TW201215395A - Substituted nucleotide analogs - Google Patents

Abstract

Disclosed herein are phosphoroamidate nucleotide analogs, methods of synthesizing phosphoroamidate nucleotide analogs and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with the phosphoroamidate nucleotide analogs.

Description

201215395 VI. Description of the invention: [Technical field to which the invention belongs] Fengjia Mingyu is in the fields of chemistry, biochemistry and medicine. More specifically, disclosed herein is a phosphatidyl nucleoside analog, a pharmaceutical composition comprising _ = a plurality of nucleotide analogs, and a method of synthesizing the same. This disclosure also discloses a method of treating a disease and/or condition with a combination of a phosphatidyl nucleoside acid analog or a combination therapy with other agents. The relevant application also refers to the US provisional application No. 61/38M25, which is filed on September 22, 2010, and the US provisional application for the month of December 22, 2G1 (). /426,467; both of which are incorporated herein by reference in their entirety, in their entirety. [Prior Art]

Nucleoside analogs are compounds that have been shown to exert antiviral and anticancer activities in vitro and in vivo, and have thus been the subject of extensive research for the treatment of viral infections and cancer. Nucleoside analogs are generally non-therapeutic active compounds which are converted by the host or viral enzyme into their respective active antimetabolites which in turn inhibit the polymerase involved in viral or cell proliferation. Activation can be accomplished by a variety of mechanisms, such as the addition of one or more phosphate groups and other metabolic processes, or in combination with other metabolic processes. SUMMARY OF THE INVENTION Some embodiments disclosed herein are directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to ameliorating and/or treating neoplastic disorders

S 158869.doc 201215395 The method of the invention may comprise administering to a subject having a neoplastic disease a therapeutically effective amount of one or more compounds of formula (1), or a pharmaceutically acceptable salt thereof, or comprising one or more compounds of formula (1) or A pharmaceutical composition of a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for ameliorating and/or treating a neoplastic disorder. Other embodiments described herein are directed to one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, useful for ameliorating and/or treating a neoplastic disorder. Some embodiments disclosed herein are directed to methods of inhibiting tumor growth, which can comprise administering to a subject having a tumor a therapeutically effective amount of one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or comprising one or A pharmaceutical composition of a plurality of compounds of formula (1) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting tumor growth. Other embodiments described herein pertain to one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof useful for inhibiting tumor growth. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a viral infection, which can comprise administering to a subject having a viral infection a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the manufacture of a medicament for ameliorating and/or treating a viral infection using one or more formula (1) human or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to one or more compounds of formula (I) useful in the modification and/or treatment of viral infections, or a salt acceptable for use in Pharmacology 158869.doc 201215395. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a viral infection, which may comprise administering a virus-infecting cell with an effective amount of one or more of the compounds herein, or one or more of the compounds described herein. A pharmaceutically acceptable salt, or a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein relate to the manufacture of a medicament for ameliorating and/or treating a viral infection using - or a plurality of compounds described herein, or one or more pharmaceutically acceptable salts of the compounds described herein. And/or treating a viral infection can comprise contacting the virus-infected cell with an effective amount of the compound or compounds. Other embodiments described herein are directed to improving and/or treating a viral infection, one or more of the compounds described herein, or - or a plurality of pharmaceutically acceptable salts of the compounds described herein, to improve and/or treat the virus Infection is achieved by contacting the virus-infected cells with an effective amount of the compound or compounds. Some embodiments disclosed herein are directed to methods of inhibiting viral replication comprising: sensitizing a virus-infecting cell with an effective amount of one or more of the pharmaceutically acceptable pharmaceutically acceptable substances, or one or more of the compounds described herein. Accepted salts, or pharmaceutical compositions comprising - or a plurality of the compounds described herein, or a pharmaceutically acceptable salt thereof, are contacted. Other embodiments described herein are directed to the use of one or more of the compounds described herein or one or more of the pharmaceutically acceptable salts of the compounds described herein to produce a medicament for inhibiting viral replication, which may include The virus-infected cells are contacted with an effective amount of the or X-equivalent alpha. Other embodiments described herein pertain to pharmaceutically acceptable salts of one or more of the compounds described herein, or one or more compounds described herein, which are useful for replication of the virus of s158869.doc 201215395, which inhibits viral replication This is achieved by contacting the virus-infected cells with an effective amount of the compound or compounds. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a parasitic disease, which can include administering to a subject having a parasitic disease a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable A salt acceptable, or a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for ameliorating and/or treating a genetic disease. Other embodiments described herein pertain to one or more compounds of formula (1), or a pharmaceutically acceptable salt thereof, useful for ameliorating and/or treating parasitic diseases. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a viral infection 'which can include administering to a subject having a viral infection a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (eg, formula (1) Compound 'a monophosphate 'diphosphate and/or triphosphate, or a pharmaceutically acceptable salt thereof' or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and From the following agents: dry g, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5 A inhibitor, other antiviral compound, compound of formula (BB) or a pharmaceutically acceptable salt thereof A compound of the formula (CC) or a pharmaceutically acceptable salt thereof and a compound of the formula (DD) or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein are directed to a method for ameliorating and/or treating a viral infection 158869. doc 201215395, which may comprise infecting a virus-infected cell with a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, a compound of formula (I), a monophosphate, a diphosphate and/or a triphosphate thereof, or a pharmaceutically acceptable salt thereof), or a compound described herein or a pharmaceutically acceptable salt thereof Pharmaceutical compositions, and agents selected from the group consisting of interferons, ribavirins, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of formula (BB) or pharmaceutically acceptable a salt, a compound of the formula (CC) or a pharmaceutically acceptable salt thereof, and a compound of the formula (DD) or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein are directed to methods of inhibiting viral replication, which can comprise administering to a subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (I), a monophosphate thereof, a bisphosphonate and/or triphosphate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and an agent selected from the group consisting of interferon , ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5 A inhibitor, other antiviral compound, compound of formula (BB) or a pharmaceutically acceptable salt thereof, a compound of formula (CC) or a pharmaceutically thereof thereof An acceptable salt, and a compound of formula (DD) or a pharmaceutically acceptable salt thereof. In some embodiments, the agent may be a compound selected from the group consisting of compounds 1001-1014, 2001-2010, 3001-3008, 4001-4005, 5001-5002, 6000-6078, 8000-8012 or 9000 or a pharmaceutically acceptable compound thereof A salt acceptable, or a pharmaceutical composition comprising one or more of the above compounds or a pharmaceutically acceptable salt thereof. In some embodiments, the method can further comprise administering a second agent selected from the group consisting of interferon, ribavirin, HCV protease inhibitor,

S 158869.doc 201215395 HCV polymerase inhibitor, NS5A inhibitor, other antiviral compound, a compound of formula (BB) or a pharmaceutically acceptable salt thereof, a compound of formula (cc) or a pharmaceutically acceptable salt thereof, And a compound of the formula (DD) or a pharmaceutically acceptable salt thereof. In some embodiments, the virus is infected with HcV. [Embodiment] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by the ordinary skill. All patents, applications, published applications, and other publications herein are hereby incorporated by reference in their entirety herein in their entirety. In the case where there are a plurality of definitions of the terms herein, unless otherwise stated, the definitions in this section are dominant. Any "R|美圃, ten U"丞圏 as used herein, such as (not limited to) R, P3a, , r > 4 s _ ic - r2 nm, R' r8, r9 rio r " R13, R14, R15 , Ri6, Rl7, RlA, r2a, r3b

R

R

R

R

R, R8A and R" indicate attachment to the indicated atom 々 substituent. The R group can be substituted or unsubstituted. If two "r" are described as "connected together, 丨吋玺, 丨吋玺" soil 11 , w S", the material group and its attached atom q form a cycloalkyl, aryl, heteroaryl or If the NRlaRlb tomb 々nla Ih is exemplified by Lu (not limited to), the Ru and Rlb of the right nr R group are indicated as "covalently bonded to each other to form a ring:", meaning /Ra —\ , Rb 彼基A group may be described as being unsubstituted as a group when the group is described as "as appropriate" or substituted by one or more of the substituents shown. Similarly 158869.doc 201215395, if unsubstituted or substituted, the substituent may be selected from one or more of the substituents indicated. If a substituent is not indicated, it is meant that the "optionally substituted" or "substituted" group as indicated may be substituted by one or more groups individually and independently selected from alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, hydroxyalkyl, (heteroalicyclic) leukoyl, thiol, protected Permeation group, alkoxy group, aryloxy group, mercapto group, mercapto group, alkylthio group, arylthio group, cyano group, halogen, thiocarbonyl group, hydrazine-amine fluorenyl group, hydrazine carbamoyl group, hydrazine sulphur Aminyl thioglycolyl, C-nonylamino, hydrazine-nonylamino, s-sulfonylamino, hydrazine-sulfonylamino, c•carboxyl, protected c•carboxyl, 〇_carboxyl, isocyanosyl, thiocyano, isothiocyano, nitro, decyl, sulfenyl, sulfinyl, sulfonyl, alkyl, haloalkoxy, trimetho A sulfonyl group, a tri-f-substrate (tetra) group, a silk, a mono-substituted amine group, a disubstituted amine group, and a protected derivative thereof. As used herein, "ca to Cb" (wherein ra" and "b" are integers) refers to the number of carbon atoms in the pendant, alkenyl or alkynyl group or a cycloalkyl, cyclodecyl, cycloalkynylaryl group, The number of carbon atoms in the ring of the heteroaryl or heteroalicyclic group. That is, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl ring, a cycloalkenyl ring, a cycloalkynyl ring, an aryl ring, a heteroaryl ring or a heteroalicyclic ring may contain "a". To "b" (including "a" and "b") carbon atoms. Thus, for example, '(^ to ^alkyl) means all alkyl groups having ! to 4 carbons, namely... ch3ch2-^ ch3ch2ch2-^(ch3)2ch-.ch3ch2ch2ch2-.ch3ch2ch(ch3)-and (CH3)3C-. If the alkyl group, the dilute group n, the cyclodextyl group, the cycloaliphatic group, the cycloalkynyl group, the aryl group, the heteroaryl group or the heteroalicyclic group are not referred to 158869.doc „ ^ 201215395 定 “a” And "b", the broadest range stated in the definitions is assumed. "Alkyl" as used herein refers to a straight or branched chain containing a completely saturated (free or double-bonded) nicotine group. Hydrocarbon chain. The yard group may have 12 carbon atoms (when it appears herein, such as Μ·), the numerical range refers to each integer in the given _: ❹ "β2 () carbon atoms" means alkyl It may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to a carbon atom (and including 20 carbon atoms), although the definition of the present invention also covers the term "calculated base" The group may also be a medium alkyl group having 1 to 10 carbon atoms. The compound group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group may be designated as "C"-C4 alkyl" or a similar private group. By way of example only, "Ci_C4 alkyl" indicates the presence of from 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of hydrazine. Base, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl and tert-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, iso The propyl, butyl, isobutyl, t-butyl, pentyl and hexyl-alkyl groups may be substituted or unsubstituted. As used herein, "alkenyl" means contained in a straight or branched hydrocarbon chain. Or a plurality of double-bonded groups. The dilute group may be unsubstituted or substituted. As used herein, "alkynyl" means an alkyl group having a bond or a bond in a straight or branched hydrocarbon chain. Unsubstituted or substituted. As used herein, "cycloalkyl" refers to a mono- or polycyclic hydrocarbon ring system that is fully saturated (without double or para-bonding). When composed of two or more rings The rings may be fused together in a fused manner. The cycloalkyl group may contain from 3 to 1 atom in the ring or from 3 to 8 atoms in the ring. 158869.doc 201215395 Substituted or left substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, % pentyl, cyclohexyl, cycloheptyl and cyclooctyl. """ refers to a single J or polycyclic ring system containing one or more double bonds in at least one ring; although if more than one double bond exists, the bond does not form a complete delocalization in all of the rings. Π-electron system (otherwise the group is "aryl" as defined herein). When composed of two or more s, Bf 5 hai can be fused together in a condensed manner. Substituted or substituted. As used herein, "cyclo-fast radical" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more reference bonds in at least one ring. If there are more than one reference key, the reference key cannot form completely delocalized in all the rings. When composed of two or more rings, the rings can be connected in a slightly connected manner. The cycloalkynyl group may be unsubstituted or substituted. As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including two carbon ring sharing-chemical bond fused ring systems) which is completely detached throughout all The domain's redundant electronic system. The number of carbon atoms in the aryl group may vary. For example, Fangmei # — square base is C6-C14 square base, c6_Cl. Aryl 5 6 square soil. Examples of square groups include, but are not limited to, benzene, naphthalene, and chamomile rings. The aryl group may be substituted or unsubstituted. As used herein, "hetero A and upper heteropoly" refers to a monocyclic or polypyrene having an element containing one or more heteroatoms, including but not limited to nitrogen, oxygen and sulfur.糸 (a ring system with a completely delocalized π-electron system). The number of atoms in the heterocyclic ring can vary. For example, a heteroaryl group may contain from 4 to 14 atoms in the ring, from 5 to 1 atom in the ring or from 5 to 6 in the ring.

158869.doc S 201215395 atoms. Further, the term "heterophasic, s ^ soil" includes a fused ring system in which two rings (such as at least one aromatic ring and at least _ squid heteroaryl ring, or at least two heterocyclic rings) share at least one chemical bond. Examples of miscellaneous soils include, but not limited to, furan, furazan, thiophene, benzothiophene, guanidine, phlulu, ° dysentery, benzopyrene, 1,2,3-evil Azole, anthracene, 2 4_ 口亚_ 'cardiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, —,,, rice sniffing, stupid β sit, D bow 丨 π, carbazole, pyrazole, benzopyrazole, ritone, ν, acesulfame, isothiazole, oxadiazole, stupid triazole, thiadiazole, Than bismuth, pyridazine, cancer bite, mouth bismuth, sputum, bite, sputum, sputum is also eight scented, 啥 ° sitting, 啥 ° Ruo Lin, Yu Lin and triazine. The heteroaryl group may be substituted or unsubstituted. As used herein, "heterocyclic group" and "heteroalicyclic group" means 3 members, 4 shells '4'6 members, 7 members' 8 members, 9 members, 1 employee up to 18 members of single-ring bicyclic and tricyclic rings. A system in which a carbon atom together with (1) a hetero atom constitutes the ring system. The heterocycle may optionally contain - or more than one unsaturated bond, however, the one or more unsaturated bonds are disposed in such a way that there is no fully delocalized pi-electron system throughout all of the rings. Heteroatoms are elements other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. The heterocyclic ring may further contain one or more carbonyl or sulfur Ik-based g Hb groups ' such that the definition includes oxo systems (〇x〇_System) and thio-systems such as indoleamines, lactones a cyclic quinone imine, a cyclic thioimine, and a cyclic amino phthalate. When composed of two or more rings, the rings may be joined together in a fused manner. Additionally, any nitrogen in the heteroalicyclic group can be ammonium quaternized. The heterocyclic or heteroalicyclic group may be unsubstituted or substituted. Examples of such "heterocyclic group" or "heteroalicyclic group" include, but are not limited to, 1,3-dioxahedene, 1,3-dioxane, 1,4-di 158869.doc - 12· 201215395 Noisy, ... dioxolane, I, dioxolane, M_dioxol, 3_oxysulfide. Mountain, "· her well, ... oxygen thiophene, 1,3-monothiol, 1,3 dithiolane, anthracene, 'oxyxanthene, tetranitrogen_ι, heart 嗟 Qin 2Η 1,2 heart Qin, maleimide, succinimide, barbituric acid, thiobarbituric acid, two-sided oxy (four), B inner gland, dihydrourin shout, three Hum, hexahydro-; L, 3,5-triazine, oxazoline, oxazolidine, isoindole. Isolate, isoxazole, oxazoline, oxazolidine, oxazolidinone, thiazoline , thiazolidine, morpholine, ethylene oxide, piperidine oxide, piperidine, piperazine, pyridoxine, pyrrolidine _, pyrrolidone (pyrr〇lidi〇ne), 4-piperidone, pyridoxine , pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholine sub-milling, thiomorpholinium, and a benzene fused analog (eg, benzimidazolone, tetrahydroquinoline, 3,4-methylenedioxyphenyl). As used herein, "aralkyl" and "aryl" (alkyl) An aryl group which is bonded as a substituent via a lower alkyl group. The lower alkyl group of the aralkyl group and the aryl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl. As used herein, "heteroarylalkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group attached as a substituent via a lower alkyl group. The lower carbon alkyl and heteroaryl groups of the heteroarylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, nonylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazole Alkyl and its benzene fused analogs. "(heteroalicyclic)alkyl" and "(heterocyclyl)alkyl" refer to a heterocyclic or heteroalicyclic group which is bonded via a lower alkylalkyl group as a substituent 158869.doc •13·201215395. (heteroalicyclic) The lower alkylalkylene group of the alkyl group and the heterocyclic group may be substituted or unsubstituted. Examples include, but are not limited to, (tetrahydro-2H-piperidin-4-yl)methyl, (n-propyl-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-21) ^_Thiothiopyran-4-yl)methyl and (1,3-thiazinyl-4-yl)methyl. The low carbon number extension group is a tethering group which forms a bond to link a molecular fragment via its terminal carbon atom. Examples include, but are not limited to, methylene (_CH2_)' exoethyl (_ch2CH2_), propyl (-CH2CH2CH2-) and butyl (_ch2CH2CH2CH2-). The low carbon number extension group may be substituted by substituting one or more hydrogens of the low carbon number extension group with the substituents listed under the definition of "substituted". "Alkoxy" as used herein refers to the formula -OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl as defined above. A non-limiting list of alkoxy groups are decyloxy, ethoxy, n-propoxy, benzyloxy(isopropoxy), n-butoxy, isobutoxy, second butoxy and Tributoxy. The alkoxy group may be substituted or unsubstituted. As used herein, "mercapto" refers to a hydrogen, alkyl, alkenyl, alkynyl or aryl group attached as a substituent via a carbonyl group. Examples include anthracenyl, ethyl fluorenyl, propyl fluorenyl, phenyl fluorenyl and acryl fluorenyl groups. The thiol group may be substituted or unsubstituted. As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. The hydroxyalkyl group may be substituted or unsubstituted. 158869.doc •14· 201215395 As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (eg, monohaloalkyl, di-alkyl, and tri-alkyl). The group includes, but is not limited to, a gas group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-chloro-2-fluoromethyl group, a 2-fluoroisobutyl group. The alkyl group may be substituted or not. As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (eg, monodentate alkoxy, di-alkoxy, and trihaloalkoxy). Such groups include, but are not limited to, gas oxime, fluoromethoxy, difluoro ru, difluoromethoxy, and chloro-2-fluoromethoxy, 2- oxetoxy. The oxy group may be substituted or unsubstituted. As used herein, "aryloxy" and "arylthio" refer to RO- and RS_, wherein R is aryl, such as, but not limited to, phenyl. And arylthio groups may be substituted or unsubstituted. "Sulfosyl" refers to a "_SR" group, wherein R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Cycloalkynyl, aryl, heteroaryl , φ heteroaliphatic, aralkyl or (heteroalicyclic)alkyl. The sulfenyl group may be substituted or unsubstituted. The "yield" refers to the "_S(= 〇)_R" group. Wherein the ruler can be the same as defined for the sulfenyl group. The sulfinyl group can be substituted or unsubstituted. "Sulfo" refers to the "S〇2R" group, wherein the ruler can be the same as defined for the sulfenyl group. Sulfhydryl group may be substituted or unsubstituted. "〇-carboxy" means a "RC(=0)〇_" group, wherein R may be hydrogen, alkyl, alkenyl, alkynyl as defined herein , cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic) alkane 158869.doc ^ 201215395. The indole-fluorenyl group may be substituted or Not taken.

The terms "vinegar" and "C-carboxy" refer to a "-cpcOOR" group, wherein R can be as defined for a 0-lower group. Ester and oxime-rebels may be substituted or unsubstituted. "Sulphur Prison" means a "-C(=S)R" group wherein R may be as defined for 〇-carboxyl. The thiocarbonyl group may be substituted or unsubstituted. "Dihalosulfonylsulfonyl" means a "X3CS02-" group wherein X is a halogen. "三_曱烧sulfonylamino" means a group of "X3CS(0)2N(RA)-", wherein X is halogen and 1^ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, ring Alkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The term "amino" as used herein refers to a _Nh2 group. The term "hydroxy" as used herein refers to an -OH group. "Cyano" means a "-CN" group. The term "azido" as used herein refers to a -N3 group. "Isocyanate base j means a "-NCO" group. "Thiocyano" means a "_CNS" group. "Isothiocyanato" means a "_NCS" group. "巯基" means the "-SH" group. "Carbonyl" means a C=〇 group. "S• Shuoamine" means a group of "_S〇2N(RARB)", wherein ~ and Rb are independently hydrogen, affiliation, a dilute radical, a cycloalkyl, a cycloalkenyl, a cycloalkyne Base, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic) 158869.doc 201215395 alkyl. The s-alkylamino group may be substituted or unsubstituted. "N-sulfonylamino" means a "RS〇2N(RA)-" group in which the suffix and independently may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or ring. Alkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The N-continuous amidino group may be substituted or unsubstituted. "Ο-Aminomethyl" refers to a group of "-〇C(=〇)n(RaRb)", wherein Ra and Rb are independently hydrogen, alkyl, dilute, alkynyl, cyclononyl, and ring. Dilute, cycloalkynyl 'aryl, heteroaryl 'heteroalicyclic' aralkyl or (heteroester® cyclo)alkyl. The oxime-amines can be substituted or unsubstituted. "N-Amine thiol" means a group of "R〇c(=〇)n(Ra)_", wherein R and Ra are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The indole-amine group can be substituted or unsubstituted. "〇·thioaminyl" means a group of "_〇c(=s)_n(RaRb)", wherein RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl , φ cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (hetero)alkyl. 〇 _ thioamine broth can be substituted or unsubstituted 「 "N-thiocarbamyl" refers to the "r〇c (= s) n (Ra) _" group, where R and RA can Independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl . The N-thioaminecarbamyl group may be substituted or unsubstituted. "C-Amino" refers to a group wherein ~ and Rb are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, Heteroalicyclic, aralkyl or (heteroalicyclic)

S 158869.doc -17- 201215395 Alkyl. The c-nonylamino group may be substituted or unsubstituted. β "N-Amino group" means a "rc(=〇)n(ra)_" group, wherein r^ra may independently be an anthracene, an alkyl group, Alkenyl 'alkynyl' cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl 'heteroalicyclic, aralkyl or (heteroalicyclic;)alkyl. The N-guanidinyl group may be substituted or unsubstituted. The term "halogen atom" or "element" as used herein means any of the radiation stability atoms of the seventh row of the Periodic Table of the Elements, such as fluorine, gas, bromine and iodine. In the case where the number of substituents (e.g., adentate alkyl group) is not illustrated, one or more substituents may be present. For example, "haloalkyl" can include one or more halo of the same or different. As another example, "Cl_c3 alkoxyphenyl" may include one or more alkoxy groups which may be the same or different containing one, two or three atoms. Unless otherwise indicated, any protecting group, amino acid, and other compounds as used herein are used in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature (c〇mmissj〇n on Biochemical Nomenclature) (see Biochem 11:942-944 (1972)). The term "nuclear bud" is used herein in its ordinary sense as understood by those skilled in the art and refers to linkage to a heterocyclic tester or tautomer thereof via an N-glycosidic linkage (such as via a purine base). A compound consisting of a substituted pentose moiety or a modified pentose moiety, optionally at the 9-position or the 1-position of the pyrimidine base. Examples include, but are not limited to, ribose cores comprising a ribose moiety and deoxyribonucleosides comprising a deoxyribose moiety. Modified pentose 158869.doc •18· 201215395 π knives are replaced by oxygen atoms and/or carbon is replaced by sulfur or oxygen atoms. And/or a monomer of the sugar moiety. In addition, the core can be incorporated into major jobs and/or RNA polymers and oligomers. In some cases, the nucleoside may be a nucleoside analog drug. The term "heterocyclic base" as used herein refers to an optionally substituted aza-containing group which may be attached to an optionally substituted pentose moiety or a modified pentose moiety. In some embodiments, the heterocyclic test group may be selected from optionally substituted purine bases, optionally substituted pyrimidine bases, and optionally substituted diazole bases (eg, 1, 2, 4-three). Oxazole). The term "purine base" is used herein in its ordinary sense as understood by those skilled in the art and includes its tautomers. Likewise, the term "pyrimidine base" is used herein in its ordinary meaning as understood by those skilled in the art, and includes its tautomers. A non-limiting list of bases that have been substituted as appropriate include sputum, adenine, guanine, hypoxanthine, scutellaria, scutellaria, 7-alkylguanine (eg, 7-mercapto guanine), cocoa beans Alkali, caffeine, uric acid and isoguanine. Examples of pyrimidine bases include, but are not limited to, cytosine, chest-nose, urinary bites, 5,6-dihydrourine, and 5-yard cells. Dense π (for example, 5 曱 cytosine). An example of a triazole base to be substituted as appropriate is 丨, 2, 4_3. Sit-3-methylamine. Other non-limiting examples of heterocyclic bases include diamino hydrazine, 8-sided oxy-N6-alkyl adenine (e.g., pendant oxy-N6-methyl adenine), 7-diazonium xanthine, 7 _ deazaguanine, 7_deaza adenine, N4, N4-vinylcytosine, n6, N6-ethylene-2,6-diaminopurine, 5-halouracil (eg 5-fluorouracil and 5- Bromouracils, pseudoisopramimes, xenotimes, guanines, and other heterocyclic bases as described in U.S. Patent Nos. 5,432,272 and 7,125,855 5 158,869. doc -19-201215395, The limited purpose of revealing other heterocyclic bases is incorporated herein by reference. In some embodiments, the heterocyclic test group may optionally be substituted with an amine or enol protecting group. s# "N-linked amino acid" means an amino acid which is attached to the indicated moiety via a backbone amino group or a monosubstituted amine group. When the amino acid is linked as an N-linked amino acid, one hydrogen belonging to the main chain amine group or the monosubstituted amine group is not present and the amino acid is linked via nitrogen. The term "amino acid" as used herein refers to any amino acid (standard amine, acid and non-standard amino acids) including, but not limited to, alpha-amino acids, beta-amino acids, gamma Amino acid and §_amino acid. Examples of suitable amino acids include, but are not limited to, alanine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, silkamine Acid, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methamidoic acid, phenylalanine, threonine, tryptophan and lysine. Other examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline , β-alanine, α-ethyl-glycine, α-propyl-glycine and orthanoic acid. The hydrazine-linked amino acid may be substituted or unsubstituted. The term "fluorene-linked amino acid ester derivative" means an amino acid in which a main chain carboxylic acid group has been converted into an ester group. In one embodiment, the ester group has a formula selected from the group consisting of alkyl-〇-C(=〇)-, cycloalkyl-〇-c(=o)-, aryl-〇-c (=o) )- and aryl (alkyl)-0-C(=0)-. A non-limiting list of ester groups includes methyl-〇_C(=〇)-, ethyl-〇-C(=〇)-, n-propyl-0-C(=〇)-, isopropyl-0 -c(=0)-, n-butyl-〇_c(=0)-, isobutyl-0-C(=〇)-, tert-butyl-〇-C(=〇)-, neopenta Base-〇_c(=〇)-, cyclopropyl-〇-c(=o)-, cyclobutyl-158869.doc 201215395 〇-c(=〇)_, cyclopentyl_0_c(=0) _, cyclohexyl_0-C(=0)_, phenyl_〇_c(=0)-, and benzoquinone_〇_c(=〇)_. The N-linked amino acid ester derivative may be substituted or unsubstituted. The term "protecting group" as used herein refers to any atom or group of groups added to a molecule to prevent unwanted groups from undergoing a chemical reaction in the molecule. Examples of the Compliance section are described in T. W. Greene and P. G. M. Wuts, Growps z.w, 3rd edition,

John Wiley & Sons, 1999 and J.F. W. McOmie, Proiecizve c/ze, Plenum Press, 1973, both of which are incorporated herein by reference for their limited purposes for the disclosure of the disclosure. The protecting group moiety can be selected in such a way that it is stable to certain reaction conditions and is readily removed at the appropriate stage using methods known from the art. A non-limiting list of protecting groups includes benzyl; substituted phenyl fluorenyl; alkyl carbonyl and alkoxycarbonyl (eg, tert-butoxycarbonyl (B0C), ethionyl or isobutyl); arylalkylcarbonyl And an arylalkoxycarbonyl group (for example, benzyloxycarbonyl); a substituted oxime ether (for example, decyloxymethyl ether); a substituted diethyl ether; a substituted benzyl group; tetrahydropyranyl ether; An alkyl group (for example, trimethyldecyl, triethylsulfanyl, triisopropyldecyl, tert-butyldimethylfluorenyl, triisopropyldecyloxymethyl, [2_(trimethyl)矽alkyl)ethoxy]indolyl or tert-butyldiphenylindolyl); ester (eg benzoate); cesium carbonate (eg methoxy decyl acrylate); Toluene acid ester or methanesulfonic acid vinegar "acyclic condensed _ (such as diacetal); cyclic ketal (such as 1,3-monoxanthate, 1,3-oxo) and this article Acyclic acetal; cyclic acetal (such as described herein); acyclic hemiacetal; cyclic

S 158869.doc -21 > 201215395 Hemi-acids; (iv) Dithio (tetra) (eg W, 3-di(tetra) or U3 dithiolane); orthoesters (such as those described herein) and triaryl Methyl (for example, trityl 'monodecyloxydiphenyl fluorenyl (MMTr); 44, dimethoxytrityl (DMTr) ' 4,4,4"-dimethoxytrityl (TMTr" and as used herein. "Leaving group" as used herein refers to any atom or moiety capable of being replaced by another atom or moiety in a chemical reaction. More particularly, in some embodiments, "Leaving group" means an atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, a "leaving group" is any atom or moiety that is a conjugate base of a strong acid. Examples of suitable leaving groups Including, but not limited to, a sulfonate 8 mercapto group and a lignin. Non-limiting features and examples of leaving groups can be found, for example, in C/zemhr;;, 2nd edition, Francis Carey (1992), 32nd - 331 冤·' Intro- to Organic Chemistry '2nd Edition' Andrew Streitwieser and Clayt〇n Heathc〇ck (1981), pp. 169-171; OgaWc C/zewbiq;, 5th ed., John McMurry (2000), pp. 398 and 408; all of which are incorporated herein by reference for their purpose of the disclosure of the features and examples of the leaving. "Pharmaceutically acceptable salt" means a salt of a compound which does not cause significant irritation to the organism to which it is administered and which does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition of the compound. A pharmaceutical salt can be obtained by reacting a compound with a mineral acid such as hydrogen dentate (for example, hydrochloric acid or negative odor acid), sulfuric acid, nitric acid, and phosphoric acid. The pharmaceutical salt can also be obtained by compounding the compound with Obtained by acid reaction: aliphatic or aromatic acid 158869.doc -22· 201215395 or sulphuric acid, such as citric acid, acetic acid, succinic acid, lactic acid, malic acid, tartar, citric acid, ascorbic acid, tobacco Alkali acid, methane sulfonic acid, ethane sulfonic acid, p-nonyl phthalic acid, salicylic acid or naphthalene sulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt or an alkali metal salt ( Such as sodium or potassium salts, Earth metal salt (such as calcium or magnesium salt), organic base (such as dicyclohexylamine, N-methyl-D-glucosamine, hydroxymethyl) amine, c "C7 alkylamine, % a salt of an amine, triethanolamine, ethylenediamine), and can be obtained by reacting a compound with an amino acid such as arginine and lysine to form a salt. Unless specifically stated otherwise, in the present application, The terms and phrases used in the scope of the accompanying application should be considered open and restrictive. As an example of the above, the term "including" shall be taken to mean "including (not limited to)", "including (but not limited to)" or the like; as used herein, the terms "including" and "including", "including" Or "characteristically" is synonymous and inclusive or open and does not exclude other undescribed elements or method steps; the term "having" should be interpreted as "having at least"; the term "including" should be interpreted as "including (but not The term "example" is used to provide an illustrative illustration of an item in the discussion rather than an exhaustive or restrictive list; and the use of the terms (such as "preferred", "required" or "desirable" and similar The wording of the meaning is not to be construed as indicating that certain features are critical, essential or essential to the structure or function of the present invention, but are merely intended to emphasize that it may be used in a particular embodiment of the invention or Alternatives or other features that may not be used. In addition, the term "comprising" is to be interpreted synonymously with the phrase "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least

158869.doc „ S 201215395 described herein may include other steps. When used in the context of a compound, composition or device, the term 'comprising' means that the compound, composition or device includes at least the recited. Features or components (components)' may also include other features or components (components). Xiao, unless otherwise expressly stated otherwise, the project group linked by the conjunction "and" should not be considered as requiring each and every one of their projects to be grouped and should be treated as "and, or". Similarly, project groups linked by the conjunction "or" should not be considered as mutually exclusive, but should be treated as "and/or" unless otherwise expressly stated. To the extent that any skill in the art is used in the singular and/or singular terms, the singular and/or singular can be interpreted as a plural, depending on the context and/or application. For the sake of clarity, various singular/complex exchanges may be explicitly set forth herein. The indefinite article "-" does not exclude plural. A single processor or other unit may fulfill the functions of several items described in the scope of the patent application. The mere fact that certain measurements are recited in mutually different <RTIgt; </ RTI> <RTIgt; </ RTI> does not indicate that the combination of such measurements is not advantageously used. Any reference mark* of the patentable towel should be considered as limiting its scope. It will be appreciated that in any of the compounds described herein having one or more pairs of palmar centers, if the absolute stereochemistry is not explicitly indicated, the centers may independently have a political or 8 configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure 'enantiomerically enriched as a racemic mixture, diastereomeric, diastereomeric, or stereo. Heterogeneous gargles Additionally, it will be appreciated that in any of the compounds described herein having one or more double bonds which produce a geometric isomer which may be defined as I58869.doc 201215395 Form E or Form Z, each double bond may Independently E-type or z-type or a mixture thereof. It is also to be understood that in any of the compounds described, it is intended to include all tautomeric forms. For example, it is intended to include all of the thiol groups of the phosphate group, including all tautomers of the heterocyclic test groups known in the art, including natural and non-natural purine bases and pyrimidine bases. Isomers. It should be understood that in the case where the compound disclosed herein has a subatomic valence, it will be filled with hydrogen or its isotope (eg, nitrogen-i (gas) and nitrogen (gas)). The compound can be isotopically labeled. Isotopes (such as phantom substitutions may provide certain therapeutic advantages due to greater metabolic stability (such as prolonged half-life in vivo or reduced dose requirements). Each chemical element represented in a compound structure may include any isotopes of that element.

In the structure of a compound, a hydrogen atom can be clearly revealed or understood to be present in a compound. At any position where a hydrogen atom in a compound may be present, the hydrogen atom may be any isotope of hydrogen, including (but * the nitrogen book therefore, unless the context clearly dictates otherwise, the reference to the compound covers all possible isotopic forms. The methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of compounds having the same elemental composition), amorphous phases, salts, solvates, and hydrates. In the examples, the compounds described herein exist in the form of a solvate with a pharmaceutically acceptable solution: such as water, ethanol or the like.

S 158869.doc • 25- 201215395 In other embodiments, the compounds described herein exist as unsolvated forms. The solvate contains a stoichiometric or non-stoichiometric amount of solvent and can be formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol or the like. A hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is an alcohol. Further compounds provided by m may be present in the form of solvates and solvates. In general, the solvate forms are considered to be equivalent to the form of the non-solvent for the purposes of the compounds and methods provided herein. / In the case of a range of values, the median values between the upper and lower limits and the upper and lower limits of the range are understood in the examples. Some of the details disclosed herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein: B1 may be an optionally substituted heterocyclic test group or an optionally substituted heterocyclic test group having a protected amine group; R1 may be an optionally substituted amine group-except N-linkage Amino acid vinegar derivative; R2 may be an Mm substituted aryl group, optionally substituted heteroaryl group and optionally substituted heterocyclic group; R3a and R3b may be independently selected from hydrogen, optionally substituted C1.6 alkyl, substituted by county, as appropriate, replaced by c2.6 block, as appropriate, c&quot; (tetra) and aryl (Cm alkyl), the restrictions are ya and RSb At least one of them may not be hydrogen; I58869.doc • 26 - 201215395 or R3a may form a group selected from the group consisting of R3b: C:3·6 cyclodyl optionally substituted, optionally substituted C3·6 cycloalkenyl, optionally substituted C3_6 aryl and optionally substituted (: 3·6 heteroaryl; R 4 may be hydrogen; R 5 may be selected from hydrogen, —OR9 and —〇C (=〇 R10; R6 may be selected from the group consisting of hydrogen, halogen, _〇Rll and -0C(=0)R12; or R5 and R6 may both be oxygen atoms and are bonded together by a carbonyl group; R7 may be selected from hydrogen, halogen, and optionally Replace Ci 6 alkyl, 〇 〇 Rn and -0C (=0) R, R may be hydrogen or optionally substituted 〇 · 6 院 ;

R, R and R may be independently selected from hydrogen and optionally substituted cw alkyl; and R1G, R12 and R14 may be independently selected from optionally substituted Cw alkyl and optionally substituted C3-6 cycloalkyl. . In some embodiments, the compound of formula (1) may have a structure selected from the group consisting of:

And for R2, in some embodiments, R2 can be an optionally substituted heteroaryl. In other embodiments, R2 can be an optionally substituted heterocyclic group. In other embodiments, R2 can be an optionally substituted aryl group. For example, R2 can be an optionally substituted phenyl group or an optionally substituted naphthyl group. If ^ 158869.doc Ο -27- 201215395 is a substituted phenyl group or a substituted naphthyl group, the benzene ring and the naphthalene ring may be substituted one or more times. Suitable substituents which may be present on the optionally substituted phenyl and optionally substituted naphthyl groups include electron-withdrawing groups and electron-withdrawing groups. In some embodiments, R2 can be a substituted phenyl group. In other embodiments 'R2 can be an unsubstituted phenyl group or an unsubstituted naphthyl group. A wide variety of amino acids and amino acid vinegar derivatives can be used, including those described herein. In one embodiment, 'r1' may be an optionally substituted N-linked a-amino acid. Suitable amino acids include, but are not limited to, alanine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, lysine, serine, Tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Other suitable amino acids include, but are not limited to, alpha-ethyl-glycine, alpha-propyl-glycine, and beta-alanine. In other embodiments, R1 can be optionally substituted. A linked alpha-amino acid ester derivative. For example, R can be an ester derivative of any of the following amino acids: alanine, aspartame k, aspartic acid, cysteine, glutamic acid, acetophenine, glycine, guanidine Aminic acid, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and amide Other examples of acid N-linked amino acid ester derivatives include, but are not limited to, any of the following amino acid vinegar derivatives: alpha-ethyl-glycine, propyl-glycine, and beta- Alanine. In one embodiment, R1 can be an ester derivative of alanine. In one embodiment, R1 may be selected from the group consisting of methyl propylamine, ethyl propylamine, isopropyl propylamine, cyclohexyl propylamine, neopentyl alamate, isopropyl valinate, and leucine 158869. .doc •28· 201215395 Propylene vinegar. In some embodiments, when R1 is an optionally substituted n-linked a-amino acid derivative, r2 may be an optionally substituted aryl group. In some embodiments, the optionally substituted N-linked amino acid or optionally substituted N-linked amino acid g|derivative may be in other embodiments as if; The acid-acceptable I-substituted N-linked amino acid ester derivative can be configured in d. In some embodiments, when R1 is an optionally substituted N-linked amino acid or an optionally substituted N-linked a-amino-derivative, r2 may be selected from the group of If I substituted An aryl group, a heteroaryl group substituted according to the case I, and optionally an N-amino acid ester derivative which is substituted by a N-substituted amino acid ester derivative, as the case may be, as the case may be, Substituted aryl. In other embodiments, when R1 is optionally substituted (X-amino acid ester derivative, R2 may be optionally substituted heteroaryl. In other embodiments) When R1 is an optionally substituted N-linked a-amino acid ester derivative, R2 may be optionally substituted heterocyclic group. 16 «17

In some embodiments, R1 may have a structure of Η'Ν-Ι, wherein Ris may be selected from a gas's optionally substituted C i .6 leucoyl group, optionally substituted 匚 3 6 cycloalkyl group, as appropriate Substituted aryl 'optionally substituted aryl (C16 alkyl) and optionally substituted C! 6 haloalkyl; and Ri6 may be selected from hydrogen, optionally substituted Cw alkyl, optionally Substituted C!.6-N-alkyl'-substituted C3-6 cycloalkyl, optionally substituted C: 6 aryl, optionally substituted (: 1 () aryl and optionally Substituted aryl (C16 alkyl); and the formula ^ can be hydrogen or optionally substituted C!-4 alkyl; or R16 can be combined with Ri7

S 158869.doc · 29 · 201215395 Forms a c3_6 cycloalkyl group which is optionally substituted. When R1 has the structure shown above, it may be a Cw alkyl group which may be optionally substituted. Examples of suitable Ci6 alkyl groups which may be substituted, as appropriate, include optionally substituted variants of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tributyl, pentyl (branched and linear) and hexyl (branched and linear). When R16 is substituted, it may be substituted with one or more substituents selected from the group consisting of N-nonylamino, thiol, alkylthio, optionally substituted aryl, hydroxy, optionally substituted heteroaryl. Base, oxime carboxyl group and amine group. In one embodiment, R16 can be an unsubstituted Cw alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branches) Chains and straight chains) and hexyl groups (branched chains and straight chains). In an embodiment, R16 can be a fluorenyl group. For R15', in some embodiments, Ri5 can be an optionally substituted q6 alkyl group. Examples of optionally substituted Cm alkyl groups include optionally substituted variants of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl 'isobutyl' tert-butyl, Amyl (branched and linear) and hexyl (branched and linear). In some embodiments, Rl5 can be indenyl or isopropyl. In some embodiments, R15 can be ethyl or neopentyl. In other embodiments, R15 can be an optionally substituted Cw cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl groups include optionally substituted variants of the following groups: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In one embodiment, cyclohexyl beta is optionally substituted. In other embodiments, R 1 5 may be an optionally substituted aryl such as phenyl and naphthyl. In other embodiments, R15 can be an optionally substituted aryl (Cw alkyl)^ in some embodiments 158869.doc -30·201215395, 'i5R 5 can be optionally substituted benzyl ^ in some In the embodiment, '11 may be an optionally substituted Cl6 alkyl group, such as CP"

In some embodiments, it can be hydrogen. In other embodiments, it may be optionally substituted c-alkyl such as methyl, ethyl, n-propyl, iso- 7 propyl, i butyl, isobutyl and tert-butyl. In an embodiment, R can be a fluorenyl group. In some embodiments, Rie can form, together with Rn, a c:3·6 cycloalkyl group substituted by the conditions. Examples of optionally substituted C3-6 cycloalkyl groups include optionally substituted variants of the following groups: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the group selected for Rl6 &amp; R! 7, the carbon to which 玟Μ and R17 are attached may be the center of the palm. In one embodiment, the carbon to which the anti-u and R17 are attached may be the (R) pair of palmar centers. In other embodiments, R'

The carbon to which R16 and R17 are connected can be (S) to the palm center. 15〇 R^6 °17

Examples of human 〇' ΗΝ-1 适 之 彳 group include the following

S 158869.doc „ 201215395

Depending on the substituent attached to the phosphorus atom, the phosphorus atom may be the center of the palm. In some embodiments, the fill can be a (R) stereocenter. In other embodiments, the fill may be (s) a stereocenter. The substituent attached to the 5' position of the compound of formula (1) may vary. In some embodiments, the rulers 33 and n3b may be the same. In other embodiments, the ruler 33 and the ruler 315 can be different. In some embodiments, less than one of R3a and R3b may not be hydrogen. In some embodiments, Rh can be hydrogen. In one embodiment, R3a can be an optionally substituted Cl-6 alkyl group. Suitable as appropriate substituted Cl-6 158869.doc -32-201215395 Examples of alkyl groups include optionally substituted variants of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, tert-butyl, fluorenyl (branched and linear) and hexyl (branched and linear). In some embodiments, R3a can be an optionally substituted 〇2. 6 alkyl group. In some embodiments, R can be a C6·6 dilute group that is optionally substituted. In some embodiments, R3a can be an optionally substituted C2-6 alkynyl group. In some embodiments, R3a can be a C! _6 halogen hospital base that is optionally substituted. An example of a 6-tooth base that is suitable for replacement as appropriate is CF3. In some embodiments, R3a can be a aryl group (Cm alkyl). An example of a suitable substituted aryl group (Ci-alkyl group) is a phenyl fluorenyl group. In some embodiments, it can be hydrogen. In some embodiments, R3b can be an optionally substituted Cw alkyl group. In some embodiments, R can be an optionally substituted C2.6 alkyl group. In some embodiments, R can be, as appropriate, substituted C; 2.6 women. In some embodiments, the C2-6 alkynyl group may be optionally substituted. In some embodiments, R3b can be a C1 haloalkyl group, as appropriate. In some embodiments, r3b can be an aryl group (Ci-6 dadyl). In some embodiments, R3a, together with R3b, can form a group selected from the group consisting of optionally substituted C3.6 cycloalkyl, optionally substituted CM cycloalkenyl, optionally substituted C3 6 aryl. And a C3·6 heteroaryl group substituted as the case may be. In some embodiments, R3a, together with R3b, can form an optionally substituted C3-6 cycloalkyl. In some embodiments A, at least one of R3a and RM can be an optionally substituted C, _6 alkyl; and the other of Rh and R3b can be hydrogen. Suitable examples of C,.6 alkyl groups which may be substituted as appropriate include variants of the following groups which are optionally substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso

S 158869.doc •33· 201215395 Butyl, tert-butyl, pentyl (branched and linear) and hexyl (branched and straight) ° In the embodiment, at least one of R3a & R3b may It is a sulfhydryl group, and the other of R and & can be hydrogen. In some embodiments, at least one of R3a and rU may be an optionally substituted C6 6 alkyl group; and the other of R3a and R3b may be hydrogen. In other embodiments, at least one of R3a and R3b may be an optionally substituted haloalkyl group, and the other of Rh and R3b may be hydrogen. An example of a C!·6 haloalkyl group which is suitably substituted as appropriate is CF3. When attached to 5, the substituent on the carbon is 5, and the carbon is palm-like, in some embodiments '5, the carbon can be the (R) stereocenter. In other embodiments, the 5' carbon can be a (S) stereocenter. Substituents linked to 2 and 3' carbon may also vary. In some embodiments 'R can be hydrogen. In other embodiments, R7 can be halogen. In other embodiments, R7 can be _〇Rl3. When it is hydrogen, r7 may be a hydroxyl group. Alternatively, when R13 is an optionally substituted C16 alkyl group, R7 may be optionally substituted Cw alkoxy. Suitable alkoxy groups include decyloxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy (branched and linear) And hexyloxy (branched chain and linear chain). In other embodiments 'R7 can be an optionally substituted Cl 6 alkyl group. Examples of substituted (^.6 alkyl) include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branches) Chains and straight chains) and hexyl groups (branched chains and straight chains) In some embodiments, R7 may be -0C(=0)R14' wherein R14 is optionally substituted Ci 6 alkyl or optionally substituted C3·6 cycloalkyl. Examples of suitable Cl 6 alkyl and C 3 6 cycloalkyl are described herein. 158869.doc • 34- 201215395 / In some embodiments, R 4 may be hydrogen. In some embodiments In other embodiments, R5 may be _〇r9, wherein r9 may be hydrogen. In other embodiments, R5 may be 9' wherein r9 may be optionally substituted alkyl. A non-limiting list of examples of R5 wherein R9 (wherein R9 can be optionally substituted C6 alkyl) is decyloxy, ethoxy, n-propoxy, isopropoxy[n-butoxy, Isobutoxy, tert-butoxy, pentyloxy (straight or knife-branched) and hexyloxy (straight or branched). In some embodiments, R5 may be -〇C(=〇) R10, wherein Ri〇 is selected from G.6 alkyl and optionally substituted C3.6 cycloalkyl, as appropriate. Substituted as appropriate

Examples of Cm alkyl and optionally substituted C3 6 cycloalkyl are described herein. In some embodiments, R6 can be hydrogen. In some embodiments, R6 can be a halogen. In other embodiments, R6 can be _〇R&quot;. In one embodiment, when R is hydrogen, R6 can be a hydroxyl group. In other embodiments, when Rn is optionally substituted C丨_6 alkyl, R6 can be an optionally substituted Ci6 alkoxy group. Suitable C. 6 alkoxy groups as appropriate are described herein. In some embodiments, R6 can be -〇C(=0)Ri2, which can be an optionally substituted Cu alkyl group, such as the optionally substituted variant of the following groups: fluorenyl, ethyl, positive Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) and hexyl (branched and linear). In other embodiments, R6 can be -〇C(=〇)R12, wherein R12 can be optionally substituted C3.6 cycloalkyl. Examples of optionally substituted (^-6 alkyl and optionally substituted C3-6 cycloalkyl are described herein. In some embodiments, 'R5 and R6' may both be hydroxyl. In other embodiments

S 158869.doc • 35- 201215395, R5 and R6 may both be oxygen atoms and are bonded together by a carbonyl group, such as θα'-. In some embodiments, at least one of rir7 can be a guilloche. In some embodiments, RlR? can be both spectrin. In other embodiments 'R can be halogen and R7 can be an optionally substituted Ci. 6 alkyl group, such as described herein. In other embodiments, R6 can be hydrogen and R7 can be dentate. In some embodiments, R5 can be -〇C(=0)R丨0 and R6 can be _〇c(=〇)r12. In some embodiments, the ruler 6 can be hydrogen and be a hydroxyl group. Those skilled in the art will appreciate that when a hydrogen atom is removed from an oxygen atom, the oxygen atom can have a negative charge. For example, when R5 and/or R6 are hydroxyl groups and hydrogen is removed, the hydrogen atom 3a

The oxygen atom to which R 3b is bonded may be 〇 - in some embodiments, R " and R 8 may be hydrogen in any of the embodiments described in this paragraph. In some embodiments, B1 is described in this paragraph. In any embodiment, it may be an optionally substituted adenine, optionally substituted guanine, and optionally substituted thymidine, optionally substituted cytosine or optionally substituted uracil. In some embodiments Wherein, R8 may be hydrogen. In other embodiments, rS may be optionally substituted C!·6 alkyl. For example, r8 may be selected from methyl, ethyl, n-propyl 'isopropyl, n-Butyl, isobutyl, tert-butyl, pentyl (branched and linear) and hexyl (branched and linear). A variety of optionally substituted heterocyclic groups can be attached to the pentose ring. In some embodiments, one or more amines and/or amine groups may be protected by a suitable protecting group. For example, an amine group can be converted to a guanamine or an amino phthalate by converting an amine and/or an amine group. Protected. In some embodiments, optionally substituted heterocyclic bases or having one or more protected amine groups The substituted heterocyclic base can be one of those having the following structure: 158869.doc -36 201215395

Its t: RA2 may be selected from the group consisting of hydrogen, halogen and NHRn, wherein RJ2 may be selected from hydrogen, -C(=0)RK2 and -C(=0)0RL2; RB2 may be halogen or NHRW2, wherein RW2 is selected from hydrogen, Optionally substituted Ck alkyl, optionally substituted C2·6 dilute, optionally substituted C3-8 cyclodextrin, -C(= 〇) RM2 and -C(=0)0RN2; RC2 Is hydrogen or NHR02, wherein R02 can be selected from the group consisting of gas, -C(=0)RP2 and -C(=0)0RQ2; RD2 can be selected from hydrogen, halogen, optionally substituted C1·6 leukox, as the case may be Substituted C2·6 dilute group and optionally substituted C: 2.6 alkynyl group; RE2 may be selected from hydrogen, optionally substituted cl 6 leunt group, optionally substituted (: 3-8 cycloalkyl, - C(=0)RR2 and -C(=〇)〇RS2 ; rF2 may be selected from hydrogen, a nutrient, optionally substituted C!·6 alkyl, optionally substituted C2·6 alkenyl, and optionally Substituted C2·6 alkynyl; Y2 may be N(nitrogen) or CR, wherein R12 may be selected from hydrogen, halogen, optionally substituted C6 alkyl, optionally substituted C2.6, and optionally Substituted 〇2_6 alkynyl; RG2 may be optionally substituted C1-6 alkyl; RH2 may be hydrogen or NHRT2, wherein RT2 may be independently selected from Hydrogen, _c 〇)RU2 and _c(=〇)〇rV2, and RK2, RL2, RN2, rP2, rQ2, rR2, rS2, rU2 and rV2

S 158869.doc •37· 201215395 is independently selected from the group consisting of c3 6 cycloalkenes, its 2·6 alkynyl group, c “cycloalkyl group” (in this case), and heteroalicyclic groups (Cl. 6 院)) "After the acquisition, the structure of the above may be replaced by a substituent selected from a list of substituents providing a definition of force > '". In the embodiment of the invention, Bl may be selected from the group consisting of adenine, guanine, chest bite, and uracil. In some embodiments, β1 can # Jl η

In other embodiments, Β1 may be 3D2. In other embodiments, Β1 may be

Rl in other embodiments nh2 can be

〇

In some embodiments, B1 can be r

Ό

N,

In other embodiments, B1 may be 1j1 and may be NH2. In a 'Ν' 4b, in some embodiments, RB2 C(=0) RM2 and rM2 are exemplified, R 2 may be NhrW2, and rW2 may be 匸!·6 alkyl. In other embodiments, B1 can be 158869.doc -38- 201215395

OR62

In some embodiments, the compound of formula (I) may not have a structure selected from the group consisting of:

In some embodiments, when R2 is a substituted or unsubstituted phenyl group, h3co h3^h soil.

R1 cannot be Q HN丨. In other R examples, when tR2 is a substituted or unsubstituted phenyl group, R1 may not be 0 HN- in other examples of the implementation of h3co, when R2 is a substituted or unsubstituted phenyl group and r 1 is cf hn At least one of 'R and R' may not be a warp group. In some embodiments,

S 158869.doc -39- 201215395 h3co as a

Called, 3a u ruler is phenyl, ruler "and J?3b * - heart and R3alR3b in the middle of s ^ ^ times one of the tombs is methyl oxime and the other is hydrogen, y is not bud, cell dense Bite or urinary pyridine. In this case 眚/—~\ In the second embodiment, when R1 is 〇|&gt;Ν-| base, R3a&amp;R3b is in the earth, R2 is benzene, R6 is not base and R And the other of the eight is hydrogen H3Vz H. In some embodiments, when 2 is the base 'R3a and R3b, +, ., ± one of the towels is methyl and R, 丨 R3b When the other is hydrogen, R5, r6 &amp; r7 h3co ~ Wang Xi is halogen. In some embodiments, when R, .MH 2 R3a & R3b soil * S'R is phenyl, one of r It is methyl and 113 &amp; and 11 out of $ ^ ^ B1 is the cell ^ timing ' R7 can not be a radical. "Others are hydrogen in some embodiments 'R, can be hydrogen. In - can not be hydrogen In one embodiment, R. is not a Cw alkyl group. In this case, the paste is used to replace the 4 alkyl group by 3b. In this case, the needle is applied. In order to replace the Cl in the case of the situation, R3a is not a nail. In less L, ~ is a methyl group. In other embodiments 2 4 = implementation of 々 之 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. 4. For example, R5 may not be hydroxy A, and r6* may be hydroxy. For the reduction of 4, both and R6 are not thiol. In some embodiments, R5 is not hydrogen. In some embodiments and 158869.doc 201215395 In other embodiments, the ruler 6 may not be -OR9. In, the horse wind. In some embodiments, the π is also halogen. In the embodiment, R6 is not rU. In the case, R7 is not qi. / Gan", 'In some embodiments', ·, ,, in his embodiment, R7 does not open 1 ^ in his embodiment , ... can not be a letter. It is a hydroxyl group. In a consistent example, R7 is not rB2. In some embodiments, B1 cannot be X N.

