removal of the tos group) with an equivalent of ЗН- Hexahydrofuro|3,2-b|pyridin-4-carboxylic acid fluoren-9-ylmethyl ether (Za5, 7ak) 3-oxo was obtained using 4 subsequent stages from hexahydrofuro-3,2-b|Ipyridin-4-carboxylic acid 2-allyl ether 1-(9H-fluoren-9-ylmethyl) loaded structure (22) building-block-linker. ether (28, 35) (3-hydroxy)pyrrolidine-1,2-

Intermediate loaded thioether (1.2 μmol of para-dicarboxylic acid in the following way: gear-shaped application) was oxidized to m- (1) Preparation of allyl ether 2 with 1-(9H-chloroperbenzoic acid (5 eq. 6595 reagent, fluoren-9-ylmethyl) ether (28, 35) (3-tert-1,bmg) in dichloromethane (200 μl) for 5 hours with butoxy)piperidine-1»2-dicarboxylic acid followed by standard washing, and then 2-adyl ether 1-(9n-fluorene- 9- was cleaved, obtaining the compound of example 129. ylmethyl) ether (22, 35) (3-hydroxy) piperidine-

Example 130. (Za5, yes) 2k-1,2-dicarboxylic acid (1.75 g, 4.30 mmol) dihexaldrofuro|3,2-B|Ipyridin-4-yl)butane-1,4-dione in a glass container (ampoules) for working under pressure and cooled to -78"C. Gaseous isobutylene (1 Oml) was condensed into the solution and conc.

On 5 BO»h (100 μl). A magnet was added for stirring, the ampoule was sealed, cooling was removed and it was stirred at room temperature for 72 hours. The soldered ampoule was cooled to 78 °C, M-methylmorpholine (200 μl, 1 wt.eq, at room temperature, corresponding to the concentration of Hg5O4) was added and left to warm to room temperature in the soldered form with stirring for 2 hours. Dichloromethane was added ( 75 ml) and the organic layer was washed with Mansoz

HPLC-MS 407.1 MANI, 833.3 (2M-Mag. (75ml), then saturated salt solution (75ml) and

As described in detail for example 77, (Ma»5O») was used. Solvents were removed in vacuo, ku (36) was condensed under standard conditions (after obtaining a mobile pale brownish-gold removal of the Ethos group) with an equivalent of 9H-oil (1.93g). The crude oil was purified on silica-fluoren-9-ylmethyl ether (Za5, 7at) 3-oxo-gel (100g), using a gradient elution of hexahydrofuro(3,2-0|pyridin-4-carboxylic acid) and a mixture of heptane-ethyl acetate 5:11 -» 371. Ci-loaded structure (22) building-block-linker, the left fractions were combined and evaporated in vacuum, and then cleaved, obtaining the compound with a thick transparent oil, yield 1.48 g of lad 130. (3 ,19mmol, 74.395). TLC (single spot in UV,

Example 131 (Example of general formula (1)). MO,50, heptane-ethyl acetate 2:11), analytical HPLC (Zab5, 7an) | A-Benzylsulfanylmethyl-2-oxo-2-(3- -24.083 minutes, HPLC-MS (single main peak of oxohexahydrofuro/3,2-b|Ipyridin-4-yl)ethyl| amide by UV with PI-11.996 minutes, 408 ,2 |(MeH-Vy"!, 486.3 of morpholine-4-carboxylic acid IM-Mar). Analysis using "H and Zb NMR showed the presence of cis and trans geometric isomers relative to the 3" amide bond. 5 "H (400MHz, SOSI"z at 298K); 1.24 (9 x C(CH3)z, s), 1.51-1.90 (2Nuk2H"5, m), 3.38-3.48/ 3.49-3.58 (1Ne, dt), 3.62-3.74 (Nv, width), 3.95-4.02/4.06-4.14 (1Nbv, dd), 4.24- 4.78 (Htos H-9 railway Etos SN» i 2 x SOO-

СНснН.сСН», width, m), 4.88/5.01 (Не, dd, У 5.8), 5.25 (1 x СООСНоСНАSN», d, У 5.7), 5.37 (1 x CO-

OSNoSNASN", d, U 16.8), 5.8-6.00 (1 x SOO-

СНСНесСН;», m), 7.28-7.39 (2Н aromatic, EGtos

H-2 and H-7), 7.39-7.46 (2H aromatic, Ethos H-3 and

H-6), 7.57-7.71 (2H aromatic, Ritos H-Yi and H-8), 8), 155.73/156.49 (q, OSOM), 169.26/169.55 ( CO- 7.78-7.86 (2H aromatic, Ritos H-4 and H-5). OH). "C (SOSIz at 298K); 23.69/24.00 (d, Sv), 28.38 (3) Preparation of 1-(9H-fluoren-9-ylmethyl) (single, C(CH333)z), 28.65 (d, C), 40.41/40.72 (d, ether (2k, 35) (3-tert-butoxy)-2-(2-

Ce), 47.61 (single, Ethos C-9), 58.46 (single diazoacetyl)piperidine-1,2-dicarboxylic acid. ny, C"), 65.67 (d, СООСН»СНСН»), 67.82 (mono-1-(9H-Fluoren-9-ylmethyl) ether (2К, 35) ční, Сv), 68.12 ( d, Ethos CH»), 74.93 (q, C(CHZ)z), (3-tert-butoxy) piperidine-1,2-dicarboxylic acid 118.46/118.57 (d, СООСНоСНеCH»), 120.40. (dilutes (830 Mmg, 1.96 mmol) were dissolved with stirring, Etos C-4 and S-B), 125.39 (single, Etos bath in dry dichloromethane (20 ml). Reaction

C-1 and C-8), 127.46 (single, Etos C-2 and C-7), the mixture was purged with a stream of nitrogen | cooled to 128.10 (single, Rtos C-3 and C-6), 132.49 (single- 0715 C. Isobutylchloroformate was added simultaneously, СООСNeСНЕСН»), 141.71 (КВ, Ethos С-410- 00/ 9bmg . , 3.92 mmol) in dry form

