RU2776918C2 - 2'-substituted-n6-substituted purine nucleotides for treatment of diseases caused by rna virus - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to the use of a compound of the formula IIIe:

or its pharmaceutically acceptable salt for the treatment of an infection caused by Flavivirus. In the formula IIIe, R⁷ is phenyl; R⁸ is hydrogen; R^9a and R^9b are independently selected from hydrogen and methyl, and R¹⁰ is C_1-6alkyl.

EFFECT: obtaining a compound for the treatment of an infection caused by Flavivirus.

24 cl, 5 tbl, 14 ex

Description

Link to related applications

The present application claims priority under U.S. Provisional Application Serial No. 62/384664, filed September 7, 2016. The entire contents of this application are hereby incorporated herein by reference for all purposes.

The field of technology to which the present invention relates

The present invention relates to nucleotide compounds, compositions and their uses for the treatment of diseases caused by RNA viruses other than HCV.

Background of the Invention

The Baltimore classification system divides viruses into groups, designated I-VII, according to their genome. DNA viruses belong to groups I, II and VII, and RNA viruses belong to groups III-VI. RNA viruses use ribonucleic acid as their genetic material. An RNA virus may be double-stranded (ds) RNA or single-stranded RNA, and may also be positive-stranded or negative-stranded. Group III viruses are double-stranded RNA viruses. Group IV and V viruses are single-stranded RNA viruses, but group IV viruses have a positive-sense strand and group V viruses have a negative-sense strand. Group VI are positive-sense single-stranded RNA viruses that replicate through a DNA intermediate.

Group III dsRNA viruses include the following eleven families: Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Quadriviridae, Reoviridae, and Totiviridae.

Group IV positive-sense ssRNA viruses include three orders and thirty-three families. The order Nidovirales includes the following families: Arteviridae, Coronaviridae, Mesoniviridae and Roniviridae. The order Picornavirales includes the following families: Dicistroviridae, Ifaviridae, Marnaviridae, Picornaviridae and Secoviridae. The order Tymovirales includes the following families: Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae and Tymoviridae. The following positive-sense ssRNA viruses include viruses from the following unrelated families: Alphatetraviridae, Alvernaviridae, Astroviridae, Barnaviridae, Benyviridae, Bromoviridae, Caliciviridae, Carmotetraviridae, Closteroviridae, Flaviviridae, Fusariviridae, Hepeviridae, Leviviridae, Luteoviridae, Narnaviridae, Nodaviridae, Permutotetraviridae, Potyviridae, Togaviridae, Tombusviridae and Virgaviridae.

Coronaviridae virus infections include those of the genera Alphacoronavirus, Betacoronavirus (which includes the severe acute respiratory syndrome coronavirus (SARS-CoV)), Gammacoronavirus, and Deltacoronavirus.

Flaviviridae virus infections include those of the Flavivirus and Pestivirus genera. Flavivirus infections include dengue fever, Kyasanur forest disease, Powassan disease, Wesselsbronn disease, West Nile fever, yellow fever, Zika virus infection, Rio Bravo virus infection, Rocío virus infection, Negishi virus infection, and encephalitis, including Californian encephalitis, Central European encephalitis, Ilheus fever virus encephalitis, Murray Valley encephalitis, St. Louis encephalitis, Japanese B encephalitis, ovine viral encephalomyelitis, and spring-summer tick-borne meningoencephalitis. Pestivirus infections mainly include diseases of farm animals, including swine fever in pigs, BVDV (bovine diarrhea virus) infection in cattle, and border disease virus infections in sheep.

Picornavirus infections include those of the genera Aphthovirus, Aquamavirus, Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus, Salivirus, Sapelovirus, Senecavirus, Teschovirus, and Tremovirus.

The Togaviridae family includes four genera: Alphavirus, Arterivirus, Rubivirus, and Pestivirus. The Alphavirus genus contains four viruses that cause encephalitis: Eastern equine encephalitis virus (EEE), Venezuelan equine encephalitis virus (VEE), Western equine encephalitis virus (WEE), and Everglade virus. In addition, the genus Alphavirus includes chikungunya virus, Mayaro virus, Oquelbo virus, o'Nyong-nyong virus, Ross river virus, Semliki forest virus, and Sindbis virus (SINV). The genus Arterivirus contains a single member, the equine arteritis virus. The genus Pestivirus contains three viruses of veterinary importance, namely bovine diarrhea virus (BVDV), swine cholera virus and sheep border disease virus. Rubella virus is the only member of the Rubivirus genus.

Group V negative-sense ssRNA viruses include the Mononegavirales order. The order Mononegavirales includes, without limitation, the following families and viruses: Bornaviridae, the virus that causes Born's disease; Filoviridae, the Ebola virus and the virus that causes "Marburg disease"; Paramyxoviridae, measles virus, mumps virus, Nipah virus, Hendra virus, respiratory syncytial virus (RSV) and Newcastle disease virus (NDV); Rhabdoviridae, rabies virus and Nyamiviridae, niavirus. Unassociated families and viruses include, without limitation, Arenaviridae, Lassa virus; Bunyaviridae, Hantavirus, the virus that causes Crimean-Congo hemorrhagic fever; Ophioviridae and Orthomyxoviridae, influenza virus.

The Bunyaviridae family contains over two hundred known viruses, and the family is divided into five genera: Hantavirus, Nairovirus, Orthobunyavirus, Phlebovirus, and Tospovirus. The genus Hantavirus includes the Hantaan virus. The Nairovirus genus includes the virus that causes Crimean-Congo hemorrhagic fever and the Dugbe viruses. The genus Orthobunyavirus consists of about one hundred and seventy viruses, which have been divided into many serogroups. The serogroups include Anopheles A serogroup, Anopheles B serogroup, Bakau serogroup, Bunyamwera serogroup, Bwamba serogroup, California serogroup, Capim serogroup, Gamboa serogroup, Group C serogroup, Guam serogroup, serogroup Kungol, Mapputta serogroup, Minatitlán serogroup, Nyando serogroup, Olifantsvlei serogroup, Patois serogroup, Simbu serogroup, Tete serogroup, Turlok serogroup, Vieomiya serogroup and unclassified group. The Anopheles A serogroup includes Anopheles A virus, Takaiuma virus, Virgin River virus, Thrombetas complex, Arumateua virus, Caraipe virus, Thrombetas virus, and Tucurui virus. The Anopheles B serogroup includes the Anopheles B virus and the Boracea virus. The Bakau serogroup includes the Bakau virus and the Nola virus. The Bunyamver serogroup includes Birao virus, Bozo virus, Bunyamver virus, Cash Valley virus, Fort Sherman virus, Germiston virus, Guaroa virus, Ilesha virus, Kairi virus, Main Drain virus, Northway virus, Place virus, Potosi virus, Shokwe, Stanfield virus, Tensau virus, Xingu virus, Batai virus, Kalovo virus, Chittoor virus, Garissa virus, KV-141 virus, and Ngari virus. The Bwamba serogroup includes Bwamba and Pongola viruses. The California serogroup includes California encephalitis virus, Chatanga virus, Inku virus, Jamestown Canyon virus, Jerry Slo virus, Keystone virus, Khatanga virus, La Crosse virus, Lumbo virus, Melao virus, Morro Bay virus, San Angelo virus, Sierra do Navio virus, hare hare virus, South River virus, Tahini virus and Trivittatus virus. The Kameem serogroup includes Acar virus, Benevides virus and Kameem virus. The Gamboa serogroup includes Alajuela virus, Gamboa virus, Pueblo Viejo virus, and San Juan virus. The serogroup Group C includes, but is not limited to, Brukong virus, Ossa virus, Apeu virus, Brukong virus, Caraparu virus, Vinches virus, Madrid virus, Gumbo-Limbo virus, Marituba virus, Murutuku virus, Nepuyo virus, Restan virus, Ithaqui virus, and oriboca virus. The Guam serogroup includes, but is not limited to, Bertioga virus, Beamity virus, Cananeya virus, Guam virus, Guaratuba virus, Itimirim virus, and Mirim virus. The Kungol serogroup includes, without limitation, Kungol virus and Wongal virus. The Mapputt serogroup includes, but is not limited to, Buffalo Creek virus, Mapputt virus, Maprik virus, Murrumbidgee virus, and Salt Ash virus. The Minatitlan serogroup includes, without limitation, Minatitlan virus and Palestine virus. The Nyando serogroup includes, without limitation, Eretmapodites virus and Nyando virus. The Olifantsvlei serogroup includes, without limitation, Botambi virus and Olifantsvlei virus. The Patois serogroup includes, but is not limited to, Abras virus, Babahoya virus, Pahajoki virus, Patois virus, and Shark River virus. The Simba serogroup includes, without limitation, Iquitos virus, Jatobal virus, Leanyer virus, Madre de Dios virus, Oropush virus, Oua virus, Timiri virus, Akabane virus, Tinaru virus, Douglas virus, Satouperi virus, Aino virus, Shuni virus , Python virus, Shamond virus, Schmallenberg virus and Simbu virus. The Tete serogroup includes, without limitation, Batam virus and Tete virus. The Turloc serogroup includes, but is not limited to, Mpoko virus, Turloc virus, and Umbre virus. The Vieomiya serogroup includes, but is not limited to, Anhembi virus, Cachoeira Porteira virus, Yaco virus, Macaua virus, Sororoca virus, Tayassuy virus, Tucunduba virus, and Vieomiya virus. The unclassified serogroup includes, without limitation, Batam virus, Belmont virus, Enseada virus, Estero-Real virus, Jurona virus, Kaeng Khoi virus, and Kowanyama virus. The Phlebovirus genus includes, without limitation, Neapolitan and Sicilian phlebotomy fever viruses and Rift Valley fever virus. The genus Tospovirus includes, but is not limited to typical tomato bronze virus species and the following species: Bean necrotic mosaic virus, Pepper chlorosis virus, Peanut bud necrosis virus, Peanut round spot virus, Ground pea yellow spot virus, Balsam necrotic spot virus, Iris yellow spot virus , melon yellow spot virus, peanut bud necrosis virus, peanut yellow spot virus, soybean vein necrosis virus, tomato chlorosis spot viruses, tomato ring spot virus, tomato yellow ring spot virus, tomato banding virus, watermelon bud necrosis virus, watermelon silver mottle virus and zucchini lethal chlorosis virus.

Picornavirus infections include those of the genera Aphthovirus, Aquamavirus, Avihepatovirus, Cardiovirus, Cosavirus, Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus, Salivirus, Sapelovirus, Senecavirus, Teschovirus, and Tremovirus. Coronavirus infections include those of the genera Alphacoronavirus, Betacoronavirus (which includes the severe acute respiratory syndrome coronavirus (SARS-CoV)), Gammacoronavirus, and Deltacoronavirus.

United States patent documents and WO applications describing nucleoside polymerase inhibitors for the treatment of viral diseases include those filed by Idenix Pharmaceuticals (Nos. ; 7384924; 7456155; 7547704; 7582618; 7608597; 7608600; 7625875; 7635689; 7662798; 7824851; 7902202; 7932240; 7951789; 8193372; 8299038; 8343937; 8362068; 8507460; 8637475; 8674085; 8680071; 8691788, 8742101, 8951985; 9109001 ; 9243025; US 2016/0002281; US 2013/0064794; WO/2015/095305; WO/2015/081133; WO/2015/061683; WO/2013/177219; WO/2013/039920; WO/2014/13 /2014/052638; WO/2012/154321); компанией Merck (№№6777395; 7105499; 7125855; 7202224; 7323449; 7339054; 7534767; 7632821; 7879815; 8071568; 8148349; 8470834; 8481712; 8541434; 8697694; 8715638, 9061041; 9156872 и WO/2013/009737); Emory University (6348587; 6911424; 7307065; 7495006; 7662938; 7772208; 8114994; 8168583; 8609627; US 2014/0212382 and WO 2014/1244430); Gilead Sciences/Pharmasset Inc. (№№7842672; 7973013; 8008264; 8012941; 8012942; 8318682; 8324179; 8415308; 8455451; 8551973; 8563530; 8841275; 8853171; 8871785; 8877733; 8889159; 8906880; 8912321; 8957045; 8957046; 9045520; 9085573; 9090642; 9139604 ; 9206217; 9284342 и 9394331) и (№№6908924; 6949522; 7094770; 7211570; 7429572; 7601820; 7638502; 7718790; 7772208; RE42015; 7919247; 7964580; 8093380; 8114997; 8173621; 8334270; 8415322; 8481713; 8492539; 8551973 ; 8580765; 8618076; 8629263; 8633309; 8642756; 8716262; 8716263; 8735345; 8735372; 8735569; 8759510 and 8765710); Hoffman La-Roche (#6660721), Roche (#6784166; 7608599, 7608601 and 8071567); by Alios BioPharma Inc. (No. 8895723; 88777731; 8871737, 8846896, 8772474; 8980865; 9012427; US 2015/0105341; US 2015/0011497; US 2010/0249068; US 2015/2015/054465; Wo 2014; 100505; WO 2014/100498; WO 2013/142159; WO 2013/142157; WO 2013/096680; WO 2013/088155; WO 2010/108135); 044030; WO 2012/125900), компанией Biota (№№7268119; 7285658; 7713941; 8119607; 8415309; 8501699 и 8802840), компанией Biocryst Pharmaceuticals (№№7388002; 7429571; 7514410; 7560434; 7994139; 8133870; 8163703; 8242085 и 8440813), Alla Chem, LLC (#8889701 and WO 2015/053662), Inhibitex (#8759318 and WO/2012/092484), Janssen Products (#8399429; 8431588, 8481510, 8552021, 8933052; 900629 ) University of Georgia Foundation (№№6348587; 7307065; 7662938; 8168583; 8673926, 8816074; 8921384 и 8946244), компанией RFS Pharma, LLC (№№8895531; 8859595; 8815829; 8609627; 7560550; US 2014/0066395; US 2014 /023 5566; US 2010/0279969; WO 2010/091386 and WO 2012/158811) by University College Cardiff Consultants Limited (WO 2014/076490, WO 2010/081082; WO 2008/062206), by Achillion Pharmaceuticals, Inc. (WO 2014/169278 and WO 2014/169280) by Cocrystal Pharma, Inc. (U.S. Patent No. 9173893), Katholieke Universiteit Leuven (WO 2015/158913), Catabasis (WO 2013/090420), Regents of the University of Minnesota (WO 2006/004637) and Atea Pharmaceuticals, Inc (WO 2016/144918 ).

Additional United States patents, United States patent applications, and PCT applications that describe nucleoside compounds as inhibitors of viral infection include US Patent Documents Nos. 7,388,002; 7560434; 8415321; 9126971; 9326991; and US 2004/0229839.

There remains an urgent need in medicine to develop therapeutic agents against RNA viruses that are safe, effective and well tolerated. The need is heightened by the expectation that RNA viruses will continue to circulate in uninfected areas of the world and that RNA viruses will mutate under drug pressure.

Therefore, it is an object of the present invention to provide compounds, pharmaceutical compositions, methods and uses for the treatment and/or prevention of RNA virus infections, in particular non-HCV RNA viruses.

Brief summary of the present invention

Compounds of formula I, formula II, formula III, formula IV, formula V and formula VI, including 2'-substituted-N ⁶ -substituted purine nucleotides, have been found to be suitable for the treatment of diseases caused by RNA viruses, in particular RNA -viruses other than HCV, when administered in an effective amount to the host if necessary. The host may be a human or any animal that carries the viral infection.

The disclosed nucleotides include those with suitable activity against, for example, bovine diarrhea virus (BVDV), dengue fever virus 2, West Nile virus (WNV), Zika virus, and yellow fever virus (YFV) in vitro. The disclosed also include nucleotides with suitable activity against Kosaki B virus subtype 5. In one embodiment, a method for treating a disease caused by a non-Hepacivirus or non-HCV single-stranded positive-sense RNA virus is provided. According to a further embodiment, a method for treating a disease caused by dengue fever virus 2 or yellow fever virus is provided. According to an alternative embodiment, a method for treating a disease caused by a single-stranded negative-sense RNA virus is provided. In an alternative embodiment, a method for treating a disease caused by a double-stranded RNA virus is provided.

The compounds of the present invention are anabolized to N ^{6 -substituted-purine 5-monophosphate without significant N 6 -deamination} and then sequentially anabolized at the 6-position to form active guanine triphosphate compounds in a manner that provides good potency and therapeutic index.

As an example, the metabolism of β-D-2'-substituted-N ⁶ -methyl-2,6-diaminopurine nucleoside as phosphoramidate involves the formation of 5'-monophosphate and subsequent anabolism of N ⁶ -methyl-2,6-diaminopurine base with the formation of 2'-substituted guanine nucleoside in the form of 5'-monophosphate. The monophosphate is then further anabolized to the active compound, which is the 5'-triphosphate.

In particular, it was found that a 5'-stabilized phosphate prodrug or a derivative of a 2'-substituted-N ⁶ -methyl-2,6-diaminopurine nucleotide, as well as a 2'-substituted-2-N ⁶ -dimethyl-2,6-diaminopurine nucleotide and other 2'-substituted-N ⁶ -substituted purine nucleotides described below are active against a number of RNA viruses. For example, discussed in example 14 and shown in table 5 connection 205 is effective against dengue fever (EC ₅₀ =0.8 μm) and yellow fever (EC ₅₀ =1.2 μm).

Thus, according to one embodiment, the present invention relates to the use of the following compound of formula I for the treatment of an RNA virus infection in a host, for example, in a human, if necessary. In one embodiment, a method is provided for treating a host, including a human, infected with a non-Hepacivirus or non-HCV single-stranded positive-sense RNA virus with an effective amount of a compound of Formula I. In an alternative embodiment, a method for treating a host is provided, including a human infected with a virus with a single-stranded positive-sense RNA from the Flaviviridae family, including, but not limited to, dengue fever virus 2 and yellow fever virus, an effective amount of a compound of formula I. According to an alternative embodiment, a method of treating a host, including a human, infected with the virus with single-stranded negative-sense RNA, an effective amount of a compound of formula I. According to an alternative embodiment, a method of treating a host, including a human infected with a double-stranded RNA virus, with an effective amount of a compound of formula I is provided:

where:

Y is NR ¹ R ² ;

R ¹ is C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl (including CH ₂ F , CHF ₂ , CF ₃ , CH ₂ CF ₃ , CF ₂ CH ₃ and CF ₂ CF ₃ ), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl) (C ₃ - C ₆ cycloalkyl), -(C ₀ -C ₂ alkyl) (heterocycle), - (C ₀ -C ₂ alkyl) (aryl), - (C ₀ -C ₂ alkyl) (heteroaryl),

-OR ²⁵ , -C(O)R ^3C (including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C(O)OCH ₃ , -C (O) OS ₂ H ₅ ,

-C(O)OC ₃ H ₇ , -C(O)OC ₄ H ₉ and -C(O)OC ₅ H ₁₁ ), -C(S)R ^3D or -SO ₂ R ²⁸ , each of which may be optionally substituted;

R ² is hydrogen, C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl (including CHF ₂ , CHF ₂ , CF ₃ , CH ₂ CF ₃ and CF ₂ CF ₃ ), -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -C(O)R ^3C (including

-C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C(O)OCH ₃ , -C(O)OC ₂ H ₅ , -C( O) OS ₃ H ₇ , -C (O) OC ₄ H ₉ and -C (O) OC ₅ H ₁₁ ), - (C ₀ -C ₂ alkyl) (aryl), - (C ₀ -C ₂ alkyl) (heterocycle), -(C ₀ -C ₂ alkyl)(heteroaryl); and

where at least one of R ¹ and R ² is methyl, CH ₂ F, CHF ₂ or CF ₃ ;

дифосфат, трифосфат, необязательно замещенную связанную карбонилом аминокислоту или -C(O)R^3C;R ³ is hydrogen,

diphosphate, triphosphate, optionally substituted carbonyl-linked amino acid or -C(O)R ^3C ;

R ^3A can be selected from O ^- , OH, -O-optionally substituted aryl, -O-optionally substituted heteroaryl, or optionally substituted heterocyclyl;

R ^3B may be selected from O ⁻ , OH, an optionally substituted N-linked amino acid, or an optionally substituted N-linked amino acid ester;

R ^3C is alkyl, alkenyl, alkynyl, -(C ₀ -C ₂ )(cycloalkyl), -(C ₀ -C ₂ )(heterocyclo), -(C ₀ -C ₂ )(aryl), -(C ₀ -C ₂ )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C ₀ -C ₂ )(cycloalkyl), -O-(C ₀ -C ₂ )(heterocyclo) , -O-(C ₀ -C ₂ )(aryl) or -O-(C ₀ -C ₂ )(heteroaryl), each of which may be optionally substituted;

R ⁴ is a monophosphate, diphosphate, triphosphate, or stabilized phosphate prodrug, including, but not limited to, phosphoramidate, thiophosphoramidate, or any other moiety that is metabolized to monophosphate, diphosphate, or triphosphate in vivo in a human or animal host; or

R ³ and R ⁴ together with the oxygen atoms to which they are attached, can form a 3',5'-cyclic prodrug, including without limitation a 3',5'-cyclic phosphate prodrug;

R ¹² is hydrogen, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ or ethynyl; and

R ¹³ represents hydrogen, fluorine, chlorine, bromine, N ₃ , NH ₂ , CN or OR ³ ;

moreover, if R ¹² is methyl, R ¹³ is bromine, chlorine, N ₃ , NH ₂ , CN or OR ³ .

According to an alternative embodiment, at least one of R ¹ and R ² is cyclopropyl.

In an alternative embodiment, at least one of R ¹ and R ² is cyclopentyl.

