UA103477C2 - Carba-nucleoside analogs for antiviral treatment - Google Patents

Abstract

Provided are imidazol [1,5-f] [1,2.4]triazinyl, traidazol [1,2,4]triazinyl, and [1,2,4] triazolo [4,3-f| [1,2,4] triazinyl nucleosides of formula I nucleoside phospliates and prodrugs thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections. Wherein Xor Xis indepently C-or N and wherein at leas1 one of Xor Xis N.

Description

FIELD OF THE INVENTION

This invention generally relates to compounds having antiviral activity, in particular to nucleosides having activity against infections caused by Riamimigida, more specifically to inhibitors of RNA-dependent RNA polymerase of the hepatitis C virus.

TECHNICAL LEVEL

Viruses belonging to the Riamimigidae family include at least three distinct genera - reziimigize5, Pamimigize5 and perasimigizez (Saiib5peg, ei ai., U. Sep. Migo!., 1993, 70, 37-43). While resimigize5 cause many economically important animal diseases, such as bovine diarrhea virus (BDIV), classical swine fever virus (C5EM, swine cholera), and ovine border disease (OBD), their contribution to human disease is less well understood ( Moeppiod, M., ei ai., Adu. Mig. Nev. 1992, 48, 53-98). Riamimigize5 causes important human diseases such as dengue fever and yellow fever, while Perasimigize5 causes hepatitis C virus infections in humans.

Other important viral infections caused by viruses of the Riamimigidae family include the virus

West Nile virus (WNIV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus and

Zika. Collectively, infections caused by viruses of the Riamimigidae family are responsible for significant mortality, morbidity, and economic losses worldwide. Thus, there is a need for the development of effective methods of treatment of viral infections caused by Riamimigidae.

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Voueg,

M. eyi ai. In Neray). 32:98-112, 2000), therefore, modern antiviral research is largely aimed at developing more advanced methods of treating chronic infectious diseases caused by HCV in humans (Oi Vezsediije, A.M. apa Wasop, V.V., Zsiepiis Ategisap, Osi.: 80-85, (1999);

Sogaop, S. R., vi ai., U. Med. Snet 2005, 48, 1-20; Magadroig, O.; Hey, May. Vem. Misgo. 2007, 5(6), 453-463). An overview of a number of methods of treatment of HCV is given in the work of VutoskK ei ai. in Apiimigai Spetivig 4

SpetoiShegaru, 11:2; 79-95 (2000).

RNA-dependent RNA polymerase (Cacr) is one of the most well-studied targets for the development of new agents for the treatment of HCV. M55B polymerase is a target for inhibitors in early stages of human clinical trials (Zottadobvi, 9U., MMO 01/90121 A2, 05 2004/0006002

JSC). These enzymes have been studied in detail at the biochemical and structural levels, including screening studies to identify selective inhibitors (JuOe Siegsa, E. (2001) U. Rpaptasoi. Ehr. Teg. 297:1-10; Oe Siegsa, E. (2001) 9. Siip. Migoi. 22:73-89). Biochemical targets such as M55B are important in the development of treatments for HCV, as HCV does not replicate in the laboratory and there are challenges associated with the development of cellular studies and preclinical animal systems.

At this time, there are mainly two antiviral compounds, ribavirin, which is a nucleoside analog, and interferon-alpha (c) (IEM), which are used to treat chronic infections in humans caused by HCV. Taken alone, ribavirin is not effective in reducing viral levels

RNA, has significant toxicity, while ribavirin is known to cause anemia. The combination of MI and ribavirin was reported to be effective in controlling the course of chronic hepatitis C (SO, Her. 9., ей а! Ogpid5 2002, 62, 507-556), but sustained improvement was observed in less than half of patients receiving this treatment. Other patent applications that propose the use of nucleoside analogs for the treatment of viral hepatitis C include UMO 01/32153, IMO 01/60315, UMO 02/057425,

UMO 02/057287, MO 02/032920 and UMO 02/18404, however, additional methods of treatment of infections caused by HCV have not yet appeared. Thus, there is an urgent need for drugs with improved antiviral and pharmacokinetic properties and increased activity in preventing the development of HCV resistance, improved oral bioavailability, increased efficacy, reduced unwanted side effects and a longer half-life of ip mimo (Oye Egapsezso, V. eyi ai. (2003) Apiimiga! Nezeagsp 58:1-16).

Some ribosides of nucleic bases pyrrolo(/1,2-C1,2,4)griazine, imidazo|1,5-C1,2,4)griazine, imidazo|1,2-4Х1,2,4)triazine and (1, 2,AIgriazolo|4,3-CP1,2,4|)triazine is described in Sagropuagas Kezeagsp 2001, 331(1), 77-82; Mysiovidez 5 Mysioide5 (1996), 15(1-3), 793-807; Temapedgop I eyeg5 (1994), 35(30), 5339-42; Neuroscience (1992), 34(3), 569-74; ). Spent boss. RegiKip Tgape. 1 1985, 3, 621-300; in.

Spent boss. ReiKkip Tgapv. 1 1984, 2, 229-38; MO 2000056734; Ogdapis I eneg5 (2001), 3(6), 839-842; 9.

Spent boss. ReiKip Tgapv. 1 1999, 20, 2929-2936; and U. Med. Spent 1986, 29(11), 2231-5. However, these compounds have not been shown to be suitable for the treatment of HCV. Vaba, U. 5. in publications UUO2008/089105 and

UMMO2008/41079 proposed ribosides of pyrrolo(/1,2-C1,2,4)triazine nucleic bases, which have antiviral activity and activity against HCV and Kakr.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides compounds that inhibit viruses of the Riamimigidae family. The invention also includes compounds that inhibit viral nucleic acid polymerases, in particular RNA-dependent

RNA polymerase (CacKr) of HCV, but not the nucleic acid polymerase of the cell. Thus, the compounds of the present invention are suitable for the treatment of infections caused by Riamimigidae in humans and other animals.

According to one aspect, the present invention provides a compound of Formula I: ve x! o v, / - M x o-- sne x M Zh. o M vo do di v! N

In the

The formula or a pharmaceutically acceptable salt thereof, where: at least one of E", B2, VU, B" or K? is M(K2)2, Mz, SM, MO", 5(O) pe, halogen, (C1-

C1-alkyl, (C1-C1) carboacyclylalkyl, substituted (C1-C1) alkyl, (C2-C1) alkenyl, substituted (C2-

C1-C8)alkenyl, (Co-C8)alkynyl, substituted (C2-C8)alkynyl or aryl(C1-C8)alkyl, and each of EB", B, VU, B" or

The remaining B5, independently of the others, are H, OKg, M(Bg)2, Mz, CM, MO», 5(O)piNa, halogen, (C1-Cv)alkyl, (C4-Cv)carboacyclylalkyl, substituted (C:-Cv)alkyl, (C2-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2-Cv)alkynyl, substituted (C2-Cv)alkynyl or aryl(C:-Cv)alkyl, or any what two K", B,

ВЗ, В" or ЕЕ with neighboring carbon atoms jointly represent -0(С2О)0-, or together with the ring carbon atoms to which they are attached, form a double bond; each n, independently of the others, is equal to 0, 1 or 2 ; each Ba independently of the others is H, (C:-Cv)alkyl, (C2-Cv)alkenyl, (C2-Cv)alkynyl, aryl(Ci-Cv)alkyl, (Ci-Cv)ucarboacyclylalkyl, -C (-0О)А", -С(-0)08", -С(-0О)MA" B, -С(-0)58", - 5(0)8", -5(0)28" , -KYUOHOV), -(0)5(O8"), -502MA "Ve;

B' represents H, -С(-0)08", -0(-03)08", -С(-О)МА"А, -Б(-0)58", -5(0)8" , -5(0)28, -

З(ОХОВ), -6(0)2(ОВ8"), -502МА "В": or

IN

- 5 umg. each U or U" independently of the others is О, 5, МЕ, "М(О)(В), ШЧО), "ШЧОХОК) or М--

MA;

MU and Me together represent -U(С(ВУ)2)з3У3-; or one of M/ or M? together with either KZ or РЕ" represents -U3-, and the other with M/ or Mug represents Formula Ia; or each of M/ and M/g independently represents a group of Formula Ia:

In вх У2-- Р у? and and

Magician

Formula Ia where: every U? independent of others is a connection, OO, SE", MA, "M(O)HA), MOV), "SHCHOHOV), M-

MA", 5, 5-5, (0) or 5(0)2; each UZ, regardless of the others, represents 0, 5 or ME;

M2 is equal to 0, 1 or 2;

each EX, independently of the others, is a KU or a formula: мы Ву ВУ ий

VU

Ug Ug chUg y Mid Me mya

Ma where: each Ma, Mis, and M'1yY, regardless of the others, is equal to 0 or 1;

M12s is equal to 0, 1.2, 3.4, 5.6, 7, 8, 9, 10, 11 or 12; each KU independently of the others represents H, E, SI, Vg, I. OH, Kk, -С(-Уы38, -С(-У3ОВ, -

C(-UUZM(A)", -M(B)2, -M(A)z, -58, -50)8, -530)28, -(F(ОВ), -5Х0)5(ОНВ) , -О0(-У)В, -ОС(-У ОВ, -

ОоС(-Ж)3(М(В)25), -50(-М)В8, -50(-МОВ, -5С(-UUM(Н)28), -М(В)С(-М)А , -SHCHA(-M)OV, Y0(-

Mm(P)C(-M UM(A)2, -502MA2, -SM, -Mz, -MO", -OK or M/Z; or two RU at the same carbon atom jointly form a carbocyclic ring containing from C to 7 carbon atoms; each K independently of the others is H, (Ci-Cv) alkyl, substituted (C:i-Cv)alkyl, (Cg-

C2-C8)alkenyl, substituted (C2-C8)alkenyl, (C2-C8)alkynyl, substituted (C2-C8)alkynyl, C2-C8 aryl, substituted C8-C8 aryl, C2-C820 heteroacyclyl, C2-C820 substituted heteroacyclyl, arylalkyl or substituted arylalkyl;

M/Z represents MU" or Mu"; MU" represents K, -C(U7)VU, -C(U ZMU", -BO2VU or -502MU5; and Mu" represents a carbocycle or heterocycle, while Mu? independent substituted by 0-3 BU groups; each X!' or X? independently of the others represents C-B'O or M, and at least one of X. and

X2 is M; each short circuit, independently of the others, is a halogen, MAE"B'2, MAO", MAMA" Be, Ma, MO,

МО», СНО, СМ, -СН(-MA"), -СН-МНМА", -СН-М(ОВ"), -СН(ОВ")», -С(-0О)МА "В, -С (-5)MA Be, -F(-F0OV", (C1-Cv)alkyl, (C2-Cv)alkenyl, (Cg-Cv)alkynyl, (C--Cv)ucarboacyclylalkyl, possibly substituted aryl, possibly substituted heteroaryl , -C(-0)(C1-Cv)alkyl, -550)4(C1-Cv)alkyl or aryl(C:1-Cv)alkyl,

ОВ" or 5281; each E? or Ko, independently of the others, is H, halogen, MK"B"2, Sh(А"3ОВ8", MAMA" B",

Mz, MO, MO», CHO, SM, -CH(-MA"), -CH-MNMA", -CH-MOV"), -CH(ОВ")», -С(-0О)MA "В, -(-5)MA "B, -O(-O0)OB8", B", OB" or ZK; each B! or B"2 independently of the others represents H, (C:1-Cv)alkyl, ( C2-Cv)alkenyl, (C2-Cv)alkynyl, (C4-Cv)carboacyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(-0)(C1-

C1-C8 alkyl, -(O)p(C:1-C8)alkyl or aryl(C1-C8)alkyl; or КК" and Кг, together with the nitrogen atom to which they are attached, form a 7-membered heterocyclic ring, while each of the carbon atoms of the specified heterocyclic ring can be replaced by -0-, -5- or -МА8-; where each ( C:-Cv)alkyl, (Cg-Cv)alkenyl, (Cg-Cv)alkynyl or aryl(C:i-Cv)alkyl in the composition of each of VE",

B2, BZ, VU, B", B" or K!:2, independently of the others, may be substituted by one or more halo, hydroxy,

SM, Mz, M(H2)25 or OVU; and where one or more non-terminal carbon atoms of each specified (Си1-

C) alkyl can be replaced by -O-, -5- or -MVe-.

According to another aspect, this invention includes compounds of Formula I and their pharmaceutically acceptable salts and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amorphous forms of said compounds.

According to another aspect, the present invention provides novel compounds of Formula I having activity against infections caused by Riamimidae viruses. Without wishing to be bound by specific theory, it is believed that the compounds of the invention can inhibit viral RNA-dependent RNA polymerase and thus inhibit viral replication. They are suitable for treating human patients infected with a human virus such as hepatitis C virus

According to yet another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula | or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

According to another embodiment, this application proposes a combined pharmaceutical agent containing: a) a first pharmaceutical composition containing a compound of Formula | or a pharmaceutically acceptable salt, solvate or ester thereof; and

B) a second pharmaceutical composition containing at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin analogs, M53 protease inhibitors, M55a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors and other drugs drugs for the treatment of HCV.

According to another embodiment, this application proposes a method of polymerase inhibition

HCV, comprising contacting a cell infected with HCV with an effective amount of the compound

Formula I or its pharmaceutically acceptable salts, solvates and/or ethers.

According to another embodiment, this application proposes a method of polymerase inhibition

HCV, comprising contacting a cell infected with HCV with an effective amount of the compound

Formulas | or its pharmaceutically acceptable salts, solvate and/or ether, and at least one additional therapeutic agent.

According to another embodiment, this application provides a method of treating and/or preventing a disease caused by a viral infection, and said viral infection is caused by a virus selected from the group consisting of dengue virus, yellow fever virus,

West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C virus, by administration to a subject, in need thereof, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

According to another embodiment, this application proposes a method of treating HCV in a patient, which includes administering to the specified patient a therapeutically effective amount of the compound

Formula I or its pharmaceutically acceptable salt, solvate and/or ether.

According to another embodiment, this application proposes a method of treating HCV in a patient, which includes administering to the specified patient a therapeutically effective amount of the compound

Formula I or its pharmaceutically acceptable salt, solvate and/or ether and at least one additional therapeutic agent.

In yet another aspect of the invention, there is provided a method of treating or preventing symptoms or manifestations of HCV infection in an infected animal, comprising administering to said animal (ie, treating said animal) a combination pharmaceutical composition or compound comprising an effective amount of a compound of Formula I and a second compound , which has properties directed against everything.

According to another aspect, the present invention also provides a method of inhibiting HCV, comprising administering to a mammal infected with HCV an amount of a compound of Formula 1 effective to inhibit replication of HCV in infected cells in said mammal.

According to a further aspect, the invention also provides methods and novel intermediates disclosed herein which are suitable for the preparation of compounds of Formula I according to the invention.

According to other aspects, new methods of synthesis, analysis, separation, isolation, purification, characterization and investigation of the compounds of the present invention are provided.

DETAILED DESCRIPTION OF ILLUSTRATIVE IMPLEMENTATION OPTIONS

This section provides a detailed description with references to specific implementations of the invention, examples of which are reflected in the attached description, structures, and formulas. Although the present invention has been described with respect to the specific embodiments shown, it should be understood that the invention is not limited to the specified embodiments. On the contrary, it is intended that the invention includes all alternatives, modifications and equivalents that are within the scope of the present invention.

According to yet another aspect, compounds of Formula I are represented by Formula II: where uh! d' / -fSchu a M

Y x ! shcha o M vo to "N

Gee in! singer

Formula II or a pharmaceutically acceptable salt of the specified compound, where: at least one of E", B2, VU, B" or K? is M(K2)2, Mz, SM, MO", 5(O) pe, halogen, (C1-

C1-alkyl, (C4-C8)carboacyclylalkyl, substituted (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C2-C8)alkenyl, (C2-C8)alkynyl, substituted (C2-C8)alkynyl or aryl (C:i-Cv)alkyl, and each of the remaining K', B, BZ, B" or P", independently of the others, represents H, OKe, M(Nag)2, Mz, CM, MO» 5(O) Be, halogen, (Si-

C1-alkyl, (C4-C8)carboacyclylalkyl, substituted (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C2-C8)alkenyl, (C2-C8)alkynyl, substituted (C2-C8)alkynyl or aryl (C:1-Cv)alkyl, or any two K", Be, BZ, B? or 5 at adjacent carbon atoms jointly represent -0(C20)0O- or together with the ring carbon atoms to which they are attached , form a double bond; each p is equal to 0, 1 or 2; each 2 independently of the others is H, (C:-Cv)alkyl, (C2-Cv)alkenyl, (C2-Cv)alkynyl, aryl(Ci -Cv)alkyl, (C4-Cv)carboacyclylalkyl, -C(-0)8", -C(-0)08", -0(-0)MA" B, -0(-0)58", -

З(О)В8", -5(0)28", -(OKHOV8), -5(002(О8), -502МА "Ве;

A" represents H, -0(-0)8", -С(-0)08", -С(-О)MA" B, -С(-0)58", -5(0)А" , -5(0)28, -

З(ОХОВ), -6(0)2(ОВ8"), -502МА "В": or

She

"--uh-

Mu? . each U or U" independently of the others is O, 5, MK, "М(О)ХР), МОВ), "Щ(ОХОК) or M-

MA;

WE and Me jointly represent -UZ(С(ВУ)2)3У3-, or one of M/ or MU? together with either RU or P" represents -U5-, and the other M/! or M/g represents Formula Ia; or each of M/ and Me independently of the other represents a group of Formula Ia:

In х У2--Р у? and

AND

Magician

Formula Ia where: every U? independent of others is a connection, OO, SE", MA, "M(O)HA), MOV), "SHCHOHOV), M-

MA", 5, 5-5, (0) or 5(O)"2; each UZ, regardless of the others, represents 0, 5 or ME;

M2 is equal to 0, 1 or 2; each Eh, independently of the others, is a KU or a formula: мы Ву ВУ ий

VU

Ugh Ugh chUgh

AND; Mid Me my

Ma where: each Ma, Mis, and M'1yY, regardless of the others, is equal to 0 or 1;

M12s is equal to 0, 1,2, 3,4,5,6, 7, 8, 9, 10, 11 or 12; each KU independently of the others represents H, E, SI, Vg, I. OH, Kk, -С(-Уы38, -С(-У3ОВ, -

С(-М MBA)», -М(В)2, -М(В)з, -5В8, -5(0)8, -5(0)28, -Б(ОХОВ), -5(0) X(ОВ), -О0(-У)В8, -ОС(-У ОВ, -

ОоС(-Ж)3(М(В)25), -50(-М)В8, -50(-МОВ, -5С(-UUM(Н)28), -М(В)С(-М)А , -SHCHA(-M)OV, Y0(-

М(В)С(-М )М(А)2, -502МА", -СМ, -Мз, -МО", -ОВ or M; or two RU at the same carbon atom jointly form a carbocyclic ring containing from 3 to 7 carbon atoms; each K independently of the others is H, (Ci-Cv) alkyl, substituted (C:i-Cv) alkyl, (Cg-

C2-C8)alkenyl, substituted (C2-C8) alkenyl, (C2-C8) alkynyl, substituted (C2-C8) alkynyl, C2-C8 aryl, substituted C8-C8 aryl, C2-C820 heteroacyclyl, substituted C2-C8 heteroacyclyl, arylalkyl or substituted arylalkyl;

M/Z represents MU" or Mu"; MU" represents K, -C(U7)VU, -C(U ZMU", -BO2VU or -502MU5; and Mu" represents a carbocycle or heterocycle, where Mu? independently from others substituted by 0-3 BU groups; each X' or X? independently of the others is C-B'O or M, and at least one of X' or X? is M; each KU independently of the others is a halogen, MA", MATOVA", MAMA" V, Mz, MO,

MOg, CHO, SM, -CH(-MA"), -CH-MNMA", -CH-MZHOV"), -CH(ОВ")", -С(-О)MA B, -б(-5) MA B", -F(-Ф0ОВ", (C1-Cv)alkyl, (C2-Cv)alkenyl, (C2-Cv)alkynyl, (C--Cv)ucarboacyclylalkyl, possibly substituted aryl, possibly substituted heteroaryl, -C (-0)(C1-Cv)alkyl, -550)4(C1-Cv)alkyl or aryl(C:1-Cv)alkyl,

ОВ" or 5281; each EK? or K'? independently of the others is H, halogen, MAE""B!2, SHATOV", MAMA "BA,

Mz, MO, MO», CHO, SM, -CH(-MA"), -CH-MNMA", -CH-MOV"), -CH(ОВ")», -С(-0О)MA "В, -(-5)MA "B, -O(-O0)OB8", B", OB" or ZK; each B! or B"2 independently of the others represents H, (C:1-Cv)alkyl, ( C2-Cv)alkenyl, (C2-Cv)alkynyl, (C4-Cv)carboacyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(-0)(C1-

C1-C8 alkyl, -(O)4(C1-C8)alkyl or aryl(C1-C8)alkyl; or K" and K"2, together with the nitrogen atom to which they are attached, form a 7-membered heterocyclic ring, and each of the carbon atoms in the specified heterocyclic ring can be replaced by -O-, -5- or -MA8 -; while each (C:-Cv)alkyl, (C2-Cv)alkenyl, (C6-Cv)alkynyl or aryl(C:i-Cv)alkyl in the composition of each

B', Be, VAZ, Vya, BA", B' or KK"?, independently of the others, may be substituted by one or more halo, hydroxy, CM, Mz, M(Nae)" or ONBe; and at the same time, one or more non-terminal atoms carbons of each specified (Ci-Cv)alkyl can be replaced by -O-, -5- or -MVa-.

According to one embodiment of Formula II B' represents (C:-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to another embodiment, B' represents (C:-Cv)alkyl. According to another version of the implementation of CC! is methyl, CH2OH, SN, ethenyl or ethynyl. According to the preferred embodiment, K' is methyl. According to another best option for implementing KE! is N.

According to one version of the implementation of Formula II, K? is Н, ОВ2, М(В2г)», Мз, СМ, МО»

C(O)pBe, halogen, (Ci-Cv)alkyl, substituted (Ci-Cv)alkyl, (C2-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2-Cv)alkynyl or substituted (C2-- St)alkynyl. According to another aspect of this embodiment, BC? is H, OKe, M(Hg)", Mz, CM, 5Be or halogen. According to another aspect of this embodiment, EC? is H, OH, MH", Mz, CM or halogen. According to another aspect of this embodiment, Kg is OR: or halogen, and B' is (Ci-Cv)alkyl, (Co-Cv)alkenyl or (C2-

St)alkynyl. According to another aspect of this embodiment, K?7 represents OK: or B, and v represents methyl, CH2OH, CNH, ethenyl or ethynyl. According to a preferred aspect of this embodiment, KE? is OH, and B' is methyl, CHnOH, SNeeE, ethenyl or ethynyl. According to another preferred aspect of this embodiment, K2 is OH, K' is H, and at least one of KZ or EK? does not represent H. According to another preferred aspect of this embodiment, K2 represents PE, and K' represents methyl, CHn2OH, SNHE, ethenyl or ethynyl. According to another preferred aspect of this implementation, Kg represents OKag, and EC! is methyl. In a particularly better aspect of this implementation, K2 is OH, and EK! is methyl.

According to one embodiment of Formula II, EZ is H, OKg, M(B2)2, Mz, CM, 5, halogen, (Ci-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to one aspect of this embodiment, C is H or PE. According to a preferred aspect of this implementation option, Z represents H. According to another preferred aspect of this implementation option, EZ represents H, B? is OK or halogen, and K! is (C:-Cv)alkyl, (C2-Cv)alkenyl or (C2-Cv)alkynyl. According to another aspect of this implementation option, C represents H, B? represents OR: or E, and B' represents methyl, CHnOH, CH", ethenyl or ethynyl. According to another aspect of this embodiment,

Does VZ represent H, B? is OR and KE" is methyl. According to yet another aspect of this embodiment, E? is H, EK? is OH and EK! is methyl. According to yet another aspect of this embodiment, KZ and KE" are H, Kg is OH, and EK" is not

N.

According to one embodiment of Formula II, K" represents H, OKg, M(B2)2, Mz, CM, 5, halogen, (Ci-Cv)alkyl, (Cg-Cv)alkenyl or (C2-Cv)alkynyl . According to the best aspect of this variant of implementation, K" is OKa. According to another preferred aspect of this embodiment, KK" is OK, B? is OH: or halogen, and KE" is (C:-Cv)alkyl, (C2-Cv)alkenyl or (C2-Cv) alkynyl According to another preferred aspect of this embodiment, EC" is OKa, ID is OK: or halogen, B' is H, and ER? is not H. According to another preferred aspect of this embodiment, KE" is OK2, B? represents OK: or halogen, BEZ represents H, and K! is (C:1-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to another preferred aspect of this embodiment, KE" is OK, B? is OK: or PE, and KE" is methyl, CHg2OH, SNeE, ethenyl or ethynyl. According to another preferred aspect of this embodiment

B" represents OKa, B2 represents ORZ or E, EZ represents H, and E! represents methyl, CHnOH,

СНеЕ, ethenyl or ethynyl. According to another preferred aspect of this embodiment, B? and Kk? independently of each other represent OK, and KE" represents methyl. According to another preferred aspect of this embodiment, KE" and BE? independently of each other represent OK, VZ represents H, and E! is methyl. According to another preferred aspect of this embodiment, one of Ki and Kg is an OK, and the other of K" or K2 is an ON. According to another preferred aspect of this embodiment, one of K7 and K2 is an OKU, where Ka is not H, and the other of EK and Kg is OH, EZ is H, and E! is methyl, CH2OH, CH", ethenyl or ethynyl. According to another preferred aspect of this embodiment, KK" and K2 are OH, EZ is H, and

B' is methyl, CHn2OH, CHnE, ethenyl or ethynyl. According to another preferred aspect of this embodiment, K" and K? jointly represent -0(CO)0O-, BZ represents H, and БЕ" represents methyl, CH2OH, SNeE, ethenyl or ethynyl.

According to one version of the implementation of Formula II, KE? is H, ОВ2, M(Н2)», Mz, CM, 52, halogen, (C1i-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to another aspect of this embodiment, KU is H, Mz, CM, (C1-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to another aspect of this embodiment, KE? is H, Mz, CM, methyl, CH2OH, ethenyl or ethynyl,

B" represents OK, and EZ represents H. According to another aspect of this embodiment, KE? represents H or M"z, B" represents OKa, BZ represents H, and K2 represents E or OK. According to another aspect of this embodiment, KE? represents H or Mz, B" represents OKU, BZ represents H, K2 represents OKA, and K! represents methyl, CHnOH, SNe, ethenyl or ethynyl. According to yet another aspect of this embodiment, KZ and E" are H, KZ, and B? independently of each other are OKaeg, and KK! is methyl, CHgOH, CH", ethenyl, or ethynyl. According to yet another aspect of this embodiment, KZ and KE? are H, KZ : and KE" is OH, and KE" is methyl, CHg2OH, SNeeE, ethenyl, or ethynyl. According to yet another aspect of this embodiment

AND! and EZ represent H, KZ: and E7 independently of each other represent OK, and BEZ represents Mz3.

According to another best aspect of this implementation option, B" and B? jointly represent -

О(СО)0-, ВЗ is H, and ВЕ! is methyl, CH2OH, SNeeE, ethenyl or ethynyl.

According to one version of the implementation of Formula II, each of the KK? and KK" represents OBU, and at least one of the groups EK", VZ and EE" does not represent H. According to another aspect of this implementation variant, each of 2 and KE" represents OKA, and VE! represents (C :-Cv)alkyl, substituted (C:-Cv)alkyl, (C2-Cv)alkenyl, substituted (C2-Cv)alkenyl, (Co-Cv)alkynyl, substituted (C2-Cv)alkynyl or aryl(C-

St) alkyl. According to one more aspect of this embodiment, each of KZ: and KE" represents an OKA, and KZ represents (Ci-Cv)alkyl, substituted (C1i-Cv)alkyl, (Co-Cv)alkenyl, substituted (C2- St)alkenyl, (C2--

C2-C8)alkynyl, substituted (C2-C8)alkynyl or aryl(C:-C8)alkyl. According to another aspect of this variant of implementation, each of 2 and KK" is an OKU, and K? is OMe, M(H2)", Mz, CM, MO", 5(O) pa, halogen, (Si- Cn)alkyl, substituted (Ci-Cn)alkyl, (C2-Cn)alkenyl, substituted (C2-Cn)alkenyl, (C2-

C2-C8)alkynyl, substituted (C2-C8)alkynyl or aryl(C:-C8)alkyl.