OSOM), 170.42/171.06 (SOOSNSNASN"). dichloromethane (2.5 ml) in b.oml aliquots for 15 minutes. Diazomethane was added to the solution of the activated amino acid ester (28, 35) (3-tert-butoxy)piperidine-1,2-lots in ether (generated from dicarboxylic acid. (9n-fluorene-9- (4O0ml)) over sodium hydroxide (2.75) in a mixture of ylmethyl) ether (28, 35) (3-tert-water (4.3ml/ethanol (8, bml)) at 60"С ) and a mixture of butoxy)piperidine-1,2-dicarboxylic acid was stirred at room temperature for 24 hours. (1.42 g, 3.07 mmol) was dissolved in dry dichloromethane. To quench the reaction, dilute acetic acid (25 ml) was added with stirring. tetrakis- ("3 ml), then triphenylphosphine palladium(0) tert-butyl methyl ether (71 mg, 0.0 b2 mmol, (10 Oml), the organic layer was washed with water 0.02 equiv.) was added, followed by the addition of phenyltrihydro- (xx150 ml), then dried ( Ma25O5). Silane solvents (0.66g, 0.581ml, 6.14mmol, 2eq.). After 1 was removed in vacuo, obtaining a sticky pale" yellow, dichloromethane (150ml) and organic oil (910mg) were added. Crude oil it was purified on a silica layer, washed with 0.01 N HCl (150 ml), saturated gel (755) using a gradient eluent, salt solution (150 ml) and dried (Mag25O4). Solution with a mixture of heptane-ethyl acetate 4:1 -» 31. The target groups were removed in vacuo, obtaining the dark gray fractions, combined and evaporated in vacuo, a solid (2.07) was obtained. The crude solid, giving a pale yellow oil/solid, the wine yield was purified on silica gel (75 g) using Zvomg (1.25 mmol, 63.996). TLC (the only basic gradient elution with a mixture of heptaneethylacetate in UV, KG-0.35, heptane-ethyl acetate 2:1), anatate 2:11 -in 122. The target fractions were combined and up-politic HPLC Ch-18.754 minutes, HPLC-MS (peaks in ruval in vacuum, obtaining a white crystalline UV with P-9.095 minutes, 364.2 (MH, 386.1 substance, yield 1.07g (2.53mmol, 82.396). TLC IMeMar, 749.2 ( gMyMar, and PT10.856 minutes, (single spot in UV, CI-0.25, heptane-ethyl acetate 420.2 |MaNAMer, 470.2 |Memag, 917.3 egMem|). 17), analytical HPLC VI-21.306 minutes, HPLC- Note that with HPLC-MS analysis, t/h

MS (the only main peak in UV with BI-10.269 waves - 364.2 corresponds to the desired bicyclic product ni, 3682 IM-H-VIy", 446.2 IMm--Ma|", 869.3 ZN-fluorene-9- yl methyl ether (Zaz, so) 3-

I (gM-Mag). "H and C NMR analysis showed the presence of oxo-hexahydrofuro|3,2-b|Ipyridine-4-carbon cis and trans geometric isomers relative to the 37 amino acids with ! ! bond. "H and C NMR analysis showed the presence of cis and "H" (400MHz, SOSIz at 298K); 1.32/1.40 (9 x trans geometric isomers relative to 3" amide

С(СНЗ)з, de), 1.43-1.59 (NU H5, m), 1.70-1.81 (1Н5, connection, and t oo greater width, mu utvo vo, "Н (SOS at 298U); 1.29/1.46 (9 x C(SNZ)5, 2.97 (1He, dt), 3.73-3.85 (He, width)), 3.92-4 .05 (IN, DS), 1.40-1.85 (2Ну2Н»5, width, m), 3.05/3.38 (1Н»e, dd), 4.23-4.32 (Ethos H -9), 4.40-4.58 (Ethos SN", dt), 3.39-3.44/3.62-3.69 (Nv, dm), 3.90-3.97 (1He, dd), width, m), 4.80-4.62/5.02-5.04 (No, dd, 4 5.7), 7.29- 4.05-4.07/4.78- 4.83 (No, width, m), 4.24-4.33 (EGtos 7.36 (2H aromatic, Etos H-2 and H-7), 7.39-7.43 H-9), 4 ... 4.68 (1 x Ptos СНе, m), 4.89/5.90 (СОСНеМ», with the same aromatic, Ethos Н-1 and Н-8), 7.77-7.802 (20 aro- /USHIR, s ), 7.28-1.39 (2H aromatic, Ptos H-2 and H-matic, Ptos H-4 and H 5), 10.80-11.15 (COOH, 7), 740-744 (28 aromatic , Rtos N-W and NE), lat. c). 7.53-7.67 (2H aromatic, Etos H-1 and H-8), 7.76-"C (SOSiz at 298Ю); 23.71/24.24 (D, Cz), 7.81 (2 aromatic, Rtos H-4 and H-5). 28.20/28.27 (single, C(CH3)"), 30.60/30.73. (d, 6 (SOSIz at 298Yu); 23.94/24.51 (d, C",

SU), 40.50/40.79 (d, Ce), 47.58/47.63 (single, 28.38/28.53 (single, С(СНЗз)з), 29.23/29.84 (d,

Ethos 0-9), 58.20/58.44 (single, So), SU), 40.83/41.45 (d, C), AT, 5TIAT, va (single, 67.77/68.33 (single, St), 68.67/68.87 (d, Ethos so wolf 55.50/56.38 solynyvve kimi Me),

CH»), 78.48/78.67 (sq, C(CH3)v), 120.30 (single, "63/62.665 (single, C"), 66.85/68.20 (d, Htos

Ethos C-4 and C-5), 125.16/125.27/125.52. (single, СНе), 69.35/69.61 (single, Св), 75.11/75.54 (sq,

Etos C-1 and C-8), 127.42/127 A48/127.59 (single, C(CHz)z), 120.29/120.32 (single, Rtos C-4 Her C-

Etos C-2 and C-7), 128.04/128.10 (single, Etos 5), 124.85/125.25/125.53 (single, Etos C71С-

C-3 and C-6), 141.57/141.69/141.78 (KV, Etos C-4 and C-8), 127.46/127.59 (single, Rtos b-2 and C- 7), 5), 144.06/14411/144.36/144, 47 (KV, Etos C-1 and C- 127.97/128.03/128.07 (single, Rtos O-3 and C- 6), 141.62/141.69/141.73 (KV, Rtos 0-4 and 00-5),

144.24/144.31/144.50/144.61 (КВ, ЕРтос С-1' ии 0-8), 3157, 19921) and the mixture was heated at boiling with water- 155.68/156.89 (KV, OSOM), 191.90/192.37 in a refrigerator for 4 hours. Adds- (SOSNAMg). (4) Cyclization in 9H-fluoren-9-ylmethyl HCl (150 ml, -rnH 3), dried (Ma»bOy) and ether (Za5, 7ak) 33-oxo-hexahydrofuro |Z3,2- was evaporated in a vacuum, obtaining crude conc.

