OA16349A - Substituted nucleotide analogs - Google Patents
Substituted nucleotide analogs Download PDFInfo
- Publication number
- OA16349A OA16349A OA1201300108 OA16349A OA 16349 A OA16349 A OA 16349A OA 1201300108 OA1201300108 OA 1201300108 OA 16349 A OA16349 A OA 16349A
- Authority
- OA
- OAPI
- Prior art keywords
- optionally substituted
- compound
- alkyl
- hydrogen
- group
- Prior art date
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- 125000003729 nucleotide group Chemical group 0.000 title 1
- 206010047461 Viral infection Diseases 0.000 claims abstract description 35
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- 235000001014 amino acid Nutrition 0.000 claims description 59
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 26
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical group NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 6
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical group NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 6
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- 108010010648 interferon alfacon-1 Proteins 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
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- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
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- 150000002596 lactones Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
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- 229940113083 morpholine Drugs 0.000 description 1
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- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
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- 230000001590 oxidative Effects 0.000 description 1
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxoallopurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 244000045947 parasites Species 0.000 description 1
- UAUIUKWPKRJZJV-MDJGTQRPSA-N paritaprevir Chemical compound C1=NC(C)=CN=C1C(=O)N[C@@H]1C(=O)N2C[C@H](OC=3C4=CC=CC=C4C4=CC=CC=C4N=3)C[C@H]2C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@@H]2\C=C/CCCCC1 UAUIUKWPKRJZJV-MDJGTQRPSA-N 0.000 description 1
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- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- GJJLNXZGOBJOFF-ZETCQYMHSA-N propan-2-yl (2S)-2-amino-3-methylbutanoate Chemical compound CC(C)OC(=O)[C@@H](N)C(C)C GJJLNXZGOBJOFF-ZETCQYMHSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- PVJNTTDWEPOEDD-UHFFFAOYSA-N propanoyl propanoate;pyridine Chemical compound C1=CC=NC=C1.CCC(=O)OC(=O)CC PVJNTTDWEPOEDD-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- GRFNBEZIAWKNCO-UHFFFAOYSA-N pyridin-3-ol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- GYESAYHWISMZOK-UHFFFAOYSA-N quinolin-5-ol Chemical compound C1=CC=C2C(O)=CC=CC2=N1 GYESAYHWISMZOK-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
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- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-XWFVQAFUSA-N sodium borodeuteride Substances [Na+].[2H][B-]([2H])([2H])[2H] YOQDYZUWIQVZSF-XWFVQAFUSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
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- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- KQBSGRWMSNFIPG-UHFFFAOYSA-N trioxane Chemical compound C1COOOC1 KQBSGRWMSNFIPG-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 229940075420 xanthine Drugs 0.000 description 1
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Abstract
Disclosed herein are phosphorothioate nucleotide analogs, methods of synthesizing phosphorothioate nucleotide analogs and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with the phosphorothioate nucleotide analogs.
Description
[0001] This application claims the benefit of U.S. Provisional Application Nos. 61/385,363, filed September 22, 2010; and 61/426,461, filed December 22, 2010; both of which are incorporated herein by reference in their entirety; including any drawings.
BACKGROUND
Field [0002] The présent application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are phosphorothioate nucléotide analogs, pharmaceutical compositions that include one or more nucléotide analogs and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a phosphorothioate nucléotide analog, alone or in combination therapy with other agents.
Description [0003] Nucleoside analogs are a class of compounds that hâve been shown to exert antîviral and anticancer activity both in vitro and in vivo, and thus, hâve been the subject of widespread research for the treatment of viral infections and cancer. Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active anti-metabolites, which, in tum, may inhibit polymerases involved in viral or cell prolifération. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.
SUMMARY [0004] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable sait thereof.
[0005] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a neoplastic disease that can include administering to a subject suffering from the neoplastic disease a therapeutically effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition 5 that includes one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for ameliorating and/or treating a neoplastic disease. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically 10 acceptable sait thereof, that can be used for ameliorating and/or treating a neoplastic disease.
[0006] Some embodiments disclosed herein relate to methods of inhibiting the growth of a tumor that can include administering to a subject having a tumor a therapeutically effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes one or more compounds of 15 Formula (I), or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for inhibiting the growth of a tumor. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable sait of thereof, that can be used for inhibiting 20 the growth of a tumor.
[0007] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes 25 one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for ameliorating and/or treating a viral infection. Still other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, that 30 can be used for ameliorating and/or treating a viral infection.
© [0008] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable sait of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable sait of one or more compounds described herein, in the manufacture of a médicament for ameliorating and/or treating a viral infection that can include contacting a cell infected with the virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable sait of one or more compounds described herein, that can be used for ameliorating and/or treating a viral infection by contacting a cell infected with the virus with an effective amount of said compound(s).
[0009] Some embodiments disclosed herein relate to methods of inhibiting réplication of a virus that can include contacting a cell infected with the virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable sait of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable sait of one or more compounds described herein, in the manufacture of a médicament for inhibiting réplication of a virus that can include contacting a cell infected with the virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable sait of one or more compounds described herein, that can be used for inhibiting réplication of a virus by contacting a cell infected with the virus with an effective amount of said compound(s).
[0010] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a parasitic disease that can include administering to a subject suffering from the parasitic disease a therapeutically effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition ©
that includes one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for ameliorating and/or treating a parasitic disease. Still other embodiments 5 described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, that can be used for ameliorating and/or treating a parasitic disease.
[0011] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of a compound described hereîn or a 10 pharmaceutically acceptable sait thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof), or a pharmaceutical composition that includes a compound described herein, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS 5A inhibitor, an other antiviral compound, a compound of Formula (AA), a mono-, di- and/or tri15 phosphate thereof, or a pharmaceutically acceptable sait of the foregoing, a compound of Formula (BB), or a pharmaceutically acceptable sait thereof, and a compound of Formula (DD), or a pharmaceutically acceptable sait thereof. Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a compound 20 described herein or a pharmaceutically acceptable sait thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof), or a pharmaceutical composition that includes a compound described herein, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a mono-, di25 and/or tri-phosphate thereof, or a pharmaceutically acceptable sait of the foregoing, a compound of Formula (BB), or a pharmaceutically acceptable sait thereof, and a compound of Formula (DD), or a pharmaceutically acceptable sait thereof. Some embodiments disclosed herein relate to methods of inhibiting réplication of a virus that can include administering to a subject a therapeutically effective amount of a compound described herein 30 or a pharmaceutically acceptable sait thereof (for ex ample, a compound of Formula (I), or a pharmaceutically acceptable sait thereof), or a pharmaceutical composition that includes a compound described herein, or a pharmaceutically acceptable sait thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (AA), a mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable sait of the foregoîng, a compound of Formula (BB), or a pharmaceutically acceptable sait thereof, and a compound of Formula (DD), or a pharmaceutically acceptable sait thereof. In some embodiments, the agent can be a compound, or a pharmaceutically acceptable sait thereof, selected from Compound 1001-1014, 2001-2010, 3001-3008, 4001-4005, 50015002, 7000-7077, 8000-8012 or 9000, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or pharmaceutically acceptable sait thereof. In some embodiments, the method can include administering a second agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS 5A inhibitor, an other antiviral compound, a compound of Formula (AA), a mono-, di- and/or triphosphate thereof, or a pharmaceutically acceptable sait of the foregoîng, a compound of Formula (BB), or a pharmaceutically acceptable sait thereof and a compound of Formula (DD), or a pharmaceutically acceptable sait thereof. In some embodiments, the viral infection is HCV.
BRIEF DESCRIPTION OF THE DRAWINGS [0012] Figure 1 illustrâtes four chromatograms, labeled A, B, C and D, from the results of a hépatocyte activation assay.
[0013] Figure 2 shows example HCV protease inhibitors.
[0014] Figure 3 shows example nucleoside HCV polymerase inhibitors.
[0015J Figure 4 shows example non-nucleoside HCV polymerase inhibitors.
[0016] Figure 5 shows example NS5A inhibitors.
|0017] Figure 6 shows example other antivirals.
[0018] Figures 7A-7I show example compounds of Formula (I).
[0019] Figures 8A-8I show example compounds of Formula (AA), and triphosphates thereof.
[0020] Figures 9Α-9Β show example compounds of Formula (BB).
[0021] Figure 10 shows Formula (DD).
DETAILED DESCRIPTION [0022] Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as is commonly understood by one of ordinary skill in the art. Ail patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of définitions for a term herein, those in this section prevail unless stated otherwise.
[00231 As used herein, any R group(s) such as, without limitation, R, R1, R2,
R3a, R3b, R4, R5, R5, R7, R8, R9, R'°, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R,a, R2A, R3a, Rîb, R4A, R5A, R6A R7a, R8A, R9a and R” represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two R groups are described as being taken together the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl or heterocycle. For example, without limitation, if Rla and R!b of an NRla Rlb group are indicated to be taken together, it means that they are covalently bonded to one another to form a ring:
—N
[0024] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted With one or more group(s) indivîdually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)aikyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thîocarbonyl, Ocarbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamîdo, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato,
isothîocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substîtuted amino group and a di-substituted amino group, and protected dérivatives thereof.
[0025] As used herein, “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Cj to C4 alkyl” ÎO group refers to all alkyl groups having from l to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these définitions is to be assumed.
[0026] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may hâve 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and 20 including 20 carbon atoms, although the présent définition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar désignations. By way of example only, “C1-C4 alkyl” indicates that there are 25 one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, îso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are în no way limited to, methyl, ethyl, propyl, isopropyl, butyl, îsobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.
« [0027] As used herem, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chaîn one or more double bonds. An alkenyl group may be unsubstituted or substituted.
[0028] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.
[0029] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typîcal cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0030] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring System that contains one or more double bonds in at Ieast one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pielectron System throughout ail the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
[0031] As used herein, “cycloalkynyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout ail the rings. When composed of two or more rings, the rings may be joined together in a fused fashion. A cycloalkynyl group may be unsubstituted or substituted.
[0032] As used herein, “aryl” refers to a carbocyclic (ail carbon) monocyclic or multicyclic aromatic ring system (including fused ring Systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout ail the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a Ce-Cu aryl group, a C6-C10 aryl group, or a Ce aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
© [0033] As used herein, “heteroaryl” refers to a monocyclic or multicyclîc aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can 5 vary. For example, the heteroaryl group can contain 4 to I4 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fiised ring Systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, 10 phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadîazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, îndazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, iso thiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purîne, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. A 15 heteroaryl group may be substituted or unsubstituted.
[0034] As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring System. A heterocycle may optionally contain one or more unsaturated bonds situated în such 20 a way, however, that a fully delocalized pi-electron system does not occur throughout ail the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the définition include oxo-systems and thiosystems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. 25 When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quatemized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4dioxane, 1,2-dioxolane, 1,3 -dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,330 oxathîolane, 1,3-dithîole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-1,216349 oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine. hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine A-Oxide, piperidine, piperazîne, pyrrolidine, pyrrolidone, 5 pyrrolidione, 4-piperidone, pyrazoline, pyrazolîdine, 2-oxopyrroIidine, tetrahydropyran, 4Hpyran, tetrahydrothîopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4methylenedioxyphenyl).
[0035] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not Iimited to benzyl, 2-phenylalkyl, 3-phenylalkyI, and naphthylalkyl.
[0036] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene 15 and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not Iimited to 2-thienylalkyl, 3-thîenylalkyI, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.
[0037] A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower 20 alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted.
Examples include but are not Iimited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yI)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (l,3-thiazinan-4-yl)methyl.
[0038] “Lower alkylene groups” are straight-chaîned -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples 25 include but are not Iimited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (CH2CH2CH2-), and butylène (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the définition of “substituted.” [0039] As used herein, “alkoxy” refers to the formula -OR wherein R îs an alkyl, 30 an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or a cycloalkynyl is defined as above. A
C non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, l -methylethoxy (isopropoxy), nbutoxy, îso-butoxy, sec-butoxy and tert-butoxy. An alkoxy may be substituted or unsubstituted.
[0040] As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl 5 connected, as substituents, via a carbonyl group. Examples include forrnyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.
[0041] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 10 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
[0042] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and trihaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2-fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
[0043] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 220 fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
[0044] As used herein, “aryloxÿ” and “arylthio” refers to RO- and RS-, in which R is an aryl, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or unsubstituted.
[0045] A “sulfenyl” group refers to an “-SR” group în which R can be hydrogen, 25 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, araikyl, or (heteroalicyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.
[0046] A “sulfïnyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.
Ο |0047] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
[0048] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalîcyclyl)alkyl, as defined herein. An O-carboxy may be substituted or unsubstituted.
[0049] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.
[0050] A “thiocarbonyl” group refers to a “-C(=S)R” group în which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
[0051] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein X is a halogen.
[0052] A “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(RA)-” group wherein X is a halogen and RA hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalîcyclyl)alkyl.
[0053] The term “amino” as used herein refers to a -NH2 group.
[0054] As used herein, the term “hydroxy” refers to a -OH group.
[0055] A “cyano” group refers to a “-CN” group.
[0056] The term “azido” as used herein refers to a ~N3 group.
[0057] An “isocyanato” group refers to a “-NCO” group.
[0058] A “thiocyanato” group refers to a “-CNS” group.
[0059] An “isothiocyanato” group refers to an “ -NCS” group.
[0060] A “mercapto” group refers to an “-SH” group.
[0061] A “carbonyl” group refers to a C=O group.
[0062] An “S-sulfonamido” group refers to a “~SO2N(RaRb)” group in which RA and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.
©
10063] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.
[0064] An “O-carbamyl” group refers to a “-OC(=O)N(RaRb)” group in which RA and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.
[0065] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.
[0066] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which Ra and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.
[0067] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.
[0068] A “C-ami do” group refers to a “-C(=O)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. A C-amido may be substituted or unsubstituted.
[0069] An “N-amido” group refers to a “RC(=O)N(RA)-” group in which R and Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. An N-amido may be substituted or unsubstituted.
C [0070] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Eléments, such as, fluorine, chlorine, bromine and iodine.
[0071} Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents présent. For example “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.
[0072] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, 10 recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).
[0073] The term “nucleoside” is used herein în its ordinary sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose moiety or modîfïed pentose moiety attached to a heterocyclic base or tautomer 15 thereof via a N-glycosidic bond, such as attached via the 9-position of a purine-base or the 1posîtion of a pyrimidine-base. Examples include, but are not limited to, a rîbonucleoside comprising a ribose moiety and a deoxyribonucleoside comprising a deoxyribose moiety. A modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a carbon has been replaced with a sulfur or an oxygen atom. A “nucleoside” 20 is a monomer that can have a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.
[0074] As used herein, the term “heterocyclic base” refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted 25 pentose moiety or modified pentose moiety. In some embodiments, the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidinebase and an optionally substituted triazole-base (for example, a 1,2,4-triazole). The term “purine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term “pyrimidine-base” is used herein in its 30 ordinary sense as understood by those skilled in the art, and includes its tautomers. A non16349
Ο limitmg list of optionally substituted punne-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, une acid and isoguanine. Examples of pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkyIcytosine (e.g., 5-methylcytosine). An example of an optionally substituted triazole-base is l,2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include dîaminopurine, 8-oxo-N6-aIkyladenine (e.g., 8-oxo-N6-methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenîne, N4,N4ethanocytosin, N6,Ns-ethano-2,6-diaminopurine, 5-halouracîl (e.g., 5-fluorouracil and 5bromouracil), pseudoisocytosîne, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos. 5,432,272 and 7,125,855, which are incorporated herein by reference for the limited purpose of disclosing additional heterocyclic bases. In some embodiments, a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).
[0075] The term “-N-iinked amino acid” refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group. When the amino acid is attached in an -N-linked amino acid, one of the hydrogens that is part of the main-chain amino or mono-substituted amino group is not présent and the amino acid is attached via the nitrogen. As used herein, the term “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, îsoleucine, leucine, lysine, méthionine, phenyialanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrullîne, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine. N-linked amino acids can be substituted or unsubstituted.
[0076] The term “-N-linked amino acid ester dérivative” refers to an amino acid in which a main-chain carboxylic acid group has been converted to an ester group. In some embodiments, the ester group has a formula selected from alkyI-O-C(=O)-, cycloalkyl-O16349
C(=O)-, aryl-O-C(=O)- and aryl(alkyl)-O-C(=O)-. A non-limiting list of ester groups include, methyl-O-C(=O)-, ethyl-O-C(=O)-, n-propyl-0-C(=0)-, isopropyl-O-C(-O)-, n-butyl-OC(=O)-, isobutyl-O-C(=O)-, tert-butyl-O-C(=O)-, neopentyl-0-C(=0)-, cyclopropyl-OC(=O)-, cyclobutyl-O-C(=O)-, cyclopentyl-O-C(=O)-, cyclohexyl-0-C(=0)-, phenyl-OC(=O)-, and benzyl-O-Ç(=O)-. N-linked amino acid ester dérivatives can be substituted or unsubstituted.
[0077] The terms “protecting group” and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molécule în order to prevent existing groups in the molécule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plénum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen în such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triîsopropylsilyl, t-butyldimethylsilyl, tri-fropropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsîlyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketai (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolanes, and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithioIane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityi (MMTr); 4,4’-dimethoxytrityl (DMTr); 4,4',4-trimethoxytrityl (TMTr); and those described herein).
[00781 “Leaving group” as used herein refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More
C specifically, în some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moîeties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, tosylates and halogens. Non-limîting characteristics 5 and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171; and Organic Chemistry, 5* ed., John McMurry (2000), pages 398 and 408; ail of which are încorporated herein by reference forthe limited purpose of disclosing characteristics and examples of leaving groups.
[0079] The term “pharmaceutically acceptable sait” refers to a sait of a compound that does not cause significant irritation to an organisai to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the sait is an acid addition sait of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or 15 hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatiç or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactîc, malic, tartaric, cîtric, ascorbîc, nicotînic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound 20 with a base to form a sait such as an ammonium sait, an alkali métal sait, such as a sodium or a potassium sait, an alkaline earth métal sait, such as a calcium or a magnésium sait, a sait of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, Cj-C? alkylamîne, cyclohexyl amine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
[0080] Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising* as used herein is synonymous with ‘including,’ ‘containing,’ or 30 ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited
Ο éléments or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ îs used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,* or ‘désirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utiîized in a particular embodiment of the invention. In addition, the term “comprising” is to be interpreted synonymously with the phrases having at least or including at least. When used in the context of a process, the term comprising means that the process includes at least the recited steps, but may include additional 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, but may also include additional features or components. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be présent in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.
[0081] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefînite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the fonctions of several items recited in the ciaims. The mere fact that certain measures are recited in mutually different dépendent ciaims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the ciaims should not be construed as limiting the scope.
[0082] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center j
may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoîsomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generatîng geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
[0083] Likewise, it is understood that, în any compound described, ail tautomeric forms are also intended to be included. For example ail tautomers of a phosphate and a phosphorothioate groups are intended to be included.
Examples of tautomers of a
O
II HS—p—O i V
OH A
ΙΟ phosphorothioate include the following:
OH
I s=p—q 1 V and OH . Furthermore, ail tautomers of heterocyclic bases known în the art are intended to be included, including tautomers of naturel and non-naturel purine-bases and pyrimidine-bases.
[0084] It is to be understood that where compounds disclosed herein hâve unfilled valencies, then the valencîes are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
[0085] It is understood that the compounds described herein can be labeled îsotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be présent in the compound. At any position of the compound that a hydrogen atom may be présent, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses ail potential isotopic forms unless the context clearly dictâtes otherwise.
© [0086] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvatés, and hydrates. In some embodiments, the compounds described herein exist in solyated forms with pharmaceutically acceptable solvents such as water, éthanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvatés contain either stoîchiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, éthanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
[0087] Where a range of values is provided, it is understood that the upper and lower Iimit, and each întervening value between the upper and lower Iimit of the range is encompassed within the embodiments.
[0088] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable sait thereof:
R4—
R6
-R9
R8 (I) wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R1 can be selected from O',· OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R2 can be selected from an optionally substituted aryl, an optionally
R21O—P— O—P substituted heteroaryl, an optionally substituted heterocyclyl and
©
T A AA Al wherein R , R and R can be independently absent or hydrogen, and n can be 0 or 1;
provided that when R1 is O' or OH, then R2 is
independently selected from hydrogen, deuterium, an optionally substituted Ci^ alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted Ci.6 haloalkyl and aryl(Ci.6 alkyl); or R3a and R3b can be taken together to form an optionally substituted C3.6 cycloalkyl; R4 can be selected from hydrogen, azîdo, an optionally substituted C).6 alkyl, an optionally substituted C2_6 alkenyl and an optionally substituted C2-6 alkynyl; R5 can be selected from hydrogen, halogen, azîdo, cyano, an optionally substituted Ci-6 alkyl, -OR10 and -OC(=O)Rn; R6 can be selected from hydrogen, halogen, azîdo, cyano, an optionally substituted Ck6 alkyl, -OR12 and -OC(=O)R13; R7 can be selected from hydrogen, halogen, azîdo, cyano, an optionally substituted C1-6 alkyl, -OR14 and -OC(=O)R15; or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, azîdo, cyano, an optionally substituted Cpe alkyl, -OR and -OC(=O)R17; R9 can be selected from hydrogen, azido, cyano, an optionally substituted Ci.6 alkyl and -OR18; R]0, R12, R14, R16 and R18 can be independently selected from hydrogen and an optionally substituted CYs alkyl; and R11, R13, R15 and R17 can be independently selected from an optionally substituted Cj.6 alkyl and an optionally substituted C3.6 cycloalkyl; with the proviso that when R3a, R3b, R4, Rs, R7, R8 and R9 are ail hydrogen, then R6 cannot be azido.
[0089] With respect to R2, in some embodiments, R2 can be an optionally substituted heteroaryl. In other embodiments, R2 can be an optionally substituted heterocyclyl. In still other embodiments, R2 can be an optionally substituted aryl. For example, R2 can be an optionally substituted phenyl or an optionally substituted naphthyl. If R2 is a substituted phenyl or a substituted naphthyl, the phenyl ring and the naphthyl ring(s) can be substituted one or more times. Suitable substituents that can be présent on optionally substituted phenyl and an optionally substituted naphthyl include electron-donating groups and electron-withdrawîng groups. In some embodiments, R2 can be a para-substituted phenyl. In other embodiment, R2 can be an unsubstituted phenyl or an unsubstituted
il.J.
Ο naphthyl.
* 2
In yet still other embodiments, R can be
wherein R19,
R20 and R21 can be independently absent or hydrogen, and n can be 0 or 1. In some embodiments, n can be 0. In other embodiments, n can be 1. Those skilled in the art understand when n is 0, R2 can- be an a-thiodiphosphate. Similarly, those skilled in the art understand when n is 1, R2 can be an a-thiotriphosphate. In some embodiments, at least one of R19, R20 and R21 can be absent. In other embodiments, at least one of R19, R20 and R21 can be hydrogen. In some embodiments, R and R can be absent. In other embodiments, R
Ί 1 10 OA A 1 and R can be hydrogen. In some embodiments, R , R and R can be absent. In some embodiments, R19, R20 and R21 can be hydrogen. Those skilled in the art understand that when any of R19, R20 and R21 are absent the oxygen atom to which R19, R20 and R21 are
AA associated with can hâve a négative charge. For example, when R is absent, the oxygen atom to which R20 is associated with can be O'. Depending upon the substituents attached to each phosphorus atoms, one or more the phosphorus atoms can be a chiral center. For example, when n is 1, the alpha-phosphorus (the phosphorus nearest to the pentose ring) can be a chiral center. In some embodiments, the alpha-phosphorus can be a (R)-stereocenter. In other embodiments, the alpha-phosphorus can be a (S)-stereocenter.
[0090] In some embodiments, R1 can be absent. In other embodiments, R1 can be hydrogen. In still other embodiments, R1 can be an optionally substituted N-linked a-amino acid. In yet still other embodiments, R1 can be an optionally substituted N-linked a-amino acid ester derivative. Various amino acids and amino acid ester dérivatives can be used, including those described herein. Suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and valine. Additional suitable amino acids include, but are not limited to, alphaethyl-glycine, alpha-propyl-glycine and beta-alanine. Examples of an N-linked amino acid ester dérivatives include, but are not limited to, an ester dérivatives of any of the following amino acids: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine,
C threonine, tryptophan and valine. Additional examples of N-Iinked amino acid ester dérivatives include, but are not limited to, an ester dérivative of any of the following amino acids: alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine.
[0091] In an embodiment, R1 can be an ester dérivative of alanine. In an embodiment, R1 can be selected from alanine methyl ester, alanine ethyl ester, alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester dérivative can be in the Lconfiguration. In other embodiments, the optionally substituted N-linked amino acid or the optionally substituted N-linked amino acid ester dérivative can be in the D-configuration.
[0092] In some embodiments, when R1 is an optionally substituted N-linked aamino acid or an optionally substituted N-linked α-amino acid ester dérivative, then R can be selected from optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl. In some embodiments, when R1 is an optionally substituted N-linked α-amino acid ester dérivative, then R can be an optionally substituted aryl. In other embodiments, when R1 is an optionally substituted N-linked α-amino acid ester dérivative, then R2 can be an optionally substituted heteroaryl. In still other embodiments, when R1 is an optionally substituted N-linked α-amino acid ester dérivative, then R2 can be an optionally substituted heterocyclyl.
R22O r23 r24 i ur ππ ς [0093] In some embodiments, R can hâve the structure ί wherein R22 can be selected from hydrogen, an optionally substituted Ci.g-alkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6 alkyl) and an optionally substituted Ci.6 haloalkyl; and R23 can be selected from hydrogen, an optionally substituted C].6 alkyl, an optionally substituted Ci_6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_6 alkyl); and R24 can be hydrogen or an optionally substituted C]^-alkyl; or R23 and R24 can be taken together to form an optionally substituted C3.6 cycloalkyl.
C 24
23 [0094] When R has the structure shown above, R can be an optionally substituted Ci-6-alkyl. Examples of suitable optionally substituted CY-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straîght-chained), and hexyi (branched and straight5 phained). When R23 is substituted, R23 can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiment, R can be an unsubstituted Ci.6-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, pentyl (branched and straight-chained), and hexyi (branched and straîght-chained). In an embodiment, R can be methyl.
[0095] As to R22, in some embodiments, R22 can be an optionally substituted Ci_6 alkyl. Examples of optionally substituted CY-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyi (branched and straight-chained). In some embodiments, R can be methyl or isopropyl. In some embodiments, R can be ethyl or neopentyl. In other embodiments, R22 can be an optionally substituted C3.6 cycloalkyl. Examples of optionally substituted C3.6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R22 can be an optionally substituted cyclohexyl. In still other embodiments, R can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R22 can be an optionally substituted aryl(Ci_6 alkyl). In some embodiments, R can be an optionally substituted benzyl. In some embodiments, R22 can be an optionally substituted C]. 6 haloalkyl, for example, CF3.
[0096] In some embodiments, R24 can be hydrogen. In other embodiments, R24 can be an optionally substituted CY-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R24 can be methyl. In some embodiments, R23 and R24 can be taken together to form an optionally substituted C3.6 cycloalkyl. Examples of optionally substituted C3.6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R23 and R24, the carbon to which R23 and R24 are attached may be a chiral center.
In some embodiment, the carbon to which R23 and R24 are attached may be a (R)-chiral center. In other embodiments, the carbon to which R23 and R24 are attached may be a (S)chiral center.
J0097]
As example of a suitable groups include the following:
©
[0098J The substituents attached to the 5’-position of a compound of Formula (I) can vary. In some embodiments, R3a and Rîb can be the same. In other embodiments, R3a and R3b can be different. In some embodiments, R3a and R3b can be both hydrogen. In some embodiments, at least one of R3a and R3b can be an optionally substituted Ci.6-alkyl; and the other of R3a and R3b can be hydrogen. Examples of suitable optionally substituted C].6 alkyls include optionally substituted variants ofthe following: methyl, ethyl, n-propyl, isopropyl, n butyl, isobutyl, tert-butyl, pentyl (branched and straight-chaîned), and hexyl (branched and straight-chained). In an embodiment, at least one of R3a and R3b can be methyl, and the other of R3a and Rïb can be hydrogen. In other embodiments, at least one of R3a and R3b can be an optionally substituted Ci_6-haloalkyl, and the other of R3a and R3b can be hydrogen. One example of a suitable optionally substituted CY-haloalkyl îs CF3. In other still embodiments, R3a and R3b can be taken together to form an optionally substituted Cj_6 cycloalkyl. When the substituents attached to the 5’-carbon make the 5’-carbon chiral, in some embodiments, the
5’-carbon can be a (R)-stereocenter. In other embodiments, the 5’-carbon can be an (S) stereocenter.
[0099J The substituents attached to the 4’-carbon can vary. In some embodiments, R4 can be hydrogen. In other embodiments, R4 can be azido. In still other embodiments, R4 can be an optionally substituted Ci_6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some
C embodiments, R4 can be an optionally substituted CJ alkenyl. In some embodiments, R can be an optionally substituted CJ alkynyl.
[0100] The substituents attached to the 2’-carbon and the 3’-carbon can also vary. In some embodiments, R5 can be hydrogen. In other embodiments, R5 can be halogen. In still other embodiments, R5 can be azido. In yet still other embodiments, Rs can be cyano. In some embodiments, R5 can be an optionally substituted Ci-6 alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In other embodiments, R5 can be -OR10, wherein R10 can be hydrogen. In still other embodiments, R5 can be -OR10, wherein R10 can be an optionally substituted Ci_6 alkyl. In yet still other embodiments, R5 can be -OC(=O)Rn, wherein R11 can be an optionally substituted Ci.6 alkyl or an optionally substituted C3.6 cycloalkyl. Examples of suitable CJ alkyls and C3_6 cycloaikyls are described herein.
[0101] In some embodiments, R6 can be hydrogen. In other embodiments, R6 can be halogen. In still other embodiments, R6 can be azido. In yet still other embodiments, R6 can be cyano. In some embodiments, R6 can be an optionally substituted CJ alkyl. In other embodiments, R6 can be -OR12, wherein R12 can be hydrogen. In still other embodiments, R6 can be -OR12, wherein R12 can be an optionally substituted CJ alkyl. A non-limiting list of examples of R6 being -OR12, wherein R12 can be an optionally substituted CJ alkyl are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched). In yet still other embodiments, R0 can be -OC(=O)R13, wherein RIJ can be an optionally substituted CJ alkyl or an optionally substituted C3-6 cycloalkyl. Examples of suitable optionally substituted C1.6 alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl pentyl (branched and straight-chained), and hexyl (branched and straight-chained). Examples of suitable optionally substituted CJ cycloaikyls include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0102] In some embodiments, R7 can be hydrogen. In other embodiments, R7 can be halogen. In still other embodiments, R7 can be azido. In yet still other embodiments, R7
G can be cyano. In some embodiments, R7 can be an optionally substituted Ci_6 alkyl. In other embodiments, R7 can be -OR14. In an embodiment, when R14 is hydrogen, R7 can be a hydroxy group. In still other embodiments, when R14 is an optionally substituted Ci-e alkyl, R7 can be an optionally substituted Cj.6 alkoxy. Examples, of R7 being -OR14, wherein R14 5 can be an optionally substituted Ct,6 alkyl include, but are not limited to, are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched). In yet still other embodiments, R can be -OC(=O)R15, wherein R15 can be an optionally substituted CY alkyl, such as optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straightchained). In some embodiments, R7 can be -OC(=O)R15, wherein R15 can be an optionally substituted C3.6 cycloalkyl [0103] In some embodiments, R8 can be hydrogen. In other embodiments, R8 can be halogen. In still other embodiments, R can be azido. In yet still other embodiments, R 15 can be cyano. In some embodiments, R8 can be -OR16. When R16 is hydrogen, R8 can be hydroxy. Altematively, when R16 is an optionally substituted C]_6 alkyl, R8 can be an optionally substituted CY alkoxy. Suitable alkoxy groups are described herein. In other embodiments, R can be an optionally substituted Ci.6 alkyl. In still other embodiments, R can be -OC(=O)R17 in which R17 is an optionally substituted Ci.ή alkyl. In yet still other 20 embodiments, R8 can be -OC(=O)R17 in which R17 is an optionally substituted C3.6 cycloalkyl. Ex amples of suitable Ci-6 alkyl and C3.6 cycloalkyl groups are described herein.
[0104] In some embodiments, R6 and R7 can both be hydroxy. In still other embodiments, R6 and R7 can both be both oxygen atoms and linked together by a carbonyl group, for example, -O-C(=O)-O-, In some embodiments, at least one of R and R can be a 25 halogen. In some embodiments, R7 and R8 can both be a halogen. In other embodiments, R7 can be a halogen and R8 can be an optionally substituted Cj.$ alkyl, such as those described herein. In other embodiments, R7 can be hydrogen and R8 can be a halogen. In still other embodiments, at least one of R6 and R7 can be a hydroxy and R8 can be an optionally substituted Ci_6 alkyl. In yet still other embodiments, R6 can be hydroxy, R7 can be hydroxy, 30 H or halogen, and R8 can be an optionally substituted CY alkyl. In some embodiments, R3a,
R , R4, R5 and R9 can be hydrogen in any of the embodiments described in this paragraph. In some embodiments, B1 can be an optionally substituted adenine, an optionally substituted guanine, and optionally substituted thymine, optionally substituted cytosine, or an optionally substituted uracil in any of the embodiments described in this paragraph.
[0105] In some embodiments, R9 can be hydrogen. In other embodiments, R9 can be azido. In still other embodiments, R9 can be cyano. In yet still other embodiments, R9 can be an optionally substituted Ci.6 alkyl, such as those described herein. In some embodiments, R9 can be -OR18. In some embodiments, when R9 is -OR18, R9 can be a hydroxy group. In other embodiments, when R9 is -OR18, R9 can be an optionally substituted Ci.6 alkoxy. Examples of optionally substituted Ci.â alkoxy include the following: methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straightchained), and hexoxy (branched and straight-chained).
[0106] Various optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more of the amine and/or amino groups may be protected with a suitable protecting group. For example, an amino group may be protected by transforming the amine and/or amino group to an amide or a carbamate. In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can hâve one of the following structures:
C wherein: can be selected from hydrogen, halogen and NHRJ2, wherein RJ2 can be selected from hydrogen, -CYOjR^ and -C^OjOR12; R82 can be halogen or NHRY wherein RW2 is selected from hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3.s cycloalkyl, -C(=O)RM2 and 5 C(=O)ORN2; RC2 can be hydrogen or NHR02, wherein R02 can be selected from hydrogen, C(=O)RP2 and -C>O)ORQ2; RD2 can be selected from hydrogen, halogen, an optionally substituted Ci.6 alkyl, an optionally substituted C2_6 alkenyl and an optionally substituted C2-6 alkynyl; RE2 can be selected from hydrogen, an optionally substituted Ci_5 alkyl, an optionally substituted C3.8 cycloalkyl, -C(=O)RR2 and -C(=O)ORS2; R1 2 can be selected from hydrogen, 10 halogen, an optionally substituted Cm alkyl, an optionally substituted C2.& alkenyl and an optionally substituted C2-6 alkynyl; Y2 can be N (nitrogen) or CR12, wherein R12 can be selected from hydrogen, halogen, an optionally substituted C[.6-alkyl, an optionally substituted C2-6-alkenyl and an optionally substituted C2_6-alkynyl; R02 can be an optionally substituted Cm alkyl; RH2 can be hydrogen or NHR12, wherein R72 can be independently 15 selected from hydrogen, -C(=O)RU2 and -C(=O)ORV2, and R142, R^, RM2, RN2, RP2, RQ2 R*2,
RS2,RU2 and RV2 can be independently selected from Cm alkyl, Cm alkenyl, C2.6 alkynyl, C3.
cycloalkyl, Cm cycloalkenyl, Cm cycloalkynyl, Ce-io aryl, heteroaryl, heteroalicyclyl, aryl(Cj_6 alkyl), heteroaryl(CM alkyl) and heteroalicyclyl(CM alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with 20 substituents selected from the list of substituents provided for the définition of “substituted.”
Suitable optionally substituted Cm alkyl groups that can be présent on an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups are described herein, and include, optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, îsobutyl, tert-butyl, pentyl 25 (branched and straight-chained), and hexyl (branched and straight-chained).
[0107] In some embodiments, B1 can be selected from adenine, guanine, thymine, cytosine and uracil. In some embodiments, RB2 can be NH2. In other embodiments, RE2 can
be hydrogen. In some embodiments, B1
In some embodiments, B1 can be
NHRW2
In some embodiments, B1 can
In some
B1 can be embodiments, when R2 is a substituted or, unsubstituted phenyl, then R1 cannot be
In other embodiments, when R2 is a substituted or unsubstituted
ο
In still other embodiments, when R2 is a phenyl, then R1 carmot be substituted or unsubstituted phenyl and R1 is
then at least one of R5 and
R6 cannot be hydroxy.
[0108] In some embodiments, when R1 is O or OH, then R2 cannot be
In some embodiments, at least one of Rîa and R3b cannot be hydrogen. In some embodiments, R4 is not azido. In some embodiments, when R4 is not azido, then R7 and R8 are not both halogen. In some embodiments, when R4 îs azido, then B1 is not an optionally substituted uracil, optionally substituted uracil with one or more protected amino groups, an optionally substituted cytosine or optionally substituted cytosine with one or more protected amino groups. In some embodiments, R6 cannot be azido. In some embodiments, when R is a methyl ester of glycine, alanine, valine, or phenylalanine; R is pchlorophenyl or p-nitrophenyl; B1 is thymine; and R3a, R3b, R4, R5, R7, R8, and R9 are ali hydrogen; then R cannot be azido. In some embodiments, at least one of R and R cannot be hydroxy. For example, R6 cannot be hydroxy, R7 cannot be hydroxy, or both of R6 and R7 cannot be hydroxy.
[0109] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable sait thereof, wherein: B1 can be an optionally substituted heterocyclic base as described in paragraph [0106]; R1 can be selected from O*, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R2 can be selected from an optionally substituted aryl and n, wherein R19, R20 and R21 can be independently absent or hydrogen,
pL
OR19
R21o—P—
I 20 , 0R and n can be 0 or 1 ; provided that when R is 0’ or OH, then R is
R3a and R3b can be hydrogen; R4 can be hydrogen; R5 can be selected from hydrogen, halogen, an optionally substituted Ci-s alkyl and -OR10; R6 can be selected from hydrogen, halogen, optionally substituted Ci.6 alkyl, -OR12 and -OC(=O)R13; R7 can be selected from 5 hydrogen, halogen, azido, cyano, an optionally substituted Ci.6 alkyl, -OR14 and -OC(=O)R15;
or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, an optionally substituted Ci_6 alkyl and -OR16; R9 can be hydrogen; R10, R12, R14 and R16 can be independently selected from hydrogen and an optionally substituted C].e alkyl; and R13 and R15 can be independently selected from an 10 optionally substituted Cj_6 alkyl and an optionally substituted Cj-e cycloalkyl.
(0110] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable sait thereof, wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group
R1 can be selected from O', OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R2 can be selected from an optionally substituted aryl and
U 1
P---Q —p-OR20 OR19 , wherein R19, R20 and R21 can be independently absent or hydrogen,
C . , OR20 OR19 and η can be 0 or 1 ; provided that when R is O or OH, then R is L Jn;
R3a and R3b can be hydrogen; R4 can be hydrogen; R5 can be selected from hydrogen, halogen, an optionally substituted Cj.6 alkyl and -OR10; R5 can be selected frotn hydrogen, halogen, optionally substituted Ci_6 alkyl, -OR12 and -OC(=O)R13; R7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cj.g alkyl, -OR14 and -OC(=O)R15; or R and R can be both oxygen atoms and linked together by a carbonyl group; R can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl and -OR16; R9 can be hydrogen; R10, R12, R14 and R16 can be independently selected from hydrogen and an optionally substituted Ci_6 alkyl; and R13 and R15 can be independently selected from an optionally substituted Ci-e alkyl and an optionally substituted C3.6 cycloalkyl.
[OUI] In some embodiments, Formula (I) can be a compound of Formula (la), wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group selected from cytosine, uridine, thymidine, guanine and adenine; R1 can be selected from O, OH, and an optionally substituted N-linked amino acid ester dérivative of alanine, valine, or leucme; R can be selected from an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted pyridyl, an optionally substituted quinolyl, and ? P—
OR19 n, wherein R19, R20 and R21 independently can be hydrogen or absent, and n can be 0 or 1; provided that when R1
R3a and R3b can be hydrogen; R4 can be hydrogen; R5 can be hydrogen; R6 can be -OR12 or -OC(=O)R13; R7 can be selected from halogen, -OR14 and -OC(=O)R15; R8 can be an optionally substituted Ci-e alkyl; R9 can be hydrogen; R12 and R14 can be independently hydrogen or an optionally substituted C]_6 alkyl; and R13 and R15 can be independently an optionally substituted Ci_6 alkyl.
[0112) Some embodiments relate to a compound of Formula (I) or a pharmaceutically acceptable sait thereof, wherein: B1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R1 can be selected from O', OH, an optionally substituted N-linked amino acid and an 5 optionally substituted N-linked amino acid ester dérivative; R2 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and n, wherein R19, R20 and R21 can be independently l 2 * absent or hydrogen, and n can be 0 or 1; provided that when R is O' or OH, then R îs
R19 | n |
R3a and R3b can be independently selected from hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2.6 alkynyl, an optionally substituted Ci_e haloalkyl and aryl(Cj.6 alkyl); or R3a and R3b can be taken together to form an optionally substituted C3_6 cycloalkyl; R4 can be selected from hydrogen, azido, an optionally substituted Ct_6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2.6 alkynyl; R5 can be selected from hydrogen, 15 halogen, azido, cyano, an optionally substituted C[.6 alkyl, -OR10 and -OC(=O)R11; R6 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C]_6 alkyl, -OR and -OC(=O)R13; R7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C[_6 alkyl, -OR14 and -OC(=O)R15; or R6 and R7 can be both oxygen atoms and linked together by a carbonyl group; R8 can be selected from hydrogen, halogen, azido, 20 cyano, an optionally substituted Çi-g alkyl, -OR16 and -OC(=O)R17; R9 can be selected from hydrogen, azido, cyano, an optionally substituted Ci_e alkyl and -OR18; R10, R12, R14, R16 and R18 can be independently selected from hydrogen and an optionally substituted C 1.6 alkyl; and R11, R13, R15 and R17 can be independently an optionally substituted Ciâ alkyl and an optionally substituted C3_6 cycloalkyl.
