UA71955C2 - Impdh (inosine-5'-monophosphate dehydrogenase) inhibitor, pharmaceutical compositions comprising this compound, method for treating and prophylaxis impdh-mediated processes, method for inhibiting viral replication, method for inhibiting cancer growth and treating cancer, method for inhibiting inflammation - Google Patents

Abstract

The present invention relates to compounds which inhibit IMPDH. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH-mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.

Description

Description of the invention

This application claims priority to prior US patent application Mob0/125507, filed March 19, 1999, and US prior application MobO/174882, filed January 7, 200Or.

This invention relates to compounds that inhibit IMFDH. This invention also relates to pharmaceutical compositions containing such compounds. The compounds and pharmaceutical compositions according to the present invention are particularly well suited for inhibiting the activity of the enzyme IMFDI and, accordingly, can be usefully used as therapeutic drugs for pathological processes mediated by IMFDI. The present invention also relates to 70 methods of inhibiting the activity of IMFDH using the compounds of the present invention and related compounds.

State-of-the-art technology

Synthesis of nucleotides in organisms is necessary for cells in these organisms to divide and reproduce. The synthesis of nucleotides in mammals can be carried out in one of two ways: by the de pomo synthesis method or by the utilization method. Different types of cells use these methods to different extents. 12 Inosine-5'-monophosphate dehydrogenase (IMFDH; EC 1.1.1.205) is an enzyme involved in the synthesis of auxiliary guanine nucleotides. IMFDG catalyzes the NAD-dependent oxidation of inositol-5-monophosphate (MF) to xanthosine-5'-monophosphate (KMF) YuaskKgop K.S. ei ai., Maikyge, 256, pp. 331-333 (1975).

There is no doubt about the presence of IMFDH in eukaryotes, bacteria and protozoa (M. Maisiteda 8 5.E. Sait. App.

M. Kh. Asai., 696, pp. 88-93 (19933). Prokaryotic forms share 30-4095 sequence identity with the corresponding human enzyme. Two isoforms of human IMFDH, designated as type I and type II, were identified and their sequence was determined |B.K. SoMai 5 E. Nyregtap, U). Vioi Spet., 263, pp. 15769-15772 (1988); IN.

Mayiviteda ei ai., 9. Vioi. Spet., 265, pp. 5292-5295 (1990). They each contain 514 amino acids, and they share 8,490 sequence identities. | type І, ІІ type ІІІ IMFDH form active tetramers in solution with a molecular weight of subunits of 56 kDa GU. Khatada ei a/i., Viospetizigu, 27, pp. 2737-2745 (1988). p 29 The synthesis of de pomo guanosine nucleotides, and therefore the activity of IMFDH, is especially important for B- and He)

T-lymphocytes. These cells depend more on de pomo synthesis than on utilization to provide sufficient levels of nucleotides necessary to initiate a proliferative response to a CA mitogen or antigen..S.

Aiizop ei ai., I apsei II, 1179 (1975) 5. A.S. AIyvop ei aiI., Syra Rotspa. Zutr., 48, 207 (1977)). Therefore, IMFDH is an attractive target for selective inhibition of the immune system without also inhibiting the proliferation of other cells. yu

Immunosuppression was achieved by inhibiting a variety of enzymes, including, for example, calcineurin phosphatases (inhibited by cyclosporine and EC-506), dihydroorotate dehydrogenase (an enzyme involved in pyrimidine biosynthesis; inhibited by leflunomide and brekinar), ECAR kinases (inhibited by rapamycin), and "- - heat shock protein yzr70 (repressed by deoxyspergualin). |See EO Kanap, Igathipoiodisa! Kemiem/v, 1836, pp. 29-49 (1993); K.E. Moitiv, Te doshgpai! oi Neagi apa I pu Tgapzriapiayop, 12(6), pp. 5275-5286 (1993)). in

IMFDH inhibitors are also known. US Patents 5,380,879 and 5,444,072, and PCT Publications UMO 94/01105 and MO 94/12184 describe mycophenolic acid (MFA) and some of its derivatives as potent, noncompetitive, reversible inhibitors

Human IMFDH type I (k-33 pM) and type II (K-9 pM). It was demonstrated that MFC blocks the reaction of B- and T-cells to a mitogen or antigen (A.S. Aiyvop eii ai., App. M. Kh. Asai. z5si., 696, 63 (1993)). WITH

Immunosuppressants, such as MFC, are used in the treatment of transplant rejection and autoimmune diseases |K.E. Moigtiv, Kidpeu IpiI., 49, Zirri. 53, 5-26 (1996)). However, IFC is characterized

With" undesirable pharmacological properties, such as gastrointestinal toxicity (H.M. ZNnam/ ei ai.,

Tpegaretsiis Ogyd Mopiogipo, 17, pp. 690-699 (1995)).

Analogues of nucleosides, such as tiazofurin, ribavirin and mizoribine, also inhibit IMPDH IS. Non-zygote ei 49 a, Viospetivigu, 29, pp. 849-854 (1990)). The disadvantage of these compounds, however, is the lack of specificity for IMFDH. it. Mycophenolate mofetil, which belongs to prodrugs and rapidly releases free MFC ip mimo, was recently approved for use in order to prevent acute rejection of a renal allograft after kidney transplantation (S.M. pp. 690-699 (19953; N.MU. ZoiIpdeg, o Tgapzriapiayop, 60, pp. 225-232 (1995))Y. However, some clinical observations limit the therapeutic potential of this drug (H.M. Zpam ei aI ., Tpegaretsiis YuOgid Mopiogippo, 17, pp. 690-699 (1995)). MFC is quickly metabolized to the inactive glucuronide ip mimo (A.S. Aizop 8 E.M. Etsii, Ittypoiodisa! Kemiemuv, 136, sl pp. 5- 28 (1993)).This glucuronide then undergoes enterohepatic recycling, leading to the accumulation of

IFC is in the gastrointestinal tract, where it cannot exert its inhibitory activity on IMFDH, and therefore on the immune system. This circumstance significantly reduces the effectiveness of the drug ip mimo, at the same time increasing its 22 undesirable gastrointestinal side effects.

GF) Recently, IMFDG inhibitors of various classes have been described, for example, in publications PCT UMO 97/40028 and MO 98/40381. o It is also known that IMFDH plays a certain role in metabolic phenomena. Increased activity of IMFDH was observed in rapidly proliferating human leukemic cell lines and in other 60 tumor cell lines, which indicates IMFDH as a target for anticancer as well as immunosuppressive therapy M. Madai et al.,

Sapseg Kev., 51, pp. 3886-3890 (1991)). It was also shown that IMFDH plays a role in the proliferation of smooth muscle cells, which suggests that inhibitors of IMFDH, such as MFC or rapamycin, may find application in the prevention of restenosis or other hyperproliferative vascular diseases |S.K. Sgedogu ei a!I., Tgapzriapiayop, 59, pp. 655-61 (1995); PCT ribiisaiop U/O 94/12184; 5 PCT ribiisaiop MO 94/01105). because In addition, it was shown that IMFDH takes a certain part in the replication of viruses and some virus-infected cell lines |5.P. Site, 9. Vioi. Spet., 268, pp. 27286-27290 (1993)). As in lymphocytes, as well as in lymphocytic and tumor cell lines, it can be concluded that de Pomo synthesis, rather than utilization, plays a crucial role in viral replication.

Therefore, there is a need for strong IMFDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anticancer drugs, antihyperproliferative vascular drugs, anti-inflammatory drugs, antifungal drugs, antiviral drugs, and drugs for the treatment of psoriasis.

Summary of the Invention 70 This invention relates to compounds and their pharmaceutically acceptable derivatives that have inhibitory properties

IMFDG. The compounds of this invention can be used alone or in combination with other therapeutic or prophylactic drugs, such as antiviral drugs, anti-inflammatory drugs, antibiotics and immunosuppressants for the treatment or prevention of transplant rejection and autoimmune diseases.

In addition, such compounds can be used, alone or in combination with other drugs, as therapeutic and prophylactic drugs for treatment regimens directed against viruses, tumors, cancer, inflammation, fungal lesions, immunosuppressive chemotherapy for psoriasis and restenosis.

The present invention also relates to pharmaceutical compositions that include compounds according to the present invention, as well as multicomponent compositions that, along with the immunosuppressant, contain additional IMFDH compounds. This invention also relates to methods of using the compounds of this invention, as well as other related compounds for inhibiting IMPDH.

Detailed description of the invention

In order for the invention described in this application to be more fully understood, the following detailed description is offered. The following abbreviations are used in this description:

Designation Reagent or fragment of

Ac acetyl

Me methyl eE ethyl yu

Vp benzyl

SO carbonyldiimidazole is) rvy 1,8-diazabicyclo|5.4.O)undec-7-ene He»)

PIEA diisopropylethylamine

LOBSTER dimethylaminopyridine --

OME dimethylformamide ch- rMBO dimethylsulfoxide

ARPA diphenyl phosphoric acid

ES 1-(3-dimethylaminopropyl)-3-" ethyl carbodiimide hydrochloride 406 EOAc ethyl acetate - with IRA isopropyl alcohol h " mesm acetonitrile schi TNE tetrahydrofuran

TEA triethylamine y-ry tert-butyl -| butyloxycarbonyl wax

The following terms are used in the description of the invention: (Ce) Unless expressly stated to the contrary, the terms "-5O 5.-7 and "-5(0)5-7, as used herein, cl 50 refer to a sulfone or a sulfone derivative (i.e. , both added groups bound to 5) rather than to the sulfinate ether. The term "halo" or "halogen" refers to a fluorine, chlorine, bromine or iodine radical.

The term "immunosuppressant" refers to a compound or drug that has the property of suppressing the immune response. Examples of such drugs include cyclosporine A, EKBOB, rapamycin, leflunomide, deoxyspergualine, prednisolone, azathioprine, mycophenolate mofetil, OKTZ, ATAS, interferon, and mizoribine.

The term "interferon" refers to all forms of interferons, including, but not limited to, alpha, beta, and gamma forms. име) IMFDH-mediated disease is any pathological condition in the metabolic pathway of which the enzyme

IMFDG plays a regulatory role. Examples of IMFDH-mediated disease include transplant rejection 60 and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory diseases, cancer, diseases associated with viral replication, and vascular diseases.

For example, the compounds, compositions, and methods of use of the present invention may find application in the treatment of transplant rejection (e.g., kidney, liver, heart, lung, pancreas 65 (islet cells), bone marrow, cornea, small intestine, as well as skin allografts and xenografts of heart valves), rheumatoid arthritis, multiple sclerosis, juvenile diabetes,

asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), lupus, diabetes, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pneumonia, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, Behçet's or Sjögren's syndrome (dry eyes /mouth), malignant or immunohemolytic anemia, idiomatic adrenal insufficiency, polyglandular autoimmune syndrome, as well as glomerulonephritis, scleroderma, lichen planus, vitiligo (skin depigmentation), autoimmune thyroiditis and alveolitis, such inflammatory diseases as osteo-arthritis, acute pancreatitis, chronic pancreatitis, asthma and respiratory distress syndrome in adults, as well as in the treatment of cancer and tumors such as solid tumors, lymphomas and leukemia, vascular diseases such as restenosis, stenosis and atherosclerosis, as well as diseases associated with 7/o replication viral DNA and RNA, such as retroviral diseases and herpes.

In addition, it is known that IMFDH enzymes are also present in bacteria, and therefore can regulate bacterial growth. As such, the IMFDH inhibiting compounds and compositions described herein, as well as methods of inhibiting IMFDH, may find use in the treatment or prevention of bacterial infection, alone or in combination with other antibiotics.

The term "treatment", as used herein, refers to the alleviation of the symptoms of a particular disorder in a patient or the improvement of some measure that is amenable to precise definition and associated with a particular disorder. The term "patient" as used herein refers to any mammal, including a human.

The terms "NVM", "NSM" and "ONOM" refer to hepatitis B virus, hepatitis C virus and hepatitis 0 virus, respectively.

