2'-Chloro-2'-fluoro-N2-amino-N6-methylaminopurine nucleotides for flavivirus therapy

Abstract

The present invention relates to a new method for treating infections caused by viruses from the Flavivirus genus, particularly Dengue virus, Yellow fever virus, Zika virus, and West Nile virus, in a host in need of treatment, typically a human.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 240,578, filed September 3, 2021, the entirety of which is incorporated by reference herein for all purposes.

[0002] The present invention relates to the treatment of infections caused by viruses from the Flavivirus genus, including Dengue virus, Yellow fever virus, Zika virus, and West Nile virus, in a host in need of treatment, typically a human. [Background technology]

[0003] Flaviviruses are a genus of vector-borne viruses that have a positive-sense, single-stranded RNA genome that can be directly translated into viral proteins without an intermediate transcription step, i.e., without the need for viral polymerase within the virion.

[0004] Infectious diseases caused by viruses of the Flavivirus genus include, but are not limited to, dengue fever, West Nile fever, yellow fever, Zika virus disease, Kyasanur Forest disease, Powassan disease, Wesselsbron disease, Rio bravo, Rocio, Negishi, and encephalitis such as California encephalitis, Central European encephalitis, Irvine virus, Murray Valley encephalitis, St. Louis encephalitis, Japanese encephalitis type B, louping ill, and Russian spring-rodents summer encephalitis.

[0005] Dengue fever is one of the most prevalent flaviviral diseases. Currently, there are no approved therapeutic treatments other than palliative care. Many clinical trials have been conducted to evaluate dengue fever treatments but have failed to meet their primary efficacy endpoints (Non-Patent Document 1). Although preventive vaccines have been developed, their efficacy varies depending on the recipient's age and the serotype of the infection (Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4). In 2021, Janssen Pharmaceuticals began clinical trials of a new therapeutic agent for dengue fever (JNJ-A07). This compound is an inhibitor of the NS3 / NS4B viral enzyme (see, for example, Non-Patent Document 5). Currently, the main recourse is supportive care for infected individuals with treatment of symptoms including high fever, headache, severe joint and muscle pain, and nausea. Fluid replacement and painkillers along with acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs may be effective. If untreated, dengue fever mortality can be as high as 30%.

[0006] There are also no approved drugs for infection caused by West Nile virus, another member of the Flavivirus genus. Doctors typically recommend intensive supportive care, which may include hospitalization, intravenous fluids, use of a ventilator to help with breathing, medications to control seizures, brain swelling, nausea, and vomiting, and antibiotics to prevent secondary bacterial infections.

[0007] The medical state of the art is similar for Zika virus disease. No vaccine or specific curative treatment is available. The focus is on symptom relief, including rest, fluids, and acetaminophen for fever and aches.

[0008] A vaccine exists for yellow fever. The Sanofi Pasteur Yellow Fever Vaccine (YF-Vax) is recommended for people aged 9 years and older traveling to high-risk areas, including South America and Africa. As there is no antiviral treatment, prevention is the only concrete option available for yellow fever. As with many flavivirus infections, the focus is on alleviating symptoms by relieving fever, muscle pain, and dehydration. This palliative care is complicated by the risk of internal bleeding, so typical antipyretics and painkillers such as aspirin and nonsteroidal anti-inflammatory drugs are not recommended.

[0009] Atea Pharmaceuticals, Inc. has announced that it has developed 2'-methyl-2'-fluoro-N 2 -Amino-N 6 Atea has disclosed 2'-methyl-2'-fluoro-N-methylaminopurine nucleotide phosphoramidates and pharma- ceutically acceptable salts thereof in Patent Documents 1, 2, 3, 4, 5, 6, 7, and 8. Atea has disclosed 2'-methyl-2'-fluoro-N-methylaminopurine nucleotide phosphoramidates and pharma- ceutically acceptable salts thereof in Patent Documents 9, 10, and 11. 2 -Amino-N 6 Atea also disclosed 2'-substituted disubstituted N-methylaminopurine nucleotide phosphoramidate hemisulfates for the treatment of positive-stranded RNA viruses, including flaviviruses such as dengue virus, West Nile virus, and yellow fever virus. 2 -Amino-N 6 Substituted purine nucleotides have also been disclosed (e.g., Patent Document 12). Atea, in Patent Document 13, reports highly active compounds against COVID-19.

[0010] U.S. patent publications and PCT applications describing 2'-disubstituted nucleotide polymerase inhibitors for the treatment of Flaviviridae include those filed by Idenix Pharmaceuticals (U.S. Patent No. 5,313,633; U.S. Patent No. 5,313,633; and U.S. Patent No. 5,313,633), Gilead Sciences (U.S. Patent No. 5,313,633), Emory University (U.S. Patent No. 5,313,633; U.S. Patent No. 5,313,633; and U.S. Patent No. 5,313,633), University College Cardiff Consultants Limited (U.S. Patent No. 5,313,633), and Medivir AB (U.S. Patent No. 5,313,633; and U.S. Patent No. 5,313,633).

[0011] The need for flavivirus treatment is increasing as flaviviruses continue to spread to uninfected areas around the world and are expected to mutate under drug pressure. The medical demand for safe, effective, and well-tolerated antiviral treatments is particularly strong because higher viremia levels are associated with more severe disease. Furthermore, the anticipated need for combination therapy to circumvent drug resistance necessitates additional treatments.

[0012] It is therefore an object of the present invention to provide new therapeutics and pharmaceutical compositions for treating Flavivirus infections. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] U.S. Patent No. 9,828,410 [Patent Document 2] U.S. Patent No. 10,239,911 [Patent Document 3] U.S. Patent No. 10,000,523 [Patent Document 4] U.S. Patent No. 10,815,266 [Patent Document 5] U.S. Patent No. 10,870,672 [Patent Document 6] U.S. Patent No. 10,870,673 [Patent Document 7] U.S. Patent No. 10,875,885 [Patent Document 8] U.S. Patent No. 10,005,811 [Patent Document 9] U.S. Patent No. 10,519,186 [Patent Document 10] U.S. Patent No. 10,906,928 [Patent Document 11] U.S. Patent No. 10,894,804 [Patent Document 12] U.S. Patent No. 10,946,033 [Patent Document 13] U.S. Patent No. 10,874,687 [Patent Document 14] International Publication No. 2013 / 177219 [Patent Document 15] International Publication No. 2015 / 081297 [Patent Document 16] International Publication No. 2015 / 081133 [Patent Document 17] International Publication No. 2012 / 012465 [Patent Document 18] International Publication No. 2015 / 164812 [Patent Document 19] International Publication No. 2017 / 165489 [Patent Document 20] International Publication No. 2015 / 038596 [Patent Document 21] International Publication No. 2014 / 076490 [Patent Document 22] US Patent Application Publication No. 2015 / 0175648 [Patent Document 23] International Publication No. 2015 / 034420 [Patent Document 24] US Patent Application Publication No. 2018 / 0036330 [Non-patent literature]

[0014] [Non-Patent Document 1] Low et al., The Journal of Infectious Diseases, 2017 March 1; 215 (Suppl 2) S96-S102 [Non-Patent Document 2] Hadinegoro et al. New England Journal of Medicine, 2015; 373:1195-206 [Non-Patent Document 3] Halstead et al. Vaccine 2016; 34:1643-1647 [Non-Patent Document 4] Biering et al. Nature News and Views, 2021, 598, 420-421 [Non-Patent Document 5] Kaptein, SJF et al. A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction. Nature, 2021, 598, 504-509 Summary of the Invention

[0015] The present invention provides an effective amount of the 2'-chloro-2'-fluoro-N 2 -Amino-N 6 The present invention provides a treatment for a flavivirus infection in a host, typically a human, in need of such treatment, comprising administering a -methylaminopurine nucleotide phosphoramidate or a pharma- ceutically acceptable salt thereof.

[0016] The present invention relates to 2'-chloro-2'-fluoro-N 2 -Amino-N 6The compounds of formula I or formula II, which are -methylaminopurine nucleotide phosphoramidates, or pharma- ceutically acceptable salts thereof, when administered in an effective amount to a host, typically a human, in need of treatment, are advantageous in the treatment of viruses from the Flavivirus genus. Alternatively, the host may be any animal that transmits Flavivirus infections.

[0017] In particular, the nucleotide phosphoramidates of formula I and the nucleotides of formula II exhibit advantageous activity against, for example, dengue virus, West Nile virus, Zika virus, and yellow fever virus. In certain embodiments, the 2'-chloro-2'-fluoro-N-phenylalanine phosphoramidates described herein are administered to a host in need of treatment, particularly a human. 2 -Amino-N 6 A method for treating dengue or yellow fever comprising administering a -methylaminopurine nucleotide phosphoramidate or a pharma- ceutically acceptable salt thereof is provided. In a primary embodiment, the nucleotide is a phosphoramidate. In certain embodiments, the nucleotide is a stabilized phosphate prodrug.

[0018] Thus, in one embodiment, the invention is a method of treating a flavivirus infection in a host, such as a human, in need of such treatment, comprising administering an effective amount of a compound of formula I. In one embodiment, a method is provided for treating a host, including a human, infected with a flavivirus with an effective amount of a compound of formula I. In certain embodiments, a host, including a human, infected with dengue virus, Zika virus, West Nile virus, or yellow fever is treated with an effective amount of a compound of formula I: [ka] (In the formula, R 1 is hydrogen, optionally substituted C 1~6 Alkyl (including methyl, ethyl, propyl, and isopropyl), optionally substituted C 3~7 cycloalkyl, or aryl (including phenyl and naphthyl); in certain embodiments, R1 is an optionally substituted -(C1-C4 alkyl)aryl, an optionally substituted heteroaryl, or an optionally substituted heteroalkyl; R 2 is hydrogen or an optionally substituted C 1~6 alkyl (including methyl, ethyl, propyl, and isopropyl); R 3a and R 3b are independently hydrogen, C 1~6 Alkyl (including methyl, ethyl, propyl, and isopropyl), and optionally substituted C 3~7 cycloalkyl, and R 4 is hydrogen, optionally substituted C 1~6 Alkyl (including methyl, ethyl, propyl, and isopropyl), optionally substituted C 1~6 haloalkyl, or optionally substituted C 3~7 In another embodiment, R 4 is indicated for use in treating a patient suffering from atopic dermatitis with a compound of -(C1-C4 alkyl)aryl (e.g., benzyl), optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroalkyl), or a pharma- ceutically acceptable salt thereof. In certain non-limiting embodiments, the salt is a hemisulfate salt.

[0019] In certain embodiments, the N 6 -Methylamino-purine compounds are N 6 -methylamino-purine is metabolized to the 5'-monophosphate, which is subsequently metabolized at the 6-position to generate the active guanine triphosphate compound resulting in good activity and therapeutic index.

[0020] As an example, 2'-chloro-2'-fluoro-N 2 -Amino-N 6 The metabolism of 5'-methylaminopurine nucleotide phosphoramidates involves the metabolism of the phosphoramidate to the 5'-monophosphate followed by the 2-Amino-N 6 This involves the metabolism of the 2'-methylaminopurine base to produce the 2'-chloro-2'-fluoroguanine nucleoside 5'-monophosphate, which is then assimilated to the active species, the 5'-triphosphate (Scheme 1).

[0021] In particular, the 2'-chloro-2'-fluoro-N 2 -Amino-N 6 5'-stabilized nucleotide phosphate prodrugs of 2'-methylaminopurine nucleotides (i.e., derivatives that can be metabolized to 5'-monophosphate, 5'-diphosphate, or 5'-triphosphate nucleotides), as well as other 2'-chloro-2'-fluoro-N-methylaminopurine nucleotides. 2 -Amino-N 6 -methylaminopurine nucleotides have also been found to be active against viruses in the Flavivirus genus. For example, as discussed in Example 5 and shown in Table 1, compound 8 inhibits dengue virus (EC 50 =0.32μM), West Nile virus (EC 50 =0.32 μM), and yellow fever virus (EC 50 =0.12 μM).

