OA17338A - Substituted nucleosides, nucleotides and analogs thereof. - Google Patents
Substituted nucleosides, nucleotides and analogs thereof. Download PDFInfo
- Publication number
- OA17338A OA17338A OA1201500242 OA17338A OA 17338 A OA17338 A OA 17338A OA 1201500242 OA1201500242 OA 1201500242 OA 17338 A OA17338 A OA 17338A
- Authority
- OA
- OAPI
- Prior art keywords
- compound
- optionally substituted
- alkyl
- group
- hydrogen
- Prior art date
Links
- 125000003729 nucleotide group Chemical group 0.000 title abstract 4
- 239000002777 nucleoside Substances 0.000 title description 21
- 239000002773 nucleotide Substances 0.000 title description 2
- 125000003835 nucleoside group Chemical group 0.000 title 1
- 201000009910 diseases by infectious agent Diseases 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 747
- 239000000203 mixture Substances 0.000 claims description 474
- 125000000217 alkyl group Chemical group 0.000 claims description 258
- -1 amino acid ester Chemical class 0.000 claims description 208
- 229910052739 hydrogen Inorganic materials 0.000 claims description 141
- 239000001257 hydrogen Substances 0.000 claims description 141
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 88
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 85
- 125000003118 aryl group Chemical group 0.000 claims description 74
- 239000008194 pharmaceutical composition Substances 0.000 claims description 71
- 235000001014 amino acid Nutrition 0.000 claims description 69
- 125000000623 heterocyclic group Chemical group 0.000 claims description 65
- 125000001072 heteroaryl group Chemical group 0.000 claims description 64
- 125000003107 substituted aryl group Chemical group 0.000 claims description 61
- 239000003795 chemical substances by application Substances 0.000 claims description 55
- 230000002401 inhibitory effect Effects 0.000 claims description 52
- 125000003342 alkenyl group Chemical group 0.000 claims description 50
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 49
- 150000001413 amino acids Chemical class 0.000 claims description 41
- 125000000304 alkynyl group Chemical group 0.000 claims description 40
- 239000003112 inhibitor Substances 0.000 claims description 38
- 241000711549 Hepacivirus C Species 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical group 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 229960000329 Ribavirin Drugs 0.000 claims description 22
- 230000002730 additional Effects 0.000 claims description 22
- 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 21
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 20
- 108010050904 Interferons Proteins 0.000 claims description 19
- 102000014150 Interferons Human genes 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 19
- 101800001014 Non-structural protein 5A Proteins 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 229940079322 interferon Drugs 0.000 claims description 18
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 16
- 230000000840 anti-viral Effects 0.000 claims description 15
- 229960003767 Alanine Drugs 0.000 claims description 14
- 235000004279 alanine Nutrition 0.000 claims description 14
- SKRDXYBATCVEMS-UHFFFAOYSA-N Isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000004475 Arginine Substances 0.000 claims description 7
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 7
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 7
- 239000004472 Lysine Substances 0.000 claims description 7
- 229960003121 arginine Drugs 0.000 claims description 7
- 229960003136 leucine Drugs 0.000 claims description 7
- 229960003646 lysine Drugs 0.000 claims description 7
- 229960001230 Asparagine Drugs 0.000 claims description 6
- 229940009098 Aspartate Drugs 0.000 claims description 6
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 6
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 6
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 6
- 229940049906 Glutamate Drugs 0.000 claims description 6
- 229960002743 Glutamine Drugs 0.000 claims description 6
- 229960002449 Glycine Drugs 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 6
- 229960000310 ISOLEUCINE Drugs 0.000 claims description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 6
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 6
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 6
- 239000004473 Threonine Substances 0.000 claims description 6
- 229960004441 Tyrosine Drugs 0.000 claims description 6
- 235000009582 asparagine Nutrition 0.000 claims description 6
- 229960001153 serine Drugs 0.000 claims description 6
- 239000004474 valine Substances 0.000 claims description 6
- 229960002885 Histidine Drugs 0.000 claims description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 5
- 229960002429 Proline Drugs 0.000 claims description 5
- 229960002433 Cysteine Drugs 0.000 claims description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 4
- 229960005190 Phenylalanine Drugs 0.000 claims description 4
- 235000018417 cysteine Nutrition 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 13
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- IGLFLAMJRDARAK-YUMQZZPRSA-N propan-2-yl (2S,3S)-2-amino-3-methylpentanoate Chemical compound CC[C@H](C)[C@H](N)C(=O)OC(C)C IGLFLAMJRDARAK-YUMQZZPRSA-N 0.000 claims 2
- 201000010099 disease Diseases 0.000 abstract description 14
- 230000002194 synthesizing Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 621
- 239000000243 solution Substances 0.000 description 335
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 240
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 146
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 146
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 144
- 239000007787 solid Substances 0.000 description 139
- 239000000741 silica gel Substances 0.000 description 120
- 229910002027 silica gel Inorganic materials 0.000 description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
- 239000012044 organic layer Substances 0.000 description 99
- 238000006243 chemical reaction Methods 0.000 description 96
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 90
- 239000012267 brine Substances 0.000 description 78
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 56
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 51
- 239000007832 Na2SO4 Substances 0.000 description 45
- 229910052938 sodium sulfate Inorganic materials 0.000 description 45
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 38
- 239000002904 solvent Substances 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000000706 filtrate Substances 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- 239000011780 sodium chloride Substances 0.000 description 31
- 239000002585 base Substances 0.000 description 30
- 239000011734 sodium Substances 0.000 description 29
- 150000003839 salts Chemical class 0.000 description 28
- 230000003612 virological Effects 0.000 description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cells Anatomy 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 21
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 239000006260 foam Substances 0.000 description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 20
- 229910052799 carbon Inorganic materials 0.000 description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 19
- 235000019253 formic acid Nutrition 0.000 description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 19
- 150000003833 nucleoside derivatives Chemical class 0.000 description 19
- 230000002829 reduced Effects 0.000 description 19