(0113] In some embodiments, a compound of Formula (I) can be a single diastereomer. In other embodiments, a compound of Formula (I) can be a mixture of
diastereomers. In some embodiments, a compound of Formula (I) can be a l:l mixture of two diastereomers. In some embodiments, a compound of Formula (I) can be diasteriometrically enriched (for example, one diastereomer can be présent at a concentration of > 55%, = 75%, = 80%, = 90%, = 95%, = 98%, or = 99% as compared to the total concentration of the other diastereomers). , l 2 [0114] Some embodiments of R and R of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, are provided in Table 1. Tables 2-4 provide the structures of the variables bb01-bbl2, aaOI-aall and es01-es!4, respectively. For example, the first entry in Table 1 is “bb01,aa01,es01,” corresponds to a compound of Formula (I),
1—ζ / H3C^ wherein R2 X— f and R1 is θ
Table 1
R2,R‘,Rtt | R2,R’,Ra | R2,R’,Ra | r2,r\r« | |
bb01,aa01,es01 | bb03,aa01,es01 | bb05,aa01,es01 | bb07,aa01,es0l | bb09,aa0l,es01 |
bb01,aa01,es02 | bbO3,aaOl,esO2 | bbO5,aaOl,esO2 | bbO7,aaOl,esO2 | bb09,aa01,es02 |
bb01,aa01,es03 | bbO3,aaOl,esO3 | bbO5,aaOl,esO3 | bb07,aa01,es03 | bbO9,aaOl,esO3 |
bb01,aaûl,es04 | bbO3,aaOl,esO4 | bb05,aa01,es04 | bb07,aa01,es04 | bb09,aa01,es04 |
bb01,aa01,es05 | bb03,aa01,es05 | bb05,aa01,es05 | bbO7,aaOl,esO5 | bbO9,aaOl,esO5 |
bb01,aa01,es06 | bb03,aa01,es06 | bb05,aa01,es06 | bb07,aa01,es06 | bb09,aa01,es06 |
bb01,aa01,es07 | bb03,aa01,es07 | bb05,aa01,es07 | bbO7,aaOI,esO7 | bb09,aa01,es07 |
bb01,aa01,es08 | bbO3,aaOl,esO8 | bb05,aa01,es08 | bb07,aa01,es08 | bb09,aa01,es08 |
bb01,aa01,es09 | bbO3,aaOl,esO9 | bb05,aa01,es09 | bb07,aa01,es09 | bb09,aa01,es09 |
bb01,aa01,esl0 | bb03,aa01,esI0 | bb05,aa01,esl0 | bb07,aa01,esl0 | bb09,aa01,esl0 |
bb01,aa01,esll | bb03,aa01,esl 1 | bb05,aa01,esl 1 | bbO7,aaÛl,esll | bb09,aa01,esl 1 |
bb01,aa01,esl2 | bb03,aa01,esl2 | bb05,aa01,esI2 | bb07,aa01,esl2 | bb09,aa01,esl2 |
bb01,aa02,es01 | bb03,aa02,es01 | bb05,aa02,es01 | bb07,aa02,es01 | bb09,aa02,es01 |
bbOI,aaO2,esO2 | bb03,aa02,es02 | bb05,aa02,es02 | bb07,aa02,es02 | bb09,aa02,es02 |
bbOl,aaO2,esO3 | 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 | bbO3,aaO2,esO6 | bbO5,aaO2,esO6 | bbO7,aaO2,esO6 | bbO9,aaO2,esO6 |
bb01,aa02,es07 | bbO3,aaO2,esO7 | bbO5,aaO2,esO7 | bbO7,aaO2,esO7 | bb09,aa02,es07 |
bb01,aa02,es08 | bbO3,aaO2,esO8 | bb05,aa02,es08 | bb07,aa02,es08 | bb09,aa02,es08 |
bb01,aa02,es09 | bbO3,aaO2,esO9 | bb05,aa02,es09 | bb07,aa02,es09 | bb09,aa02,es09 |
bb01,aa02,esI0 | bbO3,aaO2,eslO | bb05,aa02,esl0 | bb07,aa02,esl0 | bb09,aa02,esl0 |
bb01,aa02,esl 1 | bb03,aa02,esl 1 | bb05,aa02,esll | bb07,aa02,esl 1 | bb09,aa02,esl 1 |
R2,R’,Ra | R2,R’,Ra | R2,R’,Ra | R2,R’,Ra | |
bb01,aa02,esl2 | bb03,aa02,esl2 | bb05,aa02,esl2 | bb07,aa02sesl2 | bb09,aa02,esl2 |
bbOl,aaO3,esOl | bb03,aa03,es0l | bb05,aa03,es0l | bbO7,aaO3,esOl | bb09,aa03,es01 |
bbO l,aa03,es02 | bb03,aa03,es02 | bb05îaa03,es02 | bbO7,aaO3,esO2 | bb09,aa03?es02 |
bbOl,aaO3,esO3 | bb03,aa03,es03 | bbO5,aaO3,esO3 ' | bbO7,aaO3,esO3 | bbÛ9,aaO3,esO3 |
bb0l,aa03,es04 | bbO3,aaO3,esO4 | bbO5,aaO3,esO4 | bbO7,aaO3,esO4 | bb09,aa03,es04 |
bbOl,aaO3,esO5 | bbO3,aaO3,esO5 | bbO5,aaO3,esO5 | bbO7,aaO3,esO5 | bb09,aa03,es05 |
bbOl,aaO3,esO6 | bbO3,aaO3,esO6 | bb05,aa03,es06 | bbO7,aaO3,esO6 | bb09,aa03,es06 |
bbOl,aaO3,esO7 | bbO3,aaO3,esO7 | bb05,aa03,es07 | bbO7,aaO3,esO7 | bbO9,aaO3,esO7 |
bbOl,aaO3,esO8 | bbO3,aaO3,esO8 | bb05,aa03,es08 | bbO7,aaO3,esO8 | bbO9,aaO3,esO8 |
bb0l,aa03,es09 | bb03,aa03,es09 | bb05,aa03,es09 | bb07,aa03,es09 | bbO9,aaO3,esO9 |
bb0l,aa03,esl0 | bbO3,aaO3,eslO | bb05faa03,esl0 | bb07,aa03,es!0 | bb09,aa03,esl0 |
bbOl,aaO3,esl l | bbO3,aaO3,esl l | bbO5,aaO3,esll | bbO7,aaO3,esl 1 | bb09,aa03,esll |
bbOl,aaO3,esl2 | bbO3,aaO3,esl2 | bbO5,aa03,esl2 | bbO7,aaO3,esl2 | bbO9,aaO3,es!2 |
bb0l,aa04,es0l | bb03,aa04,es01 | bb05,aa04,es0l | bb07,aa04,es01 | bb09,aa04,es01 |
bb01,aa04,es02 | bb03,aa04,es02 | bb05,aa04,es02 | bb07,aa04fes02 | bbO9,aaO4,esO2 |
bb0lfaa04,es03 | bb03,aa04,es03 | bb05,aa04,es03 | bb07,aa04,es03 | bb09,aa04,es03 |
bbOl,aaO4,esO4 | bb03,aa04,es04 | bb05faa04,es04 | bb07,aa04,es04 | bb09}aa04,es04 |
bb0l,aa04,es05 | bbO3,aaO4,esO5 | bb05,aa04,es05 | bb07,aa04,es05 | bb09,aa04,es05 |
bbO l ,aa04,es06 | bbO3,aaO4,esO6 | bb05,aa04,es06 | bb07,aa04,es06 | bb09,aa04,es06 |
bb0l,aa04,es07 | bb03,aa04,es07 | bb05,aa04,es07 | bb07,aa04,es07 | bb09,aa04,es07 |
bb0l,aa04,es08 | bb03faa04,es08 | bb05,aa04,es08 | bb07,aa04,es08 | bb09 ,aaO4,esÛ8 |
bb0l,aa04,es09 | bb03,aa04,es09 | bb05,aa04,es09 | bb07,aa04,es09 | bbO9,aaO4,esO9 |
bbOfoaaiMjeslO | bbO3,aaO4,eslO | bb05,aa04,esl0 | bb07,aa04,esl0 | bb09,aa04,esl0 |
bb0l,aa04,esl l | bb03,aa04,esl l | bb05,aa04,esl l | bbO7,aaO4,esl 1 | bbO9,aaO4,esl 1 |
bb0l,aa04,esl2 | bb03,aa04,esl2 | bbO5,aaO4,esl2 | bb07,aa04,esl2 | bb09,aa04,esl2 |
bbOl,aaO5,esOl | bb03,aa05,es0l | bbO5,aaO5,esOl | bb07,aa05,es01 | bb09,aa05,es01 |
bb01,aa05,es02 | bbO3,aaO5,esO2 | bbO5,aaO5,esO2 | bb07,aa05,es02 | bbO9,aaO5,esO2 |
bbOl,aaO5,esO3 | bbO3,aaO5,esO3 | bb05,aa05,es03 | bb07,aa05,es03 | bbO9,aaO5,esO3 |
bb01,aa05,es04 | bbO3,aaO5,esO4 | bbO5,aaO5,esO4 | bb07,aa05,es04 | bb09,aa05,es04 |
bbO],aaO5,esO5 | bbO3,aaO5,esO5 | bb05,aa05,es05 | bbO7,aaO5,esO5 | bb09,aa05,es05 |
bb0l,aa05,es06 | bb03,aa05,es06 | bb05,aa05?es06 | bb07,aa05,es06 | bbO9,aaO5,esO6 |
bbOl ,aa05,es07 | bbO3,aaO5,esO7 | bb05,aa05,es07 | bb07,aa05,es07 | bbO9,aaO5,esO7 |
bbOl,aaO5,esO8 | bb03,aa05,es08 | bbO5,aaO5,esO8 | bb07,aa05,es08 | bbO9,aaO5,esO8 |
bb0l,aa05,es09 | bbO3îaaO5,esO9 | bbO5,aaO5,esO9 | bbO7,aaO5,esO9 | bb09,aa05,es09 |
bbOl,aaO5,eslO | bbO3,aaO5,eslO | bb05,aa05,esl0 | bbO7,aaO5,eslO | bb09,aa05,esl0 |
bb01,aa05,esll | bbO3,aaO5,esl l | bbO5,aaO5,esl 1 | bbO7,aaO5,esl ί | bbÛ9,aaO5,esll |
bb0l,aa05,esl2 | bb03,aa05,esl2 | bb05,aa05,esl2 | bbO7faaO5fesl2 | bb09,aa05,esl2 |
bb0l,aa06,es0l | bbO3,aaO6,esOl | bbO5,aaO6,esOl | bbO7,aaO6,esOl | bb09,aa06,es01 |
bb0l,aa06,es02 | bb03,aa06,es02 | bb05,aa06,es02 | bb07,aa06,es02 | bb09,aa06,es02 |
bb0l,aa06,es03 | bb03,aa06,es03 | bb05,aa06,es03 | bbO7,aaO6,esO3 | bb09,aa06,es03 |
bb0l,aa06,es04 | bb03,aa06,es04 | bb05,aa06,es04 | bb07,aa06,es04 | bb09,aa06,es04 |
bbOl,aaO6,esO5 | bb03,aa06,es05 | bb05,aa06,es05 | bb07,aa06,es05 | bbO9,aaO6,esO5 |
bb0l,aa06,es06 | bbO3,aaO6,esO6 | bb05,aa06,es06 | bb07îaa06îes06 | bbO9,aaO6,esO6 |
R^R^Ra | R2,R\Ra | R^R^Ra | r2,r\r« | R2,R\Ra |
bb01,aa06,es07 | bb03,aa06,es07 | bb05,aa06,es07 | bbO7,aaO6,esO7 | bb09.aa06.es07 |
bbOl.aaO6.esO8 | bb03.aa06.es08 | bb05.aa06.es08 | bbO7,aaO6,esO8 | bb09,aa06,es08 |
bb01,aa06,es09 | bb03.aa06.es09 | bb05,aa06,es09 | bb07.aa06.es09 | bb09,aa06,es09 |
bb01,aa06,esl0 | bbO3.aaO6.eslO | bb05,aa06,esl0 | bb07.aa06.es 10 | bbO9,aaO6,eslO |
bbOl,aaO6,esl I | bbO3,aaO6,esl 1 | bbO5 .aa06.es 1 1 | bb07.aa06.es 1 1 | bbO9,aaO6,esl 1 |
bb01.aa06.es 12 | bbO3,aa06.es! 2 | bb05,aa06,esl2 | bb07.aa06.es 12 | bb09.aa06.es 12 |
bb0l,aa07,es0l | bb03.aa07.es01 | bbO5.aaO7.esOl | bb07.aa07.es01 | bb09.aa07.es01 |
bb01,aa07,es02 | bb03.aa07.es02 | bb05.aa07.es02 | bb07.aa07.es02 | bbO9,aaO7,esO2 |
bb0l,aa07,es03 | bb03,aa07,es03 | bb05,aa07,es03 | bb07.aa07.es03 | bbO9,aaO7,esO3 |
bb01,aa07,es04 | bb03,aa07,es04 | bbO5,aaO7,esO4 | bb07.aa07.es04 | bb09.aa07.es04 |
bb01.aa07.es05 | bb03,aa07,es05 | bb05.aa07.es05 | bbO7,aaO7,esO5 | 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 |
bbOl,aaO7,esO8 | bbO3.aaO7.esO8 | bb05,aa07,es08 | bb07.aa07,es08 | bb09,aa07,es08 |
bb01.aa07.es09 | bbO3,aaO7,esO9 | bbO5,aaO7,esO9 | bb07,aa07,es09 | bb09.aa07.es09 |
bbOl,aaO7,eslO | bbO3,aaO7,eslO | bbO5,aaO7,esIO | bb07.aa07.es 10 | bb09.aa07.es 10 |
bb01,aa07,esl l | bbO3,aaO7,esll | bbO5,aaO7,esl 1 | bb07.aa07.es 11 | bb09,aa07,esl 1 |
bb01,aa07,esl2 | bbO3.aaO7.es 12 | bb05.aa07.es 12 | bb07.aa07.es 12 | bb09,aa07.es 12 |
bb01,aa08,es01 | bb03,aa08,es01 | bb05.aa08.es01 | bb07,aa08,es01 | bb09,aa08,es01 |
bb01,aa08,es02 | bbO3,aaO8,esO2 | bb05.aa08.es02 | bb07,aa08,es02 | bbO9,aaO8>esO2 |
bb01,aa08,es03 | bbO3.aaO8.esO3 | bbO5,aaO8,esO3 | bbO7,aaO8,esO3 | bb09.aa08.es03 |
bb01,aa08,es04 | bbO3.aaO8.esO4 | bbO5 faa08,es04 | bb07,aa08,es04 | bb09,aa08,es04 |
bbOl.aaO8.esO5 | bbO3,aaO8,esO5 | bbO5,aaO8,esO5 | bb07.aa08.es05 | bb09,aa08,es05 |
bb01.aa08.es06 | bbO3,aaO8,esO6 | bb05.aa08.es06 | bb07,aa08,es06 | bb09,aa08,es06 |
bbOl,aaO8,esO7 | bbO3,aaO8,esO7 | bbO5.aaO8.esO7 | bbO7,aaO8,esO7 | bb09,aa08,es07 |
bb01,aa08,es08 | bbO3.aaO8.esO8 | bbO5.aaO8.esO8 | bbO7.aaO8.esO8 | bb09.aa08.es08 |
bb0l,aa08,es09 | bb03.aa08.es09 | bbO5.aaO8.esO9 | bbO7.aaO8.esO9 | bb09,aa08ses09 |
bbÔl,aa08.es 10 | bb03,aa08,esl0 | bbO5.aaO8.eslO | bb07.aa08.esl0 | bbO9.aaO8.es 10 |
bb01,aa08,esl 1 | bb03,aa08,esl 1 | bbO5,aaO8,esll | bb07,aa08,esl 1 | bbO9,aaO8.esl 1 |
bbOl, aa08.es 12 | bb03,aa08,esl2 | bbO5,aa08.es 12 | bb07,aa08,esl2 | bb09,aa08,esl2 |
bb01.aa09.es01 | bbO3,aaO9,esOl | bbO5.aaO9.esOl | bbO7,aaO9,esOl | bb09,aa09,es01 |
bb01}aa09,es02 | bbO3,aaO9,esO2 | bb05.aa09.es02 | bb07,aa09,es02 | bb09,aa09,es02 |
bbOl.aaO9.esO3 | bbO3,aaO9,esO3 | bbO5.aaO9.esO3 | bb07,aa09,es03 | bb09.aa09.es03 |
bb01,aa09,es04 | bbO3.aaO9.esO4 | 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 | bbO5.aaO9.esO7 | bb07,aa09,es07 | bb09,aa09,es07 |
bb01,aa09,es08 | bb03.aa09.es08 | bb05,aa09,es08 | bbO7,aaO9,esO8 | bb09.aa09.es08 |
bb01,aa09,es09 | bb03,aa09,es09 | bb05.aa09.es09 | bb07,aa09,es09 | bb09.aa09.es09 |
bb01.aa09.es 10 | bb03.aa09.es 10 | bb05.aa09.esl0 | bb07.aa09.es 10 | bbO9,aaO9,eslO |
bb01,aa09,esll | bbO3,aaO9,esl 1 | bbO5,aaO9,esl 1 | bb07.aa09.es 1 1 | bb09,aa09,esl 1 |
bb01,aa09,esl2 | bb03,aa09,esl2 | bb05,aa09,esl2 | bb07.aa09.es 12 | bb09.aa09.es 12 |
bbOl.aalO.esOl | bbO3.aalO.esOl | bbO5,aalO,esOl | bb07.aal0.es01 | bb09.aal0.es01 |
r2,r1,r« | R2,R\Ra | R2,R1,R* | R2 fR\R« | R2,R*,Ra |
bb01,aal0,es02 | bbO3JaalO,esÛ2 | bbO5,aalO,esO2 | bb07,aal0,es02 | bbO9,aalO,esO2 |
bbOI,aalO,esO3 | bbO3,aalO,esO3 | bbO5,aalO,esO3 | bb07,aal0,es03 | bbO9,aalO,esO3 |
bb01,aal0,es04 | bb03,aal0,es04 | bb05,aal0,es04 | bb07,aal0,es04 | bb09,aal0,es04 |
bb01,aal0,es05 | bbO3,aalO,esO5 | bbO5,aalO,esO5 | bbO7,aalO,esO5 | bbO9,aalO,esO5 |
bbOfraalO^sOô | bbO3,aalO,esO6 | bbO5,aalO,esO6 | bb07,aal0,es06 | bb09,aal0,es06 |
bb0l,aal0,es07 | bbO3,aalO,esO7 | bbO5,aalO,esO7 | bb07,aal0,es07 | bb09,aal0,es07 |
bb0l,aal0,es08 | bbO3,aalO}esO8 | bbO5,aalO,esO8 | bbO7,aalO,esO8 | bbO9,aalO,esO8 |
bbOI,aalO,esO9 | bbÛ3,aaIO,esO9 | bb05,aal0,es09 | bbO7,aalO,esO9 | bb09,aal0,es09 |
bbOl,aaIO,esIO | bbO3,aalO,eslO | bbO5,aalO,eslO | bbO7,aalO,eslO | bb09,aal0,esl0 |
bbOl,aalO,esl 1 | bbO3,aalO,esll | bb05,aal0,esll | bb07,aa!0,esl 1 | bb09,aal0,esl 1 |
bb01,aal0,esl2 | bb03,aal0,esl2 | bb05,aal0,esl2 | bb07,aal0,esl2 | bb09,aal0,esl2 |
bb02,aa01,es01 | bb04,aa01,esÛJ | bb06,aa01,es01 | bbO8,aaOl,esOl | bbl0,aa01,es01 |
bb02,aa01,es02 | bb04,aa01,es02 | bb06,aa01,es02 | bb08,aa01,es02 | bblO,aaOl ,es02 |
bbO2,aaOl,esO3 | bbO4,aaOl,esO3 | bb06,aa01,es03 | bbO8,aaOl,esO3 | bblO,aaOl,esO3 |
bbO2,aaOl,esO4 | bb04,aa0ï,es04 | bb06,aa01,esÛ4 | bbO8,aaOl,esO4 | bbl0,aa01,es04 |
bbO2,aaOl,esO5 | bb04,aa01,es05 | bbOôjaaOfoesOS | bbO8,aaOl,esO5 | bblO,aaOl,esO5 |
bb02,aa01,es06 | bb04,aa01,es06 | bb06,aa01,es06 | bbO8,aaOl,esO6 | bbl0,aa01,es06 |
bb02îaa01,es07 | bbO4,aaOI,esO7 | bbO6,aaOl,esO7 | bb08,aa01,es07 | bbl0,aa01,cs07 |
bb02,aa01,es08 | bb04,aa01,es08 | bbOô^aOfresOS | bb08,aa01,es08 | bblO,aaOl,esO8 |
bb02,aa01,es09 | bb04,aa01,es09 | bb06,aa01,es09 | bbO8,aaOl,esO9 | bbl0,aa01,es09 |
bb02faa01,es!0 | bb04,aa01,eslÛ | bbO6,aaOI,eslO | bbO8,aaOI,eslO | bbiO,aaOl,eslO |
bb02,aa01,esl 1 | bb04,aa01,esl 1 | bb06,aa01,esl 1 | bb08,aa01,esl 1 | bbl0,aa01,esll |
bbO2,aaOI,esl2 | bb04,aa01,esl2 | bb06,aa01,esl2 | bb08,aa01,esl2 | bblO,aaOl,esl2 |
bb02,aa02,es01 | bb04,aa02,es01 | bb06,aa02,es01 | bbO8,aaO2,esOl | bbl0,aa02,es01 |
bbO2,aaO2,esO2 | bbO4,aaO2,esO2 | bb06,aa02,es02 | bbO8,aaO2,esO2 | bbl0,aa02,es02 |
bb02faa02,es03 | bb04,aa02,es03 | bbO6,aaO2,esO3 | bbO8,aaO2,esO3 | bblO,aaO2,esO3 |
bb02,aa02,es04 | bb04,aa02,es04 | bb06,aa02,es04 | bb08,aa02,es04 | bblO,aaO2,esO4 |
bb02,aa02îes05 | bb04,aa02,es05 | bb06,aa02,es05 | bb08,aa02,es05 | bbl0,aa02,es05 |
bb02,aa02,es06 | bb04,aa02,es06 | bbO6,aaO2,esO6 | bb08,aa02,es06 | bb 10,aa02,es06 |
bb02,aa02,es07 | bbO4,aaO2,esO7 | bb06,aa02,es07 | bb08,aa02,es07 | bbl0,aa02,es07 |
bb02,aa02,es08 | bb04,aa02,es08 | bb06,aa02,es08 | bbO8,aaO2,esO8 | bblO,aaO2,esO8 |
bb02,aa02,es09 | bb04,aa02,es09 | bb06,aa02,es09 | bb08,aa02,es09 | bbl0)aa02,es09 |
bb02,aa02,esl0 | bb04,aa02,esl0 | bb06,aa02,esI0 | bbO8,aaO2,eslO | bbl0,aa02,esl0 |
bb02,aa02,esl 1 | bb04,aa02}esl 1 | bb06,aa02,es 11 | bb08,aa02,esl 1 | bblOsaaO2,esl 1 |
bb02,aa02,esl2 | bb04,aa02,esl2 | bb06,aa02fesl2 | bb08,aa02,esl2 | bb 10,aa02,esl2 |
bb02,aa03,es01 | bbO4,aaO3,esOI | bbO6,aaÛ3,esOl | bbO8,aaO3,esOl | bbl0,aa03,es01 |
bb02faa03,es02 | bb04faa03?es02 | bbO6,aaO3,esO2 | bb08,aa03,es02 | bbl0,aa03,es02 |
bb02,aa03,es03 | bb04,aa03,es03 | bbO6,aaO3,esO3 | bbO8,aaO3,esO3 | bblO,aaO3,esO3 |
bb02,aa03,es04 | bb04,aa03,es04 | bb06,aa03,es04 | bbO8,aaO3,esO4 | bbl0,aa03,es04 |
bb02,aa03,es05 | bb04,aa03,es05 | bbOôjaaOS^sOS | bbO8,aaO3jesO5 | bblO,aaO3,esO5 |
bb02,aa03,es06 | bb04,aa03,es06 | bb06,aa03,es06 | bbO8,aaO3,esO6 | bbl0,aa03,es06 |
bb02,aa03,es07 | bb04,aa03,es07 | bb06,aa03,es07 | bbOS^aOS^sO? | bblO,aaO3,esO7 |
bb02,aa03,es08 | bb04,aa03,es08 | bbO6,aaO3,esO8 | bbO8,aaO3,esO8 | bblOfaaO3,esO8 |
R^Ra | rIr1^ | R^R’Ax | R^Ra | |
bbO2,aaO3,esO9 | bb04,aa03,es09 | bbO6,aaO3,esO9 | bb08,aa03,es09 | bbl0,aa03,es09 |
bb02,aa03,esl0 | bb04,aa03,esl0 | bbO6,aaO3,eslO | bbO8,aaO3,eslO | bblO,aaO3feslO |
bbO2faaO3,esll | bb04,aa03,esl 1 | bb06,aa03fesll | bbO8,aaO3,esl 1 | bbl0,aa03,esl I |
bb02,aa03,esl2 | bb04,aa03,esl2 | bbO6,aaO3,esl2 | bb08,aa03,esl2 | bbl0,aa03,esl2 |
bb02,aa04,es01 | bb04,aa04,es01 | bb06,aa04,es01 | bbÛ8,aa04,es01 | bbl0,aa04,es01 |
bb02,aa04,es02 | bb04,aa04,es02 | bbO6)aaO4,esO2* | bb08,aa04,es02 | bbl0,aa04,es02 |
bb02,aa04,es03 | bb04faa04,es03 | bb06,aa04,es03 | bb08,aa04,es03 | bbl0,aa04,es03 |
bb02,aa04fes04 | bbO4,aaO4,esO4 | bbO6,aaO4,esO4 | bb08,aa04,es04 | bbl0,aa04,es04 |
bb02,aa04,es05 | bb04,aa04,es05 | bb06,aa04,es05 | bb08,aa04,es05 | bblO,aaO4,esO5 |
bbO2,aaO4,esO6 | bbO4,aaO4,esO6 | bbO6,aaO4,esO6 | bb08,aa04,es06 | bb!0,aa04,es06 |
bbO2,aaO4,esO7 | bb04,aa04,es07 | bb06,aa04,es07 | bbO8JaaO4,esO7 | bbl0,aa04,es07 |
bb02,aa04,es08 | bb04,aa04fes08 | bbO6,aaO4,esO8 | bbÛ8,aaO4,esO8 | bbl0,aa04,es08 |
bbO2,aaO4,esO9 | bb04,aa04,es09 | bb06,aa04fes09 | bb08,aa04,es09 | bb!0,aa04,es09 |
bb02,aa04,esI0 | bb04,aa04,esl0 | bb06,aa04,esl0 | bbO8,aaO4,eslO | bbl0,aa04,esl0 |
bb02,aa04,esl l | bb04,aa04,esl 1 | bb06îaa04,esll | bbO8,aaO4,esl 1 | bbl0,aa04,esl 1 |
bb02,aa04,esl.2 | bb04,aa04,es!2 | bb06,aa04,esl2 | bb08,aa04,esl2 | bbl0,aa04,esl2 |
bbO2,aaO5,esOI | bb04,aa05,es01 | bbO6,aaO5,esOl | bbO8,aaO5,esOl | bbl0,aa05,es01 |
bbO2)aaO5,esO2 | bbû4,aa05,es02 | bb06,aa05,es02 | bb08,aa05,es02 | bbl0,aa05,es02 |
bbO2,aaO5,esO3 | bb04,aa05,es03 | bbO6,aaO5,esO3 | bb08,aa05,es03 | bblO,aaO5,esO3 |
bbO2,aaO5,esO4 | bb04,aa05,es04 | bb06,aa05,es04 | bb08,aa05,es04 | bblÛ,aaO5,esO4 |
bbO2,aaO5,esO5 | bbO4,aaO5,esO5 | bbO6,aaO5,esO5 | bbO8,aaO5,esO5 | bbl0,aa05,es05 |
bbO2,aaO5,esO6 | bb04,aa05,es06 | bb06,aa05,es06 | bbO8,aaO5,esO6 | bbIO,aaO5,esO6 |
bb02,aa05,es07 | bb04,aa05,es07 | bb06,aa05,es07 | bbO8,aaO5,esO7 | bbI0,aa05,es07 |
bb02,aa05,es08 | bb04,aa05,es08 | bbO6,aaO5,esO8 | bbO8,aaO5,esO8 | bblO,aaO5,esO8 |
bb02,aa05,es09 | bb04,aa05,es09 | bbO6,aa05,esO9 | bb08,aa05,es09 | bbl0,aa05,es09 |
bb02,aa05,esl0 | bb04,aa05,esl0 | bb06,aa05,esl0 | bbOS^aOS^slÛ | bbl0,aa05,esl0 |
bbO2,aaO5,esl 1 | bbO4,aaO5,esl 1 | bbO6,aaO5,esl 1 | bb08,aa05,esl 1 | bblO,aaO5,esl 1 |
bbO2,aaO5,esl2 | bbO4,aaO5,esl2 | bbO6,aaO5,esl2 | bb08,aa05,esl2 | bbl0,aa05,esl2 |
bbO2,aaO6,esOl | bb04,aa06,es01 | bb06,aa06,es01 | bbO8,aaO6,esOl | bbl0,aa06,es01 |
bb02,aa06,es02 | bb04,aa06,es02 | bb06,aa06,es02 | bb08,aa06,es02 | bbl0,aa06,es02 |
bb02,aa06,es03 | bb04,aa06,es03 | bbO6,aaO6,esO3 | bbO8,aaO6,esO3 | bbl0,aa06,es03 |
bbO2,aaO6,esO4 | bb04,aa06,es04 | bb06,aa06,es04 | bb08,aa06,es04 | bbl0,aa06,es04 |
bb02,aa06,es05 | bb04,aa06,es05 | bbO6,aaO6,esO5 | bb08,aa06,es05 | bb!0,aa06,es05 |
bb02,aa06,es06 | bb04,aa06,es06 | bb06,aa06,es06. | bbO8,aaO6,esO6 | bb!0,aa06,es06 |
bbO2,aaO6,esO7 | bb04,aa06,es07 | bb06.,aa065es07 | bbO8,aaO6,esO7 | bblO^aOô^sOÏ |
bb02,aa06,es08 | bb04,aa06,es08 | bb06,aa06,es08 | bbO8,aaO6,esO8 | bblO,aaO6,esO8 |
bb02,aa06,es09 | bb04,aa06,es09 | bbO6,aaO6,esO9 | bb08,aa06,es09 | bbl0,aa06,es09 |
bb02,aa06,esl0 | bb04,aa06,esl0 | bb06,aa06,esl0 | bbO8,aaO6,eslO | bblO,aa06,esl0 |
bb02,aa06,esl 1 | bb04,aa06,esll | bbO6,aaO6,esIl | bbO8,aaO6,esI 1 | bblC^aaOô^sl 1 |
bbO2,aaO6,es!2 | bb04,aa06,esl2 | bb06,aa06,esl2 | bbO8,aaO6,esl2 | bbl0,aa06,esl2 |
bb02,aa07,es01 | bb04,aa07,es01 | bb06,aa07,es01 | bbO8,aaO7,esOl | bblO,aaO7,esOl |
bbO2,aaO7,esO2 | bbO4,aaO7,esO2 | bb06,aa07,es02 | bb08,aa07,es02 | bbl0,aa07,es02 |
bbO2,aaO7,esO3 | bb04,aa07,es03 | bb06,aa07,es03 | bb08,aa07,es03 | bbI0,aa07,es03 |
r’jCAx | r\r*,r« | R^Ra | RM^Ra | |
bb02,aa07,es04 | bbO4,aaO7,esO4 | bb06,aa07,es04 | bbO8,aaO7,esO4 | bblO,aaO7,esO4 |
bbO2,aaO7,esÛ5 | bb04,aa07,es05 | bb06,aa07,es05 | bb08,aa07,es05 | bbl0,aa07,es05 |
bbO2,aaO7,esÛ6 | bb04,aa07,es06 | bb06,aa07,es06 | bbO8,aaO7,esO6 | 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 | bbO8.aaO7.esO8 | bbl0,aa07,es08 |
bb02,aa07,es09 | bb04,aa07,es09 | bb06,aa07,es09 | bbO8,aaO7,esO9 | bbl0,aa07,es09 |
bb02,aa07,esl0 | bb04,aa07,es!0 | bb06,aa07,esl0 | bbO8.aaO7.es 10 | bblO,aaO7,eslO |
bbO2,aaO7,esl 1 | bb04,aa07,esll | bb06,aa07,esl I | bbO8,aa07.es 11 | bbl0,aa07,esll |
bb02,aa07,esl2 | bbÛ4,aaO7,esl2 | bb06.aa07.esl2 | bbO8,aaO7,esl2 | bbl0,aa07,esl2 |
bbO2,aaO8,esOl | bb04,aa08,es01 | bb06,aa08,es01 | bbO8,aaO8,esOl | bbl0,aa08,es01 |
bb02,aa08,es02 | bb04,aa08,es02 | bbÛ6,aaO8,esO2 | 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 | bbO6,aaO8,esO4 | bb08,aa08,es04 | bbl0,aa08,es04 |
bb02,aa08,es05 | bb04,aa08,es05 | bb06,aa08,es05 | bb08,aa08,es05 | bbl0,aa08,es05 |
bb02,aa08,es06 | bb04,aa08,es06 | bb06,aa08,es06 | bbO8,aaO8,esO6 | bblO,aaO8,esO6 |
bb02,aa08,es07 | bb04,aa08,es07 | bbO6,aaO8,esO7 | bb08,aa08,es07 | bblO,aaO8,esO7 |
bb02,aa08,es08 | bbO4,aaO8,esO8 | bbO6,aaO8,esO8 | bb08,aa08,es08 | bblO,aaO8,esO8 |
bb02,aa08,es09 | bb04,aa08,es09 | bb06,aa08>es09 | bb08,aa08,es09 | bblO,aaO8,esO9 |
bbO2,aaO8,eslO | bb04,aa08,esl0 | bb06,aa08,esl0 | bbO8,aaO8,eslO | bb 10,aa08.es 10 |
bbO2,aaO8,esl 1 | bb04,aa08,esl 1 | bbO6,aaO8,esl 1 | bb08,aa08.es 11 | bblO,aaO8,esl 1 |
bbO2,aaO8,esl2 | bb04,aa08,esl2 | bbO6,aaO8,esl2 | bb08,aa08,esl2 | bbl0,aa08,esl2 |
bb02,aa09,es01 | bbO4,aaO9,esOl | bb06,aa09,es01 | bbO8,aaO9,esOl | bb!0,aa09,es01 |
bb02faa09,es02 | bb04,aa09,es02 | bb06,aa09,es02 | bbO8,aaO9,esO2 | bbl0,aa09,es02 |
bb02,aa09,es03 | bb04,aa09,es03 | bbO6,aaO9,esO3 | bb08,aa09,es03 | bblO,aaO9,esO3 |
bb02,aa09,es04 | bb04,aa09,es04 | bb06,aa09,es04 | bb08,aa09,es04 | bbl0,aa09,es04 |
bb02,aa09,es05 | bb04,aa09,es05 | bb06,aa09,es05 | bbO8,aaO9,esO5 | bblO.aaO9.esO5 |
bb02,aa09,es06 | bbO4,aaO9,esO6 | bb06,aa09,es06 | bb08,aa09,es06 | bblO,aaO9,esO6 |
bb02,aa09,es07 | bb04,aa09,es07 | bbO6,aaO9,esO7 | bbO8,aaO9,esO7 | 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 | bbO4,aaO9,eslO | bb06,aa09,esl0 | bb08,aa09,esI0 | bbl0,aa09,es!0 |
bb02,aa09,esl 1 | bb04,aa09,esll | bb06,aa09,esl 1 | bbO8,aaO9,esll | bblO,aaO9,esl 1 |
bb02,aa09,esl2 | bb04,aa09,esl2 | bb06,aa09,esl2 | bb08,aa09,esl2 | bblO,aaO9,esl2 |
bb02,aal0,es01 | bbO4,aalO,esOl | bb06,aal0,es01 | bb08,aal0,es01 | bblO,aalO,esOl |
bb02,aal0,es02 | bb04,aal0,es02 | bbO6,aalO,esO2 | bb08,aal0,es02 | bbl0,aal0,es02 |
bb02,aal0,es03 | bb04,aal0,es03 | bbO6,aalO,esO3 | bbO8,aalO,esO3 | bblO,aalO,esO3 |
bb02,aal 0,es04 | bb04,aal0,es04 | bb06,aal0,es04 | bb08,aal 0,es04 | bbl0,aal0,es04 |
bbO2,aalO,esO5 | bb04,aal0,es05 | bbO6,aalO,esO5 | bb08,aal0,es05 | bblO,aalO,esO5 |
bb02,aal0,es06 | bb04,aal 0,es06 | bb06,aal0,es06 | bb08,aal 0,es06 | bblO,aalO,esO6 |
bb02,aal0,es07 | bb04,aal0,es07 | bb06,aal0,es07 | bbO8,aalO,esO7 | bblO,aalO,esO7 |
bb02,aal 0,es08 | bbO4,aalO,esO8 | bbO6,aalO,esO8 | bb08,aal 0,es08 | bblO,aalO,esO8 |
bb02.aal0.es09 | bb04,aal0,es09 | bb06,aal0,es09 | bb08,aal0,es09 | bbl0.aal0.es09 |
bb02,aal0,esl0 | bbO4,aalO,eslO | bb06,aal0,esl0 | bb08,aaI0,esl0 | bblO.aalO,eslO |
R2,R\Ra | R^R’jRe | R^R’jRa | R^Ra | R’XRa |
bbO2,aalO,esll | bbO4,aalOfesll | bbO6,aalO,esl l | bbO8,aalO,esl l | bblO,aalO,esl 1 |
bb02,aal0,esl2 | bb04,aa!0,esl2 | bbO6,aalO,esl2 | bbO8,aalO,esl2 | bblO,aalO,esl2 |
Table 2
bbOl | -^o | bb02 | bbO3 | |||||
bb04 | K Cl | 3/ | bb05 | K | -F | bb06 | ||
,_r | =\ | |||||||
bb07 | j | J | bb08 | K | )- | °\ | bb09 | UWV 1 |
bblO | La | y |
Table 3
0 aa0! | O Il H aa02 R« \θN Y | ... - Y |
0 Il H Ra\ /X/A aa04 | 0 Il H aa05 ο γ Z | 0 aa06 |
O aa07 | 0 Il H AP Ro.\ aaOS ο Z | ... |
0 Il H Ra\ S Y A aalO La |
Table 4
esOl R^ = methyl | es02 Ra = ethyl | es03 R„ = isopropyl |
es04 Ra = propyl | es05 Ra = cyclohexyl | es06 Ra = cyclopentyl |
es07 Ra = cyclobutyl | es08 Ra = cyclopropyl | es09 R„ = benzyl |
esl 1 Ra = neopentyl | es 10 Ra = t-butyl | es 12 Ra = hydrogen |
[0115] In some embodiments, R3a, Rîb, R4, R5 and R9 can be ail hydrogens in any
7 of the embodiments described in Table 1. In some embodiments, at least one of R and R can be OH in any of the embodiments described in Table 1. In some embodiments, R can be a Ci-6 alkyl in any of the embodiments described in Table 1. In some embodiments, B1 can be adenine, guanine, uracil, thymine or cystine in any of the embodiments described in Table 1. In some embodiments, R3a, R3b, R4, R5, R6, R7, R8, R9 and B1 can be the groups provided with respect to Formula (la) in any of the embodiments described in Table 1.
[0116] Examples of compounds of Formula (I) include, but are not limited to the following:
OH OH , OH OH
OH OH , OH F
OH OH , OH OH
OH F , OH OH
OH OH , OH OH
OH F
OH F
|0117|
Additional examples of compounds of Formula (I) include, but are not
Iimited to the following:
[0118] In some embodiments, the compound of Formula (I) can be the following
O
and
[0119] Additional examples of compounds of Formula (I) include the following:
NH2
[0120] In some embodiments, neutralizing the charge on the thiophosphate group may facilitate the pénétration of the cell membrane by a compound of Formula (I) (including a compound of Formula (la)) by making the compound more lipophilie compared to a thionucleotîde having a comparable structure with one or more charges présent on the 10 phosphate. Once absorbed and taken inside the cell, the groups attached to the thiophosphate can be easily removed by esterases, proteases, or other enzymes. In some embodiments, the groups attached to the thiophosphate can be removed by simple hydrolysis. Inside the cell, the thio-monophosphate thus released may then be metabolized by cellular enzymes to the thio-diphosphate or the active thio-triphosphate. In some embodiments, the phosphorylation 15 of a thio-monophosphate of a compound of Formula (I), or pharmaceutically acceptable sait thereof, can be stereoselective. For example, a thio-monophosphate of a compound of ¥
Formula (I) (including a compound of Formula (la)) can be phosphorylated to give an alphathîodîphosphate and/or an alpha-thiotriphosphate compound that can be enriched in the (R) or (S) diastereomer with respect to the 5’-O-phosphorous atom. For example, one of the (R) and (5) configuration with respect to the 5’-0-phosphorous atom of the alpha-thiodiphosphate 5 ( and/or the alpha-thiotriphosphate compound can be présent in an amount > 50%, = 75%, = 90%, = 95% or = 99% compared to the amount of the other of the (R) or (S) configuration with respect to the S’-O-phosphorous atom. In some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable sait thereof, can resuit in the formation of a compound that has the (/^-configuration at the 5’-0-phosphorous atom. In 10 some embodiments, phosphorylation of a compound of Formula (I), or pharmaceutically acceptable sait thereof, can resuit in formation of a compound that has the (^-configuration at the 5’-0-phosphorous atom.
[0121] In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can act as a chain terminator 15 of HCV réplication. For example, incorporation of a compound of Formula (I) containing a moiety at the 2’-carbon position can terminate further élongation of the RNA chain of HCV. For example, a compound of Formula (I) can contain a 2’-carbon modification when R is a non-hydrogen group selected from halogen, azido, cyano, an optionally substituted Ci.6 alkyl, -OR16 and -0C(=O)R17.
[0122] In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can hâve increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can be more résistant to hydrolysis and/or more résistant to enzymatic transformations. For example, a 25 compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve increased metabolic stability, increased plasma stability, can be more résistant to hydrolysis and/or can be more résistant to enzymatic transformations compared to a compound that îs identical in structure but for having a phosphate attached to the 5’-carbon of the ribose ring. In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a 30 pharmaceutically acceptable sait thereof, can hâve improved properties. In previous studies,
replacing a sulfur with an oxygen on the alpha-phosphate of a nucléotide phosphoramidate has resulted in more than a lOOO-fold decrease in potency. See Venkatachalam et al. European Journal of Médicinal Chemistry (2004) 39:665-683. A non-limiting list of example properties include, but are not limited to, increased biological half Iife, increased f 5 bioavailabîlity, increase potency, a sustaîned in vivo response, increased dosing intervals, decreased dosing amounts, decreased cytotoxicity, réduction in required amounts for treating disease conditions, réduction in viral load, réduction în time to séroconversion (i.e., the virus becomes undetectable in patient sérum), increased sustaîned viral response, a réduction of morbidity or mortality in clinical outcomes, increased subject compliance, decreased liver 10 conditions (such as liver fibrosis, liver cirrohis and/or liver cancer), and compatibility with other médications. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve a biological half life of greater than 24 hours. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve a biological half life in the range of about 40 hours to about 46 hours. In some 15 embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve a biological half life greater than a compound that has a phosphate attached to the 5’carbon of the ribose ring (for example, a compound that îs identical in structure but for having a phosphate attached to the 5’-carbon of the ribose ring). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve more potent 20 antiviral activity (for example, a lower IC50 in an HCV replicon assay) as compared to the current standard of care.
Synthesis [0123] Compounds of Formula (I) (including compounds of Formula (la)), and 25 those described herein may be prepared in various ways. General synthetic routes to the compound of Formula (I), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown in Scheme I, and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able 30 to recognize modifications of the disclosed synthèses and to devise alternate routes based on
the disclosures herein; ail such modifications and altemate routes are within the scope of the claims.
Scheme 1 R3A
S f
r2o—P—Ci
R1
[0124] One method for forming a compound of Formula (I) is shown in Scheme
1. In Scheme 1, R3A, R3B, R4A, R5A, R6A, R7A, R8A, R9A and B1A can be the same as R3a, Rîb, R4, Rs, R6, R7, R8, R9 and B1 as described herein for Formula (I); and R1 and R2 can be the same as described herein for Formula (I). As shown in Scheme 1, a compound of Formula 10 (A) can be reacted with a compound having the formula R2O-P(=S)(R1)-C1 to form a compound of Formula (I).
[0125] To reduce the formation of side products, one or more the groups attached to the pentose ring can be protected with one or more suitable protecting groups. As an example, if R6A and/or R7A is/are hydroxy group(s), the hydroxy group(s) can be protected 15 with suitable protecting groups, such as triarylmethyl and/or silyl groups. Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4'dimethoxytrityl (DMTr), 4,4,,4-trimethoxytrityl (TMTr),. 4,4',4-tris- (benzoyloxy) trityl (TBTr), 4,4',4-tris (4,5-dichlorophthalîmido) trityl (CPTr), 4,4',4-tris (levulinyloxy) trityl (TLTr), p-anisyl-1- naphthylphenylmethyl, di-o-anisyl-l-naphthylmethyl, p20 tolyldipheylmethyl, 3-(îmidazolylmethyl)-4,4'-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl, 4- hexadecyloxytrityl, 4,4'dioctadecyltrityl, 9-(4- octadecyloxyphenyl) xanthen-9-yl, l,r-bis-(4-methoxyphenyl)-rpyrenylmethyl, 4,4',4-tris- (tert-butylphenyl) methyl (TTTr) and 4,4'-di-3, 5hexadienoxytrityL Examples of suitable silyl groups are described herein. Altematively, R6A 25 and/or R7A can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitable orthoesters include
methoxym ethylene acetal, ethoxymethylene acetal, 2-oxacyclopentylidene orthoester, dimethoxym ethylene orthoester, l -methoxyethylidene orthoester, l -ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester l,2-dimethoxyethylidene orthoester, and alpha-methoxybenzylidene orthoester; suitable cyclic acetals include methylene acetal, 5 ethylidene acetal, t-butylmethylidene acetal, 3-(benzyloxy)propyl acetal, benzylidene acetal,
3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; and suitable cyclic ketals include 1-t-butylethylidene ketal, 1-phenyl ethylidene ketal, isopropylidene ketal, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal and 1 -(4methoxyphenyl)ethylidene ketal.
[0126] If desired, any -NH and/or NH2 groups présent on the B1A can also be protected with one or more suitable protecting groups. Examples of suitable protecting groups include triarylmethyl groups and silyl groups. Examples of silyl groups include, but are not Iimited to, trimethylsilyl (TMS), teri-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIP S), tert-butyl diphenylsilyl (TB DP S), tri-zso-propylsilyloxym ethyl and [215 (triniethylsilyl)ethoxy]methyl.
[0127] Suitable thîophosphorochloridates can be commercially obtained or prepared by a synthetic method described herein. An example of a general structure of a thiophosphorochloridate is shown in Scheme 1. In some embodiments, the thiophosphorochloridate can be coupled to a compound of Formula (A). In some 20 embodiments, to facilitate the coupling, a Grignard reagent can be used. Suitable Grignard reagents are known to those skilled in the art and include, but are not Iimited to, alkylmagnesium chlorides and alkylmagnesium bromides. In other embodiments, the thiophosphorochloridate can be added to a compound of Formula (A) using a base. Suitable bases are known to those skilled in the art. Suitable bases are known to those skilled in the 25 art. Examples of bases include, but are not Iimited to, an amine base, such as an alkylamine (including mono-, di- and tri-alkylamînes (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidzoles (e.g., N-methylimidazole)).
[0128] When at least one of R3a and R3b is an optionally substituted Ci-6 alkyl or an optionally substituted CX haloalkyl, the optionally substituted Ci.6 alkyl or the optionally 30 substituted Cj.6 haloalkyl can be added to the 5’~position using methods known to those skilled în the art. In some embodiments, the hydroxy attached to the 5’-carbon can be oxidized to an aldéhyde. Suitable oxidation conditions include, but are not limited to, DMSO in combination with an activating agent (usually an acylating agent or an acid) and an amine base, Moffatt oxidation, Swem oxidation and Corey-Kim oxidation, and suitable oxidizing 5 agents include, but are not limited to, Dess-Martin periodinane, TPAP/NMO (tetrapropylammonîum perruthenate/N-methylmorpholine N-oxîde), Swem oxidation reagent, PCC (pyridinium chlorochromate), and/or PDC (pyridînium dichromate), sodium periodate, Collin’s reagent, ceric ammonium nitrate CAN, NaiCrjO? in water, Ag2CO3 on celite, hot HNO3 în aqueous glyme, O2-pyridine CuCl, Pb(OAc)4-pyridine and benzoyl 10 peroxide-NiBr2. The resulting aldéhyde compound can be reacted with a Grignard reagent, an organolithium reagent or trialkyl aluminum (e.g., trimethylaluminum) to form a compound of Formula (A) where at least one of R3A and R3B is an optionally substituted C|.6 alkyl or an optionally substituted C[.6 haloalkyl. Optionally, the alkylating reagents can be in the presence of a Lewis acid. Suitable Lewis acids are known to those skilled in the art.
[0129] The chirality of the 5’-carbon of compounds of Formulae (A) and/or (I) can be inverted using methods known to the skilled in the art. For example, the oxygen attached to the 5’-carbon can be oxidized, for example to an aldéhyde, for a compound of Formula (A), or ketone, for a compound of Formula (I), using a suitable oxidizing agent. The aldéhyde and/or ketone can then be reduced usîng a suitable reducing agent. Examples of 20 suitable reducing agents include, but are not limited to, NaH, LiH, NaBH4, L1AIH4 and CaH2.
Suitable oxidizing and reducing agents are known to those skilled in the art. Examples of suitable oxidizing agents and conditions are described herein.
[0130] As described herein, in some embodiments, R6 and R7 can be both oxygen atoms linked together by a carbonyl groups. The -O-C(=O)-O- group can be formed using 25 methods known to those skilled in the art. For example, a compound of Formula (I), wherein R6 and R7 are both hydroxy groups, can be treated with l,l'-carbonyldiimidazole (CDI).
[0131] In some embodiments, R6 and/or R7 can be -OC(=O)RÎ3 and -OC(=O)R15, respectively. The -OC(=0)R13 and -OC(=O)R15 groups can be formed at the 2’- and 3’positions using various methods known to those skilled in the art. As an example, a 30 compound of Formula (I), wherein R6 and R7 are both hydroxy groups, can be treated with an
alkyl anhydride (e.g., acetic anhydride and propionic anhydride) or an alkyl acid chloride (e.g., acetylchloride). If desired, a catalyst can be used to facilitate the reaction. An example of suitable catalyst is 4-dimethylaminopyridine (DMAP). Altematively, the -OC(=O)R13 and -OC(=O)R15 groups can be formed at the 2’~ and 3’-positions by reacting an alkyl acid (e.g.
acetic acid and propionic acid) in the présences of a carbodiimide or a coupling reagent. Examples of carbodiimides include, but are not limited to, N,N'-dicyclohexyl carbodiimide (DCC), Ν,Ν’-diisopropylcarbodiimide (DIC) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).
[0132] As described herein, B1A can include a carbamate and/or an amide. Those 10 skilled in the art know methods for forming a carbamate and/or an amide on B!A. In some embodiments, the carbamate can be formed using 1, Γ-carbonyldiimidazole and an alcohol.
[0133] B1A can be added to the pentose ring using various methods known to those skilled in the art. In some embodiments, a cornpound of Formula (B) can be reacted with a nitrogenous base. In some embodiments, R3A, R3B, R4A, R5A, R6A, R7A, R8A, R9A and 15 BiA of a cornpound of Formula (B) can be the same as disclosed herein, with respect to R3a,
R3b, R4, R5, R6, R7, R8, R9 and B1; and PG1 can be an appropriate protecting group. In some embodiments, PG1 can be p-nitrobenzyl group. In some embodiments, any hydroxy groups attached to the pentose ring can be protected with one or more suitable protecting groups. In some embodiments, any hydroxy groups attached to the pentose ring can be protected with 20 benzoyl groups. Examples of nitrogenous bases include an optionally substituted heterocyclic bases described herein, wherein the nitrogen atom (-N) connected to the pentose ring is -NH. If desired, any -NH and/or NH2 groups présent on the nitrogenous base can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. In some embodiments, the nitrogenous base can be added via a coupling 25 reaction in the presence of a Lewis acid orTMSOTf. Suitable Lewis acids are known to those skilled in the art.
©
[0134J
Various methods can be used to make a compound of Formula (I), wherein
O
II o—P
I
R19 | n |
Rl îs . For example, a thiophosphorochloridate having the general formula of (P(=S)Cl3) can be transformed into a phosphorus reagent having the general formula, P(=S)LG3, wherein each LG can be amine-based leaving group. In some embodiments, each LG can be a triazole. The phosphorus reagent having the general formula, P(=S)LG3, can be reacted with a compound of Formula (I). Using a suitable pyrophosphorylation reagent, the β and γ phosphates can be added. An example of a suitable 10 pyrophosphorylation reagent is tris(tetrabutyl ammonium) hydrogen pyrophosphate.
[0135| During the synthesis of any of the compounds described herein, if desired, any hydroxy groups attached to the pentose ring, and any -NH and/or NH2 groups présent on the BlA can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. Those skilled in the art will appreciate that groups attached to 15 the pentose ring and any -NH and/or NH2 groups présent on the ΒΙΛ can be protected with various protecting groups, and any protecting groups présent can be exchanged for other protecting groups. The sélection and exchange of the protecting groups is within the skill of those of ordinary skill in the art. Any protecting group(s) can also be removed by methods known in the art, for example, with an acid (e.g., a minerai or an organic acid), a base or a 20 fluoride source.
Pharmaceutical Compositions [0136] Some embodiments described herein relates to a pharmaceutical composition, that can include a therapeutically effective amount of one or more compounds
© described herein (e.g., a compound of Formulae (I) or (la)), or a pharmaceutically acceptable sait thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, the pharmaceutical composition can include a single diastereomer of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, 5 (for example, a single diastereomer is présent in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the other diastereomers). In other embodiments, the pharmaceutical composition can include a mixture of diastereomers of a compound of Formula (I), or a pharmaceutically acceptable sait thereof. For example, the pharmaceutical composition can include a concentration of one 10 diastereomer of > 50%, = 60%, = 70%, = 80%, = 90%, = 95%, or = 98%, as compared to the total concentration of the other diastereomers. In some embodiments, the pharmaceutical composition includes a 1:1 mixture of two diastereomers of a compound of Formula (I), or a pharmaceutically acceptable sait thereof.
(0137] The term “pharmaceutical composition” refers to a mixture of one or more 15 compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitâtes administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganîc or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and 20 salicylic acid. Pharmaceutical compositions will generally be tailored to the spécifie intended route of administration.
[0138] The term “physiologically acceptable” defïnes a carrier, diluent or excipient that does not abrogate the biological activîty and properties of the compound.
[0139] As used herein, a “carrier” refers to a compound that facilitâtes the 25 incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitâtes the uptake of many organic compounds into cells or tissues of a subject.
[0140] As used herein, a “diluent” refers to an ingrédient in a pharmaceutical composition that lacks pharmacological activîty but may be pharmaceutically necessary or 30 désirable. For example, a diluent may be used to increase the bulk of a potent drug whose
Ο mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
[0141] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.
[0142] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingrédients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation îs dépendent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
[0143] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g,, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingrédients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
[0144] Multiple techniques of admînistering a compound exist in the art including, but not limited to, oral, rectal, topical, aérosol, injection and parentéral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, 25 direct intraventricular, intraperitoneal, intranasal and intraocular injections.
[0145| One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-spécifie 30 antibody. The liposomes will be targeted to and taken up selectively by the organ.
[0146] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingrédient. The pack may for example comprise métal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or 5 dispenser may also be accompanied with a notice associated with the container în form prescribed by a govemmental agency regulatîng the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved 10 product insert. Compositions that can include a compound described herein formulated în a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
Methods of Use [0147] One embodiment disclosed herein relates to a method of treating and/or amelioratîng a disease or condition that can include administering to a subject a therapeutically effective amount of one or more compounds described herein, such as a compound of Formula (I) (including compounds of Formula (la)), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound described 20 herein.
[0148] Some embodiments disclosed herein relate to a method of amelioratîng or treating a neoplastic disease that can include administering to a subject suffering from a neoplastic disease a therapeutically effective amount of one or more compounds described herein (e.g., a compound of Formulae (I) and/or (la), or a pharmaceutically acceptable sait 25 thereof), or a pharmaceutical composition that includes 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 an embodiment, the neoplastic disease can be leukemia. Exemplary leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and juvénile myelomonocytic leukemia (JMML).
[0149) Some embodiments disclosed herein relate to a method of inhibiting the growth of a tumor that can include administering to a subject having a tumor a therapeutically effective amount of one or more compounds described herein (for example, a compound of
Formulae (I) and/or (la)), or a pharmaceutical composition that includes one or more compounds described herein.
{0150] Other embodiments disclosed herein relates to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from a viral infection a therapeutically effective amount of one or more compounds described herein (for example, a compound of Formulae (I) and/or (la)), or a pharmaceutical composition that 10 includes one or more compounds described herein. In an embodiment, the viral infection can be caused by a virus selected from an adenovirus, an Alphaviridae, an Arbovirus, an Astrovirus, a Bunyaviridae, a Coronaviridae, a Filoviridae, a Flaviviridae, a Hepadnaviridae, a Herpesviridae, an Alphaherpesvirinae, a Betaherpesvirinae, a Gammaherpesvîrinae, a Norwalk Virus, an Astroviridae, a Caliciviridae, an Orthomyxovîridae, a Paramyxoviridae, a 15 Paramyxoviruses, a Rubulavirus, a Morbillivirus, a Papovaviridae, a Parvoviridae, a Picomaviridae, an Aphthoviridae, a Cardioviridae, an Enteroviridae, a Coxsackie virus, a Polio Virus, a Rhinoviridae, a Phycodnaviridae, a Poxviridae, a Reoviridae, a Rotavirus, a Retroviridae, an A-Type Retrovirus, an Immunodeficiency Virus, a Leukemia Viruses, an Avian Sarcoma Viruses, a Rhabdoviruses, a Rubîviridae, a Togaviridae an Arenaviridae 20 and/or a Bomaviridae. In some embodiments, the viral infection can be a hepatitis C viral (HCV) infection. In still other embodiments, the viral infection can be HIV.
|0151] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the virus with an effective amount of one or more compounds described herein, or a pharmaceutically 25 acceptable sait of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable sait of a compound described herein, in the manufacture of a médicament for ameliorating and/or treating a viral infection that can 30 include contacting a cell infected with the virus with an effective amount of said
C compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable sait of a compound described herein, that can be used for ameliorating and/or treating a viral infection by contacting a cell înfected with the virus with an effective amount of said compound(s). ln some embodiments, the compound can be a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of a compound of Formulae (I) and/or (la), or a pharmaceutically acceptable sait of the foregoing. ln some embodiments, the virus can be a HCV virus.
|0152| Some embodiments disclosed herein relate to methods of inhibiting réplication of a virus that can include contacting a cell înfected with the virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable sait of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable sait of a compound described herein, in the manufacture of a médicament for inhibiting réplication of a virus that can include contacting a cell înfected with the virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable sait of a compound described herein, that can be used for inhibiting réplication of a virus by contacting a cell înfected with the virus with an effective amount of said compound(s). In some embodiments, the compound can be a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of a compound of Formulae (I) and/or (la), or a pharmaceutically acceptable sait of the foregoing. In some embodiments, the virus can be a HCV virus.
[0153] HCV is an enveloped positive strand RNA virus in the Flavivîridae family. There are various nonstructural proteins of HCV, such as (NS 2, NS 3, NS4, NS4A, NS4B, NS5A, and NS5B. NS5B is believed to be an RNA-dependent RNA polymerase involved in the réplication of HCV RNA.
(0154} Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity can include contactîng a cell (for example, a cell infected with HCV) with an effective amount of a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof. Some embodiments described herein relate to a 5 method of inhibiting NS5B polymerase activity can include administering a cell (for example, a cell infected with HCV) with an effective amount of a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof. In some embodiments, a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can inhibit a RNA dépendent RNA polymerase. In some embodiments, a compound 10 of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can inhibit a HCV polymerase (for example, NS5B polymerase).
[0155] Some embodiments described herein relate to a method of treating HCV infection in a subject suffering from a HCV infection that can include administering to the subject an effective amount of a compound of Formulae (I) and/or (la), or a pharmaceutical 15 acceptable sait thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof. Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrohis, and liver cancer in a subject suffering from one or more of the aforementîoned liver conditions that can include administering to the subject an effective 20 amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof). One cause of the liver fibrosis, liver cirrohis, and/or liver cancer can be a HCV infection. Some embodiments described herein relate to a method of increasing liver fonction in a subject having a HCV infection that can include administering to the subject an effective amount of a 25 compound or a pharmaceutical composition described herein (for example, a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof). Also contemplated is a method for reducing or eiiminating further virus-caused liver damage in a subject having an HCV infection by administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formulae (I) 30 and/or (la), or a pharmaceutical acceptable sait thereof). In one embodiment, this method comprises slowing or halting the progression of liver disease. In another embodiment, the course ofthe disease is reversed, and stasîs or improvement in liver function îs contemplated.
[0156] There are a variety of génotypes of HCV, and a variety of subtypes within each génotype. For example, at présent it is known that there are eleven (numbered l through
U) main génotypes of HCV, although others hâve classîfied the génotypes as 6 main génotypes. Each of these génotypes is further subdivided into subtypes (la-lc; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a- 7b; 8a-8b; 9a; 10a; and lia). In some embodiments, an effective amount of a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof, or a pharmaceutical composition that includes an effective amount of a compound of Formulae (I) 10 and/or (la), or a pharmaceutical acceptable sait thereof, can be effective to treat at least one génotype of HCV. In some embodiments, a compound described herein (for example, a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof) can be effective to treat ail 11 génotypes of HCV. In some embodiments, a compound described herein (for example, a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof) can be effective to treat 3 or more, 5 or more, 7 or more of 9 more génotypes of HCV. In some embodiments, a compound of Formula (I) and/or (la), or a pharmaceutical acceptable sait thereof îs more effective against a larger number of HCV génotypes than the standard of care. In some embodiments, a compound of Formula (I) and/or (la), or a pharmaceutical acceptable sait thereof, is more effective against a particular HCV génotype 20 than the standard of care (such as génotype 1, 2, 3, 4, 5 and/or 6).
[0157] Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a réduction in viral load, a réduction in viral réplication, a réduction in tîme to séroconversion (virus undetec table in patient sérum), an increase in the 25 rate of sustained viral response to therapy, a réduction of morbidity or mortality in clinîcal outcomes, a réduction in the rate of liver function decrease; stasis in liver function; improvement în liver function; réduction in one or more markers of liver dysfunction, including alanine transamînase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase, and/or other indicator of disease response. Similarly, 30 successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formulae (I) and/or (la), or a pharmaceutical acceptable sait thereof) can reduce the incidence of liver cancer in HCV patients.
|0158] In some embodiments, an effective amount of a compound of Formulae (I) and/or (la), or a pharmaceutically acceptable sait thereof, is an amount that is effective to 5 reduce viral titers to undetectabie levels, for example, to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL sérum. In some embodiments, an effective amount of a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, is an amount that is effective to reduce viral load compared to the virai load before administration of the compound of Formula (I) and/or (la), 10 or a pharmaceutically acceptable sait thereof. For example, wherein the viral load is measured before administration of the compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, and again after completion of the treatment régime with the compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof (for example, l month after completion). In some embodiments, an effective amount of a 15 compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, can be an amount that îs effective to reduce viral load to lower than about 100 genome copîes/mL sérum. In some embodiments, an effective amount of a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, is an amount that is effective to achieve a réduction in viral titer in the sérum of the subject in the range of about l .5-Iog to about a 2.520 log réduction, about a 3-log to about a 4-log réduction, or a greater than about 5-log réduction compared to the viral load before administration of the compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof. For ex ample, the viral load can be measured before administration of the compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, and again after completion of the treatment régime with the 25 compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof (for example, l month after completion).
10159] In some embodiments, a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, can resuit in at least a l, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more réduction in the réplication of HCV relative to pre-treatment levels 30 in a subject, as determined after completion of the treatment régime (for example l month after completion). In some embodiments, a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, can resuit in a réduction of the réplication of HCV relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, can resuit in a réduction of HCV réplication in the range of l to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more réduction of HCV réplication compared to the réduction of HCV réduction achieved by pegylated interferon in combination with ribavirin, administered according to the standard of care, or may achieve the same réduction 10 as that standard of care therapy in a shorter period of time, for example, in one month, two months, or three months, as compared to the réduction achieved after six months of standard of care therapy with ribavirin and pegylated interferon.
[0160] In some embodiments, an effective amount of a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, is an amount that is effective to 15 achieve a sustained viral response, for example, non-detectable or substantially nondetectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter sérum) is found in the subject’s sérum for 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 following 20 cessation of therapy.
[0161} In some embodiments, a therapeutically effective amount of a compound of Formula (I) and/or (la), or a pharmaceutically acceptable sait thereof, can reduce a level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 25 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, compared to the level of the marker in an untreated subject, or to a placebo-treated subject. Methods of measuring sérum markers are known to those skilled in the art and include immunological-based methods, e.g., enzymelinked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody 30 spécifie for a given sérum marker. A non-limiting list of examples of a markers includes
Ο measuring the levels of sérum alanine aminotransferase (ALT), asparatate aminotransferacse (AST), aikaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total biiirubin (TBIL) using known methods. In general, an ALT level of less than about 45 IU/L (international units/liter), an AST in the range of 10-34 IU/L, ALP in the range of 44-147 5 IU/L, GGT in the range of 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal. In some embodiments, an effective amount of a compound of Formula (I) and/or (la) is an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with what is considered a normal level.
[0162] Subjects who are clinicaliy dîagnosed with HCV infection include “naïve” 10 subjects (e.g., subjects not previously treated for HCV, particularly those who hâve not previously received IFN-alpha-based and/or ribavirin-based therapy) and indîviduals who hâve failed prior treatment for HCV (treatment failure subjects). Treatment failure subjects include “non-responders” (i.e., subjects in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV (= 0.5 log IU/mL), for example, a 15 previous TFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy); and “relapsers” (i.e., subjects who were previously treated for HCV, for example, who received a previous IFNalpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy, whose HCV titer decreased, and 20 subsequentiy increased).
[0163] In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable sait thereof, can be administered to a treatment failure subject suffering from HCV. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered to a non-responder subject suffering from HCV. In some 25 embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered to a relapsed subject suffering from HCV.
|0164| After a period of time, infectious agents can develop résistance to one or more therapeutic agents. The term “résistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, 30 after treatment with an antiviral agent, the viral load of a subject infected with a résistant
virus may be reduced to a lesser degree compared to the amount in viral load réduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered to a subject infected with an HCV strain that is résistant to one or more different anti-HCV agents. In some embodiments, development of résistant HCV strains is delayed when patients are treated with a compound of Formula (I), or a pharmaceutically acceptable sait thereof, compared to the development of HCV strains résistant to other HCV drugs.
[0165] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered to a subject for whom other 10 anti-HCV médications are contraindicated. For example, administration of pegylated interferon alpha in combination with ribavirin is contraindicated in subjects with hemoglobinopathies (e.g., thalassemia major, sickle-cell anémia) and other subjects at risk from the hématologie side effects of current therapy. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable sait thereof, can be provided to a subject that is 15 hypersensîtive to interferon or ribavirin.
[0166] Some subjects being treated for HCV expérience a viral load rebound. The term viral load rebound as used herein refers to a sustained =0.5 log IU/mL increase of viral load above nadir before the end of treatment, where nadir is a =0.5 log IU/mL decrease from baseline. In some embodiments, a compound of Formula (I), or a pharmaceutically 20 acceptable sait thereof, can be administered to a subject expertencing viral load rebound, or can prevent such viral load rebound when used to treat the subject.