[0022] [ka]

[0023] The present invention also relates to a method for producing 5 is monophosphate, diphosphate, triphosphate, or R 10A where R 10A is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate, Formula II: [ka] (In the formula, R 5 teeth, [ka] , and R 10A is selected from R 10A is a stabilized phosphate prodrug that metabolizes in vivo to the monophosphate, diphosphate, or triphosphate), or a pharma- ceutically acceptable salt thereof, for the treatment or prevention of a flavivirus, particularly a dengue virus, infection in a host in need of such treatment or prevention as described herein, and all other variables are as previously defined herein.

[0024] In certain embodiments, R 5 teeth, [ka] is selected from.

[0025] Unless otherwise specified, the compounds described herein are provided in the β-D configuration. Similarly, when in the form of phosphoramidates or thiophosphoramidates, the amino acid moiety may be in the L or D configuration. In certain embodiments, the compounds may be provided in the β-L configuration. Similarly, any substituent that exhibits chirality may be provided in racemic, enantiomeric, diastereomeric form or any mixture thereof. Phosphoramidates, thiophosphoramidates, or other stabilized phosphorus prodrugs in which phosphorus exhibits chirality may be provided as R 5 When used as a chiral phosphorus prodrug stabilized with , it can be provided as an R or S chiral phosphorus derivative, or mixtures thereof, including racemic mixtures. All combinations of these configurations are encompassed by the invention described herein.

[0026] The present invention includes the use of an effective amount of a compound of Formula I or Formula II described herein, or a pharma- ceutically acceptable composition, salt, or prodrug thereof, for treating a flavivirus, such as a dengue virus.

[0027] Methods, uses and pharmaceutical compositions are provided for treating a host, such as a human, infected with a flavivirus through administration of an effective amount of the compound or a pharma- ceutically acceptable salt thereof.

[0028] An effective amount of the compound or a formulation containing the compound can also be administered prophylactically to prevent or minimize the progression of clinical disease in flavivirus antibody-positive or flavivirus antigen-positive individuals.

[0029] The invention also includes methods for treating or preventing flaviviruses, including drug-resistant and multi-drug resistant forms of flaviviruses, and associated symptoms, conditions, or complications of flavivirus infections, as well as other conditions secondary to flavivirus infections, such as weakness, loss of appetite, weight loss, breast enlargement (especially in men), rashes (especially on the palms of the hands), difficulty in clotting blood, spider veins on the skin, confusion, coma (encephalopathy), accumulation of fluid in the abdominal cavity (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, low blood counts, anemia, thrombocytopenia, jaundice, and hepatocellular carcinoma, among others. The methods comprise administering to a host in need of treatment or prevention an effective amount of at least one 2'-chloro-2'-fluoro-N-methyl-N-pyridine derivative described herein. 2 -Amino-N 6 -methylaminopurine nucleotide phosphoramidate, optionally in combination with at least one additional therapeutic agent, such as an additional anti-flavivirus agent, further in combination with a pharmaceutically acceptable carrier, additive, and / or excipient.

[0030] Phosphorus in any of the above formulas may be chiral and therefore may be provided as either the R or S enantiomer, or mixtures thereof, including racemic mixtures.

[0031] Non-limiting embodiments include: [ka] Examples include:

[0032] In some embodiments, methods, uses, and compositions are provided for treating a host in need of treatment infected with a flavivirus described herein, such as dengue virus, Zika virus, West Nile virus, or yellow fever virus. For example, the method of the present invention may include administering an effective amount of a compound of formula I, alone or in combination with another anti-flavivirus agent, to treat an infected host in need of treatment. In certain embodiments, it is useful to administer a combination of agents that modulate the same or different pathways in the virus or inhibit different targets. The disclosed 2'-chloro-2'-fluoro-N 2 -Amino-N 6 Since -methylamino nucleotides are polymerase inhibitors, it may be advantageous to administer an effective amount of the compound to a host in need thereof in combination with an effective amount of a protease inhibitor or NS5 inhibitor. The present invention may also be used in combination with administration of an effective amount of a structurally different polymerase inhibitor, such as another compound described herein or otherwise known to those skilled in the art. The present invention may also be used in combination with administration of an effective amount of ribavirin and / or interferon. The present invention may also be used in combination with administration of an effective amount of an inhibitor of NS3 / NS4B interaction, such as, for example, but not limited to, JNJ-A07.

[0033] The 2'-chloro-2'-fluoro-N- 2 -Amino-N 6 -Methylaminopurine nucleotide phosphoramidates are typically administered orally, for example in pill or tablet form, but may also be administered via other routes as deemed appropriate by the attending physician, including via intravenous, inhaled, systemic, transdermal, subcutaneous, topical, parenteral, or other suitable route. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description of the Invention The present invention describes the methods, uses, and compositions described herein for treating flavivirus infection or exposure in humans or another host animal, comprising administering an effective amount of a compound of formula I or formula II described herein, or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds used herein either have anti-flavivirus activity or are metabolized to a compound that exhibits such activity. In certain embodiments, the treatment of dengue virus, Zika virus, West Nile virus, or yellow fever virus infection in a host, including a human in need of treatment, is indicated, comprising administering a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof.

[0035] The compounds or compositions may also be used to treat conditions associated with or resulting from flavivirus exposure, hi certain embodiments, the invention may also be used prophylactically to forestall or slow the progression of clinical disease in flavivirus antibody- or flavivirus antigen-positive individuals.

[0036] In particular, the 2'-chloro-2'-fluoro-N 2 -Amino-N 6 It has been found that 5'-stabilized phosphate prodrugs or derivatives of 2'-chloro-2'-fluoropurine nucleosides, such as 5'-methylaminopurine nucleoside phosphoramidates, are highly active against flaviviruses, such as dengue virus, West Nile virus, Zika virus, or yellow fever virus.

[0037] Unless otherwise specified, the compounds described herein are provided in the β-D configuration. In certain embodiments, the compounds may be provided in the β-L configuration. Similarly, any substituent that exhibits chirality may be provided in racemic, enantiomeric, diastereomeric form or any mixture thereof. Phosphoramidates, thiophosphoramidates or other stabilized phosphorus prodrugs that exhibit phosphorus chirality may be provided as R 5 When used as a phosphate prodrug stabilized with, it can be provided as an R or S chiral phosphorus derivative, or mixtures thereof, including racemic mixtures. The amino acids of the phosphoramidate or thiophosphoramidate can be in the D or L configuration, or mixtures thereof, including racemic mixtures. Any combination of these configurations is encompassed by the invention described herein.

[0038] The present invention includes the following features. (a) a method of treating or preventing a Flavivirus infection comprising administering an effective amount of a compound of Formula I or Formula II, as described herein, and pharma- ceutically acceptable salts and prodrugs thereof; (b) the use of an effective amount of Formula I or Formula II, and pharma- ceutically acceptable salts and prodrugs thereof, in the manufacture of a medicament for treating a Flavivirus infection; (c) a method for the manufacture of a medicament for therapeutic use in treating a flavivirus infection, comprising using an effective amount of a compound of formula I or formula II as described herein; and (d) a pharmaceutical formulation for treating a flavivirus comprising an effective host treating amount of Formula I or Formula II, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent; (e) compounds of formula I or formula II for use in treating a flavivirus infection, and (f) Any one of embodiments (a) through (e), wherein the flavivirus is selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, and Zika virus.

[0039] I. 2'-Chloro-2'-fluoro-N- 2 -Amino-N 6 -Methylaminopurine nucleotide phosphoramidate The active compounds of the present invention are, for example, of formula I: [ka] which may be provided as a pharma- ceutically acceptable composition, salt, or stabilized phosphate prodrug thereof, wherein R 1 is hydrogen, optionally substituted C 1~6 Alkyl (including methyl, ethyl, propyl, and isopropyl), optionally substituted C 3~7 cycloalkyl, or optionally substituted aryl (including phenyl and naphthyl), and in certain embodiments, R 1 is an optionally substituted -(C1-C4 alkyl)aryl (e.g., benzyl), an optionally substituted heteroaryl, or an optionally substituted heteroalkyl; R 2 is hydrogen or an optionally substituted C 1~6 alkyl (including methyl, ethyl, propyl, and isopropyl); R 3a and R 3b are independently hydrogen, optionally substituted C 1~6 Alkyl (including methyl, ethyl, propyl, and isopropyl), and optionally substituted C 3~7 cycloalkyl; R 4 is hydrogen, optionally substituted C 1~6 Alkyl (including methyl, ethyl, propyl, and isopropyl), optionally substituted C 1~6 haloalkyl, or optionally substituted C 3~7 cycloalkyl, and in certain embodiments, R 4 is an optionally substituted -(C1-C4 alkyl)aryl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heteroalkyl, and In some embodiments of Formula I, R 1 is phenyl.

[0040] In some embodiments of Formula I, R 1 is naphthyl.

[0041] In some embodiments of Formula I, R 2 is hydrogen.

[0042] In some embodiments of Formula I, R 2 is methyl.

[0043] In some embodiments of Formula I, R 3a is hydrogen and R 4b is methyl.

[0044] In some embodiments of Formula I, R 3a is hydrogen and R 4b is ethyl.

[0045] In some embodiments of Formula I, R 3a is hydrogen and R 4b is n-propyl.

[0046] In some embodiments of Formula I, R 3a is hydrogen and R 4b is isopropyl.

[0047] In some embodiments of Formula I, R 4 is methyl.

[0048] In some embodiments of Formula I, R 4 is ethyl.

[0049] In some embodiments of Formula I, R 4 is n-propyl.

[0050] In some embodiments of Formula I, R 4 is isopropyl.

[0051] In some embodiments of formula I, the compound is S p It is an isomer, the phosphoramidate being in the L configuration.

[0052] In some embodiments of formula I, the compound is R p It is an isomer, the phosphoramidate being in the L configuration.

[0053] In some embodiments of Formula I or Formula II, the pharma- ceutically acceptable salt is a hemisulfate salt.

[0054] In typical embodiments, the compound is a β-D isomer (i.e., naturally occurring configuration) with respect to the corresponding nucleoside. In certain embodiments, the compound is provided as a β-L isomer. The compound is typically 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 stated, the compound is at least 90% free of the opposite enantiomer.

[0055] 2'-Chloro-2'-fluoro-N 2 -Amino-N 6 Metabolism of 5'-methylaminopurine nucleotide phosphoramidates results in the production of the corresponding 5'-monophosphates. 2 -Amino-N 6 Subsequent metabolism of the 2'-methylaminopurine base produces the 2'-chloro-2'-fluoroguanine nucleoside as the 5'-monophosphate, which is then further metabolized to the active species, the 5'-triphosphate. 2 -Amino-N 6 The metabolic pathway for .sup.-methylaminopurine nucleotide phosphoramidates is shown in Scheme 1.