Bipyridine-4-carboxylic acid. building-block-linker truction in the form not quite

A solution of lithium chloride (494 mg, 11 mmol) in a loose crystalline substance. Yield 45Omg, analyte (3ml) and acetic acid (12ml) were added to 1-h HPLC: 2 peaks Ch-17.109 (67.65) and 18.565 waves of (9H-fluoren-9-ylmethyl) ether (2K, 35 ) (3- nes (26.395) (cis/trans geometric isomers), HPLC-tert-butoxy)-2-(2-diazoacetyl)piperidine-1,2-MS (2 peaks in UV with I-8.069 and 9.050 minutes, 561.2 of dicarboxylic acid (520mg, 1.16bmol) was isolated by IMANIUU. colored solution. After 90 minutes, the required building-block-linker construction was added, chloroform (150 ml) was added, and the organic layer was washed with water until the solid phase was obtained, obtaining a loaded

MansCOz (2x150ml), the building-block-linker structure saturated with a salt solution in the following way: (15O0ml) and dried (Mag5054). Solvents were removed in the building-block-linker construction (0.680 mmol) under vacuum, obtaining a white crystalline substance hexafluorophosphate 2-(1H-benzotriazol-1-yl)-(390mg). The crude substance was purified on silica-1,1,3,3-tetramethyluronium (NVTI, 258 mg, gels (75 g) using a gradient eluent - O, b8 Omol), 1-hydroxybenzotriazole hydrate and a mixture of heptane: ethyl acetate 3:11 -» 2 :11. Target NOVT (105mg, 0.68Omol) was dissolved in dimefraction, combined and evaporated in vacuum, ortertylformamide (Zml) and M-methylmorpholine was added chewing a white crystalline substance, yield 340mg (MMM, 150μl, 1.36mmol). After preliminary (0.94 mmol, 47.795 based on the initial acid activation for 5 minutes, the appropriate was added) TLC (a single spot in UV, 0.25, gear-shaped heptination with free amine tanch-ethyl acetate 2:1 ), analytical HPLC RI-18.563 (190x1.2 μmol) followed by the addition of dime- minutes, HPLC-MS (a single peak in the UV with MKI-9.074 tylformamide (17.5 ml) and left overnight. Then minutes, 364.2 ( Mya-NO", 386.2 |M-a-Ma!). Analysis of the spent solution was added for condensation using "H and Zb NMR showed the presence of crowns with a free amine (18x1Ommol) and residual and trans geometric isomers relative to 3 " were stirred overnight. Standard washing and analysis of the binding bond. Quantitative loading was performed in both cases. 5Н (СОСИз at 298K); 1.20-1.538 (1НУ-1Н5, m), According to the general details for the scheme 1.51-1.68 (1H5, width, m), 1.96-2.08 (1H,, width, m), 2, the necessary loaded structure of the building - 2.40-2.52/2, 53-2.67 (1Н5, m), 3.87 (СОСНа, d, The block-linker was treated with and in the solid phase in the following 16.5), 3.85-3.95 (1He, width), 4.09 (Htos H-9, width, method; t), 4.14 (Nr, width)), 4.21-4.46 (EtosСН»-СОСНе2гв, The loaded structure (22) was transformed into width, m), 4.62-4.70/5.00- 5.09 (No, 2x width)), 7.23- in the sample of example 91 - (Za5, 7an) PN- 7.27 (2H aromatic, Ethos H-2 and H-7), 7.32-7, 05 benzylsulfanylmethyl-2-oxo-2-(3-. (2H aromatic, Ethos H-Z3 and H-6), 7.41-7.53 (2H oxohexahydrofuro|3,2-bipyridin-4-yl)ethylamide aromatic , Ethos H-1 and H-8), 7.69-7.71 (2H of aro-morpholine-4-carboxylic acid with the help of stamatic, Ethos H-4 and H-5). emergency removal of the Ethos of the protective group I of the next "C" (SOSIz at 298K); 22.08 (d, Sv), 26.61 (d, SU), crosslinking with Etos-Suv(zBa21)-OH, and then with morpho- 41.67 (d, Ce), 47.58 (single, Etos C-9), 60.54 lin-4-carbonyl chloride. The crude sample was cleaved and analyzed (see general metho- (single, Ce), 67.55 (d, Ptos CH"), 68.40 (d, wild). HPLC v1-15.59 minutes (8095), HPLC-MS

SOSNgO), 72.61 (single, Sv), 120.39 (single- 449.2 MANI. ny, Ethos 0-4 and C-5), 125.42 (single, Ethos C-1 The following examples (132- 156) was obtained as well as C-8), 127.51 (single, Ptos C-2 and C-7), 128.14 as described in detail in example 131, condensing (single, Etos C-3 and C-6) , 141 Z (sq., Htos 0-4 th with the necessary reagents to obtain the molecule

C-53, 144.16 (sq. m., Ethos C-1 and 0-8), 156.20 (sq. m., with full length.

OSOM), 211.64 (sq., SOSNhO). Example 132. (Zza5, 7av) /8-(4-

According to the general details of scheme 2, Hydroxybenzyl)-2-oxo-2-(3-oxo- necessary bicyclic building block 9H-fluorene-hexahydrofuro|/3,2-bipyridin-4-yl)ethyl|iamide mor-

3-ylmethyl ether (Zaz, so) and 3-oxofolin-4-carboxylic acid hexahydrofuro3,2-b|pyridine-4-carboxylic acid was transformed into a building-block-linker structure in the following way: 9H-fluorene-9- ylmethyl ether (Zab5, 7ak) of 3-oxo-hexahydrofuro3,2-b|Ipyridine-4-carboxylic acid (290mg, 0.80mmol) was dissolved in a mixture of ethanol (14.0ml) and water (2.0ml) containing trihydr - sodium acetate (16 mg, 1.198 mmol, 1.5 equiv.).

Trifluoroacetate 4-

IShydrazinocarbonyl)amino|methyl| cyclohexanecarbonic acid (263mg, 0.80Omol, 1.Eq.,

IMygrpu A. M. ei ai., U. At. Spet. 5os, 114, 3156-

VERH-MS 418.2 (MANI.

Example 133. (Za5, so) M-(15-(4-hydroxybenzyl-2-oxo-2-(3-oxo-hexahydrofuroyl),2-b|pyridin-4-yl)/ethyl|benzamide

F HPLC -15.0 minutes (28095), HPLC-MS st and ; ; 359.2 (MANI. : cha i ! sh Example 137. (Za5, 7av) (|3-methyl-1-(3-oxo-

І I hexahydrofuroi3,2-b|pyridine-4-і »і carbonyl)butylamide of furan-3-carboxylic acid

HPLC -12.67 minutes (28095), HPLC-MS 409.1 (MANI.

Example 134. (Za5, yes) (15-(4-

Hydroxybenzyl)-2-oxo-2-(3-oxo- and hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl|iamide of naphthalene-1-carboxylic acid, etc. HPLC -13.74 minutes (28595), HPLC-MS in: p 349.2 (MANI", 371.2 |(2M-Mai". -(3-oxo- and hexahydrofuro3,2-bipyridine-4-zt,: carbonyl)butylamide of benzoic|bithiophene-2-carboxylic acid

HPLC Ri-14.87 minutes (28095), HPLC-MS 459.2 (MANI.

