Method for preparing ribonucleosides

Abstract

Provided are methods for preparing compounds and pharmaceutical compositions for treating Filoviridae viral infections. Provided are compounds, compositions and methods that are particularly useful for treating Marburg virus, Ebola virus and Campylobacter virus.

Description

[0001] This application is a divisional application of the Chinese patent application (application number 201580059613.5, application date October 29, 2015, invention name “Method for preparing ribonucleosides”) which has entered the Chinese national phase of international application PCT / US2015 / 057932. Technical Field

[0002] The present invention relates generally to methods and compounds for treating Filoviridae viral infections, and in particular to methods and nucleosides for treating Ebola, Marburg and Campylobacter viruses. Background Art

[0003] Filoviruses, such as Ebola virus (EBOV) and Marburg virus (MARV), are among the most deadly and destructive viruses. They cause severe, often fatal, viral hemorrhagic fevers in humans and non-human primates, such as monkeys, gorillas, and chimpanzees.

[0004] The incubation period for filovirus infection is 2 to 21 days. The onset of illness is sudden and is characterized by high fever, headache, joint and muscle aches, sore throat, fatigue, diarrhea, vomiting, and stomach pain. Some patients may see rashes, red eyes, hiccups, and internal and external bleeding. Within a week of contracting the virus, most patients experience chest pain and multiple organ failure, go into shock, and die. Some patients also experience blindness and heavy bleeding before death.

[0005] Filoviridae is a family of RNA viruses. Two members of the Filoviridae family have been identified: EBOV and MARV. Two key pathogenic filovirus families have been identified: Ebola virus and MARV. There is one identified variant of MARV and five identified species of Ebola virus: Zaire (i.e. Ebola virus, EBOV), Sudan, Tai Forest, Bondibuyo, and Reston. The exact origin, location, and natural habitat of the Filoviridae family are unknown. However, based on available evidence and the nature of similar viruses, it is speculated that the Filoviridae family is zoonotic (i.e. animal-borne), usually maintained in animal reservoirs native to the African continent.

[0006] For more than 30 years, Ebola virus has been associated with periodic outbreaks of hemorrhagic fever that cause severe illness in infected patients in central Africa. Mortality rates during outbreaks range from 50% for Ebola virus Sudan species (SEBOV) to as high as 90% for Ebola virus Zaire species (EBOV, ZEBOV) (Sanchez et al., Filoviridae: Marburg and Ebola Viruses, in Fields Virology (eds. Knipe, DM & Howley, PM) 1409-1448 (Lippincott Williams & Wilkins, Philadelphia)). An outbreak caused by an apparently new Ebola virus species in Uganda in late 2007 resulted in a mortality rate of about 25% (Towner et al., PLoS Pathog., 4: e1000212 (2008)). ZEBOV also killed large numbers of wild gorillas in the same region of Africa (Walsh et al., Nature, 422:611-614 (2003)).

[0007] The prevention and treatment of filovirus infections, including Ebola virus (EBOV), present many challenges. In fact, there is currently no vaccine or post-exposure treatment modality to prevent or control EBOV infection. Patients are instead treated with supportive care, i.e., electrolyte and fluid balance, oxygen, blood pressure maintenance, and treatment for any secondary infections.

[0008] Given the importance of new therapeutics for treating filovirus infections, new and efficient preparations of ribonucleosides, phosphates and prodrugs of ribonucleosides are needed. Summary of the invention

[0009] In some embodiments, the present invention provides a method for preparing a compound of formula V:

[0010]

[0011] The method for preparing the compound of formula V comprises forming a reaction mixture containing a coupling agent, a halosilane, a compound of formula VI and a compound of formula VII under conditions suitable for preparing the compound of formula V:

[0012]

[0013] Wherein each PG is independently a hydroxyl protecting group, or two PG groups on adjacent carbon atoms may together form -C(R 19 )2-group, R 10 is H or silyl, and R 19 It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0014] In some embodiments, the present invention provides a method for preparing a compound of formula Va or formula Vb:

[0015]

[0016] The method for preparing a compound of formula Va or formula Vb comprises forming a reaction mixture containing a deprotonating agent, a silylating agent, a coupling agent, an additive, a compound of formula VI-a and a compound of formula VII under conditions suitable for preparing a compound of formula Va or formula Vb:

[0017]

[0018] Among them, each R b are independently hydroxyl protecting groups, or two R b The groups can be combined to form –C(R 19 )2-group, R 10 is H or silyl, and R 19 It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0019] In some embodiments, the present invention provides a method for preparing a compound of formula XI:

[0020]

[0021] Where R c is H or a hydroxyl protecting group, or two R on adjacent carbon atoms c Can form -C(R 19 )2-group, and R 19 It is H or C1-C8 alkyl.

[0022] In some embodiments, the present invention provides a method for preparing a compound of formula XI-a:

[0023]

[0024] The method comprises forming a reaction mixture containing a cyanating agent, a Lewis acid, a Bronsted acid, a solvent and a compound of formula Va or Vb under conditions suitable for preparing a compound of formula XI:

[0025]

[0026] Where R b are independently hydroxyl protecting groups, or two R b The groups together form –C(R 19 )2-group, R 10 is H or silyl, and R 19It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0027] In some embodiments, the present invention provides a method for preparing a compound of formula XI-b:

[0028]

[0029] The method comprises forming a reaction mixture containing a Lewis acid, a base, a solvent, a filtering agent, and a compound of formula XI-a under conditions suitable for preparing a compound of formula XI-b:

[0030]

[0031] In some embodiments, the present invention provides a method for preparing a compound of formula XI-c:

[0032]

[0033] The method comprises forming a reaction mixture containing a solvent, a reactant and a compound of formula XI-b under conditions suitable for preparing a compound of formula XI-c:

[0034]

[0035] In some embodiments, the present invention provides a method for preparing a compound of formula VIII:

[0036]

[0037] wherein the method comprises forming a reaction mixture containing a coupling agent, a non-nucleophilic base, a compound of formula IX and a compound of formula X under conditions suitable for forming a compound of formula VIII:

[0038]

[0039] Among them, each R a is H or PG, each PG group is a hydroxyl protecting group, or two PG groups together form -C(R 19 )2-,R e1 and R e2 Each independently represents H, C1-C6 alkyl or benzyl, R f is H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl or –CH2-C3-C6 cycloalkyl, R 19 is H, C1-C8 alkyl, phenyl or substituted phenyl, and LG is a leaving group.

[0040] In some embodiments, the present invention provides a method for preparing a compound of formula VIII:

[0041]

[0042] wherein the method comprises forming a reaction mixture containing a coupling agent, a non-nucleophilic base, a compound of formula IX-a and a compound of formula X under conditions suitable for forming a compound of formula VIII:

[0043]

[0044] Where R a are independently H or a hydroxy protecting group, or two R on adjacent carbon atoms a Can form -C(R 19 )2-group, R 35 are independently H or a hydroxy protecting group, or two R on adjacent carbon atoms 35 Can form -C(R 19 )2-group, R 19 is H or C1-C8 alkyl, R e1 and R e2 Each independently represents H, C1-C6 alkyl or benzyl, R f is H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, or –CH2-C3-C6 cycloalkyl, R 19 is H, C1-C8 alkyl, phenyl or substituted phenyl, and LG is a leaving group.

[0045] In one embodiment, a method is provided by subjecting (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (Formula Xa) to provide (Formula Xb):

[0046] DETAILED DESCRIPTION OF THE INVENTION

[0047] I. Definitions

[0048] Unless otherwise indicated, the following terms and phrases used herein have the following meanings:

[0049] When a trade name is used herein, Applicants intend to include independently both the trade name product and the active pharmaceutical ingredient of the trade name product.

[0050] As used herein, "compounds of the present invention" or "compounds of formula V" refer to compounds of formula V or pharmaceutically acceptable salts or co-crystals thereof. In some embodiments, "compounds of the present invention" or "compounds of formula V" refer to compounds of formula V or pharmaceutically acceptable salts thereof. Similarly, with respect to isolatable intermediates, the phrase "compound of formula (number)" refers to compounds of the formula and pharmaceutically acceptable salts or co-crystals thereof. In some embodiments, with respect to isolatable intermediates, the phrase "compound of formula (number)" refers to compounds of the formula and pharmaceutically acceptable salts thereof.

[0051] "Alkyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl ( n -Pr, n -propyl, -CH2CH2CH3), 2-propyl ( i -Pr, i -propyl, -CH(CH3)2), 1-butyl ( n -Bu, n -butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i -Bu, i -butyl, -CH2CH(CH3)2), 2-butyl ( s -Bu, s -butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( t -Bu, t -butyl, -C(CH3)3), 1-pentyl ( n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH 3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0052] "Alkoxy" refers to a group having the formula -O-alkyl, wherein the alkyl group as defined above is attached to the parent molecule via an oxygen atom. The alkyl portion of the alkoxy group may have 1 to 20 carbon atoms (i.e., C1-C 20 Alkoxy), 1 to 12 carbon atoms (i.e. C1-C 12 Alkoxy), or 1 to 6 carbon atoms (i.e. C1-C6 alkoxy). Examples of suitable alkoxy include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-OC(CH3)3 or -OtBu), and the like.

[0053] "Haloalkyl" is an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group is replaced by a halogen atom. The alkyl portion of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C 20 haloalkyl), 1 to 12 carbon atoms (i.e. C1-C 12 -C1-C6 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0054] "Alkenyl" refers to a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms and having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C 20 The term "alkenyl" refers to a group of 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms (C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0055] "Alkynyl" refers to a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms and having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C 20 The term "alkynyl" refers to a group of 2 to 8 carbon atoms (i.e., C2-C8 alkynyl) or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0056] "Alkylene" refers to a saturated branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers, which is obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like.

[0057] "Alkenylene" refers to an unsaturated branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers, obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent olefin. For example, alkenylene can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene includes, but is not limited to, 1,2-vinylene (-CH=CH-).

[0058] "Alkynylidene" refers to an unsaturated branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers, obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkyne. For example, the alkynylene radical can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, ethynylene (-C≡C-), propargylene (-CH2C≡C-), and 4-pentynylene (-CH2CH2CH2C≡C-).

[0059] "Amino" generally refers to a nitrogen radical having the formula -N(X)2 that can be considered a derivative of amine, wherein each "X" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc. The hybridization of nitrogen is approximately sp 3 Hybridization. Non-limiting types of amino groups include -NH2, -N(alkyl)2, -NH(alkyl), -N(carbocyclyl)2, -NH(carbocyclyl), -N(heterocyclyl), -NH(heterocyclyl), -N(aryl), -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), etc. The term "alkylamino" refers to an amino group substituted with at least one alkyl group. Non-limiting examples of amino groups include -NH2, -NH(CH3), -N(CH3)2, -NH(CH2CH3), -N(CH2CH3)2, -NH(phenyl), -N(phenyl), -NH(benzyl), -N(benzyl)2, etc. Substituted alkylamino groups generally refer to alkylamino groups as described above, wherein at least one substituted alkyl group as defined herein is attached to the amino nitrogen atom. Non-limiting examples of substituted alkylamino groups include -NH(alkylene-C(O)-OH), -NH(alkylene-C(O)-O-alkyl), -N(alkylene-C(O)-OH)2, -N(alkylene-C(O)-O-alkyl)2, and the like.

[0060] "Aryl" refers to an aromatic hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, and the like. Other typical aryl groups include, but are not limited to, phenyl.

[0061] "Arylalkyl" refers to an acyclic alkyl group in which at least one hydrogen atom (typically terminal or sp 3Carbon atom) is replaced by aryl group. Common arylalkyl group includes but not limited to benzyl, 2-phenyl second-1-yl, naphthylmethyl, 2-naphthyl second-1-yl, naphthobenzyl, 2-naphthophenyl second-1-yl, etc. Arylalkyl group can comprise 7 to 20 carbon atoms, for example alkyl part is 1 to 6 carbon atoms, and aryl part is 6 to 14 carbon atoms.

[0062] "Arylalkenyl" refers to an acyclic alkenyl group in which at least one hydrogen atom (typically terminal or sp 3 Carbon atoms, can also be sp 2 The aryl moiety of arylalkenyl can include any aryl group disclosed herein, for example, and the alkenyl moiety of arylalkenyl can include any alkenyl group disclosed herein, for example. The arylalkenyl group can include 8 to 20 carbon atoms, for example, the alkenyl moiety is 2 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms.

[0063] "Arylalkynyl" refers to an acyclic alkynyl group in which at least one hydrogen atom (typically terminal or sp 3 The aryl moiety of the arylalkynyl group can include, for example, any aryl group disclosed herein, and the alkynyl moiety of the arylalkynyl group can include, for example, any alkynyl group disclosed herein. The arylalkynyl group can include 8 to 20 carbon atoms, for example, the alkynyl moiety is 2 to 6 carbon atoms, and the aryl moiety is 6 to 14 carbon atoms.

[0064] The term "substituted" in alkyl, alkenyl, aryl, aralkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., such as "substituted alkyl", "substituted alkenyl", "substituted aryl", "substituted aralkyl", "substituted heterocyclyl" and "substituted carbocyclyl" refers to alkyl, alkenyl, aryl, aralkyl, heterocyclyl, carbocyclyl in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents. The term "substituted phenyl" refers to phenyl in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents. Typical substituents include, but are not limited to -X, -R b , -O - ,=O,-OR b 、-SR b , -S - 、-NR b 2. -N + R b 3. =NR b , -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NHC(=O)R b、-OC(=O)R b 、-NHC(=O)NR b 2. -S(=O)2-, -S(=O)2OH, -S(=O)2R b 、-OS(=O)2OR b 、-S(=O)2NR b 2. -S(=O)R b ,-OP(=O)(OR b )2.-P(=O)(OR b )2, -P(=O)(O - )2、-P(=O)(OH)2、-P(O)(OR b )(O - ), -C(=O)R b 、-C(=O)X、-C(S)R b 、-C(O)OR b 、-C(O)O - 、-C(S)OR b 、-C(O)SR b 、-C(S)SR b 、-C(O)NR b 2. -C(S)NR b 2. -C(=NR b )NR b 2, wherein each X is independently a halogen: F, Cl, Br or I; and each R b is independently H, alkyl, aryl, aralkyl, heterocycle or protecting group or prodrug moiety.Alkylene, alkenylene and alkynylene can also be substituted similarly.Unless otherwise indicated, when the term "substituted" is used in conjunction with an arylalkyl group such as having two or more parts capable of replacing, the substituent can be connected to the aryl moiety, the alkyl moiety or both.

[0065] The term "prodrug" as used herein refers to any compound that, when administered to a biological organism, generates a drug substance, i.e., an active ingredient, due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or a metabolic chemical reaction. Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound.

[0066] Those skilled in the art will recognize that the substituents and other moieties of the compounds of formula I-IV should be selected to provide sufficiently stable compounds to provide pharmaceutically useful compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds of formula I-IV having such stability are considered to fall within the scope of the present invention.

[0067] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by heteroatoms such as O, N or S. For example, if the carbon atom of the alkyl group connected to the parent molecule is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl is an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH3, -N(CH3)2, etc.) or a thioalkyl (e.g., -SCH3). If the non-terminal carbon atom of the alkyl group that is not connected to the parent molecule is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl is an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkylamine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.) or a thioalkyl ether (e.g., -CH2-S-CH3). If the terminal carbon atom of the alkyl group is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl is a hydroxyalkyl (e.g., -CH2CH2-OH), an aminoalkyl (e.g., -CH2NH2) or an alkylthiol group (e.g., -CH2CH2-SH). The heteroalkyl group may have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. The C1-C6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

[0068] The "heterocycle" or "heterocyclic group" herein includes, for example, but not limited to, the heterocycles described in the following documents: Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds,A Series of Monographs "(John Wiley & Sons, New York, 1950 to date), especially Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82: 5566. In a specific embodiment of the invention, "heterocycle" includes a "carbocycle" as defined herein, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., O, N or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include, for example, heterocycles substituted with any substituent disclosed herein (including carbonyl). Non-limiting examples of carbonyl-substituted heterocyclyls are:

[0069]

[0070] Examples of heterocyclic rings include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrophenylthio, tetrahydrophenylthiothiosulfide, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolyl, isoquinolyl, benzimidazolyl, piperidine, pyridyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azocinyl, triazine, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl , pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl and bis-tetrahydrofuranyl:

[0071]

[0072] By way of example and not limitation, the carbon-bonded heterocycle is attached at the 2, 3, 4, 5, or 6 position of a pyridine; the 3, 4, 5, or 6 position of a pyridazine; the 2, 4, 5, or 6 position of a pyrimidine; the 2, 3, 5, or 6 position of a pyrazine; the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiophene (thiofuran, thiophene), pyrrole, or tetrahydropyrrole; the 2, 4, or 5 position of an oxazole, imidazole, or thiazole; the 3, 4, or 5 position of an isoxazole, pyrazole, or isothiazole, the 2 or 3 position of an acridine; the 2, 3, or 4 position of an azetidine; the 2, 3, 4, 5, 6, 7, or 8 position of a quinoline or the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline. More typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0073] By way of example and not limitation, nitrogen-bonded heterocycles are at the 1 position of acridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole; the 2 position of isoindole or isoindoline; the 4 position of morpholine; the 9 position of carbazole or β-carboline. More generally, nitrogen-bonded heterocycles include 1-acridinyl, 1-azetidinyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0074] "Heterocyclylalkyl" refers to a non-cyclic alkyl group in which the carbon atom (usually a terminal or sp 3 One of the hydrogen atoms bonded to a carbon atom) is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkylene-moiety). Typical heterocyclylalkyl groups include, but are not limited to, heterocyclyl-CH2-, 2-(heterocyclyl)eth-1-yl, and the like, wherein the "heterocyclyl" moiety includes any of the heterocyclyl groups described above, including Principles of Modern Heterocyclic Chemistry Those disclosed in. It will be understood by those skilled in the art that the heterocyclic group can be connected to the alkyl portion of the heterocyclic alkyl group by a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. The heterocyclic alkyl group includes 3 to 20 carbon atoms, for example, the alkyl portion of the aralkyl group is 1-6 carbon atoms, and the heterocyclic group portion is 2 to 14 carbon atoms. Examples of heterocyclic alkyl groups include, but are not limited to, 5-membered heterocycles containing sulfur, oxygen and / or nitrogen, such as thiazolylmethyl, 2-thiazolylethyl-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc.; 6-membered heterocycles containing sulfur, oxygen and / or nitrogen such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, etc.

[0075] "Heterocyclylalkenyl" refers to a non-cyclic alkenyl group in which the carbon atom (usually terminal or sp 3 Carbon atoms, can also be sp 2 One of the hydrogen atoms bonded to the carbon atom of the present invention is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkenyl-moiety). Typical heterocyclyl moieties of heterocyclylalkenyl groups include any heterocyclyl group described herein, including Principles of Modern Heterocyclic Chemistry Those disclosed in, and the alkenyl moiety of heterocyclyl alkenyl includes any alkenyl disclosed herein. It will be appreciated by those skilled in the art that the heterocyclyl group can be connected to the alkenyl moiety of the heterocyclyl alkenyl group by a carbon-carbon bond or a carbon-heteroatom bond, provided that the obtained group is chemically stable. The heterocyclyl alkenyl group includes 4 to 20 carbon atoms, for example, the alkenyl moiety of the heterocyclyl alkenyl group is 2 to 6 carbon atoms, and the heterocyclyl moiety is 2 to 14 carbon atoms.

[0076] "Heterocyclylalkynyl" refers to a non-cyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom, but also an sp carbon atom) is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkynyl-moiety). The heterocyclyl portion of the heterocyclylalkynyl group includes any of the heterocyclyl groups described herein, including Principles of Modern Heterocyclic Chemistry The heterocyclyl alkynyl group may be any of the alkynyl groups disclosed herein. It will be appreciated by those skilled in the art that the heterocyclyl group may be connected to the alkynyl group of the heterocyclyl alkynyl group by a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. The heterocyclyl alkynyl group may include 4 to 20 carbon atoms, for example, the alkynyl group of the heterocyclyl alkynyl group may be 2 to 6 carbon atoms, and the heterocyclyl group may be 2 to 14 carbon atoms.

[0077] "Heteroaryl" refers to an aromatic heterocyclic radical having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all aromatic rings listed in the definition of "heterocyclic radical", including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furyl, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl etc.

[0078] "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycyclic. Monocyclic carbocycles have 3 to 7 ring atoms, and more generally 5 or 6 ring atoms. Bicyclic carbocycles have 7-12 ring atoms, for example, arranged as a bicyclic [4,5], [5,5], [5,6] or [6,6] system, or have 9 or 10 ring atoms, arranged as a bicyclic [5,6] or [6,6] system, or a fused spirocycle. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl and phenyl. Non-limiting examples of bicyclic carbocycles include naphthyl, tetrahydronaphthalene, and decahydronaphthalene.

[0079] "Carbocyclylalkyl" refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a carbocyclic group as defined above. Typical but non-limiting carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

[0080] "Arylheteroalkyl" refers to a heteroalkyl group as defined herein in which a hydrogen atom (which may be attached to a carbon atom or a heteroatom) has been replaced by an aryl group as defined herein. The aryl group may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable group moiety. For example, an arylheteroalkyl group may have the general formula -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylenearyl, etc. In addition, any alkylene moiety in the above general formula may be further substituted with any substituent defined or exemplified herein.

[0081] "Heteroarylalkyl" refers to an alkyl group as defined herein in which a hydrogen atom has been replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl groups include -CH2-pyridyl, -CH2-pyrrolyl, -CH2-oxazolyl, -CH2-indolyl, -CH2-isoindolyl, -CH2-purinyl, -CH2-furyl, -CH2-thienyl, -CH2-benzofuranyl, -CH2-benzothienyl, -CH2-carbazolyl, -CH2-imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl, -CH2-pyrazolyl, -CH2-isothiazolyl, -CH2-quinolyl, -CH2-isoquinolyl, -CH2-pyridazinyl, -CH2-pyrimidinyl, -CH2-pyrazinyl, -CH(CH3)-pyridyl, -CH(CH3)-pyrrolyl, -CH(CH3)- -CH(CH3)-oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-purinyl, -CH(CH3)-furyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothienyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazinyl, -CH(CH3)-pyrimidinyl, -CH(CH3)-pyrazinyl, and the like.

[0082] When referring to a specific moiety of a compound of Formula I-IV (e.g., an optionally substituted aryl group), the term "optionally substituted" means wherein all substituents are hydrogen or wherein one or more hydrogens of the group moiety may be replaced with substituents such as listed under the definition of "substituted".

[0083] The term "optionally replaced" when referring to a specific moiety of a compound of Formula I-IV of the present invention (e.g., a carbon atom of the (C1-C8)alkyl group may be optionally replaced by -O-, -S-, or -NR-a -substituted) means that one or more methylene groups of the (C1-C8)alkyl group are replaced by 0, 1, 2 or more substituents as defined above (e.g., -O-, -S-, or -NR- a -)replace.

[0084] The term "non-terminal carbon atom" when referring to an alkyl, alkenyl, alkynyl, alkylene, alkenylene or alkynylene moiety refers to a carbon atom in the moiety that is inserted between the first carbon atom and the last carbon atom of the moiety. Thus, by way of example and not limitation, in the alkyl moiety -CH2(C * )H2(C * )H2CH3 or alkenyl moiety -CH2(C * )H2(C * )H2CH2-, C * The atoms may be considered as non-terminal carbon atoms.

[0085] Some Q and Q 1 Alternatives are nitrogen oxides, e.g. + N(O)(R) or + N(O)(OR). These nitrogen oxides attached to the carbon atom can also be represented by charge-separated groups, for example:

[0086]

[0087] And are intended to be equivalent to the aforementioned representatives for the purpose of describing the present invention.

[0088] "Linker" or "linker" refers to a chemical moiety comprising a covalent bond or a chain of atoms. Linkers include alkoxy repeating units (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine TM ) repeating units; and diacids and amides, including succinate, succinamide, diacetate, malonate, and caproamide.

[0089] Terms such as "oxygen-linked," "nitrogen-linked," "carbon-linked," "sulfur-linked," or "phosphorus-linked" mean that when the bond between two moieties can be formed using more than one atom type in the group moiety, the bond between the moieties is formed through the atom specified. For example, a nitrogen-linked amino acid will be bonded through the nitrogen atom of the amino acid rather than through an oxygen or carbon atom of the amino acid.

[0090] In some embodiments of the compounds of Formula I-IV, Z 1 or Z 2One or more of the groups are independently nitrogen-linked naturally occurring α-amino acid esters. Examples of naturally occurring amino acids include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine, and taurine. Esters of these amino acids include those described for the substituent R, particularly those wherein R is an optionally substituted (C1-C8)alkyl.

[0091] The term "purine" or "pyrimidine" bases include, but are not limited to, adenine, N 6 -Alkyl purine, N 6 -acylpurine (wherein acyl is C(O)alkyl, aryl, alkylaryl or arylalkyl), N 6 -Benzylpurine, N 6 -Halogenated purine, N 6 -vinylpurine, N 6 -Alkynyl purine, N 6 -Acylpurine, N 6 -Hydroxyalkyl purine, N 6 -allylaminopurine, N 6 -Thioallylpurine, N 2 -Alkyl purine, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidines, including 6-azacytosine, 2- and / or 4-mercaptopyrimidines, uracil, 5-halouracils, including 5-fluorouracil, C 5 -Alkylpyrimidine, C 5 -Benzylpyrimidine, C 5 -Halogenated pyrimidine, C 5 -vinylpyrimidine, C 5 -Alkynylpyrimidine, C 5 -Acylpyrimidine, C 5 -Hydroxyalkyl purine, C 5 -aminopyrimidine, C 5 -Cyanopyrimidine, C 5 -5-iodopyrimidine, C 6 -Iodine-pyrimidine, C 5 -Br-vinylpyrimidine, C 6 -Br-vinylpyridine, C 5 -Nitropyrimidine, C 5 -amino-pyrimidine, N 2 -Alkyl purine, N 2-alkyl-6-thiopurine, 5-azacytosine base, 5-azauracil base, triazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include but are not limited to guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine. Purine and pyrimidine bases are connected to ribose or its analogs through the nitrogen atom of the base. The functional oxygen and nitrogen groups on the base can be protected as needed or desired. Suitable protecting groups are well known to those skilled in the art, including trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, trityl, alkyl, and acyl groups such as acetyl and propionyl, mesyl and p-toluenesulfonyl.

[0092] Unless otherwise indicated, the carbon atoms of the compounds of Formula I-IV are tetravalent. In some chemical structure representations where the carbon atoms do not have a sufficient number of attached variables to produce a tetravalent compound, the remaining carbon substituents required to provide a tetravalent compound should be considered to be hydrogen. For example,

[0093] With Same meaning.

[0094] "Protective group" refers to a group part of a compound that masks or changes the properties of a functional group or the properties of the compound as a whole. The chemical substructure of the protecting group varies greatly. One function of the protecting group is to be used as an intermediate for the synthesis of the parent drug. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). See also Protective Groups in Organic Chemistry, Peter GM Wuts and Theodora W. Greene, 4th edition, 2006. Protecting groups are often used to mask the reactivity of certain functional groups to help the efficiency of the desired chemical reactions, such as preparing and destroying chemical bonds in an orderly and planned manner. In addition to reactivity, the protection of the functional groups of the compounds also changes other physical properties of the protected functional groups, such as polarity, lipophilicity (hydrophobicity) and other properties that can be determined by common analytical tools, and the chemically protected intermediates themselves may be biologically active or inactive. The "hydroxy protecting group" refers to a protecting group which can be used to protect a hydroxy group (-OH).

[0095] Protected compounds can also show changed and in some cases optimized external and internal properties, such as passing through cell membranes and being resistant to enzyme degradation or chelation. In this effect, protected compounds with expected therapeutic effects can be referred to as prodrugs. Another effect of blocking group is that the parent drug is converted into a prodrug, which is then converted in vivo to release the parent drug. Because active prodrugs can be more effectively absorbed than the parent drug, prodrugs may have greater effectiveness than the parent drug in vivo. For chemical intermediates, blocking groups are removed in vitro, and for prodrugs, blocking groups are removed in vivo. For chemical intermediates, the product obtained after deprotection, for example, alcohol is not particularly important for being physiologically acceptable, but generally speaking it is hoped that the product is pharmacologically harmless.