[0056] Exemplary embodiments of the present invention In certain non-limiting embodiments, the present invention includes:

[0057] 1. An effective amount of Formula I: [ka] (In the formula, R 1 is hydrogen, C 1~6 Alkyl, C 3~7 cycloalkyl, aryl, -(C1-C4 alkyl)aryl, heteroaryl, or heteroalkyl; R 2 is hydrogen or C 1~6 is alkyl, R 3a and R 3b are independently hydrogen, C 1~6 Alkyl, and C 3~7 cycloalkyl, and R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7 2. A method of treating a human host infected with a Flavivirus in need of treatment comprising administering a compound of the formula: -(C1-C4 alkyl), -(cycloalkyl, -(C1-C4 alkyl)aryl, aryl, heteroaryl, or heteroalkyl) or a pharma- ceutically acceptable salt thereof. 2.R 1 2. The method of embodiment 1, wherein R is hydrogen. 3.R 1 2. The method of embodiment 1, wherein R is phenyl. 4.R 2 The method of any one of embodiments 1 to 3, wherein is hydrogen. 5.R 3a and R 3b is hydrogen and C 1~6 The method of any one of embodiments 1 to 4, wherein the alkyl group is alkyl. 6.R 4 is C 1~6 The method of any one of the preceding embodiments, wherein the alkyl group is alkyl. 7.R 1 is aryl, R 2 is hydrogen, R 3a is methyl, and R 4 is C 1~6 2. The method of embodiment 1, wherein the alkyl group is alkyl. 8. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. 9. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 10. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 11. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 12. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 13. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 14. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 15. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 16. The method of any one of embodiments 1-15, wherein the pharma- ceutically acceptable salt is a hemisulfate salt. 17. The compound is [ka] 9. The method of embodiment 8, wherein 18. The compound is [ka] 9. The method of embodiment 8, wherein 19. The compound is [ka] 10. The method of embodiment 9, wherein 20. The compound is [ka] 10. The method of embodiment 9, wherein 21. The compound is [ka] 10. The method of embodiment 9, wherein 22. The compound is [ka] 10. The method of embodiment 9, wherein 23. An effective amount of Formula II: [ka] (In the formula, R 5 teeth, [ka] , and R 10A and R 10A A method of treating a human host infected with a flavivirus in need of such treatment, comprising administering a compound of the formula: 24.R 5 is R 10A 24. The method of embodiment 23, wherein 25. The method of any one of embodiments 1 to 24, wherein the virus is selected from Dengue virus, West Nile virus, Yellow fever virus, and Zika virus. 26. The method of embodiment 25, wherein the virus is a dengue virus. 27. The method of embodiment 25, wherein the virus is a yellow fever virus. 28. The method of embodiment 25, wherein the virus is West Nile virus. 29. The method of embodiment 25, wherein the virus is a Zika virus. 30. The method of any one of embodiments 1-29, wherein the compound is present in a dosage form suitable for oral administration. 31. The method of embodiment 30, wherein the oral dosage form is a solid oral dosage form. 32. The method of embodiment 31, wherein the oral dosage form is a tablet. 33. The method of embodiment 31, wherein the oral dosage form is a capsule. 34. The method of any one of embodiments 1-33, wherein about 500 mg to about 850 mg of the compound is administered. 35. The method of any one of embodiments 1-33, wherein about 500 mg to about 650 mg of the compound is administered. 36. The method of any one of embodiments 1-33, wherein about 600 mg to about 750 mg of the compound is administered. 37. The method of any one of embodiments 1-33, wherein about 650 mg to about 850 mg of the compound is administered. 38. The method of any one of embodiments 1-33, wherein at least about 550 mg of the compound is administered. 39. The method of any one of embodiments 1-33, wherein at least about 575 mg of the compound is administered. 40. The method of any one of embodiments 1-33, wherein at least about 600 mg of the hemisulfate salt of the compound is administered. 41. The method of any one of embodiments 1-33, wherein at least about 625 mg of the hemisulfate salt of the compound is administered. 42. The method of any one of embodiments 1-33, wherein at least about 700 mg of the compound is administered. 43. The method of any one of embodiments 1-33, wherein at least about 775 mg of the hemisulfate salt of the compound is administered. 44. The method of any one of embodiments 1-43, wherein the compound is administered once a day. 45. The method of any one of embodiments 1-43, wherein the compound is administered twice a day. 46. ​​The method of any one of embodiments 1-43, wherein the compound is administered four times a day. 47. A compound of formula I: [ka] (In the formula, R 1 is hydrogen, C 1~6 Alkyl, C 3~7 cycloalkyl, aryl, -(C1-C4 alkyl)aryl, heteroaryl, or heteroalkyl; R 2 is hydrogen or C 1~6 is alkyl, R 3a and R 3b are independently hydrogen, C 1~6 Alkyl, and C 3~7 cycloalkyl, and R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7-(C1-C4 alkyl)aryl, aryl, heteroaryl, or heteroalkyl), or a pharma- ceutically acceptable salt thereof. 48.R 1 is hydrogen. 49.R 1 is phenyl. 50.R 2 The compound for use according to any one of embodiments 47-49, wherein is hydrogen. 51.R 3a and R 3b is hydrogen and C 1~6 The compound for use according to any one of embodiments 47 to 50, wherein is alkyl. 52.R 4 is C 1~6 The compound for use according to any one of embodiments 47 to 51, wherein is alkyl. 53.R 1 is aryl, R 2 is hydrogen, R 3a is methyl, and R 4 is C 1~6 The compound for use according to embodiment 47, wherein said compound is alkyl. 54. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. 55. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 56. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 57. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 58. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 59. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 60. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 61. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 62. The compound for use according to any one of embodiments 47-61, wherein the pharma- ceutically acceptable salt is a hemisulfate salt. 63. The compound is [ka] 57. The compound for use according to embodiment 56, wherein 64. The compound is [ka] 58. The compound for use according to embodiment 57, wherein 65. The compound is [ka] 64. The compound for use according to embodiment 63, wherein 66. The compound is [ka] 64. The compound for use according to embodiment 63, wherein 67. The compound is [ka] 65. The compound for use according to embodiment 64, wherein 68. The compound is [ka] 65. The compound for use according to embodiment 64, wherein 69. The compound for use according to any one of embodiments 47 to 68, wherein the virus is selected from Dengue virus, West Nile fever virus, Yellow fever virus, and Zika virus. 70. The compound for use according to embodiment 69, wherein the virus is a dengue virus. 71. The compound for use according to embodiment 69, wherein the virus is a yellow fever virus. 72. The compound for use according to embodiment 69, wherein the virus is West Nile virus. 73. The compound for use according to embodiment 69, wherein the virus is Zika virus. 74. The compound for use according to any one of embodiments 47 to 73, wherein the compound is present in a dosage form suitable for oral administration. 75. The compound for use according to embodiment 74, wherein the oral dosage form is a solid oral dosage form. 76. The compound for use according to embodiment 75, wherein the oral dosage form is a tablet. 77. The compound for use according to embodiment 75, wherein the oral dosage form is a capsule. 78. The compound for use according to any one of embodiments 47-77, wherein about 500 mg to about 850 mg of the compound is administered. 79. The compound for use according to any one of embodiments 47-77, wherein about 500 mg to about 650 mg of the compound is administered. 80. The compound for use according to any one of embodiments 47-77, wherein about 600 mg to about 750 mg of the compound is administered. 81. The compound for use according to any one of embodiments 47-77, wherein about 650 mg to about 850 mg of the compound is administered. 82. The compound for use according to any one of embodiments 47-77, wherein at least about 550 mg of the compound is administered. 83. The compound for use according to any one of embodiments 47-77, wherein at least about 575 mg of the compound is administered. 84. The compound for use according to any one of embodiments 47-77, wherein at least about 600 mg of the hemisulfate salt of the compound is administered. 85. The compound for use according to any one of embodiments 47-77, wherein at least about 625 mg of the hemisulfate salt of the compound is administered. 86. The compound for use according to any one of embodiments 47-77, wherein at least about 700 mg of the compound is administered. 87. The compound for use according to any one of embodiments 47-77, wherein at least about 775 mg of the hemisulfate salt of the compound is administered. 88. The compound for use according to any one of embodiments 47 to 87, wherein the compound is administered once a day. 89. The compound for use according to any one of embodiments 47 to 87, wherein the compound is administered twice a day. 90. The compound for use according to any one of embodiments 47-87, wherein the compound is administered four times a day. 91. In the manufacture of a medicament for the treatment of a flavivirus infection in a human host, a compound of formula I: [ka] (In the formula, R1 is hydrogen, C 1~6 Alkyl, C 3~7 cycloalkyl, aryl, -(C1-C4 alkyl)aryl, heteroaryl, or heteroalkyl; R 2 is hydrogen or C 1~6 is alkyl, R 3a and R 3b are independently hydrogen, C 1~6 Alkyl, and C 3~7 cycloalkyl, and R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7 cycloalkyl, -(C1-C4 alkyl)aryl, aryl, heteroaryl, or heteroalkyl) or a pharma- ceutically acceptable salt thereof. 92.R 1 The use according to embodiment 91, wherein is hydrogen. 93.R 1 The use according to embodiment 91, wherein is phenyl. 94.R 2 The use according to any one of embodiments 91 to 93, wherein is hydrogen. 95.R 3a and R 3b is hydrogen and C 1~6 The use according to any one of embodiments 91 to 94, wherein the is alkyl. 96.R 4 is C 1~6 The use according to any one of embodiments 91 to 95, wherein is alkyl. 97.R 1 is aryl, R 2 is hydrogen, R 3a is methyl, and R 4 is C 1~6 The use according to embodiment 91, wherein the is alkyl. 98. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. 99. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 100. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 101. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 102. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 103. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 104. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 105. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 106. The use according to any one of embodiments 91 to 105, wherein the pharma- ceutically acceptable salt is a hemisulfate salt. 107. The compound is [ka] The use according to embodiment 100, wherein 108. The compound is [ka] The use according to embodiment 101, wherein 109. The compound is [ka] The use according to embodiment 107, wherein 110. The compound is [ka] The use according to embodiment 107, wherein 111. The compound is [ka] The use according to embodiment 108, wherein 112. The compound is [ka] The use according to embodiment 108, wherein 113. The use according to any one of embodiments 91 to 112, wherein the virus is selected from dengue virus, West Nile virus, yellow fever virus, and Zika virus. 114. The use according to embodiment 113, wherein the virus is a dengue virus. 115. The use according to embodiment 113, wherein the virus is a yellow fever virus. 116. The use according to embodiment 113, wherein the virus is West Nile virus. 117. The use according to embodiment 113, wherein the virus is Zika virus. 118. The use according to any one of embodiments 91 to 117, wherein the compound is present in a dosage form suitable for oral administration. 119. The use according to embodiment 118, wherein the oral dosage form is a solid oral dosage form. 120. The use according to embodiment 119, wherein the oral dosage form is a tablet. 121. The use according to embodiment 119, wherein the oral dosage form is a capsule. 122. The use according to any one of embodiments 91 to 121, wherein about 500 mg to about 850 mg of the compound is administered. 123. The use according to any one of embodiments 91 to 121, wherein about 500 mg to about 650 mg of the compound is administered. 124. The use according to any one of embodiments 91 to 121, wherein about 600 mg to about 750 mg of the compound is administered. 125. The use according to any one of embodiments 91 to 121, wherein about 650 mg to about 850 mg of the compound is administered. 126. The use according to any one of embodiments 91 to 121, wherein at least about 550 mg of the compound is administered. 127. The use according to any one of embodiments 91 to 121, wherein at least about 575 mg of the compound is administered. 128. The use according to any one of embodiments 91 to 121, wherein at least about 600 mg of the hemisulfate salt of the compound is administered. 129. The use according to any one of embodiments 91 to 121, wherein at least about 625 mg of the hemisulfate salt of the compound is administered. 130. The use according to any one of embodiments 91 to 121, wherein at least about 700 mg of the compound is administered. 131. The use according to any one of embodiments 91 to 121, wherein at least about 775 mg of the hemisulfate salt of the compound is administered. 132. The use according to any one of embodiments 91 to 131, wherein the compound is administered once a day. 133. The use according to any one of embodiments 91 to 131, wherein the compound is administered twice a day. 134. The use according to any one of embodiments 91 to 131, wherein the compound is administered four times a day. 135. In the manufacture of a medicament for treating a flavivirus infection in a host in need of treatment, an effective amount of a compound of formula II: [ka] (In the formula, R 5 teeth, [ka] , and R 10A is selected from R 10A is a stabilized phosphate prodrug that metabolizes in vivo to the monophosphate, diphosphate, or triphosphate, or a pharma- ceutically acceptable salt thereof. 136. The compound has the formula: [ka] (In the formula, R 10A The use according to embodiment 36 or 37, wherein: 137. The use according to embodiment 135 or 136, wherein the virus is selected from Dengue virus, West Nile virus, Yellow fever virus, and Zika virus. 138. The use according to embodiment 137, wherein the virus is a dengue virus. 139. The use according to embodiment 137, wherein the virus is a yellow fever virus. 140. The use according to embodiment 137, wherein the virus is Zika virus. 141. The use according to embodiment 137, wherein the virus is West Nile virus. 142. The use according to embodiment 137, wherein the host is a human. 143. A pharmaceutical composition for use in treating a human host in need of treatment infected with a flavivirus, comprising an effective amount of a compound of formula I: [ka] (In the formula, R 1 is hydrogen, C 1~6 Alkyl, C 3~7 cycloalkyl, aryl, -(C1-C4 alkyl)aryl, heteroaryl, or heteroalkyl; R 2 is hydrogen or C 1~6 is alkyl, R 3a and R 3b are independently hydrogen, C 1~6 Alkyl, and C 3~7 cycloalkyl, and R 4 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7 cycloalkyl, -(C1-C4 alkyl)aryl, aryl, heteroaryl, or heteroalkyl) or a pharma- ceutically acceptable salt thereof. 144.R 1 The pharmaceutical composition for use according to embodiment 143, wherein is hydrogen. 145.R 1 The pharmaceutical composition for use according to embodiment 143, wherein is phenyl. 146.R 2 The pharmaceutical composition for use according to any one of embodiments 143 to 145, wherein is hydrogen. 147.R 3a and R 3b is hydrogen and C 1~6 The pharmaceutical composition for use according to any one of embodiments 143 to 146, wherein R is alkyl. 148.R 4 is C 1~6 The pharmaceutical composition for use according to any one of embodiments 143 to 147, wherein R is alkyl. 149.R 1 is aryl, R 2 is hydrogen, R 3a is methyl, and R 4 is C 1~6The pharmaceutical composition for use according to embodiment 143, wherein R is alkyl. 150. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof. 151. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 152. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 153. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 154. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 155. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 156. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 157. The compound is [ka] or a pharma- ceutically acceptable salt thereof. 158. The compound is [ka] 153. The pharmaceutical composition for use according to embodiment 152, wherein 159. The compound is [ka] The pharmaceutical composition for use according to embodiment 153, wherein 160. The compound is [ka] The pharmaceutical composition for use according to embodiment 158, wherein 161. The compound is [ka] The pharmaceutical composition for use according to embodiment 158, wherein 162. The compound is [ka] The pharmaceutical composition for use according to embodiment 159, wherein 163. The compound is [ka] The pharmaceutical composition for use according to embodiment 159, wherein 164. A pharmaceutical composition for use according to any one of embodiments 150 to 163, wherein the virus is selected from dengue virus, West Nile fever virus, yellow fever virus, and Zika virus. 165. The pharmaceutical composition for use according to embodiment 164, wherein the virus is a dengue virus. 166. The pharmaceutical composition for use according to embodiment 164, wherein the virus is a yellow fever virus. 167. The pharmaceutical composition for use according to embodiment 164, wherein the virus is West Nile virus. 168. The pharmaceutical composition for use according to embodiment 164, wherein the virus is Zika virus. 169. A pharmaceutical composition for use according to any one of embodiments 150 to 168, wherein the compound is present in a dosage form suitable for oral administration. 170. The pharmaceutical composition for use according to embodiment 169, wherein the oral dosage form is a solid oral dosage form. 171. The pharmaceutical composition for use according to embodiment 169, wherein the oral dosage form is a tablet. 172. The pharmaceutical composition for use according to embodiment 169, wherein the oral dosage form is a capsule. 173. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein from about 500 mg to about 850 mg of the compound is administered. 174. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein from about 500 mg to about 650 mg of the compound is administered. 175. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein about 600 mg to about 750 mg of the compound is administered. 176. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein about 650 mg to about 850 mg of the compound is administered. 177. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein at least about 550 mg of the compound is administered. 178. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein at least about 575 mg of the compound is administered. 179. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein at least about 600 mg of the hemisulfate salt of the compound is administered. 180. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein at least about 625 mg of the hemisulfate salt of the compound is administered. 181. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein at least about 700 mg of the compound is administered. 182. A pharmaceutical composition for use according to any one of embodiments 150-172, wherein at least about 775 mg of the hemisulfate salt of the compound is administered. 183. A pharmaceutical composition for use according to any one of embodiments 150-182, wherein the compound is administered once a day. 184. A pharmaceutical composition for use according to any one of embodiments 150-182, wherein the compound is administered twice a day. 185. A pharmaceutical composition for use according to any one of embodiments 150-182, wherein the compound is administered four times a day.