According to one embodiment, the present invention relates to a compound of formula A:

Ve re

And Gee! about Vg Ge

Y A r g I

In M Y (B) o in which: each of Ku and Ko is independently selected from hydrogen; -СЕз,.-(С4-Св)- linear or branched alkyl; - (Co-Cv) - linear or branched alkenyl or alkynyl; -(C4-Ce6)- linear or branched alkyl-K7; -КС»о-Св)- about a linear or branched alkenyl or alkynyl|Y-K; or -K7; and in which at least one of K. and K»o is -(C4-Cv)- linear or branched alkyl-K7; -КСо-Св)- linear or branched alkenyl or alkynyl|-K; or K,; in which up to 4 hydrogen atoms in any of the mentioned alkyl, alkenyl or alkynyl are not necessarily and independently replaced by K"; ia or in which KK. and Co are alternatively taken together to form a tetrahydrofuranyl, in which, WHEN Co IS HYDROGEN, (ie (K)-methyl, (K)-ethyl, or (K)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran is substituted with -OK; or -K, and in which, when Ke is hydrogen, (5)-methyl, (5)-ethyl or (5)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran is optionally replaced by -OK" or -K;7; in which when Co is hydrogen, (K)-methyl, (K)-ethyl or (K)-hydroxymethyl and each of K and Co is independently hydrogen, unsubstituted -(C4-Cv)- linear or branched alkyl or unsubstituted -(Co-Seb)- linear or "branched alkenyl or alkynyl, then the part of this compound represented by -CH(К.)К" is Св-С42 linear or C 50 branched alkyl, alkenyl or alkynyl; each Kz is independently chosen from halogen, CM, -OKa or -M(Kov)2; "from K. is chosen from hydrogen, -(C4-Cv)- linear or branched alkyl; -(Co-Cv)- linear or branched alkenyl or alkynyl; - КС4-Св) - linear or branched alkyl| - K7; -КСо-Св)- linear or branched alkenyl or alkynyl) -К7, -С(0)-КС-4-Св)- linear or branched alkyl), -С(0)-КСо-Св)- linear or branched alkenyl or alkynyl), -С(0)-КС4-Св)- linear or branched alkyl| -М(Ка)», -С(0)-КС4-Св)- linear or branched alkenyl or alkynyl|-М(Ка)», -""ОХОКва)», -С(О) (OKа) (Ка) , -С(0)-К7, - КС4-Св).-- - linear or branched alkyl |-СМ, -5(0) 2М(К5)» or -(Со-Св)- linear or branched alkenyl or alkynyl |-CM; each K is independently selected from hydrogen, -(С4-Св)- linear or branched alkyl; -(Co-Cv)- linear or c 20 branched alkenyl or alkynyl, -КС4-Cv)- linear or branched alkyl|-К7; -КС»-Св)- linear or branched alkenyl or alkynyl|-К7, -КС4-Св)- linear or branched alkyl|-СМ, -КСо-Св)- linear or branched alkenyl or alkynyl|-СМ, -КС4 -Cv)- linear or branched alkyl|-OK,; -КСо-Св)-linear or branched alkenyl or alkynyl|Y-OKu, -С(0)-(КС4-Св) - linear or branched alkyl), -С(О0)-КСо-Св) - linear or branched alkenyl or alkynyl |), -С(0)-К7, -С(0)0-К7, -С(0)0- (С4-Св) - linear or branched alkyl, -С(0)0- |( (Co-Cv) - linear or branched alkenyl or alkynyl), -5 (0)5- (C4-Cv) -

HF) linear or branched alkyl, or -5(0)5-K7; or two K5 moieties, when bonded to the same Cu nitrogen atom, are taken together with that nitrogen atom to form a 3-7-membered heterocyclic ring, which heterocyclic ring may not necessarily contain 1-3 additional heteroatoms , independently selected from M, O, 5, 5(O) or (0); 60 Ke is chosen from -С(0)-СН3, -СН-С(0)-ОН, -СНо-С(0) -О-ИВы, -СНо-СМ or -СН.-С-СН; each K. is a monocyclic or bicyclic ring system in which:

Y. each ring includes 3-7 ring atoms, independently selected from C, M, O or 5;

I. no more than 4 ring atoms are selected from M, O or 5;

I. any CH" is not necessarily replaced by С(О); because THEM any C is not necessarily replaced by (0) or 5(0)";

each Ka is independently selected from hydrogen or -|С.4-С.| - linear or branched alkyl; in which in any ring system of the named compound up to 3 hydrogen atoms bound to ring atoms are not necessarily and independently replaced by halogen, hydroxy, nitro, cyano, amino, (C 4-C/) - linear or branched alkyl; O-(C4-C)u) - linear or branched alkyl, (Co-C)u) - linear or branched alkenyl or alkynyl, or O-(Co-C) - linear or branched alkenyl or alkynyl; and wherein any ring system is optionally benzo-fused;

Co is selected from hydrogen, (K)-methyl, (5)-methyl, (K)-ethyl, (5)-ethyl, (K)-hydroxymethyl or (5)-hydroxymethyl; 70 Ko is chosen from -С-. M or 5-oxazolyl; and

K.41 is selected from halogen, -O-(C4-C3) linear alkyl or -O-(C2-C3) linear alkenyl or alkynyl.

Formula (A) also covers prodrugs obtained by esterification of either K 4 or Co or both.

Examples of such prodrugs are compounds 143 through 156 in Table 1 below.

The term "monocyclic ring system, as used herein, includes saturated, partially unsaturated 7/5 | fully unsaturated ring structures. The term "bicyclic ring system, as used herein, includes systems in which each ring is independently saturated, partially unsaturated, and completely unsaturated.

Examples of monocyclic and bicyclic ring systems used in the compounds of the present invention include, but are not limited to, cyclopentane, cyclopentene, indane, indene, cyclohexane, cyclohexene, cyclohexadiene, benzene, tetrahydronaphthalene, decahydronaphthalene, naphthalene, pyridine, piperidine, pyridazine, pyrimidine , pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,4,5-tetrazine, 1,2 . ,6-naphthyridine, 2,7-naphthyridine, pteridine, acridine, phenazine, 1,10-phenathroline, dibenzopyrans, 1-benzopyrans, phenothiazine, phenoxazine, thianthrene, dibenzo-p-dioxin, phenoxanthin, phenoxthionine, morpholine, thiomorpholine, tetrahydropian , pyran, benzopyran, ch 1,4-dioxane, 1,3-dioxane, dihydropyridine, dihydropyran, 71-pyrindine, quinuclidine, thiazolopyridine, β-carboline, indolizine, quinolizidine, tetrahydronaphtheridine, diaza-phenanthrene , thiopyran, tetrahydrothiopyran, benzodioxane, (8) furan, benzofuran, tetrahydrofuran, pyrrole, indole, thiophene, benzothiopene, kaobazole, pyrrolidine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, 1,2,3-triazole , 1,2,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1, C, 4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole, 1 . at

Additional monocyclic and bicyclic structures that fall under the above description can be found in Ge! works by A.K. Kaigpy2Ku 5 S.U. Keev, Edz. "Sotrgepepzime Neyegosusis Spetivigu: bigysitsge, Keasiiopv, Zupipeviv apa ve oi Neyegosusis Sotroitspavz, Moi. 1-8", Regdatop Rgevzv, MU (1984), the disclosure of which is included here as --

Зз5 reference. Cha

It should be understood that heterocycles can be attached to the rest of such a compound by any atom of the heterocycle, resulting in the formation of a stable structure.

The term "ring atom" as used herein refers to the main atom that forms a given ring. Such ring atoms are selected from C, M, O or 5 and are bonded to 2 or C other such ring atoms (C in the case of certain ring atoms in a bicyclic ring system). The term "ring atom" does not include hydrogen.

The terms "-КС.4-Св)- linear or branched alkyl|-X" and "-КСо-Св)- linear or branched alkenyl or from alkynyl|-Х", where X is everything connected to alkyl , alkenyl or alkynyl, means that one or more X groups may be attached to the alkyl, alkenyl or alkynyl chain at any termination.

According to one preferred embodiment, the compound has the formula (1): In zo t she so. o Ne se) 2

X db 0170 meo her a sl in which MK. and Co are as defined above or have the formula (IA):

Ve kn and voi o iv) p

20th century MV (Id); name) not in which

K»e is selected from (K)-methyl, (5)-methyl, (K)-ethyl, (5)-ethyl, (K)-hydroxymethyl or (5)-hydroxymethyl; and because Co, Co, Co and K.4 are as defined above.

According to a more preferred embodiment of formula IA, Co is selected from (5)-methyl, (5)-ethyl, or (5)-hydroxymethyl methyl. Best when Co is (5)-methyl. Compounds in which Co is selected from (5)-methyl, (5)-ethyl, or (5)-hydroxymethyl methyl and in which the part of the compound represented by -CH(K 4)Co is C.-C, linear or branched alkyl or Co-C, linear or branched alkenyl or alkynyl, fall under the category of compounds as described in UUO 97/40028. However, applicants have found that the presence of (5) oriented moiety in Co results in a striking and unexpected enhancement of IMPDH inhibitory activity.

According to another preferred embodiment of formula IA, K.4 is selected from O-methyl, O-ethyl or O-isopropyl.

According to a better embodiment of formulas (I) and (IA), at least one of K and Co is selected from hydrogen, methyl, ethyl, p-propyl, isopropyl, p-butyl, butyl, p-pentyl, phenyl, pyridyl, - СНоОСН»з, -СНоСМ, -бННоОосСнН.сСнНосМ, -СНС (СнАз) "СНоСНосСМ, -СНоС(СнОСНю»СсноСНСМ, -СноСНСМ, -СНоМ(СноСНоСМ)", -СнН.щ(СнНьУИСнньсСНьсМ, -СН(МН.) СНОСМ, -СНСИ, -СНоОН, -СН.СНоООНН, -СН.СН2гОоНН, -СНоСноСносСНносСНнооН, -бNoСнNoОос(О)СНноН, -СН.СНоОоС(О)СНоОМНо, -СНо.СНоМНоСнНУ, -СНоСННОМ o (СНа)»» . .СНЖСНУСОюС(СНУ)», -СНЩ(СнОсСнНОСсМСНосСНн(СН З)», -СН(ЙЕНСЯММ(СН 3)», -СНАСН(СНОСЙМНСТoos(сН 3)), the same Agto gODh str s to sv, o g pa: sleep i and "in M MO du", where n is O or 1.

According to an even better embodiment of formula IA, one of C or C is selected from hydrogen, ethyl or phenyl; and the other from K.; or Co is chosen from -CHNOH, -СНЦСМ, -СНЦСНОСМ or -СХНМ (СНоCH»)» or K. and Co are taken together with the formation of the 3-tetrahydrofuranyl part.

According to another best embodiment of formula I, K; and Ko are taken together with the formation of the 3-tetrahydrofuranyl part, which is replaced by -OKb.

According to another preferred embodiment, the compound of formula A is selected from any of those listed in Table 1 below. with

Table 1. Compounds about ! it's C obi . and meo gnya, and yu u dk bod and o meb "Kv "-

Mi - gi va pad khum mochnchi g " i shi s 4 2" y u te o - oce tt - is, ; p. 50 Zh ki o. sp Yaru 7 ii ly o n an g

Iii (F) ii SHY o mm m damage, overcome because i b5 je Zh

Suli von I change tsi g g mrovlyi o M rogi

AND

10 khmvstny rai onnoshnn chno inche H i iodnovany i sch ly y y I" (o) oboi y o yuyu "dole i s ! oo il m ge | vu chi ots s ge . " - s z -I shk

Te) s 50 sp (F) t bo 65 tu ody doty t ! tv, no, nn a mne: yu 12 chiralny sce 1. 18. chirolny what Ж vo ADOLOG sh ov onne sh "M S t

Zra in a vovi o! p zhrolny sch is tpryrth o obo OO mV t ke Shk Io) and od yu "in chiral t b brother 5 - "Ky - " - s z -I shk (se) si sl

F) what is 65 bo"

THE HORROR from the linya bra "A

She

SHO voke Ochi DS still sewed and I 7" tr

And I with chirolny nm ve

I s z o i S" era KASAK, o

Photo "sus o yu s 9 st yuyu ti or Ge) 4 I ; pud her in i - 1 pri v i sb oh « - s z -I shk (se) sl 20 sl (F) ko vo 65 meo Mn S" sudo s Y z5 -l 6 fo o « y a kn chi yi is not 7 meb ni.