- 239000011593 sulfur Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 241000282414 Homo sapiens Species 0.000 description 18
- 230000000670 limiting Effects 0.000 description 18
- 239000001301 oxygen Substances 0.000 description 18
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 18
- 210000004185 Liver Anatomy 0.000 description 17
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 17
- 125000004429 atoms Chemical group 0.000 description 16
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 16
- 238000011068 load Methods 0.000 description 16
- PASDCCFISLVPSO-UHFFFAOYSA-N Benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 15
- 235000015076 Shorea robusta Nutrition 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- 238000002560 therapeutic procedure Methods 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atoms Chemical group C* 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 238000004007 reversed phase HPLC Methods 0.000 description 14
- ITVPBBDAZKBMRP-UHFFFAOYSA-L chloro-dioxido-oxo-$l^{5}-phosphane Chemical compound [O-]P([O-])(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-L 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 125000004093 cyano group Chemical group *C#N 0.000 description 12
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 230000004044 response Effects 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-Methylimidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 11
- 229940021015 I.V. solution additive Amino Acids Drugs 0.000 description 11
- 238000007792 addition Methods 0.000 description 11
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 11
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-Crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 10
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 229940035893 Uracil Drugs 0.000 description 10
- 239000008079 hexane Substances 0.000 description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
- 239000010452 phosphate Substances 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- 241000700605 Viruses Species 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 150000002972 pentoses Chemical class 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrugs Drugs 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 231100000486 side effect Toxicity 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 230000002459 sustained Effects 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 108020005497 Nuclear hormone receptors Proteins 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 230000000875 corresponding Effects 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 229940079593 drugs Drugs 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 101700046422 IFNA Proteins 0.000 description 7
- FTVLMFQEYACZNP-UHFFFAOYSA-N Trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 7
- 238000002648 combination therapy Methods 0.000 description 7
- 235000011180 diphosphates Nutrition 0.000 description 7
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 7
- 239000001226 triphosphate Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N Silver nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- VDZOOKBUILJEDG-UHFFFAOYSA-M Tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 6
- AVBGNFCMKJOFIN-UHFFFAOYSA-N Triethylammonium acetate Chemical compound CC(O)=O.CCN(CC)CC AVBGNFCMKJOFIN-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 6
- ANCLJVISBRWUTR-UHFFFAOYSA-M diaminophosphinate Chemical compound NP(N)([O-])=O ANCLJVISBRWUTR-UHFFFAOYSA-M 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000002905 orthoesters Chemical class 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 238000009097 single-agent therapy Methods 0.000 description 6
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 235000011178 triphosphate Nutrition 0.000 description 6
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 6
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 5
- OBOHMJWDFPBPKD-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 OBOHMJWDFPBPKD-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 108010082126 Alanine Transaminase Proteins 0.000 description 5
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 5
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 5
- 102100010966 GPT Human genes 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 5
- 206010047461 Viral infection Diseases 0.000 description 5
- 208000001756 Virus Disease Diseases 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- 230000017613 viral reproduction Effects 0.000 description 5
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 4
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N Diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 230000036499 Half live Effects 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N Hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N Trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000008351 acetate buffer Substances 0.000 description 4
- MSJFTQLFJNMAIK-UHFFFAOYSA-N bis(propan-2-yloxycarbonyloxymethyl) phosphate;triethylazanium Chemical compound CC[NH+](CC)CC.CC(C)OC(=O)OCOP([O-])(=O)OCOC(=O)OC(C)C MSJFTQLFJNMAIK-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 150000001718 carbodiimides Chemical class 0.000 description 4
- 235000011089 carbon dioxide Nutrition 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 230000003247 decreasing Effects 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 125000005842 heteroatoms Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 229920002111 mitochondrial RNA Polymers 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- UCMIRNVEIXFBKS-UHFFFAOYSA-N β-Alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 4
- 229960000643 Adenine Drugs 0.000 description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Natural products NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-O CC[NH+](CC)CC Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 3
- 244000089742 Citrus aurantifolia Species 0.000 description 3
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 229910004373 HOAc Inorganic materials 0.000 description 3
- 208000005176 Hepatitis C Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 230000036650 Metabolic stability Effects 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- 235000015450 Tilia cordata Nutrition 0.000 description 3
- 235000011941 Tilia x europaea Nutrition 0.000 description 3
- 206010066901 Treatment failure Diseases 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000001177 diphosphate Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 125000001145 hydrido group Chemical group *[H] 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000004571 lime Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 201000004044 liver cirrhosis Diseases 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006011 modification reaction Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000000865 phosphorylative Effects 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000001681 protective Effects 0.000 description 3
- YZCKVEUIGOORGS-IGMARMGPSA-N protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000005017 substituted alkenyl group Chemical group 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 230000002195 synergetic Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 3
- 125000005039 triarylmethyl group Chemical group 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 2
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- XAWJSDHWXDVXDH-UHFFFAOYSA-N 2-dichlorophosphoryloxypropane Chemical compound CC(C)OP(Cl)(Cl)=O XAWJSDHWXDVXDH-UHFFFAOYSA-N 0.000 description 2