According to another embodiment, the present invention relates to the use of the following compound of formula II for the treatment of an RNA virus infection in a host, eg a human, in need thereof. In one embodiment, a method is provided for treating a host, including a human, infected with a non-Hepacivirus or non-HCV single-stranded positive-sense RNA virus with an effective amount of a compound of formula II. In an alternative embodiment, a method is provided for treating a host, including a human, infected with a virus with a single-stranded positive-sense RNA from the Flaviviridae family, including, but not limited to, dengue fever virus 2 and yellow fever virus, with an effective amount of a compound of formula II. In an alternative embodiment, a method is provided for treating a host, including a human, infected with a single-stranded negative-sense RNA virus with an effective amount of a compound of formula II. In an alternative embodiment, a method is provided for treating a host, including a human, infected with a double-stranded RNA virus with an effective amount of a compound of Formula II:

where:

Y is NR ¹ R ² ;

R ¹ is C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl (including CH ₂ F , CHF ₂ , CF ₃ , CH ₂ CF ₃ , CF ₂ CH ₃ and CF ₂ CF ₃ ), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl) (C ₃ - C ₆ cycloalkyl), -(C ₀ -C ₂ alkyl) (heterocycle), - (C ₀ -C ₂ alkyl) (aryl), - (C ₀ -C ₂ alkyl) (heteroaryl),

-OR ²⁵ , -C(O)R ^3C (including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C(O)OCH ₃ , -C (O) OS ₂ H ₅ ,

-C(O)OC ₃ H ₇ , -C(O)OC ₄ H ₉ and -C(O)OC ₅ H ₁₁ ), -C(S)R ^3D or -SO ₂ R ²⁸ , each of which may be optionally substituted;

R ² is hydrogen optionally substituted with C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl ( including CHF ₂ , CHF ₂ , CF ₃ , CH ₂ CF ₃ and CF ₂ CF ₃ ), optionally substituted

-(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), optionally substituted -(C ₀ -C ₂ alkyl)(heterocycle), optionally substituted -(C ₀ -C ₂ alkyl)(aryl), optionally substituted -(C ₀ -C ₂ alkyl)(heteroaryl), -C(O)R ^3C (including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C (O) OCH ₃ , -C (O) OS ₂ H ₅ , -C (O) OS ₃ H ₇ , -C (O) OS ₄ H ₉ and -C (O) OS ₅ H ₁₁ ), -C(S)R ^3D or -SO ₂ R ²⁸ ; and

where at least one of R ¹ and R ² is methyl, CH ₂ F, CHF ₂ or CF ₃ ;

дифосфат, трифосфат, необязательно замещенную связанную карбонилом аминокислоту или -C(O)R^3C;R ³ is hydrogen,

diphosphate, triphosphate, optionally substituted carbonyl-linked amino acid or -C(O)R ^3C ;

R ^3A can be selected from O ^- , OH, -O-optionally substituted aryl, -O-optionally substituted heteroaryl, or optionally substituted heterocyclyl;

R ^3B may be selected from O ⁻ , OH, an optionally substituted N-linked amino acid, or an optionally substituted N-linked amino acid ester;

R ^3C is alkyl, alkenyl, alkynyl, -(C ₀ -C ₂ )(cycloalkyl), -(C ₀ -C ₂ )(heterocyclo), -(C ₀ -C ₂ )(aryl), -(C ₀ -C ₂ )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C ₀ -C ₂ )(cycloalkyl), -O-(C ₀ -C ₂ )(heterocyclo) , -O-(C ₀ -C ₂ )(aryl), -O-(C ₀ -C ₂ )(heteroaryl), -S-alkyl, -S-alkenyl, -S-alkynyl, -S-(C ₀ -C ₂ )(cycloalkyl), -S-(C ₀ -C ₂ )(heterocyclo), -S-(C ₀ -C ₂ )(aryl) or -S-(C ₀ -C ₂ )(heteroaryl), each of which may be optionally substituted;

R ^3D is alkyl, alkenyl, alkynyl, -(C ₀ -C ₂ )(cycloalkyl), -(C ₀ -C ₂ )(heterocyclo), -(C ₀ -C ₂ )(aryl), -(C ₀ -C ₂ )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C ₀ -C ₂ )(cycloalkyl), -O-(C ₀ -C ₂ )(heterocyclo) , -O-(C ₀ -C ₂ )(aryl) or -O-(C ₀ -C ₂ )(heteroaryl), each of which may be optionally substituted;

R ⁴ is a monophosphate, diphosphate, triphosphate, or stabilized phosphate prodrug, including, but not limited to, phosphoramidate, thiophosphoramidate, or any other moiety that is metabolized to monophosphate, diphosphate, or triphosphate in vivo in a human or animal host; or

R ³ and R ⁴ together with the oxygen atoms to which they are attached, can form a 3',5'-cyclic prodrug, including without limitation a 3',5'-cyclic phosphate prodrug;

R ⁵ is C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl (including CHF ₂ , CHF ₂ , CF ₃ , CH ₂ CF ₃ and CF ₂ CF ₃ ), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl) (C ₃ -C ₆ cycloalkyl), - (C ₀ -C ₂ alkyl) (heterocycle), -(C ₀ -C ₂ alkyl) (aryl), - (C ₀ -C ₂ alkyl) (heteroaryl), -OR ²⁵ , -C (O) R ^3C ( including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C(O)OCH ₃ , -C(O)OC ₂ H ₅ , -C (O)OC ₃ H ₇ , -C(O)OC ₄ H ₉ and -C(O)OC ₅ H ₁₁ ), -C(S)R ^3D or -SO ₂ R ²⁸ , each of which may be optionally substituted ;

R ⁶ is hydrogen optionally substituted with C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl ( including CHF ₂ , CHF ₂ , CF ₃ , CH ₂ CF ₃ and CF ₂ CF ₃ ), optionally substituted

-(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), optionally substituted -(C ₀ -C ₂ alkyl)(heterocycle), optionally substituted -(C ₀ -C ₂ alkyl)(aryl), optionally substituted -(C ₀ -C ₂ alkyl)(heteroaryl), -C(O)R ^3C (including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C (O) OCH ₃ , -C (O) OS ₂ H ₅ , -C (O) OS ₃ H ₇ , -C (O) OS ₄ H ₉ and -C (O) OS ₅ H ₁₁ ), -C(S)R ^3D or -SO ₂ R ²⁸ ; or

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached may form a heterocyclic ring;

R ¹² is hydrogen, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ or ethynyl;

R ¹³ represents hydrogen, fluorine, chlorine, bromine, N ₃ , NH ₂ , CN or OR ³ ;

moreover, if R ¹² is methyl, R ¹³ is bromine, chlorine, N ₃ , NH ₂ , CN or OR ³ .

R ²² is Cl, Br, F, CN, N ₃ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl,

-P(O)H(OR²⁹), -P(O)(OR²⁹)(OR³⁰), -P(O)(OR²⁹)(NR²⁹R³⁰) или -NR⁵R⁶; например, включая в себя без ограничения следующие варианты осуществления: хлор, бром, фтор, циано, азидо, этил, н-пропил, изопропил, н-бутил, изобутил, втор-бутил, трет-бутил и н-пентил, 1,1-диметилпропил, 2,2-диметилпропил, 3-метилбутил, 1-метилбутил, 1-этилпропил, винил, аллил, 1-бутинил, 2-бутинил, ацетиленил, циклопропил, циклобутил, циклопентил, циклогексил, -(СН₂)-циклопропил, -(СН₂)-циклобутил, -(СН₂)-циклопентил, -(СН₂)-циклогексил, азиридин, оксиран, тииран, азетидин, оксетан, тиетан, пирролидин, тетрагирофуран, тиолан, пиразолидин, пиперидин, океан, тиан, -(СН₂)-азиридин, -(СН₂)-оксиран, -(СН₂)-тииран, -(СН₂)-азетидин, -(СН₂)-оксетан, -(СН₂)-тиетан, -(СН₂)-пирролидин,- (C ₁ -C ₂ alkyl) (C ₃ -C ₆ cycloalkyl), - (C ₀ -C ₂ alkyl) (C ₃ -C ₆ heterocycle), - (C ₀ -C ₂ alkyl) (aryl), - (C ₀ -C ₂ alkyl)(heteroaryl); -ONHC(=O)OR ²³ , -NHOR ²⁴ , -OR ²⁵ , -SR ²⁵ , -NH(CH ₂ ) _1-4 N(R ²⁶ ) ₂ , -NHNHR26 , -N=NR ²⁷ , -NHC(O )NHNHR ²⁷ , -NHC(S)NHNHR ²⁷ , -C(O)NHNHR ²⁷ , -NR ²⁷ SO ₂ R ²⁸ , -SO ₂ NR ²⁷ R ²⁹ , -C(O)NR ²⁷ R ²⁹ , -CO ₂ R ²⁹ , -SO ₂ R ²⁹ ,

-P(O)H(OR ²⁹ ), -P(O)(OR ²⁹ )(OR ³⁰ ), -P(O)(OR ²⁹ )(NR ²⁹ R ³⁰ ) or -NR ⁵ R ⁶ ; for example, including without limitation the following embodiments: chlorine, bromine, fluorine, cyano, azido, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and n-pentyl, 1.1 -dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ₂ )-cyclopropyl , -(CH ₂ )-cyclobutyl, -(CH ₂ )-cyclopentyl, -(CH ₂ )-cyclohexyl, aziridine, oxirane, thiiran, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, piperidine, ocean, thian , -(CH ₂ )-aziridine, -(CH ₂ )-oxirane, -(CH ₂ )-thiiran, -(CH ₂ )-azetidine, -(CH ₂ )-oxetane, -(CH ₂ )-thietane, - (CH ₂ )-pyrrolidine,

-(CH ₂ )-tetragyrofuran, -(CH ₂ )-thiolane, -(CH ₂ )-pyrazolidine, -(CH ₂ )-piperidine, -(CH ₂ )-oxane, -(CH ₂ )-thian, phenyl, pyridyl, -ONHC(=O)OCH ₃ , -ONHC(=O)OCH ₂ CH ₃ , -NHOH, NHOCH ₃ ,

-OCH ₃ , OS ₂ H ₅ , -OPh, OCH ₂ Ph, -SCH ₃ , -SC ₂ H ₅ , -SPh, SCH ₂ Ph, -NH(CH ₂ ) ₂ NH ₂ , -NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , -NHNH ₂ , -NHNHCH ₃ , -N=NH, -N=NCH ₃ , -N=NCH ₂ CH ₃ , -NHC(O)NHNH ₂ ,

-NHC(S)NHNH ₂ , -C(O)NHNH ₂ , -NHSO ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -SO ₂ NHCH ₃ , -SO ₂ N(CH ₃ ) ₂ , -C(O )NH ₂ , -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ , -CO ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ , -CO ₂ Ph, -CO ₂ CH ₂ Ph, -SO ₂ CH ₃ ,

-P(O)H(OH), -P(O)H(OCH₃),-SO ₂ CH ₂ CH ₃ , -SO ₂ Ph, -SO ₂ CH ₂ Ph,

-P(O)H(OH), -P(O)H(OCH ₃ ),

-P(O)(OH)(OH), -P(O)(OH)(OCH ₃ ), -P(O)(OCH ₃ )(OCH ₃ ), -P(O)(OH)(NH ₂ ), P(O)(OH)(NHCH ₃ ), -P(O)(OH)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , -NHC( O)CH(CH ₃ ) ₂ , -NHC(O)OCH ₃ ,

-NHC(O)OCH ₂ CH ₃ , -NHC(O)OCH(CH ₃ ) ₂ , -NHC(O)OCH ₂ CH ₂ CH ₃ , -NHC(O)OCH ₂ CH ₂ CH ₂ CH ₃ and -NHC (O)OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ;

R ²³ is C ₁ -C ₅ alkyl, -(C ₀ -C ₂ alkyl) (C ₃ -C ₆ cycloalkyl), -(C ₀ -C ₂ alkyl) (heterocycle), -(C ₀ - ₂ alkyl) (aryl) or -(C ₀ -C ₂ alkyl)(heteroaryl), each of which may be optionally substituted;

R ²⁴ is hydrogen, C ₁ -C ₆ alkyl, -(C ₁ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -(C ₁ -C ₂ alkyl)(C ₃ -C ₆ heterocycle) -( C ₀ -C ₂ alkyl)(aryl) or -(C ₀ -C ₂ alkyl)(heteroaryl), with the exception of hydrogen, each of which may be optionally substituted;

R ²⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -(C ₀ - C ₂ alkyl) (C ₃ -C ₆ heterocycle), -(C ₀ -C ₂ alkyl) (aryl) or - (C ₀ -C ₂ alkyl) (heteroaryl), and, with the exception of hydrogen, each of which can be optionally substituted;

R ²⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -(C ₀ -C ₂ alkyl) (heterocycle), -(C ₀ - C ₂ alkyl)(aryl) or -(C ₀ -C ₂ alkyl)(heteroaryl), with the exception of hydrogen, each of which may be optionally substituted;

R ²⁷ is hydrogen or optionally substituted C ₁ -C ₆ alkyl;

R ²⁸ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ heterocycle), -(C ₀ -C ₂ alkyl)(aryl) or -(C ₀ -C ₂ alkyl)(heteroaryl), each of which may be optionally substituted;

R ²⁹ is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -(C ₀ - C ₂ alkyl) (C ₃ -C ₆ heterocycle), -(C ₀ -C ₂ alkyl) (aryl) or - (C ₀ -C ₂ alkyl) (heteroaryl), and, with the exception of hydrogen, each of which can be optionally substituted; or

R ²⁷ and R ²⁹ together with the nitrogen atom to which they are bonded may form a heterocyclic ring;

R ³⁰ is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), -(C ₀ - C ₂ alkyl) (C ₃ -C ₆ heterocycle), -(C ₀ -C ₂ alkyl) (aryl) or - (C ₀ -C ₂ alkyl) (heteroaryl), and, with the exception of hydrogen, each of which can be optionally substituted; or

R ²⁹ and R ³⁰ may be linked together to form a heterocyclic ring;

x represents 1, 2 or 3.

According to an alternative embodiment, at least one of R ¹ and R ² is cyclopropyl.

In an alternative embodiment, at least one of R ¹ and R ² is cyclopentyl.

According to an alternative embodiment, R ²³ is -(C ₀ -C ₂ alkyl)(heterocycle) or -(C _0-2 alkyl)(aryl).

Phosphoramidate β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynyl-N ⁶ -methyl-2,6-diaminopurine nucleoside is first metabolized to 5'-monophosphate, and then N ⁶ -methyl- The 2,6-diaminopurine base is anabolized to form β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynylguanine nucleoside as 5'-monophosphate. The monophosphate is then further anabolized to the active 5'-triphosphate compound (Scheme 1).

2'-Substituted-N ⁶ -substituted-2,6-diaminopurine nucleotides can be further substituted at the N ² position by alkylation or acylated. This may modify lipophilicity, pharmacokinetic parameters and/or nucleotide targeting to the liver. It was found that 2'-substituted-N ⁶ -substituted-2,6-diaminopurine nucleotides modified at the 2-position of diaminopurine can be dealkylated or deacylated by liver enzymes with a further increase in the specificity of nucleotide derivatives, both in vitro and in vivo, unless the N ² -amino group is completely substituted by another moiety as described herein, such as fluoro. In one embodiment, the N ² modifications will enhance cell permeability. In one embodiment, the N ² modifications will enhance liver targeting.

Unless otherwise indicated, the compounds described herein are in the β-D configuration. Similarly, in the phosphoramidate or thiophosphoramidate form, a portion of the amino acids may be in the L or D configuration. In an alternative embodiment, the compounds may be in the β-L configuration. Similarly, any substituent group that exhibits chirality may be present in racemic, enantiomeric, diastereomeric form, or any mixture thereof. When a phosphoramidate, thiophosphoramidate or other stabilized phosphorus prodrug in which phosphorus exhibits chirality is used as an ^R4 stabilized phosphate prodrug, it can be provided as an R or S chiral phosphorus derivative or a mixture thereof, including a racemic mixture. All combinations of such stereo configurations are included in the present invention as described herein.

Accordingly, the present invention includes the use of a compound of formula I, formula II, formula III, formula IV, formula V or formula VI, or a pharmaceutically acceptable composition, salt or prodrug thereof, as described herein, in an effective amount for the treatment of a disease caused by An RNA virus, such as an RNA virus other than HCV.

In one specific embodiment, the parent nucleoside, i. a nucleoside in which R ⁴ is hydrogen and the 5' position thus has a hydroxyl group is substantially not deaminated by adenosine deaminase under conditions that mimic the in vivo environment (e.g. room temperature and aqueous physiological pH) for a period of 7 minutes, 10 minutes, 30 minutes, 60 minutes or 120 minutes. Unless otherwise stated, the time period is 30 minutes. In this embodiment, the term "substantially not deaminated" means that the parent compound is not converted to the corresponding guanine derivative or 6-oxo derivative in an amount sufficient to provide a therapeutic effect in vivo.

Compounds, methods, and compositions are provided for treating a host infected with an RNA virus by administering an effective amount of the compound, or a pharmaceutically acceptable salt thereof.

The compound or formulations that include the compounds may also be used in an effective amount prophylactically to prevent or limit the progression of a clinical disease in individuals who are positive for an anti-RNA virus antibody or antigen.

According to another embodiment, the present invention relates to the use of an effective amount of the following compound of formula Ia for the treatment of an RNA virus infection in a host, eg a human, in need thereof. In some embodiments, a method is provided for treating a host infected with a non-Hepacivirus or non-HCV single-stranded positive-sense RNA virus. In an alternative embodiment, a method is provided comprising administering an effective amount of a compound of Formula Ia for treating a disease caused by a virus with single-stranded positive-sense RNA from the Flaviviridae family, including but not limited to dengue fever 2 virus and yellow fever virus, in a host, including person who needs it. In an alternative embodiment, a method is provided comprising administering an effective amount of a compound of Formula Ia for treating a disease caused by a single-stranded negative-sense RNA virus in a host, including a human, in need thereof. In an alternative embodiment, a method is provided comprising administering an effective amount of a compound of Formula Ia for treating a disease caused by a double-stranded RNA virus in a host, including a human, in need thereof.

where:

Y, R ³ , R ^3A , R ^3B , R ^3C , R ^3D and R ⁴ are defined above.

According to one embodiment of Formula Ia, R ³ is hydrogen.

According to one embodiment of Formula Ia, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of Formula Ia, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of Formula Ia, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of Formula Ia, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of Formula Ia, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of Formula Ia, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of Formula Ia, R ⁴ is a stabilized phosphoramidate.

дифосфата, трифосфата, необязательно замещенной связанной карбонилом аминокислоты и -C(O)R^3C.According to an alternative embodiment of Formula Ia, R ³ is independently selected from hydrogen,

a diphosphate, a triphosphate, an optionally substituted carbonyl-linked amino acid, and -C(O)R ^3C .

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to one embodiment of Formula Ib, R ³ is hydrogen.

According to one embodiment of formula Ib, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula Ib, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of Formula Ib, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of formula Ib, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of formula Ib, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula Ib, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of Formula Ib, R ⁴ is a stabilized phosphoramidate.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Ib', or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

m is 1, 2 or 3;

p is 0, 1 or 2;

R ⁶⁰ is independently selected from C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl (including CHF ₂ , CHF ₂ , CF ₃ , CH ₂ CF ₃ and CF ₂ CF ₃ ), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl) (C ₃ -C ₆ cycloalkyl), - (C ₀ -C ₂ alkyl) (heterocycle), - (C ₀ -C ₂ alkyl) (aryl), - (C ₀ -C ₂ alkyl) (heteroaryl),

-OR ²⁵ , -C(O)R ^3C (including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C(O)OCH ₃ , -C (O) OS ₂ H ₅ ,

-C(O)OC ₃ H ₇ , -C(O)OC ₄ H ₉ and -C(O)OC ₅ H ₁₁ ), -C(S)R ^3D and -SO ₂ R ²⁸ , each of which may be optionally substituted; and

R ³ , R ⁴ , R ^3C , R ^3D , R ²⁵ and R ²⁸ are defined above.

According to one embodiment of Formula Ib', m is 1 and p is 0.

According to one embodiment of Formula Ib', m is 2 and p is 0.

According to one embodiment of Formula Ib', m is 3 and p is 0.

According to one embodiment of formula Ib' m is 2, p is 0 and R ³ is hydrogen.

According to one embodiment of formula Ib' m is 2, p is 0, R ³ is hydrogen, and R ⁴ is a stabilized phosphoramidate.

According to one embodiment of formula Ib' m is 3, p is 0, R ³ is hydrogen, and R ⁴ is a stabilized phosphoramidate.

According to one embodiment of formula Ib' R ⁴ is a stabilized phosphoramidate.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ic, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to one embodiment of formula Ic R ³ is hydrogen.

According to one embodiment of formula Ic, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula Ic, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of formula Ic, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of Formula Ic, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of Formula Ic, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of Formula Ic, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of formula Ic R ⁴ is a stabilized phosphoramidate.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Id, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to one embodiment of formula Id R ³ is hydrogen.

According to one embodiment of formula Id, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula Id, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of formula Id, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of formula Id, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of formula Id, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula Id, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of formula Id R ⁴ is a stabilized phosphoramidate.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ie, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to one embodiment of formula Ie, R ³ is hydrogen.

According to one embodiment of formula Ie, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of Formula Ie, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to an alternative embodiment of formula Ie, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula Ie, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to one embodiment of formula Ie, R ⁴ is a stabilized phosphoramidate.

According to one embodiment, the present invention relates to the use of an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ , R ¹² , R ¹³ and R ²² are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ^3A , R ^3B , R ^3C , R ^3D , R ⁴ and R ²² are defined above.

According to one embodiment of Formula IIa, R ³ is hydrogen.

According to one embodiment of formula IIa, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula IIa, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of formula IIa, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of formula IIa, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of formula IIa, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula IIa, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of formula IIa, R ⁴ is a stabilized phosphoramidate.

дифосфата, трифосфата, необязательно замещенной связанной карбонилом аминокислоты и -C(O)R^3C.According to an alternative embodiment of formula IIa, R ³ is independently selected from hydrogen,

a diphosphate, a triphosphate, an optionally substituted carbonyl-linked amino acid, and -C(O)R ^3C .

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to one embodiment of formula IIb, R ³ is hydrogen.

According to one embodiment of formula IIb, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula IIb, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of formula IIb, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of formula IIb, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of formula IIb, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula IIb, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of formula IIb, R ⁴ is a stabilized phosphoramidate.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IIb' or a pharmaceutically acceptable salt thereof for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ²² , R ⁶⁰ , m and p are defined above.

According to one embodiment of formula IIb' m is 1 and p is 0.

According to one embodiment of formula IIb' m is 2 and p is 0.

According to one embodiment of formula IIb' m is 3 and p is 0.

According to one embodiment of formula IIb' m is 2, p is 0, R ²² is NR ⁵ R ⁶ and R ³ is hydrogen.

According to one embodiment of formula IIb' R ⁴ is a stabilized phosphoramidate.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to one embodiment of formula IIc, R ³ is hydrogen.

According to one embodiment of formula IIc, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula IIc, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of formula IIc, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of formula IIc, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of formula IIc, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula IIc, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of formula IIc, R ⁴ is a stabilized phosphoramidate.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IId, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to one embodiment of formula IId, R ³ is hydrogen.

According to one embodiment of formula IId, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula IId, if Y is NR ¹ R ² , both R ¹ and R ² are methyl.