Example 135. (Za5, 7ak) (|3-methyl-1-(3-oxo-hexahydrofuroi3,2-b|Ipyridine-4-carbonyl)butylamide of morpholine-4-carboxylic acid-M

HPLC -18.52 minutes (28095), HPLC-MS 415.2 (MANI", 851.3 (2M-Mai").

Example 139. (Za5, 7ak) 4-Dimethylamino-M-|3-methyl-1-(3-oxo-hexahydrofuro|3,2-b|pyridine-4-carbonyl)butyl|benzamide

HPLC-MS 368.2 (Me-NI", 390.2 |MA-Ma|".

Example 136. (Zab5, 7ak) mM-III-methyl-1-(3-oxo-hexahydrofuroyl3,2-b|Ipyridine-4-carbonyl)butyl|benzamide and

HPLC Ri-13.55 minutes (28095), HPLC-MS a 402.2 (MANI, 825.3 (2M-Mai). and

Example 140. (Za5, 7ak) (|3-methyl-1-(3-oxo-- hexahydrofuroi3,2-b|Ipyridine-4-cha carbonyl)butyl|amide of benzo(b|thiophene-3-carboxylic acid and ! A; and

Fo and | HPLC -16.1 minutes (28595), HPLC-MS: y and 429.6 (MANI, 451.5 |MA-Ma|". ; Example 144. (Za5, yes) M v- and o benzylsulfanylmethyl-2- oxo-2-(3-oxo-

HPLC h-18.26 minutes (8075), HPLC-MS of hexahydrofuro3,2-b|pyridin-4-yl)ethylamidthiophene- 415.2 |ME", 851.3 |gMeMa|". C-carboxylic acid

Example 141. (Za5, 7ak) (|13-methyl-1-(3-oxo-hexahydrofuroi3,2-b|Ipyridine-4- to carbonyl)butyl|amide of thiophene-3-carboxylic acid Fo od, vm y

VERH Ri-14.80 minutes (28095), VERH-MS and 365.2 (MANI, 387.2 |M-Mai".

Example 142. (Zav, yes) M B- HPLC Vi-17.23 minutes (28095), HPLC-MS benzylsulfanylmethyl-2-oxo-2-(3-oxo- 445.1 (MaNI", 911.2 |2MA -Ma/". hexahydrofuro3,2-b|pyridin-4-yl)ethyl|benzamide Example 145. (Zzab, tav) and 18-th cyclohexylmethyl-2-oxo-2-(3-oxo- and I hexahydrofuro3,2- b|Ipyridin-4-yl)ethylamide of mor-, folin-4-carboxylic acid (Я "и (7 - " и M

HPLC-17.78 minutes (28095), HPLC-MS 439.2 (MANI, 899.3 (2M-Mai).

Example 143. (Zab5, tav) HP in- HPLC-MS 408.2 (MANI. benzylsulfanylmethyl-2-oxo-2-(3-oxo-) Example 146. (za5, so) M-(15-hexahydrofuroyl3,2- b|pyridin-4-yl)ethyl|amide fu-cyclohexylmethyl-2-oxo-2-(3-oxorane-3-carboxylic acid hexahydrofuroic|3,2-b|pyridin-4-yl)ethyl|benzamide

And in ".

Vo; " HPLC K(-15.4 minutes (28590), HPLC-MS

HPLC VI-18.47 minutes (28095), HPLC-MS 375.2 (MENI, 771.9 (gMMa/". 399.2 MANI", 819.3 |(2M--Ma)". Example 150. ( Zaz, yes) (15-

Example 147. (claim 7a) 18-cyclopentylmethyl-2-oxo-2-(3-oxo-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuro|3,2-p|Ipyridin-4-yl)ethyl amide thio-hexahydrofuro|3,2-bIpyridin-4-yl)ethylamide /- fu-phen-3-carboxylic acid ran-Z-carboxylic acid

HPLC K(-16.78 minutes (28590), HPLC-MS

HPLC v-17.12 minutes (28090), HPLC-MS 391.1 (MeNi", 803.3 |2MaMai". 389.2 |MENG. Example 151. (Za5, 7av) |3,3-dimethyl-1 -(3-

Example 148. (Zav, so) P5-oxo-hexahydrofuroi|3,2-b|Ipyridine-4-cyclohexylmethyl-2-oxo-2-(3-oxO-carbonyl)butylamide of furan-3-carboxylic acid hexahydrofuroi|Z, 2-b|Ipyridin-4-yl)ethyl|amide of thio-phen-3-carboxylic acid ik, "

HPLC K(E-15.05 minutes (28590), HPLC-MS 363.2 (MaANI), 747.4 (2M--Mag.

Example 152. (Za5, 7ak) (|Z,Z-dimethyl-1-(3-

HPLC Vi-18.05 minutes (28596), HPLC-MS oxohexahydrofuro|3,2-BIpyridine-4- 405.2 (MANI 831.2 (g2mM--Mag. ! carbonyl) butylIamide thiophene-3-carboxylic acid

Example 149. (Zza5, 7at) (| 185-cyclopentylmethyl-2-oxo-2-(3-oxo-hexahydrofuro3,2-in|Ipyridin-4-yl)ethyl|amide of furan-3-carboxylic acid n

HPLC-15.76 minutes (28095), HPLC-MS 379.2 (MeANI), 779.3 (2gM-Mmag.

Example 153. (Za5, so) 15-cyclohexylmethyl-2-oxo-2-(3-oxo-hexahydrofuroi3,2-b|Ipyridin-4-yl)ethyl ether of morpholine-4-carboxylic acid;

VERH I-18.8-19.4 minutes (29095), VERH-MS 4241 (IMANI", 869.2 |(2M-Mag.

As described in detail in example 129, compound (41) was condensed under standard conditions (after removal of the Ethos group) with an equivalent of 9n-fluoren-9-ylmethyl ether (Zab5, 7anes) 3-oxo-

HPLC-MS 409.2 (MaNi", 839.5 |(2M--Ma/". hexahydrofuro|3,2-BIpyridine-4-carboxylic acid

As described in detail in example 127, the connection of the loaded structure (22) building-block-linker. (33) were condensed under standard conditions (after Intermediate loaded thioether (1.2 μmol of Ethos group removal) with an equivalent of 9H- application in the form of gears) m-fluoren-9-ylmethyl ether (Za5, 7ab) was oxidized to 3-oxo- with chloroperbenzoic acid (bequiv., 6595 reagent of hexahydrofuroic 3,2-b|Ipyridine-4-carboxylic acid gent, 1.6 mg) In dichloromethane (200 μl) for 5 loaded structure (22) building-block-linker, hours followed by standard washing and then cleaved, obtaining the compound of example 153, and 159.