NM. , point 58) tot C (4 Y "pera. in I cm m - "39 chiral - i9) chno My H ono lo o z "I yu 40 o cm b she lolyut, M loto - " i - " - s :with"

-I shk (se) slo o sl

(F) ko 60 65 i Body ru 2 « | Shh-shh- povi o. them | r of moisture "from and to "1 in I st ooo sy TS mch n | - o o X tort a o zo y | - yu «t. chiral and her and we Y -- r sh- | g tu -

HER

« - s z -I shk (Se) sya 0 sl

F) at 65 o 4 mol of Id; cv) seam with, log "

I S vi peso s - i nok S / oliolo «a | tu - Her c) o logo s a se oyu dl yus F g sy - t mts v. « - s z -I shk so s 50 sl (F) yuyu bo 65 still veoshanya

And about y ut o « y lo opola « y Y

Tao s rt o Fi o vodivo o yu bo chirol ovyu helmet AY KY F oo ch - n m « shi s z -I shk (Se) si sl

F) why 65

61 chiral F meo mno MN ІІ ko and ІІ so o "І n "a chiral o on 76 med te sm o "A

M in chiral o on " Meo mno MN Zh S t s o o. o "and their va | Her mno Ame pvovnonae n vch o 65 o

Fo and o yu do not hang Fo o o s her in "shi s"; -I shk (Se) with 50 sl

F) ko bo b5

66 chirolny g and zhm ak ; 5, ot «4 7 mrolny g 70 And another 1. - 55) p odno « 68000 chiral vo - Su» is and lodge AKA ds g o (o) z vo voi y sh ly a F lo K a p o "

Her father

She; tor and z" « Y 7 | yutos (Te; x s " | o Ah so inside, and o

Oye es, 6o " tallow" b5 "

she chu ish bod « 78 chirolny! a b 1 same A what, iy s I « iv 7 valnyy -i

But at the same time "1 about zr with from what about

WITH

4 borders Y yuyu b palm and «i F - и- « - s z -I shk te s 50 (p

F) about 65 el zuhrt sly. i me nor F sho "A 70 ra g m cher sv

She

15 x V. I work. dy and mkl "Zhk z yu KO 25 is Y . (5) pcs AI

T tuyu oto and i chiral a" Ge) shlojzh ANA, - 9 th st u « - s z -I shk (se) so sl (F) ko 60 65 y g uho i shk Z r: shrshschya S 70 her ? Ц Фасно, УОН плен кож MK p ІІ st 9 chirolny vas syu in aigo o 7 zhirolny va. water vn o

Y " IS c) chiral and

ANA F water -

And I non. - o oti « t s z -I -y ge; c 50 sl (F) o) 60 b5 your chiral and I; water Ho as 99 chiral g zano 70 and also Al, in nm g sl SU

Yu1o00 chiral chisel is t nia o dopgoe sch , I o very i « she oyu mno m Y (o) s soya - shi yi- « - s z -I r h (se) s 50 sl (F) ko 60 65 t I s cho os y a got that chiral t 4 net o v, v ey ot what

Bob

Shhhh X how

To no zovche ovo oz sh y lo vro"

And Yaru about that

Te AH o o z rr zo m. IS o) ru o IS o) bo A b» aka - ich- « - s z -I shk

Te c 50 sl (F) o bo b5

- it is about s in zzsch o Fo KA schu 9 t Y on

U shcha "gave sh so" pa oboz and st! what about (4 oouz vv shchi

HSK yu » so her what F garden what - what o I I eat- ysh I « - s z -I (Se) s 50 slo o ko 60 65 ke vozoz ned che "I bolu vv Y 7 zorId, y so zho o o Czech tire

Lu no And her tj her with what, IY Styer" m shcha " still solo with sh 45 m I yah od. (9) by A | In Y m m od. 60 t-o at 65 ate at 5 ie same yur h

F AH in Ld p g - E at 7o or with Uh. thank you "and 1 owe her o | ko (22) kt -

Y i- « shi s z - shk se) slo sl (F) ime) bo b5 r ; o choir and 0 youth against evil

UT X and Uh o - full of that o

And what I hear then "1 J F

M | che i- « shi s z -1 shk (Se) sl 20 sl (F) ko 60 b5 du dge pogoni i to Ku

Wow she is a chess player

Vr A sch ' o logo

TD. yu zo pom no A oyu g A F

There is І и че " я ишо о ув « 2 v 2 s 138 0 chiral and

I" "7 va po ih -i t iy o pivna s 20 le m ia 00 MADAME (F) J o io go vo o o i botto 65

" S sht Her Do ba totto "s ch ovche o y TO : yoob , AKA s y

S Zh me wa sch o 145 ( | | y

X MAO Fr

In SL vosch F ve - ( Y -

Y o Ho « 2 more d. she oe she oo - d som iya to

H yak pad, t o Ma ko za n

ХХ Fe kl, because i nik nn s still 65

10 g o AKA o

Y o Zh ma 151 M. o sha TO i r 152 U

Yi S. om, p

Y MN MN t "I o sh » s o 153 M. yu oo y o ROOF. os o

GO, F o o; h: m- « - s z -I shk (se) sia 0 sl (F) ko 6o 65

154 M. oh

H S t o

Y is niyu y i A m 155 M and KAH nm, ovva is s A zh ra 156 M.

AND

"OKA nm. o

I Mn MN yo s Ж s voi o 151 chiral С) и их и- M. o yu shob bo 2 -x Ж (o) her - im « - s z -I shk (se) s 20 sl

F) ko bo b5

158 chiral sho flo M. o

A, 159 chiral 70 She a 4 plural nk I ne I Io o «i

M in o on

KK

In nm. НМ about and ОМе

We are

Another 9 sh-. in y We se r. o « | OMe at 52 Chirolny m

IC c)

N o

n)

KO t u a Me. p still ch- u « t s z -i -y se) s 50 sl

F) ime) bo b5 shchi NM. oh, and I | a: o -" "Ky 164 | N. H. F. MN in she o sh ho « 165 o duti « "and chiral S. 7 va t oo o "i

M chiral S. o z 1 mno MV m Mo o ' v i iv) 168 chiral MN i ii sh ap: obi - o "An M y " 7 s g" -I shk se) sl 50 sl

F) name) because b5

159 chiral RO i p: o i, still "ii chiral - chno r vo 7170 bo ek her chiral shh s Ko o mo AMN chi iy

M

175. chiral dream of Zo S,

Mn Gei h 173 chirolny cm

Her High School. many nn. "KK Fr

Zh ay 114 Chirolny st

Ye vi o r «AK, yu o

M (22) 115 chiral so ch o i r g M. on kA KK - s . and? -i -y se) c 50 sl ime) bo b5

176 chirolnyi - inlo i t t o to to nm 17 M

And: no

Iii 1 C, Fr. vya "Ku! | no

M

118 M n n o 1 X, o. M. M.

TT and n y

M

179 chiral

ON o vl Kh

TT etc

M ' 1vo chirolny

He

And many MN A oivshosh

Her village

M; o 181 chiral tk Mn o, uk; II a: o - o I c)

She "Me it) zva SM (o) g I o. mno vm I S h , Fi I oi si 2 i -

SHEU N st.

In voi RAV « s sha le - s 184 chiral ns im o: Ischo; and about? vobi in Mi Sm 15 stv chiral

N Mi o, -I s g

M o shk o o (Se) shchi . "Me sl 50 186 s s o che A "A sl o se 187 yus o

N

52 and many NM A HA

T Mn o

F) in, 9 oh ki. ime) but y y y y - I

In the table above, some compounds are presented as salts. It should be understood that the present invention encompasses all forms of the above compound and not only the salt.

When the stereochemistry is not specifically stated, the compounds of the present invention may contain one or more asymmetric carbon atoms and, therefore, may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. All such isomeric forms of these compounds are naturally encompassed by the present invention unless otherwise indicated. Each stereogenic carbon can have a K or 5 configuration.

Combinations of substitutions and variables contemplated by this invention are only those that result in the formation of stable compounds. The term "stable" as used herein refers to a compound characterized by stability sufficient to ensure manufacture and storage in integrity for a sufficiently long time to be used for the purposes specified herein (eg, therapeutic or prophylactic administration to a mammal or for use in affinity chromatography ). Typically, such compounds are stable at 40°C or below in the absence of moisture or other chemically aggressive conditions for at least one week.

Compounds of the present invention, as defined herein, include pharmaceutically acceptable derivatives or prodrugs. "Pharmaceutically acceptable derivatives or prodrugs" means any acceptable salt, ester, ether salt, or 70 other derivative of a compound of the present invention which, when administered to a recipient, is capable of providing (directly or indirectly) a compound of the present invention. Particularly preferred derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., promote the absorption of an orally administered compound into the bloodstream), or improve the delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system). . Preferred prodrugs include derivatives in which a group, /5, which enhances water solubility or active transport across the intestinal membrane, is added to the structure of the compound of the present invention.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor 20 sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptansate, hexanosate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, lropionate, succinate, tartrate, thiocyanate, tosylate and undecanoate Basic salts include ammonium salts, alkali metal salts such as sodium and potassium salts, rare earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexamine salts, M-methyl-O-glucamine, and with amino acids such as agrinine, lysine, etc. (8)

In addition, basic nitrogen-containing groups can be quaternized with such substances as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long-chain halides, such as decyl, lauryl, myristyl, and stearyl sulfates, bromides, and iodides, aralkyl halides, such as benzyl and phenethyl bromides, and others. In this way, water- or oil-soluble products or dispersible products are obtained. i am

The compounds of this invention can be synthesized by conventional methods. their advantage is that readily available starting materials are used for synthesis. More specifically, the compounds of the present invention can be synthesized according to the schemes set forth in Examples 1 and 2, with modifications that will be apparent to those skilled in the art. uh-

The compounds of the present invention can be modified by adding appropriate functional groups that enhance the desired biological properties. Such modifications are known in the art and include those that improve biopenetration to a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility for administration by injection, change metabolism and rate excretions The new compounds of the present invention are excellent ligands for IMFDH. Accordingly, these compounds are capable of finding and inhibiting the IMFDH enzyme. Inhibition can be assessed in a variety of ways, including, for example, tests; HPLC on IMF dehydrogenase (determine the enzymatic production of CMF and NADH from IMF and NAD) and spectrophotometric analyzes on IMF dehydrogenase (determine the enzymatic production of NDCG from NAD).

See S. Mopiego ei a/!., Siipisa Spitisa Asia, 238, pp. 169-178 (1995)). -I Compositions according to the present invention contain a compound according to the present invention or its salt; an additional substance selected from an immunosuppressant, an anticancer drug, an antiviral drug, an anti-inflammatory drug, an antifungal drug, an antibiotic, or an antihyperproliferative vascular drug; and any

Ge) a pharmaceutically acceptable carrier, adjuvant or solvent. Other compositions according to the present invention contain the compound 5o according to the present invention or a salt thereof, as well as a pharmaceutically acceptable carrier, adjuvant or solvent. Such a composition may optionally contain an additional substance selected from an immunosuppressant, an anticancer drug, an antiviral drug, an anti-inflammatory drug, an antifungal drug, an antibiotic, or an antihyperproliferative vascular drug. Preferably, the compositions of the present invention are pharmaceutical compositions.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient with a compound of the present invention and that does not destroy its pharmacological activity and is (F) non-toxic when administered in doses sufficient to deliver a therapeutically effective amount of such a compound. Pharmaceutically acceptable carriers, adjuvants, and solvents that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange materials, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDFs), such as do-tocopherol, polyethylene glycol 1000, succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbitol acid, potassium sorbitol, partial glyceride, mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, 65 sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, base materials cellulose, polyethylene glycol, sodium salt of carboxymethyl cellulose,

polyacrylates, various types of wax, polymers of the polyethylene-polyoxypropylene block, polyethylene glycol and lanolin. Cyclodextrins, such as o, p- and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-VD-diclodextrins, or other solubilized derivatives may also be usefully used to enhance the delivery of the compounds herein an invention

The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, or via an implantable container. We prefer oral administration or injection. Pharmaceutical compositions according to the present invention may contain any conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants 70 or solvents. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulation or its delivery system. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion methods.

Pharmaceutical compositions can be in the form of a sterile preparation for injections, for example, in the form of a sterile aqueous or oily suspension for injections. Such a suspension may be prepared by methods known in the art using suitable dispersing or wetting agents (such as, for example,

Tween 80) and means for suspension. The sterile injection may also be a sterile solution or suspension for injection in a non-toxic, parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable diluents and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils are widely used as a solvent or suspending medium. Any pure fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are also used in the preparation of injectable HA preparations, as are natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. Such oily solutions or suspensions may also contain an alcoholic diluent and) or a long-chain dispersant such as those described in Ripagtasoreia Neimelliis, RI. German, or similar alcohol, or carboxymethyl cellulose, or similar dispersants, which are widely used in the preparation of pharmaceutically acceptable dosage forms such as emulsions and/or suspensions. Other commonly used surfactants, such as Tweens or Spans, and/or other similar emulsifiers or bioavailability enhancers that are widely used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for dosage form purposes. Ge")

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricating components such as magnesium stearate are also typically added. For oral administration in the form of a capsule, the diluents used include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase and combined with emulsifiers and/or suspending agents. If desired, certain sweeteners and/or flavors and/or colors may be added. Pharmaceutical compositions according to the present invention can also be administered in the form of suppositories for rectal use. Such compositions may be prepared by mixing a compound of the present invention with a suitable "" non-irritating excipient which is solid at room temperature but liquid at rectal temperature, and therefore will melt in the rectum to release the active ingredients. Such materials include, but are not limited to them, cocoa butter, beeswax and polyethylene glycols. -I Topical administration of the compositions according to the present invention is particularly desirable when the areas or organs to be treated are to be -3z easily accessible for topical application. For topical application to the skin, the pharmaceutical composition must be prepared in the form of an ointment containing the active ingredients suspended or (Ce) dissolved in a carrier.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum jelly, medical petroleum jelly, propylene glycol, polyoxyethylene polyoxypropylene and compound , emulsifying wax and water.Alternatively, the pharmaceutical composition may be It is prepared in the form of drops of lotion or cream containing an active compound suspended or dissolved in a carrier using appropriate emulsifiers. Suitable carriers include, but are not limited to, mineral oil, sorbitol monostearate, polysorbate 60, cetyl ethers, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Pharmaceutical

The compositions of the present invention may also be applied topically to the lower intestinal tract using a suppository or enema. Topical transdermal patches are also covered by this i) invention. ime) The pharmaceutical compositions according to the present invention can also be administered in the form of a nasal spray or inhalation. Such compositions are prepared in accordance with methods well known in the field of production of dosage forms, in the form of solutions in physiological saline, using benzyl alcohol or other acceptable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and/or other agents for solubilization or dispersion, known in the industry.

