Methods for treating viral infections of the Arenaviridae and Coronavirus families

Abstract

Provided is a method for treating Arenaviridae virus infection. 【Solution means】A method of administering a compound of formula (I). TIFF2026122993000352.tif6891 (R 1 : H, halogen. R 2 ~R 5 : H, N3, CN, etc. R 6 : N3, CN, etc. R 7 : H, COR 11 etc. (R 11 : H, (C1-C8 alkyl, etc.).)

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Patent Application No. 62 / 219,302, filed September 16, 2015, and U.S. Provisional Patent Application No. 62 / 239,696, filed October 9, 2015, under § 119(e) of the U.S. Patent Act. The aforementioned applications are incorporated in their entirety by reference.

[0002] The present invention generally relates to methods and compounds for treating Arenaviridae virus infections, particularly methods and nucleosides and prodrugs for treating Lassa virus and Junin virus. The present invention generally relates to methods and compounds for treating Coronaviridae virus infections, particularly methods and nucleosides and prodrugs for treating SARS virus and MERS virus. [Background technology]

[0003] Lassaviruses are segmented negative sense RNA viruses belonging to the Arenaviridae family. Arenaviruses are further classified into Old World and New World virus groups based on serological cross-reactivity, phylogenetic relationships, and geographical distribution (Wulff, 19). 1978; Bowen, 1997). The New World Arenaviruses group is located in North America (i.e., white This group includes viruses prevalent in Waterarroyo (WWAV) virus, Tamiami (TAMV) virus, and Bear Canyon (BCNV) virus, and in South America (i.e., Takalibe (TACV) virus, Junin (JUNV) virus, Machupo (MACV) virus, Ganalit (GTOV) virus, and Sabia (SABV) virus). The Old World group includes arenaviruses prevalent in Africa, Europe, and Asia (i.e., lymphocytic choriomeningitis (LCMV) virus and Lassa (LASV) virus). Except for LCMV, which is distributed worldwide due to its association with Mus domesticus and M. musculus, which are migrated worldwide, the geographical occurrence of arenaviruses is limited by the range of rodent species that serve as their reproductive hosts (Salazar-Bravo, 2002). LAS The host of V is endemic rodents of the genus Mastomys in sub-Saharan Africa (Salazar-Bravo, 2002). At least seven arenaviruses are known to cause severe hemorrhagic fever in humans, including LASV, JUNV, MACV, GTOV, and SABV, which are prevalent in West Africa, Argentina, Bolivia, Venezuela, and Brazil, respectively, as well as the recently discovered Lujo (LUJV) virus and Chapare (CHAPV) virus, which originate in Zambia and Bolivia, respectively (Breise, 2009; Delgado, 2008). year).

[0004] Lassa virus (LASV) is endemic to West Africa and is estimated to occur 3 times per year. 00,000 to 500,000 people are infected (McCormick, 1987). Transmission is, It is caused by contact with infected rodents (Mastomys natalensis) or rodent excrement contaminated with the virus, and human-to-human transmission has been demonstrated, particularly in hospital environments (McCormick, 1987). It is caused by LASV. The disease ranges from latent infection to moderate to severe hemorrhagic fever associated with multiple organ failure. Mortality rates associated with LASV infection vary, ranging from approximately 2% to 15% when hospitalized, and potentially exceeding 50% in some epidemic scenarios (McCormick, 1987). (Fisher-Hoch, 1995). Despite high incidence, associated morbidity, and mortality rates Furthermore, there are no approved treatments for LASV infection in humans. Supportive care and early administration of ribavirin are the current standard of treatment.

[0005] LASV initially infects monocytes, macrophages, and dendritic cells, then spreads systemically, leading to primary viremia and visceral infection. Viral replication results in elevated inflammatory cytokine levels and coagulation disorders, leading to vascular leakage, hypovolemic shock, and multiple organ failure (Hensley, 2011).

[0006] Arenavirus replication is catalyzed by L polymerase protein, which utilizes a viral RNA template consisting of genomic RNA containing viral ribonucleoprotein (RNP) and capsid encapsulation by viral nucleocapsid protein (NP) (Buchmeier, 2007). Replication begins after the virus enters the host cell and continues in the host cell. Then, L polymerase, which associates with the viral RNP, initiates transcription from the genomic promoter located at the 3'-terminus of each genomic RNA segment, L and S. The primary transcription event synthesizes L polymerase mRNA encoded in an antigenomic orientation from the NP and S segments and the L segment, respectively. Transcription terminates at the distal end of a stem-loop (SL) structure within the intergenomic region (IGR). Arenaviruses facilitate translation by utilizing a cap-snatching strategy to acquire a cap structure for cellular mRNA. Cap-snatching is mediated by the endonuclease activity of L polymerase, with the cap-binding activity of NP as a cofactor, producing capped, unpolyadenylated mRNA. Subsequently, L polymerase adopts replicase mode, travels through the IGR, and generates fully complementary antigenomic RNA (agRNA). These agRNAs act as templates for the synthesis of Z mRNA encoded by genomic orientation from the GPC and S and L segments, respectively, and for the synthesis of full-length genomic RNA (gRNA) (Buchmeier, 2007; Franze-Fernandez, 1987; Meyer, 1993; Qi, 2010; Lelke, 2010; Morin, 2010).

[0007] Human coronaviruses, first identified in the mid-1960s, are common viruses that infect most people at some point in their lives, generally causing mild to moderate upper respiratory and gastrointestinal illnesses. A novel coronavirus called "Middle East Respiratory Syndrome Coronavirus" (MERS-CoV or MERS) was first reported in Saudi Arabia in 2012 and has spread to several other countries. SARS-CoV, the coronavirus that causes Severe Acute Respiratory Syndrome (SARS), was first recognized in China in 2002 and caused a global pandemic in 2002 and 2003. [Overview of the project] [Means for solving the problem]

[0008] Methods and compounds for treating infections caused by the Arenaviridae virus family are provided.

[0009] A compound of formula I in a therapeutically effective amount:

Chemical formula

Chemical formula

Chemical formula

[0010] In another embodiment, the method includes administering a therapeutically effective amount of a racemic mixture, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate, or pharmaceutically acceptable salt or ester thereof of the compound of formula I to a mammal in need.

[0011] In another embodiment, the method involves a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable compound. The procedure includes the step of treating an Arenaviridae infection in a person who requires treatment of the Arenaviridae infection by administering a salt or ester of the Arenaviridae.

[0012] In another embodiment, the method includes the step of treating a lassa virus infection in a person who requires treatment of the lassa virus infection by administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or ester thereof.

[0013] In another embodiment, the method includes the step of treating a Junin virus infection in a person who requires treatment of the Junin virus infection by administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or ester thereof.

[0014] In another embodiment, in a person requiring treatment of an Arenaviridae infection, a method for treating an Arenaviridae infection comprises the step of administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof in combination with a pharmaceutically acceptable excipient or carrier.

[0015] In another embodiment, in a person requiring treatment of an Arenaviridae infection, a method for treating an Arenaviridae infection includes administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof in combination with at least one additional therapeutic agent.

[0016] In another embodiment, this method a) A first pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, or ester thereof, and b) A second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Arenaviridae viruses. The procedure includes administering a therapeutically effective dose of a combination of pharmaceutical agents, including [the specified ingredient].

[0017] In another embodiment, the present application provides a method for inhibiting Arenaviridae RNA-dependent RNA polymerase, comprising the step of contacting cells infected with an Arenaviridae virus with an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

[0018] Another embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate, and / or ester thereof for treating a viral infection caused by an Arenaviridae virus.

[0019] Therapeutic dose of the compound of formula I: [ka] or a pharmaceutically acceptable salt or ester thereof [In the formula, R 1 These are H or halogen, respectively. R 2 , R 3 , R 4 or R 5 These are H and OR, respectively, independently. a , N(R a )2, N3, CN, NO2, S(O) n R a , halogen, (C1~C8) alkyl, (C4~C8) carbocylylalkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl or (C2~C8) substituted alkynyl, or any two R on adjacent carbon atoms 2 , R 3 , R 4 or R 5When they are together, they are either -O(CO)O-, or when they are together with the ring carbon atom to which they are bonded, they form a double bond. R 6 is OR a , N(R a )2, N3, CN, NO2, S(O) n R a -C(=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 , halogen, (C1~C8) alkyl, (C4~C8) carbocylylalkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl, (C2~C8) substituted alkynyl or (C6~C 20 ) Aryl(C1~C8)alkyl, R 7 teeth, a) H, -C (=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ) or -SO2NR 11 R 12 (In the formula, R 11 or R 12 Each of the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C6-C) 20 Each aryl(C1-C8)alkyl group is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or ORa The substitutions are optional, and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -And it may be replaced by an optional choice.) b) [ka] c) [ka] (In the formula, R c is phenyl, 1-naphthyl, 2-naphthyl [ka] Selected from, R d is H or CH3, R e1 and R e2 Each of these is independently H, (C1-C6) alkyl, or benzyl. R f The group is selected from H, (C1-C8) alkyl, benzyl, (C3-C6) cycloalkyl and -CH2-(C3-C6) cycloalkyl. R g These are selected from (C1~C8)alkyl, -O-(C1~C8)alkyl, benzyl, -O-benzyl, -CH2-(C3~C6)cycloalkyl, -O-CH2-(C3~C6)cycloalkyl and CF3. n' is selected from 1, 2, 3 and 4); and d) The basis of the following equation: [ka] (In the formula, Q is O, S, NR, + N(O)(R), N(OR), + It is N(O)(OR) or N-NR2, Z 1 and Z 2 When combined, -Q1 (C(R y )2)3Q 1 -and, During the ceremony, Q 1 Each of these is independently O, S, or NR. R y Each of these is independently H, F, Cl, Br, I, OH, R, -C (=Q 2 )R, -C(=Q 2 )OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 )OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 )OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 )OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 If they are together, then two Rs on the same carbon atom y It forms a carbocyclic ring consisting of 3 to 7 carbon atoms. Q 2 These are O, S, NR, and each is independent. + N(O)(R), N(OR), + N(O)(OR) or N-NR2, or Z 1 and Z 2 These are, independently, the basis of equation Ia: [ka] And, During the ceremony, Q 3 Each of them is independent of the bond, O, CR2, NR, + N(O)(R), N(OR), +N(O)(OR), N-NR2, S, SS, S(O), or S(O)2, M2 is 0, 1, or 2. R x Each of them is independent of R y , or the following formula: [ka] And, During the ceremony, M1a, M1c, and M1d are each independently either 0 or 1. M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. Z 3 is, Z 4 or Z 5 And, Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y or -SO2Z 5 And, Z 5 is a carbon ring or heterocycle, Z 5 This is 0 to 3 R y (It is independently substituted in the base.) Selected from the group consisting of, R 8 Halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NNHR 11 -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 -C(=S)NR 11 R 12 , -C(=O)OR 11(C1~C8) alkyl, (C2~C8) alkenyl, (C2~C8) alkynyl, (C4~C8) carbocyaryl alkyl, (C6~C 20 ) Arbitrarily substituted, arbitrarily substituted heteroaryl, -C(=O)(C1~C8)alkyl, -S(O) n (C1~C8) alkyl, (C6~C 20 ) Aryl (C1~C8) alkyl, OR 11 or SR 11 And, R 9 or R 10 These are H, halogen, and NR, respectively, independently. 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NHNR 11 -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 -C(=S)NR 11 R 12 , -C(=O)OR 11 , R 11 , OR 11 or SR 11 And, R 11 or R 12 Each of these is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocykylalkyl, (C6-C 20 ) Arbitrarily substituted, arbitrarily substituted heteroaryl, -C(=O)(C1~C8)alkyl, -S(O) n (C1~C8) alkyl or (C6~C 20 ) Aryl(C1~C8)alkyl, or R 11 and R 12Both of these, together with the nitrogen they are bonded to, form a 3- to 7-membered heterocyclic ring, and one carbon atom in any of the heterocyclic rings is -O-, -S-, or -NR a -It can be replaced by any choice, R a Each of these is independently H, (C1~C8) alkyl, (C2~C8) alkenyl, (C2~C8) alkynyl, (C6~C 20 ) Aryl(C1~C8)alkyl, (C4~C8)carbocyarylalkyl, -C(=O)R, -C(=O)OR, -C(=O)NR2, -C(=O)SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), or -SO2NR2, During the ceremony, Each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, (C6-C 20 )aryl, (C6~C 20 ) Substitute aryl, (C2~C 20 ) Heterocyclyl, (C2~C 20 ) Substitute heterocyclyl, (C6~C 20 ) Aryl (C1~C8) alkyl or substituted (C6~C 20 ) Aryl(C1~C8)alkyl, n can be 0, 1, or 2 independently. R 2 , R 3 , R 5 , R 6 , R 11 or R 12 Each of the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C6-C) 20 Each aryl(C1-C8)alkyl group is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a The substitutions are optional, and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a-And it may be replaced by choice. A method is provided for treating a Coronaviridae infection in a person who requires treatment of a Coronaviridae infection, the method comprising the step of administering a [substance].

[0020] In another embodiment, the method includes administering a therapeutically effective amount of a racemic mixture, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate, or pharmaceutically acceptable salt or ester thereof of the compound of formula I to a mammal in need.

[0021] In another embodiment, the method treats Coronaviridae infection by administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or ester thereof. The procedure includes the step of treating Coronaviridae infection in humans who require it.

[0022] In another embodiment, the method includes the step of treating a MERS virus infection in a person who requires treatment of the MERS virus infection by administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or ester thereof.

[0023] In another embodiment, the method includes the step of treating a SARS virus infection in a person who requires treatment of the SARS virus infection by administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or ester thereof.

[0024] In another embodiment, in a human being who requires treatment for a Coronaviridae infection, a method for treating a Coronaviridae infection comprises the step of administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof in combination with a pharmaceutically acceptable excipient or carrier.

[0025] In another embodiment, in a person requiring treatment of Coronaviridae infection, a method for treating Coronaviridae infection comprises the step of administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof in combination with at least one additional therapeutic agent.

[0026] In another embodiment, this method a) A first pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, or ester thereof, and b) A second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses. The step includes administering a therapeutically effective amount of a combination drug, including [the specified drug].

[0027] In another embodiment, the present application provides a method for inhibiting Coronaviridae RNA-dependent RNA polymerase, comprising the step of contacting cells infected with a Coronaviridae virus with an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

[0028] Another embodiment provides the use of compounds of formula I or pharmaceutically acceptable salts, solvates, and / or esters thereof for treating viral infections caused by Coronaviridae viruses. [Brief explanation of the drawing]

[0029] [Figure 1] Figure 1 is a graph showing the post-infection body weight changes in vehicle-treated mice and compound 32-treated mice.

[0030] [Figure 2] Figures 2A and 2B are graphs showing the viral load in lung tissue at 2 and 5 days post-infection in vehicle-treated mice and compound 32-treated mice.

[0031] [Figure 3] Figures 3A-3F are graphs showing whole-body plethysmography of mice infected with SARS-CoV.

[0032] [Figure 4-1] Figure 4A is a graph showing the post-infection weight changes in vehicle-treated monkeys and compound 32-treated monkeys.

[0033] [Figure 4-2] Figure 4B is a graph showing the changes in body temperature after infection in vehicle-treated monkeys and compound 32-treated monkeys.

[0034] [Figure 4-3] Figure 4C is a graph showing the changes in respiratory rate after infection in vehicle-treated monkeys and compound 32-treated monkeys.

[0035] [Figure 5] Figure 5 is a graph showing the concentration of viral RNA in tissues by treatment group. Viral load was measured by qRT-PCR. [Modes for carrying out the invention]

[0036] I. Definition Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings:

[0037] Where a trademark name is used herein, the applicants intend to include, independently, the product of the trademark name and the active pharmaceutical ingredient(s) of that product.

[0038] As used herein, “compound of the present invention” or “compound of formula I” means the compound of formula I or a pharmaceutically acceptable salt thereof. Similarly, with respect to an isolable intermediate, the phrase “compound of formula (number)” means the compound of that formula and a pharmaceutically acceptable salt thereof.

[0039] "Alkyl" refers to hydrocarbons containing normal, secondary, tertiary, or cyclic carbon atoms. For example, alkyl groups contain 1 to 20 carbon atoms (i.e., C1 to C20). 20 The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). 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), and 2-butyl (s-Bu, s-butyl). 1-Pentyl(-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(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH 3)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).

[0040] "Alkoxy" refers to a group having the formula -O-alkyl, in which the alkyl group defined above is bonded to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group is 1 ~20 carbon atoms (i.e., C1~C 20 Alkyl(alkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12 It may have an alkoxy group or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -OtBu).

[0041] A "haloalkyl" is an alkyl group as defined above, in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20 Haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 They may have a haloalkyl group or 1 to 6 carbon atoms (i.e., C1 to C6 alkyl). Suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, and -CH2CF3.

[0042] "Alkenyl" has at least one unsaturated site, i.e., carbon-carbon sp 2 A hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with double bonds. For example, an alkenyl group contains 2 to 20 carbon atoms (i.e., C2 to C2). 20 The alkenyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkyl) or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Suitable examples of alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0043] "Alkynyl" is a hydrocarbon containing at least one unsaturated site, i.e., a normal, secondary, tertiary, or cyclic carbon atom having a carbon-carbon sp triple bond. For example, an alkynyl group contains 2 to 20 carbon atoms (i.e., C2 to C2). 20 The alkynyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkynes) or 2 to 6 carbon atoms (i.e., C2-C6 alkynyls). Suitable examples of alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH2C≡CH).

[0044] "Alkylene" refers to a saturated branched-chain, linear-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the 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 radicals include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0045] "Alkenylene" refers to an unsaturated branched-chain, linear-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene. For example, an alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0046] "Alkynylene" refers to an unsaturated branched-chain, linear-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. For example, an alkynylene group has 1- They can have 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CH2C≡C-), and 4-pentinyl (-CH2CH2CH2C≡C-).

[0047] "Amino" generally refers to a nitrogen radical that can be considered a derivative of ammonia having the formula -N(X)2, where "X" is independently H, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, etc. Nitrogen hybridization is approximately sp 3 The non-limiting types of amino groups include -NH2, -N(alkyl)2, -NH(alkyl), -N(carbocykrill)2, -NH(carbocykrill), -N(heterocyclyl)2, -NH(heterocyclyl), -N(aryl)2, -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(carbocykrill)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), etc. The term "alkylamino" refers to an amino group that is 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)2, -NH(benzyl), -N(benzyl)2, etc. A substituted alkylamino generally refers to an alkylamino group as defined herein, wherein at least one substituted alkyl, as defined herein, is bonded to an amino nitrogen atom. Non-limiting examples of substituted alkylaminos 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 so on.

[0048] The term "aryl" refers to an aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom in 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 radicals derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracenes, and biphenyls, but are not limited to those listed below.

[0049] "Arylalkyl" refers to carbon atoms, usually terminal carbon atoms or sp 3 This refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl. Arylalkyl groups can contain 7 to 20 carbon atoms; for example, the alkyl group may have 1 to 6 carbon atoms and the aryl group may have 6 to 14 carbon atoms.

[0050] "Arylalkenyl" refers to a carbon atom, usually a terminal carbon atom or sp. 3 Carbon atoms, and not just sp 2 This refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl radical. The aryl portion of the aryl alkenyl may include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the aryl alkenyl may include, for example, any of the alkenyl groups disclosed herein. The aryl alkenyl group may contain 8 to 20 carbon atoms, for example, the alkenyl portion may have 2 to 6 carbon atoms and the aryl portion may have 6 to 14 carbon atoms.

[0051] "Arylalkynyl" refers to a carbon atom, usually a terminal carbon atom or sp3 One of the hydrogen atoms bonded to a carbon atom, or even to an sp carbon atom, forms an aryl radical. This refers to a substituted acyclic alkynyl radical. The aryl portion of an arylalkynyl may include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of an arylalkynyl may include, for example, any of the alkynyl groups disclosed herein. An arylalkynyl group may contain 8 to 20 carbon atoms, for example, the alkynyl portion having 2 to 6 carbon atoms and the aryl portion having 6 to 14 carbon atoms.

[0052] The terms "substituted," related to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, and carbocyclyl, for example, "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl," and "substituted carbocyclyl," mean alkyl, alkylene, aryl, arylalkyl, heterocyclyl, and carbocyclyl, respectively, in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents. Typical substituents include, but are not limited to, -X and -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)(ORb )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 is included, where X is independently a halogen: F, Cl, Br or I, and R b Each of these is independently H, alkyl, aryl, arylalkyl, heterocyclic, or protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be substituted in a similar manner. Unless otherwise indicated, when the term “substituted” is used with groups such as arylalkyls having two or more substituted moieties, the substituent can be attached to the aryl moiety, the alkyl moiety, or both.

[0053] In the pharmaceutical field, a "prodrug" is defined as a biologically inactive derivative of a drug that, when administered to the human body, is converted to a biologically active parent drug via a specific chemical or enzymatic pathway.

[0054] Those skilled in the art will recognize that the substituents and other parts of the compounds of formulas I to IV should be selected to provide compounds that are sufficiently stable to yield pharmaceutically useful compounds that can be formulated into acceptable and stable pharmaceutical compositions. Compounds of formulas I to IV having such stability are intended to fall within the scope of the present invention.

[0055] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms such as O, N, or S. For example, when a carbon atom of an alkyl group bonded to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH3), an amine (e.g., -NHCH3, -N(CH3)2), or a thioalkyl group (e.g., -SCH3), respectively. When a non-terminal carbon atom of an alkyl group not bonded to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CH2CH2-O-CH3), an alkylamine (e.g., -CH2NHCH3, -CH2N(CH3)2), or a thioalkyl ether (e.g., -CH2-S-CH3), respectively. When a terminal carbon atom of an alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is These are hydroxyalkyl groups (e.g., -CH2CH2-OH), aminoalkyl groups (e.g., -CH2NH2), or alkylthiol groups (e.g., -CH2CH2-SH), respectively. Heteroalkyl groups can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C1-C6 heteroalkyl groups refer to heteroalkyl groups having 1 to 6 carbon atoms.

[0056] As used herein, “heterocyclic” means, for example and not limited to, 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, Such complex algebras are included (from 1950 to the present), particularly in volumes 13, 14, 16, 19 and 28; and in J.Am.Chem.Soc. (1960) volume 82: page 5566. In a particular embodiment of the present invention, “heterocycle” includes a “carbocyclic” as defined herein, in which one or more (e.g., one, two, three, or four) carbon atoms are replaced by heteroatoms (e.g., O, N, or S). The terms “heterocycle” or “heterocyclyl” include saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include heterocyclic rings substituted with any of the substituents disclosed herein, for example, a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclyls are: [ka] That is the case.

[0057] Examples of heterocyclic compounds include, as an example and not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indrenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperi Dinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiadinyl, 2H,6H-1,5,2-dithiadinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, clomenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridadinyl, indolidinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, prinyl, 4H-quinolidinyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenantridinyl, acridinyl, pyrimidinyl, phena Introlinil, phenadinil, phenothiazinil, flazanil, phenoxadinil, isochromanil, chromanil, imidazolidinil, imidazolinil, pyrazolidinil, pyrazolidinil, piperazinil, indolinil, isoindolinil, quinuclidinil, morpholinil, oxazolidinil, benzotriazolyl, benzoisoxazolyl, oxyndryl, benzoxazolinil, isatinoyl, and bis-tetrahydrofuranil: [ka] It includes.

[0058] For example, and not limited to, the carbon-bonded heterocycle is bonded at positions 2, 3, 4, 5 or 6 of pyridine, positions 3, 4, 5 or 6 of pyridazine, positions 2, 4, 5 or 6 of pyrimidine, positions 2, 3, 5 or 6 of pyrazine, positions 2, 3, 5 or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, positions 2, 3, 4 or 5 of oxazole, imidazole or thiazole, positions 3, 4 or 5 of isoxazole, pyrazole or isothiazole, positions 2 or 3 of aziridine, positions 2, 3 or 4 of azetidine, positions 2, 3, 4, 5, 6, 7 or 8 of quinoline, or positions 1, 3, 4, 5, 6, 7 or 8 of isoquinoline. Furthermore, typically, heterocycles with carbon atoms 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.

[0059] For example, and not limited to, nitrogen-bonded heterocycles are found at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine, and position 9 of carbazole or β-carbolin. More specifically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetezyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0060] "Heterocyclylalkyl" refers to carbon atoms, usually terminal carbon atoms or sp 3This refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heterocyclyl radical (i.e., the heterocyclyl-alkylene moiety). Typical heterocyclylalkyl groups include, but are not limited to, heterocyclyl-CH2- and 2-(heterocyclyl)ethane-1-yl, and the "heterocyclyl" part includes those described in Principles of Modern Heterocyclic Chemistry. It contains any of the heterocyclyl groups. Those skilled in the art will also understand that heterocyclyl groups can be attached to the alkyl portion of a heterocyclylalkyl by carbon-carbon bonds or carbon-heteroatom bonds, provided that the resulting group is chemically stable. Heterocyclylalkyl groups contain 3 to 20 carbon atoms, for example, the alkyl portion of an arylalkyl group has 1 to 6 carbon atoms and the heterocyclyl portion has 2 to 14 carbon atoms. Examples of heterocyclylalkyls include, and not limited to, five-membered sulfur, oxygen and / or nitrogen-containing heterocycles (e.g., thiazolylmethyl, 2-thiazolylethane-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc.) and six-membered sulfur, oxygen and / or nitrogen-containing heterocycles (e.g., piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyrididylmethyl, pyrididylmethyl, pyrazinylmethyl, etc.).

[0061] "Heterocyclylalkenyl" refers to carbon atoms, usually terminal carbon atoms or sp 3 Carbon atoms, and not just sp 2 This refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heterocyclyl radical (i.e., the heterocyclyl-alkenylene moiety). The heterocyclyl portion of the heterocyclylalkenyl group is defined in the Principles of Modern Heterocyclic Chemistry, among others. The heterocyclyl group comprises one of the heterocyclyl groups described in the substantiation, and the alkenyl portion of the heterocyclylalkenyl group comprises one of the alkenyl groups disclosed herein. Those skilled in the art will also understand that the heterocyclyl group may be bonded to the alkenyl portion of the heterocyclylalkenyl by carbon-carbon bonds or carbon-heteroatom bonds, provided that the resulting group is chemically stable. The heterocyclylalkenyl group contains 4 to 20 carbon atoms; for example, the alkenyl portion of the heterocyclylalkenyl group has 2 to 6 carbon atoms, and the heterocyclyl portion has 2 to 14 carbon atoms.

[0062] "Heterocyclylalkynyl" refers to carbon atoms, usually terminal carbon atoms or sp 3 This refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, or even to an sp-carbon atom, is replaced by a heterocyclyl radical (i.e., the heterocyclyl-alkynylene moiety). The heterocyclyl portion of the heterocyclylalkynyl group includes those described in the Principles of Modern Heterocyclic Chemistry, as detailed in this specification. The heterocyclyl group comprises one of the heterocyclyl groups described herein, and the alkynyl portion of the heterocyclylalkynyl group comprises one of the alkynyl groups disclosed herein. Those skilled in the art will also understand that the heterocyclyl group may be bonded to the alkynyl portion of the heterocyclylalkynyl by carbon-carbon bonds or carbon-heteroatom bonds, provided that the resulting group is chemically stable. The heterocyclylalkynyl group comprises 4 to 20 carbon atoms, for example, the alkynyl portion of the heterocyclylalkynyl group comprises 2 to 6 carbon atoms, and the heterocyclyl portion comprises 2 to 14 carbon atoms.

