EA026523B1 - 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment - Google Patents

Abstract

Provided are selected imidazo[1,2-f][1,2,4]triazinyl nucleosides and nucleoside phosphates of formula V, wherein the 2' position of the nucleoside sugar is substituted with fluoro. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections caused by both wild type and mutant strains of HCV.

Description

The invention relates in general to compounds with antiviral activity, in particular to nucleosides active against P1auschbae infections and, in particular, to inhibitors of RNA-dependent RNA polymerase of hepatitis C virus.

State of the art

Viruses, including the family Jauschschae, contain at least three distinguishable genes, including pestiviruses, flaviviruses and hepaciviruses (Calcif e! A1., I. Sep U1go1., 1993, 70, 37-43). While pestiviruses are the cause of many economically significant animal diseases, such as bovine diarrhea virus (WUIUV classical swine fever virus (VCLS, swine cholera) and borderline sheep disease (IIU), their significance in human diseases is less characterized (Moyishd, U. , e! a1., Λάν. U1 G. Ke8. 1992, 48, 53-98). Flaviviruses are responsible for important human diseases such as dengue and yellow fever, while hepativiruses lead to hepatitis C virus infection in humans Other important viral infections The infections caused by the P1auschbye family include West Nile virus (UI), Japanese encephalitis virus (1EU), tick-borne encephalitis virus, Murphy virus encephalitis, St. Louis encephalitis, St. Petersburg hemorrhagic fever virus, and Zika virus from Combin. P1Aushtbaye virus families cause significant mortality, morbidity and economic loss worldwide, and there is therefore a need to develop effective treatments for P1autgbaevirus infections.

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Woweg, N. e! A1. 1 Nera! O1. 32: 98-112, 2000), therefore, considerable attention in current antiviral studies is aimed at developing improved methods for treating chronic NSI infections in humans (Veksedier, A.M. apb Vasop, V.K., 8s1epyys Atepsap, Os!.: 80-85, (1999); Sogbop, S. R., e! a1., 1. Furniture.Set. 2005, 48, 1-20; Magabroig, I .; e! A1., Oa !. Keu. M1sgo. 2007, 5 (6), 453463). A number of ways to treat NSA are considered Wutosk e! a1. in ΑπΙίνίΓηΙ SNepikKu & Sjeto! Yeharu, 11: 2; 79-95 (2000).

RNA-dependent RNA polymerase (Kbcr) is one of the best-studied targets for the development of new therapeutic agents for NSOs. Ν85Ρ polymerase is a target for inhibitors at the beginning of human clinical trials (8ptabokk1, 1., AO 01/90121 A2, USA 2004/0006002 A1). These enzymes have been widely characterized at the biochemical and structural levels with screening for the detection of selective inhibitors (Xie Clegs, E. (2001) 1. Pbactaco exp. Taeg. 297: 1-10; Xe Clgts, E. (2001) 1. Cl. U1go1.22: 73-89). Biochemical goals, such as I85B, are important in the development of hepatitis C therapy since NSIs are not replicated in the laboratory, and there are difficulties in the development of cell analyzes and preclinical animal systems.

Currently, there are mainly two antiviral compounds, ribavirin, a nucleoside analogue, and interferon alpha (α) (IFN), which are used to treat chronic NSAID infections in humans. Ribavirin alone is not effective in lowering viral RNA levels, has significant toxicity, and is known to cause anemia. The combination of interferon and ribavirin has been reported to be effective in the treatment of chronic hepatitis C (8co !!, b. 1., e! A1. Ygidk 2002, 62, 507-556), but less than half of the patients infected with certain genotypes showed constant benefit with such treatment. Other patent applications disclosing the use of nucleoside analogues for the treatment of hepatitis C virus include AO 01/32153, AO 01/60315, AO 02/057425, AO 02/057287, AO 02/032920, AO 02/18404, AO 04/046331, AO2008 / 089105 and AO2008 / 141079, but additional treatment for NSO infection has not yet become available to patients.

Virological treatment of patients with chronic NSA infection is difficult to achieve due to the huge amount of daily production of the virus in chronically infected patients and the high spontaneous variability of the virus of NSA (Ieitapp, e! A1., 8aepse 1998, 282, 103-7; Rik1to! O, e ! a1., Nera! o1odu, 1996, 24, 1351-4; Yotshdo, e! a1., Sepe, 1985, 40, 1-8; Maya, e! a1., 1. U1go1. 1992, 66, 3225- nine). Experimental antiviral nucleoside analogs have been shown to cause viable mutations of the NSI virus, both w νίνΌ and wuigo (M1dbassu, e! A1., 1. Vu1. Cet. 2003, 926; Caggo11, e! A1., Aptugo1 Adep! K Ceto! Légard 2009, 926; Vgo ^ n, A.V., Ehrey Orsh. 1pukeyd. Ygidk 2009, 18, 709-725). Thus, drugs with improved antiviral properties, in particular, increased activity against resistant strains of the virus; improved oral bioavailability; fewer undesirable side effects and an extended effective half-life of w νί \ е (Ie Prgapexo, K. e! a1. (2003) Ap! Mga1 Kekeags 58: 1-16) are urgently needed.

Some ribosides from the nucleic bases of pyrrolo [1,2-1] [1,2,4] triazine, imidazo [1,5-G] [1,2,4] triazine, imidazo [1,2-1] [1, 2,4] triazine and [1,2,4] triazole [4,3-1] [1,2,4] triazine have been disclosed in Clobbie Kekeags 2001, 331 (1), 77-82; Jesus1back1back & Jesus1back (1996), 15 (1-3), 793-807; Te! Gaebbop bie !! ekg (1994), 35 (30), 5339-42; Hegosus1ek (1992), 34 (3), 569-74; 1. Eat. 8os. Regksh Tgapk. 1 1985, 3, 621-30; 1. Eat. 8os. Regksh Tgapk. 1 1984, 2, 229-38; AO 2000056734; Ogdash Leyegk (2001), 3 (6), 839-842; 1. Eat. 8os. Regksh Tgapk. 1 1999, 20, 2929-2936; and 1. Meb Seth. 1986, 29 (11), 2231-5. However, these compounds have not been disclosed as useful for the treatment of NSOs.

- 1 026523

Pyrrolo ribosides | 1.2-G || 1.2.4 | triazinyl. imidazo [1,2-G] [1,2,4] triazinyl, imidazo [1,2-ί] [1,2,4] triazinyl and [1,2,4] triazole [4,3-G] [ 1,2,4] triazinyl nucleobases with antiviral, anti-NSA and anti-Kbcr activity were disclosed Ba, Vi. 8., \ UO 2008/089105 and \ UO 2008/141079; Sio, e! A1., \ UO 2009/132123 and Rgapsot, e! a1. \ UO 2010/002877. Viig, e! A1., UO 2009/132135, disclosed antiviral pyrrolo [1,2-G] [1,2,4] triazinyl, imidazo [1,5-G] [1,2,4] triazinyl, imidazo [1,2 -G] [1,2,4] triazinyl and [1,2,4] triazole [4,3-G] [1,2,4] triazinyl nucleosides in which sugar is substituted at the 1'-position of the nucleoside.

SUMMARY OF THE INVENTION

Compounds that inhibit the Iauschsbae family viruses are provided. The invention also includes compounds of formula I or formulas 1U-U1 that inhibit viral nucleic acid polymerases, in particular, NSA RNA-dependent RNA polymerase (KbKr), rather than cellular nucleic acid polymerases. the compounds of formula I or formulas 1U-U1 were discovered to be effective against both wild-type and 8282T mutant strains of the NSU virus. Thus, the compounds of formula I or formulas 1U-U1 are useful for the treatment of IauCtbae infections in humans and other animals.

In one embodiment, provided are compounds of formula I

or a pharmaceutically acceptable salt thereof;

where K ¹ represents (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl , (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

K ² is halogen;

each K ^3, K ⁴ and K ⁵ are independently H, OK ^and AND (R ^a) 2, I3, SI, IO2, 8 (O) pK ^a, halogen, _(C1-C8) alkyl, (C ₄ - C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

or any two of K ³ , K ⁴ or K ⁵ on adjacent carbon atoms taken together are —O (CO) Oily, taken together with the carbon atoms of the ring to which they are attached, form a double bond;

K ⁶ represents H, OK ^a , I (K ^a ) 2, Ν3, SI, IO2, 8 (O) pK ^a , -C (= O) K ^P , -C (= O) OK ^P , -C ( = O) IR ^P K ¹² , -C (= O) 8K ^P , -8 (O) K ^p , -8 (O); NL -8 (O) (OK ^p ), -8 (O) 3 (OK ¹¹ ), -8O; \ HH \ halogen, (C- (Palkyl, (Cd-St) carbocyclylalkyl, (C _£ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C _£ -C ₈ ) alkyl;

each n is, independently, 0, 1 or 2;

each K ^a , independently, is H, (St-C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C1-C8) alkyl, (C4-C8) carbocyclylalkyl , -C (= O) K ^P , -C (= O) OK ^P , -C (= O) IR ¹¹ K ¹² , -C (= O) 8K ^P , -8 (O) K ^P , -8 ( O) 2K ^p , -8 (O) (OK ¹³ ), -8 (O) 2 (OK ^p ) or -8O2IK ¹¹ K ¹² ;

K ⁷ represents H, -C (= O) K ^P , -C (= O) OK ^P , -C (= O) IR ¹¹ K ¹² , -C (= O) 8K ^P , -8 (O) K ^P , -8 (O) _; nL -8 (O) (OK ³¹ ), -8 (O) 2 (OK ^p ), -8O2IK ¹¹ K ¹² , or

each Υ or Υ ¹ represents, independently, O, 8, IR, + I (O) (K), I (OK), + I (O) (OK) or ΝIK ₂ ;

XV ¹ and V ² together are ³ ^ (C (R ^y) ₂₎ ^ ³ -; or one of XV ¹ or V ² , together with either K ³ or K ⁴ , represents -Υ ³ -, and the other V ¹ or V ² is the formula Ρι; or V ¹ and V ² each independently is a group of the formula! a:

where each Υ ² is, independently, a bond, O, SK ₂ , IR, + I (O) (K), I (OK), + I (O) (OK), ΝIK ₂ , 8, 8-8, 8 (O) or 8 (O) ₂ ; each Υ represents, independently, O, 8 or IR; M2 is 0, 1

- 2 026523 or 2; each K ^x represents, independently, K ^y or the formula:

where each M1a, M1c and WE represents, independently, 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

each K ^y is, independently, H, P, C1, Br, I, OH, K, -C (= Y ¹ ) K, -C (= Y ¹ ) OK, -0 (= Υ ¹ ) Ν (Κ ) 2, -Ν (Κ) 2, - + Ν (Κ) 3, -5К, -5 (О) К, -5 (bcc, -5 (О) (ОК), -5 (О) 2 (ОК ), -ОС (= У ¹ ) К, -ОС (= У ¹ ) ОК, -ОС (= У ¹ ) (Ы (К) 2), -5 ^ = Υ ^! ) Κ, -5С (= ^) OK, -5 ^ = Υ ¹ ) (Ν (Κ) 2), -НК) С (= ^) К, -НК) С (= ^) ОК,

-Ν ^^^ Υ ¹ ) ^^, -5О ₂ PC ₂ , -СИ, -Ν ₃ , -ЫО ₂ , -ОК or XV ³ ; or, taken together, two To ^at the same carbon atoms form a carbocyclic ring of from 3 to 7 carbon atoms;

each K independently represents H, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocyclyl, C ₂ -C ₂₀ substituted heterocyclyl, arylalkyl or substituted arylalkyl ;

V ³ is V ⁴ or V ⁵ ; V ⁴ is K, -C (= Y ^! ) K ^y , -C (= Y '^ ^5. -5O ₂ K ^y or -5O ^ ⁵ ; and V ⁵ is a carbocycle or heterocycle, where V ^{5 is} independently substituted from 0 to 3 groups K ^y ;

each X ¹ or X ² is, independently, CK ¹⁰ or Ν;

each К ⁸ represents halogen, ХК ^П К ¹² , НК ^ ОК ¹¹ , Х ^ ХК ¹¹ ^ ² , Ν3, NΟ, NΟ2, СНО, ΟΝ, -С11 (\ Н-Ο ^ ΝΝΗ ^ ¹ , -СН = К (OK ^P ), -CH (OK), -C (O) \ K K 3 -C (5) \ N H'z -C (= O) OK ¹¹ , (Cr-C ₈ ) alkyl, (C2- C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C (= O) _(C1-C8) alkyl, -5 (O) _n (C1-C ₈₎ alkyl, aryl _(C1-C8) alkyl, OK or 5K every ¹¹ K ⁹ or K ¹⁰ independently represents H, halogen, ΝΡ ^ΙΙ Ρ ¹²

Ν ₃ , ΝΌ, NО ₂ , СНО, СН -СН ^ КК), -ϋ ^ ΝΗΝΕ ¹ -С (= 5) PK ¹¹ К ¹² , -С (= О) OK ¹¹ , K ¹¹ , OK ¹¹ or 5К ¹¹ ;

-CH = NOC), -CH (OK ^P ) ₂ ,

NK ^ OK ¹¹ ,

Ν ^ ΝΗ ¹¹ ^ ² ,

—C (= O) PK ¹¹ K ¹² , each K or K independently represents H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C (= O) (C ₁ -C ₈ ) alkyl, -5 (O) _P (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or K ¹¹ and K ¹² , taken together with the nitrogen to which they are both attached, form from 3 to 7 membered heterocyclic rings, where any one carbon atom of said heterocyclic ring may optionally be replaced by —O—, —5 or - ΝΚ ¹ -;

where each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of each K ¹ , K ³ , K ⁴ , K ⁵ , K ⁶ , K ¹¹ or K ¹² is independently optionally substituted with one or more halogens, hydroxy, ΗΝ, Ν3, NK ^a ) 2 or OK ^a ; and where one or more of the non-terminal carbon atoms of each of the indicated (C ₁ -C ₈ ) alkyl can optionally be replaced by -O-, -5- or -ΝΚ ¹ -.

In another embodiment, provided are compounds of formula I or formulas 1U-Y1 and their pharmaceutically acceptable salts, and all their racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, and amorphous forms.

In another embodiment, provided are new compounds of formula I or formulas RU-UT with activity against infectious viruses Pauczyas. Not wishing to be bound by theory, the compounds of the invention can inhibit viral RNA-dependent RNA polymerase and thereby inhibit virus replication. They are useful for treating human patients infected with human viruses, such as hepatitis C.

In another embodiment, pharmaceutical compositions are provided comprising an effective amount of a compound of Formula I or Formulas 1U-U1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

In another embodiment, the present application provides for a combination of a pharmaceutical agent, comprising:

a) a first pharmaceutical composition comprising a compound of formula I or formulas RU-UT, or a pharmaceutically acceptable salt, solvate, or ether thereof; and

b) a second pharmaceutical composition containing at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, NSU Ν53 protease inhibitors, Ν55α inhibitors, alpha glucosidase inhibitors 1, hepatoprotectors, decarboxylase mevalonate antagonists, rhenagon antagonists - angiotensin system, other antifibrotic agents, endothelin antagonists, nucleosides or nucleotide inhibitors of the NSU Ν55Β polymerase, non-nucleoside inhibitors of the NSU Ν55Β polymerase, NSU Ν55 inhibitors, TK-7 agonists, cyclophyllin inhibitors, NSO SHE5, pharmacokinetic enhancers, and other drugs for the treatment of hepatitis C virus; or mixtures thereof.

In another embodiment, the present application provides a method for inhibiting NSU-3 026523 polymerase, comprising contacting a cell infected with NSA with an effective amount of a compound of formula I or formulas 1U-Y1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

In another embodiment, the present application provides a method for inhibiting an NSI polymerase, comprising contacting a cell infected with an NSI with an effective amount of a compound of formula I or formulas 1U-Y1, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional therapeutic agent.

In another embodiment, the present application provides a method for treating and / or preventing a disease caused by a viral infection, wherein the 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 , Tyrp virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine diarrhea virus, Zika virus and hepatitis C virus, by administering to the subject, need arising from this, a therapeutically effective amount of a compound of formula I or formulas 1U-Y1 or a pharmaceutically acceptable salt thereof.

In another embodiment, the present application provides a method for treating hepatitis C virus in a patient, the method comprising administering to said patient a therapeutically effective amount of a compound of formula I or formulas 1U-Y1 or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

In another embodiment, the present application provides a method for treating hepatitis C virus in a patient, comprising administering to the indicated patient a therapeutically effective amount of a compound of formula I or formulas GU-U or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional therapeutic agent .

Another aspect of the invention provides a method of treating or preventing the symptoms or consequences of a hepatitis C virus infection in an infected animal, which comprises administering, i.e. treating, said animal a pharmaceutical combination of a composition or composition comprising an effective amount of a compound of formula I or formulas RU-UT and a second compound having anti-NSA properties.

In another aspect, the invention also provides a method for inhibiting NSIs, comprising administering to a mammal infected with NSIs, a certain amount of a compound of Formula I or formulas RU-UT effective to inhibit hepatitis C virus replication in infected cells in said mammal.

In another aspect, the use of a compound of Formula I or formulas RU-UT for the manufacture of a medicament for the treatment of P1a1ushbay virus infections is provided. In another aspect, a compound of Formula I or Formulas RU-UT is provided for use in the treatment of a P1au1utbae virus infection. In one embodiment, the P1au1utbae virus infection is an acute or chronic infection of an NSA. In one embodiment of each aspect of the use and compound, treatment results in a decrease in one or more viral loads or RNA clearance in a patient.

In another aspect, the invention also provides the processes and novel intermediates described herein that are useful for preparing compounds of formula I or formulas RU-UT of the invention.

In other aspects, novel methods for the synthesis, analysis, separation, isolation, purification, characterization and testing of the compounds of this invention are provided.

Detailed Description of Exemplary Embodiments

Reference will now be made in detail regarding certain embodiments of the invention, examples of which are shown in the accompanying descriptions, structures and formulas. While the invention will be described in connection with the listed embodiments, it should be understood that they are not intended to limit the invention in these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included in the scope of the present invention.

In another aspect, the compounds of formula I are represented by formula II:

or a pharmaceutically acceptable salt thereof;

- 4 026523 where R ¹ represents a _(C1-C8) alkyl, (C ₄ -C ₈₎ carbocyclylalkyl, (C'-C ₈₎ substituted alkyl, (C ₂ C ₈₎ alkenyl, (C ₂ -C ₈₎ substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

each К ³ , К ⁴ , К ⁵ independently represent Н, ОК ^а , Ν (Κ ^α ) 2, Ν3, СЫ, ΝΟ2, 8 (О) пК ^а , halogen, (С1-С ₈ ) alkyl, (С ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

or any two of K ³ , K ⁴ and K ⁵ on adjacent carbon atoms taken together are —O (CO) O— or, taken together with the carbon atoms of the ring to which they are attached, form a double bond;

K ⁶ represents H, OK ^a , N3, CU, ΝΟ2.5 (O) .K ' ^: . -C (= O) K ¹¹ , -C (= O) OK ¹¹ , -C (= O) LK ¹¹ K ¹² ,

-C (= O) 8K ¹¹ , -8 (O) K ¹¹ , -8 (O) 2K ¹¹ , -8 (O) (OK ¹¹ ), -8 (O) 2 (OK ¹¹ ), -δΟΛΗ Η ² . halogen, (C ^ Clkyl, (C4-C8) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

each n is independently 0, 1 or 2;

each K ^a independently represents H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, -C (= O) K ¹¹ , -C (= O) OK ¹¹ , -C (= O) LK ¹¹ K ¹² , -C (= O) 8K ¹¹ , -8 (O) K ¹¹ , -8 (О) 2К ¹¹ , -8 (О) (ОК ¹¹ ), -8 (О) 2 (ОК ¹¹ ) or -8О2ЫК ¹¹ К ¹² ;

K ⁷ represents H, -C (= O) K ¹¹ , -C (= O) OK ¹¹ , -C (= O) LK ¹¹ K ¹² , -C (= O) 8K ¹¹ , -8 (O) K ¹¹ , -8 (О) ₂ К ¹¹ , -8 (О) (ОК ¹¹ ), -8 (О) 2 (ОК ¹¹ ), -8О2ЫК ¹¹ К ¹² or

each Υ or Υ ¹ is independently O, 8, YK, + Y (O) (K), Y (OK), + Y (O) (OK) or Y-YK ₂ ;

A ¹ and A ² taken together are -Υ ³ (€? (Ρ? ') ₂ ) ₃ Υ ³ -; or one of A ¹ or A ² , together with either K ³ or

K ⁴ is —Υ ³ -, and the other A ¹ or A ² is formula 1a; or A ¹ and A ² each independently, a group of formula 1a:

Formula 1a where each Υ ² is independently a bond, O, CK ₂ , YK, + Y (O) (K), Y (OK), + Y (O) (OK), YK ₂ , 8, 8-8, 8 (O) or 8 (O) ₂ ;

each Υ ³ represents, independently, O, 8 or ΝΒ;

M2 is 0, 1 or 2;

each K ^x represents independently K ^y or the formula:

where each M1a, M1c and WE represents independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

each K ^y is, independently, H, P, C1, Br, I, OH, K, -Ο ^ Υ '^ ^^ Υ ^ Κ -C (= ^ LC) 2, -Ν ^ β, - ^ ( KY -8K, -8 (O) K, -8 (BCC, -8 (O) (OK), -8 (OZ (OK), -OS (= ^) K, -OS (= ^) OK, - OS ^ Д ^ КЬ), -86 (= ^) ^, ^ С ^ Г ^ ОК, ^ С ^ Х ^ КЬ), -Ν ^ Ό ^ Υ ^ Ε, -ЖК) С (= ^) ОК, - ^ K) C (= ^) LCD, ^ 0 ^ K ^ -CH- ₃ , GO3, -OK or A ³ ; or, taken together, two To ^at the same carbon atoms form carbocyclic rings of from 3 to 7 carbon atoms;

each K independently represents H, (C'-C ₈ ) alkyl, (C'-C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocyclyl, C ₂ -C ₂₀ substituted heterocyclyl, arylalkyl or substituted arylalkyl ;

A ³ is A ⁴ or A ⁵ ; A ⁴ is R, -C (= Υ ¹⁾ K ^y -SSU e A ^5, or ^at -8O2K -8O2A ^5; and A ⁵ is a carbocycle or heterocycle, where A ^{5 is} independently substituted with 0 to 3 groups K ^y ;

each X ¹ or X ² independently represents CK ¹⁰ or Ν;

each K ⁸ is halogen, NK ¹¹ K ¹² , ^ K ^ OK ¹¹ , Ν ^ ΝΗ ¹ '^ ² , Ν3, NΟ, NΟ2, ССО, SI - € Η (= Νβ. ^π ), -CH = NNNA ¹¹ , -C ^^ OK ¹¹ ), -CH (OK ¹¹ ) 2, -C ^ ОЖ ¹¹ ^ ² , -С ^ Ж ¹¹ ^ ² , -С (= О) ОК ¹¹ , (С'-С ₈ ) alkyl , (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocyclylalkyl, optionally substituted aryl,

- 5 026523 optionally substituted heteroaryl, -C (= O) _(C1-C8) alkyl, -δ (Θ) Ν (Οι -Ο ₈₎ alkyl, aryl (C ₁ -C ₈₎ alkyl, OK or 8K ^{11 11} ;

each K ⁹ and K ¹⁰ independently represents H, halogen, ΝΚ ¹¹ Κ ¹² , Ν (Κ ¹¹ ) ΘΚ ¹¹ , ΝΚ ¹¹ ΝΚ ¹¹ Κ ¹² , Ν3, ΝΘ, ΝΘ2, CHO, SL, -CH (== ΝΚ ¹¹ ), - € Η = ΝΗΝΚ ^Π , -CH = ^ OK ^P ), -CH (OK ¹¹ ) 2, - € (= Θ) ΝΚ ^η Κ ¹² , - ^ = δ) ΝΚ ^π Κ ¹² , -С (= O) OK ¹¹ , K ¹¹ , OK ¹¹ or δΚ ¹¹ ;

each K ¹¹ or K ¹² independently represents H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, optionally substituted aryl optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, ^ (O) _P (O! —C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or K ¹¹ and K ¹² , taken together with the nitrogen to which they are both attached, form from 3 to 7 membered heterocyclic rings, where any one carbon atom of said heterocyclic ring may be optionally replaced by -O-, -δ- or -ΝΕ. ' ¹ -;

where each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of each K ¹ , K ³ , K ⁴ , K ⁵ , K ⁶ , K ¹¹ or K ¹² is independently optionally substituted with one or more halogens, hydroxy, ΟΝ, Ν3, ΝΙΡ / 'ρ or OK ^a ; and wherein one or more of the nonterminal carbon atoms of each said _(C1-C8) alkyl may optionally be replaced by -O-, -δ- or -ΝΡ ^Η -,

In one embodiment of Formula II, K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl, or (C2-C8) alkynyl. In another aspect of this embodiment, K ¹ is (C1- _C8 ) alkyl. In another aspect of this embodiment, K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ¹ is methyl. In another aspect of this embodiment, K ¹ represents a _(C1-C8) alkyl, and R ⁶ is H. In another aspect of this embodiment, K ¹ represents a (C1-C8) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ¹ is (C1-C ₈ ) alkyl and K ⁶ is SI, OH or CH ₃ .

In one embodiment of Formula II K ³ is H, ^and OK, M (R ^a) 2, Ν3, SC, δ ^ ^1, halogen, _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈ ) alkynyl. In one aspect of this embodiment, K ³ is H. In another aspect of this embodiment, K ³ is H and K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl, or (C2-C8) alkynyl. In another aspect of this embodiment, K ¹ represents H and R ¹ is (C 1 -C ₈₎ alkyl. In another aspect of this embodiment, K ³ is H and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ³ is H and K ¹ is methyl. In another aspect of this embodiment, K ³ is H, K ¹ is (C1- _C8 ) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ³ is H, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ³ is H, K ¹ is (C1-C8) alkyl, and K ⁶ is CM, OH, or CH3. In another aspect of this embodiment, K ³ represents H, K ¹ represents methyl, and K ⁶ represents N.

In one embodiment of Formula II K ⁴ represents H, ^and OK, Ν ^) ^ Ν3, CN, δ ^ ^1, halogen, _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ - C ₈ ) alkynyl. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈₎ alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is CH, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is SP, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and K ⁶ is SP, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is SP, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In one embodiment of Formula II K ⁵ represents H, ^and OK, Ν ^) ^ Ν3, CO, δ ^ ^1, halogen, _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ - C ₈ ) alkynyl. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈₎ alkynyl. In another aspect of this embodiment

- 6 026523

K ⁴ represents OK ³ , and K ¹ represents (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is CH OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is CH, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and K ⁶ is CH OH or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is OH, OH, or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁵ is H.

In another aspect of the embodiment of Formula II, K ⁵ is H. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a , and K ¹ is (C1C8) alkyl, (C2-C8) alkenyl, or (C2-C8) alkynyl. In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈₎ alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K is OK ^a , K is is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C ₈ ) alkyl, and K ⁶ is ΟΧ, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is OX, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OH, K ¹ is is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and K ⁶ is OH, OH or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is OH, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula II, K ⁶ is H, OX, OK ^a or CH ₃ . In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is CH. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈₎ alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C ₁ -C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is SC, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is CM, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OH, K ¹ represents methyl, and at least one of X ¹ or X ² represents N. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and K ⁶ is CH, OH or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ^{1 is} pre-7 026523

is methyl, and K ⁶ is CH, OH or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula II, K ⁶ is CO, OK ^a, or CH3. In another aspect of this embodiment, K ⁶ is CO. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In another aspect of this embodiment, K is OK ^a , and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is SY, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is CO, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is L. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is S. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and K ⁶ is CH, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is CH, OH, or CH3.