'N

RA2 in some implementations

In the case, B1 cannot be 丄&quot;八/一一香香. In the second embodiment, B1 is not 〇 N D2 R1

for

0

. In some embodiments, B1 is not OR02

In some embodiments, B1 cannot be -... In the embodiment, B1 x ~r :* a may not be adenine in some embodiments. In other embodiments, biting. The goods are smashed for the chest. In his embodiment, B1 cannot be a bite. Less medium., B1 stone-Γ :&amp; a Second embodiment It cannot be cytosine. In other embodiments, 呤. Right 1 ^ Cannot be a guanine In other embodiments, B1 cannot be hypoxanthine. J. Some embodiments disclosed herein relate to a compound of formula (1) or a pharmaceutically thereof thereof

S 158869.doc 201215395

An acceptable salt, wherein: B1 may be optionally substituted heterocyclic base as described in paragraph [〇106]; R1 may be optionally substituted hydrazine-linked amino acid or optionally substituted And an optionally substituted aryl ester; R2 may be an optionally substituted aryl; 1133 and R3b may independently be hydrogen or optionally substituted Cu alkyl, with at least one of R3a &amp; R3b It may not be hydrogen; R4 may be hydrogen; R5 may be selected from hydrogen, 〇R9 and _〇C(=〇)R1(); R6 may be selected from hydrogen, halogen, -OR11 and -0C(=0)H12 Or R5 and R6 may each be an oxygen atom and are bonded together by a carbonyl group; R7 may be selected from hydrogen, halogen, optionally substituted Cu alkyl and -OR13; R8 may be hydrogen; R9, R&quot; and R13 may be independently The ground is hydrogen or optionally substituted Cw alkyl; and R1G and R12 may independently be optionally substituted Cw alkyl. Some embodiments disclosed herein are directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: B1 may be optionally substituted as selected from the group consisting of

a cyclic test group or an optionally substituted heterocyclic base having a protected amine group:

R1 may be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R2 may be an optionally substituted aryl group; R3a and R3b may independently be hydrogen or Optionally, the substituted Cl-6 alkyl group, with the proviso that at least one of R3a &amp; R3b is not hydrogen; 158869.doc • 42- 201215395 R can be hydrogen; R5 can be selected from hydrogen, -OR9 and -00: ( = 0) 1^1. R6 may be selected from the group consisting of hydrogen, halogen, -OR11, and -〇C(=〇)R12; or R5 and R6 may both be oxygen atoms and may be attached to each other by a base; R7 may be selected from hydrogen, halogen, and optionally substituted Ch6 alkyl and -〇R13; R8 may be hydrogen; r9, r&quot; and r13 may independently be hydrogen or optionally substituted C!_6 alkyl; and R1Q and R12 may be independently substituted as appropriate Cu alkyl.

RW2 may be -C(=0)〇R. In some embodiments, formula (I) may be a compound of formula (Ια), wherein: a heterocyclic test group which may be substituted as appropriate from the following or has a A protected heterocyclic base of the protected amine group: uridine, thymidine, guanine, gland wherein rA2 can be hydrogen, rB2 can be nhrw RN2 can be a Cu alkyl group, and γ2 can be N; An amino acid ester derivative selected from the group consisting of: methyl propylamine, ethyl propylamine, isopropyl propylamine, cyclohexyl propylamine, neopentyl alamate, and phenylalanine An oxime ester; R2 may be selected from optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted quinolinyl; R3a&amp; R3b may be selected from hydrogen and optionally Substituted C -6 alkyl group, the limitation is that at least one of amp 3&amp; and R3b may not be hydrogen; R4 may be hydrogen; R5 may be selected from hydrogen, _〇R9 and _〇c(= 〇)Rl . ; r6 may be selected from hydrogen ' _ prime, -OR&quot; and _〇C( = 〇)r12; or ruler 5 and ruler 6 may be

Site selected from hydrogen and optionally substituted C 6 alkyl; and RW and R

158869.doc -43- 201215395 Cw alkyl group substituted as appropriate. In some embodiments, the compound of formula (I) can be a single diastereomer. In other embodiments, the compound of formula (I) may be a mixture of diastereomers. In some embodiments, the compound of formula (I) may be a 1:1 mixture of two diastereomers. In some embodiments, the compound of formula (I) may be enriched by diastereomerization (eg, one diastereomer may be &gt; 55% compared to the total concentration of other diastereomers) , 275%, 280%, 290%, 295%, 298% or > 99% concentration exists). Some examples of R1 and R2 of the compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in Table 1. Tables 2 to 4 provide the structures of the variables bb01-bbl2, aa (H-aall and es01-esl4, respectively. For example, the first entry in Table 1 is "bb01, aa01, es01", which corresponds to the formula (I a compound wherein R2 is

And R1 is h3c 〇

V〇表1 R'R'Ra R'R'Ra R'R'Ra R'R'Ra R\R\Ra bb01,aa01,es01 bb03,aa01,es01 bb05,aa01,es01 bb07,aa01,es01 bb09 ,aa01,es01 bb01,aa01,es02 bb03,aa01,es02 bb05,aa01,es02 bb07,aa01,es02 bb09,aa01,es02 bb01,aa01,es03 bb03,aa01,es03 bb05,aa01,es03 bb07,aa01,es03 bb09 ,aa01,e$03 bb01,aa01,es04 bb03,aa01,es04 bb05,aa01,es04 bb07,aa01,es04 bb09,aa01,es04 bb01,aa01,es05 bb03,aa01,es05 bb05,aa01,es05 bb07,aa01,es05 Bb09,aa01,es05 bb01,aa01,es06 bb03,aa01,es06 bb05,aa01,es06 bb07,aa01,es06 bb09,aa01,es06 bb01,aa01,es07 bb03,aa01,es07 bb05,aa01,es07 bb07,aa01,es07 Bb09,aa01,es07 bb01,aa01,es08 bb03,aa01,es08 bb05,aa01,es08 bb07,aa01,es08 bb09,aa01,es08 bb01,aa01,es09 bb03,aa01,es09 bb05,aa01,es09 bb07,aa01,es09 Bb09,aa01,es09 bb01,aa01,esl0 bb03,aa01,esl0 bb05,aa01,esl0 bb07,aa01,esl0 bb09,aa01,esl0 bb01,aa01,esll bb03,aa01,esll bb05,aa01,esll bb07,aa01,esll Bb09,aa01,esll bb01,aa01,esl2 bb03,aa01,esl2 bb05,aa01,esl2 bb07,aa01,esl2 bb09,aa01,e Sl2 158869.doc • 44 - 201215395

R'R^Ra «Re R'R'Ra R'R'Ra bb01,aa02,es01 bb03,aa02,es01 bb05,aa02,es01 bb07,aa02,es01 bb09,aa02,es01 bb01,aa02,es02 bb03,aa02 ,es02 bb05,aa02,es02 bb07,aa02,es02 bb09,aa02,es02 bb01,aa02,es03 bb03,aa02,es03 bb05,aa02,es03 bb07,aa02,es03 bb09,aa02,es03 bb01,aa02,es04 bb03,aa02 ,es04 bb05,aa02,es04 bb07,aa02,es04 bb09,aa02,es04 bb01,aa02,es05 bb03,aa02,es05 bb05,aa02,es05 bb07,aa02,es05 bb09,aa02,es05 bb01,aa02,es06 bb03,aa02 ,es06 bb05,aa02,es06 bb07,aa02,es06 bb09,aa02,es06 bb01,aa02,es07 bb03,aa02,es07 bb05,aa02,es07 bb07,aa02,es07 bb09,aa02,es07 bb01,aa02,es08 bb03,aa02 ,es08 bb05,aa02,es08 bb07,aa02,es08 bb09,aa02,es08 bb01,aa02,es09 bb03,aa02,es09 bb05,aa02,es09 bb07,aa02,es09 bb09,aa02,es09 bb01,aa02,esl0 bb03,aa02 ,esl0 bb05,aa02,esl0 bb07,aa02,esl0 bb09,aa02,esl0 bb01,aa02,esll bb03,aa02?esl 1 bb05,aa02,esll bb07,aa02,esll bb09saa02,esll bb01,aa02,esl2 bb03,aa02, Esl2 bb05, aa02, esl2 bb07, aa02, esl2 bb09, aa02, esl2 bb01 Aa03,es01 bb03,aa03,es01 bb05,aa03,es01 bb07,aa03,es01 bb09,aa03,es01 bb01,aa03,es02 bb03,aa03,es02 bb05,aa03,es02 bb07,aa03,es02 bb09,aa03,es02 bb01, Aa03,es03 bb03,aa03,es03 bb05,aa03,es03 bb07,aa03,es03 bb09,aa03,es03 bb01,aa03,es04 bb03,aa03,es04 bb05,aa03,es04 bb07,aa03,es04 bb09,aa03,es04 bb01, Aa03,es05 bb03,aa03,es05 bb05,aa03,es05 bb07,aa03,es05 bb09,aa03,es05 bb01,aa03,es06 bb03,aa03,es06 bb05,aa03,es06 bb07,aa03,es06 bb09,aa03,es06 bb01, Aa03,es07 bb03,aa03,es07 bb05,aa03,es07 bb07,aa03,es07 bb09,aa03,es07 bb01,aa03,es08 bb03,aa03,es08 bb05,aa03,es08 bb07,aa03,es08 bb09,aa03,es08 bb01, Aa03,es09 bb03,aa03,es09 bb05,aa03,es09 bb07,aa03,es09 bb09,aa03,es09 bb01,aa03,esl0 bb03,aa03,esl0 bb05,aa03,esl0 bb07,aa03,esl0 bb09,aa03,esl0 bb01, Aa03,esll bb03,aa03,esll bb05,aa03,esll bb07,aa03,esll bb09,aa03,esll bb01,aa03,esl2 bb03,aa03,esl2 bb05,aa03,esl2 bb07,aa03,esl2 bb09,aa03,esl2 bb01, Aa04, es01 bb03, aa04, es01 bb05, Aa04,es01 bb07,aa04,es01 bb09,aa04,es01 bb01,aa04,es02 bb03,aa04,es02 bb05,aa04,es02 bb07,aa04,es02 bb09,aa04,es02 bb01,aa04,es03 bb03,aa04,es03 bb05, Aa04,es03 bb07,aa04,es03 bb09,aa04,es03 bb01,aa04,es04 bb03,aa04,es04 bb05,aa04,es04 bb07,aa04,es04 bb09,aa04,es04 bb01,aa04,es05 bb03,aa04,es05 bb05, Aa04,es05 bb07,aa04,es05 bb09,aa04,es05 bb01,aa04,es06 bb03,aa04,es06 bb05,aa04,es06 bb07,aa04,es06 bb09,aa04,es06 bb01,aa04,es07 bb03,aa04,es07 bb05, Aa04,es07 bb07,aa04,es07 bb09,aa04,es07 bb01,aa04,es08 bb03,aa04,es08 bb05,aa04,es08 bb07,aa04,es08 bb09,aa04,es08 bb01,aa04,es09 bb03,aa04,es09 bb05, Aa04,es09 bb07,aa04,es09 bb09,aa04,es09 bb01,aa04,esl0 bb03,aa04,esl0 bb05,aa04,esl0 bb07,aa04,esl0 bb09,aa04,esl0 s 158869.doc -45· 201215395 R'R' Rc R'R'Ra R'R'Ra R'R'Ra R^R'Ra bb01,aa04,esll bb03,aa04,esll bb05,aa04,esll bb07,aa04,esl 1 bb09,aa04,esll bb01,aa04 ,esl2 bb03,aa04,esl2 bb05,aa04,esl2 bb07,aa04,esl2 bb09,aa04,esl2 bb01,aa05,es01 bb03,aa05,es01 bb05,aa05,es01 bb07,aa05 ,es01 bb09,aa05,es01 bb01,aa05,es02 bb03,aa05,es02 bb05,aa05,es02 bb07,aa05,es02 bb09,aa05,es02 bb01,aa05,es03 bb03,aa05,es03 bb05,aa05,es03 bb07,aa05 ,es03 bb09,aa05,es03 bb01,aa05,es04 bb03,aa05,es04 bb05,aa05,es04 bb07,aa05,es04 bb09,aa05,es04 bb01,aa05,es05 bb03,aa05,es05 bb05,aa05,es05 bb07,aa05 ,es05 bb09,aa05,es05 bb01,aa05,es06 bb03,aa05,es06 bb05,aa05,es06 bb07,aa05,es06 bb09,aa05,es06 bb01,aa05,es07 bb03,aa05,es07 bb05,aa05,es07 bb075aa05?es07 Bb09,aa05,es07 bb015aa05,es08 bb03,aa055es08 bb05,aa05,es08 bb07,aa05,es08 bb09,aa05,es08 bb01,aa05,es09 bb03,aa05,es09 bb05,aa05,es09 bb07,aa05,es09 bb09,aa05, Es09 bb01,aa05,esl0 bb03,aa05,esl0 bb05,aa05,esl0 bb07,aa05,esl0 bb09,aa05,esl0 bb01,aa05,esll bb03,aa05,esll bb05,aa05,esll bb07,aa05,esll bb09,aa05, Esll bb01,aa05,esl2 bb03,aa05,esl2 bb05,aa05,esl2 bb07,aa05,esl2 bb09,aa05,esl2 bb01,aa06,es01 bb03,aa06,es01 bb05,aa06,es01 bb07,aa06,es01 bb09,aa06, Es01 bb01?aa06?es02 bb0 3,aa06,es02 bb05,aa06,es02 bb07,aa06,es02 bb09,aa06,es02 bb01,aa06,es03 bb03,aa06,es03 bb05,aa06,es03 bb07,aa06,es03 bb09,aa06,es03 bb01,aa06,es04 Bb03,aa06,es04 bb05,aa06,es04 bb07,aa06,es04 bb09,aa06,es04 bb01,aa06,es05 bb03,aa06,es05 bb05,aa06,es05 bb07,aa06,es05 bb09,aa06,es05 bb01,aa06,es06 Bb03,aa06,es06 bb05,aa06,es06 bb07,aa06,es06 bb09,aa06,es06 bb01,aa06,es07 bb03,aa06,es07 bb05,aa06,es07 bb07,aa06,es07 bb09,aa06,es07 bb01,aa06,es08 Bb03,aa06,es08 bb05,aa06,es08 bb07,aa06,es08 bb09,aa06,es08 bb01,aa06,es09 bb03,aa06,es09 bb05,aa06,es09 bb07,aa06,es09 bb09,aa06,es09 bb01,aa06,esl0 Bb03,aa06,esl0 bb05,aa06,esl0 bb07,aa06,esl0 bb09,aa06,esl0 bb01,aa06,esll bb03,aa06,esll bb05,aa06,esll bb07,aa06,esl 1 bb09,aa06,esll bb01,aa06, Esl2 bb03,aa06,esl2 bb05,aa06,esl2 bb07,aa06,esl2 bb09,aa06,esl2 bb01,aa07,es01 bb03,aa07,es01 bb05,aa07,es01 bb07,aa07,es01 bb09,aa07,es01 bb01,aa07, Es0 2 bb03,aa07,es02 bb05,aa07,es02 bb07,aa07,es02 bb09,aa07,es02 bb015aa075es03 bb03,aa07,es03 bb05,aa07,es03 bb07,aa07,es03 bb09,aa07,es03 bb01,aa07,es04 bb03,aa07 ,es04 bb05,aa07,es04 bb07,aa07,es04 bb09,aa07,es04 bb01,aa07,es05 bb03,aa07,es05 bb05,aa07,es05 bb07,aa07,es05 bb09,aa07,es05 bb01,aa07,es06 bb03,aa07 ,es06 bb05,aa07,es06 bb07,aa07,es06 bb09,aa07,es06 bb01,aa07,es07 bb03,aa07,es07 bb05,aa07,es07 bb07,aa07,es07 bb09,aa07,es07 bb01,aa07,es08 bb03,aa07 ,es08 bb05,aa07,es08 bb07,aa07,es08 bb09,aa07,es08 158869.doc -46- 201215395

R'R'Ra R'R'Ra R'R'Rc R'RijRa R'R'Ra bb01,aa07,es09 bb03,aa07,es09 bb05,aa07,es09 bb07,aa07,es09 bb09,aa07,es09 bb01, Aa07,esl0 bb03,aa07,esl0 bb05,aa07,esl0 bb07,aa07,esl0 bb09,aa07,esl0 bb01,aa07,esll bb03,aa07,esll bb05,aa07,esll bb07,aa07,esll bb09,aa07,esll bb01, Aa07,esl2 bb03,aa07,esl2 bb05,aa07,esl2 bb07,aa07,esl2 bb09,aa07,esl2 bb01,aa08,es01 bb03,aa08,es01 bb05,aa08,es01 bb07,aa08,es01 bb09,aa08,es01 bb01, Aa08,es02 bb03,aa08,es02 bb05,aa08,es02 bb07,aa08,es02 bb09,aa08,es02 bb01,aa08,es03 bb03,aa08,es03 bb05,aa08,es03 bb07,aa08,es03 bb09,aa08,es03 bb01, Aa08,es04 bb03,aa08,es04 bb05,aa08,es04 bb07,aa08,es04 bb09,aa08,es04 bb01,aa08,es05 bb03,aa08,es05 bb05,aa08,es05 bb07,aa08,es05 bb09,aa08,es05 bb01, Aa08,es06 bb03,aa08,es06 bb05,aa08,es06 bb07,aa08,es06 bb09,aa08,es06 bb01,aa08,es07 bb03,aa08,es07 bb05,aa08,es07 bb07,aa08,es07 bb09,aa08,es07 bb01, Aa08, es08 bb03, aa08, es08 bb05, aa08, es08 bb07, aa08, es08 bb09, Aa08,es08 bb01,aa08,es09 bb03,aa08,es09 bb05,aa08,es09 bb07,aa08,es09 bb09,aa08,es09 bb01,aa08,esl0 bb03,aa08,esl0 bb05,aa08,esl0 bb07,aa08,esl0 bb09, Aa08,esl0 bb01,aa08,esll bb03,aa08,esll bb05,aa08,esll bb07,aa08,esll bb09,aa08,esll bb01,aa08,esl2 bb03,aa08,esl2 bb05,aa08,esl2 bb07,aa08,esl2 bb09, Aa08,esl2 bb01,aa09,es01 bb03,aa09,es01 bb05,aa09,es01 bb07,aa09,es01 bb09,aa09,es01 bb01,aa09,es02 bb03,aa09,es02 bb05,aa09,es02 bb07,aa09,es02 bb09, Aa09,es02 bb01,aa09,es03 bb03,aa09,es03 bb05,aa09,es03 bb07,aa09,es03 bb09,aa09,es03 bb01,aa09,es04 bb03,aa09,es04 bb05,aa09,es04 bb07,aa09,es04 bb09, Aa09,es04 bb01,aa09,es05 bb03,aa09,es05 bb05,aa09,es05 bb07,aa09,es05 bb09,aa09,es05 bb01,aa09,es06 bb03,aa09,es06 bb05,aa09,es06 bb07,aa09,es06 bb09, Aa09,es06 bb01,aa09,es07 bb03,aa09,es07 bb05,aa09,es07 bb07,aa09,es07 bb09,aa09,es07 bb01,aa09,es08 bb03,aa09,es08 bb05,aa09,es08 bb07,aa09,es08 bb09, Aa09, es08 bb01, aa09, es09 bb03, aa09, es09 bb05, aa09, es09 bb07, aa09, es09 bb09, aa09 ,es09 bb01,aa09,esl0 bb03,aa09,esl0 bb05,aa09,esl0 bb07,aa09,esl0 bb09,aa09,esl0 bb01,aa09,esll bb03,aa09,esll bb05,aa09,esll bb07,aa09,esll bb09,aa09 ,esll bb01,aa09,esl2 bb03,aa09,esl2 bb05,aa09,esl2 bb07,aa09,esl2 bb09,aa09,esl2 bb01,aal0,es01 bb03,aal0,es01 bb05,aal0,es01 bb07,aal0,es01 bb09,aal0 ,es01 bb01,aal0,es02 bb03,aal0,es02 bb05,aal0,es02 bb07,aal0,es02 bb09,aal0,es02 bb01,aal0,es03 bb03,aal0,es03 bb05,aal0,es03 bb07,aal0,es03 bb09,aal0 ,es03 bb01,aal0,es04 bb03,aal0,es04 bb05,aal0,es04 bb07,aal0,es04 bb09,aal0,es04 bb01,aal0,es05 bb03,aal0,es05 bb05,aal0,es05 bb07,aal0,es05 bb09,aal0 ,es05 bb01,aal0,es06 bb03,aal0,es06 bb05,aal0,es06 bb07,aal0,es06 bb09,aal0,es06 s 158869.doc -47- 201215395 R'R'Ra R'R'Ra R'R'Ra R'R'Ra R\R\Ra bb01,aal0,es07 bb03,aal0,es07 bb05,aal0,es07 bb07,aal0,es07 bb09,aal0,es07 bb01,aal0,es08 bb03,aal0,es08 bb05,aal0,es08 Bb07,aal0,es08 bb09,aal0,es08 bb01,aal0,es09 bb03,aal0,es09 bb05,aal0,es09 bb07,aal0,es09 bb09,aal 0,es09 bb01,aal0,esl0 bb03,aal05esl0 bb05,aal0,esl0 bb07,aal0,esl0 bb09,aal0,esl0 bb01,aal0,esll bb03,aal0,esll bb05,aal0,esll bb07,aal0,esll bb09,aal0, Esll bb01,aal0,esl2 bb03,aal0,esl2 bb05,aal0,esl2 bb07,aal0,esl2 bb09,aal0,esl2 bb02,aa01,es01 bb04,aa01,es01 bb06,aa01,es01 bb08,aa01,es01 bbl05aa01,es01 bb02 ,aa01,es02 bb04,aa01,es02 bb06,aa01,es02 bb08,aa01,es02 bbl0,aa01,es02 bb02,aa01,es03 bb04,aa01,es03 bb06,aa01,es03 bb08,aa01,es03 bbl0,aa01,es03 bb02 ,aa01,es04 bb04,aa01,es04 bb06,aa01,es04 bb08,aa01,es04 bbl0,aa01,es04 bb02,aa01,es05 bb04,aa01,es05 bb06saa01,es05 bb08,aa01,es05 bbl0,aa01,es05 bb02,aa01 ,es06 bb04,aa01,es06 bb06,aa01,es06 bb08,aa01,es06 bbl0,aa01,es06 bb02,aa01,es07 bb04,aa01,es07 bb06,aa01,es07 bb08,aa01,es07 bbl0,aa01,es07 bb02,aa01 ,es08 bb04,aa01,es08 bb06,aa01,es08 bb08,aa01,es08 bbl0,aa01,es08 bb02,aa01,es09 bb04,aa01,es09 bb06,aa01,es09 bb08,aa01,es09 bbl0,aa01,es09 bb02,aa01 ,esl0 bb04,aa01,esl0 bb06,aa01 Esl0 bb08,aa01,esl0 bbl0,aa01,esl0 bb02,aa01,esll bb04,aa01,esll bb06,aa01,esll bb08,aa01,esll bbl0,aa01,esll bb02,aa01,esl2 bb04,aa01,esl2 bb06,aa01, Esl2 bb08,aa01,esl2 bbl0,aa01,esl2 bb02,aa02,es01 bb04,aa02,es01 bb06,aa02,es01 bb08,aa02,es01 bbl0,aa02,es01 bb02,aa02,es02 bb04,aa02,es02 bb06,aa02, Es02 bb08,aa02,es02 bbl0,aa02,es02 bb02,aa02,es03 bb04,aa02,es03 bb06,aa02,es03 bb08,aa02,es03 bbl0,aa02,es03 bb02,aa02,es04 bb04,aa02,es04 bb06,aa02, Es04 bb08,aa02,es04 bbl0,aa02,es04 bb02,aa02,es05 bb04,aa02,es05 bb06,aa02,es05 bb08,aa02,es05 bbl0,aa02,es05 bb02,aa02,es06 bb04,aa02,es06 bb06,aa02, Es06 bb085aa025es06 bbl0,aa02,es06 bb02,aa02,es07 bb04,aa02,es07 bb06,aa02,es07 bb08,aa02,es07 bbl0,aa02,es07 bb02,aa02?es08 bb04,aa02,es08 bb06,aa02,es08 bb08,aa02 ,es08 bbl0,aa02,es08 bb02,aa02,es09 bb04,aa02,es09 bb06,aa02,es09 bb08,aa02,es09 bbl0,aa02,es09 bb02,aa02,esl0 bb04,aa02,esl0 bb06,aa02, Esl0 bb08,aa02,esl0 bbl0,aa02,esl0 bb02,aa02,esll bb04,aa02,esll bb06,aa02,esll bb08,aa02,esll bbl0,aa02,esll bb02,aa02,esl2 bb04,aa02,esl2 bb06,aa02, Esl2 bb08,aa02,esl2 bbl0,aa02,esl2 bb02,aa03,es01 bb04,aa03,es01 bb06,aa03,es01 bb08,aa03,es01 bbl0,aa03,es01 bb02,aa03,es02 bb04,aa03,es02 bb06,aa03, Es02 bb08,aa03,es02 bbl0,aa03,es02 bb02,aa03,es03 bb04,aa03,es03 bb06,aa03,es03 bb08,aa03,es03 bbl0,aa03,es03 bb02,aa03,es04 bb04,aa03,es04 bb06,aa03, Es04 bb08,aa03,es04 bbl0,aa03,es04 158869.doc -48 · 201215395

R2,R\Ra R\R\Ra R'R'Ra R'R'Ra R2^1^ bb02,aa03,es05 bb04,aa03,es05 bb06,aa03,es05 bb08,aa03,es05 bbl0,aa03,es05 bb02 ,aa03,es06 bb04,aa03,es06 bb06,aa03,es06 bb08,aa03,es06 bbl0,aa03,es06 bb02,aa03,es07 bb04,aa03,es07 bb06,aa03,es07 bb08,aa03,es07 bbl0,aa03,es07 bb02 ,aa03,es08 bb04,aa03,es08 bb06,aa03,es08 bb08,aa03,es08 bbl0,aa03,es08 bb02,aa033es09 bb04,aa03,es09 bb06,aa03,es09 bb08,aa03,es09 bbl0,aa03,es09 bb02,aa03 ,esl0 bb04,aa03,esl0 bb06,aa03,esl0 bb08,aa03,esl0 bbl0,aa03,esl0 bb02,aa03,esll bb04,aa03,esll bb06,aa03,esll bb08,aa03,esll bbl0,aa03,esll bb02,aa03 ,esl2 bb04,aa03,esl2 bb06,aa03,esl2 bb08,aa03,esl2 bbl0,aa03,esl2 bb02,aa04,es01 bb04,aa04,es01 bb06,aa04,es01 bb08,aa04,es01 bbl0,aa04,es01 bb02,aa04 ,es02 bb04,aa04,es02 bb06,aa04,es02 bb08,aa04,es02 bbl0,aa04,es02 bb02,aa04,es03 bb04,aa04,es03 bb06,aa04,es03 bb08,aa04,es03 bbl0,aa04,es03 bb02,aa04 ,es04 bb04,aa04,es04 bb06,aa04,es04 bb08,aa04,es04 bbl0,aa04,es04 bb02,aa04,es05 bb04,aa04,es0 5 bb06,aa04,es05 bb08,aa04,es05 bbl0,aa04,es05 bb02,aa04,es06 bb04,aa04,es06 bb06,aa04,es06 bb08,aa04,es06 bbl0,aa04,es06 bb02,aa04,es07 bb04,aa04, Es07 bb06,aa04,es07 bb08,aa04,es07 bbl0,aa04,es07 bb02,aa04,es08 bb04,aa04,es08 bb06,aa04,es08 bb08,aa04,es08 bbl0,aa04,es08 bb02,aa04,es09 bb04,aa04, Es09 bb06,aa04,es09 bb08,aa04,es09 bbl0,aa04,es09 bb02,aa04,esl0 bb04,aa04,esl0 bb06,aa04,esl0 bb08,aa04,esl0 bbl0,aa04,esl0 bb02,aa04,esll bb04,aa04, Esll bb06,aa04,esll bb08,aa04,esll bbl0,aa04,esll bb02,aa04,esl2 bb04,aa04,esl2 bb06,aa04,esl2 bb08,aa04,esl2 bbl0,aa04,esl2 bb02,aa05,es01 bb04,aa05, Es01 bb06,aa05,es01 bb08,aa05,es01 bbl0,aa05,es01 bb02,aa05,es02 bb04,aa05,es02 bb06,aa05,es02 bb08,aa05,es02 bbl0,aa05,es02 bb02,aa05,es03 bb04,aa05, Es03 bb06,aa05,es03 bb08,aa05,es03 bbl0,aa05,es03 bb02,aa05,es04 bb04,aa05,es04 bb06,aa05,es04 bb08,aa05,es04 bbl0,aa05,es04 bb02,aa05,es05 bb04,aa05, Es05 bb06,aa05,es 05 bb08,aa05,es05 bbl0,aa05,es05 bb02,aa05,es06 bb04,aa05,es06 bb06,aa05,es06 bb08,aa05,es06 bbl0,aa05,es06 bb02,aa05,es07 bb04,aa05,es07 bb06,aa05, Es07 bb08,aa05,es07 bbl0,aa05,es07 bb02,aa05,es08 bb04,aa05,es08 bb06,aa05,es08 bb08,aa05,es08 bbl0,aa05,es08 bb02,aa05,es09 bb04,aa05,es09 bb06,aa05, Es09 bb08,aa05,es09 bbl0,aa05,es09 bb02,aa05,esl0 bb04,aa05,esl0 bb06,aa05,esl0 bb08,aa05,esl0 bbl0,aa05,esl0 bb02,aa05,esll bb04,aa05,esll bb06,aa05, Esll bb08,aa05,esll bbl0,aa05,esll bb02,aa05,esl2 bb04,aa05,esl2 bb06,aa05,esl2 bb08,aa05,esl2 bbl0,aa05,esl2 bb02,aa06,es01 bb04,aa06,es01 bb06,aa06, Es01 bb08,aa06,es01 bbl0,aa06,es01 bb02,aa06,es02 bb04,aa06,es02 bb06,aa06,es02 bb08,aa06,es02 bbl0,aa06,es02 c 158869.doc ·49· 201215395 R'R'Ra R 'R'Ra R'RSRa R'R'Ra R'R'Ra bb02,aa06,es03 bb04,aa06,es03 bb06,aa06,es03 bb08,aa06,es03 bbl0,aa06,es03 bb02,aa06,es04 bb04,aa06 ,es04 bb06,aa06,es04 bb08,aa06,es04 bbl0,aa06,es04 bb02,aa06,es05 bb04 Aa06,es05 bb06,aa06,es05 bb08,aa06,es05 bbl0,aa06,es05 bb02,aa06,es06 bb04,aa06,es06 bb06,aa06,es06 bb08,aa06,es06 bbl0,aa06,es06 bb02,aa06,es07 bb04, Aa06,es07 bb06,aa06,es07 bb08,aa06,es07 bbl0,aa06,es07 bb02,aa06,es08 bb04,aa06,es08 bb06,aa06,es08 bb08,aa06,es08 bbl0,aa06,es08 bb02,aa06,es09 bb04, Aa06,es09 bb06,aa06,es09 bb08,aa06,es09 bbl0,aa06,es09 bb02,aa06,esl0 bb04,aa06,esl0 bb06,aa06,esl0 bb08,aa06,esl0 bbl0,aa06,esl0 bb02,aa06,esll bb04, Aa06,esl 1 bb06,aa06,esll bb08,aa06,esll bbl0,aa06,esll bb02,aa06,esl2 bb04,aa06,esl2 bb06,aa06,esl2 bb08,aa06,esl2 bbl0,aa06,esl2 bb02,aa07,es01 bb04 ,aa07,es01 bb06,aa07,es01 bb08,aa07,es01 bbl0,aa07,es01 bb02,aa07,es02 bb04,aa07,es02 bb06,aa07,es02 bb08,aa07,es02 bbl0,aa07,es02 bb02,aa07,es03 bb04 ,aa07,es03 bb06,aa07,es03 bb08,aa07,es03 bbl0,aa07,es03 bb02,aa07,es04 bb04,aa07,es04 bb06,aa07,es04 bb08,aa07,es04 bbl0,aa07,es04 bb02, Aa07,es05 bb04,aa07,es05 bb06,aa07,es05 bb08,aa07,es05 bbl0,aa07,es05 bb02,aa07,es06 bb04,aa07,es06 bb06,aa07,es06 bb08,aa07,es06 bbl0,aa07,es06 bb02, Aa07,es07 bb04,aa07,es07 bb06,aa07,es07 bb08,aa07,es07 bbl0,aa07,es07 bb02,aa07,es08 bb04,aa07,es08 bb06,aa07,es08 bb08,aa07,es08 bbl0,aa07,es08 bb02, Aa07,es09 bb04,aa07,es09 bb06,aa07,es09 bb08,aa07,es09 bbl0,aa07,es09 bb02,aa07,esl0 bb04,aa07,esl0 bb06,aa07,esl0 bb08,aa07,esl0 bbl0,aa07,esl0 bb02, Aa07,esll bb04,aa07,esll bb06,aa07,esll bb08,aa07,esll bbl0,aa07,esll bb02,aa07,esl2 bb04,aa07,esl2 bb06,aa07,esl2 bb08,aa07,esl2 bbl0,aa07,esl2 bb02, Aa08,es01 bb04,aa08,es01 bb06,aa08,es01 bb08,aa08,es01 bbl0,aa08,es01 bb02,aa08,es02 bb04,aa08,es02 bb06,aa08,es02 bb08,aa08,es02 bbl0,aa08,es02 bb02, Aa08,es03 bb04,aa08,es03 bb06,aa08,es03 bb08,aa08,es03 bbl0,aa08,es03 bb02,aa08,es04 bb04,aa08,es04 bb06,aa08,es04 bb08,aa08,es04 bbl0,aa08,es04 bb02, Aa08,es05 bb04,a A08,es05 bb06,aa08,es05 bb08,aa08,es05 bbl0,aa08,es05 bb02,aa08,es06 bb04,aa08,es06 bb06,aa08,es06 bb08,aa08,es06 bbl0,aa08,es06 bb02,aa08,es07 bb04, Aa08,es07 bb06,aa08,es07 bb08,aa08,es07 bbl0,aa08,es07 bb02,aa08,es08 bb04,aa08,es08 bb06,aa08,es08 bb08,aa08,es08 bbl0,aa08,es08 bb02,aa08,es09 bb04, Aa08,es09 bb06,aa08,es09 bb08,aa08,es09 bbl0,aa08,es09 bb02,aa08,esl0 bb04,aa08,esl0 bb06,aa08,esl0 bb08,aa08,esl0 bbl0,aa08,esl0 bb02,aa08,esll bb04, Aa08,esll bb06,aa08,esll bb08,aa08,esll bbl0,aa08,esll bb02,aa08,esl2 bb04,aa08,esl2 bb06,aa08,esl2 bb08,aa08,esl2 bbl0saa08,esl2 158869.doc .50· 201215395

R'R'Ra R'R'Ra R'R'Ra R'RSRa R'R'Ra bb02,aa09,es01 bb04,aa09,es01 bb06,aa09,es01 bb08,aa09,es01 bbl0,aa09,es01 bb02, Aa09,es02 bb04,aa09,es02 bb06,aa09,es02 bb08,aa09,es02 bbl0,aa09,es02 bb02,aa09,es03 bb04,aa09,es03 bb06,aa09,es03 bb08,aa09,es03 bbl0,aa09,es03 bb02, Aa09,es04 bb04,aa09,es04 bb06,aa09,es04 bb08,aa09,es04 bbl0,aa09,es04 bb02,aa09,es05 bb04,aa09,es05 bb06,aa09,es05 bb08,aa09,es05 bbl0,aa09,es05 bb02, Aa09,es06 bb04,aa09,es06 bb06,aa09,es06 bb08,aa09,es06 bbl0,aa09,es06 bb02,aa09,es07 bb04,aa09,es07 bb06,aa09,es07 bb08,aa09,es07 bbl0,aa09,es07 bb02, Aa09,es08 bb04,aa09,es08 bb06,aa09,es08 bb08,aa09,es08 bbl0,aa09,es08 bb02,aa09,es09 bb04,aa09,es09 bb06,aa09,es09 bb08,aa09,es09 bbl0,aa09,es09 bb02, Aa09,esl0 bb04,aa09,esl0 bb06,aa09,esl0 bb08,aa09,esl0 bbl0,aa09,esl0 bb02,aa09,esll bb04,aa09,esll bb06,aa09,esll bb08,aa09,esll bbl0,aa09,esll bb02, Aa09,esl2 bb04,aa09,esl2 bb06,aa09,esl2 bb08,aa09,esl2 bbl0,aa09,esl2 bb02,aal0,es01 bb04,aal0,es01 bb 06,aal0,es01 bb08,aal0,es01 bbl0,aal0,es01 bb02,aal0,es02 bb04,aal0,es02 bb06,aal0,es02 bb08,aal0,es02 bbl0,aal0,es02 bb02,aal0,es03 bb04,aal0,es03 Bb06,aal0,es03 bb08,aal0,es03 bbl0,aal0,es03 bb02,aal0,es04 bb04,aal0,es04 bb06,aal0,es04 bb08,aal0,es04 bbl0,aal0,es04 bb02,aal0,es05 bb04,aal0,es05 Bb06,aal0,es05 bb08,aal0,es05 bbl0,aal0,es05 bb02,aal0,es06 bb04,aal0,es06 bb06,aal0,es06 bb08,aal0,es06 bbl0,aal0,es06 bb02,aal0,es07 bb04,aal0,es07 Bb06,aal0,es07 bb08,aal0,es07 bbl0,aal0,es07 bb02,aal0,es08 bb04,aal0,es08 bb06,aal0,es08 bb08,aal0,es08 bbl0,aal0,es08 bb02,aal0,es09 bb04,aal0,es09 Bb06,aal0,es09 bb08,aal0,es09 bbl0,aal0,es09 bb02,aal0,esl0 bb04,aal0,esl0 bb06,aal0,esl0 bb08,aal0,esl0 bblO,aalO,eslO bb02,aal0,esll bb04,aal0,esll Bb06,aal0,esll bb08,aal0,esll bblO,aalO,esll bb02,aal0,esl2 bb04,aal0,esl2 bb06,aal0,esl2 bb08,aal0,esl2 bbl0,aal0,esl2 Table 2 bb01 〉 bb02 ^~vy~F Hall, {^_CI bb04 _K } Cl· bb05 Cl bb06 s 158869.d Oc -51 - 201215395

Bb〇7 bb08 f~\ bb09 'ΛΤν, bblO Table 3

Table 4 esOl R«=mercapto es02 R〇=ethyl es03 Ra=isopropyl es04 Ra=propyleseq R«=cyclohexyl es06 Ra=cyclodecyl es07 Ra=^ butyl es08 Ra=cyclopropyl es09 Ra = benzyl esll Rct = neopentyl eslO Ra = tert-butyl esl2 Ra = hydrogen In some embodiments, one of the dents 33 and R3b is sulfhydryl and the spurs 33 and R3b 158869.doc -52- The other of 201215395 is hydrogen, and R4 and R8 may all be gas in any of the embodiments described in Table i. In some embodiments, at least one of R1 and R6 can be OH in any of the embodiments described in Table 1. In some embodiments, R7 can be hydrogen, dentate or Cl-6 alkyl in any of the embodiments described in Table 1. In some embodiments, B1 can be adenine, scorpion, uracil, thymine or cystine in any of the embodiments described in Table 1. In some embodiments, R3a, R3b, R4, R1, R6, R7, R8, and Βι can be tabulated! The group provided by the formula (Ια) in any of the examples described. Examples of compounds of formula (I) include, but are not limited to, the following:

158869.doc -53- 1 201215395

158869.doc •54 201215395

158869.doc -55- 201215395

Further examples of compounds of formula (i) are shown below.

158869.doc 56- 201215395

158869.doc 57- 201215395

158869.doc 58 201215395

Other examples of compounds of formula (i) include, but are not limited to, the following:

158869.doc -59- 201215395

° iT H0 0Η 158869.doc -60- 201215395

In some embodiments, 'neutralizes a phosphate of a nucleoside monophosphate or nucleotide

The charge on the base can facilitate oral administration of the compound of formula (1) by making the compound more lipophilic than a nucleotide having a similar structure having one or more charges present on the phosphate group ( The cell membrane is penetrated under the formula (Ια) compound. The group attached to the phosphate after absorption and uptake into the interior of the cell can be easily removed by esterases, proteases or other enzymes. In some embodiments, the group attached to the acid vinegar can be removed by simple hydrolysis. Inside the cell, the released monophosphate vinegar can then be metabolized by the cellular enzyme to diacetate or active triphosphate. s 158869.doc -61 - 201215395 In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can serve as a chain terminator for HCv replication. For example, the incorporation of a compound of formula (1) containing a moiety at the 2' carbon position can terminate the further extension of the RNA strand of HCV. For example, when R7 is a non-hydrogen group selected from halogen or, optionally, substituted Ck alkyl, the compound of formula (1) may contain 2, carbon modifications. In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof may have enhanced metabolism and/or plasma stability.

"In some embodiments, a compound of formula (1), including a formula (a phantom compound) or a pharmaceutically acceptable salt thereof, may have improved properties. A non-limiting list of exemplary properties includes, but is not limited to, Increased biological half-life, increased bioavailability, enhanced potency, sustained in vivo response, prolonged administration interval, reduced drug volume, reduced cytotoxicity, reduced amount of disease required for treatment of disease conditions, decreased disease burden, serum The time to conversion (ie, the virus becomes undetectable in the patient's serum) is shortened, sustained viral response is increased, morbidity or mortality is reduced in clinical outcomes, individual compliance is improved, liver conditions (such as liver fibrosis, cirrhosis, and /绮 cancer) reduction, and with other drugs

In some embodiments, the biological half-life of a compound of formula (I) or a pharmaceutically acceptable salt thereof is longer than 24 hours. In some embodiments, the biological half-life of the formula (2 or its pharmaceutically acceptable salt is in the range of about 28 discs = 36 hours. In some embodiments, the compound of formula (1) or the salt phase accepted (iv) is presently The standard of care may be more effective = toxic activity (eg '% in HCV replicon assay. Lower). 158869.doc • 62 - 201215395 Compounds of formula (i) (including compounds of formula (Ια)) and those described herein Various methods of preparation. The general synthetic route of the compound of formula (1) and some examples of starting materials for the synthesis of the compound of formula (1) are shown in Scheme 1 and are described herein. The pathways shown and described herein are illustrative only. It is not intended to be construed as limiting the scope of the invention in any way. Those skilled in the art will be able to identify modifications to the disclosed compositions based on the disclosure herein and contemplate alternative ways; all such modifications and alternatives In the scope of patent application scope. Process 1

One method of forming a compound of formula (I) is shown in Scheme 1. In the scheme 1, 'R3A, r3B, R4A' R5A, r6A, r7a' r8a and β1Α may be the same as R3a, R3b, r4, r5, r6, r7, ... and as described herein for the formula (I), and R1 and R2 may be the same as described herein for formula (1). The compound of the formula (A) can be reacted with a chlorophosphate of the formula R20_P(=0)(R1)_C1 as shown in Scheme 1 to form a compound of the formula (1). To reduce by-product formation, one or more groups may be attached to the pentose ring by one or more suitable protecting groups. For example, if the ruler "and/or r6A is a thiol group", the thiol group may be protected with a suitable protecting group such as a triarylmethyl group and/or a decyl group. Examples of the triarylmethyl group include, but are not limited to, three Benzoyl,

C 158869.doc -63- 201215395 Monomethoxydibenzyl (ΜΜΤϊ), 4,4,-dimethoxytriphenyl-f-yl (DMTr), 4,4·,4&quot;-trimethoxytriphenyl Methyl (TMTr), 4, 4,, 4 &quot; _ gin (benzoyloxy) benzhydryl (TBTr), 4, 4,, 4 &quot; · ginseng (4,5-dioxaphthalene) Imino)dichloromethyl (CPTr), 4,4,,4&quot; ginseng (ethoxy) methoxymethyl (TLTr) / fennel methyl] naphthylphenyl fluorenyl, Di-anisylmethyl-1-naphthylmethyl, p-tolyldiphenylmethyl, imidazolylmethyl)-4,4-methoxydiphenylmethyl, 9-phenyldibenzopyranyl (Pixyl), 9-(p-methoxyphenyl)dibenzopyran- 9-yl (indenyl), 4-decyloxytrityl-4-decene, alkoxytriphenylmethyl, 4,4 ,-Di-octadecyltrityl, 9 (4-octadecanooxyphenyl)dibenzopyran-9-yl, 1, fluorene-bis-(4-methoxyphenyl) -1'-mercaptomethyl, 4,4,,4&quot;-parath(t-butylphenyl)fluorenyl (TTTr) and 4,4--3,5-hexadienyloxybenzophenone base. Examples of suitable alkylene groups are described herein. Alternatively, and/or may be protected by a single non-palphatic or palmitic protecting group, for example by formation of orthoesters, cyclic acetals or cyclic ketals. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal '2-oxacyclopentylene orthoester, dironoxymethylene orthoester' 1-曱Oxyethylidene orthoester, κ ethoxyethylidene orthoester, methylene orthoester, benzoate orthoester, anthracene, 2-dimethoxyethyl orthoester and α- Methoxybenzylidene acid ester; suitable cyclic acetals include mercapto acetal, ethylene acetal, tert-butylmethylene acetal, 3-(benzyloxy) propyl condensate An aldehyde, a benzylidene acetal, a 3,4-dimethoxybenzylidene acetal, and a p-ethoxyoxybenzylidene acetal; and a suitable cyclic ketal includes a hydrazine-second butyl group Ethylene ketal, 1-phenylethyl ketal, isopropylidene ketal, cyclopentylene ketal, cyclohexylene ketal, cycloheptyl ketal, and 丨_(4_methoxy 158869.doc 201215395 Phenylphenyl) ethylene ketal. Any -NH and/or NH2 groups present on B1A may also be protected by one or more suitable protecting groups if desired. Examples of suitable protecting groups include triarylmethyl and dream alkyl. Examples of dreaming bases include, but are not limited to, trimethyl hard hospital (TMS), tert-butyl decyl decyl (TBDMS), triisopropyl oxalate (TIPS), and tertiary butyl Phenylnonylalkyl (TBDPS), triisopropyldecyloxymethyl and [2-(tridecylfluorenyl)ethoxy]fluorenyl.

Suitable gaseous phosphates are commercially available or can be prepared by the synthetic methods described herein. An example of the general structure of chlorophosphate is shown in Scheme 1. In some embodiments, the gas-filling acid is intended to be coupled to a compound of formula (A). In some embodiments, a Grignard reagent can be used to facilitate coupling. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, vaporized alkyl magnesium and alkyl magnesium bromide. In other embodiments, a chlorophosphate can be added to the compound of formula (A) using a base. Suitable bases are known to those skilled in the art. Examples of bases include, but are not limited to, amine bases such as alkylamines (including monoalkylamines, dialkylamines, and trialkylamines (e.g., diethylamine)); optionally substituted pyridines (e.g., top three) Pyridine); and optionally substituted imidazole (eg N-methyl beta rice bran). When at least one of Rl R3b is optionally substituted Cu thiol or optionally substituted Cl. 6i sinter, it may be replaced as appropriate by the method known to those skilled in the art. ^• Addition or replacement of the G·6 tooth-burning base to the position of 5, as appropriate. In some embodiments, the ruthenium attached to the 5&apos; carbon can be converted to an acid. Suitable oxidizing conditions include, but are not limited to, facial enamel and activator (usually a brewing agent or acid) and amine combination, Mofa

S 158869.doc -65· 201215395 Moffatt oxidation, Swern oxidation and Corey-Kim oxidation, and suitable oxidants include (but are not limited to) Dess-Martin High Dess-Martin periodinane, TPAP/NMO (tetrapropylammonium perrhenate/N-methylmorpholine N-oxide), Sven Oxidation Reagent, PCC (Pylochlorochromate) and/or PDC ( Dichromate pyridinium), sodium permanganate, Collin's reagent, ceric ammonium nitrate (CAN), Na2Cr2〇7 aqueous solution, Ag2C〇3/Shixiazao soil, heat containing HN〇 3 aqueous solution of ethylene glycol dioxime ether, 02-pyridine CuCl, Pb(OAc)4-pyridine and benzoquinone-NiBr2. The resulting aldehyde compound can be reacted with a Grignard reagent, an organolithium reagent or a trialkylaluminum such as tridecyl aluminum to form a compound of formula (A) wherein at least one of R3A and R3B is optionally substituted C. !_6 alkyl or optionally substituted Cu-alkyl. The alkylating agent can be in the presence of a Lewis acid, as appropriate. Suitable Lewis acids are known to those skilled in the art. The 5' carbon pairing of the compounds of formula (A) and/or (1) can be reversed using methods known to those skilled in the art. For example, an oxygen oxidizing to the 5' carbon can be oxidized to, for example, an aldehyde (for a compound of formula (A)) or a ketone (for a compound of formula (I)) using a suitable oxidizing agent. The reducing agent and/or ketone can then be reduced using a suitable reducing agent. Examples of suitable reducing agents include, but are not limited to, NaH, LiH, NaBH4, UA1H4, and CaH2. Suitable oxidizing agents and reducing agents are known to those skilled in the art. Examples of suitable oxidizing agents and conditions are described herein. As described herein, in some embodiments, R5 and R6 can both be oxygen atoms and are linked together by a carbonyl group. - 〇-c(=o)-o- groups can be formed using methods known to those skilled in the art 158869.doc • 66- 201215395. For example, a compound of formula (1) wherein R5 and R6 are both hydroxy can be treated with i,r-carbonyldilotazole (CDI). In some embodiments, R5 and/or R6 may be _〇C:(=〇)R10 and -〇C(=0)R12, respectively, and may be used in various locations known to those skilled in the art at the 2' position. And _〇c(=〇)r10 and -〇c(=〇)R12 groups are formed at the 3' position. For example, a compound of the formula (1) in which both the 5 and R6 are hydroxyl groups can be treated with an alkanoic anhydride (e.g., acetic anhydride and propionic anhydride) or an alkanoic acid chloride (e.g., ethyl chloroformate). If necessary, a catalyst can be used to facilitate the reaction. An example of a suitable catalyst is 4-dimethylamino group ratio (DMAP). Or ' can form -OC(=0)R10 and -〇C( = 〇 at 2, position and 31 positions by reacting a leuco acid (such as acetic acid and propionic acid) in the presence of a carbodiimide or a coupling reagent. ) R12 group. Examples of carbodiimides include, but are not limited to, ruthenium, Ν--dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and 1-ethyl- 3-(3-dimethylaminopropyl) carbodiimide (EDC). As described herein, B A may include urethane and/or decylamine. A method of forming a urethane and/or a guanamine on B1A is known to those skilled in the art. In some embodiments, 1,1,-carbonyldiimidazole and an alcohol can be used to form an amine phthalic acid vinegar. The oxime may be added to the pentose ring using various methods known to those skilled in the art. In some embodiments, a compound of formula (7)) can be reacted with a nitrogenous base. In some embodiments, the r3a, r3b, r4a, R, R6A, R7A, 118, and βΙΑ of the compound of formula (Β) may be as disclosed herein for R3a, R3b, R4, R5, R6, R7, R8, and B1. And PGi can be a suitable protecting group. In some embodiments, PG1 can be p-nitrophenyl fluorenyl. In some real

S 158869.doc • 67 201215395 In the example, n or more suitable protecting groups protect any of the thiol rings attached to the pentose ring. In some implementations, the benzyl group can be used to protect the (4) group attached to the oxime ring. Examples of nitrogen-containing counts include the optionally substituted IM group, which is attached to the nitrogen atom of the silk ring ((9) is -NH. If necessary - available - or a plurality of suitable protecting groups to protect the nitrogen-containing test group Any -NH and/or NH2 groups present on it. Suitable protecting groups are described herein. In some embodiments, they may be present in the Lewis acid or the side sulphur triterpene triacetate vinegar. Next, a gas-containing test group is added via a coupling reaction. Suitable Lewis acids are known to those skilled in the art. R3A PGi〇^R3B 〇Ac

R5A R6A (B) During the synthesis of any of the compounds described herein, any hydroxyl group attached to the pentose ring and any -NH and/or hydrazine groups present on the β1 oxime may be protected by one or more suitable protecting groups, if desired. Suitable protecting groups are described herein. Those skilled in the art will appreciate that any group attached to the pentose ring and any of the oxime groups present on the Α1 group can be protected with various protecting groups and any protecting groups present can be exchanged for other protecting groups. The choice of protection base and the parental change are within the skill of the general practitioner. Any protecting group can be removed by methods known in the art, such as with an acid (e.g., mineral or organic acid), base or fluoride source. Pharmaceutical Compositions 158869.doc • 68-201215395 Some embodiments described herein relate to pharmaceutical compositions that can include a therapeutically effective amount of one or more compounds described herein (eg, Formula (1) or (Ια) Z) or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, a pharmaceutical composition can include a single diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof (eg, a single diastereomer compared to other diastereomeric The total concentration of isomers is present in the pharmaceutical composition at a concentration greater than 99%). In other embodiments, the pharmaceutical composition may comprise a mixture of diastereomers of a compound of formula (1) or a pharmaceutically acceptable salt thereof. For example, a pharmaceutical composition can include a concentration that is greater than the total concentration of other diastereomers &gt; 50%, 260%, 270%, 80%, a〇%, y5%, or % Diastereomers. In some embodiments, the pharmaceutical composition comprises a 1:1 mixture of two diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The term "pharmaceutical composition" refers to a mixture of one or more of the compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to the organism. The pharmaceutical composition can also be obtained by reacting a compound with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid 'phosphoric acid, decanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and Salicylic acid. Pharmaceutical compositions are generally suitable for a particular intended route of administration. The physiologically acceptable "definite" carrier, diluent or excipient does not detract from the biological activity and properties of the compound. &quot;Carrier&quot; as used herein refers to a compound that facilitates the incorporation of a compound into a cell or tissue. For example (not limited to), dimethyl sulfoxide (DMSO) is a common carrier that has s 158869.doc • 69 · 201215395 for a variety of right; sputum &amp; substances absorbed into individual cells or tissues. As used herein, "diluent" means that the pharmaceutical composition lacks pharmacological activity and may be a medically necessary or desirable ingredient. For example, diluents can be used to increase the amount of effective drug (four) that is too small for manufacturing and/or administration. It may also be a liquid that dissolves the substance to be administered by injection, ingestion or inhalation. A common form of diluent in the art is buffered water such as, but not limited to, disc salt buffered saline which mimics human blood composition. &quot;Excipient&quot; as used herein refers to an inert substance that is added to a pharmaceutical composition to provide the composition with, without limitation, volume, consistency, texture, adhesion, wetting, disintegration, and the like. "Diluent" is a type of pharmaceutical composition described herein that can be administered to a human patient per se, or mixed with other active ingredients or carriers, diluents, excipients, or combinations thereof, such as in combination therapies. The pharmaceutical composition forms are administered to human patients. Appropriate formulations will depend on the route of administration chosen. Techniques for formulating and administering the compounds described herein are known to those skilled in the art. The pharmaceutical compositions disclosed herein can be made in a manner known per se, for example by conventional mixing, dissolving, granulating, preparing a dragee, water milling, milking, encapsulation, burying or tableting process. In addition, the active ingredient is included in an amount effective to achieve the intended purpose. A wide variety of compounds for use in the pharmaceutical compositions disclosed herein can be provided in the form of a pharmaceutically compatible salt-forming salt. 158869.doc -70- 201215395 There are a variety of techniques for administering compounds in this technology, including (but not limited to) oral, rectal, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous Intravenous, intramedullary, intrathecal, direct ventricular, intraperitoneal, intranasal, and intraocular injections. The compound may also be administered in a local rather than systemic manner, e.g., via direct injection of the compound into the site of infection, which is often in the form of a reservoir or sustained release formulation. In addition, the drug delivery system can be administered in the form of a liposome coated with a tissue-specific antibody, for example, in the form of a liposome coated with a tissue-specific antibody. The liposomes will selectively dry to and be absorbed by the organ. If desired, the compositions may be presented in a package or dispensing device which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise a metal or plastic drop, such as a blister pack. The package or dispenser can be accompanied by instructions for administration. The package or dispenser may also carry a notice in the form of a government agency for the manufacture, use or sale of a managed drug associated with the container, the notice reflecting that the agency approves the form of the drug for human or veterinary administration. The notice may be, for example, a product label approved for labeling or approval of a prescription drug by the US Food and Drug Administration*Γ|»J · 〇〇and Drug Administrati〇n). Compositions comprising a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and used to treat the indicated condition. Methods of Use One embodiment disclosed herein relates to the treatment and/or amelioration of a disease or condition which may comprise administering to a subject a therapeutically effective amount of one or more of the compounds described herein (such as a compound of formula (1) (including a compound of formula (Ια)) or Its medicine

S 158869.doc -71-201215395 An acceptable salt) or a pharmaceutical composition comprising a compound described herein. Some embodiments disclosed herein are directed to methods of ameliorating or treating a neoplastic disorder, which can comprise administering to a subject having a neoplastic disorder a therapeutically effective amount of one or more of the compounds described herein (eg, formula (I) and/or ( Ια) a compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein. In an embodiment, the neoplastic disease can be cancer. In some embodiments, the neoplastic disease can be a tumor, such as a solid tumor. In one embodiment, the neoplastic disease can be leukemia. Exemplary leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and adolescent bone marrow monocytic leukemia (JMML). Some embodiments disclosed herein are directed to methods of inhibiting tumor growth, which can comprise administering to a subject having a tumor a therapeutically effective amount of one or more compounds described herein (eg, a compound of formula (I) and/or (Ια)) or A pharmaceutical composition comprising one or more compounds described herein. Other embodiments disclosed herein are directed to methods of ameliorating or treating a viral infection, which can comprise administering to a subject having a viral infection a therapeutically effective amount of one or more compounds described herein (eg, Formula (I) and/or (Ια). Compound) or a pharmaceutical composition comprising one or more compounds described herein. In one embodiment, the viral infection can be caused by a virus selected from the group consisting of an adenovirus, an Alphaviridae, an Arbovirus, an Astrovirus, a Bunyaviridae, a coronal Coronaviridae, Filoviridae, Flaviviridae, Hepadnaviridae, Herpesviridae, Alphaherpesvirinae, β 158869. Doc -72- 201215395

Betaherpesvirinae, Gammaherpesvirinae, Norwalk Virus, Astroviridae, Caliciviridae, Orthomyxoviridae , Paramyxoviridae, Paramyxovirus, Rubulavirus, Morbillivirus, Papovaviridae, Parvoviridae, Small The family of RNA virus (Picornaviridae), Aphthoviridae, Cardioviridae, Enteroviridae, Coxsackie virus, Polio Virus, Rhinovirus ( Rhinoviridae), Phycodnaviridae, Poxviridae, Reoviridae, Rotavirus, Retroviridae, Retrovirus , immunodeficiency virus, leukemia virus, avian sarcoma virus, ribbed virus (Rhabdovirus), wind Rubiviridae, Togaviridae, Arenaviridae and/or Bornaviridae » In some embodiments, the viral infection may be hepatitis C virus (HCV) )infection. In other embodiments, the viral infection can be influenza. In other embodiments, the viral infection can be HIV. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a viral infection, which can comprise sensitizing a virus-infecting cell with an effective amount of one or more of the compounds described herein, or a compound described herein. A salt, or a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein relate to making

S 158869.doc -73- 201215395 The use of one or more of the compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, for the manufacture of a "ameliorating and/or treating a disease #infected drug" Or treating a viral infection can comprise contacting the virus-infected cell with an effective amount of the compound or compounds. Other embodiments described herein pertain to pharmaceutically acceptable salts of one or more compounds described herein or compounds described herein that are useful for ameliorating and/or treating a viral infection, the = and / or / alpha treatment Maternal infection is achieved by contacting the virus-infected cells with an effective compound such as 5 kel. In some embodiments, the compound can be a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound can be a monoester, a diphosphate, and/or a triphosphate of a compound of formula (I) and/or (1), or a pharmaceutically acceptable salt thereof. In some embodiments, the virus can be an Hcv virus. Some embodiments disclosed herein are directed to methods of inhibiting viral replication, which can include or in combination with an effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or Pharmaceutical, 'and &amp; Applicable to a compound described herein or a pharmaceutically acceptable salt thereof, and other embodiments described herein are directed to the use of one or more compounds described herein, or a compound described herein A salt that is acceptable for the manufacture of a medicament for inhibiting viral replication, the inhibition of viral replication can comprise contacting the virus-infected cell with an effective amount of the compound or compounds. Other embodiments described herein pertain to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, which is useful for inhibiting viral replication by sensitizing virally infected cells with an effective amount thereof. The or the compounds are contacted to achieve. In some embodiments, the compound can be a compound of formula 158869.doc-74·201215395 and/or (Ια) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound can be a monophosphate, diphosphate, and/or triphosphate of a compound of formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof. In some embodiments, the virus can be an HCV virus. HCV is an enveloped positive-stranded RNA virus in the yellow fever virus family. There are various HCV non-structural proteins such as NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is an RNA-dependent RN Α polymerase involved in HCV RNA replication. • Some embodiments described herein are directed to methods of inhibiting NS5B polymerase activity, which can include administering a cell (eg, a cell that infects HCV) to an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable compound thereof. Acceptable salt contact. Some embodiments described herein are directed to methods of inhibiting NS5B polymerase activity, which can comprise administering to a cell (eg, a cell infected with HCV) an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable compound thereof Accept the salt. In some embodiments, a compound of formula (I), including a compound of formula, or a pharmaceutically acceptable salt thereof, inhibits RNA-dependent RNA polymerase. In some embodiments, a compound of formula (I), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, inhibits HCV polymerase (e.g., NS5B polymerase). Some embodiments described herein are directed to a method of treating an HCV infection in an individual having an HCV infection, which can comprise administering to the individual an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof. Some embodiments described herein relate to a condition selected from the group consisting of liver fibrosis, cirrhosis, and liver cancer in an individual having one or more of the following liver conditions.