[0063] A "heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that may be included in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all such aromatic rings listed in the definition of "heterocyclyl," including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, prinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, and pyrazyl.

[0064] A "carbocyclic" or "carbocyclyl" refers to a saturated ring (i.e., cycloalkyl) or a partially unsaturated ring (e.g., cycloakenyl, cycloalkadienyl, etc.). Alternatively, it refers to aromatic rings having 3 to 7 carbon atoms as monocyclic rings, 7 to 12 carbon atoms as dicyclic rings, and up to approximately 20 carbon atoms as polycyclic rings. Monocyclic carbocyclic rings have 3 to 7 ring atoms, and more typically, 5 or 6 ring atoms. Dicyclic carbocyclic rings have, for example, 7 to 12 ring atoms arranged as bicyclo[4,5], [5,5], [5,6] or [6,6] systems, or 9 or 10 ring atoms arranged as bicyclo[5,6] or [6,6] systems, or have a spirocondensed ring. Non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, and phenyl. Non-limiting examples of bicyclocarbocyclic compounds include naphthyl, tetrahydronapthalene, and decalin.

[0065] A "carbocykylalkyl" refers to an acyclic alkyl (akyl) radical in which one hydrogen atom bonded to a carbon atom is replaced by a carbocykyl radical as described herein. Typical but non-limiting examples of carbocykylalkyls include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0066] An "aryl heteroalkyl" means a heteroalkyl group as defined herein, wherein a hydrogen atom (which may be bonded to either a carbon atom or a heteroatom) is 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 aryl heteroalkyl group provides a chemically stable moiety. For example, aryl heteroalkyl groups can have the general formulas -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, and so on. Furthermore, any alkylene portion in the above general formulas may be further substituted with any substituent defined or illustrated herein.

[0067] "Heteroarylalkyl" refers to an alkyl group as defined herein, in which a hydrogen atom is replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyls include -CH2-pyridinyl, -CH2-pyrrolyl, -CH2-oxazolyl, -CH2-indolyl, -CH2-isoindolyl, -CH2-prinyl, -CH2-furanyl, -CH2-thienyl, -CH2-benzofuranyl, -CH2-benzothiophenyl, -CH2-carbazolyl, -CH2-imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl, -CH2-pyrazolyl, -CH2-quinolyl, -CH2-isoquinolyl, -CH2-pyridazyl, -CH2-pyrimidyl, -CH2-pyrazyl, -CH(CH3)-pyridinyl, -CH(CH3)-pyrrolyl, -CH(CH3 This includes -oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-prinyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridadyl, -CH(CH3)-pyrimidyl, -CH(CH3)-pyrazyl, etc.

[0068] The term "optionally substituted" in relation to specific parts of the compounds of formulas I-IV (for example, optionally substituted aryl groups) means a part in which all substituents are hydrogen, or in which one or more of the hydrogens of that part may be replaced by substituents such as those listed in the definition of "substituted".

[0069] A specific portion of the compounds of formulas I to IV (for example, the carbon atoms of the (C1 to C8) alkyl group are optionally -O-, -S-, or -NR) aThe term "optionally replaced" in relation to (which may be replaced by) means that one or more methylene groups of a (C1-C8) alkyl group are replaced by a specified group (e.g., -O-, -S-, or -NR). a -) means that it may be replaced by 0, 1, 2, or more.

[0070] The term "non-terminal carbon atom" in relation to alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moieties refers to the carbon atom interposed between the first carbon atom of that moiety and the last carbon atom of that moiety. Therefore, for example... , and non-limitingly, alkyl moiety-CH2(C * )H2(C * )H2CH3 or alkylene portion -CH2(C * )H2(C * )In H2CH2-, C * The atom is considered to be a non-terminal carbon atom.

[0071] Certain Q and Q 1 The options are, + N(O)(R) or + These are nitrogen oxides such as N(O)(OR). In this case, these nitrogen oxides, shown bonded to carbon atoms, are, [ka] It can also be represented by charge-separated groups, and for the purpose of describing the present invention, it is intended to be equivalent to the above representation.

[0072] "Linking group" or "link" refers to a chemical moiety containing a covalent bond or atomic chain. Linking groups include repeating units of alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine®); as well as diacitates and amides (including succinicates, succinamides, diglycolates, malonicates, and caproamides).

[0073] Terms such as "oxygen-bonded," "nitrogen-bonded," "carbon-bonded," "sulfur-bonded," or "phosphorus-bonded" mean that the bond formed between two parts is mediated by a specified atom, if the bond between those parts can be formed by using more than one type of atom in one of the parts. For example, nitrogen-bonded amino acids are bonded via the nitrogen atom of the amino acid, rather than via the oxygen or carbon atom of the amino acid.

[0074] In some embodiments of the compounds of formulas I to IV, Z 1 or Z 2 One or more of these are independently nitrogen-linked radicals of 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 with respect to substituent R, in particular those in which R is optionally substituted with (C1-C8) alkyl.

[0075] The term "purine" or "pyrimidine" bases include, but are not limited to, adenine, N 6 -Alkylpurine, N 6 -Acylpurine (acyl is C(O)(alkyl, aryl, alkylaryl or arylalkyl)), N6 - Benzylpurine, N 6 -HaroPrin, N 6 -Vinyl pudding, N 6 - Acetylene purine, N 6 - Acylprin, N 6 -Hydroxyalkylpurine, N 6 - Allylaminopurine, N 6 - Thioallyl purine, N 2 -Alkylpurine, N 2 -Alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine (containing 6-azacytosine), 2- and / or 4-mercaptopyrmidine, uracil, 5-halo Racil (containing 5-fluorouracil), C 5 -Alkylpyrimidine, C 5 - Benzylpyrimidine, C 5 - Halopyrimidine, C 5 -Vinylpyrimidine, C 5 - Acetylenepyrimidine, C 5 - Acylpyrimidine, C 5 -Hydroxyalkylpurine, C 5 - Amidopyrimidine, C 5 -Cyanopyrimidine, C 5 -5-iodopyrimidine, C 6 -iodopyrimidine , C 5 -Br-vinylpyrimidine, C 6 -Br-vinylpyrimidine, C 5 - Nitropyrimidine, C 5 -aminopyrimidine, N 2 -Alkylpurine, N 2-Alkyl-6-thiopurine, 5-azacitidinyl, 5-azaurasilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine. Purine bases and pyrimidine bases of formulas I-III are linked to ribose sugars or their analogues via the nitrogen atom of the base. Functional oxygen and nitrogen groups on the base may be protected as needed or desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, trityl, alkyl, and It contains acyl groups (such as acetyl and propionyl), methanesulfonyl, and p-toluenesulfonyl.

[0076] Unless otherwise specified, the carbon atoms in compounds of formulas I-IV are intended to have a valency of 4. In some representations of chemical structures where the carbon atom does not have enough variable substituents to exhibit a valency of 4, the remaining carbon substituents required to exhibit a valency of 4 should be assumed to be hydrogen. For example, [ka] teeth, [ka] It has the same meaning as stab.

[0077] A "protecting group" refers to a part of a compound that, as a whole, masks or modifies the properties of a functional group or the compound as a whole. The chemical structures of protecting groups are wide-ranging and diverse. One function of a protecting group is to act as an intermediate in the synthesis of the parent drug substance. Yes, there are. Chemical protecting groups and strategies for protection / deprotection are well known in this field. ("Protective Groups in Organic Chemistry," Theodora W. Greene, John Wiley & Sons, Inc.) See (New York, 1991). Protecting groups are used in the desired chemical reaction, for example, chemical It is often used to mask the reactivity of certain functional groups in order to facilitate the efficient synthesis and cleavage of bonds in a specific sequence. Protection of functional groups in compounds is common. In addition to the reactivity of the protecting functional group, such as polarity, lipophilicity (hydrophobicity), and other properties, which can be measured by analytical means, other physical properties are also modified. Chemically protected intermediates may themselves be biologically active or inactive. "Hydroxy protecting group" refers to such protecting groups that are useful for protecting hydroxyl groups (-OH).

[0078] Protective compounds also offer modified properties, and in some cases, resistance to passage across cell membranes and enzymatic degradation or sequestration, both in vitro and in vitro. They can exhibit optimized properties in vivo. In this role, a protecting compound that has the desired therapeutic effect is sometimes called a prodrug. Another function of the protecting group is to convert the parent drug into a prodrug, thereby releasing the parent drug in vivo during the conversion to the prodrug. Since the active prodrug can be absorbed more efficiently than the parent drug, the prodrug may have higher potency in vivo than the parent drug. The protecting group is removed either in vitro in the case of a chemical intermediate, or in vivo in the case of a prodrug. In the case of a chemical intermediate, it is generally more desirable if the product is physiologically harmless, but it is not particularly important whether the product obtained after deprotection, such as an alcohol, is physiologically acceptable.

[0079] The term "chiral" refers to a molecule that cannot be superimposed on its mirror image partner, while the term "achiral" refers to a molecule that can be superimposed on its mirror image partner.

[0080] The term "stereoisomer" refers to two substances that have the same chemical composition but are different in origin. This refers to different compounds in terms of the spatial arrangement of their parent or group components.

[0081] A "diastereomer" is a stereoisomer that has two or more chiral centers, and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, reactivity, and biological properties. For example, compounds of formulas I to IV are R 7 but, [ka] Z 1 and Z 2 If the values ​​are different, it can have a chiral phosphorus atom. 1 or Z 2 If at least one of them also has a chiral center, for example, Z 1 or Z 2 If the compound is a nitrogen-linked, chiral, naturally occurring α-amino acid ester, then the compounds of formulas I-IV exist as diastereomers because they have two chiral centers in the molecule. All such diastereomers, and their uses as described herein, are encompassed by the present invention. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis, crystallization, and / or chromatography. Diastereomers may have different physical attributes such as solubility, chemical stability, and crystallinity, and may also have different biological properties such as enzyme stability, absorption, and metabolic stability, but are not limited to those listed below.

[0082] "Enantiomers" refer to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0083] The modifier "approximately," used in relation to quantity, includes a fixed value and, in its context, Therefore, it has the meaning indicated (for example, including the degree of error associated with measuring a particular quantity).

[0084] As used herein, the term “to treat” means, unless otherwise indicated, to improve, alleviate, inhibit, or prevent the progression of the disorder or condition in which such disorder or condition applies, or one or more symptoms of such disorder or condition. As used herein, the term “treatment” means a treatment action, as “to treat” is defined immediately before it.

[0085] The term "therapeutic dose," as used herein, refers to the amount of compound of formulas I-IV present in the compositions described herein that, when administered via a selected route of administration, is necessary to achieve the desired level of the drug in the secretions and tissues of the airways and lungs of the treated subject, or alternatively, in the bloodstream, thereby producing the expected physiological response or desired biological effect. The exact amount depends on numerous factors, such as the specific compound of formulas I-IV, the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, and the patient's attitude, including the severity of the disease state and the patient's cooperation, and can be readily determined by those skilled in the art based on the information provided herein.

[0086] The term "normal saline" refers to an aqueous solution containing 0.9% (w / v) NaCl.

[0087] The term "hypertonic saline solution" refers to an aqueous solution containing more than 0.9% (w / v) NaCl. For example, a 3% hypertonic saline solution contains 3% (w / v) NaCl.

[0088] "Forming a reaction mixture" refers to the process by which at least two distinct chemical species come into contact with each other so that they can mix and react together. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents, or from intermediates formed from one or more of the added reagents in the reaction mixture.

[0089] A "coupling agent" refers to an agent that can couple two different compounds. Coupling agents can be catalytic or stoichiometric. For example, coupling agents can be lithium-based or magnesium-based, such as Grignard reagents. Exemplary coupling agents include, but are not limited to, n-BuLi, MgCl2, iPrMgCl, tBuMgCl, PhMgCl, or combinations thereof.

[0090] "Silane" refers to a silicon-containing group having the formula SiR4, where the R group can be an alkyl, alkenyl, cycloalkyl, phenyl, or other silicon-containing group. When a silane is linked to another compound, it is called a "silyl" and has the formula -SiR3.

[0091] A "halo-silane" refers to a silane having at least one halogen group bonded to a silicon atom. Typical halo-silanes have the formula halo-SiR3, where the R group can be an alkyl, alkenyl, cycloalkyl, phenyl, or other silicon-containing group. Specific halo-silanes include Cl-Si(CH3)3 and Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl.

[0092] "Non-nucleophilic bases" include triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, and 4-dimethylamine. This refers to Lewis bases that act as electron donors, such as nitrogenous bases including minopyridine and quinuclidine.

[0093] A "leaving group" refers to a group that maintains a bonding electron pair during heterogeneous bond cleavage. For example, leaving groups are readily replaced during nucleophilic substitution reactions. Suitable leaving groups include, but are not limited to, chlorides, bromides, mesylates, tosylates, triflates, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, and pentafluorophenoxy. Those skilled in the art will recognize other leaving groups useful in the present invention.

[0094] A "deprotecting agent" refers to any agent capable of removing a protecting group. The deprotecting agent depends on the type of protecting group used. Representative deprotecting agents are well-known in this art, as described in ProtectiveGroupsinOrganicChemistry, by Peter G.M. Wuts and Theodora W. Greene. This can be found in the 4th edition, published in 2006. II. Compounds of the present invention

[0095] Details of certain embodiments of the present invention are referenced herein, examples of which are illustrated in the appended description, structure and formula. While the present invention is described in relation to the listed embodiments, it will be understood that they are not intended to limit the invention to such embodiments. Rather, the present invention is intended to encompass all alternatives, modifications and equivalents, which may fall within the scope of the invention.

[0096] Therapeutic dose of the compound of formula I: [ka] or a pharmaceutically acceptable salt or ester thereof [In the formula, R 1 These are H or halogen, respectively. R 2 , R 3 , R 4 or R 5 These are H and OR, respectively, independently.a , N(R a )2, N3, CN, NO2, S(O) n R a , halogen, (C1~C8) alkyl, (C4~C8) carbocylylalkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl or (C2~C8) substituted alkynyl, or any two R on adjacent carbon atoms 2 , R 3 , R 4 or R 5 When they are together, they are either -O(CO)O-, or when they are together with the ring carbon atom to which they are bonded, they form a double bond. R 6 is OR a , N(R a )2, N3, CN, NO2, S(O) n R a -C(=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 , halogen, (C1~C8)alkyl, (C4~C8) Carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl or (C6-C 20 ) Aryl(C1~C8)alkyl, R 7 teeth, a) H, -C (=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R11 -S(O)(OR 11 ), -S(O)2(OR 11 ) or -SO2NR 11 R 12 (In the formula, R 11 or R 12 Each of the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C6-C) 20 Each aryl(C1-C8)alkyl group is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a The substitutions are optional, and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -And it may be replaced by an optional choice.) b) [ka] c) [ka] (In the formula, R c is phenyl, 1-naphthyl, 2-naphthyl [ka] Selected from, R d is H or CH3, R e1 and R e2 Each of these is independently H, (C1-C6) alkyl, or benzyl. R f The group is selected from H, (C1-C8) alkyl, benzyl, (C3-C6) cycloalkyl and -CH2-(C3-C6) cycloalkyl. R gThese are selected from (C1~C8)alkyl, -O-(C1~C8)alkyl, benzyl, -O-benzyl, -CH2-(C3~C6)cycloalkyl, -O-CH2-(C3~C6)cycloalkyl and CF3. n' is selected from 1, 2, 3 and 4); and d) The basis of the following equation: [ka] (In the formula, Q is O, S, NR, + N(O)(R), N(OR), + It is N(O)(OR) or N-NR2, Z 1 and Z 2 When combined, -Q 1 (C(R y )2)3Q 1 -and, During the ceremony, Q 1 Each of these is independently O, S, or NR. R y Each of these is independently H, F, Cl, Br, I, OH, R, -C (=Q 2 )R, -C(=Q 2 )OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 )OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 )OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 )OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 If they are together, then two Rs on the same carbon atom yIt forms a carbocyclic ring consisting of 3 to 7 carbon atoms. Q 2 These are O, S, NR, and each is independent. + N(O)(R), N(OR), + N(O)(OR) or N-NR2, or Z 1 and Z 2 These are, independently, the basis of equation Ia: [ka] And, During the ceremony, Q 3 Each of them is independent of the bond, O, CR2, NR, + N(O)(R), N(OR), + N(O)(OR), N-NR2, S, SS, S(O), or S(O)2, M2 is 0, 1, or 2. R x Each of them is independent of R y , or the following formula: [ka] And, During the ceremony, M1a, M1c, and M1d are each independently either 0 or 1. M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. Z 3 is, Z 4 or Z 5 And, Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y or -SO2Z 5 And, Z 5 is a carbon ring or heterocycle, Z 5 This is 0 to 3 R y (It is independently substituted in the base.) Selected from the group consisting of, R 8 Halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NNHR 11 -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 -C(=S)NR 11 R 12 , -C(=O)OR 11 (C1~C8) alkyl, (C2~C8) alkenyl, (C2~C8) alkynyl, (C4~C8) carbocyaryl alkyl, (C6~C 20 ) Arbitrarily substituted, arbitrarily substituted heteroaryl, -C(=O)(C1~C8)alkyl, -S(O) n (C1~C8) alkyl, (C6~C 20 ) Aryl (C1~C8) alkyl, OR 11 or SR 11 And, R 9 or R 10 These are H, halogen, and NR, respectively, independently. 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, -CH(=NR 11 ), -CH=NHNR 11 -CH=N(OR 11 ), -CH(OR 11 )2, -C(=O)NR 11 R 12 -C(=S)NR 11 R 12 , -C(=O)OR 11 , R 11 , OR 11 or SR11 And, R 11 or R 12 Each of these is independently H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C4-C8) carbocykylalkyl, (C6-C 20 ) Arbitrarily substituted, arbitrarily substituted heteroaryl, -C(=O)(C1~C8)alkyl, -S(O) n (C1~C8) alkyl or (C6~C 20 ) Aryl(C1~C8)alkyl, or R 11 and R 12 Both of these, together with the nitrogen they are bonded to, form a 3- to 7-membered heterocyclic ring, and one carbon atom in any of the heterocyclic rings is -O-, -S-, or -NR a -It can be replaced by any choice, R a Each of these is independently H, (C1~C8) alkyl, (C2~C8) alkenyl, (C2~C8) alkynyl, (C6~C 20 ) Aryl(C1~C8)alkyl, (C4~C8)carbocyarylalkyl, -C(=O)R, -C(=O)OR, -C(=O)NR2, -C(=O)SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), or -SO2NR2, During the ceremony, Each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, (C6-C 20 )aryl, (C6~C 20 ) Substitute aryl, (C2~C 20 ) Heterocyclyl, (C2~C 20 ) Substitute heterocyclyl, ( C6~C 20 ) Aryl (C1~C8) alkyl or substituted (C6~C 20 ) Aryl(C1~C8)alkyl, n can be 0, 1, or 2 independently. R 2 , R 3 , R 5 , R 6 , R 11 or R 12 Each of the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C6-C) 20 Each aryl(C1-C8)alkyl group is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a The substitutions are optional, and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -And it may be replaced by choice. A method is provided for treating an Arenaviridae infection in a person who requires treatment of an Arenaviridae infection, the method comprising the step of administering a drug.

[0097] In another embodiment, a therapeutically effective amount of the compound of formula I, represented by formula II: [ka] or a pharmaceutically acceptable salt or ester thereof (In the formula, R 1 , R 3 , R 5 , R 7 , R 8 and R 9 This is defined above with respect to equation I, R 2 These are OR a or halogen, R 6 is OR a , N(R a )2, N3, CN, S(O) n R a -C(=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 (These are halogens, (C1-C8) alkyls, (C4-C8) carbocylylalkyls, (C1-C8) substituted alkyls, (C2-C8) alkenyls, (C2-C8) substituted alkenyls, (C2-C8) alkynyls, or (C2-C8) substituted alkynyls.) A method is provided for treating an Arenaviridae infection in a person who requires treatment of an Arenaviridae infection, the method comprising the step of administering a drug.

[0098] In one embodiment of a method for treating Arenaviridae infection by administering a compound of formula II, the R of formula II 1 is H. In another embodiment of this model, R of formula II 6 is N3, CN, halogen, (C1-C8)alkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl or (C2-C8)substituted alkynyl. In another embodiment of this model, R of formula II 6 is CN, methyl, ethenyl, or ethynyl. In another embodiment of this model, R of formula II 6 is CN. In another embodiment of this embodiment, R of formula II 6 is methyl. In another embodiment of this embodiment, R of formula II 5 is H. In another embodiment of this model, R of formula II 2 is OR a In another embodiment of this model, R in formula II 2 is OH. In another embodiment of this model, R of formula II 2 This embodiment is F. In another aspect, R in Equation II 3 is OR a In another embodiment of this model, R in formula II 3 OH, -OC(=O)R11 Or -OC (=O) OR 11 In another embodiment of this model, R in formula II 3 is OH. In another embodiment of this model, R of formula II 8 , NR 11 R 12 In another embodiment of this model, R in formula II 8 is NH2. In another embodiment of this embodiment, R of formula II 8 is OR 11 In another embodiment of this model, R in formula II 8 is OH. In another embodiment of this model, R of formula II 9 is H. In another embodiment of this model, R of formula II 9 , NR 11 R 12 In another embodiment of this model, R in formula II 9 is NH2. In another embodiment of this embodiment, R of formula II 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this model, R in formula II 7 is H. In another embodiment of this model, R of formula II 7 teeth, [ka] That is the case.

[0099] In another embodiment of a method for treating an Arenaviridae infection, comprising the step of administering a compound of formula II, the Arenaviridae infection is caused by an Arenaviridae virus. In another aspect of this embodiment, the Arenaviridae virus is Lassa virus or Junin virus. In another aspect of this embodiment, the Arenaviridae virus is Lassa virus. In another aspect of this embodiment, the Arenaviridae virus is Junin virus. In another aspect of this embodiment, the Arenaviridae virus is caused by Lassa virus, which is caused by a strain selected from Josiah, NL, z148, Macenta, AV, and CSF.

[0100] In another embodiment of this designation, Arenaviridae infection includes Allpahuayo virus (ALLV), Amaparivirus (AMAV), Bear Canyon virus (BCNV), Catalinavirus, Chaparevirus, Cupixi virus (CPXV), Dandenone virus, Flexal virus (FLEV), Gunaritovirus (GTOV), IPPY virus (IPPYV), Junin virus (JUNV), Kodcovirus, Lassa virus (LASV), Latinovirus (LATV), and Lymphocytic Choroidal Virus. It is caused by femortitis C virus (LCMV), Lujo virus, Machupo virus (MACV), Mobara virus (MOBV), Morogoro virus, Mopeia virus (MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pikinde virus (PICV), Pinhar virus, Pyrital virus (PIRV), Sabia virus (SABV), Skinnertank virus, Takaribe virus (TCRV), Tamiami virus (TAMV), or Whitewater Arroyo virus (WWAV).

[0101] In another embodiment, a therapeutically effective amount of the compound of formula I, represented by formula III: [ka] or a pharmaceutically acceptable salt or ester thereof (In the formula, R 6 , R 7 , R 8 and R 9 This is defined above with respect to equation II, R 2 These are OR a Or F, R 3 These are OR a (is) A method is provided for treating an Arenaviridae infection in a person who requires treatment of an Arenaviridae infection, the method comprising the step of administering a drug.

[0102] One embodiment of a method for treating an Arenaviridae infection, comprising the step of administering a compound of formula III, wherein the compound R of formula III 6 is N3, CN, halogen, (C1-C8)alkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl or (C2-C8)substituted alkynyl. In another embodiment of this model, R of formula III 6 is CN, methyl, ethenyl, or ethynyl. In another embodiment of this model, R of formula III 6 is CN. In another embodiment of this embodiment, R of formula III 6 is methyl. In another embodiment of this embodiment, R of formula III 2 is OR a In another embodiment of this design, R in formula III 2 is OH. In another embodiment of this model, R of formula III 2 is F. In another embodiment of this embodiment, R of formula III 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 3 is OH. In another embodiment of this model, R of formula III 8 , NR 11 R12 In another embodiment of this design, R in formula III 8 is NH2. In another embodiment of this embodiment, R of formula III 8 is OR 11 In another embodiment of this design, R in formula III 8 is OH. In another embodiment of this model, R of formula III 9 is H. In another embodiment of this design, R of formula III is used. 9 , NR 11 R 12 In another embodiment of this design, R in formula III 9 is NH2. In another embodiment of this embodiment, R of formula III 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this design, R in formula III 7 is H. In another embodiment of this design, R of formula III is used. 7 teeth, [ka] That is the case.

[0103] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula III, wherein R of formula III 6 R is N3, CN, halogen, (C1~C8) alkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl or (C2~C8) substituted alkynyl, 8 is NH2. In another embodiment of this embodiment, R of formula III 6 is CN, methyl, ethenyl, or ethynyl. In another embodiment of this model, R of formula III 6 is CN. In another embodiment of this embodiment, R of formula III 6 is methyl. In another embodiment of this embodiment, R of formula III2 is OR a In another embodiment of this design, R in formula III 2 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 2 is OH. In another embodiment of this model, R of formula III 2 is F. In another embodiment of this embodiment, R of formula III 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 3 is OH. In another embodiment of this model, R of formula III 9 is H. In another embodiment of this design, R of formula III is used. 9 , NR 11 R 12 In another embodiment of this design, R in formula III 9 is NH2. In another embodiment of this embodiment, R of formula III 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this design, R in formula III 7 is H. In another embodiment of this design, R of formula III is used. 7 teeth, [ka] That is the case.

[0104] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula III, wherein R of formula III 6 is CN, methyl, ethenyl or ethinyl, and R 8 NH2 is R 9 is H. In another embodiment of this model, R of formula III is used. 6is CN. In another embodiment of this embodiment, R of formula III 6 is methyl. In another embodiment of this embodiment, R of formula III 2 is OR a In another embodiment of this design, R in formula III 2 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 2 is OH. In another embodiment of this model, R of formula III 2 is F. In another embodiment of this embodiment, R of formula III 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 3 is OH. In another embodiment of this model, formula R of III 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this design, R in formula III 7 is H. In another embodiment of this design, R of formula III is used. 7 teeth, [ka] That is the case.

[0105] In another embodiment of a method for treating an Arenaviridae infection, comprising the step of administering a compound of formula III, the Arenaviridae infection is caused by an Arenaviridae virus. In another aspect of this embodiment, the Arenaviridae virus is Lassa virus or Junin virus. In another aspect of this embodiment, the Arenaviridae virus is Lassa virus. In another aspect of this embodiment, the Arenaviridae virus is Junin virus. In another aspect of this embodiment, the Arenaviridae virus is caused by Lassa virus, which is caused by a strain selected from Josiah, NL, z148, Macenta, AV, and CSF.