In one embodiment of Formula II, K ⁷ ίκ H, -C (= O) K ¹¹ , -C (= O) OK ¹¹ , -C (= O) 8K ¹¹ or o and ¹ and ² .

In an aspect of this embodiment, K ⁷ is H. In another aspect of this embodiment, K ⁷ is —C (═O) K ¹¹ . In another aspect of this embodiment, K ⁷ is —C (═O) K ¹¹ , where K ¹¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, K ⁷ is about

νν ¹ νν ² ,

In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is CO. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈₎ alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is L. In another aspect of this embodiment, K ⁴ is OK ^a , K is methyl, and at least one of X ¹ or X ² is S. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is CH, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is CO, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is L. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is S. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and K ⁶ is CH, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is CH, OH, or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In one embodiment of Formula II, X ¹ is S or CK ¹ 0. In another aspect of this embodiment, X ¹ is S. In another aspect of this embodiment, X ¹ is CK ¹ 0. In another aspect of this embodiment X ² is C H. In another aspect of this embodiment, X ¹ represents Ν and X ² represents CH. In another aspect of this embodiment, X ¹ is CK ¹⁰ , and X ² is CH. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is ΟΝ. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K is ^{4 and} OK, and R ¹ represents a _(C1-C8) alkyl, (C ₂ -C ₈₎ alkenyl or (C ₂ -C ₈₎ alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is ΟΝ, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C ₈ ) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and K ⁶ is ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is ΟΝ, OH or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula II, each K ⁸ is independently halogen, MK ¹¹ K ¹² , ^ K ^P ) OK ^P , ΝΕ ^ ΝΕ. ¹¹ ^ ² , OK ¹¹ or 8K ¹¹ . In another aspect of this embodiment, K is methyl, CH2P or ethynyl. In another aspect of this embodiment, K ¹ is methyl. In another aspect of this embodiment, K ⁹ is H, halogen, or MK ¹¹ K ¹² . In another aspect of this embodiment, K ⁹ is H, halogen, or MK ¹¹ K ¹² , and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁹ is H, halogen, or MK ¹¹ K ¹² and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is MH 2 and K ⁹ is H or halogen. In another aspect of this embodiment, K ⁸ is ΝΉ2 and K ⁹ is H or halogen, and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁸ is ΝΉ2, and K ⁹ is H or halogen, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ and K ⁹ are each MH2. In another aspect of this embodiment, K ⁸ and K ⁹ are each ΝΉ 2 and K ¹ is methyl. In another aspect of this embodiment, K ⁸ and K ⁹ are each MH2, and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁸ is OH and K ⁹ is ΝΉ2. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΉ2, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΉ2, and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is ΟΝ. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl, (C2-C8) alkenyl, or (C2-C8) alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C ₈ ) alkyl, and K ⁶ is ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and K ⁶ is ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

- 9 026523

In another embodiment of Formula II, each is independently H, halogen, CO, or optionally substituted heteroaryl. In another aspect of this embodiment, K ¹ is methyl. In another aspect of this embodiment, K ¹ is methyl, CHDR or ethynyl. In another aspect of this embodiment, K ⁹ is H, halogen, or BK ¹¹ K ¹² . In another aspect of this embodiment, K ⁹ is H, halogen, or BK ¹¹ K ¹² , and K ¹ is methyl. In another aspect of this embodiment, K ⁹ is H, halogen, or BK ¹¹ K ¹² , and K ¹ is methyl, CHDR or ethynyl. In another aspect of this embodiment, K ⁸ is ΝΗ2, and K ⁹ is H or halogen. In another aspect of this embodiment, K ⁸ is ΝΗ2, and K ⁹ is H or halogen, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is ΝΗ2, and K ⁹ is H or halogen, and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁸ and K ⁹ are each ΝΗ2. In another aspect of this embodiment, K ⁸ and K ⁹ are each ΝΗ2, and K ¹ is methyl.

In another aspect of this embodiment, K ⁸ and K ⁹ are each ΝΗ 2, and K ¹ is methyl, C ^ P or ethynyl. In another aspect of this embodiment, K ¹ is OH and K ⁹ is ΝΗ2. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΗ2, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΗ2, and K ¹ is methyl, C ^ P or ethynyl. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ represents Cu, In another aspect of this embodiment, K ⁴ represents H or OK ^{as well.} In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C _g C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is (C1-C8) alkyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is (C1-C8) alkyl, and K ⁶ is C ^ OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is C ^ OH or SS. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is itself N. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is (C1-C8) alkyl, and K ⁶ is C ^ OH or SS. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ represents C ^ OH or SS. In another aspect of this embodiment, K ⁴ represents OH, K ¹ represents methyl, and K ⁶ represents N.

In another embodiment, the compounds of formula I or formula II are represented by formula III:

or a pharmaceutically acceptable salt thereof;

where K ¹ represents C ^, C ^ P or ethynyl, and all other variables are defined as for formula I.

In one embodiment of Formula III, K ⁴ is H, OK ^a , Ν (^) 2, Ν3, C ^ 8K ^a , halogen, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl . In another aspect of this embodiment, K represents H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is ΟΗβ, C ^ P or ethynyl. In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is C ^ OH or SS. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is by itself. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is N. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ represents SC, OH or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula III, K ⁶ is H, CK, OK ^a or CH3. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is SC, OH, or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is SC, OH, or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula III, K ⁶ is SC, OK ^a or CH3. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is SC, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is SC, OH, or CH ₃ .

In another embodiment of Formula III, K ⁷ is H, —C (= O) K ¹¹ , —C (= O) OK ¹¹ , —C (= O) 8K ^11, or o

and ¹ νν ² .

In an aspect of this embodiment, K ⁷ is H. In another aspect of this embodiment, K ⁷ is —C (═O) K ¹¹ . In another aspect of this embodiment, K ⁷ is —C (═O) K ¹¹ , where K ¹¹ is (C ₁ -C ₈ ) alkyl. In another aspect of this embodiment, K ⁷ is about νν ¹ ν®.

In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is K. In another aspect of this embodiment K ⁴ is OK ^a , K ¹ is methyl , and K ⁶ represents SC, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is K. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ represents SC, OH or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In one embodiment of Formula III, X ¹ is K or CK ¹⁰ . In another aspect

- 11 026523 of this embodiment X ¹ represents N. In another aspect of this embodiment X represents CK ¹⁰ . In another aspect of this embodiment, X ² is CH. In another aspect of this embodiment, X ¹ represents Ν and X represents CH. In another aspect of this embodiment, X ¹ is CK ¹⁰ , and X ² is CH. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is SC, OH, or CH3. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is SC, OH, or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula III, each K ⁸ is independently halogen, KK ¹¹ K ¹² , K (K ¹¹ ) OK ¹¹ , KK ¹¹ KK ¹¹ K ¹² , OK ¹¹ or 8K ¹¹ . In another aspect of this embodiment, K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ¹ is methyl. In another aspect of this embodiment, K ⁹ is H, halogen, or KK ¹¹ K ¹² . In another aspect of this embodiment, K ⁹ is H, halogen, or KK ¹¹ K ¹² , and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁹ represents H, halogen or KK ¹¹ K ¹² , and K ¹ represents methyl. In another aspect of this embodiment, K ⁸ is ΝΚ. and K ⁹ represents H or halogen. In another aspect of this embodiment, K ⁸ is ΝΉ ₂ , and K ⁹ is H or halogen, and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁸ is ΝΉ2, and K ⁹ is H or halogen, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ and K ⁹ are each Ν _{4 2} . In another aspect of this embodiment, K ⁸ and K ⁹ are each KH 2, and K ¹ is methyl, CH 2 P, or ethynyl. In another aspect of this embodiment, K ⁸ and K ⁹ are each ΝΉ2, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is OH and K ⁹ is ΝΉ2. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΉ2, and K ¹ is methyl, CH2P, or ethynyl. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΉ2, and K ¹ is methyl. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH3. In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is ΗΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is ΗΝ, OH or CH ₃ . In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

In another embodiment of Formula III, each K ¹⁰ is independently H, halogen, ΗΝ, or optionally substituted heteroaryl. In another aspect of this embodiment, K ¹ is methyl. In another aspect of this embodiment, K ⁹ is H, halogen, or ΝΡ.Ρ. ¹² . In another aspect of this embodiment, K ⁹ is H, halogen or νΕΎι and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is ΝΉ2, and K ⁹ is H or halogen. In another aspect of this embodiment, K ⁸ is ΝΉ2, and K ⁹ is H or halogen, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ and K ⁹ are each ΝΉ2. In another aspect of this embodiment, K ⁸ and K ⁹ are each HH 2, and K ¹ is methyl. In another aspect of this embodiment, K ⁸ is OH and K ⁹ is ΝΉ2. In another aspect of this embodiment, K ⁸ is OH, K ⁹ is ΝΉ2, and K ¹ is methyl. In another aspect of this embodiment, K ⁶ is H. In another aspect of this embodiment, K ⁶ is SC. In another aspect of this embodiment, K ⁶ is OK ^a . In another aspect of this embodiment, K ⁶ is OH. In another aspect of this embodiment, K ⁶ is CH ₃ . In another aspect of this embodiment, K ⁴ is H or OK ^a . In another aspect of this embodiment, K ⁴ is OK ^a and K ¹ is methyl. In another aspect

- 12 026523 of this embodiment K ⁴ is OK ³ , K ¹ is methyl and at least one of X ¹ or X ² is N. In another aspect of this embodiment K is OK ^a , K ¹ is methyl and K ⁶ represents ΟΝ, OH or CH3. In another aspect of this embodiment, K ⁴ is OK ^a , K ¹ is methyl, and K ⁶ is H. In another aspect of this embodiment, K ⁴ is OH and K ¹ is methyl. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and at least one of X ¹ or X ² is Ν. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is CX OH or CH3. In another aspect of this embodiment, K ⁴ is OH, K ¹ is methyl, and K ⁶ is H.

or their pharmaceutically acceptable salts;

where K ¹ represents (C ₁ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl , (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

K ² is halogen;

K ³ , K ⁴ and K ⁵ are each independently H, halogen, OK ^a , ZhK``) 2. Ν3, ΟΝ, ΝΟ2, 8 (A) ^and pK, _(C1-C8) alkyl, (C ₄ -C ₈₎ carbocyclylalkyl, (C ₁ -C ₈₎ substituted alkyl, (C ₂ -C ₈₎ alkenyl, ( C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl or aryl (C ₁ -C ₈ ) alkyl;

or any two of K ³ , K ⁴ or K ⁵ on adjacent carbon atoms taken together are —O (CO) Oily, taken together with the carbon atoms of the ring to which they are attached, form a double bond;

each n is independently 0, 1 or 2;

each K ^a is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C2-C8) alkyl, (C4-C8) carbocyclylalkyl, -С (= О) К ¹¹ , -С (= О) ОК ¹¹ , -С (= О№ ^П К ¹² , -С (= О) 8К ¹¹ , -§ (О) К ¹¹ , -8 ( O) 2K ¹¹ , -§ (O) (OK ¹¹ ), -§ (O) 2 (OK ¹¹ ) or ^ ΝΕ ¹¹ ^ ² ;

K ⁷ represents H, -C (= O) K ¹¹ , -C (= O) OK ¹¹ , -C (= О№ ^П К ¹² , -С (= О) 8К ¹¹ , -§ (О) К ¹¹ , ^ (Bcc ¹¹ , -8 (O) (OK ¹¹ ), -§ (O) 2 (OK ¹¹ ), ^ ΝΕ. ¹¹ ^ ² , or γ

Υ represents O, δ, ΝΡ, ^ (О) (К), ЖОК), ^ (О) (ОК) or Ν-ΝΕ ₂ ; V ¹ and V ² taken together are -Υ ^^^ βΥ ³ -; or one of V ¹ or V ² , together with either K ³ or K ⁴ , represents —Υ ³ -, and the other V ¹ or V ² represents formula 1a; or

V ¹ and V ² are each independently a group of formula 1Aa:

Formula 1Aa where each Υ ¹ is, independently, О, δ, ΝΕ ^ (О) (К), ЖОК), ^ (О) (ОК), or Ν-ΝΕ2; each Υ ² independently represents a bond, O, CK2, ΝΕ, ^ (O) (K), ZhOK), ^ (O) (OK), Ν-ΝΕ ₂ , δ, δ-δ, δ (Ό) or 8 (O) ₂ ;

each Υ ³ is independently O, δ or ΝΡ;

M2 is 0, 1 or 2;

each K ^x represents a group of formula 1Yb:

- 13 026523

where each M1a, M1c and M1b is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

each K ^y represents, independently, H, P, C1, Br, I, OH, -C (= Y ¹ ) K, -C (= Y ¹ ) K ¹³ , -C (= Y ¹ ) OK, -C (= Y ¹ ) S (K) 2, -Ν (Κ) 2, - + Ν (Κ) 3, -δΚ, -δ (Ο) Κ, -δ (Ο ^ Κ, -δ (Ο) 2Κ ¹³ , -δ (Ο) (ΟΚ), -δ (ΟΧ (ΟΚ), -ОС (= У ¹ ) К, -ОС (= у ¹ ) ОК, -Ο ^ γ'χ ^ κρ), -δ® ν ') Κ. -δ® ν'ιΟκ. -δ ^ = γ ³ ) (Ν (Κ) 2), -νκ ^^ υ ^ κ, -Ν ^^^ Υ ^ ΟΚ, -ΝζΚ ^^ Υ ^ ΝζΚχ, -δΟ2ΝΚ ₂ , -MF -Ν ₃ , -ΝΟ ₂ , -ΟΚ, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl, heteroarylalkyl;

where each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl or heteroarylalkyl is optionally substituted with 1-3 Κ ²⁰ groups;

or, taken together, two To ^at the same carbon atoms form carbocyclic rings of from 3 to 7 carbon atoms;

each Κ independently represents H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl or arylalkyl;

δ (Ο) .. Κ each Κ ⁸ represents halogen, ΝΚΚ ¹² , Ν (Κ ^ΙΙ ) ΟΚ ¹¹ , ΝΚ ¹¹ ΝΚ ¹¹ Κ ¹² , Ν ₃ , ΝΟ, ΝΟ ₂ , ΟΚ ¹¹ or each Κ ⁹ represents, independently , H, halogen, ΝΚ ¹¹ Κ ¹² , Ν (Κ ¹¹ ) ΟΚ ¹¹ ,

- ^ (ΟΚ ¹ /, ^ (= Ο) ΝΚ ¹¹ Κ ¹² ,

ΝΚ ¹¹ ΝΚ ¹¹ Κ ¹² , Ν ₃ , ΝΟ, ^ (= δ) ΝΚ ¹¹ Κ ¹² ,

ΝΟ ₂ , CHO, SK, -ΟΒ (= ΝΚ), -Ο ^ ΝΉΝΚ, ^^ ΝΟΚ ¹¹ ),

- ^ = Ο) ΟΚ ^Π , Κ ¹¹ , ΟΚ ¹¹ or δ (Ο) ηΚ ¹¹ ;

each Κ ¹¹ or Κ ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, optional substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, ^ (O) _p (C ^ C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl; or Κ ¹¹ and Κ ¹² , together with the nitrogen to which they are both attached, form a 3-7 membered heterocycle, where any carbon atom of said heterocyclic ring may optionally be replaced with -O-, -δ- or -ΝΚ ¹ -;

each Κ ¹³ is independently a carbocycle or heterocycle optionally substituted with 1-3 1-320 groups;

each Κ ²⁰ is, independently, halogen, SC, Ν ₃ , Ν (Κ) ₂ , ΟΚ, -δΚ, -δ (Ο) Κ, -δ (Ο) ₂ Κ, -δ (Ο) (ΟΚ), -δ (Ο) 2 (ΟΚ), -С (= ^) К -С (= ^ Ж or С ^ Ж ^;

where each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of each Κ ¹ , Κ ³ , Κ ⁴ , Κ ⁵ , Κ ⁶ , Κ ¹¹ or Κ ¹² is, independently, optionally substituted with one or more halogens, hydroxy, CM, Ν3, Ν (Κ ^{Ι: ι} ) 2 or ΟΚ ¹ ; and where one or more non-terminal carbon atoms of each of the indicated (C ₁ -C ₈ ) alkyl may optionally be replaced by -O-, -δ- or -ΝΚ ¹ ;

each Κ ¹ is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₁ -C ₈ ) alkyl, (C ₄ -С ₈ ) carbocyclylalkyl, -С (= О) Я ²¹ , -Ο = Ο) ΟΚ ²¹ , -С (Ο) \ Κ Κ ² \ <(= Ο) δΚ ²¹ , -δ (Ο) Κ ²¹ , - δ (Ο) 2Κ ²¹ , -δ (Ο) (ΟΚ ²¹ ), -δ (Ο) 2 (ΟΚ ²¹ ) or -δΟ2ΝΚ ²¹ Κ ²² ;

each Κ ²¹ or Κ ²² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, - C (= O) (C ₁ -C ₈ ) alkyl, ^ (O) _n (C ^ C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl;

with the optional condition that compounds 1, 1b, 1e, 2, TP-1, A-1, 8 and 21 are excluded.

In another aspect of this embodiment, γ and γ ¹ is O. In another aspect of this embodiment, Κ ⁸ is halogen, ΝΚ ¹¹ Κ ¹² , Ν (Κ ¹¹ ) ΟΚ ¹¹ , ΝΚ ¹¹ ΝΚ ¹¹ Κ ¹² , ΟΚ ¹¹ or δ (Ο ) ηΚ ¹¹ . In another aspect of this embodiment, Κ ⁹ is H, halogen, δ (Ο) ηΚ ^11, or ΝΚ ¹¹ Κ ¹² . In another aspect of this embodiment, Κ ⁴ is OK '. In another aspect of this embodiment, Κ ¹ is CH ₃ . In another aspect of this embodiment, Κ ² is P. In another aspect of this embodiment, Κ is

where Υ is —O—; XV ¹ represents the formula kg and XV ² , together with Κ ⁴ , represents -O-. In another embodiment, the compounds of formula 1U are represented by formula Y:

- 14 026523

where K ¹ represents methyl or ethynyl and K ⁴ represents OK ^a . In another aspect of this embodiment, K ⁷ is H or

In another aspect of this embodiment, the compounds of formula V are represented by the following structures:

In another embodiment, provided are compounds of formula VI:

or a pharmaceutically acceptable salt thereof; Where

K ⁴ is OK ^a ;

each η is independently 0, 1 or 2;

each K ^a independently represents H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, -С (= О) К ¹¹ , -С (= О) ОК ¹¹ , -С (= О) LK ¹¹ К ¹² , -С (= О) 8К ¹¹ , -§ (О) К ¹¹ , -8 (О ) 2K ¹¹ , -§ (О) (ОК ¹¹ ), -§ (О) 2 (ОК ¹¹ ) or -§О2ЫК ¹¹ К ¹² ;

K ⁷ represents H, -C (= O) K ¹¹ , -C (= O) OK ¹¹ , -C (= O) LK ¹¹ K ¹² , -C (= O) 8K ¹¹ , -§ (O) K ¹¹ , -5 (O) _; H. -8 (O) (OK ¹¹ ), -§ (O) 2 (OK ¹¹ ), -§О2ЫК ¹¹ К ¹² or

- 15 026523

Υ represents O, δ, ΝΚ, + Ν (Ο) (Κ), Ν (ΘΚ), + Ν (Ο) (ΟΚ) or Ν-ΝΚ ₂ ;

V ¹ and V ² taken together are -Υ ³ (Ο (Κ ^γ ) ₂ ) ₃ Υ ³ -; or one of V ¹ or V ² , together with Κ ⁴ , is —Υ ³ -, and the other V ¹ or V ² is formula 1a;

or

V ¹ and V ² each independently represents a group of the formula UTa:

Formula Y1a where each Υ ¹ is independently O, δ, ΝΚ, + Ν (Ο) (Κ), Ν (ΟΚ), + Ν (Ο) (ΟΚ) or Ν-ΝΚ2; each Υ ² is independently a bond, O, CB2, ΝΚ, + Ν (Ο) (Κ), Ν (ΟΚ), + Ν (Ο) (ΟΚ), Ν-ΝΚ ₂ , δ, δ-δ, δ ( Ο) or δ (Ο) 2;

each Υ ³ is independently O, δ or ΝΚ;

M2 is 0, 1 or 2;

each Κ ^χ represents a group of the formula UT:

where each M1a, M1c and WE represents independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

each Κ ^γ independently represents H, P, C1, Br, I, OH, -0 (= Υ ¹ ) Κ, -0 (= Υ ¹ ) Κ ¹³ , -Ο (= Υ ¹ ) ΟΚ, -0 (= Υ ¹ ) Ν (Κ) 2, -Ν (Κ) 2, - + Ν (Κ) 3, -δΚ, -δ (Ο) Κ, -δ (Ο) 2Κ, -δ (Ο) 2Κ ¹³ , - δ (Ο) (ΟΚ), -δ (Ο) 2 (ΟΚ), -Ο ^ Υ ^ Κ, -Ο ^ Υ ^ ΟΚ, -Ο ^ Υ ¹ ) ^^), -δ ^ = Υ ^ Κ, -δ ^ Υ ^ ΟΚ, -δ ^ = Υ ¹ ) (Ν (Κ) 2), -Ν ^ Ό ^ Υ ^ Κ, -Ν ^^ Υ ^ ΟΚ, -Ν ^^ Υ ¹ ) ^^, - δΟ2ΝΚ2, -SK, -Ν3, -ΝΟ2, -ΟΚ, (С ^ Ся) alkyl, (С2-С) alkenyl, (С2-С) alkynyl, С6-С20 aryl, С ₃ -С ₂₀ carbocyclyl, С ₂ - C ₂₀ heterocyclyl, arylalkyl, heteroarylalkyl;

where each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C ₃ -C ₂₀ carbocyclyl, C ₂ -C ₂₀ heterocyclyl, arylalkyl or heteroarylalkyl is optionally substituted with 1-3 B ²⁰ groups;

each независимо independently represents H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, C ₆ -C ₂₀ aryl, C3-C20 carbocyclyl, C2-C20 heterocyclyl or arylalkyl;

each Κ ¹¹ or Κ ¹² is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, optionally substituted aryl optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, —δ (Ο) _η (θ! - ^) alkyl or aryl (C ₁ -C ₈ ) alkyl;

each Κ ¹³ is, independently, a carbocycle or heterocycle optionally substituted with 1-3 B ²⁰ groups;

each Κ ²⁰ is independently halogen, ΟΝ, Ν ₃ , Ν (Κ) ₂ , ΟΚ, -δΚ, -δ (Ο) Κ, -δ (Ο) ₂ Κ, -δ (Ο) (ΟΚ), -δ (Ο) 2 (ΟΚ), -С (= ^) К -С (= ^ Ж or ^ = Υ ¹ ) Ν (Κ) 2;

where each (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl or aryl (C ₁ -C ₈ ) alkyl of each Κ ⁴ , Κ ¹¹ or Κ ¹² is, independently, optionally substituted with one or more halo, hydroxy, SI, Ν3, Ν (Κ) 2 or ΟΚ ¹³ ; and wherein one or more non-terminal carbon atoms of each said _(C1-C8) alkyl may optionally be replaced by -O-, -δ- -ΝΚ or ^3;

each Κ ³ is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl (C ₂ -C ₈ ) alkyl, (C ₄ -C ₈ ) carbocyclylalkyl, - € (= Ο) Κ ²¹ , -Π ^ ΟΚ ²¹ , -ϋ ^ ΝΚ ^ Κ ²² , ^ (= Ο) δΚ ²¹ , -δ (Ο) Κ ²¹ , -δ (Ο) 2Κ ²¹ , -δ (Ο) (ΟΚ ²¹ ), -δ (Ο) 2 (ΟΚ ²¹ ) or -δΟ2ΝΚ ²¹ Κ ²² ;

each Κ ²¹ or Κ ²² is independently H, (C ₂ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, - C (= O) (C ₁ -C ₈ ) alkyl, ^ (Ο) ,, ^ - ^) alkyl or aryl (C ₂ -C ₈ ) alkyl; and with the optional condition that compounds 1, 1c, S, 1e, 2, TP-1, A-1, 8 and 21 are excluded.

In another aspect of this embodiment, K 'is H, (C ₁ -C ₈ ) alkyl or —C (═O) (C ₁ -C ₆ ) alkyl; Κ ⁷ or Κ ⁷ together with Κ ⁴ represents

- 16 026523

where a is the point of attachment to K ⁷ ;

B is the point of attachment to K ⁴ ;

Ag is phenyl or naphthyl, wherein phenyl and naphthyl are optionally substituted with 1-3 to ²⁰ groups;

each K ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, where alkyl and carbocyclyl are optionally substituted with 1-3 K ²⁰ groups;

each K independently represents H, (C ₁ -C ₆ ) alkyl or arylalkyl; and each К ²⁰ independently represents halogen, СЫ, Ν (Κ) ₂ , ОК, -§К, -§ (О) К, -§ (О) ₂ К, -8 (О) (ОК), -5 ( O) 2 (OK), -C (= O) K, -C (= O) OK or C (= O) S (K) 2.

In another embodiment, the compounds of formulas 1U-U1 are represented by compounds having the structure:

- 17 026523

or their pharmaceutically acceptable salts.

In one embodiment of the formulas and formulas GU-U! K ¹¹ or K ¹² independently represents H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₄ -C ₈ ) carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C (═O) (C ₁ -C ₈ ) alkyl, -8 (O) _P (C ₁ -C ₈ ) alkyl or aryl (C ₁ -C ₈ ) alkyl. In another embodiment, K ¹¹ and K ¹² , taken together with the nitrogen to which they are both attached, form a 3 to 7 membered heterocycle, where any carbon atom of said heterocyclic ring may optionally be replaced with -O-, -8- or -IR ^a -. Thus, by way of example, but not limitation, the residue —IR ¹¹ K ¹² can be represented by heterocycles:

and the like.

In another embodiment of the formulas and formulas RU-UT, each K ³ , K ⁴ , K ⁵ , K ⁶ , K ^11, or K ¹² is, independently, (C1-C8) alkyl, (C2-C8) alkenyl, (C2- C8) alkynyl or aryl (C1-C8) alkyl, wherein said (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or aryl (C1-C8) alkyl is independently, optionally substituted with one or more halo, hydroxy, CH H, NK ^a ) 2 or OK ^a . Thus, by way of example, but not limitation, K ³ , K ⁴ , K ⁵ , K ⁶ , K ^11, or K ¹² may represent fragments such as —CH (] UN2) CH3, —CH (OH) CH2CH3, - C11 (M MS11 (C11 _; ), -CH2CH3, - (CH2) 2CH (H) CH3, - (CH ^^ H and the like.

In another embodiment, the formulas YP and formulas SHU K ³ , K ⁴ , K ⁵ , K ⁶ , K ¹¹ or K ¹² is (C ₁ -C ₈ ) alkyl, where one or more nonterminal carbon atoms of each specified (C ₁ -C ₈ ) alkyl, optionally, may be replaced by -O-, -8-or -IK ^a -. Thus, by way of example, but not limitation, K ³ , K ⁴ , K ⁵ , K ⁶ , K ^11, or

K ¹² may represent fragments such as —CH ₂ OCH ₃ , —CH ₂ OCH ₂ CH ₃ , —CH ₂ OCH (CH ₃ ) ₂ , —CH ₂ 8CH ₃ , - (CH ₂ ) ₆ OCH ₃ , - (CH ₂ ) _& And (CH ₃ ) ₂ and the like.