[0167] The standard of care for treating HCV has been associated with several side effects (adverse events). In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can decrease the 25 number and/or severity of side effects that can be observed in HCV patients being treated with ribavirin and pegylated interferon according to the standard of care. Examples of side effects include, but are not limited to fever, malaise, tachycardia, chills, headache, arthralgias, myalgias, fatigue, apathy, loss of apetite, nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritability, confusion, dépréssion, severe dépréssion, suicidai 30 idéation, anémia, low white blood cell counts, and thinning of hair. In some embodiments, a
compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be provided to a subject that discontinued a HCV therapy because of one or more adverse effects or side effects associated with one or more other HCV agents.
[0168] Table 5 provides some embodiments of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, compared to the standard of care. Examples include the following: in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, results in a percentage of non-responders that is 10% less than the percentage of non-responders receiving the standard of care; in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, results number of 10 side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving the standard of care; and in some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, results a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving the 15 standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art.
©
Table 5
Percentage of nonresponders | Percentage of relapsers | Percentage of résistance | Percentage of viral load rebound | Number of side effects | Severity of side effects |
10% less | 10% less | 10% less | 10% less | 10% less | 10% less |
25% less | 25% less | 25% less | 25% less | 25% less | 25% less |
40% less | 40% less | 40% less | 40% less | 40?/o less | 40% less |
50% less | 50% less | 50% less | 50% less | 50% less | 50% less |
60% less | 60% less | 60% less | 60% less | 60% less | 60% less |
70% less | 70% less | 70% less | 70% less | 70% less | 70% less |
80% less | 80% less | 80% less | 80% less | 80% less | 80% less |
90% less | 90% less | 90% less | 90% less | 90% less | 90% less |
about 10% | about 10% | about 10% | about 10% to | about 10% to | about 10% to |
to about | to about | to about | about 30% | about 30% | about 30% |
30% less | 30% less | 30% less | less | less | less |
about 20% | about 20% | about 20% | about 20% to | about 20% to | about 20% to |
to about | to about | to about | about 50% | about 50% | about 50% |
50% less | 50% less | 50% less | less | less | less |
about 30% | about 30% | about 30% | about 30% to | about 30% to | about 30% to |
to about | to about | to about | about 70% | about 70% | about 70% |
70% less | 70% less | 70% less | less | less | less |
about 20% | about 20% | about 20% | about 20% to | about 20% to | about 20% to |
to about | to about | to about | about 80% | about 80% | about 80% |
80% less | 80% less | 80% less | less | less | less |
10169] Yet still other embodiments disclosed herein relates to a method of ameliorating or treating a parasitic disease that can include administering to a subject 5 suffering from a parasitic disease a therapeutically effective amount of one or more compounds described herein (for example, a cornpound of Formula (I) and/or (Ια)), or a pharmaceutical composition that includes one or more compounds described herein. In an embodiment, the parasite disease can be Chagas' disease.
[0170] As used herein, a “subject” refers to an animal that is the object of 10 treatment, observation or experiment. “Animal” includes coid- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guînea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.
ΙΟΙ 71) As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviatîon of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may 5 worsen the patient's overall feeling of well-being or appearance.
[0172] The term “therapeutically effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or médicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, allevîate or ameliorate symptoms of disease or prolong the 10 survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviatîon of the signs or symptoms of the disease being treated. Détermination of a therapeutically effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will dépend on the route of 15 administration, the type of animal, including human, being treated, and the physîcal characteristics of the spécifie animal under considération. The dose can be tailored to achieve a desired effect, but will dépend on such factors as weight, diet, concurrent médication and other factors which those skilled in the medical arts will recognize.
[0173] As will be readily apparent to one skilled in the art, the useful in vivo 20 dosage to be administered and the particular mode of administration will vary depending upon the âge, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the spécifie use for which these compounds are employed. The détermination of effective dosage levels, that is the dosage levels necessary to achieve the desired resuit, can be accomplished by one skilled in the art using routine 25 methods, for example, human clinical trials and in vitro studies.
(0174] The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Altematively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the 30 dosage can be made. The daily dosage regimen for an adult human patient may be, for
example, an oral dose of between 0.01 mg and 3000 mg of each active ingrédient, preferably between l mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a sériés of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can be administered less frequently compared to the frequency of administration of an agent within the standard of care. In some embodiments, a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can be 10 administered one time per day. For example, a compound of Formula (l), or a pharmaceutically acceptable sait thereof, can be administered one time per day to a subject suffering from a HCV infection. In some embodiments, the total time of the treatment régime with a compound of Formula (I) (including a compound of Formula (la)), or a pharmaceutically acceptable sait thereof, can less compared to the total time of the treatment 15 régime with the standard of care.
[0175] In instances where human dosages for compounds hâve been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly20 dîscovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualîfied by toxicity studies and efficacy studies in animais.
[0176] In cases of administration of a pharmaceutically acceptable sait, dosages may be calculated as the free base. As will be understood by those of skill in the art, in 25 certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressîvely treat particularly aggressive diseases or infections.
|0177] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or 30 minimal effective concentration (MEC). The MEC will vary for each compound but can be
estîmated from in vitro data. Dosages necessary to achieve the MEC will dépend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to détermine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains 5 plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or sélective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0178] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. 10 Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adéquate (precludîng toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic évaluation methods. Further, 15 the dose and perhaps dose frequency, will also vary according to the âge, body weight, and response of the individual patient. A program comparable to that dîscussed above may be used in veterinary medicine.
[0179] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicoiogy of a particular compound, or of a subset 20 of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often prédictive of toxicity in animais, such as mammals, or more specifically, humans. Altematively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The 25 efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal model s, or human clinical trials. When selecting a model to détermine efficacy, the skilled artisan can be guîded by the state of the art to choose an appropriate model, dose, route of administration and/or régime.
Combination Thérapies [0180J In some embodiments, the compounds disclosed herein, such as a compound of Formula (I) (including compounds of Formula (la)), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound described 5 herein, can be used în combination with one or more additional agent(s). Examples of additional agents that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, include, but are not limited to, agents currently used în a conventional standard of care for treating HCV, HCV 10 protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of Formula (AA) (including mono-, di, and/or tri-phosphates of Formula (AA), pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (AA), mono-, di- and/or tri- phosphates thereof, or a pharmaceutically acceptable sait of the foregoîng), compounds of Formula (BB) (including pharmaceutically 15 acceptable salts and pharmaceutical compositions that can include a compound of Formula (BB), or a pharmaceutically acceptable sait thereof), compounds of Formula (DD) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (DD), or a pharmaceutically acceptable sait thereof), and/or combinations thereof. In some embodiments, a compound of Formula (I), or a 20 pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used with one, two, three or more additional agents described herein. A non-limiting list of examples of combinations of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a 25 pharmaceutically acceptable sait thereof, is provided in Tables A, B, C and D.
|0181] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (Ί), or a pharmaceutically acceptable sait thereof, can be used in combination with an agent(s) currently used in a conventional standard of care therapy. For example, for the 30 treatment of HCV, a compound disclosed herein can be used in combination with Pegylated
înterferon-alpha-2a (brand name PEGASYS®) and ribavirin, or Pegylated înterferon-alpha2b (brand name PEG-INTRON®) and ribavirin. As another example, a compound disclosed herein can be used in combination with oseltamivir (TAMIFLU®) or zanamîvin (RELENZA®) for treating an influenza infection.
(0182] In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be substituted for an agent currently used in a conventional standard of care therapy. For example, for the treatment of HCV, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used în place of ribavirin.
I0183J In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with an interferon, such as a pegylated interferon. Examples of suitable interferons include, but are not limited to, Pegylated înterferon-alpha-2a (brand name PEGASYS®), Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferon alfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or a combination thereof.
10184] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with a HCV protease inhibitor. A non-limiting list of example HCV protease inhibitors include the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS650032, SCH 503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof. A nonlimiting list of example HCV protease inhibitors includes the compounds numbered 10011014 in Figure 2.
(0185] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with a ©
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 nonnucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not Iimited to, RG7128, PSI-7851, PSI-7977, INX-184, PS1-352938, PSI-661, 4’-azidouridine (including 5 known prodrugs of d’-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinations thereof. A non-iimiting iist of example nucleoside inhibitors includes compounds numbered 2001-2010 in Figure 3. Examples of suitable non-nucieoside inhibitors include, but are not Iimited to, ABT-333, ANA-598, VX-222, HCV-796, BI207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof. A 10 non-limiting list of example non-nucleoside inhibitors includes the compounds numbered 3001-3008 in Figure 4.
|0186J In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with a 15 NS5A inhibitor. A non-limiting list of example NS5A inhibitors include BMS-790052, PPI461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A non-limiting list of example NS5A inhibitors includes the compounds numbered 4001-4005 in Figure 5.
10187] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of 20 Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not Iimited to, Debîo-025, MIR-122 and/or combinations thereof. A non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5002 in Figure 6.
[0188| In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with a compound of Formula (AA), mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable sait of the foregoîng, or a pharmaceutical composition that includes a compound of Formula (AA), mono-, di- and/or tri-phosphate thereof, or a pharmaceutically acceptable sait of the foregoing (see, U.S. Provisionai Application Nos. 61/385,425, filed September 22,
2010, and 61/426,467, filed December 22, 2010, the contents of which are incorporated by reference in its entirety):
Formula (AA) wherein BAA1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; RAA1 can be an optionally substituted Nlinked amino acid or an optionally substituted N-linked amino acid ester derivative; RAA3 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; RAA3a and RAA3b can be independently selected from hydrogen, an optionally substituted C[.6 alkyl, an optionally substituted C2.6 alkenyl, an optionally substituted C2.s alkynyl, an optionally substituted CY haloalkyl and aryl(Cj_6 alkyl), provided that at least one of RAA3a and RAA3b is not hydrogen; or RAA3a and RAA3b can be taken together to form a group selected from an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted C3.6 aryl, and an optionally substituted CY heteroaryl; RAA4 can be hydrogen; RAA5 can be selected from hydrogen, ORaa9 and -OC(=O)RAA1°; RAA6 can be selected from hydrogen, halogen, -ORAAl1 and OC(=O)Raa12; or RAA5 and RAA6 can be both oxygen atoms and linked together by a carbonyl group; Raa7 can be selected from hydrogen, halogen, an optionally substituted Ci.6 alkyl, Oraa1î and -OC(=O)RAAI4; Raa8 can be hydrogen or an optionally substituted Cj.6 alkyl; Raa9, Raah and RAA13 can be independently selected from hydrogen and an optionally substituted Ci.6 alkyl; and RAA'°, RAA12 and RAA14 can be independently selected from an optionally substituted Ci.6 alkyl and an optionally substituted C3-6 cycloalkyl. A non-lîmiting list of examples of compounds of Formula (AA), and phosphates thereof, includes the compounds numbered 7000-7077 in Figures 8A-81. In some embodiments, Formula (AA) cannot be compound 7044, 7045, 7046, 7047, 7048, 7049, 7050, 7072, 7073, 7074, 7075,
7076 or 7077.
[0189] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with a compound of Formula (BB), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (BB), or a pharmaceutically acceptable sait thereof (see, U.S. Provisional Application No. 61/426,471, filed December 22, 2010, the contents of which are incorporated by reference in its entirety):
wherein Bbb1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; XBB can be O (oxygen) or S (sulfur); RBB1 can be selected from -ZBB-RBB9, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; ZBB can be selected from O (oxygen), S (sulfur) and N(RBB1°); RBB2 and RBB3 can be independently selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2.& alkenyl, an optionally substituted C2_6 alkynyl, an optionally substituted C]_6 haloalkyl and an optionally substituted aryl(Cj.6 alkyl); or RBB2 and RBB3 can be taken together to form a group selected from an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted C3.6 aryl and an optionally substituted C3-6 heteroaiyl; RBB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C|.(, alkyl, an optionally substituted C2.& alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted allenyl; RBB5 can be hydrogen or an optionally substituted alkyl; RBB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted Ci_6 alkyl, ORBBil and -OC(=O)RBB12; RBB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Ci-6 alkyl, -ORBB13 and -OC(=O)RBBl4; RBB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Ci.& alkyl, -ORBBl5 and OC(=O)RBB16; RBB9 can be selected from an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C(_6alkyl), an optionally substituted heteroaryl(Ci^alkyl) and an optionally substituted heterocyclyl(C]. ôalkyl); RBBl° can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(Ci_6alkyl), an optionally substituted heteroaryl(Cj.6alkyl) and an optionally substituted heterocyclyl(C], oalkyl); RBBH, RBB13 and Rbb,s can be independently hydrogen or an optionally substituted Cj.6 alkyl; and RBB12, RBBl4 and RBB,f> can be independently an optionally substituted Ci.^ alkyl or an optionally substituted C3.6 cycloalkyl. In some embodiments, at least one of RBB2 and Rbb3 is not hydrogen. A non-limiting list of example compounds of Formula (BB) includes the compound numbered 8000-8012 in Figures 9A-9B.
10190] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in combination with a compound of Formula (DD), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (DD), or a pharmaceutically acceptable sait thereof (see, U.S. Publication No. 2010-0249068, filed
March 19, 2010, the contents of which are incorporated by reference in its entirety):
Formula (DD) wherein each ------ can be independently a double or single bond; ADDI can be selected from C (carbon), O (oxygen) and S (sulfur); BDDl can be an optionally substituted heterocyclic base or a dérivative thereof; Ddd1 can be selected from C=CH2, CH2, O (oxygen), S (sulfur), CHF, and CF2; RDD1 can be hydrogen, an optionally substituted alkyl, an
optionally substituted cycloalkyl, an optionally substituted aralkyl, dialkylaminoalkylene, alkyl- C(=O)- , aryl- C(=O)- , alkoxyalkyl- C(=O)- , aryloxyalkyl- C(=O)- , alkylsulfonyl, aryl sulfonyl, aralkylsulfonyl,
an -O-linked amino acid, diphosphate, triphosphate or dérivatives thereof; RDD2 and RDD3 can be each independently selected from hydrogen, an optionally substituted C|.6 alkyl, an optionally substituted C2.6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted Ci.6 haloalkyl, provided that at least one of RDD2 and RDD3 cannot be hydrogen; or RDD2 and RDD3 are taken together to form a group selected from among C3_6 cycloalkyl, C3.6 cycloalkenyl, C3.6 aryl, and a C3_6 heteroaryl; RDD4 and RDD9 can be independently selected from hydrogen, halogen, -NH2, NHRDDa1, NRDDalRDDbl, -0RDDa1, -SRDDal, -CN, -NC, -N3, -NO2, -N(RDDc,)-NRDDalRDDbl, N(RDDcl)-0RDDal, -S-SRDDal, -C(=0)RDDal, -C(=O)ORDDa1, -C(=O)NRDDalRDDbl, -O(C=0)RDDal, -0-C(=0)0RDDal, -O-C(=O)NRDDa,RDDb', -N(RDDcl)-C(=O)NRDDa,RDDb1, S(=O)RDDa1, S(=O)2RDDal, -O-S(=O)2NRL)Da,RDDb1, -N(RÜDd)-S(=O)2NRDLîalRDDhl, an optionally substituted Ci.6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2_6 alkynyl, an optionally substituted aralkyl and an -O-linked amino acid; RDD5, RDD6 and RDD7 can be independently absent or selected from hydrogen, halogen, -NH2, NHRDDal, NRDDalRDDbl> _SRnDa1, _CN, _NC, _N^ _N(RDDcl) NRDDalRDDM _
N(RDDcl)-ORDDal, -S-SRDDal, -C(=0)RDDal, -C(=O)ORDDal, -C(=O)NRDDalRDnbl, -O (C=O)RDDal, -O-C(=O)ORDDal, -O-C(=O)NRDDa,RDDbl
-N(RDDcl)-C(=O)NRDDalRDDbl,
S(=O)RDDal, S(=O)2RDDal, -O-S(=O)2NRDDalRDDb1, -N(RDDel)-S(=O)2NRDDa,RDDbl, an optionally substituted C].6 alkyl, an optionally substituted C2_6 alkenyl, an optionally substituted C2.6 alkynyl, an optionally substituted aralkyl and an -O-linked amino acid; or RDD6 and RDD7 taken together form —O—C(=O)—O— ; RDD8 can be absent or selected from the group consisting of hydrogen, halogen, -NH2, -NHRDDa1, NRDDalRDDbl, -ORDDal, -SRDDal, CN, -NC, -N3, -NO2, -N(RDDtl)-NRDDalRDDbl, -N(RDDci)-ORDDa1, -S-SRDDa1, -C(=O)RDDal, C(=O)ORDDal, -C(=O)NRDDa1RDDbl, -O-C(=O)ORDDal, -O-C(=O)NRDDalRDDbl, -N(RDDcl)C(=O)NRDDalRDDbl, -S(=O)RDDa1, S(=O)2RDDal, -O-S(=0)2NRDDa!RDDbl, -N(RDDc1)S(=O)2NRDDa1RDDbl, an optionally substituted Ci.6 alkyl, an optionally substituted C2-6
alkenyl, an optionally substituted C2.6 alkynyl, an optionally substituted haloalkyl, an optionally substituted hydroxyalkyl and an -O-linked amino acid, or when the bond to RDD7 indicated by — is a double bond, then RDD7 îs a C2.6 alkylidene and RDD8 is absent; RDDa1, RDDbl and RDDcl can be each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and an optionally substituted hetcroaryl(C].6 alkyl); RDDl° can be selected from O~, OH, an optionally substituted aryloxy or aryl-O-,
, alkylC(=O)-O-CH2-O-, alkyl-C(=O)-S-CH2CH2-O- and an -N-linked amino acid; RDD11 can be from O , -OH, an optionally substituted aryloxy or aryl-O-, selected
rDD14 an -N-linked amino acid; each alkyl-C(=O)-O-CH2-O-, alkyl-C(=O)-S-CH2CH2-O- and RDDl2 and each RDD13 can be independently -C=N or an optionally substituted substituent selected from Ci.g organylcarbonyl, Cj-s alkoxycarbonyl and C].g organylaminocarbonyl; each RDD14 can be hydrogen or an optionally substituted Ci.6alkyl; each mDD can be independently 1 or 2, and if both RDD1° and rddu
, each R
DD12 each RDDl3, each RDD14 and each mDD can be the same or different. In some embodiments, RDD8 can be halogen, -ORDDal, an optionally substituted Ct.6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2_6 alkynyl and an optionally substituted Ci_6 haloalkyl.
|0191] Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include contacting a cell infected with the viral infection
with a therapeutically effective amount of a cornpound of Formula (I) (including a cornpound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease înhibitor, a HCV polymerase înhibitor, a NS5A inhibîtor, an antiviral cornpound, a cornpound of Formula 5 (AA), a mono-, di, and/or tri-phosphate thereof, a cornpound of Formula (BB), and a cornpound of Formula (DD), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
[0192] Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from the viral 10 infection a therapeutically effective amount of a cornpound of Formula (I) (including a cornpound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease înhibitor, a HCV polymerase înhibitor, a NS5A înhibitor, an antiviral cornpound, a cornpound of Formula (AA), a mono-, di, and/or tri-phosphate thereof, a cornpound of Formula (BB), and a 15 cornpound of Formula (DD), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
|0193] Some embodiments described herein relate to a method of inhibiting viral réplication of a virus that can include contacting a cell infected with the virus with an effective amount of a cornpound of Formula (I) (including a cornpound of Formula (Ια)), or a 20 pharmaceutically acceptable sait thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease înhibitor, a HCV polymerase înhibitor, a NS5A înhibitor, an antiviral cornpound, a cornpound of Formula (AA), a mono-, di, and/or triphosphate thereof, a cornpound of Formula (BB), and a cornpound of Formula (DD), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
|0194] Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include contacting a cell infected with the viral infection with a therapeutically effective amount of a cornpound of Formula (I) (including a cornpound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease înhibitor, a HCV 30 polymerase înhibitor, a NS5A înhibitor, an antiviral cornpound, a cornpound of Formula
C (AA), a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
]0195] Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from the viral infection a therapeutically effective amount of a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
J0196J Some embodiments described herein relate to a method of inhibiting viral réplication of a virus that can include contacting a cell înfected with the virus with an effective amount of a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, în combination with one or more agents selected 15 from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (AA), a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
[0197] In some embodiments, a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered with one or more additional agent(s) together în a single pharmaceutical composition. In some embodiments, a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait the thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of
Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I) (including a compound
of Formula (Ια)), or a pharmaceutically acceptable sait thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
[0198] The dosing amount(s) and dosing schedule(s) when using a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition 5 that includes a compound of Formula (1), or a pharmaceutically acceptable sait thereof, and one or more additional agents are within the knowledge of those skilled in the art. For example, when performîng a conventional standard of care therapy using art-recognized dosing amounts and dosing schedules, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of 10 Formula (I), or a pharmaceutically acceptable sait thereof, can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective amounts and dosing protocols as described herein.
[0199] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, with one or more additional agent(s) can vary. In 15 some embodiments, a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered prior to ail additional agents. In other embodiments, a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (I) (including a 20 compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered subséquent to the administration of at least one additional agent. In some embodiments, a compound of 25 Formula (I) (including a compound of Formula (Ια)), or a pharmaceutically acceptable sait thereof, can be administered subséquent to the administration of ail additional agents.
[0200] In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) 30 can resuit in an additive effect. In some embodiments, the combination of a compound of
Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) can resuit in a synergistic effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, în combination 5 with one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) can resuit in a strongly synergistic effect. In some embodiments, the combination of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) is not 10 antagonistic.
[0201] As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound îs determined individually (i.e. as a single compound). As used herein, the term “synergistic effect” means that the activity of the 15 combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term “additîve effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined 20 individually.
[0202] A potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) may be a réduction in the required amount(s) of one or more compounds of Figures 2-6 and 25 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, HCV), as compared to the amount required to achieve same therapeutic resuit when one or more compounds of Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) are administered without a compound of Formula (I), or a pharmaceutically acceptable sait thereof. For 30 example, the amount of a compound in Figures 2-6 and 8-10 (including a pharmaceutically
acceptable sait and prodrug thereof), can be less compared to the amount of the compound in Figures 2-6 and 8-10 (including a pharmaceutically acceptable sait and prodrug thereof), needed to achieve the same viral load réduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (I), or a pharmaceutically 5 acceptable sait thereof, in combination with one or more additional agent(s) în Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of résistant viral strains compared to the barrier when a compound is administered as monotherapy.
[0203J Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) may include little to no cross résistance between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof) thereof; different routes for élimination of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof); little to no overlapping toxîcities between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or 20 more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) in Figures 2-6 and 8-10 (including pharmaceutically acceptable salts and prodrugs thereof).
J02041 A non-limiting list of example combination of compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound described herein, with one or more additional agent(s) are provided in Tables A, B, C and D. Each numbered X and Y compound in Tables A, B, C and D has a corresponding name and/or structure provided in Figures 2 to 10. The numbered compounds 30 in Tables A, B, C and D includes pharmaceutically acceptable salts of the compounds and
pharmaceutical compositions containing the compounds or a pharmaceutically acceptable sait thereof. For example, ÎOOI includes the compound corresponding to ÎOOI, pharmaceutically acceptable salts thereof, and pharmaceutical compositions that include compound lOOl and/or a pharmaceutically acceptable sait thereof. The combinations exemplified in Tables 5 A, B, C and D are designated by the formula X:Y, which represents a combination of a compound X with a compound Y. For example, the combination designated as 1001:6001 in
Table A represents a combination of compound 1001 with compound 6001, including pharmaceutically acceptable salts of compound 1001 and/or 6001, and pharmaceutical compositions including compound 1001 and 6001 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 6001). Thus, the combination designated as 1001:6001 in Table A represents the combination of
Telaprevir (compound 1001, as shown in Figure 2) and (compound 6001, as shown in Figure 7A), including pharmaceutically acceptable salts of compound 1001 and/or 6001, and pharmaceutical compositions including compound 1001 and 6001 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 6001). Each of the combinations provided in Tables A, B, C and D can be used with one, two, three or more addîtional agents described herein. In some embodiments, embodiments described herein, the combination of agents can be used to treat, amerliorate and/or inhibit a virus and/or a viral infection, wherein the virus can be HCV and the viral infection can be an HCV viral infection.
Table A: Example combinations of a compound X with a compound Y.
X | : Y | X | Y | X | Y | X | : Y | X | Y | X | Y | X: |
1001 | 6000 | 1001 | 6001 | 1001 | 6002 | 1001 | 6003 | 1001 | 6004 | 1001 | 6005 | 1001 : |
1002 | 6000 | 1002 | 6001 | 1002 | 6002 | 1002 | 6003 | 1002 | 6004 | 1002 | 6005 | 1002 : |
1003 | 6000 | 1003 | 6001 | 1003 | 6002 | 1003 | 6003 | 1003 | 6004 | 1003 | 6005 | 1003 : |
1004 | 6000 | 1004 | 6001 | 1004 | 6002 | 1004 | 6003 | 1004 | 6004 | 1004 | 6005 | 1004: |
1005 | 6000 | 1005 | 6001 | 1005 | 6002 | 1005 | 6003 | 1005 | 6004 | 1005 | 6005 | 1005: |
1006 | 6000 | 1006 | 6001 | 1006 | 6002 | 1006 | 6003 | 1006 | 6004 | 1006 | 6005 | 1006 : |
1007 | 6000 | 1007 | 6001 | 1007 | 6002 | 1007 | 6003 | 1007 | 6004 | 1007 | 6005 | 1007 : |
1008 | 6000 | 1008 | 6001 | 1008 | 6002 | 1008 | 6003 | 1008 | 6004 | 1008 | 6005 | 1008 : |
1009 | 6000 | 1009 | 6001 | 1009 | 6002 | 1009 | 6003 | 1009 | 6004 | 1009 | 6005 | 1009: |
1010 | 6000 | 1010 | 6001 | 1010 | 6002 | 1010 | 6003 | 1010 | 6004 | 1010 | 6005 | 1010 : |
lOll | 6000 | 1011 | 6001 | 1011 | 6002 | 1011 | 6003 | 1011 | 6004 | 1011 | 6005 | 1011 : |
1012 | 6000 | 1012 | 6001 | 1012 | 6002 | 1012 | 6003 | 1012 | 6004 | 1012 | 6005 | 1012 : |
1013 | 6000 | 1013 | 6001 | 1013 | 6002 | 1013 | 6003 | 1013 | 6004 | 1013 | 6005 | 1013 : |
1014 | 6000 | 1014 | 6001 | 1014 | 6002 | 1014 | 6003 | 1014 | 6004 | 1014 | 6005 | 1014: |
2001 | 6000 | 2001 | 6001 | 2001 | 6002 | 2001 | 6003 | 2001 | 6004 | 2001 | 6005 | 2001 : |
2002 | 6000 | 2002 | 6001 | 2002 | 6002 | 2002 | 6003 | 2002 | 6004 | 2002 | 6005 | 2002 : |
2003 | 6000 | 2003 | 6001 | 2003 | 6002 | 2003 | 6003 | 2003 | 6004 | 2003 | 6005 | 2003 : |
2004 | 6000 | 2004 | 6001 | 2004 | 6002 | 2004 | 6003 | 2004 | 6004 | 2004 | 6005 | 2004 : |
2005 | 6000 | 2005 | 6001 | 2005 | 6002 | 2005 | 6003 | 2005 | 6004 | 2005 | 6005 | 2005 : |
2006 | 6000 | 2006 | 6001 | 2006 | 6002 | 2006 | 6003 | 2006 | 6004 | 2006 | 6005 | 2006: |
2007 | 6000 | 2007 | 6001 | 2007 | 6002 | 2007 | 6003 | 2007 | 6004 | 2007 | 6005 | 2007 : |
2008 | 6000 | 2008 | 6001 | 2008 | 6002 | 2008 | 6003 | 2008 | 6004 | 2008 | 6005 | 2008 : |
2009 | 6000 | 2009 | 6001 | 2009 | 6002 | 2009 | 6003 | 2009 | 6004 | 2009 | 6005 | 2009 : |
2010 | 6000 | 2010 | 6001 | 2010 | 6002 | 2010 | 6003 | 2010 | 6004 | 2010 | 6005 | 2010: |
3001 | 6000 | 3001 | 6001 | 3001 | 6002 | 3001 | 6003 | 3001 | 6004 | 3001 | 6005 | 3001 : |
3002 | 6000 | 3002 | 6001 | 3002 | 6002 | 3002 | 6003 | 3002 | 6004 | 3002 | 6005 | 3002 : |
3003 | 6000 | 3003 | 6001 | 3003 | 6002 | 3003 | 6003 | 3003 | 6004 | 3003 | 6005 | 3003 : |
3004 | 6000 | 3004 | 6001 | 3004 | 6002 | 3004 | 6003 | 3004 | 6004 | 3004 | 6005 | 3004 : |
3005 | 6000 | 3005 | 6001 | 3005 | 6002 | 3005 | 6003 | 3005 | 6004 | 3005 | 6005 | 3005 : |
3006 | 6000 | 3006 | 6001 | 3006 | 6002 | 3006 | 6003 | 3006 | 6004 | 3006 | 6005 | 3006 : |
3007 | 6000 | 3007 | 6001 | 3007 | 6002 | 3007 | 6003 | 3007 | 6004 | 3007 | 6005 | 3007 : |
3008 | 6000 | 3008 | 6001 | 3008 | 6002 | 3008 | 6003 | 3008 | 6004 | 3008 | 6005 | 3008 : |
4001 | 6000 | 4001 | 6001 | 4001 | 6002 | 4001 | 6003 | 4001 | 6004 | 4001 | 6005 | 4001 : |
4002 | 6000 | 4002 | 6001 | 4002 | 6002 | 4002 | 6003 | 4002 | 6004 | 4002 | 6005 | 4002 : |
4003 | 6000 | 4003 | 6001 | 4003 | 6002 | 4003 | 6003 | 4003 | 6004 | 4003 | 6005 | 4003 : |
4004 | 6000 | 4004 | 6001 | 4004 | 6002 | 4004 | 6003 | 4004 | 6004 | 4004 | 6005 | 4004 : |
4005 | 6000 | 4005 | 6001 | 4005 | 6002 | 4005 | 6003 | 4005 | 6004 | 4005 | 6005 | 4005 : |
5001 | 6000 | 5001 | 6001 | 5001 | 6002 | 5001 | 6003 | 5001 | 6004 | 5001 | 6005 | 5001 : |
5002 | 6000 | 5002 | 6001 | 5002 | 6002 | 5002 | 6003 | 5002 | 6004 | 5002 | 6005 | 5002 : |
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
6006
X | Y | X | Y | X | Y | X: Y | X | Y | X | Y | X | Y |
ιοοι | 6007 | 1001 | 6008 | 1001 | 6009 | 1001 : 6010 | 1001 | 6011 | 1001 | 6012 | 1001 | 6013 |
1002 | 6007 | 1002 | 6008 | 1002 | 6009 | 1002 : 6010 | 1002 | 6011 | 1002 | 6012 | 1002 | 6013 |
1003 | 6007 | 1003 | 6008 | 1003 | 6009 | 1003 : 6010 | 1003 | 6011 | 1003 | 6012 | 1003 | 6013 |
1004 | 6007 | 1004 | 6008 | 1004 | 6009 | 1004:6010 | 1004 | 6011 | 1004 | 6012 | 1004 | 6013 |
1005 | 6007 | 1005 | 6008 | 1005 | 6009 | 1005:6010 | 1005 | 6011 | 1005 | 6012 | 1005 | 6013 |
1006 | 6007 | 1006 | 6008 | 1006 | 6009 | 1006 : 6010 | 1006 | 6011 | 1006 | 6012 | 1006 | 6013 |
1007 | 6007 | 1007 | 6008 | 1007 | 6009 | 1007:6010 | 1007 | 6011 | 1007 | 6012 | 1007 | 6013 |
1008 | 6007 | 1008 | 6008 | 1008 | 6009 | 1008 : 6010 | 1008 | 6011 | 1008 | 6012 | 1008 | 6013 |
1009 | 6007 | 1009 | 6008 | 1009 | 6009 | 1009:6010 | 1009 | 6011 | 1009 | 6012 | 1009 | 6013 |
1010 | 6007 | 1010 | 6008 | 1010 | 6009 | 1010:6010 | 1010 | 6011 | 1010 | 6012 | 1010 | 6013 |
1011 | 6007 | 1011 | 6008 | 1011 | 6009 | 1011 : 6010 | 1011 | 6011 | 1011 | 6012 | 1011 | 6013 |
1012 | 6007 | 1012 | 6008 | 1012 | 6009 | 1012 : 6010 | 1012 | 6011 | 1012 | 6012 | 1012 | 6013 |
1013 | 6007 | 1013 | 6008 | 1013 | 6009 | 1013 : 6010 | 1013 | 6011 | 1013 | 6012 | 1013 | 6013 |
1014 | 6007 | 1014 | 6008 | 1014 | 6009 | 1014 : 6010 | 1014 | 6011 | 1014 | 6012 | 1014 | 6013 |
2001 | 6007 | 2001 | 6008 | 2001 | 6009 | 2001 : 6010 | 2001 | 6011 | 2001 | 6012 | 2001 | 6013 |
2002 | 6007 | 2002 | 6008 | 2002 | 6009 | 2002 : 6010 | 2002 | 6011 | 2002 | 6012 | 2002 | 6013 |
2003 | 6007 | 2003 | 6008 | 2003 | 6009 | 2003 : 6010 | 2003 | 6011 | 2003 | 6012 | 2003 | 6013 |
2004 | 6007 | 2004 | 6008 | 2004 | 6009 | 2004 : 6010 | 2004 | 6011 | 2004 | 6012 | 2004 | 6013 |
2005 | 6007 | 2005 | 6008 | 2005 | 6009 | 2005 : 6010 | 2005 | 6011 | 2005 | 6012 | 2005 | 6013 |
2006 | 6007 | 2006 | 6008 | 2006 | 6009 | 2006 : 6010 | 2006 | 6011 | 2006 | 6012 | 2006 | 6013 |
2007 | 6007 | 2007 | 6008 | 2007 | 6009 | 2007: 6010 | 2007 | 6011 | 2007 | 6012 | 2007 | 6013 |