[0106] In another aspect of this embodiment, Arenaviridae infection (infectoin) is Al Ipahuayo virus (ALLV), Amaparivirus (AMAV), Bear Canyon virus (BCNV), Catalinavirus, Chaparevirus, Cupixi virus (CPXV), Dandenone virus, Flexal virus (FLEV), Guanaritovirus (GTOV), IPPY virus (IPPYV), Junin virus (JUNV), Kodcovirus, Lassa virus (LASV), Latinovirus (LATV), Lymphocytic choriomeningitis virus (LCMV), Rujo It is caused by viruses such as Machupovirus (MACV), Mobaravirus (MOBV), Morogorovirus, Mopeiavirus (MOPV), Oliverosvirus (OLVV), Paranavirus (PARV), Pikindevirus (PICV), Pinhar virus, Pyritalvirus (PIRV), Sabiavirus (SABV), Skinnertankvirus, Takaribevirus (TCRV), Tamiamivirus (TAMV), or Whitewater Arroyovirus (WWAV).

[0107] In another embodiment, a therapeutically effective amount of the compound of formula I, represented by formula IV: [ka] or a pharmaceutically acceptable salt or ester thereof (In the formula, R 7 (This is defined above with respect to equation I.) A method is provided for treating an Arenaviridae infection in a person who requires treatment of an Arenaviridae infection, the method comprising the step of administering a drug.

[0108] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 This can be H. In another embodiment of a method for treating Arenaviridae infection, which includes the step of administering a compound of formula IV, R 7 is selected from the bases a), b), or c) defined for formula I.

[0109] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, Z 1 and Z 2 Each of these has the following independent structure: [ka] It is a group having Z 3 is Z 5 (is) That is the case.

[0110] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, Z 1 and Z 2 Each of these has the following independent structure: [ka] It is a group having Z 3 is Z 5 (is) That is the case.

[0111] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, Q 3b Each of these is independently O or N(R). In another embodiment, Q 3b Each of these is O, and R x Each of them is independent [ka] (In the formula, M12c is 1, 2 or 3, Q 3 Each of these is independently a bond (O, CR2, or S).

[0112] In some embodiments, R e1 and R e2 Each of these can independently be H, C1-C6 alkyl, or benzyl. In some embodiments, R e1 R can be H, C1-C6 alkyl or benzyl, e2 R can be H or C1-C6 alkyl. In some embodiments, e1 and R e2 Each of these can independently be H or a C1-C6 alkyl group. In some embodiments, R e1 and R e2 Each can be independently H or benzyl. In some embodiments, R e1 R can be H, methyl or benzyl, e2 H Or it can be methyl. In some embodiments, R e1can be H or methyl, and R e2 This can be H or methyl. In some embodiments, R e1 It can be methyl, R e2 This can be H or methyl. In some embodiments, R e1 It can be H or benzyl, R e2 This can be H or methyl.

[0113] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] That is the case.

[0114] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] That is the case.

[0115] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R f is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl. In another embodiment of the compound of formula IV, R f C1~C8 Aruki In another embodiment of the compound of formula IV, R f It is 2-ethylbutyl.

[0116] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R f The group is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl. R g (Selected from C1-C8 alkyl, -O-C1-C8 alkyl, benzyl, -O-benzyl, -CH2-C3-C6 cycloalkyl, -O-CH2-C3-C6 cycloalkyl, and CF3).

[0117] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R f (is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl). In another embodiment of the compound of formula IV, R f is a C1-C8 alkyl group. In another embodiment of the compound of formula IV, R f is a C1-C6 alkyl group. In another embodiment of the compound of formula IV, R f It is 2-ethylbutyl.

[0118] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R g(is selected from C1-C8 alkyl, -O-C1-C8 alkyl, benzyl, -O-benzyl, -CH2-C3-C6 cycloalkyl, -O-CH2-C3-C6 cycloalkyl and CF3). In another embodiment of the compound of formula IV, R f is a C1-C8 alkyl group. In another embodiment of the compound of formula IV, R f These are C1-C6 alkyl groups.

[0119] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] It is selected from the group consisting of the following.

[0120] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] That is the case.

[0121] Another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, Z 1 and Z 2 Each of them is, [ka] It can be done this way.

[0122] In another embodiment, a method for treating an Arenaviridae infection in a person who needs to be treated for an Arenaviridae infection, comprising the step of administering a therapeutically effective amount of a compound of formulas I to IV, wherein R 11 or R 12These independently include H, (C1~C8) alkyl, (C2~C8) alkenyl, (C2~C8) alkynyl, (C4~C8) carbocykylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1~C8) alkyl, and -S(O). n A method is provided in which the (C1-C8) alkyl or aryl(C1-C8) alkyl is used. In another embodiment, R 11 and R 12 Both of them, together with the nitrogen they are bonded to, 3~ It forms a 7-membered heterocyclic ring, and any one carbon atom in the heterocyclic ring is -O-, -S-, or -NR a -and can be replaced by choice. Therefore, as an example, and not limited to, the part -NR 11 R 12 is a complex algebra: [ka] It can be expressed by, for example, [various methods].

[0123] In another embodiment, a method for treating an Arenaviridae infection in a person who needs to be treated for an Arenaviridae infection, comprising the step of administering a therapeutically effective amount of a compound of formulas I to IV, wherein R 3 , R 4 , R 5 , R 6 , R 11 or R 12 Each of these is independently a (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or aryl(C1-C8)alkyl, and the (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or aryl(C1-C8)alkyl is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a Thus, a method is provided in which substitution is performed by choice. Therefore, as an example, and not limited to, R 3 , R 4 , R 5 , R 6, R 11 or R 12 This can represent parts such as -CH(NH2)CH3, -CH(OH)CH2CH3, -CH(NH2)CH(CH3)2, -CH2CF3, -(CH2)2CH(N3)CH3, and -(CH2)6NH2.

[0124] In another embodiment, a method for treating an Arenaviridae infection in a person who needs to be treated for an Arenaviridae infection, comprising the step of administering a therapeutically effective amount of a compound of formulas I to IV, wherein R 3 , R 4 , R 5 , R 6 , R 11 or R 12 The (C1-C8) alkyl group is such that one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -Therefore, a method is provided which may be replaced by choice. Thus, as an example, and not limited to, R 3 , R 4 , R 5 , R 6 , R 11 or R 12 This can represent parts such as -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2SCH3, -(CH2)6OCH3, and -(CH2)6N(CH3)2.

[0125] In another embodiment of a method for treating an Arenaviridae infection, comprising the step of administering a compound of formula I, the compound is [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0126] In another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula I, the compound is [ka] [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0127] In another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, the compound is [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0128] In another embodiment of a method for treating Arenaviridae infection, comprising the step of administering a compound of formula IV, the compound is [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0129] In another embodiment of a method for treating Arenaviridae infection, comprising the step of administering compounds of formulas I to IV, the compounds are: [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0130] In another embodiment of a method for treating Arenaviridae infection, comprising the step of administering compounds of formulas I to IV, the compounds are: [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0131] Therapeutic dose of the compound of formula I: [ka] or a pharmaceutically acceptable salt or ester thereof [In the formula, R 1 These are H or halogen, respectively. R 2 , R 3 , R 4 or R 5 These are H and OR, respectively, independently. a , N(R a )2, N3, CN, NO2, S(O) n R a , halogen, (C1~C8) alkyl, (C4~C8) carbocylylalkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl or (C2~C8) substituted al Is it Kinil? or any two R on adjacent carbon atoms 2 , R 3 , R 4 or R 5 When they are together, they are either -O(CO)O-, or when they are together with the ring carbon atom to which they are bonded, they form a double bond. R 6 is OR a , N(R a )2, N3, CN, NO2, S(O) n R a -C(=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R12 , halogen, (C1~C8) alkyl, (C4~C8) carbocylylalkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl, (C2~C8) substituted alkynyl or (C6~C 20 ) Aryl(C1~C8)alkyl, R 7 teeth, a) H, -C (=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ) or -SO2NR 11 R 12 (In the formula, R 11 or R 12 Each of the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C6-C) 20 Each aryl(C1-C8)alkyl group is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a The substitutions are optional, and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -And it may be replaced by an optional choice.) b) [ka] c) [ka] (In the formula, R c is phenyl, 1-naphthyl, 2-naphthyl [ka] selected from R d is H or CH3, R e1 and R e2 are each independently H, (C1-C6)alkyl or benzyl, R f is selected from H, (C1-C8)alkyl, benzyl, (C3-C6)cycloalkyl and -CH2-(C3-C6)cycloalkyl, R g is selected from (C1-C8)alkyl, -O-(C1-C8)alkyl, benzyl, -O-benzyl, -CH2-(C3-C6)cycloalkyl, -O-CH2-(C3-C6)cycloalkyl and CF3, n’ is selected from 1, 2, 3 and 4); and d) a group of the following formula:

Chemical formula

[0132] In another embodiment, a therapeutically effective amount of the compound of formula I, represented by formula II: [ka] or a pharmaceutically acceptable salt or ester thereof (In the formula, R 1 , R 3 , R5 , R 7 , R 8 and R 9 This is defined above with respect to equation I, R 2 These are OR a or halogen, R 6 is OR a , N(R a )2, N3, CN, S(O) n R a -C(=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR 11 ), -SO2NR 11 R 12 (These are halogens, (C1-C8) alkyls, (C4-C8) carbocylylalkyls, (C1-C8) substituted alkyls, (C2-C8) alkenyls, (C2-C8) substituted alkenyls, (C2-C8) alkynyls, or (C2-C8) substituted alkynyls.) A method is provided for treating a Coronaviridae infection in a person who requires treatment of a Coronaviridae infection, the method comprising the step of administering a [substance].

[0133] In one embodiment of a method for treating Coronaviridae infection by administering a compound of formula II, the R of formula II 1 is H. In another embodiment of this model, R of formula II 6 is N3, CN, halogen, (C1-C8)alkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl or (C2-C8)substituted alkynyl. In another embodiment of this model, R of formula II 6 is CN, methyl, ethenyl, or ethynyl. In another embodiment of this model, R of formula II 6is CN. In another embodiment of this embodiment, R of formula II 6 is methyl. In another embodiment of this embodiment, R of formula II 5 is H. In another embodiment of this model, R of formula II 2 is OR a In another embodiment of this model, R in formula II 2 is OH. In another embodiment of this model, R of formula II 2 is F. In another embodiment of this model, R of formula II 3 is OR a In another embodiment of this model, R in formula II 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this model, R in formula II 3 is OH. In another embodiment of this model, R of formula II 8 , NR 11 R 12 In another embodiment of this model, R in formula II 8 is NH2. In another embodiment of this embodiment, R of formula II 8 is OR 11 In another embodiment of this model, R in formula II 8 is OH. In another embodiment of this model, R of formula II 9 is H. In another embodiment of this model, R of formula II 9 , NR 11 R 12 In another embodiment of this model, R in formula II 9 is NH2. In another embodiment of this embodiment, R of formula II 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this model, R in formula II 7 is H. In another embodiment of this model, R of formula II 7 teeth, [ka] That is the case.

[0134] In another embodiment of a method for treating a Coronaviridae infection, comprising the step of administering a compound of formula II, the Coronaviridae infection is caused by a Coronaviridae virus. In another aspect of this embodiment, the Coronaviridae virus is the MERS virus or the SARS virus. In another aspect of this embodiment, the Coronaviridae virus is the MERS virus. In another aspect of this embodiment, the Coronaviridae virus is the SARS virus. In another aspect of this embodiment, the Coronaviridae virus is caused by a MERS virus, which is caused by a strain selected from known strains.

[0135] In another embodiment, a therapeutically effective amount of the compound of formula I, represented by formula III: [ka] or a pharmaceutically acceptable salt or ester thereof (In the formula, R 6 , R 7 , R 8 and R 9 This is defined above with respect to equation II, R 2 These are OR a Or F, R 3 These are OR a (is) A method is provided for treating a Coronaviridae infection in a person who requires treatment of a Coronaviridae infection, the method comprising the step of administering a [substance].

[0136] One embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula III, is R of formula III.6 is N3, CN, halogen, (C1-C8)alkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl or (C2-C8)substituted alkynyl. In another embodiment of this model, R of formula III 6 is CN, methyl, ethenyl, or ethynyl. In another embodiment of this model, R of formula III 6 is CN. In another embodiment of this embodiment, R of formula III 6 is methyl. In another embodiment of this embodiment, R of formula III 2 is OR a In another embodiment of this design, R in formula III 2 is OH. In another embodiment of this model, R of formula III 2 is F. In another embodiment of this embodiment, R of formula III 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 3 is OH. In another embodiment of this model, R of formula III 8 , NR 11 R 12 In another embodiment of this design, R in formula III 8 is NH2. In another embodiment of this embodiment, R of formula III 8 is OR 11 In another embodiment of this design, R in formula III 8 is OH. In another embodiment of this model, R of formula III 9 is H. In another embodiment of this design, R of formula III is used. 9 , NR 11 R 12 In another embodiment of this design, R in formula III 9 is NH2. In another embodiment of this embodiment, R of formula III 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this design, R in formula III 7 is H. In another embodiment of this design, R of formula III is used. 7 teeth, [ka] That is the case.

[0137] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula III, is R of formula III. 6 R is N3, CN, halogen, (C1~C8) alkyl, (C1~C8) substituted alkyl, (C2~C8) alkenyl, (C2~C8) substituted alkenyl, (C2~C8) alkynyl or (C2~C8) substituted alkynyl, 8 is NH2. In another embodiment of this embodiment, R of formula III 6 is CN, methyl, ethenyl, or ethynyl. In another embodiment of this model, R of formula III 6 is CN. In another embodiment of this embodiment, R of formula III 6 is methyl. In another embodiment of this embodiment, R of formula III 2 is OR a In another embodiment of this design, R in formula III 2 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 2 is OH. In another embodiment of this model, R of formula III 2 is F. In another embodiment of this embodiment, R of formula III 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 3 is OH. In another embodiment of this model, R of formula III 9 is H. In another embodiment of this design, R of formula III is used. 9 , NR 11 R12 In another embodiment of this design, R in formula III 9 is NH2. In another embodiment of this embodiment, R of formula III 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this design, R in formula III 7 is H. In another embodiment of this design, R of formula III is used. 7 teeth, [ka] That is the case.

[0138] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula III, is R of formula III. 6 is CN, methyl, ethenyl or ethinyl, and R 8 NH2 is R 9 is H. In another embodiment of this model, R of formula III is used. 6 is CN. In another embodiment of this embodiment, R of formula III 6 is methyl. In another embodiment of this embodiment, R of formula III 2 is OR a In another embodiment of this design, R in formula III 2 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 2 is OH. In another embodiment of this model, R of formula III 2 is F. In another embodiment of this embodiment, R of formula III 3 OH, -OC(=O)R 11 Or -OC (=O) OR 11 In another embodiment of this design, R in formula III 3 is OH. In another embodiment of this design, R in Equation III 7 H, -C(=O)R 11 , -C(=O)OR 11 or [ka] In another embodiment of this design, R in formula III 7 is H. In another embodiment of this design, R of formula III is used. 7 teeth, [ka] That is the case.

[0139] In another embodiment of a method for treating a Coronaviridae infection, comprising the step of administering a compound of formula III, the Coronaviridae infection is caused by a Coronaviridae virus. In another aspect of this embodiment, the Coronaviridae virus is the MERS virus or the SARS virus. In another aspect of this embodiment, the Coronaviridae virus is the MERS virus. In another aspect of this embodiment, the Coronaviridae virus is the SARS virus. In another aspect of this embodiment, the Coronaviridae virus is caused by a MERS virus caused by a strain selected from known strains.

[0140] In another embodiment, a therapeutically effective amount of the compound of formula I, represented by formula IV: [ka] or a pharmaceutically acceptable salt or ester thereof (In the formula, R 7 (This is defined above with respect to equation I.) A method is provided for treating a Coronaviridae infection in a person who requires treatment of a Coronaviridae infection, the method comprising the step of administering a [substance].

[0141] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 This can be H. In another embodiment of a method for treating Coronaviridae infection, which includes the step of administering a compound of formula IV, R 7 is selected from the bases a), b), or c) defined for formula I.

[0142] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, Z 1 and Z 2 Each of these has the following independent structure: [ka] It is a group having Z 3 is Z 5 (is) That is the case.

[0143] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, Z 1 and Z 2 Each of these has the following independent structure: [ka] It is a group having Z 3 is Z 5 (is) That is the case.

[0144] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, Q 3b Each of these is independently O or N(R). In another embodiment, Q 3b Each of these is O, and R x Each of them is independent [ka] (In the formula, M12c is 1, 2 or 3, Q 3 Each of these is independently a bond (O, CR2, or S).

[0145] In some embodiments, R e1 and R e2 Each of these can independently be H, C1-C6 alkyl, or benzyl. In some embodiments, R e1 R can be H, C1-C6 alkyl or benzyl, e2 R can be H or C1-C6 alkyl. In some embodiments, e1 and R e2 Each of these can independently be H or a C1-C6 alkyl group. In some embodiments, R e1 and R e2 Each can be independently H or benzyl. In some embodiments, R e1 R can be H, methyl or benzyl, e2 This can be H or methyl. In some embodiments, R e1 can be H or methyl, and R e2 This can be H or methyl. In some embodiments, R e1 It can be methyl, R e2 This can be H or methyl. In some embodiments, R e1 It can be H or benzyl, R e2 This can be H or methyl.

[0146] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] That is the case.

[0147] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] That is the case.

[0148] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R f (is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl). In another embodiment of the compound of formula IV, R f is a C1-C8 alkyl group. In another embodiment of the compound of formula IV, R f It is 2-ethylbutyl.

[0149] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R f The group is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl. R g(Selected from C1-C8 alkyl, -O-C1-C8 alkyl, benzyl, -O-benzyl, -CH2-C3-C6 cycloalkyl, -O-CH2-C3-C6 cycloalkyl, and CF3).

[0150] A method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV. In another embodiment of the method, R 7 teeth, [ka] (In the formula, R f (is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl). In another embodiment of the compound of formula IV, R f is a C1-C8 alkyl group. In another embodiment of the compound of formula IV, R f is a C1-C6 alkyl group. In another embodiment of the compound of formula IV, R f It is 2-ethylbutyl.

[0151] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] (In the formula, R g (is selected from C1-C8 alkyl, -O-C1-C8 alkyl, benzyl, -O-benzyl, -CH2-C3-C6 cycloalkyl, -O-CH2-C3-C6 cycloalkyl and CF3). In another embodiment of the compound of formula IV, R f is a C1-C8 alkyl group. In another embodiment of the compound of formula IV, R f These are C1-C6 alkyl groups.

[0152] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] It is selected from the group consisting of the following.

[0153] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, R 7 teeth, [ka] [ka] That is the case.

[0154] Another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, is Z 1 and Z 2 Each of them is, [ka] It can be done this way.

[0155] In another embodiment, a method for treating a Coronaviridae infection in a person who needs to be treated for a Coronaviridae infection, comprising the step of administering a therapeutically effective amount of a compound of formulas I to IV, wherein R 11 or R 12 These independently include H, (C1~C8) alkyl, (C2~C8) alkenyl, (C2~C8) alkynyl, (C4~C8) carbocykylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1~C8) alkyl, and -S(O). n A method is provided in which the (C1-C8) alkyl or aryl(C1-C8) alkyl is used. In another embodiment, R 11 and R 12 Both of these, together with the nitrogen they are bonded to, form a 3- to 7-membered heterocyclic ring, and one carbon atom in the heterocyclic ring is -O-, -S-, or -NR a-and can be replaced by choice. Therefore, as an example, and not limited to, the part -NR 11 R 12 is a complex algebra: [ka] It can be expressed by, for example, [various methods].

[0156] In another embodiment, the step includes administering a therapeutically effective amount of the compound of formulas I to IV, Co A method for treating Coronaviridae infection in a person who requires treatment for Coronaviridae infection, R 3 , R 4 , R 5 , R 6 , R 11 or R 12 Each of these is independently a (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or aryl(C1-C8)alkyl, and the (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, or aryl(C1-C8)alkyl is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a Thus, a method is provided in which substitution is performed by choice. Therefore, as an example, and not limited to, R 3 , R 4 , R 5 , R 6 , R 11 or R 12 This can represent parts such as -CH(NH2)CH3, -CH(OH)CH2CH3, -CH(NH2)CH(CH3)2, -CH2CF3, -(CH2)2CH(N3)CH3, and -(CH2)6NH2.

[0157] In another embodiment, a method for treating a Coronaviridae infection in a person who needs to be treated for a Coronaviridae infection, comprising the step of administering a therapeutically effective amount of a compound of formulas I to IV, wherein R 3 , R 4 , R5 , R 6 , R 11 or R 12 The (C1-C8) alkyl group is such that one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -Therefore, a method is provided which may be replaced by choice. Thus, as an example, and not limited to, R 3 , R 4 , R 5 , R 6 , R 11 or R 12 This can represent parts such as -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2SCH3, -(CH2)6OCH3, and -(CH2)6N(CH3)2.

[0158] In another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula I, the compound is [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0159] In another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula I, the compound is [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0160] In another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, the compound is [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0161] In another embodiment of a method for treating Coronaviridae infection, comprising the step of administering a compound of formula IV, the compound is [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0162] In another embodiment of a method for treating Coronaviridae infection, comprising the step of administering compounds of formulas I to IV, the compound is [ka] [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0163] In another embodiment of a method for treating Coronaviridae infection, comprising the step of administering compounds of formulas I to IV, the compound is [ka] Or a pharmaceutically acceptable salt or ester thereof.

[0164] The methods of treatment described herein include methods for treating coronavirus infections in humans, including infections caused by alpha-coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63, New Haven coronavirus), beta-coronavirus OC43 (HCoV-OC43), HKU1, SARS-CoV (the coronavirus that causes severe acute respiratory syndrome or SARS), and MERS-CoV (the coronavirus that causes Middle East respiratory syndrome).

[0165] The names of the compounds in this disclosure are given using ACD / Name software (Advanced Chemistry Development, Inc., Toronto, Canada) for naming chemical compounds. Other compounds or radicals may be named using their common names or systematic or non-systematic names. The naming and numbering of the compounds in this disclosure are illustrated using representative compounds of formula I: [ka] This is named (2S)-2-ethylbutyl2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate. Other compounds of the present invention include: [ka] This is named (S)-2-ethylbutyl2-(((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)propanoate, [ka] This is named (S)-2-ethylbutyl2-(((R)-(((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)propanoate.

[0166] Any reference to the compounds of the present invention described herein also includes references to physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the present invention include alkali metals or alkaline earth elements (e.g., Na + Li + , K + Ca +2 and Mg +2 ), ammonium and NR4 + The formula includes salts derived from suitable bases such as (wherein R is defined herein). Physiologically acceptable salts of a nitrogen atom or amino group include (a) acid addition salts formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and (b) e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethic acid. (c) Salts formed with organic acids such as ionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, and leucine, and (c) salts formed from elemental anions, such as chlorine, bromine, and iodine. Physiologically acceptable salts of compounds with a hydroxyl group include Na + and NR4 + The anions of the compound are included in combination with suitable cations such as the following.

[0167] The compounds of formulas I to IV and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means that a crystalline compound may exist in different crystalline structures. Crystalline polymorphism may result from differences in crystalline packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means that the hydrate or solvate of a compound may exist in different crystalline structures. The pseudopolymorphs of the present invention may exist due to differences in crystalline packing (packing pseudopolymorphism) or differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of the compounds of formulas I to III, as well as their pharmaceutically acceptable salts.

[0168] The compounds of formulas I-IV and their pharmaceutically acceptable salts may also exist as amorphous solids. As used herein, an amorphous solid is a solid in which there is no long-range regularity of atomic positions. This definition also applies when the crystal size is 2 nanometers or less. The amorphous forms of the present invention can be prepared using additives, including solvents. The present invention encompasses all amorphous forms of the compounds of formulas I-IV and their pharmaceutically acceptable salts.

[0169] For therapeutic use, salts of the active ingredients of the compounds of the present invention are physiologically acceptable; that is, they are salts derived from physiologically acceptable acids or bases. However, salts of physiologically unacceptable acids or bases may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases or not, are within the scope of the present invention.

[0170] Finally, it should be understood that the compositions described herein contain the compounds of the present invention in their non-ionized and amphoteric forms, as well as in combination with stoichiometric amounts of water, as in the case of the hydrate.

[0171] It should be noted that all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of compounds within the range of formulas I-IV and their pharmaceutically acceptable salts are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0172] The compounds of the present invention, exemplified by formulas I-IV, may have a chiral center, such as a chiral carbon atom or a chiral phosphorus atom. Therefore, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Furthermore, the compounds of the present invention include enriched or fragmented optical isomers in any or all asymmetric chiral atoms. In other words, the chiral centers evident from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomer mixtures, as well as isolated or synthesized individual optical isomers substantially free of their enantiomers or diastereomer partners, are all within the scope of the present invention. The compound can be separated into its individual isomers, substantially optically pure, by well-known techniques, such as the separation of diastereomer salts formed with optically active adducts, e.g., with an acid or base, and then converted back to an optically active substance. In most cases, the desired optical isomer is synthesized by starting with a suitable stereoisomer of the desired starting material and a stereospecific reaction.

[0173] The definitions and conventions of stereochemistry used herein are generally based on SP. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York. ; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) (Year) According to JohnWiley & Sons, Inc., New York. Many organic compounds exist in optically active forms; that is, they have the ability to rotate the plane of plane polarization. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l, D and L, or (+) and (-) are used to specify the sign of the rotation of plane polarization by the compound, and S, (-), or 1 means that this compound is levorotatory, while compounds prefixed with R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Certain stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and these can occur in a chemical reaction or process when there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomer species that are not optically active.

[0174] The compounds of the present invention may also exist in some cases as tautomers. Although only one delocalized resonance structure may be illustrated, all such forms are intended to be within the scope of the present invention. For example, en-amine tautomers can exist in the case of purines, pyrimidines, imidazoles, guanidines, amidines, and tetrazoles, and all possible tautomer forms of these are within the scope of the present invention.

[0175] Any formula or structure given herein, including the compound of formula I, is also intended to represent both the unlabeled and isotope-labeled forms of the compound. The isotope-labeled compound has the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure are, but are not limited to, the following: 2H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 It contains isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotope-labeled compounds of this disclosure, for example, 3 H, 13 C and 14 These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in the treatment of patients with radioactive substances.

[0176] This disclosure also includes compounds of formula I in which 1 to n hydrogen atoms bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds have shown improved resistance to metabolism and are therefore useful for improving the half-life of any of the compounds of formula I when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. See Sci. Vol. 5 (No. 12): pp. 524-527 (1984). The compounds are synthesized by means of methods well known in this field, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0177] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits, such as greater metabolic stability, e.g., increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 1F-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the scheme or in the examples and preparations described below, by using readily available isotope-labeled reagents instead of unlabeled reagents. In this context, deuterium is understood to be a substituent in the compound of formula I.

[0178] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically indicated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise specified, where a position is specifically indicated as "H" or "hydrogen," it is understood that that position has hydrogen in its isotopic composition at its natural abundance. Therefore, in the compounds of this disclosure, any atom specifically indicated as deuterium (D) is intended to represent deuterium.