- 18 026523

In another embodiment, formulas are a compound selected from the group consisting of

- 19 026523

- 20 026523

or a pharmaceutically acceptable salt or ester thereof.

In another embodiment, a compound useful for the synthesis of compounds of formula I selected from the group consisting of

or their salts or esters.

- 21 026523

Definitions

Unless otherwise specified, the following terms and phrases used here are intended to be understood in the following meanings.

When trademarks are used here, applicants intend to independently include the brand name of the product and the active pharmaceutical ingredient (s) of the brand name product.

As used herein, a compound of the invention or a compound of formula I means a compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, in relation to excreted intermediates, the phrase compound of formula (number) means a compound of this formula and its pharmaceutically acceptable salts.

Alkyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, alkyl groups can have from 1 to 20 carbon atoms (e.g., C ₁ -C ₂₀ alkyl), from 1 to 8 carbon atoms (e.g., C ₁ -C ₈ alkyl), or 1 to 6 carbon atoms (e.g., C ₁ -C ₆ alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, —CH ₃ ), ethyl (Εΐ, —CH ₂ CH ₃ ), 1-propyl (p-Pr, η-propyl, —CH ₂ CH ₂ CH ₃ ), 2-propyl (ί-Pr, ί-propyl, -CH (CH ₃ ) ₂ ), 1-butyl (p-Vi, η-butyl, -CH ₂ Sn ₂ CH ₂ CH ₃ ), 2-methyl- 1-propyl (ί-Vi, ί-butyl, -CH ₂ CH (Sn ₃ ) ₂ ), 2-butyl (8-Vi, 8-butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl -2-propyl (ΐ-Vi, ΐ-butyl, -C (CH ₃ ) ₃ ), 1-pentyl (pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2 butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2methyl-1-butyl (-CH ₂ CH (C H ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH2CH2CH2CH3), 3 hexyl (-CH (CH2CH3) ( CH2CH2CH3)), 2 methyl-2-pentyl (-C (CH3) 2CH2CH2CH3), 3methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl -2-pentyl ( -CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3pentyl (-C (CH3) (CH2CH3) 2), 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH3) 2), 2,3-dimethyl-2-butyl (-C (CH3) 2 CH (CH3) 2), 3,3-dimethyl-2-butyl (-CH (CH3) C (CH3) 3 and octyl (- (CH ^ CH3).

Alkoxy means a group having the formula —O-alkyl, in which alkyl, as defined above, is attached to the parent molecule through an oxygen atom. The alkyl part of the alkoxy group may have from 1 to 20 carbon atoms (e.g., C ₁ -C ₂₀ alkoxy), from 1 to 12 carbon atoms (e.g., C ₁ C ₁₂ alkoxy), or 1 to 6 carbon atoms (e.g., C ₁ -C ₆ alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (—O — CH ₃ or —OMe), ethoxy (—OCH ₂ CH _3, or OE1). tert-butoxy (—O — C (CH ₃ ) ₃ or —O1Bi) and the like.

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 part of the haloalkyl group may have from 1 to 20 carbon atoms (for example, C ₁ -C ₂₀ halogenated), from 1 to 12 carbon atoms (for example, C ₁ -C ₁₂ halogenated) or from 1 to 6 carbon atoms (for example, ₁ -C ₆ alkyl). Examples of suitable haloalkyl groups include, but are not limited to, —CP ₃ , —CHP ₂ —CHP ₂ , —CH ₂ CP _3, and the like.

Alkenyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one unsaturation site, i.e. carbon-carbon, 8p ² double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (e.g., C2-C20 alkenyl), 2 to 8 carbon atoms (e.g., C2-C8 alkenyl), or 2 to 6 carbon atoms (e.g., C ₂ -C ₆ alkenyl ) Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (—CH = CH ₂ ), allyl (—CH ₂ CH = CH ₂ ), cyclopentenyl (—C ₅ H ₇ ), and 5-hexenyl (—CH ₂ CH ₂ CH ₂ CH ₂ CH = CH 2).

Alkynyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one unsaturation site, i.e. carbon-carbon, 8p triple bond. For example, an alkynyl may have from 2 to 20 carbon atoms (e.g., C2-C20 alkynyl), from 2 to 8 carbon atoms (e.g., C ₂ -C ₈ alkynyl,) or 2 to 6 carbon atoms (e.g., C ₂ - C ₆ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylene (—CHCH), propargyl (—CH ₂ C = CH), and the like.

Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two carbon atoms of the starting alkane. For example, an alkylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (—CH ₂ -), 1,1-ethyl (—CH (CH ₃ ) -), 1,2-ethyl (—CH ₂ CH ₂ -), 1,1 propyl (-CH (CH ₂ CH ₃ ) -), 1,2-propyl (-CH ₂ CH (CH ₃ ) -), 1,3-propyl (-CH ₂ CH ₂ CH ₂ -), 1,4 -butyl (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like.

Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two carbon atoms of the starting alkene. For example, an alkenylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2ethylene (—CH = CH—).

Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two carbon atoms of the original alkyn. For example, an alkynylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (—C = C—), propargyl (—CH ₂ C = C—) and 4-pentynyl (—CH ₂ CH ₂ CH ₂ C = C—).

Amino generally refers to a nitrogen radical, which can be considered as an ammonia derivative having the formula —Ы ^) ^ where each X is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc. . Hybridization of nitrogen is about cr ³ . Non-limiting amino types include —YN2, —Y (alkyl) 2, YN (alkyl), —Y (carbocyclyl) 2, —YN (carbocyclyl), —Y (heterocyclyl) 2, —YN (heterocyclyl), —Y (aryl) 2, -YN (aryl), -Y (alkyl) (aryl), -Y (alkyl) (heterocyclyl), -Y (carbocyclyl) (heterocyclyl), -Y (aryl) (heteroaryl), -Y (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 —CH2, —YN (CH3), —Y (CH3) 2, —HN (CH2CH3), —Y (CH ₂ CH ₃ ) ₂ , —YN (phenyl), —Y (phenyl) ₂ , - UN (benzyl), -Y (benzyl) ₂ , etc. Substituted alkylamino generally refers to alkylamino groups as defined above in which at least one substituted alkyl, as defined herein, is attached to a nitrogen amino atom. Non-limiting examples of substituted alkylamino include —YN (alkylene-C (O) —OH), —YN (alkylene-C (O) —O-alkyl), —Y (alkylene-C (O) OH) ₂ , —Y (alkylene-C (O) -O-alkyl) ₂ , etc.

Aryl means an aromatic hydrocarbon radical obtained by removing one hydrogen atom from one carbon atom of the ring system of aromatic parents. For example, an aryl group may have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, diphenyl, and the like.

Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or cr carbon atom, is 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. The arylalkyl group may include from 7 to 20 carbon atoms, for example, the alkyl part is from 1 to 6 carbon atoms, and the aryl part is from 6 to 14 carbon atoms.

Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or kp carbon atom, as well as the carbon atom kp ² , is replaced by an aryl radical. The aryl part of the arylalkenyl may include, for example, any of the aryl groups described herein, and the alkenyl part of the arylalkenyl may include, for example, any of the alkenyl groups described herein. The arylalkenyl group may contain from 8 to 20 carbon atoms, for example, the alkenyl part, comprising from 2 to 6 carbon atoms, and the aryl part, which is from 6 to 14 carbon atoms.

Arylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or kp carbon atom, and also the kp carbon atom, is replaced by an aryl radical. The aryl part of the arylalkynyl may include, for example, any of the aryl groups described herein, and the alkynyl part of the arylalkynyl may include, for example, any of the alkynyl groups described herein. An arylalkynyl group may contain from 8 to 20 carbon atoms, for example, an alkynyl part of 2 to 6 carbon atoms and an aryl part of 6 to 14 carbon atoms.

The term substituted with respect to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, substituted alkyl, substituted alkylene, substituted aryl, substituted arylalkyl, substituted heterocyclyl and substituted carbocyclyl, unless otherwise indicated, means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl, respectively, in which one or more hydrogen atoms, independently of one another, are replaced by non-hydrogen substitute ^b -O ^- , = O, -OK ^b , -8K ^b , -8, L2O2, = L2, -L3, -NNS (= 0) K ^b , -8 (= 0) 2LK ^b 2, -8 (= 0) K ^b , lem. Typical substituents include, but are not limited to, -X, -K

-YK ^b 2, -Y + K ^b 3, YK

-YS8, -YO, -YO _2, -8 (= O) 2-, -8 (= O) 2OH, -8 (= O) 2R ^b, -O8 (= O) 2OK ^b,

-C. \ _; . -SY, -WASP, -8СЫ, -Ы = С = О,

-OS (= O) K ^b , -NS (= O) BK ^b

-OR (= O) (OK ^b ) ₂ , -P (= O) (OK) ₂ , -P (= O) (O) ₂ , -P (= O) (OH) ₂ , -P (O) (OK °) (О), -С (= О) К °, -С (= О) 0 -С (8) К ° -С (О) OK ^b , -С (О) О ^- , -С ( 8) OK ^b , -C (O) 8K ^b , -C (8) 8K ^b , -C (O) \ H \ -C (8) \ K \ -C (LK) \ K \ where each X is independent , represents a halogen: P, C1, Vg or I; and each K ^b independently represents H, alkyl, aryl, arylalkyl, heterocycle or a protective group, or part of a prodrug. Alkylene, alkenylene alkynylene groups can also be easily substituted. Unless otherwise indicated, when the term substituted is used in combination with groups such as arylalkyl that have two or more substituent moieties, substituents may be attached to the aryl part, the alkyl part, or both.

The term prodrug, as used herein, refers to any compound that, when introduced into a biological system, generates a drug substance, i.e. an active ingredient, as a result of a spontaneous chemical reaction (s), enzymatically catalyzed chemical reaction (s), photolysis and / or metabolic chemical reaction (s). A prodrug is thus a covalently modified analogue or latent form of a therapeutically active compound.

Those skilled in the art will understand that substituents and other fragments of the compounds of formulas and formulas Σν-νΣ must be selected in order to provide a compound that is stable enough to provide pharmaceutically useful compounds that can be combined into an acceptable stable pharmaceutical composition . Definitions and substituents of various kinds and subgenus of the present compounds are described and illustrated here. It should be clear to a person skilled in the art that any combination of the definitions and substituents described above should not result in the inoperability of the species or compound. Inoperative species or compounds means the combination of structures that violate relevant scientific principles (such as, for example, a carbon atom attached to more than four covalent bonds), or compounds that are too unstable to allow isolation and association in pharmaceutically acceptable dosage forms.

Heteroalkyl refers to an alkyl group in which one or more carbon atoms is replaced by a heteroatom, such as O, Ν or 8. For example, if the carbon atom of an alkyl group that is attached to the parent molecule is replaced by a heteroatom (for example, O, Ν or 8), the resulting heteroalkyl group is, respectively, an alkoxy group (e.g., OSS, etc.), an amine (e.g., -ΝΗΟΗ ₃ , -Ν (ΟΗ ₃ ) ₂ , etc.) or a thioalkyl group (e.g., -8ΟΗ ₃ ) If a nonterminal carbon atom of an alkyl group that is not attached to the original molecule is replaced by a heteroatom (for example, O, Ν or 8), the resulting heteroalkyl group is, respectively, an alkyl ether (for example, ϋΗ ^ Η-θ- ^, etc. .), alkylamine (e.g. -ί.Ή ₂ ΝΗί'.Ή _3. -ΟΗ ₂ Ν (ΟΗ ₃ ) ₂ , etc.) or thioalkyl ether (e.g., --'.Ή ₂ -8-- '.Ή ₃ ). If the terminal carbon atom of the alkyl group is substituted with a heteroatom (e.g., O, Ν or 8), the resulting heteroalkyl group is, respectively, a hydroxyalkyl group (e.g., -C ^ C ^ -OH), an aminoalkyl group (e.g., -ί'.Ή ₂ ΝΗ ₂ ) or an alkyl thiol group (e.g. -ί'.ί ₂ ί'.ί ₂ -8Η). A heteroalkyl group may have, for example, from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. C ₁ -C ₆ heteroalkyl group means a heteroalkyl group having from 1 to 6 carbon atoms.

A heterocycle or heterocycle, as used herein, includes, by way of example, but not limitation, the heterocycles described in Split, Leo Α .; Рттс1р1е8 о £ Мобеги ΗοΙοιόουοΠο Сепикю (\ ν.Λ. Вей) at1п, Mete Uogk, 1968), in particular, chapters 1, 3, 4, 6, 7, and 9; THYE SUMMERS about SECURITY osus Sotroibk, Α 8pe8o Мои Moyodgarb (1oBi νίΚν & 8oik, Pete Wogk, 1950 1o rtekei!), In particular, Volumes 13, 14, 16, 19 and 28, and 1. At. Eat. 8os. (1960) 82: 5566. In one specific embodiment, the heterocycle includes a carbocycle, as defined herein, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by a heteroatom (e.g., O, Ν or 8). The term heterocycle or heterocyclyl includes saturated rings, partially unsaturated rings and aromatic rings (i.e., heteroaromatic rings). Substituted heterocycles include, for example, heterocyclic rings substituted with any of the substituents described herein, including carbonyl groups. A non-limiting example of a carbonyl substituted heterocyclyl is:

Examples of heterocycles include, by way of example, and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolylindienol, tetrazylindiolyl, indiolyl, indiolyl, tetrazyl, indiolyl, indiol, tetrahydro, benzyl, tetrahydro, benzyl, indiol, indiol, tetra , quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroinol yl, triazinyl, 6H-1,2,5thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatin, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl indolizinyl, isoindolyl, 3Shindolil, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aN-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanil, phenoxazinyl, isochromanil, chromanil, imidazolidinyl, imidazolinyl, p irazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, ohindolyl, benzoxazolinyl, isatinoyl and bis-tetrahydrofuranyl:

By way of example, and not limitation, carbon-bound heterocycles are linked at position 2, 3, 4,

- 24 026523 or 6 pyridine, position 3, 4, 5 or 6 of pyridazine, position 2, 4, 5 or 6 of pyrimidine, position 2, 3, 5 or 6 of pyrazine, position 2, 3, 4 or 5 of furan, tetrahydrofuran, thiofuran thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 of oxazole, imidazole or thiazole, position 3, 4 or 5 of isoxazole, pyrazole or isothiazole, position 2 or 3 of aziridine, position 2, 3 or 4 of azetidine, position 2, 3, 4, 5, 6, 7 or 8 quinoline or position 1, 3, 4, 5, 6, 7 or 8 of isoquinoline. Even more typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 4-pyrimidinyl pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

By way of example, and not limitation, nitrogen-bonded heterocycles are linked at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2 imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3 pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine and position 9 of carbazole or β-carboline. Even more typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.

Heterocyclylalkyl refers to acyclic alkyl in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 8p carbon atom, is replaced by a heterocyclyl radical (i.e., a heterocyclyl alkylene fragment). Typical heterocyclyl alkyl groups include, but are not limited to, heterocyclyl-CH ₂ -, 2- (heterocyclyl) ethan-1-yl and the like, in which the heterocyclyl moiety includes any of the heterocyclyl groups described above in including those described in ΡπηοίρΙοδ о £ Мобегп НеУгосусПс Сеш181ту. It will also be apparent to those skilled in the art that a heterocyclyl group can be attached to the alkyl portion of a heterocyclyl alkyl via carbon-carbon bonds or a carbon-heteroatom bond, provided that the group is chemically stable as a result. The heterocyclyl alkyl group contains from 3 to 20 carbon atoms, for example, the alkyl part of the arylalkyl group contains from 1 to 6 carbon atoms, and the heterocyclyl part comprises from 2 to 14 carbon atoms. Examples of heterocyclylalkyls include, by way of example, and not limitation, 5-membered sulfur, oxygen, and / or nitrogen-containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur , oxygen and / or nitrogen-containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridisylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or 8p carbon atom, as well as the 8p carbon atom is replaced by a heterocyclyl radical (i.e., a heterocyclyl alkenylene fragment). The heterocyclyl part of the heterocyclylalkenyl group includes any of the heterocyclyl groups described herein, including those described in Pppar1e5 o £ Mobegp Helégosus Ps1818u, and the alkenyl part of the heterocyclyl-alkenyl group includes any of the alkenyl groups described herein. It will also be clear to those skilled in the art that a heterocyclyl group can be attached to the alkenyl portion of heterocyclyl-alkenyl via carbon-carbon bonds or a carbon-heteroatom bond, provided that the group is chemically stable as a result. The heterocyclyl-alkenyl group contains from 4 to 20 carbon atoms, for example, the alkenyl part of the heterocyclylalkenyl group is from 2 to 6 carbon atoms, and the heterocyclyl part is from 2 to 14 carbon atoms.

Heterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or 8p carbon atom, as well as the 8p carbon atom is replaced by a heterocyclyl radical (i.e., a heterocyclyl alkynylene fragment). The heterocyclyl part of the heterocyclyl-alkynyl group includes any of the heterocyclyl groups described herein, including those described in Pppar1e5 o £ Mobegp He1gosus Ps Ces181gu, and the alkynyl part of the heterocyclyl-alkynyl group includes any of the alkynyl groups described herein. It will also be clear to those skilled in the art that a heterocyclyl group can be attached to the alkynyl portion of the heterocyclylalkynyl via carbon-carbon bonds or a carbon-heteroatom bond, provided that the group is chemically stable as a result. The heterocyclylalkynyl group contains from 4 to 20 carbon atoms, for example, the alkynyl part of the heterocyclylalkynyl group is from 2 to 6 carbon atoms, and the heterocyclyl part is from 2 to 14 carbon atoms.

Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of a heteroaryl ring include all aromatic rings listed in the definition of heterocyclyl, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolazole, isoxazolazole , quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.

- 25 026523

A carbocycle or carbocyclyl refers to a saturated (e.g. cycloalkyl), partially unsaturated (e.g. cycloalkenyl, cycloalkadienyl, etc.) or aromatic ring having from 3 to 7 carbon atoms as a monocycle, from 7 to 12 carbon atoms as a bicycle, and so on. up to 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 7 atoms in the ring, even more typically 5 or 6 atoms in the ring. Bicyclic carbocycles have from 7 to 12 atoms in the ring, for example, are arranged as bicyclo [4,5], [5,5], [5,6] or [6,6] systems, or 9 or 10 atoms in the ring are located like bicyclo [5.6] or [6.6] systems, 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 phenyl, 1-cyclohex-3-enyl and phenyl. Non-limiting examples of bicyclo carbocycles include naphthyl, tetrahydronaphthalene, and decalin.

Carbocyclylalkyl refers to acyclic alkyl in which one of the hydrogen atoms bonded to the carbon atom is replaced by carbocyclyl as described herein. Typical, but not limiting examples of the carbocyclylalkyl group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

Arylheteroalkyl refers to heteroalkyl, as defined herein, in which a hydrogen atom (which can be attached to either a carbon atom or a heteroatom) has been replaced by an aryl group as defined herein. Aryl groups may be bonded to a carbon atom of a heteroalkyl group or a heteroatom of a heteroalkyl group, provided that, as a result, the aryl heteroalkyl group provides a chemically stable moiety. For example, an aryl heteroalkyl group may have the general formulas alkylene-O-aryl, -alkylene-O-alkylene-aryl, alkylene-NH-aryl, -alkylene-PN-alkylenearyl, -alkylene ^ -aryl, -alkylene ^ -alkylene-aryl etc. In addition, any of the alkylene moieties in the general formula above may be further substituted with any of the substituents defined or listed 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 heteroarylalkyl include -CH ₂ -pyridinyl, -CH ₂ -pyrrolyl, -CH ₂ -oxazolyl, -CH ₂ -indolyl, -CH ₂ -isoindolyl, -CH ₂ purinyl, -CH2-furanyl, -CH2-thienyl, - CH2-benzofuranyl, -CH2-benzothiophenyl, -CH2-carbazolyl, -CH2imidazolyl, -CH ₂ -thiazolyl, -CH ₂ -isoxazolyl, -CH ₂ -pyrazolyl, -CH ₂ -isothiazolyl, -CH ₂ -quinolyl, -CH ₂ isoquinolyl, -CH ₂ -pyridazyl, -CH ₂ -pyrimidyl, -CH ₂ -pyrazyl, -CH (CH ₃ ) -pyridinyl, -CH (CH ₃ ) pyrrolyl, -CH (CH3) -oxazolyl, -CH (CH3) -indolyl, -CH (CH3) - isoindolyl, -CH (CH3) -purinyl, -CH (CH3) -furanyl, -CH (CH3) -thienyl, -CH (CH3) -benzofuranyl, -CH (CH3) -b nzothiophenyl, —CH (CH3) carbazolyl, —CH (CH3) imidazolyl, —CH (CH3) thiazolyl, —CH (CH3) isoxazolyl, —CH (CH3) pyrazolyl, —CH (CH3) isothiazolyl, - CH (CH3) - quinolyl, -CH (CH3) -izohinolil, -CH (CH3) -piridazil, -CH (CH3) - pyrimidyl, -CH (CH ₃₎ -pirazil etc.

The term optionally substituted, with reference to a particular fragment of a compound of the formulas BU-U (for example, an optionally substituted aryl group), refers to a fragment in which all substituents are hydrogen or in which one or more of the hydrogens can be partially replaced by substituents, such as those listed under the definition of substituted, or as otherwise indicated.

The term is optionally replaced, with reference to a particular fragment of a compound of the formulas OH and formulas BU-U (for example, the carbon atoms of the indicated (C ₁ -C ₈ ) alkyl may optionally be replaced by -O-, -δ- or -ΝΕ ¹ -), means that one or more methylene groups (C ₁ -C ₈ ) of the alkyl can be replaced by 0, 1.2 or more of these groups (for example, -O-, -δ- or -ΝΚ ' ¹ -).

The term non-terminal carbon atom (s), with reference to the alkyl, alkenyl, alkynyl, alkylene, alkenylene or alkynylene part, refers to the carbon atoms in the part that is placed between the first carbon atom of the part and the last carbon atom in the part. Therefore, by way of example, and not limitation, in the alkyl moiety —CH ₂ (C *) H ₂ (C *) H ₂ CH ₃ or the alkylene group —CH ₂ (C *) H ₂ (C *) H ₂ CH ₂ - C * atoms will be considered nonterminal carbon atoms.

Some Υ and Υ ¹ alternatives are nitrogen oxides, such as + P (O) (K) or + P (O) (OK). These nitrogen oxides, as shown here attached to a carbon atom, can also be represented by separated charge groups such as o ^- o ”

1. ί respectively, and are intended to represent the aforementioned groups equivalently for the purpose of describing the present invention.

Linker or bond means a fragment of a chemical substance containing a covalent bond or chain of atoms. Linkers include alkyloxy (eg, polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (eg, polyethyleneamino, BeBBashpe ™); as well as dibasic acids, esters and amides, including succinate, succinamide, diglycolate, malonate and caproamide.

- 26 026523

Terms such as oxygen bonded, nitrogen bonded, carbon bonded, sulfur bonded or phosphor bonded mean that if a bond between two fragments can be formed using more than one type of atom in a group, then a bond is formed between the fragments through the specified atom. For example, a nitrogen-bound amino acid may be linked through the nitrogen atom of an amino acid, rather than through oxygen or a carbon atom of an amino acid.

Unless otherwise indicated, the carbon atoms of the compounds of formulas and formulas GU-UG are intended to have a valency of four. In some chemical images of structures where carbon atoms do not have enough variable binding sites to produce valency four, the remaining carbon substituents needed to ensure valency four are hydrogen. For example, it has the same meaning as

A protecting group refers to a fragment of a compound that masks or changes the properties of functional groups or the properties of the compound as a whole. The chemical base of the protective group varies widely. One of the functions of the protective group is to use the parent drug as an intermediate in the synthesis. Chemical protecting groups and protection / deprotection strategies are well known in the art. See: Prologue Otuirz ίη Ogdashe Szetzuyu, Thööoga V. Ogheepe (ZONy Shyu & 8opz, Le., \ E \ u Wogk, 1991). Protective groups are often used to mask the reactivity of certain functional groups, to assist in the effectiveness of the desired chemical reactions, for example, the formation and destruction of chemical bonds in the resulting and planned design. The protection of the functional groups of compounds changes other physical properties, in addition to the reactivity of the protected functional groups, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by general analytical tools. Chemically protected intermediates themselves can be biologically active or inactive.

Protected compounds may also exhibit alternative, and in some cases optimized, properties of ίη yyugo and ίη yyuo, such as passage through cell membranes and resistance to enzymatic degradation or absorption. In this role, protected compounds with the intended therapeutic effect may be considered prodrugs. Another function of the protective group is to transform the parent drug into a prodrug, as a result of which the parent drug releases ίη ууо by the prodrug conversion. Due to the fact that active prodrugs can be absorbed more efficiently than parent drugs, prodrugs can be more effective than ίη yuo than the parent drug. Protective groups remove either ίη yuigo in the case of intermediates or ίη yuo in the case of prodrugs. In the case of intermediate chemicals, it is not particularly important that the products obtained after deprotection of, for example, alcohols, are physiologically acceptable, although it is generally more desirable that the products are pharmacologically harmless.

A prodrug fragment means a labile functional group that is separated from the active inhibitory compound during the metabolism, systemically, inside the cell, by hydrolysis, enzymatic digestion, or some other process (Viididaa, Neufz, ^ ez ^ dη apy Arrisya-Pop oG Rgoigidz in TeXooc oG Aegis ^ ez ^ dη yapy ^ eνe1ortηΐ (1991), R. Κ ^ ozdaa ^ u- ^ a ^ zeη yapy N. Viidydaa ^, Yez. Nag ^ oy Asayetsch Rybzyegz, pp. 113-191). Enzymes that are capable of enzymatically activating a mechanism with the phosphonate compound of a prodrug of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug fragments can enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and effectiveness.

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

Examples of prodrug moieties include the hydrolytically sensitive or labile alkoxymethyl esters -CH ₂ OC (= O) To a ³⁰ and acyloxymethyl carbonates -SN2OS (= O) OK ^30, where R ³⁰ represents a C1-C ₆ alkyl, C ₁ -C ₆ substituted alkyl C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl. Acyloxyalkyl ether was used as a prodrug strategy for carboxylic acids and was then applied to the phosphates and phosphonates of Argibyl et al. (1983) E Pbmt. 8s1. 72: 324; also US patents

- 27 026523 under the numbers 4816570, 4968788, 5663159 and 5792756. In some compounds of the invention, the prodrug fragment is part of a phosphate group. Acyloxyalkyl ether can be used to deliver phosphoric acid across cell membranes and increase oral bioavailability. A closed version of the acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester (carbonate), may also increase bioavailability as a prodrug fragment in the compounds of the combinations of the invention. An exemplary acyloxymethyl ether is pivaloyloxymethoxy, (POM) -CH ₂ OC (= O) C (CH ₃ ) ₃ . An exemplary acyloxymethyl carbonate fragment of a prodrug is pivaloyloxymethyl carbonate (pOC) —CH ₂ OC (= O) OC (CH ₃ ) ₃ .

The phosphate group may be a fragment of a phosphate prodrug. A prodrug fragment may be sensitive to hydrolysis, such as, but not limited to, those containing pivaloyloxymethyl carbonate (POC) or POM group. In addition, a prodrug fragment may be susceptible to enzymatically potentiated cleavage, such as a lactate ester or phosphonamidate ester group.