2008 | 6007 | 2008 | 6008 | 2008 | 6009 | 2008 : 6010 | 2008 | 6011 | 2008 | 6012 | 2008 | 6013 |
2009 | 6007 | 2009 | 6008 | 2009 | 6009 | 2009:6010 | 2009 | 6011 | 2009 | 6012 | 2009 | 6013 |
2010 | 6007 | 2010 | 6008 | 2010 | 6009 | 2010:6010 | 2010 | 6011 | 2010 | 6012 | 2010 | 6013 |
3001 | 6007 | 3001 | 6008 | 3001 | 6009 | 3001 : 6010 | 3001 | 6011 | 3001 | 6012 | 3001 | 6013 |
3002 | 6007 | 3002 | 6008 | 3002 | 6009 | 3002 : 6010 | 3002 | 6011 | 3002 | 6012 | 3002 | 6013 |
3003 | 6007 | 3003 | 6008 | 3003 | 6009 | 3003 :6010 | 3003 | 6011 | 3003 | 6012 | 3003 | 6013 |
3004 | 6007 | 3004 | 6008 | 3004 | 6009 | 3004: 6010 | 3004 | 6011 | 3004 | 6012 | 3004 | 6013 |
3005 | 6007 | 3005 | 6008 | 3005 | 6009 | 3005 : 6010 | 3005 | 6011 | 3005 | 6012 | 3005 | 6013 |
3006 | 6007 | 3006 | 6008 | 3006 | 6009 | 3006: 6010 | 3006 | 6011 | 3006 | 6012 | 3006 | 6013 |
3007 | 6007 | 3007 | 6008 | 3007 | 6009 | 3007 : 6010 | 3007 | 6011 | 3007 | 6012 | 3007 | 6013 |
3008 | 6007 | 3008 | 6008 | 3008 | 6009 | 3008 : 6010 | 3008 | 6011 | 3008 | 6012 | 3008 | 6013 |
4001 | 6007 | 4001 | 6008 | 4001 | 6009 | 4001 : 6010 | 4001 | 6011 | 4001 | 6012 | 4001 | 6013 |
4002 | 6007 | 4002 | 6008 | 4002 | 6009 | 4002 : 6010 | 4002 | 6011 | 4002 | 6012 | 4002 | 6013 |
4003 | 6007 | 4003 | 6008 | 4003 | 6009 | 4003 :6010 | 4003 | 6011 | 4003 | 6012 | 4003 | 6013 |
4004 | 6007 | 4004 | 6008 | 4004 | 6009 | 4004 : 6010 | 4004 | 6011 | 4004 | 6012 | 4004 | 6013 |
4005 | 6007 | 4005 | 6008 | 4005 | 6009 | 4005 : 6010 | 4005 | 6011 | 4005 | 6012 | 4005 | 6013 |
5001 | 6007 | 5001 | 6008 | 5001 | 6009 | 5001 : 6010 | 5001 | 6011 | 5001 | 6012 | 5001 | 6013 |
5002 | 6007 | 5002 | 6008 | 5002 | 6009 | 5002 : 6010 | 5002 | 6011 | 5002 | 6012 | 5002 | 6013 |
X: Y | X | Y | X | Y | X | Y | X: Y | X | Y | X | Y |
ÎOOI : 6014 | 1001 | 6015 | 1001 | 6016 | 1001 | 6017 | 1001 : 6018 | 1001 | 6019 | 1001 | 6020 |
1002 : 6014 | 1002 | 6015 | 1002 | 6016 | 1002 | 6017 | 1002 : 6018 | 1002 | 6019 | 1002 | 6020 |
1003 : 6014 | 1003 | 6015 | 1003 | 6016 | 1003 | 6017 | 1003 : 6018 | 1003 | 6019 | 1003 | 6020 |
1004: 6014 | 1004 | 6015 | 1004 | 6016 | 1004 | 6017 | 1004:6018 | 1004 | 6019 | 1004 | 6020 |
1005 : 6014 | 1005 | 6015 | 1005 | 6016 | 1005 | 6017 | 1005 :6018 | 1005 | 6019 | 1005 | 6020 |
1006: 6014 | 1006 | 6015 | 1006 | 6016 | 1006 | 6017 | 1006:6018 | 1006 | 6019 | 1006 | 6020 |
1007 : 6014 | 1007 | 6015 | 1007 | 6016 | 1007 | 6017 | 1007 :6018 | 1007 | 6019 | 1007 | 6020 |
1008 : 6014 | 1008 | 6015 | 1008 | 6016 | 1008 | 6017 | 1008:6018 | 1008 | 6019 | 1008 | 6020 |
1009: 6014 | 1009 | 6015 | 1009 | 6016 | 1009 | 6017 | 1009 :6018 | 1009 | 6019 | 1009 | 6020 |
1010:6014 | 1010 | 6015 | 1010 | 6016 | 1010 | 6017 | 1010:6018 | 1010 | 6019 | 1010 | 6020 |
1011 : 6014 | 1011 | 6015 | 1011 | 6016 | 1011 | 6017 | 1011 :6018 | 1011 | 6019 | 1011 | 6020 |
1012 : 6014 | 1012 | 6015 | 1012 | 6016 | 1012 | 6017 | 1012:6018 | 1012 | 6019 | 1012 | 6020 |
1013 :6014 | 1013 | 6015 | 1013 | 6016 | 1013 | 6017 | 1013 : 6018 | 1013 | 6019 | 1013 | 6020 |
1014:6014 | 1014 | 6015 | 1014 | 6016 | 1014 | 6017 | 1014 : 6018 | 1014 | 6019 | 1014 | 6020 |
2001 : 6014 | 2001 | 6015 | 2001 | 6016 | 2001 | 6017 | 2001 : 6018 | 2001 | 6019 | 2001 | 6020 |
2002: 6014 | 2002 | 6015 | 2002 | 6016 | 2002 | 6017 | 2002 : 6018 | 2002 | 6019 | 2002 | 6020 |
2003 : 6014 | 2003 | 6015 | 2003 | 6016 | 2003 | 6017 | 2003 : 6018 | 2003 | 6019 | 2003 | 6020 |
2004 : 6014 | 2004 | 6015 | 2004 | 6016 | 2004 | 6017 | 2004 : 6018 | 2004 | 6019 | 2004 | 6020 |
2005 : 6014 | 2005 | 6015 | 2005 | 6016 | 2005 | 6017 | 2005 : 6018 | 2005 | 6019 | 2005 | 6020 |
2006 : 6014 | 2006 | 6015 | 2006 | 6016 | 2006 | 6017 | 2006 : 6018 | 2006 | 6019 | 2006 | 6020 |
2007 : 6014 | 2007 | 6015 | 2007 | 6016 | 2007 | 6017 | 2007 : 6018 | 2007 | 6019 | 2007 | 6020 |
2008 : 6014 | 2008 | 6015 | 2008 | 6016 | 2008 | 6017 | 2008 : 6018 | 2008 | 6019 | 2008 | 6020 |
2009 : 6014 | 2009 | 6015 | 2009 | 6016 | 2009 | 6017 | 2009 :6018 | 2009 | 6019 | 2009 | 6020 |
2010: 6014 | 2010 | 6015 | 2010 | 6016 | 2010 | 6017 | 2010:6018 | 2010 | 6019 | 2010 | 6020 |
3001 : 6014 | 3001 | 6015 | 3001 | 6016 | 3001 | 6017 | 3001 :6018 | 3001 | 6019 | 3001 | 6020 |
3002 : 6014 | 3002 | 6015 | 3002 | 6016 | 3002 | 6017 | 3002:6018 | 3002 | 6019 | 3002 | 6020 |
3003 : 6014 | 3003 | 6015 | 3003 | 6016 | 3003 | 6017 | 3003 : 6018 | 3003 | 6019 | 3003 | 6020 |
3004 :6014 | 3004 | 6015 | 3004 | 6016 | 3004 | 6017 | 3004 : 6018 | 3004 | 6019 | 3004 | 6020 |
3005 : 6014 | 3005 | 6015 | 3005 | 6016 | 3005 | 6017 | 3005 : 6018 | 3005 | 6019 | 3005 | 6020 |
3006: 6014 | 3006 | 6015 | 3006 | 6016 | 3006 | 6017 | 3006 : 6018 | 3006 | 6019 | 3006 | 6020 |
3007 : 6014 | 3007 | 6015 | 3007 | 6016 | 3007 | 6017 | 3007 : 6018 | 3007 | 6019 | 3007 | 6020 |
3008 : 6014 | 3008 | 6015 | 3008 | 6016 | 3008 | 6017 | 3008 : 6018 | 3008 | 6019 | 3008 | 6020 |
4001 : 6014 | 4001 | 6015 | 4001 | 6016 | 4001 | 6017 | 4001 :6018 | 4001 | 6019 | 4001 | 6020 |
4002 : 6014 | 4002 | 6015 | 4002 | 6016 | 4002 | 6017 | 4002 :6018 | 4002 | 6019 | 4002 | 6020 |
4003 : 6014 | 4003 | 6015 | 4003 | 6016 | 4003 | 6017 | 4003 : 6018 | 4003 | 6019 | 4003 | 6020 |
4004: 6014 | 4004 | 6015 | 4004 | 6016 | 4004 | 6017 | 4004 : 6018 | 4004 | 6019 | 4004 | 6020 |
4005 : 6014 | 4005 | 6015 | 4005 | 6016 | 4005 | 6017 | 4005 : 6018 | 4005 | 6019 | 4005 | 6020 |
5001:6014 | 5001 | 6015 | 5001 | 6016 | 5001 | 6017 | 5001 : 6018 | 5001 | 6019 | 5001 | 6020 |
5002 : 6014 | 5002 | 6015 | 5002 | 6016 | 5002 | 6017 | 5002 : 6018 | 5002 | 6019 | 5002 | 6020 |
X | Y | X | Y | X | Y | X | Y | X | Y | X: Y | X | Y |
ιοοι | 6021 | 1001 | 6022 | 1001 | 6023 | 1001 | 6024 | 1001 | 6025 | 1001 :6026 | 1001 | 6027 |
1002 | 6021 | 1002 | 6022 | 1002 | 6023 | 1002 | 6024 | 1002 | 6025 | 1002:6026 | 1002 | 6027 |
1003 | 6021 | 1003 | 6022 | 1003 | 6023 | 1003 | 6024 | 1003 | 6025 | 1003 : 6026 | 1003 | 6027 |
1004 | 6021 | 1004 | 6022 | 1004 | 6023 | 1004 | 6024 | 1004 | 6025 | 1004 : 6026 | 1004 | 6027 |
1005 | 6021 | 1005 | 6022 | 1005 | 6023 | 1005 | 6024 | 1005 | 6025 | 1005 : 6026 | 1005 | 6027 |
1006 | 6021 | 1006 | 6022 | 1006 | 6023 | 1006 | 6024 | 1006 | 6025 | 1006 : 6026 | 1006 | 6027 |
1007 | 6021 | 1007 | 6022 | 1007 | 6023 | 1007 | 6024 | 1007 | 6025 | 1007 : 6026 | 1007 | 6027 |
1008 | 6021 | 1008 | 6022 | 1008 | 6023 | 1008 | 6024 | 1008 | 6025 | 1008 : 6026 | 1008 | 6027 |
1009 | 6021 | 1009 | 6022 | 1009 | 6023 | 1009 | 6024 | 1009 | 6025 | 1009 : 6026 | 1009 | 6027 |
1010 | 6021 | 1010 | 6022 | 1010 | 6023 | 1010 | 6024 | 1010 | 6025 | 1010: 6026 | 1010 | 6027 |
1011 | 6021 | 1011 | 6022 | 1011 | 6023 | 1011 | 6024 | 1011 | 6025 | 1011 :6026 | 1011 | 6027 |
1012 | 6021 | 1012 | 6022 | 1012 | 6023 | 1012 | 6024 | 1012 | 6025 | 1012:6026 | 1012 | 6027 |
1013 | 6021 | 1013 | 6022 | 1013 | 6023 | 1013 | 6024 | 1013 | 6025 | 1013 : 6026 | 1013 | 6027 |
1014 | 6021 | 1014 | 6022 | 1014 | 6023 | 1014 | 6024 | 1014 | 6025 | 1014 : 6026 | 1014 | 6027 |
2001 | 6021 | 2001 | 6022 | 2001 | 6023 | 2001 | 6024 | 2001 | 6025 | 2001 : 6026 | 2001 | 6027 |
2002 | 6021 | 2002 | 6022 | 2002 | 6023 | 2002 | 6024 | 2002 | 6025 | 2002 : 6026 | 2002 | 6027 |
2003 | 6021 | 2003 | 6022 | 2003 | 6023 | 2003 | 6024 | 2003 | 6025 | 2003 : 6026 | 2003 | 6027 |
2004 | 6021 | 2004 | 6022 | 2004 | 6023 | 2004 | 6024 | 2004 | 6025 | 2004: 6026 | 2004 | 6027 |
2005 | 6021 | 2005 | 6022 | 2005 | 6023 | 2005 | 6024 | 2005 | 6025 | 2005 : 6026 | 2005 | 6027 |
2006 | 6021 | 2006 | 6022 | 2006 | 6023 | 2006 | 6024 | 2006 | 6025 | 2006:6026 | 2006 | 6027 |
2007 | 6021 | 2007 | 6022 | 2007 | 6023 | 2007 | 6024 | 2007 | 6025 | 2007 :6026 | 2007 | 6027 |
2008 | 6021 | 2008 | 6022 | 2008 | 6023 | 2008 | 6024 | 2008 | 6025 | 2008 :6026 | 2008 | 6027 |
2009 | 6021 | 2009 | 6022 | 2009 | 6023 | 2009 | 6024 | 2009 | 6025 | 2009 : 6026 | 2009 | 6027 |
2010 | 6021 | 2010 | 6022 | 2010 | 6023 | 2010 | 6024 | 2010 | 6025 | 2010 : 6026 | 2010 | 6027 |
3001 | 6021 | 3001 | 6022 | 3001 | 6023 | 3001 | 6024 | 3001 | 6025 | 3001 : 6026 | 3001 | 6027 |
3002 | 6021 | 3002 | 6022 | 3002 | 6023 | 3002 | 6024 | 3002 | 6025 | 3002 : 6026 | 3002 | 6027 |
3003 | 6021 | 3003 | 6022 | 3003 | 6023 | 3003 | 6024 | 3003 | 6025 | 3003 : 6026 | 3003 | 6027 |
3004 | 6021 | 3004 | 6022 | 3004 | 6023 | 3004 | 6024 | 3004 | 6025 | 3004:6026 | 3004 | 6027 |
3005 | 6021 | 3005 | 6022 | 3005 | 6023 | 3005 | 6024 | 3005 | 6025 | 3005 :6026 | 3005 | 6027 |
3006 | 6021 | 3006 | 6022 | 3006 | 6023 | 3006 | 6024 | 3006 | 6025 | 3006 :6026 | 3006 | 6027 |
3007 | 6021 | 3007 | 6022 | 3007 | 6023 | 3007 | 6024 | 3007 | 6025 | 3007 : 6026 | 3007 | 6027 |
3008 | 6021 | 3008 | 6022 | 3008 | 6023 | 3008 | 6024 | 3008 | 6025 | 3008 : 6026 | 3008 | 6027 |
4001 | 6021 | 4001 | 6022 | 4001 | 6023 | 4001 | 6024 | 4001 | 6025 | 4001 : 6026 | 4001 | 6027 |
4002 | 6021 | 4002 | 6022 | 4002 | 6023 | 4002 | 6024 | 4002 | 6025 | 4002 : 6026 | 4002 | 6027 |
4003 | 6021 | 4003 | 6022 | 4003 | 6023 | 4003 | 6024 | 4003 | 6025 | 4003 :6026 | 4003 | 6027 |
4004 | 6021 | 4004 | 6022 | 4004 | 6023 | 4004 | 6024 | 4004 | 6025 | 4004 :6026 | 4004 | 6027 |
4005 | 6021 | 4005 | 6022 | 4005 | 6023 | 4005 | 6024 | 4005 | 6025 | 4005 : 6026 | 4005 | 6027 |
5001 | 6021 | 5001 | 6022 | 5001 | 6023 | 5001 | 6024 | 5001 | 6025 | 5001 : 6026 | 5001 | 6027 |
5002 | 6021 | 5002 | 6022 | 5002 | 6023 | 5002 | 6024 | 5002 | 6025 | 5002 : 6026 | 5002 | 6027 |
I
X | : Y | X | Y | X | Y | X | Y | X | Y | X: Y | X | Y |
ιοοι | 6028 | ÎOOI | 6029 | 1001 | 6030 | 1001 | 6031 | 1001 | 6032 | 1001 :6033 | 1001 | 6034 |
1002 | 6028 | 1002 | 6029 | 1002 | 6030 | 1002 | 6031 | 1002 | 6032 | 1002 : 6033 | 1002 | 6034 |
1003 | 6028 | 1003 | 6029 | 1003 | 6030 | 1003 | 6031 | 1003 | 6032 | 1003 : 6033 | 1003 | 6034 |
1004 | 6028 | I004 | 6029 | 1004 | 6030 | 1004 | 6031 | 1004 | 6032 | 1004: 6033 | 1004 | 6034 |
1005 | 6028 | 1005 | 6029 | 1005 | 6030 | 1005 | 6031 | 1005 | 6032 | 1005 : 6033 | 1005 | 6034 |
1006 | 6028 | 1006 | 6029 | 1006 | 6030 | 1006 | 6031 | 1006 | 6032 | 1006 :6033 | 1006 | 6034 |
1007 | 6028 | 1007 | 6029 | 1007 | 6030 | 1007 | 6031 | 1007 | 6032 | 1007 : 6033 | 1007 | 6034 |
1008 | 6028 | 1008 | 6029 | 1008 | 6030 | 1008 | 6031 | 1008 | 6032 | 1008 : 6033 | 1008 | 6034 |
1009 | 6028 | 1009 | 6029 | 1009 | 6030 | 1009 | 6031 | 1009 | 6032 | 1009 : 6033 | 1009 | 6034 |
ΙΟΙΟ | 6028 | ÎOIO | 6029 | 1010 | 6030 | 1010 | 6031 | 1010 | 6032 | 1010:6033 | 1010 | 6034 |
IOll | 6028 | IOll | 6029 | 1011 | 6030 | 1011 | 6031 | 1011 | 6032 | 1011 :6033 | 1011 | 6034 |
1Ο12 | 6028 | I012 | 6029 | 1012 | 6030 | 1012 | 6031 | 1012 | 6032 | 1012 :6033 | 1012 | 6034 |
IO13 | 6028 | 1013 | 6029 | 1013 | 6030 | 1013 | 6031 | 1013 | 6032 | 1013 : 6033 | 1013 | 6034 |
1014 | 6028 | 1014 | 6029 | 1014 | 6030 | 1014 | 6031 | 1014 | 6032 | 1014:6033 | 1014 | 6034 |
2001 | 6028 | 2001 | 6029 | 2001 | 6030 | 2001 | 6031 | 2001 | 6032 | 2001 : 6033 | 2001 | 6034 |
2002 | 6028 | 2002 | 6029 | 2002 | 6030 | 2002 | 6031 | 2002 | 6032 | 2002 : 6033 | 2002 | 6034 |
2003 | 6028 | 2003 | 6029 | 2003 | 6030 | 2003 | 6031 | 2003 | 6032 | 2003 : 6033 | 2003 | 6034 |
2004 | 6028 | 2004 | 6029 | 2004 | 6030 | 2004 | 6031 | 2004 | 6032 | 2004 : 6033 | 2004 | 6034 |
2005 | 6028 | 2005 | 6029 | 2005 | 6030 | 2005 | 6031 | 2005 | 6032 | 2005 : 6033 | 2005 | 6034 |
2006 | 6028 | 2006 | 6029 | 2006 | 6030 | 2006 | 6031 | 2006 | 6032 | 2006 : 6033 | 2006 | 6034 |
2007 | 6028 | 2007 | 6029 | 2007 | 6030 | 2007 | 6031 | 2007 | 6032 | 2007 : 6033 | 2007 | 6034 |
2008 | 6028 | 2008 | 6029 | 2008 | 6030 | 2008 | 6031 | 2008 | 6032 | 2008 : 6033 | 2008 | 6034 |
2009 | 6028 | 2009 | 6029 | 2009 | 6030 | 2009 | 6031 | 2009 | 6032 | 2009:6033 | 2009 | 6034 |
2010 | 6028 | 2010 | 6029 | 2010 | 6030 | 2010 | 6031 | 2010 | 6032 | 2010: 6033 | 2010 | 6034 |
3001 | 6028 | 3001 | 6029 | 3001 | 6030 | 3001 | 6031 | 3001 | 6032 | 3001 : 6033 | 3001 | 6034 |
3002 | 6028 | 3002 | 6029 | 3002 | 6030 | 3002 | 6031 | 3002 | 6032 | 3002 : 6033 | 3002 | 6034 |
3003 | 6028 | 3003 | 6029 | 3003 | 6030 | 3003 | 6031 | 3003 | 6032 | 3003 : 6033 | 3003 | 6034 |
3004 | 6028 | 3004 | 6029 | 3004 | 6030 | 3004 | 6031 | 3004 | 6032 | 3004:6033 | 3004 | 6034 |
3005 | 6028 | 3005 | 6029 | 3005 | 6030 | 3005 | 6031 | 3005 | 6032 | 3005 : 6033 | 3005 | 6034 |
3006 | 6028 | 3006 | 6029 | 3006 | 6030 | 3006 | 6031 | 3006 | 6032 | 3006 : 6033 | 3006 | 6034 |
3007 | 6028 | 3007 | 6029 | 3007 | 6030 | 3007 | 6031 | 3007 | 6032 | 3007 : 6033 | 3007 | 6034 |
3008 | 6028 | 3008 | 6029 | 3008 | 6030 | 3008 | 6031 | 3008 | 6032 | 3008 : 6033 | 3008 | 6034 |
4001 | 6028 | 4001 | 6029 | 4001 | 6030 | 4001 | 6031 | 4001 | 6032 | 4001 :6033 | 4001 | 6034 |
4002 | 6028 | 4002 | 6029 | 4002 | 6030 | 4002 | 6031 | 4002 | 6032 | 4002 : 6033 | 4002 | 6034 |
4003 | 6028 | 4003 | 6029 | 4003 | 6030 | 4003 | 6031 | 4003 | 6032 | 4003 :6033 | 4003 | 6034 |
4004 | 6028 | 4004 | 6029 | 4004 | 6030 | 4004 | 6031 | 4004 | 6032 | 4004: 6033 | 4004 | 6034 |
4005 | 6028 | 4005 | 6029 | 4005 | 6030 | 4005 | 6031 | 4005 | 6032 | 4005 : 6033 | 4005 | 6034 |
5001 | 6028 | 5001 | 6029 | 5001 | 6030 | 5001 | 6031 | 5001 | 6032 | 5001 :6033 | 5001 | 6034 |
5002 | 6028 | 5002 | 6029 | 5002 | 6030 | 5002 | 6031 | 5002 | 6032 | 5002 : 6033 | 5002 | 6034 |
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X |
1001 | 6035 | 1001 | 6036 | 1001 | 6037 | 1001 | 6038 | 1001 | 6039 | 1001 | 6040 | 1001 |
1002 | 6035 | 1002 | 6036 | 1002 | 6037 | 1002 | 6038 | 1002 | 6039 | 1002 | 6040 | 1002 |
1003 | 6035 | 1003 | 6036 | 1003 | 6037 | 1003 | 6038 | 1003 | 6039 | 1003 | 6040 | 1003 |
1004 | 6035 | 1004 | 6036 | 1004 | 6037 | 1004 | 6038 | 1004 | 6039 | 1004 | 6040 | 1004 |
1005 | 6035 | 1005 | 6036 | 1005 | 6037 | 1005 | 6038 | 1005 | 6039 | 1005 | 6040 | 1005 |
1006 | 6035 | 1006 | 6036 | 1006 | 6037 | 1006 | 6038 | 1006 | 6039 | 1006 | 6040 | 1006 |
1007 | 6035 | 1007 | 6036 | 1007 | 6037 | 1007 | 6038 | 1007 | 6039 | 1007 | 6040 | 1007 |
1008 | 6035 | 1008 | 6036 | 1008 | 6037 | 1008 | 6038 | 1008 | 6039 | 1008 | 6040 | 1008 |
1009 | 6035 | 1009 | 6036 | 1009 | 6037 | 1009 | 6038 | 1009 | 6039 | 1009 | 6040 | 1009 |
1010 | 6035 | 1010 | 6036 | 1010 | 6037 | 1010 | 6038 | 1010 | 6039 | 1010 | 6040 | 1010 |
1011 | 6035 | 1011 | 6036 | 1011 | 6037 | 1011 | 6038 | 1011 | 6039 | 1011 | 6040 | 1011 |
1012 | 6035 | 1012 | 6036 | 1012 | 6037 | 1012 | 6038 | 1012 | 6039 | 1012 | 6040 | 1012 |
1013 | 6035 | 1013 | 6036 | 1013 | 6037 | 1013 | 6038 | 1013 | 6039 | 1013 | 6040 | 1013 |
1014 | 6035 | 1014 | 6036 | 1014 | 6037 | 1014 | 6038 | 1014 | 6039 | 1014 | 6040 | 1014 |
2001 | 6035 | 2001 | 6036 | 2001 | 6037 | 2001 | 6038 | 2001 | 6039 | 2001 | 6040 | 2001 |
2002 | 6035 | 2002 | 6036 | 2002 | 6037 | 2002 | 6038 | 2002 | 6039 | 2002 | 6040 | 2002 |
2003 | 6035 | 2003 | 6036 | 2003 | 6037 | 2003 | 6038 | 2003 | 6039 | 2003 | 6040 | 2003 |
2004 | 6035 | 2004 | 6036 | 2004 | 6037 | 2004 | 6038 | 2004 | 6039 | 2004 | 6040 | 2004 |
2005 | 6035 | 2005 | 6036 | 2005 | 6037 | 2005 | 6038 | 2005 | 6039 | 2005 | 6040 | 2005 |
2006 | 6035 | 2006 | 6036 | 2006 | 6037 | 2006 | 6038 | 2006 | 6039 | 2006 | 6040 | 2006 |
2007 | 6035 | 2007 | 6036 | 2007 | 6037 | 2007 | 6038 | 2007 | 6039 | 2007 | 6040 | 2007 |
2008 | 6035 | 2008 | 6036 | 2008 | 6037 | 2008 | 6038 | 2008 | 6039 | 2008 | 6040 | 2008 |
2009 | 6035 | 2009 | 6036 | 2009 | 6037 | 2009 | 6038 | 2009 | 6039 | 2009 | 6040 | 2009 |
2010 | 6035 | 2010 | 6036 | 2010 | 6037 | 2010 | 6038 | 2010 | 6039 | 2010 | 6040 | 2010 |
3001 | 6035 | 3001 | 6036 | 3001 | 6037 | 3001 | 6038 | 3001 | 6039 | 3001 | 6040 | 3001 |
3002 | 6035 | 3002 | 6036 | 3002 | 6037 | 3002 | 6038 | 3002 | 6039 | 3002 | 6040 | 3002 |
3003 | 6035 | 3003 | 6036 | 3003 | 6037 | 3003 | 6038 | 3003 | 6039 | 3003 | 6040 | 3003 |
3004 | 6035 | 3004 | 6036 | 3004 | 6037 | 3004 | 6038 | 3004 | 6039 | 3004 | 6040 | 3004 |
3005 | 6035 | 3005 | 6036 | 3005 | 6037 | 3005 | 6038 | 3005 | 6039 | 3005 | 6040 | 3005 |
3006 | 6035 | 3006 | 6036 | 3006 | 6037 | 3006 | 6038 | 3006 | 6039 | 3006 | 6040 | 3006 |
3007 | 6035 | 3007 | 6036 | 3007 | 6037 | 3007 | 6038 | 3007 | 6039 | 3007 | 6040 | 3007 |
3008 | 6035 | 3008 | 6036 | 3008 | 6037 | 3008 | 6038 | 3008 | 6039 | 3008 | 6040 | 3008 |
4001 | 6035 | 4001 | 6036 | 4001 | 6037 | 4001 | 6038 | 4001 | 6039 | 4001 | 6040 | 4001 |
4002 | 6035 | 4002 | 6036 | 4002 | 6037 | 4002 | 6038 | 4002 | 6039 | 4002 | 6040 | 4002 |
4003 | 6035 | 4003 | 6036 | 4003 | 6037 | 4003 | 6038 | 4003 | 6039 | 4003 | 6040 | 4003 |
4004 | 6035 | 4004 | 6036 | 4004 | 6037 | 4004 | 6038 | 4004 | 6039 | 4004 | 6040 | 4004 |
4005 | 6035 | 4005 | 6036 | 4005 | 6037 | 4005 | 6038 | 4005 | 6039 | 4005 | 6040 | 4005 |
5001 | 6035 | 5001 | 6036 | 5001 | 6037 | 5001 | 6038 | 5001 | 6039 | 5001 | 6040 | 5001 |
5002 | 6035 | 5002 | 6036 | 5002 | 6037 | 5002 | 6038 | 5002 | 6039 | 5002 | 6040 | 5002 |
6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041 6041
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
ιοοι | 6042 | 1001 | 6043 | 1001 | 6044 | 1001 | 6045 | 1001 | 6046 | 1001 | 6047 | 1001 | 6048 |
1002 | 6042 | 1002 | 6043 | 1002 | 6044 | 1002 | 6045 | 1002 | 6046 | 1002 | 6047 | 1002 | 6048 |
1003 | 6042 | 1003 | 6043 | 1003 | 6044 | 1003 | 6045 | 1003 | 6046 | 1003 | 6047 | 1003 | 6048 |
1004 | 6042 | 1004 | 6043 | 1004 | 6044 | 1004 | 6045 | 1004 | 6046 | 1004 | 6047 | 1004 | 6048 |
1005 | 6042 | 1005 | 6043 | 1005 | 6044 | 1005 | 6045 | 1005 | 6046 | 1005 | 6047 | 1005 | 6048 |
1006 | 6042 | 1006 | 6043 | 1006 | 6044 | 1006 | 6045 | 1006 | 6046 | 1006 | 6047 | 1006 | 6048 |
1007 | 6042 | 1007 | 6043 | 1007 | 6044 | 1007 | 6045 | 1007 | 6046 | 1007 | 6047 | 1007 | 6048 |
1008 | 6042 | 1008 | 6043 | 1008 | 6044 | 1008 | 6045 | 1008 | 6046 | 1008 | 6047 | 1008 | 6048 |
1009 | 6042 | 1009 | 6043 | 1009 | 6044 | 1009 | 6045 | 1009 | 6046 | 1009 | 6047 | 1009 | 6048 |
ΙΟΙΟ | 6042 | 1010 | 6043 | 1010 | 6044 | 1010 | 6045 | 1010 | 6046 | 1010 | 6047 | 1010 | 6048 |
loi 1 | 6042 | 1011 | 6043 | 1011 | 6044 | 1011 | 6045 | 1011 | 6046 | 1011 | 6047 | 1011 | 6048 |
1012 | 6042 | 1012 | 6043 | 1012 | 6044 | 1012 | 6045 | 1012 | 6046 | 1012 | 6047 | 1012 | 6048 |
1013 | 6042 | 1013 | 6043 | 1013 | 6044 | 1013 | 6045 | 1013 | 6046 | 1013 | 6047 | 1013 | 6048 |
1014 | 6042 | 1014 | 6043 | 1014 | 6044 | 1014 | 6045 | 1014 | 6046 | 1014 | 6047 | 1014 | 6048 |
2001 | 6042 | 2001 | 6043 | 2001 | 6044 | 2001 | 6045 | 2001 | 6046 | 2001 | 6047 | 2001 | 6048 |
2002 | 6042 | 2002 | 6043 | 2002 | 6044 | 2002 | 6045 | 2002 | 6046 | 2002 | 6047 | 2002 | 6048 |
2003 | 6042 | 2003 | 6043 | 2003 | 6044 | 2003 | 6045 | 2003 | 6046 | 2003 | 6047 | 2003 | 6048 |
2004 | 6042 | 2004 | 6043 | 2004 | 6044 | 2004 | 6045 | 2004 | 6046 | 2004 | 6047 | 2004 | 6048 |
2005 | 6042 | 2005 | 6043 | 2005 | 6044 | 2005 | 6045 | 2005 | 6046 | 2005 | 6047 | 2005 | 6048 |
2006 | 6042 | 2006 | 6043 | 2006 | 6044 | 2006 | 6045 | 2006 | 6046 | 2006 | 6047 | 2006 | 6048 |
2007 | 6042 | 2007 | 6043 | 2007 | 6044 | 2007 | 6045 | 2007 | 6046 | 2007 | 6047 | 2007 | 6048 |
2008 | 6042 | 2008 | 6043 | 2008 | 6044 | 2008 | 6045 | 2008 | 6046 | 2008 | 6047 | 2008 | 6048 |
2009 | 6042 | 2009 | 6043 | 2009 | 6044 | 2009 | 6045 | 2009 | 6046 | 2009 | 6047 | 2009 | 6048 |
2010 | 6042 | 2010 | 6043 | 2010 | 6044 | 2010 | 6045 | 2010 | 6046 | 2010 | 6047 | 2010 | 6048 |
3001 | 6042 | 3001 | 6043 | 3001 | 6044 | 3001 | 6045 | 3001 | 6046 | 3001 | 6047 | 3001 | 6048 |
3002 | 6042 | 3002 | 6043 | 3002 | 6044 | 3002 | 6045 | 3002 | 6046 | 3002 | 6047 | 3002 | 6048 |
3003 | 6042 | 3003 | 6043 | 3003 | 6044 | 3003 | 6045 | 3003 | 6046 | 3003 | 6047 | 3003 | 6048 |
3004 | 6042 | 3004 | 6043 | 3004 | 6044 | 3004 | 6045 | 3004 | 6046 | 3004 | 6047 | 3004 | 6048 |
3005 | 6042 | 3005 | 6043 | 3005 | 6044 | 3005 | 6045 | 3005 | 6046 | 3005 | 6047 | 3005 | 6048 |
3006 | 6042 | 3006 | 6043 | 3006 | 6044 | 3006 | 6045 | 3006 | 6046 | 3006 | 6047 | 3006 | 6048 |
3007 | 6042 | 3007 | 6043 | 3007 | 6044 | 3007 | 6045 | 3007 | 6046 | 3007 | 6047 | 3007 | 6048 |
3008 | 6042 | 3008 | 6043 | 3008 | 6044 | 3008 | 6045 | 3008 | 6046 | 3008 | 6047 | 3008 | 6048 |
4001 | 6042 | 4001 | 6043 | 4001 | 6044 | 4001 | 6045 | 4001 | 6046 | 4001 | 6047 | 4001 | 6048 |
4002 | 6042 | 4002 | 6043 | 4002 | 6044 | 4002 | 6045 | 4002 | 6046 | 4002 | 6047 | 4002 | 6048 |
4003 | 6042 | 4003 | 6043 | 4003 | 6044 | 4003 | 6045 | 4003 | 6046 | 4003 | 6047 | 4003 | 6048 |
4004 | 6042 | 4004 | 6043 | 4004 | 6044 | 4004 | 6045 | 4004 | 6046 | 4004 | 6047 | 4004 | 6048 |
4005 | 6042 | 4005 | 6043 | 4005 | 6044 | 4005 | 6045 | 4005 | 6046 | 4005 | 6047 | 4005 | 6048 |
5001 | 6042 | 5001 | 6043 | 5001 | 6044 | 5001 | 6045 | 5001 | 6046 | 5001 | 6047 | 5001 | 6048 |
5002 | 6042 | 5002 | 6043 | 5002 | 6044 | 5002 | 6045 | 5002 | 6046 | 5002 | 6047 | 5002 | 6048 |
©
X | Y | X | Y | X | Y | X | Y | X | Y | X. | Y | X | Y |
1001 | 6049 | 1001 | 6050 | 1001 | 6051 | 1001 | 6052 | 1001 | 6053 | 1001 | 6054 | 1001 | 6055 |
1002 | 6049 | 1002 | 6050 | 1002 | 6051 | 1002 | 6052 | 1002 | 6053 | 1002 | 6054 | 1002 | 6055 |
1003 | 6049 | 1003 | 6050 | 1003 | 6051 | 1003 | 6052 | 1003 | 6053 | 1003 | 6054 | 1003 | 6055 |
1004 | 6049 | 1004 | 6050 | 1004 | 6051 | 1004 | 6052 | 1004 | 6053 | 1004 | 6054 | 1004 | 6055 |
1005 | 6049 | 1005 | 6050 | 1005 | 6051 | 1005 | 6052 | 1005 | 6053 | 1005 | 6054 | 1005 | 6055 |
1006 | 6049 | 1006 | 6050 | 1006 | 6051 | 1006 | 6052 | 1006 | 6053 | 1006 | 6054 | 1006 | 6055 |
1007 | 6049 | 1007 | 6050 | 1007 | 6051 | 1007 | 6052 | 1007 | 6053 | 1007 | 6054 | 1007 | 6055 |
1008 | 6049 | 1008 | 6050 | 1008 | 6051 | 1008 | 6052 | 1008 | 6053 | 1008 | 6054 | 1008 | 6055 |
1009 | 6049 | 1009 | 6050 | 1009 | 6051 | 1009 | 6052 | 1009 | 6053 | 1009 | 6054 | 1009 | 6055 |
1010 | 6049 | 1010 | 6050 | 1010 | 6051 | 1010 | 6052 | 1010 | 6053 | 1010 | 6054 | 1010 | 6055 |
1011 | 6049 | 1011 | 6050 | 1011 | 6051 | 1011 | 6052 | 1011 | 6053 | 1011 | 6054 | 1011 | 6055 |
1012 | 6049 | 1012 | 6050 | 1012 | 6051 | 1012 | 6052 | 1012 | 6053 | 1012 | 6054 | 1012 | 6055 |
1013 | 6049 | 1013 | 6050 | 1013 | 6051 | 1013 | 6052 | 1013 | 6053 | 1013 | 6054 | 1013 | 6055 |
1014 | 6049 | 1014 | 6050 | 1014 | 6051 | 1014 | 6052 | 1014 | 6053 | 1014 | 6054 | 1014 | 6055 |
2001 | 6049 | 2001 | 6050 | 2001 | 6051 | 2001 | 6052 | 2001 | 6053 | 2001 | 6054 | 2001 | 6055 |
2002 | 6049 | 2002 | 6050 | 2002 | 6051 | 2002 | 6052 | 2002 | 6053 | 2002 | 6054 | 2002 | 6055 |
2003 | 6049 | 2003 | 6050 | 2003 | 6051 | 2003 | 6052 | 2003 | 6053 | 2003 | 6054 | 2003 | 6055 |
2004 | 6049 | 2004 | 6050 | 2004 | 6051 | 2004 | 6052 | 2004 | 6053 | 2004 | 6054 | 2004 | 6055 |
2005 | 6049 | 2005 | 6050 | 2005 | 6051 | 2005 | 6052 | 2005 | 6053 | 2005 | 6054 | 2005 | 6055 |
2006 | 6049 | 2006 | 6050 | 2006 | 6051 | 2006 | 6052 | 2006 | 6053 | 2006 | 6054 | 2006 | 6055 |
2007 | 6049 | 2007 | 6050 | 2007 | 6051 | 2007 | 6052 | 2007 | 6053 | 2007 | 6054 | 2007 | 6055 |
2008 | 6049 | 2008 | 6050 | 2008 | 6051 | 2008 | 6052 | 2008 | 6053 | 2008 | 6054 | 2008 | 6055 |
2009 | 6049 | 2009 | 6050 | 2009 | 6051 | 2009 | 6052 | 2009 | 6053 | 2009 | 6054 | 2009 | 6055 |
2010 | 6049 | 2010 | 6050 | 2010 | 6051 | 2010 | 6052 | 2010 | 6053 | 2010 | 6054 | 2010 | 6055 |
3001 | 6049 | 3001 | 6050 | 3001 | 6051 | 3001 | 6052 | 3001 | 6053 | 3001 | 6054 | 3001 | 6055 |
3002 | 6049 | 3002 | 6050 | 3002 | 6051 | 3002 | 6052 | 3002 | 6053 | 3002 | 6054 | 3002 | 6055 |
3003 | 6049 | 3003 | 6050 | 3003 | 6051 | 3003 | 6052 | 3003 | 6053 | 3003 | 6054 | 3003 | 6055 |
3004 | 6049 | 3004 | 6050 | 3004 | 6051 | 3004 | 6052 | 3004 | 6053 | 3004 | 6054 | 3004 | 6055 |
3005 | 6049 | 3005 | 6050 | 3005 | 6051 | 3005 | 6052 | 3005 | 6053 | 3005 | 6054 | 3005 | 6055 |
3006 | 6049 | 3006 | 6050 | 3006 | 6051 | 3006 | 6052 | 3006 | 6053 | 3006 | 6054 | 3006 | 6055 |
3007 | 6049 | 3007 | 6050 | 3007 | 6051 | 3007 | 6052 | 3007 | 6053 | 3007 | 6054 | 3007 | 6055 |
3008 | 6049 | 3008 | 6050 | 3008 | 6051 | 3008 | 6052 | 3008 | 6053 | 3008 | 6054 | 3008 | 6055 |
4001 | 6049 | 4001 | 6050 | 4001 | 6051 | 4001 | 6052 | 4001 | 6053 | 4001 | 6054 | 4001 | 6055 |
4002 | 6049 | 4002 | 6050 | 4002 | 6051 | 4002 | 6052 | 4002 | 6053 | 4002 | 6054 | 4002 | 6055 |
4003 | 6049 | 4003 | 6050 | 4003 | 6051 | 4003 | 6052 | 4003 | 6053 | 4003 | 6054 | 4003 | 6055 |
4004 | 6049 | 4004 | 6050 | 4004 | 6051 | 4004 | 6052 | 4004 | 6053 | 4004 | 6054 | 4004 | 6055 |
4005 | 6049 | 4005 | 6050 | 4005 | 6051 | 4005 | 6052 | 4005 | 6053 | 4005 | 6054 | 4005 | 6055 |
5001 | 6049 | 5001 | 6050 | 5001 | 6051 | 5001 | 6052 | 5001 | 6053 | 5001 | 6054 | 5001 | 6055 |
5002 | 6049 | 5002 | 6050 | 5002 | 6051 | 5002 | 6052 | 5002 | 6053 | 5002 | 6054 | 5002 | 6055 |
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X: | Y |
ιοοι | 6056 | 1001 | 6057 | 1001 | 6058 | 1001 | 6059 | 1001 | 6060 | 1001 | 6061 | 1001 | 6062 |
I002 | 6056 | 1002 | 6057 | 1002 | 6058 | 1002 | 6059 | 1002 | 6060 | 1002 | 6061 | 1002 | 6062 |
1003 | 6056 | 1003 | 6057 | 1003 | 6058 | 1003 | 6059 | 1003 | 6060 | 1003 | 6061 | 1003 | 6062 |
1004 | 6056 | 1004 | 6057 | 1004 | 6058 | 1004 | 6059 | 1004 | 6060 | 1004 | 6061 | 1004 | 6062 |
1005 | 6056 | 1005 | 6057 | 1005 | 6058 | 1005 | 6059 | 1005 | 6060 | 1005 | 6061 | 1005 | 6062 |
1006 | 6056 | 1006 | 6057 | 1006 | 6058 | 1006 | 6059 | 1006 | 6060 | 1006 | 6061 | 1006 | 6062 |
1007 | 6056 | 1007 | 6057 | 1007 | 6058 | 1007 | 6059 | 1007 | 6060 | 1007 | 6061 | 1007 | 6062 |
1008 | 6056 | 1008 | 6057 | 1008 | 6058 | 1008 | 6059 | 1008 | 6060 | 1008 | 6061 | 1008 | 6062 |
1009 | 6056 | 1009 | 6057 | 1009 | 6058 | 1009 | 6059 | 1009 | 6060 | 1009 | 6061 | 1009 | 6062 |
1010 | 6056 | 1010 | 6057 | 1010 | 6058 | 1010 | 6059 | 1010 | 6060 | 1010 | 6061 | 1010 | 6062 |
1011 | 6056 | 1011 | 6057 | 1011 | 6058 | 1011 | 6059 | 1011 | 6060 | 1011 | 6061 | 1011 | 6062 |
1012 | 6056 | 1012 | 6057 | 1012 | 6058 | 1012 | 6059 | 1012 | 6060 | 1012 | 6061 | 1012 | 6062 |
1013 | 6056 | 1013 | 6057 | 1013 | 6058 | 1013 | 6059 | 1013 | 6060 | 1013 | 6061 | 1013 | 6062 |
1014 | 6056 | 1014 | 6057 | 1014 | 6058 | 1014 | 6059 | 1014 | 6060 | 1014 | 6061 | 1014 | 6062 |
2001 | 6056 | 2001 | 6057 | 2001 | 6058 | 2001 | 6059 | 2001 | 6060 | 2001 | 6061 | 2001 | 6062 |
2002 | 6056 | 2002 | 6057 | 2002 | 6058 | 2002 | 6059 | 2002 | 6060 | 2002 | 6061 | 2002 | 6062 |
2003 | 6056 | 2003 | 6057 | 2003 | 6058 | 2003 | 6059 | 2003 | 6060 | 2003 | 6061 | 2003 | 6062 |
2004 | 6056 | 2004 | 6057 | 2004 | 6058 | 2004 | 6059 | 2004 | 6060 | 2004 | 6061 | 2004 | 6062 |
2005 | 6056 | 2005 | 6057 | 2005 | 6058 | 2005 | 6059 | 2005 | 6060 | 2005 | 6061 | 2005 | 6062 |
2006 | 6056 | 2006 | 6057 | 2006 | 6058 | 2006 | 6059 | 2006 | 6060 | 2006 | 6061 | 2006 | 6062 |
2007 | 6056 | 2007 | 6057 | 2007 | 6058 | 2007 | 6059 | 2007 | 6060 | 2007 | 6061 | 2007 | 6062 |
2008 | 6056 | 2008 | 6057 | 2008 | 6058 | 2008 | 6059 | 2008 | 6060 | 2008 | 6061 | 2008 | 6062 |
2009 | 6056 | 2009 | 6057 | 2009 | 6058 | 2009 | 6059 | 2009 | 6060 | 2009 | 6061 | 2009 | 6062 |
2010 | 6056 | 2010 | 6057 | 2010 | 6058 | 2010 | 6059 | 2010 | 6060 | 2010 | 6061 | 2010 | 6062 |
3001 | 6056 | 3001 | 6057 | 3001 | 6058 | 3001 | 6059 | 3001 | 6060 | 3001 | 6061 | 3001 | 6062 |
3002 | 6056 | 3002 | 6057 | 3002 | 6058 | 3002 | 6059 | 3002 | 6060 | 3002 | 6061 | 3002 | 6062 |
3003 | 6056 | 3003 | 6057 | 3003 | 6058 | 3003 | 6059 | 3003 | 6060 | 3003 | 6061 | 3003 | 6062 |
3004 | 6056 | 3004 | 6057 | 3004 | 6058 | 3004 | 6059 | 3004 | 6060 | 3004 | 6061 | 3004 | 6062 |
3005 | 6056 | 3005 | 6057 | 3005 | 6058 | 3005 | 6059 | 3005 | 6060 | 3005 | 6061 | 3005 | 6062 |
3006 | 6056 | 3006 | 6057 | 3006 | 6058 | 3006 | 6059 | 3006 | 6060 | 3006 | 6061 | 3006 | 6062 |
3007 | 6056 | 3007 | 6057 | 3007 | 6058 | 3007 | 6059 | 3007 | 6060 | 3007 | 6061 | 3007 | 6062 |
3008 | 6056 | 3008 | 6057 | 3008 | 6058 | 3008 | 6059 | 3008 | 6060 | 3008 | 6061 | 3008 | 6062 |
4001 | 6056 | 4001 | 6057 | 4001 | 6058 | 4001 | 6059 | 4001 | 6060 | 4001 | 6061 | 4001 | 6062 |
4002 | 6056 | 4002 | 6057 | 4002 | 6058 | 4002 | 6059 | 4002 | 6060 | 4002 | 6061 | 4002 | 6062 |
4003 | 6056 | 4003 | 6057 | 4003 | 6058 | 4003 | 6059 | 4003 | 6060 | 4003 | 6061 | 4003 | 6062 |
4004 | 6056 | 4004 | 6057 | 4004 | 6058 | 4004 | 6059 | 4004 | 6060 | 4004 | 6061 | 4004 | 6062 |
4005 | 6056 | 4005 | 6057 | 4005 | 6058 | 4005 | 6059 | 4005 | 6060 | 4005 | 6061 | 4005 | 6062 |
5001 | 6056 | 5001 | 6057 | 5001 | 6058 | 5001 | 6059 | 5001 | 6060 | 5001 | 6061 | 5001 | 6062 |
5002 | 6056 | 5002 | 6057 | 5002 | 6058 | 5002 | 6059 | 5002 | 6060 | 5002 | 6061 | 5002 | 6062 |
C
X: Y | X : Y | X: Y | X: Y | X : Y | X: Y | X: Y |
1001 :6063 1002 : 6063 1003 : 6063 1004: 6063 1005:6063 1006 : 6063 1007 : 6063 1008 : 6063 1009: 6063 1010: 6063 1011 : 6063 1012:6063 1013 : 6063 1014 : 6063 2001 : 6063 2002:6063 2003 : 6063 2004: 6063 2005 :6063 2006 : 6063 2007 : 6063 2008 : 6063 2009 : 6063 2010: 6063 3001 : 6063 3002:6063 3003 : 6063 3004: 6063 3005 :6063 3006 : 6063 3007 : 6063 3008 :6063 4001 : 6063 4002 : 6063 4003 :6063 4004 : 6063 4005 : 6063 5001 :6063 5002 : 6063 | 1001 : 6064 1002 : 6064 1003 : 6064 1004 : 6064 1005 : 6064 1006 : 6064 1007 : 6064 1008 : 6064 1009: 6064 1010 : 6064 1011 : 6064 1012 : 6064 1013 : 6064 1014 : 6064 2001 : 6064 2002 : 6064 2003 : 6064 2004 : 6064 2005 :6064 2006: 6064 2007 : 6064 2008 : 6064 2009 : 6064 2010 : 6064 3001 : 6064 3002 : 6064 3003 : 6064 3004 : 6064 3005 :6064 3006 : 6064 3007 : 6064 3008 : 6064 4001 : 6064 4002 : 6064 4003 : 6064 4004 : 6064 4005 : 6064 5001 : 6064 5002 : 6064 | 1001 : 6065 1002 : 6065 1003 : 6065 1004: 6065 1005 : 6065 1006 : 6065 1007 : 6065 1008 :6065 1009 : 6065 1010 : 6065 1011 : 6065 1012 : 6065 1013 : 6065 1014 : 6065 2001 :6065 2002 : 6065 2003 : 6065 2004: 6065 2005 : 6065 2006 : 6065 2007 : 6065 2008 : 6065 2009 : 6065 2010: 6065 3001 :6065 3002 : 6065 3003 : 6065 3004:6065 3005 : 6065 3006 : 6065 3007 :6065 3008 : 6065 4001 : 6065 4002 :6065 4003 : 6065 4004: 6065 4005 :6065 5001 : 6065 5002 : 6065 | 1001 : 6066 1002 : 6066 1003 : 6066 1004 : 6066 1005 : 6066 1006 : 6066 1007 :6066 1008 : 6066 1009:6066 1010:6066 1011 :6066 1012 : 6066 1013 :6066 1014:6066 2001 : 6066 2002 :6066 2003 : 6066 2004 : 6066 2005 : 6066 2006 : 6066 2007 : 6066 2008 : 6066 2009 : 6066 2010: 6066 3001 : 6066 3002 : 6066 3003 : 6066 3004 : 6066 3005 : 6066 3006 : 6066 3007 : 6066 3008 : 6066 4001 : 6066 4002 : 6066 4003 : 6066 4004: 6066 4005 : 6066 5001 : 6066 5002 : 6066 | 1001 : 6067 1002 :6067 1003 : 6067 1004 : 6067 1005 : 6067 1006 :6067 1007 : 6067 1008 : 6067 1009:6067 1010 : 6067 1011 : 6067 1012 : 6067 1013 :6067 1014 : 6067 2001 : 6067 2002 :6067 2003 : 6067 2004 : 6067 2005 :6067 2006 :6067 2007 : 6067 2008 : 6067 2009:6067 2010 : 6067 3001 : 6067 3002 :6067 3003 : 6067 3004: 6067 3005 :6067 3006 : 6067 3007 : 6067 3008 :6067 4001 : 6067 4002 : 6067 4003 :6067 4004 : 6067 4005 : 6067 5001 :6067 5002 : 6067 | 1001 : 6068 1002 : 6068 1003 :6068 1004 : 6068 1005 : 6068 1006:6068 1007 : 6068 1008 : 6068 1009 : 6068 1010:6068 1011 : 6068 1012 : 6068 1013:6068 1014 : 6068 2001 : 6068 2002 :6068 2003 :6068 2004 : 6068 2005 : 6068 2006:6068 2007 : 6068 2008 : 6068 2009:6068 2010 : 6068 3001 : 6068 3002 :6068 3003 :6068 3004 : 6068 3005 : 6068 3006 : 6068 3007 : 6068 3008 : 6068 4001 : 6068 4002 : 6068 4003 :6068 4004 : 6068 4005 : 6068 5001 :6068 5002 : 6068 | 1001 : 6069 1002 : 6069 1003 :6069 1004 : 6069 1005 : 6069 1006:6069 1007 : 6069 1008 : 6069 1009 : 6069 1010: 6069 1011 : 6069 1012 : 6069 1013 :6069 1014 : 6069 2001 : 6069 2002 : 6069 2003 : 6069 2004 : 6069 2005 : 6069 2006:6069 2007 : 6069 2008 : 6069 2009: 6069 2010 : 6069 3001 : 6069 3002 : 6069 3003 : 6069 3004 : 6069 3005 : 6069 3006: 6069 3007 : 6069 3008 : 6069 4001 : 6069 4002 : 6069 4003 : 6069 4004 : 6069 4005 : 6069 5001 : 6069 5002 : 6069 |
G
X: Y | X: Y | X: Y | X | Y | X | Y | X | Y | X | Y |
ÎOOI : 6070 | 1001 : 6071 | 1001 : 6072 | 1001 | 6073 | 1001 | 6074 | 1001 | 6075 | 1001 | 6076 |
1002 : 6070 | 1002 : 6071 | 1002 : 6072 | 1002 | 6073 | 1002 | 6074 | 1002 | 6075 | 1002 | 6076 |
1003 : 6070 | 1003 :6071 | 1003 :6072 | 1003 | 6073 | 1003 | 6074 | 1003 | 6075 | 1003 | 6076 |
1004: 6070 | 1004: 6071 | 1004 : 6072 | 1004 | 6073 | 1004 | 6074 | 1004 | 6075 | 1004 | 6076 |
1005:6070 | 1005 : 6071 | 1005 : 6072 | 1005 | 6073 | 1005 | 6074 | 1005 | 6075 | 1005 | 6076 |
1006: 6070 | 1006 : 6071 | 1006 : 6072 | 1006 | 6073 | 1006 | 6074 | 1006 | 6075 | 1006 | 6076 |
1007 : 6070 | 1007 : 6071 | 1007 : 6072 | 1007 | 6073 | 1007 | 6074 | 1007 | 6075 | 1007 | 6076 |
1008 : 6070 | 1008 : 6071 | 1008 : 6072 | 1008 | 6073 | 1008 | 6074 | 1008 | 6075 | 1008 | 6076 |
1009 : 6070 | 1009 : 6071 | 1009 : 6072 | 1009 | 6073 | 1009 | 6074 | 1009 | 6075 | 1009 | 6076 |
1010:6070 | 1010 : 6071 | 1010: 6072 | 1010 | 6073 | 1010 | 6074 | 1010 | 6075 | 1010 | 6076 |
1011 : 6070 | 1011 : 6071 | 1011 : 6072 | 1011 | 6073 | 1011 | 6074 | 1011 | 6075 | 1011 | 6076 |
1012 : 6070 | 1012 : 6071 | 1012: 6072 | 1012 | 6073 | 1012 | 6074 | 1012 | 6075 | 1012 | 6076 |
1013 : 6070 | 1013 : 6071 | 1013 : 6072 | 1013 | 6073 | 1013 | 6074 | 1013 | 6075 | 1013 | 6076 |
1014: 6070 | 1014 : 6071 | 1014 : 6072 | 1014 | 6073 | 1014 | 6074 | 1014 | 6075 | 1014 | 6076 |
2001 : 6070 | 2001 : 6071 | 2001 : 6072 | 2001 | 6073 | 2001 | 6074 | 2001 | 6075 | 2001 | 6076 |
2002 : 6070 | 2002 :6071 | 2002 : 6072 | 2002 | 6073 | 2002 | 6074 | 2002 | 6075 | 2002 | 6076 |
2003 : 6070 | 2003 : 6071 | 2003 : 6072 | 2003 | 6073 | 2003 | 6074 | 2003 | 6075 | 2003 | 6076 |
2004: 6070 | 2004 : 6071 | 2004 : 6072 | 2004 | 6073 | 2004 | 6074 | 2004 | 6075 | 2004 | 6076 |
2005 :6070 | 2005 : 6071 | 2005 : 6072 | 2005 | 6073 | 2005 | 6074 | 2005 | 6075 | 2005 | 6076 |
2006 : 6070 | 2006 :6071 | 2006:6072 | 2006 | 6073 | 2006 | 6074 | 2006 | 6075 | 2006 | 6076 |
2007 : 6070 | 2007 : 6071 | 2007 : 6072 | 2007 | 6073 | 2007 | 6074 | 2007 | 6075 | 2007 | 6076 |
2008 : 6070 | 2008 : 6071 | 2008 : 6072 | 2008 | 6073 | 2008 | 6074 | 2008 | 6075 | 2008 | 6076 |
2009:6070 | 2009 : 6071 | 2009: 6072 | 2009 | 6073 | 2009 | 6074 | 2009 | 6075 | 2009 | 6076 |
2010 : 6070 | 2010:6071 | 2010: 6072 | 2010 | 6073 | 2010 | 6074 | 2010 | 6075 | 2010 | 6076 |
3001 : 6070 | 3001 : 6071 | 3001 : 6072 | 3001 | 6073 | 3001 | 6074 | 3001 | 6075 | 3001 | 6076 |
3002 : 6070 | 3002 : 6071 | 3002 : 6072 | 3002 | 6073 | 3002 | 6074 | 3002 | 6075 | 3002 | 6076 |
3003 : 6070 | 3003 : 6071 | 3003 : 6072 | 3003 | 6073 | 3003 | 6074 | 3003 | 6075 | 3003 | 6076 |
3004 : 6070 | 3004: 6071 | 3004: 6072 | 3004 | 6073 | 3004 | 6074 | 3004 | 6075 | 3004 | 6076 |
3005 : 6070 | 3005 : 6071 | 3005 : 6072 | 3005 | 6073 | 3005 | 6074 | 3005 | 6075 | 3005 | 6076 |
3006: 6070 | 3006 : 6071 | 3006 : 6072 | 3006 | 6073 | 3006 | 6074 | 3006 | 6075 | 3006 | 6076 |
3007: 6070 | 3007 : 6071 | 3007 :6072 | 3007 | 6073 | 3007 | 6074 | 3007 | 6075 | 3007 | 6076 |
3008 : 6070 | 3008 : 6071 | 3008 : 6072 | 3008 | 6073 | 3008 | 6074 | 3008 | 6075 | 3008 | 6076 |
4001 : 6070 | 4001 : 6071 | 4001 : 6072 | 4001 | 6073 | 4001 | 6074 | 4001 | 6075 | 4001 | 6076 |
4002 : 6070 | 4002 : 6071 | 4002 : 6072 | 4002 | 6073 | 4002 | 6074 | 4002 | 6075 | 4002 | 6076 |
4003 : 6070 | 4003 : 6071 | 4003 : 6072 | 4003 | 6073 | 4003 | 6074 | 4003 | 6075 | 4003 | 6076 |
4004 : 6070 | 4004 : 6071 | 4004 : 6072 | 4004 | 6073 | 4004 | 6074 | 4004 | 6075 | 4004 | 6076 |
4005 : 6070 | 4005 : 6071 | 4005 : 6072 | 4005 | 6073 | 4005 | 6074 | 4005 | 6075 | 4005 | 6076 |
5001 : 6070 | 5001 : 6071 | 5001 : 6072 | 5001 | 6073 | 5001 | 6074 | 5001 | 6075 | 5001 | 6076 |
5002 : 6070 | 5002 :6071 | 5002 : 6072 | 5002 | 6073 | 5002 | 6074 | 5002 | 6075 | 5002 | 6076 |
C
100
X | Y | X | Y | X: Y | X | Y | X | Y | X: |
1001 | 6077 | 1014 | 6077 | 3003 : 6077 | 1001 | 6078 | 1014 | 6078 | 3003 : |
1002 | 6077 | 2001 | 6077 | 3004 : 6077 | 1002 | 6078 | 2001 | 6078 | 3004 : |
1003 | 6077 | 2002 | 6077 | 3005 :6077 | 1003 | 6078 | 2002 | 6078 | 3005 : |
1004 | 6077 | 2003 | 6077 | 3006 : 6077 | 1004 | 6078 | 2003 | 6078 | 3006: |
1005 | 6077 | 2004 | 6077 | 3007 : 6077 | 1005 | 6078 | 2004 | 6078 | 3007 : |
1006 | 6077 | 2005 | 6077 | 3008 : 6077 | 1006 | 6078 | 2005 | 6078 | 3008 : |
1007 | 6077 | 2006 | 6077 | 4001 : 6077 | 1007 | 6078 | 2006 | 6078 | 4001 : |
1008 | 6077 | 2007 | 6077 | 4002 : 6077 | 1008 | 6078 | 2007 | 6078 | 4002 : |
1009 | 6077 | 2008 | 6077 | 4003 : 6077 | 1009 | 6078 | 2008 | 6078 | 4003 : |
1010 | 6077 | 2009 | 6077 | 4004: 6077 | 1010 | 6078 | 2009 | 6078 | 4004 : |
1011 | 6077 | 2010 | 6077 | 4005 : 6077 | 1011 | 6078 | 2010 | 6078 | 4005 : |
1012 | 6077 | 3001 | 6077 | 5001 : 6077 | 1012 | 6078 | 3001 | 6078 | 5001 : |
1013 | 6077 | 3002 | 6077 | 5002 : 6077 | 1013 | 6078 | 3002 | 6078 | 5002 : |
6078
6078
6078
6078
6078
6078
6078
6078
6078
6078
6078
6078
6078
101
Table B: Example combinations of a cornpound X with a cornpound Y.