[0096] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partner, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0097] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ in the arrangement of the atoms or groups in space.

[0098] "Diastereomers" refer to stereoisomers with two or more chiral centers whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, reactivity, and biological properties. For example, when R 7 The compounds of Formula I-IV may have a chiral phosphorus atom when is:

[0099]

[0100] Where Z 1 and Z 2 Different. When Z 1 or Z 2 When at least one of the 1 or Z 2 If the chiral naturally occurring α-amino acid ester is a nitrogen-bonded chiral naturally occurring α-amino acid ester, the compounds of Formula I-IV will exist as diastereomers because there are two chiral centers in the molecule. All of these diastereomers described herein and their uses are included in the present invention. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis, crystallization and / or chromatography. Diastereomers can have different physical properties, such as but not limited to solubility, chemical stability and crystallinity, and can also have different biological properties, such as but not limited to enzyme stability, absorption and metabolic stability.

[0101] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0102] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (eg, includes the degree of error associated with measurement of the particular quantity).

[0103] Unless otherwise indicated, the verb term "treat" as used herein means to reverse, alleviate, inhibit the condition or disorder to which the term applies, or one or more symptoms of the symptom or disorder. The noun term "treating" as used herein means the act of treating as described by the verb "treat" as defined above.

[0104] As used herein, the term "therapeutically effective amount" is the amount of the compound of Formula I-IV present in the compositions described herein required to provide the desired level of drug in the secretions and tissues of the airways and lungs, or, when such a composition is administered by a selected route of administration, to produce the desired physiological response or desired biological effect in the bloodstream of the subject to be treated. The exact amount will depend on many factors, such as the specific compound of Formula I-IV, the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state, patient cooperation, etc., and can be readily determined by those skilled in the art based on the information provided herein.

[0105] The term "physiological saline" refers to an aqueous solution containing 0.9% (w / v) NaCl.

[0106] The term "hypertonic saline" refers to an aqueous solution containing greater than 0.9% (w / v) NaCl. For example, 3% hypertonic saline contains 3% (w / v) NaCl.

[0107] "Forming a reaction mixture" refers to the process of contacting at least two different substances so that they mix together and can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from intermediates that can be produced in the reaction mixture from one or more of the added reagents.

[0108] "Coupling agent" refers to a reagent capable of coupling two different compounds. The coupling agent can be catalytic or stoichiometric. For example, the coupling agent can be a lithium-based coupling agent or a magnesium-based coupling agent such as a Grignard reagent. Exemplary coupling agents include, but are not limited to, n-BuLi, MgCl2, iPrMgCl, tBuMgCl, PhMgCl, or a combination thereof.

[0109] "Silane" refers to a silicon-containing group having the formula SiR4, where each R group can be an alkyl, alkenyl, cycloalkyl, phenyl or other silicon-containing group. When the silane is attached to another compound, the silane is called a "silyl group" and has the formula -SiR3.

[0110] "Halosilane" refers to a silane having at least one halogen group attached to a silicon atom. Representative halosilanes have the formula halogen-SiR3, where each R group can be an alkyl, alkenyl, cycloalkyl, phenyl or other silicon-containing group. Specific halosilanes include Cl-Si(CH3)3 and Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl.

[0111] "Non-nucleophilic base" refers to an electron donor, a Lewis base, such as a nitrogen base including triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine and quinuclidine.

[0112] "Leaving group" refers to a group that retains a bonding electron pair during the cleavage of a heteroatom bond. For example, a leaving group is easily displaced during a nucleophilic displacement reaction. Suitable leaving groups include, but are not limited to, chloride, bromide, mesylate, tosylate, triflate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, pentafluorophenoxy, and the like. Those skilled in the art will recognize other leaving groups useful in the present invention.

[0113] "Deprotecting agent" refers to any reagent capable of removing a protecting group. The deprotecting agent will depend on the type of protecting group used. Representative deprotecting agents are known in the art and can be found in Protective Groups in Organic Chemistry, Peter GMWuts and Theodora W.Greene, 4th Ed., 2006.

[0114] II. Preparation of Compounds

[0115] The compounds of the present invention can be prepared by a variety of methods. For example, the protected nucleosides of formula V can be prepared by reacting a protected lactone with an iodine-substituted base under suitable coupling conditions. The nucleosides can then be modified with a prodrug moiety by reacting a partially protected nucleoside with a suitable prodrug moiety, and then removing the protecting group to obtain the compounds of the present invention.

[0116] A. Preparation of Nucleosides by Iodine Base

[0117] In one embodiment, the present invention provides a method for preparing a compound of formula V:

[0118]

[0119] The method for preparing the compound of formula V comprises forming a mixture containing a coupling agent, a halosilane, a compound of formula VI and a compound of formula VI under conditions suitable for preparing the compound of formula V:

[0120]

[0121] Wherein each PG is independently a hydroxyl protecting group, or two PG groups on adjacent carbons may together form -C(R 19 )2 group, R 10 is H or silyl, and R 19 It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0122] Any suitable coupling agent can be used in the method for preparing the compound of formula V. The coupling agent can be a lithium coupling agent, a sodium coupling agent, a magnesium coupling agent, etc. For example, the coupling agent can be a deprotonating agent, such as n-butyl lithium (n-BuLi), sodium hydride (NaH), lithium aluminum hydride (LAH or LiAlH4), etc. The coupling agent can also be a magnesium-based coupling agent, such as but not limited to MgCl2, iPrMgCl, tBuMgCl, PhMgCl or a combination thereof. In some embodiments, the coupling agent can be a lithium coupling agent or a magnesium coupling agent. In some embodiments, the coupling agent can be n-BuLi, MgCl2, iPrMgCl, tBuMgCl, PhMgCl or a combination thereof. In some embodiments, the coupling agent can be n-BuLi. In some embodiments, the coupling agent can be PhMgCl and iPrMgCl.

[0123] The coupling agent can be present in any suitable amount. For example, the coupling agent can be present in an amount of at least 1.0 equivalents (mol / mol) with the compound of formula V, for example, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The coupling agent can also be present in an amount of about 1.0 to about 10.0 equivalents (mol / mol) with the compound of formula V, for example, about 1.0 to about 5.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the coupling agent can be present in an amount of about 1.0 to about 5.0 equivalents (mol / mol) with the compound of formula V. In some embodiments, the coupling agent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) with the compound of formula V.

[0124] Any suitable halosilane can be used in the method for preparing the compound of formula V. For example, the halosilane can be a fluorosilane, a chlorosilane, a bromosilane or an iodosilane. The silane moiety can have any suitable substituent, such as an alkyl, an alkenyl, an alkynyl, a cycloalkyl or a phenyl. Exemplary halosilanes include but are not limited to Cl-Si(CH3)3 or Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl. In some embodiments, the halosilane can be a chlorosilane. In some embodiments, the halosilane can be Cl-Si(CH3)3 or Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl. In some embodiments, the halosilane can be TMSCl.

[0125] R 10 The silyl group of can be any suitable group, but can depend on the halosilane selected. For example, when the halosilane is TMSCl, the silyl group can be trimethylsilyl.

[0126] Halosilanes can exist in any suitable amount. For example, halosilanes can exist in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula V, for example, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). Halosilanes can also exist in an amount of about 1.0 to about 10.0 equivalents (mol / mol) relative to the compound of formula V, for example, about 1.0 to about 5.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, halosilanes can exist in an amount of about 1.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula V. In some embodiments, halosilanes can exist in an amount of about 1.0 to about 2.0 equivalents (mol / mol) relative to the compound of formula V.

[0127] The hydroxy protecting group can be any protecting group applicable to the hydroxy functional group.Representational hydroxy protecting group includes but is not limited to silane such as trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS) or tert-butyldiphenylsilane (TBDPS), ether such as methyl-methoxy (MOM), tetrahydropyran (THP), tert-butyl, allyl or benzyl, and ester such as acetyl, pivaloyl or benzoyl.In some embodiments, the hydroxy protecting group can be trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), tert-butyldiphenylsilane (TBDPS), methyl-methoxy (MOM), tetrahydropyran (THP), tert-butyl, allyl, benzyl, acetyl, pivaloyl or benzoyl.In some embodiments, the hydroxy protecting group can be benzyl.

[0128] Hydroxyl groups on adjacent carbons are called 1,2-hydroxy groups, which can form cyclic protecting groups called acetonides by reacting with diethers or ketones. Exemplary acetonides include, but are not limited to, acetonides and benzylidene acetals. In some embodiments, hydroxy protecting groups on adjacent carbon atoms can combine to form acetonides.

[0129] When R 19 The group is C1-C8 alkyl, R 19 R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, nonyl or octyl. 19 The group may be methyl.

[0130] Any suitable solvent can be used in the method of the present invention.Representative solvent includes but is not limited to pentane, different pentanes, hexane, different hexanes, heptane, different heptanes, petroleum ether, cyclopentane, different cyclohexanes, benzene, toluene, xylene, trifluorotoluene, halogenated benzene such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, methylene chloride, chloroform, acetone, ethyl acetate, diethyl ether, tetrahydrofuran or its combination.In some embodiments, solvent can be tetrahydrofuran.

[0131] The reaction mixture in the method can be any suitable temperature. For example, the reaction mixture can be about -78 ° C to about 100 ° C, or about -50 ° C to about 100 ° C, or about -25 ° C to about 50 ° C, or about -10 ° C to about 25 ° C, or about 0 ° C to about 20 ° C. In some embodiments, the temperature of the reaction mixture can be about 0 ° C to about 20 ° C.

[0132] The reaction mixture of the method can be under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0133] The methods of the invention can provide compounds of Formula V in any suitable yield. For example, compounds of Formula V can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least about 95%.

[0134] The methods of the present invention can provide any purity of the compound of formula V. For example, the compound of formula V can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, the compound of formula V can be prepared with a purity of at least 95%. In some embodiments, the compound of formula V can be prepared with a purity of at least 98%. In some embodiments, the compound of formula V can be prepared with a purity of at least 99%.

[0135] In some embodiments, the method comprises preparing a compound of formula V:

[0136]

[0137] wherein the process comprises forming a reaction mixture having TMSCl, PhMgCl, iPrMgCl, a compound of formula VI and a compound of formula VII under conditions suitable for preparing a compound of formula V:

[0138]

[0139] In some embodiments, the present invention provides compounds:

[0140]

[0141] In some embodiments, the present invention provides a method for preparing a compound of formula Va or formula Vb:

[0142]

[0143] The method for preparing a compound of formula Va or formula Vb comprises forming a reaction mixture having a deprotonating agent, a silylating agent, a coupling agent, an additive, a compound of formula VI-a, and a compound of formula VII under conditions suitable for preparing a compound of formula Va or formula Vb:

[0144]

[0145] Among them, each R b are independently hydroxyl protecting groups, or two R b The groups can be combined to form –C(R 19 )2-group, R 10 is H or silyl, and R 19 It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0146] Any suitable deprotonating agent can be used in the method for preparing the compound of formula Va or formula Vb. The deprotonating agent can be a sodium deprotonating agent, a magnesium-based deprotonating agent, a lithium-based deprotonating agent, a potassium-based deprotonating agent, and the like. For example, the deprotonating agent can be sodium hydride (NaH), isopropylmagnesium chloride (iPrMgCl), tert-butylmagnesium chloride (tBuMgCl), phenylmagnesium chloride (PhMgCl), phenylmagnesium bromide (PhMgBr), butyllithium (BuLi), methyllithium (MeLi), methylmagnesium chloride (MeMgCl), methylmagnesium bromide (MeMgBr), tert-butyllithium (tBuLi), isopropyllithium (iPrLi), phenyllithium (PhLi), lithium hydride (LiH), potassium hydride (KH), ethyllithium (EtLi), ethylmagnesium bromide (EtMgBr), ethylmagnesium chloride (EtMgCl), propyllithium (PrLi), propylmagnesium bromide (PrMgBr), propylmagnesium chloride (PrMgCl), cyclohexanelithium (cyHexLi), cyclohexanemagnesium bromide (cyHexMgBr), cyclohexanemagnesium chloride (cyHexMgCl), or a combination thereof. In some embodiments, the deprotonating agent can be PhMgCl.

[0147] Deprotonating agent can be present in any suitable amount. For example, deprotonating agent can be present in an amount of at least 0.1 equivalent (mol / mol) compared to formula VII compound, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). Deprotonating agent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to formula VII compound, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, deprotonating agent can be present in an amount of about 0.1 to 1.0 equivalents (mol / mol) compared to formula VII compound. In some embodiments, the amount of deprotonating agent is about 1.0 to about 2.0 equivalents (mol / mol) compared to formula VII compound.

[0148] Any suitable silylating agent can be used in the method for preparing the compound of formula Va or Vb. For example, the silylating agent can be fluorosilane, chlorosilane, bromosilane or iodosilane. For example, the silylating agent can be trisubstituted silyl chloride, trisubstituted silyl bromide, trisubstituted silyl iodine or trisubstituted silyl fluorine. The silyl moiety can have any suitable substituent, such as alkyl, alkenyl, alkynyl, cycloalkyl or phenyl. Exemplary silylating agents include but are not limited to Cl-Si(CH3)3, Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl or tert-butyldiphenylsilyl (TBDPS). In some embodiments, the silylating agent can be chlorosilane. In some embodiments, the silylating agent can be Cl-Si(CH3)3 or Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl. In some embodiments, the silylating agent can be TMSCl.

[0149] R 10 The silyl group of can be any suitable group, but can depend on the choice of silylating agent. For example, when the silylating agent is TMSCl, the silyl group can be trimethylsilyl.

[0150] Silylation agent can be present in any suitable amount. For example, silylation agent can be present in an amount of at least 0.0 equivalent (mol / mol) relative to formula VII compound, for example, about 0.0, 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalent (mol / mol). Silylation agent can also be present in an amount of about 0.0 to about 10.0 equivalent (mol / mol) relative to formula VII compound, for example, about 0.0 to about 3.0 equivalent (mol / mol), or about 1.0 to about 2.0 equivalent (mol / mol). In some embodiments, silylation agent can be present in an amount of about 0.0 to 1.0 equivalent (mol / mol) relative to formula VII compound. In some embodiments, the amount of silylation agent is about 1.0 to about 2.0 equivalent (mol / mol) relative to formula VII compound.

[0151] Any suitable coupling agent can be used in the method for preparing Va or Vb compound. The coupling agent can be a lithium coupling agent, a magnesium-based deprotonating agent, and the like. For example, the coupling agent can be n-butyl lithium (nBuLi), magnesium chloride (MgCl2), isopropyl magnesium chloride (iPrMgCl), isopropyl magnesium chloride-lithium chloride (iPrMgCl-LiCl), tert-butyl magnesium chloride (tBuMgCl), phenyl magnesium chloride (PhMgCl), methyl lithium (MeLi), methyl magnesium chloride (MeMgCl), methyl magnesium bromide (MeMgBr), tert-butyl lithium (tBuLi), isopropyl lithium (iPrLi), phenyl lithium (PhLi), lithium hydride (LiH), potassium hydride (KH), sodium hydride (NaH), ethyl lithium (EtLi), ethyl magnesium bromide (EtMgBr), ethyl magnesium chloride (EtMgCl), propyl lithium (PrLi), propyl magnesium bromide (PrMgBr), propyl magnesium chloride (PrMgCl), cyclohexane lithium (cyHexLi), cyclohexane magnesium bromide (cyHexMgBr), cyclohexane magnesium chloride (cyHexMgCl), or a combination thereof. In some embodiments, the coupling agent may be iPrMgCl.

[0152] The coupling agent can be present in any suitable amount. For example, the coupling agent can be present in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula VII, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The coupling agent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) relative to the compound of formula VII, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the coupling agent can be present in an amount of about 0.1 to 1.0 equivalents (mol / mol) relative to the compound of formula VII. In some embodiments, the amount of the coupling agent is about 1.0 to about 2.0 equivalents (mol / mol) relative to the compound of formula VII.

[0153] Any suitable additive can be used in the method for preparing the compound of formula Va or formula Vb. In some embodiments, the additive is a Lewis acid. In some embodiments, the additive can be BF3-OEt2, Sm(OTf)3, Sc(OTf)3, FeCl3, LiCl, LiBr, TiCl(OiPr)3, ScCl3, Bu4NBr+LaCl3-2LiCl, nLaCl3+mLiCl, wherein m is 0.5 to 50 and n is 1 to 100, LaCl3+2LiCl, Sm(OTf)3+LiCl, SmCl3, bis[2-(N,N-dimethylamino)ethyl]ether, TMEDA, NdCl3 、NdCl3+CsCl、nNdCl3+mLiCl, where m is 0.5 to 50 and n is 1 to 100、NdCl3+2LiCl、NdCl3+LiBr、NdCl3+LiI、NdBr3、NdBr3+CsCl、nNdBr3+mLiCl, where m is 0.5 to 50 and n is 1 to 100、NdBr3+2LiCl、NdBr3+LiBr、NdBr3+LiI、Nd(OTf)3、CeCl3、CeCl3+CsCl、nCeCl3+ mLiCl, where m is 0.5 to 50 and n is 1 to 100, CeCl3+2LiCl, CeCl3+LiBr, CeCl3+LiI, CeBr3, Ce(OTf)3, YCl3, YCl3+CsCl, nYCl3+mLiCl, where m is 0.5 to 50 and n is 1 to 100, YCl3+2LiCl, YCl3+LiBr, YCl3+LiI, YBr3, YBr3+CsCl, nYBr3+mLiCl, where m is 0.5 to 50 and n is 1 to 1 In some embodiments, the additive may be LiCl, Ca(OTf)2, CaCl2 and MgCl2, CeCl3, LaCl3 or a combination thereof. In some embodiments, the additive may be YCl3, CeCl3, NdCl3, LaCl3 or a combination thereof.

[0154] Additive can be present in any suitable amount.For example, additive can be present in the amount of at least 0.1 equivalent (mol / mol) compared to formula VII compound, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). Additive can also be present in the amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to formula VII compound, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, additive can be present in the amount of about 0.1 to 1.0 equivalents (mol / mol) compared to formula VII compound. In some embodiments, the amount of additive is about 1.0 to about 2.0 equivalents (mol / mol) compared to formula VII compound.

[0155] In some embodiments, the additive is LaCl3-2LiCl, and is at least 0.1 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0, 0.1, 0.3, 0.5, 1.0, 2 or about 2.0 equivalents (mol / mol). In some embodiments, the additive is LaCl3-2LiCl, and its amount is about 0 to about 2.0 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0 to about 0.3 equivalents (mol / mol), or about 0 to about 0.5 equivalents (mol / mol). In some embodiments, the additive is LaCl3-2LiCl, and its amount is about 0 to 0.5 equivalents (mol / mol) compared to the compound of formula VII. In some embodiments, the additive is LaCl3-2LiCl, and its amount is about 0.5 equivalents (mol / mol) compared to the compound of formula VII.

[0156] In some embodiments, the additive is CeCl3, and its presence is at least 0.1 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0, 0.1, 0.3, 0.5, 1.0, 2, or about 2.0 equivalents (mol / mol). In some embodiments, the additive is CeCl3, and its presence is about 0 to about 2.0 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0 to about 0.3 equivalents (mol / mol), or about 0 to about 0.5 equivalents (mol / mol). In some embodiments, the additive is CeCl3, and its presence is about 0 to 0.5 equivalents (mol / mol) compared to the compound of formula VII. In some embodiments, the additive is CeCl3, and its presence is about 0.5 equivalents (mol / mol) compared to the compound of formula VII.

[0157] In some embodiments, the additive is NdCl3, and its presence is at least 0.1 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0, 0.1, 0.3, 0.5, 1.0, 2, or about 2.0 equivalents (mol / mol). In some embodiments, the additive is NdCl3, and its presence is about 0 to about 2.0 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0 to about 0.3 equivalents (mol / mol), or about 0 to about 0.5 equivalents (mol / mol). In some embodiments, the additive is NdCl3, and its presence is about 0 to 0.5 equivalents (mol / mol) compared to the compound of formula VII. In some embodiments, the additive is NdCl3, and its presence is about 0.5 equivalents (mol / mol) compared to the compound of formula VII.

[0158] In some embodiments, the additive is YCl3, and its presence is at least 0.1 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0, 0.1, 0.3, 0.5, 1.0, 2, or about 2.0 equivalents (mol / mol). In some embodiments, the additive is YCl3, and its presence is about 0 to about 2.0 equivalents (mol / mol) compared to the compound of formula VII, for example, about 0 to about 0.3 equivalents (mol / mol), or about 0 to about 0.5 equivalents (mol / mol). In some embodiments, the additive is YCl3, and its presence is about 0 to 0.5 equivalents (mol / mol) compared to the compound of formula VII. In some embodiments, the additive is YCl3, and its presence is about 0.5 equivalents (mol / mol) compared to the compound of formula VII.

[0159] When R 19 When the group is C1-C8 alkyl, R 19 It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. In some embodiments, R 19 The group may be methyl.

[0160] When R b When the group is a hydroxyl protecting group, R b can be any example of a protecting group described in Protective Groups in Organic Chemistry, Peter GMWuts and Theodora W. Greene, 4th Ed., 2006. In some embodiments, R b The group may be benzyl. In some embodiments, R b The group may be TBS.

[0161] The hydroxy protecting group can be any protecting group suitable for hydroxy functional groups.Representative hydroxy protecting groups include but are not limited to silane, ether, ester, etc.Representative hydroxy protecting groups include but are not limited to trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), tert-butyldiphenylsilane (TBDPS), methylmethoxy (MOM), tetrahydropyran (THP), tert-butyl, allyl, benzyl, acetyl, pivaloyl or benzoyl.In some embodiments, the hydroxy protecting group can be trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), tert-butyldiphenylsilane (TBDPS), methylmethoxy (MOM), tetrahydropyran (THP), tert-butyl, allyl, benzyl, acetyl, pivaloyl or benzoyl.In some embodiments, the hydroxy protecting group can be benzyl.In some embodiments, the hydroxy protecting group can be TBS.

[0162] Hydroxyl groups on adjacent carbons are referred to as 1,2-hydroxyl groups, which can form cyclic protecting groups referred to as acetals or ketals by reacting with aldehydes, acetals, ketones, or ketals. Exemplary acetals and ketals include, but are not limited to, benzylidene acetals and acetonides. In some embodiments, the hydroxy protecting groups of hydroxyl groups on adjacent carbons can be combined to form acetonides.

[0163] Any suitable solvent can be used in the method of the present invention.Representational solvent includes but is not limited to pentane, different pentanes, hexane, different hexanes, heptane, different heptanes, petroleum ether, cyclopentane, cyclohexane, benzene, toluene, dimethylbenzene, dichloromethane, trifluorotoluene, halogenated benzene such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, methylene chloride, chloroform, acetone, ethyl acetate, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dibutyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, dioxane (1,4-dioxane), N-methylpyrrolidone (NMP), diisopropyl ether or its combination.In certain embodiments, solvent can be THF, MeTHF, toluene, THF+dioxane, THF+pyridine or THF+DCM or its combination.In some embodiments, solvent can be THF.

[0164] The reaction mixture of the method may have any suitable temperature. For example, the temperature of the reaction mixture may be from about -78°C to about 100°C, or from about -50°C to about 100°C, or from about -25°C to about 50°C, or from about -10°C to about 25°C, or from about 0°C to about 20°C. In some embodiments, the temperature of the reaction mixture may be from about 0°C to about 20°C. In some embodiments, the temperature of the reaction mixture may be from about -30°C to about -10°C.

[0165] The reaction mixture of the method can have any suitable pressure. For example, the reaction mixture can be at atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0166] The methods of the invention can provide compounds of formula Va or Vb in any suitable yield. For example, compounds of formula Va or Vb can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0167] The methods of the present invention can provide a compound of formula Va or formula Vb in any suitable purity. For example, a compound of formula Va or formula Vb can be prepared in a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, a compound of formula Va or formula Vb can be prepared in a purity of at least 95%. In some embodiments, a compound of formula Va or formula Vb can be prepared in a purity of at least 98%. In some embodiments, a compound of formula Va or formula Vb can be prepared in a purity of at least 99%.

[0168] In some embodiments, the method comprises preparing a compound of Formula Va or Formula Vb:

[0169]

[0170]

[0171] The method comprises forming a reaction mixture having TMSCl, PhMgCl, iPrMgCl, LaCl3-2LiCl, a compound of formula VI and a compound of formula VII under conditions suitable for preparing a compound of formula Va or formula Vb:

[0172]

[0173] In some embodiments, the method comprises preparing a compound of Formula Va or Formula Vb:

[0174]

[0175] The method comprises forming a reaction mixture having TMSCl, PhMgCl, iPrMgCl, CeCl3, a compound of formula VI and a compound of formula VII under conditions suitable for preparing a compound of formula Va or formula Vb:

[0176]

[0177] In some embodiments, the method comprises preparing a compound of Formula Va or Formula Vb:

[0178]

[0179] The method comprises forming a reaction mixture having TMSCl, PhMgCl, iPrMgCl, NdCl3, a compound of formula VI and a compound of formula VII under conditions suitable for preparing a compound of formula Va or formula Vb:

[0180]

[0181] In some embodiments, the method comprises preparing a compound of Formula Va or Formula Vb:

[0182]

[0183] The method comprises forming a reaction mixture having TMSCl, PhMgCl, iPrMgCl, YCl3, a compound of formula VI and a compound of formula VII under conditions suitable for preparing a compound of formula Va or formula Vb:

[0184]

[0185] In some embodiments, the method comprises preparing a compound of formula Va:

[0186]

[0187] The method comprises forming a reaction mixture having TMSCl, PhMgCl, iPrMgCl-LiCl, LaCl3-2LiCl, a compound of formula VI and a compound of formula VII under conditions suitable for preparing a compound of formula Va:

[0188]

[0189] B. Preparation of cyano nucleosides

[0190] In some embodiments, the present invention provides a method for preparing a compound of formula XI:

[0191]

[0192] Where R c is H or a hydroxyl protecting group, or two R on adjacent carbons c Can form -C(R 19 )2-group, and R 19 It is H or C1-C8 alkyl.

[0193] When R 19 When the group is C1-C8 alkyl, R 19R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. 19 The group may be methyl.

[0194] When R c When the group is a hydroxy protecting group, the hydroxy protecting group can be any protecting group suitable for the hydroxy functional group. Representative hydroxy protecting groups include but are not limited to silane, ether, ester, etc. Representative hydroxy protecting groups include but are not limited to trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), tert-butyldiphenylsilane (TBDPS), methyl-methoxy (MOM), tetrahydropyran (THP), tert-butyl, allyl, benzyl, acetyl, valeryl or benzoyl. In some embodiments, the hydroxy protecting group can be trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), tert-butyldiphenylsilane (TBDPS), methyl-methoxy (MOM), tetrahydropyran (THP), tert-butyl, allyl, benzyl, acetyl, valeryl or benzoyl. In some embodiments, the hydroxy protecting group can be benzyl. In some embodiments, the hydroxy protecting group can be TBS.

[0195] Hydroxyl groups on adjacent carbons are called 1,2-hydroxy groups, which can form cyclic protecting groups called acetals or ketals by reaction with aldehydes, acetals, ketones, or ketals. Exemplary acetals and ketals include, but are not limited to, benzylidene acetals and acetonides. In some embodiments, the hydroxy protecting groups on adjacent carbon atoms can form acetonides together.

[0196] In some embodiments, the present invention provides a method for preparing a compound of formula XI-a:

[0197]

[0198] The method comprises forming a reaction mixture having a cyanating agent, a Lewis acid, a Bronsted acid, a solvent, and a compound of formula Va or formula Vb under conditions suitable for preparing a compound of formula XI-a:

[0199]

[0200] Where R b are independently hydroxy protecting groups, or two R b Can be formed together to form –C(R 19 )2-group, R 10 is H or silyl, and R 19 It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0201] Any suitable cyanating agent can be used for the method for preparing formula XI-a compound. For example, cyanating agent can be TMSCN, TBSCN, TESCN, HCN, KCN, NaCN, 4-toluenesulfonyl cyanide, CuCN, CuCn*LiCl, LiCN, Zn(CN)2, K4[Fe(CN)6], tetrabutylammonium cyanide, tetramethylammonium cyanide, tetraethylammonium cyanide, tetrabutylammonium cyanide (including tetraalkylammonium cyanide, wherein alkyl is independently Me, Et, Pr, iPr, Bu, iBu, tert-butyl, amyl, hexyl), tributyltin cyanide, trimethyltin cyanide, triethyltin cyanide, tripropyltin cyanide, (including trialkyltin cyanide, wherein alkyl is independently Me, Et, Pr, iPr, Bu, iBu, tert-butyl, amyl, hexyl), 2-hydroxy-2-methylpropionitrile or its combination. In some embodiments, cyanating agent can be TMSCN.