[0058] Stabilized phosphate prodrugs Stabilized phosphate prodrugs are moieties that can deliver monophosphate, diphosphate or triphosphate in vivo.For example, McGuigan has disclosed phosphoramidates in U.S. Patent Nos. 8,933,053, 8,759,318, 8,658,616, 8,263,575, 8,119,779, 7,951,787 and 7,115,590.Alios has disclosed thiophosphoramidates in U.S. Patent Nos. 8,895,723 and 8,871,737, which are incorporated herein by reference.Alios has also disclosed cyclic nucleotides in U.S. Patent No. 8,772,474, which are incorporated herein by reference. Idenix disclosed cyclic phosphoramidates and phosphoramidate / SATE derivatives in US Pat. No. 5,399,613, which is incorporated herein by reference. Idenix also disclosed substituted carbonyloxymethyl phosphoramidate compounds in WO 2013 / 039920, which is incorporated herein by reference. Hostetler also disclosed lipid phosphate prodrugs. See, for example, U.S. Pat. No. 7,517,858, which is incorporated herein by reference. Hostetler also disclosed lipid conjugates of phosphate prodrugs. See, for example, U.S. Pat. Nos. 8,889,658, 8,846,643, 8,710,030, 8,309,565, 8,008,308, and 7,790,703. Emory University disclosed nucleotide sphingoid and lipid derivatives in WO 2014 / 124430, which is incorporated herein by reference. RFS Pharma disclosed purine nucleoside monophosphate prodrugs in WO 2010 / 091386. Cocrystal Pharma Inc. also disclosed purine nucleoside monophosphate prodrugs in U.S. Patent No. 9,173,893, which is incorporated herein by reference.HepDirect™ technology was disclosed in the article "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-thioester) prodrugs, and DTE (dithiodiethyl) prodrugs. For literature reviews disclosing 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 certain embodiments, a 5'-prodrug described in any of these patent applications or publications is used as the R of the presented compound. 5 It can be used in the following positions.

[0059] In certain embodiments, stabilized phosphate prodrugs include, but are not limited to, those described in U.S. Patent No. 9,173,893 and U.S. Patent No. 8,609,627, which are incorporated herein by reference, including those described in the preparation process. For example, 5'-prodrugs may be prepared by the group: [ka] (In the formula, Z is O or S; R 17 and R 18 can be represented by the formula: R is capable of providing a nucleoside monophosphate, diphosphate, or triphosphate when administered in vivo. 17 and R 18 are independently selected from: (a) OR 19 , where R 19 is selected from H, Li, Na, K, phenyl and pyridinyl, where phenyl and pyridinyl are (CH2) 0~6 CO2R 20 and (CH2) 0~6 CON(R 20 ) optionally substituted with 1 to 3 substituents independently selected from the group consisting of R 20 are independently H, C 1~20 Alkyl, carbon chain derived from fatty alcohol (oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C1~5 is alkyl; (b) [ka] (c) Esters of D- or L-amino acids: [ka] (In the formula, R 21 is limited to the side chains occurring in natural L-amino acids, R 22 is H, C 1~20 Alkyl, carbon chain derived from fatty alcohol (oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C 1~5 is alkyl); (d)R 17 and R 18 are both rings: [ka] (In the formula, R 23 is H, C 1~20 Alkyl, C 1~20 Alkenyl, carbon chain derived from fatty alcohol (oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc.), or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C 1~5 alkyl); (e)R 17 and R 18 Both, [ka] (In the formula, R 24 is H, C 1~20 Alkyl, C 1~20 Alkenyl, carbon chains derived from fatty acids (oleic acid, linoleic acid, etc.), lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 C substituted with cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl or substituted heteroaryl 1~20 alkyl, where the substituents are C 1~5 Alkyl or lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C 3~10 Cycloalkyl or cycloalkyl-substituted C 1~5 is alkyl, R 25 may form a ring selected from:

[0060] The present invention also relates to a method for producing 5 is monophosphate, diphosphate, triphosphate, or R 10A where R 10A is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate. [ka] (In the formula, R 5 teeth, [ka] , and R 10A is selected from R 10A is a stabilized phosphate prodrug that metabolizes in vivo to the monophosphate, diphosphate, or triphosphate), or a pharma- ceutically acceptable salt thereof, to treat a Flavivirus infection in a host, typically a human, in need of such treatment, where all other variables are as previously defined herein.

[0061] In some embodiments, R 5 teeth, [ka] is selected from.

[0062] In some embodiments, R 5 teeth, [ka] It is.

[0063] In some embodiments, R 5 teeth, [ka] It is.

[0064] In some embodiments, R 5 teeth, [ka] It is.

[0065] In one embodiment of Formula II, R 5 teeth, [ka] It is.

[0066] In one embodiment of Formula II, R 5 teeth, [ka] It is.

[0067] In one embodiment of Formula II, R 5 teeth, [ka] It is.

[0068] In one embodiment of Formula II, R 5 is R 10A It is.

[0069] Embodiment (i). In one embodiment of Formula I, R 1 is aryl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is C1-C6 alkyl.

[0070] (ii). In one embodiment of Formula I, R 1 is aryl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is methyl and R 4 is C1-C6 alkyl.

[0071] (iii). In one embodiment of formula I, R 1 is phenyl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is C1-C6 alkyl.

[0072] (iv) In one embodiment of formula I, R 1 is phenyl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is methyl and R 4 is C1-C6 alkyl.

[0073] (v) In one embodiment of Formula I, R 1 is aryl, and R 2 is methyl, R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is C1-C6 alkyl.

[0074] (vi). In one embodiment of formula I, R 1 is aryl, and R 2 is methyl, R 3a is hydrogen, and R 3b is methyl and R 4 is C1-C6 alkyl.

[0075] (vii). In one embodiment of formula I, R 1 is phenyl, and R 2 is methyl, R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is C1-C6 alkyl.

[0076] (viii). In one embodiment of formula I, R 1 is phenyl, and R 2 is methyl, R 3a is hydrogen, and R 3b is methyl and R 4 is C1-C6 alkyl.

[0077] (ix). In one embodiment of formula I, R 1 is aryl, and R 2 is hydrogen, and R 3a is hydrogen, and R3b is C1-C4 alkyl, and R 4 is isopropyl.

[0078] (x) In one embodiment of formula I, R 1 is aryl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is methyl and R 4 is isopropyl.

[0079] (xi). In one embodiment of formula I, R 1 is phenyl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is isopropyl.

[0080] (xii). In one embodiment of formula I, R 1 is phenyl, and R 2 is hydrogen, and R 3a is hydrogen, and R 3b is methyl and R 4 is isopropyl.

[0081] (xiii) In one embodiment of formula I, R 1 is aryl, and R 2 is methyl, R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is isopropyl.

[0082] (xiv) In one embodiment of formula I, R 1 is aryl, and R 2 is methyl, R 3a is hydrogen, and R 3b is methyl and R 4 is isopropyl.

[0083] (xv) In one embodiment of formula I, R 1is phenyl, and R 2 is methyl, R 3a is hydrogen, and R 3b is C1-C4 alkyl, and R 4 is isopropyl.

[0084] (xvi) In one embodiment of formula I, R 1 is phenyl, and R 2 is methyl, R 3a is hydrogen, and R 3b is methyl and R 4 is isopropyl.

[0085] In certain embodiments of (i)-(xvi), an L-nucleoside is used in formula I.

[0086] In certain embodiments, the treatment of a flavivirus infection in a host, including a human in need thereof, comprises administering an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharma- ceutically acceptable salt of the compound of formula I is a hemisulfate salt. Additional non-limiting examples of compounds of formula I include: [ka] TIFF2024533122000088.tif178170 is an example.

[0087] In certain embodiments, the treatment of a flavivirus infection in a host, including a human in need thereof, comprises administering an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pharma- ceutically acceptable salt of the compound of formula I is a hemisulfate salt. Additional non-limiting examples of compounds of formula I include: [ka] TIFF2024533122000090.tif196170 is an example.