[0179] The compounds described herein have two or more of the same designated group, For example, "R" or "R 1 Whenever it is substituted with ", it should be understood that the bases may be the same or different, that is, each base is chosen independently. [ka] This indicates the site of covalent bonding to adjacent substructures, groups, parts, or atoms.

[0180] The selected substituents, including those in the compounds of formulas I-IV, exist to a recursive degree. In this context, a "recursive substituent" is a substituent that exhibits multiple examples of itself. This means that many compounds can be listed. Due to the recursive nature of such substituents, theoretically, in any given embodiment, a large number of compounds can exist. For example, R x R y Contains substituents. R y This can be denoted as R. R is Z 3 It can be done as follows: Z 3 is, Z 4 It can be done as Z 4 It can be R, or R y It may include substituents containing Z. 3 is Z 5 It can be done as Z 5 R y Substituents including can be included. Those skilled in the art of medicinal chemistry will understand that the total number of such substituents is reasonably limited by the desired properties of the compound. Such properties include, and not limited to, physical properties such as molecular weight, solubility or logP, application properties such as activity against the target, and practical properties such as ease of synthesis.

[0181] For example, and not limited to, Z 3 and R yIn certain embodiments, Z 3 It appears 0 to 8 times, R y It appears 0 to 6 times. More typically, in a given embodiment, Z 3 teeth It appears 0 to 6 times, R y It appears 0 to 4 times.

[0182] Recurrent substituents are an intended embodiment of the present invention. Those skilled in the art of medicinal chemistry will understand the versatility of such substituents. The total number of recurrent substituents is determined as described above, to the extent that they are present in one embodiment of the present invention.

[0183] The compounds of the present invention can be prepared by methods known to those skilled in the art. For example, the compounds of the present invention can be prepared according to the methods described in U.S. Patent No. 8,008,264 and U.S. Patent Publication No. 2012 / 0027752. A. Compound substitution form

[0184] The compounds of formulas I to IV are R 7 It may also contain a phosphate group, R 7 The following group is selected: a) H, -C (=O)R 11 , -C(=O)OR 11 -C(=O)NR 11 R 12 -C(=O)SR 11 ,-S(O)R 11 -S(O)2R 11 -S(O)(OR 11 ), -S(O)2(OR11 ), -SO2NR 11 R 12 (In the formula, R 11 or R 12 Each of these is independently H, (C1~C8)alkyl, (C2~C8)alkenyl, (C2~C8)alkynyl, (C4~C8)carbocykylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1~C8)alkyl, -S(O) n (C1-C8) alkyl or aryl (C1-C8) alkyl, or R 11 and R 12 Both of these, together with the nitrogen they are bonded to, form a 3- to 7-membered heterocyclic ring, and one carbon atom in any of the heterocyclic rings is -O-, -S-, or -NR a -It can be replaced by any choice, R a Each of these is independently H, (C1~C8)alkyl, (C2~C8)alkenyl, (C2~C8)alkynyl, aryl(C1~C8)alkyl, (C4~C8)carbocykylalkyl, -C(=O)R, -C(=O)OR, -C(=O)NR2, -C(=O)SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), or -SO2NR2. During the ceremony, Each R is independently H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, C6-C 20 Aryl, C6~C 20 Substituting aryls, C2~C 20 Heterocycline, C2~C 20 A substituted heterocycline, arylalkyl, or substituted arylalkyl, R 11 or R 12Each of the (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or aryl(C1-C8) alkyl groups is independently one or more halo, hydroxy, CN, N3, N(R) a )2 or OR a The substitutions are optional, and one or more of the non-terminal carbon atoms of each of the (C1-C8) alkyl groups are -O-, -S-, or -NR. a -And it may be replaced by an optional choice.) b) [ka] c) [ka] (In the formula, R c is phenyl, 1-naphthyl, 2-naphthyl [ka] Selected from, R d is H or CH3, R e1 and R e2 Each of these is independently H, C1-C6 alkyl, or benzyl. R f The group is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl. R g These are selected from C1-C8 alkyl, -O-C1-C8 alkyl, benzyl, -O-benzyl, -CH2-C3-C6 cycloalkyl, -O-CH2-C3-C6 cycloalkyl and CF3. n' is selected from 1, 2, 3 and 4) and d) The basis of the following equation: [ka] (In the formula, Q is O, S, NR, +N(O)(R), N(OR), + It is N(O)(OR) or N-NR2, Z 1 and Z 2 When combined, -Q 1 (C(R y )2)3Q 1 -and, During the ceremony, Q 1 Each of these is independently O, S, or NR. R y Each of these is independently H, F, Cl, Br, I, OH, R, -C (=Q 2 )R, -C(=Q 2 )OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 2 )R, -OC(=Q 2 )OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 )OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 )OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, -OR, or Z 3 If they are together, then two Rs on the same carbon atom y It forms a carbocyclic ring consisting of 3 to 7 carbon atoms. death, Q 2 These are O, S, NR, and each is independent. + N(O)(R), N(OR), + N(O)(OR) or N-NR2, or Z 1 and Z 2 These are, independently, the basis of equation Ia: [ka] And, During the ceremony, Q 3 Each of these is independently of the bond, O, CR2, NR, + N(O)(R), N(OR), + N(O)(OR), N-NR2, S, SS, S(O), or S(O)2, M2 is 0, 1, or 2. R x Each of them is independent of R y , or the following formula: [ka] And, During the ceremony, M1a, M1c, and M1d are each independently either 0 or 1. M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. Z 3 is, Z 4 or Z 5 And, Z 4 is R, -C(Q 2 )R y , -C(Q 2 )Z 5 , -SO2R y or -SO2Z 5 And, Z 5 is a carbon ring or heterocycle, Z 5 This is 0 to 3 R y (It is independently substituted in the base.)

[0185] Z 5 Carbon ring and Z 5 A complex algebra is a set of 0 to 3 R's. y It may be independently substituted by the base. Z 5 This can be a saturated, unsaturated, or aromatic ring containing a monocyclic or bicyclic carbocyclic ring or a monocyclic or bicyclic heterocyclic ring. 5 It can have 3 to 10 ring atoms, for example, 3 to 7 ring atoms. 5A ring is saturated if it contains three ring atoms, saturated or monounsaturated if it contains four ring atoms, saturated, monounsaturated or diunsaturated if it contains five ring atoms, and saturated, monounsaturated or diunsaturated or aromatic if it contains six ring atoms.

[0186] Z 5 A heterocycle consists of 3 to 7 ring members (2 to 6 carbon atoms, as well as N, O, P, and S). It can be a monoring having 1 to 3 heteroatoms selected from, or a diring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). 5 A heterocyclic monocycle may have 3 to 6 ring atoms (2 to 5 carbon atoms, plus 1 to 2 heteroatoms selected from N, O, and S) or 5 or 6 ring atoms (3 to 5 carbon atoms, plus 1 to 2 heteroatoms selected from N and S). 5 A heterocyclic biring has 7 to 10 ring atoms (6 to 9 carbon atoms, plus 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms, plus 1 to 2 heteroatoms selected from N and S) arranged as a bicyclo[5,6] or [6,6] system. 5 Heterocycles are formed by stable covalent bonds between carbon, nitrogen, sulfur, or other atoms via Q 2 They may be bound together.

[0187] Z 5 Heterocycles include, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. 5 Also, but not limited to the following, [ka] Examples include the following.

[0188] Z 5 As defined above, the carbocyclic and heterocyclic rings may be independently substituted with 0 to 3 R groups. For example, substitution Z 5 The carbon ring is, [ka] Includes.

[0189] An example of a substituted phenyl carbon ring is, [ka] Includes.

[0190] In another embodiment, compound Z of formulas I to IV 5 is a carbon ring or heterocycle, Z 5 This is 0 to 3 R z It is independently substituted at the base, R z These are H, F, Cl, Br, I, OH, R, -C (=Q) independently of each other. 2 )R, -C(=Q 2 )OR, -C(=Q 2 )N(R)2, -N(R)2, - + N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q 1 )R, -OC(=Q 2 )OR, -OC(=Q 2 )(N(R)2), -SC(=Q 2 )R, -SC(=Q 2 )OR, -SC(=Q 2 )(N(R)2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 )OR, -N(R)C(=Q 2 )N(R)2, -SO2NR2, -CN, -N3, -NO2, or -OR.

[0191] Compounds of formulas I-IV [ka] The embodiments are, [ka] (In the formula, Q 3b Each of these independently includes a substructure such as O or N(R). In another aspect of this embodiment, Q 3b Each of these is O, and R x Each of them is independent [ka] (In the formula, M12c is 1, 2 or 3, Q 3 Each of these is independently a bond, O, CR2, or S. In another aspect of this embodiment, one of Q 3b -R x NH(R) and the other Q 3b -R x is OR x And R x teeth, [ka] (wherein M12c is 2) In another aspect of this embodiment, Q 3b Each of these is O, and R x Each of them is independent [ka] (wherein M12c is 2) In another aspect of this embodiment, Q 3b Each of these is O, and R x Each of them is independent [ka] (In the formula, M12c is 1, Q 3 This is a bond (O or CR2).

[0192] Compounds of formulas I-IV [ka] Other embodiments include: [ka] (In the formula, Q 3 Each of these independently includes a substructure such as O or N(R). In another aspect of this embodiment, Q 3 Each of these is O. In another aspect of this embodiment, the substructure is [ka] (In the formula, R y Z as defined herein 5 It is.

[0193] Equations I to IV [ka] Another embodiment of the following substructure: [ka] (In the formula, Q 2c Each of these is independent of O, N(R) y Includes ) or S).

[0194] Compounds of formulas I-IV [ka] Another embodiment of is Z 1 or Z 2 One of them is R 3 or R 4 Together with one of them, -Q 3 -and then, Z 1 or Z 2 The other side includes a substructure which is formula Ia. Such embodiments include [ka] It is represented by a compound of formula Ib selected from the following.

[0195] In another embodiment of the formula Ib, Q and Q 3 Each of these is O. In another embodiment of the embodiment of formula Ib, Z 1 or Z 2 Q 3b -R x Q, Q 3 and Q 3b Each of these is O, and R x teeth, [ka] (In the formula, M12c is 1, 2 or 3, Q 3 Each of these is independently a bond, O, CR2, or S). In another embodiment of the embodiment of formula Ib, Z 1 or Z 2 Q 3b -R x Q, Q 3 and Q 3b Each of these is O, and R x teeth, [ka] (wherein M12c is 2). In another embodiment of the Ib embodiment, Z 1 or Z 2 Q 3b -R x Q, Q 3 and Q 3b Each of these is O, and R x teeth, [ka] (In the formula, M12c is 1, Q 3 This is a bond (O or CR2).

[0196] Compounds of formulas I-IV [ka] Another embodiment of the following substructure: [ka] (In the formula, Z 5 (is a carbon ring such as phenyl or substituted phenyl). In another embodiment of this embodiment, the substructure is [ka] (In the formula, Q 3b is O or N(R), and the phenyl carbon ring is substituted with 0 to 3 R groups. In another embodiment of this substructure, R x teeth, [ka] (In the formula, M12c is 1, 2 or 3, Q 3 Each of these is independently a bond (O, CR2, or S).

[0197] Equations I to IV [ka] Another embodiment of the following substructure: [ka] Includes.

[0198] The chiral carbons of the amino acids and lactate moieties can be either R or S configurations, or a racemic mixture.

[0199] Equations I to IV [ka] Another embodiment of the following substructure: [ka] (In the formula, Q 3 Each of these is independently -O- or -NH-). In another aspect of this embodiment, R y (C1~C8) alkyl, (C1~C8) substituted alkyl, ( The C2-C8 alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, or (C2-C8) substituted alkynyl. In another aspect of this embodiment, R y is a (C1-C8) alkyl, a (C1-C8) substituted alkyl, a (C2-C8) alkenyl, a (C2-C8) substituted alkenyl, a (C2-C8) alkynyl, or a (C2-C8) substituted alkynyl, and R is CH3. In another embodiment of this embodiment, R y is a (C1-C8) alkyl, a (C1-C8) substituted alkyl, a (C2-C8) alkenyl, a (C2-C8) substituted alkenyl, a (C2-C8) alkynyl, or a (C2-C8) substituted alkynyl, where R is CH3 and Q 3 Each of these is -NH-. In another embodiment of this design, Z 1 and Z 2 Z is an independently nitrogen-linked, naturally occurring amino acid or naturally occurring amino acid ester. In another embodiment of this embodiment, Z 1 and Z 2 These are independently naturally occurring 2-hydroxycarboxylic acids or naturally occurring 2-hydroxycarboxylic acid esters, where the acid or ester is linked to P via a 2-hydroxyl group.

[0200] Equations I to IV [ka] Another embodiment of the following substructure: [ka] That is the case.

[0201] In one aspect of this embodiment, R x Each of these is independently a (C1-C8) alkyl. In another aspect of this embodiment, R x Each of these is independent of C6~C 20 Aryl or C6~C 20 It is a substitution aryl.

[0202] In a preferred embodiment, [ka] teeth, [ka] Selected from.

[0203] R x Embodiments include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups: [ka] Includes. B. Metabolites of the compound of the present invention

[0204] Similarly, in vivo metabolites of compounds described herein fall within the scope of the present invention, provided that such products are novel and not obvious compared to the prior art. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, and esterification of the administered compound, primarily by enzymatic processes. Accordingly, the present invention includes novel and non-obvious compounds produced by processes comprising the step of contacting the compounds of the present invention with a mammal for a period sufficient to produce its metabolites. Such products are typically radiolabeled (e.g., 14 C or 3H) The compounds of the present invention are prepared, administered parenterally to animals such as rats, mice, guinea pigs, monkeys, or humans in a detectable dose (e.g., greater than about 0.5 mg / kg), given sufficient time for metabolism to occur (usually about 30 seconds to 30 hours), and identified by isolating the conversion products of the compounds from urine, blood, or other biological samples. These products are labeled and therefore easily isolated (others are isolated by using antibodies capable of binding to epitopes that survive in the metabolites). The structure of the metabolites is determined in a conventional manner, e.g., by MS or NMR analysis. Generally, the analysis of metabolites is carried out in the same manner as in conventional drug metabolism studies well known to those skilled in the art. The conversion products are useful in diagnostic assays for therapeutic administration of the compounds of the present invention, even if they themselves do not possess anti-arenaviridae activity, unless otherwise found in vivo.

[0205] Formulations and methods for determining the stability of compounds in gastrointestinal secretions are known. Compounds are defined herein as being stable in the gastrointestinal tract, meaning that when incubated in intestinal fluid or gastric juice at 37°C for 1 hour, less than approximately 50 mole percent of the protecting group is deprotected. The mere fact that a compound is stable in the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. While the prodrugs of the present invention are generally stable in the digestive system, they can be substantially hydrolyzed to the parent drug in the gastrointestinal lumen, liver, or other metabolic organs, or generally intracellularly. III. Pharmaceutical Preparations

[0206] The compounds of the present invention are formulated with conventional carriers and additives, selected according to standard procedures. The tablets contain additives, flow enhancers, fillers, and binders, etc. Aqueous formulations are generally isotonic when prepared in sterile form and intended for delivery by means other than oral administration. All formulations are described in the "Handbook of Pharmaceutical Excipients" (1 The formulation optionally contains additives such as those described in 986. Additives include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, and hydroxyalkylmethylcellulose, and stearic acid. The pH of the formulation is in the range of about 3 to about 11, but is usually about 7 to 10. In some embodiments, the pH of the formulation is in the range of about 2 to about 5, but is usually about 3 to 4.

[0207] While the active ingredients can be administered individually, it is sometimes preferable to provide them as pharmaceutical formulations. For both veterinary and human use, the formulations of the present invention also comprise at least one of the active ingredients defined above, together with one or more acceptable carriers for the formulations, and optionally other therapeutic components, in particular additional such therapeutic components discussed herein. The carrier(s) must be “acceptable” in the sense that they are compatible with the other components of the formulation and are physiologically harmless to its recipient.

[0208] The formulations include formulations suitable for the above-mentioned routes of administration. The formulations may be conveniently provided in unit dosage forms and may be prepared by any method well known in the pharmaceutical field. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (MackPublishing Co., Easton, PA). Such methods involve the active ingredient and one or more formulations. The process includes a step of combining the auxiliary components with the carriers that make up the auxiliary components. Generally, formulations are prepared by uniformly and closely combining the active ingredient with a liquid carrier or a micronized solid carrier, or both, and then, if necessary, molding it into a product.

[0209] Formulations of the present invention suitable for oral administration may be provided as separate units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be administered as a bolus, lick, or paste.

[0210] Tablets are prepared by compression or molding, optionally with one or more auxiliary components. Compressed tablets can optionally be prepared by compressing an active ingredient in a fluid form, such as powder or granules, mixed with a binder, lubricant, inert excipient, preservative, surfactant, or dispersant, using a suitable machine. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid excipient, using a suitable machine. Tablets may optionally be coated or imprinted, and may optionally be formulated to provide delayed or controlled release of the active ingredient from the tablet.

[0211] In cases of infection of the eyes or other external tissues, such as the oral cavity and skin, the formulation is preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w (including, for example, 0.6% w / w, 0.7% w / w increments, with a range of 0.1% to 20% active ingredient(s)), preferably 0.2 to 15% w / w, most preferably 0.5 to 10% w / w. When formulated as an ointment, the active ingredient can be used with either a paraffin-miscible or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base.

[0212] If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations may preferably contain compounds that facilitate the absorption or penetration of the active ingredient from the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0213] The oil phase of the emulsion of the present invention may be composed of known components in a known manner. This phase may include a mere emulsifier (also known as an emulsion), but preferably includes at least one emulsifier and a fat or oil, or a mixture of both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both oil and fat. Emulsifiers (or others) with or without stabilizers collectively constitute a so-called emulsifying wax, and the wax together with oil and fat constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of a cream formulation.

[0214] Suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Further suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include Tween® 80.

[0215] The selection of oils or fats suitable for formulations is based on the realization of desired aesthetic properties. The cream should have a viscosity suitable for avoiding leakage from tubes or other containers, preferably non-greasy, stain-free, and washable. Linear or branched monobasic or dibasic alkyl esters such as diisoadipates, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, and 2-ethylhexyl palmitate, or blends of branched esters known as Crodamol CAP, the latter three being preferred esters, may be used. These may be used alone or in combination, depending on the required properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin, or other mineral oils may be used.

[0216] The pharmaceutical formulations according to the present invention include one or more pharmaceutically acceptable carriers or additives, and combinations according to the present invention with other therapeutic agents of any choice. The pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used orally, for example, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules. Formulations, syrups, or elixirs may be prepared. Compositions intended for oral use are pharmaceuticals. The composition may be prepared according to any method known in the art for the manufacture of the composition, and such composition may contain one or more activators, including sweeteners, flavorings, colorings, and preservatives, to produce a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable additives suitable for the manufacture of tablets are acceptable. These additives may be, for example, inert excipients such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby achieving a longer duration of action. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0217] Oral formulations may also be provided as rigid gelatin capsules in which the active ingredient is mixed with an inert solid excipient, such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil.

[0218] The aqueous suspension of the present invention contains an active substance in a mixture with additives suitable for the production of aqueous suspensions. Such additives include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin); condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate); condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol); and condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin. Furthermore, non-limiting examples of suspending agents include cyclodextrin and Captisol (= sulfobutyl ether beta-cyclodextrin; SEB-beta-CD).

[0219] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those mentioned above, can be added to produce an oral preparation with a pleasant mouthfeel. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0220] The dispersible powders, powders, and granules of the present invention, suitable for preparing aqueous suspensions by adding water, provide an active ingredient in a mixture of a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Further additives, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0221] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include acacia gum and tragacanthognatha. These include naturally occurring gums such as um, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids, hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxides such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, or colorings.

[0222] The pharmaceutical compositions of the present invention may also be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. These suspensions can be formulated according to known techniques using such suitable dispersants or wetting agents and suspending agents as mentioned above. The sterile injectable preparations may also be sterile solutions or suspensions for injection in non-toxic, parenterally acceptable excipients or solvents, such as solutions in 1,3-butane-diol, or they may be prepared as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils can be conventionally used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic mono or diglycerides, may be used. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injectable preparations. Acceptable vehicles and solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0223] The amount of active ingredient that can be combined with a carrier substance to produce a single dosage form varies depending on the host being treated and the specific mode of administration. For example, a sustained-release formulation for oral administration to humans may contain about 1 to 1000 mg of active ingredient mixed with an appropriate and convenient amount of carrier substance, which can vary from about 5 to about 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to supply an easily measurable amount for administration. For example, an aqueous solution for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to allow for the injection of a suitable volume at a rate of about 30 mL / hour.

[0224] Formulations suitable for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a carrier suitable for the active ingredient, particularly in an aqueous solvent. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, preferably 0.5 to 10%, and especially about 1.5% w / w.

[0225] Formulations suitable for topical administration in the oral cavity include flavored bases, lozenges containing the active ingredient typically in sucrose and acacia or tragacanth, pastels containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia, and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0226] The rectal formulation may be provided as a suppository containing, for example, a suitable base including cocoa butter or salicylate.

[0227] Formulations suitable for intrapulmonary or nasal administration have particle sizes ranging from 0.1 to 500 microns, such as 0.5, 1, 30, and 35 microns, and are administered by rapid inhalation through the nasal passage or by oral inhalation to reach the alveolar sacs. Suitable formulations include aqueous or oily liquid formulations of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods. It can be delivered together with other therapeutic agents, such as compounds already used in the treatment or prevention of Arenaviridae infections, as described below.

[0228] Formulations suitable for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, containing, in addition to the active ingredient, such carriers known to be suitable in the art.

[0229] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0230] The formulations are provided in unit dose or multi-dose containers, for example, in sealed ampoules and vials, and can be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Immediate injection solutions and suspensions are prepared from the types of sterile powders, granules, and tablets already described. Preferred unit dose formulations contain the daily dose or unit daily sub-dose of the active ingredient, or an appropriate fraction thereof, as listed above herein.

[0231] In particular, in addition to the components mentioned above, the formulations of the present invention may include other agents commonly used in the art with respect to the type of formulation in question. For example, an agent suitable for oral administration may include a flavoring agent.

[0232] The present invention further provides a veterinary composition comprising at least one active ingredient as defined above, together with a veterinary carrier therefor.

[0233] The veterinary carrier is a substance useful for administering the composition and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0234] The present invention provides a controlled-release pharmaceutical formulation ("controlled-release formulation") containing one or more of the compounds of the present invention as an active ingredient, wherein the release of the active ingredient is controlled and regulated to enable a lower administration frequency or to improve the pharmacokinetic or toxicity profile of a given active ingredient. IV. Route of administration

[0235] One or more compounds of the present invention (hereinafter referred to as active ingredients) are administered by any route suitable for the condition being treated. Preferred routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that preferred routes may vary, for example, depending on the recipient's condition. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0236] In the method of the present invention for treating Arenaviridae infection, the compounds of the present invention can be administered at any point in time to a person who has an Arenaviridae infection or a person who may come into contact with a person who has already had an Arenaviridae infection. In some embodiments, the compounds of the present invention can be administered prophylactically to a person who comes into contact with a person who has an Arenaviridae infection. In some embodiments, the compounds of the present invention can be administered to a person who has tested positive for Arenaviridae infection but has not yet shown symptoms of Arenaviridae infection. In some embodiments, the compounds of the present invention can be administered to a person at the onset of symptoms of Arenaviridae infection.

[0237] The effective dose of the active ingredient is determined by the clinician using conventional dose-escalation studies, depending at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (low dose) or for active viral infections, the method of delivery, and the pharmaceutical formulation. The effective dose can be expected to be about 0.0001 to about 100 mg / kg body weight per day, generally about 0.01 to about 10 mg / kg body weight per day, more generally about 0.01 to about 5 mg / kg body weight per day, and most commonly about 0.05 to about 0.5 mg / kg body weight per day. For example, a candidate daily dose for an adult weighing about 70 kg would be in the range of 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and can be in the form of a single dose or multiple doses.

[0238] The effective dose of the compound of the present invention for treating Arenaviridae infection may depend on whether the dose is to be used prophylactically or to treat a person already infected with Arenaviridae. Furthermore, this dose may depend on whether the person infected with Arenaviridae is not yet showing symptoms or is already showing symptoms of Arenaviridae infection. Compared to a person receiving prophylactic treatment, a higher dose may be required when treating a person who tests positive for Arenaviridae infection and when treating a person showing symptoms of Arenaviridae infection.

[0239] Any preferred duration for administering the compound of the present invention is intended. For example, administration can range from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Administration can also range from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer durations of administration are also intended. The administration time may depend on whether the compound is administered prophylactically or to treat a person infected with Arenaviridae. For example, prophylactic administration can be during periods of regular contact between a person and other persons infected with Arenaviridae, and during preferred periods after the last contact with a person infected with Arenaviridae. In individuals already infected with Arenaviridae, the duration of administration can be any length of time necessary to treat the patient, and a suitable period after a negative test for Arenaviridae infection to ensure that there is no relapse into Arenaviridae infection. V. Combination Therapy

[0240] The compositions of the present invention may also be used in combination with other active ingredients. In the case of treating Arenaviridae virus infections, preferably other active therapeutic agents are active against Arenaviridae virus infections, particularly Lassa virus infection and Junin virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof. The compounds and compositions of the present invention also include parenteral fluids (including dextrose saline and Ringer's lactate solution) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime), and / or antifungal prophylactic agents, antipyretics and analgesics, antiemetics (such as metoclopramide), and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and antimalarial agents (including artemether and artesunate-lumefantrine combination therapy), typhoid fever (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or bacterial dysentery, etc., for patients. It is also intended to be used in conjunction with general care given to patients with Arenaviridae virus infections, including medications for other common illnesses in the population.

[0241] For simultaneous or sequential administration to patients, any compound of the present invention may be combined with one or more additional active therapeutic agents in a unit dosage form. The combination therapy may be administered as a simultaneous or sequential regimen. In the case of sequential administration, the combination may be administered in two or more doses.

[0242] Co-administration of the compound of the present invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of the compound of the present invention and one or more other active therapeutic agents such that therapeutically effective amounts of both are present in the patient's body.

[0243] Co-administration includes administering a unit dose of the compound of the present invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the present invention within seconds, minutes, or hours after administering one or more other active therapeutic agents. For example, a unit dose of the compound of the present invention may be administered first, followed by a unit dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, followed by a unit dose of the compound of the present invention within seconds or minutes. In some cases, it may be preferable to administer a unit dose of the compound of the present invention first, followed by a unit dose of one or more other active therapeutic agents after a period of time (e.g., 1 to 12 hours). In other cases, it may be preferable to administer a unit dose of one or more other active therapeutic agents first, followed by a unit dose of the compound of the present invention after a period of time (e.g., 1 to 12 hours).

[0244] Combination therapy can achieve "synergistic effects" and "synergy." That is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced when the compounds are used individually. Synergistic effects can be achieved when the active ingredients are (1) administered as a co-formulation or delivered simultaneously in a combination formulation, (2) delivered alternately or in parallel as individual formulations, or (3) as part of some other regimen. When delivered in alternating therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, in individual tablets, pills or capsules, or by different injections in individual syringes. Generally, in alternating therapy, effective doses of each active ingredient are administered sequentially, i.e., consecutively, whereas in combination therapy, effective doses of two or more active ingredients are administered together. A synergistic antiviral effect means that the antiviral effect is greater than the expected purely additive effect of the individual compounds in the combination.