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 210000000170 Cell Membrane Anatomy 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 229940104302 Cytosine Drugs 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N Cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N Dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 206010019641 Hepatic cirrhosis Diseases 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N Hexamethylphosphoramide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102100008763 IFNA2 Human genes 0.000 description 2
- 108010079944 Interferon-alpha2b Proteins 0.000 description 2
- DRAVOWXCEBXPTN-UHFFFAOYSA-N Isoguanine Chemical compound NC1=NC(=O)NC2=C1NC=N2 DRAVOWXCEBXPTN-UHFFFAOYSA-N 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 230000035633 Metabolized Effects 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-Butylamine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- RGQRHSGFLNVZJK-UHFFFAOYSA-M NP([O-])(=O)N=[N+]=[N-] Chemical compound NP([O-])(=O)N=[N+]=[N-] RGQRHSGFLNVZJK-UHFFFAOYSA-M 0.000 description 2
- SNDPXSYFESPGGJ-UHFFFAOYSA-N Norvaline Chemical compound CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229940002988 Pegasys Drugs 0.000 description 2
- 229940106366 Pegintron Drugs 0.000 description 2
- 108091005771 Peptidases Proteins 0.000 description 2
- VUVGYHUDAICLFK-UHFFFAOYSA-N Perosmic oxide Chemical compound O=[Os](=O)(=O)=O VUVGYHUDAICLFK-UHFFFAOYSA-N 0.000 description 2
- 240000005158 Phaseolus vulgaris Species 0.000 description 2
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 2
- 230000036823 Plasma Levels Effects 0.000 description 2
- 230000036908 Plasma Stability Effects 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102000014961 Protein Precursors Human genes 0.000 description 2
- 108010078762 Protein Precursors Proteins 0.000 description 2
- 241000720974 Protium Species 0.000 description 2
- 101700058821 RARB Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 125000005631 S-sulfonamido group Chemical group 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- JTZZSQYMACOLNN-VDWJNHBNSA-N Simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N Theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N Thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N Tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N Xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000005282 allenyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 230000003042 antagnostic Effects 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229940000635 beta-Alanine Drugs 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 229960000517 boceprevir Drugs 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001808 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000003111 delayed Effects 0.000 description 2
- 238000001425 electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000002255 enzymatic Effects 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 150000004712 monophosphates Chemical class 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 229960002091 simeprevir Drugs 0.000 description 2
- 125000004426 substituted alkynyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 238000005987 sulfurization reaction Methods 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 229960002935 telaprevir Drugs 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- 125000005423 trihalomethanesulfonamido group Chemical group 0.000 description 2
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N α-Aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
- SLVAPEZTBDBAPI-GDLZYMKVSA-N (2R)-2-cyclopentyl-2-[2-(2,6-diethylpyridin-4-yl)ethyl]-5-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-3H-pyran-6-one Chemical compound CCC1=NC(CC)=CC(CC[C@]2(OC(=O)C(CC3=NN4C(C)=CC(C)=NC4=N3)=C(O)C2)C2CCCC2)=C1 SLVAPEZTBDBAPI-GDLZYMKVSA-N 0.000 description 1
- HLQXYDHLDZTWDW-KAWPREARSA-N (2R,4S,5R)-1-(4-tert-butyl-3-methoxybenzoyl)-4-(methoxymethyl)-2-(pyrazol-1-ylmethyl)-5-(1,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid Chemical compound C([C@]1(C[C@@H]([C@@H](N1C(=O)C=1C=C(OC)C(=CC=1)C(C)(C)C)C=1SC=CN=1)COC)C(O)=O)N1C=CC=N1 HLQXYDHLDZTWDW-KAWPREARSA-N 0.000 description 1
- MHFMTUBUVQZIRE-WINRQGAFSA-N (2S,4R)-N-[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]-1-[(2S)-3,3-dimethyl-2-(2-oxo-2-piperidin-1-ylethyl)butanoyl]-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carboxamide Chemical compound C([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C=C2N=C(C=1)C=1C=CC=CC=1)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(=O)NS(=O)(=O)C1CC1)C(C)(C)C)C(=O)N1CCCCC1 MHFMTUBUVQZIRE-WINRQGAFSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- IVJFXSLMUSQZMC-UHFFFAOYSA-N 1,3-dithiole Chemical compound C1SC=CS1 IVJFXSLMUSQZMC-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- JBYHSSAVUBIJMK-UHFFFAOYSA-N 1,4-oxathiane Chemical compound C1CSCCO1 JBYHSSAVUBIJMK-UHFFFAOYSA-N 0.000 description 1
- CPRVXMQHLPTWLY-UHFFFAOYSA-N 1,4-oxathiine Chemical compound O1C=CSC=C1 CPRVXMQHLPTWLY-UHFFFAOYSA-N 0.000 description 1
- HASUWNAFLUMMFI-UHFFFAOYSA-N 1,7-dihydropyrrolo[2,3-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1C=CN2 HASUWNAFLUMMFI-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-Naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- FHPJZSIIXUQGQE-JVZYCSMKSA-N 1-[(2R,3R,4S,5R)-5-azido-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@](CO)(N=[N+]=[N-])O[C@H]1N1C(=O)NC(=O)C=C1 FHPJZSIIXUQGQE-JVZYCSMKSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 1H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- YFXGICNMLCGLHJ-RSKRLRQZSA-N 2,2-dimethylpropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2-amino-6-methoxypurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate Chemical compound C1=CC=C2C(OP(=O)(N[C@@H](C)C(=O)OCC(C)(C)C)OC[C@H]3O[C@H]([C@]([C@@H]3O)(C)O)N3C=4N=C(N)N=C(C=4N=C3)OC)=CC=CC2=C1 YFXGICNMLCGLHJ-RSKRLRQZSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- PTRJHYDRYXRGEL-UHFFFAOYSA-N 2,3,5,6-tetrahydropyran Chemical group [CH]1CCOCC1 PTRJHYDRYXRGEL-UHFFFAOYSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 2,6-Diaminopurine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-Chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N 2-Imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- JXZYSNWHGBGZAI-GOSISDBHSA-N 2-[(1R)-5-cyano-8-methyl-1-propyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl]acetic acid Chemical compound N1C2=C(C)C=CC(C#N)=C2C2=C1[C@@](CCC)(CC(O)=O)OCC2 JXZYSNWHGBGZAI-GOSISDBHSA-N 0.000 description 1
- FISZACFWIIMVDQ-UHFFFAOYSA-N 2-[4-[[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)phenyl]methoxy]-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid;hydrochloride Chemical compound Cl.C=1C=C(OCC=2C(=CC=C(C=2)N2C(CCC2)=O)C=2C=CC(Cl)=CC=2)C=C(F)C=1C1=NC2=CC(C(=O)O)=CC=C2N1C1CCCCC1 FISZACFWIIMVDQ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- UQBOJOOOTLPNST-UHFFFAOYSA-N 2-aminoprop-2-enoic acid Chemical compound NC(=C)C(O)=O UQBOJOOOTLPNST-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-imino-7-methyl-1,2,3,7-tetrahydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 1
- SMADWRYCYBUIKH-UHFFFAOYSA-N 2-methyl-7H-purin-6-amine Chemical compound CC1=NC(N)=C2NC=NC2=N1 SMADWRYCYBUIKH-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-Piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4H-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 description 1