According to one embodiment of formula IId, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to one embodiment of formula IId, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is hydrogen.

According to an alternative embodiment of formula IId, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula IId, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to an alternative embodiment of formula IId, R ⁴ is a stabilized phosphoramidate.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to one embodiment of Formula IIe, R ³ is hydrogen.

According to one embodiment of formula IIe, if Y is NR ¹ R ² , R ¹ is methyl and R ² is hydrogen.

According to one embodiment of formula IIe, if Y is NR ¹ R ² , R ¹ is methyl and R ² is cyclopropyl.

According to an alternative embodiment of formula IIe, if Y is NR ¹ R ² , R ¹ is cyclopropyl and R ² is cyclopropyl.

According to an alternative embodiment of formula IIe, if Y is NR ¹ R ² , R ¹ is cyclopentyl and R ² is hydrogen.

According to one embodiment of formula IIe, R ⁴ is a stabilized phosphoramidate.

According to one embodiment, the present invention relates to the use of an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ⁷ is hydrogen, C _1-6 alkyl; C _3-7 cycloalkyl; heteroaryl, heterocyclic compound or aryl, which includes, without limitation, phenyl or naphthyl, where phenyl or naphthyl is optionally substituted with C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, F, Cl , Br, I, nitro, cyano, C _1-6 haloalkyl, -N(R ^7' ) ₂ , C _1-6 acylamino, NHSO ₂ C _1-6 alkyl, -SO ₂ N(R ^7' ) ₂ , COR ^7'' and -SO ₂ C _1-6 alkyl; (R ^7' is independently hydrogen or C _1-6 alkyl; R ^7'' is -OR ¹¹ or -N(R ⁷ ) ₂ );

R ⁸ is hydrogen, C _1-6 alkyl or R ^9a or R ^9b and R ⁸ together are (CH ₂ ) _n to form a cyclic ring which includes adjoining N and C atoms; where n is 2-4;

R ^9a and R ^9b (i) are independently selected from hydrogen, C _1-6 alkyl, cycloalkyl, -(CH ₂ ) _c (NR ^9' ) ₂ , C _1-6 hydroxyalkyl, -CH ₂ SH, -(CH ₂ ) ₂ S(O)(Me), -(CH ₂ ) ₃ NHC(=NH)NH ₂ , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, -(CH ₂ ) _c COR ^9'' , aryl and aryl(C _1-3 alkyl)-, aryl groups may be optionally substituted with a group selected from hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen, nitro and cyano; (ii) R ^9a and R ^9b are both C _1-6 alkyl; (iii) R ^9a and R ^9b together represent (CH ₂ ) _r to form a spiro ring; (iv) R ^9a is hydrogen and R ^9b and R ⁸ together are (CH ₂ ) _n to form a cyclic ring which includes adjoining N and C atoms; (v) R ^9b is hydrogen and R ^9a and R ⁸ together are (CH ₂ ) _n to form a cyclic ring which includes adjoining N and C atoms, where c is 1-6, n is 2 -4, g is 2-5 and where R ^9' independently represents hydrogen or C _1-6 alkyl and R ^9'' represents -OR ¹¹ or -N(R ^11' ) ₂ ; (vi) R ^9a is hydrogen and R ^9b is hydrogen, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ ) ₂ , CH(CH ₃ )CH ₂ CH ₃ , CH ₂ Ph, CH ₂ -indol-3-yl, -CH ₂ CH ₂ SCH ₃ , CH ₂ CO ₂ H, CH ₂ C (O) NH ₂ , CH ₂ CH ₂ COOH, CH ₂ CH ₂ C (O) NH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ,

-CH ₂ CH ₂ CH ₂ NHC(NH)NH ₂ , CH ₂ -imidazol-4-yl, CH ₂ OH, CH (OH) CH ₃ , CH ₂ ((4'-OH)-Ph), CH ₂ SH or lower cycloalkyl; or (vii) R ^9a is CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ ) ₂ , CH(CH ₃ )CH ₂ CH ₃ , CH ₂ Ph, CH ₂ -indole -3-yl, -CH ₂ CH ₂ SCH ₃ , CH ₂ CO ₂ H, CH ₂ C (O) NH ₂ , CH ₂ CH ₂ COOH, CH ₂ CH ₂ C (O) NH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ CH ₂ NHC (NH) NH ₂ , CH ₂ -imidazol-4-yl, CH ₂ OH, CH (OH) CH ₃ , CH ₂ ((4'-OH) - Ph), CH ₂ SH or lower cycloalkyl and R ^9b is hydrogen;

R ¹⁰ is hydrogen, C _1-6 alkyl, optionally substituted alkoxy, di(lower alkyl)amino or halogen; C _1-6 haloalkyl, C _3-7 cycloalkyl, heterocycloalkyl, aminoacyl, aryl such as phenyl; heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl;

R ¹¹ is an optionally substituted C _1-6 alkyl, an optionally substituted cycloalkyl; optionally substituted C _2-6 alkynyl, optionally substituted C _2-6 alkenyl, or optionally substituted acyl;

R ^11' is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted cycloalkyl; optionally substituted C _2-6 alkynyl, optionally substituted C _2-6 alkenyl, or optionally substituted acyl; and

variables Y, R ³ , R ¹² and R ¹³ are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment of Formula IIIa, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IIIa, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IIIa, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of formula IIIa, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

дифосфат, трифосфат, необязательно замещенную связанную карбонилом аминокислоту или -C(O)R^3C;According to an alternative embodiment of formula IIIa, R ³ is hydrogen,

diphosphate, triphosphate, optionally substituted carbonyl-linked amino acid or -C(O)R ^3C ;

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment of formula IIIb, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IIIb, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IIIb, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of formula IIIb, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIb' or a pharmaceutically acceptable salt thereof for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁶⁰ , m and p are described in the present invention.

According to one embodiment of formula IIIb' m is 1 and p is 0.

According to one embodiment of formula IIIb' m is 2 and p is 0.

According to one embodiment of formula IIIb' m is 3 and p is 0.

According to one embodiment of formula IIIb' m is 2, p is 0, and R ³ is hydrogen.

According to one embodiment of formula IIIb', the phosphoramidate is in the L-configuration.

According to one embodiment of formula IIIb', the phosphoramidate is in the D-configuration.

According to one embodiment of formula IIIb', R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula IIIb', R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of Formula IIIb', R ³ is hydrogen, m is 2, p is 0, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is is isopropyl.

According to one embodiment of Formula IIIb', R ³ is hydrogen, m is 3, p is 0, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is is isopropyl.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment of Formula IIIc, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of formula IIIc, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IIIc, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of Formula IIIc, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIId, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment of Formula IIId, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of formula IIId, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of formula IIId, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of formula IIId, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment of Formula IIIe, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IIIe, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of formula IIIe, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of Formula IIIe, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula IV, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ¹² , R ¹³ and R ²² are described in the present invention.

According to an alternative embodiment of Formula IV, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IV, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of formula IV, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of Formula IV, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ^3A , R ^3B , R ^3C , R ^3D , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to an alternative embodiment of Formula IVa, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of formula IVa, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IVa, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of Formula IVa, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

дифосфата, трифосфата, необязательно замещенной связанной карбонилом аминокислоты или -C(O)R^3C.According to an alternative embodiment of formula IVa, R ³ is independently selected from hydrogen,

diphosphate, triphosphate, optionally substituted carbonyl-linked amino acid, or -C(O)R ^3C .

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to an alternative embodiment of Formula IVb, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IVb, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IVb, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of Formula IVb, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IVb' or a pharmaceutically acceptable salt thereof for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ²² , R ⁶⁰ , m and p are described in the present invention.

According to one embodiment of formula IVb' m is 1 and p is 0.

According to one embodiment of formula IVb' m is 2 and p is 0.

According to one embodiment of formula IVb' m is 3 and p is 0.

According to one embodiment of formula IVb' m is 2, p is 0 and R ³ is hydrogen.

According to one embodiment of formula IVb' m is 2, p is 0, R ²² is NR ⁵ R ⁶ and R ³ is hydrogen.

According to one embodiment of Formula IVb', the phosphoramidate is in the L-configuration.

According to one embodiment of Formula IVb', the phosphoramidate is in the D configuration.

According to one embodiment of formula IVb', R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of Formula IVb', R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to an alternative embodiment of Formula IVc, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IVc, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IVc, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of formula IVc, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVd, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to an alternative embodiment of Formula IVd, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of Formula IVd, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IVd, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of formula IVd, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment of formula IVe, the phosphoramidate is in the L-configuration.

According to an alternative embodiment of formula IVe, the phosphoramidate is in the D-configuration.

According to an alternative embodiment of Formula IVe, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to an alternative embodiment of formula IVe, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

In an alternative embodiment, compounds of formula V are disclosed. In a further alternative embodiment, the present invention relates to a method of treating an RNA virus infection in a host, including a human in need thereof, comprising administering an effective amount of a compound of formula V, or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering an effective amount of a compound of formula V to treat a disease caused by a non-Hepacivirus or non-HCV single-stranded positive-sense RNA virus in a host, including a human, in need thereof. In an alternative embodiment, the method comprises administering an effective amount of a compound of formula V for the treatment of a disease caused by a virus with single-stranded positive-sense RNA from the Flaviviridae family, including but not limited to dengue 2 and yellow fever virus, in a host, including a human in need of in that. In an alternative embodiment, the method comprises administering an effective amount of a compound of formula V for treating a disease caused by a single-stranded negative-sense RNA virus in a host, including a human, in need thereof. In an alternative embodiment, the method comprises administering an effective amount of a compound of formula V for treating a disease caused by a double-stranded RNA virus in a host, including a human, in need thereof.

where:

Q is CHR ⁶⁵ ;

R ⁵⁰ is selected from hydrogen, NH ₂ and R ²² ;

R ⁶² is hydrogen, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ or ethynyl;

R ⁶³ represents hydrogen, fluorine, chlorine, bromine, N ₃ , NH ₂ , CN or OR ³ ;

R ⁶⁵ is C ₁ -C ₃ alkyl (including methyl, ethyl, isopropyl and cyclopropyl) or C _1-3 haloalkyl (including CH ₂ F, CHF ₂ and CF ₃ ); and

R ³ , R ⁴ , R ⁵ and R ²² are defined above.

According to one embodiment of formula VR ³ is hydrogen.

According to one embodiment of formula VR ⁶⁵ is methyl.

According to one embodiment of the formula, VR ⁵⁰ is hydrogen.

According to one embodiment of the formula, VR ⁵⁰ is -NH ₂ .

According to one embodiment of the formula, VQ is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula Va are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of Formula Va, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁴ and R ⁵⁰ are defined above.

According to one embodiment of formula Va R ³ is hydrogen.

According to one embodiment of formula Va R ⁶⁵ is methyl.

According to one embodiment of formula Va R ⁵⁰ is hydrogen.

According to one embodiment of formula Va R ⁵⁰ is -NH ₂ .

According to one embodiment of formula Va Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of formula Va Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is cyclopropyl, and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula Vb are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁴ and R ⁵⁰ are defined above.

According to one embodiment of Formula Vb, R ³ is hydrogen.

According to one embodiment of Formula Vb, R ⁶⁵ is methyl.

According to one embodiment of formula Vb, R ⁵⁰ is hydrogen.

According to one embodiment of formula Vb R ⁵⁰ is -NH ₂ .

According to one embodiment of formula Vb, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of formula Vb, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is cyclopropyl, and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula Vc are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of Formula Vc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁴ and R ⁵⁰ are defined above.

According to one embodiment of the formula, Vc R ³ is hydrogen.

According to one embodiment of formula Vc R ⁶⁵ is methyl.

According to one embodiment of the formula, Vc R ⁵⁰ is hydrogen.

According to one embodiment of the formula, Vc R ⁵⁰ is -NH ₂ .

According to one embodiment of the formula Vc Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl and R ⁵⁰ is hydrogen.

According to one embodiment of the formula Vc Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is cyclopropyl and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula Vd are disclosed. According to a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vd, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁴ and R ⁵⁰ are defined above.

According to one embodiment of the formula, Vd R ³ is hydrogen.

According to one embodiment of the formula, Vd R ⁶⁵ is methyl.

According to one embodiment of the formula, Vd R ⁵⁰ is hydrogen.

According to one embodiment of the formula, Vd R ⁵⁰ is -NH ₂ .

According to one embodiment of the formula, Vd Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of the formula, Vd Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is cyclopropyl, and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula Ve are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ve, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁴ and R ⁵⁰ are defined above.

According to one embodiment of formula Ve R ³ is hydrogen.

According to one embodiment of formula Ve R ⁶⁵ is methyl.

According to one embodiment of the formula Ve R ⁵⁰ is hydrogen.

According to one embodiment of the formula, Ve R ⁵⁰ is -NH ₂ .

According to one embodiment of formula Ve Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of formula Ve Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is cyclopropyl, and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula Vf are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vf, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁴ and R ⁵⁰ are defined above.

According to one embodiment of the formula, Vf R ³ is hydrogen.

According to one embodiment of formula Vf R ⁶⁵ is methyl.

According to one embodiment of the formula, Vf R ⁵⁰ is hydrogen.

According to one embodiment of the formula, Vf R ⁵⁰ is -NH ₂ .

According to one embodiment of the formula Vf Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl and R ⁵⁰ is hydrogen.

According to one embodiment of formula Ve Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is cyclopropyl, and R ⁵⁰ is hydrogen.

According to an alternative embodiment, compounds of formula VI are disclosed. According to a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VI, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ , R ⁶² and R ⁶³ are defined above.

According to one embodiment of Formula VI, R ³ is hydrogen.

According to one embodiment of formula VI, R ⁶⁵ is methyl.

According to one embodiment of Formula VI, R ⁵⁰ is hydrogen.

According to one embodiment of Formula VI, R ⁵⁰ is -NH ₂ .

According to one embodiment of formula VI, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of Formula VI, the phosphoramidate is in the L-configuration.

In one embodiment, the phosphoramidate is in the D-configuration.

According to one embodiment of Formula VI, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula VI, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to an alternative embodiment, compounds of formula VIa are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Via, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ^3A , R ^3B , R ^3C , R ^3D , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ⁵⁰ are defined above.

According to one embodiment of Formula VIa, R ³ is hydrogen.

According to one embodiment of formula VIa, R ⁶⁵ is methyl.

According to one embodiment of Formula VIa, R ⁵⁰ is hydrogen.

According to one embodiment of formula VIa, R ⁵⁰ is -NH ₂ .

According to one embodiment of formula VIa, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of Formula VIa, the phosphoramidate is in the L-configuration.

According to one embodiment of formula VIa, the phosphoramidate is in the D-configuration.

According to one embodiment of Formula VIa, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula VIa, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of Formula VIa, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl.

According to one embodiment of formula VIa, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, R ⁵⁰ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen; and R ¹⁰ is isopropyl.

дифосфата, трифосфата, необязательно замещенной связанной карбонилом аминокислоты или -C(O)R^3C.According to one embodiment of formula VIa, R ³ is independently selected from hydrogen,

diphosphate, triphosphate, optionally substituted carbonyl-linked amino acid, or -C(O)R ^3C .

According to an alternative embodiment, compounds of formula VIb are disclosed. According to a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ⁵⁰ are defined above.

According to one embodiment of formula VIb, R ³ is hydrogen.

According to one embodiment of formula VIb, R ⁶⁵ is methyl.

According to one embodiment of formula VIb, R ⁵⁰ is hydrogen.

According to one embodiment of formula VIb, R ⁵⁰ is -NH ₂ .

According to one embodiment of formula VIb, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of formula VIb, the phosphoramidate is in the L-configuration.

According to one embodiment of Formula VIb, the phosphoramidate is in the D configuration.

According to one embodiment of Formula VIb, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula VIb, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of Formula VIb, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl.

According to one embodiment of formula VIb, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, R ⁵⁰ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen; and R ¹⁰ is isopropyl.

According to an alternative embodiment, compounds of formula VIc are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vic, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ⁵⁰ are defined above.

According to one embodiment of formula VIc, R ³ is hydrogen.

According to one embodiment of formula VIc, R ⁶⁵ is methyl.

According to one embodiment of formula VIc, R ⁵⁰ is hydrogen.

According to one embodiment of formula VIc, R ⁵⁰ is -NH ₂ .

According to one embodiment of formula VIc, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of Formula VIc, the phosphoramidate is in the L-configuration.

According to one embodiment of formula VIc, the phosphoramidate is in the D-configuration.

According to one embodiment of formula VIc, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula VIc, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of formula VIc, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl.

According to one embodiment of formula VIc, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, R ⁵⁰ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen; and R ¹⁰ is isopropyl.

According to an alternative embodiment, compounds of formula VId are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vid, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ⁵⁰ are defined above.

According to one embodiment of formula VId, R ³ is hydrogen.

According to one embodiment of formula VId R ⁶⁵ is methyl.

According to one embodiment of formula VId, R ⁵⁰ is hydrogen.

According to one embodiment of formula VId, R ⁵⁰ is -NH ₂ .

According to one embodiment of Formula VId, the phosphoramidate is in the L-configuration.

According to one embodiment of Formula VId, the phosphoramidate is in the D configuration.

According to one embodiment of formula VId, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of formula VId, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula VId, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of formula VId, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl.

According to one embodiment of formula VId, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, R ⁵⁰ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen; and R ¹⁰ is isopropyl.

According to an alternative embodiment, compounds of the formula Vie are disclosed. In a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vie, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ⁵⁰ are defined above.

According to one embodiment of formula VIe, R ³ is hydrogen.

According to one embodiment of Formula VIe, R ⁶⁵ is methyl.

According to one embodiment of Formula VIe, R ⁵⁰ is hydrogen.

According to one embodiment of formula VIe, R ⁵⁰ is -NH ₂ .

According to one embodiment of formula VIe, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of Formula VIe, the phosphoramidate is in the L-configuration.

According to one embodiment of formula VIe, the phosphoramidate is in the D-configuration.

According to one embodiment of Formula VIe, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of Formula VIe, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of formula VIe, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl.

According to one embodiment of formula VIe, Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, R ⁵⁰ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen; and R ¹⁰ is isopropyl.

According to an alternative embodiment, compounds of formula VIf are disclosed. According to a further alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIf, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Q, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ⁵⁰ are defined above.

According to one embodiment of formula VIf R ³ is hydrogen.

According to one embodiment of formula VIf R ⁶⁵ is methyl.

According to one embodiment of formula VIf R ⁵⁰ is hydrogen.

According to one embodiment of formula VIf R ⁵⁰ is -NH ₂ .

According to one embodiment of formula VIf Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, and R ⁵⁰ is hydrogen.

According to one embodiment of formula VIf, the phosphoramidate is in the L-configuration.

According to one embodiment of Formula VIf, the phosphoramidate is in the D-configuration.

According to one embodiment of formula VIf, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the L-configuration.

According to one embodiment of formula VIf, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen and R ¹⁰ is isopropyl and the phosphoramide is in the D-configuration.

According to one embodiment of formula VIf Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen, and R ¹⁰ is isopropyl.

According to one embodiment of formula VIf Q is CHR ⁶⁵ , R ³ is hydrogen, R ⁶⁵ is methyl, R ⁵⁰ is hydrogen, R ⁷ is phenyl, R ⁸ is hydrogen, R ^9a is methyl, R ^9b is hydrogen; and R ¹⁰ is isopropyl.

Phosphorus in any of the formulas described above may be chiral and thus may be present as the R or S enantiomer or a mixture thereof, including a racemic mixture.

Non-limiting embodiments include:

In one embodiment, compounds, methods, and compositions are provided for treating a host infected with an RNA virus as described herein, eg, other than Hepacivirus or HCV. For example, the compounds of the present invention may be administered in an effective amount, alone or in combination with another anti-RNA virus agent, to treat an infected host, if desired. In some embodiments, it is useful to administer a combination of drugs that modulate the same or a different pathway, or inhibit a different target in the virus. Since the disclosed 2'-substituted-N ⁶ -substituted purine nucleotides are polymerase inhibitors, it may be useful to administer the compound to the host in combination with a protease inhibitor or an NS5A inhibitor. The compounds of the present invention may also be administered in combination with a structurally different polymerase inhibitor, such as another compound described herein or otherwise known to those skilled in the art. The compounds of the present invention may also be administered in combination with ribavirin and/or interferon.

The 2'-substituted-N ⁶ -substituted purine nucleotides of the present invention are generally administered orally, for example in the form of a pill or tablet, but they may be administered by any other route that the attending physician deems appropriate, including intravenous, transdermal, subcutaneous, topical, parenteral, or other suitable route.

Detailed description of the invention

The present invention as disclosed herein relates to the compounds and their uses, methods and compositions described herein for the treatment of infections or exposure to humans or other animal hosts of an RNA virus, which involves administering an effective amount of a compound of formula I , formula II, formula III, formula IV, formula V, or formula VI as described herein, or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds described herein either have anti-RNA activity or are metabolized to a compound that exhibits such activity. In some embodiments, the method includes administering a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or a pharmaceutically acceptable salt thereof, for treating infection with a non-Hepacivirus or non-HCV single-stranded positive-sense RNA virus in host that needs it, including humans. According to an alternative embodiment, a method is provided comprising administering a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI, or a pharmaceutically acceptable salt thereof, for the treatment of infection with a virus with single-stranded positive-sense RNA from the Flaviviridae family, including without restrictions to dengue fever virus 2 and yellow fever virus, in a host in need of it, including humans. According to an alternative embodiment, a method is provided comprising administering a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI, or a pharmaceutically acceptable salt thereof, for the treatment of an infection with a single-stranded negative-sense RNA virus in a host in need thereof, in including in humans. In an alternative embodiment, a method is provided comprising administering a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI, or a pharmaceutically acceptable salt thereof, for treating a double-stranded RNA virus infection in a host in need thereof, including person.

The compounds and compositions may also be used to treat a condition associated with or resulting from exposure to an RNA virus. In one embodiment, the compounds or formulations that include the compounds can also be used prophylactically to prevent or slow the progression of a clinical disease in individuals who are positive for an anti-RNA virus antibody or antigen.

In particular, it was found that a 5'-stabilized phosphate prodrug or a derivative of a 2'-substituted-N ⁶ -methyl-2,6-diaminopurine nucleotide, as well as a 2'-substituted-N ⁶ -dimethyl-2,6-diaminopurine nucleotide and other 2'-substituted-N ⁶ -substituted purine nucleotides described below are highly active against an RNA virus, eg, other than Hepacivirus or other than HCV.