Dosage levels between about 0.01 and about 1000 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day, of the IMFDH inhibiting compounds described herein can be used as monotherapy and/or complex therapy for the prevention and treatment of IMFDH-mediated disease. Typically, the pharmaceutical compositions of the present invention will be administered from about 1 to about 5 times per day or, alternatively, as a continuous infusion. Such administration may be used as therapy for chronic or acute disease. . The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the person being treated and the particular route of administration. A typical preparation will contain from about 595 to about 9595 of active compound (IV) Preferably, such preparations contain from about 2095 to about 805 of the active compound.

When the compositions of the present invention contain a combination of an IMPDH inhibitor of the present invention and one or more additional therapeutic or prophylactic agents, the IMPDH inhibitor and the additional agent should be present at dosage levels of from about 10 to 10095, and preferably from about 10 to 8095 of that dose , which is usually administered as monotherapy. Such additional agents may be administered separately from the compounds of the present invention as part of a multidrug regimen. Alternatively, such agents may be part of a single dosage form mixed with the compounds of the present invention in a single composition.

According to one embodiment, the pharmaceutical compositions of the present invention contain an additional component for immunosuppression. Examples of such additional immunosuppressants include, but are not limited to, cyclosporine A,

EC5BOb, rapamycin, leflunomide, de-oxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKTZ, ATAb, interferon and mizoribine.

According to another embodiment, the pharmaceutical compositions according to the present invention may additionally contain an anti-cancer component. Examples of such anticancer components include, but are not limited to, cisplatin, actinomycin O, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipazid, 20 taxol, colchocine, cyclosporin A, phenothiazines, interferon, and thioxanthers.

According to another embodiment, the pharmaceutical compositions of the present invention may additionally contain an antiviral component. Examples of such antivirus components include, but are not limited to,

Cytoven, Ganciclovir, trisodium phosphonoformate, Ribavirin, 44T, yes, AT and acyclovir.

According to yet another embodiment, the pharmaceutical compositions according to the present invention may additionally contain an anti-hyperproliferative vascular component. Examples of such anti-proliferative vascular components include, but are not limited to, NMO, Co-B, reductase inhibitors such as lovastatin, thromboxane Ag, (8) synthetase inhibitors, eicosapentaenoic acid, cyprostene, trapidyl, BCHE inhibitors, low molecular weight heparin , mycophenolic acid, rapamycin and 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate.

After the patient's condition improves, if necessary, a maintenance dose of a compound, composition, or combination of the present invention may be administered. Over time, the dose or frequency of administration, or both, can be reduced as a function of symptoms to a level where the improved condition is maintained. When the symptoms have all eased to the desired level, the treatment should be stopped. Gee!

Patients may, however, require treatment from time to time on a long-term basis if symptoms return. --

As will be appreciated by one skilled in the art, doses lower or higher than those given herein may be required. The specific dose and treatment regimen for a given patient will depend on many factors, including the activity of the compound being used, age, body weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, severity and course of the disease , the patient's attitude to the disease and the judgment of the treating physician. "

In another embodiment, the present invention relates to methods of treatment or prevention of IMFDH-mediated disease in a mammal, which involve the step of administering to said mammal any of the compositions or combinations described above. If the pharmaceutical composition as an active component contains only an IMPDH inhibitor according to;" according to the present invention, such methods may additionally include the step of administering to said mammal a drug selected from the following series: an anti-inflammatory drug, an immunosuppressant, an anti-cancer drug, an antiviral drug, or an anti-hyperproliferative vascular drug. Such an additional drug may be administered to the mammal before, simultaneously with, or after the administration of the IMPDH-inhibiting composition.

In their best embodiment, these methods are used to inhibit the immune response in a mammal. They are used to treat or prevent diseases, including transplant rejection (for example,

Ge) kidneys, liver, heart, lungs, pancreas (islet cells), bone marrow, cornea, thin 5th cat, as well as skin allografts and xenografts of heart valves), "graft against host" disease, as well as autoimmune diseases - rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), lupus, diabetes, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pneumonia, eye uveitis, hepatitis, Grave's disease, thyroiditis Hashimoto's, Behçet's or Sjogren's syndrome (dry eyes/mouth), malignant or immunohemolytic anemia, idiomatic adrenal insufficiency, polyglandular autoimmune syndrome, glomerulonephritis, scleroderma, lichen planus, vitiligo (skin depigmentation), autoimmune thyroiditis and alveolitis.

F) These methods involve the step of administering to a mammal a composition containing a compound of the present invention and a pharmaceutically acceptable adjuvant. In the best embodiment, such a specific method includes an additional step of administering to the specified mammal a composition containing an additional immunosuppressant and a pharmaceutically acceptable adjuvant.

Alternatively, such a method may include the step of administering to a mammal a composition containing a compound of the present invention, an additional immunosuppressant and a pharmaceutically acceptable adjuvant.

In another preferred embodiment, such methods are used to inhibit virus replication in mammals. They are used for the treatment or prevention of diseases caused by the replication of viral DNA and RNA, which are caused by infection, for example, orthomyxoviruses (influenza viruses of types A and B), paramyxoviruses (respiratory syncytial virus (K5M)), subacute sclerosing panencephalitis virus (SORE ), bark,

parainfluenza type Z, herpesviruses (NBM-1, NeM-2, NNM-6, NNM-7, NNM-8), Epstein-Barr virus (EBV), cytomegalovirus (NSMU), varicella viruses (MAMU), retroviruses (NIM -1, NIM-2, NTIM-1, NTIM-2), flaviviruses and pestiviruses (yellow fever virus (YFV), hepatitis C virus (HCV), tropical fever virus, bovine viral diarrhea virus (BVDV), hepatotrophic viruses (hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis Y virus (HOM), hepatitis E virus (HEM), hepatitis C virus (HOM)), Crimean-Congolese hemorrhagic fever virus (CHF), bunyaviruses (virus Punta Toro virus, Reef Valley fever virus and Sicilian fever virus), Napiaap virus, Sagaraga virus, human papilloma viruses, encephalitis viruses (Ga Sgovze virus), sand viruses (dipip 5 Tasagibe virus), re-ovirus, vesicular stomatitis virus, /o rhinoviruses, enteroviruses (poliomyelitis virus, coxsackieviruses, encephalomyocarditis virus), Lassa fever virus, togaviruses (forest virus we bBipariz 5: Zetiike), varicella viruses (cowpox virus), adenoviruses, rubella.

These methods involve the step of administering to a mammal a composition containing a compound of the present invention and a pharmaceutically acceptable adjuvant. In the best embodiment, such a specific method includes the additional step /5 of administering to the indicated mammal a composition containing an additional antiviral drug and a pharmaceutically acceptable adjuvant.

Alternatively, such a method may include the step of administering to a mammal a composition containing a compound of the present invention, an additional antiviral drug and a pharmaceutically acceptable adjuvant.

In yet another preferred embodiment, such methods are used to inhibit vascular cell proliferation in mammals. They are used to treat or prevent diseases, including restenosis, stenosis, atherosclerosis or other hyperproliferative vascular diseases.

These methods involve the step of administering to a mammal a composition containing a compound of the present invention and a pharmaceutically acceptable adjuvant. In the best embodiment, such a specific method includes additional ethane administration to the indicated mammal of a composition containing an additional anti-hyperproliferative vascular drug and a pharmaceutically acceptable adjuvant.

As an option, this method may include the step of administering to a mammal a composition containing a compound according to this i) invention, an additional anti-hyperproliferative vascular drug and a pharmaceutically acceptable adjuvant.

In yet another preferred embodiment, such methods are for the inhibition of tumors and cancer in mammals. They are used for the treatment or prevention of diseases, including tumors and malignant neoplasms, such as lymphoma, leukemia and other forms of cancer.

These methods involve the step of administering to a mammal a composition containing a compound according to the present invention and a pharmaceutically acceptable adjuvant. In a preferred embodiment, such a specific method includes an additional step b of administering to the specified mammal a composition containing an additional antitumor or anticancer drug and a pharmaceutically acceptable adjuvant. --

Alternatively, such a method may include the step of administering to a mammal a composition containing a compound of the present invention, an additional antitumor or anticancer drug and a pharmaceutically acceptable adjuvant.

In yet another preferred embodiment, such methods are used to inhibit inflammation and inflammatory diseases in mammals. They are used to treat or prevent diseases including osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, and respiratory distress syndrome in adults. "

These methods involve the step of administering to a mammal a composition containing a compound of the present invention and a pharmaceutically acceptable adjuvant. In a preferred embodiment, such a specific method includes an additional step of administering to the specified mammal a composition containing an anti-inflammatory drug and a pharmaceutically acceptable adjuvant.

In order for this invention to be more fully understood, specific examples of its implementation are given below. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

Example 1 - Synthesis of compound 41

Ge) A. Synthesis of C4 with 50 ro sl (dsorvNS si

To a solution of glacial acetic acid (4 bml), acetic anhydride (4 bml, 485 mmol) and 2-methyl-5-nitroanisole (10.0 g, bOmmol) at 0"C, concentrated NOSO (6 b, 9 ml) was added dropwise. After the addition was complete , portions

GF) during boOkhv. added SgOz. After additional shaking for 15 min. at 0"C, the reaction mixture 7 was poured onto ice. The precipitate obtained was separated by filtration and washed with cold water. Purification by means of thin-layer chromatography and elution with a gradient of 15-5095 EtOAc in hexanes gave 8.14 g (2495, 5196 based on the reduced starting material) C1 in the form of a white solid mass." IN NMR showed the correspondence of the obtained structure to the desired one. meow | /MO2 b5 c2

A shaken suspension of C1 (81.94g, 307mmol) in dioxane (100ml) was treated with concentrated HCl (20ml) and heated under an irrigation condenser overnight. After cooling to ambient temperature, product C2 was precipitated as a light yellow crystalline solid with a yield of 40.65 g (73.190).

The filtrate was concentrated to a volume of about 80 ml, and after the addition of hexanes, a second portion of the crystalline product was obtained (8.91 g, 16.095). Both portions were identical according to the results of "H NMR and TLC, their structure corresponded to the desired. The total yield of C2 was 49.56 g (89.1965). meo MO 70 o and 29) sz

A solution of C2 (456 mg, 2.51 mmol), tosylmethyl isocyanide (490 mg, 2.51 mmol) and K.CO3 (347 mg, 251 mmol) was dissolved in methyl alcohol and heated under an irrigation condenser for 1.5 hours. The resulting mixture was concentrated under vacuum, redissolved in CHCl, washed with water and brine, dried over NaCl, and concentrated again under vacuum. The purified product SZ was obtained by recrystallization (Eb2O/hexanes) in the amount of 375 mg (6895). "H NMR showed the correspondence of the obtained structure to the desired one.

Mmeo Mne «i

M si s

A solution of SZ (4.214g, 191mmol) in EtOAc (150ml) was treated with 1095 Pa/sC (1.05g, 2595 v/v of SZ) and held (5) under 40 psig (2.7atm) of hydrogen (apparatus Parra for hydrogenation) during the night.