X | Y | X | Y | X: Y | X | Y | X | Y | X | Y | X | Y |
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 | 7000 | 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 | 7000 | 6018 | 7001 | 6018: 7002 | 6018 | 7003 | 6018 | 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 |
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 |
102
X: Y | X | Y | X | Y | X: Y | X | Y | X | Y | X | Y |
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 | 7018 | 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 | 6016 | 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 |
6006 : 7021 | 6006 | 7022 | 6006 | 7023 | 6006 : 7024 | 6006 | 7025 | 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 |
103
X | Y | X: Y | X | Y | X: Y | X | Y | X | Y | X | Y |
6017 | 7021 | 6017 : 7022 | 6017 | 7023 | 6017 : 7024 | 6017 | 7025 | 6017 | 7026 | 6017· | 7027 |
6018 | 7021 | 6018 : 7022 | 6018 | 7023 | 6018 : 7024 | 6018 | 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 | 7035 | 6001 : 7036 | 6001 | 7037 | 6001 : 7038 | 6001 | 7039 | 6001 | 7040 | 6001 | 7041 |
6002 | 7035 | 6002 : 7036 | 6002 | 7037 | 6002 : 7038 | 6002 | 7039 | 6002 | 7040 | 6002 | 7041 |
6003 | 7035 | 6003 : 7036 | 6003 | 7037 | 6003 : 7038 | 6003 | 7039 | 6003 | 7040 | 6003 | 7041 |
6004 | 7035 | 6004: 7036 | 6004 | 7037 | 6004: 7038 | 6004 | 7039 | 6004 | 7040 | 6004 | 7041 |
6005 | 7035 | 6005 : 7036 | 6005 | 7037 | 6005 : 7038 | 6005 | 7039 | 6005 | 7040 | 6005 | 7041 |
6006 | 7035 | 6006 : 7036 | 6006 | 7037 | 6006 : 7038 | 6006 | 7039 | 6006 | 7040 | 6006 | 7041 |
6007 | 7035 | 6007 : 7036 | 6007 | 7037 | 6007 : 7038 | 6007 | 7039 | 6007 | 7040 | 6007 | 7041 |
6008 | 7035 | 6008 : 7036 | 6008 | 7037 | 6008 : 7038 | 6008 | 7039 | 6008 | 7040 | 6008 | 7041 |
6009 | 7035 | 6009: 7036 | 6009 | 7037 | 6009: 7038 | 6009 | 7039 | 6009 | 7040 | 6009 | 7041 |
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 |
104
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X: | Y |
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 | 7044 | 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 |
105
X | Y | X | Y | X: Y | X | Y | X | Y | X: Y | X | Y |
6013 | 7049 | 6013 | 7050 | 6013 : 7051 | 6013 | 7052 | 6013 | 7053 | 6013 : 7054 | 6013 | 7055 |
6014 | 7049 | 6014 | 7050 | 6014 : 7051 | 6014 | 7052 | 6014 | 7053 | 6014 : 7054 | 6014 | 7055 |
6015 | 7049 | 6015 | 7050 | 6015 : 7051 | 6015 | 7052 | 6015 | 7053 | 6015 : 7054 | 6015 | 7055 |
6016 | 7049 | 6016 | 7050 | 6016 : 7051 | 6016 | 7052 | 6016 | 7053 | 6016: 7054 | 6016 | 7055 |
6017 | 7049 | 6017 | 7050 | 6017 : 7051 | 6017 | 7052 | 6017 | 7053 | 6017: 7054 | 6017 | 7055 |
6018 | 7049 | 6018 | 7050 | 6018 : 7051 | 6018 | 7052 | 6018 | 7053 | 6018 : 7054 | 6018 | 7055 |
6019 | 7049 | 6019 | 7050 | 6019 : 7051 | 6019 | 7052 | 6019 | 7053 | 6019 : 7054 | 6019 | 7055 |
6020 | 7049 | 6020 | 7050 | 6020: 7051 | 6020 | 7052 | 6020 | 7053 | 6020 : 7054 | 6020 | 7055 |
6000 | 7056 | 6000 | 7057 | 6000 : 7058 | 6000 | 7059 | 6000 | 7060 | 6000 : 7061 | 6000 | 7062 |
6001 | 7056 | 6001 | 7057 | 6001 : 7058 | 6001 | 7059 | 6001 | 7060 | 6001 : 7061 | 6001 | 7062 |
6002 | 7056 | 6002 | 7057 | 6002 : 7058 | 6002 | 7059 | 6002 | 7060 | 6002 : 7061 | 6002 | 7062 |
6003 | 7056 | 6003 | 7057 | 6003 : 7058 | 6003 | 7059 | 6003 | 7060 | 6003 : 7061 | 6003 | 7062 |
6004 | 7056 | 6004 | 7057 | 6004: 7058 | 6004 | 7059 | 6004 | 7060 | 6004: 7061 | 6004 | 7062 |
6005 | 7056 | 6005 | 7057 | 6005 : 7058 | 6005 | 7059 | 6005 | 7060 | 6005 : 7061 | 6005 | 7062 |
6006 | 7056 | 6006 | 7057 | 6006: 7058 | 6006 | 7059 | 6006 | 7060 | 6006 : 7061 | 6006 | 7062 |
6007 | 7056 | 6007 | 7057 | 6007 : 7058 | 6007 | 7059 | 6007 | 7060 | 6007 : 7061 | 6007 | 7062 |
6008 | 7056 | 6008 | 7057 | 6008 : 7058 | 6008 | 7059 | 6008 | 7060 | 6008 : 7061 | 6008 | 7062 |
6009 | 7056 | 6009 | 7057 | 6009 : 7058 | 6009 | 7059 | 6009 | 7060 | 6009 : 7061 | 6009 | 7062 |
6010 | 7056 | 6010 | 7057 | 6010: 7058 | 6010 | 7059 | 6010 | 7060 | 6010: 7061 | 6010 | 7062 |
6011 | 7056 | 6011 | 7057 | 6011 : 7058 | 6011 | 7059 | 6011 | 7060 | 6011 : 7061 | 6011 | 7062 |
6012 | 7056 | 6012 | 7057 | 6012 : 7058 | 6012 | 7059 | 6012 | 7060 | 6012 : 7061 | 6012 | 7062 |
6013 | 7056 | 6013 | 7057 | 6013 : 7058 | 6013 | 7059 | 6013 | 7060 | 6013 : 7061 | 6013 | 7062 |
6014 | 7056 | 6014 | 7057 | 6014 : 7058 | 6014 | 7059 | 6014 | 7060 | 6014 : 7061 | 6014 | 7062 |
6015 | 7056 | 6015 | 7057 | 6015 : 7058 | 6015 | 7059 | 6015 | 7060 | 6015 : 7061 | 6015 | 7062 |
6016 | 7056 | 6016 | 7057 | 6016 : 7058 | 6016 | 7059 | 6016 | 7060 | 6016: 7061 | 6016 | 7062 |
6017 | 7056 | 6017 | 7057 | 6017 : 7058 | 6017 | 7059 | 6017 | 7060 | 6017: 7061 | 6017 | 7062 |
6018 | 7056 | 6018 | 7057 | 6018 : 7058 | 6018 | 7059 | 6018 | 7060 | 6018 : 7061 | 6018 | 7062 |
6019 | 7056 | 6019 | 7057 | 6019:7058 | 6019 | 7059 | 6019 | 7060 | 6019 : 7061 | 6019 | 7062 |
6020 | 7056 | 6020 | 7057 | 6020 : 7058 | 6020 | 7059 | 6020 | 7060 | 6020: 7061 | 6020 | 7062 |
6000 | 7063 | 6000 | 7064 | 6000: 7065 | 6000 | 7066 | 6000 | 7067 | 6000: 7068 | 6000 | 7069 |
6001 | 7063 | 6001 | 7064 | 6001 : 7065 | 6001 | 7066 | 6001 | 7067 | 6001 : 7068 | 6001 | 7069 |
6002 | 7063 | 6002 | 7064 | 6002 : 7065 | 6002 | 7066 | 6002 | 7067 | 6002 : 7068 | 6002 | 7069 |
6003 | 7063 | 6003 | 7064 | 6003 : 7065 | 6003 | 7066 | 6003 | 7067 | 6003 : 7068 | 6003 | 7069 |
6004 | 7063 | 6004 | 7064 | 6004 : 7065 | 6004 | 7066 | 6004 | 7067 | 6004: 7068 | 6004 | 7069 |
6005 | 7063 | 6005 | 7064 | 6005 : 7065 | 6005 | 7066 | 6005 | 7067 | 6005 : 7068 | 6005 | 7069 |
6006 | 7063 | 6006 | 7064 | 6006 : 7065 | 6006 | 7066 | 6006 | 7067 | 6006 : 7068 | 6006 | 7069 |
6007 | 7063 | 6007 | 7064 | 6007 : 7065 | 6007 | 7066 | 6007 | 7067 | 6007 : 7068 | 6007 | 7069 |
6008 | 7063 | 6008 | 7064 | 6008 : 7065 | 6008 | 7066 | 6008 | 7067 | 6008 : 7068 | 6008 | 7069 |
6009 | 7063 | 6009 | 7064 | 6009 : 7065 | 6009 | 7066 | 6009 | 7067 | 6009 : 7068 | 6009 | 7069 |
6010 | 7063 | 6010 | 7064 | 6010 : 7065 | 6010 | 7066 | 6010 | 7067 | 6010: 7068 | 6010 | 7069 |
106
X | Y | X | Y | X | Y | X | Y | X: Y | X | Y | X | Y |
6011 | 7063 | 6011 | 7064 | 6011 | 7065 | 6011 | 7066 | 6011 : 7067 | 6011 | 7068 | 6011 | 7069 |
6012 | 7063 | 6012 | 7064 | 6012 | 7065 | 6012 | 7066 | 6012 : 7067 | 6012 | 7068 | 6012 | 7069 |
6013 | 7063 | 6013 | 7064 | 6013 | 7065 | 6013 | 7066 | 6013 : 7067 | 6013 | 7068 | 6013 | 7069 |
6014 | 7063 | 6014 | 7064 | 6014 | 7065 | 6014 | 7066 | 6014 : 7067 | 6014 | 7068 | 6014 | 7069 |
6015 | 7063 | 6015 | 7064 | 6015 | 7065 | 6015 | 7066 | 6015 : 7067 | 6015 | 7068 | 6015 | 7069 |
6016 | 7063 | 6016 | 7064 | 6016 | 7065 | 6016 | 7066 | 6016 : 7067 | 6016 | 7068 | 6016 | 7069 |
6017 | 7063 | 6017 | 7064 | 6017 | 7065 | 6017 | 7066 | 6017 : 7067 | 6017 | 7068 | 6017 | 7069 |
6018 | 7063 | 6018 | 7064 | 6018 | 7065 | 6018 | 7066 | 6018 : 7067 | 6018 | 7068 | 6018 | 7069 |
6019 | 7063 | 6019 | 7064 | 6019 | 7065 | 6019 | 7066 | 6019 : 7067 | 6019 | 7068 | 6019 | 7069 |
6020 | 7063 | 6020 | 7064 | 6020 | 7065 | 6020 | 7066 | 6020: 7067 | 6020 | 7068 | 6020 | 7069 |
6000 | 7070 | 6000 | 7071 | 6000 | 7072 | 6000 | 7073 | 6000 : 7074 | 6000 | 7075 | 6000 | 7076 |
6001 | 7070 | 6001 | 7071 | 6001 | 7072 | 6001 | 7073 | 6001 : 7074 | 6001 | 7075 | 6001 | 7076 |
6002 | 7070 | 6002 | 7071 | 6002 | 7072 | 6002 | 7073 | 6002 : 7074 | 6002 | 7075 | 6002 | 7076 |
6003 | 7070 | 6003 | 7071 | 6003 | 7072 | 6003 | 7073 | 6003 : 7074 | 6003 | 7075 | 6003 | 7076 |
6004 | 7070 | 6004 | 7071 | 6004 | 7072 | 6004 | 7073 | 6004 : 7074 | 6004 | 7075 | 6004 | 7076 |
6005 | 7070 | 6005 | 7071 | 6005 | 7072 | 6005 | 7073 | 6005 : 7074 | 6005 | 7075 | 6005 | 7076 |
6006 | 7070 | 6006 | 7071 | 6006 | 7072 | 6006 | 7073 | 6006 : 7074 | 6006 | 7075 | 6006 | 7076 |
6007 | 7070 | 6007 | 7071 | 6007 | 7072 | 6007 | 7073 | 6007 : 7074 | 6007 | 7075 | 6007 | 7076 |
6008 | 7070 | 6008 | 7071 | 6008 | 7072 | 6008 | 7073 | 6008 : 7074 | 6008 | 7075 | 6008 | 7076 |
6009 | 7070 | 6009 | 7071 | 6009 | 7072 | 6009 | 7073 | 6009 : 7074 | 6009 | 7075 | 6009 | 7076 |
6010 | 7070 | 6010 | 7071 | 6010 | 7072 | 6010 | 7073 | 6010 : 7074 | 6010 | 7075 | 6010 | 7076 |
6011 | 7070 | 6011 | 7071 | 6011 | 7072 | 6011 | 7073 | 6011 : 7074 | 6011 | 7075 | 6011 | 7076 |
6012 | 7070 | 6012 | 7071 | 6012 | 7072 | 6012 | 7073 | 6012 : 7074 | 6012 | 7075 | 6012 | 7076 |
6013 | 7070 | 6013 | 7071 | 6013 | 7072 | 6013 | 7073 | 6013 : 7074 | 6013 | 7075 | 6013 | 7076 |
6014 | 7070 | 6014 | 7071 | 6014 | 7072 | 6014 | 7073 | 6014 : 7074 | 6014 | 7075 | 6014 | 7076 |
6015 | 7070 | 6015 | 7071 | 6015 | 7072 | 6015 | 7073 | 6015 : 7074 | 6015 | 7075 | 6015 | 7076 |
6016 | 7070 | 6016 | 7071 | 6016 | 7072 | 6016 | 7073 | 6016: 7074 | 6016 | 7075 | 6016 | 7076 |
6017 | 7070 | 6017 | 7071 | 6017 | 7072 | 6017 | 7073 | 6017 : 7074 | 6017 | 7075 | 6017 | 7076 |
6018 | 7070 | 6018 | 7071 | 6018 | 7072 | 6018 | 7073 | 6018 : 7074 | 6018 | 7075 | 6018 | 7076 |
6019 | 7070 | 6019 | 7071 | 6019 | 7072 | 6019 | 7073 | 6019 : 7074 | 6019 | 7075 | 6019 | 7076 |
6020 | 7070 | 6020 | 7071 | 6020 | 7072 | 6020 | 7073 | 6020 : 7074 | 6020 | 7075 | 6020 | 7076 |
6000 | 7077 | 6021 | 7000 | 6021 | 7001 | 6021 | 7002 | 6021 : 7003 | 6021 | 7004 | 6021 | 7005 |
6001 | 7077 | 6022 | 7000 | 6022 | 7001 | 6022 | 7002 | 6022 : 7003 | 6022 | 7004 | 6022 | 7005 |
6002 | 7077 | 6023 | 7000 | 6023 | 7001 | 6023 | 7002 | 6023 : 7003 | 6023 | 7004 | 6023 | 7005 |
6003 | 7077 | 6024 | 7000 | 6024 | 7001 | 6024 | 7002 | 6024: 7003 | 6024 | 7004 | 6024 | 7005 |
6004 | 7077 | 6025 | 7000 | 6025 | 7001 | 6025 | 7002 | 6025 : 7003 | 6025 | 7004 | 6025 | 7005 |
6005 | 7077 | 6026 | 7000 | 6026 | 7001 | 6026 | 7002 | 6026 : 7003 | 6026 | 7004 | 6026 | 7005 |
6006 | 7077 | 6027 | 7000 | 6027 | 7001 | 6027 | 7002 | 6027 : 7003 | 6027 | 7004 | 6027 | 7005 |
6007 | 7077 | 6028 | 7000 | 6028 | 7001 | 6028 | 7002 | 6028 : 7003 | 6028 | 7004 | 6028 | 7005 |
6008 | 7077 | 6029 | 7000 | 6029 | 7001 | 6029 | 7002 | 6029 : 7003 | 6029 | 7004 | 6029 | 7005 |
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6009 | 7077 | 6030 | 7000 | 6030 | 7001 | 6030 | 7002 | 6030 | 7003 | 6030 | 7004 | 6030 | 7005 |
6010 | 7077 | 6031 | 7000 | 6031 | 7001 | 6031 | 7002 | 6031 | 7003 | 6031 | 7004 | 6031 | 7005 |
60ll | 7077 | 6032 | 7000 | 6032 | 7001 | 6032 | 7002 | 6032 | 7003 | 6032 | 7004 | 6032 | 7005 |
6012 | 7077 | 6033 | 7000 | 6033 | 7001 | 6033 | 7002 | 6033 | 7003 | 6033 | 7004 | 6033 | 7005 |
6013 | 7077 | 6034 | 7000 | 6034 | 7001 | 6034 | 7002 | 6034 | 7003 | 6034 | 7004 | 6034 | 7005 |
6014 | 7077 | 6035 | 7000 | 6035 | 7001 | 6035 | 7002 | 6035 | 7003 | 6035 | 7004 | 6035 | 7005 |
6015 | 7077 | 6036 | 7000 | 6036 | 7001 | 6036 | 7002 | 6036 | 7003 | 6036 | 7004 | 6036 | 7005 |
6016 | 7077 | 6037 | 7000 | 6037 | 7001 | 6037 | 7002 | 6037 | 7003 | 6037 | 7004 | 6037 | 7005 |
6017 | 7077 | 6038 | 7000 | 6038 | 7001 | 6038 | 7002 | 6038 | 7003 | 6038 | 7004 | 6038 | 7005 |
6018 | 7077 | 6039 | 7000 | 6039 | 7001 | 6039 | 7002 | 6039 | 7003 | 6039 | 7004 | 6039 | 7005 |
6019 | 7077 | 6040 | 7000 | 6040 | 7001 | 6040 | 7002 | 6040 | 7003 | 6040 | 7004 | 6040 | 7005 |
6020 | 7077 | ||||||||||||
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6021 | 7006 | 6021 | 7007 | 6021 | 7008 | 6021 | 7009 | 6021 | 7010 | 6021 | 7011 | 6021 | 7012 |
6022 | 7006 | 6022 | 7007 | 6022 | 7008 | 6022 | 7009 | 6022 | 7010 | 6022 | 7011 | 6022 | 7012 |
6023 | 7006 | 6023 | 7007 | 6023 | 7008 | 6023 | 7009 | 6023 | 7010 | 6023 | 7011 | 6023 | 7012 |
6024 | 7006 | 6024 | 7007 | 6024 | 7008 | 6024 | 7009 | 6024 | 7010 | 6024 | 7011 | 6024 | 7012 |
6025 | 7006 | 6025 | 7007 | 6025 | 7008 | 6025 | 7009 | 6025 | 7010 | 6025 | 7011 | 6025 | 7012 |
6026 | 7006 | 6026 | 7007 | 6026 | 7008 | 6026 | 7009 | 6026 | 7010 | 6026 | 7011 | 6026 | 7012 |
6027 | 7006 | 6027 | 7007 | 6027 | 7008 | 6027 | 7009 | 6027 | 7010 | 6027 | 7011 | 6027 | 7012 |
6028 | 7006 | 6028 | 7007 | 6028 | 7008 | 6028 | 7009 | 6028 | 7010 | 6028 | 7011 | 6028 | 7012 |
6029 | 7006 | 6029 | 7007 | 6029 | 7008 | 6029 | 7009 | 6029 | 7010 | 6029 | 7011 | 6029 | 7012 |
6030 | 7006 | 6030 | 7007 | 6030 | 7008 | 6030 | 7009 | 6030 | 7010 | 6030 | 7011 | 6030 | 7012 |
6031 | 7006 | 6031 | 7007 | 6031 | 7008 | 6031 | 7009 | 6031 | 7010 | 6031 | 7011 | 6031 | 7012 |
6032 | 7006 | 6032 | 7007 | 6032 | 7008 | 6032 | 7009 | 6032 | 7010 | 6032 | 7011 | 6032 | 7012 |
6033 | 7006 | 6033 | 7007 | 6033 | 7008 | 6033 | 7009 | 6033 | 7010 | 6033 | 7011 | 6033 | 7012 |
6034 | 7006 | 6034 | 7007 | 6034 | 7008 | 6034 | 7009 | 6034 | 7010 | 6034 | 7011 | 6034 | 7012 |
6035 | 7006 | 6035 | 7007 | 6035 | 7008 | 6035 | 7009 | 6035 | 7010 | 6035 | 7011 | 6035 | 7012 |
6036 | 7006 | 6036 | 7007 | 6036 | 7008 | 6036 | 7009 | 6036 | 7010 | 6036 | 7011 | 6036 | 7012 |
6037 | 7006 | 6037 | 7007 | 6037 | 7008 | 6037 | 7009 | 6037 | 7010 | 6037 | 7011 | 6037 | 7012 |
6038 | 7006 | 6038 | 7007 | 6038 | 7008 | 6038 | 7009 | 6038 | 7010 | 6038 | 7011 | 6038 | 7012 |
6039 | 7006 | 6039 | 7007 | 6039 | 7008 | 6039 | 7009 | 6039 | 7010 | 6039 | 7011 | 6039 | 7012 |
6040 | 7006 | 6040 | 7007 | 6040 | 7008 | 6040 | 7009 | 6040 | 7010 | 6040 | 7011 | 6040 | 7012 |
6021 | 7013 | 6021 | 7014 | 6021 | 7015 | 6021 | 7016 | 6021 | 7017 | 6021 | 7018 | 6021 | 7019 |
6022 | 7013 | 6022 | 7014 | 6022 | 7015 | 6022 | 7016 | 6022 | 7017 | 6022 | 7018 | 6022 | 7019 |
6023 | 7013 | 6023 | 7014 | 6023 | 7015 | 6023 | 7016 | 6023 | 7017 | 6023 | 7018 | 6023 | 7019 |
6024 | 7013 | 6024 | 7014 | 6024 | 7015 | 6024 | 7016 | 6024 | 7017 | 6024 | 7018 | 6024 | 7019 |
6025 | 7013 | 6025 | 7014 | 6025 | 7015 | 6025 | 7016 | 6025 | 7017 | 6025 | 7018 | 6025 | 7019 |
6026 | 7013 | 6026 | 7014 | 6026 | 7015 | 6026 | 7016 | 6026 | 7017 | 6026 | 7018 | 6026 | 7019 |
6027 | 7013 | 6027 | 7014 | 6027 | 7015 | 6027 | 7016 | 6027 | 7017 | 6027 | 7018 | 6027 | 7019 |
6028 | 7013 | 6028 | 7014 | 6028 | 7015 | 6028 | 7016 | 6028 | 7017 | 6028 | 7018 | 6028 | 7019 |
6029 | 7013 | 6029 | 7014 | 6029 | 7015 | 6029 | :7016 | 6029 | 7017 | 6029 | 7018 | 6029 | 7019 |
108
X | : Y | X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6030 | 7013 | 6030 | 7014 | 6030 | 7015 | 6030 | 7016 | 6030 | 7017 | 6030 | 7018 | 6030 | 7019 |
6031 | 7013 | 6031 | 7014 | 6031 | 7015 | 6031 | 7016 | 6031 | 7017 | 6031 | 7018 | 6031 | 7019 |
6032 | 7013 | 6032 | 7014 | 6032 | 7015 | 6032 | 7016 | 6032 | 7017 | 6032 | 7018 | 6032 | 7019 |
6033 | 7013 | 6033 | 7014 | 6033 | 7015 | 6033 | 7016 | 6033 | 7017 | 6033 | 7018 | 6033 | 7019 |
6034 | 7013 | 6034 | 7014 | 6034 | 7015 | 6034 | 7016 | 6034 | 7017 | 6034 | 7018 | 6034 | 7019 |
6035 | 7013 | 6035 | 7014 | 6035 | 7015 | 6035 | 7016 | 6035 | 7017 | 6035 | 7018 | 6035 | 7019 |
6036 | 7013 | 6036 | 7014 | 6036 | 7015 | 6036 | 7016 | 6036 | 7017 | 6036 | 7018 | 6036 | 7019 |
6037 | 7013 | 6037 | 7014 | 6037 | 7015 | 6037 | 7016 | 6037 | 7017 | 6037 | 7018 | 6037 | 7019 |
6038 | 7013 | 6038 | 7014 | 6038 | 7015 | 6038 | 7016 | 6038 | 7017 | 6038 | 7018 | 6038 | 7019 |
6039 | 7013 | 6039 | 7014 | 6039 | 7015 | 6039 | 7016 | 6039 | 7017 | 6039 | 7018 | 6039 | 7019 |
6040 | 7013 | 6040 | 7014 | 6040 | 7015 | 6040 | 7016 | 6040 | 7017 | 6040 | 7018 | 6040 | 7019 |
6021 | 7020 | 6021 | 7021 | 6021 | 7022 | 6021 | 7023 | 6021 | 7024 | 6021 | 7025 | 6021 | 7026 |
6022 | 7020 | 6022 | 7021 | 6022 | 7022 | 6022 | 7023 | 6022 | 7024 | 6022 | 7025 | 6022 | 7026 |
6023 | 7020 | 6023 | 7021 | 6023 | 7022 | 6023 | 7023 | 6023 | 7024 | 6023 | 7025 | 6023 | 7026 |
6024 | 7020 | 6024 | 7021 | 6024 | 7022 | 6024 | 7023 | 6024 | 7024 | 6024 | 7025 | 6024 | 7026 |
6025 | 7020 | 6025 | 7021 | 6025 | 7022 | 6025 | 7023 | 6025 | 7024 | 6025 | 7025 | 6025 | 7026 |
6026 | 7020 | 6026 | 7021 | 6026 | 7022 | 6026 | 7023 | 6026 | 7024 | 6026 | 7025 | 6026 | 7026 |
6027 | 7020 | 6027 | 7021 | 6027 | 7022 | 6027 | 7023 | 6027 | 7024 | 6027 | 7025 | 6027 | 7026 |
6028 | 7020 | 6028 | 7021 | 6028 | 7022 | 6028 | 7023 | 6028 | 7024 | 6028 | 7025 | 6028 | 7026 |
6029 | 7020 | 6029 | 7021 | 6029 | 7022 | 6029 | 7023 | 6029 | 7024 | 6029 | 7025 | 6029 | 7026 |
6030 | 7020 | 6030 | 7021 | 6030 | 7022 | 6030 | 7023 | 6030 | 7024 | 6030 | 7025 | 6030 | 7026 |
6031 | 7020 | 6031 | 7021 | 6031 | 7022 | 6031 | 7023 | 6031 | 7024 | 6031 | 7025 | 6031 | 7026 |
6032 | 7020 | 6032 | 7021 | 6032 | 7022 | 6032 | 7023 | 6032 | 7024 | 6032 | 7025 | 6032 | 7026 |
6033 | 7020 | 6033 | 7021 | 6033 | 7022 | 6033 | 7023 | 6033 | 7024 | 6033 | 7025 | 6033 | 7026 |
6034 | 7020 | 6034 | 7021 | 6034 | 7022 | 6034 | 7023 | 6034 | 7024 | 6034 | 7025 | 6034 | 7026 |
6035 | 7020 | 6035 | 7021 | 6035 | 7022 | 6035 | 7023 | 6035 | 7024 | 6035 | 7025 | 6035 | 7026 |
6036 | 7020 | 6036 | 7021 | 6036 | 7022 | 6036 | 7023 | 6036 | 7024 | 6036 | 7025 | 6036 | 7026 |
6037 | 7020 | 6037 | 7021 | 6037 | 7022 | 6037 | 7023 | 6037 | 7024 | 6037 | 7025 | 6037 | 7026 |
6038 | 7020 | 6038 | 7021 | 6038 | 7022 | 6038 | 7023 | 6038 | 7024 | 6038 | 7025 | 6038 | 7026 |
6039 | 7020 | 6039 | 7021 | 6039 | 7022 | 6039 | 7023 | 6039 | 7024 | 6039 | 7025 | 6039 | 7026 |
6040 | 7020 | 6040 | 7021 | 6040 | 7022 | 6040 | 7023 | 6040 | 7024 | 6040 | 7025 | 6040 | 7026 |
6021 | 7027 | 6021 | 7028 | 6021 | 7029 | 6021 | 7030 | 6021 | 7031 | 6021 | 7032 | 6021 | 7033 |
6022 | 7027 | 6022 | 7028 | 6022 | 7029 | 6022 | 7030 | 6022 | 7031 | 6022 | 7032 | 6022 | 7033 |
6023 | 7027 | 6023 | 7028 | 6023 | 7029 | 6023 | 7030 | 6023 | 7031 | 6023 | 7032 | 6023 | 7033 |
6024 | 7027 | 6024 | 7028 | 6024 | 7029 | 6024 | 7030 | 6024 | 7031 | 6024 | 7032 | 6024 | 7033 |
6025 | 7027 | 6025 | 7028 | 6025 | 7029 | 6025 | 7030 | 6025 | 7031 | 6025 | 7032 | 6025 | 7033 |
6026 | 7027 | 6026 | 7028 | 6026 | 7029 | 6026 | 7030 | 6026 | 7031 | 6026 | 7032 | 6026 | 7033 |
6027 | 7027 | 6027 | 7028 | 6027 | 7029 | 6027 | 7030 | 6027 | 7031 | 6027 | 7032 | 6027 | 7033 |
6028 | 7027 | 6028 | 7028 | 6028 | 7029 | 6028 | 7030 | 6028 | 7031 | 6028 | 7032 | 6028 | 7033 |
6029 | 7027 | 6029 | 7028 | 6029 | 7029 | 6029 | 7030 | 6029 | 7031 | 6029 | 7032 | 6029 | 7033 |
6030 | 7027 | 6030 | 7028 | 6030 | 7029 | 6030 | 7030 | 6030 | 7031 | 6030 | 7032 | 6030 | 7033 |
6031 | 7027 | 6031 | 7028 | 6031 | 7029 | 6031 | 7030 | 6031 | 7031 | 6031 | 7032 | 6031 | 7033 |
6032 | 7027 | 6032 | 7028 | 6032 | 7029 | 6032 | 7030 | 6032 | 7031 | 6032 | 7032 | 6032 | 7033 |
109
X | Y | X | Y | X: Y | X | Y | X | Y | X | Y | X: Y | ||
6033 | 7027 | 6033 | 7028 | 6033 | 7029 | 6033 | 7030 | 6033 | 7031 | 6033 | 7032 | 6033 | 7033 |
6034 | 7027 | 6034 | 7028 | 6034 | 7029 | 6034 | 7030 | 6034 | 7031 | 6034 | 7032 | 6034 | 7033 |
6035 | 7027 | 6035 | 7028 | 6035 | 7029 | 6035 | 7030 | 6035 | 7031 | 6035 | 7032 | 6035 | 7033 |
6036 | 7027 | 6036 | 7028 | 6036 | 7029 | 6036 | 7030 | 6036 | 7031 | 6036 | 7032 | 6036 | 7033 |
6037 | 7027 | 6037 | 7028 | 6037 | 7029 | 6037 | 7030 | 6037 | 7031 | 6037 | 7032 | 6037 | 7033 |
6038 | 7027 | 6038 | 7028 | 6038 | 7029 | 6038 | 7030 | 6038 | 7031 | 6038 | 7032 | 6038 | 7033 |
6039 | 7027 | 6039 | 7028 | 6039 | 7029 | 6039 | 7030 | 6039 | 7031 | 6039 | 7032 | 6039 | 7033 |
6040 | 7027 | 6040 | 7028 | 6040 | 7029 | 6040 | 7030 | 6040 | 7031 | 6040 | 7032 | 6040 | 7033 |
6021 | 7034 | 6021 | 7035 | 6021 | 7036 | 6021 | 7037 | 6021 | 7038 | 6021 | 7039 | 6021 | 7040 |
6022 | 7034 | 6022 | 7035 | 6022 | 7036 | 6022 | 7037 | 6022 | 7038 | 6022 | 7039 | 6022 | 7040 |
6023 | 7034 | 6023 | 7035 | 6023 | 7036 | 6023 | 7037 | 6023 | 7038 | 6023 | 7039 | 6023 | 7040 |
6024 | 7034 | 6024 | 7035 | 6024 | 7036 | 6024 | 7037 | 6024 | 7038 | 6024 | 7039 | 6024 | 7040 |
6025 | 7034 | 6025 | 7035 | 6025 | 7036 | 6025 | 7037 | 6025 | 7038 | 6025 | 7039 | 6025 | 7040 |
6026 | 7034 | 6026 | 7035 | 6026 | 7036 | 6026 | 7037 | 6026 | 7038 | 6026 | 7039 | 6026 | 7040 |
6027 | 7034 | 6027 | 7035 | 6027 | 7036 | 6027 | 7037 | 6027 | 7038 | 6027 | 7039 | 6027 | 7040 |
6028 | 7034 | 6028 | 7035 | 6028 | 7036 | 6028 | 7037 | 6028 | 7038 | 6028 | 7039 | 6028 | 7040 |
6029 | 7034 | 6029 | 7035 | 6029 | 7036 | 6029 | 7037 | 6029 | 7038 | 6029 | 7039 | 6029 | 7040 |
6030 | 7034 | 6030 | 7035 | 6030 | 7036 | 6030 | 7037 | 6030 | 7038 | 6030 | 7039 | 6030 | 7040 |
6031 | 7034 | 6031 | 7035 | 6031 | 7036 | 6031 | 7037 | 6031 | 7038 | 6031 | 7039 | 6031 | 7040 |
6032 | 7034 | 6032 | 7035 | 6032 | 7036 | 6032 | 7037 | 6032 | 7038 | 6032 | 7039 | 6032 | 7040 |
6033 | 7034 | 6033 | 7035 | 6033 | 7036 | 6033 | 7037 | 6033 | 7038 | 6033 | 7039 | 6033 | 7040 |
6034 | 7034 | 6034 | 7035 | 6034 | 7036 | 6034 | 7037 | 6034 | 7038 | 6034 | 7039 | 6034 | 7040 |
6035 | 7034 | 6035 | 7035 | 6035 | 7036 | 6035 | 7037 | 6035 | 7038 | 6035 | 7039 | 6035 | 7040 |
6036 | 7034 | 6036 | 7035 | 6036 | 7036 | 6036 | 7037 | 6036 | 7038 | 6036 | 7039 | 6036 | 7040 |
6037 | 7034 | 6037 | 7035 | 6037 | 7036 | 6037 | 7037 | 6037 | 7038 | 6037 | 7039 | 6037 | 7040 |
6038 | 7034 | 6038 | 7035 | 6038 | 7036 | 6038 | 7037 | 6038 | 7038 | 6038 | 7039 | 6038 | 7040 |
6039 | 7034 | 6039 | 7035 | 6039 | 7036 | 6039 | 7037 | 6039 | 7038 | 6039 | 7039 | 6039 | 7040 |
6040 | 7034 | 6040 | 7035 | 6040 | 7036 | 6040 | 7037 | 6040 | 7038 | 6040 | 7039 | 6040 | 7040 |
6021 | 7041 | 6021 | 7042 | 6021 | 7043 | 6021 | 7044 | 6021 | 7045 | 6021 | 7046 | 6021 | 7047 |
6022 | 7041 | 6022 | 7042 | 6022 | 7043 | 6022 | 7044 | 6022 | 7045 | 6022 | 7046 | 6022 | 7047 |
6023 | 7041 | 6023 | 7042 | 6023 | 7043 | 6023 | 7044 | 6023 | 7045 | 6023 | 7046 | 6023 | 7047 |
6024 | 7041 | 6024 | 7042 | 6024 | 7043 | 6024 | 7044 | 6024 | 7045 | 6024 | 7046 | 6024 | 7047 |
6025 | 7041 | 6025 | 7042 | 6025 | 7043 | 6025 | 7044 | 6025 | 7045 | 6025 | 7046 | 6025 | 7047 |
6026 | 7041 | 6026 | 7042 | 6026 | 7043 | 6026 | 7044 | 6026 | 7045 | 6026 | 7046 | 6026 | 7047 |
6027 | 7041 | 6027 | 7042 | 6027 | 7043 | 6027 | 7044 | 6027 | 7045 | 6027 | 7046 | 6027 | 7047 |
6028 | 7041 | 6028 | 7042 | 6028 | 7043 | 6028 | 7044 | 6028 | 7045 | 6028 | 7046 | 6028 | 7047 |
6029 | 7041 | 6029 | 7042 | 6029 | 7043 | 6029 | 7044 | 6029 | 7045 | 6029 | 7046 | 6029 | 7047 |
6030 | 7041 | 6030 | 7042 | 6030 | 7043 | 6030 | 7044 | 6030 | 7045 | 6030 | 7046 | 6030 | 7047 |
6031 | 7041 | 6031 | 7042 | 6031 | 7043 | 6031 | 7044 | 6031 | 7045 | 6031 | 7046 | 6031 | 7047 |
6032 | 7041 | 6032 | 7042 | 6032 | 7043 | 6032 | 7044 | 6032 | 7045 | 6032 | 7046 | 6032 | 7047 |
6033 | 7041 | 6033 | 7042 | 6033 | 7043 | 6033 | 7044 | 6033 | 7045 | 6033 | 7046 | 6033 | 7047 |
6034 | 7041 | 6034 | 7042 | 6034 | 7043 | 6034 | 7044 | 6034 | 7045 | 6034 | 7046 | 6034 | 7047 |
6035 | 7041 | 6035 | 7042 | 6035 | 7043 | 6035 | 7044 | 6035 | 7045 | 6035 | 7046 | 6035 | 7047 |
110
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6036 | 7041 | 6036 | 7042 | 6036 | 7043 | 6036 | 7044 | 6036 | 7045 | 6036 | 7046 | 6036 | 7047 |
6037 | 7041 | 6037 | 7042 | 6037 | 7043 | 6037 | 7044 | 6037 | 7045 | 6037 | 7046 | 6037 | 7047 |
6038 | 7041 | 6038 | 7042 | 6038 | 7043 | 6038 | 7044 | 6038 | 7045 | 6038 | 7046 | 6038 | 7047 |
6039 | 7041 | 6039 | 7042 | 6039 | 7043 | 6039 | 7044 | 6039 | 7045 | 6039 | 7046 | 6039 | 7047 |
6040 | 7041 | 6040 | 7042 | 6040 | 7043 | 6040 | 7044 | 6040 | 7045 | 6040 | 7046 | 6040 | 7047 |
6021 | 7048 | 6021 | 7049 | 6021 | 7050 | 6021 | 7051 | 6021 | 7052 | 6021 | 7053 | 6021 | 7054 |
6022 | 7048 | 6022 | 7049 | 6022 | 7050 | 6022 | 7051 | 6022 | 7052 | 6022 | 7053 | 6022 | 7054 |
6023 | 7048 | 6023 | 7049 | 6023 | 7050 | 6023 | 7051 | 6023 | 7052 | 6023 | 7053 | 6023 | 7054 |
6024 | 7048 | 6024 | 7049 | 6024 | 7050 | 6024 | 7051 | 6024 | 7052 | 6024 | 7053 | 6024 | 7054 |
6025 | 7048 | 6025 | 7049 | 6025 | 7050 | 6025 | 7051 | 6025 | 7052 | 6025 | 7053 | 6025 | 7054 |
6026 | 7048 | 6026 | 7049 | 6026 | 7050 | 6026 | 7051 | 6026 | 7052 | 6026 | 7053 | 6026 | 7054 |
6027 | 7048 | 6027 | 7049 | 6027 | 7050 | 6027 | 7051 | 6027 | 7052 | 6027 | 7053 | 6027 | 7054 |
6028 | 7048 | 6028 | 7049 | 6028 | 7050 | 6028 | 7051 | 6028 | 7052 | 6028 | 7053 | 6028 | 7054 |
6029 | 7048 | 6029 | 7049 | 6029 | 7050 | 6029 | 7051 | 6029 | 7052 | 6029 | 7053 | 6029 | 7054 |
6030 | 7048 | 6030 | 7049 | 6030 | 7050 | 6030 | 7051 | 6030 | 7052 | 6030 | 7053 | 6030 | 7054 |
6031 | 7048 | 6031 | 7049 | 6031 | 7050 | 6031 | 7051 | 6031 | 7052 | 6031 | 7053 | 6031 | 7054 |
6032 | 7048 | 6032 | 7049 | 6032 | 7050 | 6032 | 7051 | 6032 | 7052 | 6032 | 7053 | 6032 | 7054 |
6033 | 7048 | 6033 | 7049 | 6033 | 7050 | 6033 | 7051 | 6033 | 7052 | 6033 | 7053 | 6033 | 7054 |
6034 | 7048 | 6034 | 7049 | 6034 | 7050 | 6034 | 7051 | 6034 | 7052 | 6034 | 7053 | 6034 | 7054 |
6035 | 7048 | 6035 | 7049 | 6035 | 7050 | 6035 | 7051 | 6035 | 7052 | 6035 | 7053 | 6035 | 7054 |
6036 | 7048 | 6036 | 7049 | 6036 | 7050 | 6036 | 7051 | 6036 | 7052 | 6036 | 7053 | 6036 | 7054 |
6037 | 7048 | 6037 | 7049 | 6037 | 7050 | 6037 | 7051 | 6037 | 7052 | 6037 | 7053 | 6037 | 7054 |
6038 | 7048 | 6038 | 7049 | 6038 | 7050 | 6038 | 7051 | 6038 | 7052 | 6038 | 7053 | 6038 | 7054 |
6039 | 7048 | 6039 | 7049 | 6039 | 7050 | 6039 | 7051 | 6039 | 7052 | 6039 | 7053 | 6039 | 7054 |
6040 | 7048 | 6040 | 7049 | 6040 | 7050 | 6040 | 7051 | 6040 | 7052 | 6040 | 7053 | 6040 | 7054 |
6021 | 7055 | 6021 | 7056 | 6021 | 7057 | 6021 | 7058 | 6021 | 7059 | 6021 | 7060 | 6021 | 7061 |
6022 | 7055 | 6022 | 7056 | 6022 | 7057 | 6022 | 7058 | 6022 | 7059 | 6022 | 7060 | 6022 | 7061 |
6023 | 7055 | 6023 | 7056 | 6023 | 7057 | 6023 | 7058 | 6023 | 7059 | 6023 | 7060 | 6023 | 7061 |
6024 | 7055 | 6024 | 7056 | 6024 | 7057 | 6024 | 7058 | 6024 | 7059 | 6024 | 7060 | 6024 | 7061 |
6025 | 7055 | 6025 | 7056 | 6025 | 7057 | 6025 | 7058 | 6025 | 7059 | 6025 | 7060 | 6025 | 7061 |
6026 | 7055 | 6026 | 7056 | 6026 | 7057 | 6026 | 7058 | 6026 | 7059 | 6026 | 7060 | 6026 | 7061 |
6027 | 7055 | 6027 | 7056 | 6027 | 7057 | 6027 | 7058 | 6027 | 7059 | 6027 | 7060 | 6027 | 7061 |
6028 | 7055 | 6028 | 7056 | 6028 | 7057 | 6028 | 7058 | 6028 | 7059 | 6028 | 7060 | 6028 | 7061 |
6029 | 7055 | 6029 | 7056 | 6029 | 7057 | 6029 | 7058 | 6029 | 7059 | 6029 | 7060 | 6029 | 7061 |
6030 | 7055 | 6030 | 7056 | 6030 | 7057 | 6030 | 7058 | 6030 | 7059 | 6030 | 7060 | 6030 | 7061 |
6031 | 7055 | 6031 | 7056 | 6031 | 7057 | 6031 | 7058 | 6031 | 7059 | 6031 | 7060 | 6031 | 7061 |
6032 | 7055 | 6032 | 7056 | 6032 | 7057 | 6032 | 7058 | 6032 | 7059 | 6032 | 7060 | 6032 | 7061 |
6033 | 7055 | 6033 | 7056 | 6033 | 7057 | 6033 | 7058 | 6033 | 7059 | 6033 | 7060 | 6033 | 7061 |
6034 | 7055 | 6034 | 7056 | 6034 | 7057 | 6034 | 7058 | 6034 | 7059 | 6034 | 7060 | 6034 | 7061 |
6035 | 7055 | 6035 | 7056 | 6035 | 7057 | 6035 | 7058 | 6035 | 7059 | 6035 | 7060 | 6035 | 7061 |
6036 | 7055 | 6036 | 7056 | 6036 | 7057 | 6036 | 7058 | 6036 | 7059 | 6036 | 7060 | 6036 | 7061 |
6037 | 7055 | 6037 | 7056 | 6037 | 7057 | 6037 | 7058 | 6037 | 7059 | 6037 | 7060 | 6037 | 7061 |
6038 | 7055 | 6038 | 7056 | 6038 | 7057 | 6038 | 7058 | 6038 | 7059 | 6038 | 7060 | 6038 | 7061 |
X: Y | X | Y | X: Y | X | Y | X | Y | X: | Y | X: | Y |
6039 : 7055 | 6039 | 7056 | 6039 : 7057 | 6039 | 7058 | 6039 | 7059 | 6039 | 7060 | 6039 | 7061 |
6040: 7055 | 6040 | 7056 | 6040: 7057 | 6040 | 7058 | 6040 | 7059 | 6040 | 7060 | 6040 | 7061 |
6021 : 7062 | 6021 | 7063 | 6021 : 7064 | 6021 | 7065 | 6021 | 7066 | 6021 | 7067 | 6021 | 7068 |
6022 : 7062 | 6022 | 7063 | 6022 : 7064 | 6022 | 7065 | 6022 | 7066 | 6022 | 7067 | 6022 | 7068 |
6023 : 7062 | 6023 | 7063 | 6023 : 7064 | 6023 | 7065 | 6023 | 7066 | 6023 | 7067 | 6023 | 7068 |
6024 : 7062 | 6024 | 7063 | 6024: 7064 | 6024 | 7065 | 6024 | 7066 | 6024 | 7067 | 6024 | 7068 |
6025 : 7062 | 6025 | 7063 | 6025 : 7064 | 6025 | 7065 | 6025 | 7066 | 6025 | 7067 | 6025 | 7068 |
6026 : 7062 | 6026 | 7063 | 6026 : 7064 | 6026 | 7065 | 6026 | 7066 | 6026 | 7067 | 6026 | 7068 |
6027 : 7062 | 6027 | 7063 | 6027 : 7064 | 6027 | 7065 | 6027 | 7066 | 6027 | 7067 | 6027 | 7068 |
6028 : 7062 | 6028 | 7063 | 6028 : 7064 | 6028 | 7065 | 6028 | 7066 | 6028 | 7067 | 6028 | 7068 |
6029: 7062 | 6029 | 7063 | 6029 : 7064 | 6029 | 7065 | 6029 | 7066 | 6029 | 7067 | 6029 | 7068 |
6030: 7062 | 6030 | 7063 | 6030: 7064 | 6030 | 7065 | 6030 | 7066 | 6030 | 7067 | 6030 | 7068 |
6031 : 7062 | 6031 | 7063 | 6031 : 7064 | 6031 | 7065 | 6031 | 7066 | 6031 | 7067 | 6031 | 7068 |
6032 : 7062 | 6032 | 7063 | 6032 : 7064 | 6032 | 7065 | 6032 | 7066 | 6032 | 7067 | 6032 | 7068 |
6033 : 7062 | 6033 | 7063 | 6033 : 7064 | 6033 | 7065 | 6033 | 7066 | 6033 | 7067 | 6033 | 7068 |
6034: 7062 | 6034 | 7063 | 6034: 7064 | 6034 | 7065 | 6034 | 7066 | 6034 | 7067 | 6034 | 7068 |
6035 : 7062 | 6035 | 7063 | 6035 : 7064 | 6035 | 7065 | 6035 | 7066 | 6035 | 7067 | 6035 | 7068 |
6036 : 7062 | 6036 | 7063 | 6036 : 7064 | 6036 | 7065 | 6036 | 7066 | 6036 | 7067 | 6036 | 7068 |
6037: 7062 | 6037 | 7063 | 6037 : 7064 | 6037 | 7065 | 6037 | 7066 | 6037 | 7067 | 6037 | 7068 |
6038 : 7062 | 6038 | 7063 | 6038 : 7064 | 6038 | 7065 | 6038 | 7066 | 6038 | 7067 | 6038 | 7068 |
6039 : 7062 | 6039 | 7063 | 6039: 7064 | 6039 | 7065 | 6039 | 7066 | 6039 | 7067 | 6039 | 7068 |
6040: 7062 | 6040 | 7063 | 6040 : 7064 | 6040 | 7065 | 6040 | 7066 | 6040 | 7067 | 6040 | 7068 |
6021 : 7069 | 6021 | 7070 | 6021 : 7071 | 6021 | 7072 | 6021 | 7073 | 6021 | 7074 | 6021 | 7075 |
6022: 7069 | 6022 | 7070 | 6022 : 7071 | 6022 | 7072 | 6022 | 7073 | 6022 | 7074 | 6022 | 7075 |
6023 : 7069 | 6023 | 7070 | 6023 : 7071 | 6023 | 7072 | 6023 | 7073 | 6023 | 7074 | 6023 | 7075 |
6024 : 7069 | 6024 | 7070 | 6024 : 7071 | 6024 | 7072 | 6024 | 7073 | 6024 | 7074 | 6024 | 7075 |
6025 : 7069 | 6025 | 7070 | 6025 : 7071 | 6025 | 7072 | 6025 | 7073 | 6025 | 7074 | 6025 | 7075 |
6026: 7069 | 6026 | 7070 | 6026 : 7071 | 6026 | 7072 | 6026 | 7073 | 6026 | 7074 | 6026 | 7075 |
6027 : 7069 | 6027 | 7070 | 6027 : 7071 | 6027 | 7072 | 6027 | 7073 | 6027 | 7074 | 6027 | 7075 |
6028 : 7069 | 6028 | 7070 | 6028 : 7071 | 6028 | 7072 | 6028 | 7073 | 6028 | 7074 | 6028 | 7075 |
6029: 7069 | 6029 | 7070 | 6029 : 7071 | 6029 | 7072 | 6029 | 7073 | 6029 | 7074 | 6029 | 7075 |
6030: 7069 | 6030 | 7070 | 6030: 7071 | 6030 | 7072 | 6030 | 7073 | 6030 | 7074 | 6030 | 7075 |
6031 : 7069 | 6031 | 7070 | 6031 : 7071 | 6031 | 7072 | 6031 | 7073 | 6031 | 7074 | 6031 | 7075 |
6032 : 7069 | 6032 | 7070 | 6032 : 7071 | 6032 | 7072 | 6032 | 7073 | 6032 | 7074 | 6032 | 7075 |
6033 : 7069 | 6033 | 7070 | 6033 : 7071 | 6033 | 7072 | 6033 | 7073 | 6033 | 7074 | 6033 | 7075 |
6034: 7069 | 6034 | 7070 | 6034: 7071 | 6034 | 7072 | 6034 | 7073 | 6034 | 7074 | 6034 | 7075 |
6035 : 7069 | 6035 | 7070 | 6035 : 7071 | 6035 | 7072 | 6035 | 7073 | 6035 | 7074 | 6035 | 7075 |
6036 : 7069 | 6036 | 7070 | 6036 : 7071 | 6036 | 7072 | 6036 | 7073 | 6036 | 7074 | 6036 | 7075 |
6037 : 7069 | 6037 | 7070 | 6037 : 7071 | 6037 | 7072 | 6037 | 7073 | 6037 | 7074 | 6037 | 7075 |
6038 : 7069 | 6038 | 7070 | 6038 : 7071 | 6038 | 7072 | 6038 | 7073 | 6038 | 7074 | 6038 | 7075 |
6039 : 7069 | 6039 | 7070 | 6039 : 7071 | 6039 | 7072 | 6039 | 7073 | 6039 | 7074 | 6039 | 7075 |
6040: 7069 | 6040 | 7070 | 6040: 7071 | 6040 | 7072 | 6040 | 7073 | 6040 | 7074 | 6040 | 7075 |
6021 : 7076 | 6021 | 7077 | 6041 : 7000 | 6041 | 7001 | 6041 | 7002 | 6041 | 7003 | 6041 | 7004 |
112
X | Y | X | Y | X | Y | x· | Y | X | Y | X: | Y | X: | Y |
6022 | 7076 | 6022 | 7077 | 6042 | 7000 | 6042 | 7001 | 6042 | 7002 | 6042 | 7003 | 6042 | 7004 |
6023 | 7076 | 6023 | 7077 | 6043 | 7000 | 6043 | 7001 | 6043 | 7002 | 6043 | 7003 | 6043 | 7004 |
6024 | 7076 | 6024 | 7077 | 6044 | 7000 | 6044 | 7001 | 6044 | 7002 | 6044 | 7003 | 6044 | 7004 |
6025 | 7076 | 6025 | 7077 | 6045 | 7000 | 6045 | 7001 | 6045 | 7002 | 6045 | 7003 | 6045 | 7004 |
6026 | 7076 | 6026 | 7077 | 6046 | 7000 | 6046 | 7001 | 6046 | 7002 | 6046 | 7003 | 6046 | 7004 |
6027 | 7076 | 6027 | 7077 | 6047 | 7000 | 6047 | 7001 | 6047 | 7002 | 6047 | 7003 | 6047 | 7004 |
6028 | 7076 | 6028 | 7077 | 6048 | 7000 | 6048 | 7001 | 6048 | 7002 | 6048 | 7003 | 6048 | 7004 |
6029 | 7076 | 6029 | 7077 | 6049 | 7000 | 6049 | 7001 | 6049 | 7002 | 6049 | 7003 | 6049 | 7004 |
6030 | 7076 | 6030 | 7077 | 6050 | 7000 | 6050 | 7001 | 6050 | 7002 | 6050 | 7003 | 6050 | 7004 |
6031 | 7076 | 6031 | 7077 | 6051 | 7000 | 6051 | 7001 | 6051 | 7002 | 6051 | 7003 | 6051 | 7004 |
6032 | 7076 | 6032 | 7077 | 6052 | 7000 | 6052 | 7001 | 6052 | 7002 | 6052 | 7003 | 6052 | 7004 |
6033 | 7076 | 6033 | 7077 | 6053 | 7000 | 6053 | 7001 | 6053 | 7002 | 6053 | 7003 | 6053 | 7004 |
6034 | 7076 | 6034 | 7077 | 6054 | 7000 | 6054 | 7001 | 6054 | 7002 | 6054 | 7003 | 6054 | 7004 |
6035 | 7076 | 6035 | 7077 | 6055 | 7000 | 6055 | 7001 | 6055 | 7002 | 6055 | 7003 | 6055 | 7004 |
6036 | 7076 | 6036 | 7077 | 6056 | 7000 | 6056 | 7001 | 6056 | 7002 | 6056 | 7003 | 6056 | 7004 |
6037 | 7076 | 6037 | 7077 | 6057 | 7000 | 6057 | 7001 | 6057 | 7002 | 6057 | 7003 | 6057 | 7004 |
6038 | 7076 | 6038 | 7077 | 6058 | 7000 | 6058 | 7001 | 6058 | 7002 | 6058 | 7003 | 6058 | 7004 |
6039 | 7076 | 6039 | 7077 | 6059 | 7000 | 6059 | 7001 | 6059 | 7002 | 6059 | 7003 | 6059 | 7004 |
6040 | 7076 | 6040 | 7077 | 6060 | 7000 | 6060 | 7001 | 6060 | 7002 | 6060 | 7003 | 6060 | 7004 |
6041 | 7005 | 6041 | 7006 | 6041 | 7007 | 6041 | 7008 | 6041 | 7009 | 6041 | 7010 | 6041 | 7011 |
6042 | 7005 | 6042 | 7006 | 6042 | 7007 | 6042 | 7008 | 6042 | 7009 | 6042 | 7010 | 6042 | 7011 |
6043 | 7005 | 6043 | 7006 | 6043 | 7007 | 6043 | 7008 | 6043 | 7009 | 6043 | 7010 | 6043 | 7011 |
6044 | 7005 | 6044 | 7006 | 6044 | 7007 | 6044 | 7008 | 6044 | 7009 | 6044 | 7010 | 6044 | 7011 |
6045 | 7005 | 6045 | 7006 | 6045 | 7007 | 6045 | 7008 | 6045 | 7009 | 6045 | 7010 | 6045 | 7011 |
6046 | 7005 | 6046 | 7006 | 6046 | 7007 | 6046 | 7008 | 6046 | 7009 | 6046 | 7010 | 6046 | 7011 |
6047 | 7005 | 6047 | 7006 | 6047 | 7007 | 6047 | 7008 | 6047 | 7009 | 6047 | 7010 | 6047 | 7011 |
6048 | 7005 | 6048 | 7006 | 6048 | 7007 | 6048 | 7008 | 6048 | 7009 | 6048 | 7010 | 6048 | 7011 |
6049 | 7005 | 6049 | 7006 | 6049 | 7007 | 6049 | 7008 | 6049 | 7009 | 6049 | 7010 | 6049 | 7011 |
6050 | 7005 | 6050 | 7006 | 6050 | 7007 | 6050 | 7008 | 6050 | 7009 | 6050 | 7010 | 6050 | 7011 |
6051 | 7005 | 6051 | 7006 | 6051 | 7007 | 6051 | 7008 | 6051 | 7009 | 6051 | 7010 | 6051 | 7011 |
6052 | 7005 | 6052 | 7006 | 6052 | 7007 | 6052 | 7008 | 6052 | 7009 | 6052 | 7010 | 6052 | 7011 |
6053 | 7005 | 6053 | 7006 | 6053 | 7007 | 6053 | 7008 | 6053 | 7009 | 6053 | 7010 | 6053 | 7011 |
6054 | 7005 | 6054 | 7006 | 6054 | 7007 | 6054 | 7008 | 6054 | 7009 | 6054 | 7010 | 6054 | 7011 |
6055 | 7005 | 6055 | 7006 | 6055 | 7007 | 6055 | 7008 | 6055 | 7009 | 6055 | 7010 | 6055 | 7011 |
6056 | 7005 | 6056 | 7006 | 6056 | 7007 | 6056 | 7008 | 6056 | 7009 | 6056 | 7010 | 6056 | 7011 |
6057 | 7005 | 6057 | 7006 | 6057 | 7007 | 6057 | 7008 | 6057 | 7009 | 6057 | 7010 | 6057 | 7011 |
6058 | 7005 | 6058 | 7006 | 6058 | 7007 | 6058 | 7008 | 6058 | 7009 | 6058 | 7010 | 6058 | 7011 |
6059 | 7005 | 6059 | 7006 | 6059 | 7007 | 6059 | 7008 | 6059 | 7009 | 6059 | 7010 | 6059 | 7011 |
6060 | 7005 | 6060 | 7006 | 6060 | 7007 | 6060 | 7008 | 6060 | 7009 | 6060 | 7010 | 6060 | 7011 |
6041 | 7012 | 6041 | 7013 | 6041 | 7014 | 6041 | 7015 | 6041 | 7016 | 6041 | 7017 | 6041 | 7018 |
6042 | 7012 | 6042 | 7013 | 6042 | 7014 | 6042 | 7015 | 6042 | 7016 | 6042 | 7017 | 6042 | 7018 |
6043 | 7012 | 6043 | 7013 | 6043 | 7014 | 6043 | 7015 | 6043 | 7016 | 6043 | 7017 | 6043 | 7018 |
6044 | 7012 | 6044 | 7013 | 6044 | 7014 | 6044 | 7015 | 6044 | 7016 | 6044 | 7017 | 6044 | 7018 |
113
X | Y | X | Y | X: | Y | X: | Y | X: | Y | X; | Y | X: | Y |
6045 | 7012 | 6045 | 7013 | 6045 | 7014 | 6045 | 7015 | 6045 | 7016 | 6045 | 7017 | 6045 | 7018 |
6046 | 7012 | 6046 | 7013 | 6046 | 7014 | 6046 | 7015 | 6046 | 7016 | 6046 | 7017 | 6046 | 7018 |
6047 | 7012 | 6047 | 7013 | 6047 | 7014 | 6047 | 7015 | 6047 | 7016 | 6047 | 7017 | 6047 | 7018 |
6048 | 7012 | 6048 | 7013 | 6048 | 7014 | 6048 | 7015 | 6048 | 7016 | 6048 | 7017 | 6048 | 7018 |
6049 | 7012 | 6049 | 7013 | 6049 | 7014 | 6049 | 7015 | 6049 | 7016 | 6049 | 7017 | 6049 | 7018 |
6050 | 7012 | 6050 | 7013 | 6050 | 7014 | 6050 | 7015 | 6050 | 7016 | 6050 | 7017 | 6050 | 7018 |
6051 | 7012 | 6051 | 7013 | 6051 | 7014 | 6051 | 7015 | 6051 | 7016 | 6051 | 7017 | 6051 | 7018 |
6052 | 7012 | 6052 | 7013 | 6052 | 7014 | 6052 | 7015 | 6052 | 7016 | 6052 | 7017 | 6052 | 7018 |
6053 | 7012 | 6053 | 7013 | 6053 | 7014 | 6053 | 7015 | 6053 | 7016 | 6053 | 7017 | 6053 | 7018 |
6054 | 7012 | 6054 | 7013 | 6054 | 7014 | 6054 | 7015 | 6054 | 7016 | 6054 | 7017 | 6054 | 7018 |
6055 | 7012 | 6055 | 7013 | 6055 | 7014 | 6055 | 7015 | 6055 | 7016 | 6055 | 7017 | 6055 | 7018 |
6056 | 7012 | 6056 | 7013 | 6056 | 7014 | 6056 | 7015 | 6056 | 7016 | 6056 | 7017 | 6056 | 7018 |
6057 | 7012 | 6057 | 7013 | 6057 | 7014 | 6057 | 7015 | 6057 | 7016 | 6057 | 7017 | 6057 | 7018 |
6058 | 7012 | 6058 | 7013 | 6058 | 7014 | 6058 | 7015 | 6058 | 7016 | 6058 | 7017 | 6058 | 7018 |
6059 | 7012 | 6059 | 7013 | 6059 | 7014 | 6059 | 7015 | 6059 | 7016 | 6059 | 7017 | 6059 | 7018 |
6060 | 7012 | 6060 | 7013 | 6060 | 7014 | 6060 | 7015 | 6060 | 7016 | 6060 | 7017 | 6060 | 7018 |
6041 | 7019 | 6041 | 7020 | 6041 | 7021 | 6041 | 7022 | 6041 | 7023 | 6041 | 7024 | 6041 | 7025 |
6042 | 7019 | 6042 | 7020 | 6042 | 7021 | 6042 | 7022 | 6042 | 7023 | 6042 | 7024 | 6042 | 7025 |
6043 | 7019 | 6043 | 7020 | 6043 | 7021 | 6043 | 7022 | 6043 | 7023 | 6043 | 7024 | 6043 | 7025 |
6044 | 7019 | 6044 | 7020 | 6044 | 7021 | 6044 | 7022 | 6044 | 7023 | 6044 | 7024 | 6044 | 7025 |
6045 | 7019 | 6045 | 7020 | 6045 | 7021 | 6045 | 7022 | 6045 | 7023 | 6045 | 7024 | 6045 | 7025 |
6046 | 7019 | 6046 | 7020 | 6046 | 7021 | 6046 | 7022 | 6046 | 7023 | 6046 | 7024 | 6046 | 7025 |
6047 | 7019 | 6047 | 7020 | 6047 | 7021 | 6047 | 7022 | 6047 | 7023 | 6047 | 7024 | 6047 | 7025 |
6048 | 7019 | 6048 | 7020 | 6048 | 7021 | 6048 | 7022 | 6048 | 7023 | 6048 | 7024 | 6048 | 7025 |
6049 | 7019 | 6049 | 7020 | 6049 | 7021 | 6049 | 7022 | 6049 | 7023 | 6049 | 7024 | 6049 | 7025 |
6050 | 7019 | 6050 | 7020 | 6050 | 7021 | 6050 | 7022 | 6050 | 7023 | 6050 | 7024 | 6050 | 7025 |
6051 | 7019 | 6051 | 7020 | 6051 | 7021 | 6051 | 7022 | 6051 | 7023 | 6051 | 7024 | 6051 | 7025 |