[0245] In yet another embodiment, the present application provides a method for inhibiting Arenaviridae polymerase in cells, comprising contacting cells infected with arenavirus with an effective amount of a compound of formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, thereby inhibiting Arenaviridae polymerase.

[0246] In yet another embodiment, the present application provides a method for inhibiting arenaviridae polymerase in cells, comprising contacting cells infected with arenavirus with an effective amount of a compound of formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional active therapeutic agent, thereby inhibiting arenaviridae polymerase.

[0247] In yet another embodiment, the present application provides a method for inhibiting Arenaviridae polymerase in cells, comprising contacting cells infected with the Arenaviridae virus with an effective amount of a compound of formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and at least one additional selected active therapeutic agent.

[0248] In yet another embodiment, the present application provides a method for treating Arenaviridae virus infection in humans, comprising the step of administering to a patient a therapeutically effective amount of a compound of formulas I to IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof.

[0249] In yet another embodiment, the present application provides a method for treating an Arenaviridae virus infection in a human, comprising administering to a patient a therapeutically effective amount of a compound of formulas I to IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, as well as at least one additional active therapeutic agent, thereby inhibiting Arenaviridae polymerase.

[0250] In yet another embodiment, the present application provides a method for treating a human Arenaviridae virus infection, comprising the step of administering to a patient a therapeutically effective amount of a compound of formulas I to IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof, as well as at least one additional active therapeutic agent.

[0251] Similarly, kits are provided that include compounds of formula I, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, stereoisomers thereof, or mixtures of stereoisomers or tautomers thereof. In individual embodiments, individual kits are provided that include compounds selected from each of the formulas and their subgroups and each group of embodiments herein, including formula II, formula IV, and individual compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32 (compounds 1-32), or pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, stereoisomers thereof, or mixtures of stereoisomers or tautomers thereof. In one embodiment, the kit includes compounds of formula I or pharmaceutically acceptable salts thereof. Each of the individual kits described herein may include a label and / or instructions relating to the use of the compound in the treatment of a disease or condition in a subject (e.g., a human) requiring treatment of the disease or condition. In some embodiments, the disease or condition is a human Arenaviridae virus infection, including Lassa virus infection or Junin virus infection. In other embodiments, each individual kit may also include instructions relating to the use of additional pharmaceuticals in combination with the compound of Formula I in the treatment of a disease or condition in a subject (e.g., a human) requiring it. In some of these embodiments, the disease or condition is a human Arenaviridae virus infection, including Lassa virus infection or Junin virus infection. Further embodiments exist in which each of the kits described herein includes individual dose units of the compound described herein, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates thereof.Examples of individual dose units may include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, etc., each containing a therapeutically effective dose of the compound, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kit may contain single-dose units, in other embodiments, etc. Multiple dose units exist, such as the number of dose units required for a defined regimen or period.

[0252] Similarly, manufactured articles and containers are also provided, comprising compounds of formula I, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, stereoisomers thereof, or mixtures of stereoisomers or tautomers thereof. In one embodiment, the manufactured article comprises formula I, formula II, formula IV and individual compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and 32 (compounds 1-32), or pharmaceutically acceptable salts thereof, and containers. In individual embodiments, the containers for the manufactured article include vials, wide-mouthed bottles, ampoules, preloaded syringes, blister packaging, tinplate It can be a flat container, can, bottle, box, or intravenous bag. Similarly, the use of each of the formulas herein, as well as compounds selected from each subgroup and its embodiments, in the preparation of pharmaceuticals for use in the treatment of Arenaviridae infections in humans, including compounds selected from one group of specific compounds of the Examples herein, including formulas (I), (II), (III), (IV), or compounds 1-32, or pharmaceutically acceptable salts, solvates, and / or esters thereof. VI. Methods for inhibiting arenaviridae polymerase

[0253] Another aspect of the present invention relates to a method for inhibiting arenaviridae polymerase activity, comprising the step of treating a sample suspected to contain arenaviridae with a compound or composition of the present invention.

[0254] The arenaviruses that can be treated using the method of the present invention are single-stranded negative sense RNA viruses that typically infect primates. Arenaviruses can replicate in substantially all cell types. Based on studies in non-human primates infected with Lassa virus, the initial cells infected appear to be dendritic cells in lymphoid tissue. Infection progresses to Kupffer cells in the liver, as well as parenchymal cells in the liver and adrenal glands, endothelial cells in various tissues including nerve tissue, and ultimately to epithelial infection. Evidence of liver infection leading to hepatitis in humans has also been established (Hensley, L., 2011, Virology Journal; Yun, NE, 2012, Viruses). Thirty species of arenaviruses have been identified: Allpahuayo virus (ALLV), Amaparivirus (AMAV), Bear Canyon virus (BCNV), Catalinavirus, Chaparevirus, Cupixi virus (CPXV), Dandenone virus, Flexal virus (FLEV), Guanaritovirus (GTOV), IPPY virus (IPPYV), Junin virus (JUNV), Kodcovirus, Lassa virus (LASV; 6 strains, namely Josiah, NL, z148, Macenta, AV, and CSF). ), latinovirus (LATV), lymphocytic choriomeningitis virus (LCMV), lujovirus, machupovirus (MACV), mobaravirus (MOBV), morogorovirus, mopeavirus (MOPV), oliverosvirus (OLVV), paranavirus (PARV), pikindevirus (PICV), pinhar virus, pyritalvirus (PIRV), sabiavirus (SABV), skinnertank virus, takaribevirus (TCRV), tamiramivirus (TAMV), or whitewater arroyovirus (WWAV). Arenavirus virions are heterogeneous structures ranging in size from 40 to over 200 nm in diameter, consisting of nucleocapsids surrounded by a lipid envelope. Electron micrographs of the inside of virions show a characteristic granular appearance due to the incorporation of host cell ribosomes into the viral particle during construction. The arenavirus genome consists of two single-stranded R The NA segment consists of a subsegment (S) and a macrosegment (L). Both genomic segments have an ambisense gene configuration, encoding two genes with opposite orientations. The L RNA (approximately 7 kb) encodes viral RNA-dependent RNA polymerase (L) and small RING zinc finger-binding protein (Z). The S RNA (approximately 3.4 kb) encodes glycoprotein precursor protein (GPC) and nucleoprotein (NP). Posttranslation, the GPC cleaves to produce two envelope glycoproteins, GP1 and GP2, as well as a stable signal peptide (SSP) (Yun, NE, 2012, Viruses).

[0255] The compositions of the present invention can act as inhibitors of arenavirus polymerase, as intermediates for such inhibitors, or have other uses as described below. These inhibitors bind to a position on the surface or in a cavity of the arenaviridae polymerase, having a shape specific to arenaviridae polymerase. The compositions that bind to arenaviridae polymerase can bind to varying degrees of reversibility. Compounds that bind substantially irreversibly are ideal candidates for use in this method of the present invention. Once labeled, compositions that bind substantially irreversibly are useful as probes for detecting arenaviridae polymerase. Therefore, the present invention relates to a method for detecting arenaviridae polymerase in a sample suspected to contain arenaviridae polymerase, comprising the steps of: treating the sample suspected to contain arenaviridae polymerase with a composition containing a compound of the present invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels include those well known in the diagnostic field and stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups, and chromogens. The compounds described herein are labeled in the conventional manner using functional groups such as hydroxyl, carboxyl, sulfidyl, or amino.

[0256] In the context of this invention, samples suspected of containing arenaviridae polymerase include natural or artificial substances, such as biological samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.) such as living organisms, tissues or cell cultures, and samples of biological materials, as well as laboratory samples, food, water or air samples, and bioproduct samples such as cell extracts, in particular recombinant cells that synthesize desired glycoproteins. Typically, these samples are suspected of containing organisms that produce arenaviridae polymerase, often pathogenic organisms such as arenaviridae viruses. Samples may be contained in any medium, including water and organic solvent / water mixtures. Samples include living organisms such as humans and artificial substances such as cell cultures.

[0257] The treatment step of the present invention includes adding the composition of the present invention to a sample, or adding a precursor of the composition to a sample. Additional steps include any of the above-described administration methods.

[0258] If desired, the activity of Arenaviridae polymerase after application of this composition can be observed by any method, including direct and indirect methods for detecting Arenaviridae polymerase activity. All quantitative, qualitative, and semi-quantitative methods for determining Arenaviridae polymerase activity are intended. Typically, one of the above screening methods is applied, but any other method is applicable, such as observing the physiological characteristics of living organisms.

[0259] Organisms containing Arenaviridae polymerase include Arenaviridae viruses. The compounds of the present invention are useful in the treatment or prevention of Arenaviridae infections in animals or humans.

[0260] However, it should be noted that in screening compounds that can inhibit human Arenaviridae viruses, the results of enzyme assays may not correlate with those of cell culture assays. Therefore, cell-based assays should be used as a primary screening method.

[0261] In another embodiment, the present application provides a method for treating an Arenaviridae virus infection in a human, comprising the step of administering to a patient a therapeutically effective amount of a compound of formulas I-IV, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. In some embodiments, the Arenaviridae infection is caused by an Arenaviridae virus. In some embodiments, the Arenaviridae infection is caused by a Junin virus. In some embodiments, the Arenaviridae infection is caused by a Lassa virus strain, such as Josiah, NL, z148, Macenta, AV, or CSF. In some embodiments, Arenaviridae polymerase is inhibited.

[0262] The compounds of the present invention can be used in the treatment of humans already suffering from Arenaviridae infection, or can be administered prophylactically to reduce or prevent the opportunity for Arenaviridae infection. Physical examination of patients infected with arenavirus often presents with purulent pharyngitis, bilateral conjunctival hemorrhage, facial edema, and generalized abdominal tenderness after the onset of fever. Macroscopic pathological changes may include pleural effusion, pulmonary edema, ascites, and bleeding symptoms of the gastrointestinal mucosa. Mortality rates for hospitalized patients vary between 5 and 10%. VII. Screening of Arenaviridae polymerase inhibitors.

[0263] The compositions of the present invention are screened for inhibitory activity against Arenaviridae polymerase by any of the conventional techniques for evaluating enzyme activity. In the context of the present invention, compositions are typically first screened in vitro for inhibition of Arenaviridae polymerase, and then screened for in vivo activity if they exhibit inhibitory activity. Approximately 5 × 10 -6 Less than M, preferably about 1 × 10 -7 Compositions having an in vitro Ki (inhibitory constant) of less than M are preferred for in vivo use.

[0264] Useful in vitro screening methods are described in detail elsewhere and will not be described in detail here. However, this example describes a suitable in vitro assay. VIII. Preparation of Compounds

[0265] The compounds of the present invention can be prepared by various means. For example, the protected nucleoside of formula V can be prepared by the reaction of a protected lactone with an iodine-substituted base under suitable coupling conditions. The nucleoside is then modified with a prodrug moiety by the reaction of the partially protected nucleoside with a suitable prodrug moiety, and then the protecting group is removed to obtain the compounds of the present invention. A. Preparation of nucleosides using iodine bases

[0266] In some embodiments, the present invention relates to a compound of formula V: [ka] A method for preparing the compound of formula V is provided. The method for preparing the compound of formula V is to use a coupling agent, a halo-silane, and the compound of formula VI under conditions suitable for preparing the compound of formula V: [ka] and compounds of formula VII: [ka] The process includes the step of forming a reaction mixture having the following: where each PG is independently a hydroxy protecting group, or two PG groups on adjacent carbons are combined to form -C(R 19 )2-groups can be formed, R 10 is H or a silyl group, and R 19 This is H, C1-C8 alkyl, phenyl, or substituted phenyl.

[0267] In the method for preparing the compound of formula V, any suitable coupling agent can be used. The coupling agent may be a lithium coupling agent, a sodium coupling agent, a magnesium coupling agent, or others. For example, the coupling agent may be a deprotonating agent such as n-butyllithium (n-BuLi), sodium hydride (NaH), and lithium aluminum hydride (LAH or LiAlH4). The coupling agent may also be a magnesium-based coupling agent such as MgCl2, iPrMgCl, tBuMgCl, PhMgCl, or a combination thereof, but is not limited to the following. In some embodiments, the coupling agent may be a lithium coupling agent or a magnesium coupling agent. In some embodiments, the coupling agent may be n-BuLi, MgCl2, iPrMgCl, tBuMgCl, PhMgCl, or a combination thereof. In some embodiments, the coupling agent may be n-BuLi. In some embodiments, the coupling agent may be PhMgCl and iPrMgCl.

[0268] 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 equivalent (mol / mol) relative to the compound of formula V, such as 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) relative to the compound of formula V, such as 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) relative to 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) relative to the compound of formula V.

[0269] In the method for preparing the compound of formula V, any suitable halo-silane can be used. For example, the halo-silane can be a fluorosilane, chlorosilane, bromosilane, or iodosilane. The silane moiety can have any suitable substituent, such as alkyl, alkenyl, alkynyl, cycloalkyl, or phenyl. Exemplary halo-silanes include, but are not limited to, Cl-Si(CH3)3 or Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl. In some embodiments, the halo-silane can be a chlorosilane. In some embodiments, the halo-silane can be Cl-Si(CH3)3 or Cl-Si(CH3)2CH2CH2Si(CH3)2-Cl. In some embodiments, the halo-silane can be TMS-Cl.

[0270] R 10 The silyl group can be any suitable group, but this depends on the choice of halo-silane. For example, if the halo-silane is TMS-Cl, the silyl group can be trimethylsilyl.

[0271] Halo-silane can be present in any suitable amount. For example, halo-silane can be present in an amount of at least 1.0 equivalent (mol / mol) relative to the compound of formula V, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9 or about 10.0 equivalents (mol / mol). Halo-silane can also be present in an amount of about 1.0 to about 10.0 equivalents (mol / mol) relative to the compound of formula V, such as about 1.0 to about 5.0 equivalents (mol / mol) or about 1.0 to about 2.0 equivalents (mol / mol). In some embodiments, halo-silane can be present in an amount of about 1.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula V. In some embodiments, halo-silane can be present in an amount of about 1.0 to about 2.0 equivalents (mol / mol) relative to the compound of formula V.

[0272] The hydroxyl protecting group can be any protecting group suitable for the hydroxyl functional group. Typical hydroxyl protecting groups include, but are not limited to, silanes such as trimethylsilane (TMS), t-butyldimethylsilane (TBDMS), or t-butyldiphenylsilane (TBDPS); ethers such as methyl-methoxy (MOM), tetrahydropyran (THP), t-butyl, allyl, or benzyl; and esters such as acetyl, pivaloyl, or benzoyl. In some embodiments, the hydroxyl protecting group may be trimethylsilane (TMS), t-butyldimethylsilane (TBDMS), t-butyldiphenylsilane (TBDPS), methyl-methoxy (MOM), tetrahydropyran (THP), t-butyl, allyl, benzyl, acetyl, pivaloyl, or benzoyl. In some embodiments, the hydroxyl protecting group may be benzyl.

[0273] A hydroxyl group on an adjacent carbon, referred to as a 1,2-hydroxyl group, can form a cyclic protecting group called an acetonide through the reaction of a ketone with a diether. Exemplary acetonides include, but are not limited to, acetonides and benzylidene acetals. In some embodiments, acetonides can be formed by combining hydroxyl protecting groups on adjacent carbons.

[0274] R 19 If the group is a C1-C8 alkyl group, R 19 R can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl (sec-buty), t-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, isohexyl, neohexyl, septyl, or octyl. In some embodiments, R 19 The group can be methyl.

[0275] Any suitable solvent can also be used in the method of the present invention. Typical solvents include The solvents include, but are not limited to, pentane, pentanes, hexane, hexanes, heptane, heptanes, petroleum ethers, cyclopentanes, cyclohexanes, benzene, toluene, xylene, trifluoromethylbenzene, halobenzenes (such as chlorobenzene, fluorobenzene, dichlorobenzene, and difluorobenzene), methylene chloride, chloroformacetone, ethyl acetate, diethyl ether, tetrahydrofuran, or combinations thereof. In some embodiments, the solvent may be tetrahydrofuran. Furthermore, typical solvents (solvents) include, but are not limited to, 2-methyltetrahydrofuran, dibutyl ether, methyl tert-butyl ether, dimethoxyethane, dioxanes (1,4-dioxane), N-methylpyrrolidinone (NMP), or combinations thereof.

[0276] The reaction mixture in this method can be at any suitable temperature. For example, the temperature of 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. In some embodiments, the temperature of the reaction mixture can be about -30°C to about -10°C.

[0277] The reaction mixture in this method can be at 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 gas or an inert gas such as nitrogen or argon.

[0278] The method of the present invention can provide compounds of formula V in any preferred yield. For example, compounds of formula V can be prepared in yields of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least about 95%.

[0279] The method of the present invention can provide a compound of formula V at any preferred purity. For example, a 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, a compound of formula V can be prepared with a purity of at least 95%. In some embodiments, a compound of formula V can be prepared with a purity of at least 98%. In some embodiments, a compound of formula V can be prepared with a purity of at least 99%.

[0280] In some embodiments, this method Compounds of formula V: [ka] The step includes preparing Here, this method uses TMS-Cl, PhMgCl, iPrMgCl, and the compound of formula VI under conditions suitable for preparing the compound of formula V: [ka] and compounds of formula VII: [ka] The process includes the step of forming a reaction mixture having the following characteristics:

[0281] In some embodiments, the present invention relates to the following compounds: [ka] To provide. B. Addition of the prodrug portion

[0282] The present invention also provides a method for obtaining the compounds of the present invention by coupling the prodrug portion to a nucleoside. In some embodiments, the present invention Compounds of formula VIII: [ka] (This method uses a coupling agent, a non-nucleophilic base, and a compound of formula IX under conditions suitable for forming the compound of formula VIII: [ka] and compounds of formula X: [ka] (Includes the step of forming a reaction mixture containing) A method for preparing is provided, in the formula, R a Each is either H or PG, and each PG group is either a hydroxy protecting group, or both PG groups are combined to form -C(R 19 )2- forms, R e1 and R e2 Each of these is independently H, C1-C6 alkyl, or b It is R f R is H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl or -CH2-C3-C6 cycloalkyl, 19is H, C1-C8 alkyl, phenyl, or substituted phenyl, and LG is a leaving group.

[0283] As described above regarding the method for preparing the compound of formula V, any suitable coupling agent can be used in the method for preparing the compound of formula VIII. In some embodiments, the coupling agent may be a magnesium coupling agent. In some embodiments, the coupling agent may be MgCl2, iPrMgCl, tBuMgCl, PhMgCl, or a combination thereof. In some embodiments, the coupling agent may be MgCl2.

[0284] In the method for preparing the compound of formula VIII, any suitable non-nucleophilic base can be used. 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 may be diisopropylethylamine (DIPEA).

[0285] As described above regarding the method for preparing the compound of formula V, the protecting group PG can be any suitable hydroxy protecting group. Exemplary protecting groups PG can be benzyl or, in combination with other PG groups, can form an acetonide. Exemplary acetonides include, but are not limited to, acetonides and benzylidene acetals. In some embodiments, hydroxy protecting groups of hydroxyl groups on adjacent carbons can be combined to form an acetonide. In some embodiments, PG groups can be combined to form -C(R 19 )2- is formed. In some embodiments, R a Each of these is a protecting group PG, and when the PG groups are combined, they form -C(Me)2-.

[0286] R e If the group is a C1-C8 alkyl group, R eEach of these can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, isohexyl, neohexyl, septyl, or octyl. In some embodiments, R e Each of the groups can be methyl.

[0287] R f If the group is a C1-C8 alkyl group, R f R can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, isohexyl, neohexyl, septyl, or octyl. In some embodiments, R f The group can be methyl, ethyl, isopropyl, t-butyl, or isohexyl. f If the group is a C3-C6 cycloalkyl group, R f R can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R f This can be cyclobutyl, cyclopentyl, or cyclohexyl.

[0288] R 19 If the group is a C1-C8 alkyl group, R 19 R can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, isohexyl, neohexyl, septyl, or octyl. In some embodiments, R 19 The group can be methyl.

[0289] The leaving group can be any suitable leaving group. Suitable leaving groups LG include, but are not limited to, chloride, bromide, mesylate, tosylate, triflate, and 4-nitrate. This includes chlorobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, and pentafluorophenoxy. In some embodiments, the leaving group LG can be 4-nitrophenoxy or pentafluorophenoxy. In some embodiments, the leaving group LG can be 4-nitrophenoxy.

[0290] In some embodiments, R a Each of these is PG, and the PG groups combine to form -C(R 19 )2- forms, R f It is a C1-C8 alkyl group, and R 19 The group is a C1-C8 alkyl group, and the leaving group LG is either 4-nitrophenoxy or pentafluorophenoxy.

[0291] In some embodiments, the coupling agent is MgCl2, and the non-nucleophilic base is di-isopropylethylamine.

[0292] In some embodiments, the compound of formula VIII is [ka] This can be done. In some embodiments, the compound of formula VIII is [ka] This can be done. In some embodiments, the compound of formula VIII is [ka] It can be done this way.

[0293] In some embodiments, the method for producing the compound of formula VIII is: [ka] Under conditions suitable for forming, MgCl2, DIPEA, compound of formula IX: [ka] and compounds of formula X: [ka] The process includes the step of forming a reaction mixture containing the following:

[0294] R of compound VIII a If the group is a hydroxy protecting group PG, this method is R a The method may include an additional step of removing a protecting group to form a compound of formula VIII in which each of the elements is H. In some embodiments, the method for preparing a compound of formula VIII is R a Under conditions suitable for forming the compound of formula VIII, where each of the elements is H, a deprotecting agent and R a The method includes the step of forming a second reaction mixture containing a compound of formula VIII, each of which is a protecting group PG. The deprotecting agent can be any suitable agent for removing the protecting group PG, such as hydrogen and a hydrogenation catalyst, or an acid. For example, if the protecting group PG is benzyl, the deprotecting agent can be hydrogen and carbon-supported platinum. Alternatively, if the protecting group PG is an acetonide, the deprotecting agent can be an acid. Typical acids include, but are not limited to, acetic acid, glacial acetic acid, trifluoroacetic acid (TFA), hydrochloric acid, and concentrated hydrochloric acid. In some embodiments, the method for preparing the compound of formula VIII is R a Under conditions suitable for forming the compound of formula VIII, where each of the elements is H, an acid and R a The bases are combined to form -C(R 19 The process includes the step of forming a second reaction mixture containing a compound of formula VIII in which )2- is formed. In some embodiments, the acid may be hydrochloric acid.

[0295] Any suitable solvent can be used in the method of the present invention. Typical solvents include, but are not limited to, pentane, pentanes, hexane, hexanes, heptane, heptanes, petroleum ethers, cyclopentanes, cyclohexanes, benzene, toluene, xylene, trifluoromethylbenzene, halobenzenes (such as chlorobenzene, fluorobenzene, dichlorobenzene, and difluorobenzene), methylene chloride, chloroformacetone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, or combinations thereof. In some embodiments, the solvent may be acetonitrile.

[0296] The reaction mixture in this method can be at any suitable temperature. For example, the temperature of the reaction mixture can be about -78°C to about 100°C, about -50°C to about 100°C, about -25°C to about 50°C, 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.

[0297] The reaction mixture in this method can be subjected to any suitable pressure. For example, the reaction mixture can be subjected to atmospheric pressure. The reaction mixture can also be exposed to any suitable environment, such as atmospheric gas or an inert gas such as nitrogen or argon.

[0298] The method of the present invention can provide compounds of formula VIII in any preferred yield. For example, compounds of formula VIII can be prepared in yields of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least about 95%.

[0299] The method of the present invention can provide a compound of formula VIII in any preferred purity. For example, a 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, a compound of formula VIII can be prepared with a purity of at least 95%. In some embodiments, a compound of formula VIII can be prepared with a purity of at least 98%. In some embodiments, a compound of formula VIII can be prepared with a purity of at least 99%.