According to another version of the implementation of Formula II, each of EK" and B? is H; one of EZ and 7 is OKA, and the other of KZ and K" is (C1-Cv)alkyl, substituted (C1-Cv) )alkyl, (Co-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2o-Cv)alkynyl, substituted (C2-Cv)alkynyl or aryl(C1-Cv)alkyl. According to yet another aspect of this embodiment, one of BEZ and E" represents OH. According to yet another aspect of this embodiment, KE" represents Oka, M(Na)", Mz, SM, MO", 5(О )pVe, halogen, (C1-Cv)alkyl, substituted (C:i-Cv)alkyl, (Cg-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2-Cv)alkynyl, substituted (C2-

C1)alkynyl or aryl(C:-C1)alkyl.

According to one variant of implementation of Formula II, B" represents H, -C(-0)8", -0(-0)ОВ, -

С(-0)58" or

AND

"-7! mg

According to a preferred aspect of this implementation option, K" represents H. According to another preferred aspect of this implementation option, K/ represents -C(-0)BA". According to another preferred aspect of this embodiment, EC" represents -C(-O)B", where K" represents (Ci1-Cv)alkyl. According to another preferred aspect of this embodiment, B" represents

AND

"-7 and mg

According to one embodiment of Formula II, X' is M or SVO. According to yet another aspect of this embodiment, X' is M. According to yet another aspect of this embodiment, X' is SEC"9. According to yet another aspect of this embodiment, X!' is CB, and Bo is H, halogen, or CM. According to another aspect of this embodiment, X' is CB, and B"? is H or PE. According to another aspect of this embodiment, X' is CH. According to yet another aspect of this embodiment, each of the X! and xg is M. According to another aspect of this embodiment, X' is M and Xg is CI. According to another aspect of this embodiment, X' is M and Xg is

SV", where K'"? is H, halogen or CM. According to yet another aspect of this embodiment, X' is M, and X?r is CI, where CO is H or P. According to yet another aspect of this embodiment, X' is M, and X?2 is CH. According to another aspect of this embodiment, X' is M; X' is CH; BK! is methyl, CHn2OH, SNeE, ethenyl or ethynyl; EZ is H; and each of KE: and E" represents OK. According to another aspect of this embodiment, X' represents M; X? is CH; Whew! is methyl, CHgOH, СНеЕ, ethenyl or ethynyl; each of EZ and EE: represents H; and each of B: and B" is an OKU.

According to another version of the implementation of Formula HER, X? is M or SEZ. According to another aspect of this embodiment, X? is M, and X' is SEK'O. According to another aspect of this embodiment, Xg is M, and X' is CA"O, where CO is H, halogen, or CM. According to another aspect of this embodiment, Xg is M, and X' represents SEC", where K'"9 represents H or P. According to another aspect of this embodiment, X2 represents M, and X' represents CH.

According to another version of the implementation of Formula II, each KU independently of the others is a halogen, MA" B, M(AL)OV", MAMA", Ma, MO, MO", CHO, SM, -CH(-MA") . (C1-Cv)alkyl, (C2-Cv)alkenyl, (Ce-

C)alkynyl, (C4--C)carboacyclylalkyl, possibly substituted aryl, possibly substituted heteroaryl, -

C(-O)(C1-Cv)alkyl, -5(O)(C1-Cv)alkyl, aryl(C:i-Cv)alkyl, OK" or ZK. According to another aspect of this implementation option, each KU independently of the others is a halogen, MA"'B"2, SHA ZOV,

MAMA" B, ОВ" or ZK". According to another aspect of this embodiment, each KZ independently of the others is a halogen, МА"'В!2, Щ(А"3ОВ8", MAMA" BA", ОВ" or 5K and B is methyl, CHnOH, CH", ethenyl or ethynyl. According to another aspect of this embodiment, each KZ independently of the others represents a halogen, MAE""B"2, SHA OB", MAMA" B, OB" or ZK", and Kt represents H, halogen or MK". According to another aspect of this embodiment, each KZ independently of the others represents a halogen, MAE""B"2, SHKA OB", MAMA" B, OB" or ZK", and E? represents H, halogen or ME" B!g, and B! represents methyl, CH2gOH, CH»E, ethenyl or ethynyl.

According to another preferred aspect of this embodiment, the short-circuit is Mi" and EE? is H or halogen. According to another best aspect of this variant of implementation, the short-circuit is a MNa", and K? is H or halogen, and KE" is methyl, CHg2OH, SNeE, ethenyl, or ethynyl. According to another preferred aspect of this embodiment, each of KZ and 2? is MH." According to another preferred aspect of this embodiment implementation, each of KZ and E? represents MH", and ВЕ" represents methyl, СНгОН, СНеЕ, ethenyl or ethynyl. According to another preferred aspect of this embodiment,

VAZ is OH, and B? is MN»g. According to another best aspect of this implementation option, the short-circuit is an OH, and KE? represents MH", and B' represents methyl, CHg2OH, CH»eE, ethenyl or ethynyl.

According to another version of the implementation of the HER Formula, each K'o independently of the others represents itself

H, halogen, MA"'B!2, M(VA'OV", MAMA" BA, Mz, MO, MO», СНО, СМ, -СН(-МА"), -СН-МНМА», -bnН- AM(ОВ"), -СН(ОВ "2, -Ф(-О)МА" В, -С(-5)5МА" В, -С0-0)О8", В", ОВ" or ZK. According in yet another aspect of this embodiment, each K'' is H, halogen, CM, or optionally substituted heteroaryl.

According to one version of implementation of Formula II, B"! or K!? independently of the others is

H, (C1-Cv)alkyl, (C2-Cv)alkenyl, (C2-Cv)alkynyl, (C4-Cv)ucarboacyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(-0)(C1-Cv)alkyl , -5(O)4(C1-C8)alkyl or aryl(C:-C8)alkyl. According to another implementation option, K" and "2, together with the nitrogen atom to which they are attached, form a 7-membered heterocyclic ring, and any carbon atom in the specified heterocyclic ring can be replaced by -0-, -5- or -MVe-. Thus, as a non-limiting example, fragment -

MA" B": can be represented by the following heterocycles:

-Ш3-м 0 -М 8 -М M -м 9 ni i i AK

According to another version of the implementation of Formula ІІ, EE", B, BZ, Be, B", A" or "2 independently of the others is (C1-Cv)alkyl, (Cg-Cv)alkenyl, (C2-Cv) alkynyl or aryl(C1-C8)alkyl, and the specified (C1-C8)alkyl, (C8-C8)alkenyl, (C2-C8)alkynyl or aryl(C:1-C8)alkyl independently of each other may be substituted by one or more halo, hydroxy, CM, Mz, M(Be)" or OB". Thus, as a non-limiting example, EC", B, VU, B", A", B' or B"? can be such fragments as -CH(MH2g)CH», - sn(nsHnsnH», -CH(IMH2)CH(CHNz)», -«СНеСЕ:, -««"CHg)2 CH(Mz)CHz, -"СНг)вМНГ, etc.

According to another version of the implementation of Formula II, E", B, VU, VU, B", B" or VC" is (S.-

C1-C1)alkyl, and one or more non-terminal carbon atoms of each specified (C1-C1)alkyl can be replaced by -O-, -5- or -МНВ2-. Thus, as a non-limiting example, P", 82, VU, B", B",

A" or K'? can represent such fragments as -CHgOSHz, -CHgOSNoCH", -CHgOSNI(SNVZ)", -

SnNegZSN", -"SNag)vOsnH", -(SNg)M(SN)", etc.

According to yet another aspect, the compounds of Formula I are represented by Formula III: where

X! d' / -U va M ug u schu o v vo du" pn vi SNz

In the

Formula II or a pharmaceutically acceptable salt of said compounds, wherein all variables are as defined for

Formula I.

According to one version of the implementation of Formula PI, K2 represents H, OKeg, M(B2)2, Mz, CM, MO".

C(O)pBe, halogen, (Ci-Cv)alkyl, substituted (Ci-Cv)alkyl, (C2-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2-Cv)alkynyl or substituted (C2-- St)alkynyl. According to another aspect of this embodiment, BC? is H, OKe, M(Hg)", Mz, CM, 5Be or halogen. According to another aspect of this embodiment, EC? is H, OH, MH", Mz, CM or halogen. According to another aspect of this embodiment, 22 is OR or halogen. According to the best aspect of this implementation option, BC? is OH. According to another preferred aspect of this embodiment, 2? is OH, and at least one of the groups KZ and K? does not represent H. According to another preferred aspect of this implementation option, K2 represents P. According to another preferred aspect of this implementation option,

B2 is OK. According to another preferred aspect of this embodiment, K2 is

He

According to one embodiment of Formula I, KZ is H, OKag, M(Nag)", Mz, CM, Za, halogen, (Ci-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to one aspect of this implementation option, the short circuit is an H or PE. According to the best aspect of this implementation option, KZ is H. According to another best aspect of this implementation option, C is H, and K2? is OR or halogen. According to yet another aspect of this embodiment, E" is H and K2 is OR: or PE. According to yet another aspect of this embodiment, C is H and B? is OR. According to yet another aspect of this embodiment, KZ is H, and B? is OH. According to another aspect of this embodiment, EZ is H, KE? is

OH, and E5 is not H.

According to one embodiment of Formula I, K" represents H, OKag, M(Nag)", Mz, CM, Za, halogen, (Ci-Cv)alkyl, (Cg-Cv)alkenyl or (C2-Cv)alkynyl . According to the best aspect of this implementation option, B" is an OKU. According to another preferred aspect of this embodiment, B" represents O2, and 2 represents OK: or halogen. According to another preferred aspect of this embodiment, KE" represents OK", B? is OB: or halogen, and 2? does not represent N.

According to another best aspect of this variant of implementation, KE" represents OR, B? represents

OB or halogen, and EZ is H. According to another preferred aspect of this embodiment, B" is Oka, and K2 is OK or P. According to another preferred aspect of this embodiment, K" is OKU, B2 represents OK: or RE, and KZ represents N. According to another best aspect of this implementation option, KE" and B? independently of each other represent OKU.

According to another preferred aspect of this embodiment, EC" and BC? independently of each other represent OB2, and VZ represents N. According to another preferred aspect of this embodiment, one of B" and KE? represents OR, and the other from VC" and K? represents OH. According to another preferred aspect of this embodiment, one from EK" and K? is ОНае, where Kg is not H, and the other of MK and K2 is OH, and KZ is H. According to another better aspect of this implementation option, BK and K2 are OH, and KZ is H. According to another preferred aspect of this embodiment, EC and KE? jointly represent -O(CO)0-, and EZ represents H.

According to one version of the implementation of Formula I, KE? is H, OKag, M(Nag)", Mz, CM, Za, halogen, (C1i-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to another aspect of this embodiment, KE? is H, Mz, CM, (C1-Cv)alkyl, (Co-Cv)alkenyl or (C2-Cv)alkynyl. According to another aspect of this embodiment, A" is H, M33, CM, methyl, CH2OH, ethenyl or ethynyl,

IN? represents Oka, and KZ represents N. According to another aspect of this implementation option, K? is H or M»z, B" is OKa, BZ is H, and K2 is E or OK. According to another aspect of this embodiment, KE? is H or Mz, B" is OKU, BZ represents H, and B? is an OV. According to another aspect of this embodiment, the 23rd B? represent H, and B: and EE" independently of each other represent OH. According to another aspect of this embodiment, EZ and E? represent H, and EK: and БЕ" represent OH. According to another aspect of this version of the implementation of the EZ is H, B: and B" independently of each other are OKA, and

AV? is Miz. According to another best aspect of this variant of implementation, КК" and К? jointly represent -О(СО)0О-, and КЗ represents Н.

According to one version of the implementation of Formula Sh, each of MK? and CC? is OKA, and at least one of KZ and KE? does not represent H. According to another aspect of this implementation, each of K2 and EK represents an OKU. According to yet another aspect of this embodiment, each of the short circuits? and

AB" represents OK, and KZ represents (C1-Cv)alkyl, substituted (Ci-Cv)alkyl, (C2-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2-Cv)alkynyl, substituted (C2 -C1)alkynyl or aryl(C:-C1)alkyl. According to another aspect of this embodiment, K2 and KE" both represent OKag, M(Na)", Mz, CM,

MO», 5(O)pHe, halogen, (C1-Cv)alkyl, substituted (C:1-Cv)alkyl, (C2-Cv)alkenyl, substituted (C2-

C2-C8)alkenyl, (C8--C8)alkynyl, substituted (C2-C8)alkynyl or aryl(C:-C8)alkyl.

According to another embodiment of Formula I, K2 is H; one of KZ and K" represents

ОВУ, and the other from ЕЗ and Е" is (C:1-Cv)alkyl, substituted (C:-Cv)alkyl, (Co-Cv)alkenyl, substituted (C2-Cv)alkenyl, (C2-Cv)alkynyl , substituted (C2-C8)alkynyl or aryl(C1-C8)alkyl. According to another aspect of this embodiment, one of ECZ and K" is OH. According to another aspect of this version of the implementation of K? is OK, M(Hg)", Ma, SM, MO", 5(O)pVe, halogen, (Ci-Cv)alkyl, substituted (C:1-Cv)alkyl, (Co-Cv)alkenyl, substituted (С2-Св)alkenyl, (С2-Св)alkynyl, substituted (С2-

C1)alkynyl or aryl(C:-C1)alkyl.

According to one version of the implementation of Formula PI, B" represents H, -C(-0)8", -C(-0)ОВ8, -

С(-0)58" or

She

"-7 ! me

According to a preferred aspect of this embodiment, KE" is H. According to another preferred aspect of this embodiment, K" is -C(-0)BA". According to another preferred aspect of this embodiment, EK" is is -C(-O)B", where K" is (Ci1-Cv)alkyl. According to another preferred aspect of this embodiment, B" represents

AND

"-7 ! me

According to one embodiment of Formula Sh, X' is M or CE"9. According to another aspect of this embodiment, X' is M. According to another aspect of this embodiment, X' is SEK"9. According to yet another aspect of this embodiment, X!' represents CB, and BO represents H, halogen, or CM. According to yet another aspect of this embodiment, X' is SVO and B" is H or PE. According to yet another aspect of this embodiment, X' is CH. According to yet another aspect of this embodiment, each X' is M. According to another aspect of this embodiment, X' is M, and X' is SEC'9. According to another aspect of this embodiment, X' is M, and X? is

SV", where B" represents H, halogen or CM. According to yet another aspect of this embodiment, X" represents M, and X? represents SV", where B" represents H or E. According to yet another aspect of this embodiment, X' represents M, and Xg is CH. According to another aspect of this embodiment, X' is M; X2 is CH; KZ is H; and each of K- and B" is OK. According to another aspect of this embodiment, X' represents M; X2 is a

CH; each of EZ and 5 is H; and each of B: and EE" represents OK.

According to yet another embodiment of Formula II, X?r is M or CI"9. According to yet another aspect of this embodiment, Xr is M and X'! is SEC'9. According to yet another aspect of this version of the implementation, Xg represents M, and X' represents CA"O, where KO represents H, halogen or CM. According to another aspect of this embodiment, X? is M, and X' is CE"O, where CO is H or PE. According to another aspect of this embodiment, X? is M, and X' is CH.

According to another version of the implementation of Formula I, each KE? independently of the others is a halogen, MA" B, M(AL)OV", MAMA", Ma, MO, MO", CHO, SM, -CH(-MA"), -CH-MNMA", -sbnH-MSH (ОВ"), -CH(ОВ 2, -Ф(-О)МА" В, -С(-5)МА"В2, -С(-0)О8, (С1-Св)alkyl, (С2-Св )alkenyl, (Se-

C1)alkynyl, (C--C1)ucarboacyclylalkyl, possibly substituted aryl, possibly substituted heteroaryl, -

C(-O)(C1-Cv)alkyl, -5(O)(C1-Cv)alkyl, aryl(C:i-Cv)alkyl, OK" or ZK". According to another aspect of this variant of implementation, each CU independently of the others is a halogen, MAE"B"2, MSH(ATOV,

MAMAYA", OB" or 51". According to yet another aspect of this embodiment, each K8 independently of the others is a halogen, MAV", MATOVA", MAMA "BA", OB" or ZK", and PE? is H , halogen or ME" B". According to another preferred aspect of this embodiment, KZ is MH", and K? is H or a halogen. According to another preferred aspect of this embodiment, each of KU and KE? represents is MN". According to another best aspect of this implementation option, EZ is OH, and ER is MN."

According to another version of the implementation of Formula I, each KE" independently of the others represents

H, halogen, MAK"'B"2, MAO", MAMA" B", Mz, MO, MO", CHO, SM, -CH(-MA"), -CH-MNMA", -bnH-AMZh(ОВ "), -СН(ОВ "2, -Ф(-О)МА" В, -С(-5)5МА" В, -С0-0)О8", В", ОВ" or ZK. According to another aspect of this embodiment, each K'? is H, halogen, CM or optionally substituted heteroaryl.

According to one version of the implementation of Formula PI, K" or Kg, regardless of the others, is

H, (C:i-Cv)alkyl, (C2-Cv)alkenyl, (C2-Cv)alkynyl, (Ca-Cv)carboacyclylalkyl, possibly substituted aryl, possibly substituted heteroaryl, -C(-0)(C1-Cv) )alkyl, -5(O)4(C1-C8)alkyl or aryl(C:-C8)alkyl. According to another implementation option, KE" and K!2, together with the nitrogen atom to which they are attached, form a 7-membered heterocyclic ring, and any carbon atom in the specified heterocyclic ring can be replaced by -0-, -5 - or -MVe-. Thus, as a non-limiting example, a fragment -

MA" B": can be represented by the following heterocycles: -k -M o 0 - mm Z -AM MA spole olaozhozhOol oo

According to another embodiment of Formula I, KE", 82, BZ, Be, B", B" or Kg independently of the others is (C1-Cv)alkyl, (Cg-Cv)alkenyl, (Co-Cv)alkynyl or aryl(C1-Cv)alkyl, where (C1-

C1-alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C:1-C8)alkyl, independently of each other, may be substituted by one or more halo, hydroxy, CM, Mz, M(H2)g or ONag. Thus, as a non-limiting example, EK", B, VU, B", A", B' or B" can represent fragments such as -CH(МН2г)CH», - сн(нсНнснН», -CH( ИМН2)СН(СНВз)», -«СНеСЕ:, -««"СНg)2 СН(Мз)СНз, -"СНg)vМНг, etc.

According to another version of the implementation of the Formula PI, E", B, VZ, VU, B", B"! or K!? is (S.-

C1-C1)alkyl, and one or more non-terminal carbon atoms of each specified (C1-C1)alkyl can be replaced by -O-, -5- or -MVeg-. Thus, as a non-limiting example, K', B, B, VU, B",

A" or K'? can represent such fragments as -CHgOSHz, -CHgOSNoCH", -CHgOSNI(SNVZ)", -

SnNegZSN", -"SNag)vOsnH", -(SNg)M(SN)", etc.

According to another embodiment, the compounds of Formula I, Formula I or Formula SH are listed below in the form of a table (Table 6) as compounds of the general Formula IM:

Not ho he he

Formula IM where X1 and X2 are substituents attached to the tetrahydrofuranyl ring as indicated in

Tables 1-2 below; B is a purine as indicated in Table 4 below; and XZ is a ring within the purine base B as indicated in Table C below.

The place of attachment of the ribose structural core is marked in each of the structures X1, X2 and B. The place of attachment of the purine structural core is marked in each of the structures XZ. Each structure in

Tables 1-4 are represented by the alphanumeric "code". Each structure of a compound of Formula IM can thus be designated in tabular form by combining the "code" representing each structural fragment using the following syntax: X1.X2.X3.B. So, for example

X1Ta.X2s.XzZa.B1 represents the following structure:

MN"

M

M t ovH i is M

Mo en

H ----H bno on

Table 1

Structures X1

Sneon structure

Table 2

Structures X2

Structure

Table C

Structures of ХЗ3

Table 4

Structures of V

Structure

Table 4

Structures of V

MN"

M in! /- m min i

M uchi U

M on

M in U - MU

M r

M ushchi MN"

M

MN"

M v / --Ch She hu r

M u- - MN"

M

MNeoN»z

M vi U - m ku i

M uchi U

M

Table 6

List of compounds of Formula ІМ

X1a.x2r.Xza.VI1, X1ta.x2r.Xza.vV2, X1a.x2r.Xza.VZ3, Xta.x2r.Xza.v4, Xta.X20.X3B.81, Xta.xX2r.khzZZ.va,

X1Ta.x2r.xX3b.83, Xta.x2r5.xX3B.84, X1a.x2r.XZs.B1, Xta.X2r.XZs.B2, X1a.X20.XZs.B3, X1a.x2gr.XZs.Va,

Х1а.Хагс.ХЗа.В1, Х1а.Хг2гс.ХЗа.В2, Хта.Ха2с.ХЗа.В3, Х1а.Х2с.ХЗа.В4, Х1а.Ха2с.хХЗр.ВИ1, Хта.Ха2с.хз3б.ва,

Х1а.Ха2гс.хХ3р.83, Х1а.Ха2гс.хХ3р.В4, Хта.Хагс.ХЗс.ВИ1, Х1та.Ха2с.ХЗс.В2, Х1а.Ха2с.ХЗс.В3, Хта.Ха2с.ХЗс.Ва,

X1r.xX2r.Xza.B1, X1r.xX2B.Xza.vg2, X16.xX2rB.Xza.VZ3, X1r.X20.Xza.v4, X1r0.X26.X3B.81, X1r.Xx2B.X3B.V2, xX1r. х2р.хХЗ.в3, Х1р0.хХх2р5.Х3B.84, Х16.Х20.ХЗс.В1, Х1р.Х20.ХЗс.В2, Х16.Х26B.ХЗс.В3, Х1р0.Х2р.ХЗс.В4,

X1r.Xa2s.Xza.B1, X1r0.X2s.Xza.B2, X1r.Xa2s.Xza.B3, X10.X2s.Xza.B4, X1r.Xa2s.xX3B.B1, X1r.X2s.xZz.va,

Х1р.Ха2гс.Х3р.83, Х10.Х2с.Х3Б.84, Х1р.Ха2с.ХЗс.В1, Х1р0.Х2с.ХЗс.В2, Х1р.Хас.ХЗс.В3, Х1р0.Х2с.ХЗс.Ва,

X1s.Xha.Xza.VI1, X1s.Xha.Xza.B2, X1s.Xha.Xza.B3, X1s.Xha.Xza.B4, X1s.Xha.khz3r.VI1, X1s.Xha.x3r. wow

X1s.Xha.x3r.83, X1s.Xha.x3r.B4, X1s.Xha.xZs.VI1, X1s.Xha.XZs.B2, X1s.Xha.xZs.B3, X1s.Xha.XZs.Ba,

X1s.X2r.Xza.B1, X1s.X2r.Xza.B2, X1s.X2r.Xza.B3, X1s.X20.Xza.B4, X1s.X2r.X3B.B1, X1s.X2r.xXZ.va,

X1s.X2r.X3r.83, X1s.X2r.X3B.84, X1s.X2r.XZs.B1, X1s.xX20B.XZs.B2, X1s.X260.XZs.B3, X1s.X2r.XZs.Va,

X1s.Xg2s.Xza.VI1, X1s.X2s.Xza.B2, X1s.Khags.Xza.B3, X1s.X2s.Xza.B4, X1s.Xa2s.XZB.B1, X1s.X2s.xZ3.va,

X1s.X2gso.X3r.83, X1s.X2s.xX3r.84, X1s.Xa2s.XZs.VI1, X1s.X2o.XZso.B2, X1s.X2s.XZs.VZ3, X1s.Xa2s.XZs.Va, x1a. Xha.XzZa.vB1, X1a.Xha.Xza.v2, X1a.Xha.Xza.v3, X1a.Xha.Xza.v4, X1a.Xha.x3r.VI1, X1a.Xha.xz3. wow

хТТа.Хга.хз3б.в3, Х1а.Хга.хз3р.в4, Хх1а.хга.хЗс.вВ1, хт1а.Хга.хзЗс.ваг, хта.Хга.хЗс.в3, хт1а.хга.хзс.ва.

According to another embodiment, Formula I-I is a compound selected from the group consisting of and

МНь МН» Nim c) but M. but hmm. My but hmm. when is something M o M smn

NU On no0Oon no on no on (in) nki r

M on biy and m MN" 7 no o o. Jh o. AND

М М МН ши Ф) х шФ) х / M- х / M-

NO On 00 no on no on MN td

M o 7 0

M. and U MN bots MN U in 2 - m no o M M no On MN and M s no bn shcha o) 0. 0 -M o) t -M MN

N M N M 2

D Y 5-X M. - lo o M MN lo o MO SM dk o ny

M) NO on 7 uv no ON (9) , С ,

МН» НМ з- и; X - t X o O-R-O o My, o 0-R-o o mine (c); c) lay ro II r II no on no on i, z o); with

Unit 0 o t : M MH g H 2

LOvm-v-o o Um V Roles im z- c) ich o MOm, m-n no he o

MN pe MN

M a gu (e ; sn ' -RO M. b o --/

RK | but he

to me

Mne M o wah sl zh (c) Kz Y e There is still HM whose Tk M S ooo DM uya!

M / 0 and, o me 9) /

And oh, /0 b. 0 My

Kk | o and o Mnh

M MN Maine

H 2

Lear o 5- hm o "o M M () M. -

Me Mch t M no on 7-5 i o) men

SI | o o) Mn

MN A IF) Met o Men 00-kh p H m her H M O-R-0-x5 o M no-v-o o M. o "M on M v - 7 g Ge) no on no on , ) - about;

Mne Mne in r

H M H M b o. know, but He o-i--b he o) | o) but Mn» -uo pe still o o-R-o M o. 7 Met

МН и ме и хм х / 2 is) NM Y (6) o Me no on hi no on

НМ чр о оо хом У 0

NO r por go o M i) iv) iv) o | х notrtolrtoteto no-rР-0-Р-0-Р-o u on on on - on ono on - M no on and no on ; or a pharmaceutically acceptable salt of said compound.

DEFINITION

In this description, the following terms and phrases are intended to have the following meanings, unless otherwise specified:

When using trade names in this specification, applicants mean that the product whose trade name is mentioned and the active pharmaceutical ingredient(s) of the product with that trade name are included in this specification.