6052 | 7019 | 6052 | 7020 | 6052 | 7021 | 6052 | 7022 | 6052 | 7023 | 6052 | 7024 | 6052 | 7025 |
6053 | 7019 | 6053 | 7020 | 6053 | 7021 | 6053 | 7022 | 6053 | 7023 | 6053 | 7024 | 6053 | 7025 |
6054 | 7019 | 6054 | 7020 | 6054 | 7021 | 6054 | 7022 | 6054 | 7023 | 6054 | 7024 | 6054 | 7025 |
6055 | 7019 | 6055 | 7020 | 6055 | 7021 | 6055 | 7022 | 6055 | 7023 | 6055 | 7024 | 6055 | 7025 |
6056 | 7019 | 6056 | 7020 | 6056 | 7021 | 6056 | 7022 | 6056 | 7023 | 6056 | 7024 | 6056 | 7025 |
6057 | 7019 | 6057 | 7020 | 6057 | 7021 | 6057 | 7022 | 6057 | 7023 | 6057 | 7024 | 6057 | 7025 |
6058 | 7019 | 6058 | 7020 | 6058 | 7021 | 6058 | 7022 | 6058 | 7023 | 6058 | 7024 | 6058 | 7025 |
6059 | 7019 | 6059 | 7020 | 6059 | 7021 | 6059 | 7022 | 6059 | 7023 | 6059 | 7024 | 6059 | 7025 |
6060 | 7019 | 6060 | 7020 | 6060 | 7021 | 6060 | 7022 | 6060 | 7023 | 6060 | 7024 | 6060 | 7025 |
6041 | 7026 | 6041 | 7027 | 6041 | 7028 | 6041 | 7029 | 6041 | 7030 | 6041 | 7031 | 6041 | 7032 |
6042 | 7026 | 6042 | 7027 | 6042 | 7028 | 6042 | 7029 | 6042 | 7030 | 6042 | 7031 | 6042 | 7032 |
6043 | 7026 | 6043 | 7027 | 6043 | 7028 | 6043 | 7029 | 6043 | 7030 | 6043 | 7031 | 6043 | 7032 |
6044 | 7026 | 6044 | 7027 | 6044 | 7028 | 6044 | 7029 | 6044 | 7030 | 6044 | 7031 | 6044 | 7032 |
6045 | 7026 | 6045 | 7027 | 6045 | 7028 | 6045 | 7029 | 6045 | 7030 | 6045 | 7031 | 6045 | 7032 |
6046 | 7026 | 6046 | 7027 | 6046 | 7028 | 6046 | 7029 | 6046 | 7030 | 6046 | 7031 | 6046 | 7032 |
6047 | 7026 | 6047 | 7027 | 6047 | 7028 | 6047 | 7029 | 6047 | 7030 | 6047 | 7031 | 6047 | :7032 |
114
X | Y | X | Y | X | Y | X | Y | X: Y | X | Y | X | Y |
6048 | 7026 | 6048 | 7027 | 6048 | 7028 | 6048 | 7029 | 6048 : 7030 | 6048 | 7031 | 6048 | 7032 |
6049 | 7026 | 6049 | 7027 | 6049 | 7028 | 6049 | 7029 | 6049 : 7030 | 6049 | 7031 | 6049 | 7032 |
6050 | 7026 | 6050 | 7027 | 6050 | 7028 | 6050 | 7029 | 6050 : 7030 | 6050 | 7031 | 6050 | 7032 |
6051 | 7026 | 6051 | 7027 | 6051 | 7028 | 6051 | 7029 | 6051 : 7030 | 6051 | 7031 | 6051 | 7032 |
6052 | 7026 | 6052 | 7027 | 6052 | 7028 | 6052 | 7029 | 6052 : 7030 | 6052 | 7031 | 6052 | 7032 |
6053 | 7026 | 6053 | 7027 | 6053 | 7028 | 6053 | 7029 | 6053 : 7030 | 6053 | 7031 | 6053 | 7032 |
6054 | 7026 | 6054 | 7027 | 6054 | 7028 | 6054 | 7029 | 6054: 7030 | 6054 | 7031 | 6054 | 7032 |
6055 | 7026 | 6055 | 7027 | 6055 | 7028 | 6055 | 7029 | 6055 : 7030 | 6055 | 7031 | 6055 | 7032 |
6056 | 7026 | 6056 | 7027 | 6056 | 7028 | 6056 | 7029 | 6056 : 7030 | 6056 | 7031 | 6056 | 7032 |
6057 | 7026 | 6057 | 7027 | 6057 | 7028 | 6057 | 7029 | 6057 : 7030 | 6057 | 7031 | 6057 | 7032 |
6058 | 7026 | 6058 | 7027 | 6058 | 7028 | 6058 | 7029 | 6058 : 7030 | 6058 | 7031 | 6058 | 7032 |
6059 | 7026 | 6059 | 7027 | 6059 | 7028 | 6059 | 7029 | 6059 : 7030 | 6059 | 7031 | 6059 | 7032 |
6060 | 7026 | 6060 | 7027 | 6060 | 7028 | 6060 | 7029 | 6060 : 7030 | 6060 | 7031 | 6060 | 7032 |
6041 | 7033 | 6041 | 7034 | 6041 | 7035 | 6041 | 7036 | 6041 : 7037 | 6041 | 7038 | 6041 | 7039 |
6042 | 7033 | 6042 | 7034 | 6042 | 7035 | 6042 | 7036 | 6042 : 7037 | 6042 | 7038 | 6042 | 7039 |
6043 | 7033 | 6043 | 7034 | 6043 | 7035 | 6043 | 7036 | 6043 : 7037 | 6043 | 7038 | 6043 | 7039 |
6044 | 7033 | 6044 | 7034 | 6044 | 7035 | 6044 | 7036 | 6044 : 7037 | 6044 | 7038 | 6044 | 7039 |
6045 | 7033 | 6045 | 7034 | 6045 | 7035 | 6045 | 7036 | 6045 : 7037 | 6045 | 7038 | 6045 | 7039 |
6046 | 7033 | 6046 | 7034 | 6046 | 7035 | 6046 | 7036 | 6046 : 7037 | 6046 | 7038 | 6046 | 7039 |
6047 | 7033 | 6047 | 7034 | 6047 | 7035 | 6047 | 7036 | 6047 : 7037 | 6047 | 7038 | 6047 | 7039 |
6048 | 7033 | 6048 | 7034 | 6048 | 7035 | 6048 | 7036 | 6048 : 7037 | 6048 | 7038 | 6048 | 7039 |
6049 | 7033 | 6049 | 7034 | 6049 | 7035 | 6049 | 7036 | 6049 : 7037 | 6049 | 7038 | 6049 | 7039 |
6050 | 7033 | 6050 | 7034 | 6050 | 7035 | 6050 | 7036 | 6050 : 7037 | 6050 | 7038 | 6050 | 7039 |
6051 | 7033 | 6051 | 7034 | 6051 | 7035 | 6051 | 7036 | 6051 : 7037 | 6051 | 7038 | 6051 | 7039 |
6052 | 7033 | 6052 | 7034 | 6052 | 7035 | 6052 | 7036 | 6052 : 7037 | 6052 | 7038 | 6052 | 7039 |
6053 | 7033 | 6053 | 7034 | 6053 | 7035 | 6053 | 7036 | 6053 : 7037 | 6053 | 7038 | 6053 | 7039 |
6054 | 7033 | 6054 | 7034 | 6054 | 7035 | 6054 | 7036 | 6054 : 7037 | 6054 | 7038 | 6054 | 7039 |
6055 | 7033 | 6055 | 7034 | 6055 | 7035 | 6055 | 7036 | 6055 : 7037 | 6055 | 7038 | 6055 | 7039 |
6056 | 7033 | 6056 | 7034 | 6056 | 7035 | 6056 | 7036 | 6056: 7037 | 6056 | 7038 | 6056 | 7039 |
6057 | 7033 | 6057 | 7034 | 6057 | 7035 | 6057 | 7036 | 6057 : 7037 | 6057 | 7038 | 6057 | 7039 |
6058 | 7033 | 6058 | 7034 | 6058 | 7035 | 6058 | 7036 | 6058 : 7037 | 6058 | 7038 | 6058 | 7039 |
6059 | 7033 | 6059 | 7034 | 6059 | 7035 | 6059 | 7036 | 6059 : 7037 | 6059 | 7038 | 6059 | 7039 |
6060 | 7033 | 6060 | 7034 | 6060 | 7035 | 6060 | 7036 | 6060 : 7037 | 6060 | 7038 | 6060 | 7039 |
6041 | 7040 | 6041 | 7041 | 6041 | 7042 | 6041 | 7043 | 6041 : 7044 | 6041 | 7045 | 6041 | 7046 |
6042 | 7040 | 6042 | 7041 | 6042 | 7042 | 6042 | 7043 | 6042 : 7044 | 6042 | 7045 | 6042 | 7046 |
6043 | 7040 | 6043 | 7041 | 6043 | 7042 | 6043 | 7043 | 6043 : 7044 | 6043 | 7045 | 6043 | 7046 |
6044 | 7040 | 6044 | 7041 | 6044 | 7042 | 6044 | 7043 | 6044 : 7044 | 6044 | 7045 | 6044 | 7046 |
6045 | 7040 | 6045 | 7041 | 6045 | 7042 | 6045 | 7043 | 6045 : 7044 | 6045 | 7045 | 6045 | 7046 |
6046 | 7040 | 6046 | 7041 | 6046 | 7042 | 6046 | 7043 | 6046 : 7044 | 6046 | 7045 | 6046 | 7046 |
6047 | 7040 | 6047 | 7041 | 6047 | 7042 | 6047 | 7043 | 6047 : 7044 | 6047 | 7045 | 6047 | 7046 |
6048 | 7040 | 6048 | 7041 | 6048 | 7042 | 6048 | 7043 | 6048 : 7044 | 6048 | 7045 | 6048 | 7046 |
6049 | 7040 | 6049 | 7041 | 6049 | 7042 | 6049 | 7043 | 6049 : 7044 | 6049 | 7045 | 6049 | 7046 |
6050 | 7040 | 6050 | 7041 | 6050 | 7042 | 6050 | 7043 | 6050 : 7044 | 6050 | 7045 | 6050 | 7046 |
115
X | Y | X | Y | X: Y | X | Y | X | Y | X: | Y | X: | Y |
6051 | 7040 | 6051 | 7041 | 6051 : 7042 | 6051 | 7043 | 6051 | 7044 | 6051 | 7045 | 6051 | 7046 |
6052 | 7040 | 6052 | 7041 | 6052 : 7042 | 6052 | 7043 | 6052 | 7044 | 6052 | 7045 | 6052 | 7046 |
6053 | 7040 | 6053 | 7041 | 6053 : 7042 | 6053 | 7043 | 6053 | 7044 | 6053 | 7045 | 6053 | 7046 |
6054 | 7040 | 6054 | 7041 | 6054 : 7042 | 6054 | 7043 | 6054 | 7044 | 6054 | 7045 | 6054 | 7046 |
6055 | 7040 | 6055 | 7041 | 6055 : 7042 | 6055 | 7043 | 6055 | 7044 | 6055 | 7045 | 6055 | 7046 |
6056 | 7040 | 6056 | 7041 | 6056: 7042 | 6056 | 7043 | 6056 | 7044 | 6056 | 7045 | 6056 | 7046 |
6057 | 7040 | 6057 | 7041 | 6057 : 7042 | 6057 | 7043 | 6057 | 7044 | 6057 | 7045 | 6057 | 7046 |
6058 | 7040 | 6058 | 7041 | 6058 : 7042 | 6058 | 7043 | 6058 | 7044 | 6058 | 7045 | 6058 | 7046 |
6059 | 7040 | 6059 | 7041 | 6059: 7042 | 6059 | 7043 | 6059 | 7044 | 6059 | 7045 | 6059 | 7046 |
6060 | 7040 | 6060 | 7041 | 6060 : 7042 | 6060 | 7043 | 6060 | 7044 | 6060 | 7045 | 6060 | 7046 |
6041 | 7047 | 6041 | 7048 | 6041 : 7049 | 6041 | 7050 | 6041 | 7051 | 6041 | 7052 | 6041 | 7053 |
6042 | 7047 | 6042 | 7048 | 6042 : 7049 | 6042 | 7050 | 6042 | 7051 | 6042 | 7052 | 6042 | 7053 |
6043 | 7047 | 6043 | 7048 | 6043 : 7049 | 6043 | 7050 | 6043 | 7051 | 6043 | 7052 | 6043 | 7053 |
6044 | 7047 | 6044 | 7048 | 6044: 7049 | 6044 | 7050 | 6044 | 7051 | 6044 | 7052 | 6044 | 7053 |
6045 | 7047 | 6045 | 7048 | 6045 : 7049 | 6045 | 7050 | 6045 | 7051 | 6045 | 7052 | 6045 | 7053 |
6046 | 7047 | 6046 | 7048 | 6046 : 7049 | 6046 | 7050 | 6046 | 7051 | 6046 | 7052 | 6046 | 7053 |
6047 | 7047 | 6047 | 7048 | 6047 : 7049 | 6047 | 7050 | 6047 | 7051 | 6047 | 7052 | 6047 | 7053 |
6048 | 7047 | 6048 | 7048 | 6048 : 7049 | 6048 | 7050 | 6048 | 7051 | 6048 | 7052 | 6048 | 7053 |
6049 | 7047 | 6049 | 7048 | 6049 : 7049 | 6049 | 7050 | 6049 | 7051 | 6049 | 7052 | 6049 | 7053 |
6050 | 7047 | 6050 | 7048 | 6050: 7049 | 6050 | 7050 | 6050 | 7051 | 6050 | 7052 | 6050 | 7053 |
6051 | 7047 | 6051 | 7048 | 6051 : 7049 | 6051 | 7050 | 6051 | 7051 | 6051 | 7052 | 6051 | 7053 |
6052 | 7047 | 6052 | 7048 | 6052 : 7049 | 6052 | 7050 | 6052 | 7051 | 6052 | 7052 | 6052 | 7053 |
6053 | 7047 | 6053 | 7048 | 6053 : 7049 | 6053 | 7050 | 6053 | 7051 | 6053 | 7052 | 6053 | 7053 |
6054 | 7047 | 6054 | 7048 | 6054 : 7049 | 6054 | 7050 | 6054 | 7051 | 6054 | 7052 | 6054 | 7053 |
6055 | 7047 | 6055 | 7048 | 6055 : 7049 | 6055 | 7050 | 6055 | 7051 | 6055 | 7052 | 6055 | 7053 |
6056 | 7047 | 6056 | 7048 | 6056: 7049 | 6056 | 7050 | 6056 | 7051 | 6056 | 7052 | 6056 | 7053 |
6057 | 7047 | 6057 | 7048 | 6057 : 7049 | 6057 | 7050 | 6057 | 7051 | 6057 | 7052 | 6057 | 7053 |
6058 | 7047 | 6058 | 7048 | 6058 : 7049 | 6058 | 7050 | 6058 | 7051 | 6058 | 7052 | 6058 | 7053 |
6059 | 7047 | 6059 | 7048 | 6059 : 7049 | 6059 | 7050 | 6059 | 7051 | 6059 | 7052 | 6059 | 7053 |
6060 | 7047 | 6060 | 7048 | 6060 : 7049 | 6060 | 7050 | 6060 | 7051 | 6060 | 7052 | 6060 | 7053 |
6041 | 7054 | 6041 | 7055 | 6041 : 7056 | 6041 | 7057 | 6041 | 7058 | 6041 | 7059 | 6041 | 7060 |
6042 | 7054 | 6042 | 7055 | 6042 : 7056 | 6042 | 7057 | 6042 | 7058 | 6042 | 7059 | 6042 | 7060 |
6043 | 7054 | 6043 | 7055 | 6043 : 7056 | 6043 | 7057 | 6043 | 7058 | 6043 | 7059 | 6043 | 7060 |
6044 | 7054 | 6044 | 7055 | 6044 : 7056 | 6044 | 7057 | 6044 | 7058 | 6044 | 7059 | 6044 | 7060 |
6045 | 7054 | 6045 | 7055 | 6045 : 7056 | 6045 | 7057 | 6045 | 7058 | 6045 | 7059 | 6045 | 7060 |
6046 | 7054 | 6046 | 7055 | 6046 : 7056 | 6046 | 7057 | 6046 | 7058 | 6046 | 7059 | 6046 | 7060 |
6047 | 7054 | 6047 | 7055 | 6047 : 7056 | 6047 | 7057 | 6047 | 7058 | 6047 | 7059 | 6047 | 7060 |
6048 | 7054 | 6048 | 7055 | 6048 : 7056 | 6048 | 7057 | 6048 | 7058 | 6048 | 7059 | 6048 | 7060 |
6049 | 7054 | 6049 | 7055 | 6049: 7056 | 6049 | 7057 | 6049 | 7058 | 6049 | 7059 | 6049 | 7060 |
6050 | 7054 | 6050 | 7055 | 6050 : 7056 | 6050 | 7057 | 6050 | 7058 | 6050 | 7059 | 6050 | 7060 |
6051 | 7054 | 6051 | 7055 | 6051 : 7056 | 6051 | 7057 | 6051 | 7058 | 6051 | 7059 | 6051 | 7060 |
6052 | 7054 | 6052 | 7055 | 6052 : 7056 | 6052 | 7057 | 6052 | 7058 | 6052 | 7059 | 6052 | 7060 |
6053 | 7054 | 6053 | 7055 | 6053 : 7056 | 6053 | 7057 | 6053 | 7058 | 6053 | 7059 | 6053 | 7060 |
116
X: Y | X | Y | X: Y | X: | Y | X: | Y | X | Y | X: | Y |
6054: 7054 | 6054 | 7055 | 6054: 7056 | 6054 | 7057 | 6054 | 7058 | 6054 | 7059 | 6054 | 7060 |
6055 : 7054 | 6055 | 7055 | 6055 : 7056 | 6055 | 7057 | 6055 | 7058 | 6055 | 7059 | 6055 | 7060 |
6056 : 7054 | 6056 | 7055 | 6056 : 7056 | 6056 | 7057 | 6056 | 7058 | 6056 | 7059 | 6056 | 7060 |
6057 : 7054 | 6057 | 7055 | 6057 : 7056 | 6057 | 7057 | 6057 | 7058 | 6057 | 7059 | 6057 | 7060 |
6058 : 7054 | 6058 | 7055 | 6058 : 7056 | 6058 | 7057 | 6058 | 7058 | 6058 | 7059 | 6058 | 7060 |
6059: 7054 | 6059 | 7055 | 6059 : 7056 | 6059 | 7057 | 6059 | 7058 | 6059 | 7059 | 6059 | 7060 |
6060 : 7054 | 6060 | 7055 | 6060: 7056 | 6060 | 7057 | 6060 | 7058 | 6060 | 7059 | 6060 | 7060 |
6041 : 7061 | 6041 | 7062 | 6041 : 7063 | 6041 | 7064 | 6041 | 7065 | 6041 | 7066 | 6041 | 7067 |
6042 : 7061 | 6042 | 7062 | 6042 : 7063 | 6042 | 7064 | 6042 | 7065 | 6042 | 7066 | 6042 | 7067 |
6043 : 7061 | 6043 | 7062 | 6043 : 7063 | 6043 | 7064 | 6043 | 7065 | 6043 | 7066 | 6043 | 7067 |
6044 : 7061 | 6044 | 7062 | 6044: 7063 | 6044 | 7064 | 6044 | 7065 | 6044 | 7066 | 6044 | 7067 |
6045 : 7061 | 6045 | 7062 | 6045 : 7063 | 6045 | 7064 | 6045 | 7065 | 6045 | 7066 | 6045 | 7067 |
6046: 7061 | 6046 | 7062 | 6046 : 7063 | 6046 | 7064 | 6046 | 7065 | 6046 | 7066 | 6046 | 7067 |
6047 : 7061 | 6047 | 7062 | 6047 : 7063 | 6047 | 7064 | 6047 | 7065 | 6047 | 7066 | 6047 | 7067 |
6048 : 7061 | 6048 | 7062 | 6048 : 7063 | 6048 | 7064 | 6048 | 7065 | 6048 | 7066 | 6048 | 7067 |
6049: 7061 | 6049 | 7062 | 6049 : 7063 | 6049 | 7064 | 6049 | 7065 | 6049 | 7066 | 6049 | 7067 |
6050 : 7061 | 6050 | 7062 | 6050: 7063 | 6050 | 7064 | 6050 | 7065 | 6050 | 7066 | 6050 | 7067 |
6051 : 7061 | 6051 | 7062 | 6051 : 7063 | 6051 | 7064 | 6051 | 7065 | 6051 | 7066 | 6051 | 7067 |
6052 : 7061 | 6052 | 7062 | 6052 : 7063 | 6052 | 7064 | 6052 | 7065 | 6052 | 7066 | 6052 | 7067 |
6053 : 7061 | 6053 | 7062 | 6053 : 7063 | 6053 | 7064 | 6053 | 7065 | 6053 | 7066 | 6053 | 7067 |
6054 : 7061 | 6054 | 7062 | 6054 : 7063 | 6054 | 7064 | 6054 | 7065 | 6054 | 7066 | 6054 | 7067 |
6055 : 7061 | 6055 | 7062 | 6055 : 7063 | 6055 | 7064 | 6055 | 7065 | 6055 | 7066 | 6055 | 7067 |
6056 : 7061 | 6056 | 7062 | 6056: 7063 | 6056 | 7064 | 6056 | 7065 | 6056 | 7066 | 6056 | 7067 |
6057 : 7061 | 6057 | 7062 | 6057 : 7063 | 6057 | 7064 | 6057 | 7065 | 6057 | 7066 | 6057 | 7067 |
6058 : 7061 | 6058 | 7062 | 6058 : 7063 | 6058 | 7064 | 6058 | 7065 | 6058 | 7066 | 6058 | 7067 |
6059 : 7061 | 6059 | 7062 | 6059 : 7063 | 6059 | 7064 | 6059 | 7065 | 6059 | 7066 | 6059 | 7067 |
6060 : 7061 | 6060 | 7062 | 6060 : 7063 | 6060 | 7064 | 6060 | 7065 | 6060 | 7066 | 6060 | 7067 |
6041 : 7068 | 6041 | 7069 | 6041 : 7070 | 6041 | 7071 | 6041 | 7072 | 6041 | 7073 | 6041 | 7074 |
6042 : 7068 | 6042 | 7069 | 6042 : 7070 | 6042 | 7071 | 6042 | 7072 | 6042 | 7073 | 6042 | 7074 |
6043 : 7068 | 6043 | 7069 | 6043 : 7070 | 6043 | 7071 | 6043 | 7072 | 6043 | 7073 | 6043 | 7074 |
6044: 7068 | 6044 | 7069 | 6044 : 7070 | 6044 | 7071 | 6044 | 7072 | 6044 | 7073 | 6044 | 7074 |
6045 : 7068 | 6045 | 7069 | 6045 : 7070 | 6045 | 7071 | 6045 | 7072 | 6045 | 7073 | 6045 | 7074 |
6046 : 7068 | 6046 | 7069 | 6046 : 7070 | 6046 | 7071 | 6046 | 7072 | 6046 | 7073 | 6046 | 7074 |
6047: 7068 | 6047 | 7069 | 6047 : 7070 | 6047 | 7071 | 6047 | 7072 | 6047 | 7073 | 6047 | 7074 |
6048 : 7068 | 6048 | 7069 | 6048 : 7070 | 6048 | 7071 | 6048 | 7072 | 6048 | 7073 | 6048 | 7074 |
6049 : 7068 | 6049 | 7069 | 6049 : 7070 | 6049 | 7071 | 6049 | 7072 | 6049 | 7073 | 6049 | 7074 |
6050 : 7068 | 6050 | 7069 | 6050: 7070 | 6050 | 7071 | 6050 | 7072 | 6050 | 7073 | 6050 | 7074 |
6051 : 7068 | 6051 | 7069 | 6051 : 7070 | 6051 | 7071 | 6051 | 7072 | 6051 | 7073 | 6051 | 7074 |
6052 : 7068 | 6052 | 7069 | 6052 : 7070 | 6052 | 7071 | 6052 | 7072 | 6052 | 7073 | 6052 | 7074 |
6053 : 7068 | 6053 | 7069 | 6053 : 7070 | 6053 | 7071 | 6053 | 7072 | 6053 | 7073 | 6053 | 7074 |
6054: 7068 | 6054 | 7069 | 6054 : 7070 | 6054 | 7071 | 6054 | 7072 | 6054 | 7073 | 6054 | 7074 |
6055 : 7068 | 6055 | 7069 | 6055 : 7070 | 6055 | 7071 | 6055 | 7072 | 6055 | 7073 | 6055 | 7074 |
6056 : 7068 | 6056 | 7069 | 6056 : 7070 | 6056 | 7071 | 6056 | 7072 | 6056 | 7073 | 6056 | 7074 |
117
X: Y | X | Y | X | Y | X: Y | X | Y | X | Y | X | Y |
6057:7068 | 6057 | 7069 | 6057 | 7070 | 6057:7071 | 6057 | 7072 | 6057 | 7073 | 6057 | 7074 |
6058 : 7068 | 6058 | 7069 | 6058 | 7070 | 6058 : 7071 | 6058 | 7072 | 6058 | 7073 | 6058 | 7074 |
6059 : 7068 | 6059 | 7069 | 6059 | 7070 | 6059: 7071 | 6059 | 7072 | 6059 | 7073 | 6059 | 7074 |
6060: 7068 | 6060 | 7069 | 6060 | 7070 | 6060: 7071 | 6060 | 7072 | 6060 | 7073 | 6060 | 7074 |
6041 : 7075 | 6041 | 7076 | 6041 | 7077 | |||||||
6042 : 7075 | 6042 | 7076 | 6042 | 7077 | 6061 : 7000 | 6061 | 7001 | 6061 | 7002 | 6061 | 7003 |
6043 : 7075 | 6043 | 7076 | 6043 | 7077 | 6062 : 7000 | 6062 | 7001 | 6062 | 7002 | 6062 | 7003 |
6044: 7075 | 6044 | 7076 | 6044 | 7077 | 6063 : 7000 | 6063 | 7001 | 6063 | 7002 | 6063 | 7003 |
6045 : 7075 | 6045 | 7076 | 6045 | 7077 | 6064: 7000 | 6064 | 7001 | 6064 | 7002 | 6064 | 7003 |
6046 : 7075 | 6046 | 7076 | 6046 | 7077 | 6065 : 7000 | 6065 | 7001 | 6065 | 7002 | 6065 | 7003 |
6047 : 7075 | 6047 | 7076 | 6047 | 7077 | 6066 : 7000 | 6066 | 7001 | 6066 | 7002 | 6066 | 7003 |
6048 : 7075 | 6048 | 7076 | 6048 | 7077 | 6067 : 7000 | 6067 | 7001 | 6067 | 7002 | 6067 | 7003 |
6049: 7075 | 6049 | 7076 | 6049 | 7077 | 6068 : 7000 | 6068 | 7001 | 6068 | 7002 | 6068 | 7003 |
6050: 7075 | 6050 | 7076 | 6050 | 7077 | 6069 : 7000 | 6069 | 7001 | 6069 | 7002 | 6069 | 7003 |
6051 : 7075 | 6051 | 7076 | 6051 | 7077 | 6070: 7000 | 6070 | 7001 | 6070 | 7002 | 6070 | 7003 |
6052 : 7075 | 6052 | 7076 | 6052 | 7077 | 6071 : 7000 | 6071 | 7001 | 6071 | 7002 | 6071 | 7003 |
6053 : 7075 | 6053 | 7076 | 6053 | 7077 | 6072 : 7000 | 6072 | 7001 | 6072 | 7002 | 6072 | 7003 |
6054 : 7075 | 6054 | 7076 | 6054 | 7077 | 6073 : 7000 | 6073 | 7001 | 6073 | 7002 | 6073 | 7003 |
6055 : 7075 | 6055 | 7076 | 6055 | 7077 | 6074 : 7000 | 6074 | 7001 | 6074 | 7002 | 6074 | 7003 |
6056 : 7075 | 6056 | 7076 | 6056 | 7077 | 6075 : 7000 | 6075 | 7001 | 6075 | 7002 | 6075 | 7003 |
6057 : 7075 | 6057 | 7076 | 6057 | 7077 | 6076 : 7000 | 6076 | 7001 | 6076 | 7002 | 6076 | 7003 |
6058 : 7075 | 6058 | 7076 | 6058 | 7077 | 6077 : 7000 | 6077 | 7001 | 6077 | 7002 | 6077 | 7003 |
6059 : 7075 | 6059 | 7076 | 6059 | 7077 | 6078 : 7000 | 6078 | 7001 | 6078 | 7002 | 6078 | 7003 |
6060: 7075 | 6060 | 7076 | 6060 | 7077 | |||||||
6061 : 7004 | 6061 | 7005 | 6061 | 7006 | 6061 : 7007 | 6061 | 7008 | 6061 | 7009 | 6061 | 7010 |
6062 : 7004 | 6062 | 7005 | 6062 | 7006 | 6062 : 7007 | 6062 | 7008 | 6062 | 7009 | 6062 | 7010 |
6063 : 7004 | 6063 | 7005 | 6063 | 7006 | 6063 : 7007 | 6063 | 7008 | 6063 | 7009 | 6063 | 7010 |
6064: 7004 | 6064 | 7005 | 6064 | 7006 | 6064 : 7007 | 6064 | 7008 | 6064 | 7009 | 6064 | 7010 |
6065 : 7004 | 6065 | 7005 | 6065 | 7006 | 6065 : 7007 | 6065 | 7008 | 6065 | 7009 | 6065 | 7010 |
6066: 7004 | 6066 | 7005 | 6066 | 7006 | 6066 : 7007 | 6066 | 7008 | 6066 | 7009 | 6066 | 7010 |
6067: 7004 | 6067 | 7005 | 6067 | 7006 | 6067 : 7007 | 6067 | 7008 | 6067 | 7009 | 6067 | 7010 |
6068 : 7004 | 6068 | 7005 | 6068 | 7006 | 6068 : 7007 | 6068 | 7008 | 6068 | 7009 | 6068 | 7010 |
6069 : 7004 | 6069 | 7005 | 6069 | 7006 | 6069 : 7007 | 6069 | 7008 | 6069 | 7009 | 6069 | 7010 |
6070: 7004 | 6070 | 7005 | 6070 | 7006 | 6070 : 7007 | 6070 | 7008 | 6070 | 7009 | 6070 | 7010 |
6071 : 7004 | 6071 | 7005 | 6071 | 7006 | 6071 : 7007 | 6071 | 7008 | 6071 | 7009 | 6071 | 7010 |
6072 : 7004 | 6072 | 7005 | 6072 | 7006 | 6072 : 7007 | 6072 | 7008 | 6072 | 7009 | 6072 | 7010 |
6073 : 7004 | 6073 | 7005 | 6073 | 7006 | 6073 : 7007 | 6073 | 7008 | 6073 | 7009 | 6073 | 7010 |
6074 : 7004 | 6074 | 7005 | 6074 | 7006 | 6074: 7007 | 6074 | 7008 | 6074 | 7009 | 6074 | 7010 |
6075 : 7004 | 6075 | 7005 | 6075 | 7006 | 6075 : 7007 | 6075 | 7008 | 6075 | 7009 | 6075 | 7010 |
6076 : 7004 | 6076 | 7005 | 6076 | 7006 | 6076: 7007 | 6076 | 7008 | 6076 | 7009 | 6076 | 7010 |
6077: 7004 | 6077 | 7005 | 6077 | 7006 | 6077: 7007 | 6077 | 7008 | 6077 | 7009 | 6077 | 7010 |
6078 : 7004 | 6078 | 7005 | 6078 | 7006 | 6078 : 7007 | 6078 | 7008 | 6078 | 7009 | 6078 | 7010 |
6061 : 7011 | 6061 | 7012 | 6061 | 7013 | 6061 : 7014 | 6061 | 7015 | 6061 | 7016 | 6061 | 7017 |
118
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6062 | 7011 | 6062 | 7012 | 6062 | 7013 | 6062 | 7014 | 6062 | 7015 | 6062 | 7016 | 6062 | 7017 |
6063 | 7011 | 6063 | 7012 | 6063 | 7013 | 6063 | 7014 | 6063 | 7015 | 6063 | 7016 | 6063 | 7017 |
6064 | 7011 | 6064 | 7012 | 6064 | 7013 | 6064 | 7014 | 6064 | 7015 | 6064 | 7016 | 6064 | 7017 |
6065 | 7011 | 6065 | 7012 | 6065 | 7013 | 6065 | 7014 | 6065 | 7015 | 6065 | 7016 | 6065 | 7017 |
6066 | 7011 | 6066 | 7012 | 6066 | 7013 | 6066 | 7014 | 6066 | 7015 | 6066 | 7016 | 6066 | 7017 |
6067 | 7011 | 6067 | 7012 | 6067 | 7013 | 6067 | 7014 | 6067 | 7015 | 6067 | 7016 | 6067 | 7017 |
6068 | 7011 | 6068 | 7012 | 6068 | 7013 | 6068 | 7014 | 6068 | 7015 | 6068 | 7016 | 6068 | 7017 |
6069 | 7011 | 6069 | 7012 | 6069 | 7013 | 6069 | 7014 | 6069 | 7015 | 6069 | 7016 | 6069 | 7017 |
6070 | 7011 | 6070 | 7012 | 6070 | 7013 | 6070 | 7014 | 6070 | 7015 | 6070 | 7016 | 6070 | 7017 |
6071 | 7011 | 6071 | 7012 | 6071 | 7013 | 6071 | 7014 | 6071 | 7015 | 6071 | 7016 | 6071 | 7017 |
6072 | 7011 | 6072 | 7012 | 6072 | 7013 | 6072 | 7014 | 6072 | 7015 | 6072 | 7016 | 6072 | 7017 |
6073 | 7011 | 6073 | 7012 | 6073 | 7013 | 6073 | 7014 | 6073 | 7015 | 6073 | 7016 | 6073 | 7017 |
6074 | 7011 | 6074 | 7012 | 6074 | 7013 | 6074 | 7014 | 6074 | 7015 | 6074 | 7016 | 6074 | 7017 |
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 | 7016 | 6076 | 7017 |
6077 | 7011 | 6077 | 7012 | 6077 | 7013 | 6077 | 7014 | 6077 | 7015 | 6077 | 7016 | 6077 | 7017 |
6078 | 7011 | 6078 | 7012 | 6078 | 7013 | 6078 | 7014 | 6078 | 7015 | 6078 | 7016 | 6078 | 7017 |
6061 | 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 | 7024 |
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 |
11»
X | Y | X | Y | X: Y | X | Y | X | Y | X | Y | X | Y |
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 |
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: 7034 | 6076 | 7035 | 6076 | 7036 | 6076 | 7037 | 6076 | 7038 |
6077 | 7032 | 6077 | 7033 | 6077 : 7034 | 6077 | 7035 | 6077 | 7036 | 6077 | 7037 | 6077 | 7038 |
6078 | 7032 | 6078 | 7033 | 6078 : 7034 | 6078 | 7035 | 6078 | 7036 | 6078 | 7037 | 6078 | 7038 |
6061 | 7039 | 6061 | 7040 | 6061 : 7041 | 6061 | 7042 | 6061 | 7043 | 6061 | 7044 | 6061 | 7045 |
6062 | 7039 | 6062 | 7040 | 6062 : 7041 | 6062 | 7042 | 6062 | 7043 | 6062 | 7044 | 6062 | 7045 |
6063 | 7039 | 6063 | 7040 | 6063 : 7041 | 6063 | 7042 | 6063 | 7043 | 6063 | 7044 | 6063 | 7045 |
6064 | 7039 | 6064 | 7040 | 6064: 7041 | 6064 | 7042 | 6064 | 7043 | 6064 | 7044 | 6064 | 7045 |
6065 | 7039 | 6065 | 7040 | 6065 : 7041 | 6065 | 7042 | 6065 | 7043 | 6065 | 7044 | 6065 | 7045 |
6066 | 7039 | 6066 | 7040 | 6066 : 7041 | 6066 | 7042 | 6066 | 7043 | 6066 | 7044 | 6066 | 7045 |
6067 | 7039 | 6067 | 7040 | 6067:7041 | 6067 | 7042 | 6067 | 7043 | 6067 | 7044 | 6067 | 7045 |
6068 | 7039 | 6068 | 7040 | 6068 : 7041 | 6068 | 7042 | 6068 | 7043 | 6068 | 7044 | 6068 | 7045 |
6069 | 7039 | 6069 | 7040 | 6069: 7041 | 6069 | 7042 | 6069 | 7043 | 6069 | 7044 | 6069 | 7045 |
6070 | 7039 | 6070 | 7040 | 6070 : 7041 | 6070 | 7042 | 6070 | 7043 | 6070 | 7044 | 6070 | 7045 |
6071 | 7039 | 6071 | 7040 | 6071 : 7041 | 6071 | 7042 | 6071 | 7043 | 6071 | 7044 | 6071 | 7045 |
6072 | 7039 | 6072 | 7040 | 6072 : 7041 | 6072 | 7042 | 6072 | 7043 | 6072 | 7044 | 6072 | 7045 |
6073 | 7039 | 6073 | 7040 | 6073 : 7041 | 6073 | 7042 | 6073 | 7043 | 6073 | 7044 | 6073 | 7045 |
6074 | 7039 | 6074 | 7040 | 6074 : 7041 | 6074 | 7042 | 6074 | 7043 | 6074 | 7044 | 6074 | 7045 |
6075 | 7039 | 6075 | 7040 | 6075 : 7041 | 6075 | 7042 | 6075 | 7043 | 6075 | 7044 | 6075 | 7045 |
120
X: Y | X | Y | X: Y | X | Y | X | Y | X | Y | X | Y |
6076 : 7039 | 6076 | 7040 | 6076 : 7041 | 6076 | 7042 | 6076 | 7043 | 6076 | 7044 | 6076 | 7045 |
6077 : 7039 | 6077 | 7040 | 6077 : 7041 | 6077 | 7042 | 6077 | 7043 | 6077 | 7044 | 6077 | 7045 |
6078 : 7039 | 6078 | 7040 | 6078 : 7041 | 6078 | 7042 | 6078 | 7043 | 6078 | 7044 | 6078 | 7045 |
6061 : 7046 | 6061 | 7047 | 6061 : 7048 | 6061 | 7049 | 6061 | 7050 | 6061 | 7051 | 6061 | 7052 |
6062 : 7046 | 6062 | 7047 | 6062 : 7048 | 6062 | 7049 | 6062 | 7050 | 6062 | 7051 | 6062 | 7052 |
6063 : 7046 | 6063 | 7047 | 6063 : 7048 | 6063 | 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 | 6074 | 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 |
121
X | Y | X | Y | X | Y | X | Y | X: Y | X | Y | X | Y |
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 |
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 | 6065 | 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 | 7067 | 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 |
122
X : Y | X : Y | X | Y | X : Y | X: Y | X : Y | X: Y | |
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 | 7077 | |||
6077: 7074 | 6077 : 7075 | 6077 | 7076 | 6077 | 7077 | |||
6078 : 7074 | 6078 : 7075 | 6078 | 7076 | 6078 | 7077 |
Table C: Example combinations of a compound X with a compound Y.
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 8000 | 6000 | 8001 | 6000 | 8002 | 6000 | 8003 | 6000 | 8004 | 6000 | 8005 |
6001 | 8000 | 6001 | 8001 | 6001 | 8002 | 6001 | 8003 | 6001 | 8004 | 6001 | 8005 |
6002 | 8000 | 6002 | 8001 | 6002 | 8002 | 6002 | 8003 | 6002 | 8004 | 6002 | 8005 |
6003 | 8000 | 6003 | 8001 | 6003 | 8002 | 6003 | 8003 | 6003 | 8004 | 6003 | 8005 |
6004 | 8000 | 6004 | 8001 | 6004 | 8002 | 6004 | 8003 | 6004 | 8004 | 6004 | 8005 |
6005 | 8000 | 6005 | 8001 | 6005 | 8002 | 6005 | 8003 | 6005 | 8004 | 6005 | 8005 |
6006 | 8000 | 6006 | 8001 | 6006 | 8002 | 6006 | 8003 | 6006 | 8004 | 6006 | 8005 |
6007 | 8000 | 6007 | 8001 | 6007 | 8002 | 6007 | 8003 | 6007 | 8004 | 6007 | 8005 |
6008 | 8000 | 6008 | 8001 | 6008 | 8002 | 6008 | 8003 | 6008 | 8004 | 6008 | 8005 |
6009 | 8000 | 6009 | 8001 | 6009 | 8002 | 6009 | 8003 | 6009 | 8004 | 6009 | 8005 |
6010 | 8000 | 6010 | 8001 | 6010 | 8002 | 6010 | 8003 | 6010 | 8004 | 6010 | 8005 |
6011 | 8000 | 6011 | 8001 | 6011 | 8002 | 6011 | 8003 | 6011 | 8004 | 6011 | 8005 |
6012 | 8000 | 6012 | 8001 | 6012 | 8002 | 6012 | 8003 | 6012 | 8004 | 6012 | 8005 |
6013 | 8000 | 6013 | 8001 | 6013 | 8002 | 6013 | 8003 | 6013 | 8004 | 6013 | 8005 |
6014 | 8000 | 6014 | 8001 | 6014 | 8002 | 6014 | 8003 | 6014 | 8004 | 6014 | 8005 |
6015 | 8000 | 6015 | 8001 | 6015 | 8002 | 6015 | 8003 | 6015 | 8004 | 6015 | 8005 |
6016 | 8000 | 6016 | 8001 | 6016 | 8002 | 6016 | 8003 | 6016 | 8004 | 6016 | 8005 |
6017 | 8000 | 6017 | 8001 | 6017 | 8002 | 6017 | 8003 | 6017 | 8004 | 6017 | 8005 |
6018 | 8000 | 6018 | 8001 | 6018 | 8002 | 6018 | 8003 | 6018 | 8004 | 6018 | 8005 |
6019 | 8000 | 6019 | 8001 | 6019 | 8002 | 6019 | 8003 | 6019 | 8004 | 6019 | 8005 |
6020 | 8000 | 6020 | 8001 | 6020 | 8002 | 6020 | 8003 | 6020 | 8004 | 6020 | 8005 |
r
123
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 8006 | 6000 | 8007 | 6000 | 8008 | 6000 | 8009 | 6000 | 8010 | 6000 | 8011 |
6001 | 8006 | 6001 | 8007 | 6001 | 8008 | 6001 | 8009 | 6001 | 8010 | 6001 | 8011 |
6002 | 8006 | 6002 | 8007 | 6002 | 8008 | 6002 | 8009 | 6002 | 8010 | 6002 | 8011 |
6003 | 8006 | 6003 | 8007 | 6003 | 8008 | 6003 | 8009 | 6003 | 8010 | 6003 | 8011 |
6004 | 8006 | 6004 | 8007 | 6004 | 8008 | 6004 | 8009 | 6004 | 8010 | 6004 | 8011 |
6005 | 8006 | 6005 | 8007 | 6005 | 8008 | 6005 | 8009 | 6005 | 8010 | 6005 | 8011 |
6006 | 8006 | 6006 | 8007 | 6006 | 8008 | 6006 | 8009 | 6006 | 8010 | 6006 | 8011 |
6007 | 8006 | 6007 | 8007 | 6007 | 8008 | 6007 | 8009 | 6007 | 8010 | 6007 | 8011 |
6008 | 8006 | 6008 | 8007 | 6008 | 8008 | 6008 | 8009 | 6008 | 8010 | 6008 | 8011 |
6009 | 8006 | 6009 | 8007 | 6009 | 8008 | 6009 | 8009 | 6009 | 8010 | 6009 | 8011 |
6010 | 8006 | 6010 | 8007 | 6010 | 8008 | 6010 | 8009 | 6010 | 8010 | 6010 | 8011 |
6011 | 8006 | 6011 | 8007 | 6011 | 8008 | 6011 | 8009 | 6011 | 8010 | 6011 | 8011 |
6012 | 8006 | 6012 | 8007 | 6012 | 8008 | 6012 | 8009 | 6012 | 8010 | 6012 | 8011 |
6013 | 8006 | 6013 | 8007 | 6013 | 8008 | 6013 | 8009 | 6013 | 8010 | 6013 | 8011 |
6014 | 8006 | 6014 | 8007 | 6014 | 8008 | 6014 | 8009 | 6014 | 8010 | 6014 | 8011 |
6015 | 8006 | 6015 | 8007 | 6015 | 8008 | 6015 | 8009 | 6015 | 8010 | 6015 | 8011 |
6016 | 8006 | 6016 | 8007 | 6016 | 8008 | 6016 | 8009 | 6016 | 8010 | 6016 | 8011 |
6017 | 8006 | 6017 | 8007 | 6017 | 8008 | 6017 | 8009 | 6017 | 8010 | 6017 | 8011 |
6018 | 8006 | 6018 | 8007 | 6018 | 8008 | 6018 | 8009 | 6018 | 8010 | 6018 | 8011 |
6019 | 8006 | 6019 | 8007 | 6019 | 8008 | 6019 | 8009 | 6019 | 8010 | 6019 | 8011 |
6020 | 8006 | 6020 | 8007 | 6020 | 8008 | 6020 | 8009 | 6020 | 8010 | 6020 | 8011 |
6000 6001 6002 6003 6004 6005 6006 6007 6008 6009 6010 6011 6012 6013 | 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 8012 | 6021 | 8000 | 6021 | 8001 | 6021 | 8002 | 6021 | 8003 | 6021 | 8004 |
6022 | 8000 | 6022 | 8001 | 6022 | 8002 | 6022 | 8003 | 6022 | 8004 | ||
6023 | 8000 | 6023 | 8001 | 6023 | 8002 | 6023 | 8003 | 6023 | 8004 | ||
6024 | 8000 | 6024 | 8001 | 6024 | 8002 | 6024 | 8003 | 6024 | 8004 | ||
6025 | 8000 | 6025 | 8001 | 6025 | 8002 | 6025 | 8003 | 6025 | 8004 | ||
6026 | 8000 | 6026 | 8001 | 6026 | 8002 | 6026 | 8003 | 6026 | 8004 | ||
6027 | 8000 | 6027 | 8001 | 6027 | 8002 | 6027 | 8003 | 6027 | 8004 | ||
6028 | 8000 | 6028 | 8001 | 6028 | 8002 | 6028 | 8003 | 6028 | 8004 | ||
6029 | 8000 | 6029 | 8001 | 6029 | 8002 | 6029 | 8003 | 6029 | 8004 | ||
6030 | 8000 | 6030 | 8001 | 6030 | 8002 | 6030 | 8003 | 6030 | 8004 | ||
6031 | 8000 | 6031 | 8001 | 6031 | 8002 | 6031 | 8003 | 6031 | 8004 | ||
6032 | 8000 | 6032 | 8001 | 6032 | 8002 | 6032 | 8003 | 6032 | 8004 | ||
6033 | 8000 | 6033 | 8001 | 6033 | 8002 | 6033 | 8003 | 6033 | 8004 | ||
6034 | 8000 | 6034 | 8001 | 6034 | 8002 | 6034 | 8003 | 6034 | 8004 | ||
6014 6015 6016 6017 6018 6019 6020 | 6035 | 8000 | 6035 | 8001 | 6035 | 8002 | 6035 | 8003 | 6035 | 8004 | |
6036 | 8000 | 6036 | 8001 | 6036 | 8002 | 6036 | 8003 | 6036 | 8004 | ||
6037 | 8000 | 6037 | 8001 | 6037 | 8002 | 6037 | 8003 | 6037 | 8004 | ||
6038 | 8000 | 6038 | 8001 | 6038 | 8002 | 6038 | 8003 | 6038 | 8004 | ||
6039 | 8000 | 6039 | 8001 | 6039 | 8002 | 6039 | 8003 | 6039 | 8004 | ||
6040 | : 8000 | 6040 | : 8001 | 6040 | 8002 | 6040 | 8003 | 6040 | 8004 |
r
X | : Y | X | : Y | X | : Y | X | : Y | X | : Y | X | : Y |
6021 | 8005 | 6021 | 8006 | 6021 | 8007 | 6021 | 8008 | 6021 | 8009 | 6021 | 8010 |
6022 | 8005 | 6022 | 8006 | 6022 | 8007 | 6022 | 8008 | 6022 | 8009 | 6022 | 8010 |
6023 | 8005 | 6023 | 8006 | 6023 | 8007 | 6023 | 8008 | 6023 | 8009 | 6023 | 8010 |
6024 | 8005 | 6024 | 8006 | 6024 | 8007 | 6024 | 8008 | 6024 | 8009 | 6024 | 8010 |
6025 | 8005 | 6025 | 8006 | 6025 | 8007 | 6025 | 8008 | 6025 | 8009 | 6025 | 8010 |
6026 | 8005 | 6026 | 8006 | 6026 | 8007 | 6026 | 8008 | 6026 | 8009 | 6026 | 8010 |
6027 | 8005 | 6027 | 8006 | 6027 | 8007 | 6027 | 8008 | 6027 | 8009 | 6027 | 8010 |
6028 | 8005 | 6028 | 8006 | 6028 | 8007 | 6028 | 8008 | 6028 | 8009 | 6028 | 8010 |
6029 | 8005 | 6029 | 8006 | 6029 | 8007 | 6029 | 8008 | 6029 | 8009 | 6029 | 8010 |
6030 | 8005 | 6030 | 8006 | 6030 | 8007 | 6030 | 8008 | 6030 | 8009 | 6030 | 8010 |
6031 | 8005 | 6031 | 8006 | 6031 | 8007 | 6031 | 8008 | 6031 | 8009 | 6031 | 8010 |
6032 | 8005 | 6032 | 8006 | 6032 | 8007 | 6032 | 8008 | 6032 | 8009 | 6032 | 8010 |
6033 | 8005 | 6033 | 8006 | 6033 | 8007 | 6033 | 8008 | 6033 | 8009 | 6033 | 8010 |
6034 | 8005 | 6034 | 8006 | 6034 | 8007 | 6034 | 8008 | 6034 | 8009 | 6034 | 8010 |
6035 | 8005 | 6035 | 8006 | 6035 | 8007 | 6035 | 8008 | 6035 | 8009 | 6035 | 8010 |
6036 | 8005 | 6036 | 8006 | 6036 | 8007 | 6036 | 8008 | 6036 | 8009 | 6036 | 8010 |
6037 | 8005 | 6037 | 8006 | 6037 | 8007 | 6037 | 8008 | 6037 | 8009 | 6037 | 8010 |
6038 | 8005 | 6038 | 8006 | 6038 | 8007 | 6038 | 8008 | 6038 | 8009 | 6038 | 8010 |
6039 | 8005 | 6039 | 8006 | 6039 | 8007 | 6039 | 8008 | 6039 | 8009 | 6039 | 8010 |
6040 | 8005 | 6040 | 8006 | 6040 | 8007 | 6040 | 8008 | 6040 | 8009 | 6040 | 8010 |
6021 | 8011 | 6021 | 8012 | 6041 | 8000 | 6041 | 8001 | 6041 | 8002 | 6041 | 8003 |
6022 | 8011 | 6022 | 8012 | 6042 | 8000 | 6042 | 8001 | 6042 | 8002 | 6042 | 8003 |
6023 | 8011 | 6023 | 8012 | 6043 | 8000 | 6043 | 8001 | 6043 | 8002 | 6043 | 8003 |
6024 | 8011 | 6024 | 8012 | 6044 | 8000 | 6044 | 8001 | 6044 | 8002 | 6044 | 8003 |
6025 | 8011 | 6025 | 8012 | 6045 | 8000 | 6045 | 8001 | 6045 | 8002 | 6045 | 8003 |
6026 | 8011 | 6026 | 8012 | 6046 | 8000 | 6046 | 8001 | 6046 | 8002 | 6046 | 8003 |
6027 | 8011 | 6027 | 8012 | 6047 | 8000 | 6047 | 8001 | 6047 | 8002 | 6047 | 8003 |
6028 | 8011 | 6028 | 8012 | 6048 | 8000 | 6048 | 8001 | 6048 | 8002 | 6048 | 8003 |
6029 | 8011 | 6029 | 8012 | 6049 | 8000 | 6049 | 8001 | 6049 | 8002 | 6049 | 8003 |
6030 | 8011 | 6030 | 8012 | 6050 | 8000 | 6050 | 8001 | 6050 | 8002 | 6050 | 8003 |
6031 | 8011 | 6031 | 8012 | 6051 | 8000 | 6051 | 8001 | 6051 | 8002 | 6051 | 8003 |
6032 | 8011 | 6032 | 8012 | 6052 | 8000 | 6052 | 8001 | 6052 | 8002 | 6052 | 8003 |
6033 | 8011 | 6033 | 8012 | 6053 | 8000 | 6053 | 8001 | 6053 | 8002 | 6053 | 8003 |
6034 | 8011 | 6034 | 8012 | 6054 | 8000 | 6054 | 8001 | 6054 | 8002 | 6054 | 8003 |
6035 | 8011 | 6035 | 8012 | 6055 | 8000 | 6055 | 8001 | 6055 | 8002 | 6055 | 8003 |
6036 | 8011 | 6036 | 8012 | 6056 | 8000 | 6056 | 8001 | 6056 | 8002 | 6056 | 8003 |
6037 | 8011 | 6037 | 8012 | 6057 | 8000 | 6057 | 8001 | 6057 | 8002 | 6057 | 8003 |
6038 | 8011 | 6038 | 8012 | 6058 | 8000 | 6058 | 8001 | 6058 | 8002 | 6058 | 8003 |
6039 | 8011 | 6039 | 8012 | 6059 | 8000 | 6059 | 8001 | 6059 | 8002 | 6059 | 8003 |
6040 | 8011 | 6040 | 8012 | 6060 | 8000 | 6060 | 8001 | 6060 | 8002 | 6060 | 8003 |
125
X | : Y | X | : Y | X | : Y | X | : Y | X | : Y | X | : Y |
6041 | 8004 | 6041 | 8005 | 6041 | 8006 | 6041 | 8007 | 6041 | 8008 | 6041 | 8009 |
6042 | 8004 | 6042 | 8005 | 6042 | 8006 | 6042 | 8007 | 6042 | 8008 | 6042 | 8009 |
6043 | 8004 | 6043 | 8005 | 6043 | 8006 | 6043 | 8007 | 6043 | 8008 | 6043 | 8009 |
6044 | 8004 | 6044 | 8005 | 6044 | 8006 | 6044 | 8007 | 6044 | 8008 | 6044 | 8009 |
6045 | 8004 | 6045 | 8005 | 6045 | 8006 | 6045 | 8007 | 6045 | 8008 | 6045 | 8009 |
6046 | 8004 | 6046 | 8005 | 6046 | 8006 | 6046 | 8007 | 6046 | 8008 | 6046 | 8009 |
6047 | 8004 | 6047 | 8005 | 6047 | 8006 | 6047 | 8007 | 6047 | 8008 | 6047 | 8009 |
6048 | 8004 | 6048 | 8005 | 6048 | 8006 | 6048 | 8007 | 6048 | 8008 | 6048 | 8009 |
6049 | 8004 | 6049 | 8005 | 6049 | 8006 | 6049 | 8007 | 6049 | 8008 | 6049 | 8009 |
6050 | 8004 | 6050 | 8005 | 6050 | 8006 | 6050 | 8007 | 6050 | 8008 | 6050 | 8009 |
6051 | 8004 | 6051 | 8005 | 6051 | 8006 | 6051 | 8007 | 6051 | 8008 | 6051 | 8009 |
6052 | 8004 | 6052 | 8005 | 6052 | 8006 | 6052 | 8007 | 6052 | 8008 | 6052 | 8009 |
6053 | 8004 | 6053 | 8005 | 6053 | 8006 | 6053 | 8007 | 6053 | 8008 | 6053 | 8009 |
6054 | 8004 | 6054 | 8005 | 6054 | 8006 | 6054 | 8007 | 6054 | 8008 | 6054 | 8009 |
6055 | 8004 | 6055 | 8005 | 6055 | 8006 | 6055 | 8007 | 6055 | 8008 | 6055 | 8009 |
6056 | 8004 | 6056 | 8005 | 6056 | 8006 | 6056 | 8007 | 6056 | 8008 | 6056 | 8009 |
6057 | 8004 | 6057 | 8005 | 6057 | 8006 | 6057 | 8007 | 6057 | 8008 | 6057 | 8009 |
6058 | 8004 | 6058 | 8005 | 6058 | 8006 | 6058 | 8007 | 6058 | 8008 | 6058 | 8009 |
6059 | 8004 | 6059 | 8005 | 6059 | 8006 | 6059 | 8007 | 6059 | 8008 | 6059 | 8009 |
6060 | 8004 | 6060 | 8005 | 6060 | 8006 | 6060 | 8007 | 6060 | 8008 | 6060 | 8009 |
6041 | 8010 | 6041 | 8011 | 6041 | 8012 | ||||||
6042 | 8010 | 6042 | 8011 | 6042 | 8012 | 6061 | 8000 | 6061 | 8001 | 6061 | 8002 |
6043 | 8010 | 6043 | 8011 | 6043 | 8012 | 6062 | 8000 | 6062 | 8001 | 6062 | 8002 |
6044 | 8010 | 6044 | 8011 | 6044 | 8012 | 6063 | 8000 | 6063 | 8001 | 6063 | 8002 |
6045 | 8010 | 6045 | 8011 | 6045 | 8012 | 6064 | 8000 | 6064 | 8001 | 6064 | 8002 |
6046 | 8010 | 6046 | 8011 | 6046 | 8012 | 6065 | 8000 | 6065 | 8001 | 6065 | 8002 |
6047 | 8010 | 6047 | 8011 | 6047 | 8012 | 6066 | 8000 | 6066 | 8001 | 6066 | 8002 |
6048 | 8010 | 6048 | 8011 | 6048 | 8012 | 6067 | 8000 | 6067 | 8001 | 6067 | 8002 |
6049 | 8010 | 6049 | 8011 | 6049 | 8012 | 6068 | 8000 | 6068 | 8001 | 6068 | 8002 |
6050 | 8010 | 6050 | 8011 | 6050 | 8012 | 6069 | 8000 | 6069 | 8001 | 6069 | 8002 |
6051 | 8010 | 6051 | 8011 | 6051 | 8012 | 6070 | 8000 | 6070 | 8001 | 6070 | 8002 |
6052 | 8010 | 6052 | 8011 | 6052 | 8012 | 6071 | 8000 | 6071 | 8001 | 6071 | 8002 |
6053 | 8010 | 6053 | 8011 | 6053 | 8012 | 6072 | 8000 | 6072 | 8001 | 6072 | 8002 |
6054 | 8010 | 6054 | 8011 | 6054 | 8012 | 6073 | 8000 | 6073 | 8001 | 6073 | 8002 |
6055 | 8010 | 6055 | 8011 | 6055 | 8012 | 6074 | 8000 | 6074 | 8001 | 6074 | 8002 |
6056 | 8010 | 6056 | 8011 | 6056 | 8012 | 6075 | 8000 | 6075 | 8001 | 6075 | 8002 |
6057 | 8010 | 6057 | 8011 | 6057 | 8012 | 6076 | 8000 | 6076 | 8001 | 6076 | 8002 |
6058 | 8010 | 6058 | 8011 | 6058 | 8012 | 6077 | 8000 | 6077 | 8001 | 6077 | 8002 |
6059 | 8010 | 6059 | 8011 | 6059 | 8012 | 6078 | 8000 | 6078 | 8001 | 6078 | 8002 |
6060 | 8010 | 6060 | 8011 | 6060 | 8012 |
©
126
X | : Y | X: Y | X: Y | X | : Y | X | : Y | X | : Y | ||
6061 | 8003 | 6061 | 8004 | 6061 | 8005 | 6061 | 8006 | 6061 | 8007 | 6061 | 8008 |
6062 | 8003 | 6062 | 8004 | 6062 | 8005 | 6062 | 8006 | 6062 | 8007 | 6062 | 8008 |
6063 | 8003 | 6063 | 8004 | 6063 | 8005 | 6063 | 8006 | 6063 | 8007 | 6063 | 8008 |
6064 | 8003 | 6064 | 8004 | 6064 | 8005 | 6064 | 8006 | 6064 | 8007 | 6064 | 8008 |
6065 | 8003 | 6065 | 8004 | 6065 | 8005 | 6065 | 8006 | 6065 | 8007 | 6065 | 8008 |
6066 | 8003 | 6066 | 8004 | 6066 | 8005 | 6066 | 8006 | 6066 | 8007 | 6066 | 8008 |
6067 | 8003 | 6067 | 8004 | 6067 | 8005 | 6067 | 8006 | 6067 | 8007 | 6067 | 8008 |
6068 | 8003 | 6068 | 8004 | 6068 | 8005 | 6068 | 8006 | 6068 | 8007 | 6068 | 8008 |
6069 | 8003 | 6069 | 8004 | 6069 | 8005 | 6069 | 8006 | 6069 | 8007 | 6069 | 8008 |
6070 | 8003 | 6070 | 8004 | 6070 | 8005 | 6070 | 8006 | 6070 | 8007 | 6070 | 8008 |
6071 | 8003 | 6071 | 8004 | 6071 | 8005 | 6071 | 8006 | 6071 | 8007 | 6071 | 8008 |
6072 | 8003 | 6072 | 8004 | 6072 | 8005 | 6072 | 8006 | 6072 | 8007 | 6072 | 8008 |
6073 | 8003 | 6073 | 8004 | 6073 | 8005 | 6073 | 8006 | 6073 | 8007 | 6073 | 8008 |
6074 | 8003 | 6074 | 8004 | 6074 | 8005 | 6074 | 8006 | 6074 | 8007 | 6074 | 8008 |
6075 | 8003 | 6075 | 8004 | 6075 | 8005 | 6075 | 8006 | 6075 | 8007 | 6075 | 8008 |
6076 | 8003 | 6076 | 8004 | 6076 | 8005 | 6076 | 8006 | 6076 | 8007 | 6076 | 8008 |
6077 | 8003 | 6077 | 8004 | 6077 | 8005 | 6077 | 8006 | 6077 | 8007 | 6077 | 8008 |
6078 | 8003 | 6078 | 8004 | 6078 | 8005 | 6078 | 8006 | 6078 | 8007 | 6078 | 8008 |
6061 | 8009 | 6061 | 8010 | 6061 | 8011 | 6061 | 8012 | ||||
6062 | 8009 | 6062 | 8010 | 6062 | 8011 | 6062 | 8012 | ||||
6063 | 8009 | 6063 | 8010 | 6063 | 8011 | 6063 | 8012 | ||||
6064 | 8009 | 6064 | 8010 | 6064 | 8011 | 6064 | 8012 | ||||
6065 | 8009 | 6065 | 8010 | 6065 | 8011 | 6065 | 8012 | ||||
6066 | 8009 | 6066 | 8010 | 6066 | 8011 | 6066 | 8012 | ||||
6067 | 8009 | 6067 | 8010 | 6067 | 8011 | 6067 | 8012 | ||||
6068 | 8009 | 6068 | 8010 | 6068 | 8011 | 6068 | 8012 | ||||
6069 | 8009 | 6069 | 8010 | 6069 | 8011 | 6069 | 8012 | ||||
6070 | 8009 | 6070 | 8010 | 6070 | 8011 | 6070 | 8012 | ||||
6071 | 8009 | 6071 | 8010 | 6071 | 8011 | 6071 | 8012 | ||||
6072 | 8009 | 6072 | 8010 | 6072 | 8011 | 6072 | 8012 | ||||
6073 | 8009 | 6073 | 8010 | 6073 | 8011 | 6073 | 8012 | ||||
6074 | 8009 | 6074 | 8010 | 6074 | 8011 | 6074 | 8012 | ||||
6075 | 8009 | 6075 | 8010 | 6075 | 8011 | 6075 | 8012 | ||||
6076 | 8009 | 6076 | 8010 | 6076 | 8011 | 6076 | 8012 | ||||
6077 | 8009 | 6077 | 8010 | 6077 | 8011 | 6077 | 8012 | ||||
6078 | 8009 | 6078 | 8010 | 6078 | 8011 | 6078 | 8012 |
Ü
127
Table D: Example combinations of a compound X with a compound Y.
