UA73843C2 - Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase - Google Patents

Abstract

The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-de-pendent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis ?? virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis ?? infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.

Description

Description of the invention

This invention relates to nucleoside compounds and some of their derivatives, to their preparation and to their 2 use as inhibitors of RNA-dependent RNA viral polymerase. The compounds of this invention are inhibitors

RNA-dependent RNA virus replication, and can be used to treat RNA-dependent RNA virus infection. They are particularly useful as inhibitors (HCMs) of hepatitis C virus M55B polymerase, as inhibitors of NSC replication, and for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is a major health problem, leading to chronic liver diseases such as cirrhosis and hepatocellular carcinoma in a significant number of infected individuals, estimated to be 2-1595 of the world population. In the United States alone, 4.5 million people have been diagnosed with the disease, according to the Centers for Disease Control and Prevention. According to the data of the World Organization

Health More than 200 million people are infected worldwide, and at least 3 to 4 million people are infected annually. After infection, about 2,095 people get rid of the virus, but others are carriers of the 15. NnsM virus for the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop cirrhosis, which destroys the liver, or liver cancer. The viral disease is transmitted parenterally through contaminated blood and products that include blood, contaminated needles, or sexually and directly from infected mothers or pregnant mothers to their offspring. Current treatments for HCM infection, which are limited to immunotherapy using recombinant interferon-A alone or in combination with the nucleoside analog ribavirin, have limited positive clinical results. Moreover, there is no recognized vaccine for NSM. Accordingly, there is an urgent need for improved therapeutic agents that effectively combat chronic HSM infection. The state of affairs that exists regarding the treatment of NSM infection is given in the reviews, references are given to the following publications: V. Butosk, ei a!., "Mome! arrgoaspesz Yuyu (Pe igeaitepi oi Peraiyiv S migiv iptesiop", Apiimigai Spetivigu 5 SpetoiPegaru, 11: 79-96 (2000); N. Kozep, ei ai., "Nerayiv s sb migpyv: sshtepi ipadegviapaitao apa rgozresiv yog yShishige (Shegaryev), Moiesciag Meaisipe Todau, 5: 393-399. (U (1999); O. Mogadroig .

Neraiyoi., 11:1189-1202 (1999); K. Vapepzspiadeg, "Sapaidayete Tagdeyiv and Tog Neraiyiv S Migiz-Zresiiis Apiimiga!

Tpegaru", Ipiegmigoisdu, 40: 378-393 (1997); S.M. Iatseg apa V.O. MuUaiKeg, "Neraiiov S Migiv Ipbesiop", M.

Epics U. Mea., 345: 41-52 (2001); VM. JuutosK, "Etegdipud (pegaryez og Peraiiv S migiv iptesiop), Etegdipa o

Ogydv, 6: 13-42 (2001); and S. Starr, "Naga-MUop Admapsez Zragk Ekhsyetepi aroshii Neraiyiv S", Zsieepse: 506-507 «f (2001); the contents of which are incorporated by reference.

Various approaches have been taken to treat NSU, which include inhibition of viral serine proteinase (M5Z3 co-protease), helicase, and RNA-dependent RNA polymerase (M55B), and vaccine development. co

The HOM virion is an enveloped positive-strand RNA virus with a single oligonucleotide genomic 325 sequence of approximately 9,600 bases that encodes a polyprotein of approximately 3,010 amino acids. -

The protein products of the NSM gene consist of structural proteins C, E1 and E2 and non-structural proteins M52, M5Z3, M54A and M548B and M55BA and M5Z5B. It is believed that non-structural proteins (M5) provide a catalytic mechanism for viral replication. M5Z protease releases M5O5B, an RNA-dependent RNA polymerase from the polyprotein chain. NSM M55B polymerase is necessary for the synthesis of double-stranded RNA from single-stranded viral RNA, which serves as a matrix in the 50th cycle of NSM replication. Therefore, M558B polymerase is considered an essential component in the NSM replication complex (see K. s Ivpi, ei aiYi.,, "Ehrgeziop oi Neraiiv S Migiv M55B Rgoieip: Spagasiegigayop oi oi (8 KMA Roiiutegase Asiimyu

Iz" apa KMA Vipaipd", Neraiyodu, 29: 1227-1235 (1999), and M. Hoptapp, ei ai., "Viospetisa! apa Kipeiis Apaiusez oi MZ5V KMA-YUOerepdepi KMA Roiutegaze oi (pe Neraiyiv S Mihyv", Migoiodu, 249: 108-118 (1998)). Inhibition

The NOM of M55B polymerase prevents the formation of double-stranded NSM RNA and is therefore an attractive approach to the development of

Non-CM-specific antiviral methods of treatment. it. In our time, it was discovered that the nucleoside compounds of this invention and some of their derivatives are effective inhibitors of RNA-dependent RNA viral replication, and in particular, HCM replication. 5'-triphosphate derivatives of these nucleoside compounds are inhibitors of RNA-dependent RNA viral polymerase, and in particular, NSM M5Z5B polymerase. because the considered nucleoside compounds are their derivatives and may be useful in the treatment of RNA-dependent RNA viral "iz" 20 infection, and in particular, NSM infection.

Therefore, the task of this invention is to create nucleoside compounds and some of their derivatives, which could be useful as inhibitors of RNA-dependent RNA viral polymerase, and in particular, as inhibitors of NSM M55B polymerase.

Another object of this invention is to create nucleoside compounds and some of their derivatives that could be useful as inhibitors of RNA-dependent RNA virus replication, and in particular, as inhibitors of hepatitis C virus replication. 25 Another object of this invention is to create nucleoside compounds and some of their derivatives , which would be useful

HF) in the treatment of RNA-dependent RNA virus infection, and in particular, in the treatment of NSM infection.

Another object of this invention is to create pharmaceutical compositions that include nucleoside compounds together with a pharmaceutically acceptable carrier.

Another object of this invention is to create pharmaceutical compositions that include nucleoside 60 compounds and their derivatives for use as inhibitors of RNA-dependent RNA viral polymerase, and in particular, as inhibitors of NCM M55B polymerase.

Another object of this invention is to create pharmaceutical compositions that include nucleoside compounds and their derivatives for use as inhibitors of RNA-dependent RNA viral replication, and in particular, as inhibitors of HCM replication. because Another object of this invention is to create pharmaceutical compositions that include nucleoside compounds and their derivatives for use in the treatment of RNA-dependent RNA virus infection, and in particular, in the treatment of NSM infection.

Another object of this invention is to create pharmaceutical compositions that include nucleoside compounds and their derivatives in combination with other agents active against RNA-dependent RNA virus, and in particular, against NSU.

Another task of this invention is to create methods of inhibiting RNA-dependent RNA viral polymerase, and in particular, inhibition of NSM M5Z5B polymerase.

Another task of this invention is to create methods of inhibiting RNA-dependent RNA viral replication, and/or in particular, inhibition of HCM replication.

Another object of this invention is to create methods for the treatment of RNA-dependent RNA virus infection, and in particular, the treatment of HCM infection.

Another object of this invention is to create methods of treatment of RNA-dependent RNA virus infection in combination with other agents active against RNA-dependent RNA virus, and in particular, treatment of NSM infection in combination with other agents active against NSU.

Another object of this invention is to create nucleoside compounds and some of their derivatives and their pharmaceutical compositions for use as drugs for inhibiting RNA-dependent RNA viral replication and/or for treatment

RNA-dependent RNA viral infection, and in particular, for inhibition of HCM replication and/or treatment of HCM infection.

Another object of this invention is to create for the use of nucleoside compounds and some of their derivatives and their pharmaceutical compositions for the preparation of drugs for the inhibition of RNA-dependent RNA viral replication and/or the treatment of RNA-dependent RNA viral infection, and in particular, for the inhibition of NCM replication and/or treatment of NSM infection.

These and other tasks will become apparent from the following detailed description.

This invention relates to compounds of the structural formula I of the specified stereochemical configuration:

Ko M 2 with ; and about | MV co v v v d'

Where is the village?

F so or their pharmaceutically acceptable salts; where

B" represents C 5,4-alkenyl, C 1-alkynyl or C 1-alkyl, where the alkyl is unsubstituted or substituted by hydroxy, - amino, C 1-4-alkyl, C 1-4-alkylthio or one to three fluorine atoms ;

IN? represents hydrogen, fluorine, hydroxy, mercapto, C 4.4- alkoxy or C../-alkyl; or iv: together with the carbon atom to which they are attached, form a 3-b--len saturated monocyclic ring system, which does not necessarily contain a heteroatom selected from 0, 5 and MCo-alkyl; with

BZ 7 is each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, C-mercapto, amino, C-1-4-alkyl, C-1-4-alkenyl, C-1-6-alkynyl, and C-1-4-alkyl , where the alkyl is unsubstituted or substituted by: hydroxy, amino, C-4-alkylthio, C-4-alkylthio or one to three fluorine atoms;

VZ is hydrogen, C 10-alkylcarbonyl, PzOonA, P»ObNaz or RIV ZVU;

BZ YV each independently represents hydrogen, methyl, hydroxymethyl or fluoromethyl; -| BZ is hydrogen, C 1-4-alkyl, C 4-alkynyl, halogen, cyano, carboxy, C-alkyloxycarbonyl, azido, amino, C-alkylamino, di(C-alkyl)damino, hydroxy, C1-6-alkylthio, C1-6-alkylthio, C1-4-alkylsulfonyl, (C1-4-alkyl)o»-aminomethyl or C1-cycloheteroalkyl, unsubstituted or substituted by one or two groups, (ee) independently selected from halogen, hydroxy, amino, C..4-alkyl, and C.i.-alkyl; what VE? represents hydrogen, cyano, nitro, C 4.3-alkyl, MNSOMNo, COM "2B"2, sam v", sov", C(-MH)MH", hydroxy, C. z-alkoxy, amino, C. -alkylamino , di(C.1-alkyl)amino, halogen, (1,3-oxazol-2-yl), c" (1,3-thiazol-2-yl) or (imidazol-2-yl); where alkyl is unsubstituted or substituted by one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 -alkoxy; 279 of its B"! each independently represents hydrogen, hydroxy, halogen, C 4 5X- alkyl )amino or Su 6-cycloheteroalkyl, unsubstituted or

HF) substituted by one or two groups, independently selected from halogen, hydroxy, amino, C4.4-alkyl and C.4.-- alkoxy; where is each B? independently represents hydrogen or C. c-alkyl; and

Each independently represents a hydroxy, OSN. ) S. u-alkyl, and tatu tisna isn» yacht visnansn

Оо(сндаСНа or ОСО(СНомаСНХ) provided that if В is D-methyl and ВЭ is hydrogen, or В" is D-methyl and В!б5 is hydrogen, K 2 and ВЗ are о, - hydroxy, KZ represents amino and K 5, KE, B", 818! represent hydrogen, then E? does not represent cyano or SOMN".

Compounds of formula I can be used as inhibitors of RNA-dependent RNA viral polymerase, and in particular,

NOSM M55V polymerase. They are also inhibitors of RNA-dependent RNA virus replication, and in particular, HCM replication, and can be used to treat RNA-dependent RNA virus infection, and in particular, to treat HCM infection.

In addition, the scope of this invention includes pharmaceutical compositions that contain the specified compounds, taken both individually and in combination with other agents active against RNA-dependent RNA viruses, and in particular, against NSMU, as well as methods of inhibiting RNA-dependent RNA of viral replication and for the treatment of RNA-dependent RNA virus infection. 70 This invention relates to compounds of structural formula I of the specified stereochemical configuration:

She 5 o'clock by M Ж " c) M in c". to

Sava vi ve (; or their pharmaceutically acceptable salts; de

B" represents C 5.4-alkenyl, C. 4-alkynyl or C. 4-alkyl, where alkyl is unsubstituted or substituted by hydroxy, amino, C. 4-alkyl, C. 4-alkylthio or one to three fluorine atoms;

IN? represents hydrogen, fluorine, hydroxy, mercapto, C 4.4- alkoxy or C../-alkyl; or iv: together with the carbon atom to which they are attached, form a 3-b--len saturated monocyclic ring system, which optionally contains a heteroatom selected from 0, 5 and MCod-alkyl; at

B3 and K7 are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C1-4-alkoxy, C1-4-alkenyl, C1-6-alkynyl, and C1-4-alkyl , where alkyl is unsubstituted or substituted by hydroxy, amino, C..4-alkylthio, C..4-alkylthio or one to three fluorine atoms; co

B is hydrogen, Si. 10-alkylcarbonyl, RzOzNa, R»OvbNaz or RIV ZVU; 25 B" each independently represents hydrogen, methyl, hydroxymethyl or fluoromethyl; c

BZ is hydrogen, C 1-4-alkyl, C 1-4-alkyl, C 1-4-alkynyl, halogen, cyano, carboxy, C 1-4-alkyloxycarbonyl, azido, (ee) amino, C 1-4-alkylamino, di(C 1-alkyl)damino . , hydroxy, amino, C..4-alkyl and C.4.,--alkoxy; -

IN? represents hydrogen, cyano, nitro, C 4.3-alkyl, MNSOMH»o, COM" ?в"?, CM в, СО", С(-МНМН", hydroxy, C. z-alkoxy, amino, C. -alkylamino , di(C.1-alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl) or (imidazol-2-yl); wherein the alkyl is unsubstituted or substituted by one to three groups, independently selected from halogen, amino, hydroxy, carboxy and C..3-alkoxy; 279 of its B"! each independently represents hydrogen, hydroxy, halogen, C 4 5X-alkoxy, amino, C. .4-alkylamino, o) c di(C.4-alkyl)amino, C.sub.6-cycloalkylamino, di(C.sub.6-cycloalkyl)amino or C), 6-cycloheteroalkyl, unsubstituted or "» substituted by one or two groups , independently selected from halogen, hydroxy, amino, C4.4-alkyl, and C.4.--alkoxy; " each B? independently represents hydrogen or C. c-alkyl; and

Each independently represents hydroxy, /-OSH oSNoZO(O) C d-alkyl, - 15 OoSHO.O(C-0)OS, /-alkyl MnNSMeSO oMe, OSN(C. 4-alkyl)uO( C-O) C. "-alkyl, o and tetu tvisnunsn" yak tottrtvisno sn" co O(СНо)всСН" or осо(сннаСнь o, 1" 50 provided that if B represents D-methyl and B" represents is hydrogen or B 7 is D-methyl and c! is hydrogen, B 2 and BZ are "o, -hydroxy, BO is amino and 25, 29, c", 88" are hydrogen, then KE? does not represent cyano or SOMN."

Compounds of formula I can be used as inhibitors of RNA-dependent RNA viral polymerase. They are also inhibitors of RNA-dependent RNA virus replication and can be used to treat RNA-dependent RNA virus infection.

GF) In one of the variants of the compound of the structural formula | are compounds of the structural formula II: dye yo bo - her vo-i o M" o yav b5 (I or their pharmaceutically acceptable salt; where

Whew! represents C 4.3-alkyl, where alkyl is optionally substituted by hydroxy, amino, C 4.3-alkyl, C. 3-alkylthio or one to three fluorine atoms;

IN? represents hydroxy, fluorine or C. . . . . - alkoxy;

EZ is hydrogen, halogen, hydroxy, amino or C. .z-alkoxy;

VZ is hydrogen, RazOvNa, RoOvNa or РозЗН";

EZ is hydrogen, amino or C. l-alkylamino; 70 VE? represents hydrogen, cyano, methyl, halogen or СОМН"; and "9" B each independently represents hydrogen, halogen, hydroxy, amino, C 4A-alkylamino, di(C, /-alkyl)amino or C" 6-cycloalkylamino; provided that if VK! represents p-methyl , K2 and BZ represent o, -hydroxy, B" represents amino and B, B 818" represent hydrogen, then KE? does not represent cyano or SOMN".

In the second variant, compounds of structural formula I are compounds of structural formula II, where:

B" represents methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl or aminomethyl;

IN? is hydroxy, fluoro or methoxy;

BZ is hydrogen, fluorine, hydroxy, amino or methoxy; 2? represents hydrogen or RaOzNu;

EZ is hydrogen or amino;

IS? represents hydrogen, cyano, methyl, halogen or СОМН"; and

IN! B" each independently represents hydrogen, fluorine, hydroxy or amino; provided that if VK! represents p-methyl, K2 and BZ represent o, -hydroxy, KO represents amino KU, B CM 29. 818" represent is hydrogen, then KZ is not cyano or SOMN". at

Illustrative, but not limiting examples of the compounds of the present invention of the structural formula I, which can be used as inhibitors of RNA-dependent RNA viral polymerase, are the following: 4-amino-7-(2-C-methyl-dr. -O-arabinofuranosyl)-7H -pyrrolo|2,3-4|Ipyrimidine, 4-amino-7-(2-C-methyl-d. -Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, o 4-methylamino-7 -(2-C-methyl-p-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, chE 4-dimethylamino-7-(2-C-methyl-p.-O-ribofuranosyl)-7 H-pyrrolo|2,3-4|pyrimidine, so 4-cyclopropylamino-7-(2-C-methyl-dD.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino- 7-(2-C-vinyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, so 4-amino-7-(2-C-hydroxymethyl-p.-O-ribofuranosyl) -7H-pyrrolo|2,3-4|pyrimidine, cha 4-amino-7-(2-C-fluoromethyl-rd -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino- 5-methyl-7-(2-C-methyl-p -O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine, 4-amino-7-(2-C-methyl-d. -O- ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine-5-carboxylic acid, « 4-amino-5-bromo-7-(2-C-methyl-d.-Y-ribofu ranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-5-chloro-7-(2-C-methyl-p. -Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, with 4-amino-5-fluoro-7-(2-C-methyl-r. -Y-ribofuranosyl)-7H-pyrrolo|2 ,3-4|pyrimidine, "» 2,4-diamino-7-(2-C-methyl-r. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, " 2-amino-7 -(2-C-methyl-d. -Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 2-amino-4-cyclopropylamino-7-(2-C-methyl- d. -O- ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, -1 395 2-amino-7-(2-C-methyl-d. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine -4(ZH)-one, 4-amino-7-(2-C-ethyl-Dr. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine, o 4-amino-7-(2 -C,2-O-dimethyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, so 7-(2-C-methyl-rd.-O-ribofuranosyl)-7H-pyrrolo |2,3-4|Ipyrimidin-4(ZH)-one, 2-amino-5-methyl-7-(2-C,2-O-dimethyl-d.-O-ribofuranosyl)-7H-pyrrolo|2 ,3-4|Ipyrimidin-4(ZN)-one, shk 4-amino-7-(3-deoxy-2-C-methyl-r. -O-ribofuranosyl)-7H-pyrrolo|2,3-4| pyrimidine, syu 4-amino-7-(3-deoxy-2-C-methyl-r.-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-2-fluoro-7- (2-C-methyl-p-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimide in, 4-amino-7-(3-C-methyl-p. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, oo 4-amino-7-(3-C-methyl-dD. -O-xylofuranosyl)-7H-pyrrolo|2,3-4| pyrimidine,

F! 4-amino-7-(2,4-di-C-methyl-p-O-ribofuranosyl)-7H-pyrrolo|2,3-d|pyrimidine and 4-amino-7-(3-deoxy-3-fluoro -2-C-methyl-D.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine o and the corresponding 5'' triphosphates; or pharmaceutically acceptable salts thereof. 60 Additional illustrations of this invention are compounds selected from the group consisting of: 4-amino-7-(2-C-methyl-dr.-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4 -amino-7-(2-C-methyl-dr. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-7-(2-C-fluoromethyl-r. -O- ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, and 4-amino-5-methyl-7-(2-C-methyl-d -O-ribofuranosyl)-7H-pyrrolo|2,3-4| pyrimidine, 4-amino-5-bromo-7-(2-C-methyl-rd. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine,

4-amino-5-chloro-7-(2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-5-fluoro-7-(2- C-methyl-dr.-O-ribofuranosyl)-7H-pyrrolo|2,3-4-pyrimidine and 4-amino-7-(2-C,2-O-dimethyl- p -O-ribofuranosyl)-7H-pyrrolo| 2,3-4|pyrimidine and corresponding 5'-triphosphates; or their pharmaceutically acceptable salts.