Example 154. (25, Zav, tab) 4-|Z-cyclohexyl- Example 156. (ab, tayu 28 2-(furan-2-ylmethanesulfanyl) propio-cyclohexylmethyl-4-morpholin-4-yl-1-(3 -oxonil|hexahydrofuro|3,2-b|pyridin-3-one hexahydrofuroi3,2-b|pyridin-4-yl)butane-1,4-dione

HPLC-MS 3921 (M.e-NI", 805.3 (2M--Ma)".

As described in detail in example 128, the compound HPLC-MO 407.2 (MENI, 833, Z gm-magr. (41)) was condensed under standard conditions (after As described in detail in example 130, the compound removed the Ethos group) with an equivalent of 9H- (36) condensed under standard conditions (after fluoren-9-ylmethyl ether (Za5, 7ag) 3-oxo removal of the Htos group) with an equivalent of /9H-hexahydrofuro/3,2-b|Ipyridine-4-carboxylic acid fluorene- 9-ylmethyl ether (Zaz, Tak) of the 3-oxo-loaded construction (22) building-block-linker, hexaldrofuro|3,2-BIpyridine-4-carboxylic acid was then cleaved, obtaining the compound of the attached-loaded construction (22) building- block-linker, du 154. was then cleaved, obtaining the compound

Example 155. (25, Zav, 7ab) 4-(Z-cyclohexyl-du 156. | | . 2-(furan-2-ylmethanesulfonyl) propio- Example A. Analyzes of the activity of cysteine protein- anilihexahydrofuro|Z,2-5|pyridine -3-on zi. y

All compounds of the present invention can be tested in one of a number of biochemical assays based on literature data and designed to elucidate the inhibitory characteristics of the compound. The data of this type of analysis make it possible to measure and quantitatively evaluate the activity of a compound and the speed of reactions. Such information, by itself or in combination with other information, allows to determine a number of necessary compounds that provide a given pharmacological effect.

General materials and methods

Unless otherwise noted, all common chemical (including EKEET-based substrates) biochemical reagents were synthesized or purchased from Zidt Ipsepia Gitjei using published

Spetis! Sotrapu, Rooie, Yuogzei, Sho. K. or from methods | Ashtegop 4 Zperraga, 5oiy Rpaze Reriide

Rizpeg Zsiepiys ShK, I opdprogotsody, I eiiseziegzpige, Zupipevib5, IC Rgez5, Ohio, 0. K., 1989| and in them

Central Committee Absorption analyzes were carried out in a plate - was AB used? (2-aminobenzoyl) as fluo- 96-well tablets (Zresiga; sgeipeg Vio-on rescent donor and Z-nitro-tyrosine (Tug(MoO»)| as da., Biopepoise, Sioyiseviegzpige, Yu. K.) with use - fluorescence quencher (Meida!, M. and Vgeddat, K., by melting a ZresigaMakh RI 05384 of the tablet rede- Apai. Viospet., 195, 141-147, 1991). Hydroxyethylpyra (Moiesshag Oemisez, Stauleu, 0. K. ).

Soviag 3705 riaie5z, Rizpeg Bsiepijs) or in 96- SNARB, zwittergents, etc.) received from SM well plates for microtitration with "SHO"- Viozsiepse5 ShK, Veeviop, Mocipdapatevpige, OO. K. with a similar bottom Misgoinog UM! (Tnegto I arzuzietv, Glycerin obtained from Ateg5pat Rnaptasia

Azptoga, Midaezeh, SHO. K.). Fluorescent analyzes Vioiesp, Gishshe Spagpopi, Viskipapatevpige, ). K. Vykhi- was controlled using fluorescent dni consumption of the substrate or inhibitor was prepared 10 mm tablet reader 5resigaMax Setipi (MoiIesshag in 100 96 dimethylsulfoxide (DMSO) (Kaiprigiv,

Oemise5). For substrates using as flu- SiIazdom, O. K.) and diluted in a suitable manner with the orophore of 7-amino-4--methylcoumarin (AMS) or 7- necessary. In all cases, the DMSO concentration of amino-4-trifluoromethylcoumarin (AES), monitoring in the analyzes was maintained equal to at least the analyzes were performed at an excitation wavelength of 190 (vol./o0b.).

From 6 to 5 nm and the emission wavelength of 45 Ohm and fluorescein. The analysis protocols are based on the literature. data Igtable 1; Vaigtei A. u., Kamlipd5 M. 0. apa

For substrates using 3-Muoezvpeg as a fluorophore. B., 1998, NaparookK oi Rgoieo|uis of amino-benzoip (AB), monitoring of conductance analyses- Eplutev5, Asadetis Rgez5, Hopdop and cited whether at the excitation wavelength З1Onm and the length there reference) and modified as it was pot- emission waves 445nm and fluorescent plan- need to satisfy this protocol, the analytical reader was calibrated with 3-amino-benzamide zu. Enzyme was added as needed for (Rick). Unless otherwise noted, all peptide initiation of the reaction and activity, according to changes in the substrates were obtained from Vaspet ShK, 51. in fluorescence upon conversion of the substrate to

Neiepv, Megzeuviaye, OK. product tracked over time. All analyzes are carried out

Substrates in which the dila technique is used at 25:170. fluorescence resonance energy transfer (i.e.

Table 1

Enzymatic analyzes given in this description were performed in accordance with literature data

CathepsinV.///// | 1 FARLEAYUAMSO 77777771

CathepsinH | 0 |VaRpeeMatayu AMS SG

Katwpsini | 1 IASRLEEACHAMSO GG

Katvpsin5 | 1 | VosManeshuvAMS 77777771

Caspases LO fAsieshsbishNvABRAMS 77777711

Caspase2 | |2-MavAvr-Magaa-AvrAеSTКyushcheSuS/С/С///7/777777777777777777777777FG111

Caspase OO fAs-Avr-Si-Mawdvrya AMS My

Caspase4 | M |byoe-stueimavdia-AvrAMSOIGLG/З777777777777777777777/FG!111

Caspase5 | LO fAsieshbishNvaBRAMS GG: S: /://:/: ОЙ.