The reaction mixture was filtered and concentrated under vacuum. The pure product C4 was obtained by thin-layer chromatography and elution with a gradient of 30-4096 EOAc in hexanes in the amount of 3.4 g (9395). "H NMR showed the correspondence of the obtained structure to the desired one. is)

V. Synthesis of compound 1113 yu o ny ra ra F

Mod; - in -

A solution of 3-aminobenzylamine (82bmg, 6b, 87mmol) and triethylamine (2.3Oml, 17.18mmol) was treated with di-i-butyldicarbonate (1.50g, 6.87mmol) and the mixture was shaken at ambient temperature for 2 hours. Then the reaction mixture was diluted with СНоСи», washed with ManСОО» (aqueous), water and brine, dried (МаСОСО)) and concentrated under vacuum. Pure E1Y was obtained using thin-layer chromatography and elution with a gradient of 2595 EOAc in hexanes in the amount of 200 mg (46965). "H NMR showed the correspondence of the obtained structure with the desired one. "» n |; o r ; sho hi Ya zhu n - s - (1113)

Ge) TNE (5 ml) was added to a solution of C4 (150 mg, 0.789 mmol) and 1,1-dicarbonyl-imidazole (160 mg, 0.98 mmol) and the mixture was shaken for hours at ambient temperature. Eil (351 mg, 11.58 mmol) and M,M-dimethylaminopyridine (97 mg, 0.789 mg, 19 mmol) were added to the imidazole precipitate, and the resulting mixture was heated overnight under an irrigation condenser. The obtained homogeneous solution was cooled to ambient temperature, diluted with EtOAc (20 ml), washed with KN; (aqueous), water and brine, dried (MazOH) and concentrated. Pure 1113 was obtained by thin-layer chromatography and elution with a gradient of two 20-30-357o acetone in hexanes in the amount of 164mg (4795). "H NMR (500 MHz, 4a5-0M50) 5 8.90 (c), 8.75 (c), 8.38 (8), 7.60 (9), 7.51 (c), 7.3- 7.46 (t), o 7.21-7.27 (9, 7.05 (ad), 6.87 (4), 4.12 (a), 3.93 (8), 1.44 ( (c). K, 0.21 (5965 Meon/СНСИ»). име) S. Synthesis of compound 1168 , nn bo | prlrutech

I

(1168) 65 A suspension of 1113 (25Omg, 5.7bmmol) in HNSCC (ml) was treated by adding several equivalents of trifluoroacetic acid dropwise at ambient temperature and shaking for 90 minutes. The resulting solution was drained under vacuum and titrated with СНоСиИ» and methyl alcohol. The pure product I168 was separated by filtration in the amount of 258 mg (9996). "H NMR showed the correspondence of the obtained structure to the desired one. Synthesis of compound 41

To a solution of 1-methoxy-2-propanol (75 mg, 832 μmol) in TNE (1.00 mL) at room temperature was added solid 1,1"-carbonyldiimidazole (121 mg, 749 μmol) in one portion. The resulting mixture was shaken at room temperature overnight , followed by sequential treatment with TEA (174 μl, 1.25 mmol), solid compound 1168 (37 bmg, 832 μmol), and OME (1.0 mL). The resulting solution was shaken at room temperature for a day, then diluted with ethyl acetate, washed sequentially with water and brine, and dried over 70 MgSO4, filtered and concentrated in vacuo. The crude product was then purified by thin layer chromatography (silica gel, 97.5/1.5 SNCI). The resulting product was triturated with a 9/1 mixture of ethyl ether and ethyl acetate to afford compound 41 (bb5mg, 56905 yield) in the form of a white powdery mass. "H NMR (500 MHz, acetone-dv): 8.34 (in, 1H); 8.21 (from, 1H); 8.12 (c, 1H); 7.67 (in, 1H); 7.65 (aa, 1H); 7.50 (a, 1); 7.47 (9, 1H); 7.43 (c, 1); 7.25 (ad, tn); 7,10 (aa, yin); 6.97 (a, 1n); 6.68 (t, 1H); 4.92 (t, 75.1H); 4.32 (y, 2H); 4.01 (in, ZN); 3.43 (aa, 1H), 3.33 (aa, 1H); 3.31 (in, ZN); 1.18 (4, ZN).

Other compounds according to this invention can be obtained in a similar way by replacing the corresponding alcohol with 1-methoxy-2-propanol (ie HO-CH(K.)) in step C.

Example 2

Preparation of compound 169

A. Preparation of the left binding intermediate (Co - cyano): in nwagon.

AND THESE s schi voi - VvOsosuMansoya in even X h o) "o kn EYUDAS/H2O/AT -0 th

I, M

Copper cyanide (I) (7.2g, 80.mmol) was combined with 2-bromo-5-nitroanisole (I) (15g, 64.mmol) in MMR (70ml) at 0°C and heated to 15073 overnight in nitrogen atmosphere. The mixture was treated with celite, cooled to room temperature, after which diluted ЕюдАс and 1.0M Masson and shaken for 15 minutes. The heterogeneous mixture was filtered through a pad of celite using E(OAc), the phases were separated, and the aqueous phase was washed three times with EtOAc. The combined organics were washed successively with 1.0 M NaCl, water, and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo The crude product was dissolved in CHCl, filtered through a thin layer of 77 silica gel to remove solids and most of the colored impurities, then concentrated in vacuo to afford II (10.41g, 90905) as a brownish-orange solid.

TN NMR (500 MHz, SOSI»v): 7.90 (4, 1H); 7.84 (in, 1H); 7.77 (a, 1H); 4, 07 (in, ZN).

To a solution of II (7.2 g, 40.4 mmol) in EUDAsS-EUN (220-15 ml) at room temperature was added 1095 Ra/С « (1.8 g), obtaining a heterogeneous black mixture. The reaction mixture was pressurized to 1 atmosphere of hydrogen (balloon), 470 was heated to 502 and shaken overnight. After that, the reaction mixture was cooled to room - s temperature, the catalyst was removed by filtration, the filtrate was concentrated in a vacuum to obtain a Sh (5.56 g, 931) in the form of a crystalline solid mass. n T"H NMR (500 MHz, SOSI"v): 7.29 (d, 1H); 6.22 (9, 1H); 6.17 (z, 1H); 4.20 (broad z, 2H); 3.85 (in, ZN).

At room temperature, to a biphasic mixture of phenyl chloroformate (1.bml, 12.82mmol) in EtOAc (2Oml) and saturated MansSoO (-1M, 1bml) was added I (95Omg, 6.41mmol) in the form of a solution in EOAc (1Oml ) during a 10-minute period. The resulting heterogeneous mixture was shaken at room temperature for 30 minutes, after which the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered through a pad of silica gel with EOAc, and concentrated in vacuo to give a thick oil. The resulting oil was diluted in toluene (3 mL) and treated with hexanes (3 mL) to obtain a thick precipitate. This mixture was shaken for 30 s and 20 min, filtered, the solid phase was washed with toluene:'hexanes 1:1, then only with hexanes and dried to constant weight under high vacuum to obtain IM sl (1.65 g, 96905) as a white powder.

TN nMR (500 MHz, as-OM0): 10.76 (z, 1H); 7.69 (a, 1); 7.44 (a, 1); 7.40 (9, 1), 7.26 (t, ZN); 7.15 (d, 1Hn); 3.85 (in, ZN). 59 B. Preparation of the right connecting intermediate product (Co - Z-methyl):

GF) n o pts

In: m 60 57 vRTNKNIYU i yana tartrat i i ud z z m m we Y I ih b5

To a solution of M (200 g, 1.21 mol) in EUN (2 L) at room temperature, Mavn (50.3 g, 1.33 mol) was added in portions over 30 minutes, making sure that the internal temperature did not rise above 40"С .

The reaction mixture was shaken at room temperature for 4 hours. Then it was quenched with water (-1O00Oml), concentrated under vacuum, diluted with E(Ac, washed twice with water, then once with a saturated solution

Mansoz, dried over M950, filtered and concentrated in vacuo to afford MI (191.7g, 9595) as a yellowish powder.

TN nMR (500 MHz, SOSIv): 8.21 (in, 1H); 8.09 (4, yin); 7.70 (a, 1); 7.49 (yes, 1H); 5.01 (yes, tn), 2.45 (5, 1H); 1.52 (y, ZN).

To a solution of MI (181g, 1.08mol) at room temperature was added ORPA (250ml, 1.1bmol) slowly enough to keep the temperature of the reaction mixture below 4570.

After completion of the ORPA addition, the mixture was treated with OVO (177 mL, 1.18 mol) slowly enough to keep the temperature of the reaction mixture below 45°C. After the addition was complete, the reaction mixture was heated to 60°C and maintained at this temperature overnight. The resulting biphasic mixture was cooled to room temperature, washed successively with water, then 0.5 M of it. The organic phase 75 was dried over NaCl5O, filtered and concentrated in vacuo to give a yellow-green oil which was not further purified.

T"H NMR (500 MHz, SOSI"): 8.21 (z, 1H); 8.18 (a, 1H); 7.68 (a, 1H); 7.56 (d, 1H); 4, 76 (aa, 1Н), 1.59 (а, ЗН).

To the MI solution! (8.17g, 42.51mmol) in TNE-water (8VOml-1Oml) at room temperature was added RPzR (12.3Hg, 46.7bmmol) in TNE (20ml) over a 10-minute period. Nitrogen began to evolve immediately and continued to evolve at 20 throughout the addition. The reaction mixture was heated to 657C overnight, then cooled to room temperature. The crude mixture was concentrated under vacuum, diluted with EtOAc, washed with brine, dried over M2O, and filtered. The resulting filtrate was treated with 1M HCl/EC2O at room temperature for minutes, resulting in the formation of a precipitate. The mixture was shaken at room temperature for 15 minutes, then filtered. The solid phase was washed with EBO to give a yellow powder. The crude amine hydrochloride "M" salt was suspended in brine/EUDAs and treated with 10M Mahon (bml, 5 mmol) at room temperature.

The resulting mixture was shaken at room temperature until the solid phase was completely dissolved. The phases were separated, the aqueous phase was washed twice with EAs, the combined organic phase was washed with brine, dried over M2O, filtered and concentrated under vacuum. The crude amine was diluted in Meon (50ml) and added to a solution of -()-tartaric acid (5.33g, 35.333mmol) in MeonH (450ml) while heating under an irrigation condenser. The precipitate, M) that formed immediately, was dissolved in the MeonH mixture after heating under an irrigation condenser for 15 minutes. The internal temperature was lowered to 50"C and maintained at this level throughout the night.

The internal temperature was then lowered to 302 and maintained at this level for another 24 hours, after which (o) it was kept at room temperature for 24 hours. The obtained crystals (spike-like) were filtered off, washed with Meon and EBSO, and the mother liquor was poured off. The resulting crystals were dissolved in 200 ml of Meon under

With an irrigation condenser, it was slowly cooled as described above, filtered and washed with MeOH, and then EPO to give the first yield of MI! (2.21g, 2095) as a white solid The mother liquor was concentrated in vacuo, the solid was dissolved in 10 mL Meon under an irrigation condenser, cooled slowly as described above, filtered and washed with Meon and then ESH2O to give a second yield "

MI (1.50 g, 1395) in the form of a white solid mass. The optical purity was determined on the corresponding phenyl carbamate, and for both outputs it was 29795. - s Enantiomeric excesses were determined using a SpPigaise column! OO (0.4bsmx25cm) of Odaise "» Spetis! Ipaivigiez, purchased from Spiga! Tesppoiodiez. As a mobile phase, a mixture of "hexane and IRA 70:30 was used in an isocratic run for up to 65 minutes at a flow rate of 0.vml/min., injection volumes

3-4 μl of a solution of 1-2 mg/ml phenyl carbamate in the specified mixture of hexane and IRA. The desired 5-methyl enantiomer eluted first at 47.2 minutes, while the undesired K-methyl enantiomer eluted at 551.7 minutes; - control was carried out at a wavelength of 214, 254 and 280 nm. - All samples were analyzed on a Neulekk RasKaga high-performance liquid chromatography column

Zegiev 1050 NRI S with a photodiode detector. d) IM Mahon sl 20 (0.77 ml, 7.72 mmol) was added to a heterogeneous suspension of MI (1.11 g, 3.5 mmol) in EtOAc (20 ml) and brine (200 ml) at room temperature. The resulting mixture was shaken at room temperature until all salts were completely dissolved. The phases were then separated and the aqueous phase was washed with E(Ac). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum.

Crude nitro-benzylamine was diluted in 7M MNaz-Meon (20ml), 2095 RY(OH)"-C was added and pressurized to 45 psig (Zatm) of hydrogen for 5 hours. The resulting mixture was filtered to remove the catalyst, concentrated under vacuum, azeotroped once with CH»-Si», and then aged under

GF! high vacuum to give IX (455 mg, 95905) as a waxy white solid. NMR (500 MHz, as-0M50): 6.91 (aa, 1H); 6.56 (z, 1H); 6.50 (a, 1H); 6.38 (a, 1H); 4.90 (wide in, 2H); where 3.82 (a, 1H); 3.31 (wide in, 2H); 1.18 (4, ЗН).

S. Preparation of compound 169 60 b5 chok MN sh ;

There are up svoonoivyule no, breath panom in shk nom them on x and | And as I solved: x 70 To a solution of 3-(K)-hydroxypentanitrile (212 mg, 2.14 mmol) at room temperature was added CO (521 ml, 3.21 mmol) in one portion. The resulting mixture was shaken at room temperature for 1 hour, after which it was treated with solid silica gel. The heterogeneous mixture was vigorously shaken for 10 minutes, filtered through a thin layer of silica gel using EYUASIR 4:1, concentrated under vacuum, azeotroped twice

Mesm, then combined with IX (350mg, 2.57mmol) in Mesm (2ml) and shaken at room temperature during the day. The resulting mixture was diluted with EIAs, washed with water, then with brine, dried over sodium sulfate, filtered, concentrated and analyzed by thin-layer chromatography (silica gel, 1/2.1/3.0/1 hexanes/!EuAcC/EuAS/RA), to obtain X (472mg, 8490) as a clear thick oil.