In one embodiment of the present invention, nucleoside compounds can be used as inhibitors of positive-sense single-stranded RNA-dependent RNA viral polymerase, inhibitors of positive-sense single-stranded RNA-dependent RNA viral replication and/or for the treatment of positive-sense single-stranded 70. RNA-dependent RNA viral infection. In the class of this embodiment, positive-sense single-stranded RNA-dependent

The RNA virus is a Riamimigidae virus or Risogpamygidae virus. In a subclass of this class Risogpamygidae, the virus is rhinovirus, poliovirus, or hepatitis A virus. In a second subclass of this class Riamimygidae, the virus is selected from the group consisting of hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, Japanese encephalitis virus, Bunzi virus and bovine viral diarrhea virus (BVDV). In a subgroup of this 75 subclass Riamimigidae, the virus is hepatitis C virus.

Another aspect of the present invention relates to a method of inhibiting RNA-dependent RNA viral polymerase, to a method of inhibiting RNA-dependent RNA viral replication, and/or to a method of treating RNA-dependent RNA viral infection in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount compounds of the structural formula |.

In one embodiment of this aspect of the present invention, the RNA-dependent RNA viral polymerase is a positive-sense single-stranded RNA-dependent RNA viral polymerase. In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA viral polymerase is Riamimigidae viral polymerase or Risogpamygidae viral polymerase. In the subclass of this class Risogpamygidae, the viral polymerase is rhinovirus polymerase, poliovirus polymerase, or hepatitis A virus polymerase. In the second subclass, CM

The viral polymerase of this Riamimigidae class is selected from the group consisting of hepatitis virus polymerase o

C, yellow fever virus polymerase, dengue virus polymerase, West Nile virus polymerase, Japanese encephalitis virus polymerase, Banzi virus polymerase, and bovine viral diarrhea virus (BVDV) polymerase.

In a subgroup of this subclass Riamimigidae, the viral polymerase is the hepatitis C virus polymerase

In a second embodiment of this aspect of the present invention, RNA-dependent RNA viral replication is positive-sense single-stranded RNA-dependent RNA viral replication. In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA viral replication is Riamimigidae viral replication or C

Risogpamigidae viral replication. In the subclass of this class Rhisogpamigidae, the viral replication is rhinovirus (se) replication, poliovirus replication, or hepatitis A virus replication. In the second subclass of this class

Riamimigidae virus replication is selected from the group consisting of hepatitis C virus replication, yellow fever virus replication, dengue virus replication, West Nile virus replication, Japanese encephalitis virus replication, Bunzi virus replication, and bovine viral diarrhea virus replication. In a subgroup of this subclass Riamimigidae, viral replication is that of the hepatitis C virus.

In a third embodiment of this aspect of the present invention, the RNase-dependent RNA virus infection is a "positive-sense single-stranded RNA-dependent RNA virus infection." In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA virus infection is Riamimigidae virus infection or Risogpamygidae virus infection. In the Rhizogpamygidae subclass of this class, the viral infection is a rhinovirus infection, a poliovirus infection, or a hepatitis A virus infection. In the second subclass of this class, the Riamimygidae viral infection is selected from the group consisting of hepatitis C virus infection, yellow fever virus infection, dengue virus infection , West Nile virus infection, Japanese encephalitis virus infection, Banzi virus infection, and Bovine viral diarrhea virus infection. In a subgroup of this subclass - and Niamimigidae, the viral infection is hepatitis C virus infection. o In the text of the application under review, the following terms shall be then the value:

The above alkyl groups include alkyl groups of the specified length in a linear or branched (ee) configuration. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, fluoro-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, etc.

The term "alkenyl" means a straight or branched alkene chain containing from two to six carbon atoms or any number in this range (eg, ethenyl, propenyl, butenyl, pentenyl, etc.).

The term "alkynyl" means a straight or branched alkyne chain containing from two to six carbon atoms or any number in this range (eg, ethynyl, propynyl, butynyl, pentynyl, etc.).

The term "cycloalkyl" refers to cyclic alkane rings containing three to eight carbon atoms or any number in that range (ie, cyclopropyl, o-cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). ime) The term "cycloheteroalkyl" includes non-aromatic heterocycles that contain one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms. Examples of 4-6-ene cycloheteroalkyls include azetidinyl, pyrrolidinyl, 60o piperidinyl, morpholinyl, thiamorpholinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazinyl, etc.

The term "Alkoxy" refers to a straight or branched chain of alkoxides containing the specified number of carbon atoms (e.g., C-4-Alkoxy) or any number in the specified range (i.e., methoxy (Meo-), ethoxy, isopropoxy, etc. .d.1. 6E The term "alkylthio" refers to a straight or branched alkylsulfide chain containing the specified number of carbon atoms (eg, C..4-alkylthio) or any number in the specified interval (ie, methylthio (Mevz-), ethylthio, isopropylthio, etc.|.

The term "alkylamino" refers to straight or branched alkylamines containing the specified number of carbon atoms (eg, C1-4-alkylamino) or any number in the specified range (ie, methylamino, ethylamino, isopropylamino, tert-butylamino, etc. .|.

The term "alkylsulfonyl" refers to straight or branched alkylsulfones containing the specified number of carbon atoms (eg, C1-6-alkylsulfonyl) or any number in the specified range (ie, methylsulfonyl (Meso-5-), ethylsulfonyl, isopropylsulfonyl etc.|.

The term "alkyloxycarbonyl" refers to straight-chain or branched esters of a carboxylic acid derivative of the present invention containing the specified number of carbon atoms (for example,

C..-alkyloxycarbonyl) or any number in the specified range (ie methyloxycarbonyl (MEOCO-), ethyloxycarbonyl or butyloxycarbonyl.

The term "aryl" includes both phenyl, naphthyl and pyridyl. The aryl group is optionally substituted with one to three groups independently selected from C..4-alkyl, halogen, cyano, nitro, trifluoromethyl, C.-4-alkyl, and C.-4-alkylthio. 15 The term "halogen" includes halogen atoms: fluorine, chlorine, bromine and iodine.

The term "substituted" includes multiple degrees of substitution with specified substituents. When a plurality of substituting groups is disclosed or claimed, the substituted compound may be independently substituted with one or more of the disclosed or claimed substituting groups, one or more at a time.

The term "5'-triphosphate" refers to the derivative of the 5-hydroxyl group of the complex ester of triphosphoric 20 Acids of the group of nucleoside compounds of this invention, which have the following general structural formula 1: don

Io) o (8) shchi shchi DY; notatoalato go ra on on on o ms sm di do o v v" vne - Tu so de BV!-K"! have the above values. It is assumed that the compounds of this invention include "Its pharmaceutically acceptable salts of the triphosphate ester, as well as pharmaceutically acceptable salts of derivatives of 5-monophosphate and 5-diphosphate esters of the structural formulas IM and M, respectively, so de vya so o

TT you Brc-nolzo and ie in Fe and ME a vo « ih i from: - s (M . i? dz v'o o o

TSI Ii in M

R. R. O NA- -i nogatogito 2 on ono Med" d) in ve di 1 so with 2 y

In general, the term "5-(5-acyl-2-thioethyl)uphosphate" or "ZATE" refers to derivatives of complex mono- or diesters of derivatives of 5'-"monophosphate nucleosides of this invention of the structural formulas MI and MII, respectively, as well as to pharmaceutically acceptable salts of complex monoesters, pe do o o Stich, 8 v Y ko tr zt ulto | ry c on o yiv o B" in 60 4 1 in B vv (MI b5 v? dya (v)

IY v y M sho o o zm td" o u V" vo tu V! r: in me? (9) then a hundred (MIR

The term "composition" in the expression "pharmaceutical composition" includes the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product that is formed directly or indirectly by combining, complexing or aggregating any two or more ingredients, or as a result of the breakdown of one or more ingredients, or as a result of other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of this invention include any compositions obtained by mixing a compound of this invention and a pharmaceutically acceptable carrier.

The terms "reception" and "administration" of a compound should be understood as providing a compound of this invention or a prodrug form of a compound to an individual in need thereof.

Another aspect of the present invention relates to a method of inhibiting HCM M5Z5B polymerase, inhibiting HCM replication, or treating HCM infection with a compound of the present invention in combination with one or more agents that can be used to treat HCM infection. Such agents active against NSMU include (but are not limited to) ribavirin, levavirin, viramidine, thymosin alfa-1, interferon-A, pegylated interferon-A (peginterferon-A), combination of interferon-A and ribavirin, combination of peginterferon-A and ribavirin, a combination of interferon-A and levavirin, and a combination of peginterferon-A and levavirin. Interferon-α includes (but is not limited to) recombinant interferon-5 2a (such as Koiegop interferon available from

Neutapp-IakKospe, Mysheu, MU), pegylated interferon-o, 2a (Redazuvtm), interferon-o, 25 (such as Ipigop-A interferon, available from Zspegipd Sogr., Kepimogy, Mu) pegylated interferon-o 265 ( Readipigoptm), a recombinant consensus interferon (such as interferon α-Irpasop-1) and a purified product of interferon-A.

Recombinant consensus interferon Atodep has the trademark Ipiegdep?. Levavirin is a

I-enantiomer of ribavirin, which exhibits immunomodulatory activity similar to ribavirin. Viramidine is an analogue of ribavirin, disclosed in MUO01/60379 (the legal successor of ISM RNagtaseciis!Iz). According to the method of the present invention, the individual components of the combination can be administered separately at different points in time during the course of treatment

35 treatment either simultaneously in a separate or single combined form. Therefore, the present invention should be understood as including all such regimens of simultaneous treatment or alternating treatment, and the term "administration" should be interpreted accordingly. It should be noted that the scope of combinations of the compounds of this invention with other agents that can be used for HCM infection includes, in principle, any combination with any pharmaceutical composition for the treatment of HCM infection. When a compound of this invention or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against NSC, the dose of each of the compounds may be the same or different from the dose in the case where this compound is used separately. "" For the treatment of HCM infection, the compounds of this invention can also be administered in combination with an agent that is an inhibitor of HCM M5Z serine protease. NCM M5Z serine protease is the major viral enzyme and has been shown to

That it is an excellent target for inhibiting HCM replication. Inhibitors of NSM MZZ protease, both on a substrate and without a substrate, disclosed in MO 98/22496, UMO 98/46630, UMO 99/07733, MO 99/07734, MO 99/38888, MO 99/50230,

MO 99/64442, MO 00/09543, MO 00/59929 and 58-2337262. NSM M53Z protease as a target for the development of inhibitors of NOM replication and for the treatment of NSM infection, discussed in V.MU. YuOutosK, "Etegaipud (Pegariyez Tog Perayyiz S

Go) migiv iptesiop", Yetegdipd YuOgidv, 6: 13-42 (2001).

Ribavirin, levavirin and viramidine can exert their anti-NSM effect by modulating the intracellular t- volume of guanine nucleotides due to inhibition of the intracellular enzyme inosine monophosphate dehydrogenase se" (IMRON). IMRON is the rate-limiting enzyme in the de pomo guanine nucleotide biosynthesis pathway. Ribavirin is easily phosphorylated intracellularly, and the monophosphate derivative is an inhibitor of IMRON. Thus, the inhibition of IMRON represents another suitable target for the discovery of inhibitors of HCM replication. Therefore, the compounds of this invention can also be administered in combination with an IMRON inhibitor, such as MX-497, disclosed in

MO 97/41211 and MO 01/00622 (successor of Meghieh); another IMRON inhibitor such as that disclosed in

F) MO 00/25780 (successor of VgizioI-Muege Zatsirb); or with mycophenolate mofetil (tusorpepoia(e togeiii) (see ko A.S. AiYizop apa E.M. Etsii, Adepiv Asiiop. 44 (Zirri.): 165 (1993)).

For the treatment of NSM infection, the compounds of this invention can also be administered in combination with the antiviral agent amantadine (1-aminoadamantane) for a detailed description of this agent, see: 3). Kiggespracht, Apai. Rgoyez Yugod

BibBvg. 12: 1-36 (1983)).

The term "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the composition and must not have a harmful effect on the recipient.

The scope of this invention also includes pharmaceutical compositions that include nucleoside compounds and their former derivatives together with a pharmaceutically acceptable carrier. Another example of this invention is a pharmaceutical composition obtained as a result of a combination of any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a method of preparing a pharmaceutical composition, which includes combining any of the compounds described above and a pharmaceutically acceptable carrier.

The scope of this invention also includes pharmaceutical compositions suitable for inhibiting RNA-dependent

RNA viral polymerase, in particular, NSM M55B polymerase, which contain an effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions suitable for the treatment of RNA-dependent

RNA viral infection, in particular, NSM infection, are also included in the scope of this invention, as well as a method of inhibiting RNA-dependent RNA viral polymerase, in particular, NSM M55B polymerase, and a method of inhibiting

RNA-dependent viral replication and, in particular, HSM replication. In addition, the present invention relates to a 7/0 pharmaceutical composition that includes a therapeutically effective amount of a compound of this invention in combination with a therapeutically effective amount of another agent active against RNA-dependent RNA virus, and in particular, against NSU. Agents active against NSU include (but are not limited to) ribavirin, levavirin, viramidine, thymosin alfa-1, NSM M53 serine protease inhibitor, interferon-A, pegylated interferon-A (peginterferon-o, ), combination of interferon-A and ribavirin , a combination of peginterferon-A and ribavirin, a combination of interferon-A 75 and levavirin, and a combination of peginterferon-o and levavirin. Interferon-a includes (but is not limited to) recombinant interferon-o 2a (such as Koiegop interferon, available from Neutapp-I akospe, Mysheu, MU), interferon-o 25 (such as Ipigop-A interferon, available from 5spegipa Sogr. , Kepimogii, Moscow State University), consensus interferon and purified interferon-o product. For a discussion of ribavirin and its activity against NSM, see:

U.O. Zashypaege apa 5.A. KaurisK, "Ipovipe Moporpozripaiie YuOepuadgodepaze: Sopvzidegayop oi Zigysiige, Kipeyisv, apa Tpegareciis Rogepia!", App. Ker. Honey. Spet., 35: 201-210 (2000).

Another aspect of this invention proposes the use of nucleoside compounds and their derivatives and their pharmaceutical compositions for the manufacture of drugs for inhibiting RNA-dependent RNA viral replication, in particular, HCM replication, and/or for the treatment of RNA-dependent RNA viral infection, in particular, HCM infection. In yet another aspect of the present invention, nucleoside compounds, their derivatives and their pharmaceutical compositions are proposed by SM as drugs for inhibiting RNA-dependent RNA viral replication, in particular, NSM replication, and/or for the treatment of

RNE-dependent RNA virus infection, in particular, NSM infection.

The pharmaceutical compositions of this invention include a compound of structural formula I as an active ingredient or a pharmaceutically acceptable salt thereof and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. co

Compositions of the invention include compositions for oral, rectal administration, external use, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ocular), pulmonary (through the nose or by inhalation) or nasal administration, although the most suitable d) in in this case, the method will depend on the nature and severity of the condition to be treated and the nature of the active ingredient. They can usually be presented in a single (standard) dosage form and prepared by any of the methods known to pharmacists. -

In practice, compounds of the structural formula | can be combined as an active ingredient in a homogeneous mixture with a pharmaceutical carrier using conventional pharmaceutical mixing techniques. The carrier can take a large number of different forms depending on the form of the drug to be administered, for example, oral or parenteral (including intravenous). In the preparation of compositions for oral dosage forms, any conventional pharmaceutical medium can be used, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, etc. in the case of liquid preparations for oral administration, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, » microcrystalline cellulose, diluents, granulating agents, lubricating agents, binders, disintegrants, etc. in the case of solid preparations for oral administration, such as, for example, powders, hard and soft capsules and tablets, and solid preparations for oral administration are more preferred than liquid preparations. Because of ease of administration, tablets and capsules are the most convenient standard unit dosage forms for oral administration, and solid pharmaceutical carriers are commonly used in this case. If desired, tablets can be coated using standard aqueous or anhydrous iz 50 techniques. Such compositions and preparations should contain at least 0.195% of the active compound. Naturally, the percentage of active compound in these compositions can vary and usually can be in the range of about 2 to about c" bOms. 96 per unit. The amount of active compound in such therapeutically suitable compositions should be such that the effective dose is achieved. The active compounds can also be administered intranasally, for example, in the form of liquid drops or sprays. 22 Tablets, pills, capsules, etc. may also contain a binding agent such as gum tragacanth, o acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a leavening agent such as corn starch, potato starch, alginic acid; a lubricating agent such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a unit dose is prepared in capsule form, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. 60 Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. The syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, coloring agents, and flavoring agents such as cherry or orange flavor.

Compounds of the structural formula | can also be administered parenterally. Solutions or suspensions of these active b5 compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol and in their mixtures in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for use in the form of injections include sterile aqueous solutions or dispersions and sterile powders for preparing sterile solutions or dispersions for injections immediately before use. In all cases, the form must be sterile and must be liquid so that it can be easily injected through a syringe. It must be stable under cooking and storage conditions and must be protected from contamination caused by the action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium that includes, for example, water, ethanol, polyol (eg, glycerin, 7/0 propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration can be used to provide a mammal, particularly a human, with an effective dose of a compound of this invention. For example, you can use oral, rectal, external, parenteral, ocular, pulmonary, nasal, etc. methods

Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Mostly compounds of the structural formula | to enter orally.

For oral administration to humans, the dose interval is from 0.01 to 100 Ωg/kg of body weight in divided doses.

In one embodiment, the dose range is from 0.1 to 1OOmg/kg of body weight in divided doses. In another embodiment, the dose range is from 0.5 to 20 mg/kg of body weight in divided doses. For oral administration, the composition is preferably prepared in the form of tablets or capsules containing from 1.0 to 100 mg of the active ingredient, in particular, 201, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250 , 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for symptomatic dose adjustment for the patient to be treated.

The effective dose of the active ingredient used may vary depending on the particular compound used, the route of administration, the condition to be treated, and the severity of the condition to be treated. Such doses can easily be determined by a specialist in this field. Such a dosage regimen can be selected to ensure an optimal therapeutic response.

The compounds of this invention contain one or more asymmetric centers and therefore can exist in the form of i) racemates or racemic mixtures, individual enantiomers, mixtures of diastereoisomers and individual diastereoisomers. It is understood that the present invention includes nucleoside compounds having the B - O stereochemical configuration of a five-membered furanose ring, as represented by the structural formula below, so z o ie nucleoside compounds in which the substituents at C-1 and C-4 of the five-membered of the furanose ring have a B -stereochemical configuration (orientation "up", as indicated by a bold line). From dov" (se) "br | y

Some of the compounds disclosed herein contain olefinic double bonds and, unless otherwise indicated, are intended to include both E- and and 2-geometric isomers.

Some of the compounds disclosed herein may exist in tautomeric form, such as ketoenol tautomers. Individual tautomers, as well as their mixtures, are included in the compounds of the structural formula I. An example of ketoenol tautomers included in the compounds of this invention is illustrated below: MK d! 4 in! machines

Fe p in them. vd? yes dg

Compounds of the structural formula | can be separated into individual diastereoisomers, for example, by fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate, or a mixture thereof, or by (F) chiral chromatography using an optically active stationary phase.

GI Alternatively, any stereoisomer of a compound of the structural formula | can be obtained as a result of stereospecific synthesis, using optically pure starting materials or reagents of known configuration. in the stereochemistry of the substituents in the C-2 and 0-3 positions of the furanose ring of the compounds of this invention of the structural formula | denoted by wavy lines, which mean that the substituents B 7, 2, BZ and c? can be in the α-(substituent "down") or p -(substituent "up") configuration independently of each other. Stereochemistry designation with a bold line, as in C-1 and C-4 of the furanose ring, means that the substituent has a p-configuration ("up" substituent).

That M yav h ; : Ko) and in M v v - 65

In in! ri o s v in 5-2 70 ()

The compounds of this invention can be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts obtained from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds covered by the term "pharmaceutically acceptable salt" refer to non-toxic salts of compounds of this 72 invention, which are usually obtained by reacting a free base with a suitable organic or inorganic acid. Representative salts of the principal compounds of this invention include (but are not limited to) the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate (satvuia(e), carbonate, chloride, clavulanate (siamciapaie), citrate, dihydrochloride . , methyl sulfate, mucate, napsylate, nitrate, ammonium salt

M-methylglucamine, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate. In addition, if the compounds of this invention contain an acidic group, then their pharmaceutically acceptable salts include (but are not limited to) salts derived from inorganic bases, including aluminum, d) ammonium, calcium, copper, iron(II), iron(I !), lithium, magnesium, manganese), manganese(II), potassium, sodium, zinc, etc. The most preferred salts are ammonium, calcium, magnesium, potassium and sodium. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, M,M-dibenzylethylenediamine, and diethylamine, 2-diethylaminoethanol, 2 -dimethylaminoethanol, ethanolamine, ethylenediamine, M-ethylmorpholine, "g

M-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. with

In addition, if the compounds of this invention contain a carboxylic acid group (-COOH) or an alcohol group,

Pharmaceutically acceptable esters of carboxylic acid derivatives, such as n-methyl, ethyl, or pivaloyloxymethyl, or acyl alcohol derivatives, such as acetate or maleate, can be used.