- MRUWJENAYHTDQG-UHFFFAOYSA-N 4H-pyran Chemical compound C1C=COC=C1 MRUWJENAYHTDQG-UHFFFAOYSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-Bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-Methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- WTDWVLJJJOTABN-UHFFFAOYSA-N 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-1-benzofuran-3-carboxamide Chemical compound C1=C2C(C(=O)NC)=C(C=3C=CC(F)=CC=3)OC2=CC(N(CCO)S(C)(=O)=O)=C1C1CC1 WTDWVLJJJOTABN-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 101710027257 5a Proteins 0.000 description 1
- PLUDYDNNASPOEE-UHFFFAOYSA-N 6-(aziridin-1-yl)-1H-pyrimidin-2-one Chemical compound C1=CNC(=O)N=C1N1CC1 PLUDYDNNASPOEE-UHFFFAOYSA-N 0.000 description 1
- LOSIULRWFAEMFL-UHFFFAOYSA-N 7-Deazaguanine Chemical compound O=C1NC(N)=NC2=C1CC=N2 LOSIULRWFAEMFL-UHFFFAOYSA-N 0.000 description 1
- PEHVGBZKEYRQSX-UHFFFAOYSA-N 7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=C1C=CN2 PEHVGBZKEYRQSX-UHFFFAOYSA-N 0.000 description 1
- PVRFQJIRERYGTQ-DSQUMVBZSA-N 9-[(2S,4aR,6R,7R,7aR)-7-fluoro-7-methyl-2-oxo-2-propan-2-yloxy-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-ethoxypurin-2-amine Chemical compound C([C@H]1O2)O[P@@](=O)(OC(C)C)O[C@H]1[C@](F)(C)[C@@H]2N1C(N=C(N)N=C2OCC)=C2N=C1 PVRFQJIRERYGTQ-DSQUMVBZSA-N 0.000 description 1
- 229940100197 ANTIMETABOLITES Drugs 0.000 description 1
- 229960000583 Acetic Acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LDDQLRUQCUTJBB-UHFFFAOYSA-N Ammonium fluoride Chemical compound [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 241001366896 Ape Aime-Itapua virus Species 0.000 description 1
- 206010003549 Asthenia Diseases 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N Asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- CUFNKYGDVFVPHO-UHFFFAOYSA-N Azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N Barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N Benzisoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N Benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N Benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N Benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N Bis(trimethylsilyl)amine Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- KBLSOCYEWZSBJM-UHFFFAOYSA-M CC(C)(C)C(=O)OCOP([O-])(=O)OCOC(=O)C(C)(C)C Chemical compound CC(C)(C)C(=O)OCOP([O-])(=O)OCOC(=O)C(C)(C)C KBLSOCYEWZSBJM-UHFFFAOYSA-M 0.000 description 1
- FNPYQXKVFWIEKS-UHFFFAOYSA-M CC(C)OC(=O)OCOP([O-])(=O)OCOC(=O)OC(C)C Chemical compound CC(C)OC(=O)OCOP([O-])(=O)OCOC(=O)OC(C)C FNPYQXKVFWIEKS-UHFFFAOYSA-M 0.000 description 1
- 229910004247 CaCu Inorganic materials 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000724565 Chorella virus Species 0.000 description 1
- PJZPDFUUXKKDNB-KNINVFKUSA-N Ciluprevir Chemical compound N([C@@H]1C(=O)N2[C@H](C(N[C@@]3(C[C@H]3\C=C/CCCCC1)C(O)=O)=O)C[C@H](C2)OC=1C2=CC=C(C=C2N=C(C=1)C=1N=C(NC(C)C)SC=1)OC)C(=O)OC1CCCC1 PJZPDFUUXKKDNB-KNINVFKUSA-N 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N Cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N Cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- ZVTDLPBHTSMEJZ-UPZRXNBOSA-N DANOPREVIR Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCC[C@H](C(N1C[C@@H](C[C@H]1C(=O)N2)OC(=O)N1CC2=C(F)C=CC=C2C1)=O)NC(=O)OC(C)(C)C)NS(=O)(=O)C1CC1 ZVTDLPBHTSMEJZ-UPZRXNBOSA-N 0.000 description 1
- 229950002891 DANOPREVIR Drugs 0.000 description 1
- FKRSSPOQAMALKA-CUPIEXAXSA-N Daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 description 1
- 229960005449 Daclatasvir Drugs 0.000 description 1
- BMAIGAHXAJEULY-UKTHLTGXSA-N Deleobuvir Chemical compound C12=CC=C(C(=O)NC3(CCC3)C=3N(C4=CC(\C=C\C(O)=O)=CC=C4N=3)C)C=C2N(C)C(C=2N=CC(Br)=CN=2)=C1C1CCCC1 BMAIGAHXAJEULY-UKTHLTGXSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N Deoxyribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102000006640 EC 2.3.2.2 Human genes 0.000 description 1
- 101700066372 ECM38 Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000033147 ERVK-25 Human genes 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010016256 Fatigue Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229950011045 Filibuvir Drugs 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- 229960002949 Fluorouracil Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 101700082072 GGT1 Proteins 0.000 description 1
- OBMNJSNZOWALQB-NCQNOWPTSA-N Grazoprevir Chemical compound O=C([C@@H]1C[C@@H]2CN1C(=O)[C@@H](NC(=O)O[C@@H]1C[C@H]1CCCCCC1=NC3=CC=C(C=C3N=C1O2)OC)C(C)(C)C)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C OBMNJSNZOWALQB-NCQNOWPTSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 206010019233 Headache Diseases 0.000 description 1
- 208000001284 Hemoglobinopathy Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N Hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940090438 Infergen Drugs 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 229940047124 Interferons Drugs 0.000 description 1
- XQCZBXHVTFVIFE-UHFFFAOYSA-N Isocytosine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N Isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N Lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- VRTWBAAJJOHBQU-KMWAZVGDSA-N Ledipasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=C3C(F)(F)C4=CC(=CC=C4C3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N([C@@H]3CC[C@H]2C3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21CC2 VRTWBAAJJOHBQU-KMWAZVGDSA-N 0.000 description 1
- 210000000265 Leukocytes Anatomy 0.000 description 1
- 101710026373 MME Proteins 0.000 description 1
- 101700038420 MVP Proteins 0.000 description 1
- 206010025482 Malaise Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 102000006404 Mitochondrial Proteins Human genes 0.000 description 1
- 108010058682 Mitochondrial Proteins Proteins 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-Methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 101700027419 NS2 Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 101800001020 Non-structural protein 4A Proteins 0.000 description 1
- 101800001019 Non-structural protein 4B Proteins 0.000 description 1
- 241000658540 Ora Species 0.000 description 1
- 229940042443 Other antivirals in ATC Drugs 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 229910003873 O—P—O Inorganic materials 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 229960002754 Paritaprevir Drugs 0.000 description 1
- 102000035443 Peptidases Human genes 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N Phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N Pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N Quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 108010012057 RNA Replicase Proteins 0.000 description 1
- FGHMGRXAHIXTBM-TWFJNEQDSA-N S-[2-[[(2R,3R,4R,5R)-5-(2-amino-6-oxo-3H-purin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-(benzylamino)phosphoryl]oxyethyl] 3-hydroxy-2,2-dimethylpropanethioate Chemical compound C([C@@H]1[C@H]([C@@](C)(O)[C@H](N2C3=C(C(NC(N)=N3)=O)N=C2)O1)O)OP(=O)(OCCSC(=O)C(C)(CO)C)NCC1=CC=CC=C1 FGHMGRXAHIXTBM-TWFJNEQDSA-N 0.000 description 1
- 101710026336 S5 Proteins 0.000 description 1
- 101700022912 S7 Proteins 0.000 description 1
- VPHXUNBMNWOYNQ-XLBCSPGISA-N SETROBUVIR Chemical compound N1([C@H]2[C@@H]3CC[C@@H](C3)[C@H]2C(=O)/C(C1=O)=C1/NC2=CC=C(C=C2S(=O)(=O)N1)NS(=O)(=O)C)CC1=CC=C(F)C=C1 VPHXUNBMNWOYNQ-XLBCSPGISA-N 0.000 description 1
- 101700042956 SYNC2 Proteins 0.000 description 1
- 101710017905 Segment 6 Proteins 0.000 description 1
- 101710033766 Segment-10 Proteins 0.000 description 1
- 101710026330 Segment-11 Proteins 0.000 description 1