Unless otherwise indicated, the compounds described herein are in the β-D configuration. In an alternative embodiment, the compounds may be in the β-L configuration. Similarly, any substituent group that exhibits chirality may be present in racemic, enantiomeric, diastereomeric form, or any mixture thereof. When a phosphoramidate, thiophosphoramidate or other stabilized phosphorus prodrug in which phosphorus exhibits chirality is used as an ^R4 stabilized phosphate prodrug, it can be provided as an R or S chiral phosphorus derivative or a mixture thereof, including a racemic mixture. The amino acid phosphoramidate or thiophosphoramidate may be in the D- or L-configuration or a mixture thereof, including a racemic mixture. All combinations of such stereo configurations are included in the present invention as described herein.

The present invention provides the following features:

(a) the compounds of formulas I-VI described herein, and their pharmaceutically acceptable salts and prodrugs for use in the treatment or prevention of infection with an RNA virus and, in one embodiment, a virus other than Hepacivirus or other than HCV;

(b) the use of compounds of formulas I-VI, as well as their pharmaceutically acceptable salts and prodrugs in the manufacture of a medicament for the treatment of infection with an RNA virus and a virus other than Hepacivirus or other than HCV;

(c) a method for the manufacture of a medicinal product intended for therapeutic use in the treatment of infection with an RNA virus, for example, a virus other than Hepacivirus or non-HCV, characterized in that the compounds of formulas I-VI described herein are used in the manufacture; and

(d) a pharmaceutical composition comprising an effective amount for treating a host of a compound of formulas I-VI or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent for treating a disease caused by an RNA virus other than Hepacivirus or other than HCV.

I. 2'-Deoxy-2'-substituted-2-modified-N ⁶ -substituted purine nucleotides of the present invention

The active compounds of the present invention are depicted, for example, in formula I, which can be provided in their pharmaceutically acceptable composition, salt or prodrug:

where:

Y is NR ¹ R ² ;

R ¹ is C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl (including CH ₂ F , CH ₂ F, CF ₃ , CH ₂ CF ₃ , CF ₂ CH ₃ and CF ₂ CF ₃ ), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -(C ₀ -C ₂ alkyl) (C ₃ -C ₆ cycloalkyl), -(C ₀ -C ₂ alkyl)(heterocycle), -(C ₀ -C ₂ alkyl)(aryl), -(C ₀ -C ₂ alkyl)(heteroaryl), -OR ²⁵ , - C(O)R ^3C (including -C(O)CH ₃ , -C(O)CH ₂ CH ₃ -C(O)CH(CH ₃ ) ₂ , -C(O)OCH ₃ , -C(O) OS ₂ H ₅ , -C (O) OS ₃ H ₇ , -C (O) OS ₄ H ₉ and -C (O) OS ₅ H ₁₁ ), -C (S) R ^3D or -SO ₂ R ²⁸ , each of which may be optionally substituted;

R ² is hydrogen optionally substituted with C ₁ -C ₅ alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and pentyl), C ₁ -C ₅ haloalkyl ( including CHF ₂ , CH ₂ F, CF ₃ , CH ₂ CF ₃ and CF ₂ CF ₃ ), optionally substituted -(C ₀ -C ₂ alkyl)(C ₃ -C ₆ cycloalkyl), optionally substituted -(C ₀ -C ₂ alkyl)(heterocycle), optionally substituted -(C ₀ -C ₂ alkyl)(aryl), optionally substituted -(C ₀ -C ₂ alkyl)(heteroaryl), -C(O)R ^3C (including -C(O ) CH ₃ , -C (O) CH ₂ CH ₃ -C (O) CH (CH ₃ ) ₂ , -C (O) OCH ₃ , -C (O) OS ₂ H ₅ , -C (O) OS ₃ H ₇ , -C(O)OC ₄ H ₉ and -C(O)OC ₅ H ₁₁ ), -C(S)R ^3D or -SO ₂ R ²⁸ ; and

where at least one of R ¹ and R ² is methyl, CH ₂ F, CHF ₂ or CF ₃ ;

дифосфат, трифосфат, необязательно замещенную связанную карбонилом аминокислоту или -C(O)R^3C;R ³ is hydrogen,

diphosphate, triphosphate, optionally substituted carbonyl-linked amino acid or -C(O)R ^3C ;

R ^3A can be selected from O ^- , OH, -O-optionally substituted aryl, -O-optionally substituted heteroaryl, or optionally substituted heterocyclyl;

R ^3B may be selected from O ⁻ , OH, an optionally substituted N-linked amino acid, or an optionally substituted N-linked amino acid ester;

R ^3C is alkyl, alkenyl, alkynyl, -(C ₀ -C ₂ )(cycloalkyl), -(C ₀ -C ₂ )(heterocyclo), -(C ₀ -C ₂ )(aryl), -(C ₀ -C ₂ )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C ₀ -C ₂ )(cycloalkyl), -O-(C ₀ -C ₂ )(heterocyclo) , -O-(C ₀ -C ₂ )(aryl) or -O-(C ₀ -C ₂ )(heteroaryl), each of which may be optionally substituted;

R ⁴ is a monophosphate, diphosphate, triphosphate, or stabilized phosphate prodrug, including, but not limited to, phosphoramidate, thiophosphoramidate, or any other moiety that is metabolized to monophosphate, diphosphate, or triphosphate in vivo in a human or animal host; or

R ³ and R ⁴ together with the oxygen atoms to which they are attached, can form a 3',5'-cyclic prodrug, including without limitation a 3',5'-cyclic phosphate prodrug;

R ¹² is hydrogen, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ or ethynyl; and

R ¹³ represents hydrogen, fluorine, chlorine, bromine, N ₃ , NH ₂ , CN or OR ³ ;

moreover, if R ¹² is methyl, R ¹³ is bromine, chlorine, N ₃ , NH ₂ , CN or OR ³ .

A stabilized phosphate prodrug is any moiety that can deliver mono-, di-, or triphosphate.

According to an alternative embodiment, at least one of R ¹ and R ² is cyclopropyl.

In an alternative embodiment, at least one of R ¹ and R ² is cyclopentyl.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Ib', or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁶⁰ , m and p are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ic, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula Id, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of Formula Ie, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ and R ⁴ are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ , R ¹² , R ¹³ and R ²² are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IIb' or a pharmaceutically acceptable salt thereof for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ²² , R ⁶⁰ , m and p are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IId, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IIe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

Y, R ³ , R ⁴ and R ²² are defined above.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ¹² and R ¹³ are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIb' or a pharmaceutically acceptable salt thereof for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁶⁰ , m and p are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIId, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IIIe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b and R ¹⁰ are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of Formula IV, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ¹² , R ¹³ and R ²² are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula IVb' or a pharmaceutically acceptable salt thereof for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ²² , R ⁶⁰ , m and p are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVd, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula IVe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where the variables Y, R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ and R ²² are described in the present invention.

According to another embodiment, the present invention relates to the use of an effective amount of a compound of formula V, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ , R ⁶² , R ⁶³ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula V, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vd, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Ve, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula Vf, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁴ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VI, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ , R ⁶² and R ⁶³ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIa, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIb, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIc, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VId, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIe, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ and Q are defined above.

According to an alternative embodiment, the present invention relates to the use of an effective amount of a compound of formula VIf, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof.

where:

R ³ , R ⁷ , R ⁸ , R ^9a , R ^9b , R ¹⁰ , R ⁵⁰ and Q are defined above.

In a typical embodiment, the compound is the β-D isomer with reference to the corresponding nucleoside (ie, in the naturally occurring configuration). In an alternative configuration, the compound is provided as the β-L isomer. Typically, the compound is at least 90% free of the opposite enantiomer and may be at least 95%, 96%, 97%, 98%, 99% or even 100% free of the opposite enantiomer. Unless otherwise described, the compound must be at least 90% free of the opposite enantiomer.

Metabolism of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-N ⁶ -substituted-2,6-diaminopurine nucleotides

Metabolism of phosphoramidate β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynyl-N ⁶ -methyl-2,6-diaminopurine nucleoside includes the formation of 5'-monophosphate and subsequent anabolism of N ⁶ - methyl-2,6-diaminopurine base to form β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynylguanine nucleoside as 5'-monophosphate. The monophosphate is then further anabolized to the active compound, 5'-triphosphate. The metabolic pathway for β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynyl-N ⁶ -methyl-2,6-diaminopurine nucleoside phosphoramidate is shown in Scheme 1.

The metabolism of β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynyl-N ⁶ -dimethyl-2,6-diaminopurine nucleotide also includes the formation of triphosphate β-D-2'-deoxy- 2'-α-fluoro-2'-β-ethynyl-N ⁶ -dimethyl-2,6-diaminopurine nucleoside, and the formation of the corresponding guanine nucleoside triphosphate. These metabolic pathways are shown in Schemes 2 and 3 below.

Stabilized phosphate prodrugs

Stabilized phosphate prodrugs are moieties that can deliver mono-, di-, or triphosphate in vivo. For example, McGuigan discloses phosphoramidates in US Pat. Nos. 8,933,053; 8759318; 8658616; 8263575; 8119779; 7,951,787 and 7,115,590. Alios discloses thiophosphoramidates in US Pat. Nos. 8,895,723 and 8,871,737, incorporated herein by reference. Alios also discloses cyclic nucleotides in US Pat. No. 8,772,474, incorporated herein by reference. Idenix discloses cyclic phosphoramidates and phosphoramidate/SATE derivatives in WO 2013/177219, incorporated herein by reference. Idenix also discloses substituted carbonyloxymethylphosphoramidate compounds in WO 2013/039920, incorporated herein by reference. Hostetler discloses lipid phosphate prodrugs, see, for example, US Pat. No. 7,517,858, incorporated herein by reference. Hostetler also discloses lipid conjugates of phosphonate prodrugs, see, for example, US Pat. Nos. 8,889,658; 8846643; 8710030; 8309565; 8008308 and 7790703. Emory University discloses nucleotide sphingoid and lipid derivatives in WO 2014/124430, incorporated herein by reference. RFS Pharma discloses purine nucleoside monophosphate prodrugs in WO 2010/091386. Cocrystal Pharma Inc. Purine nucleoside monophosphate prodrugs are also disclosed in US Pat. No. 9,173,893, incorporated herein by reference. HepDirect™ technology is disclosed in "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver" (J. Am. Chem Soc 126, 5154-5163 (2004) Additional phosphate prodrugs include, but are not limited to, phosphate esters, 3',5'-cyclic phosphates including CycloSAL, SATE derivatives (S-acyl-2-thioesters ) and DTE (dithiodiethyl) prodrugs. For literature reviews that disclose non-limiting examples, see A. Ray and K. Hostetler, "Application of kinase bypass strategies to nucleoside antivirals," Antiviral Research (2011) 277-291; M. Sofia, "Nucleotide prodrugs for HCV therapy," Antiviral Chemistry and Chemotherapy 2011; 22-23-49; and S. Peyrottes et al., "SATE Pronucleotide Approaches: An Overview," Mini Reviews in Medicinal Chemistry 2004, 4, 395. In one embodiment, the 5' prodrug described in any of these patent or literary sources, can be used in the R ⁴ position of the compounds in accordance with the present invention.

In one alternative embodiment, the stabilized phosphate prodrugs include, without limitation, the prodrugs described in US Pat. No. 9,173,893 and US Pat. No. 8,609,627, incorporated herein by reference, including methods of preparation. For example, 5'-prodrugs of formula I, formula II, formula III, formula IV, formula V and formula VI can be represented by the group:

In an alternative embodiment, the 3',5' prodrugs of Formula I-VI may be represented by the group:

where:

if chirality exists at the phosphorus center, it may be all or part of R _p or S _p or any mixture thereof.

Z is O or S;

и полученного жирного спирта (например, без ограничения:R ³³ is selected from OR ³⁴ ,

and the resulting fatty alcohol (for example, without limitation:

),

),

where R ³⁴ , R ³⁵ and R ³⁶ are defined below;

R ³¹ and R ³² , when administered in vivo, are capable of providing a monophosphate or thiomonophosphate nucleoside that may or may not be partially or completely resistant to 6-NH ₂ deamination in a biological system. The exemplary R ³¹ and R ³² are independently selected from:

(a) OR ³⁴ where R ³⁴ is selected from H, Li, Na, K, phenyl and pyridinyl; phenyl and pyridinyl are substituted with one to three substituents independently selected from the group consisting of (CH ₂ ) _0-6 CO ₂ R ³⁷ and (CH ₂ ) _0-6 CON(R ³⁷ ) ₂ ;

R ³⁷ is independently H, C _1-20 alkyl, a carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or C _1-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl, cycloalkyl, alkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl; where the substituents are C _1-5 alkyl or C _1-5 alkyl substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl or cycloalkyl;

(b)

(c) a D-amino acid or L-amino acid ester

where R ³⁶ is limited to such side chains as are found in naturally occurring L-amino acids, and

R ³⁵ is H, C _1-20 alkyl, a carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.) or C _1-20 alkyl substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl, cycloalkyl, alkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl; where the substituents are C _1-5 alkyl or C _1-5 alkyl substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl or cycloalkyl;

(d) R ³¹ and R ³² may be joined together to form a ring

where R ³⁸ is H, C _1-20 alkyl, C _1-20 alkenyl, a carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or C _1-20 alkyl substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl, cycloalkyl, alkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl; where the substituents are C _1-5 alkyl or C _1-5 alkyl substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl or cycloalkyl;

(e) R ³¹ and R ³² may be joined together to form a ring selected from

where R ³⁹ represents O or NH, and

R ⁴⁰ is selected from H, C _1-20 alkyl, C _1-20 alkenyl, a carbon chain derived from a fatty acid (such as oleic acid, linoleic acid, etc.), and C _1-20 alkyl substituted with a lower alkyl , alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl, cycloalkyl, alkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl; where the substituents are C _1-5 alkyl or C _1-5 alkyl substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, fluorine, C _3-10 cycloalkyl or cycloalkyl.

Compounds can be prepared, for example, by preparing the 5'-OH analogs, then converting them to the monophosphate analogs.

Embodiments

According to specific embodiments:

(i) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(ii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(iii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(iv) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen and R ⁴ is thiophosphoramidate:

(v) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is monophosphate;

(vi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is diphosphate;

(vii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is triphosphate;

(viii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(ix) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(x) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(xi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is thiophosphoramidate:

(xii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is monophosphate;

(xiii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is diphosphate;

(xiv) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is triphosphate;

(xv) in formula Ia, Y is NR ¹ R ² R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(xvi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(xvii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(xviii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is thiophosphoramidate:

(xix) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is monophosphate;

(xx) in formula Ia Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is methyl and R ⁴ is diphosphate;

(xxi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is triphosphate;

(xxii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(xxiii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(xxiv) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(xxv) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, and R ⁴ is thiophosphoramidate;

(xxvi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, and R ⁴ is monophosphate;

(xxvii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, and R ⁴ is diphosphate;

(xxviii) In formula Ia, Y is NR ¹ R ² , Y is NR ¹ R ² , R ¹ is methyl, R ² is propyl, R ³ is hydrogen, and R ⁴ is triphosphate;

(xxix) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(xxx) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(xxxi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(xxxii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen and R ⁴ is thiophosphoramidate:

(xxxiii) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen, and R ⁴ is monophosphate;

(xxxiv) In formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen, and R ⁴ is diphosphate;

(xxxv) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is ethyl, R ³ is hydrogen, and R ⁴ is triphosphate;

(xxxvi) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(xxxvii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(xxxviii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen and R ⁴ is phosphoramidate;

(xxxix) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen and R ⁴ is thiophosphoramidate:

(xl) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is monophosphate;

(xli) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is diphosphate;

(xlii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is methyl, R ³ is hydrogen, and R ⁴ is triphosphate;

(xliii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(xliv) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(xlv) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(xlvi) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is thiophosphoramidate;

(xlvii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is monophosphate;

(xlviii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen, and R ⁴ is diphosphate;

(xlix) in the formula lb Y is NR ¹ R ² , R ¹ is methyl, R ² is hydrogen, R ³ is hydrogen and R ⁴ is triphosphate;

(l) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, R ⁴ is a stabilized phosphate prodrug;

(li) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is a stabilized thiophosphate prodrug;

(lii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is phosphoramidate;

(liii) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is thiophosphoramidate;

(liv) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is monophosphate;

(lv) in formula Ib, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is methyl, and R ⁴ is diphosphate;

(lvi) in formula Ia, Y is NR ¹ R ² , R ¹ is methyl, R ² is cyclopropyl, R ³ is hydrogen, and R ⁴ is triphosphate.

-P(O)H(OH), -P(O)H(OCH₃), -P(O)(OH)(OH), -P(O)(OH)(OCH₃), -Р(O)(ОСН₃)(ОСН₃), -P(O)(OH)(NH₂), -P(O)(OH)(NHCH₃), -P(O)(OH)N(CH₃)₂, -NHC(O)CH₃, -NHC(O)CH₂CH₃, -NHC(O)CH(CH₃)₂, -NHC(O)OCH₃, -NHC(O)OCH₂CH₃, -NHC(O)OCH(CH₃)₂, -NHC(O)OCH₂CH₂CH₃, NHC(O)OCH₂CH₂CH₂CH₃ или -NHC(O)OCH₂CH₂CH₂CH₂CH₃;In alternative embodiments of any of the above, the compound contains an R ²² substituent. According to some of these specific embodiments, R ²² is F, an amide, or a carbamate. According to other specific aspects of the embodiments above, R ²² is chlorine, bromine, cyano, azido, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and n-pentyl, 1,1-dimethylpropyl , 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ₂ ) -cyclopropyl, - (CH ₂ )-cyclobutyl, -(CH ₂ )-cyclopentyl, -(CH ₂ )-cyclohexyl, aziridine, oxiran, thiiran, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, piperidine, ocean, thian, - (CH ₂ )-aziridine, -(CH ₂ )-oxirane, -(CH ₂ )-thiirane, -(CH ₂ )-azetidine, -(CH ₂ )-oxetane, -(CH ₂ )-thietane, -(CH ₂ )-pyrrolidine, -(CH ₂ )-tetrahyrofuran, -(CH ₂ )-thiolane, -(CH ₂ )-pyrazolidine, -(CH ₂ )-piperidine, -(CH ₂ )-oxane, -(CH ₂ ) -thiane, phenyl, pyridyl, -ONHC(=O)OCH ₃ , -ONHC(=O)OCH ₂ CH ₃ , -NHOH, NOCH ₃ , -OCH ₃ , OS ₂ H ₅ , -OPh, OCH ₂ Ph, - SCH ₃ , -SC ₂ H ₅ , -SPh, SCH ₂ Ph, -NH(CH ₂ ) ₂ NH ₂ , -N H (CH ₂ ) ₂ N (CH ₃ ) ₂ , -NHNH ₂ , -NHNHCH ₃ , -N=NH, -N=NCH ₃ , -N=NCH ₂ CH ₃ , -NHC(O)NHNH ₂ , -NHC (S)NHNH ₂ , -C(O)NHNH ₂ , -NHSO ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -SO ₂ NHCH ₃ , -SO ₂ N(CH ₃ ) ₂ , -C(O)NH ₂ , -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ , -CO ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ , -CO ₂ Ph, CO ₂ CH ₂ Ph, -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ Ph, -SO ₂ CH ₂ Ph,

-P(O)H(OH), -P(O)H(OCH ₃ ), -P(O)(OH)(OH), -P(O)(OH)(OCH ₃ ), -P(O )(OCH ₃ )(OCH ₃ ), -P(O)(OH)(NH ₂ ), -P(O)(OH)(NHCH ₃ ), -P(O)(OH)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , -NHC(O)CH(CH ₃ ) ₂ , -NHC(O)OCH ₃ , -NHC(O)OCH ₂ CH ₃ , - NHC(O)OCH(CH ₃ ) ₂ , -NHC(O)OCH ₂ CH ₂ CH ₃ , NHC(O)OCH ₂ CH ₂ CH ₂ CH ₃ or -NHC(O)OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ;

According to alternative embodiments of compounds (i) - (lvi) L-nucleoside was used in formula I-VI.

According to an alternative embodiment of formula IR ¹² , the variable is CH ₂ F.

According to an alternative embodiment of formula IR ¹² , the variable is CHF ₂ .

According to an alternative embodiment of formula IR ¹² , the variable is CF ₃ .

In one embodiment, the use of an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of compounds of Formula I include:

According to an alternative embodiment, the use of an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Additional non-limiting examples of compounds of Formula I include:

In one embodiment, the use of an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of Formula III include, without limitation:

According to an alternative embodiment, the use of an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Additional non-limiting examples of Formula III include, without limitation:

In one embodiment, the use of an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of thiophosphoramidates of formula III include, without limitation:

According to an alternative embodiment, the use of an effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Additional non-limiting examples of thiophosphoramidate of formula III include, without limitation:

In one embodiment, the use of an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of stabilized phosphate prodrugs of Formula I are provided below:

In one embodiment, the use of an effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of compounds of formula II include:

According to an alternative embodiment, the use of an effective amount of a compound of formula V, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of compounds of Formula V include:

In one embodiment, the use of an effective amount of a compound of formula VI, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of compounds of formula VI include:

In some embodiments, R ³ is H and R ⁴ is

In some embodiments, R ³ is H and R ⁴ is

In some embodiments, R ³ is H and R ⁴ is

In some embodiments, R ³ is H and R ⁴ is

In some embodiments, R ³ is H and R ⁴ is

In some embodiments, R ³ is H and R ⁴ is

In some embodiments, R ¹ is CH ₃ , R ² is H, R ³ is H, and R ⁴ is

In some embodiments, R ¹ is CH ₃ , R ² is H, R ³ is H, and R ⁴ is

In some embodiments, R ¹ is CH ₃ , R ² is H, R ³ is H, and R ⁴ is

In some embodiments, R ¹ is CH ₃ , R ² is CH ₃ , R ³ is H, and R ⁴ is

In some embodiments, R ¹ is CH ₃ , R ² is CH ₃ , R ³ is H, and R ⁴ is

In some embodiments, R ¹ is CH ₃ , R ² is CH ₃ , R ³ is H, and R ⁴ is

In some embodiments, R ¹ is cyclopropyl, R ² is CH ₃ , R ³ is H, and R ⁴ is

In some embodiments, R ¹ is cyclopropyl, R ² is CH ₃ , R ³ is H, and R ⁴ is

In some embodiments, R ¹ is cyclopropyl, R ² is CH ₃ , R ³ is H, and R ⁴ is

In one embodiment, the use of an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of an RNA virus infection in a host, including a human in need thereof. Non-limiting examples of Formula III include, without limitation:

II. Definitions

The following terms have been used to describe the present invention. In cases where the term is not specifically defined in the present description, such term is presented in the meaning accepted in the present field by specialists in the present field using such a term in the context of its use in describing the present invention.