X: Y | X : Y |
6000 : 9000 6001 : 9000 6002 : 9000 6003 : 9000 6004 : 9000 6005 : 9000 6006 : 9000 6007 : 9000 6008 : 9000 6009 : 9000 6010 : 9000 6011 : 9000 6012 : 9000 6013 : 9000 6014: 9000 6015 : 9000 6016: 9000 6017: 9000 6018 : 9000 6019:9000 | 6020 : 9000 6021 : 9000 6022 : 9000 6023 :9000 6024:9000 6025 :9000 6026:9000 6027:9000 6028 :9000 6029: 9000 6030:9000 6031 :9000 6032 : 9000 6033 : 9000 6034: 9000 6035 : 9000 6036: 9000 6037 : 9000 6038 : 9000 6039 : 9000 |
X: Y | X: Y |
6040 : 9000 6041 : 9000 6042 : 9000 6043 : 9000 6044 : 9000 6045 : 9000 6046 : 9000 6047 : 9000 6048 : 9000 6049 : 9000 6050: 9000 6051 : 9000 6052 : 9000 6053 : 9000 6054: 9000 6055 : 9000 6056: 9000 6057: 9000 6058 : 9000 6059: 9000 | 6060: 9000 6061 : 9000 6062 : 9000 6063 : 9000 6064: 9000 6065 : 9000 6066 : 9000 6067 : 9000 6068 : 9000 6069 : 9000 6070 : 9000 6071 : 9000 6072 : 9000 6073 : 9000 6074 : 9000 6075 : 9000 6076 : 9000 6077 : 9000 6078 : 9000 |
EXAMPLES [0205] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to Iimit the scope of the daims.
Example 1
General Synthesis of Reagents 1 and 2
ArOH | PSC13 | ArOP(S)CI2 1 | amino acid ester sait |
diethyl ether triethylamine | dichloromethane triethylamine |
128
Step 1: Synthesis of l-naphthyloxydichlorophosphothioate reagent (la)
S
II
CX^CI
Cl ether, triethylamine
|0206| A 500 mL round bottom flask containing a magnetic stir bar was charged with phosphorus thiotrichloride (5.7 g, 33.65 mmol) and 1-naphthol (4.85 g, 33.64 mmol), and 40 mL of diethyl ether was added. Under an argon atmosphère, the solution was cooled in a dry ice/acetone bath. After 10 minutes of cooling, triethylamine (4.7 mL, 33.7 mmol) was added, and a precipitate formed. The mixture was allowed to warrn to ambient température, and was then stirred for 2 days. The precipitated triethylammonium hydrochloride was filtered off, and was washed twice with ether. The solvents were removed under reduced pressure to leave 9.8 g of compound la as a cloudy, light yellow oil. la was used in the next step without further purification.
Step 2: Synthesis of the L-alanine methyl ester derived î-naphthyloxy-chlorophosphothioate
[0207] Into a 250 mL round bottom flask containing 1-naphtholdichlorophosphothioate reagent la (1.97 g, 7.1 mmol) and L-alanine methyl ester hydrochloride (0.99 g, 7.1 mmol) was added in 50 mL of dichloromethane. At water/ice température under an argon atmosphère, triethylamine (1 mL, 7.2 mmol) was added. The reaction was allowed to warm to ambient température and was then stirred overnight. The solvents were removed using a rotary evaporator. The residue was purified using chromatography on silica gel, and eluting with 20% ethyl acetate in hexanes. The product 2a
(l.O g) was obtained as a vîscous oil. 3IP NMR (CDCl3, 64.78, 65.0) (approximately a l:l mixture of diastereomers).
[0208] The reagents shown in Tables 6 and 7 were prepared using the procedures described for compounds la and 2a, with the ArOH compounds listed in Table 6 in place of 5 l-naphthol, and with hydrochloride salts of the amino acids listed în Table 7 in place of Lalanine methyl ester hydrochloride.
Table 6
ArOH | Dichloridates | Reagent No. |
Phénol | xv Yci Cl | Ib |
p-fluoro-phenol | T / Cl Cl | le |
p-chloro-phenol | X,. P-~.PI / Cl Cl | ld |
e
130
ArOH | Dichloridates | Reagent No. |
o-chloro-phenol | Οή. Cl / Cl Cl | le |
p-chloro-m-chloro-phenol | A LL | lf |
p-methyl-phenol | A, pA / Cî Cl | 1g |
o-methyl-phenol | /'''O S T A \ /PCI Cl | lh |
p-methoxy-phenol | A, p—-ri / Cl Cl | li |
ArOH | Dichloridates | Reagent No. |
quinolin-5-ol | Q N \ PA. \\ J / Cl V/ ci | ij |
pyridine-3-ol | A pA, / Cl Cl | lk |
Table 7
Amino Acid | Aryloxy amino acid thiophosphochloridate | Reagent No. | 3,PNMR (CDCI3) |
L-alanine isopropyl ester | A, AJyC C' | 2b | 64.75 (s) 64.65 (s) |
L-alanine cyclohexyl ester | Y-Y | 2c | 64.80 (s) 64.69 (s) |
132
Amino Acid | Aryloxy amino acid thiophosphochloridate | Reagent No. | 31P NMR (CDCIj) |
( L-alanine neopentyl ester | CK Kr | 2d | 64.59 (s) 64.31 (s) |
L-alanine isopropyl ester | cp? i 0 o—p—Cl Af- | 2e | 64.51 (s) 64.23 (s) |
L-alanine cyclohexyl ester | Cf? 0 0—p—Cl | 2f | 64.55 (s) 64.25 (s) |
L-alanine neopentyl ester | Cf? 0 o—p—Cl | 2g | 64.51 (s) 64.27 (s) |
L-valine isopropyl ester | Qî I 0 0—p—Cl Ay | 2h | 67.72 65.87 |
133
Example 2
Préparation of Z’-C-Methyluridinc 5'-(Î?-(l-napbthyl)-7V-(5)-l-(methoxvcarbonvl)ethvl) thiophosphoramidate (3a)
[0209] A solution of cyclopentylidine protected 2’-C-methyluridine (262 mg, 0.81 mmol) în 2 mL tetrahydrofuran was cooled in an ice/water bath under argon, and treated with 2.1 mL tBuMgCl (1 M, 2.1 mmol). After 10 minutes, reagent 2a (0.83 g, 2.4 mmol) was added as a solution în 2 mL of tetrahydrofuran (THF). The reaction was stirred at ambient température for 2 days. An additionaî 1 mL tBuMgCl was then added (1 mmol). After an 10 additionaî 2 days, the reaction was diluted with ethyl acetate and water. The organic layer was washed two times with brine, and dried over sodium sulfate. Chromatography on silica gel using a gradient of 1% methanol in dichloromethane to 10% methanol in dichloromethane afforded 0.2 g of a residue which was used without further purification. To the residue was added 4 mL of 80% aqueous formic acid. The mixture was heated to 50°C usîng a water 15 bath. After 2 hours, the reaction was cooled, and the solvents were removed under reduced pressure. A solution of 1:1 methanol: toluene was added to the residue. The solvents were then removed under reduced pressure. The addition of a solution of 1:1 methanol: toluene and removal of solvents were repeated 2 more times. The product was isolated following chromatography using silica gel with a gradient from 4% to 8% methanol in 20 dichloromethane. The solvent was removed, and the residue was taken up in chloroform and treated with excess hexanes. The supematant was decanted off, and the remaining solid was subjected to high vacuum overnight. Product 3a was isolated as a colorless solid (22.2 mg). 3iP NMR (CDCI3, 67.12, 67.86) and mass spectral data (M-H', 564.5) were consistent with the desired product 3a as a near 1:1 mixture of diastereomers at the phosphorus chiral center.
134
Example 3
Préparation of 2)-C-methy[uridine 5’-(6>-ρΙιοιιν1-Ν-(.9)-1(isopropoxvcarbonvl)ethvl)thiophosphoramidate (3b)
-t
3b-1
3b-2
3b +
3b(ii)-Sp [0210] Step I: Compound 3b-l - To a suspension of 2’-methyluridine (20 g,
77.52 mmol) in dry CH3CN (200 mL) were added cyclopentanone (20 mL) and trimethylorthoformate (20 mL) followed by p-toluenesulfonîc acid monohydrate (7.4 g, 38.76 mmol). The reaction mixture was stirred at 40°C overnight. The solvent was evaporated.
The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried and evaporated to give pure 3b-l as a white solid (14.5 g, 57.7%). ’H NMR (CDC13,
400 MHz) δ8.86 (s, 1H), 7.67 (d, J= 8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, 7= 8.0 Hz, 1H), 4.50 (d, 7=4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m, 1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H).
[0211] Step 2: Compound 3b-2 - To a suspension of 3b-l (20 g, 61.7 mmol) in dry CH3CN (100 mL) was added jV-methylimidazole (50 mL) and 2b (80 g, 249.2 mmol).
The reaction mixture was stirred at 70°C for 2h. Solvent was removed and the residue was
135 dissolved in ethyl acetate (500 mL). The solution was washed with brine, dried and evaporated. The residue was purified on a silîca gel column (20-50% ethylacetate (EA) in petroleum ether (PE)) to give 3b-2 as a white foam (two isomers, 12.5 g, 33%). ’H NMR (CDC13, 400 MHz) δ8.79-8.92 (m, IH), 7.55 (m, IH), 7.34 (m, 2H), 7.20 (m, 3H), 6.09 (d, J = 13.6 Hz, IH), 5.70-5.61 (m, IH), 5.06-5.01 (m, IH), 4.38-4.09 (m, 6H), 2.08 (m, IH), 1.96 (m, IH), 1.73 (m, 2H), 1.66 (m, 5H), 1.39 (m, 3H), 1.23 (m, 9H); 3,P NMR (CDClj, 162 MHz) <567.62, 67.31.
[0212] Step 3: Compound 3b - Compound 3b-2 (10 g, 16.4 mmol) was suspended in 100 mL of 80% formîc acid and the reaction mixture was stirred at 50°C for 1.5 hours. Solvent was evaporated and the residue was co-evaporated with toluene to remove traces of acid and water. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water as mobile phase) to give 3b (a mixture of two P-diastereomers, 5.6 g, 63%). ’H NMR (CD3OD, 400 MHz) δ 7.79, 7.87 (2d, J= 8.0 Hz, IH), 7.18-7.38 (m, 5H), 5.98, 6.01 (2s, IH), 5.59, 5.63 (2d, J= 8.0 Hz, IH), 4.95-5.05 (m, IH), 4.51-4.56 (m, IH), 4.30-4.44 (m, IH), 4.05-4.17 (m, 2H), 3.82-3.87 (m, IH), 1.34, 1.38 (2d, J = 7.2 Hz, 3H), 1.17, 1.25 (2d, J = 6.0 Hz, 6H), 1.24, 125 (2s, 3H); 3,P NMR (CD3OD, 162 MHz) <568.17, 68.40; ESI-LCMS: m/z 544.0 [M + H]+.
|0213] Step 4: Séparation of and 3b(ii)-5’p - Compound 3b was separated into its Rp and Sp diastereomers by two methods: (a) supercritical fluid chromatography (SFC) and (b) crystallization.
[0214] (a) Via SFC: Compound 3b (440 mg, consisting of both 3b(i)-Pp and
3b(fl)-Sp in -1:1 ratio) was subjected to séparation by SFC (chiral PAK AD, 5 um. 250*30 mm using 25% MeOH and 75% CO2 as mobile phase) to give 3b(i)-7îp (123.8 mg) and 3b(ii)-.Sp (162.5 mg) as a white solid; 3b(i)-7îp: ’H NMR (CD3OD, 400 MHz) <57.87 (d, J = 8.4 Hz, IH), 7.36 (t,J = 8.0 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.19 (t, J = 7.6 Hz, IH), 6.01 (s, IH), 5.62 (d, J= 8.0 Hz, IH), 5.03-4.97 (m, IH), 4.56-4.92 (m, IH), 4.44-4.39 (m, IH), 4.16-4.13 (m, IH), 4.10-4.05 (m, IH), 3.86 (d,.7=9.2 Hz, IH), 1.34 (d, J =7.2 Hz, 3H), 1.25 (d, J= 6.4 Hz, 6H), 1.16 (s, 3H); 31P NMR (CD3OD, 162 MHz) <568.18; ESI-LCMS: m/z = 544 [M + H]+. 3b(ii)-5p: [H NMR (CD3OD, 400 MHz) <57.89 (d, J= 8.0 Hz, IH), 7.36 (t, J = 8.0 Hz, 2H), 7.30 (d, .7=8.4 Hz, 2H), 7.20 (t, J= 8.0 Hz, IH), 5.99 (s, IH), 5.60 (d, J= 8.4
136
Hz, IH), 5.03-4.97 (m, IH), 4.56-4.51 (m, IH), 4.35-4.30 (m, IH), 4.14-4.10 (m, 2H), 3.83 (d, J=9.2Hz, IH), 1.39 (d, J=7.2 Hz, 3H), 1.25 (d, .7=6.4 Hz, 6H), 1.17 (s, 3H);31PNMR (CD3OD, 162 MHz) 068.42; ESI-LCMS: m/z = 566 [M + Na]+.
[0215] (b) Via crystallization: Compound 3b as a mixture of dîastereomers (1:1,
g) was dissolved in 100 mL of dichloromethane (DCM) / ether (1:3). Hexane was added dropwise until the solution became cloudy. The solution was left at (room température) RT for 5 h and ovemîght at -20°C. Precipitated crystals were recrystallized from DCM/ether 1:3 v/v, and one more time from DCM/ether 1:2. Compound 3b(i)-/ïp (3 g) was obtained as a pure single diastereomer. The mother liquor after first crystallization was concentrated, and then dissolved în isopropanol. Hexane was added (30% by volume). The clear solution was left ovemîght at RT to produce a small amount of crystals, which were used as seeds. The mother liquor was evaporated and crystallized 2 times from hexane/îsopropanol (4:1) to give 2.3 g of 3b(ii)-*Sp.
Example 4
Préparation of 2>,3,-O-dipropionvI-2’-C-methvluridine S'-fD-phcnvI-.V-GS')-!(isopropoxycarbonyllethyllthiophosphoramidate (4a)
propionic anhydride pyridine
[0216] Compound 3b (85 mg, 0.156 mmol) was dissolved in 3 mL of dry pyridine. Propionic anhydride (0.1 mL, 0.624 mmol) was added, and the mixture left for 18 hours at ambient température. Water (7 mL) and ethyl acetate (7 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2x5 mL). The combined organic extracts were washed with water, brine, dried overNa^SCL, and evaporated. The resulting oil was purified by flash chromatography using a gradient of methanol in dichloromethane from 0 to 4%. The fractions containing phosphorothioate were combined and concentrated in vacuum. Repurification by RP HPLC using a gradient of
137 methanol in water from 50% to 100% yielded 44 mg of product 4a.3 P NMR (CDCh, 67.71, 67.74) and mass spectral analysis (M-H’, 654.5) were consistent with the desired product 4a as near 1:1 mixture of dîastereomers at the phosphorus chiral center.
Example 5
Préparation of 2-deoxy-2'-a-niioro-2’-ÎLC-metlivluri(line S'-fO-phenyl-jV-fY)-!(isopropoxycarbonvl)ethyl)thiophosphoramidate (3c)
[0217| 2’-Deoxy-2’-fluoro-2’-methyluridine (200 mg, 0.62 mmol) was suspended in dry THF (20 mL) under N2. A solution of 2 b în dry THF (3 mL, 3 mmol), DMAP (4dimethylaminopyridine) (100 mg, 0.9 mmol) and triethylamîne (1 mL, 7 mmol) were added at RT. The reaction was stirred at 80°C for 18 hrs. The solvents were removed, and the residue was purified by column and RP HPLC (HCOOH system) to give 3c as a white solid (3.5 mg). *H NMR (CDCh) £8.49, 8.31 (m, 1H), 7.49, 7.43 (2d, J= 8.0 Hz, 1H), 7.31, 7.26 (m, 2H), 7.19, 7.11 (m, 3H), 6.17, 6.11 (2d, J= 7.2 Hz, 1H), 5.62, 5.53 (2d, 1H), 4.99, 4.93 (m, 1H), 4.54, 4.27 (m, 2H), 4.08, 4.02 (m, 3H), 3.89, 3.83 (m, 1H), 1.36, 1.22 (m, 6H), 1.20, 1.12 (m, 6H). 3IPNMR (CDClj) £68.08, 67.05. LCMS m/z 545.8 (MH+).
Example 6
Préparation of 2’-deoxv-2’-a-fluoro-2’-B-C-methyluridine 5t-(O-phenyl-A'-(5)-l(cvcIohexoxvcarbonvI)ethvDthiophosphoramidate (3d)
THF
Et3N DMAP
138 [0218] Compound 3d was prepared using the procedure for preparing compound 3c, with 2c in place of 2b. ’HNMR (DMSO-d6) δ 11.55 (s, IH), 7.61 (d, 5= 8.4 Hz, 0.43H), 7.57 (d, 5= 7.6 Hz, 0.56H), 7.40 (m, 2H), 7.21 (overlap, 3H), 6.68 (m, IH), 6.04 (m, IH), 5.95 (d, J= 7.6 Hz, 0.40H), 5.88 (d, J = 6.8 Hz, 0.60H), 5.57 (s, 0.50H), 5.55 (s, 0.50H), 4.64 (s, IH), 4.39 (m, IH), 4.23 (m, IH), 4.09-3.86 (m, 2H), 3.84 (m, IH), 1.63 (s, 2H), 1.45 (s, 2H), 1.36 (brs, IH), 1.34-1.29 (m, 11H).3,PNMR (DMSO-d6) 567.96, 67.89; MS m/z 586.2 (MH+).
Example 7
Préparation of 2,-deoxv-2’-a-fluoro-2’-IÎ-C-methvluridine 5'-(6)-phenvl-.V-(5)-l('neopentoxvcarbonvl)ethyl)thiophosphoramîdate (3e)
[0219] Compound 3e was prepared using the procedure for preparing compound 3c, with 2d in place of 2b. lH NMR (CD3OD) 57.77-7.66 (q, 5=8.0, 8.4 Hz, IH), 7.36-7.16 (m, JH), 6.13 (m, IH), 6.04 (m, IH), 5.65-5.56 (q, 5 = 8.4,8.0 Hz, IH), 4.19-4.09 (m, 2H), 3.93-3.75 (m, 2H), 1.41-1.28 (m, 6H), 0.93 (s, 9H). 3!P NMR (CD3OD) 566.9, 66.9. MS m/z 574.2 (MH+).
Example 8
Préparation of 2,-C-methyluridine 5'-(O-phenvl-.V-(5)-l(neopentoxycarbonyl)ethvl)thiophosphoramidatc (3f)
[0220] 2’-C-methyluridine (77 mg, 0.3 mmol) was dissolved in 10 mL of anhydrous acetonitrile and 2 mL of ALmethylimidazole. Compound 2d was added (0.3 g, 0.9
139 mmol) and the mixture was heated at 70°C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 30 mL of ethyl acetate, washed with 10% citric acid (2 x 10 mL), water, brine, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography on silica gel with methanol in dichloromethane (0 to 10%) to give 3f (224 mg) as light-tan solid. An analytical sample was obtained as a colorless sqlid by RP HPLC purification in gradient of methanol in water from 10% to 95% on a Synergy 4u Hydro-RP column (Phenominex). !H NMR (CDC13): δ 9.90 (bs, IH), 7.62-7.58 (m, IH), 7.32-7.28 (m, 2H), 7.20-7.16 (m, 2H), 5.97 & 5.94 (2s, IH), 5.65 & 5.52 (2d, IH), 4.54-4.46 (m, IH), 4.39-4.24 (m, IH), 4.20-4.04 (m, 3H), 3.85-3.79 (m, IH), 3.73-3.65 (m, 2H), 1.391.32 (dd, 3H), 1.16-1.14 (d, IH), 0.87-0.86 (m, 9H); 3[P NMR: £67.85, 67.16 (1:1 mixture of diastereomers); ESI-LCMS: m/z 570.4 [M + H]+.
Example 9 Préparation of 2’-C-Methyluridine 5'-(t?-phenvl- V-(M-l(cvclohexoxycarbonyl)ethyl)thiophosphoramidate (3g)
OH [0221] Compound 3g was prepared using the procedure for preparing compound 3f, with 2c in place of 2d. lH NMR (CDC13): δ 9.40 (bs, IH), 7.60-7.55 (m, IH), 7.297.11(m, 5H), 5.95 & 5.92 (2s, IH), 5.63 & 5.53 (2d, IH), 4.75-4.68 (m, IH), 4.50-4.23 (m, 2H), 4.10-4.00 (m, 3H), 3.74-3.72 (m, IH), 1.80-1.05 (m, 17H); 31P NMR: £67.80, 67.16 (3:4 mixture of diastereomers); ESI-LCMS: m/z 582.5 [M + H]+.
140
Example 10
Préparation of 2,-C-Methyluridine 5'-(O-(l-naphthvQ-jV-dS'J-l(isopropoxvcarbonvl)ethyl) thiophosphoramïdate (3h)
[0222] Compound 3 h was prepared usîng the procedure for preparing compound 3f, with 2e in place of 2d. ]H NMR (CDC13): 3 9.10 (bs, IH), 8.05-7.20 (m, 9H), S.95&5.92 (2s, IH), 5.38 & 5.33 (2d, IH), 4.99-4.91 (m, IH), 4.59-4.28 (m, 2H), 4.20-4.03 (m, 3H), 3.72-3.69 (m, IH), 1.36-1.27 (2d, 3H), 1.20-1.11 (m, 6H), 1.06-1.04 (2s, 3H); 3]P NMR: δ 67.92, 67.28 (2:3 mixture of diastereomers); ESI-LCMS: m/z 592.2 [M + H]+.
Example 11
Préparation of 2’-C-Methvluridine S'-fO-fl-naphthyll-rV-fYÎ-l(cyclohexoxvcarbonvl)ethyl) thiophosphoramïdate (3i)
[0223] Compound 3i was prepared using the procedure for preparing compound 3f, with 2f in place of 2d. ’H NMR (CDC13): δ 9.80 (bs, IH), 8.05-7.30 (m, 9H), 5.92 & 5.91 (2s, IH), 5.38-5.29 (2d, IH), 4.79-4.69 (m, IH), 4.59-4.32 (m, IH), 4.50-4.46 (m, IH), 4.38-4.03 (m, 4H), 3.70-3.66 (m, 1 H), 1.80-1.00 (m, 17H); 31P NMR: <567.74,67.43 (1:1 mixture of diastereomers); ESI-LCMS: m/z 632.5 [M + H]+.
141
Example 12
Préparation of Z’-C-Methyluridine 5'-(O-(l-naphtvl)-.V-(5j-L (neopentoxvcarbonyl)ethyl)thiophosphoramidate (3j)
[0224] Compound 3j was prepared using the procedure for preparing compound 3f, with 2g in place of 2d. 'H NMR (CDC13): δ 9.80 (bs, IH), 8.05-7.30 (m, 9H), 5.90 & 5.87 (2s, IH), 5.38 &5.30 (2d, IH), 4.60-3.60 (m, 9H), 3.72-3.69 (m, 1 H), 1.41 & 1.39 (2d, 3H), 1.08 & 1.06 (2s, 3H), 0.87 & 0.86 (2s, 9H); 31P NMR: 0 68.01, 67.35 (1:1 mixture of diastereomers); ESI-LCMS: m/z 620.8 [M + H]+.
Example 13
Préparation of S’-dideuterated 2’-C-methvluridine 5'-(O-phenyl-.V-(5j-l(isopropoxycarbonyl)ethyl)thiophosphoramidate (31)
H0 HO
31-3
[0225] Step 1. Compound 31-1 - To a suspension of 2’-C-methyluridine (2.50 g, 7.6 mmol) in acetone (100 mL) were added p-Toluenesulfonic acid monohydrate (1.76 g, 9.2 mmol) and 2,2-dimethoxypropane (20 mL). The mixture was stirred at RT for 16 h. Then saturated NaHCO3 was added to adjust the pH to between approximately 6-7. The suspension was concentrated and the residue was purified on a silica gel column (5-7% MeOH in DCM) to give 31-1 as a white solid (2.30 g, 82%).
142 [0226] Step 2. Compound 31-2 - To a solution of 31-1 (2.30 g, 7.7 mmol) in anhydrous DCM (50 mL) was added pyridinium dichromate (PDC) (5.80 g, 15.4 mmol), followed by acetic anhydride (7.87 g, 77.18 mmol) and tort-butyl alcohol (11.40 g, 154.0 mmol). The resulting solution was stirred at RT for 3 h. The mixture was loaded on a very short silica gel column and eluted with EA. The fractions containing 31-2 were combined and concentrated. Chromatography on silica gel with EA/hexanes (1:1 to 3:2) gave 31-2 as a white foam (2.07 g, 73%).
[0227] Step 3, Compound 31-3 - NaBD4 (1.10 g, 26.22 mmol) was added to a solution of 31-2 (2.07 g, 6.9 mmol) at RT and the resulting mixture stirred at 80°C overnight.
The reaction was quenched with acetic acid (AcOH) at 0°C. The mixture was diluted with EA and washed with brine. The organic phase was dried and concentrated. The residue was purified by chromatography on silica gel (2-5% MeOH in DCM) to give 31-3 as a white foam (854 mg, 50.83%).
[0228] Step 4. Compound 31-4 - Compound 31-3 (850 mg, 2.8 mmol) was 15 dissolved in 95% trifluoroacetic acid (TFA) /5% water at 0°C and then stirred at RT for 30minutes. The solvent was evaporated and the residue was purified by chromatography on silica gel (5-10% MeOH in DCM) to give 31-4 (663 mg, 90%). Ή NMR (CD3OD, 400 MHz) 5 8.16 (d, IH), 5.98 (s, IH), 5.69 (d, IH), 3.86-3.92 (m, 2H), 1.13 (s, 3H); ESI-MS: m/z 261.1 [M+H]+.
[0229] Step 5. Compound 31 - To a suspension of 31-4 (150 mg, 0.57 mmol) in anhydrous acetonitrile (1.0 mL) was added jV-methylimidazole (0.5 mL), followed by 2b (1.7 mmol, 1 M în CH3CN) at RT. The resulting solution was stirred at RT for 24h. The mixture was diluted with EA and concentrated. The residue was purified by RP HPLC (0.5 HCOOH in MeCN and water) to give 31 as a white solid (two isomers, 122 mg, 39%). ]H NMR (CD3OD, 400 MHz) 57.79, 7.87 (2d, J = 8.0 Hz, IH), 7.20-7.38 (m, 5H), 5.98, 6.01 (2s, IH), 5.59, 5.62 (2d, J = 8.0 Hz, IH), 4.99-5.01(m, IH), 4.10-4.12 (m, 2H), 3.82-3.84 (m,lH), 1.34, 1.38 (2d, 5= 7.2 Hz, 3H), 1.24, I.25(2s,3H), 1.17, 1.26 (2d, 5=6.0 Hz, 6H); 3lP NMR (CD3OD, 162 MHz) 568.42, 68.21; ESI-LCMS: m/z 546.1 [M + H]+.
143
Example 14
Préparation of .l'-O-acetvl-S'-dideuterated Z’-C-methyluridine 5*-(<?-phcnvl- V-(5l-l(isopropoxycarbonyllethvDthiophosphoramidate (4d)
[0230] To a suspension of 31 (750 mg, 1.38 mmol) in dry pyridine (50 mL) was added acetic anhydride (704 mg, 6.9 mmol). The reaction mixture was heated at 35°C for 16 h. The reaction was quenched with water and the solvent was removed. The residue was purified on a silica gel column (1-3% MeOH in DCM) to give 4d as a white solid (710 mg, 88%). 'H NMR (CD3OD, 400 MHz) 57.78, 7.84 (2d, J= 8.0 Hz, IH), 7.38-7.34 (m, 2H),
7.17-7.38 (m, 5H), 5.99, 6.02 (2s, IH), 5.59, 5.61 (2d, J= 8.0 Hz, IH), 5.13, 5.17 (2d, J= 9.2
Hz, IH), 5.04-4.97 (m, IH), 4.52-4.25 (m, 3H), 4.14-4.06 (m, IH), 2.16 (s, 3H), 1.35, 1.38 (2d, J = 7.2 Hz, IH), 1.18-1.24 (m, 9H); 3,P NMR (CD3OD, 162 MHz) 568.90, 68.23; ESILCMS: m/z = 585.9 [M+H]+.
Example 15
Préparation of 2’-C-methvlthymidine 5,-(O-phenvl-/V-(Sf)-l(isopropoxycarbon yl)eth vDthiophosph oramidate (3 m)
3m-1 3m-2 3m-3
3m
144 [0231] Step 1. Cornpound 3m-2 - To a suspension of thymine (0.869 g, 5.63 mmol) in acetonitrile (27 mL) was added AO-bis(trimethylsilyl)acetamide (5 mL) and the mixture was refluxed for 2 hours. The resulting solution was cooled to ambîent température and a solution of 3m-l (2.0 g, 3.45 mmol) în acetonitrile (10 mL) was added. Then SnCL (1.6 mL, 13.6 mmol) was slowly added and the reaction mixture was heated to 100°C for 5 h.
The reaction mixture was cooled to 0°C and solid NaHCOj was added, and a minimal amount of îce was added into the mixture. The reaction mixture was partially concentrated, diluted with EA and treated with a coid saturated aqueous solution of NaHCO3. The salts were filtered through celite and extracted with EA. The organic phase was washed successively 10 with a saturated aqueous solution of NaHCO3 and brine, dried by anhydrous Na2SÛ4, and concentrated to dryness. The residue was purified by silica gel column (0-20% EA in CH2C12) to give 3m-2 (1.6 g, 85%) as a white solid.
[0232] Step 2. Cornpound 3m-3 - Cornpound 3m-2 (1.6 g, 2.74 mmol) was dissolved in methanolic ammonia (120 mL, saturated at 0°C). The mixture was stirred at RT 15 for 20 hours. The solution was evaporated to dryness and the residue was purified on a silica gel column (DCM:MeOH=100:l to 50:1) to give 3m-3 as a light yellow foam (620 mg, 83.1 %). lH NMR (MeOD, 400 MHz) 58.05 (s, 1H), 5.93 (s, 1H), 4.01-3.97 (m, 1H), 3.91-3.86 (m, 2H), 3.80-3.76 (m, 1H), 1.85 (s, 3H), 1.13 (s, 3H).
[0233] Step 3. Cornpound 3m - To a suspension of 3m-3 (150 mg, 0.55 mmol) 20 in anhydrous CH3CN (3 mL) was added A-methylimidazole (0.4 mL), followed by addition of 2b (530 mg, 1.65 mmol) in anhydrous CH3CN (1 mL). The resulting solution was stirred at RT for 12 h. The reaction was quenched with water and the solvent was removed. The residue was purified by RP HPLC (0.5 HCOOH in MeCN and water) to gîve cornpound 3m as a white solid (two isomers, 43 mg, 14.0 %). ’H NMR (MeOD, 400 MHz) 57.54, 7.64 (2s, 25 1H), 7.16-7.36 (m, 5H), 5.98, 6.Ό1 (2s, 1H). 5.02-4.94 (m, 1H), 4.56-4.52 (m, 1H),
4.43-4.29 (m, 1H), 4.17-4.02 (m, 2H), 3.94-3.84 (m, 1 H), 1.81, 1.84 (2s, 3H), 1.31, 1.36 (2d, J = 7.2 Hz, 3H), 1.25-1.23 (m, 6H), 1,15 (s, 3H); 3,P NMR (MeOD, 162MHz) 569.17, 68.68; ESI-LCMS: m/z = 558.1 [M + H]+,
145
Example 16
Préparation of l-(2-amino-6-cvclopropvlaminopurÎn-9-yl)-2-C-methvl-ff-7)-ribofuranose
5-(C>-phenyI-/V-(5)-l-(isopropQxycarbonyl)ethvl)thiophosphoramidate (3z) /-^/θΧ^ΟΒζ Bz0 BzÛ OBz m-1
3z-3 3z [0234] Step 1. Compound 3z-l - To a solution of compound 3m-1 (20.0 g, 34.47 mmol) and 6-chloro-2-aminopurine (5.90 g, 34.91 mmol) in anhydrous MeCN (300 mL) was added l,8-diazabicycloundec-7-ene (DBU) (15.8 g, 103.9 mmol) at 0°C. The mixture was stirred at 0°C for 5 minutes and then trimethylsilyltrifluoromethane sulfonate (TMSOTf) (27.0 mL, 137.8 mmol) was added dropwise. Stirring was continued for another 30 minutes and then the mixture was heated to 70°C and stirred for 18 hour. The reaction was then cooled to RT and diluted with EA. The solution was washed with saturated NaHCO3 and brine. The organic layer was dried over NaiSCfr and then concentrated. The residue was purified by a silica gel column (20-40% EA in PE) and then RP HPLC (0.5% HCOOH in MeCN and water) to give compound 23-2 as a white solid (5.4 g , 25.6 %). ’H NMR (DMSO-d6, 400 MHz) δ 8.38 (s, IH), 7.97 -8.05 (m, 4H), 7.82-7.85 (m, 2H), 7.58-7.66 (m, 3H), 7.39-7.53 (m, 4H), 7.18-7.37 (m, 2H), 7.19 (brs, 2H), 6.61 (s, IH), 5.94 (d, J = 4.8 Hz, IH), 4.70-4.89 (m, 3H), 1.58 (s, 3H).
[0235] Step 2. Préparation of compound 3z-2 - Compound 3z-l (100 mg, 0.16 mmol) and THF (10 mL) were placed into a dry flask and then cyclopropyl amine (1.61 g, 28.21 mmol) was added. After the addition, the mixture was heated to reflux overnight. Then
146 the solvent was removed and the residue was purified on a silica gel column (2~10% MeOH in DCM) to give 3z-2 as a white solid (82 mg, 77.6%).
[0236] Step 3. Compound 3z-3 - Compound 3z-2 (402 mg, 0.62 mmol) was dissolved in methanolic ammonia (20 mL, saturated at 0°C) and the mixture was stirred at RT for 12 hours. The solvent was removed and the residue was purified on a silica gel colurnm (2-10% MeOH in DCM) to give 3z-3 as a white solid (149 mg, 72.4%). ’H NMR (CD3OD, 400 MHz) £8.14 (d, J = 11.2 Hz, IH), 5.93 (s, IH), 4.22 (d, J= 8.4 Ηζ,ΙΗ), 4.03 (d, J= 10.8 Hz, 2H), 3.86 (d, Js = 12.8 Hz, J2 = 3.2 Hz, IH), 2.91 (s, IH), 0.79-0.98 (m, 2H), 0.61-0.70 (m, 2H); ESI-LCMS: m/z 337.1 [M + H]+, 360.1 [M+Na]+.
[0237] Step 4. Compound 3z - To a stirred suspension of 3z-3 (110 mg, 0.33 mmol) in anhydrous acetonitrile (1.0 mL) was added /V-methylimidazole (0.5 mL) followed by slow addition of 2b (1.05 g, 3.273 mmol, IM in MeCN) at RT. The resulting solution was stirred at 50°C for 4 hours and then diluted with EA. The solution was washed with 10% AcOH/H2O, brine, 5% NaHCO3 aqueous solution, and dried over Na2SO4. The solvent was removed and the residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3z as a white solid (two isomers, 131 mg, 64 %). *H NMR (CD3OD, 400 MHz) £7.96, 8.00 (2s, IH), 7.28-7.36 (m, 5H), 7.14-7.20 (m, IH), 5.96, 5.99 (2s, IH), 4.92-4.98 (m, IH), 4.37-4.57 (m, 2H), 4.04-4.23 (m, 3H), 2.91 (br, IH), 1.36, 1.32 (2d, J = 7.2 Hz, 3H), 1.171.23 (m, 7H), 0.96, 0.99 (2s, 3H), 0.87-0.90 (m, 2H), 0.63-0.69 (m, 2H); J1P NMR (CD3OD, 162 MHz) δ 68.53, 68.38; ESI-LCMS: m/z 622.2 [M + H]+, 644.2 [M+Na]+.
Example 17
Préparation of l-(2,6-diaminopurin-9-yl)-2-C-methyI-/?-X>-ribofuranose 5-(77-phenvl-.Vi5)-l-(isopropoxycarbonvl)ethyl)thiophosphoramidate (3aa)
Step 1. Compound 3aa-l - Compound 3z-l (1.01 g, 1.56 mmol) was [0238] suspended in aqueous ammonia (28%, 40 mL) and dioxane (4 mL) in a sealed vessel. The mixture was heated at 100°C overnight. Then the solvent was removed and the residue was
147 purification on a silica gel column (2-10% MeOH in DCM) to give 3aa-l as a white solid (418 mg, 88.9%). 'H NMR (CD3OD, 400 MHz) £8.17 (s, IH), 5.93 (s, IH), 4.24 (d, J= 8.8 Hz, IH), 4.01-4.04 (m, 2H), 3.86 (dd, J} = 12.8 Hz, J 2 = 3.2 Hz, IH), 0.96 (s, 3H); ESILCMS: m/z 297.1 [M+H]+.
[0239] Step 2. Compound 3aa - To a stirred suspension of 3aa-l (62 mg, 0.20 mmol) in anhydrous acetonitrile (1.0 mL) was added jV-methylimidazole (0.5 mL) followed by slow addition of 2b (652 mg, 2.02 mmol, IM în MeCN) at RT. The resulting solution was stirred at RT for 24 hours. The solution was diluted with EA and washed with 10% AcOH in H2O, brine, 5% NaHCO3 aqueous solution, and dried over Na2SO4- The solvent was removed and the residue w'as purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3aa as a white solid (31 mg, 25.6%). ]H NMR (DMSO-d6, 400 MHz) 577.81, 7.83 (2s, IH), 7.337.38 (m, 2H), 7.17-7.25 (m, 3H), 6.58-6.78 (m, 3H), 5.81-5.83 (m, 3H), 5.32-5.43 (m, IH), 5.19, 5.20 (2s, IH), 4.78-4.85 (m, IH), 4.21-4.42 (m, 2H), 3.87-4.15 (m, 3H), 1.24-1.26 (m, 3H), 1.08-1.15 (m, 6H), 0.83, 0.84 (2s, 3H); 3lP NMR (DMSO-d6, 162 MHz) δ 68.19, 67.90; ESI-LCMS: m/z 589.1[M + H]+, 604.1 [M+Na]+.
Exampie 18
Préparation of l-(2-amino-6-allvlamtnopurin-9-vl)-2-C-methvl-^-P-ribofuranose 5-((7phenvI-Ar-(1y)-l-(isopropoxvcarbonvr)ethyl)thiophosphoranÎidate (3bb)
3z_1 3bb-1 3bb [0240] Step 1. Compound 3bb-l - A mixture of 3z-l (802 mg, 1.27 mmol) and ally amine (7.26 g, 127.3 mmol) in THF (30 mL) was refluxed overnight. The solvent v^as removed and the residue was purified on a silica gel column (2-10% MeOH in DCM) to give crude 3bb-l (405 mg), which was dissolved în 20 mL methanolic ammonia (saturated at 0°C). The mixture was stirred at RT for 12 hours. The solvent was removed and the residue was purified on a silica gel column (2-10% MeOH in DCM) to give 3bb-l as a white solid (153 mg, 35.9%). *H NMR (CD3OD, 400 MHz) £8.10 (s, IH), 5.92-6.03 (m, 2H), 5.27 (d, J
©
148 = 17.6 Hz, 1H), 5.14 (d, 7- 10.4 Hz, 1H), 4.18-4.24 (m, 3H), 4.03 (d, 7 = 10.0 Hz, 2H), 3.86 (d, 7= 10.4 Hz, 1H), 0.95 (s, 3H); ESI-LCMS: m/z 337.1 [M+H]+.
[0241J Step 2. Compound 3bb - To a stirred suspension of 3bb-I (200 mg, 0.59 mmol) in anhydrous acetonitrile (1.0 mL) was added iV-methylimidazole (0.5 mL) followed f 5 by 2b (573 mg, 1.79 mmol, IM in MeCN) at RT. The resulting solution was stirred at RT for 24 hrs and then was diluted with EA. The solution was washed with 10% AcOH in H2O, brine and 5% NaHCO3 aqueous solution. The organic solution was dried and concentrated. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3bb as a white solid (two isomers, 155 mg, 40.8%). ’H NMR (CD3OD, 400 MHz) δ 7.94, 7.98 (2s,
1H), 7.29-7.34 (m, 4H), 7.18-7.28 (m, 1H), 5.96-6.09 (m, 2H), 5.27, 5.31 (2s, 1H), 5.15, 5.17 (2d, 7= 1.2 Hz, 1H), 4.92-4.96 (m, 1H), 4.35-4.57 (m, 2H), 4.01-4.28 (m, 5H), 1.32, 1.36 (2d, J= 7.2 Hz, 3H), 1.16-1.25 (m, 6H), 0.97 (2s, 3H); 31P NMR (CD3OD, 160 MHz) 568.51, 68.40; ESI-LCMS: m/z 622.1 [M + H]+, 644.1 [M+Na]+.
Example 19
Préparation of l-(2-amino-6-chloropurini-9-yl)-2-C-methvl-/?-Z)-ribofuranose 5-(Ophenyl“7V-(5)-l-(isopropoxvcarbonyI)ethvI)thiophosphoramidate (3cc)
3z-1 3cc-1 3cc [0242] Step L Compound 3cc-l - Compound 3z-l (506 mg, 0.79 mmol) was dissolved în 100 mL of methanolic ammonia and the mixture was stirred at RT for 12 h. The solvent was removed and the residue was purified on a silica gel column (2-10% MeOH in DCM) to give 3cc-l as a white solid (204 mg, yield: 79.9%).
[0243] Step 2. Compound 3cc - To a stirred suspension of 3cc-l (198 mg, 0.63 mmol) in anhydrous acetonitrile (1.0 mL) was added V-methylimidazole (0.5 mL) followed 25 by 2b (611 mg, 1.904 mmol, IM in MeCN) at RT. The resulting solution was stirred at 3040°C for 12 hours and then diluted with EA. The solution was washed with 10% AcOH in H2O, brine, and 5% NaHCO3. The organic phase was dried and concentrated. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water) to give 3cc as a white solid
149 (118 mg, 31.6%). !H NMR (CD3OD, 400 MHz) £8.25, 8.28 (2s, IH), 7.27-7.35 (m, 4H),
7.15-7.18 (m, IH), 6.02, 6.05 (2s, IH), 4.93-4.98 (m, IH), 4.40-4.54 (m, 2H), 4.20-4.27 (m,
2H), 4.05-4.13 (m, IH), 1.15-1.35 (m, 9H), 0.99, 1.01 (2s, 3H) ; 3JP NMR (CD3OD, 162
MHz) £68.66, 68.53; ESI-LCMS: m/z 601.1 [M+H]+.
I
Example 20
Préparation of 2,-C-methyluridinc S’-fO-phenyl-TV-fô)-!(isopropoxvcarbonvl)isobutvl)thiophosphoramidate (3n)
[0244] To a solution of 2’-C-methyIuridine (150 mg, 0.581 mmol) in MeCN (1 mL) and jV-methylimidazole (0.7 mL) was added 2h (651 mg, 1.86 mmol). The mixture was stirred at RT for 3 days. The solvent was removed and the residue was purified by RP HPLC (0.1% HCOOH in MeCN and water) to give 3n as a white solid (two isomers, 22 mg, 6.6%).
Ή NMR (CDjOD, 400 MHz) £7.76, 7.78 (2d, J= 9.2 Hz, IH), 7.14-7.35 (m, 5H), 5.95, 5.97 (2s, IH), 5.56, 5.63 (2d, J= 8.4 Hz, IH), 4.95-5.03 (m, IH), 4.44-4.56 (m, IH), 4.30-4.41 (Μ, IH), 4.08-4.11 (m, IH), 3.75-3.90 (m, 2H), 2.00-2.07 (m, IH), 1.12-1.25 (m, 6H), 1.11, 1.15 (2s, 3H), 0.87-0.97 (m, 6H); 3tP NMR (CD3OD, 162 MHz) £70.38, 69.13; ESI-LCMS: m/z 572 [M+H]+.
150
Example 21
Préparation of 2’-C-methyIuridine 5’-(O-phcnyl-Ar-(ly)-l(ÎsopropoxYcarbonvÎ)isopentvl)thiophosphoramidate (3o)
[0245] Compound 3o was prepared using the procedure for preparing compound 3n, with 2i in place of 2h. 'H NMR (CD3OD, 400 M Hz) δ 7.77, 7.84 (2d, J= 8.0 Hz, IH), 7.14-7.35 (m, 5H), 5.96 (2s, IH), 5.57, 5.62 (2d, J= 8.0 Hz, IH), 4.84-4.98 (m, IH), 4.464.53 (m, IH), 4.28-4.42 (m, IH), 3.97-4.12 (m, 2H), 3.80 (2s, IH), 1.58-1.81 (m, IH), 1.481.56 (m, 2H), 1.20-1.23 (m, 6H), 1.13 (2s, 3H), 0.81-0.92 (m, 6H); 31P NMR (CD3OD, 400 M Hz) δ 68.56, 69.15; ESI-MS: m/z 586 [Μ + H]+, m/z 608 [M + Na]+.
Example 22
Préparation of 2’-C-methylguanosine S'-tD-phetn l-.V-fSj-l(cvclohexoxvcarbonyl)ethyl)thiophosphoramidate (3s)
[0246] To a stirred suspension of commercial 2’-C-methylguanosine (100 mg, 0.34 mmol) in anhydrous acetonitrile (1.5 mL) was added jV-methylimidazole (0.56 mL, 6.8 mmol, 20 équivalent) followed by 2c (303 mg, 0.84 mmol, IM in MeCN) at RT. The resulting solution was stirred at 40°C for 3 hours and then diluted with EA. The solution was washed with 10% AcOH in H2O, and brine. The organic layer was separated, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated în vacuum to give a residue which was purified on a silica gel column (3-7% MeOH in DCM). The collected fractions
151 were concentrated and re-purified on a silica gel column (2-5% MeOH in DCM) to give (127.8 mg, 61.2%) of 3s as a white solid. *H NMR (DMSO-d6, 400 MHz) Ô 10.6 (s, IH), 7.76 (d, J= 5.6 Hz, IH), 7.36-7.31 (m, 2H), 7.22-7.01 (m, 4H), 6.56-6.48 (m, 3H), 5.74 (d, J = 8.4 Hz, IH), 5.42 & 5.35 (2d, each J= 6.4 Hz, IH), 5.16 (d,7= 2.8 Hz, IH), 4.62-3.93 (m, 6H), 1.67-1.58 (m, 5H), 1.33-1.16 (m, 12H), 0.79 (s, 3H); 31P NMR (DMSO-d6) £68.07, 67.71; ESI-LCMS: m/z = 623.1 [M + H]+.
Example 23
Préparation of 2,-C-Methylguanosine S'-fO-phenvl-TV-ijO-l(isopropoxycarbonyl)ethyi)thiophosphoramidate (3r)
[0247] Compound 3r was prepared using the procedure for preparing compound 3s, with 2b in place of 2c. *H NMR (DMSO-d5, 400 MHz) 510.6 (s, IH), 7.76 (d, 1.6 Hz,
IH), 7.34-7.31 (m, 2H), 7.22-7.14 (m, 4H), 6.62-6.48 (m, 3H), 5.74 (d, 7= 7.2 Hz, IH), 5.42 & 5.33 (2d, each J= 6.8 Hz, IH), 5.16 (d, 7=2.4 Hz, IH), 4.84-3.77 (m, IH), 4.42-3.85 (m, 5H), 1.25-1.1 (m, 12H), 0.81 & 0.8 ( 2s, 3H); 31P NMR (DMSO-d6) 5 68.23, 67.64; ESILCMS: m/z = 583.4 [M + H]+.
Example 24
Préparation of 2,-Deoxv-2’-fluoro-2’-C-methyl-6-methoxyguanosine S’-CO-phenyl-iV-f^)l-(isopropoxycarbonyl)ethyl)-thiophosphoramidate (3t)
[0248] Compound 3t was prepared using the procedure for preparing compound 3s, with 2b in place of 2c, and with 2’-deoxy-2’-fluoro-2’-C-methyl-6-methoxyguanosine in place of 2’-C-methyiguanosîne. 'H NMR (DMSO-de, 400 MHz) 5 7.96 & 9.95 (2s, IH),
Z
152
7.36-7.29 (m, 2H), 7.21-7.14 (m, 3H), 6.57 (br s, 2H), 6.1 & 6.05 (2d, each J= S.8 Hz, 1H),
5.75 (br s, 2H), 4.82-4.76 (m, 1H), 4.45-4.04 (m, 3H), 3.93 (s, 3H), 1.24-1.13 (m, 3 H), 1.121.03 (m, 9H); 3iP NMR (DMSO-d6) 568.21, 67.82; ESI-LCMS: m/z = 599.4 [M + H]+.
Example 25
Préparation of l-(2-Amino-6-methoxypurin-9-vI)-2-C-methyl-ff-j)-ribofuranose 5-(()phenvl-Ar-(^-l-(isopropoxycarbonvI)ethyl)-thiophosphoramidate (3u)
[0249] Compound 3u was prepared using the procedure for preparing compound 3s, with 2b în place of 2c, and with l-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-β-Dribofuranose in place of 2’-C-methylguanosine. ’H NMR (DMSO-dg, 400 MHz) δ 7.93 (s, 1H), 7.35-7.30 (m, 2H), 7.22-7.14 (m, 3H), 6.61-6.52 (m, 1H), 6.48 (br s, 2H), 5.86 (d, each J = 5.2 Hz, 1H), 5.43, 5.32 (br s, 1H), 5.20 (br s, 1H), 4.84-4.76 (m, 1H), 4.36-4.04 (m, 4H), 3.93 (s, 3H), 1.24-1.15 (m, 3H), 1.19-1.06 (m, 6H), 0.8-0.78 (m, 3H); 3lP NMR (DMSO-d6) δ 68.21, 67.65; ESI-LCMS: m/z = 597.5 [M + H]+.
Example 26
Préparation of 2’-Deoxy-2:'-fl!-fluoro-2’-jg-C-methvlguanosine 5'-(O-phenyI-N-(S)-l(ncopentoxvcarbonvlethyl)thiophosphoramidate (3q)
[0250] Compound 3q was prepared using the procedure for preparing compound 3s, with 2d in place of 2c, and with 2’-deoxy-2’-a-fluoro-2’-^-C-methylguanosine in place of 2’-C-methylguanosine. 3H NMR (DMSO-d6, 400 MHz) δ 10.66 (br s, 1H), 7.79 (s, 1H), 7.36-7.30 (m, 2H), 7.22-7.15 (m, 3H), 6.61-6.52 (m, 1H), 6.48 (br s, 2H), 6.72-6.56 (m, 3H),
153
6.00, 5.95 (2d, J= 8.0, 8.4 Hz, IH), 5.75-5.82 (m, IH), 4.43-3.92 (m, 5H), 3.76-3.53 (m, 2H), 1.29-1.24 (m, 3H), 1.09-1.00 (m, 4H), 0.84, 0.81 (2s, 8H); 3]P NMR (DMSO-d6) δ 68.09, 68.03; ESI-LCMS: m/z = 613.7 [M + H]+.
* Example 27
Préparation of l’-C-Methyladenosine 5l-(O-phenvI-/V-(.S')-l(neopentoxvcarbonylÎethvl)thiophosphoramidate (3dd)
[0251] Compound 3dd was prepared using the procedure for preparing compound 3s, with 2d in place of 2c, and with 2’-C-methyladenosine in place of 2’-C-methylguanosine. ]H NMR (DMSO-ds, 400 MHz) Ô 8.22, 8.2 (2s, IH), 8.12 (s, IH), 7.36-7.13 (m, 6H), 6.616.55 (m, IH), 5.97, 5.94 (2s, IH), 5.40, 5.34, 5.31(3d, J= 6.8, 6.8, 6.0 Hz, 2H), 4.39-3.99 (m, 5H), 3.76-3.61 (m, 2H), 3.42 (d, J = 10.4 Hz, IH), 1.27-1.23 (m, 3H), 0.83, 0.77 (2s, 4H), 0.77, 0.76 (2s, 8H); 31P NMR (DMSO-d6) J68.15, 67.74; ESI-LCMS: m/z = 595.0 [M + H]+.