- 101710043164 Segment-4 Proteins 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M Sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 206010043391 Thalassaemia beta Diseases 0.000 description 1
- 229960004559 Theobromine Drugs 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N Thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N Thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N Thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N Thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229940113082 Thymine Drugs 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N Triphenylphosphine oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 101700021629 VEMP Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 101700052963 WOX3B Proteins 0.000 description 1
- GPIBKUJXKCEZOH-UHFFFAOYSA-M [Cl-].CC(C)[Mg+] Chemical compound [Cl-].CC(C)[Mg+] GPIBKUJXKCEZOH-UHFFFAOYSA-M 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- KLUDQUOLAFVLOL-UHFFFAOYSA-N acetyl propanoate Chemical compound CCC(=O)OC(C)=O KLUDQUOLAFVLOL-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 101710038776 acyI Proteins 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005275 alkylenearyl group Chemical group 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 229960003692 aminobutyric acid Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 229960002118 asunaprevir Drugs 0.000 description 1
- 101710009508 bath-15 Proteins 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- RLMHWGDKMJIEHH-QRPNPIFTSA-N benzyl (2S)-2-aminopropanoate;hydrochloride Chemical compound Cl.C[C@H](N)C(=O)OCC1=CC=CC=C1 RLMHWGDKMJIEHH-QRPNPIFTSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- BPYKTIZUTYGOLE-IFADSCNNSA-N bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- KDYLKPXMLCXEHQ-UHFFFAOYSA-N bis(2,2-dimethylpropanoyloxymethyl) phosphate;triethylazanium Chemical compound CC[NH+](CC)CC.CC(C)(C)C(=O)OCOP([O-])(=O)OCOC(=O)C(C)(C)C KDYLKPXMLCXEHQ-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000001149 cognitive Effects 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 description 1
- 229960001418 dasabuvir Drugs 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- SRXOCFMDUSFFAK-UHFFFAOYSA-N dimethyl peroxide Chemical compound COOC SRXOCFMDUSFFAK-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000001804 emulsifying Effects 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- TYRUNUXIEAQAMR-UHFFFAOYSA-N furazan Chemical compound C=1=[CH]=NON=1 TYRUNUXIEAQAMR-UHFFFAOYSA-N 0.000 description 1
- 229940013945 gamma-Aminobutyric Acid Drugs 0.000 description 1
- 125000002642 gamma-glutamyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 201000003923 hemoglobinopathy Diseases 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 101710009721 hupS Proteins 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- BZUIJMCJNWUGKQ-BDAKNGLRSA-N hypusine Chemical compound NCC[C@@H](O)CNCCCC[C@H](N)C(O)=O BZUIJMCJNWUGKQ-BDAKNGLRSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000002458 infectious Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FMSXILLOKUGXFX-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]aluminum(1-) Chemical compound [Li+].CC(C)(C)O[Al-](OC(C)(C)C)OC(C)(C)C FMSXILLOKUGXFX-UHFFFAOYSA-N 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- RLXWGEUQYNIHRM-UHFFFAOYSA-N methanetriolate Chemical compound [O-]C([O-])[O-] RLXWGEUQYNIHRM-UHFFFAOYSA-N 0.000 description 1
- TUDYPXFSYJRWDP-UHFFFAOYSA-N methoxy methyl carbonate Chemical compound COOC(=O)OC TUDYPXFSYJRWDP-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- 230000002438 mitochondrial Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxoallopurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 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
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000005642 phosphothioate group Chemical group 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
- 239000004033 plastic Substances 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
- RYXIBQLRUHDYEE-UHFFFAOYSA-M potassium;5-(cyclohexen-1-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound [K+].C1CC(OC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C([O-])=O)C(=O)C1CCC(C)CC1 RYXIBQLRUHDYEE-UHFFFAOYSA-M 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2S)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 1
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2S)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 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
- 150000003222 pyridines Chemical class 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- SSERCMQZZYTNBY-UHFFFAOYSA-M sodium;3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylate Chemical compound [Na+].C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C([O-])=O)C1CCC(O)CC1 SSERCMQZZYTNBY-UHFFFAOYSA-M 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
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YEKUWOWHPVKTCQ-UHFFFAOYSA-M tetraethylazanium;fluoride;hydrate Chemical compound O.[F-].CC[N+](CC)(CC)CC YEKUWOWHPVKTCQ-UHFFFAOYSA-M 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-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
- 231100000027 toxicology Toxicity 0.000 description 1
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- OKKJLVBELUTLKV-FIBGUPNXSA-N trideuteriomethanol Chemical compound [2H]C([2H])([2H])O OKKJLVBELUTLKV-FIBGUPNXSA-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
- 238000001665 trituration Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N α-aminoisobutanoic acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
Abstract
Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.
Description
SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
INCORPORATION B Y REFERENCE TO ANY PRIORITY APPLICATIONS [0001] Any and ail applications for which a foreign or domestic priority claîm is identified in the Application Data Sheet as filed with. the présent application», are hereby
5__incorporatedbyréférencéunder37CFR 1.57. _ .. ...___ _
REFERENCE TO SEQUENCE LISTING [0002] The présent application is being filed along with a Sequence Listing in eiectronic format. The Sequence Listing is provided as a file entitled SEQLISTINGj065.TXT, 10 created December 19,2013, which is 1 Kb in size. The information in the eiectronic format of the Sequence Listing is incorporated herein by référencé in its entirety.
BACKGROUND
Field [0003] The présent application relates to the fields of chemistry, biochcmistry and medicine. More particulariy, disclosed herein are 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 nucléotide analog, alone or in combination therapy with one or more other agents.
Description [0004] Nucleoside analogs are a class of compounds that hâve been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, hâve been the subject of widespread research for the treatment of viral infections. Nucleoside analogs are usually 25 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 [0005] Some embodiments disclosed herein relate to a compound of Formula (I) or a pharmaceutically acceptable sait thereof.
[0006] Some embodiments disclosed herein relate to a method of ameliorating and/or tæatîng a hepatitis C viral (HCV) infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutïcal composition that includes 5 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 HCV infection. Stîll other embodiments described herein relate to one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutïcal 10 composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, that can be used for ameliorating and/or treating a HCV infection.