[0088] II. Definition The following terms are used to describe the present invention. If a term is not specifically defined herein, the term is given the meaning as recognized by one of ordinary skill in the art applying the term in the context of its use in describing the present invention.

[0089] The term "alkyl", in its context, refers to a straight or branched chain, fully saturated, optionally substituted (e.g., by halogen, including F) hydrocarbon radical or alkyl group. For example, an alkyl group may have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C1-C8 alkyl), 1, 2, 3, 4, 5, or 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 4 carbon atoms (i.e., C1-C4 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0090] The term "alkenyl" refers to a non-aromatic hydrocarbon group containing at least one double bond between adjacent carbon atoms and, unless otherwise stated herein, a structure similar to an alkyl group. For example, an alkenyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-butenyl (-C=CH-CH2CH3), and 2-butenyl (-CH2CH=CHCH2). As described herein, an alkenyl group may be substituted.

[0091] The term "alkynyl" refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and, unless otherwise stated herein, a structure similar to an alkyl group. For example, an alkynyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Examples of alkynyl groups include, but are not limited to, acetylenic, or ethynyl, and propargyl. Alkynyl groups may be substituted as described herein.

[0092] The term "acyl" refers to a moiety, --C(O)R, in which a carbonyl moiety is attached to R, e.g., --C(O)alkyl. R may be selected from alkoxy, alkyl, cycloalkyl, lower alkyl (i.e., C1-C4), alkoxyalkyl, including methoxymethyl, aralkyl, including benzyl, aryloxyalkyl, including phenoxymethyl, and the like, aryl, including phenyl, which may be substituted with halogen, C1-C4 alkyl, or C1-C4 alkoxy. In one embodiment, the term "acyl" refers to a monophosphate, diphosphate, or triphosphate.

[0093] The term "lower acyl" refers to an acyl group in which the carbonyl moiety is a lower alkyl (ie, C1-C4).

[0094] The term "alkoxy" refers to the group -OR', where -OR' is -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C0-C2)(cycloalkyl), -O-(C0-C2)(heterocyclo), -O-(C0-C2)(aryl), or -O-(C0-C2)(heteroaryl), each of which may be substituted.

[0095] The term "amino" refers to the group -NH2.

[0096] The term "amino acid" or "amino acid residue" refers to D- or L-amino acids of natural or non-natural origin. Representative amino acids include, but are not limited to, 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.

[0097] The term "aryl" or "aromatic", in context, refers to a monovalent aromatic radical having a single ring (e.g., phenyl or benzyl), which may be substituted (unless otherwise stated herein) or unsubstituted, or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), and may be attached to a compound according to the invention at any available stable position on the ring(s) or as otherwise shown in the chemical structure provided. As described herein, aryl groups may be substituted.

[0098] "Cycloalkyl", "carbocycle" or "carbocyclyl" refers to a ring having from 3 to 7 carbon atoms as a monocyclic ring that may be saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.). Monocyclic carbocycles have from 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.

[0099] The term "cyano" refers to the group --CN.

[0100] The term "halogen" or "halo" refers to chloro, bromo, fluoro or iodo.

[0101] Heteroaryl ring systems are saturated or unsaturated rings containing one or more nitrogen, oxygen, or sulfur atoms in a (single) ring, including, but not limited to, imidazole, furyl, pyrrole, furanyl, thien, thiazole, pyridine, pyrimidine, purine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, etc., among others, which may be optionally substituted as described above. Heteroaryl groups include nitrogen-containing heteroaryl groups, such as, in particular, pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, purine, indazole, quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazino-pyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles, Examples include 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, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0102] The term "heterocycle" or "heterocyclo" refers to a cyclic group containing at least one heteroatom, i.e., O, N, or S, which may be aromatic (heteroaryl) or non-aromatic. Examples of 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, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide, among others, all of which may be optionally substituted.

[0103] The term "hydroxyl" refers to the group --OH.

[0104] The term "nitro" refers to the group --NO.

[0105] The term "pharmaceutical acceptable salt" or "prodrug" refers to a 2'-chloro-2'-fluoro-N-(2-fluoro-N-acetylglucosamine) salt, which, upon administration to a patient, provides the desired active compound. 2 -Amino-N 6- is used throughout the specification to describe any pharma- ceutically acceptable form of salt of methylaminopurine nucleotide (such as ester, phosphoramidate, thiophosphoramidate, phosphate ester, salt of ester or related groups). Examples of pharma-ceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylates, methanesulfonates, acetates, citrates, malonates, tartrates, succinates, benzoates, ascorbates, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can also be formed, including sulfates, nitrates, bicarbonates, and carbonates. Pharmaceutically acceptable salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid that results in a physiologically acceptable anion, using standard techniques well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

[0106] A "pharmacologically acceptable prodrug" refers to a compound that is metabolized in the host, e.g., hydrolyzed or oxidized, to form a compound of the invention. Typical examples of prodrugs include compounds that have a biologically labile protecting group on a functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, thiophosphoramidated, dethiophosphoramidated, phosphoramidated, or dephosphoramidated to produce an active compound. The compounds of the invention have antiviral activity against flaviviruses or are metabolized to a compound that exhibits such activity. 2'-chloro-2'-fluoronucleosides can also be administered as 5'-phosphoether lipids, bisphosphoramidates, 3',5'-cyclic phosphoramidates, 3',5'-cyclic thiophosphoramidates, DTE conjugates, mixed phosphoramidate-SATE derivatives, or "SATE" derivatives.

[0107] The term "phosphate" refers to the group -P(O)(OH).

[0108] The term "substituted" or "optionally substituted" refers to an alkyl group, such as azido, cyano, halogen (fluoro, chloro, bromo, or iodo), alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, haloalkyl (e.g., CHF2, CH2F, CF3), hydroxyl, alkoxy, amino, -NH(C1-C6 unsubstituted alkyl), -NH(C1-C6 substituted alkyl), -NH-(C0-C2 alkyl)(C3-C8 cycloalkyl), -NH-(C0-C2 alkyl)(C3-C8 heterocycle), This indicates that it may have at least one additional substituent selected from the group consisting of -NH-(C0-C2 alkyl) (aryl), -N(C1-C6 unsubstituted alkyl)2, -N(C1-C6 unsubstituted alkyl) (C1-C6 substituted alkyl), -N(C1-C6 substituted alkyl)2, -NH-(C0-C2 alkyl) (C3-C8 cycloalkyl), -NH-(C0-C2 alkyl) (C3-C8 heterocycle), -NH-(C0-C2 alkyl) (aryl), acyl, nitro, sulfonate, sulfate, phosphate, phosphonate or thiol.

[0109] formula R 114 S(O)2OR 115 The term "sulfonate ester" represented by R 114 where R 114 is alkyl, haloalkyl, aralkyl or aryl. R 115 is alkyl, aryl, or aralkyl.

[0110] The term "sulfonic acid" refers to the group -SO2OH.

[0111] The term "thiol" refers to the group --SH.

[0112] "Phosphate" refers to the group -OP(O)(OH).

[0113] "Phosphate ester" refers to monophosphates, diphosphates and triphosphates, unless otherwise indicated.

[0114] The term "phosphoramidate", "phosphoramidate" or "phosphoroamidate" refers to a moiety having a phosphorus bonded to three oxygen groups and an amine (optionally substituted). Suitable non-limiting phosphoramidates useful in the present invention are described by 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 disclosed in U.S. Patent Nos. 5,233,031, 7,115,590, 7,547,704, 7,879,815, 7,888,330, 7,902,202, 7,951,789, 7,964,580, 8,071,568, 8,148,349, 8,263, 575, 8,324,179, 8,334,270, 8,552,021, 8,563,530, 8,580,765, 8,735,372, 8,759,318, 6,455,513, and 8,334,270, as well as in EP 2120565 and EP 1143995. Other phosphoramidates are described in the nucleoside patents described in the Background of the Invention.

[0115] Non-limiting examples of phosphoramidates include: [ka] Examples include:

[0116] Other phosphoramidates included in the present invention are of the structure: [ka] During the ceremony, R P1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl, or heterocyclic group, or linked combinations thereof; R P2 -NR N1 R N2 group or a B′ group, During the ceremony, R N1 and R N2 are each independently H, C 1~8 alkyl, (C3-C7 cycloalkyl)C0-C4 alkyl, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, or (heteroaryl)C0-C4 alkyl-, which may be substituted, or R N1 and R N2 joins with the nitrogen atom to which it is attached to form a 3- to 7-membered heterocycle; B' is [ka] It is based on During the ceremony, R 13is hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-, or the side chain of an amino acid, for example (unless otherwise stated herein) 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 13 is hydrogen, methyl, isopropyl or isobutyl; R 14 is hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-, or the side chain of an amino acid, for example (unless otherwise stated herein) 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 14 is hydrogen, methyl, isopropyl or isobutyl; R 15 is hydrogen or C1-C3 alkyl, or R 13 and R 14 may form a (C3-C7)cycloalkyl or (C3-C7)heterocyclic group, Or R 13 and R 14 Or R 16 may form a (C3-C6) heterocyclic group, R 16is hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C8 cycloalkyl) C0-C4 alkyl, (aryl) C0-C4 alkyl-, (C3-C6 heterocyclo) C0-C4 alkyl-, (heteroaryl) C0-C4 alkyl-.

[0117] Preferred R P1 Groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, particularly groups that enhance the bioavailability of the compound in the cells of a patient (especially lipophilic groups), which show reduced toxicity, enhanced therapeutic index, and enhanced pharmacokinetics (the compound is metabolized and excreted more slowly).

[0118] The term "thiophosphoamidate", "thiophosphoramidate" or "thiophosphoroamidate" refers to a moiety having a phosphorus bonded to a sulfur, two oxygen groups and an amine (which may be substituted). Non-limiting examples of thiophosphoramidates included in the present invention are described in U.S. Pat. No. 8,772,474 and WO 2012 / 040124.

[0119] Thiophosphoramidate groups for use in the present invention include those of the following structure: [ka]

[0120] Other thiophosphoramidates included in the present invention are of the structure: [ka] During the ceremony, R P1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl, or heterocyclic group, or linked combinations thereof; R P2 -NR N1 R N2 group or a B′ group, During the ceremony, R N1 and R N2 are each independently H, C 1~ C8 alkyl, (C3-C7 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, or (heteroaryl)C0-C4 alkyl-, which may be substituted, or R N1 and R N2 joins with the nitrogen atom to which it is attached to form a 3- to 7-membered heterocycle; B' is [ka] It is based on During the ceremony, R 13 is hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-, or the side chain of an amino acid, for example (unless otherwise stated herein) 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 13 is hydrogen, methyl, isopropyl or isobutyl; R 14is hydrogen, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8 cycloalkyl)C0-C4 alkyl-, (aryl)C0-C4 alkyl-, (C3-C6 heterocyclo)C0-C4 alkyl-, (heteroaryl)C0-C4 alkyl-, or the side chain of an amino acid, for example (unless otherwise stated herein) 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 14 is hydrogen, methyl, isopropyl or isobutyl; R 15 is hydrogen or C1-C3 alkyl, or R 15 and R 13 Or R 14 may form a (C3-C7)cycloalkyl or (C3-C7)heterocyclic group, R 16 is hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C8 cycloalkyl) C0-C4 alkyl, (aryl) C0-C4 alkyl-, (C3-C6 heterocyclo) C0-C4 alkyl-, (heteroaryl) C0-C4 alkyl-.

[0121] In certain non-limiting embodiments, R P1 is selected from the group consisting of optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups.

[0122] The term "D-configuration" as used in the context of the present invention refers to the principle configuration that mimics the natural configuration of the sugar moiety, as opposed to non-naturally occurring nucleosides or the "L" configuration. The term "β" or "β anomer" is used in reference to nucleoside analogs in which the nucleoside base is formed (positioned) above the plane of the furanose moiety in the nucleoside analog.