Aryl esters of phosphorus groups, in particular phenyl ethers, have been reported to have an increased oral bioavailability (Osbabsp et al. (1994) Меб. Meb SN. 37: 498). Phenyl ethers containing the carboxyl ether ortho to phosphate have also been described (Knatpe! Apb Toggepse, (1996) Меб. Meb. Net. 39: 4109-4115). Benzyl esters have been reported to generate parent fofsonic acid. In some cases, substituents in the ortho or para position can lead to accelerated hydrolysis. Benzyl analogs with acylated phenols or alkyl phenols can generate phenolic compounds under the action of enzymes, for example, esterases, oxidases, etc., which, in turn, undergoes C-O cleavage of the benzyl bond to produce phosphoric acid and quinones methide intermediates. Examples of this class of prodrugs are described by MbsbE11 e1 a1 (1992) ΐ. Oh. δοα Regksh Tgapk. I 2345; Go to e1 a1 VΟ 91/19721. Still other benzyl prodrugs have been described as containing a group comprising a carboxylic ester bound to benzyl methylene (CHSg e1 a1 VΟ 91/19721). Thio-prodrugs have been reported to be useful for the intracellular delivery of phosphonate drugs. These proesters 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. Deesterification or reduction of a disulfide generates a free thio intermediate, which subsequently decomposes into phosphoric acid and episulfide (Riesb e1 a1 (1993) ApbuK ha1 Kek., 22: 155-174; Wep / apa e! A1 (1996) ΐ. Furniture. . 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Epop et al. US Pat. No. 6,312,662).

It should be noted that all enantiomers, diastereomers and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the framework of formula I, formula II, formula III, formula IV, formula V or formula VI and their pharmaceutically acceptable salts are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

The compound of the formulas NN and the formulas Γν-ΫΣ and its pharmaceutically acceptable salts can exist in the form of various polymorphs or pseudopolymorphs. As used here, crystalline polymorphism means the ability of a crystalline compound to exist in various crystalline structures. Crystalline polymorphism may result from differences in crystal packaging (packaging polymorphism) or differences in packaging between different conformers of the same molecule (conformational polymorphism). As used here, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in various crystalline structures. The pseudopolymorphs of the present invention may exist due to differences in crystal packaging (packaging polymorphism) or due to differences in packaging of different conformers of the same molecule (conformational polymorphism). The present invention includes all polymorphic and pseudopolymorphic compounds of the formulas YN and formulas SH-Sh and their pharmaceutically acceptable salts.

The compound of the formulas YH and formulas SH-Sh and its pharmaceutically acceptable salts may also exist as an amorphous solid. As used here, an amorphous solid is a solid in which there is no long-range atomic arrangement in the solid. This definition applies when the crystal size is two nanometers or less. Additives, including solvents, can be used to create amorphous forms of the present invention. The present invention includes all amorphous forms of a compound of formulas ES and formulas SH-Sh and their pharmaceutically acceptable salts.

Selected substituents containing compounds of formulas ES and formulas Sh-Sh are present in a recursive manner. In this context, a recursive substituent means that the substituent may have another instance similar to itself. Due to the recursive nature of such substituents, in principle, a large number of compounds may be present in any embodiment. For example, K ^x includes a substituent K ^y , K ^y can be K, K can be V ³ , V ³ can be V ⁴ and V ⁴ can be K or contain substituents containing K ^y . One skilled in the art of medical chemistry will recognize that the total number of such substituents is reasonably limited by the desired properties of the intended compound.

- 28 026523

Such properties include, by way of example, and not limitation, physical properties, such as molecular weight, solubility, or 1od P, application properties, such as activity toward the intended purpose, and practical properties, such as ease of synthesis.

By way of example, and not limitation, A ³ and K ^y are recursive substituents in some embodiments. As a rule, each recursive replacement can occur independently from each other 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 times in this embodiment. More typically, each recursive replacement can occur independently of each other 12 or fewer times in this embodiment. Even more typically, each recursive replacement can occur independently of each other 3 or less times in this embodiment. For example, A ³ will occur from 0 to 8 times, K ^y will occur from 0 to 6 times in this embodiment. Even more typically, A ³ will occur from 0 to 6 times, and K ^y will occur from 0 to 4 times in this embodiment.

Recursive substituents are included in an aspect of the invention. A person skilled in the art of medical chemistry understands the versatility of such substituents. To the extent that recursive substituents are present in an embodiment of the invention, the total amount will be determined as indicated above.

The modifier about is used in connection with the quantity and includes the indicated values, and makes sense dictated by the context (for example, includes the degree of error associated with the measurement of a certain quantity).

The compounds of formulas Ι-ΙΙΙ and formulas 1U-U1 may contain phosphate groups, such as K ⁷ , which may be a fragment of the prodrug γ

where each Υ or Υ ¹ is, independently, O, 8, IR, + I (O) (K), I (OK), + I (O) (OK) or I-IK2; A ¹ and A ² taken together are -Υ ³ (C (K ^y ) 2) s) ³ -; or one of A ¹ or A ² , together with any K ³ or K ⁴ , represents -Υ ³ -, and the other A ¹ or A ² represents formula 1a, or A ¹ and A ² , each independently, a group of formula 1a :

IR where each Υ ² is, independently, a bond, O, SK ₂ , IR, + I (O) (K), I (OK), + I (O) (OK), I8, 8-8, 8 ( O) or 8 (O) ₂ ;

each Υ ³ represents, independently, O, 8 or IR;

M2 is 0, 1 or 2;

each K ^y represents, independently, H, P, C1, Br, I, OH, K, -Ο ^ Υ ¹ ^, -C ^ ') And (K) 2, -I (K) 2, - + And (K) e, -8K, -8 (O) K, -8 (O) ₂ K, -8 (O) (OK), -8 (O) ₂ (OK), -OS (= ^) K, -OS (= ^) OK, -OS ^) (And (K) 2), -8С (= ^) К, -8С (= ^) OK, -8С ^) (And (K) 2), -I (K) C ^) K, -I (K) C (= ^) OK or

-N (K) C (= Υ ¹ ) N (K) ₂ , -8O ₂ IR ₂ , -CI, -I ₃ , -IO ₂ , -OK, a protective group or A ³ ; or, taken together, two To ^at the same carbon atoms form carbocyclic rings of from 3 to 7 carbon atoms;

each K ^x represents, independently, K ^y , a protective group or formula:

where M1a, M1c and M1b are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

each K represents H, halogen, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ - C ₈ ) alkynyl, (C ₂ -C ₈ ) substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocyclyl, arylalkyl, substituted arylalkyl or a protective group;

A ³ is A ⁴ or A ⁵ ; A ⁴ is R, -C ^ ¹⁾ ^ -C ^) A ⁵ -8O2K ^at -8O2A or ^5; and A ⁵ is a carbocycle or heterocycle, where A ⁵ is independently substituted from 0 to 3 K ^at -groups.

A ⁵ carbocycles and A ⁵ heterocycles can be independently substituted from 0 to 3 K ^at -groups. And ⁵ may be a saturated, unsaturated or aromatic ring containing a mono- or bicyclic carbocycle or heterocycle. A ⁵ may have from 3 to 10 ring atoms, for example, from 3 to 7

- 29 026523 ring atoms. rings are saturated rings that contain 3 ring atoms, saturated or monounsaturated, which contain 4 ring atoms, saturated either mono- or di-unsaturated, which contain 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic, which contain 6 ring atoms.

^ ^{5 a} heterocycle may be a monocycle having from 3 to 7 members in the ring (from 2 to 6 carbon atoms and from 1 to 3 heteroatoms selected from Ν, O, P and 8), or a bicycle having from 7 to 10 ring members (from 4 to 9 carbon atoms and from 1 to 3 heteroatoms selected from Ν, O, P and 8). ^ ⁵ heterocyclic monocycles can have from 3 to 6 ring atoms (from 2 to 5 carbon atoms and from 1 to 2 heteroatoms selected from Ν, O and 8), or 5 or 6 atoms in the ring (from 3 to 5 carbon atoms and from 1 to 2 heteroatoms selected from Ν and 8). ^ ⁵ heterocyclic bicycles have from 7 to 10 ring atoms (6 to 9 carbon atoms and from 1 to 2 heteroatoms selected from Ν, O and 8) located in the bicyclo [4,5], [5,5], [5 , 6] or [6,6] system, or from 9 to 10 ring atoms (8 to 9 carbon atoms and from 1 to 2 heteroatoms selected from Ν and 8) located in a bicyclo [5,6] or [6, 6] system. A ^ ⁵ heterocycle can be linked to Υ ² via a carbon, nitrogen, sulfur atom or other atoms by a stable covalent bond.

^ ⁵ heterocycles include, for example, pyridyl, dihydropyridinyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, 8-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiophyl, thiopyr. ^ ⁵ also includes, but is not limited to, examples such as:

^ ⁵ carbocycles and heterocycles can be independently substituted from 0 to 3 K-groups, as described above. For example, substituted ^ ⁵ carbocycles include:

Examples of substituted phenyl carbocycles include:

Embodiments of K ⁷ or K ⁷ together with K ⁴ include structures:

- 30 026523 where a represents the point of attachment to K ⁷ ; B represents the point of attachment to _K ⁴ ;

Ag is phenyl or naphthyl, where phenyl and naphthyl are optionally substituted with 1-3 K ²⁰ groups;

each K ^y is independently (C ₁ -C ₈ ) alkyl or C ₅ -C ₆ carbocyclyl, where alkyl and carbocyclyl are optionally substituted with 1-3 K ²⁰ groups;

each K is independently H, (C ₁ -C ₆ ) alkyl or arylalkyl; and each K ²⁰ is independently halogen, ίΝ, ΝΧβ, OK, -8K, -8 (O) K, -8 (O) ₂ K, -8 (O) (OK), -8 (O) ₂ (OK), -С (= О) К, -С (= О) OK or С (= ОЖК) 2.

Embodiments

compounds of formulas Ι-ΙΙΙ and formulas ΙΥ-ΥΙ include substructures such as:

where each Υ ²¹ 'is, independently, O or Ν (Β). In another aspect of this embodiment, each Υ ²¹ 'represents O, and each K ^x represents independently:

where M12c is 1, 2 or 3, and each Υ ² is independently a bond, O, CK ₂ or 8. In another aspect of this embodiment, one Υ ²¹ -K ″ is ΝΗ (Β) and the other Υ ²¹ —K ″ represents O — K ^x , where K ^x represents:

where M12c represents 2. In another aspect of this embodiment, each Υ represents O, and each K ^x represents independently:

where M12c represents 2. In another aspect of this embodiment, each Υ represents O, and each K ^x represents independently:

where M12c represents 1, and Υ ² represents a bond, O or SK ₂ . Other embodiments of compounds

Ι-ΙΙΙ formulas and ΙΥ-ΥΙ formulas include substructures such as:

where each Υ ³ is, independently, O or Ν (Β). In another aspect of this embodiment, each Υ ³ is O. In another aspect of this embodiment, the substructure is:

- 31 026523

where K ^y represents V ⁵ as defined here. Another embodiment

SP formulas and formulas includes substructures:

where each Y ^2c is, independently, O, or 5. Another embodiment

the compounds of formulas NN and formulas ^ -71 includes substructures where one V ¹ or V ² , together with either K ³ or K ⁴ represents -Υ ³ -, and the other V ¹ or V ² represents formula Sh. Such an embodiment is a compound of the formula selected from

In another aspect of an embodiment of Formula II, each Υ and Υ ³ is O. In another aspect of an embodiment of Formula II, V ¹ or V ² is Y ^{2 | 1} -K з each Υ, Υ ³ and Y ² ' ¹ is O , and K ^x represents:

where M12c is 1, 2 or 3, and each Υ is independently a bond, O, CK ₂ or 5. In another aspect of the embodiment of Formula II, V ¹ or V ² is Υ ^2Ιι -Η ^χ ; each Υ, Υ ³ and Υ ²¹ represents O, and K ^x represents:

- 32 026523

where M12c represents 2. In another aspect of the embodiment of the formula] b XV ¹ or V ² represents Υ ² -K ^x ; each Υ, Υ ³ and Y ²¹ 'represents O, and K ^x represents:

where M12c represents 1, and Υ ² represents a bond, O or SK ₂ . Another embodiment

compounds of the formulas YN and formulas BU-U includes a substructure:

where V ⁵ represents a carbocycle, such as phenyl or substituted phenyl. In another aspect of this embodiment, the substructure is:

where Υ ²⁵ represents O or LCD). and phenyl carbocycle is substituted with 0 to 3 K groups. In another aspect of this embodiment, the substructure K ^x represents:

where M12c is 1, 2 or 3, and each Υ ² is, independently, a bond, O, CK ₂ or 8.

Another embodiment

Ν '!

Ν ² formulas UN and formulas BU-U includes a substructure:

The chiral carbon amino acids and lactate fragments can be either a K- or 8-configuration, or a racemic mixture.

Another embodiment

formulas and formulas BU-U is a substructure

- 33 026523

where each Υ ² is, independently, -O- or -ΝΉ-. In another aspect of this embodiment, K ^y is (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl or (C2-C8 ) substituted alkynyl. In another aspect of this embodiment, K ^y is (C1- _C8 ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ - C ₈ ) alkynyl or (C ₂ -C ₈ ) substituted alkynyl; and K represents CH ₃ . In another aspect of this embodiment, K ^y is (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) substituted alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) substituted alkenyl, (C ₂ -C ₈ ) alkynyl or (C ₂ -C ₈ ) substituted alkynyl; K represents CH ₃ ; and each Υ ² is -Ν4-. In an aspect of this embodiment, V ¹ and V ² are, independently, nitrogen-bound, naturally occurring amino acids or natural amino acid esters. In another aspect of this embodiment, V ¹ and V ² are, independently, naturally occurring 2-hydroxy carboxylic acids or naturally occurring 2-hydroxy esters of carboxylic acids, where the acid or ester is linked to P via a 2-hydroxy group.

Another embodiment

formula I, formula II, formula III, formula IV, formula V or formula VI is a structure:

In one aspect of the embodiment, each K ^x represents, independently, (C1-C8) alkyl. In another aspect of this embodiment, each R ^x is, independently, C6-C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl.

In a preferred embodiment

selected from

Another embodiment

иν-νΤ formulas and formulas is a substructure

where V ¹ and V ² are independently selected from one of the formulas in table. 20.1-20.37 and tab. 30.1 below. Variables 34 026523 used in the table. 20.1-20.37 (for example, V ²³ , K ²¹ , etc.), refer only to the table. 20.1-20.37, unless otherwise indicated.

The variables used in the table. from 20.1 to 20.37 have the following definitions:

each K ²¹ is independently H or (C ₁ -C ₈ ) alkyl;

21 23 24 24 each K is independently H, K, K or K, where each K is independently substituted from 0 to 3 K ²³ ;

each K ²³ represents, independently, K ^23a , K ²³¹ , K ^23c or K ²³⁰ , provided that when K ²³ is bonded to a heteroatom, then K ²³ represents K ^23c or K ²³⁰ ;

each K ^23a is independently P, C1, Br, I, —CH Ν ₃ or —O ₂ ; each K ²³ is independently Υ ²¹ ;

each K ^23s is, independently, -K ^2x , -Y (K ^2x ) (K ^2x ), -5K ² 5 (O) (OK ^2x ), -5 (O) ₂ (OK ^2x ), -ΟC (= Υ ²¹ ) K ^2x , -ΟС (= Υ ²¹ ) ΟК ^2x , -ОС ^^ YANK ^) ^)), -5С (= Υ ²¹ ) K ^2x , or

-5 (O) K ^2x , -5 (O) 2K ^2x ,

-ZS ^^ OK ² *

-5С (= Υ ²¹ ) (N (К ^2x ) (К ^2x )),

-N (K ^2x ) C (= Υ ²¹ ) K ^2x ,

-N (K ^2x ) C (= Υ ²¹ ) Ο K ^2x

-N (K ^2x ) C (= Υ ²¹ ) (N (K ^2x ) (K ^2x ));

each K ²³⁰ represents, independently, -C (= Υ ²¹ ) K ^2x , -C (= Υ ²¹ ) ΟK ^2x or -C (= Υ ²¹ ) (N (K ^2x ) (K ^2x )); each K ^2x is independently H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, aryl, heteroaryl; or two K ^2x , taken together with the nitrogen to which they are both attached, form a 3-7 membered heterocycle, where any carbon atom of said heterocyclic ring may optionally be replaced with -O-, -5- or -IK ²¹ -; and where one or more non-terminal carbon atoms of each of the indicated (C ₁ -C ₈ ) alkyl may optionally be replaced by -O-, -5- or -ΝΡ ²¹ -;

each K ²⁴ is independently (C2-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl;

24 24 23 each K ²⁵ is independently K ²⁴ , where each K ^{24 is} substituted with 0 to 3 K ²³ groups; each K ^25a is independently (C ₁ -C ₈ ) alkylene, (C ₂ -C ₈ ) alkenylene or (C ₂ -C ₈ ) alkynylene, each of these (C ₁ -C ₈ ) is alkyl, (C ₂ -C ₈ ) alkenylene or (C ₂ -C ₈ ) alkynylene is substituted with 0-3 K ²³ groups;

24 25 each V is independently V or V;

each V ²⁴ is, independently, K ²⁵ , -C (= Υ ²¹ ) K ²⁵ , -C (= Υ ²¹ ) V ²⁵ , -5O ₂ K ²⁵ or -5O ^ ²⁵ ; each V ²⁵ is independently a carbocycle or heterocycle, where V ²⁵ is independently substituted with 0 to 3 K ²² groups; and each Υ ²¹ is, independently, O or 5.

Table 20.1

Table 20.2

10

CH ₃ about

- 35 026523

Table 20.3

Table 20.4

Table 20.5

- 36 026523

n o

- 37 026523

Table 20.11

Table 20.13

Table 20.14

- 38 026523

Table 20.15

Table 20.16

- 39 026523

Table 20.19

Table 20.20

Table 20.21

Table 20.22

Table 20.23

Table 20.25

Ν

I n

160 and ⁵

Ν

I

Η

161

Table 20.26

Th ²⁴ H ^ ² 'A A

162 163

and and ³

N

I n

165

H then N I p, 23

166 and

N

I p23

167 and x * ²⁴

N

I

K ²³

168

p.23

169

I

K ²³

170 ^s and ^s

N

I p23

171

- 41 026523

Table 20.28

- 42 026523

Table 20.33

- 43 026523

Table 20.34

Table 20.35

'γ'® "» 228 ° X p25a p, 'Ύ_4γ · ° Ί 229 ° r25a gt L r25a r νΖγ-Α 230 ° 231 ° > p25a p ΎΥ ¹ 232 ° ^H 233 ° 1 Ά K ²⁴ Υυ ° ' ¹ 234 ° ^H 235 ° Table 20.36

Table 20.37

Embodiments of K ^x include esters, carbamates, carbonates, thioethers, amides, thioamides and urea groups:

Any reference to compounds of the invention described herein also includes references to physiologically acceptable salts. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from appropriate bases, such as alkali metals or alkaline earth (e.g. Ν; · ι ', Ы ⁺ , K', Ca ' ² and Mg ^{+ 2} ) ₅ ammonium and ΝΒ ₄ ⁺ (where K is defined here). Physiologically acceptable salts of a nitrogen atom or an amino group include: (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (B) salts formed with 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 acids, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, poly alacturonic 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 and the like; and (c) salts formed from elemental anions, for example, chlorine, bromine and iodine. Physiologically acceptable salts of the hydroxyl group compound include an anion of the compound in combination with a suitable cation such as Ν; · ι 'and Ν ^ /.

For therapeutic use, the salts of the active ingredients of the compounds of the invention will be physiologically acceptable, that is, they will be salts derived from a physiologically acceptable acid or base. However, salts of acids and bases that are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not obtained, formed by physiologically acceptable acids or bases, are within the scope of the present invention.

Finally, it should be understood that the compositions include the compounds of the invention in their non-ionized as well as zwitterionic forms and combinations with a stoichiometric amount of water, as in hydrates.

The compounds of the invention, by the example of the иν-νΐ formulas and formulas, can have chiral centers, for example, chiral carbon or phosphorus atoms. the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers of any or all of the asymmetric chiral atoms. In other words, chiral centers are apparent from the description and are presented as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as individual optical isomers isolated or synthesized, essentially free of their enantiomeric or diastereomeric partners, are within the scope of the invention. Racemic mixtures are separated into individual, essentially optically pure isomers, by well-known methods, such as, for example, separating diastereomeric salts formed with optically active additives, for example, acids or bases, followed by conversion back to optically active substances. In most cases, the desired optical isomer is synthesized using a stereospecific reaction, starting with the corresponding stereoisomer of the desired starting material.

The term chiral refers to molecules that have the mirrorless property of a partner, while the term achiral refers to molecules that mirror overlay on their partner.

The term stereoisomers refers to compounds that have the same chemical composition, but differ due to the arrangement of atoms or groups in space.

A diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have various physical properties, for example, melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated at high resolution by analytical procedures such as electrophoresis and chromatography.

Enantiomers refer to two stereoisomeric compounds that are not superimposed mirror images of each other.

The stereochemical definitions and conventions used here tend to follow δ. R. Ragkeg, Her., MsOGa ^ -NSh Iyuopagu οί Sketua1 Tegts (1984), MsOgate-NSh Vook Sotrapu, No.ν Υοι! <; apy EIe1, E. apy KhUPep, δ., 81geosket181gu oG Ogdashs Sotroipyz (1994), 1 okp V ^ 1еу & 8пз, Шс., Νον Υο ^ к. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of polarized light. When describing an optically active compound, the prefixes Ό and b or K and δ are used to indicate the absolute configuration of the molecule relative to its chiral center (s). The prefixes u and 1, b and b, or (+) and (-) are used to indicate the sign of rotation of the plane of polarized light in conjunction with δ, (-), or 1 means that the connection is levorotatory, while the connection with the prefix K , (+), or th, is dextrorotatory. For a given chemical structure, these stereoisomers are identical, except that they are mirror images of each other. A specific stereoisomer may also be called an enantiomer, and mixtures of such isomers are often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur where there was no stereoselectivity or stereospecificity in a chemical reaction or process. The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species lacking optical activity.

Whenever a compound described herein is replaced by more than one of the same assigned group, for example, K or K ¹ , it will be understood that the groups may be the same or different, that is, each group is independently selected.

Wavy lines, ln / νννν ', indicate the site of the covalent bond of an attachment to neighboring substructures, groups, fragments or atoms.

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

Those skilled in the art will understand that pyrrolo [1,2-G] [1,2,4] triazine, imidazo [1,5-G] [1,2,4] triazine, imidazo [1,2-G ] 1,2,4] triazine and [1,2,4] triazole [4,3-G] [1,2,4] triazine nucleosides can exist in tautomeric forms. So, for example, but not for the purpose of limitation, structures (a) and (b) can have equivalent tautomeric forms, as shown below:

- 46 026523

All possible tautomeric forms of heterocycles in all embodiments described herein are within the scope of the invention.

Methods of inhibiting NSO polymerase

Another aspect of the invention relates to methods of inhibiting the activity of an NSI polymerase, comprising the step of treating a sample, presumably containing NSI, with the composition of the invention.

Compositions of the invention may act as inhibitors of NSI polymerase, as intermediates for such inhibitors, or have other utilities, as described below. Inhibitors will bind to a site on the surface or in the cavity of the NSI polymerase having a geometry unique to the NSI polymerase. NSI polymerase binding compositions may bind to varying degrees of reversibility. Those compounds for which binding is substantially irreversible are ideal candidates for use in this method of the invention. As noted, substantially irreversibly binding compositions are useful as probes for the detection of NSI polymerase. Thus, the invention relates to methods for detecting an NSI polymerase in a sample suspected of containing an NSI polymerase, comprising the steps of: reacting a sample of an allegedly containing NSI polymerase with a composition comprising a label compound; and observing the effect of the sample on label activity. Suitable labels are well known in the diagnostic field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. the compounds here are labeled in the usual manner using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino acid.

In the context of the present invention, samples suspected of containing NSU polymerases include natural or artificial materials such as living organisms, tissues or cell cultures; biological samples, such as biological samples of the material (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; samples of food, water or air; biological samples, such as an extract of cells, in particular cells synthesizing a recombinantly desired glycoprotein, and the like. Typically, the sample will presumably contain an organism that produces NSI polymerase, often pathogenic organisms such as NSI. Samples can be contained in any medium, including water and an organic solvent / water mixture. Samples include living organisms, such as humans, and artificial materials, such as cell cultures.

The processing step of the invention involves adding a composition of the invention to a sample or includes adding a precursor of the composition to a sample. An additional step includes any route of administration as described above.

If desired, the activity of the NSI polymerase after application of the composition can be observed by any method, including direct and indirect methods for the detection of NSI polymerase activity. Quantitative, qualitative and semi-quantitative methods for the determination of NSI-polymerase activity are all considered. Usually, one of the screening methods described above is used, however, any other methods, such as monitoring the physiological properties of a living organism, are also applicable.

Organisms that contain an NSI polymerase include an NSI virus. the compounds of this invention are useful in the treatment or prophylaxis of an NSA infection in animals or humans.

However, in screening for compounds capable of inhibiting human immunodeficiency viruses, it should be borne in mind that enzyme assays may not correlate with cell culture assays. Therefore, analysis-based cells should be the primary validation tool.

- 47 026523

Screening for ISU Polymerase Inhibitors

The compositions of the invention are tested for inhibitory activity against HCL polymerase by any of the usual methods for assessing enzyme activity. In the context of the present invention, as a rule, the compositions are first tested for the inhibition of the NSO polymerase ίη νίίτο, and the compositions showing the inhibitory activity are then screened for the activity of ίη νίνο. Compositions having ίη νίίτο Κι (inhibitory constants) of less than about 5x10 ^-6 M, typically less than 1 x 10 ^-7 M and preferably less than about 5x10 ^-8 M, are preferred for using ίη νίνο.

Useful tests ίη νίίτο are described in detail and will not be discussed here. However, the examples describe suitable analyzes of ίη νίίτο.

Pharmaceutical Compositions

The compounds of this invention are combined with conventional carriers and excipients, which will be selected in accordance with ordinary practice. The tablets will contain excipients that promote glidants, fillers, binders and the like. Aqueous preparations are prepared in sterile form and, when intended for delivery other than oral administration, will generally be isotonic. All compositions will additionally contain excipients, such as those set forth in Η; · ιηύ3οο1 <οί РНагтасеи 11с1 Есс1р1еШ5 (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as ΕΌΤΆ, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid and the like. The pH of the formulations ranges from 3 to 11, but usually from 7 to 10.

Although it is possible for active ingredients to be used, it may be preferable to present them as pharmaceuticals. Compositions for both veterinary use and human use according to the invention contain at least one active ingredient, as described above, together with one or more acceptable carriers, therefore, and, optionally, other therapeutic ingredients. The carrier (s) must be acceptable in the sense of being compatible with other ingredients of the composition and physiologically harmless to the recipient.

Compositions include those that are suitable for the above routes of administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Methods and compositions, as a rule, are found in Jettisnabs 8 δ ^ ιη ^ 5 (Mask Rnichimde SC, Ε'δΙοη, RA). Such methods include the step of mixing the active ingredient with a carrier, which constitutes one or more additional ingredients. In general, compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, molding the product.

Compositions of the present invention suitable for oral administration can be presented in discrete units, such as capsules, cachets or tablets, each of which contains a certain 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 as an oil-in-water liquid or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, a medicinal porridge or paste.

A tablet is made by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in granular form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may be coated or uncoated and, optionally, formed in such a way as to provide a slow or controlled release of the active ingredient from it.