[0007] Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a pharmaceutically 15 acceptable sait of one or more compounds described herein, or a pharmaceutïcal 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 HCV infection that can include 20 contacting a cell infected with the hepatitis C 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, or a pharmaceutïcal composition that includes one or more compounds described herein, or a pharmaceutically acceptable sait thereof, that can be used for ameliorating and/or treating a 25 HCV infection by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
[0008] Some embodiments disclosed herein relate to a method of inhibiting réplication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C virus with an effective amount of one or more compounds described herein, or a 30 pharmaceutically acceptable sait of one or more compounds described herein, or a pharmaceutïcal 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
hepatitis C virus that can include contacting a cell infected with the hepatitis C 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, or a pharmaceutical composition that includes one or more —- 5 - - compounds described herein, or a pharmaceutically. acceptables ait thereof,- that can be used for
- - inhibiting réplication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
[0009] Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from 10 the HCV infection an effective amount of a compound 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, or a pharmaceutically acceptable sait thereof, in combination with an agent selected from an interferon, ribavïrin, a HCV protease inhibitor, a HCV polymerase 15 inhibitor, a NS5A inhibitor, an other antivira! compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable sait of any of the foregoing. Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include contacting a cell infected with the HCV infection with an effective amount of a compound described herein or a pharmaceutically 20 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 compound of Formula (BB) and a compound of 25 Formula (CC), or a pharmaceutically acceptable sait of any of the foregoing. Some embodiments disclosed herein relate to a method of inhibiting réplication of a hepatitis C virus that can include administering to a subject identified as suffering from a HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable sait thereof (for example, a compound of Formula (I), or a pharmaceutically acceptable sait thereof), or a 30 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, another antiviral compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable sait of any of the foregoing. In some embodiments, the agent can be a compound, or a pharmaceutically acceptable sait thereof, selected from Compound 1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5012, 60016078, 7000-7027 and 8000-8016, or a pharmaceutical composition that includes one or more of the aforementioned compounds, or a pharmaceutically acceptable sait of the forcgoing. In some . 5 embodiments, the. method can include administering a second 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 compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable sait of any of the foregoîng.
[0010] [0011] [0012] [0013] [0014]
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows example HCV protease inhîbitors.
Figure 2 shows example nucleoside HCV polymerase inhîbitors.
Figure 3 shows example non-nucleoside HCV polymerase inhibîtors.
Figure 4 shows example NS5A inhîbitors.
Figure 5 shows example other antivirals.
[0015] Figure 6 shows example compounds of Formula (CC) and alphathiotriphosphates thereof, wherein Formula (CC) and alpha-thiotrîphosphâtes thereof are described herein.
[0016] Figure 7 shows example compounds of Formula (AA), wherein Formula 20 (AA) is described herein.
[0017] Figure 8 shows example compounds of Formula (BB), wherein Formula (BB) îs described herein.
[0018] Figure 9 shows example compounds of Formula (I), wherein Formula (I) is described herein.
[0019] Figure 10 shows the gels from the assessment of incorporation of several compound with a uracil base by the human mitochondrial RNA polymerase.
[0020] Figure 11 shows the gels from the assessment of incorporation of several compounds with a guanine base by the human mitochondrial RNA polymerase.
[0021] Figures 12A-D shows the results of the inhibition of mitochondrial protein 30 synthesis assays.
I
DETAILED DESCRIPTION
Définitions [0022] Unless defîned otherwise, ail technical and scientific tenus used berein hâve the same meaning as is commonly understood by one of ordinaiy skill in the art. Ail patents, .5—-applications^published applications and other publications referenced herein areincorporated by ----référencé in-their entirety unless stated otherwisezln the cvènt-that there are aplurality of définitions for a terni herein, those in this section prevail unless stated otherwise.
[0023] As used herein, any R group(s) such as, without limitation, R*. R2, R3, R4, RSA p5B pfiA p6B p6C p6D p6E p6F p6O piH p7A p7B p8 p9 ptO pli plî pl3 pl4 plS plfi t Λ y IX w IX φ *X t IX # tx Ix B IX φ IX φ IX > *X AX t (X · IX y tx * IX | K. y tx φ IX y
R17, R”, Ra1, R*2, Rw and RA4 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, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R and Rb of an NR* Rb group are indicated to be taken together, it means that they are covalently bonded to one another to 15 form a ring:
^Ra N^Rh
In addition, if two “R” groups are described as being “taken together” with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defîned previously.
[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 25 substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, Ocarbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amîdo, N-amido, S-sulfonamîdo, N-sutfonamido, C-carboxy, O-ca±oxy, isocyanato, thîocyanato, isothiocyanato, nitro, sîlyl, 30 sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
[0025] As used herein, “C» to Cb in which “a** and “b are integers refer to the number of carbon atoms in on alkyl, alkenyl or alkynyt group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the 5 . .hetemaryLor ring of the heterocyclyl can contaîn from “a” to “b”v inclusive,-carbon atoms. Thus, -----_. for ex amp le,-a “Ci to Q alkyl” group- refers to *all alkyl groups having from-1. to' 4 carbons, that is, CHr, CHjCHr, CH3CH2CHr, (CH3)2CH-, CH3CH2CH2CHr, CH3CH2CH(CH3)- and (CH3)3C-. If no “a and “b are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these 10 définitions is to be assumed.
[0026] As used herein, “alkyl” refers to a straight or branebed hydrocarbon chaîn 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 15 may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and 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 20 désignations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.
[0027] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain 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 30 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 în 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. Typical cycloalkyl groups include, but arc in no way limited to, cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0030] As used herein, “cyctoalkenyl refers to a mono- or multî- cyclic hydrocarbon ring System that contains one or more double bonds in at least one ring; although, if there is more-than one, the double bonds cannot form-a fully delocalized pi-electronsystenLthroughout all-the rings (otherwisë the group: would be “aryh” as defined herein). When composed of two or more rings, the rings may be connected together irî a fused fashion. A cycloalkenyl can contaîn 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted.
[0031] 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 CaCu aryl group, a Ce-Cio aryl group, or a Cs aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
[0032] As used hercin, “heteroaryl” refers to a monocyclic, btcyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 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 vary. For example, the heteroary! group can contaîn 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the terni “heteroaryl” includes fused 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, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazoIe, 1,2,4-oxadiazole, thiazole, 1,23-thiadiazole, 1,2,4-thiadiuzole, benzothîazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazinc, pyrimidine, pyrazine, purine, pteridîne, qui no line, isoquinoline, quinazoline, quînoxalîne, cinnoüne and triazine. A heteroaryl group may be substituted or unsubstituted.