TN nMR (5O00MHz, as-OM50): 7.73 (9.1H); 6.94 (ad, 1H); 6.51 (in, 1H); 6.47 (4, 1); 6.38 (a, 1H); 4.98 (wide in, 2H); 4.67 (t, 1H), 4.49 (t, 1H); 2.82 (t, 2H); 1.62 (t, 2H); 1.27 (9, ZN); 0.89 (aa, zn).

IM (44Omg, 1.63mmol) was added to a solution of X (47Omg, 1.860mmol) in EtOAc (5ml) at room temperature and

TEA (0.23 ml, 1.63 mmol). The resulting mixture was heated under an irrigation condenser and shaken at this temperature for 6 hours. The resulting crude mixture was cooled to room temperature, diluted with E(OAc, washed with brine/1M HCl, then only with brine, dried over NaClO), filtered, concentrated under vacuum, and analyzed by thin-layer chromatography (silica gel, 1/1.1/ 2.1/3.1/4.0/1 Ha hexanes/EuAcC/EuAC/PA) to afford compound 169 (74 Ω, 10095) as a white foamy mass. NMR (500 MHz, as-OM50): 9.21 (c, 1H); 8.84 (z, 1H); 7.93 (4, 1); 7.59 (a, 1H); 7.51 (c, 1H); 7.41 (c, o 183; 7.29 (a, tn); 7.23 (aa, tn); 7.01 (a, 1n); 6.92 (y, 1H) ; 4.69 (t, 1H); 4.63 (t, 1H); 3.89 (v, ЗН); 2.82 (t, 2H); 2.62 (t, 2H); 1.31 ( y, ZN); 0.90 (y, ZN).

Example With IS o)

Assay for IMFDH inhibition activity

IMF dehydrogenase activity was evaluated after adapting the method first described by Magazanik |V. and

Madazapik ei ai., 9. Vioi. Spet., 226, p. 339 (1957), the disclosure of which is incorporated herein by reference). The activity (o) of the enzyme was determined spectrophotometrically, by monitoring the increase in absorbance at 34O0 nm due to the formation of NADH (7340 is 6220 M cm"). The reaction mixture contained 0.1 M potassium phosphate 8.0; 0.5 mM EOTA, 2 mM t

OT, 200 μM IMR and enzyme (human IMFDH type II) in a concentration of 15 to 100 nM. This solution was incubated at 377°C for 10 minutes. The reaction was initiated by adding NAD to a final concentration of 200 mM, and the initial value was measured by monitoring the linear increase in absorbance at 340 nm for 10 minutes.

For reading on a standard spectrophotometer (path length 1 cm), the final volume in the cuvette is 1.00 ml. This assay was also adapted to a 96-well microtiter plate format; in this case, the concentrations of all reagents remain the same, and the final volume is reduced to 200 μl. For the analysis of inhibitors, the compound in question is dissolved in HOM5O to a final concentration of 20 mM and added to the initial mixture to be analyzed for preliminary incubation with this enzyme in a final volume of 2-595 0/0. The reaction is started by adding NAD, and determinations are made as described above. Definition of K; done by measuring the initial rates in the presence of varying amounts of inhibitor and processing the data using Henderson's close coupling equations |Nepaegzop, R. .). R. (1972) Viospet. U. 127, 3211. - These results are shown in Table 2. Category "A" means that K; LONNM or less, category "B" means - that K; more than 10 and less than 5OnNM, category "C" means that K; is 5 ONM or more, "MO" means that no inhibitor of activity was determined. se) poh sl r wolf sounds | A vom ko, zv z (A yu A yav|mo ko, o ak A vv ko, v 151 5 mok, t v Av | A lyu vm, vo v A 51» Ame ko, v Av | A yus ko, byu | i A yav ko, bo 13 A bo A 107 p 154 Iv)

in A v yus vo i r voi v vo v Av | A lab I Av language about b» Av | And 6 St. with | yu A wl vo and I lk m | And I kov v v | yu A I slya with A vo | in» sv in 1 in voi 0 sv cm 5 in | And | vv | m sot o in A vo vo vo bu | I speak freely in and out in A volyu yu vo kyu | And the height is high And Ky in F in | I love lo - in square | how holy are you | i 1 in | A) whether and in) in c -

Other compounds of the present invention will also have IMFDH inhibitory activity.

Example 4 "

Cell samples 70 A. Isolation of peripheral blood mononuclear cells 8 s (PBMCs): Venous blood was taken from healthy volunteers using heparin as an anticoagulant. RBMS"5 with" were isolated from blood by centrifugation on a RisoI-radoe gradient or with CRT tubes (Vesiop-Oiskipzop) using standard conditions. RBMSOSz were collected, washed and resuspended in whole milk, counted and diluted to 1x105 cells/ml. | And | but - B. Samples for the proliferation of PBMC and splenocytes: 5x104 cells (in the case of PBMC F human cells) or 1x105 cells (in the case of PBMC B human cells) were added to - each well of a 9b-well plate. For the test on T cells, phytohemagglutinin (PNA) was added to a final concentration of 10-20 μg/ml per well. For the sample on B cells, staphylococcal protein A (RAB) was added to a final concentration of 2 μg/ml per well. 1 20 Serial 4-fold dilutions of the inhibitory material were made in complete KRMI and added to the cells in such a way that the final concentration of the compounds was in the range from 20mM to 2OHM, while OM5O was maintained at a final concentration of 0.11. After that, the cells were incubated for 3 days. All samples were tested three times.

Tritiated thymidine (0.4 cCi/well) was added during the last 24 hours of testing. Cells were collected on 5 Weilaria (e) filters and counted using a scintillation counter. The concentrations of compounds required to inhibit cell proliferation by 5095 (IC values 5o) / were calculated using the computer (F) program package bZoiMakh Rgotm (MoiIesshiag Oemisev).

GI The results of these tests are shown in Table 3. Category "A" means IC 59 10O0nNM or less, category "B" means IC5o greater than 100 but less than 1000OnNM, category "C" means IC o 1000nM or greater, "MO" because means that inhibitory activity was not determined in the indicated cell sample.

ISvo bo 1 v A 48 v v 95 Iv) Iv) 143 MO zv 18 51 v | in || m | kyu (many numbers 18 1у1601060097) мб ково мо мо 41761 618 в 0 в |в А 11 merkmo mo 5601 601 в00600106|5в00vmtko mo 518 | vv ko ho (lyu v1vmeko mo 71v 18 1myuo0 mom A 111 A lyu mo mo 81 v 1 v 55 Mo / mo 2 v/v lo) mo o vv |v 60 kovo vyko mo o byu v v 16015808) A 111AO v mo mo 36) vv vv |yu60 vovkom av 18180608) A 11A mo mo with v 1 v |v v / v tyu v/v to) o m 60) 86080 voy v011 Av ko mo i 51 v 17816818 59) v/v A A 660) 60168080 in (TV language 17616050) in 860) 60160 in 00 vom. |ko mo ev 17816006 6003) 60106006 mo mo 20 byu v/v 16801812) 60106006 vv yav | 616 in vom 6001060 А AC b» in vv 16988001 vp6) sb vv zhi 6176 161 6 pf v/v 06 v v cm 5 zhi v 1 v 172 v v me v/v | mou| about | o f) A | Av 60106 0yus1bvv vv yav |v vv» v v b» OA 16 11A1 A jav) 601060 v A and zo byu 6) v vv |v v vt; os yu iambic 088001 in w) c0106008 sv i in 17 19808) 01060 sv F zv | in A, he introduced the os - with 67178 18 v/v l»yu); в в 0л6 с с с вв | vv vvyus ko mo i z» 6017618 v vm) v/v mo mo z v 1 v |v v v v 02 v/v v) su s zv) v | вв ко 0 ho mob) вс « ю в вв 18606016) в/в А А З с бю) 6 | vv A Av mob biv yav 1778 180v800vzz6) mokovi vv

And" ah! in 1 in 18111 А 11 А z mo mo la вв в/в | voi vv |z vo0koozvv) in A mi v.178 196619) Mo hol mo mo - lived | вв во мо мо кози в А в вв 001980 x50 mb) yuyu 000 t lu v | Example 5 1 Antiviral tests Antiviral efficiency of compounds can be evaluated using different tests ip mygo and ip mimo.

For example, the compounds can be tested for viral replication using IP assays. Whole cells or cellular components can be used in IP myoassays. IP mimo tests involve simulation of viral diseases in animals. Examples of such models include, but are not limited to, infection models

NVM or NSMU in rodents, the Woodchuck model for NVM infection, and the chimpanzee model of NSM infection. (F. Although we have presented here a number of embodiments of the present invention, it should be apparent that our basic construction can be modified to provide other embodiments that utilize the methods of the present invention. Therefore, it should be noted that the scope of the present invention is to be defined by the appended claims, and not by the specific embodiments that have been given here as examples.

Claims (1)