[0123] The term "host" as used herein refers to a unicellular or multicellular organism, including cell lines and animals, typically humans, in which the flavivirus can replicate. The term host specifically refers to infected cells, cells transfected with all or part of the flavivirus genome, as well as animals, particularly primates (including chimpanzees) and humans. In most animal applications of the invention, the host is a human patient. However, veterinary uses are expressly contemplated by the invention in certain indications (such as chimpanzees). The host may be, for example, a bovine, equine, avian, canine, feline, etc.

[0124] As used herein, the term "Flavivirus" or "Flaviviruses" refers to viruses of the Flavivirus genus.

[0125] Isotope Substitution The present invention involves the administration of an effective amount of a compound with substitution of a desired isotope of an atom at greater than natural abundance, i.e., enriched, isotope amount. Isotopes are atoms with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. As a general example and without limitation, for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in the depicted structures. Alternatively, or in addition, isotopes of carbon, such as 13 C and 14C may also be used. A typical isotopic substitution is the replacement of hydrogen with deuterium at one or more positions on a molecule to improve the performance of a drug. Deuterium can be attached at the position of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or adjacent to or near the site of bond cleavage (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 efficacy, including at the 5-position of the molecule.

[0126] Substitution with isotopes such as deuterium can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Substitution of hydrogen at a site of metabolic degradation with deuterium can reduce the rate of metabolism or eliminate metabolism at that bond. At any position in a compound where a hydrogen atom can be present, the hydrogen atom can be substituted with protium ( 1 H), deuterium ( 2 H) and tritium ( 3 Any isotope of hydrogen may be used, including H. Thus, unless the context clearly dictates otherwise, references herein to compounds include all possible isotopic forms.

[0127] The term "isotope-labeled" analogues refers to "deuterated analogues," 13 C-labeled analogues or deuterated / 13 The term "deuterated analog" refers to an analog that is a "C labeled analog" or a "C labeled analog" of the compounds described herein. 1 H) is converted to H-isotope, namely deuterium ( 2H). Deuterium substitution may be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium. In certain embodiments, the isotope is enriched to 90%, 95%, 96%, 97%, 98%, or 99% or more in the isotope at any desired position. In some embodiments, it is deuterium that is enriched to 90%, 95%, 96%, 97%, 98%, or 99% at the desired position. Unless specified to the contrary, deuteration is at least 80% at the selected position. Deuteration of a nucleoside may occur at any replaceable hydrogen that provides the desired result.

[0128] III. Treatment or Prevention Methods As used herein, treatment refers to the administration of an effective amount of an active compound to a host infected with a flavivirus, particularly a dengue virus, yellow fever virus, Zika virus, or West Nile virus, where the host is typically a human.

[0129] The terms "prevention" or "prophylactic" as used herein refer to the administration of an effective amount of an active compound to forestall or reduce the likelihood of a viral disorder occurring. The present invention includes both treatment and prophylactic or preventative therapies. In one embodiment, an effective amount of an active compound is administered to a host, typically a human, who has been exposed to a flavivirus infection and is therefore at risk for infection with a flavivirus infection.

[0130] The present invention includes the treatment of infections caused by flaviviruses, including drug-resistant and multi-drug resistant forms of flaviviruses, as well as associated symptoms, conditions, or complications of flavivirus infections, and other conditions secondary to flavivirus infections, such as weakness, loss of appetite, weight loss, breast enlargement (especially in men), rashes (especially on the palms of the hands), difficulty in clotting blood, spider veins on the skin, confusion, coma (encephalopathy), accumulation of fluid in the abdominal cavity (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, low blood counts, anemia, thrombocytopenia, jaundice, and hepatocellular carcinoma, among others. The treatment is accomplished by administering to a host, typically a human, an effective amount of at least one 2'-chloro-2'-fluoro-N-methyl-N-pyridine derivative as described herein. 2 -Amino-N 6 -methylaminopurine nucleotide phosphoramidate, optionally in combination with at least one additional bioactive agent, such as an additional anti-flavivirus agent, further in combination with a pharmaceutically acceptable carrier, additive, and / or excipient.

[0131] In one embodiment, the active compound is administered in an effective amount to a host, typically a human, infected with a flavivirus.

[0132] In one embodiment, the active compound is administered in an effective amount to a host, typically a human, infected with the dengue virus.

[0133] In one embodiment, the active compound is administered in an effective amount to a host, typically a human, infected with yellow fever virus.

[0134] In one embodiment, the active compound is administered in an effective amount to a host, typically a human, infected with Zika virus.

[0135] In one embodiment, the active compound is administered in an effective amount to a host, typically a human, infected with West Nile Virus.

[0136] In one embodiment, the flavivirus infection is dengue fever. In a further embodiment, the dengue fever is dengue virus type 1, dengue virus type 2, dengue virus type 3, or dengue virus 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 from Zika virus.

[0137] IV. Pharmaceutical Compositions In one embodiment of the invention, the pharmaceutical composition according to the invention comprises an anti-flaviviral effective amount of at least one 5'-stabilized 2'-chloro-2'-fluoro-N-methyl-2'-pyridine as described herein. 2 -Amino-N 6 3-methylaminopurine nucleotide compounds or pharma- ceutical acceptable salts thereof, optionally in combination with a pharma- ceutical acceptable carrier, additive, or vehicle, and optionally in combination with or in place of at least one other active compound. In certain embodiments, the virus to be treated is dengue virus. In certain embodiments, the virus to be treated is yellow fever virus. In certain embodiments, the virus to be treated is Zika virus. In certain embodiments, the virus to be treated is West Nile virus.

[0138] In one embodiment of the invention, the pharmaceutical composition according to the invention comprises an anti-flaviviral effective amount of at least one active 2'-chloro-2'-fluoro-N 2 -Amino-N 6 The .sup.-methylaminopurine nucleotide phosphoramidate compound is in combination with a pharma- ceutically acceptable carrier, excipient, or vehicle, and further in combination with an effective amount of at least one other antiviral agent, such as an anti-flavivirus agent.

[0139] Those skilled in the art will recognize that a therapeutically effective amount will vary depending on the infection or condition being treated, its severity, the treatment regimen employed, the pharmacokinetics of the drugs used, as well as the patient or subject (animal or human) being treated, and such therapeutic amount can be determined by the attending physician or specialist. In certain embodiments, the patient is a human.

[0140] The 2'-chloro-2'-fluoro-N 2 -Amino-N 6 -methylaminopurine nucleotide phosphoramidate may be formulated in a mixture with a pharma- ceutically acceptable carrier. In general, it is typical to administer pharmaceutical compositions in oral dosage form, but certain formulations may be administered by other routes, including parenteral, intravenous, intramuscular, inhalation, topical, transdermal, buccal, subcutaneous, suppository, and nasal spray. Intravenous and intramuscular formulations are often administered in sterile saline. Those skilled in the art may modify the formulation to make it more soluble in water or other vehicles, for example, this can be easily accomplished by minor modifications (salt formulations, esterification, etc.), which are well within the ordinary skill in the art. It is also within the ordinary skill in the art to modify the administration route and dosing schedule of a particular compound in order to manage the pharmacokinetics of the compound of the present invention to the maximum beneficial effect in patients.

[0141] In certain pharmaceutical dosage forms, prodrug forms of the compounds of the present invention are typical, including in particular 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.Those skilled in the art will recognize how to easily convert the compounds of the present invention into prodrug forms to facilitate the delivery of the active compound to the target site of the host organism or patient.When applicable, the favorable pharmacokinetic parameters of the prodrug forms are utilized in the delivery of the active compound to the target site of the host organism or patient to maximize the intended effect of the compounds.

[0142] The amount of compound contained in the therapeutically active formulation according to the invention is an amount effective to treat flavivirus infection, reduce the likelihood of flavivirus infection, or inhibit, reduce, and / or eliminate flavivirus, or its secondary effects, including disease states, conditions, and / or complications secondary to flavivirus infection. In general, a therapeutically effective amount of a compound of the invention in a pharmaceutical dosage form will usually range from about 0.001 mg / kg to about 100 mg / kg or more per day to a patient, often from slightly less than about 0.1 mg / kg to considerably more than about 25 mg / kg per day, depending on the compound used, the condition or infection being treated, and the route of administration. The active nucleoside compounds according to the invention are often administered in amounts ranging from about 0.1 mg / kg to about 15 mg / kg per day to a patient, depending on the pharmacokinetics of the drug in the patient. This dosage range generally results in an effective blood concentration of the active compound which may range from about 0.001 micrograms to about 100 micrograms, or from about 0.05 micrograms to about 100 micrograms per cc of the patient's blood.

[0143] Often, to treat, prevent, or delay the onset of these infections and / or to reduce the likelihood of a flavivirus infection or a secondary condition, pathology, or complication of a flavivirus infection, the compositions will be administered in an oral dosage form in an amount ranging from about 100 milligrams to about 1200 mg or more at least once daily, e.g., at least about 400 milligrams, 450 milligrams, 500 milligrams, 550 milligrams, 600 milligrams, 650 milligrams, 700 milligrams, 750 milligrams, 800 milligrams, 850 milligrams, 900 milligrams, 950 milligrams, 1000 milligrams, 1050 milligrams, 1100 milligrams, 1150 milligrams, or 1200 milligrams once daily, twice daily, three times daily, or four times daily.

[0144] In certain embodiments, 2'-chloro-2'-fluoro-N 2 -Amino-N 6The -methylaminopurine nucleotide phosphoramidate is administered in an oral dosage form at least once a day in an amount of about 500 milligrams to about 850 milligrams, for example, at least about 500 milligrams, 525 milligrams, 550 milligrams, 575 milligrams, 600 milligrams, 625 milligrams, 650 milligrams, 675 milligrams, 700 milligrams, 725 milligrams, 750 milligrams, 775 milligrams, 800 milligrams, 825 milligrams, 850 milligrams or more. In certain embodiments, the composition is administered in an oral dosage form at about 500 mg to at least about 650 mg or more once a day, twice a day, three times a day, or four times a day. In certain embodiments, the composition is administered in an oral dosage form at about 600 mg to at least about 750 mg or more once a day, twice a day, three times a day, or four times a day. In certain embodiments, the composition will be administered in an oral dosage form in an amount of about 650 mg to at least about 850 mg or more once a day, twice a day, three times a day, or four times a day. The compounds are often administered orally, but may also be administered parenterally, topically, or in suppository form, as well as intranasally as a nasal spray or as otherwise described herein.

[0145] In certain embodiments, the 2'-chloro-2'-fluoro-N 2 -Amino-N 6 -methylaminopurine nucleotide phosphoramidate compound is used as hemisulfate.In certain embodiments, the hemisulfate of the compound is administered in an oral dosage form in an amount ranging from 400 milligrams to about 1200 milligrams at least once a day, for example once a day, twice a day, three times a day, or four times a day.In certain embodiments, at least about 400 milligrams, 450 milligrams, 500 milligrams, 550 milligrams, 600 milligrams, 650 milligrams, 700 milligrams, 750 milligrams, 800 milligrams, 850 milligrams, 900 milligrams, 950 milligrams, or 1000 milligrams of the hemisulfate of the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day.

[0146] In certain embodiments, 2'-chloro-2'-fluoro-N 2 -Amino-N 6 The hemisulfate salt of the -methylaminopurine nucleotide phosphoramidate will be administered at least once a day in an oral dosage form in an amount of about 500 milligrams to about 850 milligrams, for example, about 500 milligrams, 525 milligrams, 550 milligrams, 575 milligrams, 600 milligrams, 625 milligrams, 650 milligrams, 675 milligrams, 700 milligrams, 725 milligrams, 750 milligrams, 775 milligrams, 800 milligrams, 825 milligrams, 850 milligrams or more. In certain embodiments, about 500 milligrams to at least about 650 milligrams of the hemisulfate salt of the compound will be administered once a day, twice a day, three times a day, or four times a day. In certain embodiments, about 600 milligrams to at least about 750 milligrams of the hemisulfate salt of the compound will be administered once a day, twice a day, three times a day, or four times a day. In certain embodiments, about 650 milligrams to at least about 850 milligrams of the hemisulfate salt of the compound is administered once per day, twice per day, three times per day, or four times per day.