Caspazab | M fAs-MavsishieavriAMSOIG////777777777777777777777771 11

Caspase7 | ОО fAs-Avr-Si-MawdvryaAMSOSG/З7777777777777777777777/Й|Й111

Caspase8 | OO fAsLesbietizAvrAMSOGG/////::///:(3/:-:Г/С:/:КДНСГ(|Ш|.ССЮ

Kaspazau | LO fasieshsishNvaABramSO S: G.Yu

Caspase!0 | фАсебити-АвряАМСОИГ////7777777777777777777777777/|Y1111

SRV2VASTE | XII f|RoRRLEAAMSO 77777771 5. Atsgei5 Intercellular isteinieltidava 8000 (Aoeedeletotu ozsyum

Cloztripain.i | 0 |2-6usuleАМС 77777771

Trypsin.///////// | M (2-busuleАМС 77777777

Katvyvinkhi///// THEIR THEM

I: 10 mM VTP, pH 6.5, containing 1 mM EOTA, 5 mM 2-mercaptoethanol and 1 mM Sasi»

I: 10 mm VTR, pH 6.5, containing iMM EOTA, 142 mm mass, 1 mm OTT, 1 mm Sasoy", 0.035 mm AmSchegdepi 3- 16

IP: 50MM NEREZ pH 7.2, 1095 Glycerin, 0.195 SNARB, 142MM Masi, 1MM EOTA, 5MM OtTtT

IM: 100 mM sodium phosphate, pH 6.75, containing 1 mM EOTA and 10 mM H. cysteine

In: 50 mM trisacetate, pH 8.4, containing 1 mM EOTA, 10 mM β-cysteine and 0.2595 (wt./06.) SNAP5

MI: 1 TOM STAINLESS STEEL, pH 8.0, containing 5 mM Sasig

MI: TOMM NEREKH, pH 7.5, containing 2 mM 2-mercaptoethanol and 100 µM Sasig

MI: TOMM NEREZ, pH 7.5, containing 2 mM 2-mercaptoethanol and 200 μM Sasi»

THEM: 100MM of sodium acetate; pH 5.5, containing 10 mm I-cysteine and MM EOTA

X: 100 mM sodium acetate; pH 5.5, containing 10 mM GI -cysteine; 0.059 (wt./vol.) Whi) 35 and 1mM EOTA

XI: 100 mM sodium acetate; pH 5.5, containing 10 mM /--cysteine; 142 mm of sodium chloride and 1 mm of EOTA and Vaitei! A. ., Viospet. 9., 187, 909-912, 1980 and Vaitei, A. .). and KitvsNKe, N., Meinodz Epgutoi, 80, 535-561, 1981 dtsirei, M. and Tauiog, 5., UMO0069855, 2000 a Vgotte, O., Zieipeti, Egeibe, 5., Rinkai, 5., Medegapaeg» 5, V., apa Kig5spke, N., Viospet. ., 264,475-481, 1989 e Kapo, T. A., ei. AI., Spet. Vio!., 4, 149, 1997. Taiapiap, V. M., Yei. and." in. Vioi Spet., 272, 9677, 1997 9 | a25erpik, U. A., Kashitapp, 5. N., Oezpoueg»5, 5., Roigeg, b, skh. apa Eatwepam, MU. S, Mayige., 371, 768-774, 1994 " Nai, 2., ei. ai., 9. Visi. Snet., 272, 13432, 1997 and Takanazvzni, A., ei. aI., RMAB, 93, 8395, 1996

AND! Mapipv, I. M., ei. a!., u. Vioi Spet., 272, 7421, 1997 kMadaya, 5., SeiI., 88, 355, 1997

And Nattiv, U. II.., yei. a/y., u. VioI.. Snet., 273, 27364, 1998 and, 9. 9., Sa?2tso Egapke, M. S, Mapipel, 9. apa ERgapke de Sa?2tsio, V. M., Viospet. Viorpuvz. Asia., 1037, 186-191, 1990 p bati, 9. 9., Vgamo, M., Kaitopai, A., Epdzigot, O., Hipderegod, b. apa NePtap, O., Sei! My. Vio!., 42, 691-696, 1996 " Rotetra, ., Oibrip, A., Koggi5, «. and Tgami5, 9u., Viospet. 9., 263, 2664-2667, 1988

R KetrpPami, A. A., Viyie, 0. U., Kaibeg, R. apa Vaggey, A..., REV5 I ey., 283, 277-280, 1991 h Aimev, I. S, ey. a) I., My. Viospet. Ragaviki, 116, 1-9, 2001, btsate, ei. a!., In Moi. Vioi., 302, 1227-1240, 2000 with Nayup apa Spgaik, (Vaghtei, Namiipod5 apa UUoezvpeg, edz.), ip Naparsok oi Rgoieo|uis Epgutez, Asadetis

Rgezv, Gopaop, 12-21, 1998

Her Wazaki, her. a!., (1984), 9. Axis. Spet., 259, 12489-12494, 1984 h Vozvaga, M. .., ei. a!., 9. Vioi. Spet., 21, 12517-12524, 1996

In Bapiatagi, I., her. a1., 9. Vioi. Spet., 273, 16816-16823, 1998 m Kietepsis, y), ei a!., Eig. in). Viospet., 267, 5404-5412, 2000

Analyzes of peptidase activity of cruzipain from Og. Chegetu Moigat (UmePysote Sepige g

TPurapgzota sgy?gi MoiIesciag RagaziyuIodu, Te Apaeyeizop SoiPede,

Kruzypain, a derivative of the epimaztygot of Ttgurapozhota Opimegeiu oi Siazdom, Siazdom, SHO. KO). Analyzes of sgy7 and YuOta28, received from Og. Activity assays were performed in 100 mM sodium acetate; pH (Ipeijie de Vioisisa Sapoz Spadaz Nino, 5.5, containing mM EOTA; 200 mM Masi and 10 mM

Opimegzidade Eedega! to NVio de dapeis, Nio aye OT (Aimez, I. S, ei. aI., Moi. Viospet. Ragaznyoi,

Uapeigo, Wales). Activity analyzes were carried out in 116, 1-9, 2001) using 0.258M enzyme in 100mM sodium phosphate solution, pH 6.75, which is available. Rho-Rpe-Ag9-AMS (Kmare "Z8μM) uses 1mM EOTA. Its 10mM G-cysteine was used as a substrate in a concentration equivalent to 2.58M of the enzyme. As-Rpe-Ag-AMS (Kmerr Kmerg, Rate of conversion of substrate to product -12μM) and O-Ma!-esh-Guv-AMS (KmeR? -A4AmMkM) were determined by the slope of the curve of the increase in fluorescein as substrates. Of course, the As-EN-AMS scene is continuously controlled in time. used in a concentration equivalent to Cathepsin peptidase activity assays

O-MaI-Hesh-I ug-AMC was used in the concentration of bovine cathepsin 5, human cathepsin I, at a concentration of 25 µM. The rate of conversion of the substrate into human thepsin H and human cathepsin B of the receiving product was determined by the slope of the curve of the increase from SM Viozsiepse5. Recombinant fluorescence cathepsin continuously monitored in human C, human cathepsin K and human cathepsin X. we received from Og. Vogiz TygK (doses 5 hetap