The formula of the invention v5 1. Inhibitor of the enzyme IMFDG (inosine-5'-monophosphate dehydrogenase), represented by the compound of the formula (A): Н (А) still IR in the most АЖ 1 Н Н 70 in which: each of Ki. and Co are independently selected from hydrogen; -SEz; -(C4-Cv)-linear or branched alkyl; -(Co-Cv)-linear or branched alkenyl or alkynyl; -(С4-Св)-linear or branched alkyl-К»7; -КСо-Св)-linear or branched alkenyl or alkynyl|Y-K; or -K7; and in which at least one of K. and Co. is -КС.4-Св)-linear or branched alkylI|-К7; -КСо-Св)-linear or branched alkenyl or alkynyl|-K7 or K,; in which up to 4 hydrogen atoms in any of the mentioned alkyl, alkenyl or alkynyl are optionally and independently substituted by KU; and in which one or both of K and Co are optionally esterified to obtain prodrugs; or in which K and Co are alternatively taken together to form tetrahydrofuranyl, in which, when K»e is hydrogen, (K)-methyl, (K)-ethyl, or (K)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran is replaced by -OK 85 or -K, and in which, when K 5 is (5)-methyl, (5)ethyl or (5)-hydroxymethyl, one hydrogen atom in said tetrahydrofuran is optionally replaced by -OK in or -K7; in which, when K»e is hydrogen, (K)-methyl, (K)-ethyl or (K)-hydroxymethyl and each of K and K is independently hydrogen, unsubstituted -(C4-C8)-linear or branched alkyl or unsubstituted -(Со-Св)-linear or branched alkenyl or alkynyl, then the part of this compound represented by -СН(К.)К» is С5-С1о linear or branched alkyl, alkenyl or alkynyl; o each Kz is independently chosen from halogen, CM, -OK. or -M(Kv/)"; K. is chosen from hydrogen, -(С4-Св)-linear or branched alkyl; -(Co-Cv)-linear or branched alkenyl or alkynyl; -КС.4-Св)-linear or branched alkyl|-К7; -КСо-Св)-linear or branched alkenyl or alkynyl|-К7, -С(0)-КС.4-Св)-linear or branched alkyl)Й, -С(0)-КС»о-Св)- linear or branched oalkenyl or alkynyl), -С(0)-КС4-Св)-linear /- or branched alkyl|-М(Ка)», and) -Е(0)-(Со-Св)-linear or branched alkenyl or alkynyl|-M(Ka)», -P"OHOKa)», -P(OHOKaHKa), -С(О0)-К», Fo -5(0)2М(К5)», -КС4-Св) -linear or branched alkyl|-CM or -(КСо-Св)-linear or branched alkenyl or alkynyl|-СМ; "-- each K" is independently selected from hydrogen, -(С4-Св)-linear or branched alkyl; - (Co-Cv)-linear or branched alkenyl or alkynyl, -КС.4-Cv)-linear or branched alkyl|-К7; -КС»o-Cv)-linear or branched alkenyl or alkynyl|-к7, - КС4-Св)-linear or branched alkyl|-СМ, -КСо-Св)-linear or branched alkenyl or alkynyl|-СМ, -КС.4-Св)-linear or branched alkyl|-ОК,; -КС»о -C(0)-linear or branched alkenyl or alkynyl|-OK,, -C(0)-(C4-Cv)-linear or branched alkyl, « 20 -E(0)-(Co-Cv)-linear or branched alkenyl or alkynyl), -С(0)-К7, -С(0)0О-К7, -С(0)0-( C4-Cv)-linear or branched alkyl, -C(0)0O-((Co-Cv)-linear /- or branched alkenyl or alkynyl), c -5(0)2-(C4-Cv) - linear or branched alkyl or -5(0)5-K;7; or two K" moieties, when bonded to the same nitrogen atom, are taken together with that nitrogen atom to form a 3-7-membered heterocyclic ring, which heterocyclic ring may not necessarily contain a 1- 3 additional heteroatoms, independently 415 selected from M, 0, 5, (0) or 5(0)»5; -1 Ke is chosen from -С(0)-СНаз, -СНо-С(0)-ОН, -СН.-С(0)-О-ИВы, -СНО-СМ or -СН.-С 2 СН; each K. is a monocyclic or bicyclic ring system, in which: -y i) each ring includes 3-7 ring atoms, independently selected from C, M, O or 5; so her) no more than 4 ring atoms are selected from M, O or 5; iii) any СНо is optionally replaced by С(О); about them) any 5 is optionally replaced by (0) or 5(0)"; "p each Ka is independently selected from hydrogen or -IIS.4-C.|- linear or branched alkyl; in which in any ring system of the named compound up to 3 hydrogen atoms bound to ring atoms are optionally and independently replaced by halogen, hydroxy, nitro, cyano, amino, (C 4-C.))-linear or branched alkyl; O-(C.-C.)-linear or branched alkyl, (Co-C./)-linear or branched alkenyl or alkynyl, or O-(C5-C,)-linear or branched alkenyl or alkynyl; and (F; in which any ring system is optionally benzofused; GI Co is selected from hydrogen, (K)-methyl, (5)-methyl, (K)-ethyl, (5)-ethyl, (K )-hydroxymethyl or (5)-hydroxymethyl; in Co is selected from -C-.M or 5-oxazolyl; and K.44 is selected from halogen, -O-(C4-C3) linear alkyl or -O-(C2-C3) linear alkenyl or alkynyl. 2. The compound according to claim 1, which differs in that it has the formula (1): b5 V a ;() Ina 1 MI te a | Sh-- a in - Zh M M Me NN in which K. and Co. are as defined in clause 1. Z. The compound according to claim 1, which differs in that it has the formula (IA): H ; (IA) Ka I v nai Kva a 4 IR IM 1 Н H in which K 9 is selected from (K)-methyl, (5)-methyl, (K)-ethyl, (5)-ethyl, (K)-hydroxymethyl or (5)-hydroxymethyl; and K.; and Co. are as defined in clause 1. 4. The compound according to item C, which differs in that Co is selected from (5)-methyl, (5)-ethyl or (5)-hydroxymethyl methyl. 5. The compound according to claim 4, which differs in that Ku is (5)-methyl. 6. Compound according to claim 3, which differs in that K.; is chosen from O-methyl, O-ethyl or O-isopropyl. with 7. Compound according to claim 1, which differs in that: o at least one of Ki. or Co is selected from hydrogen, methyl, ethyl, p-propyl, isopropyl, p-butyl, butyl, p-pentyl, phenyl, pyridyl, -СНОСНА, -СНоСМ, -СНоОСНо.сСнНБССМ, -СНСС(СНЗ»сСНносНосСНоСсМ, -бсн -(СснНСснНЗЗсСсНнСНСНСМ, -СНСНСНСМ, -СНаМСХ(СнОСННСНМ)», -"СНаМСХ(СНзИСнНСННСННСМ, -СН(МНо)СННСНСМ, -СН-СИ, -СНоОН, -СНоСНо.ОН, -СНо.СНоСнНоНН, -СНо.СНоСнНосСНоНН, -СНоСНоОоС(О)СнНУ, -СНоСНо.Оос(ОСНоМН., -СН.СНоМНеН», -СНСНоМ(СН 3)», -СН.М(СНоСН»)», -СНоСнНо.М(СНоСНн»)», -СнН.СнНшсСнНоМ(СН З)», -СН.СНоСНОМ'(СН3)и, -СНоОСНоСН(СНаз)", "СНСНоМ(СНзИСКОЮС(СН3)зи, /"СНоМ(СНоСНоМ)СНСН(СН3)», -сСН(СН3СММ(СН3)»), - SNASN(ISNSMIMNOSPOS(СН 3)5, o r; a rech M A re p a / / te - | r M Me ' , , , o or " o V v sh g - - r sche rey " ra sche ra sche ' ;» o bud t v - also o - r: i-o where n is O or 1. 1 20 8. The compound according to claim 2, which differs in that K.; and Ko are taken together to form З-tetrahydrofuranyl the component that is substituted in the 5th position on -OKv. sl i. I I - 9. The compound according to claim 3, which differs in that one of K. or Co is selected from hydrogen, ethyl or phenyl, and the other from Ki or Co is selected from -"СНоОН, -СНОСМ, -СНоОСНСМ or -СНоОМ(СНоСН") », or in which K. and Co are taken together to form the 3-tetrahydrofuranyl component. 10. The compound according to claim 1, which differs in that the specified compound is selected from the following compounds: F. 1 N I (8) te a 60 o X M M M Me NN b5 2 Н M ШХВ t mya ShІi pr-t o to Х Me nn s Z H 710 ІХ В) and M p sht y СХ mes Н N Ii ІК 20 4 - и 25 2 se I (о) І О "from her - ШХВ - o PI yu 30 де Х yu Me NN Ge) TSI - I 35 5 I. - What) No ch yo - 40 s ot n g z | p o more | n Maty XX claim 45 Me N i V - M b I F 50 chiral and 5 th I; X 9 sl Z vu o HOD b pe 55 si N Ge! And 7 PV on | nn o I I boru eru (8) te 8) She B And 65 -D7- and M. o with NI Her 2 Go) Her and Go) Me and - that and multiple; y ХЧ ИЙ Go) M M ru, and Go) 2 gy M 7 chiral o Z ! o no vo t NO; tr A o ke Ha 7 chiral de her and p i yad her o M M : F o n y po; in, - and and - 12 | and Z « then about M. M r : a s She. M; ho TO x y M Mn ne y s 20 o) o - Mes GY g, Mom M o obvadi u o y y utyuyu Iii I -a ves NN N TSI M b5 -AV- 15 prtnny a dam N (8) M M DI s y: M o | also H 7 5. And 16 chiral a y y TI: X y shk o 0 (in 5 « and m" schi 17 shi a N y Shko 58) o no (m so sch t h y y o 18 chiral ann Huzo o su M: a I) N more 5 and m - o - 19 chiral N « M Ma iy i Shchy o - « | sh » ХХ , -o more m M eh nn : » - multiple N y : y uh (se ) y a m p sh Ho o sl p her her 21chiral cy y, M o pey oh Y Y Her 60 - Ж 65 22 and OM chu; HM Zh She - ; MY BUT; o Ho) and -sh- 5) M OMe 23 chiral N i! M o (4 y tu o 0 y ikh si | Y -o sy ah NN 24 N I M o i. she a Go) MA a M M s | N N o 25 chiral tsya M o, oyu o what zo 5 lo still (8) a a yuyu X " y Ho) M M - N N yich- b m N a lai -IVKt p y Y ny pr « her i | - s a M moh z» | Н H 27 Н М M M Ge - 7 VIJ r - (v; | -- a re | o FA - zhk t i zh schi: sl 28 chiral o i NI; X Sho M o. n well N n: (F. o o UM in, in M bo 65 -B50- 29 pu o and that OH, N y o o nuva (U uyu 30 o h nn Me M M - Z r; Shk they Oshy nya 15 i and 31 ego 20 I a N Me with Shk even in N sh ya o she o SHE o 2 ( I 32 m n a yu i o » Bi she o She a dk i o" - I AH p "-- (8) I I NEen shchi 35 33 | a M n i z zu" a " o o M - 40 so / s I z 45 sh mn -I y t nn s Me sh- y Ж, si o | N she o s 4 / 55 35 She » Х Н N Me M M She bo | m POD o o r o M 65 - Y o : t; X eh She ch -E te 70 x and o 37 a Ez cho. AL. And Sg U rolls about | r / | r s h i z o sha s h u g I MI Sh-k II o gy g Y yad o 39 - o y o y chiral n Fu M. M. y y: m' sta" - N that GO g 7 "/ 1 M y sm yh 40 o nn - Me y y I o o - i ki -| IC z 41 o no n (Se) sh-- r KM v . i-y y y ShK 8) y sl SYA / Y M - 42 o SA I M o name) M a - S M -Z 65 And she; iy utette s Tv) x i 70 44 a i i M M he A S Y | no no; but not 15 "and I 45 CM M. Ж I ИЧ я Shk y y o О (c) с с 25 5 / о И 0- 46 SI В) И c) nn 30 sut yuyu Н Ф 8) о Shi - M 0-- m. 7 І chiral "" сх АХ " s M. M z y OM o y y -b K i -i M -Z - 48 c; (se) sya 0 m sl non Her 6 KAM lotu (F) o o I y | re with "and IM 5) 65 49 and Nv dv Io) IC - and on ; MY well Mo a o - i IM 70 50 Z I o nn y y I M u tuye y - p kh i I 51 r chiral what sch she Her? N N (8) I M rr y v: shE o SHE oyu i yy 52 shk - chiral sh o m nn o sh-- o s v " mice h o dO o sho s i / I" BZ o u non 35 May I M MISch -i | ee from NI; a em - o - o o 5) sa 0 M ov sho 1. nn med I I M: M Go) zv m POD o y a Shk yu Li 6o 65 -5D- aVp 55 o med yo s Her o Y y a Shk I 70 56 what and Per rel MY p; r y y « y I an I I y ro s non Mei -- shcha -k sm o v | И ОН и - И и | i i i Ge) A AAU A AJ: vo, z i Her i i i i i i i i i 59 o « s, Me II M s that in" another 7 g NI i s- (8) o o she z i an 60 chiral I S. V N - mes s o ut" F 7 no y s 1 7 ; ОН and В bTchiral ШЧI .E Me o ut yu y Go) o ko 5 bo MI 65 On 62 chiral a S. nn DI cm mes sor y a Y po y «i - an 70 bZchiralny I I y S on Me M I sya m as y | N o 8) - « i I 64 a nn 1 i it v i S n a se A ; by o and 65 th Z yu Y I c) o : N N H to her Me IM M - - i 7 th | N 3 ay y y 5 4 IM r h 66 70 chiral My i- WHAT) » a lyut y l y y | N o de shE a r -I V M mis) 67 t s 70 chiral and My sl I sh- MM M ia s. ех ШИ no : i o i a o u yu M 6o 65 -5v- bvchiral and with ; and ok; te ve he and | NO | N GO) te GO) -E «/ M 70 bochiralny and in ; i i SHE: OH, an sus 15 a r her in / I o I i t that | nn y o M Ya ra o y kh she nu y even s rn GO) ke s kh. Y I 7 o y yar t, y o M M o sh: tu u i a o o her 5 - and sg that ii nn y 4 o M z is o y x GO tu 5 a o sh-e s x i z » M y " 73 o UNTIL. A t, M M sh 00 t a o - o x / she is 74 a st! N N y s M M -- o to -E - I oshshO ! o (8) ke o nd m (U bo 65 75 a o nn o Mo im - r ; VIJ and same ot Ge) o -sh IM 76 i S nn o Mo im - r ty 18 a o -E 5 IM 7 o / che Mk chiral o -8 Sh u; a I n y pe s a a (o) "i I 78 o IS o) 7 chiral 0-X, o ! her o MK - r M S (8) ha « 79 o -v - chiral 0-X Also, 9 MK still -i o i oi her a shk 6 s 20 voas s GU tv MI r o N y r S in U y y ko 8) yu shcha och NN 65 M no, SHY -- vovnony -E i 4 / 82 y on i I S. I Me yo i V. o o (I 83 o an N N meo Shk shOshi o o y s va M yu i g yu N N NO X z Zhe Zeit 7 paths: to do - hi 85 M « o "zhe AL, Is z s a Z tm to SE s de --E x Y V. 86 - t (Se) | o Mt Fo nn Me S. o M M on sl She M o o t T no; Я хи Ф) ю 87 Uivalnyi a u N N