Also included are those ester and acyl groups known to those skilled in the art to modify solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

Preparation of nucleoside compounds and derivatives of this invention C c Nucleoside compounds and their derivatives of this invention can be obtained in accordance with widely known synthesis methods used in the chemistry of nucleosides and nucleotides. Reference is made to the following text for a description of the synthesis methods used in the preparation compounds of this invention: "Spetivigu oi Mysieovidez apa Mysieoyidev", 1.V. Tom/upzepa, ed., Moiv. 1-3, Riepyt Rgezz, 1988, which is incorporated herein by reference in its entirety. - A representative general method for the preparation of the compounds of this invention is presented below in Scheme 1. This 2) scheme illustrates the synthesis of the compounds of this invention of structural formula 1-7, where the furanose ring has a p-YB-ribo configuration. The starting material is a 3,5-bis-O-protected alkylfuranoside, such as methylfuranoside of the structural formula 1-1. The C-2 hydroxyl group is oxidized using a suitable oxidizing agent, such as chromium trioxide or chromate reagent, Oeevzv-Magip periodinan, or using Swern oxidation, obtaining a C-2 ketone of structural formula 1-2. Addition of a Grignard reagent such as a c» alkyl-, alkenyl-, or alkynylmagnesium halide (e.g., MemoHg, EMOVg, vinyl-MoHg, allyl-MoHg, and ethynyl-MoHg) or an alkyl-, alkenyl-, or alkynyllithium such as Mey and, on the carbonyl double bond 1-2 in a suitable organic solvent, such as tetrahydrofuran, diethyl ether, etc., leads to obtaining C-2 29 tertiary alcohol of the structural formula KZ. A suitable protecting group (such as CI, Bg and I) is then introduced at the C-1 (PI (anomeric) position of the furanose sugar derivative using treatment of the furanoside of formula 1-3 with hydrogen halide in a suitable organic solvent such as hydrogen bromide in acetic acid to give o intermediate furanosyl halide 1-4. 0-1 sulfonate, such as methanesulfonate (Mebzo 50-), trifluoromethanesulfonate (СЕР3z50О2О0-) or p-toluenesulfonate (-0OT5), can also serve as suitable leaving groups in the following reaction to obtain glycosidic (nucleoside ) bond A nucleoside bond is created by treating an intermediate of structural formula 1-4 with a metal (such as lithium, potassium, or sodium) salt of an appropriately substituted 1H-pyrrolo(2,3-4|pyrimidine 1-5 such as appropriately substituted 4-halo-1H-pyrrolo|2,3-4|pyrimidine, which can be obtained by treatment with alkali metal hydride (such as sodium hydride), alkali metal hydroxide (such as potassium hydroxide), alkali metal carbonate o metal (such as sodium carbonate) or alkali metal hexamethyldisilazide (such as Manmo5) in a suitable anhydrous organic solvent such as acetonitrile, tetrahydrofuran, 1-methyl-2-pyrrolidinone or M,M-dimethylformamide (DMF). The substitution reaction can be carried out with a catalyst using a phase transfer catalyst such as TOA-1 or triethylbenzylammonium chloride in a two-phase system (solid-liquid or liquid-liquid). Optional protective groups in the protected nucleoside of structural formula 1-6 are then cleaved off using conventional methods for removing protective groups, such as those described in T.MU. Sgeepe apa

RUM. MUtsiv, "Rgogesiime Sgoimrz ip Ogdapis Zupipeziv", Zga ed., dopp U/iIeu "« Zopv, 1999. Optional introduction of an amino group into the 4-position of pyrrolo|2,3-hy|pyrimidine nuclei is carried out using treatment of the 4-halogen intermediate compounds 1-6 with an appropriate amine, such as alcoholic ammonia or liquid ammonia, to obtain a 7/0 primary amine at the C-4 position (-MH»o), an alkylamine to obtain a secondary amine (-MNK), or a dialkylamine to obtain a tertiary amine ( - MEBE 7). The compound 7H-pyrrolo|2,3-4Ipyrimidin-4(3ZH)-one can be obtained by hydrolysis of 1-6 with an aqueous base such as aqueous sodium hydroxide. Alcoholysis (such as methanolysis) of 1-6 yields a C-4 alkoxide (-OK), while treatment with an alkyl mercaptide yields a C-4 alkylthio (-ZK) derivative. The following chemical manipulations, well known to specialists in the field of organic/medicinal 75 Chemistry, may be necessary to obtain the desired compounds of this invention.

Scheme

ROIO o RO o on oyu v'mah g t H

Rob On Rob o (X-SI, Ve or 1) in Re-protective group Ve:

C-lower alkyl

A (8)

In h

I | m

RAH Lo Rao7lo Z o 00 conditions x u " nh 4 and vo ishv Sea "

ROYU On HeS, Vgaboyi ROYU on ---38---- 5- so; 1-4 Me, Ma side

IZ - X-SI, Vgaboi so i - yah deya" r zav 0 RODO o mm tdy no o t tv" -o 1. removal of Re 4 s v' sen - in KU t 2. optional them » Ra on replacement of X by K" but on 1-6 and -- -I In the following examples, there are references to literature publications that contain detailed instructions on methods of obtaining the target compounds or intermediate compounds used in the preparation of the target compounds

Mother compounds of this invention. The nucleoside compounds of this invention were prepared according to the methods described in detail in the following examples. These examples do not in any way limit the scope of the present invention and should not be construed as such. It will be obvious to specialists in the field of synthesis of nucleosides and nucleotides that for the preparation of these and other compounds of the present invention, it is possible to use known variants of the conditions and processes of the above-mentioned preparation methods of these compounds. All temperatures are in degrees Celsius unless otherwise noted.

Example 1 4-amino-7-(2-C-methyl-r.-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine o Mn y ho m-a vo 0 o M on

To chromium trioxide (1.57g, 1.57mol) in dichloromethane (OSM) (1Oml) at 02С, acetic anhydride (145mg,

1.41 mol) and then pyridine (245 mg, 3.1 mol). The mixture was stirred for 15 minutes, then a solution of 7-I3,5-0-11,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl|- p -B-ribofuranosyl|-7H-pyrrolo| 2,Za|Ipyrimidine-4-amine (method of preparation see: 9). At. Spent Zos. 105: 4059 (1983)) (508 mg, 1.00 mol) in OSM (Zml). The resulting solution was stirred for 2 hours, then poured into ethyl acetate (10 mL) and then filtered through silica gel using ethyl acetate as eluent. The combined filtrates were evaporated under vacuum, placed in a mixture of diethyl ether/THF (1:1) (20ml), cooled to -789C and methylmagnesium bromide (ZM, in THF) (3.30ml, 1Omol) was added dropwise. The mixture was stirred at -782C for minutes, then allowed to cool to room temperature and quenched by adding saturated aqueous 70 ammonium chloride (1Oml) and extracted with OSM (2Oml). The organic phase was evaporated in vacuo and the crude product was purified on silica gel using 595% methanol in dichloromethane as eluent. Fractions containing the product were combined and evaporated in vacuo. The obtained oil was placed in THF (5 ml) and tetrabutylammonium fluoride (TVAE) on silica gel (1.1 mol/g silica gel) (15 mg) was added. The mixture was stirred at room temperature for 30 minutes, filtered and evaporated in vacuo. The crude product was purified on silica gel using 1095 methanol in 75 dichloromethane as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired compound (49 mg) as a colorless solid. 7"H-NMR (DMSO-div): 5 1.08 (p, 3H), 3.67 (m, 2H), 3.74 (m, 1H), 3.83 (m, 1H), 5, 19 (m, 1H), 5.23 (m, MN), 5.48 (m, 1H), 6.08 (1H, s), 6.50 (m, 1H), 6.93 (width , 2H), 7.33 (m, 1H), 8.02 (s, 1H).

Example 2 4-amino-7-(2-C-methyl-rd. -Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

Mne sh- p 25. BUT o M o

Mind on him

Stage A: 3,5-bis-O-(2,4-dichlorophenylmethyl)-1-O-methyl-o,-Y-ribofuranose co

Mixture of 2-O-acetyl-3,5-bis-0-(2,4-dichlorophenylmethyl)-1-0-methyl-o,-O-ribo-furanose | method of preparation see: «

German Sleep Asia 78: 486 (1995)| (52.4g, 0.1Omol) in methanolic K»CO»z (500 ml, saturated at room temperature) was stirred at room temperature for 45 minutes and then concentrated under reduced 90 pressure. The oily residue was suspended in SiO2 (500 ml), washed with water (30 ml of 5 x 200 ml) and brine (200 ml), dried (Na 2 O), filtered and concentrated to give the title compound (49.0 g) as a colorless oil, which was used without additional purification in stage B further. in.

TN-NMR (DMSO-dyv): 5 3.28 (p, ZN, OSN»U), 3.53 (d, 2H, Uvda-4.5 Hz, H-za, H-5B), 3.72 (dd, 1H, 9Uz4-3.6 Gu,

Ud»-6.6 Hz, H-3), 3.99 (ddd, 1H, 924-545 Hz, U2,on-2-9.6 Hz, H-2), 4.07 (m, 1H, H-4), 4.50 (s, 2H, SNORN), 4.52, 4.60 (2d, 2H, Odet-13.6 Hu, SNORN), 4.54 (d, 1H, OH-2) , 4.75 (d, 1H, H-1), 7.32-7.45, 7.52-7.57 (2m, OH, 2PH). « 20 ZS-NMR (DMSO-ydv): 5 55.40, 69.05, 69.74, 71.29, 72.02, 78.41, 81.45, 103.44, 127.83, 127, 95, 129.05, -in s 129.28, 131.27, 131.30, 133.22, 133.26, 133.55, 133.67, 135.45, 135.92.

Stage B: 3,5-bis-0-(2,4-dichlorophenylmethyl-1-O-methyl-o,-O-erythropento-furanose-2-ulose;» To the ice-cooled suspension of Oezv-Magiip periodinan (50.0g . 0.5 hours and then at room temperature for 3 days. The mixture was diluted with anhydrous ESO (b0Oml) and poured into an ice-cooled mixture

Ma»52Oz.5H2O (180g) in saturated aqueous MansSoO» (1400O0ml). The layers were separated and the organic layer was washed

Mn with saturated aqueous ManHsSoOz (b0Oml), water (80O0ml) and brine (bOOml), dried (Mao), (oo) filtered and evaporated to give the title compound (34.2g) as a colorless oil, which was used without additional cleaning at stage C further. e T"H-NMR (SOSIVv): 5 3.50 (p, ZN, OSN.), 3.79 (dd, 1H, Uvakhv-11.3 Hz, Uvam-3.5 Hz, N-Ba) . 4.37 (ddd, 1H, H-4), 4.58, 4.69 (2d, 2H, Odet- 13.0 Hz, SNR), 4.87 (d, 1H, H-1), 4, 78, 5.03 (2d, 2H, Udet-12.5 Hz, SNORN), 7.19-7.26, 7.31-7.42 (2m, TON, 2RN).

ISS-NMR (DMSO-iv): 5 55.72, 69.41, 69.81, 69.98, 77.49, 78.00, 98.54, 127.99, 128.06, 129.33, 129.38, 22 131.36, 131.72, 133.61, 133.63, 133.85, 133.97, 134.72, 135.32, 208.21.

F! Stage C: 3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-methyl-1-O-methyl-o,-O-ribo-furanose kyu To a solution of MemoVg in anhydrous EBO (0.48M , 30 Oml) at -552C, the solution of the stage compound was added dropwise

B (17.40 g, 36.2 mol) in anhydrous ESO (12 ml). The reaction mixture was left to heat up to -302C and stirred for 7 hours at a temperature from -302C to -1592C, then poured into ice-cooled water (500 ml) and the mixture was intensively stirred at room temperature for 0.5 hour. The mixture was filtered through a layer of celite (1 x 5 cm), which was thoroughly washed with EGO. The organic layer was dried (M950), filtered and concentrated.

The residue was dissolved in hexane (70 mL), introduced into a column with silica gel (10x7 cm, previously packed in hexane) and eluted with hexane and hexane/E(Ac (9/1), obtaining the title compound (16.7 g) as a colorless syrup. "H-NMR (SOSI"): δ 1.36 (5, ZN, Umeon-9.9 Hz, 20-Me), 3.33 (k, 1H, OH), 3.41 (d, 1H , 9Uz,4-3.3 Gu), 3.46 (c, ZN,

OSNU"), 3.66 (d, 2H, Ov, -3.7 Hz, H-5a, H-5B), 4.18 (imaginary square, 1H, H-4), 4.52 (s, 1H . -7.43 (2m, TON, 2RN).

ISS-NMR (SOS): 5 24.88, 5545, 69.95, 70.24, 70.88, 77.06, 82.18, 83.01, 107.63, 127.32, 129.36, 130.01, 130.32, 133.68, 133.78, 134.13, 134.18, 134.45, 134.58.

Stage p: 4-chloro-7-13,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-methyl-B-YB-ribo-furanosyl)-7H-pyrrolo|2,3-4 |pyrimidine

To a solution of the compound of stage C (9.42 g, 19 mol) in anhydrous dichloromethane (285 ml) at 02С was added dropwise

HBg (5.7M in acetic acid, 20ml, 114mol). The resulting solution was stirred at 02C for 1 hour and then at room temperature for 3 hours, evaporated in vacuo, and co-evaporated with anhydrous toluene (3x4O0ml). The oily residue was dissolved in anhydrous acetonitrile (5 Oml) and added to a solution of the sodium salt of 4-chloro-1H-pyrrolo|2,3-4|Ipyrimidine in acetonitrile (a mixture of 4-chloro-1H-pyrrolo|2,3-4 |Ipyrimidine |method of obtaining see u). Spent Zos: 131 (1960))| (8.76bg, 57mol) in anhydrous acetonitrile (1000ml) and Mann (6095 in mineral oil, 2.28g, 57mol) after 4 hours of vigorous stirring at room temperature|!. The combined mixture was stirred at room temperature for 24 hours and then evaporated to dryness. The residue was suspended in water (2500 ml) and extracted with EtOAc (2x50 ml).

The combined extracts were washed with saline (300 ml), dried over NaCl 5 O), filtered and evaporated.

The crude product was purified on a silica gel column (10cm x 1Ocm) using ethyl acetate/hexane (1:3 and 1:2) as eluent. Fractions containing the product were combined and evaporated in a vacuum, obtaining the desired product (B.05G) in the form of a colorless foam.

TN-NMR (SOSI): 5 0.93 (p, ZN, CH), 3.09 (s, 1H, OH), 3.78 (dd, 1H, Tv, -10.9Hz, dv 4-2 ,5 Hz, H-B'), 3.99 (dd, 1H, 95 4-22 Hz, H-5"), 4.23-4.34 (m, 2H, H-U, H-4" ), 4.63, 4.70 (2d, 2H, Udet-12.7 Hz, SNR), 4.71, 4.80 (2d, 2H, Udet-12.1 Gu, SNR), 6.54 ( d, 1H, Ov 6-3.8 Gu, H-5), 7.23-7.44 (m, TON, 2RH). high school

ISS-NMR (SOS): 5 21.31, 69.10, 7041, 70.77, 79.56, 80.41, 81.05, 91.11, 100.57, 118.21, 127.04, 127.46, 127.57, 129.73, 129.77, 130.57, 130.99, 133.51, 133.99, 134.33, 134.38, 134.74, 135.21, 151, 07, (o) 151.15, 152.47.

Stage E: 4-chloro-7-(2-C-methyl-rd. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

Boron trichloride (1M in dichloromethane, 8 vml, 8 vmol) was added dropwise to a solution of the compound of stage O (5.42 g, 8 vmol) in dichloromethane (175 ml) at a temperature of -782C. The mixture was stirred at -782C for 2.5 hours, then at a temperature from -3092C to -209C for 3 hours. The reaction was quenched by adding methanol/dichloromethane (1:11) (dFOml) and the resulting mixture was stirred at -159C for 30 minutes, then (ee) neutralized with aqueous ammonia at 02C and stirred at room temperature for 15 minutes. with

The solid part was filtered and washed with CHClCl/Meon (1/1, 250 ml). The combined filtrate was evaporated and the residue was purified using flash chromatography on silica gel using a gradient elution of СНоСИ» and its

SsnNosI.:mMeon (99:1, 98:2, 95:5 and 90:10) to give the desired compound (1.73g) as a colorless foam, which turned into an amorphous solid after treatment with Mesm.

TN-NMR (DMSO-ab): δ 0.64 (p, ЗН, СН), 3.61-3.71 (m, 1Н, Н-5), 3.79-3.88 (m, 1Н, H-5"), 3.89-4.01 (m, 2H, H-3, "

H-th), 5.15-5.23 (m, ZN, 2-OH, 3-OH, 5-OH), 6.24 (s, 1H, H-1", 6.72 (d, 1Н, Uvie-3.8 Hz, Н-5), 8.13 (d, 1ТН, Н-6), 70 8.65(s, 1Н, Н-2). n- s ISR-NMR (DMSO- av): 5 20,20, 59,95, 72,29, 79,37, 83,16, 91,53, 100,17, 117,63, 128,86,151,13,151,19, 151,45. » Stage E: 4-amino-7--2-C-methyl-p-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

To the compound of stage E (1.54g, 5.1mol) was added methanolic ammonia (saturated at 09C; 15Oml). The mixture was heated in a stainless steel autoclave at 85923 for 14 hours, then cooled and evaporated under vacuum. The crude mixture was purified on a silica gel column using SiOCl/Meon (9/1) as eluent to give the title compound as a colorless foam (0.8g), which was isolated as an amorphous solid after MeSM treatment. The amorphous solid was recrystallized from

Ho) methanol/acetonitrile; t.pl. 22296. their 50 TN-NMR (DMSO-aiv): 5 0.62 (p, ЗН, СН), 3.57-3.67 (m, 1Н, Н-5 ), 3.75-3.97 ( m, ЗН, Н-Б", Н-4, Н-3.), 5.00 (s, 1Н, 2-ОН), 5.04 (d, 1Н, with onz- 6.8 Hz, 3- OH), 5.06 (t, 1H, dv on 5.1 Gu, 5 -OH), 6.11 (s, 1H, H-1", 6.54 (d, syu 1H, ov 6-3 .6 Hz, H-5), 6.97 (width, 2H, МН»), 7.44 (d, 1H, H-6), 8.02 (s, 1H, H-2).

ISR-NMR (DMSO-α): 5 20.26, 60.42, 72.72, 79.30, 82.75, 91.20, 100.13, 103.08, 121.96, 150.37, 152.33, 158.15.

Liquid chromatography-mass spectroscopy (LC-MS): found: 279.10 (M-H 7); calculated for 29 hay: 2791. (F; Example Z

GI 4-amino-7-(2-C-ethyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

Mne bo ho zh no o M b5 no He

Stage A: 3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-ethyl-1-O-methyl-o,-B8-ribo-furanose

EMmMOVg (3.0OM, 16.bml) was slowly added to diethyl ether (300ml) at -782C and then the compound of stage B of example 2 (4.80g, 10.00mol) in anhydrous EBO (100ml) was added dropwise. The reaction mixture was stirred at -782C for 15 minutes, allowed to warm to -152C and stirred for another 2 hours, then water (300ml) and E2O (b00ml) were poured into the stirred mixture. The organic phase was separated, dried (Mao5O)) and evaporated in vacuo. The crude product was purified on silica gel using ethyl acetate/hexane (1:2) as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (3.87g) as a colorless oil.

Stage B: 4-chloro-7-(3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-ethyl- B -YB-ribo-furanosyl/|-7H-pyrrolo|2,3- 4 | Ipyrimidine

To a solution of the compound of stage A (1.02mg, 2.0mol) in dichloromethane (40ml) was added dropwise HBg (5.7M in acetic acid) (1.7bml, 10.00mol) at 02С. The resulting solution was stirred at room temperature for 2 hours, evaporated in vacuo and co-evaporated twice with toluene (1 Oml). The oily residue 72 was dissolved in acetonitrile (1 Oml) and added to a vigorously stirred mixture of 4-chloro-1H-pyrrolo|2,3-4|pyrimidine (307mg, 2.Omol), potassium hydroxide (337mg, b.Omol) and tris(2-(2-methoxyethoxy)ethylamine (13mg, 0.4mol) in acetonitrile (10ml). The resulting mixture was stirred at room temperature overnight and then poured into a stirred mixture of saturated ammonium chloride (100ml) and ethyl acetate (100 ml). The organic layer was separated, washed with saline solution (100 ml), dried over

MabBoO, was filtered and evaporated in vacuo. The crude product was purified on silica gel using ethyl acetate/hexane (1:2) as eluent to give the desired product (307mgHg) as a colorless foam.