Assays of peptidase activity of cysteine pro- Ipviyshe, TsirIapa, Ziomepia). If not indicated thease B (CRV) of Heizptapia tehisapa Recombinant - other, all assays of peptidase activity of Provone CRV of wild tyin without the C-terminal were dissolved in 10 mM bis-tris-propane (BTP), pH 6.5, which i.e. SRV2,8ASTE; Zapaekzop, 5. 9., ei. contains iMM EOTA, 5 mM 2-mercaptoethanol and a!., Viospet. .)., 347, 383-388, 2000) received 1 mM Sasi". Analysis of cathepsin H activity in human

we carried out in 10 mM BTP pH 6.5, 142 mM mass, the substrate into the product was determined by the slope of the curve of 1 mM Sas, mM EOTA, mM OTT, 0.035 mM fluorescence increase, continuously counter-2 mycegdepi 3-16. Analysis of cathepsin K was performed in a time-lapse fashion. 100 mM sodium acetate; pH 5.5, containing 20 mM I/- Analysis of the peptidase activity of intracellular cysteine and 1 mM EOTA (|Vozzaga, M. .., ei ai., 9. Vioi. cysteine peptidase 5. ashgeiz M8 (staphylopain)

Spet., 21, 12517-12524, 1996). Analysis of cathepsin 5. ashgey5 M8 was obtained from Rgoya. 5. Agmiasop,

X was carried out in 100 mM sodium acetate; pH 5.5, which KagoiiipzKa Ipziyshe, 5iosKPpoI!t, bmzhmedep. The analysis contains 20 mm of I-cysteine; 0.05905 (wt./vol.) 35 and the activity of intercellular cysteine peptidase 5. 1mm EOTA IZapatagia, !., ей. ai., 9. Vioi. Spet., atsgeiy5 M8 (staphylopain) was carried out with the use of 273, 16816-16823, 1998; Kietepsis, u, ei ai., Eshig. in the partially purified culture supernatant

Viospet., 267, 5404-5412, 20001. Final concen- 5. atsgeny5 M8 (obtained from Og. Rebeg I atreti, enzyme rations used in the analyzes were made by Aviop Opimegzyu, Vippipdapat, O.K.). Activity assays - 0О.5NM for bovine cathepsin 5, 1NM for cathepsin were carried out in 10mM VTR, pH 6.5, containing blue I, 0.1nM for cathepsin B, 0.25nM for cathepsin - 1mM EOTA, 5mM 2- mercaptoethanol and 1 mM Sasi", son K; 1 nM for cathepsin X and TONM for cathepsin using twice diluted partially diluted H. For assays of inhibition, substrates, extracted extract. For assays of Arz2 inhibition, cathepsin 5, cathepsin GH, cathepsin Pe-Aia-Aia-Rho-Tug were used. (MO»2)-С11Ш-МНг (Kmaerb -117μM; sin B, cathepsin K and cathepsin H were Ipsepia Githyei) was used as a substrate in ros-Ma!I-Gen-Huz-AMS (Kmer? "ZOμM), As -RPe-Ago- concentration equivalent to KmeRR. The speed of con-

AMS (Kmarb about -20μM), 2-Rpe-Ag9-AMS / (Kmere version of the substrate in the product was determined by the slope -"40μM), 2-Hei-Ag9-AMS (Kmer? -2μM); В2-РНе- fluorescence increase curve, continuous

MaI-Ag9-AMS (KmerR -150μM), respectively. In each- controlled in time. In this case, the concentration of the substrate used in each analysis was equivalent to Kmer. (EMOM-I R)

The rate of conversion of the substrate into the product was determined by the slope of the curve of the increase in fluorescence, the wild-type recombinant EMOM-I R. was obtained from Og. Tit ZKegp (Ipziysh yog Medigipizspe continuously controlled in time. Viospetiye, AbBieyyipud yog Viospetiye, Opim. Uep,

Analysis of peptidase activity of trypsin Muiep, A!yvigia). Activity analyzes were carried out in

Pancreatic trypsin activity assays in 5 mM trisacetate, pH 8.4, containing TMM EOTA, human (iodized quality; SM Viozsiepse5) with 10 mM G-cysteine and 0.2595 (wt./o0b) SNARB, from which was excreted in TMM NEREZB, pH 8.0, containing 3mMM using 1O0nM enzyme. For assays of inhibition

Sasi", using 0.1 nM trypsin. For the analysis of Arg-Aga-GGuv-y ets-I uz-S1u-Aia-Stu-zeglyses inhibition of /2-Siu-Siu-Ag9-AMS o (Kmere tTutsMO»)-siSh-MN»g (Km ? "51μM, Ipsepia Sityea) -"84mMKkM) was used as a substrate at a concen- used as a substrate at a concentration, tration equivalent to KmePP, Conversion rate equivalent to KmePP. The rate of conversion of substrate substrate to product was determined by the slope of the curve to the product was determined by the slope of the curve of increase in increase in fluorescence, continuously counter-fluorescence, continuously monitored in poured in time. times

Analysis of peptidase activity of clostrypain. Analysis of peptidase activity of caspase

Assays of the activity of clostripain (Zidta) pro- Caspases 1-10 were obtained from SM Viozsiepse5 were diluted in 10 mM BTP, pH 6.5, containing 1 mM or Vio Mysiop Ips. (Moshpiaip Miem, SA, O5A), and all

EOTA, 5 mM 2-mercaptoethanol and 1 mM Sasi", with analyzes carried out in 50 mM NERE5; pH 7.2, 10965 using 0.3 nM enzyme. For analyzes (vol./vol.) glycerol, 0.195 (wt./06.) SNAR5, 142 mM inhibition of 2-C1u-Siu-Aga-AMS (Kmer? -100 μM) mass, iM EOTA, 5 mM dithiothreitol (OT) with - used as a substrate in a concentration equal to 0.1-1 IU per analysis. For caspase 1 as a valence Km, the rate of conversion of substrate to substrate was used As-Yi ey-C1y-Niv-Avr- the product was determined by the slope of the curve of increase in AMC; for caspase 2, fluorescence continuously monitored in 27-MaI-Avzr-MaI-AiIa-Azr-AES was used as a substrate; for caspase C as sub-times. strata used As-Azr-sSii-MaI-Azr-AMS;

Analysis of peptidase activity of calpain for caspase 4 as a substrate used 5is-

Assays of calpain activity (erythrocyte Tug-MaI-AIa-Azr-AMS; for caspase 5, human calpain and pig kidney m-calpain were used as a substrate; SM used As-yI ei-C1ISh-Niz-Azr-AMS; for

Viozsiepse5) was carried out in 10 mm NEREZB, pH 7.5, caspase 6 was used as a substrate As-Mai!- containing 2 mm 2-mercaptoethanol and Sasig, from is-Pe-Azr-AMS; for caspase 7, 25 nM of each enzyme was used. as a substrate As-Azr-Sii-MaI-Avr-AMS; for caspase a!., u. Vioi Spet., 259, 12489-12494, 1984). For 8 As-Pe-Cs1y-TAg- assays of d-calpain inhibition were used as a substrate, the buffer contained Avr-AMS; for caspase 9, 100 µM Sasi», ii Ar?-Aia-Avp-I ei-Spu-Agd-Rgo-Aia were used as a substrate. for caspase 10

Hei-Tu(MO")-Avr-MNa (Kmeb? about -20mMkM; Ipsepia used As-IPe-c1y-Hpg-Avr-

And ityeya) was used as a substrate. For analysis, AMS IMispoizop O. MU. and Tpogpreggu M.A., TIV5, 22, inhibition of m-calpain was detected by a buffer containing 200 μM 299-306, 1997; Meppiske N. K. and zaimezep 0. 5., u.