In this specification, the terms "compound of the invention" or "compound of Formula I" mean a compound of Formula I or a pharmaceutically acceptable salt thereof. Similarly, with respect to isolated intermediates, the phrase "compound of Formula (number)" means a compound of this formula and a pharmaceutically acceptable salt thereof. "Alkyl" is a hydrocarbon containing normal, secondary, tertiary carbon atoms or ring carbon atoms. For example , the alkyl group can contain from 1 to 20 carbon atoms (i.e. C1-

C 1 -C 6 alkyl), from 1 to 8 carbon atoms (i.e. C 1 -C 4 alkyl) or from 1 to 6 carbon atoms (i.e. C 1 -C 6 alkyl). Examples of suitable alkyl groups include, among others, methyl (Me, -CH33), ethyl (EI, -

СНеснН»), 1-propyl (n-Pg, n-propyl, -"СНа.СНеСН3), 2-propyl (i-Рg, iso-propyl, -СН(СН33)")), 1-butyl (n-Vy . (CH3)CHNaSIN:), o 2-methyl-2-propyl (Vy, tert-butyl, /-C(CH3)z), 1-pentyl (n-pentyl, -CHneCH.CHnoCHneCH"), 2-pentyl. (-СН(СН3)СНа.СНеСН»), Z-pentyl. (-CH(CHeCH»Bz)2), 2-methyl-2-butyl (-C(CHh)25CHesnH:»), 3-methyl-2-butyl (-CH(CHh)CH(CHHZ)g), C -methyl-1-butyl (-СНгСНоСН(СнНЗ3)»г), 2-methyl- 1-butyl (--СНЕСН(СН3)СНесНН»), 1-hexyl (-СНЕСНаСН.СНоСНеСнН»), 2-hexyl (- СН(СНзи)СНаСнНСНеСН z),

Z-hexyl. (-СН(СНаСН3)СНоСНосСН»), 2-methyl-2-pentyl o (-С(СНаз)»СНаСНоСН33), 3-methyl-2-pentyl (-СнН(СН3)СнН(СН3)СнН»СН: I), 0 4-methyl---pentyl o (-СН(СНи)СнНоСН(СН3)»2), 3-methyl-3-pentyl o /((- сС(СН3)уСНеснНЗ3)2), 2-methyl -3-pentyl (-CH(CHNaCH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)»CH(CH3)»g),

C,3-dimethyl-2-butyl (-CH(CH3)C(CH3)»c, and octyl (-(CHg)7CH»). "Alkoxy" means a group characterized by the formula -O-alkyl, in which the alkyl a group as defined above is attached to the parent molecule through an oxygen atom.The alkyl portion of an alkoxy group may contain from 1 to 20 carbon atoms (ie, C1-C8 alkoxy), from 1 to 12 carbon atoms (ie, C1-C12 alkoxy), or from 1 to b carbon atoms (i.e., C1i-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OSH»CH3 or -OEU, tert-butoxy (-0O-C (CHbz)z or -OIVY) etc. "Haloalkyl" is an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of the haloalkyl group may contain from 1 to 20 of carbon atoms (i.e., C1-C6 haloalkyl), from 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), or from 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable haloalkyl groups are other words include -СЕз, -СНЕ», -СЕН», -СНеСЕ», etc. "Alkenyl" is a hydrocarbon containing normal, secondary, tertiary carbon atoms or ring carbon atoms containing at least one site of unsaturation, i.e. a carbon-carbon 5p" double bond. For example, an alkenyl group can include from 2 to 20 atoms carbon (i.e

C2-C8 alkenyl), from 2 to 8 carbon atoms (i.e. C2-C8 alkenyl) or from 2 to 6 carbon atoms (i.e.

C2-Cv alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH-CH"), allyl (-CHgCH-CH"), cyclopentenyl (-C5iH7), and 5-hexenyl (-ХНаСНаСнНСнНСНн-CH»). "Alkynyl" is a hydrocarbon containing normal, secondary, tertiary carbon atoms or ring carbon atoms containing at least one site of unsaturation, i.e. a carbon-carbon 5p triple bond. For example, an alkynyl group can include from 2 to 20 carbon atoms (ie, C2-

C 6 alkynyl), from 2 to 8 carbon atoms (i.e. C2-Cv alkynyl) or from 2 to 6 carbon atoms (i.e. C2-Cv alkynyl). Examples of suitable alkynyl groups include, but are not limited to, an acetylene group (-C-CH), propargyl (-CH2C-CH), and the like. "Alkylene" refers to a saturated branched or unbranched or cyclic hydrocarbon containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or from two different carbon atoms in the parent alkane. For example, an alkylene group can include from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkylene radicals, among others, include methylene (-СНе-), 1,1-ethyl (-СН(СНЗ)-),

- ), 1,4-butyl --FSNESH.SNeCH -), etc. "Alkenylene" refers to an unsaturated branched or unbranched or cyclic hydrocarbon containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or from two different carbon atoms in the parent alkene. For example, an alkenylene group can include from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkenylene radicals include, among others, 1,2-ethylene (-"CH-CH-). "Alkynylene" refers to an unsaturated branched or unbranched or cyclic hydrocarbon containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or from two different carbon atoms in the parent alkyne. For example, an alkynylene group can include from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkynylene radicals include, among others, acetylene (-С-0-), propargyl (-СНС-б-) and 4-pentynyl (-7НаСНаСНаС-с-). "Amino" refers primarily to a nitrogen-containing radical, which may be considered a derivative of ammonia, of the formula -M(X)2, where each "X" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc. The hybridization of the nitrogen atom is approximately 5p3. Non-limiting amino species include -MH", -M(alkyl)", -MH(alkyl), -M(carboacyclyl)", -MH(carboacyclyl), -M(heterocyclyl)", -

MH(heterocyclyl), -Maryl)», -MH(aryl), -Malkyl)(aryl), -M(alkyl) heterocyclyl), -

M(carboacyclyl) (heterocyclyl), -M(aryl)(heteroaryl), -M(alkyl) (heteroaryl), etc. The term "alkylamino" refers to an amino group substituted by at least one alkyl group. Non-limiting examples of amino groups include -MH», -MH(CHbz), -Ш(CHbz)g, -MH(СНеCH»), - M(СНеСНЗ)»2, -МН(phenyl), -(phenyl)», -

MH(benzyl), -M(benzyl)2, etc. Substituted alkylamino generally refers to alkylamino groups as defined above, in which at least one substituted alkyl as defined above is attached to the nitrogen atom in the amino group. Non-limiting examples of substituted alkylamino include -MH(alkylene-C(O)-OH), -MH(alkylene-C(O0)-O-alkyl), -M(alkylene-C(O)-

OH)", -M(ialkylene-C(O)-O-alkyl)", etc. "Aryl" means an aromatic hydrocarbon formed by the removal of one hydrogen atom from one carbon atom of the parent aromatic ring system. For example, an aryl group can include from b to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, radicals formed from benzene (eg, phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually the terminal or 5p3 carbon atom, has been replaced by an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. An arylalkyl group can include from 6 to 20 carbon atoms, for example, an alkyl fragment containing 1-6 carbon atoms and an aryl fragment containing 6-14 carbon atoms. "Arylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, as well as a 5p carbon atom, has been replaced by an aryl radical. The aryl part of arylalkenyl can include, for example, each of the aryl groups described herein, and the alkenyl part of arylalkenyl can include, for example, each of the alkenyl groups described in this document. An arylalkenyl group can include from 6 to 20 carbon atoms, for example, an alkenyl moiety containing 1-6 carbon atoms and an aryl moiety containing 6-14 carbon atoms. "Arylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to the carbon atom, usually the terminal or 5p3 carbon atom, as well as the 5p carbon atom, has been replaced by an aryl radical. The aryl part of arylalkynyl can include, for example, each of the aryl groups described herein, and the alkynyl part of arylalkynyl can include, for example, each of the alkynyl groups described in this document. An arylalkynyl group can include from b to 20 carbon atoms, for example, an alkynyl fragment containing 1-6 carbon atoms and an aryl fragment containing 6-14 carbon atoms.

The term "substituted" refers to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., e.g., "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl" and "substituted carbocyclyl" means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl, respectively, in which one or more hydrogen atoms are independently replaced by substituents other than hydrogen. Typical substituents, among others, include -Х, -Ве, -О7, -0, -ОВЕ, -585, -57, -МАЕ», -МеВез, -МАЕ, -СХз, -СМ, -ЮОСМ, -5СМ . , -5(-0)2-, -5(-0)2OH, -5(-0)2НЕ, -05(-0)2OH5, -5(-0)2МАР», -5(-0)8Р . -6(5)8Р, -СЩ(0ОВ», -С(000, -С(5)ОВ», -С(0)585, -С(5)585,

-СЩ(О)МА», -С(5)МА», -С(-МА)МАЭ», where each X, independently of the others, is a halogen: E, SI, Vg or I; and each E? independently of others is H, alkyl, aryl, arylalkyl, heterocycle, or a prodrug protecting group or fragment. Alkylene, alkenylene and alkynylene groups may also be substituted in a similar manner. Unless otherwise indicated, when using the term "substituted" with respect to groups such as arylalkyl that contain two or more moieties suitable for substitution, the substituents may be attached to the aryl moiety, the alkyl moiety, or both of said moieties.

The term "prodrug" in this specification refers to any compound that, when introduced into a biological system, results from an involuntary chemical reaction(s), an enzyme-catalyzed chemical reaction(s) , photolysis and/or metabolic chemical reaction(s) forms a medicinal substance, i.e. an active ingredient. Thus, prodrugs represent a covalently modified analogue or latent form of a therapeutically active compound.

It is obvious to a person skilled in the art that the substituents and other fragments of the compounds of Formulas I-I should be chosen in such a way that the resulting compound is stable enough for pharmaceutical use and can be included in an acceptably stable pharmaceutical composition. Compounds of Formulas I-I having such stability are considered to be within the scope of the present invention. "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom, such as 0, M or 5. For example, if the carbon atom of the alkyl group that is attached to the parent molecule is replaced by a heteroatom (eg, 0, M or 5), the resulting heteroalkyl groups are, respectively, an alkyl group (e.g., -OSH:, etc.), an amine (e.g., -MNOH"z, -M(CH3)", etc.) or a thioalkyl group (e.g., -5СНа). If the non-terminal carbon atom of the alkyl group, which is not attached to the original molecule, is replaced by a heteroatom (for example, O, M or 5), the resulting heteroalkyl groups are accordingly a simple alkyl ether (for example, -СНаСНг- О- СН3, etc.) , alkylamine (for example, -СНаМНОН», -СНг.М(СнН з)», etc.) or an alkyl simple thioether (for example, - СНО- 5- СН3). If the terminal carbon atom of the alkyl group is replaced by a heteroatom (for example, O, M or 5), the resulting heteroalkyl groups are correspondingly a hydroxyalkyl group (for example, -СНаСНе-

OH), an aminoalkyl group (for example, -CH»MH") or an alkylthiol group (for example, -СНаСНе-

ZN). For example, a heteroalkyl group can include from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. C1-Ce heteroalkyl group means a heteroalkyl group containing 1-6 carbon atoms. "Heterocycle" or "heterocyclyl" as used herein includes, for example, but is not limited to, the heterocycles described in Radieike, GI, and A.; Rgipsiriee oi Modegtp Neiegosusiis Spetivigu (M.A. Vepiatip,

Mem HogK, 1968), in particular, in Chapters 1, 3, 4, 6, 7 and 9; Tpe Spetizigu oi Neiegosusiis Sotroypav, A Zegiev oi

Mopodgariv5" (add. Umieu 5 Zop5, Mem/ KhogK, 1950 to the present), in particular, in Volumes 13, 14, 16, 19, and 28; and 7U. At. Spet. os. (1960) 82:5566. In In one specific embodiment of the invention, a "heterocycle" includes a "carbocycle" as defined herein, in which one or more (e.g., 1, 2, C, or 4) carbon atoms are replaced by a heteroatom (e.g., 0, M, or 5 ). The terms "heterocycle" or "heterocyclic group" include saturated rings, partially unsaturated rings, and aromatic rings (ie, heteroaromatic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with each of the substituents described herein, including carbonyl groups. A non-limiting example of a carbonyl-substituted heterocyclyl is:

Kai (c)

Non-limiting examples of heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thiananaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidyl. piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, bH-1,2,5-thiadiazinyl, 2H, 6bH-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4anH-carbazolyl, carbazolyl, |D- carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, fura zanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

to b

By way of non-limiting example, heterocycles attached through a carbon atom are attached at the 2, 3, 4, 5, or 6 position of pyridine, the 3, 4, 5, or 6 position of pyridazine, the 2, 4, 5, or 6 position of pyrimidine, the 2, 3 position, 5 or 6 pyrazine position 2, 3, 4 or 5 furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole position 2, 4 or 5 oxazole, imidazole or thiazole position 3, 4 or 5 isoxazole, pyrazole or isothiazole position 2 or From aziridine, position 2,

With or 4 of azetidine, position 2, 3, 4, 5, 6, 7 or 8 of quinoline or position 1, 3, 4,5, 6, 7 or 8 of isoquinoline. Mainly carbon-attached heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, b-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, b-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, b-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

By way of non-limiting example, nitrogen-attached heterocycles attached at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,

C-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, C-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine and position 9 of carbazole or B-carboline. Mainly nitrogen-attached heterocycles include 1-aziridyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl. "Heterocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 3-5 carbon atom, is replaced by a heterocyclic radical (ie, a heterocyclylalkylene moiety). Typical heterocyclylalkyls include, but are not limited to, heteroacylyl-CHe-, 2-(heterocyclyl)ethan-1-yl, and the like, where the "heterocyclyl" moiety includes each of the above-described heterocyclic groups, including those described in

Modegp Neiegosusiis Spetivigu. It is also understood by one skilled in the art that a heterocyclic group can be attached to the alkyl portion of a heterocyclylalkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. Heterocyclylalkyl group includes 6-20 carbon atoms, for example, an alkyl fragment of an arylalkyl group containing 1-6 carbon atoms, and a heterocyclic fragment containing 5-14 carbon atoms. Non-limiting examples of heterocyclylalkyls include 5-membered sulfur-, oxygen-, and/or nitrogen-containing heterocycles such as thiazolylmethyl, 2-thiazolylethane-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., sulfur -, oxygen- and/or nitrogen-containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc. "Heterocyclylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p' carbon atom, is replaced by a heterocyclic radical (ie, a heterocyclylalkenylene moiety). The heterocyclic portion of the heterocyclylalkenyl group includes each of the heterocyclic groups described herein, including those described in Rgipsirie5e and Modet Neuegosusiis Spetzig, and the alkenyl portion of the heterocyclylalkenyl group includes each of the alkenyl groups described herein. One skilled in the art also understands that a heterocyclic group can be attached to the alkenyl portion of a heterocyclylalkenyl by a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. The heterocyclylalkenyl group includes 6-20 carbon atoms, for example, the alkenyl part of the heterocyclylalkenyl group contains 1-6 carbon atoms, and the heterocyclic fragment contains 5-14 carbon atoms. "Heterocyclylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to the carbon atom, usually the terminal or 5p3 carbon atom, as well as the 5p carbon atom, has been replaced by a heterocyclyl radical (ie, a heterocyclylalkynylene moiety).

The heterocyclic portion of the heterocyclylalkynyl group includes each of the heterocyclic groups described herein, including those described in Rgipsirie oi Modegp Negegosusiis SPpetivig, and the alkynyl portion of the heterocyclylalkynyl group includes each of the alkynyl groups described herein. One skilled in the art also understands that a heterocyclyl group can be attached to the alkynyl portion of a heterocyclylalkynyl by a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. The heterocyclylalkynyl group includes 6-20 carbon atoms, for example, the alkynyl part of the heterocyclylalkynyl group contains 1-6 carbon atoms, and the heterocyclyl fragment contains 5-14 carbon atoms. "Heteroaryl" refers to an aromatic heterocyclyl containing at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all rings listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc. "Carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) or aromatic ring containing 3-7 carbon atoms in the case of a monocyclic structure, 7-12 carbon atoms in the case of a bicyclic structure and up to about 20 carbon atoms in the case of a polycyclic structure.

Monocyclic carbocycles contain 3-6 ring atoms, usually 5 or 6 ring atoms. Bicyclic carbocycles contain 7-12 ring atoms, for example, forming bicycloi4,51, (5,51, (5,6) or (6,6) system, or 9 or 10 ring atoms forming bicycloiІ5,6| or I |b,b6| system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl. Non-limiting examples of bicyclic carbocycles include naphthyl. "Carbocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms attached to with a carbon atom replaced by a carbocyclic radical as defined herein. Typical non-limiting examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. "Arylheteroalkyl" refers to a heteroalkyl as defined herein in which a hydrogen (which maybe e be attached to a carbon atom or a heteroatom) is replaced by an aryl group as defined herein. An aryl group can be attached to a carbon atom of a heteroalkyl group or to a heteroatom of a heteroalkyl group, provided that the resulting arylheteroalkyl group is a chemically stable fragment. For example, an arylheteroalkyl group can correspond to the general formulas -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-MH-aryl, -alkylene-MH-alkylene-aryl, -alkylene-5-aryl, -alkylene- 5-alkylene-aryl, etc. In addition, each of the alkylene groups in the general formulas may be further substituted with each of the substituents specified or exemplified herein. "Heteroarylalkyl" refers to an alkyl group as defined herein in which the hydrogen atom is replaced by a heteroaryl group as defined herein.

Non-limiting examples of heteroarylalkyls include CHe-pyridinyl, -CHe-pyrrolyl, -CHe-oxazolyl, -

SNeo-indolyl, -SNeo-isoindolyl, -SNeo-purinyl, -SNeo-furanyl, -SNeo-thienyl, -SNeo-benzofuranyl, -SNeo- benzothiophenyl, -SNeo-carbazolyl, -SNeo-imidazolyl, -SNeo-thiazolyl, -CHe-isoxazolyl, -CHe-pyrazolyl, -CHe- isothiazolyl, -CHe-quinolyl, -CHe-isoquinolyl, -CHe-pyridazyl, -CHe-pyrimidyl, -CHe-pyrazolyl, -CH(CH3)- pyridinyl, -CH (CH3)-pyrrolyl, -CH(CH3)-oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH33)- purinyl, -CH(CH3)-furanyl, -CH(CH3 )-thienyl,8 -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -

CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -"CH(CH3)-isoxazolyl, -"CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, - CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazyl, -CH(CH3)-pyrimidyl, -

CH(СнН:)-pyrazyl, etc.

The term "optionally substituted" with respect to a particular moiety in a compound of Formula I1-PI (eg, an optionally substituted aryl group) refers to a group in which all substituents are hydrogen atoms or in which one or more hydrogen atoms may be replaced by substituents such as listed in the definition of the term "substituted".

The term "possibly substituted" in relation to a specific fragment in the composition of the compound of Formula I-I (for example, the carbon atoms of the specified (Ci-Cv)alkyl may be replaced by -0-, -5- or -MAa8-) means that one or more methylene groups (C1-C8)alkyl can be replaced by 0, 1, 2 or more of the specified groups (for example, -O-, -5- or -MINa-).

The term "non-terminal() carbon atom(s)" with respect to an alkyl, alkenyl, alkynyl, alkylene, alkenylene or alkynylene fragment refers to the carbon atoms in said fragment located between the first carbon atom in the fragment and the last carbon atom in the fragment. Thus, as a non-limiting example, in the alkyl group -

СНУ ("СЗНа(С)нНСН:" or the alkylene group -"СНа(С)На(СУНоСН")- C atoms should be considered as infinite carbon atoms.

Some alternatives to M and M" are nitrogen oxides, such as "M(O)(K) or "M(O)3OK". These nitrogen oxides, shown here as attached to a carbon atom, may also be represented by in the form of groups, with separation of charges, for example, A or OB, respectively, while it is understood that they are equivalent to the above representations for the purposes of the present invention.

"Linker" or "bridge" means a chemical moiety containing a covalent bond or chain of atoms. Linkers include repeating alkyloxy units (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino units (e.g., polyethyleneamino, UePatipe); and esters and amides of dibasic acids, including succinate, succinamide, diglycolate, malonate, and caproamide.

Terms such as "oxygen-linked", "nitrogen-linked", "carbon-linked", "sulfur-linked" or "phosphorus-linked" mean that if a bond between two moieties can be formed through more than one type of atoms in the composition of the fragment, then this connection between the fragments is formed through the specified atom. For example, an amino acid attached through a nitrogen will be attached through a nitrogen atom in the amino acid, not an oxygen or carbon atom in the amino acid.

Unless otherwise stated, this description assumes that the valence of the carbon atoms is four. In the case of some representations of chemical structures where the carbon atoms do not have enough attached variables to provide a valency of four, the remaining substituents on the carbon atom required to provide a valency of four should be assumed to be hydrogen atoms. where

M

V' / i nh , shcha o M vo do

Gee in! I am

For example, in? And ryklad means the same as ve

M

V, / y h o M vo to

Gee in! t

Ver "Protecting group" refers to a group in a compound that shields or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of the protective group varies widely. One of the functions of the protective group is that this group acts as an intermediate compound in the synthesis of the original medicinal substance. Chemical protecting groups and deprotection strategies are well known in the art. See: "Rgoiesiime sSgoire ip Ogdapis Spetivigu", Tpeodoga MU. Sgeepe (Fopp Umieu 5 Bop5, Ips., Mem/ MogK, 1991). Protective groups are often used to shield the reactivity of certain functional groups, for a more efficient flow of targeted chemical reactions, for example, the formation and breaking of chemical bonds alternately and in a given order. Protection of functional groups in a compound, in addition to the reactivity of the protected functional group, also changes other physical properties such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured using common analytical tools. Chemically protected intermediates may be biologically active or inactive as such.

Protected compounds may also exhibit altered and, in some cases, improved IP and IP properties, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this capacity, protected compounds with a given therapeutic effect can be classified as prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, resulting in the release of the parent drug as a result of the conversion of the prodrug ip mimo. Because active prodrugs may be absorbed more efficiently than parent drugs, prodrugs may have greater IP mimo activity than parent drugs. Protecting groups are removed either ip miigo, in the case of chemical intermediates, or ip mimo, in the case of prodrugs. In the case of chemical intermediates, it is not so important that the end products formed after the removal of the protecting group, such as alcohols, are physiologically acceptable, although in general it is more desirable that the products are pharmacologically safe. "Prodrug fragment" means an unstable functional group that is removed from an active inhibitory compound during metabolism in the body, inside cells, by hydrolysis, enzymatic cleavage or due to some other processes (Vypadaaga, Napvkh, "Oezidp apa

Arriisayop oi Rgodgydv" ip TehirookK oi Ogyd Oezidp apa Oyemeiortenpi (1991), R. Ktgodzdaaga-I agzep apa N.

Vypadaaga, Ed5. Naglood Asadetis Rybiizpegv, 113-191). Enzymes capable of carrying out the mechanism of enzymatic activation of phosphonate prodrug compounds according to the invention include, among others, amidases, esterases, microbial enzymes, phospholipases, cholinesterases and phosphatases. Prodrug fragments can be used to increase solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy.

A prodrug fragment may include an active metabolite or the drug itself.

Typical fragments of prodrugs include hydrolysis-sensitive or labile acyloxymethyl esters -

СНегс(-0)НЗО and acyloxymethyl carbonates -СНггс(-0)ОН30, where КЗ is a C-Cv alkyl, a substituted C-Cv alkyl, a Cv-Cco aryl or a substituted Cv-Cco aryl. Acyloxyalkyl ethers were used as prodrugs for carboxylic acids and then for phosphates and phosphonates Ragdiyag ei ai (1983) U. Rpapt. All together. 72: 324; also US Patents 4,816,570, 4,968,788, 5,663,159, and 5,792,756. In some compounds of the invention, the prodrug moiety is part of the phosphate group. An acyloxyalkyl ether can be used to deliver phosphoric acids across cell membranes and to increase oral bioavailability. A close variant of the acyloxyalkyl ether, the alkoxycarbonyloxyalkyl ether (carbonate), may also increase oral bioavailability as a prodrug moiety in the compound combinations of the invention. A typical acyloxymethyl ether is pivaloyloxymethoxy, (РОМ)-СНег»с(-0)С(СН3)з.. A typical acyloxymethylcarbonate fragment of prodrugs is pivaloyloxymethylcarbonate (РОС) -

СНе с(-00ОС(СНЗз)з.

The phosphate group can be a phosphate fragment of prodrugs. A prodrug fragment may be sensitive to hydrolysis, for example, include, but not limited to, pivaloyloxymethylcarbonate (POC) or

ROM group. Alternatively, the prodrug fragment may be susceptible to enzymatic cleavage, as in the case of a lactate ester or a phosphonamidate ester.

The ability of aryl ethers with phosphorus-containing groups, especially phenyl ethers, to improve oral bioavailability has been reported (Oeiatregi ei a! (1994) U. Med. Spec. 37: 498). Also described are phenyl ethers containing a carboxylic acid ester in the ortho-position to the phosphate (Knatpei apa Toitepse, (1996) U. Med. Spec. 39:4109-4115). Benzyl ethers were reported to form the parent phosphonic acid. In some cases, substituents in the ortho- or para-position can accelerate hydrolysis. Analogues of benzyl with adylated phenol or alkylated phenol can, due to the action of enzymes, such as esterases, oxidases, etc., form a phenolic compound, which, in turn, undergoes cleavage along the benzylic C-O bond with the production of phosphoric acid and an intermediate quinonemethide. Examples of prodrugs of this class are described Miispei! Hey! (1992) U. Speth. Goiter.

Reckip Tgapv. And 2345; Wow! UMO 91/19721. Other benzylic prodrugs containing a group containing a carboxylic acid ether attached to the methylene of the benzylic group have been described (Sialieg ei ai MO 91/19721).

Thio-containing prodrugs that can be used for intracellular delivery of phosphonate drugs have been reported. These ester precursors contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. De-esterification or reduction of the disulfide leads to the formation of a free intermediate compound containing sulfur, which further decomposes into phosphoric acid and episulfide (Riesp ei ai (1993) Apiimiga! Nev., 22: 155-174; Veplagia ei a! (1996) U. Med. Speth. 39: 4958). Also described are cyclic esters of phosphonic acids as prodrugs of phosphorus-containing compounds (Egyptian AI, US patent 6312662).

It should be noted that all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs and pseudopolymorphs of compounds falling under Formula I, Formula I or Formula SHE, and their pharmaceutically acceptable salts are within the scope of the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

The compound of Formula I-III and its pharmaceutically acceptable salts can exist in the form of various polymorphic or pseudopolymorphic modifications. In this description, crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystalline structures. Crystalline polymorphism can result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of a hydrate or solvate of a compound to exist in different crystalline structures. Pseudopolymorphic modifications according to the present invention can exist due to differences in crystal packing (pseudopolymorphism of packing) or differences of packing between different conformers of the same molecule (conformational pseudopolymorphism). This invention includes all polymorphic and pseudopolymorphic modifications of the compounds of Formulas I-III with pharmaceutically acceptable salts.

The compound of Formula I-I and its pharmaceutically acceptable salts may also exist as an amorphous solid. In this description, an amorphous solid is a solid that lacks the long-range order of the atoms in the solid. This definition also applies if the crystal size is two nanometers or less. Additives, including solvents, can be used to produce amorphous forms according to the present invention. This invention includes all amorphous forms of the compounds of Formulas I-X and their pharmaceutically acceptable salts.

Selected substituents included in compounds of Formulas I-III are presented in the recursive degree.

In this context, "recursive substitute" means that a substitute can repeat another substitute of the same kind. Due to the recursive nature of such substitutions, in theory, a large number of compounds can be represented in any given implementation. For example, KH includes the substitute BU. VU can be KK. B can be a music school. MUZ can be MY, and MY can be B or include substitutes that include KU. For a specialist in the field of medicinal chemistry, it is clear that the total number of such substituents is quite limited due to the required properties of the target compound. Such properties include, by way of non-limiting example, physical properties such as molecular weight, solubility or I0d P, consumer properties such as activity against a given target, and practical properties such as ease of synthesis.

As a non-limiting example, MUZ and KU are recursive substitutes in certain implementations. Typically, each recursive substitute can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 times in a specific implementation option. In a more typical case, each recursive substitute may independently occur 12 times or less in a particular implementation. In an even more typical case, each recursive substitute can independently occur 3 times or less in a particular implementation. For example, MU? will occur from 0 to 8 times, KU will occur from 0 to 6 times in a specific implementation option. In an even more typical case, M/Z will occur 0 to 6 times, and CU will occur 0 to 4 times in a particular implementation.

Recursive substitutions are one of the target aspects of the present invention. For a specialist in the field of medical chemistry, the universality of such substitutes is clear. The degree to which recursive substituents are represented in an embodiment of the invention determines the total number of such substituents as indicated above.

The modifier "about" used in relation to a quantity includes the specified quantity and has a meaning determined by the context (for example, it contains the degree of error associated with the measurement of a particular quantitative value).