[0202] The cyaniding agent can be present in any suitable amount. For example, the cyaniding agent can be present in an amount of at least 0.1 equivalents (mol / mol) compared to the compound of formula Va or formula Vb, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The cyaniding agent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula Va or formula Vb, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the cyaniding agent can be present in an amount of about 0.1 to 1.0 equivalents (mol / mol) compared to the compound of formula Va or formula Vb. In some embodiments, the cyaniding agent is present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula Va or formula Vb.

[0203] Any suitable Lewis acid can be used in the method for preparing the compound of formula XI-a. For example, the Lewis acid can be TMSOTf, TMSOTf, TBSOTf, TESOTf, BF3, BF3-OEt2, BCl3, BF3-THF, MgCl2, MgI2, MgBr2, MgBr2-OEt2, ZnCl2, ZnBr2, ZnI2, LiCl, LiBr, LiI, AlCl3, AlBr3, AlI3, Me2Si(OTf)2, Et2Si(OTf)2, Pr2Si(OTf)2, iPr2Si(OTf)2, (tBu)2Si(OTf)2, (C6F5)3B, MeSiCl3, Me2SiCl2, SiCl4, TMSCl, TMSI, TMSVr, TBSCl, TBSBr, TBSI, TESCl, TESBr, TESI, Sm Cl3, SmBr3, SmI2, SmI3, ScI3, ScBr3, ScI3, Sm(OTf)3, Sc(OTf)3, TiCl4, Ti(OiPr)4, Ti(OiPr)3Cl, Ti(OiPr)2Cl2, Ti(OiPr)Cl3, Zn(BF4)2, LiBF4, Mg(BF4)2, ZrCl4, FeCl2, FeCl3, FeBr2, FeBr3, FeI2, FeI3, Cu(OTf), Cu(OTf)2, 4-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl triflate, benzenesulfonyl triflate, methylsulfonyl chloride, methylsulfonic anhydride, InCl3, InBr3, InI3, In(OTf)3, Mg(SO4)2, NaSO4; or a combination thereof. In some embodiments, the Lewis acid may be TMSOTf. In some embodiments, the following substances can be used in place of Lewis acid in the method for preparing the compound of formula XI-a: dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl-carbodiimide, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI; or a combination thereof.

[0204] Lewis acid can exist in any suitable amount.For example, the Lewis acid can exist in an amount of at least 0.0 equivalent (mol / mol) compared to formula Va or formula Vb compound, for example, about 0.0, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol).Lewis acid can exist in an amount of about 0.0 to about 10.0 equivalents (mol / mol) compared to formula Va or formula Vb compound, for example, about 0.0 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol).In some embodiments, Lewis acid can exist in an amount of about 0.0 to 1.0 equivalents (mol / mol) compared to formula Va or formula Vb compound.In some embodiments, Lewis acid can exist in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to formula Va or formula Vb compound.

[0205] Any suitable Bronsted acid can be used in the method for preparing the compound of formula XI-a. For example, the Bronsted acid can be TFA, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI, trifluoromethanesulfonic acid, 4-fluorobenzoic acid, pivalic acid, HBF4, nitric acid, 4-chloro-benzoic acid, pentafluorophenol, HPF6, camphorsulfonic acid; or a combination thereof. In some embodiments, the Bronsted acid can be TFA.

[0206] The Bronsted acid may be present in any suitable amount. For example, the Bronsted acid may be present in an amount of at least about 0.0 equivalent (mol / mol) compared to the compound of formula Va or Vb, for example, about 0.0, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalent (mol / mol). The Bronsted acid may also be present in an amount of about 0.0 to about 10.0 equivalent (mol / mol) compared to the compound of formula Va or Vb, for example, about 0.0 to about 3.0 equivalent (mol / mol), or about 1.0 to about 2.0 equivalent (mol / mol). In some embodiments, the Bronsted acid may be present in an amount of about 0.0 to about 1.0 equivalent (mol / mol) compared to the compound of formula Va or Vb. In some embodiments, the Bronsted acid may be present in an amount of about 1.0 to about 2.0 equivalent (mol / mol) compared to the compound of formula Va or Vb.

[0207] Any suitable solvent can be used in the method for preparing the compound of formula XI-a. For example, the solvent can be DCM, THF, MeTHF, Et2O, MeCN, EtCN, toluene, benzene, chlorobenzene, nitrobenzene, fluorobenzene, methanol, ethanol, 2-propanol, propanol, butanol, MTBE, EtOAc, iPrOAc, Me2O, (TMS)2O, acetone, 2-butanone, chloroform, 1,2-dichloroethane, diethylene glycol dimethyl ether, dioxane, acetic acid, formic acid, trifluoroacetic acid, methyl isobutyl ketone, DMAc, DMF, NMP, DMSO; or a combination thereof. In some embodiments, the solvent can be DCM.

[0208] The solvent can be present in any suitable amount. For example, the solvent can be present in an amount of at least 0.0 equivalent (mol / mol) compared to formula Va or Vb compound, for example, about 0.0, 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The solvent can also be present in an amount of about 0.0 to about 10.0 equivalents (mol / mol) compared to formula Va or Vb compound, for example, about 0.0 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the solvent can be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to formula Va or Vb compound. In some embodiments, the solvent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to formula Va or Vb compound.

[0209] The reaction mixture of the method can have any suitable temperature. For example, the temperature of the reaction mixture can be from about -150°C to about 0°C, or from about -120°C to about 0°C, or from about -100°C to about 0°C, or from about -100°C to about -50°C, or from about -100°C to about -70°C. In some embodiments, the temperature of the reaction mixture can be from about -120°C to about -70°C. In some embodiments, the temperature of the reaction mixture can be from about -120°C to about -100°C. In some embodiments, the temperature of the reaction mixture can be from -80°C to about -30°C.

[0210] The reaction mixture of the method can be carried out under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0211] The methods of the present invention can provide compounds of formula XI-a in any suitable yield. For example, compounds of formula XI-a can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0212] The methods of the present invention can provide compounds of formula XI-a of any suitable purity. For example, the compound of formula XI-a can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, the compound of formula XI-a can be prepared with a purity of at least about 95%. In some embodiments, the compound of formula XI-a can be prepared with a purity of at least about 98%. In some embodiments, the compound of formula XI-a can be prepared with a purity of at least about 99%.

[0213] In some embodiments, the methods of the present invention can be performed in a batch process. In some embodiments, the methods of the present invention can be performed by flow chemistry.

[0214] In some embodiments, the method comprises preparing a compound of formula XI-a:

[0215]

[0216] Wherein the method comprises forming a reaction mixture having TFA, TMSCN, TMSOTf and a compound of formula Va or formula Vb under conditions suitable for preparing a compound of formula XI-a:

[0217]

[0218] In some embodiments, the method of preparing Formula XI-a is carried out at about -120°C to about 20°C. In another embodiment, the method of preparing Formula XI-a is carried out at about -120°C to about 0°C. In another embodiment, the method of preparing Formula XI-a is carried out at about -40°C to about -20°C.

[0219] In some embodiments, the present invention provides a method for preparing formula XI-a 2 Compound Methods:

[0220]

[0221] The method comprises preparing a 2 The compound is formed under conditions of a cyanating agent, a Lewis acid, a Bronsted acid, a solvent, and a reaction mixture having a compound of formula Va:

[0222]

[0223] Where R b are independently hydroxy protecting groups, or two R b The groups can be combined to form –C(R 19 )2-group, R 10is H or silyl, and R 19 It is H, C1-C8 alkyl, phenyl or substituted phenyl.

[0224] Any suitable cyanating agent can be used to prepare the formula XI-a 2 Compound method. For example, the cyaniding agent can be TMSCN, TBSCN, TESCN, HCN, KCN, NaCN, 4-toluenesulfonyl cyanide, CuCN, CuCn*LiCl, LiCN, Zn(CN)2, K4[Fe(CN)6], tetrabutylammonium cyanide, tetramethylammonium cyanide, tetraethylammonium cyanide, tetrabutylammonium cyanide (including tetraalkylammonium cyanide, wherein the alkyl group is independently Me, Et, Pr, iPr, Bu, iBu, tert-butyl, pentyl, hexyl), tributyltin cyanide, trimethyltin cyanide, triethyltin cyanide, tripropyltin cyanide, (including trialkyltin cyanide, wherein the alkyl group is independently Me, Et, Pr, iPr, Bu, iBu, tert-butyl, pentyl, hexyl), 2-hydroxy-2-methylpropionitrile; or a combination thereof. In some embodiments, the cyaniding agent can be TMSCN.

[0225] The cyanating agent can be present in any suitable amount. For example, the cyanating agent can be present in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula Va, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The cyanating agent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula Va, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the cyanating agent can be present in an amount of about 0.1 to 1.0 equivalents (mol / mol) compared to the compound of formula Va. In some embodiments, the amount of the cyanating agent is present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula Va.

[0226] Any suitable Lewis acid can be used to prepare 2For example, the Lewis acid can be TMSOTf, TMSOTf, TBSOTf, TESOTf, BF3, BF3-OEt2, BCl3, BF3-THF, MgCl2, MgI2, MgBr2, MgBr2-OEt2, ZnCl2, ZnBr2, ZnI2, LiCl, LiBr, LiI, AlCl3, AlBr3, AlI3, Me2Si(OTf)2, Et2Si(OTf)2, Pr2Si(OTf)2, iPr2Si(OTf)2, (tBu)2Si(OTf)2, (C6F5)3B, MeSiCl3, Me2SiCl2, SiCl4, TMSCl, TMSI, TMSVr, TBSCl, TBSBr, TBSI, TESCl, TESBr, TESI, S mCl3, SmBr3, SmI2, SmI3, ScI3, ScBr3, ScI3, Sm(OTf)3, Sc(OTf)3, TiCl4, Ti(OiPr)4, Ti(OiPr)3Cl, Ti(OiPr)2Cl2, Ti(OiPr)Cl3, Zn(BF4)2, LiBF4, Mg(BF4)2, ZrCl4, FeCl2, FeCl3, FeBr2, FeBr3, FeI2, FeI3, Cu(OTf), Cu(OTf)2, 4-methylbenzenesulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl triflate, benzenesulfonyl triflate, methylsulfonyl chloride, methylsulfonic anhydride, InCl3, InBr3, InI3, In(OTf)3, Mg(SO4)2, NaSO4; or a combination thereof. In some embodiments, the Lewis acid may be TMSOTf. In some embodiments, the following substances can be used in place of Lewis acid to prepare formula XI-a 2 The method of the compound: dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI; or a combination thereof.

[0227] Lewis acid can exist in any suitable amount.For example, the Lewis acid can exist in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula Va, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol).Lewis acid can exist in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula Va, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol).In some embodiments, Lewis acid can exist in an amount of about 0.1 to 1.0 equivalents (mol / mol) compared to the compound of formula Va.In some embodiments, Lewis acid can exist in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula Va.

[0228] In the preparation of formula XI-a 2 Any suitable Bronsted acid can be used in the method of preparing a compound. For example, the Bronsted acid can be TFA, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI, trifluoromethanesulfonic acid, 4-fluorobenzoic acid, pivalic acid, HBF4, nitric acid, 4-chloro-benzoic acid, pentafluorophenol, HPF6, camphorsulfonic acid; or a combination thereof. In some embodiments, the Bronsted acid can be TFA.

[0229] The Bronsted acid may be present in any suitable amount. For example, the Bronsted acid may be present in an amount of at least about 0.1 equivalents (mol / mol) compared to the compound of formula Va, such as about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The Bronsted acid may also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula Va, such as about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the Bronsted acid may be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to the compound of formula Va. In some embodiments, the Bronsted acid may be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula Va.

[0230] In the preparation of formula XI or XI-a 2Any suitable solvent can be used in the method of compound. For example, the solvent can be DCM, THF, MeTHF, Et2O, MeCN, EtCN, toluene, benzene, chlorobenzene, nitrobenzene, fluorobenzene, methanol, ethanol, 2-propanol, propanol, butanol, MTBE, EtOAc, iPrOAc, Me2O, (TMS)2O, acetone, 2-butanone, chloroform, 1,2-dichloroethane, diglyme, dioxane, acetic acid, formic acid, trifluoroacetic acid, methyl isobutyl ketone, DMAc, DMF, NMP, DMSO; or a combination thereof. In some embodiments, the solvent can be DCM.

[0231] The solvent can be present in any suitable amount. For example, the solvent can be present in an amount of at least 0.0 equivalent (mol / mol) compared to the compound of formula Va, for example, about 0.0, 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The solvent can also be present in an amount of about 0.0 to about 10.0 equivalents (mol / mol) compared to the compound of formula Va, for example, about 0.0 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the solvent can be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to the compound of formula Va. In some embodiments, the solvent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula Va.

[0232] The reaction mixture of the method can have any suitable temperature. For example, the temperature of the reaction mixture can be from about -150°C to about 0°C, or from about -120°C to about 0°C, or from about -100°C to about 0°C, or from about -100°C to about -50°C, or from about -100°C to about -70°C. In some embodiments, the temperature of the reaction mixture can be from about -120°C to about -70°C. In some embodiments, the temperature of the reaction mixture can be from about -120°C to about -100°C. In some embodiments, the temperature of the reaction mixture can be from -80°C to about -30°C.

[0233] The reaction mixture of the method can be carried out under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0234] The process of the present invention can provide the compound of formula XI-a in any suitable yield. 2 For example, the compound of formula XI-a 2 The compound can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least about 95%.

[0235] The method of the present invention can provide any suitable purity of formula XI-a 2 For example, formula XI-a 2 The compound of formula XI-a can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. 2 The compound of formula XI-a can be prepared with a purity of at least about 95%. 2 The compound of formula XI-a can be prepared with a purity of at least about 98%. 2 The compounds can be prepared in a purity of at least about 99%.

[0236] In some embodiments, the methods of the present invention can be performed in a batch process. In some embodiments, the methods of the present invention can be performed continuously.

[0237] In some embodiments, the method comprises preparing a 2 Compounds:

[0238]

[0239] The method comprises preparing a 2 Compound Va is formed under the conditions of TFA, TMSCN, TMSOTf and a reaction mixture having formula Va:

[0240]

[0241] In some embodiments, the preparation of formula XI-a 2 The method is carried out at about -120°C to about 20°C. In another embodiment, the preparation of formula XI-a 2 The method is carried out at about -120°C to about 0°C. In another embodiment, the preparation of formula XI-a 2 The method is carried out at about -40°C to about -20°C.

[0242] In some embodiments, the present invention provides a method for preparing Formula XI-b:

[0243]

[0244] The method comprises forming a reaction mixture having a Lewis acid, a base, a solvent, a filtering agent, and a compound of formula XI-a under conditions suitable for preparing a compound of formula XI-b:

[0245]

[0246] Any suitable Lewis acid can be used in the method for preparing the compound of formula XI-b. For example, the Lewis acid can be TMSOTf, TMSOTf, TBSOTf, TESOTf, BF3, BF3-OEt2, BCl3, BF3-THF, MgCl2, MgI2, MgBr2, MgBr2-OEt2, ZnCl2, ZnBr2, ZnI2, LiCl, LiBr, LiI, AlCl3, AlBr3, AlI3, Me2Si(OTf)2, Et2Si(OTf)2, Pr2Si(OTf)2, iPr2Si(OTf)2, (tBu)2Si(OTf)2, (C6F5)3B, MeSiCl3, Me2SiCl2, SiCl4, TMSCl, TMSI, TMSVr, TBSCl, TBSBr, TBSI, TESCl, TESBr, TESI, S mCl3, SmBr3, SmI2, SmI3, ScI3, ScBr3, ScI3, Sm(OTf)3, Sc(OTf)3, TiCl4, Ti(OiPr)4, Ti(OiPr)3Cl, Ti(OiPr)2Cl2, Ti(OiPr)Cl3, Zn(BF4)2, LiBF4, Mg(BF4)2, ZrCl4, FeCl2, FeCl3, FeBr2, FeBr3, FeI2, FeI3, Cu(OTf), Cu(OTf)2, 4-methylbenzenesulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl triflate, benzenesulfonyl triflate, methylsulfonyl chloride, methylsulfonic anhydride, InCl3, InBr3, InI3, In(OTf)3, Mg(SO4)2, NaSO4; or a combination thereof. In some embodiments, the Lewis acid may be BCL3. In some embodiments, the following substances can be used instead of Lewis acid in the method for preparing the compound of formula XI-b: dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI; or a combination thereof.

[0247] Lewis acid can exist in any suitable amount.For example, the Lewis acid can exist in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula XI-a, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol).Lewis acid can exist in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula XI-a, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol).In some embodiments, Lewis acid can exist in an amount of about 0.1 to 1.0 equivalents (mol / mol) compared to the compound of formula XI-a.In some embodiments, Lewis acid can exist in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula XI-a.

[0248] Any suitable base may be used in the process for preparing the compound of formula XI-b. For example, the base may be (C 1-8 In some embodiments, the base may be Et3N.

[0249] Base can be present in any suitable amount.For example, the base can be present in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula XI-a, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol).Base can be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula XI-a, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol).In some embodiments, base can be present in an amount of about 0.1 to 1.0 equivalents (mol / mol) compared to the compound of formula XI-a.In some embodiments, base can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula XI-a.

[0250] Any suitable solvent can be used in the method for preparing the compound of formula XI-b. For example, the solvent can be MeOH, DCM, THF, MeTHF, Et2O, MeCN, EtCN, toluene, benzene, chlorobenzene, nitrobenzene, fluorobenzene, methanol, ethanol, 2-propanol, propanol, butanol, MTBE, EtOAc, iPrOAc, Me2O, (TMS)2O, acetone, 2-butanone, chloroform, 1,2-dichloroethane, diethylene glycol dimethyl ether, dioxane, acetic acid, formic acid, trifluoroacetic acid, methyl isobutyl ketone, DMAc, DMF, NMP, DMSO; or a combination thereof. In some embodiments, the solvent can be MeOH.

[0251] The solvent can be present in any suitable amount. For example, the solvent can be present in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula XI-a, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The solvent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula XI-a, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the solvent can be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to the compound of formula XI-a. In some embodiments, the solvent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula XI-a.

[0252] Any suitable filter can be used in the method for preparing the compound of formula XI-b. For example, the filter can be silica gel, or a combination thereof. In some embodiments, the filter may be

[0253] The filter agent can be present in any suitable amount. For example, the filter agent can be present in an amount of at least 0.1 equivalents (mol / mol) compared to the compound of formula XI-a, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The filter agent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula XI-a, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the filter agent can be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to the compound of formula XI-a. In some embodiments, the filter agent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula XI-a.

[0254] The reaction mixture of the method can be at any suitable temperature. For example, the temperature of the reaction mixture can be from about -50 ° C to about 0 ° C, or from about -40 ° C to about 0 ° C, or from about -30 ° C to about 0 ° C, or from about -20 ° C to about 0 ° C, or from about -20 ° C to about -10 ° C. In some embodiments, the temperature of the reaction mixture can be from about -30 ° C to about 0 ° C. In some embodiments, the temperature of the reaction mixture can be from about -20 ° C to about -10 ° C. In some embodiments, the temperature of the reaction mixture can be from about -25 ° C to about -15 ° C.

[0255] The reaction mixture of the method can be under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0256] The method of the present invention can provide the compound of formula XI-b with suitable yield.For example, the compound of formula XI-b can be prepared with a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0257] The methods of the present invention can provide compounds of formula XI-b in any suitable purity. For example, compounds of formula XI-b can be prepared in a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, compounds of formula XI-b can be prepared in a purity of at least about 95%. In some embodiments, compounds of formula XI-b can be prepared in a purity of at least about 98%. In some embodiments, compounds of formula XI-b can be prepared in a purity of at least about 99%.

[0258] In some embodiments, the present invention provides a method for preparing a compound of formula XI-b:

[0259]

[0260] The method comprises forming a mixture having BCL3, Et2N, MeOH, and a reaction mixture of a compound of formula XI-a.

[0261]

[0262] In some embodiments, the process for preparing Formula XI-b is carried out at a temperature between about -30°C and about 0°C. In another embodiment, the process for preparing Formula XI is carried out at a temperature between about -20°C and about 0°C.

[0263] In some embodiments, the present invention provides a method for preparing a compound of formula XI-c:

[0264]

[0265] The method comprises forming a reaction mixture having a solvent, a reagent, an acid and a compound of formula XI-b under conditions suitable for preparing a compound of formula XI-c:

[0266]

[0267] Any suitable solvent can be used in the method for preparing the compound of formula XI-c. For example, the solvent can be MeOH, DCM, THF, MeTHF, Et2O, MeCN, EtCN, toluene, benzene, chlorobenzene, nitrobenzene, fluorobenzene, methanol, ethanol, 2-propanol, propanol, butanol, MTBE, EtOAc, iPrOAc, Me2O, (TMS)2O, acetone, 2-butanone, chloroform, 1,2-dichloroethane, diethylene glycol dimethyl ether, dioxane, acetic acid, formic acid, trifluoroacetic acid, methyl isobutyl ketone, DMAc, DMF, NMP, DMSO; or a combination thereof. In some embodiments, the solvent can be acetone.

[0268] The solvent can be present in any suitable amount. For example, the solvent can be present in an amount of at least 0.1 equivalent (mol / mol) compared to the compound of formula XI-b, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). The solvent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to the compound of formula XI-b, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, the solvent can be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to the compound of formula XI-b. In some embodiments, the solvent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula XI-b.

[0269] Any suitable reagent can be used in the method of preparing the compound of formula XI-c. For example, the reagent can be 2,2-dimethoxypropane, acetone, 2-methoxypropylene, 2,2-diethylpropane, 2-ethoxypropylene, 2,2-dimethyl-1,3-dioxolane, 2,2-dimethyl-1,3-dioxane; or a combination thereof. In some embodiments, the reagent can be 2,2-dimethoxypropane.

[0270] Reagent can be present in any suitable amount. For example, reagent can be present in an amount of at least 0.1 equivalent (mol / mol) compared to formula XI-b compound, for example, about 0.1, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). Reagent can also be present in an amount of about 0.1 to about 10.0 equivalents (mol / mol) compared to formula XI-b compound, for example, about 0.1 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, reagent can be present in an amount of about 0.1 to about 1.0 equivalents (mol / mol) compared to formula XI-b compound. In some embodiments, reagent can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to formula XI-b compound.

[0271] Any suitable acid can be used in the method for preparing the compound of formula XI-c. For example, the acid can be TMSOTf, TMSOTf, TBSOTf, TESOTf, BF3, BF3-OEt2, BCl3, BF3-THF, MgCl2, MgI2, MgBr2, MgBr2-OEt2, ZnCl2, ZnBr2, ZnI2, LiCl, LiBr, LiI, AlCl3, AlBr3, AlI3, Me2Si(OTf)2, Et2Si(OTf)2, Pr2Si(OTf)2, iPr2Si(OTf)2, (tBu)2 Si(OTf)2, (C6F5)3B, MeSiCl3, Me2SiCl2, SiCl4, TMSCl, TMSI, TMSVr, TBSCl, TBSBr, TBSI, TESCl, TESBr, TESI, SmCl 3. SmBr3, SmI2, SmI3, ScI3, ScBr3, ScI3, Sm(OTf)3, Sc(OTf)3, TiCl4, Ti(OiPr)4, Ti(OiPr)3Cl, Ti(OiPr)2Cl2, Ti(O iPr)Cl3, Zn(BF4)2, LiBF4, Mg(BF4)2, ZrCl4, FeCl2, FeCl3, FeBr2, FeBr3, FeI2, FeI3, Cu(OTf), Cu(OTf)2, 4-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl trifluoromethanesulfonate, benzenesulfonyl trifluoromethanesulfonate, methylsulfonyl chloride, methylsulfonic anhydride, InCl3, InBr3, InI3, In(OTf)3, Mg(SO4)2, NaSO4, dicyclohexylcarbodiimide, 1-ethyl In some embodiments, the acid may be sulphuric acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI, TFA, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI, trifluoromethanesulfonic acid, 4-fluorobenzoic acid, pivalic acid, HBF4, nitric acid, 4-chloro-benzoic acid, pentafluorophenol, HPF6, camphorsulfonic acid; or a combination thereof. In some embodiments, the acid may be sulphuric acid.

[0272] Acid can exist in any suitable amount.For example, the acid can exist in an amount of at least 0.0 equivalent (mol / mol) compared to the compound of formula XI-b, for example, about 0.0, 0.5, 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). Acid can exist in an amount of about 0.0 to about 10.0 equivalents (mol / mol) compared to the compound of formula XI-b, for example, about 0.0 to about 3.0 equivalents (mol / mol), or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, acid can exist in an amount of about 0.0 to 1.0 equivalents (mol / mol) compared to the compound of formula XI-b. In some embodiments, acid can exist in an amount of about 1.0 to about 2.0 equivalents (mol / mol) compared to the compound of formula XI-b.

[0273] The reaction mixture of the method can be at any suitable temperature. For example, the temperature of the reaction mixture can be from about -50°C to about 50°C, or from about 0°C to about 50°C, or from about 0°C to about 40°C, or from about 0°C to about 30°C, or from about 0°C to about 25°C. In some embodiments, the temperature of the reaction mixture can be from about 0°C to about 23°C. In some embodiments, the temperature of the reaction mixture can be from about 0°C to about 25°C. In some embodiments, the temperature of the reaction mixture can be from about 0°C to about 30°C.

[0274] The reaction mixture of the method can be under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as ambient gas, or an inert gas such as nitrogen or argon.

[0275] The methods of the invention can provide compounds of formula XI-c in any suitable yield. For example, compounds of formula XI-c can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0276] The methods of the present invention can provide compounds of formula XI-c of any suitable purity. For example, compounds of formula XI-c can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, compounds of formula XI-b can be prepared with a purity of at least about 95%. In some embodiments, compounds of formula XI-b can be prepared with a purity of at least about 98%. In some embodiments, compounds of formula XI-b can be prepared with a purity of at least about 99%.

[0277] In some embodiments, the method comprises preparing a compound of formula XI-c:

[0278]

[0279] The method comprises forming a reaction mixture having acetone, 2,2-dimethoxypropane, sulfuric acid and a compound of formula XI-b under conditions suitable for preparing a compound of formula XI-c:

[0280]

[0281] In some embodiments, the method of preparing Formula XI-c is carried out at about 0°C to about 30°C. In other embodiments, the method of preparing Formula XI is carried out at about 10°C to about 30°C.

[0282] C. Addition of prodrug groups

[0283] The present invention also provides methods of coupling a prodrug moiety to a nucleoside to provide a compound of the present invention. In some embodiments, the present invention provides a method of preparing a compound of formula VIII:

[0284]

[0285] wherein the method comprises forming a reaction mixture containing a coupling agent, a non-nucleophilic base, a compound of formula IX, and a compound of formula X under conditions suitable for forming a compound of formula VIII:

[0286]

[0287]

[0288] Among them, each R a is H or PG, each PG group is a hydroxyl protecting group, or two PG groups together form -C(R 19 )2-,R e1 and R e2 Each independently represents H, C1-C6 alkyl or benzyl, R f is H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl or –CH2-C3-C6 cycloalkyl, R 19 is H, C1-C8 alkyl, phenyl or substituted phenyl, and LG is a leaving group.

[0289] Any suitable coupling agent as described above for preparing the compound of formula V can be used in the method of preparing the compound of formula VIII of the present invention. In some embodiments, the coupling agent can be a magnesium coupling agent. In some embodiments, the coupling agent can be MgCl2, iPrMgCl, tBuMgCl, PhMgCl or a combination thereof. In some embodiments, the coupling agent can be MgCl2.

[0290] Any suitable non-nucleophilic base can be used in the method for preparing the compound of formula VIII. Representative non-nucleophilic bases include, but are not limited to, triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine. In some embodiments, the non-nucleophilic base can be diisopropylethylamine (DIPEA).