Example 28
Préparation of 2’-C-Methyladenosiûe (isopropoxycarbonvl)ethyl) thiophosphoramidate (3ee)
[0252] Compound 3dd was prepared using the procedure for preparing compound 3s, with 2e in place of 2c, and with 2’-C-methyladenosîne in place of 2’-C-methylguanosine. !H NMR (DMSO-dé, 400 MHz) δ 8.28, 8.24 (2s, IH), 8.12-8.06 (m, 2H), 7.93-7.91 (m, IH), 7.29-7.68 (m, IH), 7.54-7.37 (m, 4H), 7.26 (br s, 2H), 6.82-6.72 (m, IH), 6.00, 5.98 (2s, IH), 5.47, 5.39, 5.31 (3d, J= 6.4, 6.8, 10.0 Hz, 2H), 4.82-4.74 (m, IH), 4.48-4.35 (m, 2H), 4.28-
154
4.15 (m, 2H), 4.03-3.96 (m, IH), 1.27-1.24 (m, 3H), 1.1-1.00 (m, 6H), 0.8 (s, 3H); ESILCMS: m/z = 617.1 [M + H]+.
Example 29
Préparation of î’-C-methylguanosine S'-iO-phenvI-.V-LS'i-l(neopentoxvcarbonvlÏethvQthiophosphoramidate (3p)
3p-2
[0253] Step 1, Compound 3p-l - A mixture of 2’-C-methyIguanosine (1.0 g, 3.36 mmol), trimethyl orthoformate (20 mL) and p-toluenesulfonic acid monohydrate (961 mg, 5.05 mmol) in 1,4-dioxane (30 mL) was stirred at RT for 24 h. Dowex MWA-1 basic resin we added and stirred until the solution was neutralized. The resin was filtered and washed thoroughly with MeOH and then with MeOH/DCM (1:1). The filtrate was concentrated and the residue was subjected to flash chromatography on a silica gel column eluting with 5-10% MeOH in DCM to give (0.94 g) of 3p-l as a white solid.
[0254] Step 2. Compound 3p-2 - A solution of 3p-l (0.94 g, 2.77 mmol), dimethylaminopyridine (DMAP) (338 mg, 2.77 mmol) and t-butyldimethylsilyl chloride -(TBSC1) (543 mg, 3.60 mmol) in pyridine (10 mL) was stirred at 25°C overnight. 4Methoxytrityl chloride (1.56g, 5.0 mmol) was added and the resulting mixture stirred at RT 50°C for 3 h. The mixture was diluted with ethyl acetate, and washed with brine three times. The solvent was evaporated and the residue was chromâtographed on silica gel with 3-5% MeOH in DCM to give 1.66 g of a protected intermediate as foam solid. A solution of the intermediate (1.66 g, 2.66 mmol) and 1.0 M tetrabutylammonium fluoride (TBAF) / THF (4
155 mL) in 10 mL of THF stood at RT for 20 h. The solution was concentrated. The residue was subjected to flash chromatography on silica gel with 5-6% MeOH in DCM to give 1.33 g of 3p-2 as a white foam. MS m/z 611.9 (MH+).
[0255] Step 3. Compound 3p - Compound 2d (1.0 M in MeCN, 0.5 mL) was added dropwise to a solution of 3p-2 (61 mg, 0.1 mmol) and diisopropylethylamine (0.3 mL) in anhydrous acetonitrile (0.4 mL). The resulting solution was heated at 82°C for 20 h, diluted with ethyl acetate, washed with brine three times, dried over sodium sulfate, and concentrated. Chromatography on silica gel with 20-30% ethyl acetate in hexanes gave 82 mg of a protected intermediate as a white foam, which was dissolved in a mixture of 80% formic acid and 20% water (3 mL). The solution stood at RT overnight, was concentrated, and then co-evaporated with MeOH/toluene three times. Chromatography on silica gel with 6-10% MeOH in DCM gave 27 mg of 3p as a white solid; !H NMR (acetone-Zi) δ 7.83, 7.92 (2s, IH), 7.10-7.34 (m, 5H), 5.88, 5.90 (2s, IH), 4.33-3.53 (m, 2H), 4.11-4.24 (m, 3H), 3.61-3.79 (m, 2H), 1.39, 1.36 (2d, J= 7.2 Hz, 3H), 0.94, 0.95 (2s, 3H), 0.84, 0.87 (2s, 9H); 31P NMR (acetone-de) 568.27, 67.85; ESI-LCMS: m/z 611.3 [M+H]+.
Example 30
Préparation of 2\57>y)-C,C-DÎmethvIadenosine S'-fU-phenvl-.V-Ly)-!(neopentoxvcarbonvl)ethyl)thiophosphoramidate (3hh)
[0256] Compound 3hh was prepared using the procedure for preparing compound 3p, with 2’,5’-C,C-dimethyladenosine in place of 2*-C-methylguanosine. fH NMR (CDjOD) δ 8.40, 8.36 (2s, IH), 8.22, 8.20 (2s, IH), 7.07-7.36 (m, 5H), 6.06, 6.05 (2d, J= 5.2 Hz, IH), 5.88, 5.90 (2s, IH), 4.59 (t, J= 5.2 Hz, 0.5 H), 4.50 (q, J= 5.2 Hz, IH), 4.40 (q, J= 3.6, 5.2 Hz, 0.5H), 4.04 -4.19 (m, 2H), 3.81 (d, 0.8 Hz, IH), 3.75 (d, J= 10.4 Hz, IH), 3.65 (d, J
156 = 10.4 Hz, 1H), 1.52, 1.40 (2d, J= 6.4 Hz, 3 H), 1.29, 1.30 (2s, 3H), 0.93, 0.87 (2s, 9H); 31P
NMR (acetone-d6) 568.40, 67.43; ESI-LCMS: m/z 595.1 [M+Hf.
Example 31
Préparation of l-(2-Amino-6-methoxvpurin-9-yl)-2-C-methyl-Z?-D-ribofuranose 5-(Ophenyl-jV-Cyi-l-ineopentoxycarbonvDethyD-thiophosphoramidate (3v)
[0257] Cornpound 3v was prepared using the procedure for preparing cornpound 3p, with l-(2-amino-6-methoxypurin-9-yl)-2-C-methyl^-D-ribofuranose in place of 2’-Cmethylguanosine. lH NMR (CDjOD, 400 MHz) 5 7.97, 8.00 (2s, 1H), 7.10-7.33 (m, 5H), 5.99, 5.96 (2s, 1H), 4.33-4.55 (m, 2H), 4.031, 4.034 (2s, 3H), 3.56-3.72 (m, 2H), 1.31-1.36 (m, 3H), 0.94, 0.92 (2s, 3H), 0.89, 0.85 (2s, 9H); 31P NMR (DMSO-d6) 568.52, 68.27. ESILCMS: m/z 625.3 [M+H]+.
Example 32
Préparation of l-(2-Amino-6-methoxypurin-9-vI)-2-C-niethvl-ZLD-ribofuranose 5-(<7phenyl-Ar-(5)-l-(cvclohexoxycarbonvl)ethvl)-thiophosphoramidate (3w)
[0258] Cornpound 3w was prepared using the procedure for preparing cornpound 3p, with 2c în place of 2d, and with l-(2-Amino-6-methoxypurin-9-yI)-2-C-methyl-j3Kribofuranose în place of 2’-C-methylguanosine. ]H NMR (CD3OD, 400 MHz) 57.98, 8.01 (2s, 1H), 7.24-7.32 (m, 4H), 7.10-7.17 (m, 1H), 6.00, 5.96 (2s, 1H), 4.36-4.73 (m, 3H), 4.036, 4.034 (2s, 3H), 4.01-4.22 (m, 3H), 1.60-1.80 (m, 4H), 1.19-1.55 (m, 9H), 0.92, 0.94 (2s, 3H); 31P NMR (DMSO-d6) 568.43, 68.32. ESI-LCMS: m/z 637.6 [M+H]+.
Example 33
Préparation of l-(2-Amino-6-methoxvpurin-9-vl)-2-C-methyl-/i-P-ribofuranose 5-(0-(1naphthyl)-/V-(S)-l-(neopentoxvcarbonvl)ethvl)-thiophosphoramidate (3x)
[0259] Compound 3x was prepared using the procedure for preparing compound
3p, with 2g in place of 2d, and with l-(2-Amino-6-methoxypurin-9-yl)-2-C-methyl-/-Dribofuranose in place of 2’-C-methylguanosine. *H NMR (CD30D, 400 MHz) 5 8.15-8.19 (m, IH), 8.03, 7.97 (2s, IH), 7.80-7.85 (m, IH), 7.31-7.67 (m, 5H), 6.00, 5.98 (2s, IH), 4.434.62 (m, 2H), 4.18-4.27 (m, 3H), 4.01 (s, 3H), 3.57-3.79 (m, 2H), 1.33-1.37 (m, 3H), 0.941, 10 0.946 (2s, 3H), 0.855, 0.848 (2s, 9H); 31P NMR (DMSO-d6) 568.55, 68.57. ESI-LCMS: m/z
675.3 [M+H]+.
Example 34
Préparation of additional 2’-C-methvluridine S’-thiophosphoramidates |0260] Compounds 3ii - 3w, as shown in Table 8, were prepared using a similar procedure for preparing compound 3n.
Table 8
Compound | 3,P NMR PPm | Compound | 3IP NMR PPm |
b ; ογ-° 3ii | 69.30 69.09 | Cl H 0 b s jJ 3jj | 68.92 68.58 |
Compound | 31P NMR Ppm | Compound | 31p NMR PPm |
Q - A>° Cl O-P-o'JJ ZoYNH Hd bH 3kk | 68.45 68.16 | F\ /Cl H ,o b s aj O-P-O Y A Υγ HÔ bH 311 | 69.69 69.28 |
b. Ab °AU AYnh Hd bH 3mm | 68.60 68.42 | Q s /JW. Hô ÔH 3nn | 68.25 67.79 |
'°b . Ab /JY Hd bH 3oo | 69.25 69.12 | /=X n nS) < 1 A-YÏ AYNH Hd' bH 3pp | 69.52 68.53 |
Q s γγΝΗ bH 3qq | 70.03 69.56 | θ s Ab boA ;Y£shô bn 3rr | 68.87 68.76 |
Q s Ab yyu· \ YNH Hô' bH 3ss | 70.83 69.38 | Q. Ab o-P-oAZ Hd bH 3tt | 69.12 68.45 |
159
Compound | 31P NMR ppm | Compound | 31P NMR PPm |
Q. J J o-p-o \ L· yjt Hà 0H | 69.14 68.46 | Q > bH 3w | 68.74 66.82 |
\ 3uu |
Example 35
Préparation of 2’-C-Methyl-3’-t?-propionyluridine S'-ÎO-phenvl-TV-i^-l(isopropoxycarbonvDethvO-thiophosphoramidate (4b)
[0261] Compound 3b (lg, 1.88 mmol) was dissolved în 10 mL of dry pyridine, propionic anhydride was added (385 mg, 2.81 mmol) and reaction mixture was left overnight at RT. TLC showed that reaction was not completed. More anhydride (385 mg, 2.81 mmol) was added and the mixture was heated at 40°C for 2 hours. Solvents were evaporated. The 10 residue was distributed between ethyl acetate and water. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel in a gradient of methanol in DCM from 2% to 7% resulted in 725 mg of 4b (64%). ’H NMR (CDClj): δ 8.70 & 8.66 (2s, IH), 7.59-7.48 (2d,lH), 7.30-7.08 (m, 5H), 5.93 & 5.90 (2s, IH), 5.60 & 5.49 (2d, IH), 5.01-4.94 (m, 2H), 4.50-4.38 (m, IH), 4.32-4.02 (m, 3H), 2.45-2.35 (m, 2H), 1.38-1.30 (m, 3H), 1.20-1.11 (m, 12H); 31P NMR: δ 67.72, 67.54 (1:1 mixture of diastereomers); ESI-LCMS: m/z 598.3 [M + H]+.
160
Example 36
Préparation of 2\3;-6>-diisobutvrvl-2'-C-niethvluridine 5t-(O-phenyl-Ar-(5j-l(isopropoxvcarbonvl)ethvl)tliiophosplioramidate Mc) and
Préparation of 2’-C-methyl-3’-<?-isobutvrvluridine 5'-(O-phenvl-.V-(.Sj-l(isopropoxycarbonvOethyllthiophosphoramidate (4f)
[0262] Step 1. Compound 4c - To a solution of 3b (0.1 g, 0.18 mmol) in anhydrous pyridine (2 mL), was added DMAP (22 mg, 0.18 mmol) followed by îsobutyric anhydride (0.1 mL, 0.63 mmol) under N2 atmosphère. The reaction mixture was stirred at RT for lh. The reaction was quenched by adding isopropanol (0.5 mL). The solvent was removed under vacuum and the residue was taken up into EA (100 mL). The solution was washed with saturated NaHCO3 and brine. The organic layer was separated, dried over anhydrous Na2SÛ4 and filtered. The filtrate was concentrated in vacuum to give a residue which was purified on a silica gel column (1-5% MeOH in DCM) to give the faster eluting product 4c as a white solid (36.5 mg). NMR (DMSO-dâ, 400 MHz) δ 11.46 (s, IH), 7.59& 7.55 (2d, J= 8.4, 8.4 Hz, IH), 7.37-7.32 (m, 2H), 7.21-7.15 (m, 3H), 6.67-6.66 (m, IH), 6.14 & 6.11 ( each s, IH), 5.58 (d, J=8.0 Hz, IH), 5.2 (br s, IH), 4.88-4.84 (m, IH), 4.28-4.27 (m, IH), 3.95-3.85 (m, IH), 2.54-2.49 (m, 2H), 1.38 & 1.36 (2s, 3H), 1.26-1.21 (m, 2H), 1.56-1.12 (m, 6H), 1.09-1.05 (m, 12H);31P NMR (DMSO-d6) 568.44, 68.42; ESI-LCMS: m/z = 682.4 [M-H].
161 [0263] Step 2. Compound 4f - Further elution of the residue on the silica gel column using 5% MeOH in DCM gave the slower eluting product 4f (54.5 mg) as white foam after évaporation of solvent ίη-vacuo. ]H NMR (DMSO-ds, 400 MHz) £ 11.42 (s, IH), 7.65 & 7.63 (2d, J= 8.0, 8.4 Hz, IH), 7.37-7.32 (m, 2H), 7.21-7.15 (m, 3H), 6.68-6.61 (m, IH), 5.84 & 5.81 ( each s, IH), 5.71 & 5.68 ( eàch s, IH), 5.56 & 5.47 ( each d, each J = 8.0 Hz, IH), 4.98-4.94 (m, IH), 4.87-4.82 (m, IH), 4.31-4.16 (m, 3H), 3.85-3.95 (m, IH), 2.622.58 (m, IH), 1.26 & 1.2 ( each d, J = 7.2, 6.8 Hz, 3H), 1.16-1.08 (m, 12H), 1.01 (s, 3H); 31P NMR (DMSO-dô) £68.93, 67.96; ESI-LCMS: m/z - 612.4 [M+H]+.
Example 37
Préparation of 2’-C-2’-6MioÎethvluridine 5>-(O-phenyl-Ar-(5f)-l(isopropoxvcarbonvl)ethyl)thiophosphoramidate (4e)
[0264] Step 1. Compound 4e-l - To an ice-cold solution of 2’-C-methyluridine (2.0 g, 7.6 mmol) in anhydrous pyridine (20 mL) was added 1,3-dichloro-1,1,3,3tetraisopropyldisiloxane (TIPDSCL) (2.40 g, 7.6 mmol) in small portions under N2. The reaction mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was taken up into EA (100 mL). The solution was washed with saturated NaHCCh and brine. The organic layer was separated, dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on a silica gel column (DCM/MeOH = 100/1 to 50/1) to give 4e-l (3.2 g, 85%) as a white foam.
162 [0265]
Step 2. Compound 4e-2 - To a solution of 4e-l (2.0 g, 4.0 mmol) in anhydrous THF (30 mL) was added NaH (384 mg, 16 mmol) at 0°C. The mixture was stirred at 0°C for 30minutes before CH3I (1.2 g, 8 mmol) was added. Stirring was continued for 4 h at 0°C. The mixture was diluted with EA (100 mL), washed with saturated NaHCO3 and brine. The organic layer was dried with Na2SO4 and concentrated to a residue which was purified on a silica gel column (DCM/MeOH = 100/1 to 50/1) to give 4e-2 (556 mg, 26.93%) as a white foam.
[0266] Step 3. Compound 4e-3 - To a stirred solution of 4e-2 (556 mg, 1.08 mmol) in MeOH (10 mL) was added NH4F (232 mg, 6.46 mmol). The mixture was stirred at 80°C for 12 h. The solvent was removed and the residue was purified on a silica gel column (DCM/MeOH = 100/1 to 20/1) to give 4e-3 (220 mg, 74%) as a white solid. 'H NMR (DMSO-d6, 400 MHz) £11.39 (brs, 1H), 8.07 (d, J= 8.0 Hz, 1H), 5.91 (s, 1H), 5.63 (d, J = 8.0 Hz, 1H), 5.21 (t, 7=4.8 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 3.78-3.82 (m, 2H), 3.59-3.71 (m, 2H), 3.36 (3, 3H), 1.08 (s, 3H); ESI-LCMS: m/z = 273.1 [M + H]\ [0267] Step 4. Compound 4e - To a stirred suspension of 4e-3 (170 mg, 0.63 mmol) in anhydrous THF (2mL) were added N-methylimidazole (0.5 mL) followed by 2b (598 mg, 1.875 mmol). The reaction mixture was stirred at 70°C for 1 h. Solvents were evaporated and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give 4e (two isomers, 108 mg, 30.2%) as a white solid. *H NMR (CD3OD, 400 MHz) £7.77, 7.85 (2d, 7= 8.0 Hz, 1H), 7.18-7.36 (m, 5H), 6.09, 6.12 (2s, 1H), 5.54, 5.63 (2d, J= 8.0 Hz, 1H), 4.94-5.01 (m, 1H), 4.49-4.53 (m, 1H), 4.26-4.39 (m, 1H), 4.03-4.13 (m, 2H), 3.77-3.81 (m, 1H), 3.47 (s, 3H), 1.32, 1.36 (2d, J= 7.2 Hz, 3H), 1.18-1.24 (m, 6H); 31P NMR (CD3OD, 162 MHz) £68.2, 67.7; ESI-MS: m/z 558.2 [M+H]+.
Example 38 [0268] The structures of compounds 3a through 3w and 4a through 4f are shown in Table 9.
Table 9.
Compound | Product | 31P NMR (solvent) | MS | |
Γ\_) s ’ YY \ / \ n „ l ? 0 ξ %A-nh m- À H(? %H | 3a | 67.12 67.86 (CDClj) | 564.5 (M-H) | |
M · YS αγΥύυ i H(? T)H | 3b | 67.16 67.71 (CDClj) | 543.2 (M-H’) | |
M n ΎΊ I 0 O-P-O-^\>\.N Y AV AJL 1 HO F | fQ | 3c | 67.05 68.08 (CDClj) | 545.8 (MH4) |
Q s °A \ Il «. n J, qAy | c° | 3d | 67.89 67.96 (DMSO) | 586.2 (MH+) |
Compound | Product | 31P NMR (solvent) | MS |
O s · °γγ γο_^0γο Νχ A Μ | 3e | 66.9 66.9 (CD3OD) | 574.2 (MH+) |
ζΤ . ΟγίίγΟ ο 0-ρ-οΛ^°γ·Ά zV Η- I 1 ΗΟ ΟΗ | 3f | 67.85 67.16 | 570.4 (MH+) |
Ο> <Ύγ° Oj.zIAz'kJ i Ht? OH | 3g | 67.80 67.16 | 582.5 (MH+) |
M? ΎΥ A? i HO Î)H | 3h | 67.92 67.28 | 592.2 (MH+) |
f?? -:- Οχ±°Ύ’7 A Ht? OH | 3i | 67.74 67.43 | 632.5 (MH+) |
Compound | Product | 31pnmr (solvent) | MS |
°γ'γ° ο ο-ρ-ο-Άγ^γΥ >^ογΝΗ Η- I 1 ΗΟ ΟΗ | 3j | 68.01 67.35 | 620.8 (MH+) |
V/ = OJ> ΟγΝγθ m γ ' ο τ < > i ΗΟ ΟΗ | 31 | 68.42 68.21 | 546.1 (MH4) |
νγ ΟγΝγΟ ΑλΛ r i HO ΟΗ | 3m | 69.17 68.68 | 558.1 (MH4) |
-A ο 7 1 ο ο-ρ-ο'^ΧΑΑ^ν^*' ^o^rNH ΜΙ ΗΟ ΐ)Η | 3π | 70.38 69.13 | 572 (MH4) |
s Ύ Y 1 ο ο-ρ-ο-'ΧΑΑλΝ^^ Α0ΛγΗ νΥ- 1 Ht? ΟΗ Y | 3ο | 69.15 68.56 | 586 (MH4) |
Compound | Product | 31P NMR (solvent) | MS |
Q s N NH* x-oA-nh H* A i HO OH | 3p | 68.27 67.85 | 611.3 (MH+) |
0 Q · <'ÏA θ':-ξ-οΛ/-/ N NH* H- | * HO F | 3q | 68.09 68.03 | 613.7 (MH+) |
Q > <A χτχΎ£ 1 HO OH | 3r | 68.23 67.64 | 583.4 (MH4) |
O Q. <ώ αχΓΛΎ i HO OH | 3s | 68.07 67.71 | 623.1 (MH+) |
OCH3 Q. <Ά Λχ+”ΧΖ ‘ i HO F | 3t | 68.21 67.82 | 599.4 (MH+) |
168
Compound | Product | 31P NMR (solvent) | MS |
' Q ί Ύ Λχτ-ζγ A HO OH | 3z | 68.53 68.38 | 622.2 (MH+) |
nh2 Q Yi NH’ 1 HO OH | 3aa | 68.19 67.90 | 589.1 (MH) |
NH Q. <nyS 1 HC? OH | 3bb | 68.51 68.40 | 622.1 (MH+) |
Cl Q, <Ύ 1 \\Χο-Λ/°Χ N NH’ Yy*1 H- HO OH | 3cc | 68.66 68.53 | 601.1 (MH+) |
nh2 q - χΑ· YY X 1 4 HO OH | 3dd | 68.15 67.74 | 595.0 (MH+) |
169
Compound | Product | 31P NMR (solvent) | MS |
--- ΝΗ2 //A /i 1 Λ-Ϊ-ο-ΧΖ./'Ά1 Λ\· X i HO OH | 3ee | 68.49 67.46 | 617.1 (MH+) |
3 0 AX AV n,vCΓ | 3ff | 67.78 66.86 | 569.4 (M-1)' |
O-o a CV° ? X/Wv X vu | 3gg | 68.11 67.06 | 597.5 (M-1)’ |
Qw ο NH Ai VN \\ / HO OH r— OZ ' A | 3hh | 68.40 67.43 | 595.1 (MH4) |
b = vb o-p-oV_Y Vf Hd ' | 3ii | 69.30 69.09 | 562.2 (MH4) |
Cl H 0 b. ub o-p-oXV Hd bH | 3jj | 68.92 68.58 | 578.0 (MH4) |
170
Compound | Product | 31P NMR (solvent) | MS |
ο > Cl O~P~cXA A - | 3kk | 68.45 68.16 | 578.1 (MH+) |
F\ P H 0 £=Y ^γΝΗ HÔ' 't>H | 311 | 69.69 69.28 | 618.0 (M+Na)+ |
H A Af Hô' bH | 3mm | 68.60 68.42 | 558.0 (MH*) |
p 5 A z n 0A0 A XoKH Hd' ’bH | 3un | 68.25 67.79 | 558.2 (MH+) |
'°A oA° λοΑ Ηό bH | 3oo | 69.25 69.12 | 574.0 (MH+) |
_ n γ° N -O 1 AA γγΝΗ Hd bH | 3pp | 69.52 68.53 | 595.0 (MH+) |
Compound | Product | 3IP NMR (solvent) | MS |
Q s fiA o-p-oAJ. ΛΑΓ Hb b | 3qq | 70.03 69.56 | 545.1 (MH4) |
Q s °ï/ ΥοΚβχ bH | 3rr | 68.87 68.76 | 626.2 (M+Na)+ |
Q = A?° /«A \ qAH H<î bH | 3ss | 70.83 69.38 | 530.0 (MH4) |
q s oÿJ° aa | 3tt | 69.12 68.45 | 558.0 (MH+) |
Q 5 AJ” γθΑ Hô bH | 3uu | 69.14 68.46 | 572.0 (MH4) |
Q. A A-p-o^cx \ Λα ho oh A0 V | 3vv | 68.74 66.82 | 620.0 (MH4) |
Compound | Product | 3IP NMR (solvent) | MS |
Ο , ”γγ“ λΑΎα I /θ' A 7 X | 4a | 67.71 67.74 (CDC13) | 654.5 (M-H*) |
Q T AÀAr i Ο OH i | 4b | 67.72 67.54 | 598.3 (MH+) |
J s γγ° * °=À2j° | 4c | 68.44 68.42 | 682.4 (MH+) |
r=\ /° V# s DD (f^NH mX5 T 0 OH 7° | 4d | 68.90 68.23 | 585.9 (MH+) |
Compound | Product | 31P NMR (solvent) | MS |
/ , ΟγΒγΟ A%YY i HO och3 | 4e | 68.2 67.7 | 558.2 (MH+) |
O S o Y0 YaüY 0V,NH ΰ OH 0 £ Y | 4f | 68.93 67.96 | 612.4 (MH+) |
©
174
Example 39
General Synthesis of nucleoside 5’-0-(l-thiotriphosphates)
Tris(tetrabutylammonium) hydrogen pyrophosphate
T
HO R [0269] 1,2,4-Triazole (42 mg, 0.6 mmol) was suspended 1 mL of dry CH3CN.
Triethylamine was added (0.088 mL, 0.63 mmol), and the mixture was vortexed to obtain a clear solution. After addition of PSC13 (0.01 mL, 0.1 mmol), the mixture was vortexed and left for 20minutes. The mixture was then centrifligated. The supematant was added to the nucleoside (0.05 mmol), and the mixture was kept at ambient température for 1 hour. Tris(tetrabutylammonium) hydrogen pyrophosphate (180 mg, 0.2 mmol) was added. The 10 mixture was then kept for 2 hours at RT. The reaction was cooled in an îce-water bath and quenched with water. The 5’-triphosphate, as mixture of diastereomers, was isolated by IE chromatography on an AKTA Explorer using column HiLoad 16/10 with Q Sepharose High Performance. The séparation was done using a linear gradient of NaCl from 0 ΐο IN in
50mM TRIS-buffer (pH7.5). The fractions containing the nucléotide α-thio triphosphate were combined, concentrated and desalted by RP HPLC on the same column as in Example 3. A linear gradient of méthanol from 0 to 30% in 50mM triethylammonium buffer was used for elution over 20minutes, flow lOmL/min. Two separate compounds corresponding to individual diastereomers at the phosphorus chiral center were collected. Analytical'RP HPLS was done in 50 mM triethylammonium acetate buffer, pH 7.5, containing linear gradient of acetonitrile from 0% to 25% in 7minutes on a Synergy 4 micron Hydro-RP column (Phenominex). Rétention time (R.T.) for the individual diastereomers is provided in Table 10.
Ο
175
Table 10. a-Thiotriphosphates
Structure | 31p NMR Pa | 31p NMR Ρβ | 31p NMR Ργ | MS | R.T. min | |
0 O Q S /N H il n il \ 7 1 1 νον ° OH OH OH Y Y Ht/\)H | 5b | 43,17 d | -21.69 m | -5.32 d | 513.0 | 4.17 |
JL JL JL Y HO P O P O P 0 Ν-Υθ OH OH OH Y Ί Ht/ \>H | 5a | 42.89 d | -21.75 q | -5.28 d | 513.0 | 4.50 |
O Q S Λ)ΝΗ Il ï II \ l ho—P—0—P—o—P—0—\ n N'A, Ah Ah Ah ° - d \ | 5c | 43.14 d | -23.80 m | -10.20 bs | 515.0 | 4.90 |
0 Çj) S ^^/ΝΗ HO—P—ο—P—o—P—0—* n oh Ah Ah Y/- ° Ht/ \ | 5d | 42.12 d | -23.48 q | -6.49 d | 515.0 | 5.52 |
Structure | 31p NMR Pa | 31p NMR Ρβ | 31p NMR Ργ | MS | R.T. min | |
0 <Xa „4 OH OH OH / \ HÔ > | 5e | 43.42 d | -21.93 q | -5.47 d | .554.3 | 5.39 |
0 Aa * ï î zW N NH2 HO—P—0—P—O—P—O \ / OH OH OH i \ HO F | 5f | 43.07 d | -21.90 q | -5.40 d | 554.2 | 5.79 |
0 Ar ? ? § HO-Fj^-O-lj'-O-p-O A / OH OH OH )---(--- HO OH | 5g | 43.41 d | -23.26 m | -10.10 bs | 552.2 | 5.23 |
O HO-P-O-P-O-P-O ξ J OH OH OH j--A HO OH | 5h | 43.12d | -24.20 m | -11.05 d | 552.2 | 5.82 |
R..T. = rétention time [0270] Τη Table 10, 5a and 5b are diastereomers, and distinguishable by the chirality of the alpha-thiophosphate. Lîkewise, 5b and 5c; 5d and 5e; and 5f and 5h, 5 respectively, are diastereomers and distinguishable by the chirality of the alphathiophosphate.
Example 40 HCV Replicon Assay
Cells
10271] Huh-7 cells containing the self-replicating, subgenomic HCV replicon with a stable luciferase (LUC) reporter were eultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 2mM L-glutamine and supplemented with 10% heatinactîvated fêtai bovine sérum (FBS), 1% penicillin-streptomyocin, 1% nonessential amino acids, and 0.5mg/niL G418.
Détermination of anti-HCV activity [0272] Détermination of 50% inhibitory concentration (EC$o) of compounds în
HCV replicon cells were performed by the following procedure. On the first day, 5,000 HCV replicon cells were plated per well in a 96-well plate. On the following day, test compounds were solubilîzed in 100% DMSO to lOOx the desired final testîng concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. Compounds in 15 100% DMSO are reduced to 10% DMSO by dilutîng 1:10 in cell culture media. The compounds were diluted to 10% DMSO with cell culture media, which were used to dose the HCV replicon cells in 96-well format. The final DMSO concentration was 1%. The HCV replicon cells were încubated at 37°C for 72 hours. At 72 hours, cells were processed when the cells are still subconfluent. Compounds that reduce the LUC signal are determined by 20 Bright-Glo Luciferase Assay (Promega, Madison, WI). Percent Inhibition was determined for each compound concentration in relation to the control cells (untreated HCV replicon) to calculate the EC50.
[0273] Compounds of Formula (I) are active in the replicon assay. The antiviral activity of exemplary compounds is shown in Table 11, where ‘A’ indicates an EC50 < 1 μΜ, 25 ‘B’ indicates an EC50 < 10 μΜ, and ‘C’ indicates an EC50 < 100 μΜ.
178
Table 11
Compound | ECSO | Compound | ECSo |
yY ¥nh HÔ ÔH | A | s ,(ΥγΟ . qO-P-O-A/YN^ AVh m- 1 HO F | B |
Υ·! Λ Y-Y ° HO ÔH | A | O s °YY αχογ i HO ’F | A |
O, Yy° J o-p-yY yvVH W- 1 1 H(f F | A | «j °yVo /fX X 1 i HO OH | A |
| yr T h/ L· | A | νγ; γγ ΛγΥ i HO Y | A |
QXXr T h/ A | A | <(γ¥?> °ύ -y o o-p-oY/yY >^XNH H* | I HO OH | A |
179
181
1 Compound | EC50 | Compound | EC50 |
, nh2 Q? <15 AA “ i HO OH | A | O-v o. cy° y ^ρ^·οζ*ΧχΛΥ>*ΝνΝΗ ΛΑ Nî Μ Γ [ HO OH | c |
CX-9 Ά° | C | F\ Ho Q. ;-p-o^x λθΧΗ HCl bH | A |
H ,0 h = i ü N H HO 0H | A | Q, Ci o-p-o^VX λοΚΗ Ηΰ 'bH | A |
\ P H n f. DJ χ-'χχ λ<Α Hd bH | A | h s o-p-o^XX λοΗΗ Ηΰ bH | A |
p. .X ΛΧ_0Χχ >„X » | A | 0, Xï ο-ρ-ο-χ_χ χΚΗ Ηό δΗ | A |
Compound | ec50 | Compound | EC50 |
H .0 Hj A | A | Q s zY° . Α-ο-χχ AA Hd' 'bH | A |
Q s Z-zAZ ^oR£sHd | B | Q - CX X«~qî ^oANH Hô' OH | B |
Q 5 A o-mT^. aA Hd bH | A | q s ex 0-Ρ-0-Ύ2. ZXt/ bH | A |
Q s cfi° χΥΥΐΗ | B | Q ? < Λ I o o-P-o-1 νΆ νη2 A. JL Jh LoZ ° Fi0”3 OH OH | A |
OMe Q ? < À | 0 0-P—0-1 N^N^NH, xk JI_Zh L-Oj 0 T ]—| CH® OH OH | A | OMe Q ? <n o 0—P—0—i N'^'N^'NHz Ζγ“ A OH F | A |
183
Compound | ECjq |
1 HO Uh | C |
V/ J Ογ“γΟ 1 O OH Ί | A |
S D D T d OH A | A |
Compound | ECSO |
O s °γγ ΑλΧΆα + | A |
νγ s Ύγθ αΛ^Ύα i <? \ A | A |
°W NH < ”bH 0 y -C | A |
Example 41 NS5B Inhibition Assay [0274] The enzyme activity of NS5B570-Conl (Delta-21) was measured as an incorporation of tritiated NMP into acid-insoluble RNA products. The complementary IRES (cIRES) RNA sequence was used as a template, corresponding to 377 nucléotides from the 3'-end of HCV (-) strand RNA of the Con-1 strain, with a base content of 21% Ade, 23% Ura, 28% Cyt, and 28% Gua. The cIRES RNA was transcribed in vitro using a T7 transcription kit (Ambion, Inc.) and purified using the Qiagen RNeasy maxi kit. HCV polymerase reactions contained 50 nM NS5B570-Conl, 50 nM cIRES RNA, about 0.5 pCi tritiated NTP, 1 μΜ of competing cold NTP, 20 mM NaCl, 40 mM Tris-HCl (pH 8.0), 4 mM dithiothreitol, and 4 mM MgCl2. Standard reactions were incubated for 2 hours at 37°C, in the presence of increasing concentration of inhibitor. At the end of the reaction, RNA was
precipitated with 10% TCA, and acid-insoluble RNA products were filtered on a size exclusion 96-weIl plate. After washing of the plate, scintillation liquid was added and radio labeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The compound concentration at which the enzyme-catalyzed 5 rate was reduced by 50% (IC5o) was cafculated by fitting the data to a non-lmear régression (sigmoidal). The IC50 values were derived from the mean of several independent experiments and are shown in Table 12. Compounds of Formula (I) showed activity in this assay. A value of ‘A’ in the table below indicates an IC50 of < l μΜ, a value of ‘B’ indicates an IC50 < ΙΟ μΜ, and a value of‘C’ indicates an ICjq value of < IOO μΜ.
Table 12
Structure | IC5O value | |
5a | rY 0 O S \ ZNH ho-p-o-p-o-P'O'^\/oxZ n^/ OH OH OH \ / £ / V HO OH | C |
5b | f-ï OOS \ ZNH ho-Po-Yo-p--o-^\/Ox/nY OH OH OH \ 7 £ / \ •e + HO OH | A |
5c | Y 0 O S \ /NH ho-(J4-°4“o''A/3v'n''Y OH OH OH \ / HO F | B |
5d | (N O O S \ /NH ho-p-o-p-o¥--o'^\/Ox>n^/ OH OH OH \ / 0 / X HO F | C |
5e | /=N 9 i? ? /Υ°'Ρ:·'¥/0 HO-P-O-P-O-P-O \ y | h/ 1 nh2 | A |
5f | /=N ? 9 § /YVN\À/ HO-P-O-P-O-P-O Y y OH OH OH λ NH î - J/ HO F Ύ NH2 | A |
5g | /==N 9 9 9 HO-P-O-P-O~P-O \ Y i OH OH OH ; i 'NH ΐ z. J/ HO OH | ΝΗξ | A |
5h | j--N 9 9 9 ΥΥ''\Λ/ HO-P-O-P-O-P-O \ Μ Ύ \ OH OH OH -- -- N\/NH HO OH J NHZ | B |
186
Example 42
Hépatocyte Activation Assay [0275] Plated human hépatocytes were purchased from CelIzDirect. 30 gL of test article (compound 3a) in DMSO at 5mM was dosed to the incubation medium (3 mL) of each well containing —1.5 million,human hépatocytes to reach a final concentration of 50 uM. After 6 hours of incubation at 37°C, the medium was removed and the cells were washed twice with 500 gL cold 0.9% NaCl in H2O. An aliquot of 500 gL cold methanol/H2O (70/30) was added to the well to lyse the hépatocytes. The cells were scraped off the well, and the entire content was removed to an Eppendorf tube. After more than 3 hours of storing at -20°C, the lysate was warmed to RT, vortexed, and centrifuged. The supematant was evaporated in a Speed-Vac, and the sample was reconstituted with 500 gL 1 mM ammonium phosphate in H2O. 20 gL was injected into the LC/MS/MS system for the spécifie détection of the a-thiotriphosphate of the test article (see Figure 1, panel D). A Thermo HyPurity Cl8 column (50x2.1 mm, 3u particle size) was used to achieve HPLC séparation. Mobile phase A consisted of 3 mM ammonium formate and 10 mM dimethyl-hexylamine in H2O and mobile phase B consisted of 3 mM ammonium formate and 10 mM dimethyl-hexylamine in acetonitrile/H2O (50/50). The HPLC elution was via a Iinear gradient on increased mobile phase B at a flow rate of 0.22 mL/min. Compounds 5a and 5b were detected by a Sciex API 3200 via a négative ion MRM mode.
[0276] In Figure 1, Panels A, B, C and D show the following. Panel A. HPLC chromatogram of a synthetic sample of the a-thiotriphosphate, 5a, at 300 nM in 1 mM ammonium phosphate in H2O. Panel B. HPLC chromatogram of a synthetic sample the athiotriphosphate, 5b, at 300 nM in 1 mM ammonium phosphate in H2O. Panel C. HPLC chromatogram of a purposely prepared 1:1 mixture of a synthetic sample of the athiotriphosphate diastereomers 5a and 5b, each at 150 nM in 1 mM ammonium phosphate in H2O. This shows that compounds 5 a and 5b can be distînguished. Panel D. HPLC chromatogram of the a-thiotriphosphate diastereomer formed following incubation of compound 3a in human hépatocytes. As illustrated by Panel D, only compound 5b is formed.
187
Example 43
Combination of Compounds
Combination Testing [0277] Two or more test compounds were tested in combination with each other using an HCV génotype lb HCV replicon harbored in Huh7 cells with a stable luciferase (LUC) reporter. Cells were cultured under standard conditions in Dulbecco’s modified Eagle’s medium (DMEM; Mediatech Inc, Hemdon, VA) containing 10% heat-inactivated fêtai bovine sérum (FBS; Mediatech Inc, Hemdon, VA) 2mM L-glutamine, and nonessential amino acids (JRH Biosciences). HCV replicon cells were plated in a 96-well plate at a density of 104 cells per well in DMEM with 10% FBS. On the following day, the culture medium was replaced with DMEM containing either no compound as a control, the test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO, or a combination of compound 3b with one or more test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO. The cells were incubated with no compound as a control, with the test compounds, or the combination of compounds for 72 h. The direct effects of the combination of the test compounds were examined using a luciferase (LUC) based reporter as determined by the Bright-Glo Luciferase Assay (Promega, Madison, WI). Dose-response curves were determined for individual compounds and fixed ratio combinations of two or more test compounds.
[0278] The effects of test compound combinations were evaluated by two separate methods. In the Loewe additivity model, the experimental replicon data was analyzed by using CalcuSyn (Biosoft, Ferguson, MO), a computer program based on the method of Chou and Talalay. The program uses the experimental data to calculate a combination index (CI) value for each experimental combination tested. A CI value of <1 indicates a synergîstic effect, a CI value of 1 indicates an additive effect, and a CI value of >1 indicates an antagonistic effect.
[0279] The second method utilized for evaluatîng combination effects used a program called MacSynergy II. MacSynergylI software was kindly provided by Dr. M. Prichard (University of Michigan). The Prichard Model allows for a three-dimensional examination of drug interactions and a calculation of the synergy volume (units: μΜ %) generated from running the replicon assay using a checkerboard combination of two or more
inhibitors. The volumes of synergy (positive volumes) or antagonism (négative volumes) represent the relative quantity of synergism or antagonism per change in the concentrations of the two drugs. Synergy and antagonism volumes are defined based on the Blîss independence model. In this model, synergy volumes of less than -25 indicate antagoniste 5 interactions, volumes in the -25 - 25 range indicate additîve behavior, volumes in the 25 100 range indicate synergistic behavior and volumes >100 indicate strong synergistic behavior. Détermination of in vitro additîve, synergistic and strongly synergistic behavior for combinations of compounds can be of utility in predicting therapeutic benefits for administering the combinations of compounds în vivo to infected patients.
[0280] The CI and synergy volume results for the combinations are provided în
Table 13.
189
Table 13
Combination Compound | CI at EC5q | Synergy Volume (μΜζ%) |
INX-I89 | 0.42 | 65 |
PSI-938 ' | 0.73 | 27 |
PSI-6130 | 0.78 | 15 |
PSI-7851 | U | 0 |
GS-9190 | 0.92 | 79 |
Filibuvir | 0.85 | 23 |
ANA-598 | 0.02 | 161 |
7008 | 0.01 | 127 |
VX-222 | 0.67 | 38 |
VX-950 | 0.06 | 76 |
ΓΓΜΝ-191 | 0.28 | 126 |
TMC-435 | 0.5 | 126 |
BMS-790052 | 0.64 | 26 |
Ribavirin | 1 | 22 |
Pegylated Interferon | 0.33 | 117 |
Consensus Interferon | 1 | 31 |
Cyclosporin A | 0.07 | 60 |
B1LN-2061 | 0.7 | 31 |
HCV-796 | 0.42 | 31 |
IFN-Lambda 1 | 0.35 | 116 |
IFN-Lambda 2 | 0.49 | 34 |
IFN-Lambda 3 | 0.63 | 35 |
[0281] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the présent disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the présent disclosure, but rather to also cover ail modification and alternatives
190
A compound of Formula (I) or a pharmaceutically acceptable sait thereof:
R3a
Claims (27)
- WHAT IS CLAIMED IS:wherein:B1 îs an optionally (I) substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;R1 is selected from the group consisting of O’, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative;R2 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;R3a and R3b are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C] 4 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2.6 alkynyl, an optionally substituted Ci.6 haloalkyl and aryl(C|.6 alkyl); or R3a and R3b are taken together to form an optionally substituted CA/, cycloalkyl;R4 is selected from the group consisting of hydrogen, azido, an optionally substituted C|.6 alkyl, an optionally substituted C2.6 alkenyl and an optionally substituted C2.6 alkynyl;R5 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted alkyl, -OR10 and -OC(=O)Rll;R6 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted alkyl, -OR12 and -OC(=O)R13;R7 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted C|.6 alkyl, -OR14 and -0C(=O)R15;or R6 and R7 are both oxygen atoms and linked together by a carbonyl group;R8 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted alkyl, -OR16 and -OC(=0)R17;191R9 is selected from the group consisting of hydrogen, azido, cyano, an optionally substituted Ci_6 alkyl and -OR18;R10, R12, R14, R16 and R18 are independently selected from the group consisting of hydrogen and an optionally substituted Ci.6 alkyl; andR11, R13, R15 and R17 are independently an optionally substituted C].6 alkyl or an optionally substituted C3.6 cycloalkyl;with the proviso that when R3a, R3b, R4, R5, R7, R8 and R9 are ail hydrogen, then R6 is not azido.
- 2. A compound of Formula (I), or a thio-monophosphate thereof, or a pharmaceutically acceptable sait of the foregoing:R4—R5 wherein:B1 is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R1 is O or OH;R2 is .21 n, wherein R19, R20 and R21 are independently absent or hydrogen, and n is 0 or 1;R3a and R3b are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted Cj.6 alkyl, an optionally substituted C?^ alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted CA haloalkyl and aryl(C].6alkyl); or R3a and R3b are taken together to form an optionally substituted C3-6 cycloalkyl;R4 îs selected from the group consisting of hydrogen, azido, an optionally substituted C].6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C?^, alkynyl;R5 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted Ci.6 alkyl, -OR10 and -OC(=O)R11;192R6 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -OR 2 and -OC(=O)R13;R7 is selected from the group consisting of hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -OR14 and -OC(=O)R15;or R6 and R7 are both oxygen atoms and linked together by a carbonyl group;R8 is selected from the group consisting of halogen, azido, cyano, an optionally substituted Ci.6 alkyl, -OR16 and -OC(=O)R17;R9 is selected from the group consisting of hydrogen, azido, cyano, an optionally substituted Cm alkyl and -OR18;R10, R12, R14, R16 and R18 are independently selected from the group consisting of hydrogen and an optionally substituted Cmalkyl; andR11, R13, R15 and R17 are independently an optionally substituted Cm alkyl or an optionally substituted C3-6 cycloalkyl;with the proviso that when R3a, R3b, R4, R5, R7 and R9 are ail hydrogen, then R6 îs not azido.
- 3. The compound of any one of Claims 1 to 2, wherein R8 is an optionally substituted Cm alkyl.p
- 4. The compound of Claim 3, wherein R is methyl.
- 5. The compound of any one of Claims 1 to 2, wherein R8 is halogen.
- 6. The compound of Claim 1, wherein R is hydrogen.
- 7. The compound of any one of Claims 1 or 3 to 6, wherein R is an optionally substituted aryl.
- 8. The compound of Claim 7, wherein the optionally substituted aryl is an optionally substituted phenyl.
- 9. The compound of Claim 7, wherein the optionally substituted aryl îs an optionally substituted naphthyl.
- 10. The compound of any one of Claims 1 or 3 to 6, wherein R is an optionally substituted heteroaryl.
- 11. The compound of any one of Claims 2 to 5, wherein n is 1.
- 12. The compound of any one of Claims 2 to 5, wherein n is 0.
- 13. The compound of any one of Claims 1 or 3 to 10, wherein R1 is an optionally substituted N-linked α-amino acid.193
- 14. The compound of any one of Claims 1 or 3 to 10, wherein R1 is an optionally substituted N-linked a-amino acid ester denvative.
- 15. The compound of any one of Claims 1 or 3 to 10, wherein R1 is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan, valine and ester dérivatives thereof.
- 16. The compound of Claim 15, wherein R1 is selected from the group consisting of alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester, and leucine isopropyl ester.
- 17. The compound of Claim 16, wherein R1 is alanine isopropyl ester.
- 18. The compound of any one of Claims 1 or 3 to 10, wherein R1 has the structure wherein R22 is selected from the group consisting of hydrogen, an optionally substituted Cj.6-alkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci-6 alkyl) and an optionally substituted haloalkyl; R23 is selected from the group consisting of hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted Ci_6 haloalkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C6 aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Cj_6 alkyl); and R24 is hydrogen or an optionally substituted Ci-4-alkyl; or R23 and R24 are taken together to form an optionally substituted C3.6 cycloalkyl.
- 19. The compound of Claim 18, wherein R23 is an optionally substituted Cj.6-alkyl.
- 20, The compound of Claim 19, wherein the optionally substituted Ci_6 alkyl is methyl.
- 21. The compound of any one of Claims 19 to 20, wherein the optionally substituted C|.()-alkyl is substituted with one or more substituents selected from the group consisting of N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, C-carboxy, and amino,
- 22. The compound of any one of Claims 18 to 21, wherein R24 is hydrogen.194
- 23. The compound of any one of Claims 18 to 22, wherein R is an optionally substituted C|.6 alkyl.
- 24. The compound of any one of Claims 18 to 22, wherein R is an optionally substituted C3.6 cycloalkyl.
- 25. The compound of any one of Claims
- 27. The compound of any one of Claims l to 26, wherein at least one of R3a and R3b is an optionally substituted C].6-alkyl; and the other of R3a and R3b îs hydrogen.
- 28.I5 29.30.31.32.The compound of any one of Claims l to 27, wherein R4 is hydrogen. The compound of any one of Claims l to 28, wherein R5 îs hydrogen. The compound of any one of Claims 1 to 29, wherein R is -OR .The compound of Claim 30, wherein R is hydrogen.The compound of Claim 30, wherein R12 is an optionally substitutedCi-6 alkyl.19533.The compound of any one of Claims 1 to 29, wherein R6 is OC(=O)R .34. The compound of any one of Claims 1 to 33, wherein R7 is -OR14.35. The compound of Claim 34, wherein R14 is hydrogen.36. The compound of Claim 34, wherein R14 is an optionally substituted Ci.6 alkyl.n37. The compound of any one of Claims 1 to 33, wherein R is OC(=O)R15.38. The compound of any one of Claims 1 to 33, wherein R is halogen.39. The compound of any one of Claims 1 to 29, wherein R6 and R7 are both oxygen atoms and linked together by a carbonyl group.40. The compound of any one of Claims 1 to 39, wherein R9 is hydrogen.41. The compound of any one of Claims 1 to 40, wherein B1 is selected from the group consisting of:wherein:R'42 is selected from the group consisting of hydrogen, halogen and NHRJ2, wherein RJ2 is selected from the group consisting of hydrogen, C( =O)RK? and -C(=O)ORU;Rb2 is halogen or NHRW2, wherein Rw2 is selected from the group consisting of hydrogen, an optionally substituted Ci.& alkyl, an optionally substituted C2.é alkenyl, an optionally substituted C3-8 cycloalkyl, -C(=O)RM2 and -C(=O)ORN2;196C2 * 02 * 02R is hydrogen or N HR , wherein R is selected from the group consisting of hydrogen, -C(=O)RP2 and -C(=O)ORQ2;D2R is selected from the group consisting of hydrogen, halogen, an optionally substituted CV alkyl, an optionally substituted C2_6 alkenyl and an optionally substituted C2.6 alkynyl;E2R is selected from the group consisting of hydrogen, an optionally R2 substituted Ci_6 alkyl, an optionally substituted C3.g cycloalkyl, -C(=O)R and -C(=O)ORS2;F2R is selected from the group consisting of hydrogen, halogen, an optionally substituted Ct.6 alkyl, an optionally substituted C2.6 alkenyl and an optionally substituted C2-6alkynyl;Y2 is N or CR12, wherein R12 is selected from the group consisting of hydrogen, halogen, an optionally substituted C].6-alkyl, an optionally substituted C2^-alkenyl and an optionally substituted C2.6-alkynyl;RG2 is an optionally substituted Ci_6 alkyl;R is hydrogen or NHR , wherein R is independently selected from the group consisting of hydrogen, -C(=O)RU2 and -C(=O)ORV2, and selected from the group consisting of C]_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, C3.6 cycloalkyl, C3.6 cycloalkenyl, C3.6 cycloalkynyl, C6.io aryl, heteroaryl, heteroalicyclyl, aryl(C|_6 alkyl), heteroaryl(C]_6 alkyl) and heteroalicyclyl(Ci_f, alkyl).O y N NH242. The compound of Claim 41, wherein B1 is orORG2N RH219743. The compound of Claim 41, wherein B1 is44. The compound of Claim 41, wherein B1 is Ά45. The compound of Claim 41, wherein B1 is -λΧ46. The compound of Claim 1 or 2, wherein:5 B1 is -λΑ ;R1 is selected from the group consisting of O, OH, and an N-linked amino acid selected from a methyl ester, an ethyl ester, a isopropyl ester, a benzyl ester and a tert-butyl ester of an amino acid selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, hîstidine, isoleucine,10 leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and valine;R is selected from the group consisting of an optionally substituted aryl; or R is r21o—p—o—IOR20 i îp-rjR1®J*1, wherein R19, R1 Ο 'ΪΛ 1R and R are independently absent or hydrogen, and n is 0 or 1 ;R3a, R3b, R4, R5, R9 10 * are each hydrogen;R6 îs -OH or -OC(-- O)R'3:R7 * is -OH or -OC(=O)R15;198R8 is an unsubstituted Cj.6 alkyl; andR13 and R15 are each independently an unsubstituted C 1.6 alkyl.47. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:199200201 .0.2022035 ϊ ο \ ,s204 foregoing.48. The compound of Claim 1, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.The compound of Claim 1, wherein the compound of Formula (I) isHO , or a pharmaceutically acceptable sait thereof.20550. The compound of Claim 49, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.51. The compound of Claim 49, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.5 52. The compound of Claim l, wherein the compound of Formula (I) isHÔ OH , or a pharmaceutically acceptable sait thereof.53. The compound of Claim 52, wherein the compound of Formula (I) isHÔ OH , or a pharmaceutically acceptable sait thereof.54. The compound of Claim 52, wherein the compound of Formula (I) îs , or a pharmaceutically acceptable sait thereof.20655. The cornpound of Claim l, wherein the cornpound of Formula (I) is or a pharmaceutically acceptable sait56. The cornpound of Claim 2, wherein the cornpound of Formula (I) is5 selected from the group consisting of:57. The cornpound of Claim 56, wherein the cornpound of Formula (I) is:20758. The compound of Claim 56, wherein the compound of Formula (I) is:59. The compound of Claim 56, wherein the compound of Formula (I) is:60. The compound of Claim 56, wherein the compound of Formula (I) is:61. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of Claims l to 60, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.62. Use of a compound of any one of Claims l to 60, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 61 for preparing a médicament for ameliorating or treating an HCV infection.63. Use of a compound of any one of Claims l to 60, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 61 for preparing a médicament for inhibiting NS5B polymerase activity of hepatitis C virus.64. Use of a compound of any one of Claims l to 60, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 61 for preparing a médicament for inhibiting réplication of a hepatitis C virus.20865. Use of a compound of any one of Claims l to 60, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 61 for preparing a médicament for contacting a cell infected with a hepatitis C virus, whereby ameliorating or treating the hepatitis C viral infection.66. Use of a compound of any one of Claims 1 to 60, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 61 in the préparation of a médicament for ameliorating or treating a viral infection, wherein the médicament is manufactured for use in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB) and a compound of Formula (DD), or a pharmaceutically acceptable sait any of the aforementioned compounds.67. Use of a compound of any one of Claims 1 to 60, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 61 in the préparation of a médicament for contacting a cell infected with a viral infection, wherein the médicament îs manufactured for use in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antîviral compound, a compound of Formula (BB) and a compound of Formula (DD), or a pharmaceutically acceptable sait any of the aforementioned compounds.68. The use of Claim 66 or 67, wherein the one or more agents are selected from the group consisting of Compounds 1001-1014, 2001-2010, 3001-3008, 40014005, 5001-5002, 8000-8012 and 9000, or a pharmaceutically acceptable sait of any of the aforementioned compounds.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US61/385,363 | 2010-09-22 | ||
US61/426,461 | 2010-12-22 |
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OA16349A true OA16349A (en) | 2015-05-11 |
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