Compounds of Formulas I-Z may contain a phosphate group as K", which may be a fragment

She

- did he cure Mu? , where each of the groups M or U" independently of the others represents 0, 5, ME, "MOHR), MOR), "SHCHOHOK) or MAMA"; M/ and MU? together represent -UZ(С(ВУ) d) zU5-; or one of the groups

МY or Me together with BVZa or B" represents -7U3-, and the other of the groups M/ or Me represents Formula Ia; or each of the groups M/ and MU? independently of the other is a group of Formula Ia:

U vh I U? and and

Mag where: each of the groups U? independent of others is a connection, О, SE", MA, "MSH(О)(Р), ХОВ", "SHCHOHOV),

M-MA", 5, 5-5, (0) or 5(O)2; each of the groups of UZ, independently of the others, represents 0, 5 or ME;

M2 is equal to 0, 1 or 2; each of the Ku groups, independently of the others, is H, E, SI, Vg, I, OH, B, -С(-У7)В8, -С(-М ОВ, -

С(-М MBA)», -М(В)2, -М(В)з, -5В8, -5(0)8, -5(0)28, -Б(ОХОВ), -5(0) X(ОВ), -О0(-У)В8, -ОС(-У ОВ, -

ОоФ(-ХУ)у(М(В)2г), -50(-У3В8, -50(-МОВ, -505(-М)(М(Н)2г), -М(В)С(-У) А, -МЩЧА)(-М)OK or -

М(В)С(-М )М(А)2, -502МА2, -СМ, -Мз, -МО», -OK, protective group or M/Z; or two KU at the same carbon atom jointly form a carbocyclic ring containing from 3 to 7 carbon atoms; each of the groups Ex, independently of the others, is a KU, a protective group, or corresponds to the formula: m вх ДУ m

VU che Ug Ug u where:

Ma, Miis and M1yYa are independently equal to 0 or 1;

M12s is equal to 0, 1.2, 3.4, 5.6, 7, 8, 9, 10, 11 or 12; each of the groups K represents H, halogen, (C1-Cv) alkyl, substituted (C1-Cv) alkyl, (Co-Cv) alkenyl, substituted (C2-Cv) alkenyl, (C2-Cv) alkynyl, substituted (C2 -Cv) alkynyl, Cc-Cco aryl, substituted Cc-Cco aryl, C2-Cco heterocycle, substituted C2-O2o heteroacylyl, arylalkyl, substituted arylalkyl or protective group;

M/Z is M/" or Mu"; MU" is E, -C(U) VU, -C(GU MU", -BO2VU or -BO2MU"; and MI" is a carbocycle or heterocycle in which M/" is independently replaced by 0-3 groups of KU.

Mu carbocycles and Mu heterocycles? can be independently replaced by 0-3 groups of KBU.

MU" can be a saturated, unsaturated or aromatic ring, including a mono- or bicyclic carbocycle or heterocycle. M/» can contain 3-10 ring atoms, for example, 3-7 ring atoms. M/» rings are saturated if they contain C ring atoms, saturated or monounsaturated if they contain 4 ring atoms, saturated or mono- or di-unsaturated if they contain 5 ring atoms, and saturated, mono- or di-unsaturated or aromatic if they contain 6 ring atoms atoms

Heterocycle MU? can be a monocycle containing 3-7 members in a ring (2-6 carbon atoms and 1-3 heteroatoms selected from M, O, P and 5) or a bicycle containing 7-10 members in a ring (4-9 carbon atoms and 1-3 heteroatoms selected from M, O, P and 5). Heterocyclic monocycles M/» can contain 3-6 ring atoms (2-5 carbon atoms and 1-2 heteroatoms selected from M, O and 5) or 5 or 6 ring atoms (3-5 carbon atoms and 1-2 heteroatoms, selected from M ia 5). Heterocyclic bicycles MU? contain 7-10 ring atoms (6-9 carbon atoms and 1-2 heteroatoms selected from M, O and 5), forming bicyclo!i4, 51,

IB, 51, (5,6) or Ib,6) system; or 9-10 ring atoms (8-9 carbon atoms and 1-2 heteroatoms selected from M and 5), forming bicycloi5,6| or Ib,b| system The heterocycle M/» can be attached to U? through carbon, nitrogen, sulfur or another atom by a stable covalent bond.

M/" heterocycles include, for example, pyridyl, isomers of dihydropyridyl, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, sec-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. Mu? also includes, among others, such examples as: dО | | what am i

Ma and 2 and Sun

SA, | (o ut and m /

M N hundred

M Z! M is

Carbocycles and heterocycles of MU? may be independently substituted by 0-3 P groups, as defined above. For example, substituted MU carbocycles? include: on / SI

M g -3-5 7"

SI

M|c)

M u/ MN" that g g M vyg

XM /

1st 2nd ZN , 2nd - M o 2nd ZO"

ХМ х-/ хх /

Examples of substituted phenyl carbocycles include:

NM NM Fr

You sewed. o o, o x x ih o o o CHI

Mn u-m r-n o (in) de de x

She

"-

Variants of the implementation of Mig in the compounds of Formulas I-I include such substructures as:

Her daughter A

HOW are they Ugv r where each group U? regardless of the others, is O or M(K). According to the best aspect of this variant of implementation, each group U25 represents 0, and each group Ex, independently of the others, represents: fell o

And ---y

Ugh

M12c where M12c is equal to 1, 2 or 3, and each group is Y? independently of others is a connection, O, SE" or 5.

According to another best aspect of this variant of implementation, one of the groups U25-Ax is MNK), and the other U25-Dx is O-BX, where Ex is:

SAZ

Mt2c where M12c is equal to 2. According to another preferred aspect of this embodiment, each group U25 represents 0, and each group Kx independently represents: 5 САз

M12c where M12c is equal to 2. According to another best aspect of this implementation option, each group U25 represents 0, and each group Khx independently represents: вв о о у?

M12s where M12s is equal to 1, and y? is a connection, O or SE".

She

SHVA - 5

WE /

Other variants of implementation of M in compounds of formulas I-I include such substructures as:

VU

ХЗ и ра хх и

К UZ VU v" where each group of UZ independently of the others represents O or M(K). According to the best aspect of this variant of implementation, each group of UZ represents 0. According to the best aspect of this variant of implementation, the substructure is: o (c) ;

b and o

VU where BU represents Mu" as defined in this description.

She

Shan

WE /

Another version of MI implementation? in the compounds of formulas I-Ж includes substructures, where one of the groups M/ or M/2g together with КУ or ВК" is -U3-, and the other group M/ or Uug is

Formula Ia. Such a variant of implementation is represented by the compound of Formula IB, chosen from: de uh! / i hg u / o M vo t R do

In Kch vn

UZ

Whoah whoah! / i hg u / o M vo t R do u po Kch dn

UZ dz v2 where uh! / i hg u / o M vo t R do

In Kch vn

Uz ve or de uh! / I hg in / in; M vo t R to

In Kch vn

UZ

In the

Formula IB

According to the best aspect of the implementation of Formula Ib, each group U and UZ represents 0. According to another best aspect of the implementation of Formula IB, M/ or MuUg is U2-Ax, each group U, UZ, and UU25 is O, and Ex represents: fell o

Ugh

M12c where M12c is equal to 1, 2 or 3, and each group is Y? independently of others is a connection, O, SE" or 5.

According to another preferred aspect of the embodiment of Formula IB, M/ or MuUg is U25-Dx; each group U, UZ, and U25 represents O, and Ex represents:

SAZ

M12s where M12s is equal to 2. According to another preferred aspect of the implementation of Formula IB, M/! or uug is U25-NHx; each group У, УЗ и у25 represents О, and Ех represents: в в о о у?

M12c where M12c is equal to 1, and 2 is a connection, О or CE".

She

ZSh8B 52

WE /

Another version of the implementation of Me in compounds of formulas I-I includes a substructure: her

Kk heaven yo

KO K

Yes

Ug de Mie is a carbocycle, such as phenyl or substituted phenyl. According to another aspect of this variant of implementation, the substructure is: b -ya-(8oz - (6)

HM o du 5 gr

Mov (6) where U represents O or M(K), and the phenyl carbocycle is substituted by 0-3 B groups. According to another aspect of this version of the implementation of the substructure, Ex represents: вв о уг Ух

M12c where M12c is equal to 1, 2 or 3, and each group is Y? independently of others is a connection, O, SE" or 5.

She

Z-R--

WE /

Another variant of implementation of M in compounds of formulas I-I includes substructures:

EX EX

--(8оз | --(«8оз -ЖйО- -Жй-О (v) (v) ho sleep Uh,0 sleep gay I and Ov o Ov (v) i. (v)

The chiral carbon atom in the amino acid and lactate fragments can be in the K or 5 configuration, or the substance can be a racemic mixture.

She

-R--

WE! /

Another variant of MI implementation? formulas I-II is a substructure

AND

(c) (c)

Y r 7DU (6) 2 where is each group U? regardless of the others, is -0- or -МН-. According to another best aspect of this embodiment, KU is (C1-Cv) alkyl, substituted (C1-Cv) alkyl, (C2-Cv) alkenyl, substituted (C2-Cv) alkenyl, (C2-Cv) alkynyl or substituted (C2-Cv) alkynyl. According to another best aspect of this version of the implementation of KU is (C.1-Cv) alkyl, substituted (C:1-Cv) alkyl, (C2-

Sv) alkenyl, substituted (C2-Cv) alkenyl, (Cg-Cv) alkynyl or substituted (C2-Cv) alkynyl, and KE is

SNz. According to another best aspect of this implementation option, BU is (C.:-Cv) alkyl, substituted (C:-Cv) alkyl, (C2-Cv) alkenyl, substituted (C2-Cv) alkenyl, (Cg2-Cv) alkynyl or substituted (Cg2-

Sv) alkynyl; K represents CH", and each of the groups U? is -MN-. According to the best aspect of this embodiment, M/ and Me independently represent natural amino acids or esters of natural amino acids attached through nitrogen. According to another best aspect of this version of the implementation of M/ and

MU? independently represent natural 2-hydroxycarboxylic acids or esters of natural 2-hydroxycarboxylic acids, where the acid or ether is attached to P through a 2-hydroxy group.

IN

"-7

Another version of the implementation of Mu? formula I, II or I has a substructure: (c)

HER

ZA - r vkh t o still dh

In one preferred aspect of this embodiment, each Ex group is independently (C1-C8) alkyl. According to another preferred aspect of this embodiment, each Ex group is independently a St-Cgo aryl or a substituted St-Cgo aryl.

IN

P-P--

WE /

Another variant of the implementation of M in formulas I-Ш is

She

P--- t mg where M/ and M are independently chosen from one of the formulas in Tables 20.1-20.37 and Table 30.1 below. Variables listed in Tables 20.1-20.37 (eg, M/2, B!, etc.) refer only to Tables 20.1-20.37, unless otherwise noted.

The variables specified in Tables 20.1-20.37 have the following definitions: each group KE"! independently represents H or (C:-Cv)alkyl;

each KK group? is independently H, CC", BZ or 2", where each CC group is independently substituted 0-3 23; each E23 group is independently 23a, |D235, Dg3c or 254, provided that if E2Z is attached to a heteroatom , then VZ represents 23c or 259: each group K23a independently represents BE, SI, Vg, I, -SM, Mz or -MO"; each group K22" independently represents U-!; each group K23c independently represents - Н82х, -Ш(А2(82), -582х, -«6(О)Нхх, -5(0)282х, -Б(ФО)(ОВ2), - 5(0)2(0Н82), -О0б( -m2)Нх, -О0б(-м2)3OH, -О0б(-у2 уМ(А23(Н2), -50(-М2)Н2х -5BO(-У2)ОВх - зО-УуМ(А2О(Вг)), -МЩ(Н2ОО(-м21 ух, -МЩ(А2ОО(-М2О82х or -ЩХН2ОС(- У (М(А2 (ВХ); each K234 group independently represents -С(-У21)В2х, -С(-У2 )О82х or -С(-М2 М(Б82У(А2Х)); each K?Х group independently represents H, (C:i-Cv)alkyl, (Co-Cv)alkenyl, (C2-Cv)alkynyl, aryl , heteroaryl; or two K?x together with the nitrogen atom to which they are attached form a 7-membered heterocyclic ring, while any carbon atom in said heterocyclic ring can be replaced iy on -O-, -5- or -MA2-; and at the same time, one or more non-terminal carbon atoms in the composition of each specified (C1-Cv)alkyl can be replaced by -O-, -5- or -MA2-; each K2" group independently represents (C1-C8)alkyl, (Co-C8)alkenyl or (C8-C8)alkynyl; each Kg? group independently represents 2", where each K2" group is substituted by 0-3 K28 groups; each K25a group independently represents (C.1-Cv)alkylene, (Cg-Cv)alkenylene or (C2-Cv)alkynylene, while each of the indicated (C1-Cv)alkylene, (Cg-Cv)alkenylene or (C2 -C)alkynylene is substituted by 0-3 Kg groups; each MUZ group independently represents MU? or Ugo"; each M/2? group independently represents IC25, -0(-21)825, -С(-у21)Mug5, -BO2H" or -50225; each Mu? group is independently a carbocycle or a heterocycle, where Mu? is independently substituted with 0-3 Kg groups; and each U-! group is independently O or 5.

Table 20.1 2 2 2 tot tetu dob tetu da (c) (c) (c) 1 2 Z e o e (6) e (c) ter da ter en toster sna (6) (6) (6) 4 5 6 e (c) Sn e -k Z o i I - tor ma (6) (6) 7 8

Table 20.2 et itit e -x tr (c) (6) CHz 9 10

SNz 4 oh. ter CH (c) 11

Table 20.3

СНз СНз СНз 2 2 2 in star in (c) (c) (c) 12 13 14

СНз СНз СНз e o e o; 2 in dl va en ter on, (c) (c) at 16 17

SNU SNz e Osn e o v yo! in it she (in) (in) 18 19

Table 20.4

СН» СНз will absorb teburuv» o) (in; СНз 21

22

Table 20.5

Nzo Nzo Nzo 2 2 2 father So rtche So lche o) (6) (6) 23 24 25

Us Nzo Nzo e o 2 o 2 di 5 i M tn (6) (6) (6) 26 27 28

NS No e o) sn e (c) 5 UZ 5 ma (6) (6) 293 Zo

Table 20.6

No, no, no, no, no

Go) (c) SNz 31 32

Nzo and sleep 4 I am about SN" (6)

C3

Table 20.7 umez uz muz 2 2 vk O. dez shana do zbra” da (6) (c); (6) 34 35 36 megZ dgo dgo 2 2 zobu» ve! shk zebr” ve (6) (c); (6) 37 38 39 dgo go e. shk zebra» yes! (c) (c) 40 41

Table 20.8 where di dgi 2 g 2 v zobu" vho zore" di (c) (6) (c) 42 43 44 di dg! dg! 2 h h o (c) (c) 45 46 47 yes! di e sha dob wn (c) (c) 48 49

Table 20.9

2 2 2 tatu me tatu taty i, o H (c) H (c) 51 52 e o) 2 e o) titre dl zartetu sleep

H (c) H (6) H (c) 53 5A 55 e (c) Fin! e (c) tetu Z tetu ma

H (c) H (c) 56 57

Table 20.10 of physique and SNz t

H (c) H (c) CHz 58 59

CH3 is "a tetra CH

H (c) 60

Table 20.11

СНз СНз СНз 2 2 2 raw siren of orphans

H (c) H (6) H (c); 61 62 63

СНз СНз СНз e o e o e o zi dezi en zu sleep

H (c) H (c); H (in) 64 65 66

СНз СНз e (in) Fin! e (c) zu zr Z zu it ona

H (c) H (c) 67 68

Table 20.12

СНз СНз Puburuyaya pub

H (6) H (6) СН3 69 70

SNz SNz and about ZhK in SN

H (6) 71

Table 20.13 сн сн сн нС Z Nzo z Nzo z I mug3 t V. I where

H o) H (c) H (c) 72 7Z 74 sn snego isch ots i o etsvo i o od O. di vet en vet sn y

H o H (c) H (c) 75 76 77

СНз СНз 2 Nzo o - ovo o i 3 i it ona

H (6) H (6) 78 79

Table 20.14 sleep sleep no no ecsi o sleep 6 o. JAN

M m Uuai x t Z vo 81

SNU SNU es o Zh and SN

H (6) 82

Table 20.15 umeZ uug3 mgz 2 2 2 cheese I want cheese

H (c) H (6) H (c) 83 84 85 ugz to d25 2 2 2 raw raw vyk.

H (in; H (in) H (in; 86 87 88 dgo dgo 2 2 zi raw

H (c) Hn (c) 89 90

Table 20.16 de de de di 2 2 2 cheesy I want sirens

H (6) H (c) H (c) 91 92 93 yes yes! in 2 2 2 raw cheese raw

H (c) H (c) H (c) 94 95 96 yes yes 2 2 cheese raw

H (6) H (c) 97 98

Table 20.17. c) titer Z titr it ona dez o dez o 105 106

Table 20.18 of the loss of the SNz tattoo

Vo

ЯЗ о я Osn 107 108

SNz g "I titer SN

VZ at 109

Table 20.19

СНз СНз СНз СНз 2. 2 2 ша зичречная ширечная cheese cheese pos o) VZ o VZ o VZ o 110 111 112 113

СН СНуз СНз СНз and be o e o. sne o zi i zi snz zu breath may 23 o 23 o des o des o 114 115 116 117

Table 20.20

SNz SNz sha art

AND

Z o Z o SNa 118 119

СНз СНз и о Ж зи СН

VZ at 120

Table 20.21

Нз3б 0 СНз НС 0 СН НС СНУ Нз3б 0 СН г г г в зро зро з з о о о о о о о 121 122 123 124

Нз3Сб 0 СНз Нзб 0 СНз Нз3Со0СНз ? Нз3б 0 СНз е о. ее о) е о СНз Е, о) vy en che ona che kr Z mitona doz o dez o vgz F! gz at 125 126 127 128

Table 20.22

NS SNU NS. SN Us, Snu 00 still kor ie still and; SN eh o ZK m M va M SN vz o ZO sleep vz o 129 130 131

Table 20.23 mug3 mug3 mug3 Mug3 2 2 2 2 cheese cheese cheese cheese cheese cheese des o des o des o des o 132 133 134 135 dgo to d2go d2go 2 2 g vky o. duez sha zi zhichu" to

And And | And dez o dez o dez o dez o 136 137 138 139

Table 20.24 da da da dga 2 2 2 2 ur zychrchaya zhichu zhichu dez d) dez Ge) dez Ge) dez Ge) 140 141 142 143 g ge 2 ur sha. zycherchny cheese in o des o Z o Z o 144 145 146 147

Table 20.25 2 2 2 2 2 2 touuez Ted TUdga 00 d tn TUdaz 148 149 150 151 152 153 2 umgz 2 do g da e drg! r. N re 23 a Zah Zah bu oh o 154 155 156 157 158 159

Table 20.26 r M e to ee da ee da gr dez 7 7 te 7 sha ty

N N N N i, N 160 161 162 163 164 165 21 23 I would have started riots! ! ! From | From dz dez dez A dez A 166 167 168 169 170 171

Table 20.27. o O sna ba ve" Don o ve Zh 178 179

Table 20.28 o o bo - and kuueya 180 181 SN, also ABC Ho 2 2Ba ro eye; 182 183 184 185

Table 20.29

(c) (c) b rah re b ra re (c) (c) umg3 (c) (c) dgo 186 187 (c) (c) b rai r me ra re (c) o de c) o dy 188 189 (c) (c) b rai re b ra Ж (c) (c) H (c) (c) СНз 190 191 (c) (6) СНз

Zutto Z Zlo 192 193

Table 20.30

No oz o e sn b thing Zoo Ki (c) (c)

Снз 194 195 6, about СНз and СНз there is a thing child Ki o sk Zoo СН»

SNz

Sleep 196 197 (c) (c) b ra b rai (c) (c) (c) (c); 198 199

Table 20.31

(o; more ovee DO Am o (v; (v; (v; y Av AB (v; (v; (v; 200 201 (o; ve D YAVAY o (v; (v; (v; b) Ave YOU (in; (in; (in; 202 203 r 25 І 2 b sv» To AN g va D. SN (c) (c) (c) oh - o7 Z 204 205 NS

Y Z

(c) r) zva D. - ANNK g vma D. (c) (6) (c) bo to Zo Zone 207 206

Table 20.32 is) de O sna e ve Deva L. ra bo to to bo Zo Zo ona 208 209 (v; sn (o; ee ve" D. Do budi Z SNU 07 To to on" oo ze 211 SNz 210 (o; (o; g va D. kkd KK e doa re g oso o

Zach Zo (in; SO 212 213

Table 20.33

(c) r B ni auto o7 ; re add

Zatto o7 214 215 (c) ge XX de o lo o7 ; re to vo o7 216 217

You (in) paternal ory re SNU oto To 218 me tss

Ж Z o Z scher ra re rak oto o (c) (c) (c) SNU 221 220

Table 20.34 o) r o sna and Zh e Zh ry

Tto7to7to oto Zo ona 222 223 (c) (Fin "o Zhe i di, g re

Н сн (c) (c) (c) CHz al o za Z 224 225 СНа (c)

Y C hall

But at 226,227

Table 20.35

2 25a e 25a

Zo ur oh r vo 2289 2299 2 25 ge 25a bu u da i r v 2309 2319 e 25a e 25a 7 ur te r vo

H 2329 H 2330 гe 25 g 25a zaurtya zaburtya

H gas H gzvO

Table 20.36 g 25 2 2Ba zum oblivion" dz Go) des Ge) 236 237 2 25 2 25a aura zaurtyai

VZ o dz o 238 239

HA u e di o Moz tia (c) Ho 240 241 a is 2 2

From Zh des o 242 243

Table 20.37

2 2. o v o kh si to? | -1 dg5 244 -dy- 245 and 2 2. o Z o ---d23 gav 247

Table 20.38

СНз СНз СНз e e) Snz d c) e o) sn sha yo a or Tonya zulavy a

H 587 (c) H O vv H v9 (6,

СНз СНз СНз СНз e (in) Snu ge o. The same (6) sn sha wa Z a sna vet -iloh Z

And | AND

But SNz noya N gvvO e o) Snu ee is) e o) sn oo zr z oo it ona oo la y:

N zdo N.O gav N vro

Year (6) (6)

BUT in BUT zva di 2 o 2 G | g ra: V vezo vo - same ' (A -

NM

And (6)

BUT gvz3 254 255 256 du e. then 257

Phosphate variants of implementation of Formula I-II compounds

As a non-limiting example, phosphate variants of implementation of Formulas I-I can be represented by the general formula "MVE":

She

50BBVZ-- R a

TR ra!

MVE

Each variant of MVE implementation is presented as a substituted core (5c). Cc is described in formulas A-C in Table 1.1 below, where 5c is the general formula for a compound of Formula I, Formula II or

Formulas I, and the place of joining to -Р(О)Ra Ra? indicated by a wavy line.

Table 1.1

MN" ON MN"

Х Х Х vo o) l o o) kon, vo o dr. e "zi U 1 U "1

NN N N" N Me N on on on on on On on

And in (o;

ON MN» MN» chere chen chere

X X X pud "o o D wo o de

Ku Institute, Ku t, ma - s me /

On ОН он Он он r EE E

MN" cherv x Mo - siy o y, "kn, tu Sh on on ie! .

Combinations of "Zc" and "Ra"! and PrrRag, independently selected from Table 30.1, can be expressed in the form

Zs.Ra.rRag, where 5s is represented by the corresponding letter A-C from Table 1.1, and Ra" and Ra? are represented by the corresponding number from Table 30.1. So, A.256.256 represents the following compound:

MN» zgo ho chen - 1 cho ru according to MN Kk PIN

TO o On on x

Thus, Table 7 lists a large number of specific examples of phosphate prodrugs

Formula I-Sh.

Table 7

List of MVE compounds

A.254.67, A.254.68, A.254.69, A.254.70, A.254.71, A.254.258, A.254.248, A.254.249, A.254.250,

A.254.251, A.254.252, A.254.253, B.254.67, B.254.68, B.254.69, B.254.70, B.254.71, B.254.258,

B.254.248, B.254.249, B.254.250, B.254.251, B.254.252, B.254.253, Sb.254.67, Sb.254.68, S.254.69, b.254.70, 0.254.71, 0.254258, 0.254.248 254.249, 0.254250, 0.254251, 0.254252, 0.254253, p.254.67, O0.254.68, O0.254.69, O0.254.70, OY0.25 254.252, ОЮ0.254.253, E.254.67, B.254.68, E.254.69, E.254.70, E.254.71, E.254.258,

E.254.248, E.254.249, E.254.250, B.254.251, E.254.252, B.254.253, E.254.67, E.254.68, RE.254.69,

E.254.70, B.254.71, B.254.258, R.254.248, E.254.249, R.254.250, H.254.251, E.254.252, B.254.253, so.254.67, (3.254.68, .254.69, 254.70, 254.71, 1.254258, 1.254248, ...

A.255.248, A.255.249, A.255.250, A.255.251, A.255.252, A.255.253, B.255.67, B.255.68, B.255.69,

B.255.70, B.255.71, B.255.258, B.255.248, B.255.249, B.255.250, B.255.251, B.255.252, B.255.253,

S.255.67, Sb.255.68, S.255.69, Sb.255.70, 0.255.71, Sb.255.258, 0.255.248, Sb.255.249, Sb.255.250, b.255.251, 0.255252, 0.255253, O60, O60.2 255.68. E.255.69,

E.255.70, B.255.71, E.255.258, E.255.248, E.255.249, E.255.250, E.255.251, E.255.252, E.255.253,

E.255.67, E.255.68, B.255.69, G.255.70, B.255.71, E.255.258, E.255.248, B.255.249, G.255.250,

E.255.251, E.255.252, B.255.253, (3.255.67, (3.255.68, (3.255.69, 2.255.70, 255.71, 1.255.258, so255.248, 2.255.249, .255.250, .255.25 , 1.255252, .255.253, A.67.67, A.68.68, A.69.69,

A.70.70, A.71.71, A.258.258, A.248.248, A.249.249, A.250.250, A.251,251, A252.252, A.253.253,

B.67.67, B.68.68, B.69.69, B.70.70, B.71.71, B.258.258, B.248.248, B.249.249, B.250.250, 8.251251,

B252.252, B.253.253, 0.67.67, C.68.68, C.69.69, 0.70.70, 60.71.71, 0b.258.258, C.248.248, b.249.249, 0.250.250, 0.251251, 0252.253, 0252.253. 253, 00.67.67, 00.68.68, 0.69.69, 0.70.70, 0.71.71. 67.67,

E.68.68, E.69.69, E.70.70, B.71.71, E.258.258, E.248.248, E.249.249, E.250.250, E.251,251,

E252.252, E.253.253, E.67.67, E.68.68, G.69.69, B.70.70, B.71.71, G.258.258, G.248.248, RE.249.249,

E.250.250, E.251,251, B252.252, B.253.253, Sh.67.67, (.68.68, S.69.69, (5.70.70, (35.71.71, p.258.258, 2.248.248, 2.249.249, 2.250250, 2.251,251, p252.252, 2.253253, A.256.257,

B.256.257, Sat.256.257, OYU.256.257, E.256.257, B.256.257, 2.256.257, A.256.254, B.256.254, b.256.254, OYU0.256.254, E.256.254, BE.256.254, ( ... ,

E.256.69, (x3.256.69, A.256.71, B.256.71, Sat.256.71, O0.256.71, E.256.71, B.256.71, S.256.71,

A.256.255, B.256.255, Sat.256.255, O0.256.255, E.256.255, B.256.255, (3.256.255.

Variants of implementation of Ex include ethers, carbamates, carbonates, thioethers, amides, thioamides and urea groups:

Sun

IN

: re u

M du X, Ug2 mi mm12ha U Miha

Any reference to a compound of the invention described herein also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts formed with a suitable base, such as an alkali metal or alkaline earth metal (e.g., Mak, Gi, Kk, Sazh2 and Md2), ammonium, and MXa" (where X is C1-C4 alkyl) Physiologically acceptable salts based on the nitrogen atom or amino group include (a) addition salts of acids formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid, etc.; (B) salts , formed by organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid ota, naphthalene disulfonic acid, polgalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed by elementary anions, for example, chlorine, bromine, and iodine.

Physiologically acceptable salts of compounds with a hydroxy group include the anion of said compound in combination with a suitable cation, such as Ma: and MX" (where X is independently selected from H or a C1-Cx alkyl group).