Stage C: 4-chloro-7-(2-C-ethyl-r.-O-ribofuranosyl)-7H-pyrrolo(2,3-4|pyrimidine

Boron trichloride (1M in dichloromethane) (4.50ml, 4.500mol) was added to a solution of the compound of stage B (3307mg, 0.4bmol) in dichloromethane (dml) at -782C. The mixture was stirred at -782C for 1 hour, then at -1092C for 3 hours. The reaction was quenched by adding methanol/dichloromethane (1:11) (1 Oml), stirred at -159С27.Й 4353 for 30 minutes and neutralized by adding aqueous ammonium hydroxide. The mixture was evaporated under reduced pressure and the resulting oil was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (112 mg) as a colorless foam.

Stage 0: 4-amino-7-(2-C-ethyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine chE

Saturated ammonia in methanol (4ml) was added to the compound of stage C (5Omg, O0.1bmol). The mixture was stirred at 7590 for 72 hours in a closed container, cooled and evaporated in vacuo. The crude mixture was purified on silica gel using methanol/dichloromethane (1:9) as eluent. The product-containing fractions were combined and evaporated in vacuo to give the desired product (29 mg) as a colorless powder. M "H-NMR (200 MHz, DMSO-iv): δ 0.52 (s, ЗН), 1.02 (m, 2Н), 4.01-3.24 (m, 6Н), 5.06 ( m, 1H), 6.01 (s, 1H), 6.51 (d, 1H), 6.95 (width, 2H), 6.70 (d, 1H), 7.99 (s, 1H ).

LC-MS: found: 295.2 (M.-H7); calculated for С43Н418МааОу NN: 295.14. "

Example 4 2-amino-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidin-4(ZH)-one - c o ;" Synthesis of memory Step A: 2-amino-4-chloro-7-3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-methyl- Entry 5ro "B- ribofuranosyl|-7H-pyrrolo|2,3-a4|pyrimidine Y

To an ice-cooled solution of the product of stage C of example 2 (1.27 g, 2.57 mol) in CHClCl (3 ml) was added dropwise HBg (5.7 M in acetic acid; 3 ml). The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure and evaporated together with toluene (2x15ml). The resulting oil was dissolved in acetonitrile (MesSmMm) (15 ml) and added dropwise to a well-stirred mixture of 2-amino-4-chloro-7H-pyrrolo|2,3-a|pyrimidine (for the method of preparation, see: Neyegosusiev 35 : 825 (1993)) (43µg, 2.5mol), KOH (8595, powder) (0.51g, 7.7mol), tris(2-(2-methoxyethoxy)ethylamine (1b5µl, 0.5mol) in

F) acetonitrile (ZOml). The resulting mixture was stirred at room temperature for 1 hour, filtered and evaporated. The residue was purified on a silica gel column using hexane/E(Ac, 5/1, 3/1, and 2/1) as eluent to afford the title compound as a colorless foam (0.65 g). v Step B: 2- amino-4-chloro-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine

Boron trichloride (1M in

СНоСИ2) (1Oml, 1Omol). The mixture was stirred at -782C for 2 hours, then at -202C for 2.5 hours.

The reaction was quenched using SNOCl/Meon (1:1) (1 Oml), stirred at -202C for 0.5 hour and neutralized at 09C with aqueous ammonia. The solid part was filtered, washed with СНоСИ./Меон (1711) and the combined filtrate was evaporated under vacuum. The residue was purified on a silica gel column using

CsNoCI.Meon, 50/11 and 20/1, as eluent, giving the title compound as a colorless foam

(25Omg).

Stage C: 2-amino-7-(2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidin-4(ZH)-one

A mixture of the product of stage B (ZOmg, O, Zmol) in aqueous Mahon (2N, Oml) was heated at reflux temperature for 5 hours, then neutralized at 09C with 2N aqueous HCl and evaporated to dryness. As a result of purification on a silica gel column using CH 2SiI2/Meon, 5/1, as an eluent, the title compound was obtained as a white solid (7OmgHg).

TN-NMR (200 MHz, СО300): δ 0.86 (p, ЗН), 3.79 (m, 1Н), 3.90-4.05 (m, ЗН), 6.06 (s, 1Н) , 6.42 (d, 9U-3.7

Hz, 1H), 7.05 (d, 9-3.7 Hz, 1H).

Example 5 2-amino-4-cyclopropylamino-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine nm-te M m no o M Mn.

That's it

M on the

A solution of 2-amino-4-chloro-7-(2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine (example 4, stage B) (21mg, O0.07mol ) in cyclopropylamine (O,bml) was heated at 709C for 2 days, then evaporated to an oily residue and purified on a silica gel column using CH SiO/Meon, 20/1, as eluent to give the title compound as a white solid color (17 mgH). s 25 TN-NMR (200 MHz, SOZSM): 5 0.61 (w 2H), 0.81 (m, 2H), 0.85 (s, ЗН), 2.83 (m, 1H), 3, 74-3.86 (m, 1H), o 3.93-4.03 (m, 2H), 4.11 (d, U-8.9 Hz, 1H), 6.02 (s, 1H), 6.49 (d, 9U-3.7 Hz, 1H), 7.00 (d, 9-3.7 Hz, 1H).

Example 6 4-amino-7-(2-C-methyl-dr.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine-5-carbonitrile

Mo 00 МН at 30 no-h o, so des and 35 on he i-

This compound was obtained according to the method described by U. Mygai (a). in Neb (egosusieez 33:391-404(1992).

Example 7 4-amino-7-(2-C-methyl-dr.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine-5-carboxamide « 40 o t s NM mA; ;" y i M no-- y m 45 - uh so no On so This compound was obtained according to the method described by U. Mygai ei a). in Neb (egosusieez 33:391-404(1992).

Example 8 and The general method of obtaining ZATE of a prodrug fragment with 3-acyl-2-thioethyl (ZATE) pronucleotides is discussed in S.K. UUadpeg, M.M. Iueg, apa E.). Mesipive, "Rgopisieoiidev: Toulaga (She Ip Mimo Oeiimegu oi Apiimigai apa Apiiisapseg Mysieoiidev", Mei. Kev. Chem., 20: 1-35 (2000), the contents of which are incorporated herein by reference in their entirety. BUT, nucleoside derivatives are disclosed in also in U.S. Patent Nos. 5,770,725, 5,849,905, and 6,020,482, the contents of which are also incorporated herein by reference in their entirety.(F) Bis(5-acetyl-2-thioethyl)-M,M-diisopropylphosphoramidite and 2-mercaptoethanol (5 g, 4 mmol) was dissolved in CH"oCl" (5O0ml). Triethylamine (7.67ml, 57.bmol) was added to this solution and the reaction mixture was cooled in an ice bath to 02C. In 10 minutes, acetic anhydride (4.54ml, 48mol) was added dropwise ) and the reaction mixture was stirred for 1 hour at 02 C. The reaction mixture was then allowed to warm to room temperature for 2 hours. The reaction mixture was diluted with CH 2 SiO (50 mL), washed with water (75 mL), 5956 aqueous MnSO" (75 mL), and brine (75 mL ).The organic phase was dried over anhydrous Ma»5O and concentrated in vacuo to give an oil . Then this oil was dissolved in anhydrous THF (40 ml) and anhydrous triethylamine (7.7 bml) was added. Activated molecular sieves (4E) were added to this mixture and kept at room temperature for 10 minutes. The reaction mixture was cooled in an ice bath to 02C and diisopropylphosphoramide dichloride (6.47 g, 32.0 mol) was added. The reaction mixture was stirred at

0б0еС for 2 hours in an inert atmosphere. Hexane (40 ml) was added to the reaction mixture and the resulting precipitate was filtered off. The resulting filtrate was concentrated to a quarter of the volume, purified by chromatography on a column with silica gel and eluted with hexane, which contains 395 triethylamine and increasing

of ethyl acetate (0-795), yielding the title compound as an oil (2.36g).

TN-NMR (SOSI"): δ 1.17 (p, 6H), 1.21 (s, 6H), 2.36 (s, 6H), 3.14 (t, U-6.44 Hz), 3.51-3.84 (m, 6H). 1ZS-NMR (SOSI»v): δ 24.47, 24.61, 30.48, 42.85, 43.1, 61.88, 62.23, 195.26. 1Zr-NMR (SOSI»v): 5 146.96.

Example 9 5-triphosphate derivatives

Nucleoside 5'-triphosphates of this invention were obtained according to the methods described in Spet. Kew. 100: 2047 (2000).

Example 10

Purification and analysis of the degree of purity of 5'-triphosphate derivatives

The triphosphate derivatives were purified by anion exchange (AX) chromatography using a column

30x100 mm Mopo O (Rpagtasia) with a buffer system of 5 Ω, pH 8. Elution gradients were usually from 40 mm Mass to 0.8 M Mass in two column volumes at a speed of 6 b.5 ml/min. The corresponding fractions obtained by anion exchange chromatography were collected and desalted by reverse phase chromatography (RP) using a C18 250x21 mm column (RPepotepeh) at a flow rate of 1 Oml/min.

Elution gradients were typically 195 to 9595 methanol after 14 minutes at constant concentration

B5MM of triethylammonium acetate (TEAA).

The mass spectra of the purified triphosphates were obtained using a device where HPLC and mass spectrometer Nemiei-Raskaga (Raio A, SA) MBO 1100 were combined in series. For reversed-phase HPLC, the

Rpepotepeh I pa (C 18(2)), 150x2mm, plus 30x2mm diameter column with particle size Zmkm. Gradient elution was carried out with a linear gradient from 0 to 5095 (15 minutes) of acetonitrile in 20 mm TEAA Ge) (triethylammonium acetate) pH 7 with a serially connected mass spectral detector in the negative ionization mode. Nitrogen gas and a pneumatic atomizer were used to create a flow of ions.

Masses in the range of 150-900 were obtained. Molecular weights were determined using HP analytical programs

Speptvzvgiaiop apaiuziz rasKade. Shk

The degree of purity of the purified triphosphates was determined using analytical reversed-phase HPLC and "Ж anion-exchange HPLC. Reversed-phase HPLC with a RPepotopeh I pa or dirig column (250x4,bmm), with a particle size of 5-μm was usually carried out with a gradient of 2-7095 acetonitrile in 100 mM TEAA, pH 7, after 15 09 minutes. Anion-exchange HPLC was carried out on a 1.6 x 5 mm Mopo CO column (Rpaptasia). Triphosphates were eluted with a 9 gradient from 0 to 0.4 M Mass at a constant concentration of 500 mM Ttiv, pH 8. The degree of purity of triphosphates is usually more than 8095. -

Example 11 5-monophosphate derivatives

Nucleoside 5-monophosphates of this invention were obtained according to the method described by Teigapedop Gay. 50: « du 5065 (1967). -at

Example 12 c Mass-spectral characteristics of 5'-triphosphate derivatives :z" Mass spectra of 5'-triphosphates of the compounds of this invention were obtained according to the method of example 10. The following table lists the calculated and experimental masses for representative 5'-triphosphates obtained by 15 by the method of example 9. The numbers of the examples correspond to the starting compound of 5'-triphosphate. and. s so te 7 s" Example 13

I(4-amino-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine)|-5'-monophosphate chne h (F) c) te Y ,

SHCI M - ko bu M no sn. 60 i 8 but he

Trimethyl phosphate (0.5 ml) was added to the compound of stage E of example 2 (14 mg, 0.05 mol) (dried as a result of co-evaporation with pyridine and several times with toluene). The mixture was stirred overnight in a sealed container. Then it was cooled to 02 and phosphorus chloride (0.007 Oml, 0.075 mol) was added through a syringe. 65 The mixture was stirred for 3 hours at 02C, then the reaction was quenched by adding tetraethylammonium bicarbonate (TEAB) (1M) (0.5ml) and water (5ml). The reaction mixture was purified and analyzed according to the method of example 10.

Mass spectrum with electron scattering (ЕЗ-М5): found: 359.2 (М-Н 7), calculated for С42Н47М4О7Р-Н":

Example 14

I(4-amino-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine|-5. diphosphate

Mn h

Y Y M - about your U M no no and / sna no on

To the compound of stage E of example 2 (5 mg, 0.20 mol) (dried by co-evaporation with pyridine and several times with toluene) was added trimethyl phosphate (which was stored over sieves) (1.0 ml). The mixture was stirred overnight in a sealed container. Then it was cooled to 0 C and phosphorus chloride (0.02 ml, 0.25 mol) was added through a syringe. The mixture was stirred for 2 hours at 02C, then tributylamine (0.23 in 8 ml, 1.00 mol) and tributylammonium phosphate (obtained from phosphoric acid and tributylamine in pyridine followed by azeotropic distillation with pyridine and acetonitrile) were added (1.00 mol in 3.30 ml of acetonitrile) . The mixture was stirred for additional 30 minutes at 02C, then the sealed ampoule was opened and the reaction was quenched by adding TEAV (1M) (1.Oml) and water (5ml). The reaction mixture was purified and analyzed according to the method of example 10.

E5-M8: found: 439.0 (M-H"), calculated for C42Ni8MaOchoRo-H: 439.04.

Example 15

I(4-amino-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine|-5'-triphosphate c

Mmn2 o -x a, no-v-o-R-0-rR-o oy and 1 Y (ze) zo no no no C

El - but he

To the compound of stage E of example 2 (20 mg, 0.07 mol) (dried by co-evaporation with pyridine and several hundred times with toluene) was added trimethyl phosphate (which was stored over sieves) (004 ml). The mixture was stirred overnight in a sealed container. Then it was cooled to 0 C and chlorine dioxide was added through a syringe

From phosphorus (0.007Oml, 0.075mol). The mixture was stirred for 3 hours at 02C, then tributylamine (0.083ml, 0.33B5mol), tributylammonium phosphate (127mg, 0.3Bmol) and acetonitrile (which was stored over sieves) (0.25ml) were added. The mixture was stirred for additional 30 minutes at 02C, then the sealed ampoule was opened, and the reaction was quenched by adding TEAV (1M) (0.5ml) and water (5ml). The reaction mixture was purified and analyzed according to the method "70 of example 10. -o s E5-M8: found: 519.0 (М-Н"), calculated for С42Нч19МаОч4зРа-Н: 519.01.

Example 16: 7-(2-C-methyl-p.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidin-4(ZH)-one about 2; m-n (95) Shk M (ee) | Aqueous sodium hydroxide (1M) was added to the compound of stage E of example 2 (5mg, 0.18mol). The mixture was heated at reflux for 1 hour, cooled, neutralized with aqueous NH (2M) and evaporated in vacuo. The residue was purified on silica gel using dichloromethane/methanol (4/1) as eluent.

Fractions containing the product were combined and evaporated in vacuo to give the desired product (5 mg) as a colorless oil. (F; TN-NMR (СО3СМ): 5 0.70 (р, ЗН), 3.34-4.15 (the one that overlaps m, 7Н), 6.16 (с, 1Н), 6.57 ( d, 3.6 ka Hz, 1H), 7.37 (d, 3.6 Hz, 1H), 8.83 (s, 1H).

Example 17 in 4-amino-5-chloro-7-(2-C-methyl-p.-Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine b5 si Mne

NP

M yASnz no on 70 M-chlorosuccinimide (0.075 g, O0.5 bmol) in DMF (0, 5 ml). The solution was stirred at room temperature for 1 hour, the reaction was quenched by adding methanol (4 mL), and evaporated in vacuo. The crude product was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (55 mg) as a colorless solid.

TN-NMR (СО3СМ): 5 0.80 (р, ЗН), 3.65-4.14 (the one that overlaps with m, 7Н), 5.97 (sh.s, 2Н), 6.17 (с , 1H), 7.51 (c, 1H), 8.16 (c, 1H).

E8-M8: found: 315.0 (M.--Н"7), calculated for C42Н.BSIMAO vn: 315.09.

Example 18 4-amino-5-bromo-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine

In MA; su Y "I

SHA about | and sleep about but he

M-bromosuccinimide (0.018g, 0.1Omol) in DMF (0.5ml) was added dropwise to a pre-cooled (022) solution of the compound of stage E of example 2 (28mg, 0.1Omol) in DMF (0.5ml). The solution was stirred at 02C for (ze) 20 minutes, then at room temperature for 10 minutes. The reaction solution was quenched by adding methanol (4 ml) and evaporated under vacuum. The crude product was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product d) (13.0mg) as a colorless solid. co

TH-nMR (СО3СМ): 6 0.69 (p, ЗН), 3.46-4.00 (the one that overlaps with m, 7Н), 5.83 (sh.s, 2Н), 6.06 (s ,

AN), 7.45 (s, 1H), 8.05 (s, 1H). -

E5-M8: found: 359.1 (MAN), calculated for C42Ni5VgMO4-H": 359.04.

Example 19 2-amino-7-(2-C-methyl-rd. -Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine « хх ша: о -і і-іно-х M mn, . and"? Me

HO on - 15 Mixture of 2-amino-4-chloro-7-(-2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine (example 4, stage B) (20 mg, 0.07 mol) in EUN (1.0 ml), pyridine (0.1 ml) and 1095 Ra/C (bmg) in an atmosphere of No (atmospheric pressure) and 95) were stirred overnight at room temperature. The mixture was filtered through a layer of celite, which was thoroughly washed with EN. The combined filtrate was evaporated and purified on a silica gel column using

SnNoCl.Meon, 20/1 and 10/1, as eluent, giving the title compound as a white solid (16 mg). s» TN-NMR (200 MHz, COzO0): δ 0.86 (p, ZN, 2'С-Me), 3.82 (dd, dv 4-36 Hz, Ov 5'-12.7 Hz, 1Н , H-B ), 3.94-4.03 (m, 2H, H-v, H-4), 4.10 (d, dz 4 -8.8 Hz, 1H, H-3'), 6 .02 (s, 1H, H-1"), 6.41 (d, Ov 6-38 Hz, 1H, H-5), 7.39 (d, 1H,

H-6), 8.43 (s, 1H, H-4).

E5-M5: 281.4 (Mn. o Example 20 2-amino-5-methyl-7-(2-C,2-O-dimethyl-d.-O-ribofuranosyl)-7H-pyrrolo|2, Za) pyrimidine-4(ZN)-one di Me O t no-kh o M tm,

Me vv at 0 Ohme

Stage A: 2-amino-4-chloro-7-3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-methyl-B

-B-ribofuranosyl1|-5-methyl-7H-pyrrolo|2,3-4|pyrimidine

To an ice-cooled solution of the product of stage C of Example 2 (1.57 g, 3.1 bmol) in NaCl (5 mL) was added dropwise HB (5.7 M in acetic acid; 3.3 mL). The reaction mixture was stirred at 02 for 1 hour. and then at room temperature for 2 hours, concentrated in vacuo and evaporated together with toluene (2x20ml).

The obtained oil was dissolved in MesmM (20 ml) and added dropwise to a solution of the sodium salt of 2-amino-4-chloro-5-methyl-1H-pyrrolo|2,3-4|pyrimidine in acetonitrile (obtained from the solution of 2-amino- 4-chloro-5-methyl-1H-pyrrolo|2,3-4|Ipyrimidine (method of preparation see: Gieridz App. Spet. 1984: 708-7211 (1.13g, 6b, 2mol) in anhydrous acetonitrile (15Oml) and Mann (6095 in mineral oil, 248mg, 6b,2mol), after stirring for 2 7/0 hours at room temperature. The combined mixture was stirred at room temperature for 24 hours and then evaporated to dryness. The residue was suspended in water (100ml) and extracted with EtOAc (300-150ml).The combined extracts were washed with brine (100ml), dried over (Ma»5O)), filtered and evaporated. The crude product was purified on a silica gel column (5x7cm) using ethyl acetate/hexane (0 to 3096 EAs; 5905 step gradient) as eluent. Fractions containing the product were combined and evaporated under 7/5 vacuum to give the desired product (0.96g) as a colorless foam.