For infections of the eyes or other external tissues, for example, the mouth and skin, the composition is preferably used as an ointment or cream containing the active ingredient (s) in an amount of, for example, from 0.075 to 20% w / w. (including the active ingredient (s) in the range of 0.1% to 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / weight, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When the preparation is in the form of an ointment, the active ingredients can be used with either a paraffin or water-miscible ointment. In addition, the active ingredients can be incorporated into a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream may include, for example, at least 30% w / w. polyhydric alcohol, that is, an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. Topical compositions may desirably include a compound that improves the absorption or penetration of active ingredients through the skin or other affected

- 48 026523 areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

The oil phase of the emulsions of the present invention can be composed of known ingredients in a known manner. While the phase may contain only an emulsifier (otherwise known as an emulsifier), it is desirable that it contains a mixture of at least one emulsifier with fat or oil, or with both fat and oil. Preferably, the hydrophilic emulsifier is included with the lipophilic emulsifier, which acts as a stabilizer. It is also preferred that it includes both oil and fat. Together, emulsifier (s) with or without stabilizer (s) make up the so-called emulsion wax, and wax together with oil and fat make up the so-called emulsifying ointment, which forms the oily dispersed phase of the cream compositions.

Emulsifiers and emulsion stabilizers suitable for use in preparing the preparations of the invention include ^^ 11060, 8ryap®80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate.

The selection of suitable oils or fats for the preparation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain esters, mono- or dibasic, such as diisoadipate, isoacetyl stearate, propylene glycol diester, coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate can be used, or a mixture of the last three are preferred esters. They can be used individually or in combination, depending on the required properties. Alternatively, high melting point lipids are used, such as white soft paraffin and / or liquid paraffin, or other mineral oils.

The pharmaceutical compositions of the invention comprise a combination of the invention together with one or more pharmaceutically acceptable carriers or excipients and, optionally, with other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended route of administration. When used for oral use, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, coloring agents and preservatives, so as to provide a preparation with a pleasant tasteful. Tablets containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient that is suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binding agents such as starch, gelatin or gum arabic; and lubricants, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated using known methods, including microencapsulation, delaying the breakdown and adsorption in the gastrointestinal tract, and thereby provide a stable effect over a longer period. For example, delay materials, such as glycerol or glyceryl distearate, alone or with wax, may be used.

Compositions for oral administration can also be presented in the form of hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions according to the invention contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic, and dispersing or moisturizing agents, such as natural phosphatides (for example, lecithin acid condensates, lecithin acid) (e.g. polyoxyethylene stearate), long chain aliphatic alcohol condensation product (e.g. heptadecaethylenoxycetanol), oxide condensation product Tilenau with partial esters derived from fatty acids and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl-p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may 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 liquid paraffin. Oral suspensions may contain a thickener, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those listed above, as well as flavorings, may be added to provide acceptable oral administration. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The soluble powders and granules of the invention, suitable for preparing an aqueous suspension by adding water, contain the active ingredient in admixture with a dispersing or moisturizing agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are, for example, those described above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, for example, olive oil or peanut oil, mineral oil such as liquid paraffin, or mixtures thereof. Suitable emulsifiers include natural gums such as gum arabic and tragacanth, natural phosphatides such as soya lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs can be prepared with sweeteners such as glycerin, sorbitol or sucrose. Such compositions may also contain a sedative, preservative, flavoring or coloring agent.

The pharmaceutical compositions of the invention may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. This suspension may be prepared in accordance with known techniques using suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or prepared as a lyophilized powder. Among the acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils may conventionally be used as a solvent or suspension medium. For this purpose, any soft fatty oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, can also be used in the preparation of an injection.

The amount of active ingredient that can be combined with the carrier material to produce a unit dosage form will vary depending on the person to be treated and the particular route of administration. For example, a sustained release composition for oral administration to humans may contain from about 1 to 1000 mg of active substance mixed with a suitable and convenient amount of carrier material, which may vary from 5 to 95% of the total composition (weight: weight). The pharmaceutical composition should be prepared to provide readily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from 3 to 500 μg of active ingredient per milliliter of solution for infusion, which will make it possible to make a suitable volume of about 30 ml / h.

Compositions suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, in particular in an aqueous solvent for the active ingredient. The active ingredient is preferably present in such compositions in a concentration of from 0.5 to 20%, preferably from 0.5 to 10%, and in particular about 1.5% w / w.

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

Formulations for rectal administration may be presented as a suppository with a suitable base containing, for example, cocoa butter or salicylate.

Compositions suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 μm, for example, 0.5, 1, 30, 35, etc., which are administered by rapid inhalation through the nasal passage or by inhalation through the mouth, so as to reach the alveolar sacs. Suitable compositions include aqueous or oily solutions of the active ingredient. Compositions suitable for administration in the form of an aerosol or dry powder may be prepared in accordance with conventional methods and may be delivered with other therapeutic agents, such as the compounds still used in the treatment or prophylaxis of NSA infections, as described below.

Compositions suitable for vaginal administration may be presented as vaginal suppositories, tampons, creams, gels, pastes, foams or sprays, formulations containing, in addition to the active ingredient, carriers which are known in the art and are useful.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic and dissolved substances that make the composition isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners.

The compositions are presented in a single dose or in multi-dose containers, for example, sealed ampoules and vials, and can be stored in a dry-frozen (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately before use. An improvised solution for injection and suspensions is prepared from sterile powders, granules and tablets, as described previously. Preferred are unit doses of the drug containing a daily dose or unit of a daily sub-dose, as described above, or an appropriate portion of the active ingredient.

It should be understood that in addition to the ingredients, in particular those mentioned above, the compositions of this invention may include other agents customary in the art, taking into account the type of preparation in the task, for example, suitable for oral administration may include flavorings.

In addition, the invention provides veterinary compositions containing at least one active ingredient, as defined above, therefore, together with a veterinary carrier.

Veterinary carriers are materials used for the purpose of administering the composition, and may be solid, liquid or gaseous materials that are inert and acceptable in veterinary practice and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

The compounds of the invention are used to provide controlled release of a pharmaceutical preparation containing, as an active ingredient, one or more compounds of the invention (controlled release), in which the release of the active ingredient is controlled and regulated in order to reduce the dosage frequency or to improve the pharmacokinetic parameters or toxicity profile of this active ingredient.

The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (lower doses) or against active viral infection, delivery method and pharmaceutical composition, and will be determined by the physician using routine dose escalation studies. It can be expected that this will be from about 0.0001 to about 100 mg / kg 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 body weight per day, most often from about 0.05 to about 0.5 mg / kg body weight per day. For example, the daily estimated dose for an adult with about 70 kg of body weight will range from 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and may take the form of one or more doses.

Route of administration

One or more compounds of the invention (hereinafter referred to as active ingredients) is administered via any route appropriate to the treatment conditions. Suitable routes include oral, rectal, nasal, local (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It should be borne in mind that the preferred route may vary depending, for example, on the state of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.

Combination therapy

Combinations of compounds of formulas and formulas RU-U! usually selected depending on the condition to be treated, cross-reactions of the components and pharmacological properties of the combination. For example, in the treatment of an infection (e.g., ΗΟν), the compositions of the invention are combined with other active therapeutic agents (such as those described herein).

The compositions of the invention are also used in combination with one or more other active ingredients. Preferably, other active ingredients or therapeutic agents are interferons, ribavirin or its analogues, ΗCV Ν83 protease inhibitors, I85 inhibitors, alpha glucosidases 1 inhibitors, hepatoprotectors, mevalonate decarboxylases antagonists, antagonists of the renin-angiotensin antagonists, other antagonists of the endothelin system, other nucleoside or nucleotide polymerase inhibitors ΗΟν Ν85Β, non-nucleoside polymerase inhibitors ΗΟν Ν85Β, ΗCV Ν85Α inhibitors, TK-7 agonists, cytophylline inhibitors, inhibitors Ον Gogh ^, pharmacokinetic enhancers, or other drugs for treating HCV, or mixtures thereof.

In particular, one or more compounds of the present invention can be combined with one or more compounds selected from the group consisting of:

1) interferons, for example, pegylated IRI-alpha ^ b (PEG-Intron), pegylated 51-51 026523 alpha-2a (Pegasys), ^ IΡN-alpha-2b (Intron A), ^ IPN-alpha-2a (Roferon- A), interferon alpha (MOK-22, OPC-18, ANaGsgops, ANaPaIus, MiGGetop, subaline), interferon alfacon-1 (ShGegdep), interferon alpha-p1 (Ae11Gegop), interferon alpha-^ (A1Gegop), interferon (Auopeh, Bb-8234), interferonomega (separated by BiCO8, Wutey 510), albinterferon alpha-2b (A1bGeGop), interferon alpha-Xb, BXX883 (boc1etop), BA-3021, glycosylated interferon alpha-2b (A1) PEG-SHGegdep, PEGylated Inter he lambda (PEGylated GO-29) and belerofon;

2) ribavirin and its analogues, for example, ribavirin (Rebetol, Seredik) and taribavirin (viramidine);

3) NSΥ protease inhibitors Ν83, for example, boceprevir (8CH-503034, 8CH-7), telaprevir (ΥΧ950), UH-813, TMS-435 (TMS435350), ABT-450, ΒΙ-201335, ΒΙ-1230, MK -7009, 8CH-900518, νΒΥ-376, УХ-500, 08-9256, 08-9451, ВМ8-790052, ВМ8-605339, РНХ-1766, А8-101, ΥΉ-5258, ΥΉ5530, ΥΉ5531 and Π ^ Ν -191 (K-7227);

4) alpha-glucosidase 1 inhibitors, for example, celgosivir (MX-3253), miglitol and IT-231B;

5) hepatoprotectors, for example, emerickasan (S-6556), ME-3738, 08-9450 (L-84451), silibilin and Mlots;

6) nucleoside or nucleotide polymerase inhibitors of NSU No. 5B, for example, K'626, K ⁷ 128 (K ⁴ 048), GOX184, ΙΌΧ-102, Ρ8Ι-7851, BCX-4678, valopitsitabine (MM-283) and MK-0608 ;

7) non-nucleoside polymerase inhibitors of NSU No. 5B, for example, filibuvir (PP-868554), АВТ333, АВТ-072, ВБ207127, USN-759, USN-916, LK-652, MK-3281, VΒΥ-708, USN-222, A848837, ANA598, 0L60667, 0L59728, A-63890, A-48773, A-48547, BC-2329, USN-796 (nesbuvir), 08K625433, VGOL 1941, HT-2125 and 08-9190;

8) NSU Zh5A inhibitors, for example, A2B-2836 (A-831), A2B-7295 (A-689) and BM8-790052;

9) TK-7 agonists, for example, imiquimod, 852A, 08-9524, ANA-773, ANA-975, ΛΖΩ-8848 (Ό8Ρ3025), PP-04878691 and 8M-360320;

10) cyclophilin inhibitors, for example, BEVU-025, 8CΥ-635 and No. M811;

11) NSU ΙΡΕ8 inhibitors, for example, MSB067;

12) pharmacokinetic enhancers, for example, BA8-100, 8ΡΙ-452, PP-4194477, TMS-41629, 089350, 08-9585 and roxithromycin;

13) other drugs for the treatment of hepatitis C virus, for example, thymosin alpha 1 (Zadaxin), nitazoxanide (A1chea, ΝΤΖ), ΒIΥN-401 (virostat), ΡΥΝ-17 (altirex), KRE02003002, actilon (CP010101), 08-9525 , ΚΒΝ-7000, cytacir, 0Ι-5005, ХТЬ-6865, ВГТ225, РТХ-111, ΙΤΧ2865, ΤΤ-033Ϊ, Ш 971, NΟУ-205, tarvacin, ЕНС-18, У0Х-410С, ЕМΖ-702, АУ 4065 , VM8-650032, VM8-791325, Bavituximab, MBX-1106 (ΟNΟ-4538), Oglufanid, RK-788 and UH-497 (merimepodib);

14) mevalonate decarboxylase antagonists, for example, statins, inhibitors of HM0CoA synthase (for example, chimeglusin), squalene synthesis inhibitors (for example, zaragoza acid);

15) angiotensin ΙΙ receptor antagonists, for example, losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;

16) inhibitors of the angiotensin-converting enzyme, for example, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril;

17) other antifibrotic agents, for example, amiloride and

18) endothelin antagonists, for example, bosentan and ambrisentan.

In yet another embodiment of the present application, pharmaceutical compositions are described comprising 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, the therapeutic agent used in combination with the compound or composition of the present invention can be any substance having a therapeutic effect when used in combination with a compound of the present invention. For example, the therapeutic agent used in combination with the compound or composition of the present invention may be interferons, ribavirin or its analogs, NSO inhibitors, Ν83, Ν853 inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, mevalonate decarboxylase antagonists, antagonists of the renin-renin system antifibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of the NSU No. 5B polymerase, non-nucleoside inhibitors of the NSU No. 5B polymerase, NSU No. 5A inhibitors, TK-7 agonists, cytophil ynoic inhibitors, NSO GOE8, pharmacokinetic enhancers, or other composition for treating HCV, or mixtures thereof.

In particular, compositions of one or more compounds of the present invention can be combined with one or more compounds selected from the group consisting of

1) interferons, for example, PEGylated - ^ IΡN-alpha-2b (PEG-Intron), pegylated τΙΡΝalpha-2a (Pegasys), ^ IΡN-alpha-2b (Intron A), ^ IΡN-alpha-2a (Roferon-A) , interferon alpha (MOK-22, OPC-18, A1GaGegope, A1Gapa1tue, MiGGetop, subaline), interferon alfacon-1 (IpGe ^ dep), interferon alpha-p1 (Ae11Gegop), interferon alpha-Ν (A1Gegopop, (Auopeh, B-8234), interferonomega (bye BiCO8, BSTEI 510), albinterferon alpha-2b (A1bGeGop), interferon alpha-Xb, BX-52 026523

883 (LosYugop), S-3021, glycosylated interferon alpha-2b (LU-005), PEGCnGegdep, Paglated lambda interferon (PEGylated [B-29) and belerophone;

2) ribavirin and its analogues, for example, ribavirin (Rebetol, Seredik) and taribavirin (viramidine);

3) NSI inhibitors of the азыδ3 protease, for example, boceprevir (8CH-503034, 8CH-7), telaprevir (UK950), UK-813, TMS-435 (TMS435350), ABT-450, Y-201335, Y-1230, MK -7009, δСΗ-900518, ΥΒΥ-376, УX-500, 0δ-9256, 08-9451, ΒΜδ-790052, ΒΜδ-605339, РНХ-1766, Αδ-101, Υ ^ 5258, Υ ^ 530, Υ ^ 531 and ΉΜΝ -191 (K-7227);

4) alpha-glucosidase 1 inhibitors, for example, celgosivir (MX-3253), miglitol and IT-231B;

5) hepatoprotectors, for example, emericasan ΟΟΝ-6556), ME-3738, 0δ-9450 (LB-84451), silibilin and MPoO;

6) nucleoside or nucleotide inhibitors of NSU polymerase Уδ5Β, for example, K ¹ 626, K ⁷ 128 (K ⁴ 048), 10X184, I ^ X-102, ΡδΡ7851, BCX-4678, valopicitabine (ΝΜ-283) and MK-0608;

7) non-nucleoside inhibitors of NSU polymerase Νδ5Β, for example, filibuvir (PP-868554), АВТ333, АВТ-072, ΒΡ207127, USN-759, USN-916, 1TK-652, MK-3281, ΑΒΥ-708, USN-222, Α848837 , ΑΝΑ598, 0L60667, 0L59728, A-63890, A-48773, A-48547, BC-2329, USN-796 (nesbuvir), 0δ625433, Β ^ Ν1941, XΤ ^ -2125 and 0δ-9190;

8) NSU Νδ5Α inhibitors, for example, ΑΖΏ-2836 (Α-831), ΑΖΏ-7295 (A-689) and BM8-790052;

9) TK-7 agonists, for example, imiquimod, 852Α, 0δ-9524, ΑΝΑ-773, ΑΝΑ-975, ΑΖΏ-8848 (ΏδΡ3025), ΡΡ-04878691 and 8М-360320;

10) cyclophilin inhibitors, for example, Bevyu-025, δСΥ-635 and No. М811;

11) NSU IΚEδ inhibitors, for example, MCP067;

12) pharmacokinetic enhancers, for example, ΒΑδ-100, 8PP452, ΡΡ-4194477, TMS-41629, 0δ9350, 0δ-9585 and roxithromycin;

13) other drugs for the treatment of hepatitis C virus, for example, thymosin alpha 1 (zadaxine), nitazoxanide (LPpea, ΝΤΖ), ΒIУN-401 (virostat), ΡΥΝ-17 (altirex), KRE02003002, actilon (CP010101), 0δ-9525 , ΚΚΝ-7000, tsivatsir, 005005, XΤ ^ -6865, ΒΡΤ225, PTX-111, 0X2865, ΤΤ-033Ϊ, ΑΝΑ 971, NΘU-205, tarvacin, ЕНС-18, У0X-410С, ЕΜΖ-702,, Α \ Ί 4065, VM8-650032, VM8-791325, Bavituximab, MEU-1106 (ΘNΘ-4538), Oglufanid, RK-788 and UX-497 (meriododib);

14) mevalonate decarboxylase antagonists, for example, statins, ΑCoΑ synthase inhibitors (for example, chimeglusine), squalene synthesis inhibitors (for example, zaragoza acid);

15) antagonists of angiotensin II receptors, for example, losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;

16) inhibitors of the angiotensin-converting enzyme, for example, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril;

17) other antifibrotic agents, for example, amiloride, and

18) endothelin antagonists, for example, bosentan and ambrisentan.

In yet another embodiment, the present application provides a combination of a pharmaceutical agent, comprising:

a) a first pharmaceutical composition comprising a compound of the present invention 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 HIV protease inhibitory compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors , 41 other inhibitors, CXCΚ ⁴ inhibitors, 120 other inhibitors, CCK5 receptor inhibitors, interferons, ribavirin analogues, Νδ3 protease inhibitors, Ν853 inhibitors, alpha-glucosidase 1 ing inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside inhibitors of hepatitis C virus and other drugs for the treatment of hepatitis C virus, and combinations thereof.

Combinations of compounds of UN formulas and RU-U formulas and additional active therapeutic agents can be selected for the treatment of patients infected with hepatitis C virus and other diseases such as HIV infections. Accordingly, the compounds of formulas and formulas SH can be combined with one or more compounds used in the treatment of HIV, for example, HIV protease inhibitory compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV-inhibitors integrase inhibitors, gp41 inhibitors SXSΚ ^4, gp120 inhibitors, SSK5 receptor inhibitors, interferons, ribavirin analogs, protease inhibitors Νδ3, Ν853 inhibitors, alpha-glitch zidazy 1 inhibitors, cyclophilin inhibitors, hepatoprotectors, non-nucleoside inhibitors NSO and other drugs for the treatment of NSO.

In particular, one or more compounds of 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, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir , saquinavir, tipranavir, brecanavir, darunavir, TMS-126, TMS-114, mozenavir (BMR-450),

- 53 026523 .GE-2147 (A01776), A01859, Ό035, L-756423, KO0334649, KN-272, IRS-681, IRS-684, CV640385X, Ό017, PP-100; 2) HIV non-nucleoside reverse transcriptase inhibitors, for example, caravirine, emivirin, delaviridine, efavirenza, nevirapine, (+) calanolide A, etravirine, CV ⁵ 63 4, IRS-083, IRS-961, IRS-963, MKU-150 and TMS -120, TMS-278 (rilpivirin), efavirenza, V.I. 355 B5, UKH 840773, IK-453, 061, KIEA806; 3) HIV inhibitors of reverse transcriptase nucleoside, for example, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MkU ^ Yu, racivira (± -RTS), I-fazidab, emithazidab, emithazitab, emithazitab, thidoxyl, fosalvudine tidoxil, apricitibine (AUX754), amdoxovir, KR-1461, abacavir + lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine; 4) HIV nucleotide reverse transcriptase inhibitors, for example, tenofovir, tenofovir disoproxyl fumarate + emtricitabine, tenofovir disoproxyl fumarate + emtricitabine + efavirenz and adefovir; 5) HIV integrase inhibitors, for example, curcumin, derivatives of curcumin, chicorye acid, derivatives of chicorye acid, 3,5-dicafaoylquinic acid, derivatives of 3,5-dicafaoylquinic acid, aurin tricarboxylic acid, derivatives of aurin tricarboxylic acid, caffeic phenethyl ester, caffeic acid ester, acids, tyrfostin, derivatives of tyrfostin, quercetin, derivatives of quercetin, 5-1360, zintevir (AK-177), L-870812 and L-870810, MK-0518 (raltegravir), BM5-707035, MK-2048, VA-011, BM5-538158, S5K364735C; 6) other41 inhibitors, for example, enfuvirtide, sifuvirtide, PB006M, TKG-1144, 5RS3, IE56, Losik dr41, CowX and KEP 9; 7) CXSC ⁴ inhibitors, for example, AMI-070; 8) introductory inhibitors, for example, 5P01A, ΤΝΧ-355; 9) other 120 inhibitors, for example, BM5-488043 and B1oscACe / SC; 10) C6RI and IAIN oxidase inhibitor, for example, immunitin; 10) inhibitors of CCK5 receptors, for example, aplaviroc, vicriviroc, INC-9471, PKO-140, INC-15050, PF-232798, CCC5tAB004 and maraviroc; 11) interferon, for example, pegylated hGF-alpha ^ b, pegylated gGI-alpha ^ a, gGI-alpha ^ b, interferon alpha-2b Xb, gGI-alpha ^ a, interferon alpha-consensus, IηГе ^ deη. КеЫГ, lokterona, АУГ-005, PEGCHiGegdep, PEG-interferonabet, oral interferon alpha, feron, reaferon, ShGegtakh alpha, g-SHI-beta, 1Gegdei + asyttie, SHI-omega with IIKO5 and A1iGegop; 12) analogues of ribavirin, for example, rebetol, kopegus, UH-497, viramidine (taribavirin); 13) Ν55η inhibitors, for example, A-831, A-689 and BM5-790052; 14) Ν551 polymerase inhibitors, for example, IM-283, valopitsitabine, К ¹ 626, Р5И6130 (К ¹ 656), ШХ184, Р5И7851, ВГС-796, ВІ. 1941, MK-0608, IM-107, К ⁷ 128, USN-759, PF-868554, S5K625433 and HTB-2125; 15) Ν53 protease inhibitors, for example, 5CH-503034 (5CH-7), UH-950 (telaprevir), PMI- ^ and ΒI ^ N-2065; 16) alpha-glucosidase 1 inhibitors, for example, MX-3253 (celgosivir) and UT-231B; 17) hepatoprotectors, for example, GOM-6556, ME 3738, Mioc and LB-84451; 18) non-nucleoside inhibitors of the hepatitis C virus, for example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives and phenylalanine derivatives; 19) other drugs for the treatment of hepatitis C virus, for example, Zadaxin, nitazoxanide (A1chea), ΒIУN-401 (virostat), IEHU-025, USH-410C, EM2-702, AUT 4065, bavituximaba, oglufanida, ΓΥΝ-172, КР0200 Actilon (SR0-10101), KKI-7000, Civacira, 0I5005, AMA-975, XTB-6865, AMA 971, KOU-205, Tarvacin, ENC-18 and No. M811; 19) pharmacokinetic amplifiers, for example, BA5-100 and 5RI52; 20) RNase H inhibitors, for example, ODN-93 and ODN-112; 21) other anti-HIV agents, for example, U0U-1, RA-457 (bevirimata), AtrNdei, NK0214, cytoline, polymuna, U0X-410, KI247, AM2 0026, CΥΤ 99007, HIV A-221, ΒΑΥ 50-4798 , MIKh010 (iplimumaba), PB5119, AI0889 and RA-1050040.

In addition, any compounds of the invention can be combined with one or more other active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, combinations may be administered in two or more administrations.

Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that a therapeutically effective amount of a compound of the invention and one or more other active therapeutic agents are both present in the patient.

Co-administration includes the administration of unit doses of the compounds of the invention before or after the administration of a unit dose of one or more other active therapeutic agents, for example, the administration of a compound of the invention within a few seconds, minutes or hours of administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention may be administered first, and then within a few seconds or minutes by administering a unit dose of one or more other active therapeutic agents. In addition, a dose of one or more other therapeutic agents may be administered first, followed by a single dose of a compound of the invention within a few seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, and then, after a period of several hours (e.g., 1-12 hours), by administering a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a dose of one or

- 54 026523 several other active therapeutic agents first, and then, after a period of several hours (for example, 1-12 hours), by introducing a single dose of the compounds of the invention.

Combination therapy can provide synergies and synergies, i.e. the effect achieved when the active ingredients used together are greater than the sum of the effects resulting from the use of the compounds separately. A synergistic effect can be achieved when the active ingredients are: (1) co-prepared and administered or administered simultaneously in a combination preparation, (2) are used in turn or in parallel, as separate compositions, or (3) in some other modes. When delivered in alternation therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills or capsules, or various injections in separate syringes. In general, during alternation therapy, an effective dose of each active ingredient is administered one after another, that is, sequentially, while in combination therapy, effective doses of two or more active ingredients are administered together. A synergistic antiviral effect means an antiviral effect that is greater than the predicted purely additive effect of a combination of individual compounds.

In yet another embodiment, the present application provides methods for inhibiting an NSA polymerase in a cell, comprising: contacting a cell infected with an NSA with an effective amount of a compound of formula Ι-ΙΙΙ and formulas 1U-U1 or a pharmaceutically acceptable salt, solvate and / or ester thereof, in as a result, NSU polymerase will be inhibited.

In yet another embodiment, the present application provides methods for inhibiting an NSA polymerase in a cell, comprising: contacting a cell infected with an NSA with an effective amount of a compound of formulas Ι-ΙΙΙ and formulas 1U-U1 or a pharmaceutically acceptable salt, solvate and / or ester thereof, and with at least one additional active therapeutic agent that inhibits NSA polymerase.

In yet another embodiment, the present application provides methods for inhibiting an NSA polymerase in a cell, comprising: contacting a cell infected with an NSA with an effective amount of a compound of formulas Ι-ΙΙΙ and formulas TU-U or a pharmaceutically acceptable salt, solvate and / or ester thereof, and at least one additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analogues, NSU N83 protease inhibitor, Ν85α inhibitors, alpha-glucosidase 1 inhibitor a torus, hepatoprotectors, a decarboxylase mevalonate antagonist, a renin-angiotensin system antagonist, other antifibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCC Ν 85Β polymerase, non-nucleoside inhibitors of HCl он HонитΝонΝ, УУитононΝΝΝΝ, ΝУититΝΝΝΝΝΝ, ΝУффΝΝΝΝΝΝΝ GKE8 inhibitors, pharmacokinetic enhancers and other drugs for the treatment of NSOs or mixtures thereof.

In yet another embodiment, the present application provides methods for treating an NSA in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formulas ΙΙΙΙ and Formulas У UY or a pharmaceutically acceptable salt, solvate and / or ether thereof.

In yet another embodiment, the present application provides methods for treating an NSA in a patient, comprising administering to a patient a therapeutically effective amount of a compound of Formulas ΙΙΙΙ and Formulas У UY or a pharmaceutically acceptable salt, solvate and / or ether thereof, and at least one additional active therapeutic agent which inhibits NSO polymerase.

In yet another embodiment, the present application provides methods for treating an NSA in a patient, comprising administering to a patient a therapeutically effective amount of a compound of Formulas ΙΙΙΙ and Formulas У UY or a pharmaceutically acceptable salt, solvate and / or ether thereof, and at least one additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analogues, NSI N83 protease inhibitor, Ν85α inhibitor, alpha-glucosidase 1 inhibitors, hepatoprotectors, mevalon and decarboxylases of the antagonist, antagonist of the renin-angiotensin system, other antifibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of the NSU Ν85Β polymerase, non-nucleoside inhibitors of the NSU Ν85Β polymerase, NSU Ν85Α inhibitors, 7 inhibitors, 7 inhibitors, 7 inhibitors, 7 inhibitors, other drugs for the treatment of NSOs or mixtures thereof

In yet another embodiment, the present application provides for use a compound of the present invention or a pharmaceutically acceptable salt, solvate and / or ester thereof for the manufacture of a medicament for the treatment of an NSA infection in a patient.