For therapeutic use, the salts of the active ingredients of the compounds according to the invention must be physiologically acceptable, that is, they must be salts formed by a physiologically acceptable acid or base. However, salts of acids or bases that are not physiologically acceptable can also be used, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether formed with a physiologically acceptable acid or base or not, are within the scope of this invention.

Ultimately, it should be understood that the compositions of the present invention include the compounds of the invention in both non-ionized and zwitterionic forms, and combinations with stoichiometric amounts of water in the form of hydrates.

Compounds according to the invention, represented by Formulas I-Z, may contain chiral centers, for example, chiral carbon or phosphorus atoms. Compounds according to the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropoisomers. In addition, compounds according to the invention include enriched or selected optical isomers on any or all asymmetric chiral atoms. In other words, chiral centers, as can be seen from the given images, are presented in the form of chiral isomers or racemic mixtures. racemic mixtures, and mixtures of diastereoisomers, as well as individual optical isomers, isolated or synthesized, which essentially do not contain concomitant enantiomers or diastereomers, are within the scope of the present invention. Racemic mixtures are separated into separate essentially optically pure isomers using widely known techniques, such as, for example, the separation of salts of diastereoisomers formed by optically active auxiliary substances, for example, acids or bases, followed by reverse conversion into optically active substances. In most cases, the target optical isomer is synthesized by means of stereospecific reactions, using as a starting material the corresponding stereoisomer of the required starting material.

The term "chiral" refers to molecules that have the property of not overlapping with their mirror image, while the term "achiral" refers to molecules that overlap with their mirror image.

The term "stereoisomers" refers to compounds that have the same chemical composition, but differ in the arrangement of atoms or groups in space. "Diastereomers" refers to stereoisomers with two or more centers of chirality, the molecules of which are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereoisomers can be separated using high resolution analytical techniques such as electrophoresis and chromatography. "Enantiomers" refers to two stereoisomers of a compound that are mirror images of each other and do not coincide when superimposed.

The stereochemical definitions and notations used in this description generally correspond to those given in 5. R. Ragkeg, Ed., Msdgam/-pPiY! Oisiopagus of Spetis! Teptzv (1984) Medgamu-pII!

VookK Sotrapu, Mem HogK; apa Eiiei, E. apa UmiIep, 5., 5iegeospetivhigu oi Ogdapis Sotroypaz (1994) add.

Umieu 8 Zop5, Ips., Mem HogK. Many organic compounds exist in the form of optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the absolute configuration of the molecule relative to its chiral center(s) is denoted by the prefixes О и Й or К и 5. The prefixes 9 ии, О и Й or (5 и (-)) are used to denote the sign of rotation of plane-polarized light by a compound, with 5, (-) or 1 indicating that the compound is levorotatory, while a compound prefixed with K, (g) or a is dextrorotatory.

For this chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer can also be considered an enantiomer, with a mixture of such isomers often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate; this mixture can be formed if the chemical reaction or process lacks stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two types of enantiomers that has no optical activity.

In all cases where a compound described herein is substituted by more than one group with the same designations, such as "K" or "AK", it should be understood that these groups may be the same or different, that is, each group is chosen independently. Wavy lines, lm indicate the place of attachment by means of a covalent bond to adjacent substructures, groups, fragments or atoms.

The compounds of the invention may also exist as tautomeric isomers in some cases. Although only one delocalized resonance structure may be depicted, all such forms are within the scope of the present invention. For example, en-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine and tetrazole systems, while all possible tautomeric forms of these compounds are within the scope of the present invention.

For a specialist in this field of technology, it is clear that imidazo(/1,5-4(1,2,griazine, (1,2,4)triazolo4,3-

PI1,2,4)griazine and imidazo|1,2-411,2,)griazine heterocycles can exist in the form of tautomeric forms. As a non-limiting example, structures (a) and (b) can have equivalent tautomeric forms as shown below: c) and)

KK

"AND! M u- M ne u- wa tm tm e8 kv r der

UAZ ma u o Her mb ho a

M M ra le

E Zh shi E A «U, Am u- - ko U- Ma m pom a b

All possible tautomeric forms of heterocycles in all variants of implementation are within the scope of the present invention.

Ways of inhibiting HCV polymerase

Another aspect of the invention relates to methods of inhibiting HCV polymerase activity, which include the step of treating a sample approximately containing HCV with a composition according to the invention.

Compositions according to the invention can act as inhibitors of HCV polymerase, intermediates of such inhibitors, or perform other functions as described below. Inhibitors bind to sites on the surface or in the HCV polymerase pocket that have a unique geometry. Compositions that bind HCV polymerase can bind it with varying degrees of reversibility. Compounds that bind the polymerase essentially irreversibly are ideal candidates for use in this method according to the invention. Being labeled, compositions that essentially bind irreversibly are suitable as probes for the detection of HCV polymerase. Accordingly, this invention relates to polymerase detection methods

HCV in a sample approximately containing HCV polymerase, comprising the steps of: treating a sample approximately containing HCV polymerase with a composition containing a label-linked compound of the invention; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostic art and include stable free radicals, fluorophores, radioactive isotopes, enzymes, chemiluminescent groups and chromogens. The compounds of this description are labeled in a standard manner using functional groups such as hydroxyl, carboxyl, sulfhydryl, or amino groups.

In the context of the present invention, samples approximately containing HCV polymerase include materials of natural or artificial origin, such as living organisms; tissue or cell cultures; biological samples, such as samples of biological materials (blood, serum, urine, cerebrospinal fluid, tear fluid, sputum, saliva, tissue samples, etc.); laboratory samples; samples of food, water or air; samples of bioproducts, for example cell extracts, in particular, recombinant cells that synthesize the target glycoprotein; etc. Specimens are usually assumed to contain an organism that produces HCV polymerase, most often a pathogenic organism such as HCV. Samples can be contained in any medium, including water and organic solvent/water mixtures. Samples include living organisms, such as humans, and materials of artificial origin, such as cell cultures.

The processing step according to the invention includes adding the composition according to the invention to the sample or adding the precursor of the composition to the sample. The addition step includes any input method as described above.

If desired, HCV polymerase activity after application of the composition can be observed using any method, including direct and indirect methods for detecting HCV polymerase activity. Quantitative, qualitative and semi-quantitative methods of determining HCV polymerase activity are expected to be used. One of the above-described screening methods is usually used, but any other method can also be used, for example, observing the physiological properties of a living organism

Organisms containing HCV polymerase include the HCV virus. The compounds of the present invention are suitable for the treatment or prevention of HCV infections in animals or humans.

However, when screening for compounds capable of inhibiting human immunodeficiency virus, it should be borne in mind that the results of an enzymatic assay may not correlate with the results of an assay using cell cultures. Thus, cellular analysis should be the primary screening tool.

Screening of HCV polymerase inhibitors.

Compounds according to the invention were screened for inhibitory activity against HCV polymerase using any commonly accepted methods of assessing enzymatic activity. In the context of the invention, as a rule, compositions were first tested for inhibition of HCV polymerase ip migo, and then compositions exhibiting |inhibitory activity were tested for ip mimo activity. Compositions having ip miigo Ki (inhibition constants) of less than about 5 x 10-6 M, typically less than about 1 x 10-7 M, and preferably less than about 5 x 10-8 M, are preferred for use in ip past

Screening methods used by ip migo are described in detail and are not discussed in this description. However, the examples provide a description of suitable IP research studies.

Pharmaceutical compounds

Compounds based on the compounds of this invention are prepared using conventional carriers and excipients selected in accordance with established practice. Tablets contain excipients, substances that promote gliding, fillers, binders, etc. Aqueous compounds are prepared in sterile form, while compounds intended for delivery by a route other than oral administration are generally prepared isotonic. All compounds may contain excipients listed, for example, in "NapabrookK oi Rpagtaseshisai! Ekhsiriepiv" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH of the compounds ranges from about 3 to about 11, but usually around 7-10.

In the case where it is possible to introduce the active ingredients separately, it may be better to present them in the form of pharmaceutical compounds. Compounds according to the invention, both for veterinary use and for human treatment, contain at least one active ingredient as defined above together with one or more acceptable carriers and possibly other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the compound and physiologically harmless to the recipient.

Compounds include compounds suitable for the above routes of administration. The compounds may conveniently be presented in dosage form and may be prepared by any method known in the art of pharmacy. Techniques and compounds in the general case can be found in Ketipdiopye Rpaptaseshiisai

Zsiepse5 (Mask Rybiyepipd So., Eavsiop, RA). Such methods include the step of combining the active ingredient with a carrier consisting of one or more auxiliary ingredients. In general, the compounds are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, forming the product.

Compounds according to the present invention suitable for oral administration may be presented in the form of discrete units, for example, capsules, wafers or tablets, each of which contains a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary, or paste.

Tablets are obtained by compression or molding, possibly with the use of one or more auxiliary ingredients. Compressed tablets can be obtained by pressing in suitable equipment the active ingredient in a free-flowing form, for example in the form of a powder or granules, possibly mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets can be obtained by casting in suitable equipment a powdered active ingredient moistened with an inert liquid diluent. The tablets may be coated or scored, and the composition of the tablets may be such as to provide a delayed or controlled release of the active ingredient from the tablets.

For infections of the eyes or other external tissues, for example, the oral cavity and skin, it is better to use compounds in the form of an ointment or cream for local application, containing the active) ingredient(s) in an amount, for example, 0.075-20 9o wt./wt. (including the content of the active ingredient in the range of 0.1 95-20 95 in steps of 0.1 95 wt./wt., for example, 0.6 95 wt./wt., 0.7 96 wt./wt., etc.) , better 0.2-15 95 wt./wt. and the best - 0.5-10 95 wt./wt. When preparing an ointment, an active ingredient with either a paraffin or a water-soluble ointment base is used. Alternatively, the active ingredients can be incorporated into a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may contain, for example, at least 30 95 wt./wt. polyhydric alcohol, i.e. alcohol containing two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin and polyethylene glycol (including PEG 400) and their mixtures. It may be desirable for topical compounds to include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsions according to the invention can be obtained from known ingredients in a known manner. Although this phase may include only an emulsifier (otherwise called an emulsifier), it is preferred that it include a mixture of at least one emulsifier with fat or oil, or both fat and oil. It is better to include a hydrophilic emulsifier together with a lipophilic emulsifier, which plays the role of a stabilizer. It is also better to include both oil and fat in the composition.

The emulsifier(s), with or without stabilizer(s), form a so-called emulsifying wax, and this wax, together with oil and fat, forms a so-called emulsifying ointment base, which forms the oily dispersion phase of the cream.

Emulsifiers and emulsion stabilizers suitable for use in the composition according to the invention include Tmeepe 60, brap? 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

The selection of suitable oils or fats for compounds is based on achieving the required cosmetic properties. The cream should preferably be a non-greasy, non-staining, washable product with a consistency suitable for preventing leakage from tubes or other containers. Mono- or dibasic linear or branched chain alkyl esters can be used, such as diisoadipinate, isocetyl stearate, propylene glycol diester of fatty acids of coconut oil, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched chain esters known as Stodate SAR, and the last three substances are the best ethers. They can be used individually or in combination, depending on the required properties. As an alternative, use lipids with a high melting point, such as white soft paraffin and/or paraffin oil or other mineral oils.

Pharmaceutical compounds according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or possibly other therapeutic agents. Pharmaceutical compounds containing the active ingredient can be presented in any form suitable for the intended route of administration. For oral use can be obtained, for example, tablets, lozenges, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral administration may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, coloring agents, and preservatives for the purpose of imparting a pleasant taste to the preparations. . Tablets containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient suitable for tableting are also suitable. These auxiliary agents can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be obtained without a coating or with a coating using known techniques, including microencapsulation in order to delay disintegration and adsorption in the gastrointestinal tract and, thus, provide prolonged action over a longer period of time. For example, a sustained release material such as glyceryl monostearate or glyceryl stearate may be used alone or with a wax.

Oral compounds may also be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, paraffin oil or olive oil.

Aqueous suspensions according to the invention contain active substances in a mixture with auxiliary substances suitable for obtaining aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, and dispersing or wetting agents such as a natural phosphatide (e.g., lecithin), an alkylene oxide condensation product with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethyleneoxyethanol), a condensation product of ethylene oxide with an incomplete ester derived from a fatty acid and hexitic anhydride (for example, polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as paraffin oil. Suspensions for oral administration may contain a thickener such as beeswax, hard paraffin or cetyl alcohol. To give the drug a pleasant taste, you can add sweeteners, such as those mentioned above, and flavorings. Preservation of these compositions can be ensured by adding an antioxidant, for example, ascorbic acid.

Dispersible powders and granules according to the invention, suitable for obtaining an aqueous suspension by adding water, are the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are the agents described above.

Additional excipients may also be present, such as sweeteners, flavorings, and dyes.

Pharmaceutical compounds according to the invention can also be presented in the form of "oil-in-water" emulsions. The oil phase can be a vegetable oil, such as olive or peanut oil, a mineral oil, such as paraffin oil, or a mixture thereof. Suitable emulsifiers include natural gums such as gum arabic or tragacanth, natural phosphatides such as soy lecithin, esters or incomplete esters derived from fatty acids and hexitic anhydrides, such as sorbitan monooleate, and condensation products of these incomplete esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs can be prepared using sweeteners such as glycerin, sorbitol or sucrose. Such compounds may also contain a sedative, preservative, flavoring or coloring agent.

Pharmaceutical compositions according to the invention can also be presented in the form of a sterile preparation for injections, for example, a sterile aqueous or oily suspension for injections.

This suspension can be prepared according to known techniques using the aforementioned suitable dispersing or wetting agents or suspending agents. The sterile injection may also be a sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be obtained as a lyophilized powder. Acceptable media and solvents that may be used for this purpose include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are widely used as a solvent or suspension medium. Any soft non-volatile oil can be used for this purpose, including synthetic mono- and diglycerides. In addition, in a similar way, fatty acids, for example, oleic acid, can be used in the preparation of preparations for injections.

The amount of active ingredient that can be mixed with the carrier material to produce a dosage medicine will vary depending on the recipient to be treated and the particular method of administration. For example, a sustained-release preparation intended for oral administration to humans may contain about 1-1000 mg of active material mixed with an appropriate amount of carrier material, which may vary from about 5 to about 95% of the total weight of the compound (w/w). A pharmaceutical composition can be prepared to provide an easily measurable amount required for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 ml/h.

Compounds suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable vehicle, particularly an aqueous solvent.

The active ingredient is better present in such compounds in a concentration of 0.5-20 906, better 0.5-10 95, and especially better - about 1.5 95 wt./wt.

Compounds suitable for topical oral administration include lozenges containing the active ingredient in a flavored formulation base, typically sucrose and gum arabic or tragacanth; lozenges containing the active ingredient in an inert base, such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Compounds for rectal administration can be presented as suppositories with a suitable base, including, for example, cocoa oil or salicylate.

Compounds for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1-500 microns, for example, 0.5, 1, 30, 35, etc.; they are administered by rapid inhalation through the nasal passages or inhalation through the mouth so that the drug reaches the alveolar vesicles.

Suitable compounds include aqueous or oily solutions of the active ingredient. Compounds suitable for administration as an aerosol or dry powder can be prepared according to conventional methods and delivered together with other therapeutic agents, such as compounds heretofore used to treat or prevent HCV infections, as described below.

Compounds for vaginal administration may be presented in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or aerosol preparations containing, in addition to the active ingredient, suitable carriers known in the art to be suitable.

Compounds for parenteral administration include aqueous or non-aqueous sterile solutions for injection, which may contain antioxidants, buffer mixtures, bacteriostatic agents, and solutes that render the compound isotonic with the blood of the intended recipient; and aqueous or non-aqueous sterile suspensions, which may contain suspending agents and thickeners.

The compounds are presented in single or multi-dose containers, such as sealed ampoules and bottles, and can be stored in a sublimated (lyophilized) state requiring only the addition of a sterile liquid vehicle, such as water for injection, immediately prior to use. Solutions and suspensions for injections, prepared for immediate administration, are prepared from sterile powders, granules and tablets, described earlier. Compounds with a better dosage are compounds containing a daily dose or a dose close to a daily dose, as described above in this document, or an appropriate part of a daily dose of the active ingredient.

It should be understood that in addition to the specific ingredients mentioned above, the compounds of the invention may include other agents commonly used in the art for the type of compounds in question; for example, compounds for oral administration may include flavoring agents.

In addition, the invention provides compositions for use in veterinary medicine, containing at least one active ingredient as defined above, together with a carrier used in veterinary medicine.

Carriers used in veterinary medicine are substances suitable for the purpose of administration of the composition and may be solid, liquid or gaseous substances, inert or acceptable for use in veterinary medicine and compatible with the active ingredient. These compositions for veterinary use can be administered orally, parenterally or by any other appropriate route.

The compounds of the invention have been used to prepare controlled-release pharmaceutical preparations containing one or more compounds of the invention as an active ingredient ("controlled-release preparations"), the release of the active ingredient of which can be controlled and regulated to allow for less frequent administration or improving the pharmacokinetic and toxic profile of this active ingredient.

The effective dose of the active ingredient depends at least on the nature of the condition being treated, the toxicity, whether the compound is used prophylactically (lower doses) or for the treatment of an active viral infection, the route of administration and the pharmaceutical compound, and should be determined by the physician by conventional studies with increased dosage. An approximate indicated dose is from about 0.0001 to about 100 mg/kg of body weight per day; typically from about 0.01 to about 10 mg/kg body weight per day; more typically, from about 0.01 to about 5 mg/kg of body weight per day; most typically from about 0.05 to about 0.5 mg/kg body weight per day. For example, a possible daily dose for an adult with a body weight of about 70 kg is in the range of 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and can be administered as a single dose or multiple doses.

Ways of introduction

One or more compounds of the invention (referred to herein as active ingredients) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) routes, etc. It should be noted that the preferred route of administration may vary, for example, depending on the recipient's condition. An advantage of the compounds of this invention is that they are orally bioavailable and can be taken orally.

Combined therapy

Compositions according to the invention were also used in combination with other active ingredients.

Preferably, the other therapeutically active ingredients are interferons, ribavirin analogs, M53 protease inhibitors, M5bBa inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors, and other drugs for the treatment of HCV.

Combinations of compounds of Formula I-I are generally selected based on the condition being treated, the cross-reactivity of the ingredients, and the pharmacological properties of the combination. For example, in the treatment of an infection (eg, HCV), the compositions of the invention have been combined with other therapeutically active agents (such as described herein).

Suitable therapeutically active agents or ingredients that can be used in combination with the compounds of Formulas I-III may include interferons, for example pegylated recombinant IFN alpha-2p, pegylated recombinant IFN alpha-2a, recombinant IFN alpha-2p, IFN alpha-2p

XI, recombinant IFN alpha-2a, typical IFN alpha, infergen, rebif, lokteron, AMI-005, RES- infergen, pegylated IFN beta, oral interferon alpha, feron, reaferon, intermax alfa, recombinant IFN beta, infergen - actimun, IFN omega with POKOZ5 and albuferon; analogs of ribavirin, for example, rebetol, copegus, MX-497 and viramidine (taribavirin); M55a inhibitors, for example, A-831, A-689 and BM5-790052; M550B polymerase inhibitors, for example, MM-283, valopicitabine, K1626, RBI-6130 (K1656), HCV-796, VIV 1941, MK-0608, MM-107, 87128, МСН-759, РЕ-868554, 55Кб25433 and ХТИ 2125 ; M5Z3 protease inhibitors, for example, ZSN-503034 (5SN-7), UH-950 (telaprevir), ITMM-191 and VII M-2065; alpha-glucosidase 1 inhibitors, for example, MX-3253 (celgosivir) and OT-2318B; hepatoprotectors, for example, IOM-6556, ME 3738, MiO and I 8-84451; non-nucleoside HCV inhibitors, for example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives and phenylalanine derivatives; and other drugs for treatment

HCV, for example, zadaxin, nitazoxanide (Aiipia), VIMM-401 (Migovia)), SEVIO-025, Mach-410C, EM2-702,

AMI 4065, bavituximab, oglufanid, RUM-17, KREO2003002, actylon (СРО-10101), KAM-7000, sivasir,

SI-5005, AMA-975, KhTI -6865, AMA 971, MOM-205, Taguasip, ENS-18 and MIM811.

According to another embodiment, this application provides a pharmaceutical composition containing a compound of the present invention or a pharmaceutically acceptable salt, solvate and/or ester thereof in combination with at least one additional therapeutic agent and a pharmaceutically acceptable carrier or excipient.

According to the present invention, a therapeutic agent used in combination with a compound according to the present invention may be an agent having a therapeutic effect when used in combination with a compound according to the present invention. For example, a therapeutic agent used in combination with a compound of the present invention may be interferons, ribavirin analogs, M53 protease inhibitors, M55a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors, and other drugs for the treatment of HCV. .

According to another embodiment, this application provides pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt, solvate and/or ester thereof in combination with at least one additional therapeutic agent selected from the group consisting of pegylated recombinant IFN alpha-2B, pegylated recombinant IFN alpha-2a, recombinant IFN alpha-2p, recombinant IFN alpha-20b, IFN alpha-25 Kh, recombinant IFN alpha-2a, typical IFN alpha, infergen, rebif, lokteron, AMI-005, RES -

infergen, pegylated IFN beta, oral interferon alfa, feron, reaferon, intermax alfa, recombinant IFN beta, infergen "from actimun, IFN omega from POKO5, albuferon, rebetol, copegus, UH-497, viramidine (taribavirin), A-831, A-689, MM-283, valopicitabine, K1626, RBZI-6130 (K1656), VGO-796, VIV 1941, MK-0608, MM-107, 87128, MSN-759, RE-868554, 15K625433, KhTI -2125,

ZSN-503034 (5SN-7), UH-950 (telaprevir), ITMM-191 and VISM-2065, MH-3253 (celgosivir), OT-2318,

I0M-6556, ME 3738, MiyoO and I 8-84451, derivatives of benzimidazole, derivatives of benzo-1,2,4-thiadiazine and derivatives of phenylalanine, zadaxin, nitazoxanide (AIIIIpia), VIMM-401 (Migovia)), SEVIO-025, Mach-4100,

EM2-702, AMI 4065, bavituximab, oglufanid, RUM-17, KREO2003002, actylon (СРО-10101), KAM-7000, sivasiru, I-5005, AMA-975, KhTI-6865, AMA 971, MOM-205, Tagmasip , ENS-18 and MIM811 and a pharmaceutically acceptable carrier or excipient.

According to another embodiment, this application proposes a combined pharmaceutical agent containing: a) a first pharmaceutical composition containing a compound according to the present invention or its pharmaceutically acceptable salt, solvate and/or ether; and

B) a second pharmaceutical composition containing at least one additional therapeutic agent selected from the group consisting of compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase, dr41 inhibitors, SCSKA inhibitors, dr120 inhibitors, CSK5 inhibitors, interferons, ribavirin analogs, M53 protease inhibitors, MZ5Ba inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors and other drugs for the treatment of HCV, and their combinations.

Combinations of compounds of Formulas I-I and additional therapeutically active agents may be selected to treat patients infected with HCV and other conditions, such as HIV infection. Accordingly, compounds

Formulas I-Ж can be combined with one or more compounds used in treatment

HIV, for example, by compounds inhibiting HIV protease, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, aor41 inhibitors, sche inhibitors, odr120 inhibitors, CSK5 inhibitors, interferons, ribavirin analogs, M53 protease inhibitors, M55a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors and other drugs for the treatment of HCV, and their combinations.

More specifically, one or more compounds according to the present invention can be combined with one or more compounds selected from the group consisting of 1) HIV protease inhibitors, for example, amprenavir, atazanavir, fosamprenavir, idinavir, lopinavir, ritonavir, lopinavir t ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMO-126, TMO-114, mozenavir (ОМР-450), UE-2147 (АСи1776), АСИ1859, 00235, 1-756423, VОО0334649, KМИ-272, ОРО -681, ОРО-684, and smub40385Х, 0с17, РРИ-100, 2) a non-nucleoside HIV reverse transcriptase inhibitor, for example, capravirin, emivirin, delaviridine, efavirenz, nevirapine, (w) calanolide A, etravirin, zUU5634,

ORO-083, OROS-961, ORO-963, MIM-150 and TMO-120, TMO-278 (rilpivirine), efavirenz, VIK 355 B5,

MAH 840773, OK-453,061, KOBEAV8FOb, 3) HIV nucleoside reverse transcriptase inhibitor, for example, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxavir, elvucitabine, alovudine, MiIM-210, racavir (-ETS), 0 -a4ES, emtricitabine, phosphazide, fosivudine tidoxyl, fosalvudine tidoxyl, apricitabine (AMX754), amdoxavir, KR-1461, abacavir and lamivudine, abacavir - lamivudine - zidovudine, zidovudine and lamivudine, 4) nucleotide inhibitor of HIV reverse transcriptase, for example, tenofovir , tenofovir disoproxil fumarate and emtricitabine, tenofovir disoproxil fumarate and emtricitabine and efavirenz and adefovir, 5) HIV integrase inhibitor, for example, curcumin, curcumin derivatives, chicory acid, chicory acid derivatives, C3,5-dicaffeoylquinic acid, C3 derivatives, 5-dicaffeoylquinic acid, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ether, caffeic acid phenethyl ether derivatives slots, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, 5-1360, zinteviru (AK-177), 1-870812 and 1I1-870810, MK-0518 (raltegravir), VM5-707035, MK-2048, VA-011, ВМ5-538158, О5К364735С, 6) aor41 inhibitor, for example, enfuvirtide, sifuvirtide, EVOOEM, TKI-1144, 5RSZ, CE56, I axis dr41, SouX and KER 9, 7) SHSK4 inhibitor, for example, AMO-070, 8) inhibitor cell penetration, ZROTA, TMH-355, 9) dr120 inhibitor, for example, VM5-488043 and ViosKaide/SK, 10) Ob6PO and MAON oxidase inhibitor, for example, immunitin, 10) CSK5 inhibitor, for example, aplaviroc, vicriviroc, ИМСВ9471 , REO-140,

ИМСВ15050, РЕ-232798, ССК5тАБООЯ4 and maraviroc, 11) interferon, for example, pegylated recombinant IFN alpha-2B, pegylated recombinant IFN alpha-2a, recombinant IFN alpha-2р0, recombinant IFN alpha-2р, IFN alpha-25b Х, recombinant IFN alpha-2a, typical

IFN alfa, infergen, rebif, lokteron, AMI-005, RES-infergen, pegylated IFN beta, oral interferon alfa, feron, reaferon, intermax alfa, recombinant IFN beta, infergen Z actimmune, IFN omega with OOKOZ5 and albuferon, 12) analogs ribavirin, such as rebetol, copegus,

Ух-497, viramidine (taribavirin), 13) M55ba inhibitors, for example, A-831, A-689 and ВМ5-790052, 14) polymerase inhibitors, for example, MM-283, valopicitabine, 1626, RBZI-6130 (21656), VGO-796, VII B 1941, MK-0608, MM-107, 87128, MSN-759, RE-868554, 55K625433 and KhTI -2125, 15) protease inhibitors

M53, for example, ЗСН-503034 (5СН-7), УХ-950 (telaprevir), ITMM-191 and VII/M-2065, 16) alpha-glucosidase 1 inhibitor, for example, МХ-3253 (celgosivir) and OT-2318 , 17) hepatoprotectors, for example,

I0M-6556, ME 3738, MiyoO and I 8-84451, 18) non-nucleoside inhibitors of HCV, for example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives and phenylalanine derivatives, 19) other drugs for the treatment of HCV, for example, Zadaxin , nitazoxanide (Aiipia), VIMM-401 (Migovia)), SEVIO-025, MaX-A10C,

EM2-702, AMI 4065, bavituximab, oglufanid, RUM-17, KREO2003002, actylon (СРО-10101), KAM-7000, sivasiru, 5I-5005, AMA-975, KhTI-6865, AMA 971, MOM-205, Tagmasipy . IOM-1,

RA-457 (bevirimate), ampligen, NKO214, cytolin, polymin, MOX-410, KOg247, AM7 0026, SUT 99007,

A-221 NIM, VAM 50-4798, MOHO10 (ipilimumab), RV5119, A! 889 and RA-1050040.