Stage B: 2-amino-4-chloro-7-3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C,2-O-dimethyl-B-B-ribofuranosyl|-5-methyl- 7H-pyrrolo|2,3-4|Ipyrimidine

To an ice-cooled mixture of the product of stage A (475mg, 0.7mol) in THF (/ml) was added Mann (6095 in mineral oil, 29mg) and stirred at 09C for 0.5 hour. Then they added Me! (48μl) and 20 the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with Meon and the mixture was evaporated. The crude product was purified on a silica gel column (5x3.5 cm) using hexane/ethyl acetate (9/1, 7/1, 5/1 and 3/1) as eluent. Fractions containing the product were combined and evaporated to give the desired compound (200 mgHg) as a colorless foam.

Stage C. 2-amino-7-|3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C,2-O-dimethyl- В He 25 -ЯВ-ribofuranosyl|-5-methyl-7Н -pyrrolo|2,3-a|Ipyrimidin-4(ZN)-one (5)

A mixture of the product of stage B (200mg, 0.3mol) in 1,4-dioxane (11bml) and aqueous Mahon (2n, 15ml) was heated overnight at 13592C in an autoclave. Then the mixture was cooled to 02C, neutralized with 2N aqueous NOSI and evaporated to dryness. The crude product was suspended in Meon, filtered and the solid washed thoroughly

Meon. The combined filtrate was concentrated, and the residue was purified on a silica gel column (5 hbsm), (9 30 using CHClClO/Meon (40/1, 30/1 and 20/1) as eluent) to give the desired compound (1500 mg) as a colorless foam

Stage 0: 2-amino-5-methyl-7-(2-C,2-O-dimethyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidin-4(ZH)-one d)

A mixture of the product of stage C (b4mg, O.1mol) in Meon (5ml), EBM (0.2ml) and 1095 Ra/C (24mg) was hydrogenated in a Co-hydrogenation apparatus at 50 psi at room temperature for 1.5 days , then filtered through a layer

From celite, which was thoroughly washed with MeOH. The combined filtrate was evaporated and the residue was purified on a column with silica gel (Zkha4cm), using sn.si/meon (30/11, 20/1) as an eluent, obtaining 2-amino-5-methyl-7-(5-O-benzyl-2-C,2-O-dimethyl -r./ -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine-4(ZH)-one.. This compound was further hydrogenated in ЕУН (2 ml) using 10956 Pa/C at atmospheric hydrogen pressure. After stirring for 2 days at room temperature, the reaction mixture was filtered through Celite, the filtrate 40 was evaporated and the crude product was purified on a silica gel column (1 x 7 cm) using СНоСИ-/Meon (301, С с 20/1 and 10/1) as eluent , obtaining after freeze-drying the title compound (12 mgH). z» TN-NMR (200 MHz, СО300): δ 0.81 (p, ZN, 2'С-Me), 2.16 (d, Un-vsv-me-17.3 Hz, ZN, С5-Me ), 3.41 (s, ZN, 2-OMe), 3.67 (dd, Uv 4-34 Hz, dB in -126 Hz, 1H, H-5), 3.81-3.91 (m, ZN, H-5", H-4, H-3), 6.10 (s, 1H, H-1! ), 6.66 (d, 1H, H-6). -I E8-M8: 323 ,3 (M-H)7.

Example 21 o 4-amino-5-methyl-7-(2-C-methyl-p -O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine oo Me Mne iz 50 theses s» no-- oy m ze

BUT he

HF) Stage A: 4-chloro-7-13,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-methyl-B

He -B-ribofuranosyl|-5-methyl-7H-pyrrolo|2,3-4|Ipyrimidine

HB" (5.7M in acetic acid; 2.2ml) was added dropwise to an ice-cooled solution of the product of stage C of Example 2 (1.06g, 2.1mol) in NaOH (3ml). The reaction mixture was stirred at 02С for 1 hours and then at room temperature for 2 hours, concentrated in vacuo and evaporated together with toluene (2x15ml).

The obtained oil was dissolved in MesmM (10 ml) and added dropwise to a solution of the sodium salt of 4-chloro-5-methyl-1H-pyrrolo|2,3-4|Ipyrimidine in acetonitrile (obtained from 4-chloro-5-methyl-1H -pyrrolo|2,3-4Ipyrimidine | method of preparation see: ). May Spent 33: 1984 (1990)|) (0.62g, in 53.7mol) in anhydrous acetonitrile (/Oml) and Man (6095 in mineral oil, 148mg, 3.7mol), after 2 hours of intensive stirring at room temperature Ob' the combined mixture was stirred at room temperature for 24 hours and then evaporated to dryness. The residue was suspended in water (100ml) and extracted with EtOAc (250-1000ml). The combined extracts were washed with saline solution (5 Oml), dried over

Ma»5zO,, was filtered and evaporated. The crude product was purified on a silica gel column (5x5cm) using a gradient of hexane/ethyl acetate (9/1, 5/1, 3/1) as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.87g) in the form of colorless foam.

Stage B: 4-chloro-5-methyl-7-(2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine

Boron trichloride (1M in dichloromethane, 9.Oml, 9.Omol) was added dropwise to a solution of the compound of stage A (0.87g, 0.Umol) in dichloromethane (30ml) at -7892C. The mixture was stirred at -782C for 2.5 hours, then at a temperature from -302C to -202C for 3 hours. The reaction was quenched by adding methanol/dichloromethane (1:1) (0ml), and the resulting mixture was stirred at -1592C for 30 minutes, then neutralized with aqueous ammonia at 02 and stirred at room temperature for 15 minutes. The solid part was filtered and washed

SsHnoSIUMEon (1/1, 5Oml). The combined filtrate was evaporated and the residue was purified on a silica gel column (5 x 5 cm) using SNeosi» and a SNSI./Meon gradient (40/1 and 30/1) as eluent to give the desired compound (0.22g) 75 as a colorless foam .

Stage C: 4-amino-5-methyl-7-(2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

To the compound of stage B (0.2 g, 0.64 mol) was added methanolic ammonia (saturated at 09C; 4 Oml). The mixture was heated in a stainless steel autoclave at 1002 for 14 hours, then cooled and evaporated in vacuo. The crude mixture was purified on a silica gel column (5hosm) using a SNOCI/MeeOH gradient (50/1, 30/1, 20/1) as eluent to afford the title compound as a white solid (0.120).

TN-NMR (DMSO-div): 5 0.60 (p, ZN, 2'C-Me), 2.26 (s, ZN, 5O-Me), 3.52-3.61 (m, 1H, N-B'), 3.70-3.88 (m, ZN,

H-5", NA, H-Z ), 5.00 (s, 1H, 2-OH), 4.91-4.99 (m, ЗН, 2-OH, 3-OH, 5-OH), 6.04 (s, 1H, H-1! ), 6.48 (s, 2H, sch ov MH2), 7.12 (s, 1H, H-6), 7.94 (s, 1H, H-2).

E5-M5: 295.2 (Mn. o

Example 22 4-amino-7-(2-C-methyl-d.-Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine-5-carboxylic acid рнозоно-с МН; h z » m-a

СХ and -y Sn"; - but he

The compound of example 6 (0.035 g, 0.11 mol) was dissolved in a mixture of aqueous ammonia (4 ml, 35 wt. 95) and saturated methanolic ammonia (2 ml) and a solution of NH" in water (2 ml, 35 wt. 95) was added. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the resulting residue C 50 was purified by HPLC on a reversed-phase column (AMesp AITSshta C-18, 10x299mm, A-water, with B-: acetonitrile, 10-6095 V for 50 minutes, flow rate 2 ml/ min), obtaining the title compound (0.015g, 4195) as a white solid.

TN-NMR (COz3O0): 5 0.85 (p, ZN, Me), 3.61 (m, 1H), 3.82 (m, 1H), 3.99-4.86 (m, 2H), 6.26 (s, 1H), 810 (s, 2H) 8.22 (s, 1H). -I ZS-NMR (СО30О0): 5 20.13, 61.37, 73.79, 80.42, 84.01, 93.00, 102.66, 112.07, 130.07, 151.40, 152.74, 159.12, 169.30. o High resolution mass spectrum (NKM5) (with fast atom bombardment (RAV)): calculated for (ee) Si8N./M:Ov": 325.1148, found: 325.1143.

Example 23 is 4-amino-7-(2-C-vinyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine syu» Mne 22 M - no (o) M

A name) P: non in Stage A: 3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-vinyl-1-O-methyl-o,-O-ribofuranose

Cerium chloride heptahydrate (50 g, 134.2 mol) is finely ground in a preheated mortar and transferred to a round-bottomed flask equipped with a mechanical stirrer. The flask was heated under high vacuum overnight at 16020. The vacuum was replaced with an argon atmosphere and the flask was cooled to room temperature. Anhydrous THF (300 ml) was introduced into the flask through a cannula. The resulting suspension was stirred at room temperature for 65 4 hours and then cooled to -782C. Vinylmagnesium bromide (1M in THF, 120ml, 120mol) was added and stirring was continued at -782С for 2 hours. The solution was added dropwise to this suspension

3,5-bis-O-(2,4-dichlorophenylmethyl)-1-O-methyl-o-Y-erythropentofuranose-2-ulose (14m, ZOmol) (of example 2, stage VI in anhydrous THF (100ml) at constant stirring. The reaction mixture was stirred at -782C for 4 hours. The reaction was quenched with saturated ammonium chloride solution and allowed to warm to room temperature. The mixture was filtered through celite and the residue was washed with EBO (2x500ml). The organic layer was separated and the aqueous layer was extracted with EBO (2x200ml). The combined organic layers were dried over anhydrous NaCl and concentrated to a viscous yellow oil. This oil was purified using flash chromatography (5 mL, 1095 mL of hexane in hexane) to afford the title compound (6b, 1 g, 13.2 mol). in the form of a pale yellow oil.

Stage B: 4-chloro-7-13,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-vinyl-B-YB-ribo-furanosyl/|-7H-pyrrolo|2,3-4 Ipyrimidine

To a solution of the compound of stage A (6b, 4g, 12, bmol) in anhydrous dichloromethane (1500ml) at -202С, HBg (3095 solution in AcOH, 20ml, 75, bmol) was added dropwise. The resulting solution was stirred at a temperature between -140905 and 09 for 4 hours, evaporated in vacuo and co-evaporated with anhydrous toluene (3x4Oml). 72 The oily residue was dissolved in anhydrous acetonitrile (1000 ml) and added to a solution of the sodium salt of 4-chloro-1H-pyrrolo|2,3-4|pyrimidine (5.8 g, 37.8 mol) in acetonitrile (obtained by the method of example 2 ) at -202C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. Then the mixture was evaporated to dryness, placed in water and extracted with EtOAc (2 x 300 ml). The combined extracts were dried over NaCl5O), filtered and evaporated. The crude mixture was purified using flash chromatography (Z0, 1095 EAs in hexane) and the title compound (1.75g) was isolated as a white foam.

Stage c: 4-amino-7-|3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-vinyl-B-YB-ribofuranosylide|-7H-pyrrolo|2,3-4|Ipyrimidine

The compound of stage B (8Omg) was dissolved in a minimal amount of 1,4-dioxane and placed in a stainless steel container. The container was cooled to -782C and liquid ammonia was added. The container was sealed and heated (U at 902 for 24 hours. The ammonia was allowed to evaporate and the residue was concentrated to a white solid which was used in the next step without further purification.

Stage 0: 4-amino-7-(2-C-vinyl-d. -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine so 20 To a solution of the compound of stage C (bOmg) in dichloromethane at -782С boron trichloride (1M in dichloromethane) was added dropwise. The mixture was stirred at -782С for 2.5 hours, then at a temperature from -309С to -202С - for 3 hours. The reaction was quenched by adding methanol/dichloromethane (1:1), and the resulting mixture was stirred at -459C7 for 0.5 hours, then neutralized with aqueous ammonia at 029C and stirred at room temperature for 15 minutes. The solid part was filtered and washed with methanol/dichloromethane (1:1). at

The combined filtrate was evaporated and the residue was purified using flash chromatography (5%, 1095 mg methanol in EtOAc containing 0.195 triethylamine). Fractions containing the product were evaporated to give the title compound as a white solid (1OmgHg).

TN-NMR (DMSO-adv): 6 3.6 (c, 1H, H-B' ), 3.8 (m, 1H, H-5"), 3.9 (md, 1H, H-4 ) , 4.3 (t, 1H, H-3' ), 4.8-5.3 (m, EN, "

SNASN", 2-OH, 3-OH, 5-OH), 6.12 (s, 1H, H-1", 6.59 (d, 1H, H-5), 7.1 (sh.s , 1H, МН"), 7.43 (d, 1H, H-6), 8.01 40. (s, 1H, H-7). o, s E5-M8: found: 291.1 (M- N"U), calculated for С43Н46М4О,-Н: 291.2. "from Example 24" 4-amino-7-(2-C-hydroxymethyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine

Mn. Stage A: 4-chloro-7-13,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-hydroxymethyl-B-YB-ribofuranosylide |-7H-pyrrolo|2,3-in|Ipyrimidine

To a solution of the compound of example 23, stage B (300 mg, 0.048 mol) in 1,4-dioxane (bBml) was added

T-methylmorpholine-M-oxide (ZOOmg, 2.5bmol) and osmium tetroxide (495 solution in water, 0.3ml). The mixture was stirred in the dark for 14 hours. The precipitate was removed by filtration through a layer of celite, diluted with water (3x) and (F) extracted with EtOAc. The EtOAc layer was dried over NaClO and concentrated in vacuo. The oily residue was taken up in dichloromethane (5 mL) and stirred over MAIO on silica gel (Zg, 1095 MAIO)) for 12 hours. Silica gel was removed by filtration, and the residue was evaporated and placed in absolute ethanol (5 mL). The solution was cooled in an ice bath and sodium borohydride (300 mg, vmol) was added in small portions. The resulting mixture was stirred at room temperature for 4 hours and then diluted with EtOAc. The organic layer was washed with water (2 x 20 ml), saline solution (200 ml) and dried over Na»53O). The solvent was evaporated and the residue was purified using flash chromatography (505, 2:11 hexane/!E(OAc)) to afford the title compound (160 mg, O0.25 mol) as white flakes. c5 Step B: 4-amino- 7-|3,5-bis-0-(2,4-dichlorophenylmethyl)-2-C-hydroxymethyl-B-YB-ribofuranosylide|-7H-pyrrolo|2,3-4|Ipyrimidine

The compound of stage A (150 mg, 0.2 mol) was dissolved in a minimal amount of 1,4-dioxane (1 Oml) and placed in a stainless steel container. The bomb was cooled to -782C and liquid ammonia was added. The container was sealed and then heated at 902 for 24 hours. The ammonia was allowed to evaporate and the residue was concentrated to a white solid, which was used in the next step without further purification.

Stage C: 4-amino-7-(2-C-hydroxymethyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

The compound of stage B (120 mg, 0.2 mol) was dissolved in 1:11 methanol/dichloromethane, 1095 Pa/C was added, and the resulting suspension was stirred under NO atmosphere for 12 hours. The catalyst was removed by filtration through a layer of celite and washed with large amounts of methanol. The combined filtrate was evaporated in vacuo and the residue 70 was purified using flash chromatography (5105, 1095 methanol in E(H2Ac containing 0.195 triethylamine)) to afford the title compound (5mg) as a white powder. 7"H- NMR (СО3О0): δ 3.12 (5, 1H, CH", 3.33 (d, 1H, CH"), 3.82 (m, 1H, H-5), 3.99-4.1 ( m, 2H, H-4" , H-57), 4.3 (d, 1H, H-3'), 6.2 (s, 1H, H-1! ), 6.58 (d, 1H, H-5), 7.45 (d, 1H, H-6), 8.05 (s, 1H, H-2).

LC-MS: found: 297.2 (M.--Н"), calculated for С.42Ни6МаовН: 297.3.

Example 25 4-amino-7-(2-C-fluoromethyl-p-O-ribofuranosyl)-7H-pyrrolo(2,3-4|pyrimidine

MH,

M c) to, E nb on sch

Stage A: 4-chloro-7-13,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-fluoromethyl-B o -YB-ribofuranosylide|-7H-pyrrolo|2,3-4|Ipyrimidine

4-Dimethylaminopyridine (OMAR) (2 mg, 0.015 mol) and triethylamine (b2 µl, 0.45 mol) were added to a solution of the compound of example 24, stage A (bZmg, 0.1mol) in anhydrous dichloromethane (bmL) under an argon atmosphere. The solution was cooled in an ice bath and p-toluenesulfonyl chloride (3 mg, 0.15 mol) was added. The reaction mixture 9 was stirred at room temperature overnight, washed with Manso (2x10ml), water (10ml), brine (10ml), dried over Na2O, and concentrated in vacuo to a pink solid. The solid part was dissolved in anhydrous THF (5 ml) and cooled in an ice bath. Tetrabutylammonium fluoride (1M solution in THF, 1ml, mol) was added and the mixture was stirred at room temperature for 4 hours. Solvent c was removed in vacuo, the residue was taken up in dichloromethane and washed with Manso (2 x 10 ml), water (10 ml) and saline (100 ml). The dichloromethane layer was dried over anhydrous NaCl 5 O), concentrated in vacuo and purified by flash chromatography (505, 2:11 hexane/!E(OAc)) to afford the title compound (20 mg) as a white solid.

Stage B: 4-amino-7-|3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-fluoromethyl-B « -B-ribofuranosylide|-7H-pyrrolo|2,3-da| Ipyrimidine

The compound of stage A (18 mg, 0.0 mol) was dissolved in a minimal amount of 1,4-dioxane and placed in a stainless steel container. The container was cooled to -782C and liquid ammonia was added. The container was sealed and then heated at 902 for 24 hours. The ammonia was allowed to evaporate and the residue was concentrated to a white solid which was used in the next step without further purification.

Stage C: 4-amino-7-(2-C-fluoromethyl-p-Y-ribofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine

The compound of stage B (1 mg) was dissolved in 1:1 methanol/dichloromethane, 1095 Pa/C was added and the resulting suspension

The mixture was stirred under NO atmosphere for 12 hours. The catalyst was removed by filtration through a layer of Celite and

He) was washed with large amounts of methanol. The combined filtrate was evaporated in vacuo and the residue was purified using flash chromatography (5µg, 1095 methanol in EtOAc containing 0.196 triethylamine) to give the title compound (8mg) as a white powder. sh» 50 "H-NMR (DMSO-d): 5 3.6-3.7 (sh tn, H-5 ), 3.8-4.3 (m, 5H, H-5", H-Y ) ,21 (c, 1H, H-1", 6.52 (d, 1H, H-5), 6.98 (width c, 2H, МН"), 7.44 (d, 1H, H- 6), 8.02 (s, 1H, H-2). 19g-NMR (DMSO-ybb): δ -230.2 (c).

E8-M8: found: 299.1 (M.--Н"7), calculated for С42Н/БЕМаОд NO: 299.27.

Examples 26 and 27 i) 4-amino-7-(3-deoxy-2-C-methyl-p-B-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine and ime) 4-amino-7- (3-deoxy-2-C-methyl-r.-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

MN Mn 60 b5 t Sv - on on Sn

Stage A: 0/07-(2,5-bis-O-(tert-butyldimethylsilyl)- D /-O-ribofuranosyl|-7H-pyrrolo|2,3-Phipyrimidine.// and 7-3,5-bis -O-(tert-butyldimethylsilyl)-r.-"O-ribofuranosyl-7H-pyrrolo|2,3-4|Ipyrimidine

Silver nitrate (6.36g, 38.8mol) was added to a stirred solution of tubercidin (5.0g, 18.7mol) in a mixture of pyridine (7.5ml) and DMF (18.5ml). This mixture was stirred at room temperature for 2 hours. it was cooled in an ice bath, THF (37 4 ml) and tert-butyldimethylsilyl chloride (5.6 g, 37 mol) were added and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered through a pad of celite and washed with THF. The filtrate and washings were diluted with ether containing a small amount of chloroform.

The organic layer was washed successively with sodium bicarbonate and water (333x5Oml), dried over anhydrous sodium sulfate 70 and concentrated. The pyridine was removed by evaporation along with the toluene, and the residue was purified using flash chromatography on silica gel using 5-795 MeonN in CH 2 Si as eluent; output Z,Og.

Stage B: 7-(2,5-bis-O-(tert-butyldimethylsilyl)-B-B-ribofuranosyl|i-4-I(di(4-methoxyphenyl)phenylmethyl)|amino-7H-pyrrolo|2,3 -4|Ipyrimidine and 7-I3,5-bis-O-(tert-butyldimethylsilyl)- p 75. -B-ribofuranosyl|-4-|di(4-methoxyphenyl)phenylmethyl|amino-7H-pyrrolo|2,3 -4|pyrimidine

4,4-dimethoxytrityl chloride (2.8g, 8.2mol) was added to a solution of the mixture of compounds of stage A (3.0g, b, 0mol) in anhydrous pyridine (30ml) and the reaction mixture was stirred at room temperature overnight. Then this mixture was thoroughly triturated with aqueous pyridine and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to a yellow foam (5.6 g).