The term "alkyl" within its context means straight or branched fully saturated hydrocarbon radical or alkyl group, which may be optionally substituted (for example, halogen, including F). For example, an alkyl group may contain 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C ₁ -C ₈ alkyl), 1, 2, 3, 4, 5, or 6 carbon atoms. (ie, C ₁ -C ₆ alkyl) or 1-4 carbon atoms (ie, C ₁ -C ₄ alkyl). Examples of suitable alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, t-pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

The term "alkenyl" refers to a non-aromatic hydrocarbon group that contains at least one double bond between adjacent carbon atoms and is similar in structure to an alkyl group, as otherwise described herein. For example, an alkenyl group may contain 2 to 8 carbon atoms (ie, C ₂ -C ₈ alkenyl) or 2 to 4 carbon atoms (ie, C ₂ -C ₄ alkenyl). Examples of suitable alkenyl groups include, without limitation, ethenyl or vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), 1-butenyl (-C=CH-CH ₂ CH ₃ ) and 2-butenyl ( -CH ₂ CH=CHCH ₂ ). The alkenyl group may be optionally substituted as described in the present invention.

The term "alkynyl" refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and is similar to an alkyl group in structure, as otherwise described in the present invention. For example, an alkynyl group may contain 2 to 8 carbon atoms (ie, C ₂ -C ₈ alkynyl) or 2 to 4 carbon atoms (ie, C ₂ -C ₄ alkynyl). Examples of alkynyl groups include, without limitation, an acetylenic group or ethynyl and propargyl. The alkynyl group may be optionally substituted as described in the present invention.

The term "acyl" refers to a -C(O)R moiety in which the carbonyl moiety is bonded to R, eg, -C(O)alkyl. R may be selected from alkoxy, alkyl a, cycloalkyl, lower alkyl (ie, C ₁ -C ₄ ); alkoxyalkyl including methoxymethyl; aralkyl-, including benzyl, aryloxyalkyl-, such as phenoxymethyl; aryl, including phenyl optionally substituted with halogen, C ₁ C ₄ alkyl or C ₁ -C ₄ alkoxy. According to one embodiment, the term "acyl" refers to mono-, di-, or triphosphate.

The term "lower acyl" refers to an acyl group in which the carbonyl moiety is lower alkyl (ie, C ₁ -C ₄ ).

The term "alkoxy" refers to the group -OR', where -OR' represents -O-alkyl,

-O-alkenyl, -O-alkynyl, -O-(C ₀ -C ₂ )(cycloalkyl), -O-(C ₀ -C ₂ )(heterocyclo), -O-(C ₀ -C ₂ )(aryl ) or -O-(C ₀ -C ₂ )(heteroaryl), each of which may be optionally substituted.

The term "amino" refers to the -NH ₂ group.

The term "amino acid" or "amino acid residue" refers to a D- or L-amino acid of natural or non-natural origin. Representative amino acids include, without limitation, alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine , tryptophan or tyrosine, among others.

The term "azido" refers to the -N ₃ group.

The term "aryl" or "aromatic" as used herein refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical containing single ring (e.g. phenyl or benzyl) or fused rings (e.g. naphthyl, anthracenyl, phenanthrenyl and etc.), and may be associated with the compound of the present invention at any available stable position on the ring(s) or as otherwise noted in the presented chemical structure. The aryl group may be optionally substituted as described in the present invention.

"Cycloalkyl", "carbocycle", or "carbocyclyl" refers to a saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl, cycloalkadienyl, etc.) ring containing 3 to 7 carbon atoms as a monocycle. Monocyclic carbocycles contain 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex -2-enyl and 1-cyclohex-3-enyl.

The term "cyano" refers to the -CN group.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

A heteroaryl ring system is a saturated or unsaturated ring with one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), including, but not limited to, imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, purine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, and the like, among others, which may be optionally substituted as described above. Heteroaryl groups include nitrogen containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, purine, indazole, quinoline, isoquinoline, quinolysine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazole, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazol, benzothiadiazol, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, among others, all of which may be optionally substituted.

The term "heterocycle" or "heterocyclo" refers to a cyclic group that contains at least one heteroatom, ie, O, N or S, and may be aromatic (heteroaryl) or non-aromatic. Exemplary non-aromatic heterocyclic groups for use in the present invention include, for example, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone , ethylene urea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide and succinimide, among others, all of which may be optionally substituted.

The term "hydroxyl" refers to the -OH group.

The term "nitro" refers to the -NO ₂ group.

The term "pharmaceutically acceptable salt" or "prodrug" has been used throughout this specification to describe any pharmaceutically acceptable form (such as an ester, phosphoramidate, thiophosphoramidate, phosphate ester, ester salt, or linked group) of a 2'-substituted-N ⁶ -substituted a purine nucleotide which, upon administration to a patient, provides the desired active compound. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including sulfate, nitrate, bicarbonate and carbonate salts. Pharmaceutically acceptable salts can be prepared using standard procedures well known in the art, for example by reacting a basic compound such as an amine in a sufficient manner with a suitable acid to produce a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.

A "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, eg, hydrolyzed or oxidized, in a host to form a compound of the present invention. Typical examples of prodrugs include compounds that possess biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, thiophosphoramidated, child phosphoramidated, phosphoramidated, or dephosphoramidated to give the active compound. The compounds of the present invention have antiviral activity against an RNA virus or are metabolized to a compound that exhibits such activity. 2'-Substituted-N ⁶ -substituted purine nucleoside can also be administered as 5'-phosphoester lipid, bisphosphoramidate, 3',5'-cyclic phosphoramidate, 3',5'-cyclic thiophosphoramidate, DTE conjugate, mixed phosphoramidate derivative SATE or derivative "SATE".

The term "phosphonic acid" refers to the group -P(O)(OH) ₂ .

In one embodiment, the term purine or pyrimidine base includes, but is not limited to, adenine, N ⁶ -alkylpurines, N ⁶ -acylpurines (wherein acyl is -C(O)alkyl, -C(O)(aryl)C ₀ -C ₄ alkyl or -C (O) (C ₀ -C ₄ alkyl) aryl), N ⁶ -benzylpurine, N ^{6 -halopurine, N 6 -vinylpurine} , N ⁶ -acetylenic purine, N ⁶ -acylpurine, N ⁶ -hydroxyalkylpurine, N ⁶ -thioalkylpurine, N ² -alkylpurines, N ² -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halogenuracil, including 5-fluorouracil, C ⁵ alkyl pyrimidines, C ⁵ benzyl pyrimidines, C ⁵ halopyrimidines, C ⁵ vinyl pyrimidines, C ⁵ acetylenic pyrimidines, C ⁵ acyl pyrimidines, C ⁵ hydroxyalkyl purines, C ⁵ amidopyrimidines, C ⁵ -cyanopyrimidine, C ⁵ -nitropyrimidine, C ⁵ -aminopyrimidine, N ² -alkylpurines, N ² -alkyl-6-thiopurines, 5-azacytidinyl, 5-azaracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl . Purine bases include, without limitation, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. The functional oxygen and nitrogen groups on the base may be protected as necessary or required. Suitable protecting groups are well known to those skilled in the art and include benzyl, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl groups and acyl groups such as acetyl and propionyl; methanesulfonyl and p-toluenesulfonyl. Alternatively, the purine or pyrimidine base may optionally be substituted such that it forms an acceptable prodrug that can be cleaved off in vivo. Examples of suitable substituents include an acyl moiety.

The term "substituted" or "optionally substituted" means that the fragment may contain at least one additional substituent, including, without limitation, halogen (F, Cl, Br, I), OH, phenyl, benzyl, N ₃ , CN, acyl , alkyl, including methyl; alkenyl, alkynyl, alkoxy, haloalkyl; including CHF ₂ , CH ₂ F and CF ₃ ; etc. In one embodiment, the term "substituted" or "optionally substituted" means that the moiety may contain at least one additional substituent, including, but not limited to, azido, cyano, halogen (fluorine, chlorine, bromine, or iodine), alkyl, alkenyl , alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, haloalkyl, hydroxyl, alkoxy, amino, -NH(C ₁ -C ₆ unsubstituted alkyl), -NH(C ₁ -C ₆ substituted alkyl), -NH-(C ₀ - C ₂ alkyl) (C ₃ -C ₈ cycloalkyl), -NH- (C ₀ -C ₂ alkyl) (C ₃ -C ₈ heterocycle), -NH- (C ₀ -C ₂ alkyl) (aryl),

-N(C ₁ -C ₆ unsubstituted alkyl) ₂ , -N(C ₁ -C ₆ unsubstituted alkyl)(C ₁ -C ₆ substituted alkyl),

-N (C ₁ -C ₆ substituted alkyl) ₂ , -NH- (C ₀ -C ₂ alkyl) (C ₃ -C ₈ cycloalkyl), -NH- (C ₀ -C ₂ alkyl) (C ₃ -C ₈ heterocycle), -NH-(C ₀ -C ₂ alkyl)(aryl), acyl, nitro, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate or thiol.

The term "sulfonate esters" represented by the formula R ¹⁴ S(O) ₂ OR ¹⁵ contains R ¹⁴ where R ¹⁴ is alkyl, haloalkyl, aralkyl or aryl. R ¹⁵ is alkyl, aryl or aralkyl.

The term "sulfonic acid" refers to the group -SO ₂ OH.

The term "thiol" refers to the -SH group.

As used herein, the term "nitrogen protecting group" refers to a moiety that is covalently attached to nitrogen and that can be removed, and typically replaced with hydrogen if necessary. For example, the nitrogen protecting group may be a group that is removed in vivo after administration to the host, in vitro by a cell, or it may be removed during the manufacturing process. Suitable nitrogen protecting groups useful in the present invention are described in Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

As used herein, the term "oxygen protecting group" refers to a moiety that is covalently attached to oxygen and that can be removed, and typically replaced by hydrogen, if necessary. For example, the oxygen protecting group may be a group that is removed in vivo after administration to the host, in vitro by a cell, or it may be removed during the manufacturing process. Suitable oxygen protecting groups useful in the present invention are described in Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

"Phosphate" refers to the -OP(O)(OH) ₂ group.

"Ester of phosphoric acid" refers to mono-, di - and triphosphates, unless otherwise noted.

The term "phosphoamidate", "phosphoramidate" or "phosphoramidate" is a moiety that contains phosphorus associated with three oxygen groups and an amine (which may be optionally substituted). Suitable phosphoramidates useful in the present invention are described in Madela, Karolina and McGuigan in 2012, "Progress in the development of anti-hepatitis C virus nucleoside and nucleotide prodrugs", Future Medicinal Chemistry 4(5), pages 625-650 10:1021 /jm300074y and Dominique, McGuigan and Balzarini in 2004, "Aryloxy Phosphoramidate Triesters as Pro-Tides", Mini Reviews in Medicinal Chemistry 4(4), pages 371-381. Additional phosphoramidates useful in the present invention are described in US Pat. Nos. 5,233,031; 7,115,590; 7,547,704; 8148349, 8263575, 8324179, 8334270, 8552021, 8563530, 8580765, 8735372, 8759318; EP 2120565; EP 1143995; 6,455,513 and 8,334,270. Other phosphoramidates are described in the nucleoside patents described in the prior art of the present invention.

Phosphoramidate groups for use in the present invention include the structure groups:

Other phosphoramidates for use in the present invention include phosphoramidates of the structure:

where:

R ^P1 is an optionally substituted straight, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl, or heterocyclic group, or an associated combination thereof; and

R ^P2 is -NR ^N1 R ^N2 group or B'group;

where:

R ^N1 and R ^N2 are each independently H, C _1-8 alkyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl-, (aryl) C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl- or (heteroaryl)C ₀ -C ₄ alkyl-, which may be optionally substituted; or

R ^N1 and R ^N2 together with the nitrogen atom to which they are attached are connected to form a 3-7 membered heterocyclic ring;

группу;B' represents

group;

where:

R ¹⁶ is hydrogen, (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, ( aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl or amino acid side chain, e.g. amino acid side chain (as otherwise described in the present invention), often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline , serine, threonine, valine, tryptophan or tyrosine (often R ¹⁶ is hydrogen, methyl, isopropyl or isobutyl);

R ¹⁷ is hydrogen, (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, ( aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl or amino acid side chain, e.g. amino acid side chain (as otherwise described in the present invention), often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline , serine, threonine, valine, tryptophan or tyrosine (often R ¹⁷ is hydrogen, methyl, isopropyl or isobutyl);

R ¹⁸ is hydrogen or C ₁ -C ₃ alkyl; or

R ¹⁶ and R ¹⁷ may form a (C ₃ -C ₇ )cycloalkyl or (C ₃ -C ₇ ) heterocyclic group; or

R ¹⁸ and R ¹⁶ or R ¹⁷ may form a (C ₃ -C ₆ )heterocyclic group; and

R ¹⁹ is hydrogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )alkenyl, (C ₃ -C ₆ )alkynyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, ( aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl-; or

группу;B' represents

group;

where:

R ²⁰ is hydrogen, (C ₁ -C ₃ )alkyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, (aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo) C ₀ -C ₄ alkyl- or (heteroaryl) C ₀ -C ₄ alkyl-;

R ²¹ is hydrogen, (C ₁ -C ₃ )alkyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, (aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo) C ₀ -C ₄ alkyl- or (heteroaryl) C ₀ -C ₄ alkyl-; and

R ¹⁸ and R ¹⁹ are defined above.

Exemplary R ^P1 groups include optionally substituted phenyl, naphthyl and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance the bioavailability of compounds in patient cells and which exhibit reduced toxicity, increased therapeutic index and increased pharmacokinetics (compounds metabolized and excreted more slowly).

The term phosphoramidate has been used throughout the specification to describe a group which is in the 5' or 3' position of the furanose ring of a nucleoside compound and forms a prodrug of the nucleoside compound. In one embodiment, the phosphoramidates may be present at the 5' and 3' position of the furanose ring of the nucleoside compound and form a prodrug of the nucleoside compound. In another embodiment, a phosphoramidate that is at the 5' position of the furanose ring of the nucleoside compound can form a cyclic phosphoramidate compound by bonding to a 3'-hydroxyl substituent at the 3' position of the furanose ring of the nucleoside compound and forms a prodrug of the nucleoside compound.

The term "thiophosphoamidate", "thiophosphoramidate" or "thiophosphoramidate" is a moiety that contains phosphorus associated with sulfur, two oxygen groups and an amine (which may be optionally substituted). Thiophosphoramidates useful in the present invention are described in US Pat. No. 8,772,474 and WO 2012/040124.

Thiophosphoramidate groups for use in the present invention include the structure groups:

Other thiophosphoramidates include thiophosphoramidates of the structure:

where:

R ^P1 is an optionally substituted straight, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl, or heterocyclic group, or an associated combination thereof; and

R ^P2 is -NR ^N1 R ^N2 group or B'group;

where:

R ^N1 and R ^N2 are each independently H, C ₁ -C ₈ alkyl, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl-, (aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl- or (heteroaryl)C ₀ -C ₄ alkyl-; or

R ^N1 and R ^N2 together with the nitrogen atom to which they are attached are connected to form a 3-7 membered heterocyclic ring;

группу;B' represents

group;

where:

R ¹⁶ is hydrogen, (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, ( aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl or amino acid side chain, e.g. amino acid side chain (as otherwise described in the present invention), often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline , serine, threonine, valine, tryptophan or tyrosine (often R ¹⁶ is hydrogen, methyl, isopropyl or isobutyl);

R ¹⁷ is hydrogen, (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, ( aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl or amino acid side chain, e.g. amino acid side chain (as otherwise described in the present invention), often selected from the group consisting of alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline , serine, threonine, valine, tryptophan or tyrosine (often R ¹⁷ is hydrogen, methyl, isopropyl or isobutyl);

R ¹⁸ is hydrogen or C ₁ -C ₃ alkyl; or

R ¹⁶ and R ¹⁷ may form a (C ₃ -C ₇ )cycloalkyl or (C ₃ -C ₇ ) heterocyclic group; or

R ¹⁸ and R ¹⁶ or R ¹⁷ may form a (C ₃ -C ₆ )heterocyclic group; and

R ¹⁹ is hydrogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )alkenyl, (C ₃ -C ₆ )alkynyl, (C ₃ -C ₈ cycloalkyl)C ₀ -C ₄ alkyl-, ( aryl)C ₀ -C ₄ alkyl-, (C ₃ -C ₆ heterocyclo)C ₀ -C ₄ alkyl-, (heteroaryl)C ₀ -C ₄ alkyl-; or

группу; иB' represents

group; and

R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are defined above.

Exemplary R ^P1 groups include optionally substituted phenyl, naphthyl and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance the bioavailability of compounds to patient cells and which have reduced toxicity, increased therapeutic index and increased pharmacokinetic parameters (compounds are metabolized and are released more slowly).

The thiophosphoramidate may be present at the 5' or 3' position of the furanose ring of the nucleoside compound to form a prodrug of the nucleoside compound. In one embodiment, the thiophosphoramidates can be present at both the 5' and 3' position of the furanose ring of the nucleoside compound and form a prodrug of the nucleoside compound. In another embodiment, a thiophosphoramidate located at the 5' position of the furanose ring of the nucleoside can form a cyclic thiophosphoramidate compound by bonding to a 3'-hydroxyl substituent at the 3' position of the furanose ring of the nucleoside compound and forming a prodrug form of the nucleoside compound.

Used in the context of the present invention, the term "D-configuration" refers to the main configuration, which mimics the natural configuration of sugar moieties in contrast to non-naturally occurring nucleosides or "L-configuration". The term "β" or "β-anomer" refers to nucleoside analogs in which the nucleoside base is configured (located) above the plane of the furanose moiety in the nucleoside analog.

The terms "co-administration" and "co-administration" or "combination therapy" are used to describe the administration of at least one of the 2'-substituted-N ⁶ -substituted purine nucleotide compounds of the present invention in combination with at least one other active agent, for example, where appropriate with at least one additional agent against an RNA virus, including other 2'-substituted-N ⁶ -substituted purine nucleotide agents, as disclosed herein. The timing of co-administration is best determined by the healthcare professional treating the patient. Sometimes it is preferable to administer the funds at the same time. Alternatively, the drugs selected for combination therapy may be administered to the patient at different time points. Of course, when more than one viral or other infection or other condition is present, the compounds of the present invention may be combined with other agents for the treatment of such other infection or condition, if necessary.

As used herein, the term "host" refers to a unicellular or multicellular organism in which an RNA virus can replicate, including cell lines and animals, and typically humans. The term "host" specifically refers to infected cells, cells transfected with the entire genome of the RNA virus or a portion thereof, as well as animals, in particular primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. However, in some cases, the present invention explicitly provides for veterinary applications (for example, for chimpanzees). The owner may be, for example, a bull, a horse, a bird, a dog, a cat, etc.

Isotopic substitution

The present invention includes the use of compounds with the desired isotopic substitutions of atoms in amounts above the natural abundance of the isotope, ie enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. As a general example and without limitation, isotopes of hydrogen, such as deuterium ( ² H) and tritium ( ³ H), can be used anywhere in the described structures. Alternatively or in addition, isotopes of carbon, such as ¹³ C and ¹⁴ C, can be used. A typical isotopic substitution is deuterium with hydrogen at one or more positions on the molecule to improve drug performance. Deuterium can be bound at the bond breaking position during metabolism (α-deuterium kinetic isotope effect) or near or near the bond breaking site (β-deuterium kinetic isotope effect). Achillion Pharmaceuticals Inc. (WO/2014/169278 and WO/2014/169280) describes the deuteration of nucleotides to improve their pharmacokinetics or pharmacodynamics, including at the 5 position of the molecule.

Substitution with isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage regimens. Substitution of deuterium for hydrogen at the site of metabolic decay can reduce the rate or eliminate metabolism in such a connection. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including protium ( ¹ H), deuterium ( ² H), and tritium ( ³ H). Thus, reference in the present invention to a compound encompasses all possible isotopic forms unless the context clearly indicates otherwise.

The term "isotopically labeled" analog refers to an analog that is "deuterated analog", " ¹³ C-labeled analog" or "deuterated/ ¹³ C-labeled analog". The term "deuterated analog" means a compound described in the present invention in which the H-isotope, ie, hydrogen/protium ( ¹ H), is replaced by the H-isotope, ie, deuterium ( ² H). Substitution with deuterium can be partial or complete. Partial substitution with deuterium means that at least one hydrogen is replaced by at least one deuterium. In some embodiments, the isotope is 90%, 95%, 96%, 97%, 98%, or 99% or more enriched in the isotope at any position of interest. In some embodiments, it is deuterium that is 90%, 95%, 96%, 97%, 98%, or 99% enriched at the desired position. Unless otherwise noted, deuteration is at least 80% at the selected position. The deuteration of the nucleoside can take place with any replacement hydrogen, which provides the desired results.

III. Methods of treatment or prevention

The treatment used herein refers to the administration of the active compound to a host that is infected with an RNA virus, such as a human.

As used herein, the term "prophylactic" or "preventative" refers to the administration of an active compound to prevent or reduce the occurrence of a viral disorder. The present invention provides for both treatment and prophylactic or preventative therapeutic agents. In one embodiment, the active compound is administered to a host that has been exposed to an RNA virus and is thereby at risk of contracting an RNA virus infection.

The present invention relates to a method of treating or preventing a disease caused by an RNA virus, including drug-resistant and multidrug-resistant forms of an RNA virus, and related disease conditions, conditions or complications of an RNA virus infection, as well as other conditions. that are secondary to RNA virus infection, such as weakness, loss of appetite, weight loss, breast enlargement (especially in men), rash (especially on the palms), difficulty with blood clotting, cobwebbed blood vessels on the skin, confusion consciousness, coma (encephalopathy), fluid buildup in the abdomen (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, decreased blood cells, anemia, thrombocytopenia, jaundice, and hepatic cell carcinoma, among others. The method includes administering to a host in need thereof an effective amount of at least one 2'-substituted-N ⁶ -substituted purine nucleotide described herein, optionally in combination with at least one additional bioactive agent, e.g., an additional anti-RNA agent. -virus, optionally in combination with a pharmaceutically acceptable carrier, additive and/or adjuvant.