It is also possible to combine any compound according to the invention with one or more other therapeutically active agents in a dosage form for simultaneous or sequential administration to a patient. Combined therapy can be prescribed in a simultaneous or sequential mode of administration. With sequential administration, the combination can be administered in two or more doses.

Co-administration of a compound according to the invention with one or more other therapeutically active agents generally refers to the simultaneous or sequential administration of a compound according to the invention and one or more other therapeutically active agents, such that therapeutically effective amounts of the compound according to the invention are co-present in the patient's body and one or more other therapeutically active agents.

Co-administration includes administration of single doses of compounds according to the invention before or after administration of single doses of one or more other therapeutically active agents, for example, administration of single doses of compounds according to the invention several seconds, minutes or hours before administration of one or more other therapeutically active agents. For example, a single dose of a compound of the invention may be administered first followed by a single dose of one or more other therapeutically active agents a few seconds or minutes later. Alternatively, a single dose of one or more other therapeutically active agents may be administered first followed by a single dose of a compound of the invention a few seconds or minutes later. In some cases, it may be desirable to initially administer a single dose of a compound of the invention followed several hours later (eg, 1-12 hours) by a single dose of one or more other therapeutically active agents. In other cases, it may be desirable to initially administer a single dose of one or more other therapeutically active agents, followed several hours later (eg, 1-12 hours) by a single dose of a compound of the invention.

Combination therapy can provide "synergy" and "synergistic effect", that is, the phenomenon when the effect achieved by the joint use of the active ingredients is greater than the sum of the effects achieved as a result of the separate use of these compounds. A synergistic effect can be achieved if the active ingredients: (1) are jointly prescribed and administered to the patient or are administered simultaneously in a combined compound; (2) taken alternately or parallel to each other in the form of separate compounds; or (3) in some other mode. In sequential therapy, a synergistic effect can be achieved if the compounds are administered or taken sequentially, for example, in separate tablets, pills or capsules or as separate injections in separate syringes. In general, during sequential therapy, an effective dose of each active ingredient is administered sequentially, that is, serially, while in combination therapy, effective doses of two or more active ingredients are administered together. A synergistic antiviral effect means that the antiviral effect is higher than the predicted purely additive effect of the individual compounds of the combination.

According to another embodiment, this application proposes methods of polymerase inhibition

HCV in a cell, comprising: bringing a cell infected with HCV into contact with an effective amount of a compound of Formulas I-III or a pharmaceutically acceptable salt, solvate and/or ester thereof, resulting in inhibition of HCV polymerase.

According to another embodiment, this application proposes methods of polymerase inhibition

HCV in a cell, comprising: contacting a cell infected with HCV with an effective amount of a compound of Formula I-I or a pharmaceutically acceptable salt, solvate and/or ester thereof, and at least one additional therapeutically active agent, resulting in inhibition of polymerase .

According to another embodiment, this application proposes methods of polymerase inhibition

HCV in a cell, comprising: contacting a cell infected with HCV with an effective amount of a compound of Formula I-I or a pharmaceutically acceptable salt, solvate and/or ester thereof, and at least one additional therapeutically active agent selected from the group consisting of interferons , ribavirin analogues, M53 protease inhibitors, MZ5bBa inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors and other drugs for the treatment of HCV.

According to another embodiment, this application provides methods of treating HCV in a patient, which include: administering to the patient a therapeutically effective amount of a compound of Formula I-I or a pharmaceutically acceptable salt, solvate and/or ester thereof.

According to another embodiment, this application proposes methods of treating HCV in a patient, which include administering to the patient a therapeutically effective amount of a compound of Formula 1-PI or its pharmaceutically acceptable salt, solvate and/or ether, and at least one additional therapeutically active agent, as a result which is achieved by inhibiting HCV polymerase.

According to another embodiment, this application provides methods of treating HCV in a patient, which include administering to the patient a therapeutically effective amount of a compound of Formula 1-PI or a pharmaceutically acceptable salt, solvate and/or ester thereof, and at least one additional therapeutically active agent selected from a group that includes interferons, ribavirin analogs, M53 protease inhibitors, M55a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors and other drugs for the treatment of HCV.

According to another embodiment, this application proposes the use of a compound according to the present invention or a pharmaceutically acceptable salt, solvate and/or ether thereof for the preparation of a medicinal product for the treatment of an infection caused by HCV in a patient.

Metabolites of compounds according to the invention

This invention also includes the metabolic products of the compounds described herein to the extent that such products are novel or non-obvious compared to the prior art.

Such products can be formed during oxidation, reduction, hydrolysis, amidation, esterification, etc. compounds introduced mainly as a result of enzymatic processes. Accordingly, the invention includes novel or non-obvious compounds formed by a process comprising contacting a compound of the invention with a mammal for a time sufficient to produce a corresponding metabolite. Such products have generally been identified by preparing a compound of the invention containing a radiolabel (eg, 14C or 3H), administering a detectable dose of said compound (eg, greater than about 0.5 mg/kg) parenterally to an animal , e.g., rat, mouse, guinea pig, monkey, or human, waiting for a time sufficient for metabolism to occur (typically from about 30 seconds to 30 hours) and isolating the conversion products from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated using antibodies capable of binding to epitopes stored in the metabolite). The structure of the metabolite was determined by conventional methods, for example, using mass spectrometry or NMR analysis. In general, the analysis of metabolites was carried out according to generally accepted methods of studying the metabolism of drugs, widely known to those skilled in the art. The transformation products, provided they do not occur under other conditions, are suitable for diagnostic studies of the therapeutic dosage of the compounds according to the invention, even if they themselves do not have inhibitory activity against HCV polymerases.

Known methods and methods of determining the stability of compounds in surrogate secretions of the gastrointestinal tract. In this document, compounds are considered to be stable in the gastrointestinal tract if less than about 50 molar percent of the protected groups are deprotected in a surrogate of intestinal contents or gastric juice upon incubation for 1 hour at 37°C.

The very fact that the compounds are stable in the gastrointestinal tract does not mean that they cannot undergo hydrolysis. Prodrugs of the invention are generally stable in the digestive system, but may undergo hydrolysis to parent drugs to a large extent in the digestive tract, in the liver or other organs, or within cells as a whole.

EXAMPLES

In the detailed description of the experiments, some abbreviations and acronyms are used. Although most of these are readily apparent to one skilled in the art, Table 1 lists many of these abbreviations and acronyms.

Table 1

List of Abbreviations and Acronyms Methylpropionitrile)

SSSZNNY Enzyme benzoquinone electric field highly effective liquid capacity acid TSH 500 EM of tetramethylsilane in parts per million

Preparation of compounds

Compound 1

МН» kon noi. ЗХ m. 2 o M ni on 1 вх, vok,

Ku РРТ8 chorus her: СснЗОонн her: o on o on (6) (6) a 15

Acetyl chloride (22 ml) was added dropwise to a solution of Ta (22.0 g, 54.9 mmol, prepared according to the procedures described in .0.S., 2004, 6257) in methanol (300 ml) at 0 "С using a dropper during 30 min and then stirred at room temperature for 16 h.

The mixture was concentrated, re-dissolved in ethyl acetate (400 ml), washed with ice-cold 2 N. Mahon and concentrated to dryness to give crude methyl ether 15 as an oil. M5-437.2 (Ma-Ma"). nah, and - Maosna

On. he sNnzoN no he (6) 1s 165

A 0.5 M solution of sodium methylate in methanol (20 mL, 10 mmol) was added to a solution of 16 (obtained in the previous step) in methanol (300 mL) and stirred for 16 h. at room temperature. The reaction was quenched with 4.0 n. with a solution of NSI in dioxane (2.5 ml, 10 mmol). Then the mixture was concentrated, obtaining crude 1c. M5-201.0 (MaMa"). but OA

ОО (в) у - высы, КОН ух гч 2 ---- с Tygygop Х-405 а се бака toluene 1с 1а

A mixture of 1c (obtained in the previous step), Thiyop X-405 (70 95 solution in water, 6.0 g), 50 96 KOH (in water, 85 g) in toluene (500 ml) was heated under reflux with an attached Dyna trap

Stark After 1 h, after collecting 25 ml of water, benzyl chloride (33 g, 260 mmol) was added and heating under reflux with stirring was continued for 16 h. The mixture was then cooled and fractionated between ethyl acetate (400 mL) and water (300 mL). The organic layer was washed with water (300 ml) and concentrated. The residue was purified by column chromatography on silica gel (120 96 EOAc/hexane) to give the methyl ether as an oil (22.0 g, 89 95 in triplicate). "H NMR (300 MHz, SOSI"): b 7.3 (t, 15H), 4.5-4.9 (t, 7H), 4.37 (t, 1H), 3.87 (y, 1H), 3.56 (t, 2H) , 3.52 (5, ZN), 1.40 (5, ZN).

From Psya and She Moi TU

Ye rlyasov "U za she o y Ku m Neo | Stu hu, inn dn non y ak dl b-- sni zttoic acid ya rych nt y vo y 5 oo ki tr ro she she rai zt cha yiv

3 M sulfuric acid (obtained by mixing 4.8 g of concentrated sulfuric acid with 24 ml of water) was added to a solution of 14 (22.0 g, 49.0 mmol) in acetic acid (110 ml) and stirred at 70 C for 8 h. The mixture was concentrated to a volume of approximately 20 ml and partitioned between ethyl acetate and ice-cold 2N. MaonN. The ethyl acetate layer was concentrated and purified by column chromatography on silica gel (35 95 EOAc/hexane), obtaining 1e as an oil (17.0 g, 80 9e). M5-457,2 (M--Ma").

Vp. to you

O.o8 00 RE SOS io More iy in to all SOU oso,

Don mesm, svch et

VaO OA 0 zvozslgodotbb BO 00 Ova cha y

Te (4.58 g, 10.6 mmol) was dissolved in MesM (7 mL) and the solution was transferred to a vessel for use in a microwave system. The vessel was filled with (carbethoxymethylene)utriphenylphosphorane (7.33 g, 21.2 mmol) and hermetically sealed in an Ar atmosphere. The mixture was subjected to microwave heating at 1807 for 1 hour. The solvent was removed in vacuo and the mixture was stirred with EbSO (50 mL) for 15 min.

The resulting solid was filtered, washed with Eb2O (3 x 10 ml) and the solvent was removed in vacuo. The mixture was processed by column chromatography on 120 g of 5i0" SotrShavza (0-30 95 gradient

EtOAc-thexane), yielding 11 (4.04 g, 76 95) as a mixture of isomers: clear oil; M5 (E5I) t/2 527

IM--Mach|.

V. Vo. full-time student of the National Academy of Sciences, National Academy of Sciences

M ZAZ sov x zybteono kov -TV Sl h- BV Movne

Bai Op howls 0 Ov

I; cha 17 (69.18 g, 137 mmol) in RyCH3 (540 mL) was cooled to -78 "C and treated with RIVAG-N (1.0 M in hexane, 151 mL, 151 mmol). The solution was stirred for 1 h, Meon (500 ml), and the solution was heated to room temperature. The mixture was filtered through celite, the solid particles were washed with EbO (3 x 100 ml). The solvent was removed in vacuo and the mixture was filtered through a large-pore glass filter. The mixture was subjected to column chromatography on 330 g of 5iO2

Sotria (0-30 95 gradient EtOAc-hexane), giving 19 (35.46 g, 56 95) as a mixture of isomers (data for both isomers): clear oil; "H NMR (SOCI3, 300 MHz) 9.76 (5, 1/2H), 9.73 (5, 1/2H), 7.26 (rg t, 15H), 4.86 (y, 9-11.1 Hz, 2H), 4.50 (t , 1ZN), 4.21 (t, ЗN), 3.88 (a, U-6.9 Hz, 1Н), 3.60 (t, 5Н), 2.75 (t,

2H), 2.50 (t, 2H), 1.36 (5, Z/2H), 1.19 (v, Z/2H).

VS, shi Sh VPO

Day of heating with reverse Donvnnia

You OvVa refrigerators Vp Vy

TV hours АЛЧЯ 19 (20.0 g, 43.4 mmol) in Mesm (200 mL) was treated with KgSO3 (24.0 g, 173 mmol) and AsgO (16.4 mL, 173 mmol) and the mixture was stirred under reflux for 16 h. The mixture was cooled and filtered through a large-pore glass filter, the solid particles were washed with Mesm (3 x 25 ml). The solvent was removed in vacuo, the mixture was resuspended in OSM (100 mL) and filtered through a medium-pore glass filter. The mixture was processed by column chromatography on 330 g of 5iO2

Solvent c (0-30 95 gradient EtOAc-thexane), obtaining 1P (10.3 g, 47 95) as a mixture of isomers (data for all isomers): clear oil; "H NMR (SOCI3, 300 MHz) 7.30 (Bbg t, 15H), 5.44 (t, 1H), 4.99 (Bg t, 1H), 4.60 (t, 7H), 4.21 (t, 1H), 3.72 (t, 1H), 3.62 (t, 1H), 2.11 (in, ZN), 2.03 (2, ZN), 1.31 (in, ZN), 1.26 (5, ZN); M5 (E5BI) t/2 501 (M - NO .

Vp VA. Ve and Podyh sede MV, But SN ih Z y--e KhoiOlo MVV, NO, OMBO Ho ikeno

Vk and Kt. hours 35 -ya-- vaO 0 ove VO 0 oVa yiv U 1p (12.6 g, 25.1 mmol) in OM5O (100 mL) was treated with HgO (904 μl, 50.2 mmol) and recrystallized MV5 (8.93 g, 50.2 mmol) and the mixture was stirred for 4 p.m. The mixture was treated with saturated MnHsCO3 (50 ml) and the EOAc solution (250 ml) was extracted. The organic layer was washed with HO (3 x 50 ml) and dried over Md5O5. The solvent was removed in vacuo and the mixture was subjected to column chromatography on 330 g of 50% SotbiShava (0-25 95 gradient EtOAc-thexane) to give 1 (4.53 g, 33 95) as a mixture of isomers (data for all isomers): yellow oil; "H NMR (SOSIiz, 300 MHz) 9.35 (y, 9-5.1 Hz, 1/2H), 9.33 (y, 9-6.0 Hz, 1/2H), 9.27 (5, 1H), 9.25 (5, 1H) .

Vp, B M. oyi, Ak em i . at. ar eq her ; ;

Mor sno shi VM VS SY v

I) and pnniizhiyazhnNny in p is M Me i yuSO RAS she

Wab o 0 ОВ heating from zvorotnyv U dnvsnnny refrigerator di da da -NOLV h 15 and | ZE 1 (4.5 g, 8.3 mmol) in RiCH3 (250 mL) was treated with 1) (1.6 g, 8.3 mmol; obtained according to the procedure found in U). Spent 5 persons, Regkip Tgap5. 1 1999, 2929-2936) and K2СО»z (1.4 g, 10 mmol) and stirred the mixture under reflux with water removal for 16 h.

The mixture was cooled and filtered through a medium-pore glass filter, the solid particles were washed with EOAc (3 x 10 ml). The solvent was removed in vacuo and the mixture was subjected to column chromatography on 120 g of 500% sodium chloride (0-40 95 gradient EIOAc-hexane), obtaining MK (1.0 g, 19 95) in the form of a mixture of isomers (data for the main p-isomer): pale yellow solid; "H NMR (SOSi", 300 MHz) 7.78 (5, 1H), 7.26 (Bg t, 15H), 5.71 (5, 1H), 4.74 (5, 2H), 4.59 (t, 4H), 4.35 (Bg t , 1H), 4.00 (a, 3-8.1 Gu, 1H), 3.83 (a, 9U-8.7 Hz, 1H), 3.66 (a, 9U-10.8 Hz, 1H), 2.63 (5, ЗН), 2.45 (5 , ZN), 1.05 (5, ZN); M5 (EBI) t/2 629 (MANI.

me shhn.

Mo ok Me sov u x "NYa kru u YO what s . I Va. Ve pla s M ;

TS. and Oxygen e vla, ne ba SM teme tt z a m teme tu 18 h, 74; on vyk OVO va 0 Vva as Ki.

ITC (1.0 g, 1.59 mmol) was treated with liquid Mn (20 ml) and the mixture was stirred at 80 "C for 16 h in a steel bomb. The mixture was cooled, Mn was removed, and the mixture was subjected to column chromatography on 120 g of 5iOg2 SotbyShava (0- 70 95 EIOAc-hexane gradient), yielding 11 (707 mg, 74 95) as a mixture of isomers (data for major BbB isomer): pale yellow solid; "H NMR (SOCI", 300 MHz) 7.81 (5, 1H), 7.26 (p t, 15H), 5.71 (5, 1H), 4.74 (5, 2H), 4.58 (t, AN), 4.40 (t, 1H), 4.06 (a, 9-7.2

Hz, 1TN), 3.83 (а, 9У-11.4 Hz, 1Н), 3.68 (y, 9-10.2 Hz, 1Н), 2.47 (5, ЗН), 1.18 (5, ЗН); M5 (E5I) t/: 598

IM-ANEI.

Alternative synthesis 11 (c) (c) issue rMzo issue S her AsO her restodd M

You Vp Vp You 1e 13

Anhydrous DMSO (6 mL) and anhydrous acetic anhydride (4 mL, 42.4 mmol) were added to a dry argon-purged round-bottom flask (100 mL). Then compound Te (1.0 g, 2.3 mmol) was added and the reaction mixture was allowed to stir at room temperature until the starting material completely disappeared.

After 5 p.m. the flask was placed in an ice bath and we were added. MansSoz (6 ml) to neutralize the reaction mixture. Then, the organic matter was extracted with EOAcS (3 x 10 ml) and the combined organic layers were dried with MoSO4. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography (hexane/EuAc). 955 mg (96 95) of the target substance 13. I S/M5-433.2 (M.N) were isolated. "H NMR (300 MHz, SOSI"): b 7.33 (t, 15H), 4.80 (y, 1H), 4.64 (t, 6H), 4.06 (a, 1H), 3.79 (ai, 1H), 3.64 (da , 1H), 1.54 (5, ЗН).

Me M ZZMe - X U ikh o X M o M

V ai uya MK Vy o mim - 7 V 7 vme ZMe - - iy y o o. ; oh oh

You Vp Vin You Vp

TNE

13 14

To the suspension of 7-bromo-2,4-bis-methylsulfanilimidazo|2,1-C(1,2,4|triazine (obtained according to

UMO2008116064, 600 mg, 2.06 mmol) in anhydrous THF (6 ml) was added dropwise to Vig and (1.6 M solution in hexane, 1.75 ml, 2.81 mmol) at -78 "C. After 5 min, the suspension became a red-brown solution, after to which 13 (810 mg, 1.87 mmol) in THF (0.6 mL) was added dropwise to the mixture. The mixture was then allowed to warm to room temperature. After 30 min, a saturated solution of MNACI was added to quench the reaction. The mixture was diluted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40 95 EtOAc/hexane) to give 14 as a mixture of isomers (0.77 g, 64 95).M5-645.2 (M.H).

ZMe M MN" - I zo

Vp, M. - Vp (c) M- he them: - 2 l o, o Vp Vp vyt? "Vp 14 15

MN» TEVIN, VEz-OEЬ mere

Vp, hom o Ge) M ZMe vaitU o you 1I

Compound 14 (2.0 g, 3.10 mmol) was transferred to a high-pressure steel reactor and cooled to -78 C. Liquid ammonia (720 mL) was collected at -78 "C and added to the reactor. The reactor was tightly closed, warmed to room temperature, and then heated at 50 "C for 20 hours. The reaction was brought to completion. After degassing, the residue was purified by column chromatography on silica gel (EuAcC/hexane), obtaining 15 as a pale yellow solid (1.78 g, 94 95). Boron trifluoride diethyl etherate (2.2 ml, 17.4 mmol) and triethylsilane (2.8 ml, 17.4 mmol) were added to the product in SNeSi" (15 ml) at -78 "C. Then the mixture was left to stir at 0-10 C for 3 h. Slowly saturated aqueous NaH2SO4 was added to quench the reaction, and then CH2Cl3 was added to dilute the mixture. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (450 96 EAs / hexane) to give 11 as a white solid (0.81 g, 47 95). "H NMR (300 MHz, SOSI"): b 7.67 (5, 1H), 7.20-7.45 (t, 15H), 5.77 (5, 1H), 4.80-4.92 (t, 2H ), 4.57-4.72 (t, 4H), 4.43 (a, U-7.8 Hz, 1H), 4.08 (a, 9U-8.7 Hz, 1H), 3.95 (j, 2-10.8

Hz, 1H), 3.74 (y, 9-10.8 Hz, 1H), 2.48 (5, ЗН), 1.16 (5, ЗН). M5-598.3 (MN).

Many

OK More

A em She Mat tn diai M i tovVA pn i CHI

BNO With Mo dme -- and io vh che "VO

M a POM. art., 24 hours i i I vn : Tu Ak vyb Ov Vo OBp 4 it 1I (707 mg, 1.18 mmol) in DCM (20 ml) was treated with tsRVA (460 mg, 2.66 mmol) and the mixture was stirred for 16 h. An additional amount of tsRBA (203 mg, 1.18 mmol) was added and the mixture was stirred for 8 h. The mixture was treated with a saturated solution of Mansoz (10 ml) and the solution was extracted

EUAs (250 ml). The organic layer was washed with saturated Mansoz solution (10 ml) and saline solution (10 ml) and dried over M95O05. The solvent was removed in vacuo and the mixture was subjected to column chromatography on 40 g 5iO2 SotriShawza (0-100 95 gradient EtAs-hexane) to give 1t (571 mg, 77 U) as a mixture of isomers (data for major p-isomer): white solid ; "H NMR (SOSiz, 300 MHz) 7.77 (5, 1H), 7.26 (Bg t, 15H), 5.61 (5, 1H), 4.59 (t, 6H), 4.35 (Bg t, 1H), 4.00 (a, 9U-7.2 Hz, 1H), 3.83 (a, 9-8.7 Hz, 1H), 3.70 (a, 9U-10.8 Hz, 1H), 3.06 (5, ЗН), 1.05 (5, ЗН); M5 (EI) t/7,630 MANI".

IVF Gy, S

Vp 5. "in a Me and | and from Vp. B "m and ta nin MeOH, kt. Zo already and hours 1.8 mmol) and the mixture was stirred for 1 h. An additional amount of MavNa (170 mg, 4.5 mmol) was added and the mixture was stirred for 2 h. An additional amount of MavNa (340 mg, 9.0 mmol) was added and the mixture was stirred for 2 h. 10 ml) and extracted with EIAs solution (100 ml). The organic layer was washed with saturated NaOH solution (10 ml) and brine (2 x 10 ml) and dried over NaOH. The solvent was removed in vacuo and the mixture was subjected to column chromatography on 40 g of 5% Tritd (0-100 95 gradient EIOAc-hexane) to give n (144 mg, 29 95) as a mixture of isomers (data for the major pB isomer): white solid; "H NMR (COsizv, 300

MHz) 8.08 (5, 1H), 7.87 (5, 1H), 7.26 (rg t, 15H), 5.63 (5, 1H), 4.76 (t, 2H), 4.62 (t, 6H), 4.36 (ri t, 1H), 4.00 (9, 9-7.2 Hz, 1H), 3.81 (t, 1H), 3.63 (t, 1H), 1.07 (5, ЗН); M5 (EB5I) t/2 552 MANI".

We are MM;

Marek still attended Mosh en uch in Am - VN. OM, ZV and MO, M SHI and 2 | 2 hours 3,055 pecks and kh bashes of 0 Ov on Bn

With 1 1Tp (144 mg, 0.26 mmol) in OSM (5.2 ml) was cooled to -78 "С, treated with VViz (1.0 M solution in

OSM, 1.3 ml, 1.3 mmol) and the mixture was stirred for 2 h. The mixture was treated with 4:11 MeOH-pyridine (500 μL) and the solution was warmed to room temperature. The solvent was removed in vacuo and the mixture was treated with concentrated MNAOH (2 ml) followed by removal of the solvent (x3). The mixture was treated with reversed-phase HPLC (0-95 95 gradient MesSmM-He2gO) to give 1 (21 mg, 30 95): white solid; "H NMR (020, 300 MHz) 7.85 (5, 1H), 7.45 (5, 1H), 5.26 (5, 1H), 3.82 (t, 2H), 3.78 (t, 1H), 3.68 (ad, 9U- 12.6, 4.5 Hz, 1H), 0.81 (5, ZN); M5 (EI) t/2 282 MANI".

Compound Z

M But meren no them on he with

МН» МН» megn mayor

Vp, x Mu Z Vp X Mu Z is) is) MO ZMe 1, MORVA, SNSI" o o M'MN" and 2. MNz / 0 o. 5 p

You" Vp vp U O. Vp 1I Za

MSRBA (610 mg, 2.72 mmol) was added to a solution of 11 (0.81 g, 1.36 mmol) in SNeoSi (7 ml) at 0 °C.

The mixture was stirred at 0 °C for 3 h. 1 M MgO 2 O in HgO (2 mL) was added to quench the reaction. After stirring at room temperature for 10 min, the organic layer was washed with saturated aqueous MgO 2 (10 mL x 2), brine, dried (Mag50") and concentrated in vacuo. The residue was transferred to a high-pressure steel reactor and cooled at -78 "С. Liquid ammonia (410 ml) was collected at -78 "C and added to the reactor. The reactor was tightly closed and heated to room temperature. Then the mixture was heated at 110 "C for 48 hours. The reaction continued until the end. The residue was purified by column chromatography on silica gel (100 95 EtOAc/hexane), obtaining Za as a white solid (0.63 g, 74 95). "H NMR (300 MHz, SOSI"): 6 7.55 (5, 1H), 7.20-7.45 (t, 15H), 5.65 (5, 1H), 4.50-4.82 (t, 6H), 4.38-4.42 (t, 1H), 4.05 (a, 9-7.8 Hz, 1H), 3.87 (a, 9U-9.9 Hz, 1H), 3.71 (a, 9U-8.4 Hz, 1H), 1.17 (5, ЗН). M5-567.3 ( MAN).

MN" MN"

Vp MM. 2 all x AZ x - Mu, 2

SNІІІІ vyt Ov no ОН

According to Z

To a solution of Za (61 mg, 0.11 mmol) in CHClCl (1 ml) at -78 °C was added boron trichloride (1 M solution in CHClCl, 1.5 ml, 1.5 mmol). The reaction mixture was stirred at -78 "C for 3 hours, then the reaction was quenched by adding pyridine/MeOnH (1:2, 14 ml). The mixture was then allowed to warm to room temperature. The mixture was concentrated to remove all solvents. The residue was then co-evaporated with Men (5 ml x 3), and then with 27 95 aqueous solution of MNEeSi (5 ml x 3). The crude material was purified by reversed-phase HPLC (MesSM-HgO gradient) to give Compound C as a white solid (16.8 mg). "H NMR (300 MHz, 020): b 7.31 (5, 1H), 5.20 (5, 1H), 3.82-3.88 (t, ЗН), 3.68-3.71 (t, 1Н), 0.89 (5, ЗН). M5-297.2 (MAN).