mmEy I I r 60 se Z t GY « sho -e » y b5 88 where Ge) n n Me M I AH p. ! corner of N Y | in Y o "at. M chiral a M. Zh Mei M M y zsrorrtrya that GO x and 90 shk Z ; N N o sya M M M y o ne S nt o hi yu 7 91 y o vy pla F j ho - N Ii - 7 9 o s shk N c) 9 Oi " -o "and other 92 " S o - Mei M M XX, and A GO sl 50 S hi sl 93 and o moe about THEM. N N we) M vo ih IC re te y: M a still with po bo a - a shk / M b5 94 i chiral a Meo M M r XX. Shsh- v z o N I i o -e yu zi M 95 TV it, chiral a a mes M M D II y p M o y (4 and IC 96 ov ! - | Ton sch chiral y N her o May M M A I z i i oyu zo Go) Go) yu 5. MI Ge) she her Her Her sh o M M D R N M z | i y: ali ato Ho) o o shE n' «i « m - s 98 "» chiral M nn g - i N - S o she hi sho M slo 99 sl Sho S chiral M y ШЧI Za th teh o y | S kyu « o deshe y 60 M 65 cm Mey y | i zo TV TV - 5 I 101 M chiral a b N Me I N AH She: shsh-kh vovni « she -e x U |, 102 that IR chiral a s y meondre o SHCHI no o N (8) y Shu yu zo 5. her I 103 M Ge) YN : shlya M sht yi- Su o de v. zh s « yu m oMme o s 104 M Io) ; » N N M IM sh 45 o y r V i y M OoMe sp 105 ry sp chiral schi nn y o M. OM A Za Tya 7 s 5 VIJ | ti F) o o o still --E to x i M bo 65 106 ran chiral and 2 | nn her a M M , -e E -h onnovny o ke o -E i chi M 107. M still si | She a sht and N -o what else pe | M in p i n i o re E o s E N U Ge) E 108. M dk Io) o I c) I o N o F AKA i z, z y i at i- o mini E i A. " 109. M y Z s s / ;" o N y -0 DA ICH E N - In her re. a t i Ge) Zh sa 70 mom s (4 r a o N -o sha o t (F, NE'n VIJ uo yuyu o E Ul 60 Zh 65 111. m. and o c o and DS! o M i z Bak shchi E me E 70 i 112. M h / o o nN tru HM S i 0 Ii o E t E s o 113. M.S. «-o yu 114 M s S . o Y "» o N tru XX Sv 0 Iii o MOm with B on -I N N na shchi E t a; F 5 so sl 115. M s. o o nN o - HM M o her IC I 7 a ii with ro o E bo SE 65 116. m i o o N p ZH M 0 Ii p) MM SCHI E N N N at shchi E yu Skh: 117. M h / o o nN - ХМ M o 7 2 y y, g E y; (8) E 9 in E s o 118. M i i yu U : A M M o m: T y o o -- E N v. - E about M. and Y " 119. M not with 5 :z» o SHE: (6) in | MI No with m: T - y SCHO (Se) uro GU slo o E and E sp 120. M (Ya i o yu Y o M o Sho M m v vo N N o (v) E N D ia ro g E 65 Azh g p moto o N N S Y i U N » and 70 122. M sche si She: a de N no y SHI Go o ie E en a: ro E 123. M do s s y (o) SHI DAK mia yu zo N N Y ila a F yu Mi E chi: E G che 124. M -y ІІ « o a - s XX sik, g» o "Sche p a 7 -1 uro M. -3z E y re so 125. M y (o sp i Y o N o 0 o) a E N M bo roya zt E 65 126. M dksi N - she M Go Kiya g o a y shchi E N M ia E 127. M še si She: a de N -v tcho - Shk so N Go o iye E N a: sch re: (o) E 128. M 2 yu 30 and oyu te o F -o | rya ХК ухо «- N y ny - o E N y ro. prot "E - p. 129. M i" 5; and | with her N it. -o j OK M o - N Nn pd (se) a o FO E AN M sprya t E (F) o) bo 65 "y j ch o ov still and not o o E IN M gro y E 131 7 y o N - Ж p M o zh sha o t) E N M sh E o y o E IS y 132 y her N o MM M - ur S IV) She M cho « lyu o No sh - eDya z gu, 8 " o o Sho v r -1 NN z 134. M re d o F si s 70 t) i y rysy nn TL a GO) Pt a i ka E E bo 65 135 I sh a o y X Her M o II IC zh NN (8) a m 70 -y ryu E 136 IC F ; at and o SHO sh- XX pr | M (v. y i I (8) a Mn ro A s E (o) E 137 I Fr p i y I FO i yy nN A No F I ICH Bez NN - p a Pt - uro A E ! « 70 138 chiral tsn- s y-o M. 00. nya m SHHI still doo- (8) Still about it. | ХК 0-8 M. Sho ah M Osn - N N a (se) 139 II dk s 50 27 8) sl a A M. o to mm Z N N y (FI a ka E rai y" bo y E 65 140 7 de 1 I with- And and Tyuya to her about c) and IC Bak she 141 | Y an 15 chiral nn Her o Pe: in OH, an H 20 (8) o «i M 142 r sch 25 u (o) a may N N ru ueute ; 30 o she o IY yuyu and F " - 143. M 5 ich- y | She a shsh- N a re vk that M 0. a « 7 | She T (J 7 s o ! ;» : 144. M de - s |; - | She a N o o y M " still a s | N n t MD ot slo o : a I (F) to bo b5 145 U v z. y o i g HM S ki a M M " ЦС) НН TS ж 70 n : и an 146. M chu Y o AH to M o. 1 her y p is o Ж lin o : y s o SHV an 147. M p z o i i i o to | what about in xx and also a? N N p -- o Dzh m a : - « another 2 s 148. M I» U sh a - A I o a pe 5 shi ge so o Z ml si y : sl pany ke (F) ko 60 65 149. M vo! o t-e m s o o Kn 70: 150 M la ? still s vne o m b i sch 7 t o 151 M vo A o IS c) N DI. о, и чн - Й ми и и- ХГ « s 70 152 и, n- - 7 о МИ о В | NN tsva sl 50 : : y y 153 I o o and I de M o. o and b5 154 7 pe i i o vo Z SI o o M ICH Z o N N HOD 70 9 : no 155. M dya i 27 a 6; H S ko o M I m a i yav GTS zh at ran 156. M s U / o o her S. N M o o a and Ou : a o : F 7 - r- yno 157 " khirvalnyi N y ne) - o :" o - 7 SHI t SHV tru o still - I 7 o whose N N ise) 158 p: AH sp hinapnyi y M M o. from nYA - SHV SHE: Ge) o tru i de to sly at N N bo 65 159 chiral a Mne o Z non o M M a p he M a H 8) o - ( I 160 sor MN Y S. I i t5 y: pd M o N o - o « M M o Me 161 a pl. NN M. Am SHO p i sch a Go! o ( M OMe 162 M y ACTIONS of chiral Ge) t o ch- p | Shshsh-i a M o shk m'Ya « dO - s 163 Ch a -a with what;" M schi - o o o AND V. to mom -from nn 164 and | N t Fo o M. I: AH. it's time to sl | N o a -E 5 52 IM! Yi F! 165 o t | nd o M y on poru 6o | N o a -E 5 x and 65 166 | - chiral I ' a Z y M. M MI She Z M ag N (8) not (8) 5 хи 167 | - chiral I a Z i nn DI She Z M ag N (8) ne (8) si hi 168 chiral N M a. what about - z "zh t still o v Y - a Ж НН that Zo 169 chiral no m a Shcheo, what - m Z s o z I lo HO or АХ - и ІЧ 170 I m n chiral no M a M s i M 8 s (in) ;" -Щ- Х и Ч Я » 171 chiral iv. о - мя 65 -1й5- 173 chiral SI nn Her (8) M MI Ye and m a N (8) -- m 70 174 chiral SI nn Her o M M ia A I (8) and MY 0 i a - still Chi 175 chiral Ch a MI SCHI Zhe a in (8) an so A nn s 176 chiral no Ch a o m GO Zhe a in (in) ОН o » H o l-d I I NN F 177 IC de - shk o s (8) I I r y ee 7 shop M a" NN sh o r « sho M - s 178 I . dO y | (IN Y o M. M r V. r -d o de M shk shch (Se) 179 chiral on sl (8) i i And also o | also m iF) 180 chiral ka on nn I 6o | heh and NO: a N Iv) t st st st st 65 181 chiral N WHAT ABOUT Ap her, and ki we tem sh-E GO) (8) dk -o m J. dn N N 182 SI g sh o M M a Z z -- m a N o j se 183 N no , And about . -o cha y po She o Y oh Y SI to Ж Н N 184 хи Х N sch v chiralny na, M a. m B; She oh Yi | and IS) Nzs---., HM o I M to nn yu 185 kh i N chiral o M o b what -- and in Y I | i Y No -4 vach Н N « 186 and t NS yes that N I s : NI; AK St o s she tya -I 187 nsa . - s nd ХК i y -t o a e) s | Claim 11. A compound according to claim 10, which differs in that the indicated compound is selected from any of the compounds 1 Н И (8) b5 H 23 M a S tu niv, owner: M. at 6 a.m. That Her S o. that's all ! M. o sho s u y dk Y sha ta sly a: ts NN Y i nn a I p uyu i o o o her uyu x) i And M. about her 32 ts in gu - and dk and about DOD 4 only | « 76 a s / - utry to " o 9 0 - 45 A i - 8o what (se) x s 50 y , ! sl sa ky Y ШХВ o Y o cha och o NN bo 65 M. and A a M o o -E 5. M 70 89 da pe N N a M M sh | here and there; (c) j o EE 4 and M 98 that N N sh a M M DI p. s In what: a (6) ш-E t I zo 101 dey oyu Ge! H s s NN (in; х ІЧ se m. - Shk Shsh-e M a N Y | 7 t S 4 i « " no 70 103 s o Be » M A sho She Sh-x M a 600 Kut -1 S - o - V i (He; M. KD sp M vono -E si and (F) M she o) bo b5 106 ac mo TO) N y 0. market vornovny o te o -E 108. M p (u o ZHAKA ya- sht se M o po i still o mia Y A 110 M d is; and a and is, I zh pyv o yu z0 M OH o - 157 | ) and Y N Sh- MI at. " "z t " s--E 8) s o oto y? -o zh Yi yi No n - 163 No o - ak niy o so sho y o "Zh, sl No NN 169 o o cha y TT o Go) sha 60 Н H 65 ts 8) B ik kl AL Zh V What (8) (8). web page, page 186 and others: page 187 - . ok and s II and - Me (8) -E 12. A composition containing a compound according to claim 1 in an amount effective to inhibit IMFDH, and a pharmaceutically acceptable carrier, adjuvant or solvent. " 13. A composition according to claim 12, containing a compound according to the present invention and an additional drug selected from an immunosuppressant, an anticancer drug, an antiviral drug, an anti-inflammatory drug, an antifungal drug, an antibiotic, or an antihyperproliferative vascular drug. h 14. A method of treating or preventing a disease or condition mediated by IMFDH in a mammal, which differs in that the composition according to claim 12 or claim 13 is administered to said mammal. 15. The method of claim 14, wherein the IMFDH-mediated disease or condition is selected from graft rejection, graft-versus-host disease, or autoimmune disease. and 16. The method according to claim 14, which is characterized by the fact that the specified mammal is administered an additional immunosuppressant in - a separate dosage form or as a component of the specified composition. 17. The method of inhibiting the replication of a virus in a mammal, which is characterized by the fact that the specified mammal is administered the composition according to claim 12 or claim 13. c 20 18. The method according to claim 17, which is characterized by the fact that the specified mammal suffers from a viral infection caused by a virus selected from orthomyxovirus, paramyxovirus, herpesvirus, retrovirus, flavivirus, sl pestivirus, hepatotrophic virus, bunyavirus, Napiaap virus, Sagaraga virus, human papillomavirus, encephalitis virus, arenavirus, reovirus, vesicular stomatitis virus, rhinovirus, enterovirus, Lassa fever virus , togavirus, varicella virus, adenovirus, or rubella. 22 19. The method according to claim 17, which differs in that the indicated mammal is administered an additional antiviral Ge! the drug in a separate dosage form or as a component of the specified composition. 20. A method of inhibiting vascular cell hyperproliferation in a mammal, which differs in that the composition according to claim 12 or claim 13 is administered to said mammal. 21. The method according to claim 20, which differs in that the indicated method is used in the treatment or prevention 60 of restenosis, stenosis, atherosclerosis or other hyperproliferative vascular disease. 22. The method according to claim 20, which differs in that the specified mammal is administered an additional anti-hyperproliferative vascular drug in a separate dosage form or as a component of the specified composition. 23. A method of inhibiting tumors and cancer in a mammal, which is characterized by the fact that the composition of claim 12 or claim 13 is administered to said mammal. 24. The method according to claim 23, which differs in that the indicated method is used for the treatment or prevention of lymphoma, leukemia and other types of cancer. 25. The method according to claim 24, in which the specified mammal is administered an additional antitumor or anticancer drug in a separate dosage form or as a component of the specified composition. 26. A method of inhibiting inflammation or an inflammatory disease in a mammal, which differs in that said mammal is administered the composition according to claim 12 or claim 13. 27. The method according to claim 26, which differs in that the specified method is used for the treatment or prevention of osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma or respiratory distress syndrome in adults. 70 28. The method according to claim 27, which differs in that the specified mammal is administered an additional anti-inflammatory drug in a separate dosage form or as a component of the specified composition. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 1, 15.01.2005. State Department of Intellectual Property of the Ministry of Education and/5 Science of Ukraine. 6) IF) IF) (o) "- and - - and? -i - se) 1 sl ime) 60 b5