According to a further aspect, the present invention relates to a method for preventing or preventing an RNA virus infection, or disease state, or a related or subsequent disease state, condition, or complication of an RNA virus infection, including hepatotoxicities, weakness, anorexia, weight loss, gain breast (especially in men), rashes (especially on the palms), difficulty with blood clotting, spidery blood vessels on the skin, confusion, coma (encephalopathy), fluid buildup in the abdomen (ascites), esophageal varices, portal hypertension , renal failure, enlarged spleen, decreased blood cells, anemia, thrombocytopenia, jaundice, and hepatocellular (liver) cancer, among others, said method comprising administering to a patient at risk an effective amount of at least one compound of the present invention described above, in combination with a pharmaceutically acceptable with a carrier, additive or adjuvant, optionally in combination with another anti-RNA virus agent.

The 5'-stabilized 2'-substituted-N ⁶ -substituted purine nucleotide may be administered, if desired, in the form of any salt or prodrug which, when administered to the recipient, is capable of providing the parent compound directly or indirectly, or which exhibits activity. Non-limiting examples are pharmaceutically acceptable salts and a compound that has been modified at a functional group such as a hydroxyl or amine functional group to modify biological activity, pharmacokinetic parameters, half-life, controlled delivery, lipophilicity, absorption kinetic parameters, ease of phosphorylation to an active 5' -triphosphate or delivery efficiency using the desired route of administration of the compound. Methods for modifying the properties of the active compound to achieve the desired properties are known to those skilled in the art or can be easily determined by standard methods, for example, acylation, phosphorylation, thiophosphoramidation, phosphoramidation, phosphonation, alkylation, or PEGylation.

In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus.

In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus.

In one embodiment, the active compound is administered to a host that is infected with a negative-sense RNA virus.

In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Amalgaviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Birnaviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Chrysoviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Cystoviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Endornaviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Hypoviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Megabirnaviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Partitiviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Picobirnaviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Quadriviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Reoviridae family. In one embodiment, the active compound is administered to a host that is infected with a double-stranded RNA virus from the Totiviridae family.

In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the order Nidovirales. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the order Picornavirales. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the order Tymovirales. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Arteviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Coronaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Mesoniviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Roniviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Dicistroviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Ifaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Marnaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Picornaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Secoviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Alphaflexiviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Betaflexiviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Gammaflexiviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Tymoviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Alphatetraviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Alvernaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Astroviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Barnaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Benyviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Bromoviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Caliciviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Carmotetraviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Closteroviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Fusariviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Hepeviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Leviviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Luteoviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Narnaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Nodaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Permutotetraviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Potyviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Togaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Tombusviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Virgaviridae family. In one embodiment, the active compound is administered to a host that is infected with a positive-sense RNA virus from the Flavivirus and Pestivirus genera of the Flaviviridae family.

In one embodiment, the Flavivirus infection is dengue fever. In a further embodiment, dengue fever is caused by dengue fever virus type 1, type 2, type 3, or type 4. In one embodiment, the Flavivirus infection is West Nile fever. In one embodiment, the Flavivirus infection is yellow fever. In one embodiment, the Flavivirus infection is caused by the Zika virus. In one embodiment, the Pestivirus infection is BVDV.

In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the order Mononegavirales. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Bornaviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Filoviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Paramyxoviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Rhabdoviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Nyamiviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Arenaviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Bunyaviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Ophioviridae family. In one embodiment, the active compound is administered to a host that is infected with a negative-sense ssRNA virus from the Orthomyxoviridae family.

In one embodiment, the active compound is administered to a host that is infected with a virus that causes Born's disease. In one embodiment, the active compound is administered to a host that is infected with the Ebola virus. In one embodiment, the active compound is administered to a host that is infected with a Marburg disease virus. In one embodiment, the active compound is administered to a host that is infected with the measles virus. In one embodiment, the active compound is administered to a host that is infected with the mumps virus. In one embodiment, the active compound is administered to a host that is infected with the Nipah virus. In one embodiment, the active compound is administered to a host that is infected with Hendra virus. In one embodiment, the active compound is administered to a host that is infected with Newcastle disease virus (NDV). In one embodiment, the active compound is administered to a host that is infected with Rhabdoviridae. In one embodiment, the active compound is administered to a host that is infected with the rabies virus. In one embodiment, the active compound is administered to a host that is infected with Nyamiviridae. In one embodiment, the active compound is administered to a host that is infected with a niavirus. In one embodiment, the active compound is administered to a host that is infected with Arenaviridae. In one embodiment, the active compound is administered to a host that is infected with the Lassa virus.

In one embodiment, the active compound is administered to a host that is infected with Bunyaviridae. In one embodiment, the active compound is administered to a host that is infected with hantavirus. In one embodiment, the active compound is administered to a host that is infected with Crimean Congo hemorrhagic fever. In one embodiment, the active compound is administered to a host that is infected with Ophioviridae. In one embodiment, the active compound is administered to a host that is infected with Orthomyxoviridae. In one embodiment, the active compound is administered to a host that is infected with an influenza virus. In one embodiment, the active compound is administered to a host that is infected with Kosaki B virus subtype 5.

IV. Pharmaceutical compositions

According to an aspect of the present invention, the pharmaceutical compositions of the present invention comprise an effective against RNA virus amount of at least one of the 5'-stabilized 2'-substituted-N ⁶ -substituted purine nucleotide compounds described herein, optionally in combination with a pharmaceutical an acceptable carrier, additive or adjuvant, further optionally in combination or in alternation with at least one other active compound. In some embodiments, the virus causing the infection to be treated is other than Hepacivirus or other than HCV.

According to an aspect of the present invention, the pharmaceutical compositions of the present invention comprise an effective against RNA virus amount of at least one of the active 2'-substituted-N ⁶ -substituted purine nucleotide compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, an additive or adjuvant, further optionally in combination with at least one other antiviral agent, such as an anti-RNA virus agent.

The present invention includes pharmaceutical compositions which contain an effective amount for the treatment of a disease caused by an RNA virus infection of one of the 2'-substituted-N ⁶ -substituted purine nucleotide compounds of the present invention, or a salt or prodrug thereof, in a pharmaceutically acceptable carrier. or an aid. In an alternative embodiment, the present invention includes pharmaceutical compositions which comprise an effective amount of one of the 2'-substituted-N ⁶ -substituted purine nucleotide compounds of the present invention, or a salt or prodrug thereof, in a pharmaceutically acceptable carrier to prevent infection of an RNA virus. or an aid.

One skilled in the art will appreciate that a therapeutically effective amount will vary depending on the infection or condition being treated, its severity, the treatment regimen used, the pharmacokinetic parameters of the agent used, and the patient or subject (animal or human) being treated, and such a therapeutic amount may be determined by the attending physician or specialist. In one embodiment, the patient is a human.

The 5'-stabilized 2'-substituted-N ⁶ -substituted purine nucleotide compounds of the present invention may be formulated in admixture with a pharmaceutically acceptable carrier. In general, the pharmaceutical composition is usually administered in an orally administered form, but some formulations may be administered by parenteral, intravenous, intramuscular, topical, transdermal, buccal, subcutaneous, suppository, or other route, including intranasal aerosol. Intravenous and intramuscular formulations are often administered in sterile saline. One of ordinary skill in the art will be able to modify the formulations to make them more soluble in water or other carrier medium, for example, this can easily be achieved with minor modifications (salt composition, esterification, etc.) that are well known to one of ordinary skill in the art. . In addition, it is known to those skilled in the art how to modify the route of administration and dosing regimen of a particular compound in order to control the pharmacokinetic parameters of the compounds of the present invention in order to achieve maximum benefit in patients.

In some pharmaceutical dosage forms, the prodrug form of the compounds is typical, especially including acylated (acetylated or otherwise) and ether (alkyl and related) derivatives, phosphate esters, thiophosphoramidates, phosphoramidates, and various salt forms of the compounds of the present invention. One of ordinary skill in the art will recognize how easily the compounds of the present invention can be modified into prodrug forms to facilitate delivery of the active compounds to the target site in the host or patient. Rutiner will also take advantage of the favorable pharmacokinetic parameters of the prodrugs when needed to deliver the compounds of the present invention to a target site in the host or patient to maximize the intended effect of the compound.

The amount of a compound contained in therapeutically active compositions of the present invention refers to an effective amount to treat an RNA virus infection, reduce the likelihood of an RNA virus infection, or inhibit, reduce and/or eliminate the RNA virus or its secondary effects, including disease states, conditions and/or complications that are secondary to RNA virus infection. In general, a therapeutically effective amount of a compound of the present invention in a pharmaceutical dosage form will typically range from about 0.001 mg/kg to about 100 mg/kg per day or more, more commonly from slightly less than about 0.1 mg/kg to more than about 25 mg/kg patient weight per day, or significantly more, depending on the compound used, the condition or infection being treated, and the route of administration. The active nucleoside compound of the present invention is often administered to a patient in amounts ranging from about 0.1 mg/kg to about 15 mg/kg per day, depending on the pharmacokinetic parameters of the agent in the patient. This dosage range generally provides effective blood concentration levels of the active compound, which can range from about 0.001 to about 100, from about 0.05 to about 100 micrograms/cm ^{3 of} blood in a patient.

Often, in order to treat, prevent, or slow the onset of these infections and/or to reduce the likelihood of an RNA virus infection or a secondary disease condition, condition, or complication of an RNA virus infection, the compositions will be administered in oral dosage form, in amounts ranging from about 250 micrograms to about 500 mg or more at least once a day, for example at least 25, 50, 100, 150, 250 or 500 milligrams up to four times a day. Compounds of the present invention are often administered orally, but may be administered parenterally, topically or in the form of a suppository, as well as intranasally, in the form of a nasal spray, or otherwise described herein.

In the case of co-administration of the compounds of the present invention in combination with another compound against an RNA virus, as otherwise described herein, the amount of the compound of the present invention to be administered to a patient varies from about 0.01 mg/kg to about 500 mg/kg or more, or significantly more depending on the second agent to be co-administered and its effectiveness against the virus, the patient's condition and the severity of the disease or infection being treated, and the route of administration. Another RNA virus agent, for example, may be administered in amounts ranging from about 0.01 mg/kg to about 500 mg/kg. In some embodiments, these compounds can often be administered in amounts ranging from about 0.5 mg/kg to about 50 mg/kg or more (typically up to about 100 mg/kg), generally depending on the pharmacokinetic parameters of the two agents. at the patient. Such a dosage range will generally give effective blood levels of the active compound in the patient.

For the purposes of the present invention, the prophylactic or prophylactic effective amount of the compositions of the present invention falls within the same concentration range as indicated above for a therapeutically effective amount, and is generally the same as for a therapeutically effective amount.

Administration of the active compound may vary from continuous intravenous drip to multiple oral or intranasal administrations per day (e.g. four times a day) or transdermal administration and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), buccal, and suppository administration, among other routes of administration. Enteric-coated oral tablets can also be used to increase the bioavailability of compounds by the oral route. The most effective dosage form will depend on the bioavailability/pharmacokinetic parameters of the particular agent chosen, as well as the severity of the disease in the patient. Oral dosage forms are particularly characteristic due to ease of administration and expected patient compliance.

To prepare pharmaceutical compositions in accordance with the present invention, a therapeutically effective amount of one or more compounds in accordance with the present invention is often intimately mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical formulation techniques to obtain a dose. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral. When preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives may be used, including, but not limited to, water, glycols, oils, alcohols, flavors, preservatives, coloring agents. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives may be used, including, without limitation, starches, sugar carriers such as dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrators. If necessary, tablets or capsules can be provided with an enteric coating or sustained release using standard techniques. The use of such dosage forms can significantly increase the bioavailability of the compounds in a patient.

For parenteral formulations, the carrier will typically contain sterile water or an aqueous sodium chloride solution, although other ingredients, including those that provide dispersion, may also be included. Of course, if sterile water is to be used and sterility is maintained, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, and the like may be used.

Liposomal suspensions (including liposomes targeted to viral antigens) can also be prepared by conventional methods to provide pharmaceutically acceptable carriers. This may be suitable for the delivery of free nucleosides, acyl/alkyl nucleosides or phosphate ester prodrugs of nucleoside compounds in accordance with the present invention.

In exemplary embodiments of the present invention, the compounds and compositions are used to treat, prevent, or delay an RNA virus infection or a secondary disease condition, condition, or complication of an RNA virus infection.

V. Combination and alternative therapy

It is well known that drug-resistant variants of viruses can occur after long-term treatment with an antiviral agent. Drug resistance most often results from a mutation in a gene that codes for an enzyme used in viral replication. The efficacy of a drug against RNA virus infection can be prolonged, enhanced or restored by administering the compound in combination or alternating with another and possibly even two or three other antiviral compounds that induce a different mutation or act in a different pathway than main drug. Alternatively, the pharmacokinetic parameters, biodistribution, half-life or other parameter of the drug may be altered by such combination therapy (which may include alternating therapy if deemed consensual). Since the disclosed 2'-substituted-N ⁶ -substituted purine nucleotides are polymerase inhibitors, they may be useful for administering the compound to a host in combination with, for example,

(1) a protease inhibitor such as an NS3/4A protease inhibitor;

(2) an NS5A inhibitor;

(3) another polymerase inhibitor;

(4) a non-substrate NS5B inhibitor;

(5) interferon alfa-2a, which may be PEGylated or otherwise modified, and/or ribavirin;

(6) a non-substrate inhibitor;

(7) a helicase inhibitor;

(8) antisense oligodeoxynucleotide (S-ODN);

(9) aptamer;

(10) nuclease-resistant ribozyme;

(11) iRNA, including miRNA and SiRNA;

(12) an antibody, partial antibody, or domain antibody against a virus, or

(13) a viral antigen or partial antigen that induces an antibody response in the host.

The drugs currently approved for influenza are amantadine, rimantadine, oseltamivir and Rapivab®. Any of these drugs can be used in combination or in alternation with the active compound provided herein for the treatment of a viral infection susceptible to it. Ribavirin is useful in the treatment of measles, influenza A, influenza B, parainfluenza, severe RSV-induced bronchiolitis and SARS, as well as other viral infections, and is therefore particularly useful in combination with a compound of the present invention for the treatment of a host infected with a single-stranded RNA virus. .

There are currently no approved drugs for West Nile virus. Physicians are advised to provide intensive supportive care, which may include hospitalization, intravenous fluids, a ventilator to help with breathing, medications to control seizures, brain swelling, nausea, and vomiting, and antibiotics to prevent bacterial infections that lead to to more severe illness. This highlights the importance of the compounds of the present invention for antiviral drug therapy.

In addition, there is no vaccine or specific treatment for the Zika virus. Instead, the focus is on symptom relief, which includes rest, rehydration, and acetaminophen for fever and pain.

There is also no vaccine or specific treatment for dengue fever. Maintenance cases for those infected include fluid replacement and analgesics, as well as acetaminophen, aspirin, and non-steroidal anti-inflammatory drugs to treat fever and other symptoms.

Yellow fever vaccine (YF-Vax) is manufactured by Sanofi Pasteur, Inc. and is recommended for persons aged 9 years and over who travel to high-risk areas, including South America and Africa. In one embodiment, a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI is administered to the host in combination with YF-Vax. There is no cure for yellow fever, but the focus is on relieving fever, muscle pain, and dehydration. Due to the risk of internal bleeding, aspirin and non-steroidal anti-inflammatory drugs are not recommended.

VI. The method of obtaining 2'-substituted-2-N ⁶ -substituted purine nucleotides according to the present invention

General methods for preparing the compounds of the present invention are known in the art or described in the present invention. The synthesis of 2'-chloronucleotides is described in US Patent Application No. 20150366888, WO 2014058801, WO 2015/066370 and WO 2015200219.

The following abbreviations were used in the synthesis schemes.

n-BuLi: n-butyllithium

BSA: N,O-bis(trimethylsilyl)acetamide

CBr ₄ : carbon tetrabromide

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DAST: diethylaminosulfur trifluoride

DCM: dichloromethane

DIEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

EA: ethyl acetate

EtOAc: ethyl acetate

EtOH: ethanol

Et ₃ N: triethylamine

Na ₂ SO ₄ : sodium sulfate (anhydrous)

MeCN: acetonitrile

MeNH ₂ : methylamine

MeOH: methanol

NaOH: sodium hydroxide

Na ₂ SO ₄ : sodium sulfate

Na ₂ S ₂ O ₃ : sodium thiosulfate

NaHCO ₃ : sodium bicarbonate

NH ₄ Cl: ammonium chloride

NH ₄ OH: ammonium hydroxide

NLT: no less than

PE: petroleum ether

Ph ₃ P: triphenylphosphine

pTSA H ₂ O: para-toluenesulfonic acid monohydrate

k.t.: room temperature

silica gel (230-400 mesh, sorbent)

TBAF: tetrabutylammonium fluoride

THF: tetrahyrofuran (THF), anhydrous

TMSCl: chlorotrimethylsilane

TMSOTf: trimethylsilyl trifluoromethanesulfonate

TIPDSiCl ₂ : 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane

tert-BuMgCl: tert-butyl magnesium chloride

tert-BuOK: sodium tert-butoxide

tert-BuOH: tert-butanol

Examples

General methods

с преобразованием Фурье. Спектры получали из образцов, полученных в пробирках диаметром 5 мм в CDCl₃, CD₃OD или DMSO-d₆. Спиновые мультиплетности обозначали символами s (синглет), d (дублет), t (триплет), m (мультиплет) и br (широкий). Константы связи (J) описаны в Гц. MS спектры получали с применением ионизации электрораспылением (ESI) на приборе Agilent Technologies 6120 с квадрупольной масс-спектрометрией. Реакции обычно проводили в атмосфере сухого азота с применением безводных растворителей Sigma-Aldrich. Все традиционные химические вещества покупали у коммерческих источников. ¹ H, ¹⁹ F, and ³¹ P NMR spectra were recorded on a 300 MHz spectrometer

with Fourier transform. Spectra were obtained from samples obtained in test tubes with a diameter of 5 mm in CDCl ₃ , CD ₃ OD or DMSO-d ₆ . Spin multiplicities were denoted by symbols s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Coupling constants (J) are described in Hz. MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 instrument with quadrupole mass spectrometry. Reactions were typically carried out under dry nitrogen using anhydrous Sigma-Aldrich solvents. All conventional chemicals were purchased from commercial sources.

Preparation of stereospecific phosphorus enantiomers

Certain active compounds described in the present invention contain a chiral phosphorus moiety. Any of the active compounds described in the present invention may be provided as an isolated phosphorus enantiomeric form, for example, at least 80%, 90%, 95%, 96%, 97% or 98% of the R or S enantiomer, using methods known to the person skilled in the art. For example, there are many publications that describe how to obtain such compounds, including without limitation column chromatography, for example, as described in US patent No. 8859756; 8642756 and 8333309 Ross, et al.

Example 1 Modification of the 2-amino moiety in Active Compounds

One skilled in the art can add a substituent to the 2-aminopurine moiety by methods well known to those skilled in the art. One non-limiting method is presented in the present description, and others can be easily adapted. ((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetragyrofuran-2-yl)methylbenzoate was treated with commercially available 2,6-dichloropurine, base and a mixture of organic solvents at elevated temperature to form (2R,3R,4R,5R)-5-(2,6-dichloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fotr-4-methyl-tetrahyrofuran-3-ylbenzoate . In one embodiment, the base is potassium t-butoxide. According to one embodiment, the mixture of organic solvents includes tert-butanol and acetonitrile. Compound (2R,3R,4R,5R)-5-(2,6-dichloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahyrofuran-3-ylbenzoate was treated with amine, base and an organic solvent at ambient temperature to give 2-chloro-N ⁶ -substituted purines. In one embodiment, the amine is methylamine. In one embodiment, the base is triethylamine. According to one embodiment, the organic solvent is ethanol. One skilled in the art will also recognize that upon treatment with an amine and a base, the benzoate groups on the nucleoside will be simultaneously removed to form an unprotected furanose moiety. The 2-Chloro-N ⁶ -substituted purines can then be treated with an amine and an organic solvent in a stoppered tube at an elevated temperature of approximately 100° C. to form the N ² ,N ⁶ -disubstituted purine nucleosides of the present invention. In one embodiment, the amine is methylamine. According to one embodiment, the organic solvent is ethanol. The N ² ,N ⁶ -disubstituted purine nucleosides of the present invention can be treated with base, isopropyl ((R,S)-(pentafluorophenoxy)-phenoxyphosphoryl)-L-alaninate and an organic solvent at reduced temperature to form compounds of formulas I-VI. In one embodiment, the base is tert-butyl magnesium chloride. In one embodiment, the organic solvent is tetrahydrofuran.

Example 2: Getting PPAL-S

Stage 1. Obtaining racemic PPAL

To a stirred solution of phenyl dichlorophosphate (250 g) in EtOAc (800 ml) was added isopropyl-L-alaninate (200 g) in triethylamine (120 g) at -10°C. The reaction mixture was stirred at -10°C for 1 h. 5°C for 0.5 h. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 2 h. The solution was filtered, washed with EtOAc (2×200 ml) and the combined organic phases were evaporated under vacuum to obtain a solid PPAL-RS compounds (racemate).

Stage 2. Obtaining PPAL-RS

To a stirred solution of PPAL-RS in EtOAc (200 ml) and n-heptane (1.4 L) was added 2,3,4,5,6-pentafluorophenol (10.1 g) in triethylamine (6 g) and the reaction mixture was stirred approximately 4-8 hours. After the R-isomer of the solid was less than 0.5% of the reaction mixture, the solid was filtered. The solid was dissolved in EtOAc (4 L), washed with water (2×100 ml), brine (1 L), dried over anhydrous Na ₂ SO ₄ and filtered. The solvent was removed under vacuum to give compound PPAL-S (350 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.42-7.40 (m, 2H), 7.24-7.22 (m, 3H), 6.87 (dd, J=14.1, 9.9 Hz, 1H), 4.90-4.84 ( m, 1H), 3.94-3.88 (m, 1H), 1.27 (dd, J=7.1, 1.1 Hz, 3H), 1.15 (dd, J=6.2, 1.2 Hz, 6H) ppm. ¹³ P NMR (160 MHz, DMSO-d ₆ ) δ=0.37 ppm.