[0033] As used herein, “heterocyclyl” or “heteroalicyclyl refers to three-, four-, five, six-, seven-, eîght-, 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 contai π one or more unsaturated bonds situated in such a way, however, that a fully deîocalîzed 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 fiirther contain one or more carbonyl or thiocarbonyl functionalities,
---^5—so-as ta. make the-définition include oxo-systemsand thio-systems such as lactams, lactones,
- cyclic-imidesfcyclic thioimides-and cyclîc carbamates-Wheri composed of two or more rings, ' the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be qualemized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyr or “heteroalicyclyl” groups include but are not 10 limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, lj-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxaztne, maleimide, succtnimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazolîne, îsoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, 15 thiazolidine. moipholine, oxirane, piperidine MOxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyTazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and theîr benzo-fused analogs (e.g., bcnzimîdazolidinone, tetrahydroquinolîne and 3,4-methylenedioxyphenyl).
[0034] 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 aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2phenylalkyl, 3-phenylalkyl and naphthylalkyl.
[0035] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a 25 heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylaIkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pynolylalkyl, pyridylalkyl, isoxazolylalkyl, îmidazolylalkyl and their benzo-fused analogs.
[0036] A “(heteroalicyclyl)alkyr and “(heterocyclyl)alkyr refer to a heterocycüc or 30 a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidîn-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl and (l,3*thiazinan-4-yl)methyl.
[0037] “Lower alkylene groups” are straight-chained -CHr tethering groups, forming bonds to connect molecular fragments via tbeîr terminal carbon atoms. Examples include but are not llmited to methylene (-CHr). ethylene (-CHiCHr), propylene (CHîCHiCHr) and butylène (-CH2CH2CH2CH2-)· A lower alkylene group can be substituted by
-----5 — replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the —* — — définition of “substituted.— - =——-— -—---===-^.-^-7[0038] As used herein, alkoxy refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyt, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl is defined herein. A non-Iimiting list of alkoxys are 10 methoxy, ethoxy, n-propoxy, l-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.
[0039] As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include foimyl, acetyl, propanoyl, benzoyl and acry). An acyl may be substituted or unsubstituted.
[0040] 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 2,2dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
[0041] As used herein, “haloalkyl” refers to an alkyl group in which one or more of 20 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, l-chIoro-2-fluoromethyI and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
[0042] As used herein, “haloalkoxy” refers to an -O-alkyl group in which one or 25 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, l-chloro2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.
[0043] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, 30 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.
[0044] A “sulfinyl” 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.
[0045] A “sulfonyl” group refers to an “SO2R group in which R can be the same as defined with respect to sulfenyl. A suifonyl may be substituted or unsubstituted.
[0046] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, aikenyl, alkynyl, cycloalkyl, cydoalkenyi, aryl, heteroaryl, heterocyclyl, ^_5^aryl(a!kyl), (heteroaryl)alkyLor(heterocyclyOalkyl. aSy deflned herein.-Aji O<arboxy may be —substitutedorunsubstituted.- ..... '......-[0047] 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.
[0048] A “thiocarbonyr group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocaibonyl may be substituted or unsubstituted.
[0049] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.
[0050] A “trihalomethanesulfonamido” group refers to an “XjCS(O)2N(Ra)-” group wherein each X is a halogen, and Ra is hydrogen, alkyl, aikenyl, alkynyl, cycloalkyl, cydoalkenyi, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.
[0051] The term “amino as used herein refers to a -NHj group.
[0052] As used herein, the term “hydroxy” refers to a -OH group.
[0053] A “cyano” group refers to a “-CN” group.
[0054] The term “azido” as used herein refers to a -Nj group.
[0055] An “isocyanato” group refers to a “-NCO” group.
[0056] A “thiocyanato” group refers to a “-CNS group.
[0057] An “îsothiocyanato” group refers to an “ -NCS” group.
[0058] A “mercapto” group refers to an “-SH” group.
[0059] A “carbonyl” group refers to a C=O group.
[0060] An S-sulfonamido group refers to a “-SO2N(RaRb)” group in which Ra and
Rb can be independently hydrogen, alkyl, aikenyl, alkynyl, cycloalkyl, cydoalkenyi, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may be substituted or unsubstituted.
[0061] An “N-sulfonamido group refers to a “RSO2N(RA)-’‘ group in which R and
Ra can be independently hydrogen, alkyl, aikenyl, alkynyl, cycloalkyl, cydoalkenyi, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocydyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.
I [0062] 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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (hetcrocydyl)alkyl, An O-carbamyl may be substituted or unsubstituted.
5«-^ —[0063] -—.An -“N-carbamyl- group refers to an “ROC(=O)N(Ra)'” group in which R and —·—RX-can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.
[0064] An “O-thiocarbamyl” group refers to a **-OC(=S)-N(RaRb)” group in whîch
Ra and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.
[0065] An “N-thiocarbamyl” group refers to an “ROC(=S)N(Ra)-“ group in which R and R a can be independently hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl, aryl, 15 heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.
[0066] A “C-amido group refers to a “-C(=O)N(RaRbÏ* group in which Ra and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substituted 20 or unsubstituted.
[0067] 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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substituted or unsubstituted.
[0068] 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, bromîne and iodine.
[0069] Where the numbers of substituents is not spccified (e.g. haloalkyl), there may be one or more substituents présent For example “haloalkyl” may include one or more of the 30 same or different halogens. As another example, “Ci-Cj alkoxyphenyl” may include one or more of the same or different alkoxy groups containîng one, two or three atoms.
[0070] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage.
recognized abbrcviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See,
Biochem. 11:942-944 ( 1972)).
[0071] The term “nucleoside” is used herein in its ordinaiy sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose - -5 — moiety or modified pentose.moiety-attachèd-tom heterocyclic-base-or-tautomer thereof via a N-----glycosidic-bond,· such as attachèd via the-9-position of a purine-base or-the -1-position of a pyrimidine-base. Examples include, but are not limited to, a ribonucleoside comprising a ribcse 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 10 carbon has been replaced with a sulfur or an oxygen atom. A “nucleoside” is a monomer that can hâve a substituted base and/or sugar moiety. Additionally, a nucleoside can bc incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.
[0072] The term “nucléotide” is used herein in its ordinary sense as understood by 15 those skilled in the art, and refers to a nucleoside having a phosphate ester bound to the pentose moiety, for example, at the 5’-position.
[0073] As used herein, the term “heterocyclic base” refers to an optionally substituted nîtrogen-containing heterocyclyl that can be attachèd to an optionally substituted pentose moiety or modified pentose moiety. In some embodiments, the heterocyclic base can be selected from 20 an optionally substituted purine-base, an optionally substituted pyrimidine-base 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 ordinary sense as understood by those skilled in the art, and includes its tautomers. A non-limiting list of 25 optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine, caffeine, une acid and isoguanine. Examples of pyrimîdine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). An example of an optionally substituted triazole-base is l,2,4-triazole-3-carboxamide. Other non-limiting 30 examples of heterocyclic bases include diaminopurine, e-oxo-l^-alkyladenine (e.g., 8-oxo-N*methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N4,N4-ethanocytosin, N^N6ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos. 5,432,272 and 7,125,855, which are incorporated herein by référencé for the limited purpose of disclos ing additional hcterocyclic bases. In some embodîments, a heterocyclic base can be optionally substituted with an amine or an enol protecting groupfs).