[0291] The protecting group PG can be any suitable hydroxy protecting group as described above in the method for preparing the compound of formula V. An exemplary protecting group PG can be benzyl, or the PG groups can be taken together to form an acetonide. Exemplary acetonides include, but are not limited to, acetonides and benzylidene acetals. In some embodiments, hydroxy protecting groups on adjacent carbon atoms can be taken together to form an acetonide. In some embodiments, multiple PG groups can be taken together to form -C(R 19 )2-. In some embodiments, each R a is the protecting group PG, wherein the PG groups together form –C(Me)2-.

[0292] When R e When the group is a C1-C8 alkyl group, each R e R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. e The group may be methyl.

[0293] When R f When the group is C1-C8 alkyl, R f R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. f The group may be methyl, ethyl, isopropyl, tert-butyl, or isohexyl. f When the group is a C3-C6 cycloalkyl group, R f It can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R f It may be cyclobutyl, cyclopentyl or cyclohexyl.

[0294] When R 19 When the group is C1-C8 alkyl, R 19 It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. In some embodiments, R 19 The group may be methyl.

[0295] The leaving group can be any suitable leaving group. Suitable leaving groups LG include, but are not limited to, chloride, bromide, mesylate, tosylate, triflate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, pentafluorophenoxy, etc. In some embodiments, the leaving group LG can be 4-nitrophenoxy or pentafluorophenoxy. In some embodiments, the leaving group LG can be 4-nitrophenoxy.

[0296] In some embodiments, each R a is a PG wherein the PG groups together form -C(R 19 )2-,R f is C1-C8 alkyl, R 19 is a C1-C8 alkyl group, and the leaving group LG is a 4-nitrophenoxy group or a pentafluorophenoxy group.

[0297] In some embodiments, the coupling agent is MgCl2 and the non-nucleophilic base is diisopropylethylamine.

[0298] In some embodiments, the compound of formula VIII may be

[0299]

[0300] In some embodiments, the compound of formula VIII may be

[0301]

[0302] In some embodiments, the compound of formula VIII may be

[0303]

[0304] In some embodiments, the method of preparing a compound of Formula VIII comprises in a reaction suitable for forming a compound of Formula VIII:

[0305] A reaction mixture containing MgCl2, DIPEA, a compound of Formula IX and a compound of Formula X is formed under conditions of:

[0306]

[0307] When R of the compound of formula VIII a When the group is a hydroxyl protecting group PG, the method may further comprise removing the protecting group to form a a In some embodiments, the method of preparing the compound of formula VIII comprises removing the protecting group PG to form a compound of formula VIII wherein each R ais H, forming a second reaction mixture comprising a deprotecting agent and wherein R a The group is a compound of formula VIII in which the protecting group is a PG protecting group. The deprotecting agent can be any suitable reagent for removing the protecting group PG, such as hydrogen and a hydrogenation catalyst or an acid. For example, if the protecting group PG is a benzyl group, the deprotecting agent can be hydrogen and carbon-supported platinum. Alternatively, when the protecting group PG is an acetone compound, the deprotecting agent can be an acid. Representative acids include, but are not limited to, acetic acid, glacial acetic acid, trifluoroacetic acid (TFA), hydrochloric acid, concentrated hydrochloric acid, and the like. In some embodiments, the method for preparing the compound of formula VIII comprises forming a compound in which each R a is H, and a second reaction mixture is formed comprising an acid and a compound of formula VIII (wherein R a The groups combine under appropriate conditions to form -C(R 19 )2-). In some embodiments, the acid may be hydrochloric acid.

[0308] Any suitable solvent can be used in the method of the present invention.Representational solvent includes but is not limited to pentane, different pentanes, hexane, different hexanes, heptane, different heptanes, petroleum ether, cyclopentane, cyclohexane, benzene, toluene, dimethylbenzene, trifluorotoluene, halogenated benzene such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, methylene chloride, chloroform, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile or its combination.In some embodiments, solvent can be acetonitrile.

[0309] The reaction mixture of the method can be at any suitable temperature. For example, the temperature of the reaction mixture can be from about -78°C to about 100°C, or from about -50°C to about 100°C, or from about -25°C to about 50°C, or from about -10°C to about 25°C, or from about 0°C to about 20°C. In some embodiments, the temperature of the reaction mixture can be from about 0°C to about 20°C.

[0310] The reaction mixture of the method can be under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0311] The methods of the invention can provide the compound of formula VIII in any suitable yield. For example, the compound of formula VIII can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0312] The methods of the present invention can provide compounds of formula VIII of any suitable purity. For example, compounds of formula VIII can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, compounds of formula VIII can be prepared with a purity of at least 95%. In some embodiments, compounds of formula VIII can be prepared with a purity of at least 98%. In some embodiments, compounds of formula VIII can be prepared with a purity of at least 99%.

[0313] In some embodiments, the present invention provides the following compounds

[0314]

[0315] In some embodiments, the present invention provides a method for preparing a compound of formula VIII:

[0316]

[0317] wherein the method comprises forming a reaction mixture containing a coupling agent, a non-nucleophilic base, a compound of formula IX-a, and a compound of formula X under conditions suitable for forming a compound of formula VIII:

[0318]

[0319] Where R a are independently H or a hydroxy protecting group, or two R on adjacent carbons a Can form -C(R 19 )2-group, R 35 are independently H or a hydroxy protecting group, or two R on adjacent carbons 35 The groups can be combined to form -C(R 19 )2-group, R 19 is H or C1-C8 alkyl, R e1 and R e2 Each independently represents H, C1-C6 alkyl or benzyl, R f is H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, or –CH2-C3-C6 cycloalkyl, R 19 is H, C1-C8 alkyl, phenyl or substituted phenyl, and LG is a leaving group.

[0320] Any suitable coupling agent described in the method for preparing the compound of formula VIII can be used in the method for preparing the compound of formula V as described above. In some embodiments, the coupling agent can be a magnesium coupling agent. In some embodiments, the coupling agent can be MgCl2, iPrMgCl, tBuMgCl, PhMgCl, or a combination thereof. In some embodiments, the coupling agent can be MgCl2.

[0321] Any suitable non-nucleophilic base can be used in the method for preparing the compound of formula VIII. Representative non-nucleophilic bases include, but are not limited to, triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine. In some embodiments, the non-nucleophilic base can be diisopropylethylamine (DIPEA).

[0322] The hydroxy protecting groups are as described above in the method for making the compound of formula V. Exemplary hydroxy protecting groups can be benzyl, SiR3, where each R group can be hydrogen, alkyl, alkenyl, cycloalkyl, phenyl or other silicon-containing groups, or the PG groups can be taken together to form an acetonide. Exemplary silanes include, but are not limited to, tert-butyldimethylsilyl (TBS). Exemplary acetonides include, but are not limited to, acetonides and benzylidene acetals. In some embodiments, the hydroxy protecting groups on adjacent carbon atoms can be taken together to form an acetonide. In some embodiments, the PG groups are taken together to form -C(R 19 )2-. In some embodiments, each R a is a PG group, wherein the PG groups together form -C(Me)2-. In other embodiments, PG is SiR3. In other embodiments, PG is tert-butyldimethylsilyl (TBS).

[0323] When R e When the group is a C1-C8 alkyl group, each R e R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. e The group may be methyl.

[0324] When R f When the group is C1-C8 alkyl, R f R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. f The group may be methyl, ethyl, isopropyl, tert-butyl, or isohexyl. f The group is C3-C6 cycloalkyl, R f It can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R f It may be cyclobutyl, cyclopentyl or cyclohexyl.

[0325] When R 19 When the group is C1-C8 alkyl, R 19R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl or octyl. 19 The group may be methyl.

[0326] When R 35 When the group is a hydroxyl protecting group, R 35 can be any of the example protecting groups described in Protective Groups in Organic Chemistry, Peter GMWuts and Theodora W. Greene, 4th Ed., 2006. In some embodiments, R 35 The group may be benzyl. In some embodiments, R 35 The group is TBS.

[0327] The leaving group can be any suitable leaving group. Suitable leaving groups LG include, but are not limited to, chloride, bromide, mesylate, tosylate, triflate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, pentafluorophenoxy, etc. In some embodiments, the leaving group LG can be 4-nitrophenoxy or pentafluorophenoxy. In some embodiments, the leaving group LG can be 4-nitrophenoxy.

[0328] In some embodiments, each R a is PG, wherein the PG groups together form -C(R 19 )2-,R f is C1-C8 alkyl, R 19 is a C1-C8 alkyl group, and the leaving group LG is a 4-nitrophenoxy group or a pentafluorophenoxy group.

[0329] In some embodiments, the coupling agent is MgCl2 and the non-nucleophilic base is diisopropylethylamine.

[0330] In some embodiments, the compound of formula VIII may be:

[0331]

[0332] In some embodiments, the compound of formula VIII may be:

[0333]

[0334] In some embodiments, the compound of formula VIII may be:

[0335]

[0336] In some embodiments, the method of preparing a compound of formula VIII comprises in a suitable method for preparing a compound of formula VIII

[0337]

[0338] A reaction mixture containing MgCl2, DIPEA, a compound of formula IX and a compound of formula X is formed under conditions of:

[0339]

[0340] When R of the compound of formula VIII a When the group is a hydroxyl protecting group PG, the method may further comprise removing the protecting group to form a a In some embodiments, the method of preparing the compound of formula VIII comprises forming a compound of formula VIII in which each R a is H, and a second reaction mixture is formed comprising a deprotecting agent and wherein each R a The compound of formula VIII is a protective group PG. The deprotecting agent can be any suitable reagent for removing the protective group PG, such as hydrogen and a hydrogenation catalyst or an acid. For example, if the protective group PG is a benzyl group, the deprotecting agent can be hydrogen and carbon-supported platinum. Alternatively, when the protective group PG is an acetone compound, the deprotecting agent can be an acid. Representative acids include, but are not limited to, acetic acid, glacial acetic acid, trifluoroacetic acid (TFA), hydrochloric acid, concentrated hydrochloric acid, formic acid, toluenesulfonic acid, sulfuric acid, and the like. Other representative acids include, but are not limited to, those described in Greene, TW; Wuts, PGM Protective Groups In Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006. In some embodiments, the method for preparing the compound of formula VIII includes in a suitable for forming a compound wherein R a A second reaction mixture is formed under conditions wherein the compound of formula VIII is H and the acid and R a The groups together form -C(R 19 )2-is a compound of formula VIII. In some embodiments, the acid may be hydrochloric acid. Alternatively, when the protecting group PG is SiR3, the deprotecting agent may be TBAF, pyridine HF, HCl, TsOH, camphorsulfonic acid, AcCl dissolved in MeOH, BF 3 OE 2 , TFA, AcOG, formic acid, HBr, F, HF, Et3N-HF, KF-H2O, KHF2, NaF, LiF, LiCl, LiBr, LiI, etc.

[0341] Any suitable solvent can be used in the method for the present invention.Representational solvent includes but is not limited to pentane, different pentanes, hexane, different hexanes, heptane, different heptanes, sherwood oil, cyclopentane, cyclohexane, benzene, toluene, dimethylbenzene, trifluorotoluene, halogenated benzene such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, methylene chloride, chloroform, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile or its combination.In some embodiments, solvent can be acetonitrile.In some embodiments, solvent can be MeCN.In some embodiments, solvent can be tetrahydrofuran.

[0342] The reaction mixture of the method can be at any suitable temperature. For example, the temperature of the reaction mixture can be from about -78°C to about 100°C, or from about -50°C to about 100°C, or from about -25°C to about 50°C, or from about -10°C to about 25°C, or from about 0°C to about 20°C. In some embodiments, the temperature of the reaction mixture can be from about 0°C to about 20°C.

[0343] The reaction mixture of the method can be under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0344] The methods of the invention can provide the compound of formula VIII in any suitable yield. For example, the compound of formula VIII can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0345] The methods of the present invention can provide any suitable purity of the compound of formula VIII. For example, the compound of formula VIII can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, the compound of formula VIII can be prepared with a purity of at least 95%. In some embodiments, the compound of formula VIII can be prepared with a purity of at least about 98%. In some embodiments, the compound of formula VIII can be prepared with a purity of at least 99%.

[0346] In some embodiments, the compound of formula VIII may be:

[0347]

[0348] In some embodiments, the method of preparing a compound of formula VIII comprises in a suitable manner for preparing a compound of formula VIII

[0349]

[0350] Under the conditions of forming MgCl2, DIPEA formula IX-a 2A reaction mixture of a compound and a compound of formula X:

[0351]

[0352] The method may include the further step of removing the protecting group to form a compound of formula VIII wherein each TBS is H.

[0353] The reaction mixture of the method can be at any suitable temperature. For example, the temperature of the reaction mixture can be from about -78°C to about 100°C, or from about -50°C to about 100°C, or from about -25°C to about 50°C, or from about -10°C to about 25°C, or from about 0°C to about 20°C. In some embodiments, the temperature of the reaction mixture can be from about 0°C to about 20°C.

[0354] The reaction mixture of the method can be under any suitable pressure. For example, the reaction mixture can be under atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gases, or inert gases such as nitrogen or argon.

[0355] The methods of the invention can provide the compound of formula VIII in any suitable yield. For example, the compound of formula VIII can be prepared in a yield of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least about 95%.

[0356] The methods of the present invention can provide any suitable purity of the compound of formula VIII. For example, the compound of formula VIII can be prepared with a purity of at least about 90%, 95%, 96%, 97%, 98%, or at least about 99%. In some embodiments, the compound of formula VIII can be prepared with a purity of at least 95%. In some embodiments, the compound of formula VIII can be prepared with a purity of at least about 98%. In some embodiments, the purity of the compound of formula VIII can be prepared with a purity of at least 99%.

[0357] D. Preparation of Formula Xb by Crystallization-Induced Dynamic Resolution

[0358] In one embodiment, a method for dynamic resolution of (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (Formula Xa) by crystallization induction is provided:

[0359]

[0360] to provide (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester (Formula Xb). The method comprises subjecting a solution comprising: a) a suitable solvent; b) a suitable base; c) (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester; and optionally d) one or more (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester to conditions that provide epimerization of the phosphorus center under conditions suitable for providing selective crystallization of (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester.

[0361] Crystallization can be carried out in any suitable solvent. For example, it can be carried out in an aprotic organic solvent or a mixture thereof. For example, an aprotic organic solvent can include ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, methylene chloride, acetone, methyl ethyl ketone, methyl tert-butyl ether, toluene or acetonitrile, or a mixture thereof. In one embodiment, the solvent includes acetonitrile.

[0362] The resolution can be carried out in the presence of any suitable base. For example, the resolution can be carried out in a base selected from 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo [4.4.0] dec-5-ene (MTBD), triethylamine (Et3N), Hunig base (iPr2NEt), tetramethylguanidine, Verkade base (e.g., 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane), metal carbonate (e.g., M x CO3), metal phenolate (M +- OPh) and PhOTMS base and fluoride ion source (e.g., R4N +- F, TASF (tris(dimethylamino)sulfonium difluorotrimethylsilicate) or TBAT (tetrabutylammonium triphenyldifluorosilicate) and mixtures thereof, wherein each M is a suitable metal such as an alkali metal or alkaline earth metal, and each R is, for example, a (C1-C6) alkyl group. In a specific example, the base is DBU.

[0363] The resolution can also be performed at any suitable temperature, for example, within the temperature range of about 0°C to about 50°C. In a specific embodiment, the resolution is performed at a temperature of about 0°C.

[0364] In a specific embodiment, the resolution is performed in the presence of phenol.

[0365] The percentage of 2-ethylbutyl (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate in the starting mixture of diastereomers can be any number from about 0% to about 99%. In one embodiment of the present invention, the percentage of 2-ethylbutyl (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate in the starting mixture of diastereomers is from about 0% to about 20%. In one embodiment, the percentage of 2-ethylbutyl (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate in the starting mixture of diastereomers is from about 20% to about 99%. In one embodiment, the percentage of 2-ethylbutyl (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate in the starting mixture of diastereomers is from about 50% to about 99%. In one embodiment, the final compound (S)-2-ethylbutyl 2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate is at least about 90%, about 95%, about 97%, or about 99% diastereomerically pure. In one embodiment, the final compound (S)-2-ethylbutyl 2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate contains less than 1% diastereomeric impurities. In one embodiment, the final compound (S)-2-ethylbutyl 2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate does not contain any detectable diastereomeric impurities. Example

[0366] Some abbreviations and acronyms are used to describe the details of the experiments. Although most of these are understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0367] Table 1: List of abbreviations and acronyms

[0368]

[0369]

[0370]

[0371] E. Preparation of Compounds

[0372] Example 1: Ethyl (2S)-2-(chloro(phenoxy)phosphorylamino)propionate (chloride A)

[0373]

[0374] Alanine ethyl ester hydrochloride (1.69 g, 11 mmol) was dissolved in anhydrous CH2Cl2 (10 mL), and the mixture was stirred and cooled to 0 ° C under N2 (g). Phenyl dichlorophosphate (1.49 mL, 10 mmol) was added, and then Et3N was added dropwise in about 10 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for about 12 hours. Anhydrous Et2O (50 mL) was added and the mixture was stirred for about 30 minutes. The solid formed was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with a hexane solution of 0-50% EtOAc to obtain intermediate A. 1 H NMR (300MHz, CDCl3) δ7.39-7.27(m, 5H), 4.27(m, 3H), 1.52(m, 3H), 1.32(m, 3H). 31 P NMR (121.4MHz, CDCl3) δ8.2, 7.8.

[0375] Example 2: (2S)-2-(Chloro(phenoxy)phosphorylamino)propionic acid 2-ethylbutyl ester (chloride B)

[0376]

[0377] 2-Ethylbutylalanine chlorophosphoramidoester B was prepared in the same manner as chloride A, except that 2-ethylbutylalaninate was used in place of ethylalaninate. This material was used crude in subsequent reactions. Treatment with methanol or ethanol formed a displacement product with the desired LCMS signal.

[0378] Example 3: (2S)-2-(Chloro(phenoxy)phosphorylamino)propionic acid isopropyl ester (chloride C)

[0379]

[0380] Isopropylalanine chlorophosphoramidoester C was prepared using the same method as chloride A except that isopropylalaninate was used instead of ethylalaninate. This material was used crude in the next reaction. Treatment with methanol or ethanol formed a displacement product with the desired LCMS signal.

[0381] Example 4: (2R, 3R, 4S, 5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3,4-di Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (Compound 1)

[0382]

[0383] The preparation of (2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile is described below.

[0384]

[0385] Under N2(g), the commercially available lactone (10 g, 23.8 mmol) was dissolved in anhydrous DMSO (30 mL). Ac2O (20 mL) was added and the resulting reaction mixture was stirred at room temperature for about 48 hours. The reaction mixture was poured into ice H2O (500 mL) and the mixture was stirred for 20 minutes. The mixture was extracted with EtOAc (3×200 mL) and the combined organic extracts were washed with H2O (3×200 mL). The organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and subjected to silica gel chromatography, eluting with 25% EtOAc in hexane to give the lactone. 1 H NMR (400 MHz, DMSO) δ 7.30-7.34 (m, 13H), 7.19-7.21 (m, 2H), 4.55-4.72 (m, 6H), 4.47 (s, 2H), 4.28 (d, J=3.9 Hz, 1H), 3.66 (m, 2H). LCMS m / z 436.1 [M+H2O], 435.2 [M+OH]-Tr=2.82 min. HPLC Tr=4.59 [2-98% ACN in H2), flowing at 2 mL / min in 5 minutes.

[0386]

[0387] Under N2(g), bromopyrazole (prepared according to WO2009 / 132135) (0.5g, 2.4mmol) was suspended in anhydrous THF (10mL). The suspension was stirred, and TMSCl (0.67mL, 5.28mmol) was added. The mixture was stirred at room temperature for 20 minutes. Then it was cooled to about -78°C, and then a solution of n-BuLi (6mL, 1.6N in hexane, 9.6mmol) was slowly added. The reaction mixture was stirred at about -78°C for 10 minutes, and then lactone (1g, 2.4mmol) was added by syringe. When the reaction was determined to be complete by LCMS, AcOH was added to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was dissolved in a mixture of CH2Cl2 and H2O (100mL, 1:1). The organic layer was separated and washed with H2O (50mL). The organic layer was dried, filtered and concentrated under reduced pressure with anhydrous MgSO4. The residue was chromatographed on silica gel, eluting with 0-50% EtOAc in hexanes to afford the product as a 1:1 mixture of anomers. LCMS m / z 553 [M+H].

[0388]

[0389] Under N2(g), hydroxy nucleoside (1.1 g, 2.0 mmol) was dissolved in anhydrous CH2Cl2 (40 mL), and the solution was cooled to -78°C. TMSCN (0.931 mL, 7 mmol) was added, and the mixture was stirred for another 10 minutes. TMSOTf (1.63 mL, 9.0 mmol) was slowly added to the reactant, and the mixture was stirred for 1 hour. The reaction mixture was then diluted with CH2Cl2 (120 mL), and an aqueous NaHCO3 solution (120 mL) was added to quench the reaction. The reaction mixture was stirred for another 10 minutes, and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (150 mL), and the combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in a minimum amount of CH2Cl2, and subjected to silica gel chromatography, with a gradient elution of 0-75% EtOAc and hexane to obtain tribenzyl cyano nucleoside as a mixture of end isomers. 1 H NMR(300MHz,CD3CN)δ7.94(s,0.5H),7.88(s,0.5H),7.29-7.43(m,13H),7.11-7.19(m,1H),6.82-6.88(m,1H),6.70-6.76(m,1H) LCMS m / z 562[M+H].

[0390]

[0391] Under N2(g), tribenzyl cyanide nucleoside (70mg, 0.124mmol) was dissolved in anhydrous CH2Cl2 (2mL) and cooled to about -20°C. BCl3 solution (1N in CH2Cl2, 0.506mL, 0.506mmol) was added and the reaction mixture was stirred at -78°C for 1 hour. When the reaction was confirmed to be complete by LC / MS, MeOH was added to quench the reaction. The reaction mixture was warmed to room temperature and the solvent was removed under reduced pressure. The residue was subjected to C18 reverse phase HPLC, eluted with H2O (0.1% TFA) for 5 minutes, followed by 0-70% MeCN in H2O (0.1% TFA) gradient elution over 35 minutes to elute the α-anomer and β-anomer 1. (α-anomer) 1H NMR (300 MHz, D2O) δ 7.96 (s, 1H), 7.20 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 4.97 (d, J = 4.4 Hz, 1H), 4.56-4.62 (m, 1H), 4.08-4.14 (m, 1H), 3.90 (dd, J = 12.9, 2.4 Hz, 1H), 3.70 (dd, J = 13.2, 4.5 Hz, 1H). (β-anomer) 1 H NMR (400MHz, DMSO) δ7.91 (s, 1H), 7.80-8.00 (br s, 2H), 6.85-6.89 (m, 2H), 6.07 (d, J=6.0Hz, 1H), 5.17 (br s, 1H), 4.90 (br s, 1H), 4.63 (t, J=3.9Hz, 1H), 4.02-4.06 (m, 1H), 3.94 (br s, 1H), 3.48-3.64 (m, 2H).LCMS m / z 292.2[M+H], 290.0[MH].Tr=0.35min.13C NMR (400MHZ, DMSO), 156.0, 148.3, 124.3, 117.8, 117.0, 111.2, 101.3, 85.8, 79.0, 74.7, 70.5, 61.4. HPLC Tr=1.32min

[0392] Example 4-a: (2R, 3R, 4S, 5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3,4- Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (Compound 1)

[0393]

[0394] The preparation of (2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile is described below.

[0395] Preparation of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-1 ... 2-((benzyloxy)methyl)tetrahydrofuran-2-ol

[0396]

[0397] A solution of 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (7.5 g, 28.8 mmol, 1.0 equiv) was prepared in THF (67 mL). The solution was cooled to about 0°C and TMSCl (3.3 mL, 30.3 mmol, 1.05 equiv) was added. The reaction mixture was stirred for about 30 minutes and then PhMgCl (2M in THF; 28 mL, 56.8 mmol, 1.97 equiv) was added while keeping the internal temperature below 5°C. The reaction mixture was stirred at about 0°C for about 35 minutes and then cooled to about -15°C. iPrMgCl (2M in THF, 14 mL, 30.2 mmol, 1.05 equiv) was then added while keeping the internal temperature below about -10°C. After about 15 min at about -15° C., LaCl 3-2LiCl (0.6 M in THF, 50 mL, 14.4 mmol, 0.5 eq.) was added while maintaining the internal temperature below about -15° C. The reaction mixture was stirred at about -20° C. for about 25 min.

[0398] In a separate flask, a solution of (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one (10.0 g, 23.9 mmol, 0.83 equiv) was prepared in THF (45 mL). The solution was cooled to about -20°C and then transferred to the Grignard solution while maintaining the internal temperature below about -15°C. The resulting reaction mixture was stirred at about -20°C for about 30 minutes.

[0399] The reaction was quenched with 2M HCl (53 mL) and the mixture was warmed to about 15°C. iPrOAc (38 mL) was added and the organic and aqueous phases were separated. The bottom aqueous layer was drained and the upper organic layer was washed sequentially with 2.5 wt% NaHCO3 (53 mL), 2.5 wt% NaHCO3 (53 mL) and 10 wt% NaCl (53 mL).

[0400] The organic phase was concentrated to about 45 mL and then diluted with iPrOAc (75 mL). The solution was concentrated again to about 45 mL and then diluted with iPrOAc (23 mL). The solution was concentrated to about 45 mL and then filtered on a pad of Celite. The filtered solution was concentrated to about 26 mL and then diluted with MTBE (75 mL). After 2 hours, heptane (23 mL) was slowly added and the slurry was stirred at about 25 ° C for about 2 hours and then cooled to about -5 ° C in about 8 hours. The solid was separated by filtration and the filter cake was washed with MTBE / heptane (4:1, 23 mL). The solid was dried in a vacuum oven at no more than about 35 ° C to obtain (3R, 4R, 5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol.

[0401] Preparation of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4- Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol

[0402]

[0403] Iodopyrazole (5.02 g, 19.3 mmol) was dissolved in THF (45 g), and the solution was cooled to about 0 ° C with stirring. TMSCl (2.04 g, 18.7 mmol) was added, and after about 1 hour, phenylmagnesium chloride (2.0 M in THF, 19.9 g, 38.2 mmol) was added. The reaction mixture was cooled to about -20 ° C, and isopropylmagnesium chloride (2.0 M in THF, 9.99 g, 20.5 mmol) was slowly added. After about 30 minutes, the reaction mixture was transferred to a mixture of anhydrous cerium chloride (4.75 g, 19.3 mmol) in THF (22 g) at about -20 ° C. After about 1.5 hours, a solution of lactone (6.73 g, 16.1 mmol) in THF (22 g) was slowly added, and the resulting reaction mixture was stirred for about 1 hour. 2M HCl (41 g) was added, the mixture was warmed to about 15 ° C, and isopropyl acetate (35 g) was added. The layers were separated and the organic layer was washed with 2.5% NaHCO (2 x 40 g), 10% NaCl (1 x 35 g) and concentrated to about 30 mL volume. Isopropyl acetate (44 g) was added and the solution was concentrated to about 30 mL volume. Isopropyl acetate (43 g) was added and the solution was concentrated to about 30 mL volume. The solution was filtered and the filtrate was concentrated to about 18 mL volume. Tert-butyl methyl ether (37 g) was added and then product seed (10.7 mg) was added. After about 14 hours, n-heptane (10.5 g) was added and the mixture was cooled to about -5 ° C and filtered. The solid was washed with tert-butyl methyl ether (9 g) at about -5 ° C and dried under vacuum at about 34 ° C for about 15 hours to provide the product.