Metabolites of the compounds of the invention

Also subject to the scope of this invention are the products of the exchange of the compounds ίη γί \ Ό described herein, to the extent that such products are new and not obvious in comparison with the prior art. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, and the like. administered compounds mainly due to enzymatic processes. Accordingly, the invention includes novel and non-obvious compounds obtained by a process comprising contacting a compound of this invention.

- 55 026523 with mammals for a time sufficient to obtain metabolic products. Such products are usually identified by a prepared radioactive label (e.g., ¹⁴ C or ³ N) of the compound of the invention, when administered parenterally at a dose that is detected (e.g., greater than about 0.5 mg / kg) in animals such as rats, mice , guinea pigs, monkeys, or humans, providing sufficient time for metabolism (usually from about 30 seconds to 30 hours) and isolating metabolic products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated using antibodies that can bind surviving epitopes in the metabolite). The structure of the metabolite is determined in the usual way, for example, by analysis of M8 or NMR. In general, the analysis of metabolites is carried out in the same way as conventional studies of the metabolism of the drug, well known to specialists in this field. Metabolic products, until they are found ίη νίνο, can be used in diagnostic tests for the therapeutic dosage of the compounds of the invention, even if they do not have their own inhibitory activity against NSU polymerase.

Recipes and methods for determining the stability of compounds in surrogates of gastrointestinal secretion are known. the compounds are defined here to be stable in the gastrointestinal tract, when less than about 50 molar percent of the protected groups deprotects the intestinal or gastric juice substitutes upon incubation for 1 hour at 37 ° C. Just because these compounds are stable in the gastrointestinal tract does not mean that they cannot be hydrolyzed ίη νίνο. The prodrugs of the invention will usually be stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the gastrointestinal tract, liver or other metabolic organs, or within the cells as a whole.

Some abbreviations and acronyms are used to describe experimental details. Although most of them should be clear to a person skilled in the art, tab. 1 contains a list of many of these abbreviations and acronyms.

Table 1. List of abbreviations and acronyms

Abbreviation Value AsgO Acetic Anhydride ΑΙΒΝ 2,2’-azobis (2-methylpropionitrile) Vp benzyl VpVg benzyl bromide B8A bis (trimethylsilyl) acetamide Βζϋΐ Benzoyl chloride get out to arbon and l diim and dazo l 1ELVS0 1,4-diazabicyclo [2.2.2] octane ΟΒΝ 1,5-diazabicyclo [4.3.0] non-5-ene ϋος 2,3-dichloro-5,6-dicyan-1,4-benzo quinone ovi 1,5-diazabicyclo [5.4 0] undec-5-ene WASP dichloroacetamide oss dicyclohexylcarbo diimide osm dichloromethane ϋΜΑΡ 4 - dimethyl amin opiridi and ϋΜΕ 1,2-dimethoxyethane ϋΜΤΟ Dimethoxytrityl chloride ϋΜ8Ο dimethyl sulfoxide OMTg 4, 4’-dimethoxytrityl ϋΜΡ d and methyl l forms amide ESAc ethyl acetate Ε8Ι Eletroaerosol ionization ΗΜϋδ hexamethyldisilazane NRS High pressure liquid chromatography BOA Lithium diisopropylamide ΙΚΜ8 Low Resolution Mass Spectrum IRAW meta-chloroperbenzoic acid- Mesi acetonitrile Meon methanol MMTS monomethoxytrityl chloride

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ιη / ζ or pt / e Mass to charge ratio mn ⁺ Mass plus 1 Mn ' Weight minus 1 Maon Methanesulfonic acid M8 OR GP5 Mass spectrum ΝΒ8 N - bromo su ktsi n them id Pb phenyl Γί or d. 1. Room temperature TVAR Tetrabutylammonium fluoride TM8S1 chlorotrimethylsilane TMZVg bromotrimethylsilane ΤΜ8Ι iodtri m eti ls ila and TM8OTG (trimethylsilyl) trifluoromethyl sulfonate TEM triethylamine TVA tributylamine TVAR Tributylammonium pyrophosphate TV8S1 tert-butyldimethylsilyl chloride ΤΕΑΒ Triethylammonium Bicarbonate TRA Trifluoroacetic acid Thc or Hc Thin layer chromatography Tg triphenylmethyl To1 4-methylbenzoyl Tigyo Opppagy 1: 1 mixture of isopropyl magnesium chloride and lithium chloride δ ppm to field from tetramethylsilane

Getting connections

To a suspension of 7-bromo-2,4-bis-methylsulfanyl-imidazo [2,1-ί] [1,2,4] triazine (prepared in accordance with ^ O2008116064, 500 mg, 1.72 mmol) in anhydrous THF ( 5 ml), Liu (1.6 M in hexane, 1.61 ml, 2.41 mmol) was added dropwise at -78 ° C. The suspension became a red-brown solution within 5 minutes, and then a mixture of 1a (prepared in accordance with UO 200631725, 675 mg, 1.81 mmol) and boron trifluoride etherate (2.40 ml, 1.89 mmol) in THF ( 5 ml) was added dropwise to the mixture. After stirring for 2 hours at −78 ° C., saturated KH ₄ Cl 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 silica gel column chromatography (EluAc / Hexane) to give 1b as a rich yellow foam (650 mg, 67%). ¹ H NMR (400 ΜΗζ, SBS13): δ 8.13 (b, 2H), 8.03 (b, 2H), 7.81 (b, 1H), 7.59 (ΐ, 1H), 7.45 (t, 3H), 7.36 (ΐ, 2H), 6.40 (bg8, 1H), 6.01 (bb, 1H), 4.78 (t, 2H), 4.60 (bb, 1H), 2.68 (5, 3H), 2.45 (5, 3H), 1.62 (b, 3H) ) ¹⁹ P NMR (376 ΜΗζ, SBS13): δ -167.5. Μδ = 585.1 (M + H +).

To a solution of 1b (820 mg, 1.40 mmol) in dichloromethane (20 ml) was added boron trifluoride etherate (2 ml) and triethylsilane (2 ml) and stirred at room temperature for 16 hours. Additionally, boron trifluoride etherate (1 ml) and triethylsilane (1 ml) were added and stirred for 7 days. The mixture was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was washed successively with water, a saturated solution of ammonium chloride and a saturated solution

- 57 026523 salts, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (EuAc / Hexane) to give 1c (605 mg, 76%). ¹ H NMR (400 MN /, SES13): δ 8.10 (b, 1 = 7.2Н /, 2Н), 8.00 (b, 1 = 7.2 Ng, 2Н), 7.66 (5, 1Н), 7.61 (ί, 1 = 7.2 Ng, 1H), 7.53 (ί, 1 = 7.2 Ng, 1H), 7.46 (ί, 1 = 7.2 Ng, 2H), 7.38 (ί, 1 = 7.2 Ng, 2H), 5.78 (t, 2H), 4.80 (bb, 1H), 4.68 (t, 1H), 4.60 (bb, 1H), 2.68 (5, 3H), 2.65 (5, 3H), 1.32 (b, 3H). ¹⁹ P NMR (376 MH /, COC13): δ -149.9. M8 = 569.1 (M + H +).

Compound 1c (635 mg, 1.12 mmol) was placed in a steel bomb of the reactor. Liquid ammonia (~ 30 ml) was added and the reactor bomb was tightly closed. The mixture was stirred at 50 ° C. for 16 hours. After cooling to room temperature, ammonia was evaporated and the solid residue was dissolved in THF (10 ml) and MeOH (10 ml). Sodium ethoxide (25% weight, 0.63 ml) was added and stirred at 60 ° C for 40 minutes. The mixture was neutralized with acetic acid and concentrated. The residue was purified by Raman HPLC to give product 1b (175 mg, 48%). ¹ H NMR (400 MH, PM8O-b6): δ 8.21 (L5, 2H), 7.60 (5, 1H), 5.45 (L5, 1H), 5.43 (b, 1H), 4.91 (ί, 1H), 3.92 (t, 1H), 3.76 (t, 2H), 3.57 (t, 1H), 2.44 (5, 3H), 1.09 (b, 3H). ¹⁹ P NMR (376 MH /, OM8O-b6): δ -153.5. M8 = 330.1 (M + H +).

To a solution of 1b (175 mg, 0.53 mmol) in dichloromethane (11 ml) was added MCPBA (370 mg, ~ 1.5 mmol) and stirred at room temperature for 16 hours. The mixture was concentrated to give crude 1e, which was used for the next reaction without further purification. M8 = 362.0 (M + H +).

Compound 1e (obtained from the previous reaction) was placed in a steel bomb of the reactor. Liquid ammonia (~ 30 ml) was added and the reactor bomb was tightly closed. The mixture was stirred at 115 ° C for 3 days. After cooling to room temperature, ammonia was evaporated. The solid residue was purified by Raman HPLC to give compound 1 (105 mg, 66% in two steps). ¹ H NMR (400 MH, O2O): δ 7.31 (5, 1H), 5.43 (b, 1 = 25.2 Ng, 1H), 4.07 (bb, 1 = 9.6, 23.2, 1H), 3.89 (t, 1H) , 3.83 (bb, 1 = 2.4, 12.8 Ng, 1H), 3.67 (bb, 1 = 4.8, 12.8 Ng, 1H), 1.05 (b, 1 = 22.8 Ng, 3H). ¹⁹ P NMR (376 MH, P2O): δ -153.5. M8 = 299.2 (M + H +).

To a solution of compound 1 (82 mg, 0.28 mmol) in water (340 ml) was added adenosine deaminase (A5168 bovine spleen type IX from 81 dta-A1bps11. 0.125 units per ml of water), and stirred at 37 ° C for 4 hours . The mixture was concentrated and purified by RP-HPLC to give compound 2 (56 mg, 68%). ¹ H NMR (400 MH, P2O): δ 7.35 (5, 1H), 5.46 (b, 1 = 25.2 Ng, 1H), 4.08 (bb, 1 = 9.6, 22.6, 1H), 3.93 (t, 1H), 3.87 (bb, 1 = 2.4, 12.8 Ng, 1H), 3.71 (bb, 1 = 4.8, 12.8 Ng, 1H), 1.12 (b, 1 = 23.2 Ng, 3H). ¹⁹ P NMR (376 MH, E 2 O): δ -153.4. M8 = 300.2 (M + H +).

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To a suspension of 7-bromo-pyrrolo [2.1-1 | [1,2,4] triazin-4-ylamine (prepared in accordance with ^ O2007056170, 2.13 g, 10 mmol) in THF (20 ml) was added TM8C1 (2.66 ml, 21 mmol) and stirred at room temperature for 16 hours under argon. After cooling to −78 ° C., a solution of CuB (1.6 M, 21 ml, 33 mmol) in hexane was added dropwise. The mixture was stirred for 1 hour at the same temperature. A solution of 1a (prepared in accordance with UO 200631725, 4.46 g, 12 mmol) in THF (10 ml) was then added. After stirring for 2 hours at -78 ° C, a saturated solution of ammonium chloride was added to stop the reaction. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 3b as a yellow solid (1.6 g, 32%). M8 = 507.1 (M + H +).

Alternative procedure for compound 3b using 1,2-bis - [(chlorodimethyl) silanyl] ethane instead of chlorotrimethylsilane

To a suspension of 7-bromo-pyrrolo [2.1-1] [1,2,4] triazin-4-ylamine (500 mg, 2.35 mmol) in THF (6.5 ml) was added ViO (1.6 M in hexane, 1.6 ml) at -78 ° C. After 30 minutes a solution of 1,2-bis [(chlorodimethyl) silanyl] ethane (538 mg, 2.4 mmol) in THF (1.2 ml) was added. After 45 min, ViO (1.6 ml) was added. After an additional 30 minutes, ViO (1.5 ml) was added. After 30 minutes, a solution of 1a (610 mg, 1.64 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -78 ° C for 2 hours under argon. Acetic acid (0.7 ml) was added dropwise to stop the reaction, followed by the addition of a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 3b (320 mg, 40%). Starting compound 1a was also reduced (350 mg) by chromatography.

To a solution of compound 3b (50 mg, 0.1 mmol) and TM8CY (67 μl, 0.5 mmol) in acetonitrile (2.0 ml) at 0 ° C was added TM8OT1 (91 μl, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 h, then at 65 ° C for 3 days. The reaction was stopped with saturated NaHCO ₃ at room temperature and diluted with CH ₃ CO ₂ E1. The organic phase was separated, washed with brine, dried over Na ₂ 8 O ₄ , filtered and concentrated. The residue was purified by RP-HPLC (acetonitrile / water) to give the desired compound 3c (28 mg, 54%). M8 = 516.1 (M + H +).

Ammonium hydroxide (28% in water, 0.8 ml) was added to a solution of 3c (56 mg, 0.11 mmol) in methanol (1.2 ml) and stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified with using Raman HPLC (water / acetonitrile) to give compound 3 (20 mg, 60%). ¹ H NMR (500

MN /, 1UO): δ 7.88 (q, 1H), 7.07 (b, 1H), 6.92 (b, 1H), 4.17 (t, 2H), 4.04 (bb, 1H), 3.87 (bb, 1H), 1.15 (b, 3H). M8 = 308.1 (M + H ⁺ ).

Compound 4

To a solution of compound 3b (60 mg, 0.12 mmol) in methanol (0.5 ml) was added ammonium hydroxide (28% in water, 0.5 ml) and stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by Raman HPLC (water / acetonitrile) to give compound 4 (25 mg, 70%). M8 = 299.1 (M + H ⁺ ).

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Compound 5

Compound 3b was converted to compound 5a in a manner analogous to the conversion of 1b to 1c. Compound 5a is then converted to compound 5 by a procedure similar to the conversion of 3c to 3. ¹ H NMR (300 MH, O 2 O): δ 7.68 (q, 1H), 6.75 (b, I = 4.5 Ng, 1H), 6.65 (b , 1 = 4.5 Ng, 1H), 5.65 (b, 1 = 25.2 Ng, 1H), 3.95 (t, 3H), 3.74 (bb, 1H), 0.98 (b, 1 = 22.8 Ng, 3H). ¹⁹ P NMR (282 MNg, P2O): δ -154.2. Mδ = 283.2 (M + H +).

General procedure for the preparation of nucleoside triphosphate

A nucleoside (~ 20 mg) was placed in a pear-shaped flask (5-15 ml). Trimethyl phosphate was added (0.51.0 ml). The solution was cooled in an ice water bath. POC1 ₃ (40-45 mg) was added and stirred at 0 ° C until completion of the reaction (from 1 to 4 hours; the progress of the reaction was monitored by ion-exchange HPLC, analytical samples were prepared by taking ~ 3 μl of the reaction mixture and diluting it with 1.0 M Е ₃ NH ₂ CΟ ₃ (30-50 μl)). A solution of pyrophosphate-Βυ ₃ Ν (250 mg) and Βυ ₃ Ν (90-105 mg) in acetonitrile or dimethylformamide (11.5 ml) was then added. The mixture was stirred at 0 ° C for 0.3 to 2.5 hours, and then the reaction was stopped with 1.0 M Еΐ ₃ НН ₂ СΟ ₃ (~ 5 ml). The resulting mixture was stirred for an additional 0.5-1 h while warming to room temperature. The mixture was concentrated to dryness, redissolved in water (4 ml) and purified by ion exchange HPLC. Fractions containing the desired product were concentrated to dryness, dissolved in water (~ 5 ml), concentrated to dryness and again dissolved in water (~ 5 ml). NaHCΟ ₃ (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated to dryness again. This process is repeated 2-5 times. The residue was then purified by C-18 HPLC to give the desired product as sodium or salt. In addition, the crude reaction mixture was subjected to C-18 HPLC and then ion-exchange HPLC purification to obtain the desired product as a triethylammonium salt.

Compound TP-1 was obtained by the main method using compound 2 as starting material. ¹ H NMR (300 MNg, P2O): δ 7.44 (q, 1H), 5.45 (b, 1 = 25.5 Ng, 1H), 4.0-4.4 (t, 4H), 3.05 (t, MZN2CH3), 1.10 (t, ΝΟΙΙ; ΟΙΙ; and 2'-C-CH3). ³¹ P NMR (121.4 MNg, P2O): δ -9.5 (b, 1 = 22.1 Ng), -11.0 (b, 1 = 19.9 Ng), -23.2 (ΐ, I = 23.0 Ng). ¹⁹ P NMR (282 MNg, P ₂ O): δ -153.9.

Compound TP-2 was obtained by the main method using compound 3 as starting material. ¹ H NMR (300 MNg, P2O): δ 7.82 (q, 1H), 7.03 (b, 1H), 6.90 (b, 1H), 4.1-4.4 (t, 4H), 3.05 (t, ^ Н2СН3), 1.10 (t, H2CH3 and 2'-C-CH3). ³¹ P NMR (121.4 MNg, P2O): δ -10.7 (b, 1 = 19.5 Ng), -11.3 (b, 1 = 19.8 Ng), -23.1 (ΐ, I = 19.8 Ng).

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Compound TP-3 was obtained by the main method using compound 5 as starting material. ¹ H NMR (300 MN /, Ό2Ο): δ 7.73 (5, 1H), 6.87 (b, 1H), 6.82 (b, 1H), 5.71 (b, 1 = 24.6 Ng, 1H), 4.0-4.4 (t , 4H), 3.05 (t, ΝΟ ^), 1.14 (t, ΝΟϊ ^), 1.00 (b, 1 = 22.8 Ng, 3H, 2'-C-CH3). ³¹ P NMR (121.4 MNg, Ό2Ο): δ -8.1 (b, 1 = 22.1 Ng), -11.1 (b, 1 = 19.9 Ng), -22.7 (1, 1 = 23.0 Ng). ¹⁹ P NMR (282 MH, Ό ₂ Ο): δ -155.6. Mδ = 520.9 (M - H +).

Compound TP-8a was obtained by the main method using Compound 8 as starting material. ¹ H NMR (300 MH, Ό2Ο): δ 7.95 (5, 1H), 7.68 (5, 1H), 5.63 (b, 1 = 25.5 Ng, 1H), 4.0-4.4 (t, 4H), 3.05 (t, NCH2CH3), 1.10 (t, and 2'-C-CH3). ³¹ P NMR (121.4 MH, Ό2Ο): δ -9.20 (b, 1 = 22.1

Ng), -11.07 (b, 1 = 19.9 Ng), -23.82 (ί, 1 = 23.0 Ng). ¹⁹ P NMR (282 MH, Ό ₂ Ο): δ -155.9. Mδ = 521.6 (M-H +).

General procedure for obtaining nucleoside prodrugs (method A)

To a solution of nucleoside (0.1 mmol) in trimethylphosphite (1.0 ml) was added 1H-tetrazole (42 mg, 0.6 mmol) followed by the addition of 2,2-dimethylthiopropionic acid δ- (2- {diisopropylamino [2 ( 2,2-dimethyl-propionylsulfanyl) ethoxy] phosphanyloxy} ethyl) ether (prepared in accordance with 1. Meb Cet, 1985, 38, 3941, 90 mg, 0.2 mmol) at 0 ° C. After stirring for 2 hours, 30% hydrogen peroxide in H 2 O (140 μl) was added to the mixture. Then the mixture was allowed to warm to room temperature. After 30 minutes of stirring, 1M Ν α ₂ δ ₂ Ο ₃ in H ₂ O (5 ml) was added to stop the reaction. The organic layer was washed with a saturated aqueous solution _of Ν α ₂ мл ₃ (10 ml x 2), brine, and concentrated in vacuo. The residue was purified using β-HPC (MeCY-H ₂ O gradient) to obtain prodrug A.

Compound A-1 was obtained by method A using compound 1 as starting material. ¹ H NMR (400 MH, ΟΌΟ13): δ 7.42 (5, 1H), 5.47 (b, 1 = 26.4 Ng, 1H), 4.95 (L5, 2H), 4.59 (t, 2H), 4.35 (t, 1H, 4'-H), 4.18 (t, 2H, 5'-H), 4.10 (t, 4H), 3.13 (t, 4H), 1.24 (b, 3H), 1.22 (5, 9H), 1.19 (b, 9H). ³¹ P NMR (161.9 MH, ΟΌΟ13): δ -1.26. Mδ = 667.1 (M + H +).

General procedure for obtaining nucleoside prodrugs (method B)

Non-limiting examples of monophosphoramidate prodrugs containing the present invention can be prepared in accordance with General Scheme 1.

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The general procedure involves reacting an ester salt of amino acid 19b, for example a hydrochloric acid salt, with aryl dichlorophosphate 19a in the presence of about two to ten equivalents of a suitable base to give phosphoramidate 19c. Suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and IMLR, tertiary amines such as triethylamine and ILVCO, and substituted amidines such as ΌΒΝ and IVI. Tertiary amines are particularly preferred. Preferably, the product at each step is used directly in subsequent steps without recrystallization or chromatography. Specific, but non-limiting examples 19a, 19b, 19c can be found in VO 2006/121820, which is hereby incorporated by reference in its entirety. The nucleoside base 19th reacts with phosphoramidate 19c in the presence of a suitable base. Suitable bases include, but are not limited to, imidazoles, pyridines, such as lutidine and IMLR, tertiary amines, such as triethylamine and ELVCO, and substituted amidines, such as И and IVI. Product B can be isolated by recrystallization and / or chromatography.

Phenyl ethoxyalaninyl phosphorochloridate (124 mg, 0.42 mmol; prepared according to McCodd e! A1, 1. Mei. Cet. 1993, 36, 1048-1052) was added to a mixture of compound 3 (20 mg, 0.065 mmol) and Νmethylimidazole (42 μl, 0.52 mmol) in anhydrous trimethyl phosphate (0.8 ml). The reaction mixture was stirred for 3 hours at room temperature, and then methanol was added to stop the reaction. The methanol solvent was removed under reduced pressure. The residue was purified by reverse phase HPLC and then column chromatography on silica gel (100% ethyl acetate) to give compound B-1 (10 mg, 27%). ³¹ P NMR (121.4 MH /, SPS1 ₃ ): δ -3.42, 3.77. Mδ = 563.0 (M + H +), 561.0 (M - H +).

About 3.1 mmol of 4-chlorophenyl 2-propyloxyalanyl phosphorochloridate (prepared in accordance with McCodd e! A1, 1. Mei. Cet. 1993, 36, 1048-1052) is added to the mixture, about 0.5 mmol of compound 3 and about 3, 8 mmol of Ν-methylimidazole in approximately 3 ml of anhydrous trimethylphosphate. The reaction mixture was stirred for approximately one hour to 24 hours at room temperature and methanol was added to base the reaction. The methanol solvent is removed under reduced pressure. The residue was purified by reverse phase HPLC to give compound B-2.

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Compound B-3 was obtained by a similar procedure used for compound B-1. ³¹ P NMR (121.4 MH /, SIS1 ₃ ): δ -3.50, 3.76. M8 = 577.2 (M + H +).

Compound B-4 was obtained by a similar procedure used for compound B-1. ³¹ P NMR (162 MH /, SYSOI): δ 2.2. M8 = 633.4 (M + H +).

Compound B-5 was obtained by a similar procedure used for compound B-1. ³¹ P NMR (162 MH /, SIS1 ₃ ): δ 4.15, 4.27. M8 = 549.3 (M + H +).

Compound B-6 was obtained by a similar procedure used for compound B-1. ³¹ P NMR (162 MH /, SIS1 ₃ ): δ 3.50, 4.07. M8 = 613.1 (M + H +).

Compound B-7 was obtained by a similar procedure used for compound B-1, using compound 5 as the parent nucleoside. ³¹ P NMR (162 MH /, SIS1 ₃ ): δ 3.37, 3.97. M8 = 538.1 (M + H +).

Compound B-8 was obtained by a similar procedure used for compound B-1, using compound 5 as the parent nucleoside. ³¹ P NMR (162 MH /, SIS1 ₃ ): δ 3.69, 4.39. M8 = 588.1 (M + H +).

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An alternative procedure for obtaining a nucleoside prodrug (method C)

In a flask containing L-valine hydrochloride ethyl ester (2.5 g, 13.8 mmol, 1 equiv.), CH ₂ Cl ₂ (46 ml, 0.3 M) and phenyl dichlorophosphate (2.1 ml, 13, 8 mmol, 1 equiv.), And then cooled to -10 ° C. After 10 minutes, TEM (3.8 ml, 13.8 mmol, 1 equiv) was slowly added to the reaction mixture over five minutes. The reaction was carried out for one hour before the addition of p-nitrophenol (1.9 g, 13.8 mmol, 1 equiv.) To the reaction mixture, followed by the addition of more than TEM (3.8 ml, 13.8 mmol, 1 equiv.) Over five minutes. The reaction mixture was heated and continued for another two hours. The reaction mixture was concentrated in vacuo and dissolved in diethyl ether (200 ml). Insoluble salts were filtered off and the filtrate was concentrated in vacuo.

Flash column chromatography was performed using 4/1 Hex / E1OAc to a clear oil as C-1a.

¹ H NMR (400 MH, SBS13): δ 8.21 (q, 2H), 7.41 - 7.20 (t, 7H), 4.22 -4.05 (t, 3H), 2.46 (q, 2 H), 1.99 (bb, 1 = 23.0, 20.1 Ng, 2H), 1.68 (q, 1H), 1.20-1.05 (t, 8H). ³¹ P NMR (162 MH /, SBS13): δ -2.79 (bb, 1 = 28.0, 4.2 Ng). Lc M8 t / z 422.99 [M + H +].

THF (1 ml, 0.2 M) was added to a flask containing compound 3 (70 mg, 0.23 mmol, 1 equiv.), And NMR (1 ml, 0.2 M) was cooled to 0 ° C. Tert-ViMGC1 (560 μl, 2.5 eq., 1M THF) was slowly added and stirred for 5 min before C-1a phenolate (207 mg, 0.46 mmol, 2 eq. Dissolved in 500 μl THF). The reaction mixture was heated to 50 ° C. The reaction was monitored by bCM8. After completion of the reaction, the mixture was concentrated in vacuo and the residue was purified by HPLC to give compound C-1. ¹ H NMR (400 MH, SBS 13) δ 7.87 (q, 1H), 7.24 - 7.10 (t, 4H), 7.03 (1, 1 = 7.2 Ng, 1H), 6.81 (b, 1 = 4.6 Ng, 1H), 6.52 (b, 1 = 4.7 Ng, 1H), 5.61 (k, 2H), 4.46 (bb, 1 = 24.0, 11.4 Ng, 2H), 4.33 - 4.14 (t, 2H), 4.06 (b1, 1 = 7.2, 4.2 Ng, 2H), 3.82 - 3.70 (t, 1H), 3.63 (1, 1 = 10.6 Ng, 2H), 1.98 (q, 1H), 1.17 (bb, 1 = 14.8, 7.6 Ng, 3H), 0.82 ( bb, 1 = 22.8, 6.8 Ng, 6 N). ³¹ P NMR (162 MNg, SBS13): δ 5.11. ¹⁹ P NMR (376 MH, SBS1 ₃ ): δ 152.28. Lc M8 t / z 591.21 [M + H +].

S-2a

Compound C-2a was obtained by a method analogous to the example for compound C-1a, but using methionine ester. ¹ H NMR (400 MH, SBS13) δ 8.19 (q, 2H), 7.44-7.03 (t, 7H), 4.11 (q, 2H), 3.81 (b, 1 = 44.5 Ng, 1H), 2.04 (q, 3H ), 1.61 (q, 2H), 1.21 (b, 1 = 6.1 Ng, 2H), 1.01 - 0.65 (t, 4H). ³¹ P NMR (162 MNg, SBS13) δ -2.00 (b, 1 = 12.9 Ng). L8 M8 t / g 455.03 [M + H +].