The method of S 158869. doc-75-201215395 'which may comprise administering to the individual an effective amount of a compound or pharmaceutical composition described herein (eg, a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable compound thereof salt). One cause of liver fibrosis, cirrhosis, and/or liver cancer can be HCV infection. Some embodiments described herein are directed to methods of increasing liver function in an individual having an hcv infection, which can include administering to the individual an effective amount of a compound or pharmaceutical composition described herein (eg, formula (1) and/or (Ια). a compound or a pharmaceutically acceptable salt thereof). Also contemplated is a method of reducing or eliminating liver damage caused by a virus in an individual having an HCV infection by administering to the individual an effective amount of a compound or pharmaceutical composition described herein (eg, as in formula (I) and/or Or (Ια) compound or a pharmaceutically acceptable salt thereof). In one embodiment, the method comprises slowing or halting progression of liver disease. In another embodiment, the course of the disease is reversed and liver function is expected to be maintained or improved. There are a variety of HCV genotypes, and there are multiple subtypes within each genotype. For example, the major Hcv genotypes of the genus (numbered 丨 to 丨丨) are currently known, but others have been classified into six major genotypes. Each of these genotypes is further subdivided into subtypes (la_lc; 2a_2c; 3a_3b; 4 hearts; · 5a; 6a; 7a-7b; 8a-8b; 9a; l〇a; and 11&amp;). In some embodiments, an effective amount of a compound of formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof, or an effective amount of a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable compound thereof The pharmaceutical composition of the accepted salt is effective in treating at least the Hcv genotype. In two embodiments, the compounds described herein (e.g., a compound of formula (1) and/or (d) or a pharmaceutically acceptable salt thereof) are effective for treating all (iv) concentrated genotypes. In some implementations, the compounds described herein (eg, formula (1) and / 158869.doc • 76· 201215395 or (Ια) compounds or pharmaceutically acceptable salts thereof) are effective for treating three or more, five or five Or 5 or more, 7 or more, 9 or more HCV genotypes. In some embodiments, Formula (I) and/or (1 〇〇 compound or a pharmaceutically acceptable salt thereof is more effective against a plurality of HCV genotypes than the care standard. In some embodiments, The (1) and/or (Ια) compound or a pharmaceutically acceptable salt thereof is more effective against a particular HCV genotype (such as genotypes 1, 2, 3, 4, 5, and/or 6) than the care standard. Various indicators for determining the effectiveness of a method of treating HCV infection are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, reduced viral load, reduced viral replication, and clearing of the virus (the virus is not detectable in the patient's serum). Reduced time, increased sustained viral response to therapy, decreased morbidity or mortality in clinical outcomes, decreased rate of liver function reduction; stable liver function; improved liver function; decreased markers of one or more liver dysfunctions Including alanine transaminase, aspartate transaminase, total bilirubin, bound bilirubin, gamma glutamine transpeptidase; and/or other disease response indications. Similarly, in an effective amount of the text Compound Successful treatment of a pharmaceutical or pharmaceutical composition (eg, a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof) can reduce the incidence of liver cancer in HCV patients. In some embodiments, formula (I) An effective amount of the (or alpha) compound or a pharmaceutically acceptable salt thereof is effective to reduce viral titer to an undetectable level 'e.g., to about 1000 to about 5000 per milliliter of serum, about 500 to about An amount of 1000, or from about 100 to about 500 genomic copies. In some embodiments, 'the effective amount of the formula (I) and/or (1 〇〇 compound or a pharmaceutically acceptable salt thereof is effective to make the virus The load is reduced compared to the viral load prior to administration of formula (I) and/or (Ια) 158869.doc -77·201215395 or its pharmaceutically acceptable salt. For example, 'where The viral load is measured prior to administration of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof, and is accomplished using a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof. After the treatment plan (for example, 1 month after completion), measure the viral load again. In embodiments, an effective amount of a compound of formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof, can be an amount effective to reduce viral load to less than about one genome copy per milliliter of serum. In some embodiments, an effective amount of a compound of formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof, is effective to effect a viral challenge price in an individual's serum as compared to formula (1) and/or Or the viral load prior to the (Ια) compound or its pharmaceutically acceptable salt achieves a reduced amount in the range of from about 1.5 to about 〇§ to about 2.5 to 1 (^ decrease, from about 3 〇§ to about 4 〇) § decrease or greater than about 5_1 〇 § reduction. For example, the viral load can be measured before administration of the compound of formula (1) and / or (1 〇 1) or its pharmaceutically acceptable salt, and using formula (1) and / or (Ια) The compound or its pharmaceutically acceptable salt is measured for viral load after completion of the treatment regimen (eg, 1 month after completion). In some embodiments, a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof can be assayed for HCV in an individual as described in &amp; after completion of the treatment regimen (example # months after completion) Reproduction is at least 1x 2x, 3x, 4x, 5x, 1x, 15x, 2x, 25x, 5x, 75x, 1x or 1〇 reduction compared to pre-treatment levels More than 〇. In some embodiments, a compound of formula (1) and/or (Ια), or a pharmaceutically acceptable salt thereof, reduces the replication of hcv by from about 2 fold to about 5 fold to about 1 fold to about 2 fold relative to the pre-treatment level. Multiplier, about 15 times to about 4G times or about 5G times to about (10) times. In some embodiments, 158869.doc -78· 201215395 cut) and/or (Ια) compounds or pharmaceutically acceptable salts thereof can cause HCV replication to produce a reduction in the following dry circumference: ratio according to care standards The Hey replication achieved by the combination of polyethylated interferon and ribavirin is reduced by 1 ^8^1'5 1〇§ ' l〇g^2 log &gt; 2 logj.2.5 log &gt; 2.5 l〇g ^ 3 log, 3 log to 3.5 1〇g or 3 5 1〇§ to 4 1〇g of hcv replication reduced or compared to the use of viral money Polyethylene: alcoholized interferon for standard treatment after six months of reduction The same reduction as that achieved by standard care for care can be achieved in a shorter period of time, such as within one month, two months, or three months. In some embodiments, an effective amount of a compound of formula (1) and/or (Ια), or a pharmaceutically acceptable salt thereof, is an amount effective to achieve a sustained viral response, such as undetectable or in the serum of an individual. HCV RNA that is substantially undetectable (eg, less than about 5,000, less than about 4, less than about 200, or less than about 1 genome copy per milliliter of serum) and after stopping therapy A period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months is maintained. In some embodiments, a therapeutically effective amount of formula (I) and/or (1 〇〇 compound or a pharmaceutically acceptable salt thereof results in a liver fibrosis marker content compared to an untreated individual or placebo The amount of the marker in the treated individual is reduced by at least about 10%, at least about 20%, at least about 25%, at least about 3%, at least about 35%, at least about 40%, at least about 45%, at least about 50%. At least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more than 80%. The method of measuring blood-clearing labels is familiar with the art. It is known and includes immunological-based methods using 158869.doc •79·201215395 antibodies specific for a given serum marker, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and the like. A non-limiting list of examples of markers includes measuring serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamate using known methods. The content of transpeptidase (GGT) and total bilirubin (TBIL). In general, the ALT content is less than about 4 5 IU/L (International Units/Liter), AST in the range of 10 to 34 111/B, 八1^ in the range of 44-147 111/1^, 0卩 in the range of 0-51111/1^, D The ratio of 3 is in the range of 0.3-1.9 11^/(^ is considered normal. In some embodiments, the effective amount of the compound of formula (I) and/or (Ια) is effective to make ALT, AST, ALP, GGT and/ Or the amount of TBIL is reduced to an amount considered to be a normal amount. Individuals diagnosed with HCV infection clinically include "naiive" individuals (eg, individuals not previously treated for HCV, especially previously not receiving IFN-based) -tx and/or individuals based on ribavirin therapy) and individuals previously ineffective against HCV therapy ("treatment-ineffective" individuals). Treatment-ineffective individuals include "non-responders" (ie, previous treatments for HCV were not significant) Or an individual who substantially reduces the HCV titer (^0.5 log IU/mL), such as previous treatments for HCV such as previous IFN-α monotherapy, previous IFN-ot and viral saliva combination therapy, or previous PEGylated IFN-a Combined with viral beta therapy; and "relapsed" (ie previously for HCV) Treatment, for example, receiving prior IFN-a monotherapy, combination therapy with previous IFN-α and ribavirin, or combination therapy with previously PEGylated IFN-cx and ribavirin, and HCV titer has been reduced and subsequently elevated). In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof 158869.doc • 80 - 201215395 can be administered to a treatment-ineffective individual with HCV. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a non-responsive individual having HCV. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a relapsed subject having HCV. After a certain period of time, the infectious agent may develop resistance to one or more therapeutic agents. The term "resistance" as used herein refers to a strain of a virus that exhibits a delayed, attenuated, and/or ineffective response to a therapeutic agent. For example, after treatment with an antiviral agent, the viral load of an individual infected with a resistant virus may be reduced to a lesser extent than the amount of viral load exhibited by an individual infected with a non-resistant viral strain. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to an individual infected with an HCV strain that is resistant to one or more different anti-HCV agents. In some embodiments, when a patient is treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the production of a HCV strain can be delayed compared to the production of a HCV strain resistant to other HCV drugs. . In some embodiments, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to an individual who is contraindicated against other anti-HCV drugs. For example, individuals with hemoglobin (eg, thalassemia major, sickle cell anemia) and other individuals at risk of hematologic side effects of current therapies combine pegylated interferon ex with ribavirin There are contraindications to the administration. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be provided to an individual who is allergic to interferon or ribavirin. Some individuals who are treated for HCV experience a viral load recovery. As used herein, the term "recovery of viral load" means that the viral load continues to rise above the lowest point by 20.5 log IU/mL before the end of treatment, with the lowest point

S 158869.doc -81 - 201215395 is 0.5 log iu/mL reduced from baseline. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof, can be administered to an individual undergoing a viral load recovery, or can be prevented from recovering from the viral load when used to treat the individual. The standard of care for the treatment of HCV is associated with several side effects (adverse events). In some embodiments, a compound of formula (I), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, can be reduced in HCV patients treated with ribavirin and pegylated interferon according to care standards The number and/or severity of side effects observed. Examples of side effects include (but are not limited to) fever, discomfort, tachycardia, chills, headache, joint pain, muscle pain, fatigue, apathy, loss of appetite, nausea, vomiting, cognitive changes, weakness, lethargy, lack of initiative, and ease Anger, confusion 'depression, severe depression, suicidal ideation, anemia, low white blood cell count and hair refinement. In some embodiments, a compound of formula (1) or a pharmaceutically acceptable salt thereof can be provided to an individual who discontinues HCV therapy by one or more adverse effects or side effects associated with one or more other HCV agents. Table 5 provides some examples of comparing a compound of formula (I) or a pharmaceutically acceptable salt thereof to a standard of care. Examples include the following: In some embodiments, the percentage of non-responders receiving a compound of formula (I) or a pharmaceutically acceptable salt thereof is 1% less than the percentage of non-responders receiving care standards; in some embodiments The number of side effects experienced by an individual receiving a compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 10% to about 30% less than the number of side effects experienced by an individual receiving the care standard; and in some embodiments The side effects experienced by an individual receiving a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as one of the side effects described herein, are more severe than those of the I58869.doc • 82 · 201215395 The severity of the same side effects is 25% lower. Methods for quantifying the severity of side effects are known to those skilled in the art. Table 5 Percentage of non-responders Percentage of percent relapse Percentage of viral load recovery percentage of side effects Number of side effects less than 10% less 10% less 10% less 10% less 1Q% (lower 10% less 25% less 25%) 25% less 25% less 25% lower 25% less 40% less 40% less 40% less 40% less 40% lower 40〇/〇 less 50% less 50% less 50% less 50% less 50% lower 50% 60% less 60% less 60% less 60% less 60% lower 60% less 70% less 70% less 70% less 70% less 70% lower 70% less 80% less 80% less 80% less 80% less 80 % 80% less 90% less 90% less 90% less 90% less 90% lower 90% less than 10% less than about 10% at least about 10% to about 10% less to about 10% less to about 10% lower % to about 30% about 30% 30% 30% ϊ} 30% 30% less about 20% less than about 20% at least about 20% to about less than about 20% to about less than about 20% to about 20% to about About 50% about 50% 50% 50% about 50% 50% less about 30°/〇 at least about 30% at least about 30% to about less than about 30% to about less than about 30% to about 30% to about 70. % about 70% 70% 70% about 70% 70% less about 20% at least about 20% at least about 20% to about less than about 20% to about less than about 20% to about 20% to about 80% to about 80% 80% 80% about 80% 80%

Other embodiments disclosed herein are directed to methods of ameliorating or treating a parasitic disease, which can include administering to a subject having a parasitic disease a therapeutically effective amount of one or more compounds described herein (eg, formula (I) and/or ( Ια) a compound), or a pharmaceutical composition comprising one or more compounds described herein. In one embodiment, the parasitic disease can be Chagas' disease. &quot;Individual&quot; as used herein refers to an animal that is a subject of treatment, observation or experimentation. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and especially mammals. "Nursing - 83 - 158869.doc 201215395" includes (not limited to) mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, blacks Comet and cockroaches, and especially humans. In some embodiments, the individual is a human. The term "treatment" or "therapy" as used herein does not necessarily mean that the disease or condition is generally cured or removed. Any reduction in any unnecessary signs or symptoms of a disease or condition can be considered as a treatment and/or therapy to any degree. In addition, treatment may include effects that may worsen the overall well-being or appearance of the patient.

The term "therapeutically effective amount" is used to indicate the amount of a biological or pharmaceutical reaction of an active compound or pharmaceutical agent as indicated. For example, treatment of a compound is effective in preventing, alleviating or ameliorating the symptoms of the disease or prolonging the individual being treated

The amount required for survival. This reaction can occur in tissues, systems, animals or humans and includes alleviation of signs or symptoms of the disease being treated. In view of the disclosure of this article, it is decided that the therapeutically effective amount should be completely within the skill of those skilled in the art. The therapeutically effective amount required for the compound disclosed herein will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal under consideration. The dosage may be adapted to achieve the desired: use, but will depend on factors such as weight, diet, concomitant use, and other factors recognized by those skilled in the art. For those who are familiar with the technology, it is obvious that the application of the dosage and specific injections (4) the age, weight, severity of illness and the specific compounds used in the mammalian species The specific use of the temple compound is not ^ ^ . J wrong by familiar with the technology of the rules (such as human clinical trials and in vitro studies) to determine the achievement of the need for the results of j 158869.doc -84 · 201215395 The effective dose of the dose. The dosage range can be broad, depending on the desired effect and the therapeutic indication. Alternatively, the dosage can be based on the body surface area of the patient and will vary depending on the body surface area of the patient, as will be appreciated by those skilled in the art. Although the exact dose should be determined on a drug-by-drug basis, in most cases an overview of the dose can be made. Tincture for adult patients

The oxime scheme may be, for example, 口服.1111§ to 3〇〇〇111§, preferably 1111§ to 7〇〇111§, for example an oral dose of 5 mg to 200 mg of each active ingredient. The dose may be administered in a single administration or in two or more than one or more times in one or more days, depending on the individual needs. In some embodiments, the compound will be administered for a period of continuous therapy, such as one week or more, or months or years. In some of the shell examples, the compound of formula (1) (including the compound of formula (Ια)) or its pharmaceutically acceptable salt may be administered at a frequency less than the frequency of administration of the agent within the standard of care. In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered once daily. For example, a compound of formula (1) or a pharmaceutically acceptable salt thereof can be administered once daily to an It with hcv infection. In some embodiments, the total time of treatment of a compound of formula (1) (including a mouthpiece of formula (10)) or a pharmaceutically acceptable salt thereof may be shorter than the total time of the treatment regimen of the standard of care. Where the human dose of the compound has been established for at least a certain condition, the same agent i may be used, or the use of the established human dose is about 11% to 5 〇〇 ° / °, more preferably about 25 % to 250% of the dose. In the absence of a defined dose, as in the newly discovered pharmaceutical composition, the ED^ or Liao 158 869.doc -85 - 201215395 value of the Institute for Toxicity Research and Efficacy of the Animals can be freely obtained or by living organisms. Other suitable values obtained from external or in vivo studies are inferred to be suitable for human doses. In the case of administration of a pharmaceutically acceptable salt, the dose may be measured as a free test. As will be appreciated by those skilled in the art, in certain instances, it may be desirable to administer a compound disclosed herein in an amount that exceeds, or even far exceeds, the above preferred dosage range to effectively and aggressively treat particularly aggressive. Disease or infection. The dose and time interval can be adjusted individually to provide a plasma concentration of the active portion sufficient to maintain a modulating effect or a minimum effective concentration (MEC) "the MEC is different for each compound" but can be estimated from in vitro data. The dose required to achieve mec will depend on the individual characteristics and route of administration. However, HPlc assays or bioassays can be used to determine plasma concentrations. The dosing interval can also be determined using the Mec value. The composition should be administered using a regimen that maintains a plasma level above mec over a period of from 10% to 9% (preferably from 3% to 9% and optimally from 50% to 90%). In the case of topical administration or selective absorption, the effective local concentration of the drug may be independent of plasma concentration. It should be noted that the attending physician should know how and when to terminate, interrupt or modulate the administration due to toxicity or organ dysfunction. On the contrary, the attending physician should also understand that the right clinical response is not sufficient to adjust the treatment to a higher level (avoiding toxicity). The amount of the dose administered in the management of the relevant condition will vary with the severity of the condition being treated and the route of administration. change. The severity of the condition can be assessed, for example, to some extent by standard prognostic assessment methods. In addition, the dose and perhaps the frequency of administration will vary depending on the age of individual patients 'weight and response@. A protocol similar to that discussed above can be used in veterinary medicine. 158869.doc -86- 201215395 The efficacy and toxicity of the compounds disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing certain chemical moieties can be established by determining the in vitro toxicity against a cell line, such as a mammal and preferably a human cell line. The results of such studies often predict toxicity to animals, such as mammals, or more particularly humans. Alternatively, known methods can be used to determine the toxicity of a particular compound to an animal model, such as a mouse, mouse, rabbit or monkey. Several recognized methods, such as in vitro methods, animal models, or human clinical trials, can be used to establish the efficacy of a particular compound. When selecting a model to determine efficacy, the skilled artisan can select an appropriate model, dosage, route of administration, and/or regimen based on the state of the art. Combination Therapy In some embodiments, a compound disclosed herein (such as a compound of formula (I) (including a compound of formula (Ια))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein Used in combination with one or more other pharmaceutical agents. Examples of other agents which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, Agents currently used in the standard of care for the treatment of HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5 A inhibitors, other antiviral compounds, compounds of formula (BB) (including pharmaceutically acceptable salts and A pharmaceutical composition comprising a compound of formula (BB) or a pharmaceutically acceptable salt thereof, a compound of formula (CC), including a pharmaceutically acceptable salt, and a compound of formula (CC) or a pharmaceutically acceptable compound thereof Pharmaceutical compositions of the accepted salts), compounds of formula (DD) (including pharmaceutically acceptable salts, and pharmaceutical combinations which may include a compound of formula (DD) or a pharmaceutically acceptable salt thereof 158869.doc -87 - 201215395 (), and / or a combination thereof. In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, can be combined with one, two, three or Use three or more other medicines together. A non-limiting list of examples of combinations of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, is provided in Tables A, B. , C and D. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, is currently used in the context of conventional care standards The agents in the therapy are used in combination. For example, to treat HCV, the compounds disclosed herein can be combined with pegylated interferon-a-2a (trade name: PEGASYS®) and ribavirin, or pegylated interferon-a-2b (trade name) : PEG-INTRON®) and ribavirin are used in combination. As another example, the compounds disclosed herein can be used in combination with oseltamivir (TAMIFLU®) or zanamivin (RELENZA®) for the treatment of influenza infection. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, may be substituted for use in conventional standard care for care Pharmacy. For example, for the treatment of HCV, a viral composition can be replaced with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical group comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is 158869.doc-88 - 201215395 Used in combination with interferons such as pegylated interferon. Examples of suitable interferons include, but are not limited to, pegylated interferon-a-2a (trade name: PEGASYS®), pegylated interferon-a-2b (trade name: PEG-INTRON®), complex Interferon (interferon alfacon-Ι) (trade name: INFERGEN®), pegylated interferon λ and/or combinations thereof. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with an HCV protease inhibitor. A non-limiting list of exemplary HCV protease inhibitors includes the following: 乂乂-950 (TELAPREVIR®), ΜΚ-5172, ΑΒΤ-450, BILN-2061, BI-201335 'BMS-650032, SCH 503034 (BOCEPREVIR®), GS-9256, GS-945 1, IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or combinations thereof. A non-limiting list of exemplary HCV protease inhibitors includes the compounds numbered 1001-1014 in Figure 1. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with an HCV polymerase inhibitor . In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189, PSI-352938, PSI-661, 4·-azidourea (including 4'-stacks) Known prodrugs of nitrogen-based uridine, GS-6620, IDX-184, and TMC649128, and/or combinations thereof. Unrestricted exemplified nucleoside inhibitors

S 158869.doc •89- 201215395 The list of sexes includes the compounds numbered 2001-2010 in Figure 2. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497, and / or a combination thereof. A non-limiting list of exemplary non-nucleoside inhibitors includes the compounds numbered 3001-3008 in Figure 3. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with an NS5 A inhibitor. A non-limiting list of exemplary NS5A inhibitors includes BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393, and/or combinations thereof. A non-limiting list of exemplary NS5A inhibitors includes the compounds numbered 4001-4005 in Figure 4. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122, and/or combinations thereof. A non-limiting list of exemplary other antiviral compounds includes the compounds numbered 5001-5002 in Figure 5. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be combined with a compound of formula (BB) or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising a compound of the formula (BB) or a pharmaceutically acceptable salt thereof, is used in combination (see U.S. Provisional Application No. 61/426,471, filed on December 22, 2010, Its content is incorporated herein by reference in its entirety): 158869.doc -90· 201215395

Wherein bBB1 may be optionally substituted heterocyclic base or optionally substituted heterocyclic base having a protected amine group; χΒΒ may be 〇 (oxygen) or 3 (sulfur); RBB1 may be selected from -ZBB -RBB9, optionally substituted hydrazine-linked amino acid and optionally substituted N-linked amino acid ester derivative; zbb may be selected from the group consisting of Φ 氧 (oxygen), S (sulfur) and N (RBB1Q); RBB2 and RBB3 may be independently selected from hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C2.6 alkenyl, optionally substituted CM alkynyl, optionally substituted Ci 6 haloalkyl, and Optionally substituted aryl (C!·6 yard base); or RBB2 may together with ρΒΒ3 form a group selected from the group consisting of C:3·6 cycloalkyl optionally substituted, optionally substituted CM a cycloalkenyl group, optionally substituted C3.6 aryl, and optionally substituted C:3·6 heteroaryl; RBB4 may be selected from the group consisting of hydrogen, halogen, azide, cyano, optionally substituted C 6 alkyl, optionally substituted c26 alkenyl, optionally substituted C2. 6 alkynyl and optionally substituted allenyl; rBB5 may be hydrogen or optionally substituted Cl.6 Alkyl; RBW may be selected from the group consisting of hydrogen, a hydroxyl group, an azide group, an amine group, a cyano group, an optionally substituted C16 alkyl group, _〇rBB11 and -0C(=0)R_; RBB7 may be selected from hydrogen, teeth. , a group of aryl groups, optionally substituted Ci_6 》, 〇RBB13 and _〇C( = 〇)RBB14; RBB8 can be selected from hydrogen, halogen 'azido, cyano, as appropriate Alkyl, -〇RBB15 and -〇c(=〇)rbbi6; 11 mail 9 may be selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, as appropriate

S 158869.doc • 91· 201215395 Conditionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic , optionally substituted aryl (C!·6 alkyl)', optionally substituted heteroaryl (C!.6 alkyl) and optionally substituted heterocyclic (c) 6 alkyl); rBB1〇 may be selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryl (CM alkyl), optionally substituted heteroaryl (Cl-6 alkyl) And optionally substituted heterocyclic groups (Cm alkyl); RBB11 'rBBU&amp; rBB 〖5 may independently be hydrogen or optionally substituted (: 丨_6 alkyl; and RBB12, rBBI4 and RBB16 may be independently The ground is replaced by c! _6 or the C 3 6 ring base, as appropriate. In some embodiments, in HBB2 and RBB3 At least one of them is not hydrogen. A non-limiting list of exemplary compounds of formula (BB) includes the compound numbered 8000-8012 in Figures 8A-8B. In some embodiments, the compound of formula (I) or pharmaceutically acceptable thereof A salt or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, may be combined with a compound of formula (CC) or a pharmaceutically acceptable salt thereof, or a compound of formula (CC) or a pharmaceutical thereof A combination of pharmaceutical compositions with acceptable salts (see US Provisional Application No. 61/385, September 22, 2010, 3β3, and US Provisional Application, No. 61/, filed on February 22, 2012 426,461, the contents of which are incorporated herein by reference in its entirety): 158869.doc •92· 201215395

Wherein BCC1 may be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; Rcci may be selected from 〇., 〇h, optionally substituted N-linked amino acid and optionally substituted amino acid vinegar derivative; RCC2 substituted heteroaryl 0 RCC210-P-ORCC20 〇Λ II 0 Ρ- ORCC19

And CC may be selected from optionally substituted aryl, optionally substituted heterocyclic groups, and wherein RCC19, RCC20 and Rccn may be independently absent or are nitrogen, when OH, RCC2 is and ncc may be 0. Or 1; the restriction is when rcci is 〇. or

0 RCC21〇—JL I 〇RCC20 ο- Ο II -ρ- ORCC19 „cc

R CC3; and Rec: 3b can be independently

An alkyl group selected from the group consisting of hydrogen, hydrazine, optionally substituted Cw alkyl, optionally substituted C2. 6 alkenyl, optionally substituted c2-6 alkynyl, optionally substituted cK6 haloalkyl and aryl (Cw alkane) Or RCC3a may be substituted as appropriate with RCC3b (: 3.6 cycloalkyl; RCC4 may be selected from hydrogen, azide, optionally substituted Cu alkyl, optionally substituted C2_6 alkenyl And optionally substituted C2_6 alkynyl; RCC5 may be selected from the group consisting of hydrogen, halogen, azido, cyano, optionally substituted iCw alkyl, -ORcclG and -0C(=0)Rccl1; RCC6 may be selected from hydrogen, Halogen, azido, cyano, optionally substituted Cu alkyl, _〇RCC12 and _〇c(= 〇)RCC13; rCC7 may be selected from hydrogen, halogen, azide, cyano, as appropriate Cu alkyl, -〇 Reei4 and

S 158869.doc -93- 201215395 -OC(=0)Rccl5; or RCC6 and RCC7 may both be oxygen atoms and are linked together by a carbonyl group; RCC8 may be selected from hydrogen, a hydroxyl group, an azide group, a cyano group, optionally Substituted Cu alkyl, -ORCC16 and -〇C(=〇)Rcc"; RCC9 may be selected from hydrogen, azide, cyano, as appropriate (^.6 alkyl and -0RCC1*; RCC10 , RCC12, RCC14, pCC16 a dCC18_t Pour, ", ^ KRRR and ruler can be independently selected from hydrogen and optionally substituted Ci_6 alkyl; and RCC11, RCC13, RCC15 &amp; rCC17 can be independently selected from the case as appropriate a Ci.6 alkyl group and optionally a substituted c3.6 cycloalkyl group. In some embodiments, when RCC3a, RCC3b, RCC4, rCC5, RCC7, RCC8, and RCC9 are all hydrogen, Rea is not an azide group. A non-limiting list of examples of compounds of formula (cc) includes the compounds numbered 6000-6078 in Figures 6A-6I. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or A pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (DD) or a pharmaceutically acceptable salt thereof, or A pharmaceutical composition of the compound of the formula (DD) or a pharmaceutically acceptable salt thereof is used in combination (see U.S. Patent Application Serial No. 2,0249,068, filed on March 19, 2010, the content of In this article): RDD2 RDD1〇· , RDD3

Bdd1 rdd4-J^d\J__R rDD5—A*|d1:^^—rdc DD9 pDD8 RDD6 RDD7 Formula (DD) where each = can independently be a double bond or a single bond; addi can be selected from c (carbon), 〇 (oxygen) and S (sulfur); BDD1 may be optionally substituted heterocyclic base or a derivative thereof; D' may be selected from C=CH2, CH2, 0 (oxygen), S (sulfur), CHF and 158869 .doc 201215395 CF2 ; rdd1 can be hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, dialkylaminoalkyl, alkyl-C (= 0)-, aryl-c(=0)-, alkoxyalkyl·c(=〇)_, aryloxyalkyl-c(=g)_, alkylsulfonyl, arylsulfonyl Alkyl, aralkylsulfonyl RDD10-P-^, RDD11,-0-linked amino acid, bisphosphate, triphosphate or derivative thereof; RDD2 and RDD3 may each independently be selected from hydrogen, as the case may be Substituted C!·6 alkyl, optionally substituted c26 alkenyl, optionally substituted C2·6 alkynyl and optionally substituted C!·6 haloalkyl, restricted to rDD2 and RDD3 At least one of them may not be hydrogen; or RDD2 together with rDD3 form a group selected from the group consisting of Cw cycloalkyl, C 3-6 cycloalkenyl, C3-6 aryl and C3_6 heteroaryl; rDD4 and rDD9 may be independently selected from hydrogen, dentate, _Nh2, _NHRDDal, NRDDalRDDbl, _〇RDDal, _SRDDal, _cN, Nc, -N3 ' -N〇2 ' -N(RDDcl)-NRDDalRDDbl ' -N(RDDcl)-〇RDDal , -S_SRDDal, -C(=0)RDDal, -C(=0)0RDDa], -C(=0)NRDDal RDDbl -〇-(C=0)RDDal ' -0-C(=0)0RDDal ^ -0-C(=0)NRDDal RDDbi,_N(RDDcl)-C(=0)NRDDalRDDbl, -S(=0) RDDal, S(=0)2RDDal, -〇-S(=0)2NRDDalRDDbl, -N(RDDc1)-S(=〇)2 NR DalRDDbl, optionally substituted Cu-based, optionally substituted 〇2 · 6 dilute, optionally substituted C 2 · 6 fast radicals, optionally substituted aryl alkyl and - hydrazine - linked amino acids; rDD5, rDD6 and rDD7 may be independently absent or selected from hydrogen, , -NH2, -NHR°Dal, NRDDalRDDbi, -〇RDDal, -SRDDal, _CN, _NC, -N3, -N02, _N(RDDc1)_ NRDDalRDDbl, -N(RDDcl)-〇RDDal, -S-SRDDal, _C(=〇)RDDal, s 158869.doc -95- 201215395 -C(=0)ORDDal ' -C(=0)NRDDalRDDbl ' -0-(C=0)RDDal &gt; -OC(=0)ORDDal, -0-C(=0)NRDDalRDDbl, -N(RDDcl)-C(=0)NRDDal RDDbl, -S(=〇)RD Dal, S(=0)2RDDal, -0-S(=0)2NRDDalRDDbl, -N(RDDc:1)-S(=0)2NRDDalRDDb丨, optionally substituted Cu alkyl, optionally substituted C2 a -6 alkenyl group, optionally substituted C2.6 alkynyl group, optionally substituted aralkyl group and -Ο-linked amino acid; or Rdd6 together with RDD7 form -oc(=o)-o-; Rdd8 may be absent or selected from the group consisting of hydrogen, halogen, -NH2, -NHRDDal, NRDDalRDDbl, -ORDDal, -SRDDa, -CN, -NC, -N3, -N〇2, -N(RDDc) -· NRDDalRDDbl, -N(RDDcl)-ORDDal, -S-SRDDal, -C(=0)RDDal, -C(=0)0RDDal, -C(=0)NRDDalRDDbl,-0-C(=0)0RDDal , -0-C(=0)NRDDalRDDbl, -N(RDDcl)-C(=0)NRDDalRDDbl, -S(=0)RDDal,S(=0)2RDDal,-0-S(=0)2NRDDalRDDbl, - N(RDDel)-S(=0)2NRDDalRDDbl, optionally substituted (^-6 alkyl, optionally substituted C2_6 alkenyl, optionally substituted C2_6 alkynyl, optionally substituted haloalkyl , optionally substituted hydroxyalkyl and - hydrazine-linked amino acid, or when the bond to RDD7 indicated by = is a double bond, RDD7 is a C2.6 alkylene group and RDD8 is absent; RDDal, RDDbl and RDDel Each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally Substituted aralkyl and optionally substituted heteroaryl (Ci-6 alkyl); RDD1Q may be selected from the group consisting of 0_, -OH, and optionally 158869.doc • 96-201215395 aryloxy or aryl base-

RDD14 alkyl-C(=0)-0-CH2-0-, alkyl·ί:(=0)-8_(:Η2ί:Η2-〇- and·Ν·linked amino acids; RDD&quot; From Ο-, _0Η, optionally substituted aryloxy or aryl-Ο-

rDD14 alkyl-c(=o)-o-ch2-o-, burn

a group of -C(=0)-S_CH2CH2-0- and -N-linked amino acids; each RDD12 and each RDD13 may independently be -on or selected from the group consisting of Cw organocarbonyl, Cw alkoxycarbonyl and Cw organoamine Substituted substituents of a carbonyl group; each rDD14 may be hydrogen or optionally substituted cN6 alkyl; each mDD may independently be 1 or 2 and if RDD1Q and RDD11

rDD14

Each RDM2, each RDD 丨3, each ruler 4, and each mDD may be the same or different. In some embodiments, 'RDD8 can be a worm, -ORDDal, as appropriate.

Ck alkyl, optionally substituted C: 2·6 alkenyl, optionally substituted c 2-6 alkynyl and optionally substituted Cu haloalkyl. Some embodiments described herein are directed to methods of ameliorating or treating a viral infection 'which can include contacting a virus-infected cell with a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I) (including formula (Ια) a compound), a compound 7072, a compound 7073, a compound 7〇74', a compound 7075, a compound 7076, and a compound 7077, a monophosphate of any of the above, and a diphosphate of any of the above, or a pharmaceutically acceptable compound thereof Salt

S 158869.doc -97- 201215395 and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (BB), (CC) a compound and a compound of formula (DD), or a pharmaceutically acceptable salt of any of the above. Some embodiments described herein are directed to methods of ameliorating or treating a viral infection, which can comprise administering to a subject having a viral infection a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I) (including formula ( 1〇〇 compound), compound 7072, compound 7073, compound 7074, compound 7075, compound 7076, and compound 7077, a monophosphate of any of the above, and a diphosphate of any of the above, or a pharmaceutically acceptable compound thereof a salt; and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (BB), compound of formula (CC), and formula (DD) a compound, or a pharmaceutically acceptable salt of any of the above compounds. Some embodiments described herein are directed to a method of inhibiting viral replication, which can comprise contacting a virus-infected cell with an effective amount selected from the group consisting of: The following compounds: a compound of the formula (I) (including a compound of the formula (Ια)), a compound 7072, a compound 7073, a compound 7074, a compound 7075, and a compound Compound 7076 and compound 7077, a monophosphate of any of the above, and a diphosphate of any of the above, or a pharmaceutically acceptable salt thereof; and one or more agents selected from the group consisting of interferon, virus σ Sit, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (ΒΒ), compound of formula (CC) and compound of formula (DD), or any of the above compounds, pharmaceutically acceptable Some embodiments described herein are directed to methods of ameliorating or treating a viral infection, which can comprise contacting a virus-infected cell with a therapeutically effective amount of a compound selected from formula (I). a compound comprising a compound of the formula (Ια) or a pharmaceutically acceptable salt thereof, and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor , an antiviral compound, a compound of the formula (ΒΒ), a compound of the formula (CC) and a compound of the formula (DD), or a pharmaceutically acceptable salt of any of the above compounds. The present invention relates to a method for ameliorating or treating a viral infection, which may comprise administering to a subject having a viral infection a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I) (including a compound of formula (Ια)) or a medicament thereof a physiologically acceptable salt, and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (BB), formula ( CC) a compound and a compound of formula (DD), or a pharmaceutically acceptable salt of any of the foregoing. ^ Some embodiments described herein are directed to methods of inhibiting viral replication, which may include contacting a virus-infected cell with An effective amount of a compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof, and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerization An enzyme inhibitor, an NS5A inhibitor, an antiviral compound, a compound of the formula (ΒΒ), a compound of the formula (CC) and a compound of the formula (DD), or a pharmaceutically acceptable compound of any of the above Acceptable salt. In some embodiments, a compound of formula (I) (including a compound of formula (1〇〇) or

S 158869.doc -99- 201215395 The salt on the paclitaxel can be administered in a single pharmaceutical composition together with one or more other pharmaceutical agents. In some embodiments, the compound of the formula (1) (including the compound of the formula (Ια)) or a pharmaceutically acceptable salt thereof may be administered in combination with one or more other pharmaceutical agents in two or more separate pharmaceutical compositions. For example, S, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition, and at least one other agent can be administered as a second pharmaceutical composition. If at least two other agents are present, one or more of the other agents may be in a first drug and a delta comprising a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof And at least one additional additional agent can be in the second pharmaceutical composition. When the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of the formula (1) or a pharmaceutically acceptable salt thereof, and one or more other agents are administered and administered The course is within the knowledge of those skilled in the art. For example, when a standard of care for a known standard of care is administered using the amount of administration and time course of administration of the art, in addition to the therapies, an effective amount and dosage regimen as described herein can also be used. (I) a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, or may be administered using an effective amount and dosage regimen as described herein One of the agents for substance replacement combination therapy. The order in which the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered and the administration of one or more other agents may vary. In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered prior to all other agents. In other embodiments, a compound of formula (1) (including a compound of formula 158869.doc 201215395 (Ια)) or a pharmaceutically acceptable salt thereof can be administered prior to at least one other agent. In other embodiments, a compound of formula (1) (including a compound of formula (ΐα)) or a pharmaceutically acceptable salt thereof can be administered simultaneously with one or more other pharmaceutical agents. In other embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered after administration of at least one other agent. In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered after administration of all other agents. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more other agents of Figures 1-6 and 8-9 (including pharmaceutically acceptable salts and prodrugs thereof) The combination can produce an additive effect. In some embodiments, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more other pharmaceutical agents of Figures 1-6 and 8-9, including pharmaceutically acceptable salts and prodrugs thereof, can be produced Synergistic effect. In some embodiments, a combination of a compound of formula (1) or a pharmaceutically acceptable salt thereof with one or more other pharmaceutical agents of Figures 1-6 and 8.9, including pharmaceutically acceptable salts and prodrugs thereof, can be produced Strong synergy. In some embodiments, a combination of a compound of formula (1) or a pharmaceutically acceptable salt thereof with one or more other pharmaceutical agents of Figures 1-6 and 8-9, including pharmaceutically acceptable salts and prodrugs thereof No antagonistic effect. As used herein, "uplifting effect" means that the activity of the combination of compounds is less than the sum of the activities of the individual compounds in the combination when the activity of each compound is determined individually (i.e., in the form of a single compound). The term "synergistic effect" as used herein means that the activity of the combination of compounds is greater than the sum of the activities of the individual compounds in the combination when the activity of each compound is determined individually. As used herein, the term "additive effect" as used herein means that the activity of a combination of compounds is about equal to the sum of the individual compounds in the combination when the activity of each compound is measured individually. A potential advantage of using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more of the other pharmaceutical agents of Figures 16 and 8 (including pharmaceutically acceptable salts and prodrugs thereof) Comparing the amount required for the treatment of one or more of the compounds of Figure 8 and 9 (including pharmaceutically acceptable salts and prodrugs thereof) to treat the disease conditions (e.g., HCV) disclosed herein as compared to when administered in Figures 1-6 And the amount of one or more compounds (including pharmaceutically acceptable salts and prodrugs thereof) of 8-9 which are not administered to the compound of formula (I) or a pharmaceutically acceptable salt thereof, to achieve the same therapeutic result Reduced. For example, the amount of the compound (including its pharmaceutically acceptable salts and prodrugs) may be less than that of the compounds in Figures K and 8-9 (including its pharmaceutically acceptable salts and before). The amount required to achieve the same viral load reduction effect when administered as a monotherapy. Another potential advantage of using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more of the other pharmaceutical agents of Figures 16 and 89, including pharmaceutically acceptable salts and prodrugs thereof, is the use of Two or more compounds having different mechanisms of action can cause greater resistance to the production of resistant strains than to the compounds when administered in a monotherapy form. Other advantages of using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more of the other pharmaceutical agents of Figures 1-6 and 8-9, including pharmaceutically acceptable salts and prodrugs thereof, may include There is little to no cross-resistance between a compound of formula (1) or a pharmaceutically acceptable salt thereof and one or more other pharmaceutical agents of Figures i6 and 8-9, including pharmaceutically acceptable salts and prodrugs thereof; 158869.doc -102· 201215395

The compound or a pharmaceutically acceptable salt thereof is different from the elimination route of the 1-3 and 8-9 or a plurality of other pharmaceutical agents (including pharmaceutically acceptable salts and prodrugs thereof), and the formula (1) Compound or its pharmaceutically acceptable salt and figure! Between -6 and 8_9 I or a plurality of other agents (including pharmaceutically acceptable salts and prodrugs thereof) with no to no overlapping toxicity; with little or no significant effect on cytochrome p; and/or There is almost no drug between the compound of formula (1) or a pharmaceutically acceptable salt thereof and those of Figures 16 and 8-9 or a plurality of other agents, including pharmaceutically acceptable salts and prodrugs thereof. Kinetic interactions. A non-limiting list of exemplary combinations of a pharmaceutical composition of formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, with one or more other pharmaceutical agents is provided in Tables A, B, C &amp;D; . Further, a compound selected from the compounds 7072-7077 or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be used in combination with one or more other pharmaceutical agents as provided in Tables A, B, and Ca. Each of the compounds numbered X and γ in Tables A, B, C and D has the corresponding names and/or structures provided in Figures 1 to 9. The compounds numbered in Tables A, B, 〇 and 包括 include pharmaceutically acceptable salts of such compounds and pharmaceutical compositions containing such compounds or pharmaceutically acceptable salts thereof. For example, '1001 includes a compound corresponding to 1001, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising Compound 1 and/or a pharmaceutically acceptable salt thereof. The combinations exemplified in Tables A, B, C and D are designated by the formula X: γ, which represents a combination of the compound X and the compound γ. For example, the combination of the formula A1 in the table A is a combination of the compound 1〇〇1 and the compound 7001, including the compound ^(^ and/or pharmaceutically acceptable salt of Sichuan) and includes Pharmaceutical compositions of compounds 1001 and 7001 (including

A S 158869.doc -103- 201215395 A pharmaceutical composition of a pharmaceutically acceptable salt of Compound 1001 and/or Compound 7001). Thus, the combination designated as 1001:7001 in Table A indicates Telaprevir (compound 1001, as shown in Figure 1) and

A pharmaceutically acceptable salt of the compound 1001 and/or 7001, and a pharmaceutical composition comprising the compounds 1001 and 7001 (including a pharmaceutical composition comprising the compound 1001 and/or the pharmaceutically acceptable salt of the compound 7001). Each combination provided in Tables A, B, C, and D can be used with one, two, three, or three other agents as described herein. In some embodiments, the embodiments described herein, combinations of agents are useful for treating, ameliorating, and/or inhibiting viral and/or viral infections, wherein the virus can be HCV and the viral infection can be an HCV viral infection. Table A: Exemplary combinations of Compound X and Compound Y: Υ X: Υ X: Υ Χ: Υ Υ: Υ X: Υ X: Υ 1001 : 7000 1001 : 7001 1001 : 7002 1001 : 7003 1001 : 7004 1001 : 7005 1001 : 7006 1002 : 7000 1002 : 7001 1002 : 7002 1002 : 7003 1002 : 7004 1002 : 7005 1002 : 7006 1003 : 7000 1003 : 7001 1003 : 7002 1003 : 7003 1003 : 7004 1003 : 7005 1003 : 7006 1004 : 7000 1004 : 7001 1004 : 7002 1004 : 7003 1004 : 7004 1004 : 7005 1004 : 7006 1005 : 7000 1005 : 7001 1005 : 7002 1005 : 7003 1005 : 7004 1005 : 7005 1005 : 7006 1006 : 7000 1006 : 7001 1006 : 7002 1006 : 7003 1006 : 7004 1006 : 7005 1006 : 7006 1007 : 7000 1007 : 7001 1007 : 7002 1007 : 7003 1007: 7004 1007 : 7005 1007 : 7006 1008 : 7000 1008 : 7001 1008 : 7002 1008 : 7003 1008 : 7004 1008 : 7005 1008 : 7006 1009 : 7000 1009 : 7001 1009 : 7002 1009 : 7003 1009 : 7004 1009 : 7005 1009 : 7006 1010 : 7000 1010:7001 1010 : 7002 1010 : 7003 1010: 7004 1010 : 7005 1010 : 7006 1011 : 7000 1011 : 7001 1011 : 7002 1011 :7003 1011 :7004 1011 : 70 05 1011 : 7006 158869.doc -104- 201215395