[0404] Preparation of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine using CeCl3 and iPrMgCl-LiCl (benzyloxy)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol

[0405]

[0406] Under N2(g), iodine pyrazole (5.03 g, 19.3 mmol) was dissolved in THF (45 g), and the solution was stirred and cooled to about 0°C. TMSCl (2.06 g, 19.0 mmol) was added, and after about 1 hour, magnesium chloride (2.0 M in THF, 20.23 g, 38.8 mmol) was added. The reaction mixture was cooled to about -20°C, and isopropylmagnesium chloride-lithium chloride complex (2.0 M in THF, 15.37 g, 21.0 mmol) was slowly added. After about 1 hour, the reaction mixture was transferred to a mixture of cerium chloride (4.77 g, 19.4 mmol) in THF (22 g) at about -20°C. After about 1 hour, a solution of lactone (6.75 g, 16.1 mmol) in THF (23 g) was slowly added, and the resulting reaction mixture was stirred for about 1.5 hours. 2M HCl (40 g) was added, the mixture was warmed to about 15°C, and isopropyl acetate (35 g) was added. The layers were separated, and the organic layer was washed with 2.5% NaHCO3 (2×40 g), 10% NaCl (1×36 g), and concentrated to about 30 mL volume. Isopropyl acetate (44 g) was added, and the solution was concentrated to about 30 mL volume. The solution was filtered and the filtrate was concentrated to about 18 mL volume. Tert-butyl methyl ether (37 g) was added, followed by product seed crystals (10.5 mg). After about 14 hours, n-heptane (11 g) was added, the mixture was cooled to about -5°C and filtered. The solid was washed with tert-butyl methyl ether (9 g) at about -5°C and dried under vacuum at about 34°C for about 15 hours to provide the product.

[0407] Preparation of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-diol using YCl3 (Benzyloxy)-5-((Benzyloxy)methyl)tetrahydrofuran-2-ol

[0408]

[0409] Iodopyrazole (4.99 g, 19.2 mmol) was dissolved in THF (44 g), and the solution was cooled to about 0°C with stirring. TMSCl (2.45 mL, 19.4 mmol) was added, and after about 30 minutes, phenylmagnesium chloride (2.0 M in THF, 20.29 g, 39.0 mmol) was added. The reaction mixture was cooled to about -20°C, and isopropylmagnesium chloride (2.0 M in THF, 9.85 g, 20.1 mmol) was slowly added. After about 30 minutes, the reaction mixture was transferred to a mixture of anhydrous yttrium chloride (3.76 g, 19.3 mmol) and lactone (6.68 g, 16.0 mml) in THF (24 g) at about -20°C. After about 2.5 hours, 2M HCl (30 g) was added, the mixture was warmed to about 15°C, and isopropyl acetate (22 g) was added. The layers were separated and the organic layer was washed with 2.5% NaHCO3 (2 x 40 g), 10% NaCl (1 x 35 g) and concentrated to about 30 mL volume. Isopropyl acetate (44 g) was added and the solution was concentrated to about 30 mL volume. Isopropyl acetate (45 g) was added and the solution was concentrated to about 30 mL volume. The solution was filtered and the filtrate was concentrated to about 18 mL volume. Tert-butyl methyl ether (37 g) was added and then product seed crystals (11.5 mg) were added. After about 1 hour, n-heptane (15 mL) was added and the mixture was cooled to about -5°C and stirred for about 17 hours. The slurry was filtered and the solid was washed with a mixture of tert-butyl methyl ether (8 g) / n-heptane (2 g) pre-cooled to about -5°C. The resulting solid was dried under vacuum at about 34°C for about 22 hours to give the product.

[0410] Preparation of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4- Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol

[0411]

[0412] Under N2(g), iodopyrazole (5.02 g, 19.3 mmol) was dissolved in THF (38 g), and the solution was stirred and cooled to about 0°C. TMSCl (2.45 mL, 19.4 mmol) was added, and after about 1 hour, phenylmagnesium chloride (2.0 M in THF, 19.75 g, 38.0 mmol) was added. The reaction mixture was cooled to about -20°C, and isopropylmagnesium chloride (2.0 M in THF, 9.40 g, 19.2 mmol) was slowly added. After about 1.5 hours, the reaction mixture was transferred to a mixture of anhydrous neodymium (III) chloride (4.03 g, 16.1 mmol) and lactone (6.70 g, 16.0 mml) in THF (22 g) at about -20°C. After about 1.5 hours, the reaction mixture was warmed to -10°C, and after another 2 hours, 2M HCl (36 g) was added. The mixture was warmed to about 15°C and isopropyl acetate (23 g) was added. The layers were separated and the organic layer was washed with 2.5% NaHCO3 (2×44 g), 10% NaCl (1×41 g) and concentrated to about 30 mL volume. Isopropyl acetate (44 g) was added and the solution was concentrated to about 30 mL volume. Isopropyl acetate (45 g) was added and the solution was concentrated to about 30 mL volume. The solution was filtered and the filtrate was concentrated to about 18 mL volume. Tert-butyl methyl ether (37 g) was added and then product seed crystals (11.9 mg) were added. After about 1 hour, n-heptane (15 mL) was added and the mixture was cooled to about -5°C and stirred for about 15 hours. The slurry was filtered and the solid was washed with a mixture of tert-butyl methyl ether (8 g) / n-heptane (11 g) precooled to about -5°C. The resulting solid was dried under vacuum at about 34°C for about 25 hours to obtain the product.

[0413] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)- Preparation of 5-((Benzyloxy)methyl)tetrahydrofuran-2-carbonitrile

[0414]

[0415] To a precooled (-40 °C) solution of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (10.0 g, 18.1 mmol, 1.0 equiv) in DCM (100 mL) was added trifluoroacetic acid (6.19 g, 54.3 mmol, 3.0 equiv) followed by a precooled (-30 °C) solution of TMSOTf (24.1 g, 108.6 mmol, 6.0 equiv) and TMSCN (10.8 g, 108.6 mmol, 6.0 equiv) in DCM (50 mL) while keeping the internal temperature below about -25 °C. The reaction mixture was stirred at below about -30°C for no less than 10 minutes and added to a pre-cooled (about -10°C) 20 wt% aqueous KOH solution (120 mL) to quench the reaction. The biphasic mixture was warmed to ambient temperature. The organic layer was separated and washed with 10 wt% aqueous NaCl solution (3×50 mL). The organic phase was filtered, concentrated in vacuo to about 50 mL, rediluted with toluene (200 mL) and concentrated in vacuo to 140 mL at about 50°C. The solution was seeded with (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile at about 55°C. Stirred at about 55°C for about 1 hour and cooled to about 0°C over about 6 hours. The solid was isolated by filtration and the filter cake was washed with toluene (30 mL). The solid was dried under vacuum at about 50°C.

[0416] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1, 2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile

[0417]

[0418] A solution of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (23.0 g, 460.07 g DCM), TMSOTf (55.81 g, 138.07 g DCM) and TMSCN (25.03 g, 138.10 g DCM) was pumped into a tubular reactor in sequence at about -40°C. The reaction mixture was collected in a flask containing 20% ​​aqueous KOH (46.91 g KOH and 210 g water) maintained in an ice bath. The layers were separated and the organic phase was washed with 10% aqueous KOH (10 g KOH and 90 mL water) and 10% brine (2 x 100 g) in sequence. The organic phase was concentrated to about 4 volumes under vacuum, isopropanol (162.89 g) was added, and the mixture was concentrated to about 10 volumes under vacuum. The contents were heated to about 60° C., then adjusted to about 0° C. over about 6.5 hours, and stirred at about 0° C. for about 15.5 hours. The resulting slurry was filtered, the solids were rinsed with isopropanol (61.79 g), and then dried under reduced pressure at about 50° C. overnight to give the product.

[0419] (2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5- Preparation of (Hydroxymethyl)tetrahydrofuran-2-carbonitrile

[0420]

[0421] Tribenzyl cyanide nucleoside (48.8 g, 86.9 mmol, 1.0 eq) was dissolved in anhydrous CH2Cl2 (244 mL) and cooled to about -20°C. BCl3 solution (1M in CH2Cl2, 295 mL, 295 mmol, 3.4 eq) was added dropwise, keeping the internal temperature below about -15°C. After addition, the reaction mixture was stirred at about -20°C for 1 hour. MeOH (340 ml) was added dropwise, keeping the internal temperature below -15°C. The resulting solution was distilled to about 250 ml and then supplemented with about 250 ml MeOH. The resulting solution was distilled again to about 250 ml, then supplemented with about 250 ml MeOH, and finally distilled to about 125 ml. Water (125 ml) was added, followed by K2CO3 solution (20 wt% in water, 125 ml). The pH was checked and found to be ~3. K2CO3 solution (20 wt% in water, 50 ml) was added, and the pH was ~8. The resulting slurry was stirred overnight then filtered and washed with water (50 ml) and MeOH (50 ml).The wet product cake was dried at about 40°C overnight. 1H NMR (300MHz, D2O) δ7.96 (s, 1H), 7.20 (d, J = 4.8Hz, 1H), 6.91 (d, J = 4.8Hz, 1H), 4.97 (d, J = 4.4Hz, 1H) , 4.56-4.62 (m, 1H), 4.08-4.14 (m, 1H), 3.90 (dd, J=12.9, 2.4Hz, 1H), 3.70 (dd, J=13.2, 4.5Hz, 1H).

[0422] Example 5: (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-fluoro-4- Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (Compound 2)

[0423]

[0424] The preparation of (2R,3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile is described below.

[0425]

[0426] 2-Deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose. A solution of 1'-methoxy-2-deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose (1.0 g, 2.88 mmol) in TFA (13.5 mL) was treated with H2O (1.5 mL) and the resulting mixture was stirred for 5 hours. The mixture was then diluted with EtOAc (100 mL) and treated with saturated NaHCO3 (50 mL). The organic layer was separated and washed with NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (80 g SiO2 Combiflash HP Gold Column) eluting with 0-100% EtOAc in hexanes to give 2-deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose as a white solid: R f = 0.52 (25% EtOAc in hexanes). 1 H NMR (300MHz, CDCl3) δ7.30 (m, 10H), 5.35 (m, 1H), 4.68-4.29 (m, 7H), 3.70 (d, J=10.5Hz, 1H), 3.50 (d, J=10.5Hz, 2H). 19 F NMR (282.2MHz, CDCl3) δ-207(m), -211(m). LCMS m / z 350[M+H2O].

[0427]

[0428] (3R, 4R, 5R)-4-(Benzyloxy)-5-(Benzyloxymethyl)-3-fluorodihydrofuran-2(3H)-one. 2-Deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose (4.3 g, 12.8 mmol) was dissolved in CH2Cl2 (85 mL) and the mixture was stirred for 2 h. MS (10 g) and pyridinium dichromate (14.4 g, 38.3 mmol) were treated. The resulting mixture was stirred for 24 hours and then The eluate was concentrated under reduced pressure and the residue was chromatographed on silica gel (120 g SiO2 HP Gold Combiflash Column) using 0-100% EtOAc in hexane to give (3R, 4R, 5R)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorodihydrofuran-2(3H)-one (3.5 g, 83%) as a clear oil: f = 0.25 (25% EtOAc in hexane). 1 HNMR (300MHz, CDCl3) δ7.37 (m, 10H), 5.45 (dd, J=49, 5.7, Hz, 1H), 4.85 (d, J=1 1.7Hz, 1H), 4.52 (m, 4H), 4.29 (d, J=5.4Hz, 1H), 2.08 (dd, J=15.3, 10.2Hz, 2H). 19 F NMR (282.2 MHz, CDCl3) δ-216. LCMS m / z 348 [M+H2O]. HPLC (6-98% MeCN-H2O gradient, 0.05% TFA modification) t R =5.29min. Phenomenex Synergi 4m Hydro-RP 80A, 50×4.60mm, 4 microns; 2mL / min flow rate

[0429]

[0430] (3R, 4R, 5R) -2- (4-aminopyrrolo [1, 2-f] [1, 2, 4] triazine-7-yl) -4- (benzyloxy), 5- (benzyloxymethyl) -3-fluorotetrahydrofuran-2-ol. A solution of 7-bromopyrrolo [1, 2-f] [1, 2, 4] -triazine-4-amine (68 mg, 0.319 mmol) in THF (1.4 mL) was treated with TMSCl (89 μL, 0.703 mmol) and the mixture was stirred for 2 hours. The mixture was then cooled to about -78 ° C and treated with nBuLi (1.0 M in hexanes, 1.09 mL, 1.09 mmol). The solution was stirred for about 30 minutes, and then (3R, 4R, 5R)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorodihydrofuran-2(3H)-one (106 mg, 0.319 mmol) in THF (1.4 mL) was added dropwise for treatment. The resulting mixture was stirred for 30 minutes, and then AcOH (83 μL, 1.44 mmol) in THF (1.0 mL) was added to quench the reaction. The mixture was warmed to room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with saturated NaCl solution (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (40 g SiO2 HP Gold Combiflash Column) eluting with 0-100% EtOAc in hexanes followed by a 0-100% gradient (20% MeOH in EtOAc) in EtOAc to afford (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-ol as a white solid (68 mg, 44%, 60 / 40 mixture of α / β isomers). f =0.32 (EtOAc). 1 H NMR (300MHz, CDCl3) δ8.05 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.26 (m, 1 0H), 6.95(m, 1H), 6.71(m, 1H), 6.08(m, 1H), 5.34(m, 1H), 4.65(m, 6H), 4.71(m, 2H). 19 F NMR (282.2 MHz, CDCl3) δ-211 (m). LCMS m / z 465 [M+H]. HPLC (6-98% MeCN-H2O gradient, 0.05% TFA modifier) ​​t R =4.37min.(α-isomer), 4.54min.(β-isomer).

[0431]

[0432] (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-carbonitrile. (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-ol (195 mg, 0.42 mmol) was dissolved in MeCN (1.4 mL) and treated with TMSCN (336 μL, 2.52 mmol) and In(OTf)3 (708 mg, 1.26 mmol). The solution was stirred at about 70°C for 18 hours and then cooled to about 0°C. The mixture was treated with saturated NaHCO3 solution (20 drops), then warmed to room temperature and diluted with EtOAc (100 mL) and H2O (50 mL). The organic layer was separated and washed with saturated NaCl solution (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (40 g SiO2 HP Gold Combiflash Column) and eluted with 0-100% EtOAc in hexanes to give (3R, 4R, 5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-carbonitrile as a white solid (60 / 40 mixture of α / β isomers). Data for the two isomers: R f =0.53 (EtOAc). 1 H NMR (300MHz, CDCl3) δ8.01 (s, 1H), 7.94 (s, 1H), 7.30 (m, 10H), 7.00 (d, J=4.5Hz, 1H), 6.93 (d, J=4.8Hz, 1H), 6.87 (d, J=5.4H z, 1H), 6.70 (d, J=4.8Hz, 1H), 5.85 (dd, J=52, 3.3Hz, 1H), 5.55 (dd, J=53, 4.5Hz, 1H), 4.71 (m, 7H), 3.87 (m, 2H), 3.72 (m, 2H). 19 F NMR (282.2 MHz, CDCl3) δ -196 (m), -203 (m). LCMS m / z 474 [M+H]. HPLC (6-98% MeCN-H2O gradient, 0.05% TFA modifier) ​​t R =4.98min.

[0433]

[0434] (2R,3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (2) (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-carbonitrile (110 mg, 0.23 mmol) was dissolved in CH2Cl2 (1.5 mL) and cooled to about 0° C. The reaction mixture was treated with BCl3 (1.0 M in CH2Cl2, 766 μL, 0.77 mmol) and stirred for 2 h. The mixture was then cooled to about -78 ° C and treated with Et3N (340 μL, 2.44 mmol), followed by MeOH (2 mL) and then warmed to room temperature. The reaction was concentrated under reduced pressure and then co-evaporated with MeOH (3×5 mL). The residue was then suspended in H2O (5 mL) and treated with NaHCO3 (1 g). The solution was stirred for 10 minutes and then concentrated under reduced pressure. The residue was filtered and washed with MeOH (3×10 mL) on a sintered glass funnel (thick) and the eluent was concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (6-98% MeCN in H2O gradient with 0.05% TFA modifier) ​​to afford the α-isomer of (2R,3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile 2 as a white solid. Data for the β-isomer: R f =0.13 (10% MeOH in EtOAc). 1 H NMR (300MHz, CD3OD) δ8.09 (s, 1H), 7.28 (d, J=5.1Hz, 1H), 7.17 (d, J=5.1Hz, 1H), 5. 42 (dd, J=53, 3.3Hz, 1H), 4.20 (m, 2H), 3.99 (d, J=3.6Hz, 1H), 3.77 (d, J=3.6Hz, 1H). 19 F NMR (282.2 MHz, CDCl3) δ-197 (m). LCMS m / z 294 [M+H]. HPLC (2-98% MeCN-H2O gradient, 0.05% TFA modifier) ​​t R =1.49min.

[0435] Example 6: (2R, 3R, 4R, 5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-fluoro-2- (Hydroxymethyl)-5-methyltetrahydrofuran-3-ol (Compound 3)

[0436]

[0437] The preparation of (2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-2-(hydroxymethyl)-5-methyltetrahydrofuran-3-ol is described below.

[0438]

[0439] Under N2(g), the starting nucleoside (prepared as described in the synthesis of compound 2) (0.355 g, 0.765 mmol) was dissolved in anhydrous THF (35 mL) and cooled to about 0°C with stirring. A solution of methylmagnesium chloride (2 mL, 6 mmol) (3N in THF) was added and the resulting mixture was stirred overnight. Acetic acid (7 mmol) was added to quench the reaction and the solvent was then removed by rotation under reduced pressure. The residue was redissolved in CH2Cl2 and the solution was passed through a silica gel plug to isolate the product (0.355 g) from the crude mixture. LC / MS (m / z: 480, M +1 ). The crude material was dissolved in anhydrous CH2Cl2 (20 mL) and placed under N2(g). The solution was stirred and treated with methanesulfonic acid (0.2 mL, 2.74 mmol). The reaction mixture was stirred at room temperature for about 12 hours and then quenched by adding Et3N (3.5 mmol). The mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography to obtain methyl-substituted nucleosides, which were 4:1 mixtures of β- and α-anomers. 1 H NMR (300 MHz, CD3CN) major anomer δ 7.87 (s, 1H), 7.27-7.40 (m, 10H), 6.77 (d, J = 4.5 Hz, 1H), 6.70 (d, J = 4.5 Hz, 1H), 6.23 (br s, 2H), 5.53 (dd, J = 55, 3.3 Hz, 1H), 4.42-4.75 (m, 4H), 4.19-4.26 (m, 1H), 3.65-4.00 (m, 3H), 1.74 (d, J = 3.9 Hz, 3H). 19 F NMR (282.2MHz, CD3CN) major anomer δ-207 (m, 1F). LCMS m / z 463 [M+H].

[0440]

[0441] The benzylated nucleoside material (0.134 g, 0.290 mmol), Degussa catalyst (0.268 g) and AcOH (30 mL) were mixed together. In the reaction atmosphere, H2 (g) was added and the reactant was stirred for about 2 hours. The catalyst was removed by filtration and the mixture was concentrated under reduced pressure. The residue was dissolved in a minimum amount of H2O and subjected to reverse phase HPLC (C18 hydro RP column) to separate the β-anomer 3. 1 H NMR (300MHz, D2O) δ7.87 (s, 1H), 7.22 (d, J = 4.8Hz, 1H), 6.87 (d, J = 4.8Hz, 1H), 5.35 (dd, J = 54, 3.6Hz, 1H ), 3.97-4.10 (m, 2H), 3.81 (dd, J=12.6, 2.1Hz, 1H), 3.64 (dd, J=12.6, 4.8Hz, 1H), 1.65 (d, J=4.2Hz, 3H). 19 F NMR (282.2MHz, CD3CN) δ-207 (m, 1F).

[0442] The minor α anomer was characterized as follows. 1 H NMR (300MHz, D2O) δ7.86 (s, 1H), 7.26 (d, J=4.8Hz, 1H), 6.85 (d, J=4.8Hz, 1H), 5.31 (dd, J=54, 3.9Hz, 1H), 4.39 (ddd , J=26.1, 9.9, 3.6Hz, 2H), 4.00-4.05 (m, 1H), 3.90 (dd, J=12.3, 2.1Hz, 1H), 3.66 (dd, J=12.6, 4.8, 1H), 1.56 (s, 3H). 19 F NMR (282.2MHz, CD3CN) δ-198 (dd, J=54, 26Hz, 1F).

[0443] Example 7: (2S)-2-((((2R,3R,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7- (4-fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)-methoxyphenoxy)phosphoryl)amino)propionic acid isopropyl ester (compound Object 4)

[0444]

[0445] Nucleoside 3 (0.011g, 0.04mmol) is dissolved in trimethyl phosphate (2mL) and is cooled to 0 ℃.Mixture is stirred in N2(g) atmosphere and 1-methylimidazole (0.320mL, 5mmol), then add alanyl monoisopropyl monophenol phosphoryl chloride C (0.240mL, 4.4mmol).Reaction mixture is stirred 2 hours at 0 ℃, then slowly warming up to room temperature, monitored by LC / MS simultaneously.When determining to complete by LCMS, reaction mixture is handled with H2O (5mL), then concentrated under reduced pressure.Residue is dissolved in CH2Cl2 and carries out silica gel chromatography, eluted with the hexane solution of 0-100%EtOAc.Collect product fractions and concentrate.Residue is carried out preparation HPLC, obtain the monoamino compound prodrug 4 of alanine isopropyl as isomer mixture. 1HNMR (300MHz, CD3CN) δ7.87 (s, 1H), 7.17-7.44 (m, 5H), 6.71-6.83 (m, 2H), 6.14 (br, s, 2H), 5.38 (dd, J= 56, 3.3Hz, 1H), 4.92-5.01(m, 1H), 3.86-4.46(m, 6H), 3.58(m, 1H), 1.73(m, 3H), 1.18-1.34(m, 9H).LCMS m / z 552[M+H].

[0446] Example 8: (2S)-2, (((((2R, 3R, 4R, 5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine, 7- (4-fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionic acid ethyl ester (compound Object 5)

[0447]

[0448] Nucleoside 3 (0.026 g, 0.092 mmol) was dissolved in trimethyl phosphate (2 mL) and cooled to 0 ° C. The mixture was stirred under N2 (g), 1-methylimidazole (0.062 mL, 0.763 mmol) was added, and then chloride A (0.160 g, 0.552 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and then slowly warmed to room temperature. H2O (5 mL) was added to quench the reaction, and then the mixture was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and subjected to silica gel chromatography, eluted with 0-100% EtOAc in hexane. The product fractions were collected and concentrated. The crude product was eluted with 0 to 100% EtOAc in hexane. The crude product was collected and concentrated under reduced pressure. The residue was subjected to preparative HPLC to obtain compound 5. LCMS m / z 538 [M+H].

[0449] Example 9: ((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-fluoro- 3-Hydroxy-5-methyltetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 6)

[0450]

[0451] Nucleoside 3 (0.022 g, 0.056 mmol) was dissolved in trimethyl phosphate (1 mL) and stirred under N2 (g). Phosphorus oxychloride (0.067 mL, 0.73 mmol) was added and the mixture was stirred for about 2 hours. The time when >80% monophosphate was formed was determined by monitoring with an analytical ion exchange column. A solution of tributylamine (0.44 mL, 1.85 mmol) and triethyl pyrophosphate (0.327 g, 0.72 mmol) dissolved in anhydrous DMF (1 mL) was added. The reaction mixture was stirred for 20 minutes and then quenched by adding 1N triethylammonium bicarbonate solution to H2O (5 mL). The mixture was concentrated under reduced pressure and the residue was redissolved in H2O. The solution was subjected to ion exchange chromatography to obtain the title product compound 6. LCMS m / z 521 [MH]. Tr = 0.41. HPLC ion exchange TR = 9.40 min

[0452] Example 10: (2R, 3R, 5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-hydroxy-5- (Hydroxymethyl)-tetrahydrofuran-2-carbonitrile (Compound 7)

[0453]

[0454] The preparation of (2R,3R,5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile is as follows.

[0455]

[0456] ((3αR,5S,6αR)-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxolan-5-yl)methanol. The acetate material (1.2 g, 5.5 mmol) (J. Org. Chem. 1985, 50, 3577, De Bernardo et al.) was dissolved in a 1:1 mixture of MeOH and THF (10 mL). 1N NaOH aqueous solution (10 mL) was added until the pH was 13. The reaction mixture was stirred for about 2 hours and then neutralized to pH 8-9 by the addition of AcOH. The mixture was extracted with EtOAc (10×30 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-70% EtOAc in hexanes to give the desired product (866 mg, 90%). 1 H NMR (300MHz, CDCl3) δ5.84 (d, J=3.6Hz, 1H), 4.78 (t, J=4.5Hz, 1H), 4.38 (m, 1H), 3.93-3.54 (m, 2H), 2.04-1.84 (m, 2H), 1.52 (s, 3H), 1.33 (s, 3H).

[0457]

[0458] (3αR, 5S, 6αR)-5-(benzyloxymethyl)-2,2-dimethyl-tetrahydrofuran [2,3-d] [1,3] dioxole. Sodium hydride (188mg, 7.46mmol) was dissolved in anhydrous THF (5mL) and stirred at room temperature under N2(g). Alcohol (866mg, 4.97mmol) was dissolved in anhydrous THF (3mL) and then added to the sodium hydride mixture in batches over 5 minutes. The resulting mixture was stirred for about 20 minutes, and then benzyl bromide (892μL, 7.46mmol) was added. The reactant was stirred for about 2 hours and then poured into a mixture of ice-cold NaHCO3 aqueous solution and EtOAc (30mL). The organic layer was separated and the aqueous layer was then re-extracted with EtOAc (30mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-40% EtOAc in hexanes to give the benzyl ether product. 1 H NMR (300MHz, CDCl3) δ7.35-7.27 (m, 5H), 5.86 (d, J=3.6Hz, 1H), 4.74 (t, J=4.2Hz, 1H), 4.60 (s, 2H) , 4.42(m, 1H), 3.69-3.53(m, 2H), 2.10-2.04(m, 1H), 1.83-1.77(m, 1H), 1.52(s, 3H), 1.33(s, 3H).

[0459]

[0460] (3R,5S)-5-(Benzyloxymethyl)-tetrahydrofuran-2,3-diol. The benzyl ether (910 mg, 3.44 mmol) was dissolved in a 1:1 mixture of AcOH and H2O (20 mL) and stirred at about 60°C for about 7 hours. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel using 0-70% EtOAc in hexanes to give the diol product (705 mg, 91%). 1 H NMR (300MHz, CDCl3) δ7.36-7.27 (m, 5H), 5.40 (d, J=3.9Hz, 0.5H), 5.17 (s, 0.5H), 4.67-4.56 (m, 3H), 4.33 (m, 0.5H), 4.24(d, J=4.8Hz, 0.5H), 3.71-3.67(m, 1H), 3.56-3.42(m, 2H), 2.31-2.22(m, 1H), 2.08-1.89(m, 2H).

[0461]

[0462] (3R, 5S)-5-(benzyloxymethyl)-3-hydroxy-dihydrofuran-2(3H)-one. The diol (705 mg, 3.14 mmol) was dissolved in benzene (30 mL) and treated with a silver carbonate celite mixture (3.46 g, 6.28 mmol). The resulting mixture was stirred at about 80° C. under N2(g) for about 2 hours. The mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-70% EtOAc in hexane to give the lactone product. 1 H NMR (300MHz, CDCl3) δ7.39-7.27(m, 5H), 4.75-4.68(m, 1H), 4.60-4.49(m, 2H), 3.74-3.54(m, 2H), 2.61-2.35(m, 2H), 2.38-2.28(m, 1H).

[0463]

[0464] (3R, 5S)-3-(Benzyloxy)-5-(Benzyloxymethyl)-dihydrofuran-2(3H)-one. The lactone (600 mg, 2.7 mmol) was dissolved in EtOAc (30 mL), treated with silver oxide (626 mg, 2.7 mmol), and then treated with benzyl bromide (387 μL, 3.24 mmol). The reaction mixture was then stirred at about 50° C., N2(g) for about 8 hours. Additional silver oxide (300 mg) was then added, and the resulting mixture was stirred at about 50° C. for about 16 h. Additional benzyl bromide (50 uL) and silver oxide (150 mg) were added, and the mixture was stirred for another about 8 hours. The reaction mixture was cooled, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with 0-20% EtOAc in hexanes to give the title product. 1 H NMR (300MHz, CDCl3) δ7.39-7.27 (m, 10H), 4.99 (d, J=11.4Hz, 1H), 4.72 (m, 2H ), 4.56 (m, 2H), 4.39 (t, J=8.1Hz, 1H), 3.72-3.51 (m, 2H), 2.42-2.25 (m, 2H).