Example 3 Preparation of PPAL-R Compound

Phenyl dichlorophosphate (189.6 g, 0.90 mol) and anhydrous EtOAc (750 mL) were added to a three neck round bottom flask equipped with a mechanical stirrer. The solution was cooled to -10° C. under nitrogen. Isopropyl-L-alaninate (118 g, 0.90 mmol) and triethylamine (100 g, 1.1 eq.) were added to the above solution. A pre-chilled (below 10°C) mixture of 2,3,4,5,6-pentafluorophenol (165 g, 1 eq.) and triethylamine (90.5 g, 1 eq.) in EtOAc (300 mL) was added to the mixture at using an addition funnel at -5°C and the resulting mixture was stirred at 20-25°C for 1 hour. The white precipitate (TEA⋅HCl) was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure to give PPAL-RS compound (ca. 280 g (S/R=1/1)) as a white solid. Compound PPAL-RS (280 g) was triturated in 300 ml heptane/EtOAc (20:1) at room temperature for 5 minutes. The white suspension was filtered and the solid washed with heptane/EtOAc (20:1). The filtrate was cooled to 8°C and the solid was collected by filtration. The crude compound PPAL-R (10 g) was obtained with 95% chiral purity. The crude product was purified based on the above step. Connection PPAL-R (5 g) was obtained with no less than 98% chiral purity.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.43-7.39 (m, 2H), 7.27-7.22 (m, 3H), 6.87 (dd, J=14.1, 9.9 Hz, 1H), 4.89-4.85 ( m, 1H), 3.95-3.90 (m, 1H), 1.27 (dd, J=7.1, 1.1 Hz, 3H), 1.14 (dd, J=6.2, 1.2 Hz, 6H). ¹³ R NMR (160 MHz, DMSO-d ₆ ) δ=0.35.

Stereospecific synthesis of compounds of formulas I-IV

Synthesis of β-D-2'-deoxy-2'-α-for-2'-β-ethynyl-N ⁶ -substituted-2,6-diaminopurine nucleotides

Example 4 General Pathway for β-D-2'-deoxy-2'-α-fluoro-2'-β-ethynyl-N ⁶ -substituted-2,6-diaminopurine nucleotides

Stage 1. Preparation of compound 8.

To a solution of 6-chloroguanosine (100 g, 332 mmol) in pyridine (400 ml) was added dropwise TIPDSiCl ₂ (110 ml, 1.05 eq.) at -5~5°C under N ₂ atmosphere. After stirring at -5~5°C for 2 hours, consumption of starting material was observed by TLC. DCM (600 ml) was added and TMSCl (85 ml, 2 equiv.) was added dropwise at 0-5°C. After stirring at 0-5° C. for 2 hours, consumption of the intermediate was observed by TLC. Isobutyryl chloride was added dropwise at 0-5°C. After stirring at 0-5° C. for 2 hours, consumption of the intermediate was observed by TLC. Water was added and the contents were extracted with DCM. The organic phase was washed with 0.5 N HCl to remove the pyridine. The pH value of the contents was washed to 5~6 and para-TSA⋅H ₂ O (9.2 g, 484.5 mmol) was added at 0-5°C. After stirring at 0-5° C. for 1 hour, consumption of the intermediate was observed by TLC. Water was added and the organic phase was washed with water, saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The residue was purified by column chromatography (PE/EA=100->10/1) to give a light yellow solid (82 g, 40%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.55 (s, 1H), 5.91 (d, 7=1.6 Hz, 1H), 5.53 (d, J=4.6 Hz, 1H) , 4.72-4.58 (m, 2Н), 4.16 (dd, J=12.4, 4.8 Hz, 1H), 4.00 (ddd, J=7.7, 4.8, 2.6 Hz, 1H), 3.93 (dd, J=12.4, 2.7 Hz , 1H), 2.78 (h, J=6.9 Hz, 1H), 1.26-1.12 (m, 3Н), 1.10 (d, J=6.7 Hz, 6Н), 1.09-0.88 (m, 24Н).

Stage 2. Preparation of compound 9.

To a solution of compound 8 (10.0 g, 16.3 mmol) in DCM (100 ml) was added Dess-Martin periodinan at rt and the reaction mixture was stirred for 12 h. Using TLC, consumption of the starting material was observed. The reaction mixture was then diluted with DCM (200 ml) and washed with saturated aqueous Na ₂ S ₂ O ₃ and brine. The organic phase was then dried over Na ₂ SO ₄ and concentrated to give the crude compound 9 as a light yellow solid (12 g). The crude product can be used directly in the next step without purification.

Step 3: Preparation of compound 10.

To a solution of ethynyltrimethylsilane (18.6 ml, 142.7 mmol) in THF (240 ml) was added n-BuLi (46 ml, 2.5 M, 115.0 mmol) dropwise at -15~20°C under N ₂ . After stirring for 30 min, the reaction mixture was cooled to -70°C and compound 9 (crude, 16.3 mmol) in THF (60 ml) was added at 15~20°C. The contents were then heated to 0°C. Using TLC, consumption of the starting material was observed. Added saturated aqueous NH ₄ Cl and the reaction mixture was extracted with EA (100 ml) three times. The organic phase was combined, washed with saline and additionally dried over Na ₂ SO ₄ . After concentration in vacuo, the residue was purified by column chromatography (PE/EA=100->10/1) to give a light yellow solid (6.0 g, 52%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 8.07 (s, 1H), 6.18 (s, 1H), 4.42 (d, J=7.2 Hz, 1H), 4.21-4.02 (m, 3Н), 2.94 (d, J=8.5 Hz, 1H), 1.25 (t, J=8.8 Hz, 3Н), 1.12-1.01 (m, 30H), 0.17 (d, J=1.4 Hz, 9Н).

Step 4 Preparation of Compound 11

To a solution of compound 10 (6.0 g, 8.4 mmol) in DCM (240 ml) was added pyridine (4.2 ml, 52.9 mmol) under N ₂ atmosphere. The reaction mixture was cooled to -70° C. and DAST (12 ml, 90.4 mmol) was added. The contents were then heated to -30°C. Using TLC, consumption of the starting material was observed. The reaction mixture was poured into saturated aqueous NaHCO ₃ and then extracted with DCM (200 ml). The organic phase was washed with saline and dried over Na ₂ SO ₄ . After concentration in vacuo, the residue was purified by column chromatography (PE/EA=100->10/1) to give a light yellow solid (3.8 g, 63%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.37 (s, 1H), 6.24 (s, 1H), 5.98 (s, 2H), 5.32 (s, 1H), 4.44 (d, J=8.0 Hz, 1H), 4.23-4.07 (m, 4H), 2.91 (m, 1H) 1.32-1.27 (m, 10 H), 1.13-1.06 (m, 24H), 0.23 (s, 9H).

Step 5: Preparation of Compound 12.

To a solution of compound 11 (3.8 g, 5.3 mmol) in THF (120 ml) was added AcOH (1.3 g, 22 mmol) and TBAF (4.2 g, 15.9 mmol) at r.t. The reaction mixture was stirred at room temperature for 30 min. Using TLC, consumption of the starting material was observed. After concentration in vacuo, the residue was purified by column chromatography (EA) to give the product as a white solid (2.0 g, 95%).

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 8.75 (s, 1H), 6.57 (d, J=16.4 Hz, 1H), 4.99 (dd, J=21.7, 9.3 Hz, 1H), 4.14-3.95 ( m, 2Н), 3.91 (dd, J=12.8, 3.8 Hz, 1H), 3.14 (d, J=5.3 Hz, 1H), 2.81 (dt, J=13.7, 6.8 Hz, 1H), 1.22 (dd, J =6.9, 3.1 Hz, 6H).

The general way to replace and deprotect aminos is:

To a solution of compound 12 (350 mg, 0.88 mmol) in dioxane (20 ml) was added a methanolic or aqueous solution of the appropriate amine (free base or salt as hydrochloride plus DIEA) at rt. within 1-12 hours Using TLC observed the consumption of the original substance. After concentration in vacuo, the residue was used immediately in the next step without purification. The residue was dissolved in methanol (10 ml) and aqueous NaOH (2.5 N, 10 ml) was added. After stirring overnight at rt, consumption of starting material was observed by TLC. The pH value of the contents was adjusted to 7-8 with 1 N HCl. The solution was concentrated and purified by column chromatography (DCM/MeOH=100->20/1) to give the product as an off-white solid (yield: 40-80% over two steps). Table 1 shows the structures of compounds 1, 3 and 5 and the corresponding mass spectra and ¹ H NMR for the respective compounds.

Example 5 Synthesis of 6-N-alkylnucleoside pronucleotides

Preparation of (2S)-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin-9-yl)-4-ethynyl-4 -fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (2).

To a solution of compound 1 (30 mg, 0.09 mmol) in dry THF (2.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (125 μl, 0.13 mmol) at 0°C. The solution was stirred for 15 minutes at 0° C. and for 45 minutes at room temperature (RT). The reaction mixture was cooled to 0° C. and a solution of isopropyl ((R,S)-(pentafluorophenoxy)-phenoxyphosphoryl)-L-alaninate (49 mg, 0.11 mmol) in dry THF (1.0 ml) was added dropwise. The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was then diluted with EtOAc (10 ml) and saturated vaughn. NH ₄ Cl solution (8 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×5 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 2 (12 mg, 22%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.79 (s, 0.5H), 7.77 (s, 0.5H), 7.36-7.14 (m, 5H), 6.28 (d, J=17.4 Hz) and 6.26 (d , J=17.5 Hz, 1H), 5.00-4.44 (m, 5H), 4.23-4.16 (m, 1H), 3.69-3.81 (m, 1H), 3.42 (bs, 3H), 3.40 (bs, 3H), 1.32-1.26 (m, 3H), 1.20-1.15 (m, 6H). ³¹ Р NMR (121 MHz, CD ₃ OD) δ 4.04 (s), 3.98 (s). MS (ESI) m/z calc. for C ₂₆ H ₃₄ FN ₇ O ₇ P [M+H] ⁺ 606.2; received 606.2.

Preparation of (2S)-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-ethynyl-4 -fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-amino)propanoate (4).

To a solution of compound 3 (30 mg, 0.09 mmol) in dry THF (2.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (112 μl, 0.11 mmol) at 0°C. The solution was stirred for 15 min at 0°C and for 45 min at r.t. (51 mg, 0.11 mmol) in dry THF (1.0 ml). The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was then diluted with EtOAc (10 mL) and saturated aq. NH ₄ Cl solution (8 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×5 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 4 (9 mg, 16%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.81, 7.79 (s+s, 1H), 7.36-7.14 (m, 5H), 6.26 (d, J=17.4 Hz, 0.1H), 6.24 (d, J =17.4 Hz, 0.9H), 4.93-4.89 (overlapped by H ₂ O, m, 1H), 4.80-4.78 (m, 1H), 4.53-4.49 (m, 2H), 4.21-4.18 (m, 1H), 3.95 -3.84 (m, 1H), 3.23-3.20 (m, 1H), 3.04 (bs, 1H), 1.31-1.14 (m, 9H). ³¹ Р NMR (121 MHz, CD ₃ OD) δ 4.06 (s), 3.97 (s). MS (ESI) m/z calc. for C ₂₅ H ₃₂ FN ₇ O ₇ P [M+H] ⁺ 592.2; received 592.2.

Preparation of (2S))-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)-4-ethynyl- 4-fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (6).

To a solution of compound 5 (30 mg, 0.09 mmol) in dry THF (3.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (120 μl, 0.12 mmol) at 0°C. The solution was stirred for 15 min at 0°C and for 45 min at r.t. (47 mg, 0.10 mmol) in dry THF (1.0 ml). The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was then diluted with EtOAc (10 mL) and saturated aq. NH ₄ Cl solution (8 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×5 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 6 (19 mg, 35%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.82, 7.79 (s+s, 1H), 7.44-7.17 (m, 5H), 6.26 (d, J=17.1 Hz), 6.24 (d, J=17.1 Hz , 1H), 4.93-4.89 (overlapped with H ₂ O, m, 1H), 4.79-4.46 (m, 3Н), 4.24-4.07 (m, 1H), 3.92-3.83 (m, 1H), , 1H), 2.92-2.89 (m, 1H), 1.31-1.14 (m, 9H), 0.85-0.82 (m, 2H), 0.63-0.57 (m, 2H). ³¹ Р NMR (121 MHz, CD ₃ OD) δ 4.03 (s), 3.94 (s). MS (ESI) m/z calc. for C ₂₇ H ₃₄ FN ₇ O ₇ P [M+H] ⁺ 618.2; received 618.2.

Example 6 Synthesis of β-D-2'-α-hydroxy-2'-β-methyl-N ⁶ -substituted-2,6-diaminopurine nucleotides

Stage 1. Preparation of compound 151.

To a pre-chilled (0°C) solution containing 1,2,3,5-tetra-O-benzoyl-2-C-methyl-D-ribofuranose, compound 150, (2.50 g, 4.3 mmol), 2-amino-6-chloropurine (0.8 g, 4.68 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.94 g, 12.75 mmol) and anhydrous acetonitrile (50 ml), trimethylsilyl triflate (3.8 g, 17.2 mmol) was added dropwise. The reaction mixture was heated at 65°C for 4 h, left to cool to room temperature, poured into saturated aqueous sodium solution (150 ml) and was extracted with dichloromethane (3×100 ml). The combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The residue was purified over silica gel using hexane/ethyl acetate (4:1) as eluent to give compound 151 (3.5 g, 73%) as a colorless foam.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.04 (ddt, J=22.8, 6.9, 1.4 Hz, 4H), 7.98-7.83 (m, 3H), 7.74-7.59 (m , 3H), 7.63-7.46 (m, 4H), 7.40 (t, J=7.8 Hz, 2H), 7.22 (s, 2H), 6.64 (s, 1H), 5.97 (d, J=4.5 Hz, 1H) , 4.92-4.75 (m, 3H), 2.90 (s, 3H), 2.74 (s, 3H), 1.61 (s, 3H).

Stage 2. Preparation of compound 152.

A solution containing compound 151 (0.65 g, 1.03 mmol) and saturated methanolic ammonia (15 ml) was stirred in a stoppered container for 7 h. The solvent was removed and the residue was purified on silica gel using methanol/DCM (1:40 ) as an eluent. Product-containing fractions were combined and concentrated in vacuo to give compound 152 (0.30 g, 92%) as a colorless powder.

Step 3 Preparation of Compound 106

To a solution containing compound 152 (0.3 g, 1.0 mmol) and 1,4-dioxane (2 ml) was added methylamine solution (1 ml). The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was purified on silica gel using methanol/DCM (1:40) as eluent. Product-containing fractions were combined and concentrated in vacuo to give compound 106 (0.150 g, 50%) as a colorless powder.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (s, 1H), 7.24 (s, 1H), 5.89 (s, 2H), 5.79 (s, 1H), 5.20 (dd, J=6.2, 3.2 Hz, 2H), 5.05 (s, 1H), 4.11 (q, J=5.2 Hz, 1H), 4.08-3.97 (m, 1H), 3.89-3.77 (m, 2H), 3.66 (ddd, J=12.2, 5.4, 3.3 Hz, 1H), 3.17 (d, J=5.3 Hz, 3H), 0.79 (s, 3H).

Step 4 Preparation of Compound 107

(2S)-Isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxy- 4-methyltetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (107).

To a solution of compound 106 (55 mg, 0.18 mmol) in dry DMF (4.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (265 μl, 0.27 mmol) at 0°C. The solution was stirred for 15 min at 0°C and for 45 min at rt. The reaction mixture was cooled to 0°C and a solution of isopropyl-((R,S)-(pentafluorophenoxy)-phenoxyphosphoryl)-L- alaninate (105 mg, 0.23 mmol) in dry THF (2.0 ml). The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was then diluted with EtOAc (15 mL) and saturated aq. NH ₄ Cl solution (10 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×10 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (15 ml) and brine (15 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 107 (23 mg, 22%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.84 (s, 1H), 7.38-7.16 (m, 5H), 5.96-5.93 (s+s, 1H), 4.97-4.90 (m, 1H), 4.63- 4.42 (m, 2H), 4.26-4.15 (m, 2H), 3.98-3.87 (m, 1H), 3.06 (s, 3H), 1.33-1.29 (m, 3H), 1.22-1.15 (m, 6H), 0.98-0.95 (s + s, 3H). ³¹ R NMR (121 MHz, CD ₃ OD) δ 4.18 (s), 4.05 (s). MS (ESI) m/z calc. for C ₂₄ H ₃₅ N ₇ O ₈ P [M+H] ⁺ 580.2; received 580.2.

Step 5 Preparation of Compound 100

To a solution containing compound 152 (0.3 g, 1.0 mmol) and 1,4-dioxane (2 ml) was added a solution of dimethylamine (1 ml). The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was purified on silica gel using methanol/DCM (1:40) as eluent. Product-containing fractions were combined and concentrated in vacuo to give compound 100 (0.200 g, 70%) as a colorless powder.

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.10 (s, 1H), 5.95 (s, 1H), 4.24 (d, J=8.7 Hz, 1H), 4.08-3.99 (m, 2H), 3.91- 3.82 (m, 1H), 3.42 (s, 6H), 3.37 (s, 2H), 0.95 (s, 3H).

Step 6 Preparation of Compound 101

(2S)-Isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin-9-yl)-3,4-dihydroxy- 4-methyltetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (101)

To a solution of compound 100 (30 mg, 0.09 mmol) in dry THF (2.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (130 μl, 0.13 mmol) at 0°C. The solution was stirred for 15 min at 0°C and for 45 min at r.t. (46 mg, 0.11 mmol) in dry THF (1.0 ml). The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was then diluted with EtOAc (10 mL) and saturated aq. NH ₄ Cl solution (8 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×5 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 101 (30 mg, 55%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.81, 7.80 (s+s, 1H), 7.37-7.15 (m, 5H), 5.97, 5.95 (s+s, 1H), 4.96-4.88 (overlapped H ₂ O, m, 1H), 4.60-4.42 (m, 2Н), 4.19-3.90 (m, 3Н), 3.41 (ls, 6Н), 1.33-1.15 (m, 10Н), 0.96, 0.93 (s+s , 3H). ³¹ R NMR (121 MHz, CD ₃ OD) δ 4.16 (s), 4.07 (s). MS (ESI) m/z calc. for C ₂₅ H ₃₇ N ₇ O ₈ P [M+H] ⁺ 594.2; received 594.2.

Example 7 Synthesis of (2S)-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(cyclopropyl(methyl)amino)-9H-purin-9-yl )-3,4-dihydroxy-4-methyltetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (103)

Step 1: Preparation of (2R,3R,4R,5R)-2-(2-amino-6-chloro-9H-purin-9-yl)-5-((benzoyloxy)methyl)-3-methyltetragyrofuran-3,4 -diyldibenzoate (151).

To a suspension of 2-amino-6-chloropurine (1.17 g, 6.90 mmol) in dry acetonitrile (100 ml) was added N,O-bis(trimethylsilyl)acetamide (2.50 ml, 10.20 mmol). The mixture was heated at reflux for 2 hours. The resulting solution was cooled to rt and compound 150 (2.00 g, 3.45 mmol) was added. The solution was cooled to 0°C and TMSOTf (1.87 ml, 10.20 mmol) was added dropwise over 2 minutes. The reaction mixture was heated at reflux for 2 h, cooled to rt and concentrated. The residue was partitioned between EtOAc (100 ml) and saturated aq. NaHCO ₃ solution (80 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×40 ml). The combined organics were washed with saturated aq. NaHCO ₃ solution (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, PE/EtOAc 10-80%). Product 151 (1.75 g, 81%) was obtained as a white foam.

Step 2. Preparation of (2R,3R,4R,5R)-2-(2-amino-6-(cyclopropyl(methyl)amino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetragyrofuran- 3,4-diols (102).

To a suspension of compound 151 (610 mg, 0.97 mmol) in MeOH (30 ml) was added N-methylcyclopropylamine hydrochloride (313 mg, 2.91 mmol) and triethylamine (410 μl, 2.91 mmol). The reaction mixture was heated at 100°C in a sealed container for 15 h and cooled to rt. Then 30% NH ₄ OH (5 ml) was added and the mixture was heated at 100°C in a sealed container for 2 h. kt and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-15%). Product 102 (245 mg, 72%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.14 (s, 1H), 5.94 (s, 1H), 4.21 (d, J=8.7 Hz, 1H), 4.02-3.98 (m, 2H), 3.83 (dd , J=3.0, 12.9 Hz, 1H), 3.31 (covered with MeOH, s, 3H), 3.16-3.09 (m, 1H), 0.93-0.90 (m, 5H), 0.72-0.69 (m, 2H). MS (ESI) m/z calc. for C ₁₅ H ₂₃ N ₆ O ₄ [M + H] ⁺ 351.2; received 351.2.

Step 3. Preparation of (2S)-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(cyclopropyl(methyl)amino)-9H-purin-9-yl )-3,4-dihydroxy-4-methyltetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (103).

To a solution of compound 102 (60 mg, 0.17 mmol) in dry THF (4.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (240 μl, 0.24 mmol) at 0°C. The solution was stirred for 15 min at 0°C and for 45 min at r.t. (85 mg, 0.19 mmol) in dry THF (1.5 ml). The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was then diluted with EtOAc (10 mL) and saturated aq. NH ₄ Cl solution (8 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×5 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (10 ml), brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 103 (51 mg, 48%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.84 (s+s, 1H), 7.35-7.15 (m, 5H), 5.98, 5.96 (s+s, 1H), 4.95-4.86 (overlapped with H ₂ O, m, 1H), 4.60-4.43 (m, 2H), 4.24-4.14 (m, 2H), 3.96-3.87 (m, 1H), 3.35.3.34 (s+s, 3H), 3.17-3.11 (m , 1H), 1.32-1.27 (m, 3Н), 1.20-1.15 (m, 6Н), 0.97-0.90 (m, 5Н), 0.73-0.69 (m, 2Н). ³¹ Р NMR (121 MHz, CD ₃ OD) δ 4.06 (s), 3.97 (s). MS (ESI) m/z calc. for C ₂₇ H ₃₉ N ₇ O ₈ P [M+H] ⁺ 620.3; received 620.2.

Example 8 Synthesis of (2S)-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)-3, 4-dihydroxy-4-methyltetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (105)

Step 1. Preparation of (2R,3R,4R,5R)-2-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetragyrofuran-3,4- diol (104).

To a suspension of compound 151 (1.00 g, 1.59 mmol) in MeOH (40 ml) was added cyclopropylamine (1.45 ml, 20.67 mmol). The reaction mixture was heated at 100°C in a sealed container for 15 h and cooled to rt. Then 30% NH ₄ OH (5 ml) was added and the mixture was heated at 100°C in a sealed container for 3 h. kt and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-20%). Product 104 (438 mg, 82%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.09 (s, 1H), 5.91 (s, 1H), 4.23 (d, J=8.7 Hz, 1H), 4.04-3.99 (m, 1H), 3.87 (dd , J=3.3, 12.6 Hz, 1H), 2.92-2.90 (m, 1H), 0.94 (s, 3H), 0.85-0.82 (m, 2H), 0.62-0.60 (m, 2H). MS (ESI) m/z calc. for C ₁₄ H ₂₁ N ₆ O ₄ [M+H] ⁺ 337.2; received 337.2.