X: Υ X: Υ X: Υ X: Υ X: Υ Χ: Υ X: Υ 1012 : 7000 1012 : 7001 1012 : 7002 1012 : 7003 1012 : 7004 1012 : 7005 1012 : 7006 1013 : 7000 1013 : 7001 1013 : 7002 1013 : 7003 1013 : 7004 1013 : 7005 1013 : 7006 1014 : 7000 1014 : 7001 1014 : 7002 1014 : 7003 1014 : 7004 1014 : 7005 1014 : 7006 2001 : 7000 2001 : 7001 2001 : 7002 2001 : 7003 2001 : 7004 2001 : 7005 2001 : 7006 2002 : 7000 2002 : 7001 2002 : 7002 2002 : 7003 2002 : 7004 2002 : 7005 2002 : 7006 2003 : 7000 2003 : 7001 2003 : 7002 2003 : 7003 2003 : 7004 2003 : 7005 2003 : 7006 2004 : 7000 2004 : 7001 2004 : 7002 2004 : 7003 2004 : 7004 2004 : 7005 2004 : 7006 2005 : 7000 2005 : 7001 2005 : 7002 2005 : 7003 2005 : 7004 2005 : 7005 2005 : 7006 2006 : 7000 2006 : 7001 2006 : 7002 2006 : 7003 2006 : 7004 2006 : 7005 2006 : 7006 2007 : 7000 2007 : 7001 2007 : 7002 2007 : 7003 2007 : 7004 2007 : 7005 2007 : 7006 2008 : 7000 2008 : 7001 2008 : 7002 2008 : 7003 2008 : 7004 2008 : 7005 2008 : 7006 2009 : 7000 2009 : 7001 2009 : 7002 2009 : 7003 2009 : 7004 2009 : 7005 2009 : 7006 2010 : 7000 2010 : 7001 2010 : 7002 2010 : 7003 2010 : 7004 2010 : 7005 2010 : 7006 3001 : 7000 3001 : 7001 3001 : 7002 3001 : 7003 3001 : 7004 3001 : 7005 3001 : 7006 3002 : 7000 3002 : 7001 3002 : 7002 3002 : 7003 3002 : 7004 3002 : 7005 3002 : 7006 3003 : 7000 3003 : 7001 3003 : 7002 3003 : 7003 3003 : 7004 3003 : 7005 3003 : 7006 3004 : 7000 3004 : 7001 3004 : 7002 3004 : 7003 3004 : 7004 3004 : 7005 3004 : 7006 3005 : 7000 3005 : 7001 3005 : 7002 3005 : 7003 3005 : 7004 3005 : 7005 3005 : 7006 3006 : 7000 3006 : 7001 3006 : 7002 3006 : 7003 3006 : 7004 3006 : 7005 3006 : 7006 3007 : 7000 3007 : 7001 3007 : 7002 3007 : 7003 3007 : 7004 3007 : 7005 3007 : 7006 3008 : 7000 3008 : 7001 3008 : 7002 3008 : 7003 3008 : 7004 3008 : 7005 3008 : 7006 4001 : 7000 4001 : 7001 4001 : 7002 4001 : 7003 4001 : 7004 4001 : 7005 4001 : 7006 4002 : 7000 4002 : 7001 4002 : 7002 4002 : 7003 4002 : 7004 4002 : 7005 4002 : 7006 400 3 : 7000 4003 : 7001 4003 : 7002 4003 : 7003 4003 : 7004 4003 : 7005 4003 : 7006 4004 : 7000 4004 : 7001 4004 : 7002 4004 : 7003 4004 : 7004 4004 : 7005 4004 : 7006 4005 : 7000 4005 : 7001 4005 : 7002 4005 : 7003 4005 : 7004 4005 : 7005 4005 : 7006 5001 : 7000 5001 : 7001 5001 : 7002 5001 : 7003 5001 : 7004 5001 : 7005 5001 : 7006 5002 : 7000 5002 : 7001 5002 : 7002 5002 : 7003 5002 : 7004 5002 : 7005 5002 : 7006 1001 : 7007 1001 : 7008 1001 : 7009 1001 : 7010 1001 : 7011 1001 : 7012 1001 : 7013 1002 : 7007 1002 : 7008 1002 : 7009 1002 : 7010 1002: 7011 1002 : 7012 1002 : 7013 1003 : 7007 1003 : 7008 1003 : 7009 1003 : 7010 1003 : 7011 1003 : 7012 1003 : 7013 1004 : 7007 1004 : 7008 1004 : 7009 1004 : 7010 1004: 7011 1004 : 7012 1004 : 7013 s 158869.doc -105· 201215395 X: Υ X: Υ X: Υ X: Υ Χ: Υ X: Υ X: Υ 1005 : 7007 1005 : 7008 1005 : 7009 1005 : 7010 1005 : 7011 1005 : 7012 1005 : 7013 1006 : 7007 1006 : 7008 1006 : 7009 1006 : 7010 1006:7011 1006 : 7012 1006 : 7013 1007 : 7007 1007 : 7008 1007 : 7009 1007 : 7010 1007 : 7011 1007 : 7012 1007 : 7013 1008 : 7007 1008 : 7008 1008 : 7009 1008 : 7010 1008: 7011 1008 : 7012 1008 : 7013 1009 : 7007 1009 : 7008 1009 : 7009 1009 : 7010 1009:7011 1009 : 7012 1009 : 7013 1010 : 7007 1010 : 7008 1010 : 7009 1010 : 7010 1010:7011 1010:7012 1010 : 7013 1011 :7007 1011 : 7008 1011 : 7009 1011 :7010 1011 :7011 1011 :7012 1011 : 7013 1012 : 7007 1012 : 7008 1012 : 7009 1012: 7010 1012: 7011 1012: 7012 1012 : 7013 1013 : 7007 1013 : 7008 1013 : 7009 1013 : 7010 1013 : 7011 1013 : 7012 1013 : 7013 1014 : 7007 1014 : 7008 1014 : 7009 1014:7010 1014:7011 1014:7012 1014:7013 2001 : 7007 2001 : 7008 2001 : 7009 2001 : 7010 2001 :7011 2001 : 7012 2001 : 7013 2002 : 7007 2002 : 7008 2002 : 7009 2002 : 7010 2002 :7011 2002 : 7012 2002 : 7013 2003 : 7007 2003 : 7008 2003 : 7009 2003 : 7010 2003 : 7011 2003 : 7012 2003 : 7013 2004 : 7007 2004 : 7008 2004 : 7009 2004 : 7010 2004:7011 2004 : 7012 2004 : 7013 2005 : 7007 2005 : 7008 2005 : 7009 2005 : 7010 2005 : 7011 2005 : 7012 2005 : 7013 2006 : 7007 2006 : 7008 2006 : 7009 2006 : 7010 2006:7011 2006 : 7012 2006 : 7013 2007 : 7007 2007 : 7008 2007 : 7009 2007 : 7010 2007 : 7011 2007 : 7012 2007 : 7013 2008 : 7007 2008 : 7008 2008 : 7009 2008 : 7010 2008 : 7011 2008 : 7012 2008 : 7013 2009 : 7007 2009 : 7008 2009 : 7009 2009 : 7010 2009:7011 2009 : 7012 2009 : 7013 2010 : 7007 2010 : 7008 2010 : 7009 2010 : 7010 2010 :7011 2010 : 7012 2010 : 7013 3001 : 7007 3001 : 7008 3001 : 7009 3001 : 7010 3001:7011 3001 : 7012 3001 : 7013 3002 : 7007 3002 : 7008 3002 : 7009 3002 : 7010 3002:7011 3002 : 7012 3002 : 7013 3003 : 7007 3003 : 7008 3003 : 7009 3003 : 7010 3003 : 7011 3003 : 7012 3003 : 7013 3004 : 7007 3004 : 7008 3004 : 7009 3004 : 7010 3004 : 7011 3004 : 7012 3004 : 7013 3005 : 7007 3005 : 7008 3005 : 7009 3005 : 7010 3005 : 7011 3005 : 7012 3005 : 7013 3006 : 7007 3006 : 7008 3006 : 7009 3006 : 7010 3006 : 7011 3006 : 7012 3006 : 7013 3007 : 7007 3007 : 7 008 3007 : 7009 3007 : 7010 3007 : 7011 3007 : 7012 3007 : 7013 3008 : 7007 3008 : 7008 3008 : 7009 3008 : 7010 3008 : 7011 3008 : 7012 3008 : 7013 4001 : 7007 4001 : 7008 4001 : 7009 4001 : 7010 4001 :7011 4001 : 7012 4001 : 7013 4002 : 7007 4002 : 7008 4002 : 7009 4002 : 7010 4002:7011 4002 : 7012 4002 : 7013 4003 : 7007 4003 : 7008 4003 : 7009 4003 : 7010 4003 : 7011 4003 : 7012 4003 : 7013 4004 : 7007 4004 : 7008 4004 : 7009 4004 : 7010 4004:7011 4004 : 7012 4004 : 7013 4005 : 7007 4005 : 7008 4005 : 7009 4005 : 7010 4005 : 7011 4005 : 7012 4005 : 7013 158869.doc -106- 201215395

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7073 2005 : 7074 2005 : 7075 2005 : 7076 2006 : 7070 2006 : 7071 2006 : 7072 2006 : 7073 2006 : 7074 2006 : 7075 2006 : 7076 2007 : 7070 2007 : 7071 2007 : 7072 2007 : 7073 2007 : 7074 2007 : 7075 2007 : 7076 2008 : 7070 2008 : 7071 2008 : 7072 2008 : 7073 2008 : 7074 2008 : 7075 2008 : 7076 2009 : 7070 2009 : 7071 2009 : 7072 2009 : 7073 2009 : 7074 2009 : 7075 2009 : 7076 2010 : 7070 2010 : 7071 2010 : 7072 2010 : 7073 2010 : 7074 2010 : 7075 2010 : 7076 3001 : 7070 3001 : 7071 3001 : 7072 3001 : 7073 3001 : 7074 3001 : 7075 3001 : 7076 3002 : 7070 3002 : 7071 3002 : 7072 3002 : 7073 3002 : 7074 3002 : 7075 3002 : 7076 3003 : 7070 3003 : 7071 3003 : 7072 3003 : 7073 3003 : 7074 3003 : 7075 3003 : 7076 3004 : 7070 3004 : 7071 3004 : 7072 3004 : 7073 3004 : 7074 3004 : 7075 3004 : 7076 3005 : 7070 3005 : 7071 3005 : 7072 3005 : 7073 3005 : 7074 3005 : 7075 3005 : 7076 3006 : 7070 3006 : 7071 3006 : 7072 3006 : 7073 3006 : 7074 3006 : 7075 3006 : 7076 3007 : 70 70 3007 : 7071 3007 : 7072 3007 : 7073 3007 : 7074 3007 : 7075 3007 : 7076 3008 : 7070 3008 : 7071 3008 : 7072 3008 : 7073 3008 : 7074 3008 : 7075 3008 : 7076 4001 : 7070 4001 : 7071 4001 : 7072 4001 : 7073 4001 : 7074 4001 : 7075 4001 : 7076 4002 : 7070 4002 : 7071 4002 : 7072 4002 : 7073 4002 : 7074 4002 : 7075 4002 : 7076 4003 : 7070 4003 : 7071 4003 : 7072 4003 : 7073 4003 : 7074 4003 : 7075 4003 : 7076 4004 : 7070 4004 : 7071 4004 : 7072 4004 : 7073 4004 : 7074 4004 : 7075 4004 : 7076 4005 : 7070 4005 : 7071 4005 : 7072 4005 : 7073 4005 : 7074 4005 : 7075 4005 : 7076 5001 : 7070 5001 : 7071 5001 : 7072 5001 : 7073 5001 : 7074 5001 : 7075 5001 : 7076 5002 : 7070 5002 : 7071 5002 : 7072 5002 : 7073 5002 : 7074 5002 : 7075 5002 : 7076 s 158869.doc -117- 201215395 X: Υ X: Υ X: Υ X: Υ X: Υ X: Υ X: Υ 1001 : 7077 1011 : 7077 2007 : 7077 3007 : 7077 1002 : 7077 1012 : 7077 2008 : 7077 3008 : 7077 1003 : 7077 1013 : 7077 2009 : 7077 4001 : 7077 1004 : 7077 1014 : 7077 2010 : 7077 4002 : 7077 1005 : 7077 2001 : 7077 3001 : 7077 4003 : 7077 1006 : 7077 2002 : 7077 3002 : 7077 4004 : 7077 1007 : 7077 2003 : 7077 3003 : 7077 4005 : 7077 1008 : 7077 2004 : 7077 3004 : 7077 5001 : 7077 1009 : 7077 2005 : 7077 3005 : 7077 5002 : 7077 1010 : 7077 2006 : 7077 3006 : 7077 — Table B : Exemplary combination of compound X and compound Y Υ: Υ X: Υ X: Υ Χ: Υ X :Υ X: Υ Χ:Υ 6000 : 7000 6000 : 7001 6000 : 7002 6000 : 7003 6000 : 7004 6000 : 7005 6000 : 7006 6001 : 7000 6001 : 7001 6001 : 7002 6001 : 7003 6001 : 7004 6001 : 7005 6001 : 7006 6002 : 7000 6002 : 7001 6002 : 7002 6002 : 7003 6002 : 7004 6002 : 7005 6002 : 7006 6003 : 7000 6003 : 7001 6003 : 7002 6003 : 7003 6003 : 7004 6003 : 7005 6003 : 7006 6004 : 7000 6004 : 7001 6004 : 7002 6004 : 7003 6004 : 7004 6004 : 7005 6004 : 7006 6005 : 7000 6005 : 7001 6005 : 7002 6005 : 7003 6005 : 7004 6005 : 7005 6005 : 7006 6006 : 7000 6006 : 7001 6006 : 7002 6006 : 7003 6006 : 7004 6006 : 7005 6006 : 7006 6007 : 7000 6007 : 7001 6007 : 7002 6007 : 7003 6007 : 7004 6007 : 7005 6007 : 7006 6008 : 7000 6008 : 7001 6008 : 7002 6008 : 7003 6008 : 7004 6008 : 7005 6008 : 7006 6009 : 7000 6009 : 7001 6009 : 7002 6009 : 7003 6009 : 7004 6009 : 7005 6009 : 7006 6010 : 7000 6010 : 7001 6010 : 7002 6010 : 7003 6010 : 7004 6010 : 7005 6010 : 7006 6011 : 700 6011 : 7001 6011 : 7002 6011 : 7003 6011 : 7004 6011 : 7005 6011 : 7006 6012 : 7000 6012 : 7001 6012 : 7002 6012 : 7003 6012 : 7004 6012 : 7005 6012 : 7006 6013 : 7000 6013 : 7001 6013 : 7002 6013 : 7003 6013 : 7004 6013 : 7005 6013 : 7006 6014 : 7000 6014 : 7001 6014 : 7002 6014 : 7003 6014 : 7004 6014 : 7005 6014 : 7006 6015 : 7000 6015 : 7001 6015 : 7002 6015 : 7003 6015 : 7004 6015 : 7005 6015 : 7006 6016 : 7000 6016 : 7001 6016 : 7002 6016 : 7003 6016 : 7004 6016 : 7005 6016 : 7006 6017 : 7000 6017 : 7001 6017 : 7002 6017 : 7003 6017 : 7004 6017 : 7005 6017 : 7006 6018 : 700 6018 : 7001 6018 : 7002 6018:7003 601 8 : 7004 6018 : 7005 6018 : 7006 6019 : 7000 6019 : 7001 6019 : 7002 6019 : 7003 6019 : 7004 6019 : 7005 6019 : 7006 6020 : 7000 6020 : 7001 6020 : 7002 6020 : 7003 6020 : 7004 6020 : 7005 6020 : 7006 6000 : 7007 6000 : 7008 6000 : 7009 6000 : 7010 6000:7011 6000 : 7012 6000 : 7013 6001 : 7007 6001 : 7008 6001 : 7009 6001 : 7010 6001 : 7011 6001 : 7012 6001 : 7013 158869.doc -118- 201215395

Χ:Υ Χ:Υ X: Υ X: Υ Χ:Υ Χ:Υ X: Υ 6002 : 7007 6002 : 7008 6002 : 7009 6002 : 7010 6002 :7011 6002 : 7012 6002 : 7013 6003 : 7007 6003 : 7008 6003 : 7009 6003 : 7010 6003 : 7011 6003 : 7012 6003 : 7013 6004 : 7007 6004 : 7008 6004 : 7009 6004 : 7010 6004 : 7011 6004 : 7012 6004: 7013 6005 : 7007 6005 : 7008 6005 : 7009 6005 : 7010 6005 : 7011 6005 : 7012 6005 : 7013 6006 : 7007 6006 : 7008 6006 : 7009 6006 : 7010 6006 : 7011 6006 : 7012 6006:7013 6007 : 7007 6007 : 7008 6007 : 7009 6007 : 7010 6007:7011 6007 : 7012 6007 : 7013 6008 : 7007 6008 : 7008 6008 : 7009 6008 : 7010 6008 : 7011 6008 : 7012 6008 : 7013 6009 : 7007 6009 : 7008 6009 : 7009 6009 : 7010 6009:7011 6009 : 7012 6009 : 7013 6010 : 7007 6010 : 7008 6010 : 7009 6010: 7010 6010 : 7011 6010:7012 6010:7013 6011 : 7007 6011 :7008 6011 : 7009 6011 :7010 6011 :7011 6011 :7012 6011 : 7013 6012 : 7007 6012 : 7008 6012 : 7009 6012 : 7010 6012 : 7011 6012:7012 6012 : 7013 6013 : 7007 6013 : 7008 6013 : 7009 6013 : 7010 6013 : 7011 6013 : 7012 6013 : 7013 6014 : 7007 6014 : 7008 6014 : 7009 6014: 7010 6014 : 7011 6014 : 7012 6014: 7013 6015 : 7007 6015 : 7008 6015 : 7009 6015 : 7010 6015 : 7011 6015 : 7012 6015 : 7013 6016 : 7007 6016 : 7008 6016 : 7009 6016 : 7010 6016 : 7011 6016 : 7012 6016:7013 6017 : 7007 6017 : 7008 6017: 7009 6017 : 7010 6017 : 7011 6017 : 7012 6017:7013 6018 : 7007 6018:7008 6018:7009 6018 :7010 6018 : 7011 6018 :7012 6018 : 7013 6019 : 7007 6019 : 7008 6019 : 7009 6019:7010 6019:7011 6019 : 7012 6019:7013 6020 : 7007 6020 : 7008 6020 : 7009 6020 : 7010 6020 : 7011 6020 : 7012 6020 : 7013 6000 : 7014 6000 : 7015 6000 : 7016 6000 : 7017 6000 : 7018 6000 : 7019 6000 : 7020 6001 : 7014 6001 : 7015 6001 : 7016 6001 : 7017 6001 : 7018 6001 : 7019 6001 : 7020 6002 : 7014 6002 : 7015 6002 : 7016 6002 : 7017 6002:7018 6002 : 7019 6002 : 7020 6003 : 7014 6003 : 7015 6003 : 7016 6003 : 7017 6003 : 7018 6003 : 7019 6003 : 7020 6004 : 7014 6004 : 7015 6004: 7016 6004 : 7017 6004:7 018 6004 : 7019 6004 : 7020 6005 : 7014 6005 : 7015 6005 : 7016 6005 : 7017 6005 : 7018 6005 : 7019 6005 : 7020 6006 : 7014 6006 : 7015 6006 : 7016 6006 : 7017 6006:7018 6006 : 7019 6006 : 7020 6007 : 7014 6007 : 7015 6007 : 7016 6007 : 7017 6007:7018 6007 : 7019 6007 : 7020 6008 : 7014 6008 : 7015 6008 : 7016 6008 : 7017 6008 : 7018 6008 : 7019 6008 : 7020 6009 : 7014 6009 : 7015 6009 : 7016 6009 : 7017 6009 : 7018 6009 : 7019 6009 : 7020 6010 : 7014 6010 : 7015 6010 : 7016 6010 : 7017 6010 : 7018 6010 : 7019 6010 : 7020 6011 : 7014 6011 : 7015 6011 : 7016 6011 : 7017 6011 : 7018 6011 : 7019 6011 : 7020 6012 : 7014 6012 : 7015 6012 : 7016 6012 : 7017 6012 : 7018 6012 : 7019 6012 : 7020 6013 : 7014 6013 : 7015 6013 : 7016 6013 : 7017 6013 : 7018 6013 : 7019 6013 : 7020 6014 : 7014 6014 : 7015 6014: 7016 6014 : 7017 6014 : 7018 6014 : 7019 6014 : 7020 6015 : 7014 6015 : 7015 6015 : 7016 6015 : 7017 6015 : 7018 6015 : 7019 6015 : 7020 6016 : 7014 6016 : 7015 6016 : 7016 6016 : 7017 6 016:7018 6016 : 7019 6016 : 7020 6017 : 7014 6017 : 7015 6017: 7016 6017 : 7017 6017:7018 6017 : 7019 6017:7020 6018 : 7014 6018 : 7015 6018 : 7016 6018 : 7017 6018:7018 6018 : 7019 6018: 7020 6019 : 7014 6019 : 7015 6019:7016 6019 : 7017 6019:7018 6019 : 7019 6019 : 7020 6020 : 7014 6020 : 7015 6020 : 7016 6020 : 7017 6020 : 7018 6020 : 7019 6020 : 7020 6000 : 7021 6000 : 7022 6000 : 7023 6000 : 7024 6000 : 7025 6000 : 7026 6000 : 7027 6001 : 7021 6001 : 7022 6001 : 7023 6001 : 7024 6001 : 7025 6001 : 7026 6001 : 7027 6002 : 7021 6002 : 7022 6002 : 7023 6002 : 7024 6002 : 7025 6002 : 7026 6002 : 7027 6003 : 7021 6003 : 7022 6003 : 7023 6003 : 7024 6003 : 7025 6003 : 7026 6003 : 7027 6004 : 7021 6004 : 7022 6004 : 7023 6004 : 7024 6004 : 7025 6004 : 7026 6004 : 7027 6005 : 7021 6005 : 7022 6005 : 7023 6005 : 7024 6005 : 7025 6005 : 7026 6005 : 7027 s 158869.doc -119- 201215395 X: Υ X: Υ X: Υ X: Υ Χ: Υ X: Υ Χ: Υ 6006 : 7021 6006 : 7022 6006 : 7023 6006 : 7024 6006 : 702 5 6006 : 7026 6006 : 7027 6007 : 7021 6007 : 7022 6007 : 7023 6007 : 7024 6007 : 7025 6007 : 7026 6007 : 7027 6008 : 7021 6008 : 7022 6008 : 7023 6008 : 7024 6008 : 7025 6008 : 7026 6008 : 7027 6009 : 7021 6009 : 7022 6009 : 7023 6009 : 7024 6009 : 7025 6009 : 7026 6009 : 7027 6010 : 7021 6010 : 7022 6010 : 7023 6010 : 7024 6010 : 7025 6010 : 7026 6010 : 7027 6011 : 7021 6011 : 7022 6011 : 7023 6011 : 7024 6011 : 7025 6011 : 7026 6011 : 7027 6012 : 7021 6012 : 7022 6012 : 7023 6012 : 7024 6012 : 7025 6012 : 7026 6012 : 7027 6013 : 7021 6013 : 7022 6013 : 7023 6013 : 7024 6013 : 7025 6013 : 7026 6013 : 7027 6014 : 7021 6014 : 7022 6014 : 7023 6014 : 7024 6014 : 7025 6014 : 7026 6014 : 7027 6015 : 7021 6015 : 7022 6015 : 7023 6015 : 7024 6015 : 7025 6015 : 7026 6015 : 7027 6016 : 7021 6016 : 7022 6016 : 7023 6016 : 7024 6016 : 7025 6016 : 7026 6016 : 7027 6017 : 7021 6017 : 7022 6017 : 7023 6017 : 7024 6017 : 7025 6017 : 7026 6017 : 7027 6018 : 7021 6018 : 7022 6018 : 7023 6018 : 7024 6 018 : 7025 6018 : 7026 6018 : 7027 6019 : 7021 6019 : 7022 6019 : 7023 6019 : 7024 6019 : 7025 6019 : 7026 6019 : 7027 6020 : 7021 6020 : 7022 6020 : 7023 6020 : 7024 6020 : 7025 6020 : 7026 6020 : 7027 6000 : 7028 6000 : 7029 6000 : 7030 6000 : 7031 6000 : 7032 6000 : 7033 6000 : 7034 6001 : 7028 6001 : 7029 6001 : 7030 6001 : 7031 6001 : 7032 6001 : 7033 6001 : 7034 6002 : 7028 6002 : 7029 6002 : 7030 6002 : 7031 6002 : 7032 6002 : 7033 6002 : 7034 6003 : 7028 6003 : 7029 6003 : 7030 6003 : 7031 6003 : 7032 6003 : 7033 6003 : 7034 6004 : 7028 6004 : 7029 6004 : 7030 6004:7031 6004 : 7032 6004 : 7033 6004 : 7034 6005 : 7028 6005 : 7029 6005 : 7030 6005 : 7031 6005 : 7032 6005 : 7033 6005 : 7034 6006 : 7028 6006 : 7029 6006 : 7030 6006:7031 6006 : 7032 6006 : 7033 6006 : 7034 6007 : 7028 6007 : 7029 6007 : 7030 6007:7031 6007 : 7032 6007 : 7033 6007 : 7034 6008 : 7028 6008 : 7029 6008 : 7030 6008 : 7031 6008 : 7032 6008 : 7033 6008 : 7034 6009 : 7028 6009 : 7029 6009 : 7030 6009 : 7031 6009 : 7032 6009 : 7033 6009 : 7034 6010 : 7028 6010 : 7029 6010 : 7030 6010:7031 6010 : 7032 6010 : 7033 6010 : 7034 6011 : 7028 6011 : 7029 6011 : 7030 6011 : 7031 6011 : 7032 6011 : 7033 6011 : 7034 6012 : 7028 6012 : 7029 6012 : 7030 6012:7031 6012 : 7032 6012 : 7033 6012 : 7034 6013 : 7028 6013 : 7029 6013 : 7030 6013 : 7031 6013 : 7032 6013 : 7033 6013 : 7034 6014 : 7028 6014 : 7029 6014 : 7030 6014 : 7031 6014 : 7032 6014 : 7033 6014 : 7034 6015 : 7028 6015 : 7029 6015 : 7030 6015 : 7031 6015 : 7032 6015 : 7033 6015 : 7034 6016 : 7028 6016 : 7029 6016 : 7030 6016 : 7031 6016 : 7032 6016 : 7033 6016 : 7034 6017 : 7028 6017 : 7029 6017 : 7030 6017 : 7031 6017 : 7032 6017 : 7033 6017 : 7034 6018:7028 6018 : 7029 6018 :7030 6018 : 7031 6018 : 7032 6018 : 7033 6018 : 7034 6019 7028 6019 : 7029 6019 : 7030 6019:7031 6019 : 7032 6019 : 7033 6019 : 7034 6020 : 7028 6020 : 7029 6020 : 7030 6020 : 7031 6020 : 7032 6020 : 7033 6020 : 7034 6000 : 7035 6000 : 7036 6000 : 7037 6000 : 7038 6000 : 7039 6000 : 7040 6000 : 7041 6001 : 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X: Υ X: Υ X: Υ X : Υ Χ: Υ X: Υ Χ: Υ 6010 : 7035 6010 : 7036 6010 : 7037 6010 : 7038 6010 : 7039 6010 : 7040 6010 : 7041 6011 : 7035 6011 : 7036 6011 : 7037 6011 : 7038 6011 : 7039 6011 : 7040 6011 : 7041 6012 : 7035 6012 : 7036 6012 : 7037 6012 : 7038 6012 : 7039 6012 : 7040 6012 : 7041 6013 : 7035 6013 : 7036 6013 : 7037 6013 : 7038 6013 : 7039 6013 7040 6013 : 7041 6014 : 7035 6014 : 7036 6014 : 7037 6014 : 7038 6014 : 7039 6014 : 7040 6014 : 7041 6015 : 7035 6015 : 7036 6015 : 7037 6015 : 7038 6015 : 7039 6015 : 7040 6015 : 7041 6016 : 7035 6016 : 7036 6016 : 7037 6016 : 7038 6016 : 7039 6016 : 7040 6016 : 7041 6017 : 7035 6017 : 7036 6017 : 7037 6017 : 7038 6017 : 7039 6017 : 7040 6017 : 7041 6018 : 7035 6018 : 7036 6018:7037 6018 : 7038 6018 : 7039 6018 : 7040 6018 : 7041 6019 : 7035 6019 : 7036 6019 : 7037 6019 : 7038 6019 : 7039 6019 : 7040 6019 : 7041 6020 : 7035 6020 : 7036 6020 : 7037 6020 : 7038 6020 : 7039 6020 : 7040 6020 : 7041 6000 : 7042 6000 : 7043 6000 : 7 044 6000 : 7045 6000 : 7046 6000 : 7047 6000 : 7048 6001 : 7042 6001 : 7043 6001 : 7044 6001 : 7045 6001 : 7046 6001 : 7047 6001 : 7048 6002 : 7042 6002 : 7043 6002 : 7044 6002 : 7045 6002 : 7046 6002 : 7047 6002 : 7048 6003 : 7042 6003 : 7043 6003 : 7044 6003 : 7045 6003 : 7046 6003 : 7047 6003 : 7048 6004 : 7042 6004 : 7043 6004 : 7044 6004 : 7045 6004 : 7046 6004 : 7047 6004 : 7048 6005 : 7042 6005 : 7043 6005 : 7044 6005 : 7045 6005 : 7046 6005 : 7047 6005 : 7048 6006 : 7042 6006 : 7043 6006 : 7044 6006 : 7045 6006 : 7046 6006 : 7047 6006 : 7048 6007 : 7042 6007 : 7043 6007 : 7044 6007 : 7045 6007 : 7046 6007 : 7047 6007 : 7048 6008 : 7042 6008 : 7043 6008 : 7044 6008 : 7045 6008 : 7046 6008 : 7047 6008 : 7048 6009 : 7042 6009 : 7043 6009 : 7044 6009 : 7045 6009 : 7046 6009 : 7047 6009 : 7048 6010 : 7042 6010 : 7043 6010 : 7044 6010 : 7045 6010 : 7046 6010 : 7047 6010 : 7048 6011 : 7042 6011 : 7043 6011 : 7044 6011 : 7045 6011 : 7046 6011 : 7047 6011 : 7048 6012 : 7042 6012 7043 6012 : 7044 6012 : 7045 6012 : 7046 6012 : 7047 6012 : 7048 6013 : 7042 6013 : 7043 6013 : 7044 6013 : 7045 6013 : 7046 6013 : 7047 6013 : 7048 6014 : 7042 6014 : 7043 6014 : 7044 6014 : 7045 6014 : 7046 6014 : 7047 6014 : 7048 6015 : 7042 6015 : 7043 6015 : 7044 6015 : 7045 6015 : 7046 6015 : 7047 6015 : 7048 6016 : 7042 6016 : 7043 6016 : 7044 6016 : 7045 6016 : 7046 6016 : 7047 6016 : 7048 6017 : 7042 6017 : 7043 6017 : 7044 6017 : 7045 6017 : 7046 6017 : 7047 6017 : 7048 6018:7042 6018 : 7043 6018 : 7044 6018 : 7045 6018 : 7046 6018 : 7047 6018 : 7048 6019 : 7042 6019 : 7043 6019 7044 6019 : 7045 6019 : 7046 6019 : 7047 6019 : 7048 6020 : 7042 6020 : 7043 6020 : 7044 6020 : 7045 6020 : 7046 6020 : 7047 6020 : 7048 6000 : 7049 6000 : 7050 6000 : 7051 6000 : 7052 6000 : 7053 6000 : 7054 6000 : 7055 6001 : 7049 6001 : 7050 6001 : 7051 6001 : 7052 6001 : 7053 6001 : 7054 6001 : 7055 6002 : 7049 6002 : 7050 6002 : 7051 6002 : 7052 6002 : 7053 6002 : 7054 6002 : 7055 6003 : 7049 6003 : 7050 6003 : 7051 6003 : 7052 6003 : 7053 6003 : 7054 6003 : 7055 6004 : 7049 6004 : 7050 6004 : 7051 6004 : 7052 6004 : 7053 6004 : 7054 6004 : 7055 6005 : 7049 6005 : 7050 6005 : 7051 6005 : 7052 6005 : 7053 6005 : 7054 6005 : 7055 6006 : 7049 6006 : 7050 6006 : 7051 6006 : 7052 6006 : 7053 6006 : 7054 6006 : 7055 6007 : 7049 6007 : 7050 6007 : 7051 6007 : 7052 6007 : 7053 6007 : 7054 6007 : 7055 6008 : 7049 6008 : 7050 6008 : 7051 6008 : 7052 6008 : 7053 6008 : 7054 6008 : 7055 6009 : 7049 6009 : 7050 6009 : 7051 6009 : 7052 6009 : 7053 6009:7054 6009 : 7055 6010 : 7049 6010 : 7050 6010 : 7051 6010 : 7052 6010 : 7053 6010 : 7054 6010 : 7055 6011 : 7049 6011 : 7050 6011 : 7051 6011 : 7052 6011 : 7053 6011 : 7054 6011 : 7055 6012 : 7049 6012 : 7050 6012 : 7051 6012 : 7052 6012 : 7053 6012 : 7054 6012 : 7055 6013 : 7049 6013 : 7050 6013 : 7051 6013 : 7052 6013 : 7053 6013 : 7054 6013 : 7055 s 158869.doc -121 - 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6075 : 7011 6075 : 7012 6075 : 7013 6075 :7014 6075 :7015 6075 : 7016 6075 :7017 6076:7011 6076: 7012 6076: 7013 6076:7014 6076:7015 6076 ········································· 7018 6061 : 7019 6061 : 7020 6061 : 7021 6061 : 7022 6061 : 7023 6061 : 7024 6062 : 7018 6062 : 7019 6062: 7020 6062: 7021 6062 : 7022 6062 : 7023 6062 : 7024 6063 : 7018 6063 : 7019 6063 : 7020 6063 :7021 6063 :7022 6063 :7023 6063 :7024 6064 : 7018 6064 : 7019 6064:7020 6064:7021 6064 :7022 6064 :7023 6064 :7024 6065 : 7018 6065 : 7019 6065 : 7020 6065 :7021 6065 :7022 6065 :7023 6065 : 7024 6066 : 7018 6066 : 7019 6066:7020 6066:7021 6066 :7022 6066 : 7023 6066:7024 6067 : 7018 6067 : 7019 6067:7020 6067:7021 6067 :7022 6067 :7023 6067 :7024 6068 : 7018 6068 : 7019 6068 : 7020 6068 : 7021 6068 : 7022 6068 : 7023 6068 : 702 4 6069 : 7018 6069 : 7019 6069:7020 6069:7021 6069 :7022 6069 : 7023 6069 :7024 6070 : 7018 6070 : 7019 6070:7020 6070:7021 6070 : 7022 6070 : 7023 6070 : 7024 6071 :7018 6071 : 7019 6071 :7020 6071 :7021 6071 :7022 6071 : 7023 6071 :7024 6072 : 7018 6072 : 7019 6072 : 7020 6072:7021 6072 :7022 6072 : 7023 6072 :7024 6073 : 7018 6073 : 7019 6073 : 7020 6073 : 7021 6073 : 7022 6073 : 7023 6073 : 7024 6074 : 7018 6074 : 7019 6074 : 7020 6074:7021 6074 : 7022 6074 : 7023 6074:7024 6075 : 7018 6075 :7019 6075 : 7020 6075 :7021 6075 :7022 6075 :7023 6075 :7024 6076 : 7018 6076: 7019 6076: 7020 6076:7021 6076:7022 6076: 7023 6076: 7024 6077 : 7018 6077 :7019 6077: 7020 6077: 7021 6077 :7022 6077 : 7023 6077: 7024 6078 : 7018 6078 : 7019 6078 : 7020 6078 : 7021 6078 : 7022 6078 : 7023 6078 : 7024 6061 : 7025 6061 : 7026 6061 : 7027 6061 : 7028 6061 : 7029 6061 : 7030 6061 : 7031 6062 : 7025 6062 : 7026 6062 : 7027 6062 : 7028 6062 : 7029 6062 : 7030 6062 : 7031 6063 : 7025 6063 : 7026 6063 : 7027 6063 : 7028 6063 : 7029 6063 : 7030 6063 : 7031 6064 : 7025 6064 : 7026 6064 : 7027 6064 : 7028 6064 : 7029 6064 : 7030 6064: 7031 6065 : 7025 6065 : 7026 6065 : 7027 6065 : 7028 6065 : 7029 6065 : 7030 6065 : 7031 6066 : 7025 6066 : 7026 6066 : 7027 6066 : 7028 6066 : 7029 6066 : 7030 6066:7031 6067 : 7025 6067 : 7026 6067 : 7027 6067 : 7028 6067 : 7029 6067 : 7030 6067:7031 6068 : 7025 6068 : 7026 6068 : 7027 6068 : 7028 6068 : 7029 6068 : 7030 6068: 7031 6069 : 7025 6069 : 7026 6069 : 7027 6069 : 7028 6069 : 7029 6069 : 7030 6069: 7031 6070 : 7025 6070 : 7026 6070 : 7027 6070 : 7028 6070 : 7029 6070 : 7030 6070:7031 158869.doc 134- 201215395

Χ:Υ X: Υ X: Υ X : Υ X: Υ X: Υ X: Υ 6071 : 7025 6071 : 7026 6071 : 7027 6071 : 7028 6071 : 7029 6071 : 7030 6071 : 7031 6072 : 7025 6072 : 7026 6072 : 7027 6072 : 7028 6072 : 7029 6072 : 7030 6072 : 7031 6073 : 7025 6073 : 7026 6073 : 7027 6073 : 7028 6073 : 7029 6073 : 7030 6073 : 7031 6074 : 7025 6074 : 7026 6074 : 7027 6074 : 7028 6074 : 7029 6074 : 7030 6074 : 7031 6075 : 7025 6075 : 7026 6075 : 7027 6075 : 7028 6075 : 7029 6075 : 7030 6075 : 7031 6076 : 7025 6076 : 7026 6076 : 7027 6076 : 7028 6076 : 7029 6076 : 7030 6076 : 7031 6077 : 7025 6077 : 7026 6077 : 7027 6077 : 7028 6077 : 7029 6077 : 7030 6077:7031 6078 : 7025 6078 : 7026 6078 : 7027 6078 : 7028 6078 : 7029 6078 : 7030 6078 : 7031 6061 : 7032 6061 : 7033 6061 : 7034 6061 : 7035 6061 : 7036 6061 : 7037 6061 : 7038 6062 : 7032 6062 : 7033 6062 : 7034 6062 : 7035 6062 : 7036 6062 : 7037 6062 : 7038 6063 : 7032 6063 : 7033 6063 : 7034 6063 : 7035 6063 : 7036 6063 : 7037 6063 : 7038 6064 : 7032 6064 : 7033 6064 : 7034 6064 : 7035 6064 : 7036 6064 : 7037 6064 : 7038 6065 : 7032 6065 : 7033 6065 : 7034 6065 : 7035 6065 : 7036 6065 : 7037 6065 : 7038 6066 : 7032 6066 : 7033 6066 : 7034 6066 : 7035 6066 : 7036 6066 : 7037 6066 : 7038 6067 : 7032 6067 : 7033 6067 : 7034 6067 : 7035 6067 : 7036 6067 : 7037 6067 : 7038 6068 : 7032 6068 : 7033 6068 : 7034 6068 : 7035 6068 : 7036 6068 : 7037 6068 : 7038 6069 : 7032 6069 : 7033 6069 : 7034 6069 : 7035 6069 : 7036 6069 : 7037 6069 : 7038 6070 : 7032 6070 : 7033 6070 : 7034 6070 : 7035 6070 : 7036 6070 : 7037 6070 : 7038 6071 : 7032 6071 : 7033 6071 : 7034 6071 : 7035 6071 : 7036 6071 : 7037 . 6071 : 7038 6072 : 7032 6072 : 7033 6072 : 7034 6072 : 7035 6072 : 7036 6072 : 7037 6072 : 7038 6073 : 7032 6073 : 7033 6073 : 7034 6073 : 7035 6073 : 7036 6073 : 7037 6073 : 7038 6074 : 7032 6074 : 7033 6074 : 7034 6074 : 7035 6074 : 7036 6074 : 7037 6074 : 7038 6075 : 7032 6075 : 7033 6075 : 7034 6075 : 7035 6075 : 7036 6075 : 7037 6075 : 7038 6076 : 7032 6076 : 7033 6076 : 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: 7049 6063 : 7050 6063 : 7051 6063 : 7052 6064 : 7046 6064 : 7047 6064 : 7048 6064 : 7049 6064 : 7050 6064 : 7051 6064 : 7052 6065 : 7046 6065 : 7047 6065 : 7048 6065 : 7049 6065 : 7050 6065 : 7051 6065 : 7052 6066 : 7046 6066 : 7047 6066 : 7048 6066 : 7049 6066 : 7050 6066 : 7051 6066 : 7052 6067 : 7046 6067 : 7047 6067 : 7048 6067 : 7049 6067 : 7050 6067 : 7051 6067 : 7052 6068 : 7046 6068 : 7047 6068 : 7048 6068 : 7049 6068 : 7050 6068 : 7051 6068 : 7052 6069 : 7046 6069 : 7047 6069 : 7048 6069 : 7049 6069 : 7050 6069 : 7051 6069 : 7052 6070 : 7046 6070 : 7047 6070 : 7048 6070 : 7049 6070 : 7050 6070 : 7051 6070 : 7052 6071 : 7046 6071 : 7047 6071 : 7048 6071 : 7049 6071 : 7050 6071 : 7051 6071 : 7052 6072 : 7046 6072 : 7047 6072 : 7048 6072 : 7049 6072 : 7050 6072:7051 6072 : 7052 6073 : 7046 6073 : 7047 6073 : 7048 6073 : 7049 6073 : 7050 6073 : 7051 6073 : 7052 6074 : 7046 6074 : 7047 6074 : 7048 6074 : 7049 607 4 : 7050 6074 : 7051 6074 : 7052 6075 : 7046 6075 : 7047 6075 : 7048 6075 : 7049 6075 : 7050 6075 : 7051 6075 : 7052 6076 : 7046 6076 : 7047 6076 : 7048 6076 : 7049 6076 : 7050 6076 : 7051 6076 : 7052 6077 : 7046 6077 : 7047 6077 : 7048 6077 : 7049 6077 : 7050 6077 : 7051 6077 : 7052 6078 : 7046 6078 : 7047 6078 : 7048 6078 : 7049 6078 : 7050 6078 : 7051 6078 : 7052 6061 : 7053 6061 : 7054 6061 : 7055 6061 : 7056 6061 : 7057 6061 : 7058 6061 : 7059 6062 : 7053 6062 : 7054 6062 : 7055 6062 : 7056 6062 : 7057 6062 : 7058 6062 : 7059 6063 : 7053 6063 : 7054 6063 : 7055 6063 : 7056 6063 : 7057 6063 : 7058 6063 : 7059 6064 : 7053 6064 : 7054 6064 : 7055 6064 : 7056 6064 : 7057 6064 : 7058 6064 : 7059 6065 : 7053 6065 : 7054 6065 : 7055 6065 : 7056 6065 : 7057 6065 : 7058 6065 : 7059 6066 : 7053 6066 : 7054 6066 : 7055 6066 : 7056 6066 : 7057 6066 : 7058 6066 : 7059 6067 : 7053 6067 : 7054 6067 : 7055 6067 : 7056 6067 : 7057 6067 : 7058 6067 : 7059 6068 : 7053 6068 : 7054 6068 : 7055 6068 : 7056 6068 : 7057 6068 : 7058 6068 : 7059 6069 : 7053 6069 : 7054 6069 : 7055 6069 : 7056 6069 : 7057 6069 : 7058 6069 : 7059 6070 : 7053 6070 : 7054 6070 : 7055 6070 : 7056 6070 : 7057 6070 : 7058 6070 : 7059 6071 : 7053 6071 : 7054 6071 : 7055 6071 : 7056 6071 : 7057 6071 : 7058 6071 : 7059 6072 : 7053 6072 : 7054 6072 : 7055 6072 : 7056 6072 : 7057 6072 : 7058 6072 : 7059 6073 : 7053 6073 : 7054 6073 : 7055 6073 : 7056 6073 : 7057 6073 : 7058 6073 : 7059 6074 : 7053 6074 : 7054 6074 : 7055 6074 : 7056 6074 : 7057 6074 : 7058 6074 : 7059 6075 : 7053 6075 : 7054 6075 : 7055 6075 : 7056 6075 : 7057 6075 : 7058 6075 : 7059 6076 : 7053 6076 : 7054 6076 : 7055 6076 : 7056 6076 : 7057 6076 : 7058 6076 : 7059 6077 : 7053 6077 : 7054 6077 : 7055 6077 : 7056 6077 : 7057 6077 : 7058 6077 : 7059 6078 : 7053 6078 : 7054 6078 : 7055 6078 : 7056 6078 : 7057 6078 : 7058 6078 : 7059 6061 : 7060 6061 : 7061 6061 : 7062 6061 : 7063 6061 : 7064 6061 : 7065 6061 : 7066 6062 : 7060 6062 : 7061 6062 : 7062 6062 : 7063 6062 : 7064 6062 : 7065 6062 : 7066 6063 : 7060 6063 : 7061 6063 : 7062 6063 : 7063 6063 : 7064 6063 : 7065 6063 : 7066 6064 : 7060 6064 : 7061 6064 : 7062 6064 : 7063 6064 : 7064 6064 : 7065 6064 : 7066 6065 : 7060 6065 : 7061 6065 : 7062 6065 : 7063 6065 : 7064 6065 : 7065 6065 : 7066 6066 : 7060 6066 : 7061 6066 : 7062 6066 : 7063 6066 : 7064 6066 : 7065 6066 : 7066 6067 : 7060 6067 : 7061 6067 : 7062 6067 : 7063 6067 : 7064 6067 : 7065 6067 : 7066 6068 : 7060 6068 : 7061 6068 : 7062 6068 : 7063 6068 : 7064 6068 : 7065 6068 : 7066 6069 : 7060 6069 : 7061 6069 : 7062 6069 : 7063 6069 : 7064 6069 : 7065 6069 : 7066 6070 : 7060 6070 : 7061 6070 : 7062 6070 : 7063 6070 : 7064 6070 : 7065 6070 : 7066 6071 : 7060 6071 : 7061 6071 : 7062 6071 : 7063 6071 : 7064 6071 : 7065 6071 : 7066

lS8869.doc -136· 201215395

X : Υ X: Υ X: Υ X: Υ X : Υ X: Υ X: Υ 6072 : 7060 6072 : 7061 6072 : 7062 6072 : 7063 6072 : 7064 6072 : 7065 6072 : 7066 6073 : 7060 6073 : 7061 6073 : 7062 6073 : 7063 6073 : 7064 6073 : 7065 6073 : 7066 6074 : 7060 6074 : 7061 6074 : 7062 6074 : 7063 6074 : 7064 6074 : 7065 6074 : 7066 6075 : 7060 6075 : 7061 6075 : 7062 6075 : 7063 6075 : 7064 6075 : 7065 6075 : 7066 6076 : 7060 6076 : 7061 6076 : 7062 6076 : 7063 6076 : 7064 6076 : 7065 6076 : 7066 6077 : 7060 6077 : 7061 6077 : 7062 6077 : 7063 6077 : 7064 6077 : 7065 6077 : 7066 6078 : 7060 6078 : 7061 6078 : 7062 6078 : 7063 6078 : 7064 6078 : 7065 6078 : 7066 6061 : 7067 6061 : 7068 6061 : 7069 6061 : 7070 6061 : 7071 6061 : 7072 6061 : 7073 6062 : 7067 6062 : 7068 6062 : 7069 6062 : 7070 6062 : 7071 6062 : 7072 6062 : 7073 6063 : 7067 6063 : 7068 6063 : 7069 6063 : 7070 6063 : 7071 6063 : 7072 6063 : 7073 6064 : 7067 6064 : 7068 6064 : 7069 6064 : 7070 6064 : 7071 6064 : 7072 6064 : 7073 6065 : 7067 6065 : 7068 6 065 : 7069 6065 : 7070 6065 : 7071 6065 : 7072 6065 : 7073 6066 : 7067 6066 : 7068 6066 : 7069 6066 : 7070 6066 : 7071 6066 : 7072 6066 : 7073 6067 : 7067 6067 : 7068 6067 : 7069 6067 : 7070 6067 : 7071 6067 : 7072 6067 : 7073 6068 : 7067 6068 : 7068 6068 : 7069 6068 : 7070 6068 : 7071 6068 : 7072 6068 : 7073 6069 : 7067 6069 : 7068 6069 : 7069 6069 : 7070 6069 : 7071 6069 : 7072 6069 : 7073 6070 : 7067 6070 : 7068 6070 : 7069 6070 : 7070 6070 : 7071 6070 : 7072 6070 : 7073 6071 : 7067 6071 : 7068 6071 : 7069 6071 : 7070 6071 : 7071 6071 : 7072 6071 : 7073 6072 : 7067 6072 : 7068 6072 : 7069 6072 : 7070 6072 : 7071 6072 : 7072 6072 : 7073 6073 : 7067 6073 : 7068 6073 : 7069 6073 : 7070 6073 : 7071 6073 : 7072 6073 : 7073 6074 : 7067 6074 : 7068 6074 : 7069 6074 : 7070 6074 : 7071 6074 : 7072 6074 : 7073 6075 : 7067 6075 : 7068 6075 : 7069 6075 : 7070 6075 : 7071 6075 : 7072 6075 : 7073 6076 : 7067 6076 : 7068 6076 : 7069 6076 : 7070 6076 : 7071 6076 : 7072 6076 : 7073 6077 : 7 067 6077 : 7068 6077 : 7069 6077 : 7070 6077 : 7071 6077 : 7072 6077 : 7073 6078 : 7067 6078 : 7068 6078 : 7069 6078 : 7070 6078 : 7071 6078 : 7072 6078 : 7073 6061 : 7074 6061 : 7075 6061 : 7076 6061 : 7077 6062 : 7074 6062 : 7075 6062 : 7076 6062 : 7077 6063 : 7074 6063 : 7075 6063 : 7076 6063 : 7077 6064 : 7074 6064 : 7075 6064 : 7076 6064 : 7077 6065 : 7074 6065 : 7075 6065 : 7076 6065 : 7077 6066 : 7074 6066 : 7075 6066 : 7076 6066 : 7077 6067 : 7074 6067 : 7075 6067 : 7076 6067 : 7077 6068 : 7074 6068 : 7075 6068 : 7076 6068 : 7077 6069 : 7074 6069 : 7075 6069 : 7076 6069 : 7077 6070 : 7074 6070 : 7075 6070 : 7076 6070 : 7077 6071 : 7074 6071 : 7075 6071 : 7076 6071 : 7077 6072 : 7074 6072 : 7075 6072 : 7076 6072 : 7077 6073 : 7074 6073 : 7075 6073 : 7076 6073 : 7077 6074 : 7074 6074 : 7075 6074 : 7076 6074 : 7077 6075 : 7074 6075 : 7075 6075 : 7076 6075 : 7077 6076 : 7074 6076 : 7075 6076 : 7076 6076 : 7 077 6077 : 7074 6077 : 7075 6077 : 7076 6077 : 7077 6078 : 7074 6078 : 7075 6078 : 7076 6078 : 7077 s 158869.doc 137· 201215395 Table C: Exemplary combination of compound X and compound Y X: Υ Χ:Υ X: Υ X : Υ X: Υ X : Υ 8000 : 7000 8000 : 7026 8000 : 7052 8001 : 7000 8001 : 7026 8001 : 7052 8000 : 7001 8000 : 7027 8000 : 7053 8001 : 7001 8001 : 7027 8001 : 7053 8000 : 7002 8000 : 7028 8000 : 7054 8001 : 7002 8001 : 7028 8001 : 7054 8000 : 7003 8000 : 7029 8000 : 7055 8001 : 7003 8001 : 7029 8001 : 7055 8000 : 7004 8000 : 7030 8000 : 7056 8001 : 7004 8001 : 7030 8001 : 7056 8000 : 7005 8000 : 7031 8000 : 7057 8001 : 7005 8001 : 7031 8001 : 7057 8000 : 7006 8000 : 7032 8000 : 7058 8001 : 7006 8001 : 7032 8001 : 7058 8000 : 7007 8000 : 7033 8000 : 7059 8001 : 7007 8001 : 7033 8001 : 7059 8000 : 7008 8000 : 7034 8000 : 7060 8001 : 7008 8001 : 7034 8001 : 7060 8000 : 7009 8000 : 7035 8000 : 7061 8001 : 7009 8001 : 7035 8001 : 7061 8000 : 7010 8000 : 7036 8000 : 7062 8001 : 7010 8001 : 70 36 8001 : 7062 8000:7011 8000 : 7037 8000 : 7063 8001 : 7011 8001 : 7037 8001 : 7063 8000 : 7012 8000 : 7038 8000 : 7064 8001 : 7012 8001 : 7038 8001 : 7064 8000 : 7013 8000 : 7039 8000 : 7065 8001 :7013 8001 : 7039 8001 : 7065 8000 : 7014 8000 : 7040 8000 : 7066 8001 : 7014 8001 : 7040 8001 : 7066 8000 : 7015 8000 : 7041 8000 : 7067 8001 : 7015 8001 : 7041 8001 : 7067 8000 : 7016 8000 : 7042 8000 : 7068 8001 : 7016 8001 : 7042 8001 : 7068 8000 : 7017 8000 : 7043 8000 : 7069 8001 : 7017 8001 : 7043 8001 : 7069 8000 : 7018 8000 : 7044 8000 : 7070 8001 : 7018 8001 : 7044 8001 : 7070 8000 : 7019 8000 : 7045 8000 : 7071 8001 : 7019 8001 : 7045 8001 : 7071 8000 : 7020 8000 : 7046 8000 : 7072 8001 : 7020 8001 : 7046 8001 : 7072 8000 : 7021 8000 : 7047 8000 : 7073 8001 : 7021 8001 : 7047 8001 : 7073 8000 : 7022 8000 : 7048 8000 : 7074 8001 : 7022 8001 : 7048 8001 : 7074 8000 : 7023 8000 : 7049 8000 : 7075 8001 : 7023 8001 : 7049 8001 : 7075 8000 : 7024 8000 : 7050 8000 : 7076 8001 : 7024 800 1 : 7050 8001 : 7076 8000 : 7025 8000 : 7051 8000 : 7077 8001 : 7025 8001 : 7051 8001 : 7077 8002 : 7000 8002 : 7026 8002 : 7052 8003 : 7000 8003 : 7026 8003 : 7052 8002 : 7001 8002 : 7027 8002 : 7053 8003 : 7001 8003 : 7027 8003 : 7053 8002 : 7002 8002 : 7028 8002 : 7054 8003 : 7002 8003 : 7028 8003 : 7054 8002 : 7003 8002 : 7029 8002 : 7055 8003 : 7003 8003 : 7029 8003 : 7055 8002 : 7004 8002 : 7030 8002 : 7056 8003 : 7004 8003 : 7030 8003 : 7056 8002 : 7005 8002:7031 8002 : 7057 8003 : 7005 8003 : 7031 8003 : 7057 8002 : 7006 8002 : 7032 8002 : 7058 8003 : 7006 8003 : 7032 8003 : 7058 8002 : 7007 8002 : 7033 8002 : 7059 8003 : 7007 8003 : 7033 8003 : 7059 8002 : 7008 8002 : 7034 8002 : 7060 8003 : 7008 8003 : 7034 8003 : 7060 8002 : 7009 8002 : 7035 8002 : 7061 8003 : 7009 8003 : 7035 8003 : 7061 8002 : 7010 8002 : 7036 8002 : 7062 8003 : 7010 8003 : 7036 8003 : 7062 8002 : 7011 8002 : 7037 8002 : 7063 8003 : 7011 8003 : 7037 8003 : 7063 8002 : 7012 8002 : 7038 8002 : 7064 8003 : 7012 8003 : 7038 8003 : 7064 8002 : 7013 8002 : 7039 8002 : 7065 8003 : 7013 8003 : 7039 8003 : 7065 8002 : 7014 8002 : 7040 8002 : 7066 8003 : 7014 8003 : 7040 8003 : 7066 8002 : 7015 8002 : 7041 8002 : 7067 8003 : 7015 8003 : 7041 8003 : 7067 8002 : 7016 8002 : 7042 8002 : 7068 8003 : 7016 8003 : 7042 8003 : 7068 158869.doc -138- 201215395