Compound C-2 was obtained in a manner analogous to the example for compound C-1 using compound 3 and C-2a.

^! H NMR (400 MH, SBS13) δ 7.96 (b, 1 = 15.8 Ng, 1H), 7.40 - 7.06 (t, 13H), 6.93 (b, 1 = 6.7 Ng, 1H), 6.70 (q, 1H), 5.98 (q, 1H), 4.54 (bb, 1 = 21.6, 11.7 Ng, 2H), 4.32 (b, 1 = 12.0 Ng, 2H), 4.14 (b1, 1 = 13.0, 6.4 Ng, 4H), 2.44 (b, 1 = 7.5 Ng, 2H), 2.00 (b, 1 = 16.2 Ng, 5H), 1.89 (q, 2H), 1.35 - 1.13 (t, 7H). ³¹ P NMR (162 MNg, SBS13) δ 4.12, 3.58. ¹⁹ P NMR (376 MH, SBS1 ₃ ) δ -152.28 (q). L8 M8 t / g 623.27 [M + H +].

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For

Compound C-3a was obtained by a method analogous to the example for compound C-1a, but using tryptophan ether.

'H NMR (400 MH /, SBS1 ₃ ) δ 8.18 - 8.03 (t, 3H), 7.29 - 7.08 (t, 8 H), 7.36 - 6.98 (t, 3H), 4.41 -4.11 (t, 1H), 4.15 -3.95 (t 2H), 3.68-3.80 (t, 1H), 3.33 - 3.04 (t, 2H), 1.06-1.17 (t, 3H). ³¹ P NMR (162 MH /, SBS1 ₃ ) δ -2.87, -2.99. BC M8 t / ζ 510.03 [M + H +].

Compound C-3 was obtained in a manner analogous to the example for compound C-1 using compound 3 and C-3a.

'H NMR (400 MH /, SBS1 ₃ ) δ 8.27 (5, 1H), 7.84 (s, 1H), 7.47 (s, 1H), 7.36 - 6.77 (t, 11H), 6.57 (s, 1H), 4.40 - 3.96 (t, 6H), 3.20 (5, 4H), 2.60 (5, 1H), 1.30 - 1.04 (t, 6H). ³¹ P NMR (162 MS, SBS) δ 4.02, 3.75 ¹⁹ L NMR (376 MH, SBS _{1 3} ) δ -152.13. BC M8 t / ζ 678.32 [M + H +].

S-4a

Compound C-4a was obtained by a method analogous to the example for compound C-1a by substituting phenylalanine ether.

'H NMR (400 MP /, OC) δ 8.15 (ί, 1 = 8.7 4ζ, 2H), 7.43-7.11 (t, 10 N), 7.04 (bbb, b = 11.4, 6.7, 2.9 4ζ, 2H), 4.32 (bbb, 6 = 15.3, 11.3, 6.1 Ng, 4H), 4.15 - 3.99 (t, 7H), 3.74 (1b, b = 11.0, 5.0 Ng, 8H), 3.01 (b, 6 = 5.7 Ng, 2H), 1.17 (1b, 6 = 7.1, 5.2 4ζ, 2H). ³¹ P NMR (162 MSH, AXIS) δ -2.97, -2.99. BC M8 t / ζ 471.03 [M + H +].

Compound C-4 was obtained in a manner analogous to the example for compound C-1 using compound 3 and C-4a.

'H NMR (400 MH, OC1 ₃ ) δ 7.92 (b, 6 = 13.2 4ζ, 1H), 7.46-6.97 (t, 17H), 6.91 (5, 1H), 6.75 (5, 1H), 4.10 (bb, b = 29.6, 19.2 4ζ, 8H), 2.97 (5, 3H), 1.32 - 1.05 (t, 7H). ³¹ P NMR (162 MS, OS 13) δ 5.11. ¹⁹ b NMR (376 MH /, OC13) δ -152.34 (5). BC M8 t / ζ 639.24 [M + H +].

S-5th

Compound C-5a was obtained by a method analogous to the example for compound C-1a, but using proline ether.

'H NMR (400 MH /, OC1 ₃ ) δ 8.20 (b,> 7.8 4ζ, 2H), 7.45-7.08 (t, 7H), 4.37 (1b,> 8.0, 3.8 4ζ, 2H), 4.17-3.98 (t , 2H), 3.61-3.34 (t, 2H), 2.21-1.77 (t, 3H), 1.19 (1b, 1 = 7.1, 3.8 4ζ, 3H). ³¹ P NMR (162 MSh,

- 65 026523

SIS) δ -3.92, -3.96. L M8 t / ζ 420.98 [Μ + Η +].

Compound C-5

Compound C-5 was obtained in a manner analogous to the example for compound C-1 using compound 3 and C-5a.

¹ H NMR (400 ΜΗζ, SISI) δ 7.95 (b, 1 = 4.5 Ηζ, 1Η), 7.39 - 7.10 (t, 4Η), 6.92 (bb, 1 = 16.0, 4.6 Ηζ, 1Η), 6.69 (q, 1Η ), 6.03 (bk, 2Η), 4.46-4.36 (t, 1Η), 4.36 - 3.96 (t, 4Η), 3.37 (b, 1 = 58.9 Ηζ, 2Η), 2.26-1.66 (t, 4Η), 1.39- 1.12 (t, 8Η). ³¹ P NMR (162 ΜΗζ, SIS) δ 3.47, 2.75. ¹⁹ P NMR (376 ΜΗζ, SIS) δ -152.36. BC M8 t / ζ 589.14 [M + Η].

Compound C-6.

Compound C-6 was obtained in a manner analogous to the example for compound C-1 using compound 3 and a sulfonic analogue of C-1a.

> H NMR (400 MF, SOSI 5 7.93 (k, I Η), 7.89 (k, I Η), 7.35 - 7.01 (t, 5 N), 6.93 (b, 1 = 2.8 Ηζ ,, 1Η), 6.58 ( b, 1 = 2.8 Ηζ, 1Η), 5.79 (bk, 2Η), 4.30 (q, 6 Η), 4.11 (b, 1 = 7.0 Ηζ, 6Η), 3.10 -2.84 (t, 3Η), 2.75 (k, 3Η), 2.54 (q, 6 Η), 1.31-1.15 (t, 6 Η). ³¹ Р NMR (162 М№, СИСИ) b 3.39, 3.33. ¹⁹ Р NMR (376 М№, SOSI δ -152.40 bС М8 t / ζ 655.24 [M + Η].

To a solution of compound 8 (200 mg, 0.71 mmol) in THF (1 ml) and NMR (1 ml) in an argon atmosphere at 0 ° C was added magnesium tert-butyl chloride (1.0 M in THF, 1.06 ml, 1.06 mmol). After 15 minutes, Compound 30b-1 (280 mg, 0.71 mmol) was added as a solution in THF. After 5 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C, stopped with methanol and concentrated. The reaction mixture was purified by silica gel chromatography and then Raman HPLC to give P1) -A-8b (225 mg, 59%). ¹ H NMR (400 MS, SOS: δ 8.09 (! Teo k, 1Η), 7.54 (! Teo k, 1Η), 7.31-7.12 (t, 5Η), 5.66 (bb, 1Η), 4.52-4.45 (t, 2Η), 4.19-4.03 (t, 4Η), 3.87-3.69 (t, 1Η), 1.35-1.15 (t, 9Η). ³¹ Р NMR (161 М№, SPS1 ₃ ): δ 4.14 (к), 3.55 ( k) .C / M8 = 539 (M + H). Retention time: 1.94 min. C: Terto L1c1goi 8igueuog HPLC M8: P1ii1dai LSC AbuShade ΜΑX Mass spectrometer Column: Pyeotex Polar Raman 30 mm x 4 mm : acetonitrile with 0.1% formic acid, water with 0.1% formic acid.

Gradient: 0-0.1 min 5% ACH 0.1-1.95 min 5-100% ACX 1.95-3.5 min 100% ASI, 3.5-3.55 min 1005% ASX 3.55 -4 min 5% ACX.

Getting 30b-1

- 66 026523

Compound 30b-1 was obtained from 30a in a basis similar to 30b-2, replacing alanine ethyl ester hydrochloride with alanine isopropyl ether hydrochloride.

The compound (b) -RE-L-8c was obtained in the basis similar to RE-A-8b. replacing ^) - 30b-2 with 30b-1 ¹ H NMR (400 MH, ΟΌΟ13): δ 8.14 (q, 1H), 7.60 (q, 1H), 7.1-7.3 (t, 5H), 5.66 (bb, 1H ), 5.02 (t, 1H), 4.50 (t, 1H), 4.40 (t, 1H), 4.1-4.3 (t, 2H), 3.98 (t, 1H), 3.78 (t, 1H), 3.18 (bq, 1H), 1.15-1.4 (t, 12H). ³¹ P NMR (161 MH, ΟΌΟ13): δ 3.70 (q). Lc / M8 = 553 (M + H +).

Getting ^) - 30b-2

Alanine isopropyl ether hydrochloride (7.95 g, 47.4 mmol) was suspended in dichloromethane (100 ml). Compound 31a (10 g, 47.4 mmol) was added. Triethylamine (13.2 ml, 95 mmol) is then added dropwise over 15 minutes (internal reaction temperature; -10 ° C to 3 ° C). When the reaction was almost complete (by NMR phosphorus), p-nitrophenol (6.29 g, 45.0 mmol) was added as a solid in one portion. Triethylamine (6.28 ml, 45 mmol) was added to the resulting suspension over 15 minutes. Then the mixture is warmed to room temperature. When the reaction was completed, MTBE (100 ml) was added. The white precipitate was removed by filtration. The filter cake was washed with MTBE (3x50 ml). The filtrate and washings are combined and concentrated. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate / hexane) to give compound 30b-2 as a diastereomeric mixture in a 1: 1 ratio (14.1 g, 77%). 'H NMR (300 MH, ΟΌΟ1 ₃ ): δ 8.22 (2b, 2H), 7.27.4 (t, 7H), 5.0 (t, 1H), 4.09 (t, 1H), 3.96 (t, 1H), 1.39 (2b, 3H); 1.22 (t, 6H). Mδ = 409.0 (M + H +), 407.2 (M - H ⁺ ).

Separation of two diastereomers of compound 306-2

(C) -30 (1-2

Two diastereomers were separated by chiral column chromatography under the following conditions:

Column: Syga1rak Yu, 2 x 25 cm.

Solvent system: 70% heptane and 30% isopropanol (TPA).

Flow rate: 6 ml / min.

Volume loading in one pass: 1.0 ml.

Sample loading concentration: 150 mg / ml in 70% heptane and 30% GOA.

^ Compounds 30b-2: retention time 43 min. ³¹ P NMR (162.1 MH, ΟΌΟ1 ₃ ): δ -2.99 (q).

- 67 026523 (S-Compound 30ά-2: retention time 62 min. ³¹ P NMR (162.1 MN /, СОС1 ₃ ): δ -3.02 (δ).

In addition, two diastereomers were separated by crystallization in the following order:

Compound 30ά-2 was dissolved in diethyl ether (~ 10 ml / g). Hexane was then added with stirring until the solution became cloudy. Grain crystals (~ 10 mg / gram of compound 30ά-2) were added to promote crystallization. The resulting suspension was gently stirred for 16 hours, cooled to ~ 0 ° C, stirred for another 2 hours and filtered to collect crystalline material (restored crystalline yield 35% -35%). The crystalline material contains ~ 95% ^ compounds 30ά-2 and ~ 5% (^ compounds 30ά-2. Recrystallization provides 99% of the diastereomerically pure ^) isomer.

The following Ρϋ-Α compounds, by way of example, were prepared according to the general procedures. Connection ΡΌ-Α-80

General Procedure for the Preparation of a Nucleoside Prodrug (Method ϋ) Non-limiting examples of 3'-O-acylated monophosphoramidate prodrugs containing the present invention can be prepared in accordance with General Scheme 2.

The general procedure involves the reaction of ΡΌ-Α (Κ ⁴ = OH) with a carboxylic acid or activated carboxylic acid, such as acid chloride or acid anhydride, which is generally known to those skilled in the art (1οιΐΓη; · ι1 οί Мейюша1 SNetMgu, 2006 , 49, 6614 and Ογ ^ πιΚ Leyegs, 2003, 6, 807). When Κ ⁸ = ΝΗ ₂ , protection of the amino group may be necessary. In short, to the solution

- 68 026523 of the RE-L compound in acetonitrile (2 ml) was added with I, I-dimethylformamide dimethylacetal (~ 1.1 eq.) And stirred at room temperature for 1 h. When the protection of the 6-amino group was completed, the mixture was concentrated to dryness. To the residue are added a dehydrating agent such as ESS (~ 4 equiv.), Acetonitrile and carboxylic acids (~ 2 equiv.). The mixture was stirred at room temperature for 24-48 hours. Water (0.2 ml) and trifluoroacetic acid (0.1 ml) were added at 0 ° C and stirred at room temperature for 64 hours. Sodium bicarbonate was added at 0 ° C. . The mixture was stirred at room temperature for 0.5 hours and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain RE-B compound. If acid chloride or acid anhydride is used, a suitable base such as triethylamine is added in place of the desiccant.

To a solution of RE-L-8L (100 mg, 0.19 mmol) in an ESM (1.0 ml) in an argon atmosphere at room temperature, I, I-dimethylformamide-dimethylacetal (25 μl, 0.19 mmol) was added. After 30 minutes, the reaction mixture was concentrated. The reaction was taken in an ESM and concentrated. This process is repeated twice. The resulting residue was dissolved in THF (1.0 ml) and cooled to 0 ° C. under argon. Triethylamine (79 μl, 0.57 mmol) and OMAP (5 mg, 0.04 mmol) were added to the solution. After 5 minutes, isobutyryl chloride (60 μl, 0.57 mmol) was added. After 10 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was cooled to 0 ° C, stopped with a 5% TPA solution in water, and then stirred at room temperature for 4 hours. The resulting mixture was extracted with ethyl acetate (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by Raman HPLC (acetonitrile / water) to give RE-B-81 (71 mg, 61%). ¹ H NMR (400 MH, COC13): δ 8.17 (SHO, 1H), 7.66 (SHO, 1H), 7.34-7.14 (t, 5H), 5.69 (s, 1H), 5.56-5.43 (t, 1H), 4.55-4.01 (t, 5H), 3.79-3.69 (t, 1H), 2.70-2.64 (t, 1H), 1.37-1.17 (t, 15H). ³¹ P NMR (161 MH /, COC13): δ 2.99 (s), 2.88 (s). BS / M8 = 609 (M + H +).

Retention time: 2.21 minutes BC: TG, E1c1gon 8iguog HPLC M8: Ρίιπ ^ αη BSO LiuShade MAX Mass spectrometer.

Column: RIe ^ te ^ x Polar Raman 30 mm x 4.6 mm.

Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid.

Gradient: 0-0.1 min 5% ASI, 0.1-1.95 min 5-100% ASI, 1.95-3.5 min 100% ASI, 3.5-3.55 min 1005 ASI, 3 55-4 min. 5% ASI.

The following RE-B compounds, by way of example, were prepared according to general procedures:

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General Procedure for the Preparation of a Nucleoside Prodrug (Method E) Non-limiting examples of 3 ′, 5′-cyclic monophosphoramidate prodrugs containing the present invention can be prepared in accordance with General Scheme 3.

Scheme 3 illustrates chemical processes that may be useful for the preparation of ΡΌ-C compound. Accordingly, ΡΌ-Α1 is converted to ΡΌ-C in the presence of a base when Ar is replaced by an electron of a leaving group, such as a p-nitro or p-chloro group (Eigoreap 1oigpa1 οί Mebu1pa1 CHeisch1gu, 2009, 44, 3769). In addition, Compound 40 is converted to Compound 41 in accordance with Vyugods apb Mebusha 1 CHeisenbut Lebeg5, 2007, 17, 2452, which then forms α-C together with the amino acid ester salt.

A solution of ΡΌ-Α-8ρ in DMSO was treated at room temperature with potassium tert-butoxide (~ 1 equiv.) And the resulting mixture was stirred for about 10 minutes for about 2 hours. Then the mixture was cooled

- 70 026523 to 0 ° C and neutralized with 1 HCl to ~ pH 6. The mixture was purified by HPLC to give compound RI-C-8c.

In addition, the following RE-C compounds are prepared by way of example according to general procedures. Compound RI-S-8g

Connection RO-E-8i

Compound 8 is dissolved in PO (OMe) 3 (0.1-0.5 M solution) and cooled to 0 ° C in argon atmosphere. To this end, POC1 (1.0-5.0 equiv.) Was added dropwise to the solution with stirring, and the reaction mixture was warmed to room temperature for 2-16 hours. The resulting solution was added dropwise to a rapidly stirred solution of acetonitrile and 0.05 -0.5 M aqueous solution of KOH. When the addition is complete, the solvents are removed under reduced pressure. The resulting residue was dissolved in water and purified by HPLC to give compound 41-1.

A solution of compound 41-1 in an ESM and PO (OMe) ₃ is prepared and cooled to 0 ° C. To this solution was added oxalyl chloride (1.0-5.0 equiv.) Followed by a catalytic amount of DMF. The mixture was stirred for about 10 minutes. up to about 1 hour When fully activated, a large volume of 2-propanol was added to the reaction mixture and stirred and warmed to room temperature. The solvents were removed under reduced pressure, and the resulting crude product was purified by preparative HPLC to give PO-E-8i.

Connection RE-E-8u

Compound RE-E- ^ is prepared from compound 41-1 based on a compound similar to RI-O8i when 2-aminopropane is replaced by 2-propanol.

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Compound RB-P-8 \ y is prepared on the basis of a similar compound 20, replacing compound 8 with compound 18.

Connection RB-O-8x

About 90 mM Compound 8 in THF is cooled to −78 ° C., and about 2.2 to about 5 equivalents of tert-butyl magnesium chloride (about 1Μ in THF) are added. The mixture is heated to 0 ° C for 30 minutes and again cooled to -78 ° C. A solution of (2§) -2 - {[chloro (1-phenoxy) phosphoryl] amino ethyl isobutyrate (\ UO 2008085508) (1Μ in THF, about 2 equivalents) is added dropwise. Cooling was stopped and the reaction mixture was stirred for about one to 24 hours. The reaction was stopped with water and the mixture was extracted with ethyl acetate. The extracts were dried and evaporated, and the residue was purified by chromatography to give RB-O-8x.

Compound 6

Compound 4 (about 0.04 mmol) and anhydrous methanol (about 5 ml) are treated with acetic acid (about 5 ml) and the reaction mixture is stirred overnight at room temperature. A saturated solution of CaHCO _{3 was} added to neutralize the reaction mixture and the crude material was purified using an HPLC system (acetonitrile-H ₂ O) to obtain 6.

Compound 7

Compound 3b (about 0.39 mmol) and anhydrous dichloromethane (about 10 ml) are added to a round-bottomed dry argon-flask (50 ml). The flask was placed in a dry ice / acetone bath (-78 ° C) and the solution was stirred for about 10 minutes. BP ₃ -EO (about 0.10 ml) was added dropwise and the reaction mixture was stirred for 10 minutes. Α1Μβ ₃ (about 1.16 mmol, 2.0 M in toluene) is then added. After a few minutes, dry ice / acetone was removed and the reaction mixture was stirred at room temperature to about 45 ° C for about 4 hours to 4 days. A solution of pyridine (about 2 ml) in methanol (about 10 ml) was added and the solvent was removed under reduced pressure. The crude product is purified by chromatography and treated with ammonium hydroxide in methanol for 16 hours at room temperature. The mixture was concentrated and the residue was purified by HPLC to give 7.

To a suspension of 7-bromimidazo [1,2-P] [1,2,4] triazin-4-amine (prepared in accordance with AC8 Μ β- 72 026523 bouche1 Cb181gu Bieegk, 2010, 1, 286; 375 mg, 1.75 mmol) in THF (4.0 ml) in an argon atmosphere was added 1,2-bis - [(chlorodimethyl) silanyl] ethane (452 mg, 2.10 mmol). After 60 minutes, the reaction mixture was cooled to −78 ° C. and CuB (1.6 M in THF, 3.8 ml, 6.10 mmol) was added. After 10 min at -78 ° C, a solution of 1a (prepared in accordance with UO 200631725, 782 mg, 2.10 mmol) in THF (1.0 ml) was added dropwise. The resulting mixture was stirred at -78 ° C for 1 h. A saturated aqueous solution of ammonium chloride was added and heated to 0 ° C. Water is added until all solids have become soluble. The mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 8b (606 mg, 59%) as a yellow solid. BC / Mg = 508 (M + H ′) Retention time: 2.17-2.26 min. Bc: Th eGo E1c) Hop §igueuog HPLC Mg: Iptdp LSC AbuShade MAX Mass spectrometer Column: Pepotepech Polar Raman 30 mm x 4.6 mm.

Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid. Gradient: 0-0.1 min. 5% 0,1, 0.1-1.95 min. 5-100% ΑΟΝ, 1.95-3.5 min 100% ΑΟΝ, 3.5-3.55 min 100

-5% ΑΟΝ, 3.55-4 min 5% ΑΟΝ.

To a solution of compound 8b (510 mg, 1.39 mmol) in dichloroethane (10.0 ml) at 0 ° C under argon, add triethylamine silane (1.77 ml, 11.09 mmol), and then BP ₃ -E1 ₂ O (1.41 ml, 11.09 mmol). The reaction mixture was stirred at 55 ° C for 16 hours. The reaction mixture was cooled to 0 ° C and stopped with saturated NaHCO 3 (aq). The reaction products are extracted with an ESM and then with EYAc. The combined organic phase is dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 8c (453 mg, 64%). 'H NMR (400 MH /, SES1 ₃ ): δ 8.10-7.94 (t, 5H), 7.6-7.33 (t, 7H), 5.91 (bb, 1H), 5.78 (b, NH24.6 Ng, 1H), 4.87 (bb, 1H), 4.70 (t, 1H), 4.58 (bb, 1H), 1.31 (b, .1 22.4 Ng, 3H). Lc / M8 = 491 (M +). Retention time: 2.36 min. Bc: Th eGo E1c) gop §scheuog HPLC Mg: Yptdp bcc AbuShade MAX Mass spectrometer Column: Pepotepech Polar Raman 30 mm x 4.6 mm.

Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid.

Gradient: 0-0.1 min 5% ΑΟΝ, 0.1-1.95 min 5-100% ΑΟΝ, 1.95-3.5 min 100% ΑΟΝ, 3.5-3.55 min 1005% ΑΟΝ, 3.55-4 min 5% ΑΟΝ.

To a solution of 8c (500 mg, 01.02 mmol) in THF (5.0 ml) was added lithium hydroxide (122 mg, 5.09 mmol) as a solution in H ₂ O (5.0 ml) and stirred at room temperature within 1 hour The reaction mixture was cooled to 0 ° C and neutralized with 1Ν HCl in water (5.1 ml). The mixture was concentrated and the residue was purified by Raman HPLC (water / acetonitrile) to give compound 8 (185 mg, 64%). ¹ H NMR (400 MH, SEZOE): δ 7.97 (5.1H), 7.63 (5, 1H), 5.54 (b, W 24.8 Ng, 1H), 4.03 (bb, 1H), 3.88 (t, 1H) ), 3.71 (bb, 1H), 1.80 (b, ί = 22.1 Ng, 3H). L / M8 = 284 (M + H +).

Retention Time: 1.06 min.

Bc: Thtglo E1c) gop §scheuog HPLC.

Mg: Yptdap LSC AbuShade MAX Mass spectrometer.

Column: Pepotepech Polar CR 30 mm x 4.6 mm.

Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid.

Gradient: 0-0.1 min 5% ΑΟΝ, 0.1-1.95 min 5-100% ΑΟΝ, 1.95-3.5 min 100% ΑΟΝ, 3.5-3.55 min 1005% ΑΟΝ, 3.55-4 min 5% ΑΟΝ.

Alternative procedure for compound 8

Compound 1e (crude is obtained from the previous reaction step) is dissolved in ethanol. Excess sodium borohydride is added in portions until the reaction is almost complete. The mixture is neutralized with acetic acid. The mixture was concentrated and the solid residue was purified by column chromatography on silica gel (0-10% methanol / dichloromethane) to give compound 27 (210 mg, 50% in two steps). Additional alternative procedure for compound 8

Raney Nickel (about 500 mg) was neutralized by washing with H2O, and added to a solution of 1st (about 100 mg) in ethanol (about 10 ml). Then the mixture was heated to 80 ° C until completion of the reaction. The catalyst was removed by filtration and the solution was concentrated in vacuo. The mixture was concentrated and the residue was purified by HPLC to give 8.

Compound 9

In a flask containing compound 3 (120 mg, 0.39 mmol, 1 eq.) Add PO (OMe) ₃ (1.5 ml, 0.25 M) and cool to 0 ° C before adding POC1 ₃ (125 μl, 1.37 mmol, 3.5 equiv.). The reaction mixture was stirred for 5 hours until the reaction stopped with water. It was directly purified by HPLC until the monophosphate of compound 9 was isolated. Lc Mδ m / s 387.95 [M + H +].

To a flask containing compound 9 (30 mg, 0.078 mmol, 1 equiv.) Was added NMR (0.8 ml, 0.1 M), followed by the addition of TEM (43 μl, 0.31 mmol, 4 equiv.), Tetrabutylammonium bromide ( 25 mg, 0.078 mmol, 1 equiv.) Before the addition of chloromethylisopropyl carbonate (60 μl, 0.38 mmol, 5 equiv.). The reaction mixture was heated to 50 ° C and stirred overnight. It was purified directly by high performance liquid chromatography to give compound 10.

¹ H NMR (400 MH /, δ 7.98 (s, 1H), 7.01 (s, 1 = 4.7 H, 1H), 6.72 (s, 1 = 4.7 Ng, 1H), 6.04 (b3, 2H),

5.74-5.61 (t, 4H), 4.91 (d !, !, 1 = 12.6, 9.4, 6.3 Ng, 2H), 4.64-4.28 (t, 4H), 1.37-1.19 (t, 15H). ³¹ P NMR (162 MH, δ -4.06. ¹⁹ P NMR (376 MH, CISE) δ -76.58, -151.95 TPA sol. LС Mδ t / ζ 620.03 [M + H +].

A solution of compound B-2 in DMSO was treated with about 3 mol equivalents of potassium tert-butoxide for 15 minutes to 24 hours. The reaction was stopped with 1Ν HCl and compound 11 was isolated by reverse phase HPLC.

Compound 1b (about 1 mmol) is placed in a steel bomb of the reactor. Liquid ammonia (about 30 ml) was charged into the reactor and the mixture was stirred at 0 ° C to about 50 ° C for about 16 hours. The ammonia was evaporated and the residue was purified to obtain 12a. A solution of 12a (about 100 mg) in ethanol (about 10 ml) was treated with Raney nickel (about 500 mg), which was neutralized by washing with H ₂ O. The mixture was then heated to about 35 to about 80 ° C until the reaction was completed. The catalyst was removed by filtration and the solution was concentrated in vacuo. The mixture was concentrated and the residue was purified by HPLC to give 12b. To a solution of compound 12b (about 50 mg) and ΤM8CN (about 0.5 mmol) in acetonitrile (about 2.0 ml) at about 0 ° C was added TM8OTG (about 0.5 mmol). The reaction mixture was stirred at room temperature for 1 h, then at 65 ° C for 3 days. The reaction was stopped with saturated NaHCO 3 at room temperature and the mixture was diluted with CH ₃ CO ₂ E1. The organic phase is separated by washing with brine, dried over No. ₂ 8O ₄ , filtered and concentrated. The residue was purified using KP-HPBC, then dissolved in methanol (about 1 ml). Ammonium hydroxide (28% in water, about 0.8 ml) was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified by Raman HPLC to give 12.