[0300] In some embodiments, the present invention relates to the following compounds: [ka] To provide. IX. [Examples]

[0301] Certain abbreviations and acronyms are used when describing the details of the experiment. While most of these will be understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms. [Table 1-1] [Table 1-2] [Table 1-3] A. Preparation of compounds (Example 1) (2S)-Ethyl 2-(chloro(phenoxy)phosphorylamino)propanoate (chloride A) [ka]

[0302] Ethyl alanine hydrochloride (1.69 g, 11 mmol) was dissolved in anhydrous CH2Cl2 (10 mL), and the mixture was stirred while cooling to 0°C under N2 (g). Phenyl dichlorophosphate (1.49 mL, 10 mmol) was added, and then Et3N was added dropwise over 10 minutes. Next, the reaction mixture was slowly warmed to room temperature and stirred for 12 hours. Anhydrous Et2O (50 mL) was added, and the mixture was stirred for 30 minutes. The formed solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography in hexane with 0-50% SiO to obtain intermediate A (1.13 g, 39%). 1 HNMR(300MHz,CDCl3)δ 7.39-7.27 (m, 5H), 4.27 (m, 3H), 1.52 (m,3H),1.32 (m, 3H). 31 PNMR (121.4 MHz, CDCl3)δ8.2,7.8. (Example 2) (2S)-2-ethylbutyl 2-(chloro(phenoxy)phosphorylamino)propanoate (chloride B) [ka]

[0303] 2-ethylbutylalanine chlorophosphorumidate B was prepared using the same procedure as chlorideate A, except that 2-ethylbutylalanine ester was used instead of ethylalanine ester. This crude substance was used in the following reaction: methanol Alternatively, treatment with ethanol can be used to form a substitution product having the desired LCMS signal. (Example 3) (2S)-Isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate(chloride C) [ka]

[0304] Isopropylalanine chlorophosphorumidate ester C was prepared using the same procedure as chloridate A, except that isopropylalanine ester was used instead of ethylalanine ester. This crude material was used in the following reaction. Treatment with methanol or ethanol formed a substitution product having the desired LCMS signal. (Example 4) (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) [ka]

[0305] The preparation of (2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile is described below. [ka]

[0306] Commercial lactol (10 g, 23.8 mmol) was dissolved in anhydrous DMSO (30 mL) under N2 (g). Ac2O (20 mL) was added, and the resulting reaction mixture was stirred at room temperature for 48 hours. This reaction mixture was poured into ice H2O (500 mL), and the mixture was stirred for 20 minutes. This mixture was extracted with RINKAN (3 × 200 mL), and then the combined organic extract was washed with H2O (3 × 200 mL). The organic extract was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and subjected to silica gel chromatography with elution using 25% RINKAN in hexane to obtain lactone (9.55 g, 96%). 1 HNMR(400MHz,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=3.9Hz,1H),3.66 (m, 2H).LCMS m / z 436.1[M+H2O], 435.2[M+OH ]-Tr=2.82 minutes. HPLC Tr=4.59 [in H2, 2~98%ACN), Flow rate of 2 ml / min for 5 minutes. [ka]

[0307] Bromopyrazole (prepared according to WO2009 / 132135) (0.5 g, 2.4 mmol) was suspended in anhydrous THF (10 mL) under N2 (g). The suspension was stirred, and TMSCl (0.67 mL, 5.28 mmol) was added. The mixture was stirred at room temperature for 20 minutes, then cooled to -78°C, and then n-BuLi (6 mL, in hexane, 1.6 N, 9.6 mmol) solution was slowly added. The reaction mixture was stirred at -78°C for 10 minutes, and then lactone (1 g, 2.4 mmol) was added by syringe. When the reaction was complete, as measured by LC-MS, 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 (100 mL, 1:1). The organic layer was separated and washed with H2O (50 mL). Next, the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography with elution in hexane with 0-50% RINKAN to obtain a 1:1 anomeric mixture (345 mg, 26% yield). LCMS m / z 553 [M+H]. [ka]

[0308] Hydroxynucleoside (1.1 g, 2.0 mmol) was dissolved in anhydrous CH2Cl2 (40 mL), and the solution was cooled to 0°C with stirring under N2 (g). TMSCN (0.931 mL, 7 mmol) was added, and the mixture was stirred for a further 10 minutes. TMSOTf (1.63 mL, 9.0 mmol) was slowly added to this reaction. The mixture was stirred for 1 hour. Next, the reaction mixture was diluted with CH2Cl2 (120 mL), and aqueous NaHCO3 (120 mL) was added to quench the reaction. The reaction mixture was stirred for a further 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 the smallest amount of CH2Cl2 and eluted with a gradient of 0-75% siRNA and hexane. Silica gel chromatography yielded a tripenzylcyanonucleoside as an anomeric mixture (0.9 g, 80%). 1 HNMR(300MHz,CD3CN)δ 7.94 (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), 6.41 (bs,2H),5.10 (d, J = 3.9Hz,0.5H),4.96 (d, J =5.1 Hz, 0.5H), 4.31-4.85 (m, 7H), 4.09-4.18 (m, 2H),3.61-3.90 (m, 2H).LCMS m / z 562[M+H]. [ka]

[0309] Tribenzylcyanonucleoside (70 mg, 0.124 mmol) was dissolved in anhydrous CH2Cl2 (2 mL) and cooled to -78°C under N2 (g). BCl3 solution (1N in CH2Cl2, 0.506 mL, 0.506 mmol) was added, and the reaction mixture was stirred at -78°C for 1 hour. Once the reaction was complete by LC / MS, MeOH was added to quench the reaction. The reaction mixture was warmed to room temperature (roomRT), and the solvent was removed under reduced pressure. The residue was removed. The residue was subjected to C18 reverse-phase HPLC, and eluted with H2O (0.1% TFA) for 5 minutes, followed by elution with a gradient of 0-70% MeCN in H2O (0.1% TFA) for 35 minutes, to elute α-anomer (20 mg, 37%) and β-anomer 1 (20 mg, 37%). (α-anomer) 1 HNMR(300MHz,D2O)δ 7.96 (s, 1H), 7.20 (d,J = 4.8 Hz,1H), 6.91 (d, J =4.8Hz, 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-anomeric) 1 HNMR(400 MHz, DMSO) δ7.91 (s, 1H),7.80-8.00(br s,2H), 6.85-6.89 (m, 2H), 6.07(d,J = 6.0 Hz,1H), 5.17 (br s, 1H),4.90 (brs,1H), 4.63 (t, J = 3.9 Hz,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. 35 minutes. 13C NMR (400 MHZ, 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=1.32 min (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) [ka]

[0310] The preparation of (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 is described below. [ka]

[0311] 2-Deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose. TFA 1.0 g, 2.88 mmol of 1'-methoxy-2-deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose (13.5 mL) was treated with H2O (1.5 mL), and the resulting mixture was stirred for 5 hours. Next, this mixture was diluted with siRNA (100 mL) and treated with saturated NaHCO3 (50 mL). This organic layer was separated, washed with NaCl (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. When this residue was subjected to silica gel chromatography (80 g SiO2 Combiflash HP Gold Column) with elution using 0-100% siRNA in hexane, 2-deoxy-2-fluoro-4,5-O,O-dibenzyl-D-arabinose (695 mg, 72%) was obtained as a white solid:R f = 0.52 (25% δ in hexane). 1 HNMR(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 = 10.5 Hz, 2H). 19 F NMR (282.2 MHz, CDCl3)δ-207 (m), -211 (m).LCMS m / z 350[M+H 20]. [ka]

[0312] (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 treated with 4 Å MS (10 g) and pyridinium dichromate (14.4 g, 38.3 mmol). The resulting mixture was stirred for 24 hours and then filtered through a Celite bat. The eluate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (120 g SiO2HP Gold Combiflash Column) with elution in hexane with 0-100% siRNA, yielding (3R,4R,5R)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorodihydrofuran-2(3H)-one as a clear oily substance (3.5 g, 83%). f = 0.25 (25% δ in hexane). 1 HNMR (300 MHz, CDCl3) δ 7.37 (m, 10H), 5.45 (dd, J = 49, 5.7, Hz,1H), 4.85 (d, J = 11.7Hz, 1H), 4.52 (m, 4 H), 4.29 (d, J = 5.4 Hz, 1H), 2.08 (dd, J = 15.3, 10.2 Hz,2H). 19 FNMR (282.2MHz, CDCl3) δ-216.LCMS m / z 348[M+H2O]. HPLC(6~98% MeCN-H2O gradient, 0.05% TFA modifier) R = 5.29 mins. Phenomenex Synergi 4m Hydro-RP 80A, 50 x 4.60 mm, 4 microns; flow rate 2 mL / min. [ka]

[0313] (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-ol. 7-bromopyrrolo[1,2-f][1,2,4]-triazine-4-amine (68 mg, 0.319 mmol) in THF (1.4 mL) The mixture was treated with TMSCl (89 μL, 0.703 mmol) and stirred for 2 hours. Next, the mixture was cooled to -78°C and treated with nBuLi (1.0 M in hexane, 1.09 mL, 1.09 mmol). This solution was stirred for 30 minutes and then treated dropwise with (3R,4R,5R)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorodihydrofuran-2(3H)-one (106 mg, 0.319 mmol) in THF (1.4 mL). The resulting mixture was stirred for 30 minutes and then quenched by adding AcOH (83 μL, 1.44 mmol) in THF (1.0 mL). The mixture was warmed to room temperature and then concentrated under reduced pressure. The residue was diluted with ELISA (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 subjected to silica gel chromatography (40 g SiO2HP Gold Combiflash Column) with elution in hexane with 0-100% siRNA, followed by a 0-100% gradient in siRNA (20% MeOH in siRNA). (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-ol was obtained as a white solid (68 mg, 44%, 60 / 40 mixture of α / β isomers). f = 0.32(Â). 1 HNMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H),7.64 (s, 1H), 7.26(m,10H),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)R =4.37 minutes. (α-isomer), 4.54 minutes. (β-isomer). [ka]

[0314] (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-(benzyloxy)-5-(benzyloxymethyl)-3-fluorotetrahydrofuran-2-carbonitrile:(3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-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 70°C for 18 hours and then cooled to 0°C. This mixture was treated with saturated NaHCO3 solution (20 drops), then warmed to room temperature and diluted with siRNA (100 mL) and H2O (50 mL). The organic layer was separated, washed with saturated NaCl solution (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (40 g SiO2HP Gold Combiflash Column) eluted with 0-100% siRNA in hexane, yielding (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 (110 mg, 55%, 60 / 40 mixture of α / β isomers). Data for both isomers: R f = 0.53(Â). 1 HNMR(300MHz,CDCl3)δ 8.01 (s, 1H), 7.94 (s, 1H), 7.30 (m, 10H), 7.00 (d, J = 4.5 Hz,1H), 6.93 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 6.70 (d, J = 4.8Hz, 1H), 5.85 (dd, J = 52, 3.3 Hz, 1H), 5.55 (dd, J = 53, 4.5 Hz, 1H), 4.71 (m,7H), 3.87(m,2H), 3.72 (m, 2H). 19 FNMR (282.2MHz, CDCl3)δ-196 (m), -203 (m).LCMS m / z 474[M+H]. HPLC(6~9 (8% MeCN-H2O gradient, 0.05% TFA modifier) R =4.98 minutes. [ka]

[0315] (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 (2). (3R,4R,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-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 0°C. This reaction mixture was treated with BCl3 (1.0 M in CH2Cl2, 766 μL, 0.77 mmol) and stirred for 2 hours. Next, the mixture was cooled to -78°C and treated with Et3N (340 μL, 2.44 mmol), then MeOH (2 mL), and then warmed to room temperature. The reaction was concentrated under reduced pressure, and then MeOH (3 × Co-evaporation was performed using 5 mL of water. Next, the residue was suspended in H₂O (5 mL) and treated with NaHCO₃ (1 g). This 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 frit glass funnel (coarse), and the eluate was concentrated under reduced pressure. When this residue was subjected to reverse-phase HPLC (a gradient of 6-98% MeCN in H₂O containing 0.05% TFA modifier), (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 2 was obtained as a white solid (16.8 mg, 25%) and as an α-isomer. β-isomer data: R f =0.13 (10% MeOH in EtOAc). 1 HNMR(300MHz,CD3OD)δ 8.09 (s, 1H), 7.28 (d, J = 5.1 Hz, 1H), 7.17(d, J= 5.1Hz, 1H),5.42 (dd, J = 53, 3.3 Hz, 1H), 4.20 (m, 2H), 3.99 (d, J =3.6 Hz, 1H), 3.77 (d, J = 3.6 Hz, 1H). 19 F NMR (282.2 MHz, CDCl3)δ-197(m).LCM S m / z 294 [M+H]. HPLC (2-98% MeCN-H2O gradient, 0.05% TFA modifier) R =1.49 minutes. (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) [ka]

[0316] (2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4] The preparation of triazine-7-yl)-4-fluoro-2-(hydroxymethyl)-5-methyltetrahydrofuran-3-ol is described below. [ka]

[0317] 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 0°C with stirring under N2 (g). Methylmagnesium chloride (2 mL, 6 mmol) solution (in THF, 3N) 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 this solution was subjected to a silica gel plug to isolate the product (0.355 g) as a crude mixture. LC / MS (m / z: 480, M) +1 The crude substance 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 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 (0.174 g, 0.377 mmol, 44% yield) as a 4:1 mixture of beta-anomeric and alpha-anomeric, respectively. 1 HNMR (300 MHz, CD3CN) Main anomer δ 7.87 (s, 1H), 7.27-7.40 (m, 10 H), 6.77(d, J =4.5HZ, 1H),6.70 (d, J = 4.5 Hz, 1H), 6.23 (br s, 2H), 5.53 (dd, J=55,3.3Hz,1H),4.42-4.75 (m, 4H), 4.19-4.26 (m, 1H), 3.65-4.00 (m, 3H), 1.74(d,J=3.9Hz,3H). 19 F NMR (282.2 MHz, CD3CN) Main anomer δ-207 (m,1F).LCMS m / z 46 3[M+H]. [ka]

[0318] A benzylated nucleoside substance (0.134 g, 0.290 mmol), Degussa catalyst (0.268 g), and AcOH (30 mL) were mixed together. H2 (g) was added to the reaction atmosphere, and the reaction was stirred for 2 hours. The catalyst was filtered. Further removal was performed, and the mixture was concentrated under reduced pressure. The residue was dissolved in the minimum amount of H2O and subjected to reverse-phase HPLC (C 18 The sample was subjected to a hydro RP column to isolate β-anomer 3 (0.086 g, 0.217 mmol, 57% yield). 1 HNMR(300MHz,D2O)δ 7.87 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 6.87(d, J =4.8Hz,1H),5.35 (dd, J = 54, 3.6 Hz, 1H), 3.97-4.10 (m, 2H), 3.81 (dd, J =12.6,2.1Hz, 1H), 3.64 (dd, J = 12.6, 4.8 Hz,1H),1.65 (d, J = 4.2 Hz,3H). 19 FNMR(282.2 MHz, CD3CN) δ-207(m,1F).

[0319] The small amounts of alpha-anomeric were characterized as follows: 1 H NMR (300 MHz, D2O) δ7.86(s,1H),7.26(d,J= 4.8 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H), 5.31 (dd, J =54, 3.9 Hz, 1H), 4.39 (ddd, J = 26.1, 9.9, 3.6 Hz, 2H), 4.00 - 4.05 (m,1H),3.90(dd, J = 12.3, 2.1 Hz, 1H), 3.66 (dd, J =12.6,4.8, 1H), 1.56 (s,3H). 19 FNMR(282.2 MHz, CD3CN) δ-198 (dd, J = 54, 26 Hz, 1F). (Example 7) (2R)-Isopropyl 2-((((2R,3R,4R,5S)-5-(4-Aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-Fluoro-3-Hydroxy-5-methyltetrahydrofuran-2-yl)methoxy)-(Phenoxy)phosphorylamino)propanoate (Compound 4) [ka]

[0320] Nucleoside 3 (0.011 g, 0.04 mmol) was dissolved in trimethyl phosphate (2 mL) and cooled to 0°C. This mixture was stirred under an atmosphere of N2 (g), and 1-methylimidazole (0.320 mL, 5 mmol), followed by alaninyl monoisopropyl monophenol phosphorchloridate C (0.240 mL, 4.4 mmol), was added. The reaction mixture was stirred at 0°C for 2 hours, and then slowly warmed to room temperature while monitoring by LC / MS. After completion by LC / MS, the reaction mixture was treated with H2O (5 mL) and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and subjected to silica gel chromatography elution with 0-100% siRNA in hexane. The product fraction was collected and concentrated. When this residue was subjected to preparative HPLC, alanine isopropyl monoamide prodrug 4 was obtained as a mixture of isomers (4.7 mg, 0.003 mmol, 6%). 1 HNMR (300MHz, CD3CN) δ 7.87 (s, 1H), 7.17-7.44 (m, 5 H), 6.71-6.83 (m, 2H),6.14 (br, s,2H),5.38(dd,J = 56, 3.3 Hz, 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]. (Example 8) (2R)-Ethyl 2-((((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-4-fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (compound 5) [ka]

[0321] Nucleoside 3 (0.026 g, 0.092 mmol) was dissolved in trimethyl phosphate (2 mL) and cooled to 0°C. This mixture was stirred under N2 (g) and 1-methylimidazole (0.062 mL, 0.763 mmol) was added, followed by chloride A (0.160 g, 0.552 mmol). This reaction mixture was stirred at 0°C for 2 hours and then slowly warmed to room temperature. The reaction was quenched by adding H2O (5 mL), and then this mixture was... The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and subjected to silica gel chromatography, eluted with 0-100% siRNA in hexane. The product fraction was collected and concentrated. The crude product was eluted with 0-100% siRNA in hexane. The crude product was collected and concentrated under reduced pressure. The residue was subjected to preparative HPLC, yielding 5 (2.0 mg, 4% yield). LCMS m / z 538 [M+H]. (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)methyltetrahydrogentriphosphate (compound 6) [ka]

[0322] 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 2 hours. The time at which more than 80 percent monophosphate was formed was determined by monitoring with an analytical ion exchange column. A solution of tributylamine (0.44 mL, 1.85 mmol) and triethylammonium pyrophosphate (0.327 g, 0.72 mmol), dissolved in anhydrous DMF (1 mL), was added. This reaction mixture was stirred for 20 minutes, and then quenched by adding a 1N triethylammonium bicarbonate solution (5 mL) in H2O. The mixture was concentrated under reduced pressure, and the residue was redissolved in H2O. This solution was subjected to ion exchange chromatography to obtain the title product 6 (1.7 mg, 6% yield). LCMS m / z 521 [MH]. Tr=0.41. HPLC ion exchange TR=9.40 mins (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) [ka]

[0323] The preparation of (2R,3R,5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile is described below. [ka]

[0324] ((3αR,5S,6αR)-2,2-dimethyltetrahydrofluoro[2,3-d][1,3]dioxol-5-yl)methanol. Acetate material (1.2g, 5.5mmol) (J.Org.Chem. 1985, Vol. 50, p. 3547, DeBernardo et al.) It was dissolved in a 1:1 mixture of THF (10 mL). A 1N solution of NaOH (aqueous solution) (10 mL) was added until the pH reached 13. The reaction mixture was stirred for 2 hours, and then neutralized to pH 8-9 by adding AcOH. This mixture was extracted with toluene (10 × 30 mL), and the combined organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography with elution using toluene at 0-70% toluene in hexane to obtain the desired product (866 mg, 90%). 1 HNMR(300MHz,CDCl3)δ 5.84 (d, J = 3.6 Hz, 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). [ka]

[0325] (3αR,5S,6αR)-5-(benzyloxymethyl)-2,2-dimethyltetrahydrofl[2,3-d][1,3]dioxol. Sodium hydride (188 mg, 7.46 mmol) was dissolved in anhydrous THF (5 mL) and stirred at room temperature under N2 (g). Alcohol (866 mg, 4.97 mmol) was dissolved in anhydrous THF (3 mL) and added to the sodium hydride mixture in fractions over 5 minutes. The resulting mixture was stirred for 20 minutes, and then benzyl bromide (892 μL, 7.46 mmol) was added. This reaction was stirred for 2 hours, and then poured into a mixture of ice-cold aqueous NaHCO3 and toluene (30 mL). The organic layer was separated, and then the aqueous layer was re-extracted with toluene (30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. When this residue was subjected to silica gel chromatography in which it was eluted with 0-40% siRNA in hexane, a benzyl ether product (912 mg, 69%) was obtained. 1 HNMR(300MHz,CDCl3)δ 7.35-7.27 (m, 5H), 5.86 (d, J = 3.6 Hz, 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). [ka]

[0326] (3R,5S)-5-(benzyloxymethyl)-tetrahydrofuran-2,3-diol. Benzyl ether (910 mg, 3.44 mmol) was dissolved in a 1:1 mixture of AcOH and H2O (20 mL) and stirred at 60°C for 7 hours. This mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography in hexane with 0-70% phenylethylamine to obtain the diol product (705 mg, 91%). 1HNMR(300MHz,CDCl3)δ 7.36-7.27 (m, 5H), 5.40 (d, J = 3.9 Hz,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). [ka]

[0327] (3R,5S)-5-(benzyloxymethyl)-3-hydroxy-dihydrofuran-2(3H)-one 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 80°C for 2 hours under N2 (g). Next, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography in hexane with 0-70% phenyl to obtain the lactone product (600 mg, 86%). 1 HNMR(300MHz,CDCl3)δ 7.39-7.27 (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). [ka]

[0328] (3R,5S)-3-(benzyloxy)-5-(benzyloxymethyl)-dihydrofuran-2(3H)-one. Lactone (600 mg, 2.7 mmol) was dissolved in RINKAN (30 mL) and treated with silver oxide (626 mg, 2.7 mmol), followed by benzyl bromide (387 μL, 3.24 mmol). The reaction mixture was then stirred at 50°C for 8 hours under N2 (g). An additional 300 mg of silver oxide was added, and the resulting mixture was stirred at 50°C for 16 hours. An additional 50 μL of benzyl bromide and 150 mg of silver oxide were added, and the mixture was stirred for a further 8 hours. The reaction mixture was cooled and filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with 0-20% RINKAN in hexane, to obtain the title product (742 mg, 88%). 1 HNMR(300MHz,CDCl3)δ 7.39-7.27 (m, 10H), 4.99 (d, J = 11.4 Hz, 1H), 4.72 (m, 2H), 4.56(m, 2H), 4.39 (t, J = 8.1 Hz,1H),3.72-3.51(m,2H),2.42-2.25 (m, 2H). [ka]

[0329] (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 arginine. TMSCl (1.1 mL, 8.55 mmol) was added dropwise, and the mixture was stirred for 2 hours. The reaction product was concentrated under reduced pressure and then dried under high vacuum. The residue was suspended in THF (20 mL) and stirred at -78°C under arginine. 2.28 mL, 5.7 mmol) of 2.5 M n-BuLi solution in hexane was added dropwise over 10 minutes, and the resulting mixture was stirred for 60 minutes. Anhydrous THF (7 mL) The dissolved lactone (742 mg, 2.37 mmol) was added to the above mixture over 20 minutes. The reaction mixture was stirred for 2 hours and then quenched with AcOH until the pH was 5-6. The mixture was warmed to room temperature and then diluted with siRNA. This solution was washed with saturated NaHCO3 solution and saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography in hexane with 0-80% siRNA to obtain the title product (250 mg, 24%). LCMS m / z 447.2 [M+H], 445.1 [MH]. [ka]

[0330] (3R,5S)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-(benzyloxy)-5-(benzyloxymethyl)-tetrahydrofuran-2-carbonitrile. Alcohol (250 mg, 0.56 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and stirred under Ar(g) at -15°C. TMSCN (448 μL, 3.36 mmol) was added dropwise, and the mixture was stirred for 10 minutes. TMSOTf (466 μL, 2.58 mmol) was added dropwise over 10 minutes, and the resulting mixture was stirred at -15°C for 90 minutes. Additional TMSCN (224 μL, 3 equivalents) and TMSOTf (202 μL, 2 equivalents) were added, and stirring was continued for 5 hours. The reaction was quenched by adding a saturated aqueous solution of NaHCO3, and the mixture was stirred for 10 minutes. The organic layer was separated, washed with saturated aqueous solution of NaHCO3 and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography in hexane with 0-70% toluene to obtain the title product (150 mg, 59%). LCMS m / z 456.3 [M+H], 454.1 [MH]. [ka]

[0331] (2R,3R,5S)2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile(7). Benzyl ether (150 mg, 0.329 mmol) was dissolved in anhydrous CH2Cl2 (2 mL), and the mixture was stirred under Ar(g) at -20°C. 1 M BCl3 solution in CH2Cl2 (724 μL, 0.724 mmol) was added dropwise, and the resulting mixture was stirred for 2 hours. Additional 1 M BCl3 in CH2Cl2 (724 μL, 0.724 mmol) was added, and stirring was continued for 2 hours. Next, the mixture was cooled to -78°C and slowly treated with a 2:1 mixture of Et3N and MeOH (3 mL). The mixture was stirred for 10 minutes, and then treated with MeOH (10 mL). The reaction mixture was warmed to room temperature and then concentrated under reduced pressure. The residue was dissolved in MeOH and concentrated under reduced pressure. The residue was again dissolved in MeOH and treated with solid NaHCO3. This mixture was stirred for 5 minutes, and then the solid was removed by filtration. This solution was concentrated under reduced pressure, When subjected to preparative HPLC, the desired product 7 (10 mg, 11%) was obtained. 1 HNMR (300MHz, D2O) δ7.71(s, 1H), 6.75 (d, J = 4.5 Hz,1H),6.65 (d,J = 4.8Hz, 1H),4.91 (t, J = 6.3 Hz,1H), 4.57 (m, 1H), 3.67-3.47(m, 2H),2.18(m, 2H).LCMS m / z 276.1[M+H], 274.0[MH]. (Example 11) (2S)-Isopropyl 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)(Phenoxy)-Phosphorylamino)propanoate (Compound 8) [ka]

[0332] Nucleoside 1 (45 mg, 0.15 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL), and this solution was stirred under N2 (g) at 0°C. Methylimidazole (36 μL, 0.45 mmol) was added to this solution. Chlorophosphoramide C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. After this reaction was completed by LC-MS, the reaction mixture was diluted with RINKAN, washed with saturated NaHCO3 aqueous solution and saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography by elution with 0-5% MeOH in CH2Cl2, followed by preparative HPLC, to obtain the product (20.9 mg, 25%). 1 HNMR(300MHz,CD3OD)δ 7.95 (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 PNMR(121.4MHz, CD3OD) δ3.8.LCMS m / z 561.0 [M+H], 559.0 [MH]. (Example 12) (2S)-2-ethylbutyl2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (compound 9)

[0333] Compound 9 can be prepared by several methods described below. Step 1 [ka]

[0334] Compound 8 was prepared from compound 1 and chloride B according to the same method as the preparation of compound 8. 1 H NMR (300 MHz, 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 PNMR(121.4MHz, CD3OD)δ3.7.LCMS m / z 603.1[M+H], 601 0[MH]. Step 2 [ka]

[0335] (2S)-2-ethylbutyl 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)propanoate. (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred at room temperature under a nitrogen atmosphere. To this reaction mixture, (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (350 mg, 1.2 mmol) was added in one addition. Next, a solution of t-butylmagnesium chloride in THF (1 M, 1.8 mL, 1.8 mmol) was added dropwise to the reaction mixture over 10 minutes. The reaction mixture was stirred for 2 hours, at which point the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution (3 × 15 mL) and then saturated sodium chloride aqueous solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (0-10% MeOH in DCM) to obtain (2S)-2-ethylbutyl 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)propanoate (311 mg, 43%, a diastereomer mixture in a 1:0.4 ratio in phosphorus) as a white solid. 1 HNMR(400MHz,CD3OD)δ 7.85 (m, 1H), 7.34 - 7.23 (m, 2H), 7.21 -7.09 (m, 3H), 6.94 - 6.84(m, 2H), 4.78 (d, J = 5.4 Hz, 1H), 4.46 - 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 (162 MHz, CD3OD) δ3.71, 3.65.LCMS m / z 603.1[M+H], 600.9[MH]. HPLC(8 (0.5 minutes, 2-98% MeCN-H2O gradient containing 0.1% TFA modifier, 1.5 mL / min, column: Phenomenex Kinetex C18, 2.6 μm 100 Å, 4.6 x 100 mm) R = 5.544 minutes, 5.601 minutes Separation of (S) and (R) diastereomers

[0336] (2S)-2-ethylbutyl 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)propanoate was dissolved in acetonitrile. The resulting solution was loaded onto a Lux Cellulose-2 chiral column, equilibrated in acetonitrile, and eluted with a fixed-composition acetonitrile / methanol (95:5 vol / vol). The first diastereomer eluted had a retention time of 17.4 minutes, and the second diastereomer eluted had a retention time of 25.0 minutes.

[0337] The first diastereomer to elute was (S)-2-ethylbutyl2-(((R)-(((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)propanoate: [ka] That is the case. 1 HNMR(400 MHz, CD3OD) δ 8.05 (s, 1H), 7.36(d,J=4.8Hz,1H), 7.29 (br t, J = 7.8 Hz, 2H), 7.19 - 7.13 (m, 3H), 7.11 (d, J =4.8Hz,1H),4.73 (d, J = 5.2 Hz, 1H), 4.48 - 4.38 (m, 2H), 4.37 - 4.28 (m,1H), 4.17 (t,J =5.6 Hz, 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 = 7.2 Hz,3H), 0.87 (t, J = 7.4Hz, 6H). 31 PNMR (162MHz, CD3OD) δ 3.71 (s). HPLC (over 8.5 minutes) with a 2-98% MeCN-H2O gradient containing 0.1% TFA modifier, 1.5 mL / min, column: Phenomenex Kinetex C18, 2.6um 100Å, 4.6x100mm)t R =5.585 minutes.