Χ:Υ X: Υ X: Υ X: Υ X: Υ X: Υ 8002 : 7017 8002 : 7043 8002 : 7069 8003 : 7017 8003 : 7043 8003 : 7069 8002:7018 8002 : 7044 8002 : 7070 8003 : 7018 8003 : 7044 8003 : 7070 8002 : 7019 8002 : 7045 8002 : 7071 8003 : 7019 8003 : 7045 8003 : 7071 8002 : 7020 8002 : 7046 8002 : 7072 8003 : 7020 8003 : 7046 8003 : 7072 8002 : 7021 8002 : 7047 8002 : 7073 8003 : 7021 8003 : 7047 8003 : 7073 8002 : 7022 8002 : 7048 8002 : 7074 8003 : 7022 8003 : 7048 8003 : 7074 8002 : 7023 8002 : 7049 8002 : 7075 8003 : 7023 8003 : 7049 8003 : 7075 8002 : 7024 8002 : 7050 8002 : 7076 8003 : 7024 8003 : 7050 8003 : 7076 8002 : 7025 8002 : 7051 8002 : 7077 8003 : 7025 8003 : 7051 8003 : 7077 8004 : 7000 8004 : 7026 8004 : 7052 8005 : 7000 8005 : 7026 8005 : 7052 8004 : 7001 8004 : 7027 8004 : 7053 8005 : 7001 8005 : 7027 8005 : 7053 8004 : 7002 8004 : 7028 8004 : 7054 8005 : 7002 8005 : 7028 8005 : 7054 8004 : 7003 8004 : 7029 8004 : 7055 8005 : 7003 8005 : 7029 8005 : 7055 8004 : 7004 8004 : 7030 8004 : 7056 8005 : 7004 8005 : 7030 8005 : 7056 8004 : 7005 8004 : 7031 8004 : 7057 8005 : 7005 8005 : 7031 8005 : 7057 8004 : 7006 8004 : 7032 8004 : 7058 8005 : 7006 8005 : 7032 8005 : 7058 8004 : 7007 8004 : 7033 8004 : 7059 8005 : 7007 8005 : 7033 8005 : 7059 8004 : 7008 8004 : 7034 8004 : 7060 8005 : 7008 8005 : 7034 8005 : 7060 8004 : 7009 8004 : 7035 8004 : 7061 8005 : 7009 8005 : 7035 8005 : 7061 8004 : 7010 8004 : 7036 8004 : 7062 8005 : 7010 8005 : 7036 8005 : 7062 8004:7011 8004 : 7037 8004 : 7063 8005 : 7011 8005 : 7037 8005 : 7063 8004 : 7012 8004 : 7038 8004 : 7064 8005 : 7012 8005 : 7038 8005 : 7064 8004 : 7013 8004 : 7039 8004 : 7065 8005 : 7013 8005 : 7039 8005 : 7065 8004 : 7014 8004 : 7040 8004 : 7066 8005 : 7014 8005 : 7040 8005 : 7066 8004 : 7015 8004 : 7041 8004 : 7067 8005 : 7015 8005 : 7041 8005 : 7067 8004 : 7016 8004 : 7042 8004 : 7068 8005 : 7016 8005 : 7042 8005 : 7068 8004 : 7017 8004 : 7043 8004 : 7069 8005 : 7017 8005 : 7043 8005 : 70 69 8004:7018 8〇〇4 : 7044 8004 : 7070 8005 : 7018 8005 : 7044 8005 : 7070 8004 : 7019 8004 : 7045 8004 : 7071 8005 : 7019 8005 : 7045 8005 : 7071 8004 : 7020 8004 : 7046 8004 : 7072 8005 : 7020 8005 : 7046 8005 : 7072 8004 : 7021 8004 : 7047 8004 : 7073 8005 : 7021 8005 : 7047 8005 : 7073 8004 : 7022 8004 : 7048 8004 : 7074 8005 : 7022 8005 : 7048 8005 : 7074 8004 : 7023 8004 : 7049 8004 : 7075 8005 : 7023 8005 : 7049 8005 : 7075 8004 : 7024 8004 : 7050 8004 : 7076 8005 : 7024 8005 : 7050 8005 : 7076 8004 : 7025 8004 : 7051 8004 : 7077 8005 : 7025 8005 : 7051 8005 : 7077 8006 : 7000 8006 : 7026 8006 : 7052 8007 : 7000 8007 : 7026 8007 : 7052 8006 : 7001 8006 : 7027 8006 : 7053 8007 : 7001 8007 : 7027 8007 : 7053 8006 : 7002 8006 : 7028 8006 : 7054 8007 : 7002 8007 : 7028 8007 : 7054 8006 : 7003 8006 : 7029 8006 : 7055 8007 : 7003 8007 : 7029 8007 : 7055 8006 : 7004 8006 : 7030 8006 : 7056 8007 : 7004 8007 : 7030 8007 : 7056 8006 : 7005 8006:7031 8006 : 7057 8007 : 70058007 : 7031 8007 : 7057 8006 : 7006 8006 : 7032 8006 : 7058 8007 : 7006 8007 : 7032 8007 : 7058 8006 : 7007 8006 : 7033 8006 : 7059 8007 : 7007 8007 : 7033 8007 : 7059 8006 : 7008 8006 : 7034 8006 : 7060 8007 : 7008 8007 : 7034 8007 : 7060 8006 : 7009 8006 : 7035 8006 : 7061 8007 : 7009 8007 : 7035 8007 : 7061 8006 : 7010 8006 : 7036 8006 : 7062 8007 : 7010 8007 : 7036 8007 : 7062 s 158869.doc -139- 201215395 Χ:Υ X: Υ Χ:Υ X: Υ X: Υ Χ:Υ 8006:7011 8006 : 7037 8006 : 7063 8007:7011 8007 : 7037 8007 : 7063 8006 : 7012 8006 : 7038 8006 : 7064 8007 : 7012 8007 : 7038 8007 : 7064 8006 : 7013 8006 : 7039 8006 : 7065 8007 : 7013 8007 : 7039 8007 : 7065 8006 : 7014 8006 : 7040 8006 : 7066 8007 : 7014 8007 : 7040 8007 : 7066 8006 : 7015 8006 : 7041 8006 : 7067 8007:7015 8007 : 7041 8007 : 7067 8006 : 7016 8006 : 7042 8006 : 7068 8007:7016 8007 : 7042 8007 : 7068 8006 : 7017 8006 : 7043 8006 : 7069 8007:7017 8007 : 7043 8007 : 7069 8006 : 7018 8006 : 7044 8006 : 7070 8007:701 8 8007 : 7044 8007 : 7070 8006 : 7019 8006 : 7045 8006 : 7071 8007:7019 8007 : 7045 8007 : 7071 8006 : 7020 8006 : 7046 8006 : 7072 8007 : 7020 8007 : 7046 8007 : 7072 8006 : 7021 8006 : 7047 8006 : 7073 8007 : 7021 8007 : 7047 8007 : 7073 8006 : 7022 8006 : 7048 8006 : 7074 8007 : 7022 8007 : 7048 8007 : 7074 8006 : 7023 8006 : 7049 8006 : 7075 8007 : 7023 8007 : 7049 8007 : 7075 8006 : 7024 8006 : 7050 8006 : 7076 8007 : 7024 8007 : 7050 8007 : 7076 8006 : 7025 8006 : 7051 8006 : 7077 8007 : 7025 8007 : 7051 8007 : 7077 8008 : 7000 8008 : 7026 8008 : 7052 8009 : 7000 8009 : 7026 8009 : 7052 8008 : 7001 8008 : 7027 8008 : 7053 8009 : 7001 8009 : 7027 8009 : 7053 8008 : 7002 8008 : 7028 8008 : 7054 8009 : 7002 8009 : 7028 8009 : 7054 8008 : 7003 8008 : 7029 8008 : 7055 8009 : 7003 8009 : 7029 8009 : 7055 8008 : 7004 8008 : 7030 8008 : 7056 8009 : 7004 8009 : 7030 8009 : 7056 8008 : 7005 8008 : 7031 8008 : 7057 8009 : 7005 8009:7031 8009 : 7057 8008 : 7006 8008 : 7032 8008 : 7058 8009 : 7006 8009 : 7032 8009 : 7058 8008 : 7007 8008 : 7033 8008 : 7059 8009 : 7007 8009 : 7033 8009 : 7059 8008 : 7008 8008 : 7034 8008 : 7060 8009 : 7008 8009 : 7034 8009 : 7060 8008 : 7009 8008 : 7035 8008 : 7061 8009 : 7009 8009 : 7035 8009 : 7061 8008 : 7010 8008 : 7036 8008 : 7062 8009 : 7010 8009 : 7036 8009 : 7062 8008:7011 8008 : 7037 8008 : 7063 8009 : 7011 8009 : 7037 8009 : 7063 8008 : 7012 8008 : 7038 8008 : 7064 8009 : 7012 8009 : 7038 8009 : 7064 8008 : 7013 8008 : 7039 8008 : 7065 8009 : 7013 8009 : 7039 8009 : 7065 8008 : 7014 8008 : 7040 8008 : 7066 8009 : 7014 8009 : 7040 8009 : 7066 8008 : 7015 8008 : 7041 8008 : 7067 8009:7015 8009 : 7041 8009 : 7067 8008 : 7016 8008 : 7042 8008 : 7068 8009 : 7016 8009 : 7042 8009 : 7068 8008 : 7017 8008 : 7043 8008 : 7069 8009 : 7017 8009 : 7043 8009 : 7069 8008 : 7018 8008 : 7044 8008 : 7070 8009 : 7018 8009 : 7044 8009 : 7070 8008 : 7019 8008 : 7045 8008 : 7071 8009 : 7019 8009 : 7045 8009 : 7071 8008 : 702 0 8008 : 7046 8008 : 7072 8009 : 7020 8009 : 7046 8009 : 7072 8008 : 7021 8008 : 7047 8008 : 7073 8009 : 7021 8009 : 7047 8009 : 7073 8008 : 7022 8008 : 7048 8008 : 7074 8009 : 7022 8009 : 7048 8009 : 7074 8008 : 7023 8008 : 7049 8008 : 7075 8009 : 7023 8009 : 7049 8009 : 7075 8008 : 7024 8008 : 7050 8008 : 7076 8009 : 7024 8009 : 7050 8009 : 7076 8008 : 7025 8008:7051 8008 : 7077 8009 : 7025 8009 : 7051 8009 : 7077 8010 : 7000 8010 : 7026 8010 : 7052 8011 : 7000 8011 : 7026 8011 : 7052 8010 : 7001 8010 : 7027 8010 : 7053 8011 : 7001 8011 : 7027 8011 : 7053 8010 : 7002 8010 : 7028 8010 : 7054 8011 : 7002 8011 : 7028 8011 : 7054 8010 : 7003 8010 : 7029 8010 : 7055 8011 : 7003 8011 : 7029 8011 : 7055 8010 : 7004 8010 : 7030 8010 : 7056 8011 : 7004 8011 : 7030 8011 : 7056 158869.doc - 140- 201215395

X: Υ X: Y Χ: Υ X: Υ X: Υ X : Υ 8010 : 7005 8010 : 7031 8010 : 7057 8011 : 7005 8011 : 7031 8011 : 7057 8010 : 7006 8010 : 7032 8010 : 7078 8011 : 7006 8011 : 7032 8011 : 7058 8010 : 7007 8010 : 7033 8010 : 7059 8011 : 7007 8011 : 7033 8011 : 7059 8010 : 7008 8010 : 7034 8010 : 7060 8011 : 7008 8011 : 7034 8011 : 7060 8010 : 7009 8010 : 7035 8010 : 7061 8011 :7009 8011 :7035 8011 :7061 8010:7010 8010 : 7036 8010 : 7062 8011 :7010 8011 :7036 8011 :7062 8010:7011 8010 : 7037 8010 :7063 8011 :7011 8011 :7037 8011 :7063 8010 : 7012 8010 : 7038 8010:7064 8011 :7012 8011 :7038 8011 :7064 8010:7013 8010 :7039 8010:7065 8011 :7013 8011 :7039 8011 :7065 8010 : 7014 8010 : 7040 8010 :7066 8011 :7014 8011 :7040 8011 :7066 8010: 7015 8010 : 7041 8010:7067 8011 :7015 8011 :7041 8011 :7067 8010:7016 8010 : 7042 8010: 7068 8011 :7016 8011 :7042 8011 :7068 8010 : 7017 8010 : 7043 8010:7069 8011 :7017 8011 :7043 8011 :7069 8010:7018 8010 : 7044 8010 :7070 8011 :7018 8011 :7044 8011 :7070 8010:701 9 8010 : 7045 8010:7071 8011 :7019 8011 :7045 8011 :7071 8010 : 7020 8010 : 7046 8010:7072 8011 :7020 8011 :7046 8011 :7072 8010 : 7021 8010 : 7047 8010:7073 8011 :7021 8011 :7047 8011 :7073 8010 : 7022 8010 : 7048 8010:7074 8011 :7022 8011 :7048 8011 :7074 8010 : 7023 8010 : 7049 8010 :7075 8011 :7023 8011 :7049 8011 :7075 8010 : 7024 8010 : 7050 8010:7076 8011 :7024 8011 : 7050 8011 : 7076 8010 : 7025 8010 : 7051 8010: 7097 8011 : 7025 8011 : 7051 8011 : 7097 8012 : 7000 8012 : 7026 8012 : 7052 8012 : 7001 8012 : 7027 8012 : 7053 8012 : 7002 8012 : 7028 8012 : 7054 8012 : 7003 8012 : 7029 8012 : 7055 8012 : 7004 8012 : 7030 8012 : 7056 8012 : 7005 8012 : 7031 8012 : 7057 8012 : 7006 8012 : 7032 8012 : 7058 8012 : 7007 8012 : 7033 8012 : 7059 8012 : 7008 8012 : 7034 8012 : 7060 8012 : 7009 8012 : 7035 8012 : 7061 8012 : 7010 8012 : 7036 8012 : 7062 8012:7011 8012 : 7037 8012 : 7063 8012:7012 8012 : 7038 8012 : 7064 8012: 7013 8012 : 7039 8012 : 7065 8012:7014 8012 : 7040 8012 : 7066 8012:7015 8012 : 7041 8012 : 7067 8012:7016 8012 : 7042 8012 : 7068 8012:7017 8012 : 7043 8012 : 7069 8012 : 7018 8012 : 7044 8012 : 7070 8012 : 7019 8012 : 7045 8012 : 7071 8012 : 7020 8012 : 7046 8012 : 7072 8012 : 7021 8012 : 7047 8012:7073 8012 : 7022 8012 : 7048 8012 : 7074 8012 : 7023 8012 : 7049 8012 : 7075 8012 : 7024 8012 : 7050 8012 : 7076 8012 : 7025 8012 :7051 8012 : 7077 S 158869.doc -141 - 201215395 Table D: Exemplary combination of compound X and compound Y X: Υ X: Υ X: Υ 9000 : 7000 9000 : 7026 9000 : 7052 9000 : 7001 9000 : 7027 9000 : 7053 9000 : 7002 9000 : 7028 9000 : 7054 9000 : 7003 9000 : 7029 9000 : 7055 9000 : 7004 9000 : 7030 9000 : 7056 9000 : 7005 9000 : 7031 9000 : 7057 9000 : 7006 9000 : 7032 9000 : 7058 9000 : 7007 9000 : 7033 9000 : 7059 9000 : 7008 9000 : 7034 9000 : 7060 9000 : 7009 9000 : 7035 9000 : 7061 9000 : 7010 9000 : 7036 9000 : 7062 9000 : 7011 9000 : 7037 9000 : 7063 9000 : 7012 9000 : 7038 9000 : 7064 9000 : 7013 9000 : 7039 9000 : 7065 9000 : 7014 9000 : 7040 9000 : 7066 9000 : 7015 9000 : 7041 9000 : 7067 9000 : 7016 9000 : 7042 9000 : 7068 9000 : 7017 9000 : 7043 9000 : 7069 9000 : 7018 9000 : 7044 9000 : 7070 9000 : 7019 9000 : 7045 9000 : 7071 9000 : 7020 9000 : 7046 9000 : 7072 9000 : 7021 9000 : 7047 9000 : 7073 9000 : 7022 9000 : 7048 9000 : 7074 9000 : 7023 9000 : 7049 9000 : 7075 9000 : 7024 9000 : 7050 9000 : 7076 9000 : 7025 9000 : 7051 9000 : 7077

EXAMPLES Other embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims. 158869.doc •142- 201215395 Example 1 Preparation of 1-0-ethylindenyl-2,3-0-dibenzoylindolyl-5〇S)-C-methyl-5-0-(4-nitrobenzene甲毛基)-Nero-ribofuranose (P1)

NaOMe

Thick h2so4 HOAc, Ac20

BzCI PNBO

0 bite

PNBO

BzO OBz P1-7

OAc Bz0 OBz P1

HO 1 pH Concentration H2S〇4 HO' &quot;CV〇H TSCI .Ts〇)f''.( 丫Η(5 \ 丙酿 I, CuS〇4 ό ό ° bite / \ Ρ1-1 P1-2 P1 -3

OH Step 1. Preparation of 2,3-0-isopropylidene-L-furan rhamnose (Pl-2)

To hydrated L-rhamnose (Pl-1) (550 gx3, 3354 mmolx3) and anhydrous CuS〇4 (1000 g&gt;&lt;3,6250 mmol&gt;&lt;3) in acetone (4000 mL&gt;&lt;3) Concentrated H2S04 (98%, 20 mL x 3) was added dropwise to the suspension. The mixture was stirred at room temperature for 20 hours. The mixture was neutralized with saturated ammonia and the precipitate was removed by filtration through celite. The filtrate was concentrated to near dryness and then a gas mixture (5000 mL) was added. The mixture was stirred at room temperature for 2 hours, and the precipitate was removed by filtration. The filtrate was concentrated to give EtOAc EtOAc (EtOAc:EtOAc: Step 2. Preparation of 2,3-0-isopropylidene-5-0-toluenesulfonyl-L-furan rhamnose (P1-3) 158869.doc -143 - 201215395 at 0 ° C, to the compound A solution of TsCl (749 gx3, 3933 mmol x 3) in anhydrous CHC13 was added dropwise to a solution of Pl-2 (670 gx3, 3267 mmol &lt;3) in anhydrous pyridine (1000 mL x 3). After the addition, the mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction was quenched with H20 and the solution was concentrated under reduced pressure. The residue was dissolved in EA (ethyl acetate) and washed sequentially with water, cold H2S04 (5%), sat. The organic phase was dried <RTI ID=0.0></RTI> to EtOAc (EtOAc) Step 3. Preparation of 1-0,5 (anaerobic)-(:-dimethyl-2,3-0-isopropylidene 4-furan nucleus% sugar (P1-4) to compound Pl at 〇 ° C -3 (450 gx4, 1257 mmolx4) NaOMe (137 gx4, 2537 mmolx4) was added portionwise with stirring over anhydrous MeOH (1000 mL×4). The mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure to adjust the pH to ca. 8 s. The residue was dissolved in EA and washed with brine. The organic layer was dried over Na.sub.2SO.sub. For further purification, use in the next-step towel. ® Step 4. Prepare 1-0,5(8)-(:-dimethyl-2,3-0-isopropylidene-5-0-(4- Benzylbenzhydryl)-D-ribofuranosylose (P1-5) to PP, at 〇 °C, 166 gx3,761 mmol&gt;&lt;3&gt; Addition of DEAD (diethyl azodicarboxylate) (400 gx3, 2290 mmol&gt;&lt;3) dropwise to a stirred solution of mmolx3) and PPh3 (600 gx3, 2290 mmolx3) in anhydrous THF (tetrahydrofuran) (1200 mL x 3) After the addition, the mixture was allowed to warm to room temperature and stirred overnight. Transfer 158869.doc -144- 20121 5395 The solvent was removed and the residue was redissolved in DCM (dichloromethane). The mixture was then treated with H202 (10% aqueous) at 0 ° C to 5 ° C. The organic phase was concentrated and dissolved in MTBE ( The crude product was purified by a hydrazine column (pure PE (petroleum ether): EA = 5:1 gradient) to afford a white solid. Pl-5 (400 g, 48%) ° Step 5. Prepare 1-0,5(5)-0-dimethyl-5-0-(4-nitrobenzylidene)-0-. Suppressed ribose (P1-6) Compound Pl-5 (200 gx2, 545 mmolx2) was dissolved in concentrated HCl and MeOH (2000 mL &lt;2,1% HCl in MeOH) and the mixture was refluxed for 8 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. EtOAc EtOAc m. g), which was used in the next step without further purification. Step 6. Preparation of 2,3-0-dibenyl-1-yl,5(S)-C-dimethyl-5-0- (4-Phenylbenzoyl)-D-ribofuranosyl (P1-7) to 粗Pl-6 at 〇°C 160 gx2, 489 mmol x 2) BzCl (212 gx2, 1 504 mmol χ2) was added dropwise to the stirred solution in anhydrous (2000 mL&gt;&lt;2&gt;). After the addition, the mixture was allowed to be allowed to stand at room temperature for 20 hours while being examined by TLC. The reaction was quenched with H20 and concentrated. The residue was dissolved in EA and washed sequentially with saturated aqueous NaHCO3, 5% cold H.sub.2, and brine. The organic phase was dried with EtOAc (EtOAc) Step 7. Preparation of 1-0-ethylindenyl-2,3-0-dibenridinyl-5(S)-C-methyl-5-

S 158869.doc -145- 201215395 0-(4-Nitrobenzimidyl)-D-ribofuranosyl (PI) to 0°C to crude Pl_7 (130 gx4,243 mmolx4) to HOAc (1000 mL×4) Concentrated H2SO4 (70 mL x 4) was added dropwise to the stirred solution in Ac2O (70 mL x 4). After the addition, the mixture was allowed to warm to room temperature and stirred for 20 hours while being examined by TLC. The mixture was poured into ice water with vigorous stirring. The precipitate was collected by filtration, and the filter cake was washed with water. The filter cake was then dissolved in EA and washed with saturated aqueous NaHCO3. The organic phase was dried over Na 2 SO 4 and concentrated. The residue was purified by EtOAc (EtOAc: EtOAc = EtOAc = EtOAc: EtOAc: (i?)-C-mercapto-5-0-(4-nitrobenzylidene)-/)-ribofuranose (Pl) (270 g, 49%); *H NMR (CDC13) δ 8.31- 7.29 (m, 14H), 6.74 and 6.42 (d, J = 4.8 Hz), brs, 1H), 5·85 (dd, J = 4.8, 7.2 Hz, 1H), 5.74-5.43 (m, 2H), 4.65 -4.61-5.43 (m, 1H), 2.19, 2.14 (2s, 3H), 1.55, 1.49 (2d, J=6.4 Hz, 3H) » ESI-LCMS: m/z 586.2 [M+Na]+ o Example 2 Tremose (P2)

158869.doc -146- 201215395

BzCI /A h2so4 V -- BzO V_T 〇 咬 i~l HOAc, AC2〇Bzd 0Bz BzO OBz P2-3 P2 Step 1. Preparation 5-0-benzoyl-1-0,5(R)-C - Dimercapto-2,3-0-isopropylidene-D-ribofuranosyl (P2-1) at 0 ° C, to l-oxime, 5 (i?)-C-dimethyl-2, 3-0-isopropylidene-D-ribofuranosylose (Pl-4) (30 g, 137.61 mmol) BzCl (3 8.53 g, 275.23) was added dropwise to a stirred solution of anhydrous 0-bit (300 mL). Mm). The mixture was then stirred at room temperature for 20 hours while being examined by TLC. The reaction was quenched with water and the solution was concentrated. The residue was diluted with EA and washed sequentially with aq. NaH. The organic phase was dried over Na2SO4, Step 2. Preparation of 5-0-phenylhydrazin-1-0,5(R)-C-dimethyl-D-ribofuranosylose (P2-2) Compound P2-l (40 g) was dissolved in concentrated HC1 And MeOH (300 mL, 1% HCl in MeOH). The mixture was refluxed for 4 hours while being examined by TLC. The mixture was then cooled to room temperature and concentrated. The residue was diluted with DCM and washed with aq. The organic phase was dried <RTI ID=0.0>(Na~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2,3,5-0-triphenylmethyl-D-ribofuranose (P2-3) to a stirred solution of crude P2-2 (38 g) in anhydrous pyridine (350 mL) at 〇 °C BzCl (66.03 g, 471.63 mmol) was added dropwise. After the addition, 158869.doc -147· 201215395 The mixture was allowed to warm to room temperature and allowed to mix for 2 hours while being examined by TLC. The reaction was quenched with water and the solution was concentrated. The residue was diluted with EA and washed sequentially with aq. NaH. The organic phase was dried <RTI ID=0.0>: </RTI> </RTI> <RTI ID=0.0> Step 4. Preparation of 1-0-acetamido-5 (1〇-(:-mercapto-2,3,5-fluorene-triphenylphosphonate_D-pyranose (P2) at 〇°C To the crude P2-3 (40 g) in a stirred solution of HOAc (500 mL) and Ac.sub.2 (35 mL), a concentrated portion of H2S04 (98%, 20. After addition, in the TLC test, The mixture was stirred at room temperature for 2 hours. The solution was poured into ice water with vigorous stirring. The precipitate was collected by transfer and washed with water. The filter cake was then dissolved in Ea and saturated with NaHC. The aqueous solution was washed with brine, and the organic phase was dried over Na 2 〇 4 and concentrated. The residue was purified by a silica gel column (PE: EA = 100:1 to 5:1) to give 1 acetamido-5 (magic-C-A) Base-2,3,5-0-triphenylmethyl-D-noose (P2) (25 g '59.12%); 4 NMR (CDC13) 3 8.10-7.26 (m, 15H), 6.61 &amp; 6.37 (2d, J=4.8, 0.8Hz, lH), 6.03-5_96 (m 1H), 5·75, 5.59 (2dd, J=4.8, 0.8 and J=4.4, 6.4 Hz, 1H), 5·5ΐ_ 5.45 ( m,1H), 4.62-4.59 (m,1H), 2.12, 1.81 (2s,3H), 1.51, 1.45 (2d, J=6.4 Hz, 3H) » ESI-LCMS: m/z 541.4 [M+Na] + 〇Example 3 Preparation 2',3'-i&gt;-A Oxymethylene methoxytriphenyl fluorenyl) 5'(S)-C:-methyladenosine (P3) 158869.doc -148- 201215395

Step 1. Preparation of 9-(2,3-0-dimercaptomethyl-5-0-4-nitrobenzhydryl-5(S)-C-methyl-β-D-ribofuranosyl) -6-chloropurine (P3-1)

To 0-0C, to 1-0-acetamido-2,3-0-diphenylmethyl-5(*S)-C:-mercapto-5-0-(4-nitrophenyl Mercapto)-Z)-ribofuranose (Pl) (75 gx3, 133 mmol x 3) and 6-chlorine (20.9 gx 3,135 mmol) &lt;3) were stirred in anhydrous MeCN (400 mL&gt;&lt;3) DBU (1,8-diazabicyclo(5.4.0) eleven-7-ene) (61 gx3, 400 mmol &gt;&lt; 3) was added to the suspension. The mixture was stirred at 0 ° C for 5 minutes, and then TMSOTf (105 mL &gt; 3,536 mmol x 3) was added dropwise at 0 °C. After the addition, the mixture was stirred at 0 ° C for 20 minutes until a clear solution was obtained. The mixture was then heated to 70 ° C and stirred for 3 hours. The reaction was cooled to room temperature and diluted with EA. The solution was washed successively with saturated NaHC03 and brine. The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc Step 2. Preparation of 5'(S)-C-methyladenosine (P3-2)

S 158869.doc -149- 201215395 Compound P3-l (l〇〇gx2, 152 mmolx2) was dissolved in 1,4-dioxane (200 ml&gt;&lt;2), and then saturated aqueous ammonia (200 mL) was added. &lt;2). At 1〇〇. The mixture was stirred in a sealed container for 10 hours. The mixture was cooled to room temperature and diluted with MeOH. The solvent was removed under reduced pressure, and the residue was purified to purified crystals eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted g, 88%) ; 4 NMR (CD3〇D) δ 8.31 (s, 1H), 8.17 (s, 1H), 5.95 (d, 7=6.8 Hz, 1H), 4.73 (m, 1H), 4.27 (dd , 7=5.2 Hz, 2.4 Hz, 1H), 4.07 (t, 7=2.4 Hz, 1H), 3.96-3.91 (m, 1H), 3.30 (m, 1H), 1.25 (d, &lt;/=6.8 Hz , 3H) ; ESI-LCMS: m/z 282 [M+H]+. Step 3·Preparation of 2Ι,3·-0-methoxymethylene methyl gland (pH) Compound P3-2 (17 g, 60.5 mmol) and tribasic acid formic acid (170 mL) were mixed at 50 °C. And a mixture of p-toluenesulfonic acid monohydrate (18 g, 94.7 mm 〇l) in hydrazine-dioxane (160 mL) for 12 hours, cooled with ice and triethylamine (15 mL) &gt; The mixture was concentrated. The residue was purified with EtOAc (EtOAc) elut elut Step 4. Preparation of 2',3'-0-methoxymethylene·ν6·(4,-methoxytrityl)_y(S)-C-methyladenosine (Ρ3) P3-3 (15 g, 46.4 mmo b was co-evaporated twice with anhydrous pyridine) and a mixture of MMTrCl (21 g, 68 mm 〇l) was suspended in anhydrous pyridine U50 mL). The mixture was mixed for 12 hours at 50 t; The mixture was then quenched with H2 and concentrated. The residue was purified by a hydrazine gel column (ΡΕ/ΕΑ=3αΐι: ι) to give 2,3, _(^曱oxymethylene 曱158869.doc -150- 201215395 oxytriphenylbenzene as a white foam. Methyl)-5' (phantom-0:-mercapto adenosine (P3) (12 g, 44%). Example 4 Preparation of 2',3'-0-methoxymethylenemethoxytriphenyl Base)-5'〇S)-C-decyl cytosine nucleoside (P4)

, 〇, λλ〇α. ΡΝΒ〇- T + ΗΝ

Ο

ΝΗΒζ

°VN NHMMTr

NHMMTr TBAF THF 1)TBSCI/AgN03

-TBSO

Y

2) MMTrCI P4

Step 1. Preparation of y(S)-C-methyl-5'-0-(4-nitrobenzhydryl OJH-tribenylcytidine nucleoside (P4-1Q) under argon Treatment of phenylhydrazine in anhydrous di-ethane (100 mL) with excess 1,1,1,3,3,3-hexyl-diazane (15 mL) in the presence of ammonium sulfate (1 mg) Mercaptocytosine (3.5 g, 16.87 mmol) and refluxed at 125 ° C for 2 hours until all solids dissolved. Excess solvent was evaporated under reduced pressure and the obtained syrup was dissolved in anhydrous dichloroethane (100 The compound P1 (5 g, 8.88 mmol) was added, followed by the addition of SnCl4 (1 mL). The mixture was heated under reflux s 158869.doc - 151 - 201215395 overnight, cooled with ice and diluted with ethyl acetate. The mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous Na.sub.2.sub.4 and concentrated. S)-C-decyl cytidine (P4-2) The compound 卩4-1 (5.5 g, 7.66 mmol) in saturated MeOH solution (200 mL) was stirred overnight at room temperature. The residue was redissolved in MeOH. Precipitation in MeOH/DCM gave P4-2 (1.5 g, 76.19%). 4 NMR (400 MHz,MeOD): δ 8·08 (d, = 7.6 Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 5.82 (d, J=3.6 Hz, 1H), 4.11-4.13 (m, 1H), 4.05-4.08 (m, 1H), 3.89-3.94 (m; 1H), 3.79-3.81 (m, 1H) , 1.27 (d, J = 6.8 Hz, 3H); ESI-MS: m/z 515 [2M+H] + , 258 [M+H]+. Step 3. Preparation of 2',3^0-methoxy Methylene-5\R)-C-methylcytosine nucleus (P4-3) Stir compound P4-2 (500 mg, 1.95 mmol) and tridecyl decanoate (3 mL) at room temperature A mixture of p-toluenesulfonic acid monohydrate (450 mg, 2.33 mmol) in 1,4-dioxane (10 mL), EtOAc (EtOAc) . The residue was purified with EtOAc EtOAc (EtOAc) Step 4. Preparation of 5'-0-(t-butyldidecylfluorenyloxymethylene-N4-(4-decyloxytrityl)-5'(S)-C-methyl Cytosine nuclear (P4-4) 158869.doc -152· 201215395 To the stirred solution of compound P4-3 (450 mg, 1.51 mmol) in σ ratio (5 ml), add TBSC1 (third butyl Methyl chlorodecane) (450 mg, 3.01 mmol) and AgNO3 (0.51 g, 3.01 mmol) » The mixture was stirred at 50 ° C to 60 ° C for 3 hours. Then MMTrCl (0.93 g, 3.01 mmol) was added at 50 ° The mixture was scrambled overnight at C to 60 ° C until the reaction was completed as determined by TLC. The reaction was cooled to room temperature and diluted with EA. The precipitate was removed by filtration, and the filtrate was washed sequentially with brine. The organic layer was dried over Na 2 SO 4 and then concentrated to give &lt S)-C-methylcytosine (P4) Compound P4-4 (800 mg, crude) in 1 M TBAF in THF (20 mL) was stirred overnight at room temperature. Purify the residue and then purify by preparative TLC , P4 (100 mg), 4 NMR (400 MHz, CDC13): δ 7.25-6.76 (m, 14H), 5.79 (d, 1H), 5.28-4.99 (m, 4H), 4.09 (m, 3H), 3.72 (s, 3H), 3.28, 3.21 (2s, 3H), 1.17 (brs, 3H); ESI-MS: m/z 572 [M+H]+. Example 5 Synthesis 2', 3'-0-A Oxymethylene-N4-(4-methoxytrityl)-5'(J?)-C-methylcytosine nucleoside (P5)

s 158869.doc -153- 201215395

Nh2 1) TBSCI, AgN03 2) MMTrCI

Step 1. Preparation of thiol-5'-0-(4-nitrobenzylidene)-2\3'-0, N4-tritylmercapto cytidine (P5-1) under argon Treatment of benzene in anhydrous di-ethane (100 mL) with excess 1,1,1,3,3,3-hexyl-diazane (15 mL) in the presence of ammonium sulfate (75 mg) The cells were incubated (1·5 g, 6.95 mmol) and refluxed at 125 °C for 2 hours until all solids dissolved. The excess solvent was evaporated under reduced pressure, and the obtained syrup was dissolved in anhydrous dichloroethane (100 mL). Compound P2 (3 g, 5.79 mmol) was added followed by SnCl4 (5 mL). The mixture was heated with EtOAc (EtOAc)EtOAc. The ruthenium chromatography (10% to 15 ° / ethyl acetate in DCM) was carried out to give 2.8 g of compound P5-1. Step 2. Preparation of 5'(R)-C-methylcytosine (P5-2) Stir in dioxane (5 mL) and saturated aqueous ammonia (30 mL) at 100 ° C in a sealed vessel. Compound P5-l (2.8 g, 4.16 mmol) was obtained overnight. The solvent was removed and the residue was redissolved in MeOH. Precipitating from MeOH/DCM gave 5,(and)-C-decyl cytidine (P5-158869.doc -154-201215395 2) (750 mg » 70.1%) 〇!H NMR (400 MHz , MeOD): δ 7.87 (d5 J=7.6 Hz, 1H), 5.81 (d, /=7.2 Hz, 1H), 5.75 (d, 7=4.8 Hz, 1H), 4.10-4.15 (m, 2H), 3.90 -3.96 (m, 1H), 3.76-3.78 (m, 1H), 1.16 (d, /=6.8 Hz, 3H) ; ESI-LCMS: m/z 515 [2M+H]+, 258 [M+H] +. Step 3. Preparation of 2\3·-0-decyloxymethylene-5YI0-C-methylcytosine bud (Ρ5-3) Stir compound P5-2 (750 mg, 2.92 mmol) at room temperature, A mixture of tridecyl decanoate (5 mL) and monohydrate hydrazine sulfonate (670 mg, 3.5 mmol) in 1,4-dioxane (10 mL) for 24 hours, cooled with ice, and added Triethylamine (5 mL) was quenched and concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) Base alkyl)-2,3匕Ο-decyloxymethylene-Ν4-(4-methoxytrityl)-5'(R)-C-methylcytosine nucleocaprin (P5- 4) TBSC1 (700 mg, 4.68 mmol) and AgNO3 (0.79 g, 4.68 mmol) were added to a stirred solution of compound P5-3 (700 mg, 2.34 mmol) in pyridine (5 mL). The mixture was stirred at 50 ° C to 60 ° C for 3 hours while being inspected by LCMS. MMTrCl (1.44 g, 4.68 mmol) was added. At 50. (The mixture was stirred overnight at 60 ° C. The reaction was cooled to room temperature and diluted with EA. The precipitate was removed by filtration, and the filtrate was washed with brine. The organic layer was dried over Na 2 EtOAc and then concentrated to give compound P5 -4 crude product 0

S 158869.doc -155· 201215395 Step 5·Preparation of I'J'-O-methoxymethylene-N4-(4-methoxytrityl)-5'(R)-C-methyl Cytosine (P5) Compound P5-4 (1.2 g, crude) in 1 M TBAF in THF (20 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by preparative TLC to afford &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& (P5). Example 6 Preparation of 2',3'-0-methoxymethylene-5'(S)-C-methyluridine (P6) ΡΝΒΟ&quot;

OAc

HMDS SnCI4

Ο

Step L Preparation of 2·,3'-0-dibenridinyl-5'(S)-C-indenyl-5'-0-(4-nitrophenylhydrazino) urinary argon under argon Treatment of urinary mouth in anhydrous dichloroethane (50 mL) with excess 1,1,1,3,3,3-hexamethyl-dioxane (20 mL) in the presence of ammonium sulfate (100 mg) Bite (2 g, 8.25 mmol). The mixture was refluxed at 125 ° C for 2 hours until all solids dissolved. The excess solvent was evaporated under reduced pressure, and the obtained syrup was dissolved in anhydrous dichloroethane (50 mL). Add 1-0-acetamido-2,3-0-diphenylindol-5(S)-C-mercapto-5-0-(4-nitro-benzoquinone)-/)- 0 ribose ribose (Pl) (4 g, 7.10 mmol), followed by 158869.doc -156- 201215395

SnCldIO mL). The mixture was heated with EtOAc (EtOAc)EtOAc. A silica gel chromatography (DCM containing 1% to 15% ethyl acetate) was carried out to give 4 g of P6-1. Step 2, Preparation of 5'(S)-C-methyluridine (P6-2) 2', 3'- in methanol (1 mL) and saturated ammonia MeOH solution (200 mL) at room temperature 0-Bistylmethyl-5,-0-(4-nitrophenylhydrazino)uridine (P6-l) (4 g ' 6.51 mmol) overnight. The solvent was removed and the residue was redissolved in MeOH. Precipitation from MeOH/DCM gave 1.5 g of 51(5)-0-methyluridine (P6-2) as a white solid.咕NMR (400 MHz, CD3OD): δ 8.07 (d, J=8.0 Hz, 1H), 5.88 (d, /=5.2 Hz, 1H), 5.67 (d, 7=8.0 Hz, 1H), 4.15 (s, 1H), 4.10-4.08 (m, 1H), 3.92-3.90 3.80 (dd, 1^4.4 Hz, J2=2.4

Hz, 1H), 1.25 (d, J = 6.4 Hz, 3H); ESI-LCMS: m/z 281 [M+Na]+, 259 [M+H]+. Step 3. Preparation of U'-O-methoxymethylene-5, (S)_C_methylurea (P6) Stir 5 丫f uridine (P6_2) at room temperature (500 mg, 1.8 mmol a mixture of trimethyl orthoformate (2.5 mL) and monohydrate hydrazine sulfonate (500 mg, 0.6 mmol) in THF (100 mL). ',3'-0-methoxymethylene-5'(5*)-C-decyluridine (P6); 4 NMR (400 MHz, CD3OD)·· δ 8.04 (brs, 1H), 7.30 , 7.25 (2xd, J=8.0 Hz, 1H), 5.88, 5.92 (2xs, 1H), 5.70, 5.68 (dd, J=2.8, 8.0 Hz, 1H), 5.6, 5.52 (2xd, J=3.2 Hz, 1H ,,,,,,,,,,,,, 6.8, 5.6 Hz, 1H), 1.23, 1.21 (2xd, J=2.4, 2.8 Hz, 3H); ESI-LCMS: m/z 323.08 [M+Na]+. Example 7 Preparation of decyloxymethylene-5, (i?)-C-methyluridine (p7)

Step I to prepare 2,3',5,0-tritylhydrazino _5, (1 (b (:_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Treatment of uracil g ' 8 9 mm in anhydrous dichloroethane (5 〇 mL) with excess 1,1,1,3,3,3-hexamethyl-dioxane (2 〇 mL) in the presence of excess 〇1). When the mixture is refluxed at 125 ° C. until all the solids are dissolved. Excess solvent is evaporated under reduced pressure' and the obtained syrup is dissolved in anhydrous dichloroethane (5 〇 mL). Base-2,3,5-0-triphenylsulfonylfurfuryl ribose (P2) (2.3 g, 4.5 mmol), followed by the addition of SnCl4 (5 mL). The mixture was heated under reflux overnight and cooled with ice. Dilute with ethyl acetate, wash with aqueous sodium bicarbonate, dry over Naj.sub.O.sub.4 and concentrate. 〇(tri)-C-methyluridine (P7-2) 步骤 苯 苯 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 158 Stir in decyl alcohol (100 mL) and saturated ammonia MeOH solution (200 mL) in a sealed vessel at 100 °C. 2,,3·,5,·〇-triphenylindenyl·5ι(λ)ί-uridine (?7-1) (1.2§, 2_1111111〇1) 1〇hour. Cool the mixture to room temperature And the residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: 4 NMR (400 MHz, CD30D): (5 7.95 (d, J=8.4 Hz, 1H), 5.89 (d, J=6 Hz, 1H), 5.69 (d, J=S.4 Hz, 1H), 4.21 -4.15 (m, 2H), 3.97-3.95 (m, 1H), 3.80 (t, J=3.2

Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H); MS: m/z 259 [M+H]+. Step 3. Preparation of uo-methoxymethylene-5, (R)-a-based uridine (P7) Stir the cadaveric (8)-C-f uridine (P7_2) (500 mg, 18 mmol) at room temperature, A mixture of trimethyl ortho-decanoate (2.5 mL) and p-toluene acid (500 rng '0.6 mmol) in THF (100 mL) was purified by reverse phase HPLC (HCOOH) to afford 320. Mg 2,,3'-0-decyloxyindenyl-5'(and)-C-methyluridine (P7); NMR (400 MHz, CD3OD): δ 9.04, 8.98 (2x brs, 1Η) , 7.30, 7.26 (2xd, J=8.0 Hz, 1H)S 5.97, 5.91 (2xs, 1H), 5.73 (d, J=8.0 Hz, 1H), 5.58, 5.48 (2xd, J=2.8 Hz, 1H), 5.16-5.08 (m, 2H), 4.15-3.97 (m, 2H), 3.37, 3.31 (2xs, 3H), 1.26, 1.25 (2xd, J=2.4, 2.8 Hz, 3H) ; ESI-LCMS: m/z 301·1 [M+H]+. Example 8 Preparation of 2'-deoxy-2'-α-fluoro-3,-0,N4-bis(4-methoxytrityl)-2'-oxime, 5'(5·)-0 Methylcytosine nucleoside (P8)

S 158869.doc -159· 201215395

NHMMTr

Step 1. Preparation of yO-(t-butyldimethylmethylalkyl)-2'-deoxy-2'-(X-fluoro-2'-β-&lt;2-mercaptocytosine nucleoside (Ρ8- 2) Add TBSC1 to aliquots of 2'-α-fluoromethylcytosine (P8-l) (2.5 g, 9.6 mmol) in ice-cold solution in anhydrous σ ratio (20 mL) under Ν2 (1.6 g, 10.6 mmol). The reaction mixture was stirred EtOAc EtOAc EtOAc m. The Na2SO4 was dried and filtered. The filtrate was concentrated in vacuo to give crude compound <RTI ID=0.0>#</RTI> </RTI> <RTIgt; Oxyfluorin-decyl cytidine (P8-3) to Ρ2 to crude 8-2 (3·5 g, 9.38 mmol), AgN03 (3.1 g, 18.7 mmol) and tridecylpyridine (3.4 g, 28.1 mmol) MMTrCl (6.1 g, 20 158869.doc -160 - 201215395 mmol) was added in small portions of a mixture of anhydrous DCM (300 mL). The reaction mixture was stirred overnight at room temperature under N2. Soil transition reaction mixture. Dissolved with saturated NaHC03 The filtrate was washed with EtOAc (3 mL) (EtOAc m. 3: Preparation of 21-deoxy-2·-α-fluoro-3'-0^4-bis(4-methoxytrityl)-2'-β-(:-methylcytosine nucleoside ( Ρ8-4) Under Ν2, TBAF (1 M THF solution, 26 mmol) was added dropwise to ice-cold crude P8-3 (4.8 g, 5.2 mmol). The reaction mixture was stirred overnight at room temperature. The residue was dissolved in EtOAc (EtOAc) (EtOAc)EtOAc. Purification from =6/1 to 2/1) gave compound P8-4 (4.8 g, 62%). Step 4 · Preparation 2·-Deoxy-5'-C, 5'-0-dihydro-hydrogen-3 '-0,N4-bis(4-methoxytrityl)-2^α-fluoromethylcytidine (P8-5) to anhydrous pyridine at 0 ° C to 5 ° C (567 To a stirred solution of anhydrous DMSO (10 mL) was added TFA (trifluoroacetic acid) (681 mg, 5.98 mmol). The mixture was stirred at room temperature until a clear solution formed. The solution was then added to a mixture of compound P8-4 (4.8 g, 5.98 mmol) and DCC (N-dicyclohexylcarbodiimide) (4.9 g, 17.9 mmol) in 15 mL of anhydrous DMSO under N.sub.2. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EA (200 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na.sub.2.sub.4 and dried. Concentrate the filtrate in the air to obtain an oil which is passed through a rubber column.

Purification of S 158869.doc -161 - 201215395 (PE/EA = 10/1 to 2/1) gave compound P8-5 (3.5 g, 72%). Step 5: Preparation of 2'-deoxy-3'-0,N4-bis(4-methoxytrityl)-2'-fi,5'(S)-C-dimethyl-2'- A-fluorocytosine (P8) MeMgBr (3) was added dropwise to a solution of the compound P8-5 (3.5 g, 4.3 mmol) in anhydrous THF (10 mL) at -78. Ethyl ether solution) (4.4 mL, 13.1 mmol). The reaction mixture was stirred overnight at room temperature while being monitored by TLC. The mixture was cooled to 〇 ° C. The mixture was then quenched with saturated EtOAc (EtOAc) (EtOAc) The combined organic layers were dried over anhydrous Na.sub. The crude product was purified via a hydrazine column (PE/EA = 3/1 to 1/1) to give 1.5 g (42.8%) of 2'-deoxybis(4-decyloxytriphenyl)-2'- 5. (5)-ί:-Dimercapto-2'-α-fluoro-cytosine nucleoside (Ρ8). Further purification by preparative HPLC gave the pure compound Ρ8; *H NMR (400 Hz, CDC13): 7.45-6.78 (m, 30H), 6.19 (m, 1H), 4.90 (d, 7 = 7.6 Hz, 1H) , 4.08 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.50-3.52 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 0.78 ( d, J=22 Hz, 3H) ; MS: w/z 918 [M+H]+. Example 9 Preparation of 2,-deoxy-3,-0,N4-bis(4-methoxytrityl)-2'-/?,5'-(i?)·C-dimethyl-2 '-α-fluorocytosine nucleoside (P9)

158869.doc -162- 201215395

Step 1. Preparation of 2'-deoxy-5'-C,5,-0-didesin-3'-0,N4-bis(4-methoxytrityl)-2U(R)-C -Dimethyl-12'-α-fluorocytosine (P9-1) was added to an ice-cold suspension of CrO3 (100 mg, 1 mmol) in anhydrous DCM (5 mL). Anhydrous n bite (0.14 mL, 1.8 mmol) and Ac2O (0.1 mL, 0.8 mmol). The mixture was stirred at room temperature for about 10 minutes until the mixture became homogeneous. The mixture was cooled to 0&lt;0&gt;C, and a solution of compound P8 (240 mg, 0.3 mmol The resulting mixture was stirred at room temperature for 1 hour. The reaction was carried out until it was completed as determined by TLC. The reaction mixture was diluted with DCM (50 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give 1J P9-1 (200 mg, 83%). Step 2. Preparation of 2'-deoxy-3'-0,N4-bis(4-methoxytrityl)-2'-P,5'(R)-C-dimethyl-2^α -Fluorocytosine (P9) KiaBH4 (19 mg, 0.5 mmol) was added to an ice-cold solution of Compound P9-1 (200 mg, 0.25 mmol) in anhydrous EtOH (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction was carried out until it was completed as determined by TLC. Evaporate the solvent. The residue was diluted with EA (30 mL). The organic layer was separated, dried over anhydrous Na.sub. Purification by preparative TLC to give 2'-deoxy-bis(4-decyloxytrityl)-2U'(i?)-C-dimercaptofluoride 158869.doc-163- 201215395 cytosine nucleus Glycoside (P9) (190 mg, 95%). Example 10 Preparation 5, 〇R)-C-methyl-2,,3,-〇34-tris(4-decyloxytrityl) cytosine nucleoside (P10)

Nh2

NHMMTr

HO

NHMMTr MMTrO' ΌΜΜΤγ P10-4

NHMMTr

NHMMTr

NHMMTr

NHMMTr

Step 1. Preparation of 5'-0-(t-butyldidecyldecylalkyl) cytarose nucleoside (P10-1) Under N2, to cytosine nucleoside (P10-l) (20.0 g , 82.2 mmol) in anhydrous. TBSC1 (14.9 g, 98.7 mmol) was added in small portions of the ice-cold solution in 唆 (200 mL). The reaction mixture was stirred at room temperature for 158869.doc -164 - 201215395 nights. The solvent was removed under vacuum and the residue was diluted with EA (300 mL) and washed with water and brine. The organic layer was separated and dried over anhydrous Na.sub.2.sub.4. The filtrate was concentrated in vacuo to give a white solid. 10-2 (25.1 g, 85.4%), which was used without further purification. Step 2. Preparation of 5'-0-(t-butyldimethylmethylalkyl)-2',3^0^4-5(4-methoxytrityl)arabinium nucleoside (P10) -3) Under N2, to compound P10-2 (15,0 g, 41.96 mmol), AgN03 (43.5 g, 252 mmol), and trimethyl 0 ratio (61 g, 503.5 mmol) in anhydrous DCM (3) MMTrCl (77.7 g, 252 mmol) was added in small portions of the mixture in 00 mL). The reaction mixture was stirred at N2 for two days at room temperature. The reaction mixture was filtered through celite. The filtrate was washed with a saturated NaHCO 3 solution and then washed with brine. The organic layer was separated, dried over anhydrous Na.sub.2.sub.4 and filtered. The filtrate was concentrated in vacuo to give a crystallite crystallite. Step 3, Preparation of 2',3'-0,N4-tris(4-decyloxytrityl) cytarose nucleocapsid (P10-4) Under N2, to compound P10-3 (10.45. g) 8.9 mmol) TBAF (1 M THF solution) (49.8 mL, 49.8 mmol) was added dropwise in ice-cooled THF (50 mL). The reaction mixture was scrambled overnight at room temperature. The solvent was removed and the residue was dissolved in EA (1 80 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na 2 EtOAc and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified eluted from EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc ° s 158869.doc -165- 201215395 Step 4. Preparation of 5'-C,5,-0-di-argon-2,3,-0^4-tris(4-methoxytrityl) Acytosine nucleoside (P10-5) TFA (707 mg, 5) was added to a stirred solution of anhydrous σ ratio (588 mg, 7.44 mmol) in anhydrous DMSO (12 mL) at about 5 °C. · 79 mmol). The mixture was stirred at room temperature for 30 minutes until it became a clear solution. The solution was added dropwise to a solution of DCC (5.2 g, 25.2 mmol) and compound </RTI> <RTI ID=0.0># </RTI> </RTI> </RTI> <RTIgt; The mixture was stirred overnight at room temperature. The reaction was quenched with H20 and the precipitate was removed by filtration. The filtrate was diluted with EA and washed with brine. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified with EtOAc (EtOAc: EtOAc = EtOAc) Step 5. Preparation of y(S)-C-methyl-2',3·-0,Ν4-tris(4-methoxytrityl) cytosine nucleoside (Ρ10-6) at -78 MeMgBr (3 Μ ether solution) (6.27 mL, 15.8 mmol) was added dropwise to a solution of Compound Pl </RTI> <RTI ID=0.0>(</RTI> </RTI> <RTIgt; The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was cooled to 〇 ° C and quenched by saturated NH 4 C1. The product was extracted with EA (150 mL x 2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.sub.sub. Step 6. Preparation of 5'-C,5'-0-dihydro-5'(S)-C-methyl-2,,3'-0,N4-tris(4-methoxytritylmethyl) Ara- cytosine (P10-7) Under N2, an anhydrous solution was added to the ice-cooled suspension of Cr〇3 (697.5 mg, 6.98 mmol) in anhydrous DCM (12.5 mL). · 12 5 158869.doc -166- 201215395 mL, 13.98 mmol) and Ac2O (0.7 mL, 6_98 mmol). The mixture was stirred at room temperature for about 10 minutes until the mixture became homogeneous. The mixture was cooled to 0.degree. C. and a solution of compound P10-6 (2.5 g, 2.33 mmol) in anhydrous DCM (12.5 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EA (100 mL), washed twice with NaHC03 and brine. The organic layer was separated, dried over anhydrous Na.sub.2.sub.4 and filtered. The filtrate was concentrated under vacuum to give crude material &lt;RTI ID=0.0&gt;&gt; Step 7. Preparation of 5'(R)-C-methyl-2',3'-0,N4-tris(4-methoxytrityl) cytosine nucleoside (P10) under N2, To a cold solution of the compound EtOAc (2.5 g, 2.33 mmol) elute The reaction mixture was stirred at room temperature overnight. Evaporate the solvent. The residue was diluted with EtOAc (30 mL)EtOAc. The organic layer was separated, dried over anhydrous Na.sub. The crude material was further purified by preparative TLC to give 5'(i?)-C-mercapto-2,3.-0, Λ^-tris(4-methoxytriphenylmethyl) cyanosine. Nucleoside (P10) (1.4 g, 95% purity). ESI-MS: m/z 1074.2 [M+H]+. Example 11 Preparation of 2',3'-0-methoxymethylene-N2-(4-methoxytrityl)-5'〇S)-C-nonylguanosine (P11)

158869.doc -167- 201215395

HO OH P11-2 Nc

°\ P11-3 °\ P11 Step 1. Preparation of 9-(2',3'-0-dibenridinyl-5'(S)-C-methyl-5'-0-(4-decyl) Benzoyl)-β-indole-ribofuranosyl-2-amino-6-chloroindole (Pll-1) to Pl (l〇g, 17.8 mmol) and 2 (3.1 g) at 〇 °C , 18.2 mmol) DBU (8.1 g, 53.4 mmol) was added to a stirred suspension in anhydrous MeCN (200 mL). The mixture was stirred at 0 ° C for 5 minutes. TMSOTf (13.9 mL, 71.2 mmol) was added dropwise at 0 °C. After the addition, the mixture was stirred at 0 ° C for 20 minutes until a clear solution was reached. The mixture was heated to 70 ° C and stirred for 3 hours. The reaction was cooled to room temperature and diluted with EA. The solution was washed sequentially with saturated NaHC03 and brine. The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified by silica gel chromatography (EtOAc: EtOAc = EtOAc: Step 2. Preparation of 5'(S)-C-methyl uridine (P11-2) in MeOH (200 mL) with 2-M-ethanol (4.6 ml, 64.4 mmol) and methanol (3.5 g, 64.8 mmol) The compound Pll-1 (7 g, 10.4 mmol) was treated. The mixture was refluxed at 70 ° C to 80 ° C for 24 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 to 0 by using glacial acetic acid. The solvent was evaporated, and the crude was purified by HPLC to afford compound P11-2 (2.4 g, 77%). 4 NMR (400 MHz, CD3OD): δ 7.89 (s, 1 Η), 5.76 (d, J = 7.2 Hz, 1H), 4.63 (dd, J = 1.2, 5.6 Hz, 1H), 4.29 (dd, 7=5.2 , 1.6 Hz, 1H), 4.02 (m, 1H), 3.93 (dd, J=3.2, 1.6 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H). 158869.doc -168- 201215395 Step 3. Preparation of 2',3'-0-methoxymethylene_y(S)_C_methylguanosine (pll_3) Stir compound Pll_2 (1.0 g, at room temperature 3.4 mmol), trimethyl orthoformate (5.0 mL) and a mixture of p-toluenesulfonic acid monohydrate (io g, 5.8 mmol) in 1,4-one D (130 mL) for 24 hours, cooled with ice It was quenched by the addition of triethylamine (4 mL) and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) Step 4. Preparation of 2',ro-decyloxymethylene-m-(4.methoxytrityl)_51S)-C-methylguanosine (P11) Under the 20C, the compound Pll- 3 (500 mg, 1.47 mmol) and 4-methoxytriphenylsulfanyl (500 mg, 1.62 mmol). The solution in 唆 (1 〇 mL) was used for 48 hours. The solution was then diluted with ethyl acetate and washed three times with brine. The solvent was evaporated, and the residue was subjected to chromatography (yield: 1% to 2% of decyldichloromethane) to afford 187 mg of 2, -3 - iV2-(4-methoxytrityl)-5, oxime S &gt; C-methylguanosine (P11). Example 12 Preparation of 2',3'-fluorene-methoxymethylene-N2-(4-decyloxytrityl)-5f(i?)-C-methylguanosine (P12)