Compound 17 /

NM dk u

Swing

Vp M.M. 2 (c) in M m 1. memnN», TNE Me! and We can

Vp o MK - 565 5 5 42 o i (TON ZMe 2, tTEVIiN, VEZ-OEY s bo o o. you "Vp Vp" Vp 14 17a

To a solution of 14 (120 mg, 0.186 mmol) in THF (0.5 mL) was added methylamine (2 M in THF, 0.46 mL, 0.92 mmol). The hermetically closed reaction mixture was heated at 45"C for 15 min. The mixture was concentrated in a vacuum and then dried in a deep vacuum. To the crude product in

Boron trifluoride diethyl etherate (136 μl, 1.086 mmol) and triethylsilane (174 μl, 1.086 mmol) were added to SNeSi (1 ml) at -78 "C. Then the mixture was left to stir at 0-10 "C for 3 hours. A saturated aqueous solution of ManHsSOO was added slowly to quench the reaction, and then

SNeSig for diluting the mixture. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography on silica gel (50 95 EOAc / hexane) to give 17a as a white solid (74 mg, 67 95 ω 2 vvrv). "H NMR (300 MHz, SOSI"): b 7.83 (B, 1H), 7.63 (v, 1H), 7.20-7.45 (t, 15H), 5.76 (v, 1H), 4.80-4.92 (t, 2H) . 9U-11.1 Hz, 1H), 2.50 (5, ЗН), 1.15 (5,

ZN). M5-612.3 (M.N). /

NM Nm

Vp, X MU Z Vp, x my o o M ZMe Vapeu mi o is) s / EYUN --i

From p. 6. you are in Vp" Vp 17a 175

Raney nickel (500 mg) was added to compound 17a (180 mg, 0.29 mmol) in ethanol (10 mL), which was neutralized by washing with water. The mixture was then heated at 80 "C for 4 h. The catalyst was removed by filtration and washed with Meon (5 mL x 6). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (750 95 EOAc/hexane) to give 176 as a white solid (118 p g, 71 95). "H NMR (300 MHz, COzOb): 6 8.10 (5, 1H), 7.63 (5, 1H), 7.20-7.45 (t, 15H), 5.69 (5, 1H), 4.54-4.80 (t, 6H), 4.27-4.32 (t, 1H), 4.15 (y, 9-8.1 Hz, 1H), 3.84-3.89 (t, 1H), 3.70-3.76 (t, 1H), 3.11 ( in, ZN), 1.09 (5, ZN). M5-566.3 (M.--NU). nm nm gu mer

Vp, M MU 2 X y o-- 0 Y M ALL no- O de - СНСИЙ and / сх o. with 2 vp U Vy no on 175 17

Boron trichloride (1 M in

SNesig, 3.2 ml, 3.2 mmol). The reaction mixture was stirred at -78 "C for 3 h and then the reaction was quenched by adding pyridine/Men (1:2, 20 ml). The mixture was then allowed to warm to room temperature. The mixture was concentrated to remove all solvents. The residue was then co-evaporated with Men (10 mL x 3) and then with 27,956 MNACI aqueous solution (10 mL x 3).The crude product was purified by PF-HPLC (MesmMm-NgO gradient) to give Compound 17 as a white solid (45 mg, 74 Fo) . "H NMR (300 MHz, COzO0): b 8.11 (5, 1H), 7.62 (5, 1H), 5.44 (5, 1H), 3.90-4.00 (t,

ZN), 3.73-3.84 (t, 1H), 3.13 (5, ZN), 1.00 (5, ZN). M5-296.1 (M.N).

Compound 4

Mn" o kv OYI nn

NO-aya 2 kt, so that NO -e- Ж -M nev yet. 54 M MN; -- i -k ve and pl. and adenosine deaminase in-and-e but he is not him

K

A solution of C (220 mg) in approximately 1000 mL of water was treated with bovine spleen adenosine deaminase type IX (0.125 units/mL, Zidt) at 37 °C for 4 hours. The mixture was concentrated and the residue was purified by HPLC to give Compound 4 (152 mg) . "H NMR (300 MHz, 020): b 7.34 (5, 1H), 5.21 (5, 1H), 3.82-3.87 (t, ЗН), 3.70 (0, 1Н), 0.93 (5, ЗН) , 1.00 (5, ZN). M5-298.1 (MaASU).

Compound 5 - 5 U ia o che Ya ke m can oxalin chloride, ray Be y. with Re SI o SHK OME fa a i yno me her reee I SNO", o x chrya SHK dk pak t, E Z

B her

OMA M ev | And what is the renown: Nom Star and Mn o and Mn OsssteessttttttttttttttttttThteteeesesssessssssssstttttttttttttttttttttttttttttttt.

TE p she in: 7 x a I sh- Na rya iy Ki nni

Oxalyl chloride (275 μl) was added dropwise to a solution of 5a (1.27 g, 2.32 mmol), obtained according to the methods similar to those described in the paper Sottipisaiop5, 1992, 2815) in dichloromethane (30 ml) at 0 "С, followed by the addition of C drops DMF. The mixture was allowed to stir at room temperature for 1.5 h. The solvents were removed in vacuo. The residue was evaporated with toluene. The crude product 56 was dissolved in anhydrous THF (43 mL) and added dropwise to a cooled (0-57) solution of 5c in water (4.3 mL) containing potassium hydroxide (278 mg, 4.2 mmol) for 30 min with stirring. Chloroform was added to extract the mixture. The organic layer was concentrated in vacuo. The residue was purified by FT-HPLC (acetonitrile/water) to give 54 (0.41 g , 34 95) in the form of a white solid substance. М5-671.5 (М.Н). ne" pd shn also: yo m, NK trosom mayu" Be shhAMA ethylene glycol, m gu "se o: НВЧ zda s.: Czech Republic

She is also in C 5

Me and the sword, I'm still Be

A solution of 5a (200 mg, 0.30 mmol) in ethylene glycol (5.5 ml) in a hermetically closed vessel for use in a microwave system was subjected to microwave heating at 200 "C for 2.5 h. The mixture was diluted with MEn and purified by HPLC (acetonitrile/water), yielding 5e (80 mg, 41 95) as a white solid. MMA (300 MHz, COzO0): b 7.95 (y, 9-7.8 Hz, 2H), 7.92 (a, 9-7.8 Hz, 2H), 7.79 ( a, U-8.1

Hz, 2H), 7.26 (y, 9-7.8 Hz, 2H), 7.21 (a, 9U-8.1 Hz, 2H), 7.14 (a, 90-7.5 Hz, 2H), 6.01 (5, 1H), 5.97 ( a, U-4.8

Gu, 1), 4.72-4.84 (t, 2H), 4.60-4.68 (t, 1H), 2.40 (5, ZN), 2.37 (v5, ZN), 2.36 (5, ZN), 1.74 (5, ZN) .

M5-653.5 (M--NU). c) c) fo Ko

M YAM NM - M

NOM M sh!

M M y pn c) F) MaOMe --- Yu no o

IF) : and IF) meon oo M8- no on

Be

To a solution of 5e (80 mg, 0.12 mmol) in anhydrous methanol (4 mL) was added a 1 M solution of sodium methylate in methanol (150 μL) and stirred for 18 h. at room temperature. Added 1.0 n. aqueous HCl solution, bringing the pH to 7. The mixture was purified by HPLC (acetonitrile/water) to give 5 (30 mg, 84 95) as a white solid. "H NMR (300 MHz, COzOb): b 5.28 (5, 1H), 3.9-4.0 (t, 2H), 3.86 (a, U-8.7H, 1H), 3.72-3.78 (t, 1H), 0.93 ( 5, ZN). M5-299.0 (M.--NU).

Compound 6 o shi u a t

Y V she ZY and Y OO p flow not and tm. MA in | in rya and dig t REY

L and I g and Um and I MI ts u and also Me

I VM oman b, un iy shchen On o pet - I j -i 5 i Khshchi. heating with Zhi

MULTIPLY x by the inverse Y 77 ba shk xZOlodylnykOoM

5e (220 mg, 0.34 mmol) and anhydrous dioxane (20 mL) were added to a dry argon-purged round-bottom flask (100 mL). Rob5 (200 mg, 0.44 mmol) and OMAR (28 mg, 0.23 mmol) were then added, and the reaction mixture was heated under reflux for 25 min. Another portion of P2b5 (200 mg, 0.44 mmol) was added and the reaction mixture was heated under reflux for an additional 45 min. Then the reaction mixture was cooled to room temperature and poured into the flask

Erlenmeyer flask containing ice water (10 ml). The organic matter was extracted with chloroform after saturating the aqueous Masi solution. The combined organic layers were dried using Mdzboch and the solvent was removed under reduced pressure. The crude substance was purified by flash chromatography (Hexane/EIUAs). 200 mg (88 95) of the desired material was isolated. And S/M5-669.2 (MN). "H NMR (300

MHz, SOSIz): b 7.99 (t, 2H), 7.89 (t, 4H), 7.19 (t, 2H), 7.16 (I, 4H), 6.31 (5, 1H), 5.11 (t, 1H), 4.92 ( t, 1H), 4.76 (t, 2H), 2.45 (5, ЗН), 2.40 (5, ЗН), 2.37 (5, ЗН), 2.01 (5, 2Н), 1.74 (в, ЗН). o) ih o MN sleep purely M - M-- opy yk o) m О0 : 7 shФ 0 sh her MN» man her MN» oo - with oo

OM ba bb

Ba (200 mg, 0.30 mmol), anhydrous

DMF (4 mL) and anhydrous SNessig (4 mL). Then Man (20 mg, 0.50 mmol, 60 95 in mineral oil) was added and the heterogeneous mixture was stirred at room temperature for 30 min. It was added to the flask

Me! (60 mg, 0.42 mmol) and continued to stir the reaction mixture at room temperature for 2 h. The flask was then placed in an ice bath and the pH was adjusted to 5 using 1M NOSI.

The organic substances were extracted with EtOAc and the combined layers were dried with Ma5O. The solvent was removed under reduced pressure and the crude material was purified using Rgeragaphog sisop

NRHS zu«et (acetonitrile/water). 150 mg (74 95) of the desired material 6B was isolated. GS/M5-683.2 (MN).

NMR (300 MHz, SOSI): b 7.99 (t, 2H), 7.89 (t, 4H), 7.19 (t, 2H), 7.16 (i, 4H), 6.31 (5, 1H), 5.13 ( t, 1Н), 4.92 (t, 1Н), 4.76 (t, 2Н), 2.69 (5, ЗН), 2.44 (в, ЗН), 2.40 (5, ЗН), 2.37 (5, ЗН), 2.01 (в , 2H), 1.74 (in,

ZN). -M Z- -- o M x (in) m Z

H o. A B; " at 0's (c) in M o M M

M- M- and 500 Mn evoomo o: -yu oo z» oo

TNE would be

65 (225 mg, 0.33 mmol) and anhydrous

THF (21 ml). Then tert-butyl nitrite (0.30 ml, 2.32 mmol) was added and the flask was placed in a heated oil bath at 50 "C. After 2.5 h of stirring, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Then the flask was placed overnight in a deep vacuum and the crude material was purified with the help of hyssop Rgeragagu NRIS zu«et (acetonitrile/water). 190 mg (86 95) of the desired material was obtained bs. I S/M5-668.2 (MAN). "H NMR (300 MHz, SOS") : b 7.99 (t, ZH), 7.89 (t, 4H), 7.19 (t, 2H), 7.16 (i, 4H), 6.31 (5, 1H), 5.13 (t, 1H), 4.92 (t, 1H) , 4.76 (t, 2H), 2.69 (v, ZN), 2.44 (5, ZN), 2.40 (5, ZN), 2.37 (5, ZN), 1.76 (5, ZN). - mmM MN» o KO o already 9: 7 MN LO M-/ oo - - -» goi no on bs 6

BS (190 mg, 0.28 mmol) was added to a dry Parr bomb vessel purged with argon. Then added

MNase/mMeon (60 ml, 7M solution) and the bomb was placed in a heated oil bath at 80 "C. After 18 h, the bomb was cooled to room temperature and the solvent was removed under reduced pressure. The crude material was purified using bisop Rgeragaig NRI C z5uziet (acetonitrile /water), yielding 56 mg (70 95) of the desired product 6. I! С/М5-283.1 (МН). "H NMR (300 MHz, 020): b 8.09 (5, 1Н), 5.54 (5, 1Н) , 4.19 (t, 1H), 4.11 (t, 1H), 3.99 (t, 1H), 3.85 (t, 1H), 1.01 (v, ЗН).

Compound 7

(c) (c) (6) - (6) b o o o

NA mn and Nei Mn, t

TEA, OME (6) (c) (c) (c) -- M. 2

Fo yuyu M7OMN oo 7s

To a suspended mixture of 7a (1.7 g, 2.64 mmol) and 76 (0.516 g, 2.91 mmol, obtained according to the procedures described in .).Neiegosus.Spet, 1984, 21, 697) in DMF (10 mL) was added TEA (0.365 g, 3.61 mmol). The resulting mixture was stirred at room temperature for 1 hour, then for an additional 1 hour. at 45"C. The reaction mixture was diluted with ethyl acetate and washed with water.

The organic phase was dried over Ma5O5, filtered and concentrated. The precipitate was purified by chromatography on silica gel using 15,905 g of methanol-ethyl acetate as an eluent to give compound 7c (0.45 g, 26 g) as a colorless solid. M5-670.0 (Man). (c) (c) (c) (c) (c) and | MN

Od g: tyu My oo

ROSIv 7s СНІСІСІНСЯ vo es o chu y

M--

OZ ::: HyuYu still bo 2 7a

ROS (0.56 g, 3.6 mmol) was added to a suspension of 7c (0.45 g, 0.67 mmol) in 1,2-dichloroethane (50 mL).

The reaction mixture was stirred at 82"C for 8 h. After cooling to room temperature, the reaction mixture was treated with NaHCO3 (5 g) and water (0.5 mL) for 3 h and concentrated. The residue was fractionated between ethyl acetate and water. The organic phase was separated, dried over Mu9B2O», filtered and concentrated. The residue was purified by silica gel chromatography using ethyl acetate as eluent to give compound 84 (0.26 g, 59 95). H NMR (300 MHz, OM50O-av): b 11.0 (5 1H) , 7.95 (y, 9-7.68 Hz, 2H), 7.85 (t, 4H), 7.77 (5, 1H), 7.36 (a, 9U-7.8 Gu,

2H), 7.27 (t, 4H), 6.33 (5, 2H), 6.20 (a, 9U-6.9 Hz, 1H), 6.11 (5, 1H), 4.6 (t, ЗН), 2.40 (5, ЗН), 2.37 (5, ZN), 2.35 (5, ZN), 1.62 (5, ZN). M5-652.1 (M-NU). at 7 ooo SHT 7

M maОMe o) (c) EN (c) МНно--- -TF) M МН bo 2 and / M-

Meon-tTNE Her 2 MN but he? 7a 7

To a solution of 7a (0.26 g, 0.399 mmol) in Meon (10 ml) and THF (10 ml) at 0 °C was added MaOMe (0.1 ml, 4.3 M). The resulting mixture was stirred at 0 °C for 0.5 h. , and then at room temperature for 2 h. The reaction mixture was cooled to 0 "C, neutralized with HCIII (1 ml, 0.5 N), treated with Mansoz (0.1 g) and then concentrated. The residue was purified by C-18 HPLC, obtaining compound 7 (0.1 g, 84 95). "H NMR (300 MHz, 020): b 7.63 (5, 1H), 5.31 (5, 1H), 3.70-3.95 (t, 4H), 0.88 (5, ЗН).

M5-298.0 (M--NU).

Compound 11 is chva so; i ze, p

AND! i Y M 5-Y

More ЭЙ 2 1 Ки ия и d Е Й.

І V o ke ru MM Rok і VI shi І s і ше ші шхіх Mne Omav ba MN»

IN; іya OO, schi 2 x OO g Z duksan more: 2» che hunnnn y E: i Hshn t ta tu, heating with rya yah and " reverse 7th refrigerator

74 (40 mg, 0.067 mmol) and anhydrous dioxane (4 mL) were added to a dry argon-purged round-bottom flask (50 mL). Then P255 (68.2 mg, 0.15 mmol) and OMAR (6.1 mg, 0.05 mmol) were added, and the reaction mixture was heated under reflux to a gentle boil for 25 min. Another portion of Rob (50 mg) was added and the reaction mixture was heated at reflux for an additional 45 min. The reaction mixture was then cooled to room temperature and poured into an Erlenmeyer flask containing ice water (3.0 mL). The organic matter was extracted with chloroform after saturating the aqueous Masi solution. The combined organic layers were dried with Mdb5O.4 and the solvent was removed under reduced pressure. The crude material (20 mg) was used as is for the next transformation. And S/M5-668.2 (MAN). 2 7 HER IN HIM o o M MN o o M M

M- CH M- o 5 Mn, man a Mn oo - - 55 oo

OME and 11

Thioketone adduct 11a (20 mg, 0.03 mmol), anhydrous DMF (0.25 mL), and anhydrous SNCl (0.25 mL) were added to a dry argon-purged round-bottom flask (5 mL). Then Man (1.4 mg, 0.035 mmol, 60 95 in mineral oil) was added and the heterogeneous mixture was stirred at room temperature for a min. Mei (4.69 mg, 0.033 mmol) was added to the flask and the reaction mixture was stirred at room temperature for 2 h. Then the flask was placed in an ice bath and the pH was adjusted to 5 with 1M HCl. The solvent was removed under reduced pressure and the crude product 116 (10 mg) was used as is for the next transformation. And S/M5-682.2 (MN).

І le І U ih o o M M o o M Me

M- M- y 5 Mnevoomo a Yy o Ge) 2 1-Vy o o ---

TNE

11h 11s

Methyl sulfide adduct 1156 (10 mg, 0.0147 mmol) and anhydrous THF (1 mL) were added to a dry argon-purged round-bottom flask (5 mol). Then tert-butyl nitrite (0.012 mL, 0.10 mmol) was added and the flask was placed in a heated oil bath at 50°C. After 3 h of stirring, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Then the flask was placed overnight in deep vacuum and used 11c (10 mg) as crude material as it is for the next reaction.GS/M5-667.2 (M'iNU).

І In them

О0:7 ,yu MNz no M M bo poloyu hi M

BUT he is 11s 11

Into a dry, argon-purged Parr bomb vessel was added crude reduced methyl sulfide adduct 11c (30 mg, 0.107 mmol). Then, Mn/Meon (5 ml, 7M solution) was added and the bomb was placed in a heated oil bath at 80 °C. After 18 h, the bomb was cooled to room temperature and the solvent was removed under reduced pressure. acetonitrile/water), yielding 2 mg (50 95) of the desired product 11.

And S/m5-282.1 (M--NU). "H NMR (300 MHz, 020): b 7.99 (5, 1H), 7.34 (5, 1H), 5.45 (5, 1H), 4.01 (5, 1H), 3.90 (t, 1H), 3.79 (t, 1H), 3.69 (t, 1H), 0.91 (5, ЗН).

Phosphate prodrugs

Non-limiting examples of phosphate prodrugs within the scope of the present invention can be obtained according to general Scheme 1.

Scheme 1

And oh in Ayu-R-O

About 2 m - 3-35 MN

I U, d y (c) 2a 26 2s vo ve h! oh - at 2

KA U Ag. r, Kh mat no M. -Y o / To o M. -

C 1 and C 1 in iii in «uro c - B vv b vv 2a 2e

The general procedure involves the reaction of an amino acid ester salt 2B, e.g., an HC salt, with an aryl dichlorophosphate 2a in the presence of about two to ten equivalents of a suitable base to give the phosphoramidate 2c. Suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and OMAR, tertiary amines such as triethylamine and SAVCO, and substituted amidines such as OVM and OBO. Tertiary amines are especially preferred. Preferably, the product from each step is used directly in subsequent steps without recrystallization or chromatography.

Specific non-limiting examples 2a, 25 and 2c can be found in MO 2006/121820, the contents of which are fully incorporated herein by reference. Nucleoside base 24 reacts with phosphoramidate 2c in the presence of a suitable base. Suitable bases include, but are not limited to, imidazoles, pyridines, such as lutidine and OMAR, tertiary amines, such as triethylamine and SAVSO, and substituted amidines, such as OVM and OBO. Product 2e can be isolated by recrystallization and/or chromatography.

Additional examples of types of phosphate prodrugs are described in U. May. Spent 2007, 50(16) 3891-96, fully incorporated herein by reference.

Compound 8 et, o o I Ma ; ; ny x borders V VN r Y I and Zh

Where is IN m

EE Oh MN. on the UN 5 t - y. i EK kish, s z ad / ee o i ZA melon and ba ; GK still sih Va

T-methypimidazole HAC, yut.

With more ; more

From Na ve

Li" and kashe and Me in Odesa B

Х What is he?

I am

Compound 7 was treated with chlorinated phosphorus-containing compound 8a (obtained according to Mesiidap eii ai, u). Honey. Spent 1993, 36, 1048-1052), according to the general protocol, using 1-methylimidazole as a base and obtaining compound 8 (20 mg, 50 95 yield). "H NMR (300 MHz, COzOb): b 7.61 (5, 1H), 7.20-7.32 (t, 4H), 5.47 (5, 1H), 4.9 (t, 1H), 4.5 (t, 2H), 4.18 ( riv, 2H), 3.9 (t, 1H), 1.3 (t, ЗН), 1.15 (t, 6Н), 0.99 (riv, ЗН). Z'R MME (300 MHz, СозОб): 4.04, 4.09. M5- 601.0 (M.N).

Compound 9 x and i i i i i i i

N forces of zones that Me mash ai schu no san Mn; в я с ши т 5 ше : E uch sne, y і

Kt and ek and what am I

T-methypimidazole TNE; t.: on an I

SV o to Shk sha i what Dy a 3 sny i in I. "a ey Hv i M ko y

Compound 5 was treated with the phosphorus-containing chlorinated compound 8a (prepared according to Mespidap et al., U. Mei. Spec. 1993, 36, 1048-1052) according to the general protocol using 1-

methylimidazole as a base and obtaining compound 9. "H NMR (300 MHz, CO3Ob): b 7.14-7.27 (t, AN), 5.37 (5, 1H), 4.9 (t, 1H), 4.5 (t, 2H), 4.20 (riv, 2H), 3.9 (t, 1H), 1.3 (t, ZN), 1.14 (t, 6H), 1.02 (riv, ZN). UR MMA (300 MHz, SOzO0): 4.00, 4.06; "EE MMA (СозО0, 282 MHz) -78 (5, ZE); M5-601.9 (M.--NU).

Compound 12 si Kaya y i y x z tone a would sne in -ch ma MA

Tmethylimidalol, MKU KO

Zo ro -

Y YAN IM 00 Mshchn.

A Shi in v and M, cancer

J y J « Ke m o it: i | Msh and sem le and what 2

Compound 12 was obtained according to the procedure described for the preparation of compounds 8 and 9. "H NMR (300

MHz, COzO0): b 8.08 (25, 1Н), 7.1-7.4 (t, 4Н), 5.58 (5, 1Н), 4.75 (t, 1Н, overlay on the solvent peak), 4.5 (t, 1Н), 4.45 ( t, 1H), 4.25 (t, 2H), 3.85 (t, 1H), 1.3 (t, ЗН), 1.2 (t, 6Н), 1.02 (riv, ЗН). UR NMR (300

MHz, 0300): 3.91, 4.02; M5-586.3 (MAN).

Compound 16

I hate AJ o) but e) M MN". in

By

EE 1 O-v-k

From c) 1H-tetrazole, O-P(OSH»Z)z 2. 3095 NhO»

MNo rya o June -XX and ho

St. o- 5 Z, c) no on (o);

To a solution of Compound C (13 mg, 0.044 mmol) in trimethyl phosphate (0.4 ml) was added 1 1H-tetrazole (9.5 mg, 0.132 mmol) Kk! by the subsequent addition of 2,2-dimethylthiopropionic acid c-(2-Idiisopropylamino-(2-(2,2-dimethylpropionylsulfonyl)-ethoxy|-phosphanyloxy)-ethyl) ester (40 mg, 0.088 mmol) at 0 "C. After stirring 30 95 hydrogen peroxide in H2O (60 µL) was added to the mixture over 2 h. The mixture was then allowed to warm to room temperature. After stirring for 1 min, 1 M Mag52Oz in H2O (2 mL) was added to quench the reaction. The organic layer was washed with sat. aq. MgSO3 (10 mL x 2) and brine and concentrated in vacuo. The residue was purified by PF-HPLC (MesSMm-NegO gradient) to give Compound 16 as a white solid (6 mg). "H NMR (300 MHz, SOSI") : b 7.45 (5, 1H), 5.29 (5, 1H), 4.40-4.50 (t, 1H), 4.28-4.40 (t, 1H), 4.10-4.25 (t, 6H), 3.14-3.21 (t, 4H ), 1.237 (5, 9H), 1.227 (in, 9H), 1.06 (5, ЗН); "P MMA (121.4 MHz, SOSIv): 6 -1.322. M5-665.0 (MAN).

Compound 18 is prepared with VTBA, acetone, ! set kechshne Heating with reverse

He has a refrigerator

It is now

Noya " Ku ya

She / she o and x

ET Otto no oon u y Zh 47 na still sho t

I t:

NC

1btetrazal SRM

And mon V ro

ZI MSRVA, SNYS o eko ru M outvs tFfu in NO h orky and tr ne on St 18

To a solution of 17 (12 mg, 0.04 mmol) in acetone (0.5 mL) and DMF (0.1 mL) was added trimethyl orthoformate (36 μL, 0.32 mmol) and p-toluenesulfonic acid monohydrate (8 mg, 0.04 mmol).

The mixture was heated under reflux for 1 hour. 28 95 was added to neutralize the mixture

MNAOH and concentrated the mixture to dryness. The product was isolated using a short layer of silica gel (10 95 MeOH in SneoSi»2). The white solid was dissolved in CH3CM (0.4 ml), 1H-tetrazole was added, followed by the addition of 5-(2-diisopropylamino-(2-(2,2-dimethylpropionylsulfonyl)-ethoxy|-phosphanyloxy)-ethyl) ether 2, of 2-dimethylthiopropionic acid (41 mg, 0.09 mmol) in CH3Cl (0.2 ml) at 0 °C. After stirring for 40 min, the mixture was cooled to -40 °C. It was added to the mixture

MSRPVA (40 mg, 0.09 mmol) in SNeSi". The mixture was then allowed to warm to room temperature.

After 10 min of stirring, 1 M Mag52Oz in HO (2 mL) was added to quench the reaction. The organic layer was washed with a saturated aqueous solution of MagSoOz (10 ml x 2) and brine and concentrated in vacuo. The residue was purified by HPLC (MesSM-NegO gradient) to give the bound product as a white solid. The solid was dissolved in cooled 75 95 TFO in NgO. The mixture was left to stir at 0-10"C for 3 hours. The resulting mixture was diluted with EtOAc, washed with a saturated solution of ManNsoz and concentrated in vacuo. The residue was purified by PF-HPLC (gradient MeS M--

Ngo), giving Compound 18 as a white solid (12 mg, 44 95 in step 4). "H NMR (300

MHz, SOSI"): 6 8.17 (5, 1H), 7.52 (5, 1H), 7.24 (B, 1H), 5.38 (5, 1H), 4.57 (B, 1H), 4.34-4.45 (t, 2H) . 4H), 1.234 (5, 6H), 1.230 (5, 6H), 1.227 (5, 6H), 1.03 (5, ЗН); Ur. MMK (121.4 MHz, SOS): 6 -1.347. M5-664.0 (M.--NU).

Compound 20

Y I) ra Eh // WE MN o NM-R-o Ge) X M, - o Mn,

With c

Approximately 3.1 mmol of phenylmethoxyalanyl phosphorochloridate (prepared according to

U. Med. Spent 1993, 36, 1048-1052) in about 3 ml of THF, about 0.5 mmol was added to the mixture

Compound 4 and about 3.8 mmol of M-methylimidazole in about 3 mL of THF. The reaction mixture was stirred for about 24 and the solvent was removed under reduced pressure. The residue was purified by reversed-phase HPLC to give Compound 20.

Compound 21 va (c)

M MN

H 2

To ra | Z X /» o M M oo M-/ y) no he

SI

21

Approximately 3.1 mmol of 2-propyloxyalanyl phosphorochloridate (obtained according to Mesiidap eyi ai, U.

Honey. Spent 1993, 36, 1048-1052) in about 3 ml of THF, about 0.5 mmol was added to the mixture

Compound 1 and about 3.8 mmol of M-methylimidazole in about 3 mL of THF. The reaction was stirred for about 24 and the solvent was removed under reduced pressure. The residue was purified by reverse-phase HPLC to give Compound 21.

Compound 22

MN"

Ka

M no-h o. L-M, -

Itya r-4 22

A mixture of about 0.52 mmol of Compound 1 and about 12 mL of dry acetone, about 0.7 mL of 2,2-dimethoxypropane, and about 1.28 mmol of di-p-nitrophenylphosphoric acid was stirred for about 24 hours to about seven days. The reaction mixture was neutralized with approximately 20 ml of 0.1 N. ManHsSoO»z and evaporated acetone. The desired material was fractionated in chloroform, the chloroform solution was dried and the solvent was evaporated. Compound 22 was isolated from the residue by conventional means.