[0338] The second diastereomer eluted was (S)-2-ethylbutyl2-(((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)propanoate: [ka] That is the case. 1HNMR(400 MHz, CD3OD) δ 8.08 (s, 1H),7.36-7.28(m,3H),7.23 - 7.14 (m, 3H), 7.08 (d, J = 4.8 Hz, 1H), 4.71 (d, J =5.3Hz,1H),4.45 -4.34 (m, 2H), 4.32 - 4.24 (m,1H), 4.14 (t, J = 5.8 Hz, 1H),4.08-3.94(m,2H), 3.93 - 3.85 (m, 1H), 1.47 (sep,J = 6.2 Hz, 1H), 1.38 -1.26(m,7H),0.87(t, J = 7.5 Hz, 6H). 31 PNMR (162 MHz, CD3OD) δ 3.73 (s). HPLC (over 8.5 minutes) containing 0.1% TFA modifier. 2-98% MeCN-H2O gradient, 1.5 mL / min, column: Phenomenex Kinetex C18, 2.6 μm 100 Å, 4.6 x 100 mm) R =5.629 minutes. (Example 13) (2S)-Ethyl 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)(phenoxy)phosphorylamino)propanoate (compound 10) [ka]

[0339] The preparation of (2S)-ethyl 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)propanoate is described below. Step 1. Preparation with Chloride A [ka]

[0340] Compound 8 was prepared from compound 1 and chloride A using the same method as the preparation of compound 8. 1 H NMR (300 MHz, 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 (121.4 MHz, CD3OD)δ 3.7.LCMS m / z 547.0[M+H], 545.0[MH]. Step 2. Preparation with nitrobenzene compound L [ka]

[0341] Compound 1 (50 mg, 0.17 mmol) was dissolved in NMP-THF (1:1 mL) and cooled in an ice bath. Next, tBuMgCl (0.257 mL, 0.257 mmol) was added over 5 minutes. The resulting mixture was warmed to room temperature and stirred for 30 minutes. Next, a solution of compound L (prepared according to US20120009147, 74.6 mg, 0.189 mmol) in THF (2 mL) was added. After 30 minutes, the reaction mixture was purified by HPLC (10-80% acetonitrile in water) to obtain compound 29 as a yellow solid. This solid was further purified by silica gel chromatography (DCM with 0-20% MeOH) to obtain compound 29 (23 mg, 24% as a 2.5:1 diastereomer mixture). 1 HNMR(400MHz,CD3OD)δ 7.76 (d, J = 6.0 Hz, 1H), 7.25 - 7.14 (m, 2H), 7.11 - 6.99 (m, 3H),6.87 - 6.72 (m, 2H), 4.70 (d, J = 5.4 Hz,1H),4.39-4.24 (m, 2H), 4.20 (dddd,J = 9.7, 7.9, 5.1, 2.8 Hz, 1H), 4.10 (dt, J=12.8,5.5 Hz, 1H), 4.06 - 3.91(m, 2H), 3.72 (ddq, J = 14.3, 9.3, 7.1 Hz, 1H), 1.17 (dd, J = 7.1, 1.0 Hz, 1H),1.14 - 1.06 (m, 5H). 31 P NMR (162 MHz, CD3OD)δ3.73,3.68. MS m / z = 547(M+1) + . (Example 14) (2S)-Ethyl 2-((((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-cyano-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate (compound 11) [ka]

[0342] Compound 11 was prepared from compound 2 and chloride A using the same method as for the preparation of compound 8. 1 HNMR(300MHz,CD3OD)δ 7.91 (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 PNMR (121.4 MHz, CD3OD)δ3.8.LCMS m / z 549.0[ M+H], 547.1[MH]. (Example 15) (2S,2'S)-Diethyl 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(azandiyl)dipropanoate (Compound 12) [ka]

[0343] 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 60 minutes. Alanine ethyl hydrochloride (61 mg, 0.4 mmol) was added, followed by Et3N (70 μL, 0.5 mmol). The resulting mixture was stirred for 15 minutes. An additional Et3N (70 μL, 0.5 mmol) was then added to obtain a solution with a pH of 9-10. This mixture was stirred for 2 hours, then diluted with RINKAN, and washed with saturated NaHCO3 aqueous solution, followed by saturated NaCl aqueous solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to preparative HPLC (C) analysis. 18 When subjected to column chromatography, product 12 (5.5 mg, 16%) was obtained. 1 HNMR(400MHz,CD3OD)δ 8.13 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H), 7.18(d, J= 4.8Hz,1H),4.78 (d, J = 5.6 Hz, 1H), 4.36 (m, 1H), 4.25-4.08 (m,7H),3.83(m,2H),1.33-1.23 (m, 12H). 31 P NMR (121.4 MHz, CD3OD)δ13.8.LCMS m / z 570.0[M +H], 568.0[MH]. (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) [ka]

[0344] The preparation of (2S,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-2-ethynyl-5-(hydroxymethyl)tetrahydrofuran-3,4-diol is described below. [ka]

[0345] 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 0°C, and then treated with a 0.5 N ethynyl magnesium bromide solution (17.2 mL, 17.2 mmol) in THF. The reaction mixture was stirred overnight at room temperature. AcOH (1.5 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was redissolved in CH2Cl2. This solution was subjected to a silica gel plug eluted with 0-80% HCl in hexane to obtain the title product as a crude mixture. LCMS m / z 579 [M+H]. [ka]

[0346] 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 12 hours. After completion by LC-MS, Et3N (0.56 mL) was added to quench the reaction. The reaction product was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with 0-75% RINKAN in hexane, yielding ethynyl nucleoside as an anomeric mixture (0.200 g, 33%, total for 2 steps). LC-MS m / z 561[M+H]. [ka]

[0347] Tribenzyl nucleoside (0.650 g, 1.16 mmol) was dissolved in anhydrous CH2Cl2 (30 mL) and cooled to -78°C under N2 (g). A solution of boron tribromide (1N in CH2Cl2, 5.5 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was quenched by adding solutions of MeOH (10 mL) and pyridine (2 mL), and the mixture was raised to room temperature. The mixture was concentrated under reduced pressure and subjected to preparative HPLC to obtain α-anomer (20 mg) and β-anomer 13 (110 mg). (β-anomer) 1 HNMR(300MHz,DMSO)δ 7.81 (s, 1H), 7.76 (br s, 2H),6.80-6.85 (m,2H), 5.11 (d, J =7.2Hz, 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, 5.7Hz, 1H), 3.61-3.67 (m, 1H), 3.47-3.55 (m, 1H), 3.52 (d, J = 0.9 Hz, 1H). (α-anomal) -) 1 H NMR (300 MHz, DMSO) δ 7.80(s, 1H), 7.59 (bs, 2H), 6.80(d,J=4.5Hz, 1H), 6.54 (d, J = 4.2 Hz, 1H),5.00 (d, J = 7.2 Hz, 1H), 4.89 (d,J=4.8 Hz, 1H), 4.74 (t, J = 5.7 Hz, 1H),4.58 (t, J = 4.5 Hz, 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 = 0.6 Hz, 1H).LCMS m / z 2 91[M+H]. (Example 17) (2R,3R,4R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-1,3,4-tris(benzyloxy)hexane-2,5-diol (compound 14) [ka]

[0348] The preparation of (2R,3R,4R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-1,3,4-tris(benzyloxy)hexane-2,5-diol is described below. [ka]

[0349] Tribenzyl alcohol (0.250 g, 0.453 mmol) derived from the synthesis of compound 1 was dissolved in anhydrous THF (25 mL) and stirred under N2 (g). This reaction mixture 0 The mixture was cooled to °C, and then 1.2 mL (3.62 mmol) of 3.0 N methylmagnesium chloride solution in THF was added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with 1.5 mL of acetic acid, and then the mixture was concentrated under reduced pressure. The residue was redissolved in CH2Cl2 and subjected to a silica gel plug to be eluted with 0-80% RINKAN in hexane. The crude product (0.452 g) was then used in the next reaction without further purification. LCMS m / z 569 [M+H]. [ka]

[0350] 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 mixture was stirred at room temperature for 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, eluted with 0-75% SiO2 in hexane, to obtain the product as an anomeric mixture (0.20 g, 46%, total for 2 steps). LCMS m / z 551 [M+H]. [ka]

[0351] Tribenzyl nucleoside (0.20 g, 0.364 mmol) was dissolved in AcOH (30 mL), and Pd / C(Degussa) (400 mg) was added. N2 (g) was vigorously passed through this stirred mixture three times, followed by the introduction of H2 (g). The reaction mixture was stirred under H2 (g) for 2 hours. The catalyst was then removed by filtration. This solution was concentrated under reduced pressure, and the residue was redissolved in H2O. Preparative HPLC of this solution under neutral conditions yielded α-anomer and β-anomer 14 in 81% yield. (α-anomer) 1HNMR(300MHz,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-anomeric) 1 H NMR (300 MHz, D2O) δ 7.91 (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]. (Example 18) S,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(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate)(compound 15) [ka]

[0352] Nucleoside 1 (0.028 g, 0.096 mmol) was dissolved in trimethyl phosphate (1 mL). This reaction mixture 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 phosphan (Nucleoside Nucleotides, Nucleicacids; Vol. 14; Nos. 3-5; 1995; 763- Page 766. Lefebvre, Isabelle; Pompon, Alain; Perigaud, Christian; Girardet, Jean-Luc; Gosselin, Gilles et al. (87 mg, 0.192 mmol) was added. The reaction mixture was 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 (1 mL). The mixture was stirred for 10 minutes. It was then concentrated under reduced pressure. The residue was subjected to preparative HPLC to isolate the title product 15. 1 HNMR(300MHz,CD3CN)δ 7.98 (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 (121.4 MHz, CD3CN) δ -1.85 (s).LCMS m / z 661[M+H]. (Example 19) S,S'-2,2'-((((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl)bis(2,2-dimethylpropanethioate)(compound 16) [ka]

[0353] 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)δ 7.91 (s, 1H), 6.86 (d, J = 4,8 Hz, 1H), 6.76 (d, J =4.5 Hz, 1H),6.29 (bs, 2H), 4.69 (t, J = 2.7Hz,1H), 4.58 (d, J = 5.7 Hz, 1H),4.14-4.33(m, 5H), 3.99-4.07 (m, 4H), 3.53 (d, J = 5.4 Hz, 1H), 3.11 (q, J = 5.7 Hz, 4H),1.22 (s, 18H).LCMS m / z 658. 9[M+]. Tr=2.31 (Example 20) ((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogentriphosphate (Compound 17) [ka]

[0354] Compound 17 was prepared from compound 1 using the same procedure as that used for the preparation of compound 6. The product was isolated as a sodium salt. 1 HNMR(400MHz,D2O)δ 7.76 (s, 1H), 6.88 (d, J = 4.8 Hz, 1H), 6.73 (d,J =4.4Hz, 1H),4.86 (d, J = 5.2 Hz, 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. (Example 21) ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogent triphosphate (compound 18) [ka]

[0355] Compound 18 was prepared from compound 13 using the same procedure as for the preparation of compound 6. The product was isolated as a TEA salt. 1 HNMR(300MHz,D2O)δ 7.85 (s, 1H), 7.09 (d, J = 4.6 Hz, 1H), 6.95 (d, J = 4.7Hz, 1H),4.23 (m, 2H), 4.08 (m, 2H), 3.06 (q, J = 7.4 Hz, 20H), 1.14 (t, J = 7.3 Hz,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. (Example 22) ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)methyltetrahydrogent triphosphate (compound 19) [ka]

[0356] Compound 19 was prepared from compound 14 using the same procedure as that used for the preparation of compound 6. 1 HNMR (400 MHz, 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 (161 MHz, D2O)δ-10.6(m),-23.0 (m).LCM S m / z 521.0[M+H]. (Example 23) ((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazine-7-yl)-5-cyano-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyltetrahydrogentriphosphate (compound 20) [ka]

[0357] Compound 20 was prepared from compound 2 using the same procedure as that used for the preparation of compound 6. 1 H NMR (400 MHz, D2O)δ7.78(s,1H),6.93(d,J = 4.4 Hz, 1H), 6.78 (d, J = 4.8 Hz, 1H), 5.45 (dd, J =53,4.4Hz,1H),4.38-4.50 (m, 2H), 4.13-4.20 (m, 2H). 31 PNMR (161MHz, 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 minutes. HPLC ion exchange Tr=11.0 min. (Example 24) (2S)-Ethyl 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-phenylpropanoate(21) [ka]

[0358] The preparation of (2S)-ethyl 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-phenylpropanoate is described below. Preparation of (S)-ethyl 2-amino-3-phenylpropanoate hydrochloride. [ka]

[0359] L-phenylalanine (5 g, 30 mmol) was dissolved in EtOH (30 mL). TMSCl (6.915 mL, 54 mmol) was added to this reaction mixture at room temperature. A reflux condenser was attached to the reaction vessel, and the reaction mixture was placed in an 80°C bath. The reaction mixture was stirred overnight. The next day, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was EtOH. It was dissolved in 2O. The resulting slurry was filtered, and the isolated solid was further washed with Et2O. When the washed solid was placed under high vacuum, the (S)-ethyl 2-amino-3-phenylpropanoate hydrochloride (6.86 g, 99%) of the example was obtained. 1 HNMR(400MHz, DMSO-d6) δ8.52(s, 3H), 7.30 (m, 5H), 4.24 (AB X ,J AX =7.8Hz, J BX =6.2 Hz, 1H), 4.11 (m, 2H), 3.17, 3.05( AB X, J AB = -14 Hz, J BX = 5.8Hz, J AX =7.6 Hz, 2H), 1.09 (t, J=6.8Hz, 3H). Preparation of (2S)-ethyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoate (compound D) [ka]

[0360] (S)-ethyl 2-amino-3-phenylpropanoate hydrochloride (1.01 g, 4.41 mmol) was dissolved in DCM (50 mL). This solution was cooled to 0°C, and PhOP(O)Cl2 (0.656 mL, 4.41 mmol) was added, followed by the slow addition of Et3N (1.62 mL, 11.5 mmol) over 5 minutes. The cooling bath was removed, and the reaction mixture was warmed to room temperature and stirred for 80 minutes. p-NO2PhOH (0.583 g, 4.19 mmol) was added, followed by a further addition of Et3N (0.3 mL, 2.1 mmol). The progress of the reaction was monitored by LC / MS. Once the reaction was complete, the solution was diluted with Et2O, and the resulting solid was removed by filtration. The filtrate was concentrated, and compound D (1.25 g, 60%, as a mixture of diastereomers) was isolated by silica gel column chromatography (25 g dry-load cartridge, 120 g column; eluent: gradient from 100% hexane to 55% siRNA in hexane). 1 HNMR (400 MHz, CD3OD) δ 8.17 (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). 31 PNMR(162MHz,DMSO-d6) δ-1.479(s), -1.719 (s).MS m / z=471.01[M+1]. Preparation of (2S)-ethyl 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-phenylpropanoate (compound 21) [ka]

[0361] Compound 1 (0.030 g, 0.103 mmol) was dissolved in DMF (1 mL), and then THF (0.5 mL) was added. While vigorously stirring, t-BuMgCl (1 M / THF, 154.5 μL, 0.154 μmol) was added dropwise to the reaction mixture. The resulting white slurry was stirred at room temperature for 30 minutes. To this reaction mixture, a solution of Compound D (0.058 g, 0.124 mmol) in THF (1 mL) at room temperature was added dropwise. The reaction proceeded as follows: The reaction was monitored by LC / MS. When the reaction proceeded to a 50% conversion rate, the reaction product was cooled in an ice bath and quenched with glacial acetic acid (70 μL). The reaction product was concentrated, and compound 21 (22 mg, 34%, as a mixture of 2.6:1 diastereomers) was isolated from the residue by reverse-phase HPLC. 1 HNMR(400MHz, DMSO-d6) δ7.91(d, J = 4 Hz, 1H), 7.90 (brs,2H),7.09-7.30 (m,8H), 7.01,(t, J = 8.2 Hz, 2H), 6.89 (d, J = 4.4 Hz, 1H), 6.82 (t, J = 4.4 Hz, 1H), 6.27(m, 1H), 6.14 (m, 1H), 5.34(m,1H), 4.62 (t, J = 5.6 Hz, 1H), 4.15 (m, 1H),3.78-4.01 (m, 6H), 2.92 (m, 1H),2.78 (m, 1H), 1.04 (m, 3H). 31 PNMR (162 MHz, DMSO-d6) δ3.69(s),3.34(s).MS m / z = 623.0[M+H]. (Example 25) (2S)-Ethyl 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-methylbutanoate(22) [ka]

[0362] The preparation of (2S)-ethyl 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-methylbutanoate is described below. Preparation of (2S)-ethyl 3-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)butanoate (compound E) [ka]

[0363] (S)-ethyl 2-amino-3-methylbutanoate (0.351 g, 1.932 mmol) was dissolved in DCM (17 mL). This solution was cooled in an ice bath, and PhOP(O)Cl2 (0.287 mL, 1.932 mmol) was added, followed by the slow addition of Et3N (1.62 mL, 11.4 mmol) over 5 minutes. The cooling bath was removed, and the reaction mixture was warmed to room temperature and stirred for 1 hour. p-NO2PhOH (0.255 g, 1.836 mmol) was added, and the progress of the reaction was monitored by LC / MS. Once the reaction was complete, the mixture was diluted with Et2O, and the resulting solid was removed by filtration. The filtrate was concentrated, and compound E (0.642 g, 79%, as a mixture of diastereomers) was isolated by silica gel column chromatography (12 g dry-load cartridge, 80 g column; eluent: gradient from 100% hexane to 55% siRNA in hexane). 1 HNMR(400MHz,DMSO-d6)δ 8.30 (d, J = 9.2 Hz, 2H), 7.48 (t, J = 9.6Hz,2H), 7.40 (t, J =7.8 Hz, 2H), 7.20-7.27 (m, 3H), 6.60 (quartet, 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 PNMR (16 2 MHz, DMSO-d6) δ -0.342(s),-0.578 (s).MS m / z=422.9[M+H]. Preparation of (2S)-ethyl 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-methylbutanoate (compound 22) [ka]

[0364] Compound 1 (0.040 g, 0.137 mmol) was dissolved in NMP (1.5 mL), and then THF (0.25 mL) was added. This solution was cooled in an ice bath, and t-BuMgCl (1 M / THF, 425.7 μL, 0.426 μmol) was added dropwise while vigorously stirring. The ice bath was removed, and the resulting white slurry was stirred at room temperature for 15 minutes. To this reaction mixture, a solution of compound E (0.081 g, 0.192 mmol) in THF (0.5 mL) was added dropwise at room temperature. The progress of the reaction was monitored by LC / MS. When the reaction progressed to a 50% conversion rate, the reaction mixture was cooled in an ice bath and quenched with glacial acetic acid (70 μL). The reaction mixture was concentrated, and compound 22 (22 mg, 34%) was semi-purified from the residue by reverse-phase HPLC. Further purification of this semi-purified substance by silica gel column chromatography (12 g dry-load cartridge, 40 g column; eluent: increased from 100% SiO₂ to 10% MeOH in SiO₂) yielded compound 22 (as 0.034 g, 43%, 1.8:1 diastereomer mixture). 1 HNMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 1.6 Hz, 1H), 7.88(brs,2H),7.32(m,2H), 7.15 (m,3H), 6.90 (t, J = 4.2 Hz, 1H), 6.84 (d, J = 4.8 Hz, 1H),6.26(dd, J=13.4,6.2Hz, 1H), 5.87 (quartet. J = 11.2 Hz, 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 (162 MHz, DMSO-d6)δ4.59(s),4.47 (s).MS m / z=575.0 2[M+H]. (Example 26) (S)-Isopropyl 2-(((R)-(((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)propanoate(23) [ka]

[0365] The preparation of (S)-isopropyl 2-(((R)-(((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)propanoate is described below. [ka]

[0366] Compound 1 (60.0 mg, 206 μmol) was dissolved in NMP (0.28 mL). Under an argon atmosphere, THF (0.2 mL) was added at room temperature, followed by tert-butylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.309 mL). After 20 minutes, compound F (Cho, A. et al., J. Med. Chem. 2014, Vol. 57) was dissolved in THF (0.2 mL). The solution (81 mg, 206 μmol) was added according to pages 1812-1825, and the resulting mixture was warmed to 50°C. After 3 hours, the reaction mixture was cooled to room temperature and purified directly by preparative HPLC (Phenominex Synergi 4u Hydro-RR 80 Å 150 × 30 mm column, 5-100% acetonitrile / water gradient) to obtain compound 23 (44 mg, 38% as a single diastereomer). 1 HNMR(400MHz,CD3OD)δ 7.86 (s, 1H), 7.34 - 7.26 (m, 2H), 7.21 -7.12 (m,3H),6.91(d, J= 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 4.92 (septet, J=6.3 Hz,1H),4.80 (d, J = 5.4 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.33 - 4.24 (m,1H), 4.18 (t, J=5.6Hz, 1H), 3.82 (dq, J = 9.7, 7.1 Hz, 2H), 1.27 (dd, J =7.1, 1.0 Hz, 3H),1.18(dd, J (= 6.3, 4.8 Hz, 6H). 31 P NMR (162MHz, CD3OD) δ 3.72(s).LC / MS:t R = 1.39 min, MS m / z=561.11[M+H]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50x4.6mm; Solvent: ACN with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 2 μl / min, 0 min to 2.0 min, 2% to 100% ACN, 2.0 min to 3.05 min, 100% ACN, 3.05 min to 3.2 min, 100% to 2% ACN, 3.2 min to 3.5 min, 2% ACN. HPLC:t R =2.523 mins; HPLC system: Agilent 1100 series; Column: Gemini 5μ C18 110A, 50x4.6mm; Solvent: ACN with 0.1% TFA, water with 0.1% TFA; Gradient: 2 mL / min, 0 min to 5 min, 2 to 98% ACN; 5 to 6 min, 98% ACN (Example 27) (2S)-Cyclobutyl 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)propanoate(24) [ka]

[0367] The preparation of (2S)-cyclobutyl 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)propanoate is described below. Preparation of (2S)-cyclobutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (compound G) [ka]

[0368] Phenyl dichlorophosphate (1.49 mL, 10 mmol) was dissolved in 10 mL of anhydrous DCM and stirred in an ice bath under atmospheric pressure and nitrogen. L-alanine isobutyl hydrochloride (0.9 g, 5 mmol) was added in one addition. Then, triethylamine (765 μL, 5.5 mmol) was added dropwise. The reaction mixture was stirred for 1 hour. Further triethylamine (765 μL, 5.5 mmol) was added dropwise, and the reaction mixture was stirred for 45 minutes. p-nitrophenol (1.25 g, 9 mmol) was added in one addition, and the mixture was stirred for 30 minutes. Triethylamine (765 μL, 5.5 mmol) was added, and the reaction mixture was stirred for 2 hours. Then, additional p-nitrophenol (1.25 g, 9 mmol) and triethylamine (765 μL, 5.5 mmol) were added, and the reaction mixture was stirred for a further 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained crude product was diluted with siRNA and washed twice with a 5% citric acid aqueous solution, followed by a saturated sodium chloride aqueous solution. Next, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column (0-20-50% siRNA in hexane) to obtain compound G (1.48 g, 70% yield as a mixture of diastereomers). 1 HNMR (400MHz, CD3OD) δ 8.33 - 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]. Preparation of (2S)-cyclobutyl 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)propanoate (compound 24) [ka]

[0369] 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 in one step. The reaction mixture was heated to 50°C. DIPEA (87 μL, 0.5 mmol) was added, and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a 5% aqueous citric acid solution, followed by a saturated aqueous sodium chloride 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 (0-2-5% MeOH in DCM) to obtain Compound 24 (42 mg, 37% yield as a mixture of diastereomers). 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 (162 MHz, cd3od) δ 3.70, 3.65.MS m / z=573.0[M+H]. (Example 28) (2S)-Isopropyl 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-phenylpropanoate(25) [ka]

[0370] The preparation of (2S)-isopropyl 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-phenylpropanoate is described below. Preparation of (2S)-isopropyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoate (compound H) [ka]

[0371] Phenyl dichlorophosphate (718 μL, 4.8 mmol) was dissolved in 10 mL of anhydrous DCM and stirred in an ice bath under a nitrogen atmosphere. L-phenylalanine isopropyl hydrochloride (1 g, 4.1 mmol) was added in one addition. Another 10 mL of anhydrous DCM was added. Triethylamine (736 μL, 5.3 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. Next, a further triethylamine (736 μL, 5.3 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. Next, an additional triethylamine (736 μL, 5.3 mmol) was added dropwise, and the reaction mixture was stirred for 15 minutes. Next, p-nitrophenol (600 mg, 4.32 mmol) was added. Finally, the cold bath was removed, and the reaction mixture was warmed to room temperature and stirred for 2 hours. Further p-nitrophenol (50 mg) and triethylamine (736 μL, 5.3 mmol) were added, and the reaction mixture was stirred for 1 hour.