-

Bzd *〇Βζ Ν&lt;Υ Ρ12-1 ΝΗ2

S 158869.doc •169· 201215395 Step 1. Preparation of 9-(2^3^-0-tritylmethyl-5'(R)-C-methyl-β-D-pyranosyl)-2 -Amino-6-chloroindole (P12-1) at 0 °〇, to 卩2 (8§, 15.4 111111〇1) and 2-amino-6-chloroindole (2.7 g, 15.8 mmol) in anhydrous DBU (7 g, 46.1 mmol) was added to a stirred suspension of MeCN (150 mL). The mixture was stirred at 0 °C for 5 minutes, and then TMSOTf (12.1 mL, 62 mmol) was added dropwise at EtOAc. After the addition, the mixture was stirred at 〇 ° C for 20 minutes until a clear solution was reached. The mixture was heated to 70 ° C and stirred for 3 hours. The reaction was cooled to room temperature and diluted with EA. The solution was washed sequentially with saturated NaHC03 and brine. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (PE: EA = 4:1 to 2:1) to afford P12-l (5.5 g, 57%) as pale yellow foam. Step 2. Preparation 5'(R)- Methylguanosine (P12-2) Compound P12-l (3.5 g) was treated with 2-mercaptoethanol (2.5 ml, 35 mmol) and sodium decylate (1.8 g, 33·3 mmol) in MeOH (100 mL) , 17.1 mmol), and the mixture was refluxed for 24 hours. The reaction mixture was then cooled to room temperature and the pH was adjusted to 7.0 by using acetic acid. The solvent was evaporated, and the crude was purified by HPLC to give the product P12-2 (11 g, 67%); NMR (400 MHz, CD3 〇D): δ 7.89 (s, 1H), 5.76 (d, 7 = 7.2 Hz, 1H), 4.63 (dd, J=7.2, 5.6 Hz, 1H), 4.29 (dd, J=5.2, 1.6 Hz, 1H), 4.02 (m, 1H), 3.93 (dd, /=3.2, 1.6 Hz, 1H), 1.270 (d, J=6.4 Hz, 3H) ° Step 3. Preparation of 2',3'-0-methoxymethylene-5 乂R)-C-methylguanosine (P12- 3) Stir compound P12-2 (ll g, 3.7 mmol), protopanaxane 158869.doc, 170-201215395 decyl ester (5 mL) and mono-p-toluenesulfonic acid (1·1 g, at room temperature A mixture of 6.4 mmol, EtOAc (EtOAc m. The residue was purified by EtOAc (EtOAc): Step 4. Preparation of 2',3·-0-methoxymethylene-N2-(4-methoxytrityl)-5'(R)-C-methyl uridine (P12) at 20 A solution of compound P12-3 (700 mg, 2.06 mmol) and 4-decyloxytrityl (700 mg, 2.27 mmol) in pyridine (10 mL) The mixture was diluted with ethyl acetate and washed three times with brine. The solvent was evaporated, and the residue was subjected to silica gel chromatography (1% to 2% methanol in dioxane) to give 317 mg of 2',3'-0-decyloxyindenyl-iV2 as a foamy solid. -(4-decyloxytritylmethylguanosine (P12). MS w/z 611.9 (MH+). Example 13 Preparation of 2',3'-0-methoxyindenyl-5'〇S )-C-methylinosine (P13)

A solution of the compound P3-l (2 g, 2.97 mmol), 2-mercaptoethanol (1.3 mL, 18.2 mmol) and MeOH (1.0 g, 18.5 mmol) in MeOH (100 mL) The reaction mixture was cooled to room temperature and neutralized with acetic acid to pH 7.0. The solvent was evaporated, and the crude product was purified by reverse phase HPLC to yield 65 g (77%) of 5' (5&gt; C- decylinosine; 158869.doc • 171 - 201215395 ln NMR (CD3OD) δ 8.37 (S, 1H), 8.06 (s, 1H), 4.01 (d, J=6.0 Hz, 1H), 4.61 (t, J=5.6 Hz, 1H), 4.28 (dd, J=5.2, 3.2 Hz, 1H), 4.02 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H). Stir 5'(5*)-C-methylinosine (657 mg, 2.3 mmol) to m· a mixture of trimethyl decanoate (5.0 mL) and p-toluenesulfonic acid monohydrate (io g, 5.8 mmol) in 1,4-dioxane (no mL) for 24 hours. The mixture was then cooled with ice by adding Triethylamine (4 mL) was quenched and concentrated. EtOAc (EtOAc) (s)_c_methylinosine (P13); iH NMR (CD3OD) δ 8.37, 8.36 (2s, 1H), 8.06, 8.04 (2s, 1H), 6.34, 6.18 (2d, J=3.2 Hz, 1H) , 6.08, 5.98 (2s, 1H), 5.28, 5.23 (2m, 1H), 5.04, 4.96 (2m, 1H), 4.21, 4.09 (2m, 1H), 2.95 (m, 1H), 1.21, 1.17 (2d, J = 6.4 Hz, 3H) MS m/z 324.8 (MH+). Example 14 Preparation of 2'-deoxy-2, ,2,-difluoro-3,-0-(4-methoxytrityl)-5, (*S&gt; C-mercapto uridine

158869.doc • 172· 201215395

Preparation of yo-(t-butyldidecylfluorenyl)-2, deoxy-2\2, difluoro-1-indole, N4-bis(4-methoxytrityl)cytosine nucleoside (P14) -2)

TBSC1 (29.2 g, 194.4 mmol) was added in small portions to a solution of gemcitabine (P14-l) (48.3 g, 162 mmol) in anhydrous pyridine (500 mL) at EtOAc. . The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was diluted with EtOAc (EtOAc) The organic layer was separated, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated to give 62 g (92%) of 3· -0 - (Nongsan 7 &quot;po-didecylalkyl)-2^deoxy-2',2'-difluorocytosine ' It is ready for use without further purification. Under Ν2, to 5'-0-(#3: Γ 曱 曱 矽 矽 alkyl)-2·-deoxy-2·, 2'-difluorocytosine (60 g '160 mmol), AgN03 (77.8 g, 510 mmol) and a mixture of symmetrical tridecylpyridine (159_8 g' i·32 mo1) in anhydrous DCM (800 mL) in small portions of MMTrCl (156.8 g, 5 10 mmol) » at room temperature The reaction mixture was stirred overnight. The reaction mixture was then passed through a Buchner funnel. The filtrate was washed with a saturated NaHC〇3 solution and then washed with brine. The organic layer was separated, dried over anhydrous Na. The gelatin chromatography (pE/EA=3/l to 2/1) was carried out to obtain 200 g of 5'4_(Nandridin-2-yl)alkyl-2,-deoxy-2, which was contaminated with tridecylpyridine. , 2,-Difluorobis(4-decyloxytriphenyl) cytidine nucleoside (Ρ14-2). 158869.doc • 173· 201215395 Preparation of 2'-deoxy-5'-C, 5'-0-didehydro-2,, 2丨-difluoro-3,-0,N4-bis(4-methoxy Trityl phenyl cytidine (P14-3) was dropped in a solution of compound P14-2 (200 g, crude) in anhydrous THF (3 22 mL) at 0 ° C. TBAF (1 M THF solution) (85.3 g, 33 0 mmol) was added. The reaction mixture was stirred at room temperature overnight. Remove the solvent. The residue was dissolved in EA (800 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na.sub. Chromatography (CH2C12/EA=10/1 to 5/1) was carried out to obtain 128 g of 2'-deoxy-2,21-difluorobis(4-methoxytriphenyl) cytosine. Nucleosides. To a solution of pyridine (2.85 g, 36 mmol) in anhydrous EtOAc (30 mL). After the addition, the mixture was stirred at room temperature until a clear solution was formed. The solution was then added dropwise to 2·-deoxy-2',2·-difluorobis(4-methoxytriphenyl) cytidine (24.2 g, 30 mmol) at 1 °C. And DCC (18.6 g, 90 mmol) in anhydrous DMSO. Stirring was continued for 12 hours at room temperature. Water (200 mL) was then added and the mixture was stirred at room temperature for an additional 1 hour. The precipitate was removed by filtration and the filtrate was extracted with EtOAc (EtOAc). The organic layer was washed with brine (200 mL) and dried over Na2SO. The solvent was removed and the residue was purified via a hydrazine column (EA:PE = 1/1 to 2/1) to yield 21.0 g (88%) of 2'-deoxy-5'-C,5'-(9- Dihydrodifluoro-3'-bis(4-decyloxytriphenyl) cytidine (P14-3). Preparation of 2'-deoxydifluoropurine-Ο, Ν^2 (4-A) Oxytriphenylmethyl)-5彳S)-C-methylcytosine nucleoside (Ρ14-4) to N.sub.2 at -78 ° C to compound P14-3 (26 g, 32.3 mmol) 158869 .doc • 174-201215395 MeMgBr (3 Μ ether solution) (80 mL, 161.5 mmol) was added dropwise with stirring over anhydrous THF (250 mL). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated NH4C1 and mixture was extracted with EA (500 mL &gt;&lt;3&gt;). The combined organic layers were dried over anhydrous Na2SO~ The obtained residue was purified twice by a silica gel column (EA: PE = 10/1 to 3/2) to obtain 8 g (44%) of crude 2·-deoxy-2',2·-difluorodi(4) -decyloxytrityl)-5i(*S)-C-nonylcytidine nucleoside (P14-4). 4 NMR (400 Hz, CDC13) S 7.44-7.48 (m, 4H), 7.08-7.37 (m, 21H), 6.92 (br, 1H), 6.81-6.84 (m, 4H), 6.28 (t, /=8.4 Hz, 1H), 4.99 (d, 7=7.6 Hz, 1H), 4.20-4.25 (m, 1H), 3.81 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.07-3.12 (m, 1H), 1.05 (d, 7 = 6.4 Hz, 3H); ESI-MS: 822 [M+H]+. Preparation of 21-deoxy-2,,2,-difluoro-5,(3)-(:-methyl-31,5,-0"4-triphenylnonylcytidine (P14-5) Compound P14-4 (8 g, 9.73 mmol) was dissolved in 125 mL of AcOH / H.sub.2 (v/v = 4:1). The mixture was stirred at 60 ° C for 6 hours. The solvent was removed and the cartridge was passed through a cartridge. (CH2Cl2: MeOH = 100/1 to 10/1, containing 0.5% TEA) Purify the residue twice to give 2.0 g of 2,-deoxy-2,2,-difluoro-5' as a white solid. 5&gt;C-mercapto nucleoside nucleoside. 4 NMR (CD3OD) (5 7.87 (d5 /=7.6 Hz, 1H), 6.18 (t, J=7.6 Hz, 1H), 5.90 (d, /=7.6 Hz, 1H), 4.25-4.17 (m, 1H), 3.97 (dd, J=6.4 Hz, 3.6 Hz, 1H), 3.68 (dd, /=8.4 Hz, 2.8 Hz, 1H), 1.31 (d, 7=6.4 Hz , 3H) ; 13C NMR (100 Hz, CD3〇D): δ 166.3, 156.5, 141.2, 122.6 (t, /=267 Hz ), 94.9, 84.6 (t, J=30.6 Hz ), 83.4 (t, s 158869 .doc •175· 201215395 J=25 Hz ), 70.2 (t, /=23 Hz ), 65.0, 18.2 ; ESI-MS: 555 [2M+H]+,278 [M+H]+. In 〇°C Next, under &amp;, 2'-deoxy-2',2f-difluoro-5,(7)-C-methylcytidine nucleoside (0.975 g, 3.5 mmol' co-evaporated with anhydrous pyridine bzC1 (1 73 g, 12 mmol) was added dropwise to a stirred solution in anhydrous aq. (40 mL). After addition, the mixture was warmed to room temperature and stirred for 3 hr. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc EtOAc EtOAc EtOAc EtOAc 3:1) Purification of the residue gave 2,3 g (yield: 69%) as a white solid as a white solid, 2,-deoxy-2', 2'-difluoroindolyl-3', 5'-0, #, triphenyl Thiocytosine nucleoside (P14-5). Preparation of 5,-〇-phenylhydrazino 2,-deoxydifluoro- 5, (8)_c_methyluria (P14-6) Compound P14-5 ( 1.43 g) Dissolved in a mixture of DME (dimethoxyethane) (36 mL) and H.sub.2 (24 mL), and then at 125. Kneel under the seal

The 4 liquid separator of the If mixed in the grain. The solvent was removed under reduced pressure, and the residue was purified eluted with EtOAc (4): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> , rolling, 5 a thiol-2ΐ, 2·-difluoro_5, (is)-C-methyluridine, dissolved in methanol (30 mL), added gas water (25%, 30 red And the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed, and the residue was purified by column chromatography (using 1 〇:1 to 3:2 order of the mixture) to obtain 0.58 g (75%) of 5,-indole-benzoquinone- 2, _deoxy-2,, 2, digas _ 5' (7)-c-decyl uridine (Ρ14·6). 158869.doc -176· 201215395 Preparation of 2'-deoxy-2',2'-di'-5'(S)-C-methyl-3^0-(4-methoxymethyl)uridine ( P14) To a solution of the compound P14-6 (0.53 g, 1.39 mmol) in anhydrous DCM (25 mL) was added AgNO3 (0.29 g, 1.67 mmol) and 2,4,6-trimethyl 0 to sigma (0.22) g, 1.8 mmol). A solution of MMTrCl (0.51 g, 1.67 mmol) in dry DCM (15 mL) The resulting mixture was stirred overnight at room temperature and filtered over Celite. The filter cake was washed with EA (300 mL). The combined organics were washed with brine, dried over Na2~~ The residue was purified by hydrazine gel column chromatography (dissolving from 10:1 to 3:1 PE: EA mixture) to yield 0.8 g (88%) of 5'-0-phenyl-l-yl-deoxy-2 ',2·-Difluoro-5'(*S)-C-indolyl-3·-0-(4-decyloxytriphenyl) uridine was dissolved in MeOH (40 mL). The resulting solution was bubbled with ammonia gas at -78 °C for 30 minutes. Further, 30 mL of aqueous ammonia was added to the mixture and heated overnight at 40 ° C to 50 ° C. The mixture was concentrated and purified by column chromatography (5:1 to 2:1 PE: EA mixture) to afford 0.2 g (29%) as a white solid. ·-Difluoromethyl-3'-0-(4-methoxyindolyl)uridine (P14); lU NMR (CDC13, 400 MHz): δ 8.52 (s, 1H), 7.50-7.47 (m, 5H), 7.37 (d, J=8.8 Hz, 2H), 7.32-7.26 (m, 4H), 6.85 (d, /=8.8 Hz, 1H), 6.19 (t, J=9.6 Hz, 1H), 5.63 ( d, J=7.6 Hz, 1H), 4.27 (dd, J =11.6, 18.4 Hz, 1H), 3.84 (d, J=6'8 Hz, 1H), 3.18 (br s, 1H) ; ESI-MS: m/z 573 [M+Na]+. Example 15

S 158869.doc - 177- 201215395 Preparation of 5'(S)-C-methyladenosine 5,-[1-naphthyl(cyclohexyloxy-L-propylamine fluorenyl)]phosphoric acid vinegar (A1)

Under argon, to 2,3,0-methoxymethylene-#6·(4-methoxytrismethyl)-5'〇S)-methyladenosine (ρ3) 595, ι·〇mm〇l) A solution of 1.0 Μί-BuMgBr in THF (3.0 mL) was added dropwise to a solution in THF (8 mL). Add (cyclohexyloxy-L-alanamine oxime) gas naphthyl phosphate (0.95 M THF solution, 4.0 mL) prepared according to the general procedure (McGuigan et al., jc/zem. 2008, 57, 5807) ° at room temperature The reaction mixture was stirred with EtOAc EtOAc m. Chromatography (ethyl acetate/hexane (3:2 to 4:1)) was carried out to give a mixture of four isomers. The mixture was dissolved in 80% citric acid (25 mL) and the resulting solution was allowed to stand overnight at room temperature. The solvent was evaporated at room temperature and co-evaporated three times with MeOH / toluene. Chromatography (DCM containing 5% to 8 〇/〇 MeOH) gave 112 mg of pure 5, (S)-C-methyladenosine 5·-[1-naphthyl (cyclohexyl) Oxy-L-propylaminoindenyl)]phosphate (A1). The impure fraction was chromatographed to give 322 mg of pure product, which was subsequently chromatographed to afford 101 mg of pure product. The total yield of 5i〇S)-C-mercaptoadenosine 5,-[1-naphthyl(cyclohexyloxy-L-propylamine)-filled vinegar was 535 mg, as a white solid; 4 NMR ( CD3OD, two isomers) 3 1.20, 1.23 (2dd, 158869.doc • 178· 201215395 /=7.2, 1.2 Hz, 3H), 1.41, 1.56 (2d, 7=6.4 Hz, 3H), 1.16-1.76 ( m, 10H), 3.88-3.99 (m, 1H), 4.05-4.08 (m, 1H), 4.02-4.06 (m, 1H), 4.32-4.65 (m, 3H), 4.82-4.97 (m, 1H), 5.96, 6.03 (2d, /=4.4 Hz, 1H), 7.31, 7.38 (2t, /=8.0 Hz, 1H), 7.39-7.53 (m, 3H), 7.62, 7.68 (2d, J=8.0 Hz, 1H) , 7.81, 8.06 (2m, 1H), 7.87, 8.12 (2m, 1H), 8.09, 8.20 (2s, 1H), 8.15, 8.28 (2s, 1H) ; 31P NMR (CD3OD, two isomers) 3 3.31 (s), 3.48 (s). MS 641.4 (MH+). • Example 16 Preparation of methyl adenosine 5'-[l-naphthyl(neopentyloxyl-propylamine sulfhydryl) phosphate (A2)

Following the general procedure described for 5,〇S&gt;C-mercaptoadenosine 5,-[1-naphthyl(cyclohexyloxy-L-propylamine)]phosphate (A1), from 714 mg (1.2 Ment) 2,3'-fluorene-methoxy hydrazino group 6-(4-decyloxytrityl)_5, (5&gt; methyladenosine (P3) and according to the general procedure (McGuigan et al, /. Med. Chm. 2〇〇8, w, 58〇7) Preparation of (neopentyloxy-L-propylaminoindenyl)] naphthyl chlorophosphate gives 509 mg as a white solid 5, (5 &gt; 0- Sulfhydryls 5,-naphthyl (neopentyloxy-L-alaninyl)]phosphate (A2). NMR (CD3〇D, two isomers) 5 〇83, 〇87 (2s, 9H ), 1 23,1 26 (2dd, /=7.2, 0.8 Hz, 3H), 1.40, 1.66 (2d, /=6.4 Hz, 3H), s 158869.doc •179· 201215395 3.64, 3.71 (2AB, /= 35.2/29.2, 10.4 Hz, 2H), 3.95-4.06 (m, 2H), 4.42-4.58 (m, 2H), 4.81-4.96 (m, 1H), 5.96, 6.02 (2d, J=4.4 Hz, 1H) , 7.31, 7.38 (2t, J=8.0 Hz, 1H), 7.39-7.53 (m, 3H), 7.62, 7.68 (2d, /=8.0 Hz, 1H), 7.81, 8.05 (2d, J=8.〇Hz , 1H), 7.86, 8.12 (2m, 1H), 8.10, 8.20 (2s, 1H), 8.15, 8.27 (2s, 1H); 31P NMR (CD3OD, two isomers) d 3.3 6 (s), 3.48 (s) MS m/z 629.5 (MH+). Example 17 Preparation of 2',3'-indole-carbonyl-5'(*S)-C-methyladenosine 5'-[l -naphthyl (cyclohexyloxy-L-propylamine thiol)]phosphate (A3)

Stir at room temperature 5, 〇S)-C-mercaptoadenosine 5'-[1-naphthyl(cyclohexyloxy-L-propylaminoindenyl)]phosphate (Al) (159 mg, 0.248 mmol) And a solution of carbonyl dimer 0 (97 mg, 0.6 mmol) in dry DMF (2.5 mL) &lt;RTI ID=0.0&gt; The crude material was purified via EtOAc (EtOAc EtOAc EtOAc) The collected fractions were concentrated and purified by reverse phase HPLC (C-18) (EtOAc/water). The collected fractions were concentrated again and chromatographed (DCM with 6% to 8% EtOAc). The collected fractions were concentrated and purified by silica gel eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Glycosides 5,-[1-naphthyl(1⁄4 hexyloxy-L-propylaminoindenyl)]phosphate (A3); NMR (CDC13, two 158869.doc-180-201215395 isomers) &lt;5 1.20, 1.26 (2d, "7=7.2 Hz, 3H), 1.31,1·53 (2d, J=6A Hz, 3H), 1.28-1.81 (m, 10H), 3.87, 4.38 (2t, J=l〇.4 Hz, 1H), 3.92-4.08 (m, 1H), 4.30-4.34 (m, 1H), 4.67-4.75 (m, 1H), 4.80-4.92 (m, 1H), 5.15, 5.23 (2dd, /=7.6 , 3.6/2.4 Hz, 1 H)s 5.64, 5.95 (2dd, 7=7.6, 3.6/2.0, Hz, 1 H), 5.90, 6.13 (2s, br, 2H), 6.07, 6.20 (2d, 7=6.8 /6.0 Hz, 1 H), 7.32, 7.33 (2t, /=8.0/7.6 Hz, 1H), 7.35-7.51 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.72, 8.07 (2s , 1H), 7.78-7.83 (m, 1H); 7.87-7.91 (m, 1H), 7.95-8.0 (m, 1H), 8.25, 8.29 (2s, 1H); 31P NMR (CD3OD, two isomers) &lt;5 2.41 (s), 2.80 (s). Example 18 Preparation of 2',3'-0-carbonyl-5'〇S)_C-mercaptoadenosine 5,-[1.naphthyl (pivalopentene) ke-L-propylamine aryl)) sulphonate (a4)

oxy-L-propylaminoindenyl)] acid-g is the general procedure described in (A3), from 126 mg (0-2 mmol) of 5'(S)-C-mercaptoadenosine 5'-[1-naphthyl (N-pentyloxy-L-propylaminoindenyl)]phosphate (A2) and (neopentyloxy-1-laminoguanidine) 1 -naphthyl phosphate give 67 mg as a white solid 2',3, -0-carbonyl-5WC-mercaptoadenosine 5'-[1-naphthyl(neopentyloxy-L-propylamine)]-glycolate (Eight 4) (two isomers). 4 NMR (CDC13, two isomers) j 0.88, 0.92 (2s, 9H),

S 158869.doc -181- 201215395 (2d, /=7.2 Hz, 3H), 1.25, 1.54 (2d, J=6.8 Hz, 3H), 1.27-1.30 (2d, J=7.2 Hz, 1H), 3.70, 3.84 (2dd, 7=11.6/16.0, 10.4 Hz, 1H), 3.82, 4.52 (2t, /=10.0 Hz, 1H), 3.96-4.15 (m, 1H), 4.30-4.36 (m, 1H), 4.82-4.93 (m, 1H), 5.21, 5.30 (2dd, 7=7.6, 3.6/2.8 Hz, 1 H), 5.63, 5.93 (2dd, J=7.2, 4.0/2.4, Hz, 1 H), 5.99, 6.29 (2s , br, 2H), 6.09, 6.19 (2d, J=2.8/2.0 Hz, 1 H), 7.32, 7.33 (2t, /=8.0/7.6 Hz, 1H)S 7.35-7.51 (m, 3H), 7.62 ( d, J = 7.6 Hz, 1H), 7.76, 8.10 (2s, 1H), 7.79-8.0 (m, 2H); 8.24, 8.29 (2s, 1H); 31P NMR (CD3〇D, two isomers) &lt;5 2.39 (s), 2.80 (s). Example 19 Preparation of 2',3'-0-carbonyl-N6-decyloxycarbonyl-5'〇S)-C-mercaptoadenosine 5'-[1-naphthyl (cyclohexyloxy-L-alanamine) Phosphate (A5) and N6-methoxycarbonyl-5\5&gt;C-methyladenosine 5'-[1-naphthyl(cyclohexyloxy-L-propylamine fluorenyl)phosphate A6)

158869.doc -182 201215395 Stir 5' (Fantasy-(:-mercapto adenosine 5,-[i-naphthyl(cyclohexyloxy)-L-propylamine)) phosphate (Al) at room temperature (130) a solution of mg, 0.20 mm 〇i) and carbonyldiimidazole (810 mg, 5.0 mm 〇l) in anhydrous DMF (12 mL) t for 5 h, and then evaporated to dryness under two vacuums. (including. to 8%

The crude material was purified by DCM from MeOH. The higher dissolved fractions of the heart were collected and evaporated. Further purification of a portion of the lower Rf product by gelatin chromatography gave 17 mg of a 2,3,0-carbonyl-indole-methoxycarbonyl group as a white solid. -naphthyl (cyclohexyloxy-L-alaninyl)]phosphoric acid vinegar (A5); 咕NMR (two isomers of acetonitrile) ji 13,]19(10), ^=7.2, 0.8 Hz, 3H), 1.41, 1.55 (2d, J=6.4 Hz, 3H), 1.21-1.76 (m, 10H), 3.79-4.93 (m, 1H), 3.798, 3.803 (2s, 3H), 4.13, 4.25 (2t, J=l〇. 4 Hz, 1H), 4.46, 4.50 (2dd, 7=6.4/4.8, 4.4 Hz, 1H), 4.55-4.66 (m, lH)5 4.82-4.98 (m, 1H), 5.50, 5.60 (2dd, ^= 8.0 4 0 bfy iu, c

Hz, 1H), 5.63, 5.87 (2dd, /=8.0, 2.4/2.0 Hz, 1 H), 6.38, 6.46 (2d, 7=2.4/2.0 Hz, 1 H), 7.28- π 〇n, 4H), 7.3, 7.69 (2dd, 〇8 Hz, ih), 7 Μ』〇3 K 2H), 8·19, 8 29 (2S, 1H), called (10) to 1H); wake up (CD3OD, two isomers) j 2 5〇&amp; , DU (s), 2.87 (s) 〇MS m/z 725.3 (MH+). The remaining eight, 〜 to the remaining four knives of the product of Rf were dissolved in acetonitrile/water, and the resulting solution was allowed to stand at room temperature for 5 days. Into the stone 々瞪 々瞪 1 , a

仃 胶 gel chromatography (DCM containing 6% to 10% i-PrOH), yielding 15.5 mg of white AM, g white solid AT5·methoxycarbonyl-5'(S)-C-曱基腺苦5'-[l-naphthalene a- « ', soil (hexyloxy_L-propylamine fluorenyl)] phosphate (A6);] H NMR (CD3〇D two chains s Shangshe' Two isomers) 3 1,18,1·21 (2dd, s 158869.doc •183- 201215395 /=7.2, 1.2 Hz, 3H), 1.42, 1.57 (2d, J=6A Hz, 3H), 1.2 -1.78 (m, 10H), 3.84 (s, 3H), 3.85-3.97 (m, 1H), 4.02-4.09 (m, 1H), 4.37, 4.48 (2t, J=5.2 Hz, 1H), 4.48 (2dd , J=5.2, 4.4 Hz, 1H), 4.48-4.64 (m, 1H), 4.82-4.98 (m, 1H), 6.04, 6.11 (2d, /=4.8/4.4 Hz, 1 H), 7.29, 7.37 ( 2t, J=8.0/7.6 Hz, 1H), 7.36-7.52 (m, 3H), 7.59, 7.67 (2d, J=8.0 Hz, 1H), 7.79, 8.00 (2m, 1H), 7.83-7.87, 8.08- 8.13 (2m, 1H), 8.31, 8.52 (2s, 1H), 8.47, 8.58 (2s, 1H); 31P NMR (CD3OD, two isomers) 3 3.23 (s), 3_43 (s). MS w/z 699.4 (MH+), 828.5 (MH.s. Example 20 Preparation of 2',3'-0-carbonyl-N6-methoxycarbonyl-5, oxime S)-C-methyladenosine 5,-[1-naphthyl (neopentyloxy-L-alanamine) Phosphate (A7)

Stirring adenosine 5,-[1-naphthyl(pivaloxy-L-alaninyl)] ate (A2) (126 mg, 0.20 mmol) and carbonyl diimidazole (810 mg) at room temperature , 5_0 mm 〇l) a solution in anhydrous DMF (12 mL) for 5 hrs, and then evaporated at high temperature under high vacuum. The crude material was purified via EtOAc (EtOAc EtOAc) The higher soluble fraction of Rf was collected and purified by gelatin chromatography to obtain a white solid. 2,3,_〇_carbonyl- 158869.doc -184· 201215395 methoxycarbonyl-S' CT-C-methyladenosine 5'-fluorenyl-naphthyl (neopentyloxy-ethylamino)phosphonate (A7); 4 NMR (acetonitrile-4, two isomers) 3 0.87, 0.90 (2s, 9H), 1.17, 1.22 (2dd, /=7.2, 0.8/1.2 Hz

3H), 1.41, 1.55 (2d, J=6.4 Hz, 3H), 3.68, 3.72 (2AB /=18.4/37.2, 10.4 Hz, 2H), 3.802, 3.807 (2s, 3H), 3.88-4&gt;〇4 ( m, 1H), 4.17, 4.28 (2t, 7=10.4 Hz, 1H), 4.46, 4.51 (2dd /=6.0/4.8, 4.4/4.0 Hz, 1H), 4.82-4.98 (m, 1H), 5.52, 5.6 〇 (2dd, J=8.0, 4.0 Hz, 1H), 5.64, 5.87 (2dd, J=8.0, 2.4 Hz, !H), 6.39, 6.46 (2d, /=2.4/2.8 Hz, 1 H), 7.29- 7.57 (m, 4H), 7.63, 7.70 (2d, 7=8.0 Hz, 1H), 7.82-8.03 (m, 2H), 8.22, 8.62 (2s,1H), 8.31, 8.54 (2s,1H) ; 31P NMR (CD3〇D, two isomers) &lt;5 2.58 (s), 2.83 (s). MS m/z 713.4 (MH+) &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&

Step 1. Prepare (isopropoxy-L-propylamine thiol) phenyl phosphate. Under vigorous extraction, under the conditions of '78 Τ: triethylamine (5 7 g, 56 4 mmol) in anhydrous di-methane The solution in (5 〇 mL) was added dropwise to a gas acid vinegar (6 g, 28.4 mmol) and L-alanine isopropyl ester (4.7 g ' 28.1 mm 〇i) in two hours over 2 hours. In a solution of methane (12 〇 mL). add

S 158869.doc 201215395 After the addition, the reaction was gradually warmed to room temperature and stirred for 2 hours. The solvent was removed under vacuum and anhydrous diethyl ether (20 mL) was evaporated. The precipitated salt was filtered and the filtrate was washed with EtOAc. The combined filtrate was concentrated and purified by flash chromatography (DCM) to afford (p.p. Step 2. Preparation of 5'(S)-C-mercaptoadenosine 5, _[phenyl(isopropoxy-L-alaninyl)]phosphate (A8) under argon at 〇 ° C Add 1 () to a solution of 2,3,-〇-methoxy-indenyl fluorenyl diphenylmethyl decyl adenosine g, 16 8 mm 〇l) in THF (30 mL) i i-BuMgBr in THF (5·0 mL '5·0 mmol). The resulting solution was stirred at room temperature for 3 minutes and phenyl (isopropoxy-L-alaninyl) chlorophosphate (5 mL, 丨M THF solution was stirred at room temperature for 2 hrs at 0 ° C. The mixture was cooled with EtOAc (EtOAc). 1:1) Purify the residue to give 丨3 g (89%) of the product, which was dissolved in EtOAc (25 mL). The mixture was stirred overnight at room temperature The residue was purified by Shihic acid chromatography (DCM containing 丨〇% to i Me〇H). Repurified by reverse phase HpLC (Hc/h containing hc〇〇h) Methyladenosine 5'-[styl (isopropoxypropylamine fluorenyl)] phosphate (A8) (370 mg, 36%) in the form of a mixture of two P_isomers; *H NMR (CD3OD, δ 1.13, 1.19 (2dd, 6H), 1.223, 1.226 (2d, J=7.2, 3H), 1.42, 1.51 (2d, J=6A Hz, 3H), 3.8-3.9 (m, 2H), 4.0-4.05 (m , 1H), 4.33, 4.42 (2t, 158869.doc •186- 201215395 •/=5.2 Hz, 1H), 4.52, 4.56 (2t, "7=5.2 Hz, 1H), 4.75-4.85 (m, 1H), 4.94 (m, 1H), 6.02 6.03 (2s, 1H), 7.19-7.34 (m, 5H), 8.18, 8.20 (2s, 1H) , 8.26, 8.30 (2s, 1H); 3, P NMR (CD3 〇 D, two isomers) 3 0.78 (s), 0.85 (s) MS m/z 550.9 (MH+). Example 22 Preparation 2' ,3'-carbonyl-5'〇S&gt;C-methyladenosine 5f-[phenyl(isopropoxy-L-alaninyl)]phosphate (A9)

Compound A8 (110 mg, 0_2 mmol) in anhydrous dichloride at room temperature

CDI (1,1,-carbonyldiimidazole) (1 mg, 0.6 mmol) was added to the solution in decane (20 mL). The mixture was stirred for about 2 hours. The solvent was removed under ye under vacuum and purified by preparative HPLC to afford 46 mg (4%) as a mixture of two isomers of 2,3,-carbonylmethyladenosine 5, _ [ Phenyl (isopropoxypropylamine sulfhydryl)]phosphate (A9); 3 lp nMR (CD3 〇 D, two isomers) 3 ! 95 (4), 2 32 (s). Hall 577" (MH+). Example 23 Preparation of 5,〇5)-C-mercaptoadenosine 5,_[phenyl(cyclohexyloxy-L-propylamino)phosphonate (A10)

S 158869.doc -187- 201215395

Step L·Preparation of (cyclohexyloxy-L-alaninhydrazino) phenylphosphoric acid phenyl ester at -78 ° C to phenyl dichlorophosphate (6.33 g, 30 mmol) and acetaminocyclohexane hydrochloride ( A solution of TEA (triethylamine) (8.3 mL, 60 mmol) in DCM (20 mL) EtOAc. After the addition, the mixture was gradually warmed to room temperature and stirred overnight. The solvent was removed and the residue was dissolved in methyl butyl ether. The precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column (DCM) toield (p-hexyloxy-L- propylamine) phenyl phenyl phosphate (7.20 g, 70%). Step 2. Preparation of 5'(S)-C-mercaptoadenosine 5'-[phenyl(cyclohexyloxy-L-propylaminoindenyl)]phosphate (A10) to compound P3 at 0 ° C ( 850 mg, 1.43 mmol) of i-BuMgCl solution (4 mL, 1 M in THF) was added dropwise to a stirred solution in anhydrous THF (20 mL). The mixture was then stirred at room temperature for 40 minutes and then cooled to 0 °C. A solution of (cyclohexyloxy-L-propylamine sulfhydryl) gas phenyl phosphate (4 mL, 1.00 M in THF) was added dropwise. After the addition, the mixture was stirred at room temperature for 40 hours. The reaction was quenched with hydrazine 20 and extracted with hydrazine. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by a hydrazine column (PE: EA = 2:1 to 1:1) to afford 1.1 g of the protected form of A10 (85%). The protected form of 10 (81〇11^) was dissolved in 80% 11 (:0011 aqueous solution 158869.doc -188-201215395, and the mixture was stirred at room temperature for 50 hours. The solvent was removed and by RP HPLC (HCOOH system) purification of the residue to give 5' (5&gt; C-methyladenosine 5'-[phenyl(cyclohexyloxy-L-propylamine fluorenyl) as a mixture of two /&gt;-isomers Phosphate (A10) (370 mg, 59%); 31P NMR (CD3OD, two isomers) &lt;5 〇·74 (s), 0.80 (s) MS m/z 591.0 (MH+). Example 24 Preparation of 5'〇S&gt;C-methyladenosine 5'-[Phenyl(neopentyloxy-L-alanamine)] Phosphate (All)

Step 1. Preparation of (neopentyloxy-L-propylamine thiol) gas phenyl phosphate

A solution of triethylamine (6 g, 59.4 mmol) in dry methylene chloride (50 mL) was added dropwise to phenyl di-phenyl phosphate (hexane) at -78. g, 28.2 mmol) and a solution of neopentyl alamate hydrochloride (6 g, 28.4 mmol) in DCM (120 mL). After the addition, the temperature of the reaction was gradually raised to room temperature and stirred for about 2 hours. The solvent was removed in vacuo and anhydrous diethyl ether (20 mL) was evaporated. The precipitated salt was filtered, and the residue was washed with diethyl ether. The combined organic phases were concentrated and purified by column chromatography eluting EtOAc EtOAc Step 2. Preparation of 5'(S)-C-methyladenosine y-[phenyl(neopentyloxy-L-alaninyl)]phosphate (All) at 〇 ° C under argon, To a solution of compound P3 (850 mg, 1.43 mmol) s 158 869. The resulting solution was stirred at room temperature for 30 minutes and (p-pentyloxy-L-propylamine sulfhydryl) phenylphosphonate (4.3 mL, 1 M in THF) was added at 0 °C. The reaction mixture was stirred at room temperature for 20 hr then EtOAc EtOAc m. After concentration, the residue was purified by a silica gel column (PE: EA = 2:1 to 1:1) to give 1.1 g of the protected product which was dissolved in 80% decanoic acid (25 mL) Stir under temperature overnight. The solvent was evaporated at rt and the residue was purified EtOAc EtOAc EtOAc The residue was then re-purified by reverse phase HPLC (acetonitrile/water) to afford 5 &lt;RTI ID=0.0&gt;&gt; -L-alaninyl)]phosphate (All) (240 mg, 34%); 31P NMR (CD3OD, two isomers) d 2.26 (s), 2.36 (s) ° MS m/z 578.9 (MH+ ° Example 25 Preparation of 2',3'-0-carbonyl-5'(*S)-C-methyladenosine 5'-[phenyl(neopentyloxy-L-propylamine)]phosphate ( A12)

CDI (120 mg, 0.70 mmol) was added to a solution of compound All (132 mg, 0.23 mmol) in anhydrous dichloromethane (20 mL) and stirred for about 2 hr. The solvent was removed under vacuum at 0 ° C, and purified by preparative muscle C (neutral) from 158869.doc -190 - 201215395 to give 8 g mg (47%) of S 2 P-isomers. 2,3'-〇_carbonyl_5, (iS)cmethyladenosine 5, [phenyl(pivalooxy-L-propylamine)]phosphate (Al2); 31P NMR (CDsOD , two isomers: U 2.03 (s), 2.44 (s). MS w/2 605.2 (MH+). Example 26 Preparation of 2',3'-〇-carbonylmethyladenosine 5,-[phenyl ( Cyclohexyloxy_L-propylamine aryl)]phosphate (A13)

To a solution of Compound A10 (120 mg, 0.30 mmol) in dry m. m. The mixture was stirred for about 2 hours. The solvent was removed under vacuum at 0&lt;0&gt;C and purified by preparative HPLC (neut.) to afford 60 mg (32%) as a mixture of two P-isomers. ;-carbonyl-5'(5&gt;C-decyladenosine 5'-[phenyl(cyclohexyloxy-L-propylaminoindenyl)]phosphate (A13); 31P NMR (160 MHz, CDC13): &lt;;5 1.98 (s), 2.35 (s). MS m/2 617.1 (MH+) 〇 Example 27 Preparation of 2,3,-0-dipropenyl-5'〇S&gt;C-methyladenosine 5, -[Phenyl(isopropoxy-L-alaninhydrazino)]phosphate (A14) 5 158869.doc • 191 - 201215395

To a solution of the compound A8 (150 mg, 0.27 mmol) in anhydrous pyridine (5 mL) was added 5 〇mg, 1 15 and DMAP (4-didecylaminopyridine). (5〇mg, 〇41 mm〇1). The mixture was stirred for about 18 hours. The solvent was removed under vacuum in EtOAc and purified by column chromatography to yield 120 mg (67%) of 2,3'-0-dipropyl as a mixture of two P-isomers. Mercapto-5,(1s)-C-mercaptoadenosine 5,-[phenyl(isopropoxy-L-propylamine)]phosphate (A14); 31P NMR (160 MHz, CDC13): &lt;;5 1 98 (s), 2.35 (s). MS w/z 663.2 (MH+). Example 28 Preparation of 5*〇S)-C·methyladenosine 5'-[Phenyl(methoxy-L-alaninhydrazino)] discic acid ester (A15) with 2,3,-0-carbonyl- 5, 〇S)-C-methyladenosine 5, · [phenyl (methoxy-L-propylamine brewing)] dish vinegar (A16)

138869.doc -192· 201215395 Step 1 'Preparation of (methoxy-L-alaninhydrazino) chlorodisic acid phenyl vinegar at -78 ° C with vigorous stirring, TEA (6 g, 59 4 mm 〇 1 The solution in anhydrous di-methane (50 mL) was added dropwise over a period of 2 h to diphenyl acid (6 g, 28.4 mmol) and methyl propylamine hydrochloride (4 g, 28.8 mmol) In a solution in DCM (120 mL). After the addition, the degree of the reaction was gradually increased / JHL to the temperature and disturbed for about 2 hours. The solvent was removed under vacuum. Anhydrous diethyl ether (20 mL) was added. The precipitated salt was filtered, and the precipitate was washed with diethyl ether. The combined organic phases were concentrated and purified by column chromatography to give: </RTI> <RTIgt; </RTI> </RTI> <RTIgt; Step 2. Preparation of 5'(S)-C-methyladenosine 5, _[phenyl(decyloxy-L-propylamine decyl)] phosphate (A15) at 〇 ° C under argon, To 2',3,-0-methoxymethylenemethoxytrityl)-5·〇5)-methyladenosine (?3) (500 mg, 〇84 mm〇1) in THF A solution of μ /-BuMgBr in THF (2.1 mL, 2.1 mm 〇l) was added to the solution in (30 mL). The resulting solution was stirred at room temperature for 3 且 and added at 〇 ° C (methyl-L- Phenyl chlorophenyl chlorophosphate (700 mg, 2.5 mM). Mix the reaction mixture at room temperature for 2 hrs, cool with ice, quench with water, dilute with acetic acid and wash with brine. Extracted three times with ethyl acetate vinegar and dried over MgSCU. After concentrating the organic layer, the product was obtained as a solid product of A15. The protected product of A15 was dissolved in 8 % decanoic acid (25 mL) at room temperature Stir overnight. Evaporate the solvent at room temperature and co-evaporate three times with MeOH/toluene to carry out gelatin chromatography (DCM containing 1% to 15 〇 / 〇 MeOH) and then repurified by reverse phase HPLC (acetonitrile / water) , obtained 10 mg (iS)_c_ thiol gland in the form of a white solid 5, · [Phenyl (methoxy _ 5 158869. doc • 193 · 201215395 L-propylamine thiol)] phosphate (A15) (two separate household - isomers A15-1 and A15-2); !H NMR (major isomer A15-1, CD3OD) &lt;5 1.24 (d, J = 6.8 Hz, 3H), 1.43 (d, J = 6.4 Hz, 3H), 3.58 (s, 3H), 3.88- 3.95 (m, 1H), 4.02-4.05 (m, 1H), 4.42 (t, J=4.4 Hz, 1H), 4.58 (t, J=4.8 Hz, 1H), 4.74-4.83 (m, 1H), 6.04 (d, J = 4.8 Hz, 1H), 7.15-7.36 (m, 5H), 8.21 (s, 1H), 8.31 (s, 1H); MS w/art 522·8 (MH+) ; !H NMR (CD3OD , minor isomer A15-2) 5 1.24 (d, J = 6.8 Hz, 3H), 1.52 (d, J = 6.4 Hz, 3H), 3.66 (s, 3H), 3.91-3.95 (m, 1H) , 4.06-4.08 (m, 1H), 4.35 (t, J=4.4 Hz, 1H), 4.52 (t, J=5.2 Hz, 1H), 4.82-4.85 (m, 1H), 6.05 (d, J= 5.2 Hz, 1H), 7.13-7.31 (m, 5H), 8.20 (s, 1H), 8.29 (s, 1H); MS m/z 522.9 (MH+) ° Step 3. Preparation 2^3^0-carbonyl-5 '(S)-C-methyladenosine 5,-[phenyl(methoxy-L-propylaminoindenyl)]phosphate (A16) to compound A15-1 (200 g, 0.38 at room temperature) Add CDI (200 g, 1.23 mmol) to a solution of methylene chloride (20 mL) Stirred for about 2 hours. The solvent was removed in vacuo and purified by preparative HPLC (neut.) to afford 20 mg (10%) as a white solid. 〇S)-C-methyladenosine 5,-[phenyl(decyloxy-L-alaninyl)]phosphate (A16); 咕NMR (CDC13) Θ 1.26 (d, J=6.8 Hz, 3H ), 1.50 (d, J=6.4 Hz, 3H), 3.68 (s, 3H), 3.71-3.76 (m, 1H), 3.92-3.98 (m, 1H), 4.37 (t, J= 4 Hz, 1H) , 4.77-4.82 (m, 1H), 5.42 (dd, J!= 7.6 Hz, J2= 3.6 Hz, 1H), 5.67 (dd, J,= 7.6 Hz, J2= 2.0 Hz, 1H), 5.77 (s, 2H), 6.05 (d, J= 4.8 Hz, 1H), 158869.doc -194· 201215395 6.95-6.98 (m, 2H), 7.08-7.12 (m, 1H), 7.19-7.23 (m, 2H), 7.91 (s, 1H), 8.30 (s, 1H); 31P NMR (160 MHz, CDC13): s 1.70 (s). MS m/z 549.0 (MH+). Example 29 Preparation of 2,3,0-dipropionylmethyladenosine 5,-[phenyl(pivaloyl-L-propylamine)]phosphate (A17)

To the compound All (200 mg' 0.35 mmol) in anhydrous at room temperature. Propionic anhydride (182 mg, 1.4 mm 〇l) and DMAP (68 mg, 0-52 mmol) were added to the solution in pyridine (10 mL). While the LCMS test was used, the mixture was stirred for about 18 hours. The solvent was removed under reduced pressure at room temperature, and the residue was purified by reverse phase HPLC to afford 1 2 mg (43%) as a mixture of two /&gt;-isomers 2,3,- 0-dipropionyl decyl adenosine 5, _[phenyl(neopentyloxy-L-propylaminoindenyl)]phosphate (A17); NMR (16〇ΜΗζ, CDC13): (5 1.88 (s) MS tw/z 690.9 (ΜΗ+). Example 30 Preparation of 2',3,-〇-dipropenyl-5' ("S)-C-methyladenosine 5, _[phenyl (pivalopentene) --L-propylamine brewing base)] phosphate vinegar (A18) 158869.doc -195- 201215395

To a solution of Compound A10 (270 mg, 0.46 mmol) in anhydrous ratio (10 mL) was added to a solution of sodium lactate (270 mg, 2_07 mmol) and DMAP (65 mg, 0-53 mmol) at room temperature. The resulting mixture was stirred for about 18 hours. The solvent was removed under vacuum at rt and purified by reverse phase HPLC to afford &lt;RTI ID=0.0&gt;&gt;'(*S&gt;C-Mercaptoadenosine 5'-[Phenyl(pivaloyl-L-alaninhydrazino)]phosphate (A18), 31P NMR (160 MHz, CDC13): 3 1.92 (s) MS m/z 703.5 (MH+). Example 31 Preparation of 5'〇S)-C-mercaptoadenosine 5'-[Phenyl(ethoxy-L-alaninhydrazino)]phosphate (A19) Ν ΝΗΜΜΤΓ

Follow the general procedure for 5' (5&gt;C-methyladenosine 5·-[1-naphthyl(cyclohexyloxy-L-propylamine fluorenyl)] phosphate from 112 mg 2', 3'- 6&gt;-methoxymethylene-#6-(4-decyloxytriphenyl)-5i〇S)-methyladenosine (P3) gives 50 mg as a white solid 5' (5&gt; C: -Methyladenosine 5'-[l-naphthyl (ethoxy-L-propyl 158869.doc -196-201215395 two isomers) 3 Aminoguanidino)]phosphate (A19). <RTIgt; </RTI> <RTIgt Alanine)) Phosphate (A2〇)

Follow the general procedure for 5'(5&gt;(:-mercaptoadenosine 5,-[l-naphthyl (cyclohexyl-L-propylamine)) phosphate from 121 mg 2,,3 , - 〇 _ review 6 〒 曱 曱 - - - ( 4- 曱 三 三 ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审 审C-mercaptoadenosine 5, Π 萘 naphthyl (isopropyl isopropyl amide) phosphate (A20). 31P NMR (CDbOD, two isomers) &lt;5 3.41 (s), 3.51 (s ) MS w/z 601.2 (MH+) 〇

Example 33 Preparation of 5,e)-C-methyladenosine 5,·[Phenyl(phenylmethoxyindole-propylamine)] Phosphate (A21)

A21 follows the general procedure for 5'〇S)-C-mercapto-adenosylnaphthyl (cyclohexyloxyindolyl) phosphate from 87 mg 2,3,_〇_曱oxy曱基_

S 158869.doc -197· 201215395 #6-(4·曱oxydimethane)-5′(5&gt;decyl adenosine (P3) gives 5 g of methyl gland in the form of a white solid 5,- Π-naphthyl (benzyloxy-L-propylamine)]phosphoric acid (A21). 31P NMR (CD3〇D, two isomers)^ 5·88 (s), 5.90 (s). MS m /z 647.4 (M_). Example 34 Preparation of 2,3,-0-monopropyl-5,-($)_C-methylglycol s'-[1-naphthyl(isopropoxy-L - propylamine brewing base)] sucrose brewing (A22)

To 5'-(5&gt;C-decyladenosine-5·-[1-naphthyl-(isopropoxy-L-propylamine decyl phosphate (A20) (148 mg, 0.25 mmol) in DMF ( Add DCC (153 mg '0.74 mmol), propionic acid (55 μΐ, 0.74 mmol), DMAP (30 mg '0.25 mmol) to the solution in 3 mL). Mix the mixture overnight at room temperature. Filter the reaction mixture' The filtrate was concentrated with a rotary evaporator until one and a half of its original volume. EA was added to the reaction mixture. The reaction mixture was washed with water then washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. MeOH = 95:5) Purified residue 'after lyophilization afforded 110. 〇 11 (62%) as a white foam, 2,,,,,,,,,,,,,,,,,,,,,,, Mercaptoadenosine 5,-[p-naphthyl(isopropoxy-L-alaninyl)]phosphate (A22); 4 NMR (DMSO-A, two isomers) J 1.01-1.16 (m, 10H) , 1.26, 1.42 (2d, /=6.4 Hz, 2H), 1.27, 1.42 (2d, J=6.4 Hz, 3H), 2.24-2.31 (m, 4H), 3.82-3.87 (m, 158869.doc 201215395 1H) , 4.24-4.26 (m, 1H), 4.7-4.4.81 (m, 2H), 5.69-4.5.7 (m, 1H), 5.85-5.89 (m, 1H), 6.10 (dd, /=10.4, 2 Hz 1H), 7.34 (br s, 2H), 7.38-7.54 (m, 4H), 7.88-7.92 (m, 1H), 8.05-8.09 (m, 1H), 8.10, 8.13 (2s, 1H), 8.16, 8.27 (2s, 1H); 31P NMR (DMSO-s, two isomers) 3 3.36 (s), 4.03 (s); MS m/z 713.4 (MH+).