Compound 23

MN"

Main o'clock

LISH: but yu X M o- M, -

S o o me

Kk

A solution of about 0.53 mmol of Compound 22 in about 5 mL of DMF was treated with about 1 mL of a 1 M solution of tert-butylmagnesium chloride in THF. After a period of time from about 30 min to about 5 hours, a solution of about 0.65 mmol of trans-4-(5)-pyridin-4-yl|-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinane was added (Keaadu, Teigapedgop Geyeg5 2005, 4321-4324) and stirred the reaction for about one to about 24 hours. The solution was concentrated in vacuo and the residue was purified by chromatography to give Compound 23.

Compound 24

MN"

Men (in) zach / x S Po) X M o- g, M.

In, o me no he 24

A solution of about 7095 aqueous trifluoroacetic acid was cooled to 0 °C and treated with about 0.32 mmol of Compound 23 for about one to 24 hours. The solution was concentrated and the residue was purified by chromatography to give Compound 24.

Compound 25

MN"

M

7 tr 7 in Х O M M o- o) M,

Friends (6)

A solution of about 1.56 mmol of Compound 24 in about 15 mL of THF was treated with about 4.32 mmol of CO. After about one to about 24 hours, the solvent was evaporated and the residue was purified by chromatography to give Compound 25.

Compound 26 - OO

M MN

H 2

To about | -Hoo lo o M M c) M-/

M) but he

SI

26

Approximately 3.1 mmol of 4-chlorophenyl 2-ethoxyalanyl phosphorochloridate (obtained according to

Mesicidap eyi a), U. Med. Spent 1993, 36, 1048-1052) in about 3 ml of THF was added to a mixture of about 0.5 mmol of Compound 1 and about 3.8 mmol of M-methylimidazole in about 3 ml of TG/F.

The reaction mixture was stirred for about 24 hours and the solvent was removed under reduced pressure. The residue was purified by reversed-phase HPLC to give Compound 26.

Compound 27

MN" r

In: x. | oh me

Yu go u « t o) men (in) 27

A solution of Compound 26 in UM5BO was treated with approximately 3 mole equivalents of potassium i-butoxide for approximately 15 min to 24 h. The reaction was quenched with 1 n. NSI and isolated Compound 27 by reversed-phase HPLC.

Compound 28

MN» o pu no-R-o Ge) M. -i on M no on 28

A mixture of about 0.05 mmol of Compound 1 and about 0.5 mL of trimethyl phosphate was sealed in a container for about one to about 48 hours. The mixture was cooled to a temperature of about -10 to about 10°C and about 0.075 mmol of phosphorus chloride was added. After about one to about 24 hours, the reaction was quenched with about 0.5 mL of 1 M tetraethylammonium bicarbonate and the target fraction was isolated by anion exchange chromatography.

Then the desired fractions were desalted by reversed-phase chromatography, obtaining Compound 28.

Compound 29 c) МН» оо и те

SCHI M ti o- --i z-o-4 but he (in) 23

Compound 28 (approximately 1.19 mmol) was dried over phosphorus pentoxide under vacuum overnight. The dried material was suspended in about 4 mL of anhydrous DMF and about 4.92 mmol

BIREA. About 7.34 mmol of isopropylchloromethylcarbonate (Apiimigai Spetivtsgu 85

SpetoiPegaru 8:557 (1997)) and heated the mixture to about 25-60°C for about 30 min to about 24 hours. The heating was stopped for about one to about 48 hours and the reaction mixture was filtered. The filtrate was diluted with water, Compound 29 fractionated in SNES", the organic solution was dried and evaporated, and the residue was purified by reversed-phase HPLC, isolating

Compound 29.

Compound 30

MN" r

A: (c) h- me bo 1. no-v-b. UN c) zo

Compound 30 was prepared by treating Compound 28 with about 1-5 equivalents of OSS in pyridine and heating the reaction mixture under reflux for about one to about 24 hours. Compound 30 was isolated using traditional ion-exchange HPLC and reversed-phase HPLC.

Compound 31

MN" er hmm

M

0-5 9) X she: her o---0w he c)

WITH

A solution of approximately 0.4 mmol of Compound 30 in approximately 10 mL of DMF was treated with approximately 0.8 mmol

BIREA and approximately 0.8 mmol of chloromethylisopropyl carbonate (M/02007/027248). The reaction mixture was heated from about 25 to about 80 °C for about 15 min to about 24 hours.

The solvent was removed in vacuo and the residue was purified by HPLC to give Compound 31.

Compound 34

MNOMT of my no. She and d o m mnoMtt ni on 34

Compound C (approximately 0.22 mmol) was dissolved in anhydrous pyridine (approximately 2 mL) and chlorotrimethylsilane (approximately 0.17 mL) was added. The mixture was stirred at about 0 to about 25°C for about one to about 24 hours. An additional amount of chlorotrimethylsilane (about 0.1 mL) was added and the reaction mixture was stirred for about one to about 24 hours. 4,4'- dimethoxytrityl chloride (about 0.66 mmol) and OMAR (about 0.11 to about 0.22 mmol). The mixture was stirred for about one to about 24 hours. A solution of TVAE (1.0 M, about 0.22 mL) in TI was added and the reaction was stirred for about one to about 24 hours. The mixture was fractionated between ethyl acetate and water. The ethyl acetate layer was dried and concentrated. The residue was purified by chromatography to give Compound 34, which may be a mixture of mono- and ditritylated compounds.

Compound 35

Not) MNOMTt -o8 and o Oo-R-o0 X M

And oh MAX

N MNOMTtg but he

A mixture of approximately 1.25 mmol of Compound 34 and approximately 1.9 mmol of triethylammonium 2-(2,2-dimethyl-3-(trityloxy)upropanoylthiodethylphosphonate (ММО2008082601) was dissolved in anhydrous pyridine (approximately 19 mL). Trimethylacetic acid chloride (approximately 2.5 mmol) at a temperature from about -30 to about 0 "C and the solution was stirred for about 30 min to about 24 hours. The reaction mixture was diluted with methylene chloride and neutralized with aqueous ammonium chloride (about 0.5 M). The methylene chloride phase was evaporated, the residue was dried and purified by chromatography to give Compound 35, which may be a mixture of mono- and ditritylated compounds.

Compound 36

Not) MNOMTt in Go a o o-R-o In m

And oh meh

MN MNOMtt

Z no On 36

Benzylamine (approximately 2.45 mmol) was added dropwise to a solution of approximately 0.49 mmol of Compound 35 in anhydrous carbon tetrachloride (approximately 5 mL). The reaction mixture was stirred for about one to about 24 hours. The solvent was evaporated and the residue was purified by chromatography to give Compound 36, which may be a mixture of mono- and ditritylated compounds.

Compound 37

Sha MN

Man

M IF) 5 o o-R-o Ge) in M. A

MN MOm, 7 no on 37

A solution of about 2 mmol of Compound 36 in methylene chloride (about 10 mL) was treated with an aqueous solution of trifluoroacetic acid (90 95, about 10 mL). The reaction mixture was stirred at about 25 to about 60°C for about one to about 24 hours. The reaction mixture was diluted with ethanol, the volatiles were evaporated, and the residue was purified by chromatography to give Compound 37.

Compound 38. MN" -X PO X M o M

S ve 38

About 90 mM of Compound 1 in THF was cooled to about -78 °C and about 2.2 to about 4.4 equivalents of tert-butylmagnesium chloride (about 1 M in THF) was added. The mixture was heated to about 0 °C for about 30 min and cooled again to about -78 "С. A solution of (25)-2-Chloro(1-phenoxy)phosphoryliamino)propyl pivaloate (M/O2008085508) (1 M in

TIF, about 2 equivalents). Cooling was stopped and the reaction mixture was stirred for about one to about 24 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate.

The extracts were dried and evaporated, the residue was purified by chromatography to give Compound 38.

Triphosphates of nucleosides

Non-limiting examples of nucleoside triphosphates within the scope of the present invention can be obtained according to general Scheme 2.

Scheme 2 in i

I'm a whale

Ov

BUT Mn: 5 Ж и Ше ш-

With x and 2

PROS RIS OM ev PO.

YOU and 2r pyrophosphate-Vozim, Meiem and ki and

KY dit ooo COULD nave oon

Also E and Ai shcha

I he he she 7 that 2

Nucleoside 24 (20 mg) was placed in a flask (5-15 ml). Trimethyl phosphate (0.5-1.0 ml) was added. The solution was cooled in an ice bath. ROSIiz (40-45 mg) was added and stirred at 0 "C until the reaction was complete (1-4 hours; the course of the reaction was monitored using ion-exchange HPLC; samples for analysis were obtained by taking 3 μl of the reaction mixture and diluting them with 1.0 M EivMnHSO: » (30-50 μl)). Then a solution of pyrophosphate-VizZM (250 mg) and VizZM (90-105 mg) in MesM or DMF (1-1.5 ml) was added. The mixture was stirred at 0 "C for 0.3-2.5 hours and then the reaction was quenched with 1.0 M EuBMN»CO3 (5 ml).

The resulting mixture was stirred for an additional 0.5-1 h. until heating to room temperature. The mixture was concentrated to dryness, redissolved in water (4 ml), and purified by ion exchange

TOP. Fractions containing the target product were concentrated to dryness and co-evaporated with water.

The residue was dissolved in water (75 ml). ManHSO»z (- 30 mg) was added and the mixture was evaporated to dryness. The residue was dissolved in water and evaporated again. The residue was subjected to C-18 HPLC purification, obtaining the target product in the form of sodium salts.

Compound 10 - M M. know y. in her and M

BUT even now ROS NOM, SUN

She shchen -Viishchm, MeV in I pay

M ne wa what about: oh her her and what en no-veoonveoveo and M m noono ono no on

Triphosphate 10 (4 mg, tetrasodium salts, 35 96) was prepared according to the procedure described beginning with Compound 1. "H NMR (300 MHz, 020): b 7.96 (5, 1H), 7.68 (5, 1H), 5.40 ( 5, 1H), 4.07-4.30 (t,

AN), 0.91 (5, ZN). UR MMA (300 MHz, 020): -5.6 (y, 92-48 Hz), -10.6 (a, 9-48 Hz), -21.5 (Her, 9-48 Hz).

M5-521.8 (M--NU).

Compound 19

NM June oh oh ha

Y Y Y o M no-v-0-v-0-rRo on on on shk; but he is 19

Compound 19 was prepared starting from 17 according to a standard triphosphate synthesis procedure.

IN NMR (300 MHz, 020): b 7.97 (5, 1H), 7.60 (5, 1H), 5.37 (5, 1H), 4.00-4.30 (t, AN), 2.97 (5, ЗН), 0.91 (in ,

ZN); R MMK (121.4 MHz, 020): b -21.6 (I, 9U-19.4 Hz), -10.6 (y, 9-18.7 Hz), -5.7 (y, 9U-20.1 Hz).

Antiviral activity

Another aspect of the invention relates to methods of suppressing viral infections, which include the steps of treating a sample or a subject, possibly in need of such suppression, with a composition according to the invention.

In the context of the present invention, samples that may contain a virus include materials of natural or artificial origin, such as living organisms; tissue or cell cultures; biological samples, such as samples of biological materials (blood, serum, urine, cerebrospinal fluid, tear fluid, sputum, saliva, tissue samples, etc.); laboratory samples; samples of food, water or air; samples of bioproducts, for example cell extracts, in particular, recombinant cells synthesizing the desired glycoprotein; etc. Specimens are usually assumed to contain an organism that causes a viral infection, most commonly a pathogenic organism such as an oncogenic virus. Samples can be contained in any medium, including water and organic solvent/water mixtures. Samples include living organisms, such as humans, and materials of artificial origin, such as cell cultures.

If desired, the antiviral activity of the compounds according to the invention can be observed by any method, including direct and indirect methods of detecting such activity. Quantitative, qualitative and semi-quantitative methods of determining such activity are expected to be used. One of the above-described screening methods is usually used, but any other method can also be used, for example, observing the physiological properties of a living organism.

Antiviral activity of compounds according to the invention can be measured using known standard screening techniques. For example, the antiviral activity of compounds can be measured using the following general techniques.

Cellular immunodetection of flaviviruses

VNK21 or A549 cells were treated with trypsin, counted and diluted to 2 x 105 cells/ml in Nat5 E-12 (A549 seiII5 cells) or ERMI-1640 (VNK21 cells) media supplemented with 2 95 fetal bovine serum (EB5) and 1 95 penicillin / streptomycin. 2 x 102 cells were distributed in transparent 96-well plates for tissue culture and placed overnight at 37 "С, 595 СО". The next day, cells were infected with viruses at a multiplicity of infection (MOI) equal to 0.3 in the presence of various concentrations of compounds , which are tested, for 1 hour at 37 "С and 595 СО" for the next 48 hours. Cells were washed once with RVZ and fixed with cold methanol for 10 min. After washing PB5 twice, the fixed cells were blocked with PB5 containing 1 95 EB5 and 0.05 95 Tumeep- for 1 hour at room temperature. Then a solution of primary antibodies (452) was added at a concentration of 1:20-1:100 in PB5 containing 1 95 ЕВ5 and 0.05 95 PGyep-20 for 3 hours. Then the cells were washed three times with PB5, followed by incubation for an hour with anti-mouse antibodies conjugated with horseradish peroxidase (PC) (5IDTA, dilution 1:2000). After washing three times

50 microliters of the substrate solution - 3,3,5,5-tetramethylbenzidine (TMV) (bidta) was added to each well of the RVZ for 2 minutes. The reaction was quenched by adding 0.5 M sulfuric acid. The plates were read at absorbance at 450 nm to count viral After measurement, the cells were washed three times with PB5 followed by incubation with propidium iodide for 5 min.

The plate was read on a Tesap Zaiygate reader (disruption at 537 nm, emission at 617 nm) to count the number of cells. The "dose-response" curves were constructed in the coordinates of the average absorption from the logarithm of the concentration of the tested compounds. ESvo was calculated by non-linear regression analysis.

A positive control such as M-nonyldeoxynopyrimicin can be used.

Cellular analysis of the cytopathogenic effect of flaviviruses

To assess activity against West Nile virus or Japanese encephalitis virus cells

VNK21 was treated with trypsin and diluted to a concentration of 4 x 105 cells/ml in KRMI-1640 medium supplemented with 2 95 EV5 and 1 95 penicillin/streptomycin. To evaluate the activity against dengue virus cells

Nipe was treated with trypsin and diluted to a concentration of 4 x 105 cells/ml in OMEM medium supplemented with 5 95 EV5 and 1 95 penicillin/streptomycin. The cell suspension was distributed at 50 microliters (2 x 102 cells) per well in 96-well plates based on RIT polymer with a transparent bottom (Mips). Cells were grown overnight in culture medium at 37 °C, 5 95 °C, and then infected with virus

West Nile virus (e.g. strain B956) or Japanese encephalitis virus (e.g. strain

Makauata) at MOI-0.3 or dengue virus (for example, strain OEM-2 MOSS) at MOI1-1, in the presence of different concentrations of the tested compounds. Plates containing the virus and compounds were incubated at 37°C, 595°C for 72 hours. At the end of incubation, 100 microliters of the SeyiTieg-SioM reagent was added to each well. The contents were mixed for 2 minutes on an orbital shaker to induce cell lysis. Tablets were incubated at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence was read using a tablet reader. A positive control such as M-nonyldeoxynopyrimicin can be used.

Antiviral activity in a mouse model of dengue infection.

The compounds were tested ip mimo in a model of dengue virus infection in mice (zspii ei ai. 9. Iptesioiz biv. 2007; 195:665-74). Six- to ten-week-old AC129 mice (AGE Opimegza! YES, NO, OK) were housed in individually ventilated cages. Mice were injected intraperitoneally with 0.4 ml of dengue 2 virus suspension

T5MO01. Blood samples were collected by extraorbital puncture under isoflurane anesthesia. Blood samples were collected in tubes containing sodium citrate at a final concentration of 0.4 95, and immediately centrifuged for 3 minutes at 6000 rpm to obtain plasma. Plasma (20 microliters) was diluted in 780 microliters of KRMI-1640 medium and snap-frozen in liquid nitrogen for plaque formation analysis. The remaining plasma was stored for determination of cytokine and protein levels

M51. The mice developed dengue viremia, which increased over several days with a peak on the 3rd day after infection.

To assess antiviral activity, the compounds according to the invention were dissolved in a carrier liquid, for example, 10 95 ethane, 30 95 RES 300 and 60 95 OBMU (5 95 dextrose solution in water); or 6 n. NSI (1.5 eq) n. Mahon (pH adjusted to 3.5): 100 mm citrate buffer pH 3.5 (0.9 95 vol./06.:2.5 95 vol./06.: 96.6 95 vol./06.). Thirty-six AC129 mice aged 6-10 weeks were divided into six groups of six mice each. All mice were challenged with dengue virus as described above (day 0). Group 1 was administered by gavage 200 ml/mouse with 0.2 mg/kg of the compound according to the invention twice a day (once early in the morning and once later in the afternoon) for three consecutive days, starting from day 0 (the first dose just before dengue infection). Groups 2, 3, and 4 were similarly administered 1 mg/kg, 5 mg/kg, and 25 mg/kg of the compound, respectively. A positive control can be used, for example (2, ZK, 4K, 5K)-2-(2-amino-6-hydroxypurin-9-yl)-5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol, administered via gastric probe of 200 ml/mouse similarly to the previous groups. The next group was treated only with the carrier liquid.

Blood samples of approximately 100 microliters (with sodium citrate to prevent clotting) were taken from mice on day 3 after infection by transorbital puncture under isoflurane anesthesia. Plasma was obtained from each blood sample by centrifugation and quickly frozen in liquid nitrogen for plaque formation analysis. Collected plasma samples were subjected to the analysis of plaque formation according to the description of spi! oh oh oh Cytokine analysis was also performed according to the description of ZsPPii. M51 protein levels were assayed using the Rialeyite diagnostic kit (Vioguide Iabrogaiogie5). An indicator of antiviral activity was a decrease in cytokine levels and/or MO1 protein levels.

As a rule, when using dosages of the compounds according to the invention, equal to 5-50 mg/kg, a decrease in viremia by approximately 5-100 times, more typically by 10-60 times, most typically by 20-30 times, was observed.

Definition of ISvo HCV

Analysis protocol: the M55b polymerase assay (40 μl) was performed by adding 28 μl of the polymerase mixture (final concentration: 50 mM Ttg5-HCI at pH 7.5, 10 mM KSI, 5 mM Masi), 1 mM OT, 10 mM

EOTA, 4 ng/μl mRNA and 75 nM polymerase A21 M5Z5b HCV) into tablets for analysis, followed by the addition of 4 μl titer of the compound. The polymerase and compound were pre-incubated at 35 °C for 10 minutes before adding 8 μl of the nucleotide substrate mixture (Z33P-a-labeled competing nucleotide at the concentration of CM and 0.5 mM of the remaining three nucleotides). The assay plates were covered and incubated at 35 "C within 90 min. Then the contents were filtered in a vacuum using 9b-well filter tablets OEAE-81. The filter plates were then washed under vacuum with multiple volumes of 0.125 M ManNHRoO»x, water, and ethanol to remove unincorporated label.

Plates were then read on a TorSosp to assess the level of product synthesis compared to the background control. IC50 values were determined using the Rgizt approximating program.

Preferably, the compounds described herein inhibit M55B polymerase with an IC of less than 1000 µM, more preferably less than 100 µM, and most preferably less than 10 µM. Exemplary examples of the activity of the compounds of the invention are shown in Table 30 below. A represents ICho less than 10 μM, B represents ICho from 10 to 200 μM, and C represents ICho greater than 200 μM.

Table 30

Typical ISvo for triphosphates according to the following examples 51 111v' ( 1161 111111c 711v' 11v',

Definition of EC5oHCV

Replicon cells were seeded in 96-well plates at a density of 8 x 103 cells per well in 100 μl of culture medium with the exception of geneticin. The compound was serially diluted in 100 95 DMSO and then added to the cells at a dilution of 1:200, reaching a final concentration of 0.5 95 DMSO and a total volume of 200 μl. The plates were incubated at 37°C for 3 days, after which the culture medium was removed and the cells were lysed in the lysis buffer provided by the Rgoted luciferase assay system. Following the manufacturer's instructions, 100 μl of luciferase substrate was added to the lysed cells and luciferase activity was measured on a TorSoip luminometer. compounds described herein had ECs of less than 1000 µM, more preferably less than 100 µM and most preferably less than 10 µM For example, compounds 1, 17 and 18 had ECs of less than 10 µM, while compounds 9 and C had

ESvo is less than 250 μm

The cytotoxicity of the compounds of the invention can be determined using the following general protocol.

Analysis of cytotoxicity using cell cultures (Determination of CC50):

The analysis is based on the evaluation of the cytotoxic effect of the tested compounds using a metabolic substrate.

Analysis protocol for determining SS50: 1. MT-2 cells were maintained on KERMI-1640 medium with the addition of 5 95 fetal bovine serum and antibiotics. 2. Cells were distributed in a 96-well plate (20,000 cells in 100 μl medium per well) and different concentrations of test compounds were added in triplicate (100 μl/well). An untreated control was included. 3. Incubate the cells for 5 days at 37 (C. 4. Prepare the HTT solution (b ml per tablet for analysis) in the dark at a concentration of 2 mg/ml in phosphate-salt buffer solution pH 7.4. Heat the solution in a water bath at 55 ( C for minutes. 50 μl of M-methylphenazonium metasulfate (5 μg/ml) was added to 6 ml of CTT solution. 5. 100 μl of the medium was removed from each well of the tablet for analysis and 100 μl of the CTT substrate solution was added. Incubated at 37 (C) for 45 -60 min in an incubator in a CO 2 atmosphere. 6. 20 μl of 2 95 Top X-100 was added per well to stop the metabolic conversion of HIT. 7. The absorbance was read at 450 nm, subtracting the background signal at 650 nm. 8. The absorbance graph was constructed in percentages of the untreated control and calculated values

CC50 as the drug concentration that leads to 50 95 inhibition of cell growth. Absorption was considered to be directly proportional to cell growth.

The contents of all publications, patents, and patent documents mentioned above in this specification are incorporated herein by reference as if each of said documents were separately incorporated by reference.

This invention is described with reference to various specific and preferred embodiments and techniques.

However, for a specialist in this field of technology, it is obvious that various options and modifications of the invention are possible, which will also be within the scope of the present invention.

Claims (14)

1. The compound of the formula I Кк х/ -к в7 и ех М М М Ж - - о-сн, о - в Кк е3 в! H 4 b2 Kk Formula I or its pharmaceutically acceptable salt; in which: KE! is (Ci-Cv)alkyl; E" represents OKU; E" represents H; KE" represents OK"; or K" 1 E" taken together represent -0(C-0)0O- or -"OC(CH3"O-; E" represents H; each K" independently represents H, (Se-Silaryl(Si- Cy)alkyl or -"C(C-O)K; E" is H, (Ce-Si)aryl(Ci-Cv)alkyl, -C(C-O)K" or U - m 2 M. each У or У" represents О; М 1 ХУ", when taken together, represent -У (С(КУ)2)зУ7-; or one of M" or Hu" together with either EE or B" represents -U7-, and another of M! or U? corresponds to Formula Ia; or each of UM! 1 M independently represents a group of Formula Ia: U 2 | | 2 х У--Р У. І, х и мг; Formula Ia in which: each У? independently represents a connection, О., SE", ME or 5; each У?" is 0; MO takes the value 0, 1 or 2; each K" independently represents H or a formula: У" BU BU m" RU У У У МИ12s МИС ma Mta , in which: each MiIa, Mis 1 Mii independently takes the value 0 or 1; MiI2s takes the value 0, 1, or 2; each KU is independently H, E or M"; each K is independently H, (Ci-C8)alkyl, (C1-C8) substituted alkyl, (Ce-C00)aryl, (C8-C80)substituted aryl or ( Ce-Cyz)aryl(Ci-Cv)alkyl; XU" is pyridinyl; every X! or X" independently represents C-K" or M, and at least one of X' or X" represents M; each E? independently represents ME/ B", ОВ! 58" or MNOMTTt; E? represents H, ME" KN, OK", KE" or MNOMT g; each n independently takes the value 0, 1 or 2; KE" represents H; each K" or K"" independently represents H, (Ci-C3)alkyl or (C1-C3)alkyl(Ce-Ci4)aryl; where substituted means that one or more hydrogen atoms are each independently replaced by a non-hydrogen substituent; and where the non-hydrogen substituent is -X, -K" or -OK", and each X is independently a halogen, and each K? independently represents H, (Ci-Cv)alkyl, (Ce-Coo)aryl or (Ci-Cv)substituted alkyl. 2. The compound according to claim 1, in which ЕВ" is MK"K", OK" or 5K. 3. The compound according to claim 1 or 2, in which E" is H or MEI/K". 4. The compound according to any of claims 1-3, represented by Formula P - x/ -k 7 u She M (c) X Mu A 9 (c) M Kk ve be pan Hu ia kA Formula P. 5. The compound according to any of claims 1-4, in which KE" is H or U - m mu? 6. The compound according to any of claims 1-5, in which X' represents M. 7. A compound according to any of claims 1-6, in which each K" 1 E" is an OKU. 8. The compound according to any of claims 1-7, in which X" is CH and E' is methyl. 9, The compound according to any of claims 1-7, in which KE! is methyl. 10. The compound according to claim 1, selected from the group of compounds, which includes: МН, МН, nm is) o on ZH M M their NOSES and more MN M MN, - lo I KZ o M MN, o o M M no X chl no ОН no ОН no ОН va is) N and MM and k-x (c) I o 0-4 M MN o M MN M no x- V i Mn, and no he me MN, but he SI va Ge! M (c) N M MN M M | UF 2 a ih MYKH ra o M MN ikh o o - (8) MM M M no x-/ Go g MN, kh no on no ОН si va (c) Х Ge) Myh MN; She | y X / ho iv) M M is) h-/ M) i SI Mn, ih (c) BACH AJ I o-y--o o M Mn, ry chi 5 / 7 no OH o nmshi 5 (c) vach khm o Y o " ry cha 5 -3- no OH o o z о и M ra - о я и ДЙ Х M МН no o К M o Мн, и M МН Н (c) 2 и - Ко в) М M IF) M--/ ОО no ОН SI Мn, 5-x o and whether B; M ope) (c) izno ON Mn, M x S Y hm chn! Y " O-no Ge) M - -- || M o what o t M MN H (c) 2 uh I o What « l m " (c) h-/ y) kv si Mn, M MN АХ o A M Mkh o ev) || M M M v E o p, 6) K- »Х- X KU U iv) as: on shchi - 7 o no on vk MA (c) Mkh vkh u- 0-5 «| HM M SA, o- 56--o0 M -u SY c) 0-7 - Z no on no-R- 5 5-5 Y o on z o z Mn, 5-x i A o 6) Ko 0-4. With Oo-x - o-rR-d 7 on c) Mn, but M o vah m b- M m o-- ozh o sei o | M MN Mn, but he Mn, sh M 6) U KU Ge! 5-x SCHI x o) nM-»-o0 o) yo - M (c) ne M ah o o o M m AV I ІІ II o m no-y-o---o-V on on on! but he or M MN, Oh c) o c) ih po o ushu; no--v--o--E-o- h-/ he he he I I no he ! or a pharmaceutically acceptable salt thereof. 11. The compound according to any one of claims 1-10 for use in a method of treatment of a viral infection caused by a virus of the Riachihygiidae family. 12. A pharmaceutical composition for the treatment of NKiauihigiChae virus infection, containing a therapeutically effective amount of a compound according to any one of claims 1-10 in a pharmaceutically acceptable carrier. 13. Pharmaceutical composition according to claim 12, which additionally contains at least one additional therapeutic agent. 14. Pharmaceutical composition according to claim 13, in which the additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, M53 protease inhibitors. M55a inhibitors, M555 polymerase inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside inhibitors of the hepatitis C virus (HCV) and other drugs for the treatment of HCV.