The residue was purified using flash chromatography on silica gel using 20-2595 EUtAs in hexane as eluent. The corresponding fractions were collected and concentrated, obtaining 2",5'-bis-O-(tert-butyldimethylsilyl)- and 35'-bis-O-(tert-butyldimethylsilyl)-protected nucleosides in the form of a colorless foam (2.2g and 1.0g , respectively).

Stage c: 7-(2,5-bis-O-(tert-butyldimethylsilyl)-3-O-tosyl-B-YB-ribofuranosyl|i-4-I(di(4-methoxyphenyl)phenylmethylIamino-7H-pyrrolo |2,3-4|Ipyrimidine p

To an ice-cooled solution of 2",5'-bis-O-(tert-butyldimethyl-silyl)protected nucleoside of stage B (2.0 g, 2.5 mol) in pyridine (22 ml) was added p-toluenesulfonyl chloride (1.9 g, 9 ,vmol). The reaction mixture was stirred at room temperature for 4 days. Then it was thoroughly triturated with aqueous pyridine (5095, 1Oml) and extracted with ether (3x5Oml), which contains a small amount of CH 2Si" (1Oml). The organic layer was washed with sodium bicarbonate and with water (300 ml). The organic layer was dried over anhydrous Ma»5O) and concentrated.

Pyridine was removed by co-evaporation with toluene (3x25ml). The remaining oil was filtered through a pad of silica gel using hexane:ethyl acetate (70:30) as eluent; output 1.4 g.

Stage p: 4-(di(4-methoxyphenyl)phenylmethyl|amino-7-|IZ-O-tosyl-Bc-B-ribofuranosyl-7H-pyrrolo|2,3-4|pyrimidine co

A solution of the compound of stage C (1.0 g, 1.1 mol) and THF (10 ml) was mixed with tetrabutylammonium fluoride (1 M solution in

From THF, 2.Bml) for 0.5 hour. The mixture was cooled and diluted with ether (5 mL). The solution was washed in with water (Zh5Oml), dried over anhydrous Ma»zo), and concentrated to an oil. The residue was purified by passing through a layer of silica gel using hexane-ethyl acetate (1:1) as an eluent; output 78 Ohm.

Stage E: 4-amino-7-(3-deoxy-2-C-methyl-B-B-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine and « 4-amino-7-(33-deoxy -2-C-methyl-r.-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine

A solution of SnemoAia (3.0 M solution in ether, 3.0 mL) in anhydrous toluene (3.75 mL) was cooled in an ice bath. To this was added a solution of the compound of stage ХО (500 mg, 0.vmol) in anhydrous toluene (3.7 ml). The resulting mixture was stirred at room temperature for 3.5 hours. It was cooled and treated with an aqueous solution of MNACI and extracted with simple ether (5 mL containing 1 mL of CH»OCl). The organic layer was separated and washed with brine (2 x 30 mL) and water (2 x 25 mL), dried over anhydrous NaCl, and concentrated to 49% as an oil, which was purified by flash chromatography on silica gel using 495 Meon in CH 2 to give the compound 2-S-o; -methyl (149mg) and the compound 2-C-d-methyl (34mg). These derivatives were separately treated with 8090 (4) acetic acid and the reaction mixture was stirred at room temperature for 2.5 hours. Acetic acid was removed by repeated co-evaporations with ethanol and toluene. The residue was partitioned between co chloroform and water. The aqueous layer was washed with chloroform and concentrated. After evaporation, the residue g" 50 was purified on silica gel, using 5-1095 MeonN in CH 2 SiO 2 as eluent, obtaining the desired compounds in the form of a white solid. c» 4-amino-7-(3Z-deoxy-2-C-methyl-p-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine (9Omg)

TN-NMR (DMSO-dv): δ 0.74 (p, ZH, CH"), 1.77 (dd, 1H, H-3'), 2.08 (t, 1H, H-3"), 3.59 (m, 1H, H-5' ), 3.73 (m, vv 1H, H-5U, 4.15 (m, TN, H-Y), 5.02 (t, IN, OH- 5), 5.33 (s, IN, OH-2"), 6.00 (s, 1H, H-1"), 6.54 (d, 1H, H-7), 6.95 (width с, 2Н, МН»), 7.47 (d, 1Н, Н-8), 8.00 (с, 1Н, Н-2). iF) ЕВ-М8: 2631 |М-НИ. ka 4-amino -7-(3Z-deoxy-2-C-methyl-p-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine (15mg)

TN-NMR (DMSO-yv): 5 1.23 (p, ZH, SNU), 2.08 (ddd, 2H, H-Z3' and 3"), 3.57 (m, 2H, H-B' and 5"), 4.06 (m, 1H, H-4), 60 5.10 (s, IN, OH-2), 5.24 (t, YAN, OH-5 ), 6.01 (s , 1H, H-1! ), 6.49 (d, 1H, H-7), 6.89 (width, 2H, МН»), 7.35 (d, 1H,

H-8), 8.01 (s, Sh, H-2).

EB5-M8: 265.2 |MANI.

Example 28 4-amino-7-(2,4-С-dimethyl-рд-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine b5

Mne so me | Me on him

Stage A: 5-deoxy-1,2-O-isopropylidene-O-xylofuranose to 1,2-O-isopropylidene-O-xylofuranose (38.4g, O0.2mol), 4-dimethylaminopyridine (5g), triethylamine (55.7ml,

0.4 mol) was dissolved in dichloromethane (300 ml). p-toluenesulfonyl chloride (38.13 g, O0.2 mol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate (50 Oml) and the two layers were separated. The organic layer was washed with an aqueous solution of citric acid (2095, 200 ml), dried (MgSO)) and evaporated to give a solid (70.0 g). The solid part was dissolved in dry THF (300 ml) and HyAIN was added in portions over 30 minutes; (16.0 g, O0.42 mol).

The mixture was stirred at room temperature for 15 minutes. Ethyl acetate (10 mL) was added dropwise over 30 minutes and the mixture was filtered through a layer of silica gel. The filtrate was concentrated and the obtained oil was chromatographed on silica gel (EuAc/hexane 1/4), obtaining the product as a solid (32.5 g).

Stage B: 3,5-bis-0-(2,4-dichlorophenylmethyl)-1-O-methyl-4-methyl-o,-O-ribofuranose

Chromium oxide (50g, 0.5mol), acetic anhydride (5Oml, 0.5Zmol) and pyridine (100ml, 1.24mol) were added to dichloromethane (7L) in an ice bath and the mixture was stirred for 15 minutes. 5-deoxy-1,2-O-isopropylidene-O-xylofuranose (32g, 0.18mol) in dichloromethane (200ml) was added and the mixture was stirred vigorously at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (1 L) and filtered through a layer of silica gel. The filtrate was concentrated to give a yellow oil. This oil was dissolved in (o) 1,4-dioxane (1 L) and formaldehyde (3795, 200 ml). The solution was cooled to 092C and solid KOH (50 g) was added.

The mixture was stirred at room temperature overnight and then extracted with ethyl acetate (6x200ml).

After concentration, the residue was chromatographed on silica gel (EUAs), obtaining the product as a sodium oil (1.5 g).

This oil was dissolved in 1-methyl-2-pyrrolidinone (20 ml) and 2,4-dichlorophenylmethyl chloride (4 g, 20.5 mol) - and manne (6095, 0.8 g) were added. The mixture was stirred overnight and diluted with toluene (100 ml). Then the mixture was washed with saturated aqueous sodium bicarbonate (3x5Oml), dried (Ma».5O)) and evaporated. The residue was dissolved in methanol (50 ml) and NCI in dioxane (4 M, 2 ml) was added. The solution was stirred overnight and evaporated. co

The residue was chromatographed on silica gel (EuAc/hexane: 1/4), obtaining the desired product in the form of a black oil (2.01 g).

Stage C: 3,5-bis-O-(2,4-dichlorophenylmethyl)-2,4-di-C-methyl-1-O-methyl-o, -XO-ribofuranose

The product (2.0g, 4.0mol) of stage B and periodinan YuOezv-Magip (2.0g) in dichloromethane (30ml) were stirred overnight at room temperature and then concentrated under reduced pressure. The residue was thoroughly washed with ether (5 Oml) and filtered. The filtrate was washed with a solution of Ma»52O3.5HNO (2.5 g) in a saturated aqueous solution of sodium bicarbonate (5 Oml), dried (M950), filtered and evaporated. The residue was dissolved in anhydrous EGO (20 ml) and added dropwise to a solution of MemoVg in EGO (ZM, 10 ml) at -7890. "» The reaction mixture was allowed to warm to -302С and was stirred at a temperature from -302С to -159С5 for 5 hours, then poured into a saturated aqueous solution of ammonium chloride (50ml). The two layers were separated and the organic layer was dried (Ma5O)), filtered and concentrated. The residue was chromatographed on silica gel - I (EOAc/hexane: 1/9), obtaining the title compound as a syrup (1.40 g). c Stage p: 4-chloro-7-3,5-bis-O-( 2,4-dichlorophenylmethyl)-2,4-di-C-methyl-B -YB-ribofuranosylide|-7H-pyrrolo|2,3-4|Ipyrimidine (ee) To the compound of stage C (0.70g, 1.3mol ) was added HBg (5.7M in acetic acid, 2ml). The resulting solution was stirred at room temperature for 1 hour, evaporated in vacuo and co-evaporated with anhydrous toluene (3x10ml). 4-chloro-7H-pyrrolo|2,3 -4|Ipyrimidine (0.5g, 3.3mol) and KOH powder (8595, 150mg, 2.3mol) were stirred in 1-methyl-2-pyrrolidinone (5ml) for 30 minutes and the mixture was evaporated together with toluene (10ml) The resulting solution was poured into the indicated tank e bromosugar residue and the mixture was stirred overnight. The mixture was diluted with toluene (50ml), washed with water (3x50ml) and concentrated under reduced pressure.

The residue was chromatographed on silica gel, eluting with a mixture of E(Ac/hexane (15/85), obtaining a solid substance (27 mg).

Stage E: 4-amino-7-(2,4-C-dimethyl-d -O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine ime) The compound of stage ХО (27 Омг) was dissolved in dioxane (2 ml) and liquid ammonia (20 g) was added to a stainless steel autoclave. The mixture was heated at 1002 for 15 minutes, then cooled and evaporated. The residue 60 was chromatographed on silica gel (E(SUAs), obtaining a solid (200mg). The solid (15mgH) and

Ra/C (1095, 150mg) in methanol (200ml) was shaken under NO (30 psi) for 3 hours, filtered and evaporated. The residue was chromatographed on silica gel (MeOnH/CH 5Si: 1/9), obtaining the desired product as a solid (35 mgH). "NA-NMR (DMSO-yv): 5 0.65 (s, ZN), 1.18 (s, ZN), 343 (m, 2H), 4.06 (d, IN, 4-6.3 Hz ), 4.87 (s, 1H), bo 5.26 (width, 1H), 5.08 (d, 1H, 9U-6.3 Hz), 5.25 (t, 1H, 9-30 Hz ), 6.17 (s, 1H), 6.54 (d, 1H, 9U-3.5 Hz), 6.97

(width s, 2H), 7.54 (d, 1H, 9U-3.4 Hz), 8.02 (s, 1H).

ISR-NMR (DMSO-ydv): 5 18.19, 21.32, 65.38, 73.00, 79.33, 84.80, 90.66, 99.09, 102.41, 121.90, 149.58, 151.48, 157.38.

LC-MS: found: 295.1 (MAN"), calculated for C43NivMaOd vn: 295.1.

Example 29 4-amino-7-(3Z-deoxy-3-fluoro-2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

Mn, oh that's another thing

I Me 18 E on

Stage A: 3-deoxy-3-fluoro-1-O-methyl-5-O-toluene-o,-O-ribofuranose 1,2-O-isopropylidene-O-xylofuranose (9.0g, 5Omol) and n- Tolusyl chloride (7.0 ml, 5 mol) in pyridine (5 mol) was stirred for 30 minutes. Water (1 Oml) was added and the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (b0Oml) and the solution was washed with water (200ml) and a saturated aqueous solution of sodium bicarbonate (200ml). The two layers were separated and the organic layer was evaporated. The residue was dissolved in methanol (100 ml) and NCI in dioxane (A4AM, 10 ml) was added. The mixture was stirred at room temperature overnight and then evaporated under reduced pressure. The obtained oil was chromatographed on silica gel (EuAc/hexane: 1/1) to obtain an oil (10.1 g). This oil was dissolved in dichloromethane (100 ml) and diethylaminosulfur trifluoride (OAZT) (5.7 ml) was added. The mixture was stirred overnight and then poured into a saturated aqueous solution of sodium bicarbonate (1000 ml). The mixture was extracted with toluene (2x50Oml) and the combined organic layers were concentrated. The residue was chromatographed on silica gel (EtOAc/hexane: 15/85) to give the title compound as an oil (1.50 g).

Stage B: 3-deoxy-3-fluoro-2-C-methyl-1-O-methyl-5-O-toluoyl-o,-O-ribofuranose

The product of stage A (1.0g, 3.5mol) and Vevz-Magip periodinan (2.5g) in dichloromethane (20ml) were stirred overnight at room temperature and then concentrated under reduced pressure. The residue was thoroughly triturated with diethyl ether (50 ml) and filtered. The filtrate was washed with a solution of Ma»52O3-5NHO (12.5 g) in saturated aqueous sodium bicarbonate (100 ml), dried (M950)), filtered and evaporated. The residue was dissolved in anhydrous THF (5 Oml). At -782C, TiCl (3ml) and methylmagnesium bromide in simple ethyl ether (3M, 10ml) were added and the mixture was stirred at a temperature from -50 to -302C for 2 hours. The mixture was poured into 32 saturated aqueous sodium bicarbonate solution (100 ml) and filtered through celite. The filtrate was extracted with toluene (100 ml) and evaporated. The residue was chromatographed on silica gel (E(Ac/hexane: 15/85)) to give the title compound as an oil (15mgHg).

Stage C: 4-amino-7-(3Z-deoxy-3-fluoro-2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|)pyrimidine «

The product of stage B (15Omg, 0.bmol) was dissolved in HBr (3090) in acetic acid (2ml). After one hour, the mixture 50 was evaporated under reduced pressure and co-evaporated with toluene (10ml). 4-Chloro-7H-pyrrolo|2,3-4|pyrimidine (0.5 g, 3 s 3 mol) and powdered KOH (8595, 150 mg, 2.3 mol) were stirred in DMF (3 mL) for 30 minutes and mixture

It was evaporated together with toluene (2 ml). The resulting solution was poured into the bromosugar mixture indicated above and stirred overnight. The mixture was diluted with toluene (50 Oml), washed with water (3x5 Oml) and concentrated under reduced pressure. The residue was chromatographed on silica gel (EtOAc/hexane: 15/85) to give an oil (bOmg). This oil was dissolved in dioxane (2ml) and liquid ammonia (20g) was added to a stainless steel autoclave. and the mixture was heated at 859C for 18 hours, then cooled and evaporated. The residue was chromatographed (4) on silica gel (methanol/dichloromethane: 1/9) to give the title compound as a solid (29mgHg). 7"H-NMR (DMSO-yv): 5 0.81 (p, ZH), 3.75 (m, 2H), 4.16 (m, 1H), 5.09 (dd, 1H, U-53 ,2, 7.8 Hz), 5.26 (width, t. 20 1H), 5.77 (s, 1H), 6.15 (d, 1H, 9U-2.9 Hz), 6.59 (d, 1H, U-3.4 Gu), 7.02 (width, 2H), 7.39 (d, 1H, U-3.4 Hz), 8.06 (s, 1H). ISR-NMR (DMSO-α): 5 19.40, 59.56, 77.24, 79.29, 90.15, 91.92, 99.88, 102.39, 121.17, 149.80, 151.77, 157 47. 19g-NMR (DMSO-d5): δ 14.66 (ju.

E5-M8: found: 283.1 (MAN); calculated for C42Ni5EMaOzH: 283.1.

Example 30 about 4-amino-7-(2-C,2-O-dimethyl-rd-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine

МН име) bo g - no o M uvno osn 65 Stage A: 4-chloro-7-13,5-bis-0-(2,4-dichlorophenylmethyl)-2-C,2-O-dimethyl- B - YV-ribofuranosylide|-7H-pyrrolo|2,3-4|Ipyrimidine

Methyl iodide (709 mg, 5.0 mol) and Man (6095 in mineral oil) (44 mg, 1.1 mol) were added to a pre-cooled (022) solution of the compound of example 2, stage OO (618 mg, 1.0 mol) in THF (8 mL). The resulting mixture was stirred overnight at room temperature and then poured into a stirred mixture of saturated aqueous ammonium chloride (500 mL) and dichloromethane (50 mL). The organic layer was washed with water (50 ml), dried (M9503) and evaporated in a vacuum. The obtained crude product was purified on silica gel using ethyl acetate/hexane as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (735 mgHg) as a colorless foam.

Stage B: 4-amino-7-I|3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C,2-O-dimethyl- B 70. -B-ribofuranosyl|-7H-pyrrolo| 2,3-4|Ipyrimidine

To the compound of stage A (735mg, 1.1bmol) was added methanolic ammonia (saturated at 02) (20ml). The mixture was heated in a stainless steel autoclave at 802 overnight, then cooled and the contents evaporated in vacuo. The crude mixture was purified on silica gel using ethyl acetate/hexane as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (504 mg) as a colorless foam.

Stage C: 4-amino-7-(2-C,2-O-dimethyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

A mixture of the product of stage C (b4mg, O,Tmol), Meon (5ml), EBM (0.2ml) and 1095 Ra/C (b1mg) was hydrogenated in the apparatus

Steam at 50 psi at room temperature overnight. The mixture was filtered through celite, evaporated in vacuo and filtered through a pad of silica gel using 2956 methanol in dichloromethane as eluent. The desired product was collected and evaporated in a vacuum. This compound was redissolved in methanol (10 ml) and 1095 Pa/sC (61 mg) was added. The mixture was hydrogenated in a Steam apparatus at 55 psi at room temperature for two weeks. The mixture was filtered through celite, evaporated in vacuo and purified on silica gel using 1095 methanol in dichloromethane as eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (11OmgHg) as a colorless foam. 136-NMR (DMSO-α): δ 0.68 (p, ZN), 3.40 (s, ZN), 3.52-3.99 (the one that overlaps m, 4H), 4.92 (d , s 1H), 5.07 (t, 1H), 6.26 (s, 1H), 6.55 (d, 1H), 7.00 (width s, 2H), 7.46 (d, 1H ), 8.05 (s, 1H). heh)

LC-MS: found: 293.1 (M-H"); calculated for С12Н46Миоу-Н": 293.12.

Example 31 4-methylamino-7-(2-C-methyl-dr.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine so 20 MiMe - -x go y

My dream

He didn't care about them

The compound of Step E of Example 2 (200 mg, 0.67 mol) was added to methylamine (5 mL, condensed in a small stainless steel autoclave) and heated at 8593 for 48 hours, then cooled and evaporated under 20° vacuum. The crude mixture was purified on silica gel using ethanol as an eluent to give the title compound, which was isolated as an amorphous solid after treatment with MesM. The amorphous solid was dissolved in water and lyophilized to obtain a colorless powder (144 mg). with TN-NMR (DMSO-α): δ 0.63 (p, ЗН, СН»), 3.32 (s, ЗН, M-СН»), 3.58-3.67 (m, 1Н, Н -B'), 3.79-3.39 (m, ЗН, Н-Б", Н-4" ; Н-3'), 5.03 (с, 1Н, 2-ОН), 5.04- 5.11 (1H, 3-OH, 1H, 5-OH), 6.14 (s, 1H, H-17), 6.58 (d, 1H, dv, 6-3.6 Hz, H-5 ), 7.46 (D, 1H, H-6), 7.70 (width, 1H, МН), 8.14 (c, 1H, H-2). - and LC-MS: found: 295.1 (M-H"7); calculated for C153Ni8MAaO tn: 294.3. Example 32 4-dimethylamino-7-(2-C-methyl-r. -O-ribofuranosyl )-7H-pyrrolo|2,3-4|pyrimidine (ee) MMeg i 50 h o no-ya i m dos 29 no on iF) The compound of stage E of example 2 (200 mg, O0.67 mol) was added to dimethylamine (bml, condensed in a small stainless steel autoclave) and heated at 859 for 48 h, then cooled and evaporated in vacuo. The crude mixture was purified on silica gel using ethanol as eluent to afford the title compound 60, which was isolated as an amorphous solid after processing Mesm.