[0465]

[0466] (3R,5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-(benzyloxy)-5-(benzyloxymethyl)-tetrahydrofuran-2-ol. 7-Bromopyrrolo[1,2-f][1,2,4]triazine-4-amine (607 mg, 2.85 mmol) was dissolved in anhydrous THF (10 mL) and stirred at room temperature under Ar(g). TMSCl (1.1 mL, 8.55 mmol) was added dropwise and the mixture was stirred for about 2 hours. The reactants were concentrated under reduced pressure and then dried under high vacuum. The residue was suspended in THF (20 mL) and stirred at about -78°C under Ar(g). 2.5 M n-BuLi hexane solution (2.28 mL, 5.7 mmol) was added dropwise over about 10 minutes and the resulting mixture was stirred for about 60 minutes. The lactone (742 mg, 2.37 mmol) dissolved in anhydrous THF (7 mL) was added to the above mixture over about 20 minutes. The reaction mixture was stirred for about 2 hours and then quenched with AcOH until the pH was 5-6. The mixture was warmed to room temperature and then diluted with EtOAc. The solution was washed with saturated NaHCO3 solution, saturated NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with 0-80% EtOAc in hexane to obtain the title product. LCMSm / z 447.2 [M+H], 445.1 [MH].

[0467]

[0468] (3R, 5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-(benzyloxy)-5-(benzyloxymethyl)-tetrahydrofuran-2-carbonitrile. The alcohol (250 mg, 0.56 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and stirred at about -15°C under Ar(g). TMSCN (448 μL, 3.36 mmol) was added dropwise and the mixture was stirred for about 10 minutes. TMSOTf (466 μL, 2.58 mmol) was added dropwise over 10 minutes and the resulting mixture was stirred at about -15°C for about 90 minutes. Additional TMSCN (224 μL, 3 equiv.) and TMSOTf (202 μL, 2 equiv.) were added and stirring continued for about 5 hours. Saturated aqueous NaHCO3 was added to quench the reaction and the mixture was stirred for about 10 minutes. The organic layer was separated, washed with saturated NaHCO3 solution, saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with 0-70% EtOAc in hexane to give the title product. LCMS m / z 456.3 [M+H], 454.1 [MH].

[0469]

[0470] (2R,3R,5S)2,(4,aminopyrrolo[1,2,f][1,2,4]triazine-7-yl)-3-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile (7). The benzyl ether (150 mg, 0.329 mmol) was dissolved in anhydrous CH2Cl2 (2 mL) and the mixture was stirred at about -20°C under Ar(g). A 1M solution of BCl3 in CH2Cl2 (724 μL, 0.724 mmol) was added dropwise and the resulting mixture was stirred for about 2 hours. Additional 1M BCl3 in CH2Cl2 (724 μL, 0.724 mmol) was added and stirring continued for 2 hours. The mixture was then cooled to about -78°C and slowly treated with a 2:1 mixture of Et3N and MeOH (3 mL). The mixture was stirred for about 10 minutes and then treated with MeOH (10 mL). The reaction was allowed to warm to room temperature and then concentrated under reduced pressure. The residue is dissolved in MeOH and concentrated under reduced pressure. The residue is dissolved in MeOH again and treated with solid NaHCO 3 . The mixture is stirred for about 5 minutes, then the solid is removed by filtration. The solution is concentrated under reduced pressure and preparative HPLC is carried out to provide the required product 7. 1 H NMR (300MHz, D2O) δ7.71 (s, 1H), 6.75 (d, J = 4.5Hz, 1H), 6.65 (d, J = 4.8Hz, 1H), 4.91 (t, J = 6.3Hz, 1H), 4.57 (m, 1H), 3.67-3.47 (m, 2H), 2.18 (m, 2H). LCMS m / z276.1[M+H], 274.0[MH].

[0471] Example 11: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7- (5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)-phosphorylamino) propionic acid isopropyl ester ( Compound 8)

[0472]

[0473] Nucleoside 1 (45mg, 0.15mmol) is dissolved in anhydrous trimethyl phosphate (0.5mL), and solution is stirred under N (g) at approximately 0 ℃.Methylimidazole (36 μ L, 0.45mmol) is added in this solution.Chloroaminophosphoric acid ester C (69mg, 0.225mmol) is dissolved in anhydrous THF (0.25mL) and is added drop-wise in the nucleoside mixture.When determining that the reaction is complete by LCMS, the reaction mixture is diluted with EtOAc and washed with saturated NaHCO The aqueous solution, saturated NaCl are washed with anhydrous Na SO Drying is filtered and concentrated under reduced pressure.Residue is carried out silica gel chromatography, with the CH of 0-5%MeOH Cl Wash-out, then by preparation HPLC, obtains product.1 H NMR (300MHz, CD3OD) δ7.95 (m, 1H), 7.31-6.97 (m, 7H), 4.94 (m, 1H), 4.78 (m, 1H), 4.43 (m, 3H), 4.20 (m, 1H), 3.80 (d, 1H), 1.30-1.18 (m, 9H). 31 P NMR (121.4MHz, CD3OD) δ3.8.LCMS m / z 561.0[M+H], 559.0[MH].

[0474] Example 12: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7- 2-Ethylbutyl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (Compound 9)

[0475] Compound 9 can be prepared by several methods as described below.

[0476] Method 1

[0477]

[0478] Prepared from Compound 1 and chloride B according to the same method as that of Compound 8. 1 H NMR (300MHz, CD3OD) δ7.87 (m, 1H), 7.31-7.16 (m, 5H), 6.92-6.89 (m, 2H), 4.78 (m, 1H), 4.50-3.80 (m, 7H), 1.45-1.24 (m, 8H), 0.95-0.84 (m, 6H). 31 P NMR (121.4MHz, CD3OD) δ3.7.LCMS m / z 603.1[M+H], 601.0[MH].

[0479] Method 2

[0480]

[0481] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1,f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester. (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred at room temperature under nitrogen atmosphere. (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (350 mg, 1.2 mmol) was added to the reaction mixture in one portion. Then a solution of tert-butylmagnesium chloride in THF (1M, 1.8 mL, 1.8 mmol) was added dropwise to the reaction over about 10 minutes. The reactants were stirred for about 2 hours, at which time the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (3×15 mL) and then with saturated aqueous sodium chloride (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (0-10% MeOH in DCM) to give (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester (311 mg, 43%, 1:0.4 diastereomeric mixture on phosphorus). 1 H NMR(400MHz,CD3OD)δ7.85(m,1H),7.34–7.23(m,2H),7.21–7.09(m,3H),6.94–6.84(m,2H),4.78(d,J=5.4Hz,1H),4.4 6–4.33(m,2H),4.33–4.24(m,1H),4.18(m,1H),4.05–3.80(m,3H),1.52–1.39(m,1H),1.38–1.20(m,7H),0.85(m,6H). 31 P NMR (162MHz, CD3OD) δ3.71, 3.65. LCMS m / z 603.1 [M+H], 600.9 [MH]. HPLC (2–98% MeCN–H2O gradient, containing 0.1% TFA modifier, within 8.5 min, 1.5 mL / min, column: Phenomenex Kinetex C18, 2.6 um 4.6x100mm)t R=5.544min,5.601min

[0482] Separation of (S) and (R) diastereomers

[0483] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester was dissolved in acetonitrile. The resulting solution was loaded onto a Lux Cellulose-2 chiral column, equilibrated with acetonitrile, and eluted with an isotropic solution of acetonitrile / methanol (95:5 vol / vol). The retention time of the first eluting diastereomer was 17.4 minutes and the retention time of the subsequent eluting diastereomer was 25.0 minutes.

[0484] The first eluting diastereomer is (S)-2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester:

[0485]

[0486] 1 HNMR (400MHz, CD3OD) δ8.05 (s, 1H), 7.36 (d, J = 4.8Hz, 1H), 7.29 (br t,J=7.8Hz,2H),7.19–7.13(m,3H),7.11(d,J=4.8Hz,1H),4.73(d,J=5.2Hz,1H),4.48–4.38(m,2H),4.37–4.28(m,1H),4.17(t,J=5.6Hz,1H ),4.08–3.94(m,2H),3.94–3.80(m,1H),1.48(sep,J=12.0,6.1Hz,1H),1.34(p,J=7.3Hz,4H),1.29(d,J=7.2Hz,3H),0.87(t,J=7.4Hz,6H). 31 PNMR (162MHz, CD3OD) δ3.71(s).HPLC (2–98% MeCN–H2O gradient, with 0.1% TFA modifier, 8.5min, 1.5mL / min, column: Phenomenex Kinetex C18, 2.6um 4.6x100mm)t R =5.585min.

[0487] The next eluting diastereomer was (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester:

[0488]

[0489] 1 HNMR(400MHz,CD3OD)δ8.08(s,1H),7.36–7.28(m,3H),7.23–7.14(m,3H),7.08(d,J=4.8Hz,1H),4.71(d,J=5.3Hz,1H),4.45–4.34(m,2H),4.3 2–4.24(m,1H),4.14(t,J=5.8Hz,1H),4.08–3.94(m,2H),3.93–3.85(m, 1H), 1.47 (sep, J=6.2Hz, 1H), 1.38-1.26 (m, 7H), 0.87 (t, J=7.5Hz, 6H).

[0490] 31 PNMR (162 MHz, CD3OD) δ 3.73 (s). HPLC (2-98% MeCN-H2O gradient, containing 0.1% TFA modifier, 8.5 min, 1.5 mL / min, column: Phenomenex Kinetex C18, 2.6 um 4.6x100mm)t R =5.629min.

[0491] Example 13: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propionic acid ethyl ester (compound 10)

[0492]

[0493] The preparation of ethyl (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is described as follows.

[0494] Method 1: Preparation via Chloride A

[0495]

[0496] Prepared from compound 1 and chloride A using the same method as compound 8. 1 H NMR (300MHz, CD3OD) δ7.95 (m, 1H), 7.32-6.97 (m, 7H), 4.78 (m, 1H), 4.43-4.08 (m, 6H), 3.83 (m, 1H), 1.31-1.18 (m, 6H). 31 P NMR (121.4MHz, CD3OD) δ3.7.LCMS m / z 547.0[M+H], 545.0[MH].

[0497] Method 2: Preparation via nitrobenzene compound L

[0498]

[0499] Compound 1 (50 mg, 0.17 mmol) was dissolved in NMP-THF (1: 1 mL) and cooled with an ice bath. Then tBuMgCl (0.257 mL, 0.257 mmol) was added in about 5 minutes. The resulting mixture was warmed to room temperature and stirred for about 30 minutes. A solution of compound L (prepared according to US20120009147, 74.6 mg, 0.189 mmol) in THF (2 mL) was then added. After about 30 minutes, the reaction mixture was purified by HPLC (acetonitrile 10-80% aqueous solution) to obtain compound 29 as a yellow solid. The solid was further purified by silica gel chromatography (MeOH 0 to 20% DCM) to obtain compound 29. 1 H NMR (400MHz, CD3OD) δ7.76 (d, J=6.0Hz, 1H), 7.25-7.14 (m, 2H), 7.11-6.99 (m, 3 H), 6.87-6.72 (m, 2H), 4.70 (d, J=5.4Hz, 1H), 4.39-4.24 (m, 2H), 4.20 (dddd, J= 9.7, 7.9, 5.1, 2.8Hz, 1H), 4.10 (dt, J=12.8, 5.5Hz, 1H), 4.06-3.91 (m, 2H), 3.7 2 (ddq, J=14.3, 9.3, 7.1Hz, 1H), 1.17 (ddq, J=7.1, 1.0Hz, 1H), 1.14-1.06 (m, 5H). 31 P NMR (162MHz, CD3OD) δ3.73, 3.68.MS m / z=547 (M+1) + .

[0500] Example 14: (2S)-2-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7- (5-cyano-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphorylamino) propionic acid ethyl ester (compound 11)

[0501]

[0502] Compound 11 was prepared from Compound 2 and chloride A using the same method as that used to prepare Compound 8. 1 H NMR (300MHz, CD3OD) δ7.91 (m, 1H), 7.33-7.16 (m, 5H), 6.98-6.90 (m, 2H), 5.59 (m, 1H), 4.50-4.15 (m, 4H), 4.12-3.90 (m, 3H), 1.33-1.18 (m, 6H). 31 P NMR (121.4MHz, CD3OD) δ3.8.LCMS m / z 549.0[M+H], 547.1[MH].

[0503] Example 15: (2S,2'S)-2,2'-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4] triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropionic acid di Ethyl ester (Compound 12)

[0504]

[0505] Nucleoside 1 (14.6 mg, 0.05 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and stirred at room temperature under N2 (g). POCl3 (9.2 μL, 0.1 mmol) was added and the mixture was stirred for about 60 minutes. Alanine ethyl ester hydrochloride (61 mg, 0.4 mmol) was added, followed by Et3N (70 μL, 0.5 mmol). The resulting mixture was stirred for about 15 minutes, and then additional Et3N (70 μl, 0.5 mmol) was added to obtain a solution with a pH of 9-10. The mixture was stirred for about 2 hours, then diluted with EtOAc, washed with saturated NaHCO3 aqueous solution, and then washed with saturated NaCl aqueous solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to preparative HPLC (C18 column) to obtain product 12. 1 H NMR (400MHz, CD3OD) δ8.13 (s, 1H), 7.41 (d, J=4.8Hz, 1H), 7.18 (d, J=4.8Hz, 1H), 4.7 8(d, J=5.6Hz, 1H), 4.36(m, 1H), 4.25-4.08(m, 7H), 3.83(m, 2H), 1.33-1.23(m, 12H). 31 P NMR (121.4MHz, CD3OD) δ13.8.LCMSm / z 570.0[M+H], 568.0[MH].

[0506] Example 16: (2S,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-2-ethynyl 5-(Hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 13)

[0507]

[0508] The preparation of (2S,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-2-ethynyl-5-(hydroxymethyl)tetrahydrofuran-3,4-diol is as follows.

[0509]

[0510] The nucleoside alcohol (0.6 g, 1.08 mmol) (prepared as described in the synthesis of compound 1) was dissolved in anhydrous THF (8 mL) and placed under N2(g). The reaction mixture was stirred and cooled to about 0°C and then treated with 0.5N ethynylmagnesium bromide in THF (17.2 mL, 17.2 mmol). The reaction mixture was stirred at room temperature overnight. AcOH (1.5 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure and the residue was redissolved in CH2Cl2. The solution was treated with a silica gel plug and eluted with 0 to 80% EtOAc in hexanes to give the title product as a crude mixture. LCMS m / z 579 [M+H].

[0511]

[0512] The crude ethynyl alcohol (0.624 g, 1.08 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and placed under N2(g). The mixture was stirred and sulfonic acid (0.2 mL, 2.74 mmol) was added. The reaction mixture was stirred at room temperature for about 12 hours. When completion was confirmed by LCMS, Et3N (0.56 mL) was added to quench the reaction. The reactant was concentrated under reduced pressure and the residue was subjected to silica gel chromatography, eluted with 0 to 75% EtOAc in hexane to obtain an ethynyl nucleoside of a mixture of anomers. LCMS m / z 561 [M+H].

[0513]

[0514] The tribenzyl nucleoside (0.650 g, 1.16 mmol) was dissolved in anhydrous CH2Cl2 (30 mL) and cooled to -78°C under N2(g). Boron tribromide solution (1N in CH2Cl2, 5.5 mL) was added and the reaction mixture was stirred at -78°C for 1 hour. A solution of MeOH (10 mL) and pyridine (2 mL) was added to quench the reaction and the mixture was warmed to room temperature. The mixture was concentrated under reduced pressure and subjected to preparative HPLC to give the α-anomer (20 mg) and the β-anomer 13 (110 mg). (β-anomer) 1HNMR (300 MHz, DMSO) δ 7.81 (s, 1H), 7.76 (br s, 2H), 6.80-6.85 (m, 2H), 5.11 (d, J = 7.2 Hz, 1H), 4.90 (d, J = 6.0 Hz, 1H), 4.82 (dd, J = 7.2, 4.8 Hz, 1H), 4.62 (t, J = 6.3 Hz, 1H), 3.95-3.99 (m, 1H), 3.85-3.91 (dd, J = 11.4, 5.7 Hz, 1H), 3.61-3.67 (m, 1H), 3.47-3.55 (m, 1H), 3.52 (d, J = 0.9 Hz, 1H). (α-anomer) 1 H NMR (300MHz, DMSO) δ7.80 (s, 1H), 7.59 (bs, 2H), 6.80 (d, J = 4.5Hz, 1H), 6.54 (d, J = 4.2Hz, 1H), 5.00 (d, J = 7.2Hz, 1H), 4.89 (d, J = 4.8Hz, 1H) , 4.74 (t, J = 5.7Hz, 1H), 4.58 (t, J = 4.5Hz, 1H), 4.27 (m, 1H), 3.88 (m, 1H), 3.64-3.72 (m, 1H), 3.51-3.59 (m, 1H), 3.48 (d, J = 0.6Hz, 1H). LCMS m / z 291[M+H].

[0515] Example 17: (2R, 3R, 4R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-1,3,4-triazine (Benzyloxy)hexane-2,5-diol (Compound 14)

[0516]

[0517] The preparation of (2R,3R,4R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-1,3,4-tri(benzyloxy)hexane-2,5-diol is as follows.

[0518]

[0519] The benzyl alcohol (0.250 g, 0.453 mmol) synthesized from compound 1 was dissolved in anhydrous THF (25 mL) and stirred under N2 (g). The reaction mixture was cooled to 0 ° C, and then a 3.0 N solution of methylmagnesium chloride in THF (1.2 mL, 3.62 mmol) was added. The reaction mixture was stirred at room temperature overnight. Acetic acid (1.5 mL) was added to quench the reaction, and the mixture was then concentrated under reduced pressure. The residue was redissolved in CH2Cl2 and treated with a silica gel plug, eluted with a hexane solution of 0 to 80% EtOAc. The crude product (0.452 g) was then used in the next reaction without further purification. LCMS m / z 569 [M+H].

[0520]

[0521] The crude methyl nucleoside (0.452 g, 0.796 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and stirred under N2(g). Methanesulfonic acid (0.2 mL, 2.78 mmol) was added and the reaction was stirred at room temperature for about 12 hours. Et3N (0.56 mL) was added to quench the reaction and the mixture was then concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with 0 to 75% EtOAc in hexane to give the product as a mixture of anomers. LCMS m / z 551 [M+H].

[0522]

[0523] Tribenzyl nucleoside (0.20 g, 0.364 mmol) was dissolved in AcOH (30 mL). Pd / C (Degussa) (400 mg) was added. The stirred mixture was flushed with N2(g) three times, and then H2(g) was added. The reaction was stirred under H2(g) for 2 hours. The catalyst was then removed by filtration. The solution was concentrated under reduced pressure, and the residue was redissolved in H2O. The solution was subjected to preparative HPLC under neutral conditions to obtain the α-anomer and β-anomer 14. (α-anomer) 1 H NMR (300 MHz, D2O) δ 7.81 (s, 1H), 7.22 (d, 1H), 6.75 (d, 1H), 4.47 (d, 1H), 4.25-4.31 (m, 1H), 3.88-4.95 (m, 1H), 3.58-3.86 (dd, 2H), 1.50 (s, 3H). (β-anomer) 1 H NMR (300MHz, D2O) δ7.91 (s, 1H), 7.26 (d, 1H), 6.90 (d, 1H), 4.61 (d, 1H), 4.00-4.09 (m, 2H), 3.63-3.82 (dd, 2H), 1.67 (s, 3H). LCMS m / z 281 [M+H].

[0524] Example 18: S,S′-2,2′-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine (oxazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diol 1-(2-(2-methylthio)propionate) (Compound 15)

[0525]

[0526] Nucleoside 1 (0.028 g, 0.096 mmol) was dissolved in trimethyl phosphate (1 mL). The reaction was stirred under N2 (g) and then treated with 1H-tetrazole (0.021 g, 0.29 mmol). The reaction mixture was cooled to 0°C and phosphane (87 mg, 0.192 mmol) (Nucleoside Nucleotides, Nucleic acids; 14; 3-5; 1995; 763-766. Lefebvre, Isabelle; Pompon, Alain; Perigaud, Christian; Girardet, Jean-Luc; Gosselin, Gilles et al.) was added. The reactants were stirred for 2 hours and then quenched with 30% hydrogen peroxide (0.120 mL). The mixture was stirred at room temperature for 30 minutes and then treated with saturated aqueous sodium thiosulfate solution (1 mL). The mixture was stirred for 10 minutes and then concentrated under reduced pressure. The residue was subjected to preparative HPLC to separate the title product 15. 1 H NMR (300MHz, CD3CN) δ7.98 (s, 1H), 6.92 (d, 1H), 6.81 (d, 1H), 6.44 (bs, 2H), 4.82 (m, 2H), 4.47(m, 1H), 4.24(m, 2H), 4.00(m, 4H), 3.80(bs, 1H), 3.11(m, 4H), 1.24(s, 9H). 31 P NMR(121.4MHz, CD3CN)δ-1.85(s).LCMS m / z 661[M+H].

[0527] Example 19: S,S′-2,2′-((((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine (oxazine-7-yl)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1- Dimethyl)bis(2,2-dimethylthiopropionate) (Compound 16)

[0528]

[0529] Compound 16 was prepared using the same method as compound 15, except that compound 13 was used as the starting nucleoside. 1 HNMR (300MHz, CD3CN) δ7.91 (s, 1H), 6.86 (d, J=4, 8Hz, 1H), 6.76 (d, J=4.5Hz, 1H), 6.29 (bs, 2H), 4.69 (t, J=2.7Hz, 1H), 4.5 8(d, J=5.7Hz, 1H), 4.14-4.33 (m, 5H), 3.99-4.07 (m, 4H), 3.53 (d, J=5.4Hz, 1H), 3.11 (q, J=5.7Hz, 4H), 1.22 (s, 18H).LCMS m / z658.9[M+].Tr=2.31

[0530] Example 1: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2,f][1,2,4]triazine-7-yl)-5-cyano 3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 17)

[0531]

[0532] Compound 17 was prepared from Compound 1 using a method similar to that of Compound 6. The product was isolated as a sodium salt. 1 HNMR (400MHz, D2O) δ7.76 (s, 1H), 6.88 (d, J = 4.8Hz, 1H), 6.73 (d, J = 4.4Hz, 1H ), 4.86 (d, J=5.2Hz, 1H), 4.43 (m, 1H), 4.39 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H). 31 P NMR (121.4 MHz, D2O) δ-5.4 (d, 1P), -10.8 (d, 1P), -21.1 (t, 1P). LCMS m / z 530 [MH], 531.9 [M+H] Tr = 0.22 min. HPLC ion exchange Tr = 9.95 min.

[0533] Example 2. ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-ethynyl 3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 18)

[0534]

[0535] Compound 18 was prepared from compound 13 using a procedure similar to that of compound 6. The product was isolated as a TEA salt. 1 H NMR (300MHz, D2O) δ7.85 (s, 1H), 7.09 (d, J = 4.6Hz, 1H), 6.95 (d, J = 4.7Hz, 1H ), 4.23(m, 2H), 4.08(m, 2H), 3.06(q, J=7.4Hz, 20H), 1.14(t, J=7.3Hz, 30H). 31 P NMR (121.4 MHz, D2O) δ -10.8 (d, 1P), -11.2 (d, 1P), -23.2 (t, 1P). LCMS m / z 530.8 [M+H], Tr = 0.46. HPLC ion exchange Tr = 9.40 min.

[0536] Example 3. ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3,4-di Hydroxy-5-methyltetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 19)

[0537]

[0538] Compound 19 was prepared from Compound 14 using a procedure similar to that of Compound 6. 1H NMR (400MHz, D2O) δ7.78 (s, 1H), 6.98 (m, 1H), 6.84 (m, 1H), 4.45 (m, 1H), 4.04 (m, 4H), 1.54 (s, 3H). 31 P NMR(161MHz, D2O)δ-10.6(m),-23.0(m).LCMS m / z 521.0[M+H].

[0539] Example 4. ((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-cyano 4-(4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 20)

[0540]

[0541] Compound 20 was prepared from Compound 2 using a procedure similar to that of Compound 6. 1 H NMR (400MHz, D2O) δ7.78 (s, 1H), 6.93 (d, J=4.4Hz, 1H), 6.78 (d, J=4.8Hz, 1H), 5.45 (dd, J=53, 4.4Hz, 1H), 4.38-4.50 (m, 2H), 4.13-4.20 (m, 2H). 31 P NMR (161 MHz, D2O) δ -5.7 (d, 1P), -11.0 (d, 1P), -21.5 (t, 1P). LCMS m / z 533.9.0 [M+H], 532.0 [MH] Tr = 1.25 min. HPLC ion exchange Tr = 11.0 min.

[0542] Example 5: (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7- (5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) (methoxy) (phenoxy) phosphoryl) amino) -3-phenylpropionic acid ethyl ester (21)

[0543]

[0544] The preparation of ethyl (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoate is as described below.

[0545] Preparation of (S)-2-amino-3-phenylpropionic acid ethyl ester hydrochloride.

[0546]

[0547] L-phenylalanine (5 g, 30 mmol) was dissolved in EtOH (30 mL). TMSCl (6.915 mL, 54 mmol) was added to the reaction at room temperature. The reaction vessel was equipped with a reflux condenser and the reactants were placed in an 80°C bath. The reaction was stirred overnight. The next day, the reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was dissolved in Et2O. The resulting slurry was filtered and the separated solid was further washed with Et2O. The washed solid was placed under high vacuum to obtain the present embodiment (S)-2-amino-3-phenylpropionic acid ethyl ester hydrochloride. 1 H NMR(400MHz,DMSO-d6)δ8.52(s,3H),7.30(m,5H),4.24(AB X ,J AX =7.8Hz,J BX =6.2Hz,1H),4.11(m,2H),3.17,3.05( AB X,J AB =-14Hz,J BX =5.8Hz,J AX =7.6Hz,2H),1.09(t,J=6.8Hz,3H).

[0548] Ethyl (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoate (Compound D) preparation

[0549]

[0550] (S)-2-amino-3-phenylpropionic acid ethyl ester hydrochloride (1.01 g, 4.41 mmol) was dissolved in DCM (50 mL). The solution was cooled to about 0 ° C, PhOP (O) Cl2 (0.656 mL, 4.41 mmol) was added, and then Et3N (1.62 mL, 11.5 mmol) was slowly added over 5 minutes. The cold bath was removed, the reaction was warmed to room temperature, and stirred for 80 minutes. p-NO2PhOH (0.583 g, 4.19 mmol) was added, followed by more Et3N (0.3 mL, 2.1 mmol). The reaction progress was monitored by LC / MS. After the reaction was completed, Et2O was diluted and the resulting solid was removed by filtration. The filtrate was concentrated and compound D was separated by silica gel column chromatography (25 g dry load column, 120 g column; eluent: 100% hexane to 55% EtOAc in hexane). 1 H NMR (400MHz, CD3OD) δ8.17(m,2H),7.33(m,2H),7.09-7.25(m,10H),4.17(m,1H),4.07(m,2H),3.08(m,1H),2.84(m,1H),1.14(m,3H). 31P NMR (162MHz, DMSO-d6)δ-1.479(s),-1.719(s).MS m / z=471.01[M+1].

[0551] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano (3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-phenylpropionic acid ethyl ester (compound 21) Preparation

[0552]

[0553] Compound 1 (0.030 g, 0.103 mmol) was dissolved in DMF (1 mL), and then THF (0.5 mL) was added. Under vigorous stirring, t-BuMgCl (1 M / THF, 154.5 μ L, 0.154 μ mol) was added dropwise to the reaction. The resulting white slurry was stirred at room temperature for about 30 minutes. A solution of compound D (0.058 g, 0.124 mmol) in THF (1 mL) was added dropwise at room temperature. The reaction progress was monitored by LC / MS. When the reaction was carried out to 50% conversion, the reaction was cooled in an ice bath and quenched with glacial acetic acid (70 μ L). The reaction was concentrated and compound 21 was isolated from the residue by reversed-phase HPLC. 1 H NMR (400MHz, DMSO-d6) δ7.91 (d, J=4Hz, 1H), 7.90 (brs, 2H), 7.09-7.30 (m, 8H), 7.01, (t, J=8.2Hz, 2H), 6.89 (d, J=4.4Hz, 1H), 6.82 (t, J=4.4H z, 1H), 6.27 (m, 1H), 6.14 (m, 1H), 5.34 (m, 1H), 4.62 (t, J=5.6Hz, 1H), 4 .15(m, 1H), 3.78-4.01(m, 6H), 2.92(m, 1H), 2.78(m, 1H), 1.04(m, 3H). 31 P NMR (162MHz, DMSO-d6) δ3.69(s), 3.34(S).MS m / z=623.0[M+H].