Preparation of 2',3'-0-carbonyl-5'-(9)-C-methyladenosine 5,·[1-naphthyl(isopropoxy-L-propylamine)]phosphate (Α23)

Νη2 to 5'(&lt;S)-C-mercaptoadenosine-5'-[1·naphthylisopropoxy-L-alaninyl)]phosphate at 〇 ° C to 5 ° C ( A20) (1 〇〇 mg, 〇 17 mm 〇 1) DCC (62 mg, ο. "mm 〇 1) was added to a solution in DMF (2 mL). The mixture was warmed to room temperature and stirred for 2 hours. The rotary evaporator removes the solvent' and the residue is subjected to a gel column chromatography (containing 5% to 8% MeOH in DCM) and gives 18 mg of pure 2i,3,-carbonyl adenosine 5, [naphthyl (different) Propyl-L-alaninyl)]phosphate. The insoluble fraction was repurified by ruthenium (DCM containing 5% to 1% isopropyl alcohol) to give 61 mg of white foam as 2',3,- 〇_carbonyl thioglycine adenyl naphthyl (isopropoxy _ L propylamine aryl)] acid vinegar (A23) (total = 79 mg, 74%); NMR (DMSO-A, two isomers) 3 1.01-1.16 (m,10H), 1.26,1·42 s 158869.doc -199- 201215395 (2d,&gt;6.4 Hz, 2H), 3.76-3.83 (m, 1H), 4.41-4.46 (m, 1H ), 4.72-4.86 (m, 1H), 5.46, 5.24 (2x dd, J=8.8, 14.0 Hz, 1H), 5-77-5.87 (m, 1H), 5.92, 6.08 (2x dd, /=3.2, l〇.〇Hz, 1H), 6.45, 6.47 (2X d, J=3.6 Hz, 1H), 7.35 (br s, 2H), 7.38-7.70 7H), 7.85-7.95 (m, 2H), 8.11, 8.22 (2s, 1H), 8.24, 8.26 (2s, 1H) ; "p NMR (dms〇j6, two Isomers) j 3 〇 5 (4), 3.93 (s). Ms m/z 627.3 (MH+). Example 36 Preparation 5, 〇 5) _ 〇: _ methyl uridine 5, · [phenyl (methoxy_L_ propylamine thiol)] phosphate (B1)

A solution of j 〇 μ '_BuMgBr in THF (0.52 mL) was added dropwise to a solution of methyl acetate (Pll) (79 mg, 0.13 mmol) in THF (1.3 mL). The resulting solution was stirred at room temperature for 3 minutes and phenyl (methoxy-l-propylamine) chlorophosphate (1.0 M in THF, 0.65 mL) was added. The reaction mixture was stirred at room temperature for 3 days. The mixture was then cooled with ice, EtOAc (EtOAc)EtOAc. A mixture of four isomers was prepared by silica gel chromatography (containing 5% to 7% MeOH in DCM). The mixture was dissolved in 8% formic acid (9 mL), and the resulting solution was stood at room temperature overnight. Evaporation/treat at room temperature 158869.doc -200- 201215395 and co-evaporated three times with MeOH/methyl. Purified by reverse phase HpLC (cj 8) using acetonitrile containing 1% formic acid and water, and then lyophilized to give 5 as a white solid. (RC- fluorantyl bird bud 5, -[phenyl (methoxy oxime) Alanamine)]phosphate (Bl) (9.9 mg major isomer and 2.2 mg minor isomer); ιΗ NMR (CD3〇D, major isomer) j 1&gt;17 (dd, J=72, 12 Hz,

3H), 1.43 (d, 7=6.4 Hz, 3H), 3.58 (s, 3H), 3.81-3.89 (m, 1H), 3.93 (m, 1H), 4.24 (dd, J=5.2, 4.0 Hz, 1H ), 4.33 (t, /=5.2 Hz, 1H), 4.70-4.78 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), • 7.03-7.10 (m, 3H), 7.19-7.23 (m , 2H), 7.78 (s5 1H); 31P NMR (CD3OD, major isomer) (5 3,09 (s). MS /2 539 3 (MH+). Example 37 Preparation 5'(i?)-C -methylguanosine 5'-[phenyl(methoxy-L-propylamine)]phosphate (B2)

.0 , 9 ? f 〇〇-P-〇^V〇x^N^ NH , 0 persons 丫 NH V_7 N=&lt;丫 Hd bn NH B2

Follow the general procedure for 5'〇S&gt;C-methylguanosine 5,-[phenyl(methoxy-L-alaninyl)] acid ester (B1) from 120 mg (0.2 mmol) 2 ,,3,-(7-decyloxyindenyl-#2-(4-methoxytriphenylhydrazino)-5, (and)-nonylguanosine (P12) gave 20.1 mg as a white solid 5, (i?)-C-methylguanosine 5,·[phenyl(methoxy-L-alaninhydrazino)]wall acid ester (B2). NMR (CD3OD, two isomers) 5 1.12 , 1.20 (2dd, *7=6.4, 1.2/0.8 Hz, 3H), s 158869.doc -201 · 201215395 1.34 (d, 7=6.4 Hz, 3H), 3.53, 3.57 (2s, 3H), 3.73-3.89 (m, 2H), 4.32, 4.46 (2dd, /=5.6, 3.2/4.0 Hz, 1H), 4.62. 4.63 (2t, 7=6.0/5.6 Hz, 1H), 4.78-4.87 (m, 1H), 5.69 , 5.73 (2d, /=6.0/5.6 Hz, 1H), 7.05-7.15 (m, 3H), 7.22-7.29 (m, 2H), 7.78 (2s, 1H) ; 31P NMR (CD3OD, two isomers) 5 2.93 (s), 3.23 (s) MS m/z 539.0 (MH+). Example 38 Preparation of 5'(i?)-C-methylguanosine 5,-[l-naphthyl (isopropoxy) _L·propylamine thiol)]phosphate ester (B3)

Following the general procedure for 5' (5 &gt; C-methylguanosine 5,-[phenyl(methoxy-L-alaninyl)]phosphate (B1), from 73 mg (0.12 mmol) 2, , 3'-0-methoxyindenyloxytriphenylnonylguanosine (P12) and (isopropoxy-L-alaninyl) chloro acid 1-naphthyl ester give 11 mg 5, (i?)-C-methylguanosine 5,-[1-naphthyl(isopropoxy-L-propylamine)]phosphate (B3) (two isomers) as a white solid NMR (CD3OD, two isomers) (5 1.12-1.20 (m, 6H), 1_22, 1.26 (2dd, "7=7.2, 1.2 Hz, 3H), 1.35, 1.46 (2d, J=6.8/6.4 Hz, 3H), 3.89-3.99 (m, 2H), 4.41, 4.51 (2dd, J=5.6, 3.2 Hz, 1H), 4.63, 4.71 (2t, J=6.0 Hz, 1H), 4.87-5.02 (m, 2H), 5.77, 5.79 (2d, /=6.0 Hz, 1 H), 7.35-7.54 (m, 4H), 7.67, 7.05 (2d, J=8.0 Hz, 1H), 158869.doc •202· 201215395 31p m /z 7.83-7.89 (m,1H); 7.85 (s,1H), 8.09-8.16 (m' 1H)

NMR (CD3OD, two isomers) 3 3.32 (s), 3.58 (s). MS 746.6 (MH + 6-methyl-2-heptylamine). Example 39 Preparation of 5'〇S)-C-methylguanosine 5,-U-naphthyl (isopropoxy-L-propylamine thiol)]phosphate (B4)

Methoxymethylene decyloxytriphenyl fluorenyl) _5, (8) guanosine guanosine (P11) and (isopropoxy-L-alanamine fluorenyl) bismuth chlorophosphonate naphthalate give 8.5 alkyl] phosphine General procedure for ester (Bi) from 73 mg (012 mm〇i) m

Methyl anthraquinone 5,_π_naphthyl(isopropoxy-l-propylamino)phosphonate (B4) as a white solid (two separate households - isomers nmr (CD3OD, isomer IW) 1.09, lu (2d, &gt; 64 Hz, 6H), 1.21 (dd, "7-7.2, 0.8 Hz, 3H), 1.40 (d, "/=6.4 Hz, 3H), 3.86-3.95 (m, 1H) , 3.98 (m, 1H), 4.42-4.50 (m, 2H), 4.79-4.89 (m, 2H), 5.85 (d, J = 4.8 Hz, 1 H), 7.40 (t, /=8.0 Hz, 1H) , 7.45-7.56 (m, 3H), 7.69 (d, J=8.0 Hz, 1H), 7.85-7.89 (m, 1H); 7.89 (s, 1H), 8.12-8.17 (m,1H) ; 31p NMR ( CD3OD, isomer I) ¢5 3.62(s). MS w/z 746.5 (MH++6-decyl-2-heptylamine). 4 NMR (CD3OD, isomer II) &lt;5 1.13,1 ·15 (2d, J=6.4 Hz, 6H), s 158869.doc -203- 201215395 1.23 (dd, J=7.2, 1.2 Hz, 3H), 1.55 (d, 7=6.4 Hz, 3H), 3.89- 3.98 (m, 1H), 4.00 (m, 1H), 4.22 (t, J=5.6 Hz, 1H), 4.29 (dd, /=5.6, 4.0 Hz, 1H), 4.85-4.96 (m, 2H), 5.77 ( d, J=5.6

Hz, 1 H), 7.27-7.51 (m, 4H), 7.63 (d, J=S.O Hz, 1H), 7.71

(s, 1H), 7.81-7.84 (m, 1H); 8.04-8.08 (m, 1H); 31P NMR (CD3OD, isomer II) (5 3_46 (s). MS m/z 746.5 (MH++) 6-Methyl-2-heptylamine)q Example 40 Preparation of s'csvc-methylinosine 5,_U_naphthyl (isopropoxy-L-propylamine)]phosphate (B5)

Ϊ H (5 bH B5 follows the general procedure for 5'〇S&gt;C-methylguanosine 5,_[phenyl(decyloxypropylguanidino)]phosphate (B1), from 45 5 mg (〇 14 mm〇i) 2,,3,^_ 曱oxymethylene-5, (external muscarinic (P13) and (isopropoxy _L propylamino) chlorophosphoryl naphthyl ester gave 44.4 mg 5, white solid, (phantom_c_methylinosine 5'-[1_naphthyl(isopropoxy-L-propylamine)) phosphate (B5) (two isolated, isomers) NMR (CD&quot;!), household _ isomer υ J丨13, M4 (2d, /=6.0 HZ, 6H), ^ (dd, J=7 2, 1 2 Hz, 3H), i % ( d, /=6.4 Hz, 3H), 3.88-3.96 (m, 1H), 4.04 (dt, J=4.〇, 1.2 Hz, m), 4.32 (d〇5.6, 4.〇Hz, 1H), 4 % (t,5' 6 Hz,'ih), 4.87 9q, /=6.0 Hz, 1H), 4.90-4.98 (m, lH), 5.95 (d, 7=4.8 158869.doc -204· 201215395

Hz, 1 H), 7.31 (t, 0 Hz, 1H), 7.42-7.51 (m, 3H), 7.63 (d, J = 8.0 Hz, 1H), 7.80-7.84 (m, 1H); 7.92 (s, 1H), 8.03-8.05 (m, 1H), 8.06 (s, 1H); 31P NMR (CD3OD, isomer I) J 3.38 (s). MS w/2 731.5 (MH++6-methyl-2-heptylamine). 4 NMR (CD3OD, P-isomer II) J 1.09, 1·11 (2d, /=6.4 Hz, 6H), 1.21 (dd, /=7.2, 0.8 Hz, 3H), 1.40 (d, 7=6.4 Hz, 3H), 3.85-3.93 (m, 1H), 4.03 (dt, J=4.4, 1.2 Hz, 1H), 4.45 (t, J=5.2 Hz, 1H), 4.57 (t, 5.2 Hz, 1H), 4.79-4.90 (m, 2H), 6.03 (d, /=5.2 Hz, 1 H), 7.39 (t, J=8.0 Hz, 1H), 7.46-7.55 (m, 3H), 7.69 (dd, /=8.0 , 0.8 Hz, 1H), 7.85-7.89 (m, 1H); 8.02 (s, 1H), 8.11-8.16 (m, 1H), 8.24 (s, 1H); 31P NMR (CD3OD, isomer II) 3 3.55 (s). MS m/z 731_4 (MH++6-decyl-2-heptylamine) oxime Example 41 Preparation 2,-deoxy-2,-β,5'(*5)-(:-dimercapto-2, · α-fluorocytosine nucleoside 5, _ [phenyl (methoxy-L-alanamine fluorenyl)] dish vinegar (ci)

S acid vinegar (1 M THF solution, 〇.5〇 -205- 158869.doc 201215395 mL). The reaction mixture was stirred at room temperature for 5 days. The mixture was then quenched with ice-cooled &lt;RTI ID=0.0&gt;&gt; Chromatography (Et0AC/hexane (2·· 1 to 9:1)) was carried out to obtain 2'-deoxy-α,#, bis(4·decyloxytriphenyl)-2 -/?,5 (5&gt;匸-曱曱基_2'_α_fluorocytosine 5·_[phenyl(methoxy-L-alaninyl)]phosphate (18 mg household_isomer 1 and wide Isomer π). The oxime-isomer π was dissolved in 80% formic acid (3 mL), and the resulting solution was allowed to stand at room temperature overnight and then allowed to stand at 4 (rc for 2 hours). The MeOH/indole was co-evaporated three times. Purified by reverse phase HpLC (ci8) using acetonitrile containing 1% formic acid and water, and then lyophilized to give 1 〇 2 mg as a white solid 2,-deoxy-2 W 〇S&gt;; C-dimethyl-2, + fluorocytocarcinoma bite nucleus 5, _ [stupyl (methoxy-L-propylamine fluorenyl)] acid ester (C1); nmR (DMSO- 4 Ρ-isomer Body II) 5 1.19 (d, &gt; 22.4 Ηζ, 3 Η), 1.25 (d, "7=7.2

Hz, 3H), 1.38 (d, ./=6.4 Hz, 3H), 3.55 (s, 3H), 3.75-3.96 (m, 3H), 4.69 (m, 1H), 5.74 (d, 7=7.6 Hz, 1H), 5.95 (s, br, 1H), 6.14 (d, br, J=20 Hz, 1H), 7.16-7.24 (m, 4H), 7.32 (s, br, 1H), 7.36-7.41 (m, 2H), 7.53 (d, J = 7.6 Hz, 1H); 31P NMR (DMSO-A, major isomer) j 3 63 (s). Ms/z 644.3 (MH++6-methyl-2-heptylamine). Example 42 Preparation of 5'〇S&gt;C-methylcytidine nucleoside_[naphthyl(isopropoxy-L-alanamine)]phosphate (C2) 158869.doc _206_ 201215395 NHMMTr

Preparation of 57 mg 5,-C-(S)-fluorenyl-2f 31 〇-decyloxy fluorenyl-N4-decyloxytrimethylene)cytosine nucleoside (p4) using the procedure for the synthesis of compound B1 5^〇S&gt;C:-mercapto-cytosine-[naphthyl(isopropoxy-L-alaninyl)]phosphorus

Acid ester (C2) (20 mg). A NMR (CD3OD, two P-isomers) occupies 8.38 (2H, bs); 8.10-8.04 (1H, m), 7.82-7.78 (1H, m), 7.63- 7.58 (2H, m), 7.47- 7.26 (5H, m), 5.78-5.74 (1H, two doublets), 5.71-5.56 (1H, two 3.85 (6H, m), 1.49-1.34 (3H, two doublets), 1.22 1.18 (4H, m)' 1.09-1.04 (6H, m). 31P NMR (CD3OD, two isomers): § 3.70 (s), 3.43 (s). MS: m/z 706.4 (M+H+ 129). Example 43

Preparation of 2'-deoxy-2'-p,5'(i?)-C-dimethyl-2,-α-fluorocytosine 5,-[1-naphthyl (isopropoxy-L) -propylamine thiol)]phosphate (C3)

NHMMTr

NH2 follows the general procedure for 2·-deoxydimethyl-2,-ct-cytosine 5'-[phenyl(decyloxy)-L-propylamine) phosphate from 122 mg (0.15 mmol W-deoxybis(4-decyloxytrityl)-s 158869.doc -207- 201215395 2*-久5'(5&gt;C-dimethyl-2'-α-fluorocytosine Nucleoside (p9) and (decyloxy-L-alaninyl) 1-naphthyl chlorophosphate give 41 mg as a white solid 2,_deoxy_ 2'Y,5' (/〇-C-II Methyl 2'-α-fluorocytosine 5,_[phenyl(methoxy-L-propylamine)]phosphate (C3) (two kinds of isomers). iH NMR (CD3〇 d, two household-isomers) c5 1.14,117 (2d, J=6 〇Hz, 6H), 1.20 (d, /=22.4 Hz, 3H), 1.24, 1.30 (2dd, /=7.6, 1.2 Hz , 3H), 1.58 (d, J-6.8 Hz, 1H), 3.88-4.16 (m, 3H), 4.87-4.97 (m, 1H), 5.05-5.17 (m, 1H), 5.55, 5.73 (2d, / =7.6 Hz, 1H), 6.20 (d, br, 7=20.4 Hz, 1H), 7.24, 7.43 (2t, 7=8.0 Hz, 1H), 7.49-7.56 (m, 3H), 7.61, 7.75 (2d, J=7.6 Hz, 1H), 7.69-7.4 (m, ih)' 7.85-7.91 (m, 1H), 8.16-8.21 (m, 1H); 31P NMR (CD3〇D) j 3.21 (s), 3.3 8 ( s) MS m/2 722.3 (MH++6-methyl-2-heptylamine). Example 44 Preparation of 2'-deoxy-2',2'-difluoro·5'(6)_c-methylcytosine nucleus Bitter 5, [phenyl (methoxy-L-propylamine decyl)] phthalate (C5)

5·-[Procedure of the synthesis of phenyl (methoxy-L-propylamine decyl phosphate),

Mercapto nucleoside nucleoside 5·-[phenyl (methoxyl_L_porous difluoro]5, (&gt;s)_ ''propylamine aryl))] disc acid g 158869.doc •208· 201215395 (C5 ) (5 mg). H NMR (CD3OD, two _ isomers): j 7·53_ 7,51 (1H, two doublets); 7 47_7 1〇(5H,6 i5 6 〇8 (ih, m), 5.85 -5.79 (1H, two doublets); 4 2〇3 72 (3H, melon); 3 6〇_ 3_58 (3H, two single peaks), i 48"21 (6H, m). 31p Li & (CD3〇D, two isomers): &lt;5 3.08 (bs). MS m/z 517.5 (Ml). Example 45 Preparation of 5'(5)-(:-methylcytosine 5, _[Phenyl (methoxy-L propylamine fluorenyl)] phosphate (C6)

Procedure for the synthesis of 5, 〇S)-C-mercaptoadenosine 5·_Π_naphthyl (cyclohexyloxy-L-propylamine sulfhydryl)] sulphate from 86 mg 5'-C-(*S )-Mercapto-2',3'-0-methoxyindenyl-(4-methoxytriphenylhydrazino) cytidine nucleoside preparation φ 曱 胞 胞 5 5 5'_[phenyl (Methoxy-L-alaninyl)]phosphate (C6) (12 mg). NMR (CD3OD, two isomers): j 7.71-7.68 (1H, t); 7.29-7.06 (5H, m); 5.81-5.74 (2H, m); 4.72-3.62 (1H, m); 3.82 (4H, m); 3.60-3.58 (3H, two single bees), 1·46-1·19 (6H, m). 31P NMR (CD3OD, two isomers): $ 3.15, 2.9 ό (1:1). MS: m/z 628.4 (MH.sup.- 2-decylheptylamine). Example 46 Preparation of 5' (and)-C-methylcytosine 5,-[phenyl (methoxy-L-alanine 醯 £ 158869.doc -209-201215395 base)]phosphate (C7)

The procedure for the synthesis of 5' (&lt;S)-C-methyladenosine 5,-[l-naphthyl(cyclohexyloxy-L-propylaminoindenyl)]phosphate from 57 mg methyl-2' , 3,-0-methoxy-indenylmethoxytrityl)cytidine (P5) to prepare 5i(R)_C-methylcytosine 5'-[phenyl (methoxy) _L-propylaminoindenyl)]phosphate (C7) (6.7 mg). 4 NMR (CD3OD, two isomers): δ 7.82, 7.61 (0.8 Η, two broad single peaks); 7.49-7.41 (1Η, d); 7.02-6.81 (5Η, m); 5.55-5.54 (1H , d); 5.45-5.43 (1H, d); 4.72-3.62 (1H, m); 3.88-3.85 (1H, m); 3.62-3.58 (3H, m), 3.30-3.29 (3H, 3); -1.11 (311, two single peaks), 〇97_〇96 (311, two single peaks). 31P NMR (CD3OD, two isomers): δ 2 86. Ms: m/z 497 3 (M-H). Example 47 Preparation of 5'(S)-C-methylcytosine 5,_Phenyl(isopropoxy-L-propylamine fluorenyl)phosphate (C8)

158869.doc -210- 201215395 Procedure for the synthesis of 5, 〇S &gt; C_methylglycol 5,_π_naphthyl(cyclohexyloxycyanidinyl)phosphate, from 57 mg 5,_c_(iS&gt ; methyl 2,, 3 methoxymethoxymethyl TV - (4-methoxy dimethylene) cell, biting nucleoside (ρ4) injury 5, (7) cardiac methyl cough bite [phenyl (Isopropoxy-L-propylamine aryl (10) acid ester (C8) (6.4 mg). iH NMR (CD3〇D, two p isomers): Valley 7.79-7.78 (1Η, d); 7.53-7.14 (5H, m); 5.93-5.88 (2H, m); 5.00-4.80 (1H, m); 4.25·3_85 (4H, m); 1.53-1.44 (3H, two doublets); 1.32-1.05 ( 7H, m) 31p NMR (CD3 〇d, two isomers): δ 3.32, 2.97 (1:1) MS: m/z 656.4 (M+H+129). Example 48 Preparation 2'- Oxygen-2,-CP-fluoromethylcytidine-5,-[phenyl-(methoxy-L-alaninyl)]-lactate (C9)

According to the procedure described in Example 41, from 8 〇.〇mg (0.1 mmol) 2'-deoxy-3'-0, iV4-bis(4-decyloxytriphenyl) 2, _C- The synthesis of fluoromethylcytosine nucleoside--the sylvestre of '-deoxy------------------------ cytosine-5'-[phenyl-(曱oxy_L-alaninyl)]phosphate (C9). Hey!! NMR (CD3OD, four isomers) 3 1.21, 1.24, 1.27 (3d, "7=7.2, 6.8, 7.2 Hz, 3H), 1.31, 1.39, 1.44 (4d, *7=6.4, 6.4, 6.8, 6.4 Hz, 3H), 3.55, 3.58 (2s, 3H), 3.75-3.78 (m, 1H), 3.86-3.91 (m, 1H), 4.19-4.26 (m, 1H), 4.61-4.66 (m,

S 158869.doc •211 - 201215395 1H), 4.83, 4.97 (2dd, 1H), 5.67, 5.79 (2d, 1H), 7.09-7.17 (m, 3H), 7.18-7.28 (m, 2H), 7.74 (dd , 7=7.6Hz 1H); 19F NMR (CD3OD) 5 -200.56 to _200.85 (m) ; 31P NMR (CD3OD, four isomers) 3 2.59 (s), 2_78 (s), 2.9(s), 2.99 (s) ; MS w/z 499.4 (MH+) ° Example 49 Preparation 2, _deoxy-2,-CP-methyl-5, (i?/S)-C.methylcytidine 5, _ [1-Naphthyl(isopropoxy-L-alaninhydrazino)]phosphate (CIO)

Step 1. Preparation of yO-(t-butyldidecyldecylalkyl)-2'-deoxy-3'-0-(4-methoxytrityl)-2^,5' (R/S )-C-dimethyl-3^0-(4-methoxytriphenylhydrazinyl)uridine (C12)

To 2'-deoxy-2'W(i?/&lt;S)-C:-dimercaptomethoxytriphenylhydrazine) urinary (Cll) (390 mg, 0.74 mmol) in DMF (10 mL) Sigma rice 0 (251 mg, 3.7 mmol), TBSC1 (334 mg, 2.21 mmol), DMAP (180 mg, 1.47 mmol) were added sequentially to the solution. The reaction mixture was stirred overnight at 65 ° C under 158, 869.doc -212 - 201215395. The reaction was monitored by TLC until the reaction was completed. The reaction mixture was then cooled, diluted with EtOAc EtOAc m. The residue was purified by EtOAc (EtOAc: EtOAc: EtOAc: 5i〇RAS)-C-dimercapto-3,-0-(4-methoxytriphenylhydrazino)uridine (C12) (416 g, 88%). Step 2. Preparation of 5'-0-(t-butyldimethylmethylalkyl)-2'-deoxy-2'-P,5YR/S)-C-dimethyl-3'-0-(4 -methoxytrityl)cytosine nucleoside (C13)

To 5·-0-(#三T差二曱基矽alkyl)-2·-deoxy-2'-儿 5'(i?/5&gt;C-dimethyl-3·-0-(4- Methoxytriphenylsulfonyl)uridine (C12) (160 mg, 0.25 mmol) in anhydrous CH3CN (3.0 mL) was added with TEA (0.11 mL, 0·75 mmol), N-fluorene base σ定(50 μίν, 0·5 mmol) and TsCl (143 mg, 0.75 mmol). The resulting mixture was stirred at room temperature for 2 hours. After cooling the reaction to 〇 ° C, then 29% NH 4 OH (2.5 mL) The resulting mixture was stirred at room temperature for 2 h and evaporated. EtOAc mjjjjjjjj Tri-T-dioxacarbonyl-alkyl-2)-deoxy-2'-炙5·(/?Λ5)-(:-dimercapto-3'-0-(4-decyloxytriphenyl) Cytosine nucleoside (C13) (131 mg, 82%). 158869.doc -213· 201215395 Step 3. Preparation 2·-Deoxy-3·-0, Ν4-bis(4-methoxytrityl) Base)-2'-p,5\R/S)-C-dimethylcytosine nucleoside (C15)

Add MMTrCl (452 mg, 1_47 mmol) to 5,-0-(#3-7-dioxadecylalkyl)-2'-deoxy-2U\^S)-C-dimethyl-3'- A solution of 0-(4-methoxytrityl)cytosine nucleoside (C13) (378 mg, 0.49 mmol) in anhydrous DCM (6 mL). Add AgN〇3 (250.0 mg, 1.47 mmol) and triterpene 0 to bite (178 mg, 1.47 mmol). The reaction mixture was stirred overnight at rt under N2. The reaction was monitored by TLC. The reaction mixture was filtered. The mixture was then washed with saturated NaHC03 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by hydrazine (DCM / MeOH; 95:5) to give 5'-0- (#3 7 &quot;poor dimethylalkyl)-2'-deoxy-3I-0, #4-二( 4-Methoxytriphenylhydrazino)-2'-^,5·(Brother AS)-C-dimercaptocytidine nucleoside (C14) (527 mg). TBAF (tetra-n-butylammonium fluoride) (1.0 M THF solution) (1.1 ml, 1.1 mmol) was added to the bis- 7-yldidecylcarbamate-2'-deoxy-3匕&lt;9, #4-二-(4-decyloxytriphenyl)-2'-匸-〇5)-mercapto_5'(/?/15)-(:-曱 曱 胞 咬 ( ( (500 The reaction mixture was stirred overnight at room temperature and the reaction was monitored by TLC. EA was added to the reaction mixture. The mixture was then washed with water and brine. The dried Na2SO4 was dried and concentrated in vacuo. The residue was purified by silica gel 158869.doc-214-201215395 (DCM/MeOH-95:5) to give 2,-deoxy_3,_〇,#4_二(4- Methoxy triclinyl μ, #_) c dimethyl cytosine nucleus (C15) (414 mg, 94%) Step 4. Preparation of 2'-deoxy-2'-C+methyl _5 ,(R/S)_C_methylcytidine nucleoside-5-[1-naphthyl(isopropoxy-L-propylamino)phosphonate (ci〇)

C15 NHMMTr

ΝΗ, according to the procedure described for Example 41, from U1 mg (〇 14 mm〇1) 2,_deoxy-3'-O, TV4-bis(4-decyloxytrityl)dimethylidene

Mercaptonucleoside-5,-[p-naphthyl(isopropoxy-L-propylamine)]phosphate (CIO). 4 NMR (CD3OD, two isomers) 5 0 83 (d, J = 7.2 Hz, 3H), 1.13-1.15 and 1-16-1.19 (2m, 6H), 1.31 (d, /=6.8 Hz, 3H ), 1.44, 1.57 (2d, J = 6.4 Hz, 3H), 2.50-2.50 (m, 1H), 3.67-3.7 (m, 1H), 3,78 (t, y=6.4 Hz, 1H), 3.96 (dd, /=6.8, 9.6 Hz, 1H), 4.85-4.88 (m, 1H), 5.77, 6.2 (d, 7=7.2, 7.6 Hz, 1H), 7.43 (d, /=8.0 Hz, 1H), 7.51-7.54 (m, 4H), 7.66 (d, /=8.0 Hz, 1H), 7.72 (d, 7=8.4 Hz, 1H), 7.88-7.90 (m, lH), 8.16-8.18 (m, 1H) 31P NMR (CD3〇D, major isomer) 3 3.49 (s); MS w/z 704.5 (MH++ 2-decylheptylamine). Example 50 158869.doc 215-201215395 Preparation of 2'0,5'(i?)-C-dimethylcytosine 5'-[phenyl(isopropoxy-L-propylamine)]phosphate (C16)

Step 1. Preparation of yO-(t-butyldimethylmethylalkyl)-2,0,5'(R)-C-dimethyl-3'-0-(4-methoxytrityl) Uridine (C18)

MMTrO t»〆C17 MMTrO '〇—C18 To a solution of compound C17 (140 mg, 0.26 mmol) in DMF (2.5 mL), M.sub.2 (87 mg, 1.28 mmol), TBSC1 (194 mg, 1.28 mmol) DM AP (4-didecylamino group 0 bite) (156 mg, 1.28 mmol). The reaction mixture was stirred overnight at 80 ° C under N 2 . TLC showed the completion of the reaction. The reaction mixture was cooled and diluted with EtOAc EtOAc m. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) ?)-C-Dimercapto-3'-0-(4-decyloxytrityl) uridine (C18) (101 mg, 5.9). Step 2. Preparation of yO-(t-butyldimethylmethylalkyl)-2'-0,5^R)-C-dimercapto-3'-0-(4-methoxytriphenylmethyl) Cytosine nucleoside (C19) 158869.doc -216- 201215395 Η 〇

C18

C19 ΝΗ, To a solution of compound C18 (160 mg, 0.24 mmol) in dry CH3CN (2.0 mL), EtOAc (EtOAc, EtOAc, EtOAc) (139 mg, 0.72 mmol). The resulting mixture was stirred at room temperature for 2 hours. After cooling the reaction to 〇 ° C, 29% NH 4 OH (1.5 mL) was then added. The resulting mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) -0,5^R)-C-Dimercapto-3'-0-(4-methoxytrityl)cytidine nucleoside (C19) (131 mg, 82%). Step 3. Preparation of 3'-0,N4-bis(4-methoxytrityl)-2'-0,5'(R)-C-dimethylcytosine nucleoside (C21)

NHMMTr C19 C20 C21 MMTrCl (184 mg, 0.6 mmol) was added to a solution of compound C19 (13 1 mg 5 0.2 mmol) in anhydrous DCM (4 mL). Add AgN〇3 (l〇2 mg, 0.6 mmol) and trimethyl D to bite (73 pL, 0.6 mmol). The reaction mixture was stirred overnight at rt under N2. The reaction was monitored by TLC. Filter the reaction mixture and use saturated NaHC03 solution and

S 158869.doc -217- 201215395 Washing with salt water. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by hydrazine (〇0 //]^6〇11; 95:5) to give 5,-〇-(|3-7-dioxadecylalkyl)-3·-0, Λ^- (4-Methoxytriphenylmethyl)-2'-0,5'(i?)-C-dimercapto cytidine (C20) (180 mg, 97%). TBAF (1.0 M THF solution) (0.6 mL, 0.6 mmol) was added to a solution of compound C20 (180 mg, 0.19 mmol) in anhydrous THF (2 mL). TLC showed the completion of the reaction. EA was added to the reaction mixture and the mixture was washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHH 4-decyloxytrityl)-2^0,5\i?)-C-dimethylcytosine (C21) (100.4 mg, 65%) ° Step 4. Preparation of r-0,5 '(R)-C-dimethylcytosine 5'-[phenyl(isopropoxy-L-alaninyl)]phosphate (C16)

Preparation of 4-7 mg 2'-0,5' from 100 mg (0.12 mmol) of 3'-bis(4-decyloxytrityldidecylcytidine nucleoside (C21) according to the procedure described for Example 41. (Phantom-0 dimercapto nucleoside nucleoside 5·-[phenyl(isopropoxy-L-propylaminoindenyl)]phosphate (C16). 4 NMR (CD3OD, two isomers) &lt;5 1.18-1.37 (m,9H), l_47(d, J=6.8 Hz, 3H), 3.46, 3.49 (2s, 3H), 3.71-3.94 (m, 3H), 4.28, 158869.doc -218- 201215395 4.37( Each triplet, J=5_6,6·0 Hz, 1H), 4.91-4.96 (m,1H), 5.78-5.91 (m, 1H), 5.95, 5.98 (2d, J=4.4, 4.4 Hz, 1H), 7.16-7.26 (m, 3H), 7.33-7.37 (m, 2H), 7.53, 7.79 (2d, J=7.2, 7.6 Hz, 1H); 31P NMR (CD3OD, two isomers) 5 2.95 (s) , 3.11 (s) MS m/z 670.5 (MH++ diisopropylethylamine). Example 51 Preparation of 5'〇R)-C-methylarabinosine 5'-[phenyl (methoxy) -L-alaninyl)]phosphate (C22)

According to the procedure described for Example 41, from 100 mg (0.09 mmol) of 5' (and)-C-mercapto-2',3'-0,#-tris(4-methoxytriphenylhydrazinyl) Preparation of cytosine nucleoside (?10) 5.8 111§5' (fanta-purine-methylarabinosine 5,-[phenyl(decyloxy-L-alaninyl)) phosphate (C22 4 NMR (CD3OD, two isomers) (5 1.28, 1.33 (2d, "/= 7.2 Hz, 3H), 1.43, 1.47 (2d, "7=6.4, 6.8 Hz, 3H), 3.65, 3.66 (2s, 3H), 3.74-3.77 (m, 1H), 3.92-3.97 (m, 1H), 4.13-4.18 (m, 1H), 4.28-4.29 (m, 1H), 5.77, 5.82 (2d, / =7.6, 7.2 Hz, 1H), 6.15, 6.17 (2d, /=3.6, 4.0 Hz, 1H), 7.16-7.25 (m, 3H), 7.32-7.37 (m, 2H), 7.71 (d, J=7.6 Hz, 1H); 31P NMR (CD3〇D, major isomer) occupies 2.38 (s), 2.65 (s). MS w/z 497.3 (MH+). Example 52 s 158869.doc -219- 201215395 Preparation 5' (/?)-C-methylarabinoglucoside 5,-[phenyl(methoxy-L-alaninyl)]phosphate (D1)

Follow the general procedure for 2'-deoxy J'-PC-ACR-C-dimercaptofluorocytosine 5'-[phenyl(decyloxy-L-propylamine)) phosphate 160 mg (0.2 mmol) of 2',3,-0-bis(4-methoxytrityl)-5, 〇R)-C-methylarabinidine (P6) gave 24.7 mg as a white solid 5'(i?)-C-decyl uridine 5'-[phenyl(decyloxy-L-propylaminoindenyl)]phosphate (Dl) (both isomers). 4 NMR (DMSO-A, major isomer) (M.22 (d, *7 = 6.8, Hz, 3H), 1.28 (d, J = 6.0 Hz, 3H), 3.6 (s, 3H), 3.66 ( Dd, ^=7.2, 3.2 Hz, 1H), 3.81-3.94 (m, 2H), 3.97-4.01 (m, 1H), 4.61_4.70 (m, 1H), 5.40 (d, "7=8.0 Hz, 1H), 5.58 (d, *7=4.8

Hz, 1H, OH), 5.66 (d, J=4.4 Hz, 1 H, OH), 5.85 (dd, 7=12.4, 10.0 Hz, 1H, NH), 7.15-7.23 (m, 3H), 7.35-7.40 (m, 2H), 7.3 (d, / = 8.0 Hz, 1H); 31P NMR (DMSO-^, major isomer) (5 3.54 (s). MS m/z 629.4 (MH++6-fluorenyl) -2-heptylamine). Example 53 Preparation of 5'(S)-C-methylaraminouridine 5'-[phenyl(methoxy-L-alaninhydrazino)]phosphate (D2) 158869.doc - 220- 201215395

Followed for 2'-deoxy HC-, 5'〇S&gt;C-dimethyl-2,-ct-fluorocytosine 5'-[phenyl(decyloxy_L_propylamine)) The general procedure for phosphate esters, from 160 mg (0.2 mmol) of 2',3'-0-bis(4-decyloxytrimethane)-5'(&lt;S)-C-decyl glucoside ( P7) Obtained 3.1 mg as a white solid 5, (5 &gt; ί: - decyl urethane 5'-[phenyl (methoxy-L-propylamine thiol phosphate (D2) (two isomers) NMR (CD3〇D, two isomers) j 1 29, 1.31 (2dd, /=7.2, 1.2/0.8 Hz, 3H), 1.45, 1.49 (2d, /=6.4/6.0 Hz, 3Η) 9 3.65, 3.66 (2s, 3Η), 3.73-3.78 (m, 1H), 4.12, 4.17 (2dd, /=4.0, 2.0 Hz, 1H), 4.26, 4.30 (2dd, /=3.6/4.0, 2.4 Hz, 1H), 4.78-4.90 (m, 1H), 5.57, 6.20 (2d, J=8.0 Hz, 1 H), 6.12, 6.14 (2d, /=4.0/4.4 Hz, 1H), 7.16-7.26 (m, 3H ), 7.33-7.38 (m, 2H), 7.69, 7.70 (2d, /=8.0 Hz, 1H); 31P NMR (CD3OD, two isomers) 3 2 41 (8), 2 62 (s). MS w/ z 629.4 (MH +6-decyl-2-heptylamine). Example 54 Preparation of 5'(*S)-C-methyluridine 5,-[i-phenyl (methoxy-L-propylamine) Phosphate ester (D3)

158869.doc 201215395 2,3,-0-decyloxymethylene_5, (phantom-mercaptopurine (P6) (l〇6.2 mg) in 2 mL under argon at 〇 °C To the solution in THF, t-BuMgCl (0.88 mL '1 M THF solution) was added dropwise over 5 minutes. After 15 minutes, a solution of (methoxy-L-propylamine thiol) phenylphosphoric acid (1 mL) was added. 1 〇M THF solution). The reaction was allowed to warm to ambient temperature and stirred for 2 days. After cooling to Ot, the reaction was quenched with saturated EtOAc &lt; Dissolved in 8 〇% formic acid in water and briefly warmed to 60. (: Evaporate the solvent. The residue was co-evaporated with Me 〇 H / 三次 three times. The obtained material was subjected to silica gel chromatography, containing 3% to 1% by weight. A gradient of one of the methanolic chloroforms was dissolved to give 4 mg of 5' (5 &gt; 匸-mercaptouridine 5'-[1-phenyl(methyl-L-propylaminoindenyl)] phosphate (D3). 31p NMR (cdCl two isomers) &lt;5 2.30 (s), 2.52 (s) MS m/z 498.3 (Μ·1)-. Example 55 Preparation 2'-Deoxy-2,, 2,- ke-L-j difluoromethyl urinary acetonide 5,-[phenyl(methoxypropionyl fluorenyl)]phosphorus Acid ester (D4)

5^)-(7-methyluria preparation 2'_i'2'-difluoro·3'-(4-〇-methoxytrityl)_-deoxy-2,,2'· Difluoro-5, (幻_C_methyluridine 158869.doc -222- 201215395

5'-[Phenyl(methoxy-L-propylamine decyl phosphate (D4) (7.5 mg). 31P NMR (CD3OD, two isomers δ 3.09, 3_08 (1:1). NMR (CD3OD, Two isomers): δ 7 57_7.48 (m, two doublets); 7.32-7·26 (2H, m); 7.19-7.11 (3H, m); 6.08-6.03 (1H, m) ; 5.68-5.63 (1H, two doublets); 4 25·415 (1H, m); 3.98_386 (1H, m); 3.82-3_80 (lH, m); 3.60-3.58 (3H, two orders Peak), 1.54-1.3 8 (3H, two doublets), [π"2〇(3H,m). MS: m/z 518.4 (Ml). Example 56 Preparation of 2'-deoxyindole-β- Δ'β/Ά-Ο:-Dimethyl-3,-0-(4-methoxytrityl)uridine 5'-[phenyl(methoxy-l-alanamine)]phosphoric acid Ester (D7)

• Step i Preparation of y-〇-(t-butyldimethylmethylalkyl)_2'-deoxy-3,·0_(4-methoxytrityl)-2,-(:-β-methyl Uridine (D8)

Add TBSC1 (1.39 g' 8.84 mmol) to 2'-deoxy-2'-(々/α about 9:1)-C-methyluridine under 〇C under 'N2' according to published procedures 158869.doc -223-

S 201215395 Preparation · Journal of Organic Chemistry, 2003, 68, 6799) (1.78 g, 7.37 mmol) in a solution of anhydrous 0 to 0 (30 mL). The reaction mixture was stirred at room temperature overnight and the reaction was monitored by TLC. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc (EtOAc m. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc) /a about 9:1)-mercapto uridine (1.6 g, 60%) ° Add MMTrCl (407 mg, 1.32 mmol) to 5,-0-(agricultural _£7~po-didecyl fluorenyl)- 2'-Deoxy-2' (A/c〇-C:-mercaptouridine (314 mg, 0.88 mmol) in anhydrous DCM (4 mL). Add σ AgN〇3 (225.0 mg, The reaction mixture was stirred overnight at rt. EtOAc was evaporated. The organic layer was dried <RTI ID=0.0>(Na2</RTI> </RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0> 3·-0-(4-methoxytriphenylmethyl)-2'-Cj/a(9:l)-hydrazinopurine (D9) (542 mg, 98%). Step 2. Preparation 2' -Deoxy 1-0-4-methoxytriphenylmethyl uridine (D10)

158869.doc -224- 201215395 Add TEA-3HF (0.28 m Bu 1.72 mmol) / TEA (0.25 ml, 1.72 mmol) dropwise to 5·-0-(Nongsan 7&quot; dimethyl oxime) 2'-Deoxy-3·-&lt;9-(4-decyloxytriphenyl)-2'-Cj/ct-methyluridine (D9) (542 mg, 0.86 mmol) in anhydrous THF ( In a solution of 13 mL). The reaction mixture was scrambled overnight at room temperature. The reaction was monitored by TLC. The reaction was not completed by TLF. TEA.3HF (0.54 ml '3.3 mmol) and TEA (0.6 ml, 4.15 mmol) were added until TLC showed the reaction was completed. The solvent was removed at room temperature in vacuo. Add DCM. The residue was washed with water and brine, dried over anhydrous Na. The residue was purified by hydrazine (hexane/EA = 1:9) to give 2·-deoxy-3'-0-(4-decyloxytriphenyl)-2'-C-, thiol Glycoside (D10) (347 mg, 78%). Step 3. Preparation of 2'-deoxy-5-C,5'-0-diderazin-3'-0-(4-methoxytritylmercapto-uridine (mi)

D10

MMTr (5 D11 at 0 ° C, under N2, add β to mouth (0.68 mL, 8.55 m.mol) and Dess-Martin reagent (324 mg, 0.76 mmol) to 2'-deoxy-3' a solution of -0-4-(decyloxytrityl)-2'-C-,decyluridine (D10) (295 mg, 0.57 mmol) in anhydrous CH2C12 (7 mL). The reaction mixture was stirred for 4 h. The reaction was monitored by EtOAc (EtOAc) eluting with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc.矽 s 158869.doc -225· 201215395 (DCM/EA=1/1) Purify the residue to give 2,-deoxy_5_c,5,_〇_dihydrogen_3'-&lt;9-(4-曱oxytrisylmethyl)-2'-C-,methyl-uridine (D11) (273 mg, 94%) ° Step 4·Preparation 2·-Deoxidation m-5'(R/S)- C-dimethylg'-indole-(4-methoxytrityl) uridine (C11) 0

MMTrOi' D11

C11

MeMgBr (1.52 mL '2·13 mmol) was added dropwise to 2'-deoxy-5-C, 5'-0-didehydro-3.-indole-(4-methoxytritylmethyl) a solution of basal-urine (Dll) (273 mg, 0.53 mmol) in anhydrous THF (10 mL)

in. The reaction mixture was cooled by an ice-EtOH bath under N2. The reaction mixture was scrambled at room temperature for 6 hours. The reaction was monitored by TLC. The reaction mixture was quenched with saturated NH4C1. EA was added and the organic layer was washed with water and brine, dried over Naz. Purification of the residue by hydrazine (hexane/EA = 1/1 to 1/1) gave 2,-deoxydimethyl-31-(9-(4-decyloxytriphenylmethyl)uridine j6 Mg, 41%). Step 5. Preparation of 2·-deoxy-2,_C^_5, (R/S)_C-dimethyl_3,_〇_(4-methoxytrityl)uridine [phenyl (曱) oxy_L_propylamine thiol]]phosphate (D7)

158869.doc -226- 201215395 According to the procedure described for Example 41, from 60.0 mg (0-ll mmol) 2,-deoxymethoxytriphenylmethylmethyl-5, (brother /&lt;S&gt;C:- Preparation of 22.1 mg of 2·-deoxydimethyl-3'-0-(4-decyloxytrimethane) uridine 5, _[phenyl (methoxyl_L_) by mercaptouridine (C11) Aminoguanidine)]phosphate (D7). 4 NMR (DMSO-d6) 3 0.75, 0.82 (2d, 1/=7.2 112,311), 1.19, 1.24 (2 (1, each 1/=7.2 1 € 2,311) , 1,35, 1.39, 1.44 (3d, /=6.4, 6.8, 6.4 Hz, 3H), 2.43-2.47 (m, 1H), 3.54, 3.56 (2s, 3H), 3.59 (m, 1H)} 3.75- 3.81 (m, 1H), 3.86-3.90 (m, 1H), 4.67-4.72 (m, 1H), 5.44 (d, J=5.6 Hz, 1H), 5.48, 5.52 (2d, J=8.4, 8.0 Hz, 1H), 5.86 (t, J=12.0 Hz, 1H), 6.11 (d, /=7.6 Hz, 1H), 7.16-7.23 (m, 1H), 7.34-7.40 (m, 1H), 7.62 (d, J =B.〇Hz, 1H), 11.34 (s, 1H); 31P NMR (DMSO-d6, four isomers) ¢5 3.33 〇), 3.59 (s), 3.64 (s), 3.70 (s); MS w/z 496.4 (M-H+). Example 57 Preparation of 2'〇,5'(and)-C-dimethyluridine-5*-[l-naphthyl (isopropoxy-L-propylamine) Phosphate (D12)

Step 1. Preparation of γ-ο-(t-butyldimethyl decyl methoxy triphenylmethyl)-2^0-decyl uridine (D15)

S 158869.doc • 227· 201215395

TBSC1 (7.0 g, 46.5 mmol) and DMAP (0.95 g, 7.76 mmol) were added to commercially available 2'-(9-methyluridine (D13) (10.0 g, 38.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was stirred with EtOAc EtOAc (EtOAc). Drying over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss (12.6 g), which was used in the next step without further purification. MMTrCl (7.5 g, 24.5 mmol) was added to 5'-0-(#_ΞT-di-didecylalkyl)-2·-( Add 9-methyluridine (D14) (7.0 g, 18.8 mmol) in anhydrous DCM (50 mL). Add AgN03 (4.2 g, 24.5 mmol) and trimethyl 0 oxime (3.4 ml, 37.6 mmol) The reaction mixture was stirred overnight at rt. EtOAc (EtOAc m. DCM/MeOH; 97:3) Purify the residue to give 5'-0-(茗3T-didimethylalkyl)-31-0-(4-decyloxytriphenylmethyl) 4-0- Uridine (D15) (9.5 g, 78%) Step 2. Preparation of 3'-0-(4-decyloxytrityl)-2'0-methyl urethane (D16) 158869.doc - 228- 201215395

, * ·〆 * MMTrd t) One MMTrC5 t) One D15 D16

TEA-3HF (7.1 ml, 44.3 mmol) and TEA (10.6 ml, 73.8 mmol) were added dropwise to 5'-0-(black 2 T-based fluorenyl)-3'-(9-(4) - a solution of 9-methyluridine (D15) (9.5 g, 14.8 mmol) in anhydrous THF (90 mL). TLC showed the reaction was not completed. TEA-3HF (0.54 ml, 3.3 mmol) and hydrazine (0.66 ml, 4.15 mmol) were added. TLC showed the reaction was completed. The solvent was removed at room temperature in vacuo. The mixture was washed with water and brine, dried over anhydrous NaH~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Oxytriphenylmethyl)-2·0-decyluridine (D16) (7.01 g, 90%) ° Step 3. Preparation of 3'-0-(4-methoxytrityl)-5- C,5'-0-dihydro-2'-indole-methyluridine (D17)

D16 D17 Pyridine (15.4 mL) and Dess-Martin reagent (6.7 g, 15.8 mmol) were added to 3'-0-(4-decyloxytriphenyl) at 〇 ° C under N 2 2·-0-decyluridine (D16) (7.01 g, 13.2 mmol) in aq. CH2C12 (100 mL). The reaction mixture was stirred at room temperature for 4 hours. TLC show

S 158869.doc -229- 201215395 The reaction was completed. The reaction mixture was diluted with EA. The organic layer was washed twice with 10% Na.sub.2SO.sub.2, then washed with water and brine, dried and evaporated. The residue was purified by hydrazine (DCM / EtOAc = 1 / 1) to afford 3'-0-(4-methoxytriphenylmethyl)-5-C,5'-0-di-dehydro-2.- Indole-hydrazinoside (D17) (7.6 g). Step 4. Preparation of 2,-0-methyl-3,-0-(4-methoxytrityl)-5,-(S)-C-methyluridine (D18) and 2,-0 -methyl-3,-0-(4-methoxytrityl)-5,-(R)-C-methyluridine (D19)

MeMgBr (31 mL, 43.2 mmol; 1.4 Μ hexane solution) was added dropwise to N.O-(4-methoxytriphenyl fluorenyl)-5-C cooled in an ice-EtOH bath under N2. 5'-(9-Dihydro--2'-&lt;9-fluorenyl (D 17) (7.6 g, 14.4 mmol) in anhydrous THF (120 mL). The mixture was stirred for 4 hours. TLC showed the reaction was completed. The mixture was crystallised from EtOAc (EtOAc m. The residue gave 2·-0-methyl-3·-0-(4-decyloxytrimethane)-5-(5)-(7-decyluridine (D18) (3.04 g, 39 〇/〇) and 2'0-methyl-3'-0-(4-methoxytriphenylmethyl)-5'(i?/&lt;S)-C-indenyl glucoside (1.54 g, 200/〇) (D18+D19). Further purified by a Shihite cartridge (DCM/EA = 1:1) to give 210-methyl-3'-(9-(4-methoxy) as a white solid. Trityl)_5'(and)·(:-methyluridine (D19) (140 158869.doc -230· 201215395 mg, 2%) 〇Step 5. Preparation of 2'0-methoxy-5^ (R)-C-methyluridine-5^[1-naphthyl(isopropoxy-L-alaninyl)phosphorus Ester (D12)

ΜΜΤγΟ p D18/D19

According to the procedure described for Example 41, from 100 mg (0.18 mmol) of 2,-O-methyl-3'-0-(4-methoxytriphenylmethyl)-5(i?/5&gt;C- Preparation of 25.1 mg of 2·-0-decyloxymethyluridine-5L[1-naphthyl(isopropoxy-L-propylaminoindenyl)]phosphate by methyl uridine. 1H NMR (CD3〇D, two Isomers accounted for 1.14-1.32 (m, 9H), 1.44 (2d, J=6.4, 1.55 Hz, 3H), 3.47, 3.49 (2s, 3H), 3.76-3.78 (m, 2H), 3.90-3.98 ( m, 2H), 4.17, 4.26 (each triplet, */=5,2, 6.0 Hz, 1H), 4.8-5.01 (m,1H), 5.39, 5.51 (2d, J=8.0 Hz, 1H), 5.85 , 5.89 (2d, J=4.8, 3.6 Hz, 1H), 7.39-7.44 (m, 1H), 7.45 (d, 7=8.4 Hz, 1H), 7.53-7.55 (m, 3H), 7.64 (d, / = 8.0 Hz, 1H), 7.71 (t, 1H), 7.87-7.91 (m, 1H), 8.16-8.19 (m, 1H); 31P NMR (CD3OD, two isomers) &lt;5 3.39 (s) , 3.74 (s) MS m/z 721.2 (MH++ diisopropylethylamine). Example 58 Preparation of 5'(i?)-C-methyluridine-5'-[phenyl (methoxy-L) -propylamine thiol)]phosphate

S 158869.doc •231 · 201215395

According to the procedure described for Example 54, 167 mg of 5, (fantasy_c_ fluorenyl) was prepared from 60 mg (〇.2 mmol) of 2,,3,-indole-decyloxymercaptopurine (p7). Uridine 5·_[phenyl(methoxy-L-alaninyl)]phosphate. 1H NMR (CD3OD, major isomer) 5 1H nmr (Cd3〇d, major isomer) (5 1.31, (d, J=7.2, Hz, 3H), 1.44 (d, *7=6.4, Hz, 3H), 3.64 (s, 3H), 3.90-3.91 (m, 2H), 4.03 (t, "7 =4.0, Hz, 1H), 4.23 (t, 7=4.0, Hz, 1H), 4.75 (m, 1H), 4.24 (dd, J=5.2, 4.0 Hz, 1H), 4.33 (t, /=5.2 Hz , 1H), 4.70-4.78 (m, 1H), 5.55 (d, J=8.4 Hz, 1H), 5.85 (d, J=6.0 Hz, 1H), 7.18-7.24 (m, 3H), 7.33-7.37 ( m, 2H), 7.69 (d, J = 8.0 Hz, 1H); 31P NMR (CD3OD, major isomer) β 2.88 (s, major), 2.96 (s, minor). MS w/z 498.0 (M -H+); 31P NMR (CD3OD, major isomer) 5 2_38 (s), 2_65 (s) MS m/z 497.3 (MH). Example 59 Preparation of 2'-deoxy-2'-pC-methyl _5'〇S)-C-methyl-2*-α-fluorouridine-5^ [Phenyl (methoxy-L-alanamine)] phosphate

MMTrd F P9

158869.doc -232- 201215395 According to the procedure described for Example 41, from 6 〇 mg (0-ll mmol) 2'-deoxy-3 bis(4'-methoxytrityl)-2, + C-曱基-5'(5&gt;C-methylfluorouridine (P9) preparation 6.0 mg 2,-deoxy-2,jC-methyl C-methyl-2'-«-fluorouridine_5,_ [Phenyl (oxyl_L_ propylamine decyl phosphate) (D21) ° 4 NMR (CD3 〇 D, major isomer) 3 1.32-1.38 (m, 6H)» 1.47 (d, J = 6.8 Hz, 3H), 3.63 (s, 3H), 3.90-3.40 (m,

2H),4,80 (m,ih), 5.69 (d, "7=8.0 Hz,1H), 6.01 (brs,1H), 7.16-7.38 (m, 5H), 7.64 (d, J=8.0 Hz, 1H) ; 31P NMR

(CD3〇D, major isomer) &lt;5 2_93 (s). MS m/z 514.0 (MH) 〇 Example 60 Preparation of 1-(2,6-diaminopurin-9-ylfuran ribose 5-[phenyl(isopropoxy-L-propylamine fluorenyl)]phosphate (El )

P18 #杂人农潆PJT6-在在. DBxj (3.84 g, 24 mmol) was added to the stirred suspension of P15 (4 5 g, 7.99 mmol) and 6-gas guanine (1.35 g' 7.99 mmol) in anhydrous MeCN (50 mL). ). The mixture was stirred at 0 °C for 5 minutes, and then TMS 〇Tf (7.1 mL, 32 mmol) was added dropwise. The mixture was stirred at 0 ° C for 2 min and then at 7 ° C for 3 h. The reaction was cooled to room temperature and diluted with ea. Saturate in sequence

S 158869.doc -233 · 201215395

NaHC03 and brine wash solution "The organic layer was dried over Na2SO4 and then concentrated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: Step Nong 77 - Compound P16 (7.74 g, 11.2 mmol) was dissolved in a small amount of 1,4-dioxane and then saturated aqueous ammonia (100 mL) was added. The mixture was stirred in a sealed container at 100 ° C for 10 hours. The mixture was cooled to room temperature and diluted with MeOH. The solvent was removed under reduced pressure and EtOAc EtOAcjjjjjjjj NMR (DMSO-M, 400 MHz) 5 · 8.13 (s, 1H), 6.78 (brs, 2H), 5.78 (d, 7 = 7.2 Hz, 1H), 4.70-4.73 (m, 1H), 4.22-4.24 ( m, 1H), 3.91-3.97 (m, 1H), 3.99 (t, J=2.0 Hz, 1H), 1.24 (d, J=6A Hz, 3H) 〇Agriculture to P17 (600 mg, 2.0 mmol) To a suspension of 〇mL anhydrous THF was added tridecanoate (1.06 g, 10.0 mmol) and TsOH.H2O (510 mg, 3.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched by NaHC03 and concentrated. The residue was purified by hydrazine (MeOH: DCM = 1: 20 to 1: 10) to afford white powder as a white powder _ P18 (410 mg, 60.6%) ° #耀矣#潆五将化合物P18(310 mg, 0.92 mmol) was dissolved in DMF-dimercaptoacetamide (10 mL) and the mixture was refluxed for 16 h. The solvent was removed to give a crude, completely blocked nucleoside (410 mg, 100%). To a solution of the crude nucleoside (410 mg, 0.92 mmol) in THF (3 mL), EtOAc (EtOAc (EtOAc) L-propylamine thiol) chlorate benzene vinegar (5 64 158869.doc -234- 201215395

A solution of mg, 1.84 mmol) in 2 mL THF. The mixture was stirred at room temperature for 16 hours and then quenched with water. The solvent was removed in vacuo. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc The solvent was removed and the residue was purified EtOAcjjjjjjjjjjj 'H NMR (DMSO-4 400 MHz) 3 7.86 (s, 1H), 7.42 (t, 7=8.0 Hz, 2H), 7.20-7.35 (m, 3H), 6.88 (bs, 1H), 6.01-6.07 ( m, 1H), 5.97 (bs, 1H), 5.85 (d, J=6A Hz, 1H), 5.54 (d, J=6.0 Hz, 1H), 5.31 (d, J=5.2 Hz, 1H), 4.94- 4.97 (m, 1H), 4.73-4.80 (m, 1H), 4.37-4.44 (m, 1H), 4.25-4.30 (m, 1H), 3.96-3.98 (m, 1H), 3.83-3.91 (m, 1H) ), 1.46 (d, J=6A Hz, 3H), 1.24-1.29 (m, 9H); 31P NMR (DMSO-J6, 162 MHz) 3 3.44 ; ESI-LCMS: m/z 566 [M+H]+ . Example 61 Preparation of 5'〇y)-C-ethyladenosine 5'-[Phenyl(isopropoxy-L-propylamine)]phosphate (A24)

ΜΜΤγΟ ΟΜΜΤγ Ρ21

158869.doc -235· 201215395

HO

P24 NHMMTr

A24 ##厂袅~ At 0〇C, TBSC1 (30.0 g, 200 mmol) was added to a suspension of P19 (50.0 g, 187 mmol) in anhydrous pyridine (500 mL). The mixture was scrambled at room temperature for 5 hours and then concentrated to dryness. The residue was dissolved in dry DCM (500 mL). EtOAc EtOAc (EtOAc (EtOAc) The mixture was stirred at room temperature for 24 h, quenched with EtOAc EtOAc. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) The solvent was removed and the residue was purified EtOAc EtOAcjjjjjj #锵2_ 裘# Under N2, DMP (1.27 g, 3.0 mmol) was added to a suspension of P20 (2.0 g, 1.8 mmol) in anhydrous DCM (50 mL). The mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous Na.sub.2SO.sub. The mixture was extracted with DCM. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; EtMgBr (1.0 M in THF, 1 mL, 10 mmol) was added dropwise over ice-EtOAc. The reaction mixture was stirred overnight at room temperature. The mixture was cooled to 0 ° C and was quenched by saturated NH4CI float 158869.doc • 236-201215395. The solution was extracted with EA. The organic layer was dried over anhydrous Na.sub.2.sub.4 and concentrated. The residue was purified with EtOAc EtOAc (EtOAc/EtOAc) #耀义农# Dissolve Compound P22 (200 mg' 0.18 mmol) in 15 mL Ac0H/H20 (v/v = 4:1) t » at 50. (The mixture was stirred overnight. The solvent was removed in vacuo and the residue was purified eluted with EtOAc EtOAc EtOAc EtOAc EtOAc 4 NMR (DMSO-c/5, 400 Hz) δ 8.31 (s, 1H), 8.08 (s, 1H), 7.34 (s, 2H), 5.82 (d, J=6A Hz, 1H), 5.44 ( d, J= 4.0 Hz, 1H), 5.37 (d, /=6.8 Hz, 1H), 5.08 (d, 7=4.0 Hz, 1H), 4.51-4.53 (m, 1H), 4.07-4.10 (m, 1H) ), 3.87-3.88 (m, 1H), 3.41-3.47 (m, 1H), 1.37-1.44 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). ##•5.农#户2 To the suspension of P23 (200 mg '0.68 mmol) in 1 mL of dry THF was added trimethyl orthophthalate (1% g, 1 〇〇mmQl) and Ts0H.H20 (171 mg '1.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. (180 mg). The intermediate (180 mg, 〇53 mm 〇1) was dissolved in anhydrous EtOAc (1 mL) and cooled to the next. TMSC1 (215 mg, 2.0 mmol) was added dropwise. The mixture was stirred for 3 hours. Afterwards, MMTrCl (400 mg, 1.3 mmol) was added. The mixture was allowed to boil for 16 hours at 5 Torr. The reaction was quenched by ΝΗβΗ, and the mixture was concentrated and purified from EtOAc (1% MeOH in DCM). Foamy p24 (22 mg, 53%).