[0147] 2'-Chloro-2'-fluoro-N 2 -Amino-N 6 When the 2'-methylaminopurine nucleoside phosphoramidates are co-administered in combination with another anti-flavivirus compound described elsewhere herein, the amount of compound administered ranges from about 0.01 mg per kg of patient to about 500 mg per kg of patient or more, or even more, depending on the second agent co-administered and its potency against the virus, the condition of the patient, and the severity of the disease or infection being treated, and the route of administration. 2 -Amino-N 6-methylaminopurine nucleotide phosphoramidates, when administered in combination with another anti-flavivirus compound described herein, are administered in an amount ranging from about 500 milligrams to about 850 milligrams once a day, twice a day, three times a day, or four times a day. The other anti-flavivirus agent may be administered, for example, in an amount ranging from about 0.01 mg / kg to about 500 mg / kg. In certain embodiments, the compound may be administered in an amount ranging from about 0.5 mg / kg to about 50 mg / kg or more (usually up to about 100 mg / kg), often depending on the pharmacokinetics of the two agents in the patient. These dosage ranges generally provide effective blood levels of the active compound in the patient.

[0148] For purposes of this invention, a preventatively or prophylactically effective amount of a composition according to the invention falls within the same concentration ranges as set forth above for a therapeutically effective amount, and is usually the same as the therapeutically effective amount.

[0149] Administration of an effective amount of the active compound may include continuous intravenous infusion to several oral or nasal administrations per day (e.g., QID), or transdermal administration, as well as 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 may also be used to enhance the bioavailability of the compound for oral routes of administration. The most effective dosage form depends on the bioavailability / pharmacokinetics of the particular drug selected, as well as the severity of the patient's disease. Oral dosage forms are particularly typical due to ease of administration and expected favorable patient compliance.

[0150] To prepare pharmaceutical compositions according to the invention, a therapeutically effective amount of one or more compounds according to the invention is often mixed essentially with a pharma- ceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dosage. The carrier may take a variety of forms, depending on the dosage form desired, for example, for oral or parenteral administration. In preparing pharmaceutical compositions into oral dosage forms, any of the usual pharmaceutical media may 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, flavorings, preservatives, and coloring agents. For solid oral preparations such as powders, tablets, capsules, and solid preparations such as suppositories, suitable carriers and additives may be used, including, but not limited to, sugar carriers such as starch, dextrose, manifolds, lactose, and related carriers, diluents, granulating agents, lubricants, binders, and disintegrants. If desired, tablets or capsules may be enteric coated or sustained release by standard techniques. The use of these dosage forms can significantly enhance the bioavailability of the compound in the patient.

[0151] For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, but may contain other ingredients, including those that aid in dispersion. Where sterile water is to be used and maintained as sterile, the composition and carrier must, of course, also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be utilized.

[0152] Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharma- ceutically acceptable carriers, which may be suitable for delivery of the free nucleoside, acyl / alkyl nucleoside, or phosphate ester prodrug forms of the nucleoside compounds according to the invention.

[0153] In an exemplary embodiment according to the invention, the compounds and compositions are used to treat, prevent, or delay a flavivirus infection, or a disease state, condition, or complication secondary to a flavivirus infection.

[0154] V. Combination and Alternative Therapy It is well recognized that drug-resistant mutants of the virus may emerge after prolonged treatment with antiviral agents. Drug resistance most typically occurs through mutations in genes that code for enzymes used in viral replication. The efficacy of a drug against flavivirus infections may be extended, increased, or restored by administering the compound in combination with or alternating with another (perhaps even two or three other) antiviral compound that induces a different mutation or acts through a different pathway than that of the principle drug. Alternatively, the pharmacokinetics, biodistribution, half-life, or other parameters of the drug may be altered by such combination therapy (which may include alternation therapy, if deemed coordinated). The disclosed 2'-chloro-2'-fluoro-N 2 -Amino-N 6 -Methylaminopurine nucleotide phosphoramidates are polymerase inhibitors, so an effective amount of 2'-chloro-2'-fluoro-N 2 -Amino-N 6 -methylaminopurine nucleotide phosphoramidate is administered to a host in need thereof in an effective amount, e.g. (1) protease inhibitors such as NS2B / NS3 protease inhibitors, (2) Compounds that disrupt the NS3 / NS4B complex, such as, but not limited to, JNJ-A07; (3) another polymerase inhibitor, (4) interferon α-2a, which may be pegylated or otherwise modified, and / or ribavirin; (5) non-substrate-based inhibitors (6) helicase inhibitors, (7) antisense oligodeoxynucleotide (S-ODN), (8) aptamers, (9) nuclease-resistant ribozymes, (10) iRNA, including microRNA and siRNA, (11) An antibody, partial antibody, or domain antibody against a virus, or (12) A viral antigen or partial antigen that induces a host antibody response, It may be useful to administer it in combination with

[0155] VI. 2'-Chloro-2'-fluoro-N 2 -Amino-N 6 Method for preparing -methylaminopurine nucleotide phosphoramidates - Patent Application 20070223333 General methods for providing the compounds of the invention are known in the art or described herein. The synthesis of 2'-chloro nucleotides is described in US Patent Publication No. 20150366888, WO 2014058801, WO 2015 / 066370, and WO 2015200219.

[0156] The following abbreviations are used in the synthetic schemes:

[0157] n-BuLi: n-butyl lithium BSA: N,O-bis(trimethylsilyl)acetamide CBr4: 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 Et3N: Triethylamine Na2SO4: Sodium sulfate (anhydrous) MeCN: Acetonitrile MeNH2: Methylamine MeOH: Methanol NaOH: Sodium hydroxide Na2SO4: Sodium sulfate Na2S2O3: Sodium thiosulfate NaHCO3: Sodium bicarbonate NH4Cl: Ammonium chloride NH4OH: Ammonium hydroxide NLT: or above PE: Petroleum ether Ph3P: Triphenylphosphine pTSA H2O: p-Toluenesulfonic acid monohydrate RT: room temperature Silica gel (230 mesh to 400 mesh, adsorbent) TBAF: Tetrabutylammonium fluoride THF: Tetrahydrofuran (THF), anhydrous TMSCl: chlorotrimethylsilane TMSOTf: Trimethylsilyl trifluoromethanesulfonate TIPDSiCl2: 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane t-BuMgCl: t-butylmagnesium chloride t-BuOK: Sodium tert-butoxide t-BuOH: tert-butanol. EXAMPLES

[0158] general law 1 H, 19 F and 31P NMR spectra were recorded on a Bruecker 300 MHz Fourier transform spectrometer. Spectra were obtained from samples prepared in CDCl3, CD3OD, or DMSO-d6 in 5 mm diameter tubes. Spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Coupling constants (J) are reported in Hz. MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS instrument. Reactions were generally carried out under a dry nitrogen atmosphere using anhydrous solvents from Sigma-Aldrich. All common chemicals were purchased from commercial sources.

[0159] NMR spectra of compounds 1-11 were recorded on a Bruecker 400 MHz Fourier transform spectrometer. Spectra were obtained from samples prepared in CDCl3, CD3OD, or DMSO-d6 in 5 mm diameter tubes. Spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Coupling constants (J) are reported in Hz. MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS instrument. Reactions were generally carried out under a dry nitrogen atmosphere using anhydrous solvents from Sigma-Aldrich. All common chemicals were purchased from commercial sources.

[0160] Preparation of stereospecific phosphorus enantiomers Certain active compounds described herein have a chiral phosphorus moiety. Any of the active compounds described herein can be provided as isolated phosphorus enantiomer forms, for example, at least 80%, 90%, 95%, 96%, 97%, or 98% R or S enantiomers, using methods known to those skilled in the art. There are numerous publications that describe methods for obtaining such compounds, including, but not limited to, column chromatography, as described in, for example, US Pat. Nos. 8,859,756, 8,642,756, and 8,333,309 to Ross et al. As described in Ross et al. J. Org. Chem. 2011, 76, 8311, PPAL-RS can be separated into PPAL-R and PPAL-S by supercritical fluid chromatography.

[0161] Example 1. Modification of the 2-amino moiety in an active compound Those skilled in the art can add substituents to the 2-aminopurine moiety by methods well known to those skilled in the art. One non-limiting process is shown here, but other processes can be easily adapted. ((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate is treated with a mixture of commercially available 2,6-dichloropurine, base, and organic solvent at elevated temperature to produce (2R,3R,4R,5R)-5-(2,6-dichloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyl-tetrahydrofuran-3-yl benzoate. In one embodiment, the base is potassium tert-butoxide. In one embodiment, the mixture of organic solvents includes tert-butanol and acetonitrile. The compound (2R,3R,4R,5R)-5-(2,6-dichloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate is treated with an amine, a base, and an organic solvent at ambient temperature to give 2-chloro-N 6In one embodiment, the amine is methylamine. In one embodiment, the base is triethylamine. In one embodiment, the organic solvent is ethanol. One of skill in the art will also recognize that treatment with an amine and a base simultaneously removes the benzoate group in the nucleoside to produce a deprotected furanose moiety. 2-Chloro-N 6 The N-substituted purine of the present invention is treated with an amine and an organic solvent at elevated temperatures of about 100° C. in a sealed tube to form the N-substituted purine of the present invention. 2 ,N 6 In one embodiment, the amine is methylamine. In one embodiment, the organic solvent is ethanol. 2 ,N 6 A -disubstituted purine nucleoside can be treated with a base, isopropyl((R,S)-(pentafluorophenoxy)-phenoxy-phosphoryl)-L-alaninate and an organic solvent at reduced temperature to produce a compound of formula I or formula II. In one embodiment, the base is tert-butylmagnesium chloride. In one embodiment, the organic solvent is tetrahydrofuran.

[0162] Example 2a. Preparation of PPAL-S [ka]

[0163] Step 1. Preparation of 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 was stirred at -10°C for 1 h. 2,3,4,5,6-pentafluorophenol (220 g) in triethylamine (120 g) and EtOAc (400 mL) was added at -5°C and stirred at -5°C for 0.5 h. The reaction mixture was warmed to 25°C and stirred at 25°C for 2 h. The solution was filtered, washed with EtOAc (2 x 200 mL) and the combined organic phase was evaporated under vacuum to give PPAL-RS (racemic) as a solid.

[0164] Step 2. Preparation of PPAL-S 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 was stirred for about 4-8 h. After the solid R-isomer 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 Na2SO4, and filtered. The solvent was removed under vacuum to give PPAL-S (350 g).

[0165] 1 H NMR (400 MHz, DMSO-d6) 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-d6) δ = 0.37 ppm.

[0166] Example 2b. Preparation of PPAD-S [ka]

[0167] Step 1. Preparation of racemic PPAD (PPAD-RS) Isopropyl-D-alaninate is added to a stirred solution of phenyl dichlorophosphate in EtOAc. The reaction is stirred at -10°C for 1 hour. 2,3,4,5,6-pentafluorophenol in triethylamine is then added at -5°C and stirred at -5°C for 0.5 hours. The reaction mixture is warmed to 25°C and stirred at 25°C for 2 hours. The solution is filtered, washed with EtOAc and the combined organic phase is evaporated under vacuum to give isopropyl((perfluorophenoxy)(phenoxy)phosphoryl)-D-alaninate (PPAD-RS) as a racemate.

[0168] Step 2. Preparation of PPAD-R and PPAD-S Isopropyl((perfluorophenoxy)(phenoxy)phosphoryl)-D-alaninate (PPAD-RS) is purified by supercritical fluid chromatography using a chiral stationary phase to give PPAD-R and PPAD-S.