[0554] Example 6: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7- (5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) (methoxy) (phenoxy) phosphoryl) amino) -3-methylbutanoic acid ethyl ester (22)

[0555]

[0556] The preparation of ethyl (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-methylbutanoate is as described below.

[0557] Ethyl (2S)-3-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)butanoate (Compound E) preparation

[0558]

[0559] (S)-2-amino-3-methylbutyric acid ethyl ester (0.351g, 1.932mmol) was dissolved in DCM (17mL). The solution was cooled in an ice bath, PhOP(O)Cl2 (0.287mL, 1.932mmol) was added, and then Et3N (1.62mL, 11.4mmol) was slowly added in about 5 minutes. The cold bath was removed, and the reaction was warmed to room temperature and stirred for 1 hour. p-NO2PhOH (0.255g, 1.836mmol) was added and the reaction progress was monitored by LC / MS. After the reaction was completed, the mixture was diluted with Et2O and the obtained solid was removed by filtration. The filtrate was concentrated and compound E was separated by silica gel column chromatography (12g dry load cartridge, 80g column; eluent: 100% hexane to 55% EtOAc in hexane solution). 1 H NMR(400MHz, DMSO-d6)δ8.30(d,J=9.2Hz,2H),7.48(t,J=9.6Hz,2H),7.40(t,J=7.8Hz,2H),7.20-7.27 (m,3H),6.60(quart,J=11.6Hz,1H),4.01(m,2H),3.61(m,1H),1.93(m,1H),1.11(m,3H),0.79(m,6H). 31 P NMR (162MHz, DMSO-d6)δ-0.342(s),-0.578(s).MS m / z=422.9[M+H].

[0560] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano (3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-methylbutyric acid ethyl ester (compound 22) Preparation

[0561]

[0562] Compound 1 (0.040 g, 0.137 mmol) was dissolved in NMP (1.5 mL) and THF (0.25 mL) was added. The solution was cooled in an ice bath and t-BuMgCl (1 M / THF, 425.7 μL, 0.426 μmol) was added dropwise under vigorous stirring. The ice bath was removed and the resulting white slurry was stirred at room temperature for about 15 minutes. A solution of compound E (0.081 g, 0.192 mmol) in THF (0.5 mL) was added dropwise to the reaction at room temperature. The reaction progress was monitored by LC / MS. When the reaction was carried out to 50% conversion, the reaction was cooled in an ice bath and quenched with glacial acetic acid (70 μL). The reaction was concentrated and compound 22 was semi-purified from the residue by reverse phase HPLC. The semi-pure material was further purified by silica gel column chromatography (12 g dry load column, 40 g column; eluent: 100% EtOAc to 10% MeOH in EtOAc) to afford compound 22. 1 H NMR (400MHz, DMSO-d6) δ7.91 (d, J=1.6Hz, 1H), 7.88 (brs, 2H), 7.32 (m, 2H), 7.1 5 (m, 3H), 6.90 (t, J = 4.2Hz, 1H), 6.84 (d, J = 4.8Hz, 1H), 6.26 (dd, J = 13.4, 6.2Hz , 1H), 5.87 (quart.J=11.2Hz, 1H), 5.35 (m, 1H), 4.64 (m, 1H), 4.25 (m, 2H), 3.93 -4.15(m, 4H), 3.45(m, 1H), 1.87(m, 1H), 1.09-1.16(m, 3H), 0.70-0.83(m, 6H). 31 P NMR (162MHz, DMSO-d6) δ4.59(s), 4.47(s).MS m / z=575.02[M+H].

[0563] Example 7: (S)-2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine (oxazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionic acid isopropyl Esters (23)

[0564]

[0565] The preparation of isopropyl (S)-2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is described below.

[0566]

[0567] Compound 1 (60.0 mg, 206 μmol) was dissolved in NMP (0.28 mL). THF (0.2 mL) was added, and then tert-butylmagnesium chloride (1.0 M tetrahydrofuran solution, 0.309 mL) was added at room temperature under an argon atmosphere. After 20 minutes, a solution of compound F (prepared according to Cho, A. et al J. Med. Chem. 2014, 57, 1812-1825, 81 mg, 206 μmol) in THF (0.2 mL) was added, and the resulting mixture was heated to about 50 ° C. After 3 hours, the reaction mixture was cooled to room temperature and purified by preparative HPLC (Phenominex Synergi 4u The product was purified directly by HPLC (column, 5-100% acetonitrile / water gradient) to afford compound 23. 1 H NMR (400MHz, CD3OD) δ7.86 (s, 1H), 7.34–7.26 (m, 2H), 7.21–7.12 (m, 3H), 6.91 (d,J=4.6Hz,1H),6.87(d,J=4.6Hz,1H),4.92(sept,J=6.3Hz,1H),4.80(d,J=5 .4Hz,1H),4.43–4.34(m,1H),4.33–4.24(m,1H),4.18(t,J=5.6Hz,1H),3.82(d q,J=9.7,7.1Hz,2H),1.27(dd,J=7.1,1.0Hz,3H),1.18(dd,J=6.3,4.8Hz,6H). 31 P NMR(162MHz,CD3OD)δ3.72(s).LC / MS:t R =1.39min, MS m / z=561.11[M+H]; LC system: ThermoAccela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50x4.6mm; Solvent: CAN containing 0.1% acetic acid, water containing 0.1% acetic acid; Gradient: 0min-2.0min 2-100% ACN, 2.0min-3.05min 100% ACN, 3.05min-3.2min 100%-2% ACN, 3.2min-3.5min 2% ACN at 2μl / min.HPLC: t R=2.523min; HPLC system: Agilent 1100 series.; Column: Gemini 5μ C18 110A, 50x4.6mm; Solvent: ACN containing 0.1% TFA, water containing 0.1% TFA; Gradient: 0min-5.0min 2-98% ACN, 5.0min-6.0min 98% ACN, at 2mL / min.

[0568] Example 27: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine- 7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid cyclobutyl ester (24)

[0569]

[0570] The preparation of cyclobutyl (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is described as follows.

[0571] Preparation of cyclobutyl (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (Compound G) Preparation

[0572]

[0573] Dichlorophenyl phosphate (1.49mL, 10mmol) was dissolved in 10mL of anhydrous DCM and stirred in an ice bath under a nitrogen atmosphere. L-alanine isobutyl ester hydrochloride (0.9g, 5mmol) was added once. Then triethylamine (765μL, 5.5mmol) was added dropwise. The reaction was stirred for about 1 hour. Triethylamine (765μL, 5.5mmol) was added dropwise again and the reactant was stirred for about 45 minutes. p-nitrophenol (1.25g, 9mmol) was added once and stirred for about 30 minutes. Triethylamine (765μL, 5.5mmol) was added and the reaction mixture was stirred for about 2 hours. Then additional p-nitrophenol (1.25g, 9mmol) and triethylamine (765μL, 5.5mmol) were added and the reactant was stirred for about 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting crude product was diluted with EtOAc and washed twice with 5% citric acid aqueous solution, and then washed with saturated sodium chloride aqueous solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column (0-20-50% EtOAc in hexanes) to give Compound G. 1HNMR(400MHz,CD3OD)δ8.33–8.23(m,2H),7.52–7.33(m,4H),7.33–7.17(m,3H),4.96–4.85(m,1H),4 .07–3.96(m,1H),2.27(m,2H),2.07–1.91(m,2H),1.83–1.70(m,1H),1.70–1.55(m,1H),1.32(m,3H). 31 P NMR (162MHz, CD3OD) δ-1.36,-1.59.MS m / z=420.9[M+H].

[0574] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano (3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid cyclobutyl ester (Compound 24) Preparation

[0575]

[0576] Compound 1 (58 mg, 0.2 mmol) was mixed with compound G (101 mg, 0.24 mmol) in 2 mL of anhydrous DMF. Magnesium chloride (42 mg, 0.44 mmol) was added once. The reaction mixture was heated to about 50 ° C. DIPEA (87 μL, 0.5 mmol) was added and the reactant was stirred at about 50 ° C for about 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with 5% citric acid aqueous solution and then with saturated sodium chloride aqueous solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified with a silica gel column (0-2-5% MeOH in DCM solution) to obtain compound 24. 1 H NMR (400 MHz, methanol-d4) δ 7.85 (m, 1H), 7.34–7.22 (m, 2H), 7.22–7.08 (m, 3H), 6.94–6.84 (m, 2H), 4.95–4.85 (m, 1H), 4.79 (m, 1H), 4.46–4.34 (m, 2H), 4.34–4.24 (m, 1H), 4.19 (m, 1H), 3.81 (m, 1H), 2.27 (m, 2H), 2.01 (m, 2H), 1.84–1.68 (m, 1H), 1.62 (m, 1H), 1.30–1.16 (m, 3H). 31 P NMR(162MHz,cd3od)δ3.70,3.65.MS m / z=573.0[M+H].

[0577] Example 8: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7- Isopropyl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoic acid Esters (25)

[0578]

[0579] The preparation of isopropyl (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoate is as described below.

[0580] (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)-3-phenylpropionic acid isopropyl ester (Compound H) Preparation

[0581]

[0582] Phenyl dichlorophosphate (718 μL, 4.8mmol) was dissolved in 10mL of anhydrous DCM and stirred in an ice bath under a nitrogen atmosphere. L-phenylalanine isopropyl hydrochloride (1g, 4.1mmol) was added once. Another 10mL of anhydrous DCM was added. Triethylamine (736 μL, 5.3mmol) was added dropwise and the reaction mixture was stirred for about 30 minutes. Then more triethylamine (736 μL, 5.3mmol) was added dropwise and the reaction mixture was stirred for 30 minutes. Then another triethylamine (736 μL, 5.3mmol) was added dropwise and the reaction mixture was stirred for about 15 minutes. Then p-nitrophenol (600mg, 4.32mmol) was added. Then the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for about 2 hours. More p-nitrophenol (50mg) and triethylamine (736 μL, 5.3mmol) were added and the reaction mixture was stirred for about 1 hour.

[0583] The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc and washed twice with 5% aqueous citric acid solution, and then washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column (0-15% EtOAc in hexane) to obtain compound H. 1 H NMR (400MHz, CDCl3) δ8.17(m,2H),7.38–7.13(m,10H),7.13–7.02(m,2H),4.95( m,1H),4.31(m,1H),3.69(m,1H),3.02(dd,J=6.1,1.8Hz,2H),1.21–1.08(m,6H). 31 P NMR (162MHz, cdcl3)δ-2.96,-2.98.MS m / z=485.0[M+H].

[0584] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano (3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3-phenylpropionic acid isopropyl ester ( Preparation of Compound 25)

[0585]

[0586] Compound 1 (58 mg, 0.2 mmol) and compound H (116 mg, 0.24 mmol) were mixed and 2 mL of anhydrous DMF was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere. A THF solution of 1M tBuMgCl (300 μL, 0.3 mmol) was added dropwise within 3 minutes, and the reaction mixture was then stirred for about 16 hours. The reaction mixture was diluted with EtOAc and washed with 5% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified with a silica gel column (0-5% MeOH in DCM solution) to obtain compound 25. 1 H NMR (400MHz, CD3OD) δ7.84(m,1H),7.27–7.08(m,8H),7.08–6.97(m,2H),6.88(m,2H),4.91–4.84(m,1H),4.74( m,1H),4.26(m,1H),4.19–4.04(m,2H),4.04–3.91(m,2H),2.97(m,1H),2.82(m,1H),1.14(m,3H),1.06(m,3H). 31 P NMR (162MHz, CD3OD) δ3.63,3.25.MS m / z=637.0[M+H].

[0587] Example 29: (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine (oxazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionic acid methyl ester (26)

[0588]

[0589] The preparation of methyl (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is as described below.

[0590]

[0591] Compound 1 (100mg, 0.34mmol) is dissolved in THF (2mL), and cooled with ice-water bath. Then 1Mt-BuMgCl (0.52mL, 0.77mmol) is slowly added dropwise. The resulting mixture is stirred at room temperature for about 30 minutes. Then a solution of compound 1 (prepared according to WO 2012142085, 219mg, 0.52mmol) in THF (2mL) is added within 5 minutes, and the resulting mixture is stirred at room temperature for about 24 hours. Then the reaction mixture is diluted with EtOAc, cooled under ice-water bath, washed with NaHCO3 aqueous solution (2mL), washed with salt water, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture is purified by silica gel column chromatography (MeOH0 to 20% DCM solution) and preparative HPLC (acetonitrile 10 to 80% aqueous solution) to obtain compound 26. 1 HNMR (400MHz, CD3OD) δ7.86 (s, 1H), 7.29 (dd, J=8.6, 7.2Hz, 2H), 7.21-7.09 (m, 3H), 6.94-6.81 (m, 2H), 4.79 (d, J=5.4Hz, 1H), 4.38 (ddq, J =10.8, 5.3, 2.7Hz, 2H), 4.33-4.23 (m, 1H), 4.18 (t, J = 5.5Hz, 1H), 3.86 (dq, J = 9.9, 7.1Hz, 1H), 3.62 (s, 3H), 1.27 (dd, J = 7.2, 1.1Hz, 3H).MS m / z=533(M+1) + .

[0592] Example 30: (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine (oxazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionic acid neopentyl Esters (27)

[0593]

[0594] The preparation of (S)-neopentyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is described as follows.

[0595]

[0596] Compound 1 (100mg, 0.34mmol) is dissolved in THF (2mL), and cooled under ice-water bath. Then 1M t-BuMgCl (0.52mL, 0.77mmol) is slowly added dropwise. The resulting mixture is stirred at room temperature for about 30 minutes. Then compound J (prepared according to WO2012075140, 248mg, 0.52mmol) is added in about 5 minutes, and the resulting mixture is stirred at room temperature for about 24 hours, diluted with EtOAc, cooled under ice-water bath, and treated with NaHCO3 aqueous solution (2mL), washed with salt water, dried over sodium sulfate, and concentrated in vacuo. The resulting mixture is purified by silica gel column chromatography (MeOH 0 to 20%, in DCM) and preparative HPLC (acetonitrile 10 to 80% aqueous solution), to obtain compound 27. 1 H NMR (400MHz, CD3OD) δ7.86 (s, 1H), 7.36-7.24 (m, 2H), 7.23-7.10 (m, 3H), 6.96-6. 85(m, 2H), 4.78(d, J=5.4Hz, 1H), 4.38(tdd, J=10.0, 4.9, 2.5Hz, 2H), 4.32-4.24(m , 1H), 4.17 (t, J=5.6Hz, 1H), 3.91 (dq, J=9.8, 7.1Hz, 1H), 3.81 (d, J=10.5Hz, 1H), 3.69 (d, J=10.5Hz, 1H), 1.31 (dd, J=7.2, 1.1Hz, 3H), 0.89 (s, 9H). MSm / z=589 (M+1) + .

[0597] Example 31: (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine- 7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid cyclopentyl ester (28)

[0598]

[0599] The preparation of cyclopentyl (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is as described below.

[0600]

[0601] Compound 1 (100mg, 0.34mmol) is dissolved in THF (2mL), and cooled under ice-water bath. Then 1M t-BuMgCl (0.52mL, 0.77mmol) is slowly added dropwise. The resulting mixture is stirred at room temperature for about 30 minutes. Then compound K (prepared according to WO2012075140, 247mg, 0.52mmol) in THF (2mL) is added in about 5 minutes, and the resulting mixture is stirred at room temperature for about 24 hours, diluted with EtOAc, cooled in ice-water bath, and treated with NaHCO3 aqueous solution (2mL), washed with salt water, dried over sodium sulfate, and concentrated in vacuo. The resulting mixture is purified by silica gel column chromatography (MeOH 0 to 20% in DCM) and preparative HPLC (acetonitrile 10 to 80% aqueous solution), to obtain embodiment 28. 1 H NMR (400MHz, CD3OD) δ7.85 (s, 1H), 7.33-7.22 (m, 2H), 7.14 (tdd, J=7.6, 2.1, 1.1Hz, 3 H), 6.95-6.87 (m, 2H), 5.13-5.00 (m, 1H), 4.78 (d, J=5.4Hz, 1H), 4.48-4.35 (m, 2H), 4. 30(ddd, J=10.6, 5.7, 3.6Hz, 1H), 4.19 (t, J=5.4Hz, 1H), 3.78 (dq, J=9.2, 7.1Hz, 1H), 1.81 (dtd, J=12.5, 5.9, 2.4Hz, 2H), 1.74-1.49 (m, 6H), 1.21 (dd, J=7.1, 1.2Hz, 3H).MS m / z=587(M+1) + .

[0602] Example 9. (2S)-2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7- (5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionic acid cyclohexyl ester (29)

[0603]

[0604] At about 0 ° C, diisopropylethylamine (0.075 mL, 0.43 mmol) was added dropwise to a mixture of compound 1 (50 mg, 0.343 mmol), compound M (prepared according to US20130143835, 93 mg, 0.209 mmol) and MgCl2 (24.5 mg, 0.257 mmol) in DMF (1 mL) in about 5 minutes. The resulting mixture was stirred at about 50 ° C for about 1 hour. The reaction mixture was then cooled with an ice-water bath, treated with 1 M citric acid (0.5 mL), and directly purified by preparative HPLC (ACN 0 to 70% in water) to obtain compound 29. 1H NMR (400MHz, CD3OD) δ7.84 (s, 1H), 7.32-7.23 (m, 2H), 7.18-7.10 (m, 3H), 6.93 -6.87(m, 2H), 4.78(d, J=5.4Hz, 1H), 4.67(td, J=8.7, 4.2Hz, 1H), 4.48-4.35( m, 2H), 4.30 (ddd, J=10.8, 5.7, 3.7Hz, 1H), 4.20 (t, J=5.4Hz, 1H), 3.88-3.71 ( m, 1H), 1.83-1.63 (m, 4H), 1.58-1.46 (m, 1H), 1.46-1.24 (m, 5H), 1.24 (s, 3H). 31 P NMR (162MHz, CD3OD) δ3.75.MS m / z=601 (M+1) + .

[0605] Example 10. 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7- (5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) (methoxy) (phenoxy) phosphoryl) amino) -2-methylpropionic acid ethyl ester (30)

[0606]

[0607] The preparation of ethyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate is described below.

[0608] Preparation of ethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate

[0609]

[0610] Triphenylphosphine (6.18 g, 25.00 mmol) was added to THF (30 mL). DIAD (4.92 mL, 25.00 mmol) was then added and stirred at room temperature for 10 minutes. 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (5.08 g, 25.00 mmol) was dissolved in THF (20 mL) and added to the reaction mixture, followed by ethanol (2.19 mL, 37.49 mmol). The reaction was stirred at room temperature for about 1 hour. The solvent was removed under reduced pressure and the crude product was dissolved in 1:1 Et2O:hexane (120 mL). The solid triphenylphosphine oxide was filtered off and the solvent was removed under reduced pressure. The crude product was added to a minimum amount of CH2Cl2 and purified by silica gel chromatography with 0-50% EtOAc / Hex to give ethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate. 1H NMR (400 MHz, chloroform-d) δ 4.18 (q, J = 7.1 Hz, 2H), 1.49 (s, 6H), 1.43 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H).

[0611] Preparation of ethyl 2-amino-2-methylpropionate hydrochloride

[0612]

[0613] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid ethyl ester (2.71 g, 11.72 mmol) was added to CH Cl (25 mL), and a solution of 4N HCl in dioxane (25 mmol) was slowly added and stirred at room temperature. After 1 hour, the reaction was complete as determined by TLC. The solvent was removed under reduced pressure, and the crude product was coevaporated with Et O twice, then placed under high vacuum to obtain 2-amino-2-methylpropionic acid ethyl ester hydrochloride. 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 3H), 4.18 (q, J = 7.1Hz, 2H), 1.46 (s, 6H), 1.21 (t, J = 7.1Hz, 3H).

[0614] Preparation of ethyl 2-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionate (Compound N)

[0615]

[0616] Phenyl dichlorophosphate (0.97 mL, 6.50 mmol) and ethyl 2-amino-2-methylpropanoate hydrochloride (1.09 g, 6.50 mmol) were added to CH2Cl2 (50 mL). The reaction mixture was cooled to about 0°C and TEA (1.75 mL, 12.45 mmol) was slowly added. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After about 2 hours, the mixture was stirred by 31 P NMR confirmed that the addition of the amino acid was complete. p-Nitrophenol (0.860 g, 6.17 mmol) was added, followed by TEA (0.87 g, 7.69 mmol). The reaction was stirred at room temperature. After about 2 hours, the reaction was determined to be complete by LCMS. The reaction was diluted with Et2O and the TEA·HCl salt was filtered out. The crude product was concentrated and purified by silica gel chromatography (0-50% EtOAc / Hex) to give Compound N. 1H NMR(400MHz,DMSO-d6)δ8.37–8.21(m,2H),7.55–7.44(m,2H),7.43–7.33(m,2H),7.30–7.0 9(m,3H),6.57(d,J=10.1Hz,1H),3.99(q,J=7.1Hz,2H),1.39(s,6H),1.08(t,J=7.1Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ-2.87.LC / MS:t R =1.65min, MS m / z=408.97[M+1].; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50x3.00mm; Solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 0min-2.4min 2-100% ACN, 2.4min-2.80min 100% ACN, 2.8min-2.85min 100%-2% ACN, 2.85min-3.0min 2% ACN, at 1.8mL / min.

[0617] 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropionic acid ethyl ester (Compound 30) preparation

[0618]

[0619] Compound 1 (66 mg, 0.23 mmol) was added to NMP (2.0 mL). The mixture was cooled to about 0 ° C, and tBuMgCl (1.0 M THF solution, 0.34 mL, 0.34 mmol) was slowly added. The reactant was stirred at about 0 ° C for about 30 minutes, and then a solution of compound N (139 mg, 0.34 mmol) dissolved in THF (1.0 mL) was added. The cold bath was removed and the reaction was placed in a preheated oil bath at about 50 ° C. After about 2 hours, the reaction was cooled to room temperature and quenched with acetic acid and methanol. The crude product was concentrated and purified by reverse phase HPLC without a modifier to obtain compound 30. 1H NMR(400MHz, DMSO-d6)δ7.89(m,3H),7.31(q,J=8.1Hz,2H),7.22–7.05(m, 3H),6.87(d,J=4.5,1H),6.80(d,J=4.5Hz,1H),6.27(d,J=11.7,1H),5.81( d,J=9.7,1H),5.35(d,J=5.6Hz,1H),4.64(dt,J=9.0,5.6Hz,1H),4.24(m,2 H),4.11(m,1H),4.04–3.90(m,3H),1.39–1.23(m,6H),1.10(t,J=7.1,3H). 31 P NMR(162MHz,DMSO-d6)δ2.45,2.41.LC / MS:t R =1.03min, MS m / z=561.03[M+1]; LC system: ThermoAccela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50x3.00mm; Solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 0min-2.4min 2-100% ACN, 2.4min-2.80min 100% ACN, 2.8min-2.85min 100%-2% ACN, 2.85min-3.0min 2% ACN, at 1.8mL / min.

[0620] Example 34: 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- Isopropyl 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate (31)

[0621]

[0622] The preparation of isopropyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate is described below.

[0623] Preparation of Isopropyl 2-((tert-Butoxycarbonyl)amino)-2-methylpropanoate

[0624]

[0625] Triphenylphosphine (6.17 g, 25.00 mmol) was added to THF (30 mL). DIAD (4.92 mL, 25.00 mmol) was then added and stirred at room temperature for about 10 minutes. 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (5.07 g, 25.00 mmol) was dissolved in THF (20 mL) and added to the reaction mixture, followed by isopropanol (1.91 mL, 25.00 mmol). The reaction was stirred at room temperature for about 1 hour. The solvent was removed under reduced pressure and the crude product was dissolved in 1:1 Et2O:hexane (120 mL). The solid triphenylphosphine oxide was filtered off and the solvent was removed under reduced pressure. The crude product was dissolved in a minimum amount of CH2Cl2 and purified by silica gel chromatography (0-50% EtOAc / Hex) to give isopropyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate. 1 H NMR (400 MHz, chloroform-d) δ 5.03 (p, J = 6.2 Hz, 1H), 1.48 (s, 6H), 1.40 (d, J = 6.2 Hz, 9H), 1.24 (d, J = 6.3 Hz, 6H).

[0626] Preparation of 2-amino-2-methylpropionic acid isopropyl ester hydrochloride

[0627]

[0628] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid isopropyl ester (4.09 g, 16.67 mmol) was added to CH2Cl2 (50 mL), 4N HCl in dioxane (50 mmol) was slowly added, and stirred at room temperature. After about 1 hour, the reaction was complete by TLC. The solvent was removed under reduced pressure, and the crude product was coevaporated twice with Et2O and then placed under high vacuum to give 2-amino-2-methylpropionic acid isopropyl ester hydrochloride. 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 3H), 4.96 (p, J = 6.2Hz, 1H), 1.44 (s, 6H), 1.22 (d, J = 6.2Hz, 6H).

[0629] Preparation of isopropyl 2-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionate (compound O) Preparation

[0630]

[0631] Phenyl dichlorophosphate (0.83 mL, 5.58 mmol) and isopropyl 2-amino-2-methylpropanoate hydrochloride (1.01 g, 5.58 mmol) were added to CH2Cl2 (50 mL). The reaction mixture was cooled to 0°C and TEA (1.61 mL, 11.45 mmol) was slowly added. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After about 2 hours, the mixture was stirred by 31 P NMR confirmed that the addition of the amino acid was complete. p-Nitrophenol (0.74 g, 5.30 mmol) was added, followed by TEA (0.81, 5.87 mmol). The reaction was allowed to stir at room temperature. After about 2 hours, the reaction was determined to be complete by LCMS. The reaction was diluted with Et2O and the TEA·HCl salt was filtered out. The crude product was concentrated and purified by silica gel chromatography (0-50% EtOAc / Hex) to give Compound O. 1 H NMR (400MHz, DMSO-d6) δ8.42–8.19(m,2H),7.55–7.43(m,2H),7.39(dd,J=8.6,7.2Hz,2H),7.30– 7.12(m,3H),6.53(d,J=10.1Hz,1H),4.82(hept,J=6.3Hz,1H),1.38(s,6H),1.09(d,J=6.3,6H). 31 P NMR(162MHz,DMSO-d6)δ-2.84.LC / MS:t R =1.73min, MS m / z=422.92[M+1]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18100A, 50x3.00mm; Solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 0min-2.4min 2-100% ACN, 2.4min-2.80min 100% ACN, 2.8min-2.85min 100%-2% ACN, 2.85min-3.0min 2% ACN, at 1.8mL / min.

[0632] 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3, Isopropyl (4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2-methylpropanoate (Compound 31) Preparation

[0633]

[0634] Compound 1 (66 mg, 0.23 mmol) was added to NMP (2.0 mL). The mixture was cooled to about 0 ° C, and tBuMgCl (1.0 M in THF, 0.57 mL, 0.57 mmol) was slowly added. The reactant was stirred for about 30 minutes at about 0 ° C, and then a solution of compound O (143 mg, 0.34 mmol) in THF (1.0 mL) was added. The cold bath was removed and the reactant was placed in a preheated oil bath at about 50 ° C. After about 2 hours, the reaction was cooled to room temperature and quenched with acetic acid and methanol. The crude product was concentrated and purified by unmodified reverse phase HPLC to obtain compound 31. 1 H NMR(400MHz, DMSO-d6)δ7.88(m,3H),7.30(td,J=8.5,7.0Hz,2H),7.20–7.04(m ,3H),6.87(d,J=4.5,1H),6.80(d,J=4.5Hz,1H),6.27(d,6.1Hz,1H),5.75(t,J= 9.1Hz,1H),5.34(d,J=5.7Hz,1H),4.81(p,J=6.3Hz,1H),4.71–4.50(m,1H),4.2 3(m,2H),4.11(m,1H),4.03–3.83(m,1H),1.37–1.23(m,6H),1.18–1.04(m,6H). 31 PNMR(162MHz,DMSO)δ2.47,2.43.LC / MS:t R =1.08min, MS m / z=575.06[M+1]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50x3.00mm; Solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 0min-2.4min 2-100% ACN, 2.4min-2.80min 100% ACN, 2.8min-2.85min 100%-2% ACN, 2.85min-3.0min 2% ACN, at 1.8mL / min.