S 158869.doc 237- 201215395 Step by step (ί.Nongguang 4*2 heart at 4〇C) Add to P24 (220 mg, 0.36 mmol) in anhydrous THF (4 mL) with stirring solution ί -BuMgCl solution (0.72 mL, 1 M in THF). The mixture was then stirred at 40 ° C for 40 min. (Isopropoxy-L-propylamine decyl) phenyl chlorophosphate (219 mg, 0-72 mmol) was added dropwise. After the addition, the mixture was stirred at 40 ° C for 16 hours. The reaction was then quenched with H20 and extracted with EtOAc. The organic layer was dried over Na 2 EtOAc and concentrated. The residue was purified to give the title compound (yield: 52 mg) as a white solid. The product was dissolved in aqueous 60% HCOOH and the mixture was stirred at 25 ° C for 16 hours. The residue was purified by EtOAc (EtOAc (EtOAc) elute Compound A24 (9.24 mg, 9.5%) as a solid. 4 NMR (DMSO-J5, 400 MHz) δ 8.35, 8.29 (2 s, 1 Η), 8.22, 8.20 (2s, 1H), 7.15-7.36 (m, 5 H ), 6.04 (s, 1H), 4.51-4 .77 (m, 3H), 4.40 (s, 1H), 4.23, 4.65 (2d, /=4.0 Hz, 1H), 3.82-3.87 (m, 1H), 1.91-1.95 (m, 1H), 1.82-1.85 (m, 1H), 1.21 (s, 6H), 1.05-1.09 (m, 3H), 0.99-1.03 (m, 3.2H); 31P NMR (DMSO-162 MHz) ¢5 1.71, 1.43; ESI-LCMS: m/z 565 [M+H]+. Example 62 Preparation of 5'(i?)-C-ethyladenosine 5'-[Phenyl(isopropoxy-L-propylamine)] Phosphate (A25) ) 158869.doc •238 · 201215395

NHMMTr MMTrO ΟΜΜΤγ Ρ22

NHMMTr

P27 MMTrO OMMTr P26

Η0 &amp;H A25

〇步杂/.# 潆 25 25- Under N2, add anhydrous pyridine (〇_25 mL, 2.7 mmol) to an ice-cold suspension of Cr03 (135 mg, 1.35 mmol) in anhydrous DCM (5 mL) And Ac2O (0.13 mL ' 1.13 mmol). The mixture was stirred at room temperature for about 1 minute until the mixture became homogeneous. The mixture was cooled to 0 &lt;0&gt;C and a solution of &lt;RTI ID=0.0&gt;&gt; The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM (50 mL) and washed with NaCI EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. Concentrate the filtrate in vacuo to give P25 (406 mg, 81%) ° ##2. 潆 潆 PM - in N2, in an ice-cold solution of P25 (400 mg, 0.36 mmol) in 95% EtOH (10 mL) NaBH4 (126 mg '3.6 mmol) was added. The reaction was stirred at room temperature overnight. Evaporate the solvent. The residue was diluted with EtOAc (30 mL)EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc #腐3·农菜P27-Dissolve compound P26 (22〇 mg, 〇.2 mmo1) in

S 158869.doc -239- 201215395 15 mL Ac0H/H20 (v/v=4:1). The mixture was stirred at 50 ° C overnight. The solvent was removed under vacuum and the residue was purified eluting with EtOAc EtOAc (EtOAc:EtOAc 4 NMR (DMSO-i/6, 400 MHz) δ 8.31 (s, 1 Η), 8.11 (s, 1H), 7.38 (s, 2H), 5.82 (d, 7=8.0 Hz, 1H), 5.72 (d, J=4.0 Hz, 1H), 5.36 (d, J=6.8

Hz, 1H), 5.14 (d, J=4.0 Hz, 1H), 4.64-4.67 (m, 1H), 4.12- 4.13 (m, 1H), 3.82-3.83 (m, 1H), 3.56-3.59 (m, 1H), 1.31- 1.36 (m, 2H), 0.91 (t, /= 7.2 Hz, 3H). #杂么农# To a suspension of P27 (400 mg, 1.1 mmol) in 10 mL of dry THF THF was added trimethyl orthoformate (636 mg, 6.0 mmol) and TsOH.H2O (200 mg, 1.2 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched by NaHC03 and concentrated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: The product (340 mg, 0.91 mmol) was dissolved in anhydrous pyridine (10 mL) and cooled to 0. TMSC1 (260 mg, 2.4 mmol) was added dropwise and the mixture was stirred at room temperature for 3 h then MMTrCl (480 mg, 1.6 mmol). The mixture was stirred at 50 ° C for 16 hours. The reaction was quenched with NH4OH and concentrated. The residue was purified with a EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc , 0.29 mmol) t-BuMgCl solution (0.9 mL, 1 M THF solution) was added dropwise to a stirred solution in anhydrous THF (5 mL). The mixture was then stirred at 40 ° C for 40 minutes. A solution of phenyl (isopropoxy-L-alaninyl) chlorophosphate (270 158869.doc • 240-201215395 mg, 0.885 mmol) in THF (1 mL) was added dropwise. After adding, at 4〇. The mixture was stirred under stirring for 16 hours. The reaction was then quenched with H.sub.2 and extracted with EtOAc. The residue was purified via hydrazine (PE: EA = 2:1 to 1:1) to afford crude crude material (170 mg), which was treated with 60% aqueous HCOOH for 16 hours. The solvent was removed and the residue was purified with EtOAc EtOAc (EtOAc: EtOAc (EtOAc:EtOAc) Compound A25 ( 18.73 mg, 12.5%) as a white solid. 4 NMR (DMSO-^5, 400 MHz) δ 8.30, 8.27 (2s, 1Η), 8.12-8.18 (m, lH), 7.28 (t, /=8.4 Hz, 2H), 7.10-7.15 (m, 3H) , 6.04, 5.95 (2d, J=4.8 Hz, 1H), 4.44-4.95 (m, 1 H), 4.71-4.74 (m, 2H), 4.45-4.49 (m, 1H), 4.11-4.15 (m, 1H) ), 3.84-3.86 (m, 1H), 1.84-1.86 (m, 2H), 1.26 (d, J = 7.2 Hz, 3H), 1.17-1.23 (m, 7H), 0.96-1.09 (m, 3H); 31P NMR (DMSO-i/(5, 162 MHz) δ 3.19, 2.82; ESI-LCMS: m/z 565 [M+H] + ° Example 63 Preparation 5, 〇S&gt; C-trifluoromethyladenosine 5 '-[Phenyl(isopropoxy-L-propylamine)]phosphate (A26)

158869.doc -241 - 201215395

#,骤人农广PM- Add concentrated h2S〇4 (1.2 mL) to a solution of D-ribose (30.0 g, 1.33 mol) in acetone (285 mL) and MeOH (15 mL). The solution was refluxed for 24 hours. The reaction was cooled and neutralized with ammonia. The mixture was poured into H20 (500 mL) and extracted with hydrazine. The combined organic layers were dried with MgS〇4. The solvent was removed and the residue was purified EtOAcjjjjjjjjjjj #耀2·农潆 At 0°C, under the solution of P30 (25.5 g, 125 mmol) in anhydrous DCM (800 mL), Days-Martin South Blast (78.2) g ' 0.1 8 mol). The resulting mixture was scrambled overnight at 15 °C. The mixture was washed with a saturated aqueous Na 2 SO 3 solution and a NaHCO 3 solution. The organic layer was separated, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give compound P31 as a syrup, which was used in the next step (16.5 g, 66%) 〇#杂3·Agronomy at -50 ° C under N2 A solution of TMSCF3 (65.2 g, 459 mmol) was added to a solution of P31 (4.6 g, 22.8 · mmol) and tetrabutylammonium acetate (TBAA) (345 mg, 1 · 15 mmol) in dry THF (150 mL). After the addition, the reaction mixture was warmed to 0 ° C and stirred for 4 hours. The mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous MgS 4 and filtered. The filtrate was concentrated in vacuo to give a crystallite crystallite. The reaction mixture was stirred for 2 hours and then quenched with water using 158869.doc -242 - 201215395

Extracted with EtOAc, EtOAc (EtOAc)EtOAc. #摩次裳/潆尸以- Under the N2, BzCl (5.8 g, 38 mmol) was added dropwise to the ice-cooled solution of crude P32 in anhydrous pyridine (70 mL). The reaction mixture was stirred overnight at room temperature. EA (300 mL) was added to the mixture and then washed with water (200 mL) and saturated aqueous NaHCO3 (200 mL). The organic layer was separated, dried over anhydrous Na 2 EtOAc and filtered. The filtrate was concentrated in vacuo to give crystals crystals crystals crystals crystalsssssssssssssssss To a solution of compound P33 (3.6 g, 9.6 mmol) in MeOH (EtOAc) The resulting mixture was refluxed for 16 hours. The solvent was removed under vacuum. The residue was dissolved in EtOAc (EtOAc)EtOAc. The organic layer was separated, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give a syrup, which was purified from EtOAc (EtOAc/EtOAc) The crude material (2.73 g, 8.12 mmol) was dissolved in anhydrous EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature overnight. EA (200 mL) was added to the mixture and then washed with water (100 mL) and saturated aqueous NaHC03 (100 mL). The organic layer was separated, dried over anhydrous Na.sub.2, and filtered. The filtrate was concentrated in vacuo to give a crystallite. The residue was dissolved in HOAc (30 mL) and Ac.sub.2 (3.3 mL) and the solution was cooled to 10 °C. Concentrated H2S〇4 was added dropwise. The resulting mixture was stirred at room temperature for 5 hours and then poured onto ice water. The precipitate was collected by filtration. Dissolve the collected solid

S 158869.doc -243 - 201215395 was washed in EA (60 mL) with aq. The organic layer was separated, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified eluted with EtOAc EtOAc EtOAc EtOAc EtOAc Add DBU (912 mg '6 mmol) to an ice-cooled solution of P34 (1.14 g, 2.0 mmol) and 6-chloro-9i/- oxime (5 08 mg, 3.0 mmol) in anhydrous MeCN (20 mL) The mixture was stirred for 30 minutes' then TMSOTf (1 · 44 mL, 8.0 mmol) was added dropwise under N. The mixture was stirred at 70 ° C overnight and then cooled to room temperature. The solution was diluted with EA and aqueous NaHCO3 and brine Washing. The organic layer was dried over anhydrous Na 2 SO 4 and filtered. (1·1 g, 80.6%). Purified by preparative TLC to obtain pure P35 (660 mg, 60%) ° #杂 7. Agricultural 潆 PM- 1,4-dioxane (10 mL) and Compound P35 (1.1 g, 1.6 mmoL) in NH3.MeOH (30 mL) was added to a sealed thick-walled pressure tube, and the mixture was stirred overnight at 100 ° C. Concentrated and purified by a silica gel column to give compound P36 ( 503 mg, 94 NMR (CD3OD, 400 MHz) δ 8.31 (s, 1H), 8.17 (s, 1H), 5.99 (d, J=6A Hz, 1H), 4.69 (t, /=4.8 Hz, 1H), 4.31 -4.36 (m, 2H), 4.22-4.24 (m, 1H). #杂与amp;袅 Add P3 (670 mg, 2.0 mmol) to a suspension of 20 mL of anhydrous THF to add tridecyl orthophthalate (1.27). g, 12·0 mmol) and monohydrate TsOH (400 mg, 2.4 mmol). The mixture was stirred at room temperature 158869.doc • 244-201215395 for 16 hours. The reaction was quenched with NaHC03 and concentrated. The residue was purified by EtOAc (EtOAc: EtOAc) (520 mg, 4_8 mmol). The mixture was stirred at room temperature for 3 hours, then MMTrCl (960 mg, 3.2 mmol) was added. The mixture was stirred at 5 ° C for 16 hours. The reaction was quenched from NH 4 OH. Purification of the column (1M MeOH in EtOAc) #耀久农广 Add a mixture of compound P37 (323 mg, 0.5 mmol), hydrazine, hydrazine-diisopropylethylamine (2 mL) and CH3CN (20 mL) (isopropoxy-L-propylamine oxime) A solution of phenylphosphoric acid phenyl ester (610 mg, 2.0 mmol) in THF. After the addition, the mixture was refluxed for 16 hours. The solvent is then removed in vacuo. The residue was purified via hydrazine (PE: EA = 2:1 to 1:1) to afford to afforded to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford to afford afford afford afford afford afford afford The solvent was removed and the residue was purified EtOAc EtOAc EtOAc EtOAc EtOAc Compound Α26 (17·44 mg, 6.2%) as a solid. 4 NMR (DMSO-4 400 MHz) occupies 8.23 (s, 1H), 8.19 (s, 1H), 7.28 (t, 7 = 8.0 Hz, 2H), 7.08-7.15 (m, 3H), 6.06 (d, 7 =3.2 Hz, 1H), 5.29 (d, /=7.2 Hz, 1H), 4.95 (brs, 1 H), 4.49-4.53 (m, 2H), 4.41 (d, J=4.4 Hz, 1H), 3.81- 3.88 (m, 1H), 1.26 (d, J = 7.2 Hz, 3 H), 1.15-1.19 (m, 6H); 31P NMR (DMSO-^, 162 MHz) δ 2.32 ; ESI-LCMS: m/z 605 [M+H]+. s 158869.doc -245· 201215395 Example 64 Preparation of 5'〇R)-C-trifluoromethyladenosine 5'-[phenyl(isopropoxy-L-propylaminoindenyl)]phosphate (A27)

HO OH P39

#锵人农7 添加Add DBU (912 mg) to P34 (1.14 g, 2.0 mmol) and 6-gas-9 ugly-嘌呤 (508 mg, 3.0 mmol) in anhydrous MeCN (20 mL). , 6 mmol). The mixture was stirred for 30 minutes, then TMSOTf (1.44 mL, 8.0 mmol) was added dropwise under N2. The mixture was stirred overnight at 7 ° C and then cooled to room temperature. The solution was diluted with EA and washed with aqueous NaHCI3 and brine. The organic layer was dried over anhydrous Na 2 SO 4 and dried. The mash was concentrated in vacuo to give a residue which was purified from EtOAc EtOAc (EtOAc/EtOAc/EtOAc/EtOAc Further purification by preparative TLC gave pure P38 (230 mg, 21%).

#杂2·Shoulder at 100 ° C, stir P38 (230 mg, 0.35 mmoL) in a sealed container in 1,4 - 2 ° smoldering (2 mL) and concentrated ammonia (10 mL, 28%) Liquid overnight. The solvent was removed, and the residue was purified by a silica gel column to afford compound P39 (41.5 mg, 35.4 / /). 4 NMR 158869.doc •246- 201215395 (CD3OD, 400 MHz) δ 8.24 (s, 1H), 8.18 (s, 1H), 5.95 (d, /=8.0 Hz, 1H), 4.79-4.82 (m, 1H) , 4.43-4.47 (d, J=5.6 Hz, 1H), 4.27-4.30 (m, 2H).

Adding Trimethyl orthoformate (320 mg, 3.0 mmol) and Ts0H.H20 (51 mg, 0.3 mmol) to a suspension of P39 (90 mg, 0.27 mmol) in 1 mL of dry THF. . The mixture was stirred at room temperature for 16 hours. The reaction was quenched with NaHC03 (pH </RTI> &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt;&gt;&gt;&gt;&gt;&gt;&gt;&gt; , 97%). The crude product was dissolved in anhydrous pyridine (5 mL) and cooled to 0. TMSC1 (52 mg, 0_48 mmol) was added. The mixture was spoiled at room temperature for 3 hours before MMTrCl (200 mg, 0.67 mmol) was added. The mixture was stirred at 50 ° C for 16 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Add (isopropoxy-1^ propylamino) chlorophenyl phenyl phosphate (122 mg, 0.4) to a solution of N,N-diisopropylethylamine (2 mL) and CH3CN (10 mL) Methyl) solution in THF. The mixture was refluxed for 16 hours. The solvent is then removed under vacuum. The residue was purified with EtOAc (EtOAc:EtOAc:EtOAc The protected precursor (100 mg, 0.11 mmol) was dissolved in 60% aqueous HCOOH and the mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) Purification of water containing 0.1% HCOOH afforded Compound A27 (17.5 mg, 26%) as a white solids: 4 NMR (DMSO-J5, 400 MHz) δ 8.35 (s, 1H), 8.23 (s, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.15-7.18 (m, 3H), 5.97 (d, J=7.2 Hz, 1H), 5.34-5.38 (m, 1H), 4.89-4.93 (m, 1H) , 4.55-4.60 (m, 1H), 4.31-4.35 (m, 1H), 3.82-3.88 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.19 (br, 6H) ; 31P NMR ( DMSO-^, 162 MHz) δ 3.53; ESI-LCMS: m/z 605 [M+H]+. Example 65 Preparation of 5' (5&gt;C-mercaptoadenosine 5' (A-[Phenyl(cyclohexyloxyl-propylaminomethyl)]phosphate (A10a) and 5'〇S)-C-A Adenosine 5' (phanyl-[phenyl(cyclohexyloxy-L-propylamine)) phosphate (A10b)

Compound P41 (1.2 g, 2.0 mmol) was dissolved in an aqueous 80% HCOOH solution and the mixture was stirred at room temperature for 16 hr. The solvent was removed and the residue was purified by RP HPLC (column type: 15 〇 x 21 _ 5 mm, organic phase gradient: 28% to 8% acetonitrile in a neutral system) to give A10a (22.7 mg, 158869.doc • 248- 201215395 1.9%) with A10b (189 mg, 16%). Compound AlOa : 4 NMR (CD3〇D, 400 MHz) 5 8.34 (s, 1H), 8.24 (s, 1H), 7.20-7.38 (m, 5H), 6.06 (d, J=4.4 Hz, 1H), 4.79 -4.84 (m, 1H), 4.62-4.66 (m, 1H), 4.56 (t, J=5.2 Hz, 1H), 4.49 (t, J=5.2 Hz, 1H), 4.04-4.07 (m, 1H), 3.85- 3.93 (m, 1H), 1.26-1.76 (m, 16H); 31P NMR (CD3OD, 162 MHz) 3 3.13; ESI-LCMS: m/z 591 [M+H]+.

Compound AlOb : NMR (CD3〇D, 400 MHz) 3 8.26 (s, 1H), 8.19 (s, 1H), 7.10-7.30 (m, 5H), 6.03 (d, "7=5.2 Hz, 1H), 4.80 -4.84 (m, 1H), 4.67-4.73 (m, 1H), 4.50 (t, */= 5.2

Hz, 1H), 4.33 (t, J=4.8 Hz, 1H), 4.04-4.06 (m, 1H), 3.85- 3.93 (s, 1H), 1.24-1.78 (m, 16H); 31P NMR (CD3〇D , 162 MHz) J 3.14 ; ESI-LCMS: m/z 591 [M+H]+. Example 66 Preparation of 5'〇S)-C-methyladenosine 5'-[2-Phenylphenyl(cyclohexyloxy-L-propylamineindolyl)phosphate (A28)

谬7 .· #潆 at _78 ° C, to phosphine trichloride (3. 〇 6 g, 20 mmol) and 2-chlorobenzene (2.56 g, 20 mmol) in anhydrous DCM (l 〇〇 mL) A solution of TEA (2.04 mL, 20 mmol) in DCM (20 mL) was added dropwise. After the addition, the mixture is gradually warmed to the chamber

S 158869.doc • 249· 201215395 When mixing 2 b. The solution was then cooled to hydrazine and added (w-aminopropionic acid ring-branched hydrochloride (3·73 g, i 8 丨. 丨), followed by dropwise addition of hydrazine (3·67 g, 36 mm 〇1) The mixture was gradually warmed to room temperature and stirred for 2 hours. Then the solvent was removed and the residue was dissolved in methyl butyl sulphate. The sputum was taken out and the liquid was concentrated. The Shixi rubber column (pure dcm) Purify the residue to give a gas chromate (3.1 g, 40.9%) as a colorless oil. #如..农漠岁- at _78. Underarm, to p3 (595 6 mg, i _〇1) Add caffeol (10) solution (3 mL, 1 M THF solution) dropwise to the drop solution in anhydrous THF (1 〇 mL), then stir the mixture at room temperature for 3 4 4 liters and cool to _78 C. The Ρ41 solution (3 mL·1 M THF solution) was added dropwise and then the mixture was stirred overnight at room temperature. The reaction was quenched with EtOAc and extracted with hydrazine. The organic layer was dried over NaJO 4 and concentrated. :EA=l:1 to 1:3) Purify the residue to give a protected prodrug (67 〇mg). Treated with 65% aqueous HCOOH at room temperature overnight. The solvent was removed under reduced pressure. by The residue was purified by EtOAc EtOAc (EtOAc) eluting , 400 MHz) δ 8.28 (s, 1H), 8.19 (s, 1H), 7-39-7.46 (m, 2H), 7.07-7.20 (m, 2H), 6.03 (d, 7=5.2 Hz, 1H) , 4.90-4.95 (m, 1H), 4.67-4.73 (m, 1H), 4.51 (dd5 J;= J2 = 5.6 Hz, 1H), 4.38 (dd, J;=4.0 Hz, J2=5.6 Hz, 1H) , 4.05-4.08 (m, 1H), 3.91-3.99 (m, 1H), 1.66-1.82 (m, 4H), 1.54 (d, J=6.4 Hz, 3H), 1.28-1.51 (m, 9H); 31P NMR (CD3〇D, I58869.doc -250-201215395 162 MHz) (5: 2·91; ESI-LCMS: m/z 625 [M+H]+. Example 67 Preparation 5'-C-(S)- Methyladenosine 5'-phosphonate A variety of 5'-C-(*S)- were prepared by a similar procedure as described in Example 66 using the appropriate chlorophosphonium aminopropionate instead of P41. Methyl adenosine 5'-phosphonate. The structure and corresponding characterization of 5'-C-(S)-methyladenosine 5'-phosphoramidite are shown in Table 6. Table 6. Various 5'_C_(S)-methyladenosine 5'-phosphoramidate compound number structure 31pnmr ppm ESI-LCMS m/z A29 Fv .Cl .. /=Κ /ΓΝ-ίν-ΝΗ2 Q. υ 〇.χΓΗ°ΤΤΝ&quot;Ν 1 HO OH 3.12 643.1 (M+1)+ A30 OPO \JN=/ 3.27 605.1 (M+l)+ A31 0-〒-0 \_J N=/ 〇λΝΗ H“H 6.04 6.03 609.3 (M+l)+ A32 OPO N=/ Q^H h“H 3.18 3.00 625.4 (M+l)+

S 158869.doc -251 201215395 Compound number structure 31pnmr ppm ESI-LCMS m/z A33 OPO \_J Q^h H"H 3.56 621.3 (M+l)+ A34 Q, 0-|j-0 \_J N=/ 3.38 605.3 (M+l)+ A35 W bH 3.59 3.12 642.0 (M+l)+ A36 Q^〇&gt;^H Ηό' bH 3.64 3.37 592.1 (M+l)+ A3 7 οΛη Hd.bH 3.23 605.2 (M +l)+ A3 8 q wv/yr ΟΛ; H“H 3.32 3.29 619.3 (M+l)+ A3 9 Q, vAT OPO \_J N=/ 3.85 3.78 619.3 (M+l)+ A40 a vAT OF^- O \_J N^7 3.32 3.16 633.1 (M+l)+ 158869.doc -252- 201215395 Compound number structure 31pnmr ppm ESI-LCMS m/z A41 q , v/yr 0-^-0 \JN=/ s~ 3.22 3.18 651.1 (M+l)+ A42 Q, OPO N=/ bH 2.92 2.58 667.1 (M+l)+ A43 Q, \\ NH , , · V u H0 0 4.52 3.98 577.3 (M+l)+ Table 7 : Other nucleosides/nucleotides/nucleotide derivatives/compounds

S 158869.doc -253 - 201215395

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158869.doc -256- 201215395 Structure Structure

OH s 158869.doc 257- 201215395

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s 158869.doc -259· 201215395

158869.doc 260- 201215395

I Lai

H2 N

_2 NH

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5'-alkylated nucleoside 5'-triphosphate The following 5'-alkylated nucleoside 5 was prepared according to the procedure described in US Publication No. 2010-0249068, which is incorporated herein by reference. '-Triphosphate: 158869.doc • 263 - 201215395 nh2 9 9 9 j {X^jj HO-POPOPOl 〇N^N OH OH OH \_L HOCDH MS: 534.1 (Ml). 31PNMR (D20): -8.75 (d, IP); -11.45 (d, 1P), -22_48 (t, IP). Nh2. . 〇 1 &lt;NT^ II II II i \, Jl J HO-P-O-P-O-P-O^, 〇 N^N OH OH OH \_L HO7 OH MS: 534.4 (M-l). 31PNMR (D20): -8.58 (bs, IP); -11.09 (d, 1P), -22.15 (t, IP). Nh2 9 9 9 _/ (Λ1 HO-POPOPOC 〇N^V OH OH OH V Υρ HO^V MS: 526.2 (Ml). 31PNMR (D20): -9.58 (bs, IP); -11.65 (d, 1P) , -21.92 (bs, IP). nh2 9 9 9 Y (S: H〇-P-〇-P-〇-P-〇-&lt; 〇N^V OH OH OH VVF HO^V MS: 529.9 (Ml 31PNMR (D20): -10.15 (d, IP); -11.20 (d, 1P), -22.45 (t, IP). nh2 ? ? / rS OH OH OH \ 7 \_L^oh HO MS: 496.0 (Ml) 31PNMR(D20): -10.15 (d, IP); -11.30 (d, IP), -22.54 (t, IP). nh2 9 9 9 I {χ1)1 HO-POPOPOl 〇OH OH OH Y ^y HO7 OH MS: 520.1 (Ml). 31PNMR (D20): -9.75 (d, IP); -11.41 (d, 1P), -22.54 (t, IP). nh2 9 9 9 / rV HO-POPOPOC 〇 OH OH OH V YF HO7 F MS: 516.0 (Ml). 31P NMR (D20): -9.50 (bs, IP); -11.30 (d, 1P), -22.33 (t, IP). Example 69 HCV Replicon Test - 264- 158869.doc 201215395 Cells containing 2 mM L-glutamic acid supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% clarithin-streptomyocin, 1% non- Dukacco's modified Ig's medium with essential amino acid and 0.5 mg/ml G418 (Dulbecco's modi Huh-7 cells containing self-replicating subgenomic HCV replicons with a stable luciferase (LUC) reporter gene were cultured in fied Eagle's medium (DMEM). Determination of anti-HCV activity Compounds were assayed for HCV replicon cells by the following procedure 50% inhibition concentration 〇5 ()). On the first day, 5,000 11 (:¥ replicon cells per well) were seeded in 96-well plates. On the next day, test compounds were dissolved in 100% DMSO to 10 〇χ required final test concentration. Each compound was serially diluted (1:3) to 9 different concentrations. 100% DMSO containing the compound was reduced to 10% DMSO by dilution 1:10 in cell culture medium. Compounds were diluted to 10% DMSO with cell culture medium, This was used to administer HCV replicon cells in a 96-well format. The final DMSO concentration was 1%. HCV replicon cells were incubated at 37 ° C for 72 hours. At 72 hours, the cells were still not confluent (subconfluent Time-treated cells. Compounds that reduce LUC signaling were determined by Bright-Glo luciferase assay (Promega, Madison, WI). Inhibition at each compound concentration was determined relative to control cells (untreated HCV replicons) Percentage to calculate EC50. The antiviral activity of the exemplary compounds is shown in Table 8, where "A" represents EC5" &lt; l μΜ, "Β" means EC5〇 &lt;30 μΜ, "(:" means EC5〇&lt; 100 μΜ and “D” means EC5〇&lt;1000 μΜ. In Table 9, “A” indicates

S 158869.doc -265 - 201215395 EC50&lt;5 μΜ, "B" means EC50&lt;30 μΜ, and "C" means Ε〇5〇&lt;200 jiM 〇 Table 8

Structural Compound Number HCV Replicon Activity /=\ ΓΝνΝΗ2 Qo , V .0λ^νη XT 1 HO 'OH A15 B NH2 Υί°^Ν^ ^0]&quot; hc5 bH B /N NH2 , J'L NH ·~· CH3 0 ud bH DB /=\ /Tnv-nh2 0〇7 V 1 0〇-Ρ-〇Ά/°'ν*Ν^Ν 人ΤΓ 1 HO t)H A8 A fjr^ .n nh2 person V〇jN ^0JCnh yJ N=/ I HO, &amp;H A19 A 158869.doc -266- 201215395

Structural Compound No. HCV Replicon Activity jC) / /N NH2 X0\^ ΛΤ n=/ 1 HO, t)H A20 A jT) Ok 〇J 〇fW&quot;2 [j^J 1 HO' OH A21 A jC) /N NH2 i HO' t»H A1 A [jr^ .n nh2 Ho-lo^LoJ^ ^οΛ,νη Yt w Ύ 0 \ Hd bH A2 A q 〇"众, 〇,Xt0\r^NI HO' bH A10 A /=\ /Γ\-ΝΗ2 Q. /0Nrt n HOT'· bH AlOa A /=\ /TV-NHz Q w〇Nr&lt; AlOb A s 158869.doc •267- 201215395

Structure Compound No. HCV Replicon Activity /=\ /Γ&quot;Ν-ν-ΝΗ2 9j_. people. Ϊϊί &gt;τΛ^ X All A Q ν》νη2 Factory γ 0 A12 A ^ ο All - H^!f〇\!rN-N r V 0 A13 A Ο nCtnH2 乂. \VtN JT ln0( t. A14 A /N NH2 °Y° A3 A public.々r^K2 ^〇Yh jr ^ A4 A 158869.doc 268- 201215395

Structure Compound No. HCV Replicon Activity ^^0 3^°ν〇ΎΝΗ2 Λ V 7ΐ ΰ X A23 A ^J-〇Vtn//yNH2 r° A22 A c〇 Force. Oh. Hey. A5 B rP r〇°H Ho-lo^LoJ^ 5 N=/ T A7 B c〇Λ°η i H0 t)H A6 B /=\ /Γΐν^ΝΗ2 Q〇7 V 0〇-P-〇- ^&gt;S/0n&gt;N^N .0a.nh xr Y° A16 B s 158869.doc -269· 201215395

Structural Compound Number HCV Replicon Activity QN^V-NH2 Plant V5 〇A9 A 〇化 2 A17 A, H2 U VNH P r 〇w 〇{_ A18 AQ 〇) fNy-T2 \ Ο&quot; \!rN^N / 0 i H0 OH A24 C Cm. f&gt;T v ^η°Ύτνλ^ν /^0 1 HO OH A25 D Q q wNH2 / 0 i H0 OH A26 C Q 0 ?F3 乂 / 0 i ho' oh A27 B

158869.doc -270· 201215395

Structural Compound No. HCV Replicon Activity 〇-P-〇/\_J N=/ 〇V^NH Ηό bH A31 A Clx /=\ r^N NH2 M 9 VyN^N 0-P-0^\_7 N=/ 〇〇&gt;^NH Hd bH A32 AQ, Vr^H2 Cl _〇-P-〇N=/ Hd ~ A28 A OPO \_7 N=/ Qj^NH Hd. bH A29 A fN NH2 M 9 VyN^n OPO X7 N=/ 〇-〇^ΝΗ Η0 bH A30 A /=\ 〆叫 H ^ Vyn^n ' OPO \_J N=/ 〇0^H Hd bH A37 A NH2 M 9 ^〇υν%Ην OPO \JN= / Q^c/^NH Hd bH A33 A

s 158869.doc -271 - 201215395

Structural Compound No. HCV Replicon Activity ν/ΚΗ2 OPO \JN=/ A35 B [^NWNH2 M 9 VyN^n OPO^V/ N=/ 〇0^NH Hd bH A3 6 BQ, Vr^H2 〇-『 -〇\_J N=/ A34 AQ 9 VtAT OPO \JN=/ A3 8 AQ, OPO \JN=/ Oo^ H〇A39 A OPO \_J N=/ A40 A qv/yH2 S-— A41 A 158869.doc 272- 201215395

Structural Compound No. HCV Replicon Activity Q, Vr^: 2 A42 BQ, Vr^NH2 opo \_J 〆〇〇&gt;-NH Hd bH A43 A 0^0 J fV° xXl°\rN^NH T HO' t) H B5 C ί? j 0 0 op-oA^^n^T=/nh 1 hc5 bH B5 C /^X /NH2 〇/ f〇-P-〇\〇y^ . Human rNH M 0 * HO' t)H C6 c /=\ ) /NH2 Mi / j,Xi〇JXr^〇 h&lt;5' bH C2 c nh2 0JH3(A0 OH F C5 A 158869.doc 273 - 201215395

Structural Compound Number HCV Replicon Activity /=\ ^/NH2 1 HO' 'OH C8 C KI .nh2 °HNN〇^Y°yN^ ο-Λ /0 H0 C9 C &lt;i? Λ 1 〇〇—P— 〇—, N人私 OH CIO B QoioVvC^ γγ t 1 H0 OH D1 DO, 〇ji^r° .0JCnh χγτ 1 HO' 〇H D2 DQ s Λ Ο Ο—P—0~[ N OH F D4 B 9j_ ^6: 〇OH D7 B 158869.doc 274- 201215395 Structural Compound No. HCV Replicon Activity 〇 ^j ^v&lt;NH2 El B Table 9: Activity of Exemplary Compounds (C &lt; 200 μΜ, Β &lt; 30 μΜ, A &lt; 5

μΜ) Structure HCV replicon active structure HCV replicon activity nh2 η/ \η Β Q η Ν?Γ c ^\^νη2 H〇Apr:r Η0 Β .Ο丫%^ΝΗ2 Η〇Λ/γθ η/ \ Β ΗΛ^γΓ η/ ^ F &amp; A ΝΗ Χ0χ^Χγ 乂/ ν ο 0 A η—Ν ν y—ΝΗ2 ! Ω Η η/ \η Β /ΝΗ2 η/ \ FA s 158869.doc .275 · 201215395

Structure HCV Replicon Active Structure HCV Replicon Activity Plant V 1 Ny=( NH2 η/ \η C &gt;^F〇A . °ν-\ ηλ〇&gt;ΟνΗ2 H(f OH c /NH2 Hcf FA Η2Ν 丄. HC?' \&gt;H c ^,nh2 Everyone. A ry. Bz0 person^丫丫nh BzO* OBz B i=\ ( -〇V hX A 1 \^n\^nh2 H〇H(f Η A &lt;V^N\r-NH2 HO, 丫N's^T HCf OH A q.j # 〇〇—p—AQ “N?TC Example 70 Compound Combination 158869.doc •276- 201215395 Combination Test Using Huh7 Cells The HCV genotype lb HCV replicon with a stable luciferase (LUC) reporter gene is tested in combination with two or more test compounds in combination with each other under standard conditions, containing 10% heat inactivated fetal calf Cultured cells in serum (FBS; Mediatech Inc, Herndon, VA), 2 mM L-face lysine and non-essential amino acid (JRH Bio sciences) in Duchenne modified Ig's medium (DMEM; Mediatech Inc, Herndon, VA) HCV replicon cells were seeded in 96-well culture plates at a density of 104 cells per well in DMEM containing 10% FBS. On the second day, DMEM containing no compound (as a control) was included. DMEM in which the test compound was serially diluted in the presence of 2% FBS and 0.5% DMSO, or a DMEM replacement medium containing a combination of compound Α10 and one or more test compounds in serial dilution in the presence of 2% FBS and 0.5% DMSO. Incubation for 72 hours in the absence of a compound (as a control), in the presence of a test compound, or in the presence of a combination of compounds. Using luciferin-based assay as determined by Bright-Glo Luciferase Assay (Promega, Madison, WI) The reporter gene study of the enzyme (LUC) tests the direct effect of the combination of compounds. The dose-response curves for the combination of individual compounds and fixed ratios of two or more test compounds are determined. The test compound combinations are evaluated by two separate methods. In the Loewe additivity model, the experimental replicon is analyzed by using CalcuSyn (Biosoft, Ferguson, MO) (a computer program based on the method of Chou and Talalay) Data. The program uses experimental data to calculate the combinations of experiments tested.

S 158869.doc -277- 201215395 Combination index (CI) value. A CI value &lt;1 indicates a synergistic effect, a CI value of 1 indicates an additive effect, and a CI value &gt; 1 indicates an antagonistic effect. The second method for evaluating combinations uses a program called Mac Synergy II. The MacSynergy II software is courtesy of Dr. M. Prichard (University of Michigan). The Prichard Model allows for a three-dimensional study of drug interactions and calculates the synergy volume produced by a replica assay using a checkerboard combination of two or more inhibitors (unit: μΜ2) %). The synergistic capacity (forward capacity) or the antagonistic capacity (negative capacity) indicates the relative amount of synergy or antagonism at each change in the concentration of the two drugs. Collaborative capacity and antagonistic capacity are defined based on the Bliss independence model. In this model, a synergistic capacity of less than -25 indicates an antagonistic interaction, a capacity in the range of -25 to 25 indicates an additive effect, a capacity in the range of 25 to 100 indicates synergy and a capacity > 100 indicates a strong synergy . In vitro exostatic, synergistic, and strong synergistic effects of assay compound combinations can be used to predict the therapeutic benefit of administering a combination of compounds in vivo to an infected patient. The combined CI and synergistic capacity results are provided in Table 10. Table 10 CI synergistic capacity of composite compounds at EC5G (μΜ2%) INX-189 0.67 31 PSI-938 1 36 PSI-6130 1 21 PSI-7851 1.2 14 GS-9190 0.45 112 philippwavir (filibuvir) 0.46 38 ANA -598 0.67 32 158869.doc -278- 201215395 Cl Synergistic capacity of compound compounds under ECSG (μΜ2%) VX-222 1.1 52 VX-950 0.56 34 ITMN-191 0.84 39 TMC-435 0.85 104 BMS-790052 0.48 25 6002 0.01 127 Virus 嗤0.88 0 Pegylated interferon 1 13 Complex interferon 1.1 18 Cyclosporin A 0.75 67 BILN-2061 0.86 12 HCV-796 0.39 35 IFN-λΙ 0.64 43 IFN-X2 0.56 31 ΙΡΝ -λ3 0.87 33

In addition, the present invention has been described in detail by way of illustration and example, Therefore, it is to be understood that the invention is not to be construed as limited to the scope of the invention BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows an exemplary HCV protease inhibitor. Figure 2 shows an exemplary nucleoside HCV polymerase inhibitor. Figure 3 shows an exemplary non-nucleoside HCV polymerase inhibitor. Figure 4 shows an exemplary NS5 A inhibitor. Figure 5 shows exemplary other antiviral agents. Figures 6A-6I show exemplary compounds of formula (CC). 158869.doc -279- 201215395 Figures 7A-7I show exemplary compounds of formula (I) and their triphosphates. Figures 8A-8B show exemplary compounds of formula (BB). Figure 9 shows the formula (DD). 158869.doc -280-

Claims (1)

201215395 VII. Scope of Application: A compound of formula (I) or a pharmaceutically acceptable salt thereof, R5 R6 (I) where: Optionally substituted heterocyclic test group or optionally substituted heterocyclic base having - or more protected amine groups; R is an optionally substituted amino acid or optionally substituted N-linked amino acid ester derivative; R2 is selected from the group consisting of an optionally substituted aryl group, optionally substituted heteroaryl group and optionally substituted heterocyclic group; RlR3b is independently selected Free group consisting of hydrogen, optionally substituted CN6 alkyl, optionally substituted c26 dilute, optionally substituted C2·1 alkynyl, optionally substituted t-alkyl and aryl (Cm At least one of the alkyl)μ restrictions is not hydrogen; or Rh together with R3b form a group selected from the group consisting of Cw cycloalkyl optionally substituted, optionally substituted C3 6 a cycloalkenyl group, optionally substituted C3·1 aryl group, and optionally substituted (: 36 heteroaryl; R4 is hydrogen; R2 is selected from the group consisting of hydrogen, _0R9 and _〇c (=〇) Rl0; R6 is selected from the group consisting of hydrogen, halogen, -〇Rll, and -0C(=0)R12; 1 158869.doc 2 201215 395 or R and R are both oxygen atoms and are attached to each other by a base; free radical consisting of hydrogen, halogen, optionally substituted 16 alkyl, -〇R13 and -oc(=〇)Ri4; Is a hydrogen or optionally substituted Ci6 alkyl; and R is independently selected from the group consisting of hydrogen and optionally substituted Ci 6 alkyl; and R12 and R14 are independently selected from the group consisting of Group: Cl. 6 alkyl group substituted as appropriate and optionally substituted (: 3-6 cycloalkyl group; the limitation is that the compound of formula (1) may not have a structure selected from the group consisting of: 2. The compound of claim 1 wherein at least one of R3a and R3b is a Cl_6 alkyl group optionally substituted; and the other of R3a &amp; R3b is hydrogen. 3. A compound according to claim 2, wherein the optionally substituted c u alkyl group is an indenyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group. 158869.doc -2- 201215395 4. The compound of claim 2, wherein the optionally substituted Cw alkyl group is a methyl group. 5. If requested! A compound wherein at least one of R3a &amp; R3b is a CM alkyl group which is optionally substituted; and the other of R3a and is hydrogen. 6. The compound of claim 1 or 2, wherein R2 is an optionally substituted aryl group. 7. The compound of claim 6 wherein the optionally substituted aryl group is an optionally substituted phenyl group. 8. The compound of claim 6, wherein the optionally substituted aryl group is an optionally substituted naphthyl group. 9. A compound according to claim 1 or 2, wherein R2 is optionally substituted heteroaryl. π 10. The compound of claim 2 or 2, wherein R1 is an optionally substituted N-linked a-amino acid. 11_ The compound of claim 2 or 2, wherein R1 is an optionally substituted a-amino acid ester derivative. 12. The compound of claim 1 or 2, wherein R1 is selected from the group consisting of alanine, aspartic acid, aspartic acid, cysteine, cholic acid, glutamic acid, glycine Aminic acid, valine acid, serine acid, tyrosine acid, arginine, histidine, isoleucine, leucine, lysine, methionine, albendine, threonine, color Amine acid, valine acid and ester derivatives thereof. 13. The compound of claim 12, wherein the Ri is selected from the group consisting of isopropyl propyl acrylate, cyclohexyl propylamine, alaegyl vinegar, and amine-like milk S 158869.doc 201215395 isopropyl ester and white amine Isopropyl broth. 14. The compound of claim 13 wherein R1 is cyclohexyl propylamine. R15o R1® R17 1 5 · A compound according to claim 1 or 2, wherein Ri has the structure 〇HN—^ wherein R 15 is selected from the group consisting of hydrogen, optionally substituted Cm alkyl, optionally substituted A6 cycloalkyl, optionally substituted aryl, optionally substituted aryl (Ci-6 alkyl) and optionally substituted ha haloalkyl; and R16 is selected from the group consisting of: hydrogen, optionally Substituted Cw alkyl, optionally substituted Ci_6-alkyl, optionally substituted C3.6 cycloalkyl 'optionally substituted c6 aryl, optionally substituted 0:1() aryl And optionally substituted aryl (Ci 6 alkyl); and R17 is hydrogen or optionally substituted 匚!·4 alkyl; or! ^6, together with R!7, form an optionally substituted (: 3-6 cycloalkyl group. 16. The compound of claim 15 wherein the compound is substituted by Ci6 alkyl. 17. The compound of claim 16 Wherein the optionally substituted C1-6 alkyl group is methyl, ethyl, n-butyl, isobutyl or tert-butyl. 1 8. The compound of claim 17 wherein the condition is substituted c The compound of claim 16 is the compound of claim 16, wherein the optionally substituted (:丨6 alkyl group is substituted with one or more substituents selected from the group consisting of: Ν- Amidino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted heteroaryl, fluorenyl-carboxy and amine. 20. A compound of claim 15 wherein R17 is hydrogen. The compound of claim 15, wherein R15 is an optionally substituted Ci6 alkyl group. 6 &amp; 22. The compound of claim 15 which is an optionally substituted cycloalkyl group. °~〇H 丨 25. The compound of claim 1 or 2 wherein R7 is hydrogen. 26. The compound of claim 1 or 2, wherein 117 is _〇R!3. 27. The compound of claim 26, wherein R is 3 is hydrogen. 28. The compound of claim 1 or 2, wherein R7 is a pixel. 29. The compound of claim 1 or 2, β 7 in the bean, and f R is optionally substituted Cj S \5SS69.doc -5- 201215395. 30. The compound of claim 1 or 2, wherein R5 is hydrogen. 31. The compound of claim 1 or 2, wherein R5 is -OR9. 32. The compound of claim 31, wherein R9 is hydrogen. 33. The compound of claim 3, wherein r9 is optionally substituted Cϊ_6 alkyl. 34. The compound of claim 1 or 2, wherein R5 is _〇c(=〇)Rio. 3. The compound of claim 1 or 2, wherein R6 is _〇r&quot;. 3. The compound of claim 35, wherein R11 is hydrogen. 37. The compound of claim 35, wherein R&quot; is an optionally substituted Ci6 alkyl group. 38. The compound of claim 1 or 2, wherein R6 is -〇C(=〇)R12. 39. The compound of claim 1 wherein R5 and R6 are both oxygen atoms and are joined together by a plurality of groups. 40. The compound of claim 1 or 2, wherein R5 and R6 are both hydrogen. 41. The compound of claim 1 or 2, wherein R5 is -OH; and R6 is _〇H. 42. The compound of claim 1 or 2, wherein R5 is -OC(=0)R10, and R6 is -〇C(=〇)R12 〇43. The compound of claim 1 or 2, wherein R6 and R7 are It is halogen. 44. The compound of claim 1 or 2, wherein R6 is hydrogen; and R7 is selected from the group consisting of halogen, optionally substituted Ci-6 alkyl and -OR13. A compound according to claim 1 or 2, wherein R6 is halogen; and R7 is optionally substituted Ci_6 alkyl. 46. The compound of claim 1 or 2, wherein R8 is argon. 158869.doc 201215395 47. The chemical base of claim 1 or 2. The compound wherein R8 is optionally substituted by Ci. 6 48. The compound of claim 1 or 2: wherein B1 is selected from the group consisting of The RA2 is selected from the group consisting of the group Rn selected from the group consisting of: hydrogen, halogen and NHRn, wherein: hydrogen, -C(=0)RK2 and -C(=〇) g 2 % are dentine or NHRW2 'wherein RW2 is selected from the group consisting of hydrogen, optionally substituted Cm alkyl, optionally substituted C26 alkenyl, optionally substituted CM cycloalkyl, -c(=〇)rM2&amp; _ or N2 ; RC2 is hydrogen or NHR02, wherein R〇2 is selected from the group consisting of hydrogen, -C(=〇)RP2, and _C(=〇)〇rQ2; rD2 is selected from the group consisting of: Hydrogen, dentate, optionally substituted Cw, and optionally substituted C: 2·6 alkenyl and optionally substituted c2.6 alkynyl; S 158869.doc 201215395 R is selected from the group consisting of Group: hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C: 3·8 cycloalkyl, _c(=〇)rR2, and c(7) 0RS2; RF2 is selected from the group consisting of: Hydrogen, dentate, optionally substituted core, 6 alkyl, optionally substituted C26 alkenyl, and optionally substituted C2-6 fast radical; Y2 is N or CR12' wherein RI2 is selected from the group consisting of group Gas, i, optionally substituted Cm alkyl, optionally substituted 'base and optionally substituted c2.6 alkynyl; 26 6 rG2 is optionally substituted cN6 alkyl; RH2 is hydrogen Or NHRT2, wherein the group is independently w, _C(=0)RU2 and -C(=〇)〇RV2, and R K2 RL 2 _ ύλ M2 τ&gt; N2 τϊΡ2 ^R , R , R 2. rQ2, rR2, rS2, and core RV2 are independently selected from the group consisting of: 仗m 1-6 vana, C2, 6 bauxite, 2-6 alkynyl, C3·6% alkyl 'C3. 6 cycloalkenyl, C3·6 ring block C6-1G aryl, heteroaryl, heteroalicyclic, aryl (Ci 0 alkyl), heteroaryl (Cb6 alkyl) and heteroalicyclic (Cu alkane base). earth 49. The compound of claim 48, wherein B1 is upper N NH2 50. The compound of claim 48, wherein B1 is 丄 158 158869.doc • 8 · 201215395 ο sF2 ΝΗ ^ΛΑΛ/» 51. The compound of claim 48, wherein Β1 is R1 D2 52. The compound of claim 48, wherein B1 is 53_, the compound of claim 52, wherein RE2 is hydrogen nhre *N N νΛΛΛΛ R1 Β2 54. The compound of claim 48, wherein Β1 is 55-a compound of claim 54, wherein RB2 is NHRW2 and RW2 is hydrogen orG2 R H2 56. The compound of claim 48, wherein B1 is 57. The compound of claim 1 or 2, wherein when R 2 is phenyl, R 1 is not H ^ CO / Ο HN- 58. A compound, wherein the compound of formula (1) is selected from the group consisting of: OH OH , OH OH 158869.doc -9- 201215395 158869.doc 10- 201215395 201215395 158869.doc -12- 201215395 Nh2 158869.doc -13- 201215395 158869.doc 201215395 s 158869.doc -15- 201215395 201215395 , or pharmaceutically acceptable 59. The compound of claim 1, wherein the compound of formula (I) is 60. The compound of claim 1, wherein the compound of formula (I) is S 158869.doc -17- 201215395 61. Or a pharmaceutically acceptable salt thereof. Wherein the compound of formula (1) is ' or pharmaceutically acceptable thereof. 62. The combination of claim 1 a compound wherein the compound of the formula (1) is a pharmaceutically acceptable composition thereof, or a pharmaceutically acceptable composition thereof, which comprises a therapeutically effective amount of a sigma compound as claimed in the claims or a pharmaceutically acceptable substance thereof. Salts and pharmaceutically acceptable carriers, diluents, excipients or combinations thereof. A use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable orphaned pharmaceutical composition thereof, for use in the manufacture of a medicament for ameliorating or treating a viral infection. The use of the claim 64 wherein the viral infection is caused by a virus selected from the group consisting of adenovirus, Aiphaviridae, Arbovirus, Astroviral (Astr〇vjrus), Ben Bunyaviridae, Coronaviridae (c〇r〇naviridae), filamentous disease 158869.doc 201215395 Filoviridae, Flaviviridae, Hepadnaviridae, Herpesviridae, Alphaherpesvirinae, Betaherpesvirinae, γ Gammaherpesvirinae, Norwalk Virus, Astroviridae, Caliciviridae, Orthomyxoviridae, Paramyxoviridae, deputy Paramyxovirus, Rubulavirus, Morbillivirus, Papovaviridae, Parvoviridae, Picornaviridae, Foot and Mouth Disease Virus Aphthoviridae), Cardioviridae, Enteroviridae 'Coxsaekie virus, Polio Virus, Rhinoviridae, Phycodnaviridae, Poxviridae, Reoviridae, Rotav Irus), Retroviridae, Retrovirus, immunodeficiency virus, leukemia virus, avian sarcoma virus, rhabdovirus, Rubiviridae and Phytophthora (Togaviridae) 〇 66. The use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63, for use in the preparation of an ameliorating or treating HCV infection The drug. 67. Use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for inhibiting NS5B polymerase activity. 68. Use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting viral replication. 69. Use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for contact with a virus-infected cell for the purpose of ameliorating or treating the viral infection. 70. The use of claim 67, 68 or 69, wherein the medicament improves or treats an HCV viral infection. 71. Use of a compound selected from the group consisting of a compound according to any one of claims 1 to 62, a compound 7072, a compound 7073, a compound 7074, a compound 7075, a compound 7076, a compound 7077, a monophosphate of any of the above An ester, a diphosphate of any of the above, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for ameliorating or treating a viral infection, wherein the medicament is manufactured with one or more selected from the group consisting of Combination of agents: interferon, virus. Ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5 A inhibitor, antiviral compound, compound of formula (BB), compound of formula (CC) and compound of formula (DD), or any of these compounds One of the pharmaceutically acceptable salts. 72. The use of claim 71, wherein the one or more agents are selected from the group consisting of: compounds 1001 to 1014, 2001 to 2010, 3001 to 3008, 4001 to 4005, 5001 to 5002, 6000 to 6078 '8000 to 8012 and 9000, or a pharmaceutically acceptable salt of any of the above compounds. 158869.doc -20- 201215395 73. The use of claim 71 or 72, wherein the medicament ameliorates or treats an HCV infection. 74. Use of a compound selected from the group consisting of the compound of any one of claims 1 to 62, the compound 7072, the compound 7073, the compound 7074, the compound 7075, the compound 7076, and the compound 7077, and the monophosphate of any of the above An ester, a diphosphate of any of the above, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for contact with a virus-infected cell, wherein the medicament is manufactured and one or more selected from the group consisting of a combination of agents: interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (BB), compound of formula (CC) and compound of formula (DD), Or a pharmaceutically acceptable salt of any of the above compounds. 75. The use of claim 74, wherein the one or more agents are selected from the group consisting of: compounds 1001 to 1014, 2001 to 2010, 3001 to 3008, 4001 to 4005, 5001 to 5002, 6000 to 6078, 8000 to 8012 and 9000, or a pharmaceutically acceptable salt of any of the above compounds. 76. The use of claim 74 or 75, wherein the medicament improves or treats an HCV infection. 158869.doc -21 -