SasSi", and AbB-Guvz-I ei-Suv(B21I)-Rpe-5ei-I uv-S1p- Visi. Spet., 272 (41), 25719-25723, 1997; TaIapiap

Tu(MO»2)-Avzr-MNeg (Kmor? -22μM; Ipsepia I ityea) A. M., ei. ai., u. Vioi Spet., 272 (15), 9677-9682, was used as a substrate. In both cases, 1997; Moi, V. V. and Sgeep 0. K., in: Vioi. Spet., 274, the concentration of the substance used in the analyzes (29), 20049-20052, 1999)|. The rate of rate conversion was equivalent to KmeRR. The rate of conversion of the substrate to the product was determined by the slope of the curve of fluorescence increase, continuously monitored over time.

Measurement of the apparent constants of macroscopic In the equation З m" represents the residual active binding (Mispaeii5) Km? of substrates, the observed "P" is the difference

Apparent constants of the macroscopic connection between the maximum activity (that is, during KmeR? for each substrate was calculated in the absence of an inhibitor) and the minimum activity from the dependence of the enzyme activity as a function of the enzyme, "Es represents the total concentration of the substrate concentration. A graph was built of the rapid tion of the enzyme, KigRR represents the apparent observed constants (ordinate) with respect to the dissociation constant, and Chol represents the concentration of the concentration of the substrate on the abscissa, and the data were processed using the inhibitor. regression analysis (Rgizt) using (Rgiet m 3.02; SgarpRaid, Zap Oiedo, О5А) with rolling out a fixed value for the concentration of equation 1 (Sogpizp-Vomdep, A. enzyme. Equation 4 was used to dis- "Eopdatepia !5 ой епгуте Кипейійсв" Roshap Rgev5; account of substrate kinetics, where "Ki! represents 1995,93-128). inhibition constant, iZo| represents the initial concentration of the substrate, and Kmer? is 7 Twornkyar's apparent constant of macroscopic binding of the substrate (Moitizop, 1982).

Rate constants of the second-order reaction of the inhibitor with the enzyme.

In the equation, 1 m" represents the initial speed. In those cases where it was possible to use the observed rate, "Mmax represents the concentration dependence of the maximum observed activity, at the observed reaction rate, was analyzed (Koposter. ) saturation concentration of the substrate, Km? represents each compound with an enzyme by defining the apparent constant of the macroscopic binding- rate of enzyme inactivation in the conditions of pseudo-substitution (Mispaeii5) of the substrate, YTZo! is of the first order in the presence of the substrate. the initial concentration of the substrate. Imoitizop, 5. R. TIV5, Lb2-105, 1982; Tiap, M. Kh. and

Measurement of inhibition constants by Tzom, also Viospetivigh, 21, 1028-1032, 1982;

The apparent inhibition constant (Ki) for each Motgtizop, .). R. ii Umai5p, S. T., yiot Meizivg (Ea.), the compounds were determined on the basis of the fact that the inhibitor Aamapsez ip Epgutoi., 61, 201-301, 1988; T5om, Snya is reversible and occurs by a purely competitive mechanism. Ki values were calculated from 381-436, 1988). Analyzes were performed by adding the activity of the enzyme as a function of concentration of different concentrations of the inhibitor to the holding concentration of the inhibitor using the direct regression of the substrate buffer for the analysis. Assays of the initiation analysis (Rgizt m 3.02) using the shaft by adding an enzyme to the reaction mixture of equation 2 (Sogpiznovopdet, A., 1995). and monitored changes in fluorescence over time. Less than 1095 substances were consumed in the analysis process

IvInkmere (Dicky), Ratu. as (2) (ho -uv)1st che

Е-УВЕКА- и -Ч ш 65 -Я и и - irsyu (5)

In equation 2, m" represents the observed residual activity, "Mtahero" represents Curves of changes in the fluorescence activity of the treatment - the maximum observed activity, nm pi (that is, in the absence of the inhibitor), Kier? represents the curves using a nonlinear regression is the apparent constant of the macroscopic bond- 1969. М З op ovle g with З (Mogtivop, (Mispaeii5) of the substrate, |5| is a po- " MOPZOP, ); where w is the sooo initial substrate concentration, Ki is the bottom fluorescence response, y is time, the apparent dissociation constant, and ХІ is Mo initial rate, В is the rate at the inhibitor concentration. changes in equilibrium Kposter Speed CONSTANT,

In a situation where the apparent dissociation constant is pseudo-first order, i.o

Kir approaches the concentration of the enzyme, is a signal at time zero (the value of KigRR was calculated using the placement of the ordinate on the curve). Out of laziness! quadratic solution in the form that describes - for the kposter graph. from the concentration of the inhibitor by equation 3 (Moggizop, U.E. Thepaz Viospet. (i.e., Xposter//Y) the rate constant of the second order was obtained. 8i., 7, 102-105, 1982; To correct the kinetics

Viorruv Asia? 185, 269-286, 1969; Biope, 5. V. and the substrate was used equation 6, where Zo

Noiviespde, 4. Viospeti and represents the initial concentration of the substrate, " sho 2 " Kmerg is an imaginary constant of macroscopies -iyu -KIARR that -o -karr | t4-kyaPP) permanent binding (Mispaeii5) of the substrate. НииипжиижижижиппжижОжтЖтоТЛХТЛЩЦФГОООІІІ ZY kobe| Ж IVoi/kmere ) (3) Kipasi nyny t (c)

The compounds of the invention were tested in epiteases with an inhibition constant Ki lower than the above analyzes and at the same time it was observed, or equal to 100 μm. Illustrative data of the inhibition that they possess inhibitory activity in a number of examples of compounds are presented in the table of cruzipain or inhibitory activity in these 2. in relation to the alternative CA SI cysteinepro-

Table 2

Illustrative inhibition data ("Ki expressed in µM)

Example M 771769 | .YuyuYuyu»5 2 2 ЮЩ | that 9 |! 08 5 5shushch | 00

Computer layout 0. Gaponenko Signature Circulation 26 approx.

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