Step 2. Preparation of (2S)-isopropyl-2-(((((2R,3R,4R,5R)-5-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)-3, 4-dihydroxy-4-methyltetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (105).

To a solution of compound 104 (104 mg, 0.31 mmol) in dry THF (6.0 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (430 μl, 0.43 mmol) at 0°C. The solution was stirred for 15 min at 0°C and for 45 min at rt. Then the reaction mixture was cooled to 0°C and a solution of isopropyl ((R,S)-(pentafluorophenoxy)-phenoxyphosphoryl)-L- alaninate (154 mg, 0.34 mmol) in dry THF (2.5 ml). The resulting solution was slowly warmed to rt and stirred for 15 h. The reaction mixture was diluted with EtOAc (20 ml) and saturated aq. NH ₄ Cl solution (15 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×10 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 105 (75 mg, 40%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.83 (s, 1H), 7.36-7.17 (m, 5H), 5.95-5.92 (s+s, 1H), 4.97-4.84 (overlapped with H ₂ O, m, 1H), 4.60-4.44 (m, 2H), 4.25-4.16 (m, 2H), 3.95-3.86 (m, 1H), 2.94-2.87 (m, 1H), 1.31-1.28 (m, 3H), 1.20- 1.14 (m, 6Н), 0.97-0.94 (s+s, 3Н), 0.86-0.83 (m, 2Н), 0.63-0.56 (m, 2Н). ³¹ Р NMR (121 MHz, CD ₃ OD) δ 4.00 (s), 3.92 (s). MS (ESI) m/z calc. for C ₂₆ H ₃₇ N ₇ O ₈ P [M+H] ⁺ 606.2; received 606.2.

Example 9 Synthesis of (S)-isopropyl-2-(((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl )-4-fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-amino)propanoate (201)

Step 1. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahyrofuran-3-ol (200).

Compound 250 can be prepared according to Tuttle, J.V. et al., "Purine 2'-Deoxy-2'-fluororibosides as Antiinfluenza Virus Agents", J. Med. Chem. 36:119-125 (1992). A solution of compound 250 (5.2 g, 17.3 mmol) in methylamine (33% in EtOH) (150 ml) was heated at 85° C. in a stoppered container for 3 hours, cooled to rt and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-15%). The product, compound 200 (4.9 g, 95%) was obtained as a white solid.

¹ H NMR (300 MHz, DMSO-D ₆ ) δ 7.94 (s, 1H), 7.30 (bs, NH), 6.06 (dd, J=3.3, 16.5 Hz, 1H), 5.93 (bs, NH ₂ ), 5.68 (bs, OH), 5.32 (dt, J=53.1, 3.6 Hz, 1H), 5.30 (bs, OH), 4.40 (dt, J=16.8, 4.5 Hz, 1H), 3.96-3.94 (m, 1H), 3.76-3.56 (m, 2H), 2.89 (bs, 3H). MS (ESI) m/z calc. for C ₁₁ H ₁₆ FN ₆ O ₃ [M+H] ⁺ 299.1; received 299.2.

Step 2 Preparation of (S)-isopropyl-2-(((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl )-4-fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (201).

To a solution of compound 200 (70 mg, 0.23 mmol) in dry DMF (3 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (310 μl, 0.31 mmol) at 0°C. The solution was stirred for 20 minutes at 0°C and for 40 minutes at r.t. 118 mg, 0.27 mmol) in dry DMF (3 ml). The resulting solution was slowly heated to 10° C. and stirred for 15 h at this temperature. The reaction mixture was diluted with EtOAc (20 ml) and saturated aq. NH ₄ Cl solution (15 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×10 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 201 (22 mg, 17%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.82 (s, 1H), 7.33-7.13 (m, 5H), 6.13 (dd, J=18.6, 1.9 Hz, 1H), 5.39 (ddd, J=52.9, 4.5, 2.0 Hz, 1H), 4.94-4.88 (m, 1H), 4.81-4.68 (m, 1H), 4.46 (ddd, J=11.5, 6.3, 2.6 Hz, 1H), 4.32 (m, 1H), 4.20 (m, 1H), 3.87 (dq, J=9.6, 7.2 Hz, 1H), 3.03 (s, 3H), 1.28 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.2 Hz), 1.16 (d, J=6.2 Hz). ³¹ R NMR (121 MHz, CD ₃ OD) e 2.40 (s). MS (ESI) m/z calc. for C ₂₃ H ₃₂ FN ₇ O ₇ P [M+H] ⁺ 568.2; received 568.2.

Example 10 Synthesis of (S)-isopropyl-2-(((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin-9-yl )-4-fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (203)

Step 1. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetragyrofuran-3-ol (202).

To a solution of compound 250 (10.5 g, 35 mmol) in EtOH (220 ml) was added dimethylamine hydrochloride (14.0 g, 173 mmol) and triethylamine (24.0 ml, 173 mmol). The reaction mixture was heated at 85° C. in a sealed container for 3 hours, cooled to room temperature (rt) and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%). The product, compound 202 (10.8 g, 99%), was obtained as a white solid.

¹ H NMR (300 MHz, DMSO-D ₆ ) δ 7.97 (s, 1H), 6.07 (dd, J=3.0, 16.5 Hz, 1H), 5.91 (bs, NH ₂ ), 5.66 (bs, OH), 5.27 (dt, J=53.1, 3.3 Hz, 1H), 5.25 (t, J=5.4 Hz, OH), 4.44-4.33 (m, 1H), 3.94-3.92 (m, 1H), 3.76-3.54 (m, 2H ), 3.34 (s, overlapped with H ₂ O, 6H). MS (ESI) m/z calc. for C ₁₂ H ₁₈ FN ₆ O ₃ [M+H] ⁺ 313.1; received 313.2.

Step 2: Preparation of (S)-isopropyl-2-(((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin-9-yl )-4-fluoro-3-hydroxytetragyrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (203).

To a solution of compound 202 (70 mg, 0.22 mmol) in dry DMF (3 ml) was added dropwise tert-butyl magnesium chloride (1 N in THF) (305 μl, 0.31 mmol) at 0°C. The solution was stirred for 20 min at 0°C and for 40 min at r.t. 116 mg, 0.27 mmol) in dry DMF (3 ml). The resulting solution was slowly heated to 10° C. and stirred for 15 h at this temperature. The reaction mixture was then diluted with EtOAc (20 ml) and saturated aq. NH ₄ Cl solution (15 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (2×10 ml). The combined organics were washed with saturated aq. NH ₄ Cl solution (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 0-10%) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 0-100%). Product 203 (27 mg, 21%) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.80 (s, 1H), 7.33-7.13 (m, 5H), 6.14 (dd, J=18.7, 2.0 Hz, 1H), 5.38 (ddd, J=53.0, 4.6, 2.1 Hz, 1H), 4.95-4.89 (m, 1H), 4.72 (ddd, J=19.7, 7.6, 4.7 Hz, 1H), 4.46 (ddd, J=11.5, 6.2, 2.6 Hz, 1H), 4.32 (ddd, J=10.8, 5.9, 4.6 Hz, 1H), 4.20 (m, 1H), 3.88 (dq, J=9.7, 7.0 Hz, 1H), 3.39 (s, 6H), 1.28 (dd, J=7.1 , 0.6 Hz, 3Н), 1.18 (d, J=6.2 Hz), 1.17 (d, J=6.3 Hz). ³¹ R NMR (121 MHz, CD ₃ OD) δ 2.41 (s). MS (ESI) m/z calc. for C ₂₄ H ₃₄ FN ₇ O ₇ P [M+H] ⁺ 582.2; received 582.2.

Example 11 Synthesis of (2S)-isopropyl-2-(((S)-(((1R,3R,4S,5R)-3-(6-amino-9H-purin-9-yl)-4,5- dihydroxy-2-methylcyclopentyl)methoxy)(phenoxy)phosphoryl)amino)propanoate (compound 204)

Step 1. Preparation of ((3aR,4R,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2,5-trimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)methanol (212).

To a solution of compound 206 (32 mg, 0.115 mmol) in acetone (5.0 ml) was added 2,2-dimethoxypropane (300 μl, 2.30 mmol) and concentrated H ₂ SO ₄ (1 drop). The reaction mixture was stirred at rt. Then triethylamine (100 µl) was added and the solvent was removed. The residue was purified by column chromatography (silica gel, DCM/MeOH 100:0-90:10) to give compound 212 (33 mg, 0.102 mmol, 89%) as a white solid.

Step 2. Preparation of (2S)-isopropyl-2-(((S)-(((3aR,4R,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2, 5-trimethyltetrahydro-3aH-cyclopenta[c][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (213).

To a solution of compound 212 (32 mg, 0.10 mmol) in dry THF (2 ml) at 0°C was added tert-butyl magnesium chloride (1.0 M in THF, 150 μl, 0.15 mmol) dropwise over 10 min. The reaction mixture was stirred for 15 min at 0°C and then another 15 min at room temperature. The reaction mixture was cooled to 0°C, before which a solution of isopropyl ((S)-(pentafluorophenoxy)-phenoxyphosphoryl)-L-alaninate (61 mg, 0.14 mmol) dissolved in dry THF (1 ml) was added dropwise over 10 min. The reaction mixture was stirred at 0°C for 30 min and 18 h at room temperature. The reaction was quenched with saturated aqueous NH ₄ Cl (4 ml) and was extracted with EtOAc (3×5 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 100:0-90:10) to give compound 213 (26 mg, 0.04 mmol, 44%) as a white solid.

Step 3. (2S)-Isopropyl-2-(((S)-(((1R,3R,4S,5R)-3-(6-amino-9H-purin-9-yl)-4,5-dihydroxy -2-methylcyclopentyl)methoxy)(phenoxy)phosphoryl)amino)propanoate (204).

Compound 213 (26 mg, 0.04 mmol) was treated with a solution of HCl (2 N in 2-propanol) (3 ml) for 30 min at 0° C. and for 2 h at RT. The reaction mixture was concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH 100:0-90:10) and reverse phase column chromatography (C-18 silica gel, H ₂ O/MeOH 100:0-0:100). Compound 204 (mixture of 2 diastereoisomers, 6 mg, 0.01 mmol, 25% yield) was obtained as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.25-8.09 (m, 2H), 7.42-7.14 (m, 5H), 5.05-4.90 (m, 1H, H ₂ O overlapped), 4.63-4.20 (m, 4Н), 4.11-3.84 (m, 2Н), 2.91-1.87 (m, 2Н), 1.40-1.18 (m, 9Н), 1.00 (d, J=6.7 Hz) and 0.57 (d, J=7.6 Hz, 3Н ). ³¹ Р NMR (121 MHz, CD3OD) δ 2.14 (s), 2.09 (s). MS (ESI) m/z calc. for C ₂₄ H ₃₄ N ₆ O ₇ P [M+H] ⁺ 549.2; received 549.2.

Example 12 Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro- 3-hydroxy-4-methyltetragyrofuran-2-yl)methoxy)-phenoxyphosphoryl)-L-alaninate (205).

Step 1: Preparation of ((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetragyrofuran-2-yl)methylbenzoate (215).

To a solution of (2R)-3,5-di-O-benzoyl-2-fluoro-2-C-methyl-D-ribono-γ-lactone (compound 214, 24.8 g, 66.6 mmol) in dry THF (333 ml) under nitrogen atmosphere and cooled to -30°C, lithium tri-tert-butoxyaluminum hydride (1.0 M in THF, 22.6 ml, 22.6 mmol) was added dropwise. After completion of the addition, the reaction mixture was slowly heated to -15°C for 90 minutes. EtOAc (300 ml) was added and the mixture was quenched with saturated aq. NH ₄ Cl solution (200 ml). The resulting solution was filtered on Celite® and the filtrate was extracted twice with EtOAc. The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was taken up in dry DCM (225 ml) under nitrogen, cooled to -20° C. and PPh ₃ (19.1 g, 72.8 mmol) was added. After 10 min stirring at -20° C. CBr ₄ (26.0 g, 78.4 mmol) was added and the reaction mixture was allowed to warm slowly to 0° C. over 2 h. The resulting mixture was poured onto a silica gel column and eluted with PE/EtOAc (gradient 100:0-80:20). Fractions containing α-bromofuranoside were collected and concentrated to give product 215 (18.1 g, 41.3 mmol, 62% over two steps) as a thick colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15-8.11 (m, 2H), 8.04-8.01 (m, 2H), 7.64-7.55 (m, 2H), 7.51-7.41 (m, 4H), 6.34 (d , J=1.6 Hz, 1H), 5.29 (dd, J=5.5, 3.1 Hz, 1H), 4.89-4.85 (m, 1H), 4.78 (dd, J=12.5, 3.2 Hz, 1H), 4.63 (dd, J=12.5, 4.5 Hz, 1H), 1.72 (d, J=21.6 Hz, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -150.0.

Step 2: Preparation of (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetragyrofuran-3- ylbenzoate (216).

2-Amino-6-chloropurine (2.63 g, 15.5 mmol) was suspended in tert-BuOH (54 ml) under nitrogen atmosphere. The reaction mixture was heated to 30° C. and potassium tert-butoxide (1.69 g, 15.1 mmol) was added. After 45 minutes, a solution of bromofuranoside 2 (2.24 g, 5.12 mmol) dissolved in anhydrous MeCN (6 ml) was added, the reaction mixture was heated to 65° C. for 16 h and then cooled to room temperature. Added saturated aq. NH ₄ Cl solution (70 ml) and the resulting solution was extracted with EtOAc (3×60 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified twice by column chromatography (PE/EtOAc gradient 80:20-0:100 then 60:40-20:80) to give product 216 (1.56 g, 2.96 mmol, 57%) as a white solid substances.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05-8.02 (m, 2Н), 7.95-7.92 (m, 2Н), 7.88 (s, 1H), 7.63-7.57 (m, 1H), 7.53-7.41 (m , 3Н), 7.35-7.30 (m, 2Н), 6.43 (dd, J=22.6, 9.1 Hz, 1H), 6.12 (d, J=18.3 Hz, 1H), 5.34 (br s, 2Н), 5.00 (dd , J=11.9, 4.5 Hz, 1H), 4.79-4.73 (m, 1H), 4.60 (dd, J=11.9, 5.3 Hz, 1H), 1.34 (d, J=22.6 Hz, 3H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -157.0. MS (ESI) m/z calc. for C ₂₅ H ₂₂ FN ₅ O ₅ [M+H] ⁺ 526.9; received 527.0.

Step 3. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetragyrofuran- 3-ola (217).

To a solution of compound 216 (575 mg, 1.09 mmol) in MeOH (9 ml) was added methylamine (33% in absolute EtOH, 1.7 ml, 1.81 mmol). The reaction mixture was heated to 85° C. in a stoppered tube for 16 h, cooled to room temperature and concentrated. The residue was purified by column chromatography (DCM/MeOH gradient 100:0-85:15) and reverse phase column chromatography (H ₂ O/MeOH gradient 100:0-0:100) to give product 217 (286 mg, 0. 91 mmol, 84%) as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.06 (s, 1H), 6.11 (d, J=18.1 Hz, 1H), 4.41 (dd, J=24.4, 9.1 Hz, 1H), 4.07-4.01 (m , 2Н), 3.86 (dd, J=12.9, 3.3 Hz, 1H), 3.04 (br s, 3Н), 1.16 (d, J=22.3 Hz, 3Н). ¹⁹ F NMR (282 MHz, CD ₃ OD) δ -163.7. MS (ESI) m/z calc. for C ₁₂ H ₁₉ FN ₆ O ₃ [M+H] ⁺ 313.1; received 313.2.

Step 4. Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro- 3-hydroxy-4-methyltetragyrofuran-2-yl)methoxy)phenoxyphosphoryl)-1,-alaninate (205).

To a solution of compound 217 (114 mg, 365 µmol) in dry THF (4 ml) under nitrogen atmosphere and cooled to 0°C was added tert-butyl magnesium chloride (1.0 M in THF, 0.66 ml, 660 µmol) dropwise within 10 min. The reaction mixture was stirred for 15 min at 0°C and then another 15 min at room temperature. The reaction mixture was cooled to 0°C, before that a solution of isopropyl ((R,S)-(pentafluorophenoxy)-phenoxyphosphoryl)-L-alaninate, Ross, BS, Reddy, PG, Zhang, HR, Rachakonda, S., and Sofia, MJ, J. Org, Chem., (2011), (253 mg, 558 µmol) dissolved in dry THF (1 ml) was added dropwise over 10 min. The reaction mixture was stirred at 0° C. for 30 minutes and then for 18 hours at room temperature. The reaction was quenched with saturated aq. NH ₄ Cl solution (4 ml) and extracted with EtOAc (3×5 ml). The combined organics were dried, filtered (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (DCM/MeOH gradient 100:0-90:10) and reverse phase column chromatography (H ₂ O/MeOH gradient 100:0-0:100) to give product 205 (mixture of diastereomers, 101 mg , 174 µmol, 48%) as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.83 (s, 0.55H), 7.82 (s, 0.45H), 7.38-7.16 (m, 5H), 6.15 (d, J=18.5 Hz, 0.45 H), (d, J=18.8 Hz, 0.55 H), 4.99-4.88 (overlapped H ₂ O, m, 1H), 4.65-4.36 (m, 3H), 4.25-4.17 (m, 1H), 3.97-3.85 (m, 1H), 3.05 (br s, 3Н), 1.32-1.28 (m, 3Н), 1.25-1.15 (m, 9Н). ¹⁹ F NMR (282 MHz, CD ₃ OD) δ -162.8 (s), -163.3 (s). ³¹ R NMR (121 MHz, CD ₃ OD) δ 4.10 (s), 3.99 (s). MS (ESI) m/z calc. for C ₂₄ H ₃₄ FN ₇ O ₇ P [M+H] ⁺ 582.2; received 582.2.

Table 2 shows the structures of compounds 207, 208, 209 and 210 along with the corresponding mass spectra and ¹ H NMR for the respective compounds. Compounds were synthesized in the general manner shown in Example 4.

Example 13 Non-limiting Examples of the Compounds of the Present Invention

The compounds of the present invention include the compounds shown in Table 3 and Table 4. The compound number, structure, and molecular weight of exemplary compounds of the present invention are also shown.

Example 14 Compounds of the present invention are active against dengue virus type 2 and yellow fever virus

The activity of the compounds according to the present invention against dengue fever type 2 virus (DENV-2) and yellow fever virus (YFV) was measured. Inhibition of virus-induced cytopathic effects (CPE) and cell viability after YFV replication in BHK21 cells was measured by XTT tetrazolium staining. Cells (3×10 ³ cells/well) were plated in 98-well flat bottom tissue culture plates and allowed to adhere overnight. After overnight incubation, diluted test compounds and virus diluted to a predetermined titer were added to the plate to obtain 85-95% killed cells 6 days post infection. After incubation at 37° C., 5% CO ₂ for six days, cell viability was measured by XTT staining. The absorbance in the cell culture plate was determined spectrophotometrically at 450 and 650 nm using Softmax Pro 4.6 software. The percentage reduction in CPE in virus-infected wells and the percentage cell viability of uninfected drug control wells were calculated to determine EC ₅₀ values using a four-parameter curve fitting analysis.

The results are shown in Table 5. Compound 205 is the most potent compound with an EC _{50 of} 0.8 μM in the DENV-2 assay and an EC ₅₀ value of 1.2 μM in the YFV assay.

The present description has been described with reference to embodiments of the present invention. Given the foregoing herein, one of ordinary skill in the art will be able to modify the present invention for the desired purpose, and such variations are contemplated within the scope of the present invention.

Claims (53)

1. Use of a compound of formula IIIe:

or a pharmaceutically acceptable salt thereof for the treatment of a Flavivirus infection in a host in need thereof, where: R ⁷ is phenyl; R ⁸ is hydrogen; R ^9a and R ^9b are independently selected from hydrogen and methyl; and R ¹⁰ is C _1-6 alkyl. 2. Application according to claim 1, where R ⁷ is phenyl; R ⁸ is hydrogen; R ^9a is methyl; and R ^9b is hydrogen; and R ¹⁰ is isopropyl. 3. Application according to claim 1, in which R ⁷ is phenyl; R ⁸ is hydrogen; R ^9a is methyl; R ^9b is hydrogen; R ¹⁰ is isopropyl; and phosphoramidate is in the L-configuration. 4. Application connection

or a pharmaceutically acceptable salt thereof for the treatment of a Flavivirus infection in a host in need thereof. 5. Use according to claim 4, wherein the compound is

or a pharmaceutically acceptable salt thereof. 6. Use according to claim 4, wherein the compound is

or a pharmaceutically acceptable salt thereof. 7. Connection application

or a pharmaceutically acceptable salt thereof for the treatment of a Flavivirus infection in a host in need thereof. 8. Use according to claim 7, where the compound is

or a pharmaceutically acceptable salt thereof. 9. Use according to claim 7, where the compound is

or a pharmaceutically acceptable salt thereof. 10. Application according to any one of paragraphs. 1-3 and 7-9, wherein the virus is selected from dengue fever, West Nile fever, yellow fever, Zika virus, and Japanese encephalitis. 11. Use according to claim 10 wherein the virus is dengue fever. 12. Application according to any one of paragraphs. 1-3, 7-9, in which the owner is a person. 13. Application according to any one of paragraphs. 4-6, wherein the virus is selected from dengue, West Nile, yellow fever, Zika virus, and Japanese encephalitis. 14. Use according to claim 13 wherein the virus is dengue fever. 15. Application according to any one of paragraphs. 4-6, 13, 14, in which the owner is a person. 16. Use according to claim 11 wherein dengue fever is caused by dengue fever virus type 2. 17. Use according to claim 11, wherein dengue fever is caused by dengue fever virus type 3. 18. Use according to claim 10 wherein the virus is Zika virus. 19. Use according to claim 10, wherein the virus is a yellow fever virus. 20. Use according to claim 14, wherein dengue fever is caused by dengue fever virus type 2. 21. Use according to claim 14, wherein dengue fever is caused by dengue fever virus type 3. 22. Use according to claim 13, wherein the virus is Zika virus. 23. Use according to claim 13, wherein the virus is a yellow fever virus. 24. Application according to paragraphs. 16-19 and 20-23, in which the owner is a man.