[0372] Next, the reaction mixture was concentrated under reduced pressure, diluted with toluene, and washed twice with 5% citric acid aqueous solution, followed by saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-15% toluene in hexane) to obtain compound H (1.57 g, 68% yield as a mixture of diastereomers). 1 HNMR(400MHz,CDCl3)δ 8.17 (m, 2H), 7.3 8 - 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, 1.8 Hz, 2H), 1.21 - 1.08(m, 6H). 31 PNMR (162MHz, cdcl3) δ-2.96, -2.98.MS m / z=485.0[M+H]. Preparation of (2S)-isopropyl 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-phenylpropanoate (compound 25) [ka]

[0373] 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. This reaction mixture was stirred at room temperature under a nitrogen atmosphere. 1 M tBuMgCl (300 μL, 0.3 mmol) in THF was added dropwise over 3 minutes, and the reaction mixture was then stirred for 16 hours. The reaction mixture was diluted with RINKAN and washed with 5% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and then saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column (0-5% MeOH in DCM) to obtain Compound 25 (40 mg, 32% yield as a mixture of diastereomers). 1 HNMR(400MHz,CD3OD)δ 7.84 (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 PNMR (162 MHz, CD3OD) δ 3.63, 3.25.MS m / z=637.0[M+H]. (Example 29) (S)-methyl 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)propanoate(26) [ka]

[0374] The preparation of (S)-methyl 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)propanoate is described below. [ka]

[0375] Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled in an ice bath. Next, 1 M t-BuMgCl (0.52 mL, 0.77 mmol) was slowly added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. Next, Compound I (prepared according to WO2012142085, 219 mg, 0.52 mmol) in THF (2 mL) was added over 5 minutes, and the resulting mixture was stirred at room temperature for 24 hours. Next, this reaction mixture was diluted with RINKAN, cooled in an ice bath, washed with aqueous NaHCO3 (2 mL), washed with brine, dried over sodium sulfate, and concentrated under vacuum. The resulting mixture was purified by silica gel column chromatography (in DCM, MeOH 0-20%) and preparative HPLC (in water, acetonitrile 10-80%) to obtain Compound 26 (12 mg, 6.6% as a single diastereomer). 1HNMR(400MHz,CD3OD)δ 7.86(s, 1H), 7.29 (dd, J = 8.6, 7.2 Hz, 2H),7.21- 7.09(m,3H), 6.94 - 6.81 (m,2H), 4.79 (d, J = 5.4 Hz, 1H), 4.38 (ddq, J = 10.8, 5.3, 2.7 Hz, 2H), 4.33 -4.23 (m, 1H), 4.18 (t, J = 5.5 Hz, 1H), 3.86 (dq, J =9.9,7.1Hz,1H),3.62(s, 3H), 1.27 (dd, J = 7.2, 1.1 Hz, 3H).MS m / z=533(M+1) + . (Example 30) (S)-Neopentyl 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)propanoate(27) [ka]

[0376] The preparation of (S)-neopentyl 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)propanoate is described below. [ka]

[0377] Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled in an ice bath. Next, 1 M t-BuMgCl (0.52 mL, 0.77 mmol) was slowly added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. Then, compound J (prepared according to WO2012075140, 248 mg, 0.52 mmol) was added over 5 minutes, and the resulting mixture was stirred at room temperature for 24 hours, diluted with phenylethylamine, cooled in an ice bath, treated with aqueous NaHCO3 (2 mL), washed with brine, dried over sodium sulfate, and concentrated under vacuum. The resulting mixture was purified by silica gel column chromatography (in DCM, 0-20% MeOH) and preparative HPLC (in water, 10-80% acetonitrile) to obtain compound 27 (12 mg, 10% as a single diastereomer). 1 HNMR(400MHz,CD3OD)δ 7.86 (s, 1H), 7.36 - 7.24 (m, 2H), 7.23 -7.10 (m,3H), 6.96 - 6.85(m, 2H), 4.78 (d, J = 5.4 Hz, 1H), 4.38 (tdd, J =10.0, 4.9, 2.5Hz, 2H), 4.32- 4.24 (m, 1H), 4.17 (t, J = 5.6 Hz, 1H), 3.91 (dq,J=9.8,7.1Hz, 1H), 3.81(d, J = 10.5 Hz, 1H), 3.69 (d, J = 10.5 Hz, 1H), 1.31(dd,J= 7.2,1.1Hz,3H), 0.89 (s, 9H).MS m / z=589(M+1) + . (Example 31) (2S)-Cyclopentyl 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)propanoate(28) [ka]

[0378] The preparation of (2S)-cyclopentyl 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)propanoate is described below. [ka]

[0379] Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled in an ice bath. Next, 1 M t-BuMgCl (0.52 mL, 0.77 mmol) was slowly added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. Next, Compound K (prepared according to WO2012075140, 247 mg, 0.52 mmol) in THF (2 mL) was added over 5 minutes, and the resulting mixture was stirred at room temperature for 24 hours, diluted with SiO2, cooled in an ice bath, treated with aqueous NaHCO3 (2 mL), washed with brine, dried over sodium sulfate, and concentrated in vacuum. The resulting mixture was purified by silica gel column chromatography (in DCM, 0-20% MeOH) and preparative HPLC (in water, 10-80% acetonitrile) to obtain Example 28 (47 mg, 23% as a 27:1 diastereomer mixture). 1H NMR (400 MHz, CD3OD) δ 7.85 (s, 1H), 7.33 - 7.22 (m, 2H), 7.14 (tdd,J =7.6,2.1, 1.1Hz, 3H), 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, 3.6 Hz, 1H), 4.19 (t, J = 5.4 Hz, 1H), 3.78 (dq, J=9.2,7.1 Hz, 1H), 1.81 (dtd, J = 12.5, 5.9, 2.4 Hz, 2H), 1.74 - 1.49 (m, 6H),1.21(dd, J = 7.1, 1.2 Hz, 3H).MS m / z=587(M+1) + . (Example 32) (2S)-Cyclohexyl 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)propanoate(29) [ka]

[0380] The preparation of (2S)-cyclohexyl 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)propanoate is described below. [ka]

[0381] A mixture consisting 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) was to be added dropwise with diisopropylethylamine (0.075 mL, 0.43 mmol) over 5 minutes at 0°C. The resulting mixture was stirred at 50°C for 1 hour. Next, the reaction mixture was cooled in an ice bath and treated with 1 M citric acid (0.5 mL). Direct purification by preparative HPLC (0-70% ACN in water) yielded compound 29 (20 mg, 19% as a mixture of diastereomers). 1 HNMR(400MHz,CD3OD)δ 7.84 (s, 1H), 7.32 - 7.23 (m, 2H), 7.18 - 7.10 (m, 3H), 6.93 - 6.87(m, 2H), 4.78 (d, J = 5.4 Hz, 1H), 4.67(td,J=8.7,4.2 Hz, 1H), 4.48 - 4.35(m, 2H), 4.30 (ddd, J = 10.8, 5.7, 3.7Hz,1H),4.20 (t,J =5.4 Hz, 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 (162 MHz, CD3OD)δ3.75.MS m / z=601( M+1) + . (Example 33) Ethyl 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-methylpropanoate(30) [ka]

[0382] The preparation of ethyl 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-methylpropanoate is described below. Preparation of ethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate [ka]

[0383] THF (30 mL) contains triphenylphosphine (6.18 g, 25.00 mmol) Dissolve the methylpropanoate. Next, add DIAD (4.92 mL, 25.00 mmol) and stir at room temperature for 10 minutes. Dissolve 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (5.08 g, 25.00 mmol) in THF (20 mL) and add it to this reaction mixture, then add ethanol (2.19 mL, 37.49 mmol). Stir this reaction mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and dissolve the crude product in 1:1 Et2O:hexane (120 mL). Filter off the solid triphenylphosphine oxide and remove the solvent under reduced pressure. Dissolve the crude product in the smallest amount of CH2Cl2 and purify by silica gel chromatography (0-50% siRNA / hexane) to obtain ethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (2.71 g, 47%). 1 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). Preparation of ethyl 2-amino-2-methylpropanoate hydrochloride [ka]

[0384] Ethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (2.71 g, 11.72 mmol) was dissolved in CH2Cl2 (25 mL), and 4N HCl (25 mmol) in dioxane was slowly added, and the mixture was stirred at room temperature. After 1 hour, the reaction was determined to be complete by TLC. The solvent was removed under reduced pressure, and the crude product was co-evaporated twice with Et2O, and then placed under high vacuum to obtain ethyl 2-amino-2-methylpropanoate hydrochloride (2.02 g, 102%). 1 HNMR(400MHz,DMSO-d6)δ 8.70 (s, 3H), 4.18 (q, J = 7.1 Hz, 2H),1.46 (s,6H),1.21(t, J =7.1 Hz, 3H). Preparation of ethyl 2-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (compound N) [ka]

[0385] Dissolve phenyl dichlorophosphate (0.97 mL, 6.50 mmol) and ethyl 2-amino-2-methylpropanoate hydrochloride (1.09 g, 6.50 mmol) in CH2Cl2 (50 mL). Cool this reaction mixture to 0°C and slowly add TEA (1.75 mL, 12.45 mmol). Remove the cooling bath and stir the reaction mixture at room temperature. After 2 hours, confirm that the addition of amino acids is complete. 31 The reaction was determined by 1P NMR. p-nitrophenol (0.860 g, 6.17 mmol) was added, followed by TEA (0.87, 7.69 mmol). The reaction mixture was stirred at room temperature. After 2 hours, the reaction was determined to be complete by LC-MS. The reaction mixture was diluted with Et2O and TEA was added. * The HCl salt was filtered off. The crude product was concentrated and purified by silica gel chromatography (0-50% siRNA / hexane) to obtain compound N (1.79 g, 68%). 1 HNMR(400MHz,DMSO-d6)δ 8.37 - 8.21 (m, 2H), 7.55 - 7.44 (m, 2H), 7.43 - 7.33 (m, 2H), 7.30- 7.09 (m, 3H), 6.57 (d, J = 10.1 Hz, 1H),3.99(q,J=7.1 Hz, 2H), 1.39 (s,6H), 1.08 (t, J = 7.1 Hz, 3H). 31 PNMR (162MHz, DMSO-d6) )δ -2.87.LC / MS:t R=1.65 min, MS m / z=408.97[M+1];LC system: Thermo Accela 1250 UHPLC;MS system: Thermo LCQ Fleet;Column: Kinetex 2.6μ XB-C18 100A, 50x3.00mm;Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid;Gradient: 1.8 mL / min, 2-100% ACN from 0 min to 2.4 min, 100% ACN from 2.4 min to 2.80 min, 100%-2% ACN from 2.8 min to 2.85 min, 2% ACN from 2.85 min to 3.0 min. Preparation of ethyl 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-methylpropanoate (compound 30) [ka]

[0386] Compound 1 (66 mg, 0.23 mmol) was dissolved in NMP (2.0 mL). This mixture was cooled to 0°C, and tBuMgCl (1.0 M in THF, 0.34 mL, 0.34 mmol) was slowly added. The reaction mixture was stirred at 0°C for 30 minutes, and then a solution of Compound N (139 mg, 0.34 mmol) dissolved in THF (1.0 mL) was added. The cooling bath was removed, and the reaction mixture was placed in a preheated oil bath at 50°C. After 2 hours, the reaction mixture was cooled to room temperature and quenched with acetic acid and methanol. The crude product was concentrated and purified by reverse-phase HPLC without modifiers to obtain Compound 30 (32 mg, 25% as a mixture of diastereomers). 1 HNMR(400MHz,DMSO-d6)δ 7.89 (m, 3H), 7.31 (q, J = 8.1 Hz, 2H),7.22 - 7.05 (m, 3H), 6.87(d, J = 4.5, 1H), 6.80 (d, J = 4.5 Hz, 1H), 6.27 (d, J = 11.7, 1H), 5.81 (d, J= 9.7, 1H), 5.35 (d, J = 5.6 Hz,1H),4.64 (dt, J = 9.0, 5.6 Hz, 1H), 4.24 (m,2H), 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 =1.03 min, MS m / z=561.03[M+1];LC system System: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50x3.00mm; Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 1.8 mL / min, 0-2.4 min: 2-100% ACN, 2.4-2.80 min: 100% ACN, 2.8-2.85 min: 100%-2% ACN, 2.85-3.0 min: 2% ACN. (Example 34) Isopropyl 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-methylpropanoate(31) [ka]

[0387] The preparation of isopropyl 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-methylpropanoate is described below. Preparation of isopropyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate [ka]

[0388] Dissolve triphenylphosphine (6.17 g, 25.00 mmol) in THF (30 mL). Next, add DIAD (4.92 mL, 25.00 mmol) and stir at room temperature for 10 minutes. Dissolve 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (5.07 g, 25.00 mmol) in THF (20 mL) and add to this reaction mixture, then add isopropanol (1.91 mL, 25.00 mmol). Stir this reaction mixture at room temperature for 1 hour. Remove the solvent under reduced pressure and dissolve the crude product in 1:1 Et2O:hexane (120 mL). Filter off the solid triphenylphosphine oxide and remove the solvent under reduced pressure. The crude product was dissolved in the smallest amount of CH2Cl2 and purified by silica gel chromatography (Â / hexane 0-50%) to obtain isopropyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (4.09 g, 67%). 1 1H 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). Preparation of isopropyl 2-amino-2-methylpropanoate hydrochloride [ka]

[0389] Isopropyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (4.09 g, 16.67 mmol) was dissolved in CH2Cl2 (50 mL), and 4N HCl (50 mmol) in dioxane was slowly added, and the mixture was stirred at room temperature. After 1 hour, the reaction was determined to be complete by TLC. The solvent was removed under reduced pressure, and the crude product was co-evaporated twice with Et2O, and then placed under high vacuum to obtain isopropyl 2-amino-2-methylpropanoate hydrochloride (3.06 g, 101%). 1 HNMR (400 MHz, DMSO-d6) δ 8.61 (s, 3H), 4.96 (p, J = 6.2Hz,1H),1.44(s,6H), 1.22 (d, J = 6.2 Hz, 6H). Preparation of isopropyl 2-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (compound O) [ka]

[0390] Dissolve phenyl dichlorophosphate (0.83 mL, 5.58 mmol) and isopropyl 2-amino-2-methylpropanoate hydrochloride (1.01 g, 5.58 mmol) in CH2Cl2 (50 mL). Cool this reaction mixture to 0°C and slowly add TEA (1.61 mL, 11.45 mmol). Remove the cooling bath and stir the reaction mixture at room temperature. After 2 hours, confirm that the addition of amino acids is complete. 31 The reaction was determined by 1P NMR. p-nitrophenol (0.74 g, 5.30 mmol) was added, followed by TEA (0.81, 5.84 mmol). The reaction mixture was stirred at room temperature. After 2 hours, LC-MS determined that the reaction was complete. The reaction mixture was diluted with Et2O, and TEA was added. * The HCl salt was filtered off. The crude product was concentrated and purified by silica gel chromatography (0-50% siRNA / hexane) to obtain compound O (1.45 g, 62%). 1HNMR(400MHz,DMSO-d6)δ 8.42 - 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 = 10.1 Hz, 1H),4.82 ( Septet, J =6.3 Hz,1H), 1.38 (s, 6H), 1.09 (d, J = 6.3, 6H). 31 PNMR(162MHz,DMSO-d6)δ-2.84.LC / MS:t R =1.73 min, MS m / z=422.92[ [M+1];LC system: Thermo Accela 1250 UHPLC;MS system: Thermo LCQ Fleet;Column: Kinetex 2.6μ XB-C18 100A, 50x3.00mm;Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid;Gradient: 1.8 mL / min, 0 min to 2.4 min: 2 to 100% ACN, 2.4 min to 2.80 min: 100% ACN, 2.8 min to 2.85 min: 100% to 2% ACN, 2.85 min to 3.0 min: 2% ACN. Preparation of isopropyl 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-methylpropanoate (compound 31) [ka]

[0391] Compound 1 (66 mg, 0.23 mmol) was dissolved in NMP (2.0 mL). This mixture was cooled to 0°C, and tBuMgCl (1.0 M in THF, 0.57 mL, 0.57 mmol) was slowly added. The reaction mixture was stirred at 0°C for 30 minutes, and then a solution of Compound O (143 mg, 0.34 mmol) dissolved in THF (1.0 mL) was added. The cooling bath was removed, and the reaction mixture was placed in a preheated oil bath at 50°C. After 2 hours, the reaction mixture was cooled to room temperature and quenched with acetic acid and methanol. The crude product was concentrated and purified by reverse-phase HPLC without modifiers to obtain Compound 31 (48 mg, 37% as a mixture of diastereomers). 1 HNMR(400MHz,DMSO-d6)δ 7.88 (m, 3H), 7.30 (td, J = 8.5, 7.0 Hz, 2H), 7.20 - 7.04(m,3H),6.87 (d, J = 4.5, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.27 (d, 6.1 Hz, 1H), 5.75 (t,J = 9.1 Hz, 1H), 5.34 (d, J=5.7Hz,1H),4.81 (p, J = 6.3 Hz, 1H), 4.71 -4.50 (m, 1H), 4.23 (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)δ 2.47, 2.43.LC / MS:t R =1.08 min, MS m / z=575.06[M+1];LC System: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50x3.00mm; Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 1.8 mL / min, 0-2.4 min: 2-100% ACN, 2.4-2.80 min: 100% ACN, 2.8-2.85 min: 100%-2% ACN, 2.85-3.0 min: 2% ACN. (Example 35) (S)-2-ethylbutyl2-(((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)propanoate(32) [ka]

[0392] The preparation of (S)-2-ethylbutyl 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)propanoate is described below. Preparation of (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one. [ka]

[0393] (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), K2HPO4 aqueous solution (2.5 M, 14.3 mL), and TEMPO (56 mg). This mixture was cooled to approximately 1°C. An aqueous bleaching solution (7.9% by weight) was slowly added in small amounts until the starting materials were completely consumed, as indicated by the starch / iodine test. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic phase was dried over MgSO4 and concentrated under reduced pressure to obtain the product as a solid. Preparation of (4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine) [ka]

[0394] To a cold solution of 4-aminopyrrolo[2,1-f][1,2,4]-triazine (10.03 g; 74.8 mmol) in N,N-dimethylformamide (70.27 g), N-iodosuccinimide (17.01 g; 75.6 mmol) was added in small quantities while maintaining the contents at approximately 0°C. After the reaction was complete (approximately 3 hours at approximately 0°C), the reaction mixture was transferred to a 1 M sodium hydroxide aqueous solution (11 g NaOH and 276 mL of water) while maintaining the contents at approximately 20-30°C. The resulting slurry was stirred at approximately 22°C for 1.5 hours and then filtered. The solid was rinsed with water (50 mL) and dried under vacuum at approximately 50°C to obtain 4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine as a solid. 1 HNMR(400MHz,DMSO-d6)δ 7.90 (s, 1H), 7.78 (br s, 2H), 6.98 (d, J = 4.4 Hz, 1H), 6.82 (d, J= 4.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ155.7,149.1,118.8,118.1,104.4, 71.9.MS m / z=260.97[M+H]. 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 using (4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine) [ka]

[0395] Under a nitrogen atmosphere, iodobase 2 (81 g) and THF (1.6 L) were added to the reactor. The resulting solution was cooled to approximately 5°C, and TMSCl (68 g) was added. Next, while maintaining the internal temperature below approximately 5°C, PhMgCl (345 mL, 1.8 M in THF) was slowly added. This reaction mixture was stirred at approximately 0°C for 30 minutes, and then cooled to approximately -15°C. While maintaining the internal temperature below approximately -12°C, iPrMgCl-LiCl (311 mL, 1.1 M in THF) was slowly added. After stirring at approximately -15°C for approximately 10 minutes, this reaction mixture was cooled to approximately -20°C, and a solution of lactone 1 (130 g) in THF (400 mL) was added. Next, this reaction mixture was stirred at approximately -20°C for approximately 1 hour and quenched with AcOH (57 mL). The reaction mixture was warmed to approximately 0°C and the pH was adjusted to 7-8 with aqueous NaHCO3 (5% by weight, 1300 mL). Next, the reaction mixture was diluted with HCl (1300 mL) and the organic and aqueous layers were separated. The organic layer was washed with 1N HCl (1300 mL), aqueous NaHCO3 (5% by weight, 1300 mL), and brine (1300 mL), and then dried over anhydrous Na2SO4 to concentrate and dry. The product was obtained by purification using silica gel column chromatography with a gradient consisting of a mixture of MeOH and HCl. Preparation of ((2S)-2-ethylbutyl 2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate) (a mixture of Sp and Rp): [ka]

[0396] L-alanine 2-ethylbutyl ester hydrochloride (5.0g, 23.84 mmol) Combine with methylene chloride (40 mL) cooled to -78 °C, and phenyl dichlorophosphate ( 3.65 mL (23.84 mmol) was added. Triethylamine (6.6 mL, 47.68 mmol) was added over approximately 60 minutes at approximately -78°C, and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was cooled to approximately 0°C, and pentafluorophenol (4.4 g, 23.84 mmol) was added. Triethylamine (3.3 mL, 23.84 mmol) was added over approximately 60 minutes. The mixture was stirred at ambient temperature for approximately 3 hours and concentrated under reduced pressure. The residue was dissolved in toluene, 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 (0-30%) of toluene and hexane. When the product-containing fraction was concentrated under reduced pressure, (2S)-2-ethylbutyl 2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate was obtained as a solid. 1 HNMR (400MHz, 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 1P NMR (162 MHz, chloroform-d) δ-1.52. 19 FNMR (377 MHz, chloroform-d) δ -153.63, -153.93 (m), -160.05 (td, J = 21.9, 3.6 Hz), -162.65 (qd, J = 22.4, 20.5, 4.5 Hz). MS m / z = 496 [M + H]. Preparation of the title compound (a mixture of Sp and Rp): [ka]

[0397] Nucleoside (29 mg, 0.1 mmol), phosphonamide (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 mixture 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 over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a methanol and CH2Cl2 gradient (0-5%). The product-containing fraction was concentrated under reduced pressure to obtain the product. Preparation of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofloxacin[3,4-d][1,3]dioxol-4-carbonitrile: [ka]

[0398] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5.8g, 0.02mol), 2,2-dimethoxypropyl A mixture of pan (11.59 mL, 0.09 mol) and acetone (145 mL) was mixed with sulfuric acid (18 M, 1.44 mL) at ambient temperature. This mixture was heated to approximately 45°C. After approximately 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 obtain crude (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitride. 1 HNMR(400MHz, CD3OD) δ7.84(s, 1H), 6.93 (d, J = 4.6 Hz, 1H), 6.89(d, J = 4.6 Hz, 1H),5.40 (d, J = 6.7 Hz, 1H),5.00(dd,J = 6.7, 3.3 Hz, 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]. Preparation of (2S)-2-ethylbutyl 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)propanoate: [ka]

[0399] At ambient temperature, acetonitrile (100 mL) was combined with (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)-amino)propanoate (9.6 g, 21.31 mmol), substrate alcohol (6.6 g, 0.02 mol), and magnesium chloride (1.9 g, 19.91 mmol). This mixture was stirred for about 15 minutes, and N,N-diisopropylethylamine (8.67 mL, 49.78 mmol) was added. After about 4 hours, the reaction product was diluted with ethyl acetate (100 mL), cooled to about 0°C, and combined with citric acid aqueous solution (5% by weight, 100 mL). The organic phase was washed with citric acid aqueous solution (5% by weight, 100 mL), saturated ammonium chloride aqueous solution (40 mL), potassium carbonate aqueous solution (10% by weight, 2 × 100 mL), and saturated brine aqueous solution (100 mL). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to obtain the crude product. 1 HNMR(400MHz,CD3OD)δ 7.86 (s, 1H), 7.31 - 7.22 (m, 2H), 7.17 -7.09 (m,3H),6.93 -6.84(m, 2H), 5.34(d, J = 6.7 Hz, 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, 5.7 Hz, 1H), 3.83 (dq, J = 9.7, 7.1 Hz, 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]. Preparation of (S)-2-ethylbutyl 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)propanoate (compound 32) [ka]

[0400] Crude acetonide (12.85 g) was combined with tetrahydrofuran (50 mL) and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), cooled to approximately 0°C, and concentrated HCl (20 mL) was slowly added. The mixture was warmed to ambient temperature. After the starting acetonide was consumed as shown by HPLC analysis, water (100 mL) and then saturated sodium bicarbonate aqueous solution (200 mL) were added. This mixture was extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine aqueous solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a methanol and ethyl acetate gradient (0-20%). The product-containing fraction was concentrated under reduced pressure to obtain the product. B. Antiviral activity

[0401] Another aspect of the present invention relates to a method for inhibiting a viral infection, comprising the step of treating a sample or subject suspected to require such inhibition with a composition of this specification.

[0402] In the context of this invention, samples suspected of containing viruses include natural or artificial substances such as living organisms, biological samples such as tissues or cell cultures, samples of biological materials (such as blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, and tissue samples), laboratory samples, food, water or air samples, bioproduct samples such as cell extracts, and in particular recombinant cells that synthesize desired glycoproteins. Typically, samples are suspected of containing organisms that induce viral infection, often pathogenic organisms such as tumor viruses. Samples can be contained in any medium, including water and organic solvent / water mixtures. Samples include living organisms such as humans, and artificial substances such as cell cultures.

[0403] If desired, the antiviral activity of the compounds of the present invention after application of the composition may be observed by any means, including direct and indirect methods for detecting such activity. All quantitative, qualitative, and semi-quantitative methods for determining such activity are intended. Typically, one of the above screening methods is applied, but any other method is applicable, such as observing the physiological characteristics of living organisms.

[0404] The antiviral activity of the compounds of the present invention can be measured using known standard screening protocols. For example, the antiviral activity of the compounds can be measured using the following general protocol. [Table 6] (Example 36) Antiviral activity and cytotoxicity assays of Lassa virus and Junin virus

[0405] The antiviral activity of compounds 1, 9, and 32 against Lassa virus (LASV) and Junin virus (JUNV) was measured. All studies using wild-type viruses were conducted in a biosafety level 4 containment (BSL-4) environment at the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID). Antiviral assays using attenuated JUNV strains were performed in a BSL-2 laboratory at Utah State University. Antiviral assays for Lassa virus were performed in HeLa cells. Antiviral assays for Junin virus were performed in Vero and HeLa cells.

[0406] Antiviral assays were performed in 384 or 96-well plates within BSL-4 containment using a high-content imaging system to quantify viral antigen production as a measure of viral replication. Each plate included a control (column 2) that was "virus-free" and a control (column 3) that was "1% DMSO" to determine 0% and 100% viral replication signals, respectively. The primary antibodies used for detecting viral antigens were mm L52-161-6 anti-GP;LASV and mm Y-GQC03_BF11 anti-GP, while JUNV and DyLight 488 anti-mouse-IgG were used as secondary detection antibodies. The primary antibodies were diluted 1000-fold in blocking buffer (1x PBS containing 3% BSA) and added to each well of the assay plate. The assay plates were incubated at room temperature for 60 minutes. The primary antibodies were removed, and the cells were washed three times with 1x PBS. The secondary antibodies were diluted 1000-fold in blocking buffer and added to each well of the assay plate. These assay plates were incubated at room temperature for 60 minutes. Nuclei were stained using Draq5 (Biostatus, Shepshed Leicestershire, UK, catalog number DR05500) diluted with 1x PBS. Cell images were acquired using a Perkin Elmer Opera confocal microscope (Perkin Elmer, Waltham, MA) with a 10x air objective lens, per well. Five images were collected. Virus-specific antigens were quantified by measuring fluorescence emission at a wavelength of 488 nm, and nuclei were quantified by measuring fluorescence emission at a wavelength of 640 nm. The Z' values ​​for all antiviral assays were greater than 0.3.

[0407] These inhibition percentages were calculated for each test concentration relative to 0% and 100% inhibition controls, and the EC of each compound was calculated. 50 The values ​​were determined by nonlinear regression as the effective concentration of a compound that inhibits viral replication by 50%. (Example 37) Junin virus assay-Vero

[0408] Vero cells or Vero E6 cells were seeded in 100 μL of MEM + 2% FBS at a rate of 20,000 cells per well in 96-well plates. Compounds diluted in DMSO were mixed with 120 μL of MEM + 2% FBS. 100 μL of each test compound was transferred to two wells of the 96-well plate. 20 μL of virus solution in MEM + 20% FBS was added to achieve final test concentrations of 47, 4.7, 0.47, and 0.047 μM, with an infection multiplicity of 0.003 pfu / cell. The test plates were incubated until the untreated virus control approached the maximum cytopathic effect (CPE) (5–7 days). The plates were then stained with neutral red dye for 2 hours, followed by elution in citrate / ethanol buffer and read by spectrophotometer at 540 nm. The EC50 value, which represents the concentration of the test compound required to reduce virus-induced CPE by 50%, as measured by neutral red staining, is calculated using regression analysis. (Example 38) Junin virus assay - HeLa

[0409] HeLa cells were seeded at a rate of 2000 cells per well in 384-well plates, and the compound was added to the assay plate as described in section 3.2.1. The assay plate was transferred to a BSL-4 suite and infected with 0.3 pfu per JUNV cell, resulting in approximately 50% of cells expressing the viral antigen over a 48-hour period. The assay plate was incubated for 48 hours, and viral replication was quantified by immunostaining using an antibody that recognizes the viral glycoprotein. (Example 39) Lassa virus assay

[0410] HeLa cells were seeded at a rate of 2000 cells per well in 384-well plates, and the compound was added to the assay plate as described in section 3.2.1. The assay plate was transferred to a BSL-4 suite and infected with 0.1 pfu per LASV cell, resulting in over 60% of cells expressing the viral antigen over a 48-hour period. The assay plate was incubated for 48 hours, and viral replication was quantified by immunostaining using an antibody that recognizes the viral glycoprotein. Table 2: Antiviral assays of Lass...

Claims

[Claim 1] The need for a method for treating a viral infection.

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