The amorphous solid was dissolved in water and lyophilized to give a colorless powder (164 mgHg). 7"H-NMR (DMSO-yv): 5 0.64 (p, ZN, CH), 3.29 (s, ZN, M-SNUz), 3.32 (s, ZN, M-CHz), 3 ,60-3.66 (m, 1Н, Н-5), 3.77-3.97 (m, ЗН, Н-5", Н-4", Н-3, 5.04 (s, 1Н, 2-OH), 5.06-5.11 (1H, 3-OH, 1H, 5-OH), 6.21 (s, 1H, H-1", 6.69 (dD, 1H, Ov, in-3.6 Hz, H-5), 7.55 (d, 1H,H-6),8.13(s, 1H,H-2). because LC-MS: found: 309.3 (M -Н"), calculated for С44НооМаО НН": 308.33.

Example 33 4-cyclopropylamino-7-(2-C-methyl-p-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine name sv) M

Se 70 77 non

The compound of Step E of Example 2 (200 mg, 0.w/mol) was added to cyclopropylamine (5 mL, condensed in a small stainless steel autoclave) and heated at 859 for 48 hours, then cooled and evaporated in vacuo. The crude mixture was purified on silica gel using ethanol as eluent to afford the title compound 75 which was isolated as an amorphous solid after treatment with Mesm.

The amorphous solid was dissolved in water and lyophilized to give a colorless powder (148 mg). "H-NMR (DMSO-α): 5 0.51-0.58 (w, 2H), 0.64 (s, ЗН, СНУ), 0.74-0.76 (m, 2Н), 3, 62-3.67 (m, 1Н, Н-5'), 3.79-3.82 (m, ЗН, Н-5"), 3.92-3.96 (m, НА, Н-3 ) , 5.03 (s, 1H, 2-OH), 5.05-5.10 (1H, 3-OH, 1H, 5-OH), 6.15 (s, IN, H-7 ), 7, AB (d, 1H, Ov 6-36 Hz, H-5), 7.59 (d, 1H, H-6), 8.13 (s, 1H, H-2).

LC-MS: found: 321.1 (M-H7), calculated for Si5NooMAN: 320.3.

Example 34 4-amino-7-(3-C-methyl-d.-O-xylofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

Mne s shchi tr o m-a no

Ash t, oh me on "

Stage A: 7-(2,5-bis-O-(tert-butyldimethylsilyl)-B co -B-ribofuranosyl-4-((4-methoxyphenyl)diphenylmethylamino-7H-pyrrolo|2,3-4|Ipyrimidine and 7-13,5-bis-O-(tert-butyldimethylsilyl)-r-O-ribofuranosyl-4-((4-methoxyphenyl)diphenyl and) c5 methyl|amino-7H-pyrrolo|2,3-4|pyrimidine h-

Monomethoxytrityl chloride (0.30g, 0.9v8mol) was added to a solution of the mixture of stage A compounds of examples 26 and 27 (0.32g, 0.65mol) in anhydrous pyridine (bml) and the reaction mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was partitioned between CH 25Si" (70ml) and water (20ml). The organic layer was washed with water and brine, dried (MgSO) and concentrated. The residue was purified on a silica gel column using 5-13956 EOAc in hexane as eluent. The corresponding fractions were collected and concentrated, thereby obtaining 2,5'-bis-O-(tert-butyldimethylsilyl)- and 3,5'-bis-O-(tert-butyldimethylsilyl)-protected nucleosides in the form of colorless foams ( 34Zmg and 4mg, respectively). and Stage B: 7-(2,5-bis-O-(tert-butyldimethylsilyl)-B-O-erythropentofuranos-3-ulosyl-4-((4-methoxyphenyl)diphenylmethyl|amino- 7H-pyrrolo|2,3-4|pyrimidine

To a thoroughly stirred suspension of chromium trioxide (91 mg, O0.9 mol) in CH 5 SiO (4 ml) at 02 C was added -I pyridine (147 μl, 1.82 mol) and then acetic anhydride (8 bml, 0.9 mol). The mixture was stirred at room temperature for 0.5 hour. Then, 2",5'-bis-O-(tert-butyldimethylsilyl)protected nucleoside of stage A (34 µg, 0.45 mol) in СНоСИ" (2.5 ml) was added and the mixture was stirred at room temperature for 2 hours. ee) The mixture was then poured into ice-cold E(OAc) (1 mL) and filtered through a short column of silica gel using EtOAc as eluent. The filtrate was evaporated and the residue was purified on a silica gel column, e using hexane and hexane/E(OAc (7/1 ) as an eluent and yielding the title compound (180 mgG). (4-Methoxyphenyl)diphenylmethyliamino-7H-pyrrolo|2,3-4|pyrimidine and 7-(2,5-bis-O-(tert-butyldimethylsilyl)-3-C-methyl-r.-O-xylofuranosyl- 4-((4-Methoxyphenyl)diphenyl methyl|amino-7H-pyrrolo|2,3-4|Ipyrimidine o To a mixture of MemaoVg (3.0M solution in ether; 0.17ml, 0.bmol) in anhydrous hexane (1 .5 ml) at room temperature was added dropwise to a solution of the compound of stage B (78 mg, 0.1 mol) in anhydrous hexane (0.5 ml ). After stirring for 2 hours at room temperature, the reaction mixture was poured into ice-cooled water (10 mL) and diluted with EtOAc (20 mL), then filtered through celite and then thoroughly washed with E(Ac. 60). The layers were separated and the organic layer was washed with brine, dried (Ma »5ZO)) and concentrated. The residue was purified on a silica gel column using 8-2595 E(OAc in hexane as eluent to give 3-C-methylxylo- (60 g) and 3-C-methyl riboisomer (20 ΩgHg).

Stage 0: 4-amino-7-(3-C-methyl-d -O-xylofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

65 TVABE (IM in THF; 0.32ml, 0.32mol) was added to an ice-cooled solution of the 3-C-methylxyloisomer of stage C (bOmg, 0.008mol) in THF (2ml). The reaction mixture was stirred at room temperature for 5 hours and then diluted with CH 2Si" (50ml), washed with water (3x15ml), dried and evaporated. The residue was dissolved in dioxane (0.3 ml) and 8095 acetic acid (3 ml) was added. The reaction mixture was stirred at room temperature for 1 day and then evaporated. The residue was evaporated together with dioxane, placed in water (5 Oml) and washed with СНоСии» (2x10 ml). The aqueous layer was concentrated and then freeze-dried. The residue was purified on a silica gel column using SNCI/Meon (20/1 and 10/1) as eluent to give the title compound as a white fluffy compound after freeze-drying (1mg).

TN-NMR (SOZSM): 5 1.28 (p, ЗН, СН), 3.56 (shr.s, 1Н, ОН), 3.78 (m, ЗН, Н-4", Н-5, Н -5"), 4.10 (width, 1H,

OH), 4.44 (d, 1H, 05 1. -3.9 Hz, H-2! ), 5.58 (d, 1H, H-1! ), 5.85 (sh.c, 2H, МН»), 6.15 (width, 1H, ОН), 6.48 (d, W,

Uv 623.7 Hz, H-5), 7.23 (d, 1H, H-6), 8.11 (s, 1H, H-2).

E5-M5:281 NOUNS.

Example 35 4-amino-7-(3-C-methyl-r. -Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine

I'm sorry about M

Me but him

The riboisomer (20mg) of stage C of example 32 was deprotected using the method described in stage O of example 32 to give the title compound (4mgHg).

TN-NMR (SOZSM): δ 1.43 (p, ЗН, СН), 3.28 (shr.s, 1Н, ОН), 3.58 (m, 2Н, Н-5, Н-Б5"), 3.99 (m, 1H, H-4.), 4.10 (width, 1H, OH), 4.62 (d, 1H, 9" 1-81 Hz, H-2'), 5, 69 (d, 1H, H-1! ), 5.88 (width s, ЗН, ОН, МН»), 6.45 (width s, 1H, s

OH), 6.51 (d, 1H, dv 6-3.7 Hz, H-5), 7.19 (d, 1H, H-6), 8.12 (s, 1H, H-2). Go)

E5-M5: 281|MNI.

Example 36 2,A4-diamino-7-(2-c-methyl-p.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine so zo Mo « yoech

M vi y

M --

KU M mno s - Me m non

A mixture of the product of step 4 (24mg) in aqueous ammonia (3095, 1TOml) was heated in a stainless steel autoclave at 1002 overnight, then cooled and evaporated. The residue was purified on a du silica gel column using SNOSII/Meon (10/1 and 5/1) as eluent to give the title compound - (15mg). c 7H-NMR (DMSO-(c): 5 0.68 (p, ЗН, СН), 3.48-3.58 (m, 1Н, Н-5' ), 3.68-3.73 (m , 2H, H-B", H-4 ), 3.84 (m, 1H, with H-3), 4.72 (s, 1H, 2-OH), 4.97-5.03 (m, 2H, 3-OH, 5-OH), 5.45 (s, 2H, MH"), 6.00 (s, 1H, H-1", 6.28 (d, 1H, 93.7 Hz, H-5), 6.44 (width, 2H, МН»), 6.92 (d, 1H, 9U-3.7 Hz, H-6).

E58-M8: 2941 (M-H7). -I Example 37 4-Amiso-2-fluoro-7-(2-C-methyl-d-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine

More than 50 of her sm e re so pose fe sh:

Me nO on 59 To a solution of the HE/pyridine mixture (7095, 2 ml) diluted with pyridine (ml), at -309С, compound (F) of example 36 (bOmg, 0.2 mol) in 0.5 ml of pyridine was added, and then tert-butyl nitrite (Zbmkl, O, Zmol). Mixing

He continued for 5 minutes at -252С. Then the solution was poured into a mixture of water and ice (5 ml), neutralized with 2N aqueous MaosOH and evaporated to dryness. The residue was purified on a silica gel column using Ssnos./mMeon (20/1 and 10/1) as eluent to give the title compound.

Example 38 4-amino-5-fluoro-7-(2-C-methyl-r.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine b5

E MN

Ts 2 nn o M u» no on

Stage A: 4-acetylamino-7-(2,3,5-tri-O-acetyl-2-C-methyl-d.-O-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine to solution to the compounds of stage E of example 2 (28Omg, 1.00mol) in pyridine, acetic anhydride (61Omg, b.Omol) was added. The resulting solution was stirred overnight at room temperature, evaporated in vacuo and the resulting crude mixture was purified on silica gel using ethyl acetate/hexane as eluent. Fractions containing the desired product were combined and evaporated in vacuo to give the desired product.

Stage B: 4-acetylamino-5-bromo-7-(2,3,5-tri-O-acetyl-2-C-methyl-B-B-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine

To the pre-cooled solution (022) of the compound of stage A (46b0Omg, 1.00 mol) in DMF was added

M-bromosuccinimide (178 mg, 1.0 mol) in DMF. The resulting solution was stirred at 02C for 30 minutes, then at room temperature for another 30 minutes. The reaction was quenched by adding methanol and evaporated in vacuo. The resulting crude mixture was purified on silica gel using ethyl acetate/hexane as eluent. Fractions containing the desired product were combined and evaporated in vacuo to give the desired product.

Stage C: 4-amino-5-fluoro-7-(2-C-methyl-rd. -O-ribofuranosyl)-7H-pyrrolo|2,3-4F|pyrimidine

Butyllithium (2M in hexane) (0.5ml, 1.00mol) was added to a pre-cooled (-782С) solution of the compound of stage B (529mg, 1.00mol) in THF. The resulting solution was stirred at -782C for 30 minutes and then quenched using M-fluorobenzenesulfonimide (315 mg, 1.00 mol) in THF. The resulting solution was allowed to cool very slowly (5) to room temperature and then poured into a stirred mixture of saturated aqueous ammonium chloride and dichloromethane. The organic phase was evaporated in vacuo and treated with ammonium hydroxide at 55922 in a sealed container overnight. The resulting crude mixture was purified on silica gel using dichloromethane/methanol as an eluent. Fractions containing the desired product were combined and evaporated in vacuo to give the desired product. "

Biological tests

Next, the tests used to determine the inhibition of NSM M55B polymerase and NSMU co-replication are described. co

The effectiveness of the compounds of this invention as inhibitors of NSM M5Z5B RNA-dependent RNA polymerase (Kakr)

Zo was determined using the following analysis. in.

A. Analysis of NSM M55B polymerase inhibition

This analysis was used to determine the ability of nucleoside derivatives of this invention to inhibit the enzymatic activity of RNA-dependent RNA polymerase (M5Z5B) of the hepatitis C virus (HCV) on a heteromeric RNA matrix.

Procedure: With c Buffer for: (5 Омкл - total for the reaction) "» 20ОММ Tgtgiv, рН 7.5 " 5О0МКкМ EOTA 5MM OT 2MM Mas

Suture of KSI with 0.4 baud/μl RNAZzip (KMAzip) (Rgoteda, output volume 4bod/µl)

0.75 μg 1500 (500-nuisiotide RNA, obtained using T7 hypo-transcription with a sequence from the M52/3 region of the hepatitis C virus genome) and 50 1.bmkg of purified M55B hepatitis C virus (obtained with truncation of the C-terminus of 21 amino acids ) 1 mM A, C, O, OTR (nucleoside triphosphate mixture) c» Ialpha-Z2RI-OTR or (alpha-ZRI-STR

The compounds were tested at various concentrations up to a final concentration of 100 µM.

The necessary volume of the reaction buffer was prepared, including the enzyme and matrix 1500. Nucleoside derivatives 22 of this invention were placed with a pipette in the wells of a 96-well tablet. A mixture of nucleoside triphosphates was prepared

F! (MTR'5), including radiolabeled STR, and pipetted into the wells of a 96b-well plate. The reaction was initiated by adding the enzyme-matrix reaction solution and left for the reaction to proceed at room temperature for 1-2 hours. The reaction was quenched by adding 20 μl of 0.5 M EOTA, pH 8.0. Blank reactions were also carried out, in which the quenching solution was added to MTP3 before the addition of the reaction buffer. 60 BOmcl of quenched reaction solution was applied with spots on OE81 filter discs (U/paitap) and left to dry for 30 minutes. Filters were washed with 0.3 M ammonium formate, pH 8 (1500 ml/wash until the number of pulses per minute (srt) in one ml of washing becomes less than 100, usually 6 washes). Pulses on the filters were determined in 5-ml scintillation liquid in a scintillation counter.

The percentage of inhibition was calculated according to the following equation: 95 inhibition - |(1-(CRT in the test reaction - CRT in the blind) / (CRT in the control reaction - CRT in the blind)|x100.

Representative compounds tested in the NSM M55B polymerase assay showed ICoo values of less than 100 μmol.

B. Analysis of NSM inhibition of RNA replication

The compounds of this invention were also evaluated for their ability to influence the replication of hepatitis virus RNA

C in hepatoma cells (Nyn-7), which are cultivated, containing the subgenomic NSM replicon. The details of the analysis are disclosed below. This replicon assay is a modification of the assay described by MU. Hoptapp, R. Koteg, 4-0.

Kos. 70 Protocol:

The assay is an IP protection ribonuclease plate assay based on ZsypiiPyop Rgohitiu (RA).

From 10,000 to 40,000 cells were plated in 100-200 μl of medium containing 0.8 mg/ml (3418 in 96-well Sufoviag plates (Ateghzpat). Compounds were added to the cells at various concentrations, up to 100 μM in 190 DMSO at time points from 0 for up to 18 hours and then cultured for 24-96 hours.Cells were fixed (20 minutes, 1090 7/5 formalin), permeabilized (20 minutes, 0.2595 Tgiop X-100/RV5) and hybridized (overnight, 5025 ) with a single-stranded ZZR RNA probe complementary (7) to the M55B chain (or other genes) contained in the RNA of the viral genome.Cells were washed, treated with RNase, washed, heated to 652C and counted in

Thor-Sotspi. Inhibition of replication was defined as a decrease in the number of pulses per minute (bpm).

Human hepatoma NinH-7 cells, which were selected as containing a subgenomic replicon, contained cytoplasmic RNA consisting of NCM 5 / untranslated region (MTK), a neomycin-selectable marker, EMCM IKE5 (internal ribosome entry site) (ipiegpa! gyrozote epigu zyge), and NSM of non-structural proteins MZ3-M55B, followed by 3' MTK.

Representative compounds tested in the replication assay exhibited EC50 of less than 100 μmol.

Nucleoside derivatives of this invention were also evaluated for cellular toxicity and antiviral specificity of SM screening of possible inhibition (soshipiegssgeepv), which is described below. at

S. Sotspiegssgeepz

The ability of nucleoside derivatives of this invention to inhibit human DNA polymerases was determined using the following assays. and. Inhibition of human DNA alpha- and beta-polymerases: o

Reaction conditions «

The reaction volume is 540 μl

Components of the reaction buffer: 20mM Ttgiv-HCII, pH 7.5, 200μg/ml calf serum albumin, 100mM Kei - 2mM dD-mercaptoethanol, 10mM Masio, 1.6mM YaA,as,asatteR « a-ZZr-DATP Z 50 Enzyme and matrix c 0 ,Oo5mg/ml DNA matrix of fish sperm with hepa "with O,O1od/μl DNA o; - or p -polymerase" Preparation of DNA matrix of fish sperm with hepa

Add μl of 1M Mosi" to 500 μl of activated fish sperm DNA (058 70076);

It was heated to 372C and 3 μl of bbod/μl of exonuclease II (sirsovk 18013-011) was added; They were incubated for 5 minutes at 372C; (95) The reaction was terminated by heating to 652C for 10 minutes; oo 50-100μl aliquots were injected into chromatographic columns Vio-zrip 6 (Vio-Kai 732-6002), balanced 20MM

Tgiv-NSI, pH 7.5; - Eluted by centrifugation at 1000x9 for 4 minutes; c» The eluate was combined and the absorbance at 260 nm was measured to determine the concentration.

The DNA matrix was diluted to the appropriate volume of 20 mM Tgiz-HCI, pH 7.5, and the enzyme was diluted to the appropriate volume of 20 mm Tgiz-HCI containing 2 mM p-mercaptoethanol and 100 mm KSI. The matrix and enzyme 5B were pipetted into ampoules for microcentrifugation or a 96-well plate. Blank reactions without enzyme and control reactions without test compound were also prepared using enzyme dilution buffer and (F) solvent for test compound, respectively. The reaction was initiated with a reaction buffer with the components listed above. The reaction mixture was incubated for 1 hour at 372C. The reaction was quenched by adding 20 μl of 0.5M

EOTA. 5 µl of the quenched reaction mixture was applied as a spot on filter discs M/paytap OE81 and dried in air. The filter disks were repeatedly washed with 150 ml of 0.3 M ammonium formate, pH 8, until the number of pulses in Tml of washing was less than 100 srt. The disks were washed twice with 150 ml of absolute ethanol and once with 150 ml of anhydrous simple ether, dried and pulses were counted in 5 ml of scintillation liquid.

The percentage of inhibition was calculated according to the following equation: 95 inhibition - |(1-(crt in the test reaction - crt in the blind) / (crt in the control reaction - crt in the blind))x100. 65. Inhibition of human DNA gamma polymerase

The effectiveness of inhibition of human DNA gamma-polymerase was determined in reactions that include 0.5 ng/μl of the enzyme; 10 μM aATP, STR, STR and TTR; 2μCurie/reaction (a-ZRI|-ZATP, and 0.4μg/μl of activated fish sperm DNA (supplied by OZ Viospetisai) in a buffer containing 20mM Ttiz, pH 8, 2mM p-mercaptoethanol, 50mM KSI, 10mM

MaSI" and 0.1 μg/μl VZA. The reactions were allowed to proceed for 1 hour at 372C and quenched by adding 0.5M EOTA to a final concentration of 142mM. Product formation was quantified using binding to an anion exchange filter and scintillation counting. The compounds were tested up to a concentration of 5 Ωm.

Percent inhibition was calculated using the following equation: 905 inhibition - (1-(CRT in test reaction - CRT in blank) / (CRT in control reaction - CRT in blank))x100.