[0169] [ka]

[0170] Example 3. Preparation of (S)-isopropyl-2-(((S)-(((2R,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (8) [ka]

[0171] Process 1. (3S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-3-fluorodihydrofuran-2(3H)-one (2) Commercially available compound 1 (4.0 g, 12.1 mmol, 1.0 equiv) and NCS (2.4 g, 18.2 mmol, 1.5 equiv) were dissolved in THF (60 mL) under N2 atmosphere and cooled to -78 °C. LiHMDS (24 mL, 24.0 mmol, 2 equiv) was added dropwise over 20 min and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by column chromatography (petroleum ether / EtOAc, gradient 100:0 -> 80:20 -> 0:100) to give product 2 (1.35 g, 31% yield) as a glass-like solid.

[0172] Process 2. (3S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-3-fluorotetrahydrofuran-2-ol (3) Compound 2 (1.35 g, 3.7 mmol, 1.0 equiv) was dissolved in dry toluene (40 mL) under N2 atmosphere and cooled to -78 °C. DIBALH (5.5 mL, 5.5 mmol, 1.5 equiv) was added dropwise and the reaction mixture was stirred at -78 °C for 45 min. The reaction mixture was quenched with MeOH at -78 °C and then warmed to room temperature. A saturated aqueous solution of Rochelle's salt (1000 mL) was added and the reaction mixture was stirred for 30 min before being extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by column chromatography (petroleum ether / EtOAc, gradient 100:0 to 0:100) to give product 3 (1.15 g, 85% yield) as a colorless oil.

[0173] Process 3. (9-((2R,3S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-3-fluorotetrahydrofuran-2-yl)-6-chloro-9H-purin-2-yl)-imidodicarbonic acid 1,3-bis(1,1-dimethylethyl) ester (5) Compound 3 (1.15 g, 3.1 mmol, 1 equiv.) was dissolved in THF under N2 atmosphere, and protected base 4 (1.74 g, 4.7 mmol, 1.5 equiv.) and PPh3 (987 mg, 3.8 mmol, 1.2 equiv.) were added at room temperature. DIAD (864 μL, 4.4 mmol, 1.4 equiv.) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. Silica gel was added to the reaction mixture, which was then concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc, gradient 100:0→0:100) to give a mixture of α- and β-anomers (1.7 g, 75% yield) as a pale yellow solid, which was separated after a second purification by column chromatography (petroleum ether / EtOAc, gradient 100:0→0:100) to give pure β-anomer 5 (720 mg, 32% yield) and pure α-anomer (420 mg, 19% yield).

[0174] Steps 4 and 5 9-((2R,3S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-3-fluorotetrahydrofuran-2-yl)-N 6 -Methyl-9H-purine-2,6-diamine (6) Compound 5 (470 mg, 0.65 mmol, 1 equiv.) was dissolved in a solution of MeNH2 (33% in EtOH, 5 mL) and stirred at 80° C. for 1 h in a sealed tube. The reaction mixture was evaporated to dryness and treated with a solution of TFA / H2O (4 mL / 2 mL) at room temperature for 2 h, followed by concentration. The residue was purified by column chromatography (petroleum ether / EtOAc, gradient 100:0→0:100) to give product 6 (310 mg, 92% yield) as a white solid.

[0175] Process 6. (2R,3R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol (7) To a solution of compound 6 (271 mg, 0.53 mmol, 1.0 equiv) in dry DCM (10 mL) was added boron trichloride (1 M in DCM, 2.1 mL, 2.11 mmol, 4.0 equiv) dropwise under N2 atmosphere at -80 °C, and the reaction mixture was stirred at -80 °C to -30 °C for 1 h. The reaction mixture was cooled to -80 °C again, and ammonia (2 M in MeOH, 2.11 mL, 4.22 mmol, 8 equiv) was added. The reaction mixture was warmed to room temperature under N2 atmosphere, loaded directly onto a silica gel-packed precolumn, and purified by flash column chromatography (silica gel, DCM / MeOH, 100:0 → 0:100 gradient). After a second purification by reverse-phase C18 chromatography (0:100 → 100:0 MeOH / H2O gradient), the product 7 was obtained as a white solid (140 mg, 79% yield). 1 H NMR (400 MHz, CD3OD): δ 8.04 (s, 1H), 6.29 (d, J = 14.8 Hz, 1H), 4.56 (dd, J = 19.2 Hz, 8.8 Hz, 1H), 4.04-4.01 (m, 2H), 3.87 (dd, J = 13.2, 3.3 Hz, 1H), 3.03 (s, 3H). C 11 H 15 ClFN6O3[M+H] + MS(ESI) m / z calculated for 333.7, found 333.7.

[0176] Step 7. (S)-Isopropyl-2-(((S)-(((2R,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (8) To a solution of compound 7 (56 mg, 0.168 mmol, 1 equiv) in dry DMF (3 mL) was added tert-butylmagnesium chloride (1M in N-methyl THF) (340 μL, 0.337 mmol, 2 equiv) dropwise at −10° C. under N2 atmosphere. The solution was stirred at 0° C. for 20 min and at room temperature for 40 min. The reaction mixture was then cooled to −10° C. and a solution of isopropyl((S)-(pentafluorophenoxy)-phenoxy-phosphoryl)-L-alaninate (91 mg, 0.202 mmol, 1.2 equiv) in dry DMF (1.0 mL) was added dropwise. After stirring the reaction from 0° C. to room temperature overnight, MeOH was added to quench the reaction and the reaction mixture was concentrated. The residue was purified by two successive column chromatographies (silica gel, 90:10→0:100 petroleum ether / EtOAc gradient followed by 100:0→90:10 DCM / MeOH) to give the product 8 (11.2 mg, 11% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.36-7.16 (m, 5H), 6.30 (d, J = 15.3 Hz, 1H), 4.87 (overlaps with m, 2H,H2O), 4.53-4.51 (m, 2H), 4.19-4.17 (m, 1H), 3.92-3.87 (m, 1H), 3.04 (br. s, 3H), 1.30 (dd, J = 7.11, 0.74 Hz, 3H), 1.18-1.15 (m, 6H). 31 P NMR (121 MHz, CD3OD) δ 3.76 (s). C 23 H 31 ClFN7O7P[M+H] + MS(ESI) m / z calculated for 602.9; found 603.0.

[0177] Example 4. Preparation of 2-amino-9-((2R,3S,4R,5R)-3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (10) [ka]

[0178] Process 1. 2-Amino-9-((2R,3S,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-chloro-3-fluorotetrahydrofuran-2-yl)-1H-purin-6(9H)-one (9) Compound 5 (371 mg, 0.52 mmol, 1 equiv.) was dissolved in aqueous formic acid (80%, 5 mL). The reaction mixture was stirred at 60° C. overnight, then evaporated to dryness and coevaporated with toluene. The residue was purified by column chromatography (DCM / MeOH, 100:0→9:1 gradient) to give product 9 as a white solid (190 mg, 74% yield).

[0179] Process 2. 2-Amino-9-((2R,3S,4R,5R)-3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (10) To a solution of compound 9 (190 mg, 0.38 mmol, 1.0 equiv) in dry DCM (10 mL) was added boron trichloride (1 M in DCM, 0.15 mL, 1.52 mmol, 4.0 equiv) dropwise under N2 atmosphere at -80 °C, and the reaction mixture was stirred at -80 °C to -30 °C for 1 h. The reaction mixture was cooled to -80 °C again, and ammonia (2 M in MeOH, 1.5 mL, 3.04 mmol, 8 equiv) was added. The reaction mixture was warmed to room temperature under N2 atmosphere, loaded directly onto a silica gel-packed precolumn, and purified by flash column chromatography (silica gel, DCM / MeOH, 100:0 → 0:100 gradient). After a second purification by reversed-phase C18 chromatography (10:90 → 100:0 MeOH / H2O gradient), product 11 was obtained as a white solid (94 mg, 77% yield). 1 H NMR (400 MHz, CD3OD): δ 8.10 (s, 1H), 6.29 (d, J = 14.8 Hz, 1H), 4.65 (dd, J = 19.2 Hz, 8.9 Hz, 1H), 4.03-3.98 (m, 2H), 3.87-3.83 (m, 1H). C10 H 12 ClFN5O4[M+H] + MS(ESI) m / z calculated for 320.7; found 320.0.

[0180] Example 5. Antiviral activity of compound 8 in cells infected with various flaviviruses Huh-7 (human hepatoma, AcceGen Biotechnology, Fairfield, NJ) cells were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 100 μg / mL penicillin and 100 μg / mL streptomycin (Lonza, Walkersville, MD). Cell cultures were maintained at 37°C in an atmosphere of 5% CO2 and >95% humidity. Infections were performed in EMEM supplemented with 5% FBS and 50 μg / mL gentamicin. Dengue virus (DENV-2) was obtained from ATCC (Manassas, VA). West Nile (WN02 Kern 515) and Yellow Fever (YFV 17D) were obtained from the University of Texas Medical Branch (Galveston, TX).

[0181] Test compounds were dissolved in DMSO at a concentration of 10 mM and serially diluted using eight half-log dilutions to achieve a highest test concentration of 100 μM. Each dilution was added to five wells of a 96-well plate containing 80%-100% confluent Huh-7 cells. Three wells of each dilution were infected with virus and two wells were left uninfected as toxicity controls. Six untreated wells were infected as virus controls and six untreated wells were left uninfected to serve as virus controls. Virus was administered at approximately 0.001 CCID per cell. 50The plates were diluted to achieve an MOI of 100 μg / mL (50% cell culture infectious dose). Plates were incubated at 37°C in a humidified atmosphere containing 5% CO2. On day 5 (YFV) or 6 (WNV and DENV-2) post-infection, when untreated virus control wells reached maximum cytopathic effect (CPE), plates were stained with neutral red dye for approximately 2 hours (±15 minutes). Supernatant dye was removed, wells were rinsed with PBS, and incorporated dye was extracted in 50:50 Sorensen's citrate buffer / ethanol for >30 minutes. Optical density was read at 540 nm in a spectrophotometer and converted to a percentage of control. The concentration of test compound required to inhibit 50% of virus-induced CPE (EC 50 ), and the concentration of test compound required to cause 50% cell death in the absence of virus (CC 50 The results are shown in Table 1.

[0182] [Table 1]

[0183] The present specification is described with reference to the embodiments of the present invention. With the teachings herein, those skilled in the art can modify the present invention for the desired purpose, and such modifications are intended to be within the scope of the present invention.

Claims

Claim 1: A pharmaceutical composition for the treatment of a human host infected with a flavivirus, comprising a compound of formula I: 【Chemical 1】 (In the formula, R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, aryl, -(C 1 -C 4 alkyl)aryl, heteroaryl, or heteroalkyl; R 2 is hydrogen or C 1-6 alkyl; R 3a and R 3b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-7 cycloalkyl; and R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, -(C 1 -C 4 alkyl)aryl, aryl, heteroaryl, or heteroalkyl; or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein R 1 is phenyl.

3. The pharmaceutical composition of claim 1, wherein R 3a and R 3b are hydrogen and C 1-6 alkyl.

4. The pharmaceutical composition of claim 1, wherein R 4 is C 1-6 alkyl.

5. The compound of claim 1, wherein the compound has the formula: 【Chemistry 2】 2. The pharmaceutical composition of claim 1, wherein the compound is:

6. The compound is 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

7. The compound is 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

8. The compound is 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

9. The compound is 【Chemistry 6】 6. The pharmaceutical composition of claim 5, wherein the compound is selected from the group consisting of:

10. The compound comprising: 【Chemistry 7】 The pharmaceutical composition according to claim 6, wherein 11. The compound comprising: 【Chemistry 8】 The pharmaceutical composition of claim 7, wherein 12. The compound comprising: 【Chemistry 9】 The pharmaceutical composition of claim 8, wherein 13. The compound comprising: 【Chemistry 10】 The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is selected from the group consisting of:

14. A pharmaceutical composition described in any one of claims 1 to 13, wherein the virus is a dengue virus.

15. A pharmaceutical composition described in any one of claims 1 to 13, wherein the virus is a yellow fever virus.

16. A pharmaceutical composition described in any one of claims 1 to 13, wherein the virus is West Nile virus.

17. A pharmaceutical composition described in any one of claims 1 to 13, wherein the virus is Zika virus.

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