[0635] Example 35: (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine (oxazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionic acid 2-ethyl Butyl ester(32)

[0636]

[0637] The preparation of 2-ethylbutyl (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is as described below.

[0638] Preparation of (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one.

[0639]

[0640] (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (15.0 g) was combined with MTBE (60.0 mL), KBr (424.5 mg), aqueous K2HPO4 (2.5 M, 14.3 mL) and TEMPO (56 mg). The mixture was cooled to about 1°C. Aqueous bleach solution (7.9% by weight) was added slowly in portions until complete consumption of starting material as indicated by starch / iodide test. The layers were separated and the aqueous layer was extracted with MTBE. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give the product as a solid.

[0641] Preparation of (4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine)

[0642]

[0643] To a solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine (10.03 g; 74.8 mmol) in N,N-dimethylformamide (70.27 g) was added N-iodosuccinimide (17.01 g; 75.6 mmol) in portions while maintaining the contents at about 0°C. After the reaction was complete (about 3 hours at about 0°C), the reaction mixture was transferred to a 1 M aqueous sodium hydroxide solution (11 g NaOH and 276 mL water) while maintaining the contents at about 20-30°C. The resulting slurry was stirred at about 22°C for 1.5 hours and then filtered. The solid was rinsed with water (50 mL) and dried under vacuum at about 50°C to give 4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine as a solid. 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.78 (br s, 2H), 6.98 (d, J = 4.4Hz, 1H), 6.82 (d, J = 4.4Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ155.7,149.1,118.8,118.1,104.4,71.9.MS m / z=260.97[M+H].

[0644] Preparation of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine via (4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine) Pyrrol[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol

[0645]

[0646] Iodine alkali 2 (81 g) and THF (1.6 L) were added to the reactor under nitrogen atmosphere. The resulting solution was cooled to about 5 ° C and TMSCl (68 g) was added. PhMgCl (345 mL, 1.8 M in THF) was then slowly added while keeping the internal temperature at about ≤ 5 ° C. The reaction mixture was stirred at about 0 ° C for 30 minutes and then cooled to about -15 ° C. iPrMgCl-LiCl (311 mL, 1.1 M in THF) was slowly added while keeping the internal temperature below about -12 ° C. After stirring for about 10 minutes at about -15 ° C, the reaction mixture was cooled to about -20 ° C and a THF (400 mL) solution of lactone 1 (130 g) was added. The reaction mixture was then stirred at about -20 ° C for about 1 hour and quenched with AcOH (57 mL). The reaction mixture was warmed to about 0 ° C and adjusted to pH 7-8 with NaHCO3 aqueous solution (5 weight %, 1300 mL). The reaction mixture was then diluted with EtOAc (1300 mL), and the organic layer and aqueous layer were separated. The organic layer was washed with 1N HCl (1300 mL), NaHCO3 aqueous solution (5 wt%, 1300 mL) and salt solution (1300 mL), then anhydrous Na2SO4 was used and concentrated to dryness. The product was obtained by silica gel column chromatography using the gradient purification consisting of a mixture of MeOH and EtOAc.

[0647] Preparation of 2-ethylbutyl ((2S)-2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate) (Sp and Mixture of Rp)

[0648]

[0649] L-alanine 2-ethyl butyl ester hydrochloride (5.0g, 23.84mmol) was combined with methylene chloride (40mL), cooled to about -78°C, and dichlorophenyl phosphate (3.65mL, 23.84mmol) was added. Triethylamine (6.6mL, 47.68mmol) was added at about -78°C in about 60 minutes, and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was cooled to about 0°C, and pentafluorophenol (4.4g, 23.84mmol) was added. Triethylamine (3.3mL, 23.84mmol) was added in about 60 minutes. The mixture was stirred at ambient temperature for about 3 hours and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed several times with aqueous sodium carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, using a gradient elution of EtOAc and hexane (0 to 30%). The fractions containing the product were concentrated under reduced pressure to give 2-ethylbutyl (2S)-2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate as a solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.41–7.32 (m, 4H), 7.30–7.17 (m, 6H), 4.24–4.16 (m, 1H), 4.13–4.03 (m, 4H), 4.01–3.89 (m, 1H), 1.59–1.42 (m, 8H), 1.40–1.31 (m, 8H), 0.88 (t, J = 7.5 Hz, 12H). 31 P NMR (162 MHz, chloroform-d) δ-1.52. 19 F NMR (377MHz, chloroform-d) δ-153.63,-153.93(m),-160.05(td,J=21.9,3.6Hz),-162.65(qd,J=22.4,20.5,4.5Hz).MS m / z=496[M+H].

[0650] Preparation of 2-ethylbutyl ((2S)-2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate).

[0651]

[0652] L-Alanine 2-ethylbutyl ester hydrochloride (40.10 g, 0.191 mmol) was dissolved in dichloromethane (533 g) and stirred under N2(g) until the solution cooled to about -15°C. Phenyl dichlorophosphate (40.32 g, 0.191 mol) was added, followed by the slow addition of triethylamine (41.58 g, 0.411 mmol), and the reaction mixture was stirred at about -15°C for about 1.5 hours. Pentafluorophenol (35.14 g, 0.191 mol) was added, followed by the addition of triethylamine (19.23 g, 0.190 mol), and the reaction mixture was stirred for about 2 hours. The reaction mixture was warmed to about 0°C, and 0.5 M HCl (279.19 g) was added. The mixture was warmed to about 22°C, the organic layer was separated and washed with 5% aqueous KHCO3 (281 g), and then with water (281 g). The aliquoted organic layer (453.10 g, 604.30 g solution) was concentrated to a volume of about 120 mL, isopropyl acetate (157 g) was added, and the solution was concentrated to dryness. The residue was dissolved in isopropyl acetate (158 g). The resulting solution was concentrated to a volume of about 120 mL, and the temperature was adjusted to about 45° C. n-heptane (165 g) was added, and the mixture was cooled to 22° C. over about 1 hour. n-heptane (167 g) was added, and the mixture was cooled to about 0° C. Triethylamine (2.90 g, 0.0287 mol) was added, and the mixture was stirred at 0° C. for about 17 hours. The mixture was filtered, the solid was rinsed with n-heptane (145 g), and the solid was dried under vacuum at about 40° C. for about 15 hours to obtain ((S)-(pentafluorophenoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester.

[0653] Preparation of ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester:

[0654]

[0655] A slurry of L-alanine 2-ethylbutyl ester hydrochloride (20.08 g, 95.8 mmol) and isopropyl acetate (174 g) was stirred and cooled to about -20°C. Phenyl dichlorophosphate (20.37 g, 96.5 mmol) was added, followed by the slow addition of triethylamine (20.97 g, 207.2 mmol), and the mixture was stirred at about -20°C for about 1 hour. 4-Nitrophenol (13.23 g, 95.1 mmol) was added, followed by the slow addition of triethylamine (10.01 g, 98.8 mmol), and the reaction mixture was stirred for about 1.5 hours. The reaction mixture was warmed to about 0°C and 0.5 M HCl (140 g) was added. The organic layer was separated and washed with 5% Na2CO3 (2×100 g) and 10% NaCl (2×100 g). The organic layer was then concentrated to a volume of about 80 mL, and isopropyl acetate (4 g) was added, followed by n-heptane (110 g). Product seed crystals (0.100 g) were added, followed by a second portion of n-heptane (110 g), and the mixture was cooled to about 0°C. 1,8-diazabicycloundec-7-ene (1.49 g, 9.79 mmol) was added, and the mixture was stirred at about 0°C for about 21 hours. The resulting solid was filtered and washed first with n-heptane (61 g), then with H2O (2×100 g). The solid was stirred with H2O (200 g) for about 1.5 hours, filtered, and washed with H2O (3×100 g), then rinsed with n-heptane (61 g). The resulting solid was dried under vacuum at about 40°C for about 19 hours to give ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester.

[0656] Preparation of the title compound (mixture of Sp and Rp):

[0657]

[0658] Nucleoside (29 mg, 0.1 mmol) and phosphamide (60 mg, 0.12 mmol) and N, N-dimethylformamide (2 mL) were combined at ambient temperature. Tert-butylmagnesium chloride (1 M in THF, 0.15 mL) was slowly added. After about 1 hour, the reaction was diluted with ethyl acetate and washed with citric acid aqueous solution (5% by weight), saturated NaHCO3 aqueous solution and saturated brine solution. The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and CH2Cl2 (0 to 5%). The fraction containing the product was concentrated under reduced pressure to give the product.

[0659] (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)- Preparation of 2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxole-4-carbonitrile:

[0660]

[0661] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5.8 g, 0.02 mol), 2,2-dimethoxypropane (11.59 mL, 0.09 mol) and acetone (145 mL) was added sulfuric acid (18 M, 1.44 mL) at ambient temperature. The mixture was warmed to about 45°C. After about 30 minutes, the mixture was cooled to ambient temperature, and sodium bicarbonate (5.8 g) and water (5.8 mL) were added. After 15 minutes, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give the crude product (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile. 1 H NMR (400MHz, CD3OD) δ7.84(s,1H),6.93(d,J=4.6Hz,1H),6.89(d,J=4.6Hz,1H),5.40(d,J=6.7Hz,1 H),5.00(dd,J=6.7,3.3Hz,1H),4.48–4.40(m,1H),3.81–3.72(m,2H),1.71(s,3H),1.40(s,3H).MS m / z=332.23[M+1].

[0662] (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)- Preparation of 2,2-dimethyltetrahydrofuran [3,4-d] [1,3] dioxole-4-carbonitrile TsOH salt:

[0663]

[0664] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5.0 g, 17.2 mmol, 1.0 equiv), 2,2-dimethoxypropane (10.5 mL, 86 mmol, 5.0 equiv) and acetone (25 mL) was added p-toluenesulfonic acid (3.59 g, 1.1 equiv) at ambient temperature. The mixture was stirred at ambient temperature. After about 30 minutes, isopropyl acetate (25 mL) was added over about 1 hour. The resulting slurry was filtered and rinsed with 2:1 heptane:isopropyl acetate (25 ml). The product was dried under vacuum at about 40 °C.

[0665] (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)- Preparation of 2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxole-4-carbonitrile:

[0666]

[0667] To (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5 g, 17.2 mmol, 1.0 eq), 2,2-dimethoxypropane (10.5 mL, 86 mmol, 5.0 eq) and acetone (25 mL) was added p-toluenesulfonic acid (3.59 g, 1.1 eq) at ambient temperature. The mixture was stirred at ambient temperature. After 30 minutes, isopropyl acetate (25 mL) was added over 1 hour. The resulting slurry was filtered and rinsed with 2:1 heptane:isopropyl acetate (25 ml). The product was dried under vacuum at 40°C. The isolated solid was added to a reactor and 5% K2CO3 solution (50 ml) and ethyl acetate (50 mL) were added. The layers were separated and the aqueous layer was washed with ethyl acetate (25 ml). The combined organic layers were washed with water (25 ml) and then concentrated to about 25 ml. The reactor was refilled with isopropyl acetate (25 ml) and concentrated to about 25 ml. The reactor was refilled with isopropyl acetate (25 ml) again and concentrated to 25 ml. The resulting solution was inoculated to produce a thick slurry. Heptane (25 ml) was added thereto within 1 hour. The resulting slurry was filtered and rinsed with 2:1 heptane: isopropyl acetate (25 ml). The product was dried under vacuum at 40°C. (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxole-4-carbonitrile. 1 H NMR (400MHz, CD3OD) δ7.84(s,1H),6.93(d,J=4.6Hz,1H),6.89(d,J=4.6Hz,1H),5.40(d,J=6.7Hz,1 H),5.00(dd,J=6.7,3.3Hz,1H),4.48–4.40(m,1H),3.81–3.72(m,2H),1.71(s,3H),1.40(s,3H).MS m / z=332.23[M+1].

[0668] (2S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano Preparation of 2-ethylbutyl (3,4-dihydroxytetrahydrofuran-2-yl)methoxy (phenoxy)phosphoryl)amino)propanoate:

[0669]

[0670] Acetonitrile (100 mL) was mixed with (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)-amino)propionic acid 2-ethylbutyl ester (9.6 g, 21.31 mmol), substrate alcohol (6.6 g, 0.02 mol), magnesium chloride (1.9 g, 19.91 mmol) at ambient temperature. The mixture was stirred for about 15 minutes, N,N-diisopropylethylamine (8.67 mL, 49.78 mmol) was added, and after about 4 hours, the reaction was diluted with ethyl acetate (100 mL), cooled to about 0°C, and mixed with aqueous citric acid solution (5% by weight, 100 mL), and the organic phase was washed with aqueous citric acid solution (5% by weight, 100 mL) and saturated aqueous ammonium chloride solution (40 mL), aqueous potassium carbonate solution (10% by weight, 2×100 mL), and saturated brine solution (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. 1 H NMR(400MHz,CD3OD)δ7.86(s,1H),7.31–7.22(m,2H),7.17–7.09(m,3H),6.93–6.84(m,2H ),5.34(d,J=6.7Hz,1H),4.98(dd,J=6.6,3.5Hz,1H),4.59–4.50(m,1H),4.36–4.22(m,2H ),4.02(dd,J=10.9,5.7Hz,1H),3.91(dd,J=10.9,5.7Hz,1H),3.83(dq,J=9.7,7.1Hz,1H) ,1.70(s,3H),1.50–1.41(m,1H),1.39(s,3H),1.36–1.21(m,7H),0.86(t,J=7.4Hz,6H).MS m / z=643.21[M+1].

[0671] (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 2-Ethylbutyl 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (Chemical Preparation of Compound 32

[0672]

[0673] Crude acetone compound (12.85g) is combined with tetrahydrofuran (50mL) and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (100mL), cooled to about 0°C, and concentrated HCl (20mL) is slowly added. The mixture is warmed to ambient temperature. After HPLC analysis shows that the initial acetone compound is consumed, water (100mL) is added, followed by saturated sodium bicarbonate aqueous solution (200mL). The mixture is extracted with ethyl acetate (100mL), and the organic phase is washed with saturated common salt solution (50mL), dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using a gradient of methanol and ethyl acetate (0 to 20%). The fraction containing the product is concentrated under reduced pressure to obtain the product.

[0674] (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 2-Ethylbutyl 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (Chemical Preparation of Compound 32

[0675]

[0676] To a vial containing (S)-2-(((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid 2-ethylbutyl ester (30 mg, 0.05 mmol) was added 80% aqueous formic acid (1.5 mL). After 18 hours at about 20 °C, complete conversion was confirmed by HPLC and LC-MS. MS (m / z) = 603 (M+1) + .

[0677] Preparation of (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1, 2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-Ethyl butyl ester (Compound 32)

[0678]

[0679] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (0.5 g, 2 mmol), (S)-2-ethylbutyl 2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (0.9 g, 2 mmol) and MgCl2 (0.2 g, 2 mmol) was added N,N-dimethylacetamide (10 mL). The resulting mixture was heated to about 30°C under constant stirring. N,N-diisopropylethylamine (0.7 mL, 4 mmol) was then slowly added and the reaction mixture was stirred for about 6 hours. Water (10 mL) H2O was added followed by 2-MeTHF (10 mL) and the organic and aqueous phases were separated. The aqueous layer was then back extracted with 2-MeTHF (10 mL). The organic layers were combined and washed with 10% by weight citric acid solution (10 mL), followed by 10% by weight K2CO3 solution (10 mL) and H2O (10 mL). A small amount of saline was added to decompose the emulsion in the washing water before the layers were separated. The organic layer was evaporated to dryness to obtain 0.65 g of foam. iPrOAc (2.6 mL) was added, and the mixture was then heated to about 40 ° C for separation. The solution was cooled to about 20 ° C, and the mixture was stirred for about 3 days. The solid was separated by filtration, and the filter cake was washed with a small amount of iPrOAc. The solid was dried to obtain (S)-2-(((S)-(((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester.

[0680]

[0681] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (0.2 g, 0.7 mmol), (S)-2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester (0.3 g, 0.7 mmol) and MgCl2 (0.1 g, 1 mmol) was added N,N-dimethylacetamide (4 mL). The resulting mixture was heated to about 30°C under constant stirring. N,N-diisopropylethylamine (0.3 mL, 2 mmol) was then slowly added and the reaction mixture was stirred for 5 hours. Product conversion was confirmed by UPLC analysis.

[0682] (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis((tert-butyldimethoxy) Preparation of 5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-ol

[0683]

[0684] A solution of 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (13.9 g, 53.5 mmol) was prepared in THF (280 mL). The solution was cooled to about 0°C and TMSCl (13.6 mL, 107 mmol) was added. The reaction mixture was stirred for about 20 minutes, and then PhMgCl (2M in THF; 53.5 mL, 56.8 mmol) was added while keeping the internal temperature below about 5°C. The reaction mixture was stirred at about 0°C for about 30 minutes, and then cooled to about -20°C. iPrMgCl-LiCl (1.3 M in THF, 43.1 mL, 56 mmol) was then added while keeping the internal temperature below about -15°C. The reaction mixture was stirred at about -20°C for about 30 minutes.

[0685] In a separate flask, a solution of (3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (25.0 g, 50.9 mmol, 0.83 equiv) in LaCl3-2LiCl (0.6 M in THF, 85 mL, 50.9 mmol) was prepared. The solution was then transferred to the Grignard solution while maintaining the internal temperature below -20°C. The resulting reaction mixture was stirred at about -20°C for about 4 hours.

[0686] The reaction was quenched with 1M HCl (140 mL), and the mixture was heated to ambient temperature. EtOAc (140 mL) was added, and the organic and aqueous phases were separated. The aqueous layer was extracted with EtOAc (200 mL). The combined EtOAc layers were extracted with saturated aqueous NaHCO3 (2×200 mL), water (200 mL), and brine (200 mL) in sequence. The organic layer was concentrated and then purified by silica gel chromatography (30% EtOAc / hexanes) to give (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-ol. 1H NMR (300MHz, CDCl3) δ8.15–7.88(m,1H),7.51(d,J=4.8Hz,0.5H),7.02–6.92(m,0.5H),6.65–6.57(m,1H),5.66–5.2 4(m,3H),4.49–3.50(m,4H),0.97–0.78(26H),0.65(s,1.5H),0.19–0.00(m,15.5H),–0.22(s,1H),–0.55(s,1H)..MS m / z=626(M+H).

[0687] (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis((tert-butyl Preparation of dimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile

[0688]

[0689] A solution of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-ol (1.50 g, 2.40 mmol) in CHCl (15 mL) was cooled to about -40°C. Trifluoroacetic acid (0.555 mL, 7.20 mmol) was added, keeping the temperature below -20°C. In a separate flask, trimethylsilyl trifluoromethanesulfonate (2.60 mL, 14.4 mmol) was added to 5 ml CHCl (5 mL) at about 15°C, followed by trimethylsilyl cyanide (1.92 mL, 14.4 mmol), and the solution was cooled to about -30°C. The cooled solution was added to (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-ol while maintaining the temperature below -25°C. The reaction mixture was stirred at about -30°C for 15 minutes. The reaction was quenched with triethylamine (3.34 mL, 24.0 mmol) and the mixture was warmed to about 0°C. Water (50 mL) was added while maintaining the temperature below about 20°C. When the addition was complete, the mixture was stirred at room temperature for 15 minutes. The layers were separated and the organic layer was washed sequentially with KOH (20 mL), water (20 mL), and brine (20 mL). The organic layer was dried over Na2SO4, concentrated, and then purified by silica gel chromatography (30% EtOAc / hexanes) to give the product as a 3.8:1 mixture of diastereomers. The mixture was further purified by preparative HPLC (ACN 0 to 95% in water) to give the product as a single diastereomer. 1H NMR (400MHz, DMSO-d6) δ8.14-7.92(m,2H),7.89(s,1H),6.95(d,J=4.8Hz,1H),6.88(d ,J=4.4Hz,1H),5.27(d,J=4.6Hz,1H),5.10(dd,J=7.7,4.6Hz,1H),4.31(dd,J=4.7,1.4 Hz,1H),4.12(ddd,J=5.9,4.1,1.4Hz,1H),3.80–3.69(m,1H),3.56(td,J=7.8,3.9Hz,1 H),0.93(s,9H),0.75(s,9H),0.11(s,3H),0.09(s,3H),-0.15(s,3H),-0.62(s,3H).MS m / z=520(M+H).

[0690] (S)-2-(((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 3,4-bis((tert-butyldimethylsilyl)oxy)-5-cyanotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl) Preparation of 2-ethylbutyl aminopropionate

[0691]

[0692] To a mixture of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (16 mg, 0.03 mmol), (S)-2-(((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoic acid 2-ethylbutyl ester (17 mg, 0.04 mmol) and MgCl2 (4 mg, 0.05 mmol) was added THF (0.3 mL). The resulting mixture was heated to about 50°C with constant stirring. N,N-diisopropylethylamine (0.013 mL, 0.08 mmol) was then added and the reaction mixture was stirred for 21 hours. Conversion of the product was confirmed by UPLC and LC-MS analysis. MS m / z = 831 (M+H).

[0693]

[0694] A solution of (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[2, 1-f][1, 2, 4] triazine-7-yl)-3, 4-bis((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (16 mg, 0.03 mmol) in THF (0.3 mL) was cooled to -10 °C. tBuMgCl (0.07 mL, 0.07 mmol) was added dropwise, followed by a solution of (S)-2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester (22 mg, 0.04 mmol) in THF (0.15 mL). The reaction mixture was heated to 5 °C and stirred for 16 hours. The reaction was terminated with MeOH, concentrated, and then purified by silica gel chromatography (EtOAc / hexanes) to give the product. 1H NMR (400MHz, CDCl3) δ7.97(s,1H),7.38–7.29(m,2H),7.25–7.21(m,2H),7.21–7.13(m,1H),7.11(d,J=4.6Hz,1H),6.65(d,J=4.6Hz,1H),5.88(br s,2H),5.35(d,J=4.4Hz,1H),4.49–4.41(m,1H),4.41–4.35(m,1H),4.32–4.26(m, 1H),4.24(dd,J=4.5,1.7Hz,1H),4.10–3.99(m,2H),3.96(dd,J=10.9,5.7Hz,1H),3 .80–3.72(m,1H),1.48(h,J=6.2Hz,1H),1.39–1.28(m,7H),0.96(s,9H),0.85(t,J= 7.5Hz,6H),0.80(s,9H),0.08(s,3H),0.07(s,3H),-0.13(s,3H),-0.56(s,3H).31P NMR (162MHz, CDCl3) δ2.74 (s).MS m / z=831 (M+H).

[0695] (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester preparation

[0696]

[0697] The crude solution of (S)-2-(((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-cyanotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoic acid 2-ethylbutyl ester was cooled to about 0°C and concentrated HCl (0.05 mL, 0.62 mmol) was slowly added. The reaction mixture was stirred at about 20°C for about 72 hours. Conversion to product was confirmed by UPLC and LC-MS analysis. MS m / z=603 (M+H).

[0698]

[0699] A solution of (S)-2-(((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-cyanotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester in fluoride or acid can be deprotected to form (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid 2-ethylbutyl ester. Representative fluorides include, but are not limited to, TBAF, KF, pyridinium hydrofluoride, triethylammonium hydrofluoride, hydrogen fluoride, hydrochloric acid, toluenesulfonic acid, or any other suitable fluoride source. Representative acids include, but are not limited to, those found in Greene, TW; Wuts, PGM Protective Groups In Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006.

[0700] All publications, patents, and patent documents cited above are incorporated herein by reference as if individually incorporated by reference.

[0701] The invention has been described with reference to various specific and preferred embodiments and techniques. However, those skilled in the art will appreciate that many variations and modifications can be made while remaining within the spirit and scope of the invention.

Claims

1. Preparation of Formula XI-a 2 Compound method, The method includes: In the preparation of formula XI-a 2 The compound is formed under conditions including a cyaniding agent, a Lewis acid, A reaction mixture of a Bronsted acid, a solvent and a compound of formula Va: in Each R b For TBS; R 10 is H; The cyaniding agent is TMSCN, TBSCN, TESCN, HCN, KCN, NaCN, 4-Toluenesulfonyl cyanide, CuCN, CuCn*LiCl, LiCN, Zn(CN)2, K4[Fe(CN)6], Tetrabutylammonium cyanide, Tetramethylammonium cyanide, Tetraethylammonium cyanide, Tetrabutylammonium cyanide, Cyanide Tributyltin cyanide, trimethyltin cyanide, triethyltin cyanide, tripropyltin cyanide, 2-hydroxytin 2-Methyl-2-propionitrile or any combination thereof; The Lewis acid is TMSOTf, TMSOTf, TBSOTf, TESOTf, BF3, BF3-OEt2, BCl3, BF3-THF, MgCl2, MgI2, MgBr2, MgBr2-OEt2, ZnCl2, ZnBr2, ZnI2, LiCl, LiBr, LiI, AlCl3, AlBr3, AlI3, Me2Si(OTf)2, Et2Si(OTf)2, Pr2Si(OTf)2, iPr2Si(OTf)2, (tBu)2Si(OTf)2, (C6F5)3B, MeSiCl3, Me2SiCl2, SiCl4, TMSCl, TMSI, TMSVr, TBSCl, TBSBr, TBSI, TESCl, TESBr, TESI, SmCl3, SmBr3, SmI2, SmI3, ScI3, ScBr3, ScI3, Sm(OTf)3, Sc(OTf)3, TiCl4, Ti(OiPr)4, Ti(OiPr)3Cl, Ti(OiPr)2Cl2, Ti(OiPr)Cl3, Zn(BF4)2, LiBF4, Mg(BF4)2, ZrCl4, FeCl2, FeCl3, FeBr2, FeBr3, FeI2, FeI3, Cu(OTf), Cu(OTf)2, 4-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl chloride Acyl trifluoromethanesulfonate, benzenesulfonyl trifluoromethanesulfonate, methylsulfonyl chloride, methylsulfonyl Acid anhydride, InCl3, InBr3, InI3, In(OTf)3, Mg(SO4)2, NaSO4, or any thereof combination; and The Bronsted acid is TFA.

2. The method of claim 1, wherein the solvent is DCM, THF, MeTHF, Et2O, MeCN, EtCN, toluene, benzene, chlorobenzene, nitrobenzene, fluorobenzene, methanol, ethanol, 2-propanol, propanol, butanol, MTBE, EtOAc, iPrOAc, Me2O, (TMS)2O, acetone, 2-butanone, chloroform, 1,2-dichloroethane, diglyme, dioxane, acetic acid, formic acid, trifluoroacetic acid, methyl isobutyl ketone, DMAc, DMF, NMP, DMSO, or any combination thereof.

3. The method of claim 1, wherein The cyaniding agent is TMSCN; The Lewis acid is TMSOTf; and The solvent was DCM.

4. The process of any one of claims 1 to 3, wherein the cyanating agent is present in the reaction mixture in an amount of 0.1 to 10.0 equivalents (mol / mol) compared to the compound of formula Va.

5. The process of any one of claims 1-3, wherein the Lewis acid is present in the reaction mixture in an amount of 0.1 to 10.0 equivalents (mol / mol) compared to the compound of formula Va.

6. The process of any one of claims 1-3, wherein the Bronsted acid is present in the reaction mixture in an amount of 0.1 to 10.0 equivalents (mol / mol) compared to the compound of formula Va.

7. The process of any one of claims 1-3, wherein the solvent is present in the reaction mixture in an amount of 0.1 to 10.0 equivalents (mol / mol) compared to the compound of formula Va.

8. The process according to any one of claims 1 to 3, wherein the preparation of formula XI-a 2 The process of the compounds is carried out between -120°C and 20°C.

9. The method of claim 1 for preparing formula XI-a 2 Compound: The method includes: In a method suitable for preparing formula XI-a 2 Compounds under the conditions of TFA, TMSCN, The reaction mixture of TMSOTf and the compound of formula Va:

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