The ability of nucleoside derivatives of this invention to inhibit HIV (HIV) infectivity and spread of HIV 70 was determined in the following analyses: p. Analysis of HIV infectivity

The analysis was carried out with the type of cells of Her! a Madi expressing both SHOSKA and CSK5 were selected for low background expression of p-galactosidase (p-dai). The cells were infected for 48 hours and yes! production from the integrated HIV-1 GTK promoter was counted using a chemiluminescent substrate (Saiasioidni 75 Riv, Tgorich, Vedioga, MA). Inhibitors were titrated (in duplicate) with two-fold serial dilutions, starting from 10O0μM; the percentage of inhibition for each of the concentrations was calculated relative to the control infection. and. Inhibition of the spread of HIV

The ability of the compounds of this invention to inhibit the spread of the human immunodeficiency virus (HIV) was determined by the method described in the US patent Mo5413999 (May 9, 1995) and 9.R. Massa, ei ai., Rgos. Mai). Asai. Zei., 91: 4096-4100 (1994), incorporated herein by reference.

Nucleoside derivatives of this invention were also screened for cytotoxicity against cultured hepatoma (Nin-7) cells containing a subgenomic NSM replicon using an assay based on MTZ cells, as described in the analysis below. NiH-7 cell line is described in N. MaKabauavznpi, ei aYi., Sapseg Kev., 42: 3858 (1982). c e. Cytotoxicity analysis o

Cell cultures were prepared in the appropriate medium at concentrations of approximately 1.5xX10 9 cells/ml for suspension cultures for 3 days of incubation and 5.0x10 7 cells/ml for adherent cultures for 3 days of incubation. 9 µl of the cell culture was transferred to the wells of a 9b-well tablet and 100 times the final concentration of the test compound in DMSO was added. The tablet was incubated at 372C and 59565 СО" for a specified period of time. After the end of the incubation period, 20 μl of the reagent for the analysis of cell proliferation was added to each cell (SePTyeg 96 Adceoiz Ope Zoishiop Seii| RgoiYiegayop Avzzau geadep) (MT5) (Rgoteda) and the plate was incubated at 372С and 595 СО" for an additional period of time up to 3 hours . The contents of the tablet were stirred to obtain a homogeneous mixture and the absorbance was measured at a wavelength of 49 nm using a tablet reader. A standard curve for suspension culture cells was obtained for a known number of cells immediately before the addition of MT5 reagent. Metabolically active cells change MT5 to formazan. Formazan absorbs at a wavelength of 49O0nm. Absorbance at 490 nm in the presence of compound was compared with absorbance in wells to which no compound was added. Reference: Sogu, A.N. ei ai., "Ove oi ap adceoivz zoiYShbie (eigagoiit/Logthalap avzvau yog sei dhomlLpy azzauz ip syyige", Sapseg Sottyp. « du 3:207(1991). -o

The following analyzes were used to determine the activity of the compounds of this invention against other RNA-dependent RNA viruses. :z» a. Determination of ip-omygo antiviral activity of compounds against rhinovirus (analysis of inhibition of the cytopathic effect)

The conditions of the analysis are described by Ziyzhshe! and Nyitap, "Ove oi aizrozarie tisgoiiizzce syMige riafev og - 15 apiimiga! apa ipiepegop ipdysiop visaiiev", Arri. Misgobioi!. 22: 797-801 (1971).

Viruses (95) Rhinovirus type 2 (KM-2), strain NOR, was used with KV cells and medium (0.195 MansSoO, without so antibiotics) as indicated in reference Ziyzhmei! and Nyiytap. This virus obtained from ATSS was obtained from a throat swab of an adult man with moderately acute inflammation of the upper respiratory tract.

Her 50 Rhinovirus type 9 (KM-9), strain 211, and rhinovirus type 14 (KM-14), strain Tomu, were also obtained from the American Type Culture Collection (ATSC) in Rockville, MO. KM-9 was obtained from a human throat wash and

KM-14 was obtained from a throat swab of a young person with upper respiratory tract disease. Both of these viruses were used with Nei and OpPio-1 cells (Og. Egea Naudep, Opim. oi MA), which are human epithelioid carcinoma cells. As a growth medium, MEM (minimum necessary 59 Igla medium) with the addition of 595 fetal calf serum and 0.196 MansSoOz was used.

GF) Antiviral test medium for all three types of viruses was MEM with 595 EB5, 0.190 Manso with, 7 5 µg gentamicin/ml and Massey's TMM.

The concentration of 2000 μg/ml was the highest of the concentrations used for the analysis of the compounds of this invention.

The virus was added to the assay plates approximately 5 minutes after the test compound. 60 corresponding control measurements were also carried out. The analyzed tablets were incubated in moist air with a CO content of 590 at 372. Cytotoxicity was determined in control cells by examining morphological changes using a microscope. Regression analysis of CPE results for viruses and control toxicity results gave values of EO 50 (5096 effective dose) and SS50 (5096 cytotoxic concentration). The selectivity index (SI) in5 was calculated according to the formula: ZI-SSBUEOrvo.

B. Determination of the anti-viral activity of compounds against dengue fever. Bunzi and yellow fever (CRE inhibition assay)

The details of the analysis are presented in the above link of Ziduea! and Niithap.

Viruses

Dengue virus type 2, a strain from New Guinea, was obtained from the Center for Disease Control (Sepieg etog Oizease Sopigo!). Two lines of kidney cells from African green monkeys were used for virus cultures (Mego) and for antiviral tests (MA-104). Both the yellow fever virus, strain 170, obtained from the brain of an infected mouse, and the Bunzi fever virus, strain H 336, isolated from the serum of a feverish boy in South Africa, were obtained from the ATCC. For both these viruses and for the assays, 7/0 Mego cells were used.

Cells and environments

MA-104 cells (WiouUpinakeg, Ips., UMaiKegemiPMe, MO) and Mego cells (ATSS) were used in medium 199 supplemented with 595 EB5 and 0.195 Manso" and without the addition of antibiotics.

MEM, 296 IU, 0.1896 Manso" and 5 µg gentamicin/ml were used as an analytical medium for dengue, Banzi and yellow fever viruses.

Tests for antiviral activity of the compounds of this invention were carried out in accordance with references 5bidmei! and

In the same way as the rhinovirus testing mentioned above. Adequate values for cytopathic effect (CPE) were reached after 5-6 days for each of these viruses. with. Determination of immunological antiviral activity of compounds against the West Nile virus (MUevi Me Migiv) 2o (CRE inhibition analysis)

The details of the analysis are presented in the above link by BJ! and Niithap. West Nile virus, an isolate from

of New York, derived from chicken brain, was obtained from the Centers for Disease Control (Sepieg og

Oivease Sopigo!J. Mego cells were grown and used as above. MEM, 195 EU5, 0.195 Manso's and 5 µg of gentamicin/ml were used as a test medium. with

Testing of the antiviral activity of the compounds of this invention was carried out according to the methods of bidmei! and

Niitap, which are similar to those used in the activity assays against rhinoviruses. Adequate values i) for cytopathic effects (CRE) were reached after 5-6 days. 4. Determination of the antiviral activity of the compounds against rhinoviruses, yellow fever virus, dengue, banzi, and West Nile viruses (neutral red capture assay) c zo Ipiepegop: Misgozresigorpoioteigis Otsapiiatsyop oi -

Suoraiis EPesi", Arri. Epmigop. Misgobioi. 31: 35-38 (1976). To read readings from the tablet being analyzed, a Moadei EI! 309 microplate reader (Vio-Tek Ipvigitepiv Ips.) was used.

Ebbo and SOvo values were calculated as above. at

Examples of pharmaceutical compositions

With regard to specific oral formulations of the compounds of the present invention, 5 mg of the compound of Example 1 or Example 2 was combined with a sufficient amount of finely divided lactose to give a total amount of 580-590 mg to fill a size 0 hard gelatin capsule.

Although the present invention has been described and illustrated with reference to specific embodiments thereof, it should be apparent to those skilled in the art that various changes, modifications, and substitutions may be made without departing from the spirit and scope of the present invention. For example, effective doses, the values of which differ from those indicated above, can be used depending on the differences in the patient's reactions and the severity of the NSM infection. Similarly, ;" the pharmacological responses observed may vary according to (and depending on) the particular compounds chosen, or depending on whether pharmaceutical carriers are present, as well as the type of formulation and

The method of administration used, and it is assumed that such expected variants or differences in -I results are consistent with the purposes and practice of this invention. Therefore, it must be understood that the invention is limited only by the scope of the claims and this claim must be interpreted as broadly as is reasonable. (ee) drive 70

Claims (1)

The formula of this invention" 1. The compound of the structural formula I: do d'o (F,; do M and M z po M i 1z "Mr M v bo V V v v v v ve b5 (I) or a pharmaceutically acceptable salt thereof; where B" represents C 5,4-alkenyl, C 1-4-alkynyl or C 1-4-alkyl, where the alkyl is unsubstituted or substituted by hydroxy, amino, C 1-4-alkoxy, C 1-4-alkylthio or one to three fluorine atoms ; B? represents hydrogen, fluorine, hydroxy, mercapto, C 4,4- alkoxy or C 1-6 alkyl; or iv: together with the carbon atom to which they are attached, form a 3-bene saturated monocyclic ring system, which optionally contains a heteroatom selected from 0, 5 and C 1 -alkyl; B3 and E7 are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C-4-alkyl, Co-alkenyl, Co-6-alkynyl and C-6-alkyl, where the alkyl is unsubstituted or substituted by 70 hydroxy, amino, C-4-alkyl, C-4-alkylthio or one to three fluorine atoms; B is hydrogen, C 10-alkylcarbonyl, PzOzNa, P»ObNaz or RIV ZVU; BZ YIV is each independently hydrogen, methyl, hydroxymethyl or fluoromethyl; BZ is hydrogen, C 1-4-alkyl, Co.4- alkynyl, halogen, cyano, carboxy, S. --alkyloxycarbonyl, azido, /5 amino, C1-alkylamino, di(C4.1-alkyl)amino, hydroxy, C1-6-alkyl, C1-6-alkylthio, C6-alkylsulfonyl, (Ci.4-alkyl)o»-aminomethyl or C,-cycloheteroalkyl, unsubstituted or substituted by one or two groups independently selected from halogen, hydroxy, amino, C..4-alkyl and C.i.--alkyl; IN? represents hydrogen, cyano, nitro, C 4.3-alkyl, МНСОМНо, СОМ В", itself В, Сов, С(-МНМН», hydroxy, С. з-аклокы, amino, С. ,-alkylamino, di(С4. 1-alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl) or (imidazol-2-yl); wherein the alkyl is unsubstituted or substituted with one to three groups , independently selected from halogen, amino, hydroxy, carboxy and C..3-alkyl; 279 of its B"! each independently represents hydrogen, hydroxy, halogen, C 4 5X-alkoxy, amino, C..4-alkylamino, di (C.-4-alkyl)amino, C.sub.6-cycloalkylamino, di(C.sub.3-6-cycloalkyl)amino or C.sub.6-cycloheteroalkyl, unsubstituted or substituted by one or two groups independently selected from halogen, hydroxy, amino, C4. 4-alkyl and C.4.,--alkoxy; c each B? independently represents hydrogen or C. c-alkyl; and BZ her and" each independently represents hydroxy, OSN "СНоЗС(-О)С 4 "- alkyl, OSNoOS(C-FOOS 4 d-alkyl, o MnoenMeso»oMe, OSN(S. -alkyl/O(C-O) S. y-alkyl, fro- ro o 5 TO tu visn sn» or tvisnatsn» her О(СНИвСН "li ОСО(СноаСНю . , (ee) on the condition that if В represents is B-methyl and B 7 is hydrogen, or B 7" is B-methyl and B! so is hydrogen, B 2 and BZ are A-hydroxys, B. 79 is amino, and 27, 25, 8", 88" are hydrogen, then E? does not represent cyano or SOMN". 2. The compound according to claim 1 of the structural formula II: to v'o « s - s d? i AH M z» tu- o M and another 45 where, d! yes vd? o (C iz 20 or its pharmaceutically acceptable salt; where B" represents C 4-3-alkyl, where the alkyl is optionally substituted by hydroxy, amino, C 4-3-alkyl, C 4-3-alkylthio or c" by one - by three fluorine atoms; B? represents hydroxy, fluorine or C../-alkoxy; EZ represents hydrogen, halogen, hydroxy, amino or C../-alkoxy; 25 BZ represents hydrogen, PaOzoNa, PaOvNa or POZN" ; (F) EZ is hydrogen, amino or C. d-alkylamino; where EB is hydrogen, cyano, methyl, halogen or SOMH"; and BO and B" are each independently hydrogen, halogen, hydroxy, amino, C 4A-alkylamino, 6o di(C,y-alkyl)amino or C3 6-cycloalkylamino; provided that if BK is B-methyl, K 2 and BZ are A-hydroxy, B 79 is amino, and K5 BVE" represent hydrogen, then B? does not represent cyano or SOMN". Z. The compound according to claim 2, where: B" represents methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl or aminomethyl; B" represents hydroxy, fluoro or methoxy; BZ is hydrogen, fluorine, hydroxy, amino or methoxy; 2? represents hydrogen or RaOzNu; EZ is hydrogen or amino; 9 V? represents hydrogen, cyano, methyl, halogen or СОМН"; and BO" each independently represents hydrogen, fluorine, hydroxy, or amino; provided that if BK represents B-methyl, K 2 and BZ represent A-hydroxy, B 79 represents amino, and K5 viv" represents hydrogen , then VE? does not represent cyano or SOMN". 70 4. The compound according to claim 1, selected from the group consisting of: 4-amino-7-(2-C-methyl-B-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4- amino-7-(2-C-methyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-methylamino-7-(2-C-methyl-B-Y-ribofuranosyl)- 7H-pyrrolo|2,3-4|Ipyrimidine, 4-dimethylamino-7-(2-C-methyl-B-Y-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine, 4-cyclopropylamino-7- (2-C-methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-7-(2-C-vinyl-B-ХО-ribofuranosyl)-7H-pyrrolo |2,3-4|Ipyrimidine, 4-amino-7-(2-C-hydroxymethyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-7-(2- C-fluoromethyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-5-methyl-7-(2-C-methyl-B-ХО-ribofuranosyl)-7 H- pyrrolo|2,3-4|pyrimidine, 4-amino-7-(2-C-methyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine-5-carboxylic acid, 4-amino -5-bromo-7-(2-C-methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-5-chloro-7-(2-C-methyl -B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine, 4-amino-5-fluoro-7-(2-C-methyl-B -O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 2,4-diamino-7-(2-C-methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4 |pyrimidine, sc 2-amino-7-(2-C-methyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 2-amino-4-cyclopropylamino-7-(2-C -methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, o) 2-amino-7-(2-C-methyl-B-O-ribofuranosyl)-7H-pyrrolo|2 ,3-4|Ipyrimidin-4(ZH)-one, 4-amino-7-(2-C-ethyl-B-Y-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino -7-(2-C,2-O-dimethyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 7-(-2-C-methyl-B-O-ribofuranosyl) )-7 H-pyrrolo|2,3-4|Ipyrimidin-4(ZH)-one, 2-amino-5-methyl-7-(2-C,2-O-dimethyl-B-ХО-ribofuranosyl)- 7 H-pyrrolo|2,3-4|Ipyrimidin-4(ZH)-one, « 4-amino-7-(3-deoxy-2-C-methyl-B-ХО-ribofuranosyl)-7 H-pyrrolo| 2,3-4|pyrimidine, c 4-amino-7-(3-deoxy-2-C-methyl-B-O-arabinofuranosyl)-7 H-pyrrolo|2,3-4|pyrimidine, 4-amino- 2-fluoro-7-(2-C-methyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, o 4-amino-7-(3-C-methyl-B-O- ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, i.e. 4-amino-7- (3-C-methyl-B-YOO-xylofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-7-(2,4-di-C-methyl-B-O-ribofuranosyl)- 7H-pyrrolo|2,3-4|pyrimidine and 4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4 |pyrimidine, and the corresponding 5'-triphosphates; « 20 or their pharmaceutically acceptable salts. with p 5. The compound according to claim 4, selected from the group consisting of: 4-amino-7-(2-C-methyl-B-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, ; t 4-amino-7-(2-C-methyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-7-(2-C-fluoromethyl-B-O- ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine, 4-amino-5-methyl-7-(2-C-methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4| pyrimidine, -1 4-amino-5-bromo-7-(2-C-methyl-B-ХО-ribofuranosyl)-7 H-pyrrolo|2,3-4|pyrimidine, 4-amino-5-chloro-7 -(2-C-methyl-B-ХО-ribofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine, o 4-amino-5-fluoro-7-(2-C-methyl-B-O-ribofuranosyl )-7H-pyrrolo|2,3-4|pyrimidine and co 4-amino-7-(2-C,2-O-dimethyl-B-O-ribofuranosyl)-7H-pyrrolo|2,3-4|pyrimidine , 20 and their corresponding 5'-triphosphates; ve or their pharmaceutically acceptable salts. c 6. The compound according to claim 5, which is 4-amino-7-(2-C-methyl-B-O-arabinofuranosyl)-7H-pyrrolo|2,3-4|Ipyrimidine or its pharmaceutically acceptable salt. 7. The compound according to claim 5, which is 4-amino-7-(2-C-methyl-B-Y-ribofuranosyl)-7H-pyrrolo|2,3-4-pyrimidine or its pharmaceutically acceptable salt. 8. The compound according to claim 5, which is 4-amino-7-(2-C-fluoromethyl-B-XO-ribofuranosyl)-7H-pyrrolo|2,3-4-pyrimidine or (F. its pharmaceutically acceptable salt. ko 9. The compound according to claim 5, which is 4-amino-5-chloro-7-(2-C-methyl-B-Y-ribofuranosyl)-7H-pyrrolo|2,3- 4|Ipyrimidine or its pharmaceutically acceptable salt. in 10. The compound according to claim 5, which is 4-amino-5-bromo-7-(2-C-methyl-B-Y-ribofuranosyl)-7H-pyrrolo|2,3 -4 Ipyrimidine or its pharmaceutically acceptable salt. 11. The compound according to claim 1 for inhibition of RNA-dependent RNA viral polymerase or inhibition of RNA-dependent RNA viral replication in mammals. 12. The compound according to claim 1 as an active agent for the treatment of RNA-dependent RNA virus infection in mammals. c5 13. The compound according to claim 12, wherein said RNA-dependent RNA viral infection is hepatitis C infection. 14. The compound according to claim 1 for the manufacture of drugs for inhibiting RNA-dependent RNA viral polymerase or for inhibiting RNA-dependent RNA viral replication in mammals. 15. The compound according to claim 1 for the manufacture of drugs for inhibiting RNA-dependent RNA virus infection in mammals. 16. The compound of claim 15, wherein said RNA-dependent RNA viral infection is hepatitis C infection. 17. A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically acceptable carrier. 18. Pharmaceutical composition according to claim 17, intended for inhibition of RNA-dependent RNA viral polymerase, inhibition of RNA-dependent RNA replication and/or for treatment of RNA-dependent RNA viral infection. 19. Pharmaceutical composition according to claim 18, where said RNA-dependent RNA viral polymerase is NSM M55B polymerase, said RNA-dependent RNA viral replication is NSM replication and said RNA-dependent RNA 7/o Viral infection is NSM infection. 20. A method of inhibiting RNA-dependent RNA viral polymerase and/or inhibiting RNA-dependent RNA viral replication, in which an effective amount of the compound according to claim 1 is administered to a mammal in need of such inhibition. 21. The method according to claim 20, where the specified RNA-dependent RNA viral polymerase is NSM M55B polymerase and the specified RNE-dependent RNA viral replication is NSM viral replication. 22. A method of treating an RNA-dependent RNA virus infection, in which an effective amount of the compound according to claim 1 is administered to a mammal in need of such treatment. 23. The method according to claim 22, where the specified RNA-dependent RNA viral infection is an HCM infection. 24. The method according to claim 23, in which the compound according to claim 1 is administered in combination with a therapeutically effective amount of another agent active against NSU. 25. The method according to claim 24, where the specified agent active against NSU is ribavirin, levavirin, thymosin alpha-1; M5Z serine protease inhibitor; inhibitor of inosine monophosphate dehydrogenase; interferon-A or pegylated interferon-A, alone or in combination with ribavirin or levavirin. 26. The method according to claim 25, wherein said agent active against NSM is interferon-A or pegylated interferon-A, alone or in combination with ribavirin. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 9, 15.09.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. so "s so m. shi s z -I (95) (ee) iz 50 syu" F) ime) 60 b5