Compound 13 is prepared in the same manner as compound 9, using compound 12 as starting material.

Compound 14 was prepared by treating compound 13 from about one to about five equivalents of BSS in pyridine and heating the reaction mixture to a boil for about one to about 24 hours. Compound 14 was isolated by conventional ion exchange and reverse phase HPLC.

A solution of about 0.4 mmol of compound 14 in about 10 ml of DMF is treated with about 0.8 mmol of B1REA and about 0.8 mmol of chloromethyl isopropyl carbonate (LUO 2007/027248). The reaction mixture is heated to about 25 to about 80 ° C for about 15 minutes. up to about 24 hours. The solvent was removed in vacuo and the residue was purified by HPLC to give compound 15.

Compound 16

Compound 3 (about 0.22 mmol) was dissolved in anhydrous pyridine (about 2 ml) and chlorotrimethylsilane (about 0.17 ml). The mixture was stirred at about 0 to 25 ° C. for about one to about 24 hours. 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 BMAP (about 0.11 to about 0.22 mmol) are sequentially added. The mixture was stirred for one to about 24 hours. A solution of TBAP (1.0 M, about 0.22 ml) in THF was added and the reaction mixture was stirred for about one to about 24 hours. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated. The residue was purified by chromatography to give compound 16.

Compound 17

- 75 026523

A mixture of about 1.25 mmol of compound 16 and about 1.9 mmol of triethylammonium 2- (2,2-dimethyl-3 (trityloxy) propanoylthio) ethylphosphinate (\ νΟ2008082601) was dissolved in anhydrous pyridine (about 19 ml). Pivaloyl chloride (about 2.5 mmol) is added dropwise at a temperature of from about -30 to about 0 ° C and the solution is stirred for about 30 minutes to about 24 hours. The reaction mixture is diluted with methylene chloride and neutralized with an aqueous solution of ammonium chloride (about 0.5 M ) The methylene chloride phase was evaporated and the residue was dried and purified by chromatography to give compound 17.

To a solution of about 0.49 mmol of compound 17 in anhydrous carbon tetrachloride (about 5 ml), benzylamine (about 2.45 mmol) is added dropwise. The reaction mixture was stirred for one to about 24 hours. The solvent was evaporated and the residue was purified by chromatography to give compound 18.

A solution of about 2 mmol of compound 18 in methylene chloride (about 10 ml) is treated with an aqueous solution of trifluoroacetic acid (90%, about 10 ml). The reaction mixture was stirred at a temperature of about 25 to about 60 ° C. for 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 20.

About 90 mM of compound 2 was cooled in THF for about minutes at a temperature of about −78 ° C. and about 2.2 to about 5 equivalents of t-butyl magnesium chloride (about 1 M in THF) were added. The mixture was heated to approximately 0 ° C. over approximately 30 minutes and cooled again to approximately −78 ° C.

A solution of ^) - 2 - {[chloro (1-phenoxy) phosphoryl] amino} propyl pivaloate (νΟ2008085508) (1M in THF, about 2 equivalents) was added dropwise. Cooling was stopped and the reaction mixture was stirred for about one to about 24 hours. The reaction was stopped with water and the mixture was extracted with ethyl acetate. The extracts were dried and evaporated, and the residue was purified by chromatography to give compound 21.

Compound 22

Compound 22a was obtained in a similar manner to C-1a. ^! H NMR (400 MH, ΟΌΟ13) δ 8.11 (b, 1 = 9.0 Ng, 2H), 8.02 (5, 1H), 7.48 (ί, 1 = 7.5 Ng, 2H), 7.42-7.25 (t, 4H), 7.21 (b1, 1 = 14.9, 5.5 Ng, 2H), 7.08 (ί, 1 = 7.3 Ng, 2H), 5.17-5.03 (t, 2H), 4.99 (bb, 1 = 16.5, 9.7 Ng, 2H), 3.44 ( 5, 1H), 3.35-3.21 (t, 2H), 3.19 (b, 1 = 9.2 Ng, 1H), 3.00 - 2.80 (t, 2H). ³¹ Ρ NMR (162 MH, ΟΌΟ13) δ 4.27. Bc Mδ t / ζ 452.09

- 76 026523 [M + H ⁺ ].

Compound 22b was prepared in a similar manner to C-1 using compounds 3 and 22a. Ή NMR (400 MN /, C1) _; O1)) δ 7.76 (b, 1 = 6.3 Ng, 1H), 7.38 (!, 1 = 8.2 N, 1H), 7.27-7.12 (t, 4H), 7.06-6.81 (t, 3H), 6.74 (bb, 1 = 4.6, 3.5 H, 1H), 4.95 - 4.79 (t, 1H), 4.35-3.90 (t, 4H), 3.23 (b !, 1 = 3.2, 1.6 Ng, 3H), 3.18 - 3.05 (t, 2H) ), 2.82 (b !, 1 = 14.7, 7.3 H, 2H), 1.15 (b, A = 22.4 H, 3H). ³¹ P NMR (162 MH /, □) /) ()! δ 10.76, 10.71. BC M8 t / ζ 620.05 [M + H +].

Ethanol (4 ml) was added to a flask containing 22L (50 mg, 0.08 mmol, 1 equiv.), Then Pb (OH) ₂ (56 mg, 0.08 mmol, 1 equiv.) And ammonium formate (42 mg 0.64 mmol, 8 equiv.). The reaction mixture is heated to 80 ° C for one hour. The solid is filtered off and the material is purified by HPLC. 'H NMR (400 MS, IM8O-b ₆ ) δ 10.72 (q, 1H), 7.91 (q, 1H), 7.95-7.89 (bk, 2H), 7.41 (b, I = 7.7 N, 1H), 7.26 ( b, 1 = 8.1 Ng, 1H), 7.19-6.66 (t, 3H), 4.20-3.75 (t, 3H), 2.99 (bb, I = 16.5, 9.6 N, 2H), 2.89-2.70 (t, 2H) , 2.48-2.58 (t, 8H), 1.10 (b, 1 = 22.3 N, 3H). ³¹ P NMR (162 MS, 1) \ 18O-s% δ 7.49. ¹⁹ P NMR (376 MS, 1) \ 18O-s% δ -154.89. BC M8 t / ζ 530.21 [M + H +].

Compound 23

Compound 3 (250 mg, 0.82 mmol) was dissolved in PO (OM) ₃ (5 ml, 0.16 M) and cooled to 0 ° C in an argon atmosphere. For this stirring, the solution was added with POC1 ₃ (0.32 ml, 4.1 mmol) slowly, dropwise, and the reaction mixture was warmed to room temperature for 16 hours. The resulting solution was added dropwise with rapid stirring to a solution of acetonitrile (400 ml) and 0.08 M aqueous KOH (300 ml). When the addition was complete, the progress of the reaction was checked by LBC8. When the reaction was completed, the solvent was removed under reduced pressure. The resulting solid residue was dissolved in water and purified by HPLC to give 140 mg of compound 23 (yield: 47%). 'H-NMR (400 MS; C1) _; O1)): δ 8.15 (q, 1H), 7.40 (b, 1H; I = 4.8Ng), 7.09 (b, 1H; I = 4.8Ng), 4.64 (bb, 1H; I = 24Sh, 7.2H), 4.50-4.36 (t, 3H), 1.32 (b, 3H; 1 = 22Sh). ¹⁹ P-NMR (376 MS; C1); O1)): δ -153.11. ³¹ NMR (162MSH; C1); O1)): δ -2.20. M8 [M + H +] = 370.2.

Compound 24

A solution of compound 23 (7 mg, 0.02 mmol) in an ESM (2 ml) and PO (OMe) ₃ (1 ml) was prepared and cooled to 0 ° C. To this solution, oxalyl-C1 (10 μl) was added, followed by DMF (2 μl). The mixture was stirred for 1 min, an aliquot was taken out and cooled in methanol and then checked with L8M8 for activation. Successive amounts of oxalyl-C1 (10 μl) and DMF (2 μl) are added until complete activation. At this point, a large volume of 2-propanol (5 ml) is added to the reaction mixture and stirred and warmed to room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the resulting crude product was purified by preparative HPLC to give 5.5 mg of compound 24 (70% yield). 'H-NMR (400 MS; IM8O- ₆ ): δ 8.26 (L, 1H), 8.15 (L, 1H), 7.97 (q, 1H), 7.00 (b, 1H; I = 4.4Ng), 6.88 (b) , 1H; I = 4.4H), 4.59-4.51 (t, 2H), 4.37-4.25 (t, 2H), 1.23 (b, 3H; 1 = 22.8W). ¹⁹ P-NMR (376 MS; C1); O1)): δ -151.72. ³¹ P-NMR (162 MS; C1); O1)): δ -5.69. M8 [M + H +] = 412.0.

- 77 026523

Compound 25

Compound 25 was prepared from compound 23 similar mainly to Compound 24, replacing alanine heptyl ester with 2-propanol (yield 5.3%) - ¹ H-NMR (400MN /; ί'.Ό3, ΟΟ): δ 7.91 (δ, 1H ), 6.98 (ά, 1H; 1 = 4.8Ng), 6.92 (ά, 1H; 1 = 4.8Ng), 5.29 (άά, 1H; 1 = 24.4¾ 8.8Ng), 4.66-4.60 (t, 2H), 4.48 -4.40 (t, 1H), 4.15-4.11 (t, 3H), 3.92 (άά, 1H; 1 = 9.6¾ 7.2Ng), 1.67-1.64 (t, 3H), 1.40-1.27 (t, 15H), 0.91 -0.87 (t, 6H). ¹⁹ P-NMR (376MN /; Π) :() Ι) ί: δ -151.46. ³¹ P-NMR (162 MB; (ΊλΟΙ)): δ 7.36. Mδ [M + H +] = 539.4.

Compound 26 is prepared from compound 22 substantially similar to the preparation of compound 10.

Antiviral activity

Another aspect of the invention provides methods for inhibiting viral infections, including the step of treating a sample or object suspected of requiring such inhibition by the composition of the invention.

In the context of the present invention, samples suspected of containing viruses include natural or artificial materials, such as living organisms; tissues or cell cultures; biological samples, such as biological samples of material (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; samples of food, water or air; bioproducts of samples, such as an extract of cells, in particular cells synthesizing a recombinant desired glycoprotein, and the like. Typically, the sample will presumably contain an organism that causes a viral infection, often pathogenic organisms such as a tumor virus. Samples can be contained in any medium, including water and organic solvent / water mixtures. Samples include living organisms, such as humans, and artificial materials, such as cell cultures.

If desired, the antiviral activity of the compounds of the invention after application of the composition can be observed by any method, including direct and indirect methods for detecting such activity. Quantitative, qualitative and semi-quantitative methods for determining such activity are all being considered. Usually one of the screening methods described above is used, however, any other methods, such as monitoring the physiological properties of a living organism, are also applicable.

The antiviral activity of a compound of the invention can be measured using standard screening protocols that are known. For example, the antiviral activity of a compound can be measured using the following general protocols.

Cellular PowMysis immunological assay

BHK21 or A549 cells are trypsinized, counted and diluted to 2x10 ⁵ cells / ml in Natk P-12 medium (A549 cells) or IRM1-1640 medium (BHK21 cells) with 2% fetal calf serum (ΡΒδ) and 1% penicillin / streptomycin. 2x10 ⁴ cells per well are placed in the wells of a 96-well tissue culture plate and left at 37 ° C, 5% CΟ ₂ overnight. The next day, cells infected with viruses with a multiplicity of infection ^ ΟΙ) 0.3 in the presence of various concentrations of the test compounds are incubated for 1 h at 37 ° C and 5% CΟ ₂ and left for another 48 hours. The cells are washed once with иδ and fixed with cold methanol for 10 minutes After washing twice with ΡΒδ, the fixed cells are blocked with ΡΒδ containing 1% ΡΒδ and 0.05% Tween-20 for 1 h at room temperature. The initial antibody solution (402) is then added at a concentration of 1:20 to 1: 100 in ΡΒδ containing 1% ΡΒδ and 0.05% Tween-20 and incubated for 3 hours. Then the cells are washed three times with ΡΒδ, followed by one hour of incubation with conjugated with horseradish peroxidase (NSAID) anti-mouse antibodies (mouse dilution 1: 2000). After washing three times with ΡΒδ, 50 μl of 3.3 ', 5.5'-tetramethylbenzidine (TMB) substrate solution (δίβΐηη) was added to each well for two minutes. The reaction is stopped by the addition of 0.5 M sulfuric acid. Plates are read at 450 nm absorbance to quantify viral load. After measurement, the cells are washed three times with ΡΒδ followed by incubation with propidium

- 78 026523 iodide for 5 minutes. Plates are read in a Tesap δ3Γ ^ ™ photometer (excitation 537 nm, radiation 617 nm) to quantify the cells. Dose-response curves are plotted by mean optical density versus decimal logarithm of the concentration of the test compounds. EC _{50 is} calculated by non-linear regression analysis. A positive control such as Ν-nonyldioxinoyrimicin may be used.

Cellular analysis of the cytopathic effect Πανϊνϊΐ'υχ

For testing for West Nile virus or Japanese encephalitis virus, BHK21 cells are treated with trypsin and diluted to a concentration of 4x10 ⁵ cells / ml in KREM1640 medium with 2% ΡΒδ and 1% penicillin / streptomycin. For tests against dengue virus, Lb7 cells are trypsinized and diluted to a concentration of 4x10 ⁵ cells / ml in EMEM medium supplemented with 5% δ and 1% penicillin / streptomycin. 50 μl of the cell suspension (2 × 10 ⁴ cells) are dispensed per well into 96-well polymer-based plates optically accessible from the bottom of P G (No. TCP). Cells are grown overnight in a culture medium at 37 ° C, 5% CO ₂ , and then infected with West Nile virus (e.g. strain B956) or Japanese encephalitis virus (e.g. strain Nakayama strain) at MΟI = 0.3, or with virus dengue (for example, ΌΕΝ-2 ΝΟΟ strain) at МΟI = 1, is studied in the presence of various concentrations of the studied compounds. The virus-containing plate and compounds are further incubated at 37 ° C, 5% CO ₂ for 72 hours. At the end of the incubation, 100 μl of Ce11TPeg-C1o ™ reagent is added to each well. The contents are mixed for 2 minutes on an orbital shaker to cause cell lysis. The plates are incubated at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence is read from recorded tablets using a tablet reader. A positive control such as Ν-nonyldioxinoyrimicin may be used.

Antiviral activity in a mouse model of dengue infection

Compounds are tested by W1U0 on a mouse model of dengue virus infection (Lc1sh1 e! A1.1. ShesLoik 2007. 2007; 195: 665-74). Six to ten week-old AO129 mice (B & K &ndash; 1 Pb. H11, IR) are placed in individual ventilated cells. Mice were injected intraperitoneally with 0.4 ml of TδV01 of dengue 2 virus in suspension. Blood samples were taken via retro-orbital puncture under isoflurane anesthesia. Blood samples were collected in tubes containing sodium citrate to a final concentration of 0.4%, and immediately centrifuged for 3 min at 6000 g to obtain plasma. Plasma (20 μl) was diluted in 780 μl of KPME1640 and frozen in liquid nitrogen until further epidemic analysis. The remaining plasma was reserved for determining the level of cytokines and protein белкаδ1. Dengue fever developed with mice with increasing viremia for several days, peaking on day 3 after infection.

For testing antiviral activity, the compounds of the invention were dissolved in a carrier fluid, for example, 10% ethanol, 30% PEG-300 and 60% ^ 5V (5% dextrose in water, or 6 N HCl (1.5 eq): 1 n No. JUN (pH to 3.5): 100 mM citrate buffer pH 3.5 (0.9% v / v: 2.5% v / v: 96.6% v / v). Thirty-six 6-10 weekly AO129 mice were divided into six groups of six mice each.All mice were infected with dengue virus as described above (day 0) .Group 1 was injected with a 200 ml / mouse gastric tube with 0.2 mg / kg of the compound of the invention twice a day (once early in the morning and od n times in the afternoon) for three days starting from day 0 (the first dose immediately before dengue infection). Groups 2, 3 and 4 are dosed in the same way, with 1 mg / kg, 5 mg / kg and 25 mg / kg of compound, respectively. A positive control can be used, for example, (2K, 3K, 4K, 5K) -2- (2-amino-6-hydroxy-purin-9-yl) -5-hydroxymethyl-3-methyl-tetrahydro -furan-3,4diol dosed through a gastric tube 200 μl / mouse in the same way as in the previous groups. The other group is considered only with a carrier fluid.

On the 3rd day after infection, approximately 100 μl of blood (anticoagulated with sodium citrate) was taken from mice by retroorbital puncture under isoflurane anesthesia. Plasma was obtained from each blood sample by centrifugation and frozen in liquid nitrogen for subsequent epidemic analysis. Collected plasma samples are analyzed by epidemic analysis as described δθιιι1 e! a1. Cytokines were also analyzed as described by δθιιι1. Νδ1 protein levels were analyzed using the P1a1ePa ™ kit (VuKab LaLaYupek). An antiviral effect is indicated by a decrease in the level of cytokines and / or Νδ1 protein.

Typically, a decrease in viremia is about 5-100 times, more typically 10-60 times, most often 20-30 times, obtained at 5-50 mg / kg dose volume of the compounds of the invention.

The definition of NSU 1C ₅₀

Protocol analysis: either wild-type or δ282T (Msbassu, e! A1, I. Vu1. Cet. 2003, 49164-49170; K1itrr, e! A1., I. Vu1. Cet. 2006, 3793-3799) the mutant polymerase enzyme was used in this analysis. LC5 polymerase for analysis (40 μl) was collected by adding 28 μl of the polymerase mixture (final concentration: 50 mM Tris-HCl at pH 7.5, 10 mM KCl, 5 mM MgCl ₂ , 1 mM OTT, 10 mM BETA, 4 ng / μl RNA template, and 75 nM HCV A 21 G5b polymerase) for analysis of the plates, then 4 μl of the dissolved compound was added. The polymerase and compound were preincubated with

- 79 026523

35 ° C for 10 min before adding 8 μl of the nucleotide mixture of the substrate (33P-labeled nucleotide at a competitive value of K _m and 0.5 _mm from the remaining three nucleotides). The assay plates were closed and incubated at 35 ° C for 90 minutes. The reaction mixtures were then filtered through 96 and ΌΕΑΕ-81 filter plates using vacuum. The filter plates were then washed under vacuum with several volumes of 0.125 M CaHPO ₄ , water and ethanol to remove unincorporated labels. Then the tablets were analyzed on TorSoy to assess the level of synthesis products compared with the background control elements. Κ. ' ₅₀ volume was determined using the installed RP5Sh program

Preferably, the compounds described herein inhibit Kg5b polymerase with Κ. ' ₅₀ below 1000 μM, more preferably below 100 μM, and most preferably below 10 μM. For example, compound TP-1 has Κ. ' ₅₀ 0.15 μM and against wild-type HCV polymerase and 8282T mutant enzyme. Table II below shows the activity of TP-1 and TP-2 against both wild-type and mutant enzyme 8282T compared with the activity obtained with 2'-methylguanidine triphosphate and triphosphate (2K, 3K, 4K, 5K) -2- (4-aminopyrrolo [1,2-G] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-carbonitrile. This suggests that the replacement of 2'OH pyrrolo | 1,2-G] [1,2,4] triazin-7-yl nucleosides with 2'P unexpectedly gives activity against stable 8282T NSU mutant virus strains.

Table II

Triphosphate νπ 1С ₅₀ (μM) 5282T 1C ₅₀ (μM) Note ooo Ch'L BUT-P-0-P-0-P-0-. oh ^Ν— \ ^{ί ΝΗ} he he he is at D An ₂ but he 0.1 twenty out of 4 Βίο. Sb., 2003,278.49164 (200-fold shift) 2-S-MeSTR ooo no-r-o-r-o-r-o- » ₀ Ϊ-Ν,! he he he y ' ^Ν ' νη ₂ BUT E THREE 0.15 0.15 (1 x shift) νη ₂ LLC ^{11 11 11} \\ 'N НО-Р-О-Р-О-Р-О— * ₀ V — Ν _χ he he he V 4> _sn 0.525 111 1LGO / 2009/132135 (242-fold shift) nb & n νη ₂ ooo (Г ^ гЧ · but-r-o-r-o-r-o— » ₀ Ϊ-Ν, it is OH IT at НО Р ТР-2 νη ₂ ооо НО-Р-О-Р- O-R-O-1 _about Ϊ-Ν, he he he \ / ^Ν ”” 0.24 0,034 1,60 (7x shift) but E TR-3 νη ₂ ί? ί? ί? ΛΆ but-P-o-P-o-P-o ^ o Κν, ^ν he OH IT \ / ^Ν BUT E 0.30 1.6 (5.3x shift) TR-8a

EU NSO definition ₅₀

Replicon cells were plated in 96-well plates at a density of 8 x 10 ³ cells per well in 100 μl of culture medium, except for Geneticin. The compound was serially diluted in 100% DMSO and then added to the cells at a dilution of 1: 200 to achieve a final concentration of 0.5% 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 lysis buffer provided by the Rgoted luciferase assay system. Following manufacturer's instructions, 100 μl of luciferase substrate was added to

- 80 026523 lysed cells and luciferase activity were measured in TorCoip! luminometer. Preferably, the compounds described herein have an EC ₅₀ below 1000 μM, more preferably below 100 μM, and most preferably below 10 μM. The activity of the compounds of formula I are shown in table. III below.

Table III

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

Metabolism study

Applicants noted that monophosphate prodrugs of nucleoside analogs with nitrogen at the X ¹ position may have increased activity compared to their partners with carbon at the X ¹ position. This difference in activity correlates with the amount of active triphosphate analogs of the compounds in the cells. This can be quantified by the study of metabolism, which quantifies intracellular concentrations of triphosphate analogues. An increased intracellular concentration of metabolite triphosphate correlates with a prodrug with increased activity.

For example, a comparison of the prodrug of compound B-7 with the prodrug of compound RE-A-8b shows increased activity when nitrogen is in the X ¹ position. This can be observed in table. III, where the EU is ₅₀ NSU for the compound, where in the X ¹ position the nitrogen (compound RE-A-8b) is 0.68 μM compared with 63-73 μM for compound B-7. Activation of the prodrug of the analogue RE-A-8b (its triphosphate analogue TP-8a) showed that it is more than two orders of magnitude more effective than that observed for its counterpart prodrugs, where in the X ¹ position is carbon, B-7 (in its triphosphate analog TR-3), as shown in table. IV.

Experimental data

The Li-IIS / peo replicons of the cell containing the HCV genotype 1 subgenomic replicons were stored in Dulbecco's modified Eagle medium containing O1iAtakh with the addition of 10% heat-inactivated calf serum, penicillin-streptomycin and O418 saline disulfate. Cells were transferred to a twelve-well culture tissue plate, trilonated, and grown to fusion (0.88 x 10 ⁶ cells / well). Cells were treated for 24 hours with 10 μM nucleosides, or 10 μM prodrugs. After 24 hours, the cells were washed 2 times with 2.0 ml of ice-cold 0.9% saline sodium chloride solution. Cells were then injured with 0.5 ml of 70% methanol (MeOH) and frozen overnight to facilitate extraction of nucleotide metabolites. The recovered cell material in 70% MeOH was transferred to test tubes and dried. After drying, the samples were resuspended in 1 mM ammonium phosphate, pH 8.5, containing an internal standard (100 nM C1ATP). The intracellular level of nucleoside triphosphates was quantified on the basis of authentic standard curves using liquid chromatography associated with tandem mass spectrometry.

- 81 026523

results

Table IV. Intracellular concentrations of triphosphate analogues formed in NiB-1is / peo replicon cells after 24 hours of incubation with 10 μM RI-A-8b and B-

Prodrug Triphosphate Intracellular concentration of triphosphate analogue (μm / million) AT 7 TR-3 <0.11 “ RG) -A-8b TR-8a 20.5 ^{b a} Intracellular concentrations were below the lower limit of quantitation. ^l Value is the average of 2 separate wells.

Analysis of cytotoxicity in cell culture (determination of CC50)

The analysis is based on the assessment of the cytotoxic effect of the test compounds using a metabolic substrate.

Analysis protocol for determining CC50:

1. Maintain MT-2 cells in KPM1-1640 medium supplemented with 5% fetal calf serum and antibiotics.

2. Distribute the cells into a 96-well plate (20,000 cells in 100 μl of medium per well) and add different concentrations of the test compound in triplicate (100 μl / well). Enable raw control.

3. Incubate cells for 5 days at 37 ° C.

4. Prepare an XTT solution (6 ml for tablet analysis) in the dark at a concentration of 2 mg / ml in phosphate-buffered saline pH 7.4. Heat the solution in a water bath at 55 ° C for 5 minutes. Add 50 μl of Ν-methylphenazonium metasulfate (5 μg / ml) to 6 ml of XTT solution.

5. Remove 100 μl of medium from each well on the assay plate and add 100 μl of XTT substrate solution per well. Incubate at 37 ° C for 45 to 60 minutes in a CO ₂ incubator.

6. Add 20 μl of 2% Τπίοη X-100 per well to stop metabolic conversion

HTT.

7. Read the absorbance at 450 nm with subtracting the background at 650 nm.

8. Build the percentage of absorption compared with the untreated control and evaluate the value of CC50 as the concentration of the drug resulting in 50% inhibition of cell growth. Consider uptake in direct proportion to cell growth.

All publications, patents and patent documents cited above are hereby incorporated by reference, as if individually, by reference. The invention has been described with reference to various specific and preferred embodiments and methods. However, it will be understood by those skilled in the art that many changes and modifications can be made while remaining within the spirit and scope of the invention.

Claims (7)

CLAIM 1. The compound of formula V or its pharmaceutically acceptable salt; where R ¹ represents a (Ci-C ₈₎ alkyl; K ^a represents H or —C (= O) K ²¹ ; K ⁷ represents γ Υ represents O; Y ¹ and Y ² are each independently a group of formula 1Aa - 82 026523 formula 1Ua where each Υ ¹ represents O; each Υ ² represents O or IR; M2 is 0, 1 or 2; each K ^x represents a group of the formula! Ub where each M1a, M1c and M1y represents 0; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each K ^y represents, independently, H, -OC (= Υ ¹ ) K, -8C (= Υ ¹ ) K, (C1-C ₈ ) alkyl, C ₆ -C ₂₀ aryl or C ₇ -C ₂₀ arylalkyl; wherein each C ₆ -C ₂₀ aryl in R ^y is optionally substituted with 1-3 To ²⁰ -groups; each K is independently H, _(C1-C8) alkyl or C ₃ -C ₂₀ carbocyclyl; wherein each (C1- _C8 ) alkyl in K is optionally substituted with one or more hydroxyls; K ⁸ represents IR ^P K ¹² ; each K ¹¹ is independently H or (C1- _C8 ) alkyl; K ¹² is H and each K ²⁰ is independently halogen. 2. The compound according to claim 1, characterized in that K ¹ represents CH ₃ . 3. The compound having the structure: 83 026523 or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition for treating a YauMpyee virus infection, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 5. A method of treating an infection caused by the Iaushpyae virus, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1. 6. The method according to claim 5, characterized in that the viral infection is a viral infection of hepatitis C. 7. The method according to claim 6, characterized in that the viral infection is caused by a δ282Τ hepatitis C virus mutant.