[0074] The term “-N-lînked amîno acid refers to an amino acid that is attached to the indicated moiety via a main-chain amîno or mono-substituted amîno group. When the amîno =-5 — acid is-attached inan—N-linked amîno acid,-one of ih&hydrogens that-is part of the main-chain —— amino or-mono-substitutedamino-group-is not présent-and the-amino acid-is-attached via the nitrogen. N-linked amino acids can be substituted or unsubstituted.
[0075] 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 10 embodîments, the ester group has a formula selected from a!kyl-O-C(=O)-, cycloalkyl-0-C(=0), aryl-O-C(=O)- and aryl(alkyl)-O-C(=O)-. A non-limiting lîst of ester groups include substituted and unsubstituted versions of the following: methyI-O-C(=O)-, ethyl-O-C(=O)-, npropyl-O-C(=O)-, isopropyl-0-C(=0)-( n-butyl-O-C(=0)-, isobuty!-0-C(=0)-t tert-butyl-OC(=O)-, neopenty!-0-C(=0)-, cyclopropyl-O-C(=O)-, cyclobutyl-O-C(-O)-, cyclopentyl-O15 C(=O)-, cyclohexyl-0-C(=0)-, phenyl-O-C(=O)-, benzyl-O-C(=O)- and naphthyl-O-C(=O)-. Nlinked amino acid ester dérivatives can be substituted or unsubstituted.
[0076] The term “-O-linked amino acid refers to an amino acid that is attached to the indicated moiety via the hydroxy from ils main-chain carboxylic acid group. When the amîno acid is attached in an -O-linked amino acid, the hydrogen that is part of the hydroxy from 20 its main-chain carboxylic acid group is not présent and the amîno acid is attached via the oxygen. O-linked amino acids can be substituted or unsubstituted.
[0077] 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, γamino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited 25 to, alanine, asparagine, aspartate, cysteîne, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, hîstidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and vaüne. Additional examples of suitable amino acids include, but are not limited to, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citnrlline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norieucine.
[0078] The terms phosphorothïoate” and “phosphothioate” refer to a compound of î -4 -i s=^>—o—| s o—| the general formula O* * its protonated forms (for example, O* and
OH ) and its tautomers (such as ÔH ).
[0079] As used herein, the terrn “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example.
O: and ÔH ). As used herein, the terms “monophosphate,” “diphosphate,1 and “triphosphate are used in their ordinary sense as understood by those skilled in the art, and include protonated forms.
[0080] The terms “protecting group and “protecting groups” as used herein refer to 10 any atom or group of atoms that is added to a molécule in 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 référencé for the limited purpose 15 of disclostng suitable protecting groups. The protecting group moiety may be chosen in 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 20 methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, tbutyldimethylsilyl, tri-Îro-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyI or tbutyldîphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic kctal (e.g. dimethyl acetal); cyclic ketals (e.g., 1325 dîoxane, l,3-dtoxo!anes and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 13-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl;
► monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4-trimethoxytrityl (TMTr); and those described herein).
[0081] 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 -5*~-abrogate the biological activity and properties of.the compound. In some embodiments, the sait ^MsTah 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 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 aliphatic or aromatic carboxylic or sulfonic 10 acids, for example formic, acetic, succinic, lactic, malic, tartane, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a sait such as an ammonium sait, an alkalî 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 15 dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamîne, trietbanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
[0082] Ternis and phrases used in this application, and variations thereof, especially in the appended daims, unless otherwise expressly stated, should be construed as open ended as 20 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 ‘characterized by,’ and is inclusive or open-ended and does not exetude additional, unrecited éléments or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be 25 interpreted as ‘includes but is not limited to;’ the term ‘example’ is 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 fonction, but instead as merely intended to highlight alternative or additional 30 features that may or may not be utilized in a particular embodiment. 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,
I6 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 cveiy one of those items be présent in the grouping, but rather should be read as ‘and/or* unless expressly stated otberwise. Simitarly, a group of __. 5 items linked-with the conjunction -‘or’ should jiot be read as requiring mutual exclusivity among ' -r- — - that group; but rather should be read as ‘and/or-’ unless expressly stated otherwise^ ?— - —r [0083] 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 10 singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an does not exclude a plurality. A single processor or other unit may folfill the fonctions of several items recited in the daims. The mère fact that certain measures are recited in mutually different dépendent daims does not indicate that a combination of these measures cannot be used to advantage. Any référencé signs in the daims should not be construed as 15 limiting the scope.
[0084] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemîstry is not expressly indicated, then each center 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 20 mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) gencrating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
[0085] Likewise, it is understood that, in 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 phosphorothioate include the following:
and
Furthermore, ail tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of naturel and non-natural purine-bases and pyrimidinebases.
[0086] It is to be understood that where compounds disclosed herein hâve unfïlled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 -5—(protium)and hydrogen-2 (deuterium).- ~ ---— — ———- [0087]—It-is' understood' that~the'compounds-described herein can be labeled isotopically. Substitution with isotopes Such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for exampte, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound 10 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, référencé herein to a compound encompasses ail potential isotopîc forms 15 unless the context clearly dictâtes otherwise.
[0088] 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 solvated 20 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 stoichiometric 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 25 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.
[0089] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed 30 within the embodiments.
Compounds [0090] Some embodiments disclosed herein relate to a compound of Formula (1) or a pharmaceutically acceptable sait thereof:
substituted jvlzv· , an optionally , an optionally substituted , an optionally
substituted
, an optionally substituted optionally substituted ; R* can be selected from an optionally substituted Ci^ alkyl, an optionally substituted C2^ alkenyl, an optionally substituted C2.6 alkynyl and an optionally substituted cycloalkyl; each------can be absent or a single bond, provided that both-----are each absent or both------are each a single bond; when both----are each a single bond, then R2 can be halo, N3, -OR7A or —N(R7aR7C); R4 can be absent; R3 can be oxygen (O); and Rp V can be Rp1 -r' , wherein ΖΓ can be oxygen (O) or sulfur (S) and RpI can be selected from O',
OH, an -O-optionally substituted alkyl.
RP9 ' s an , , <ui optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; when both----are each absent, then Rp can be absent; R2 can be halo, Nj, -OR7A or -NfR^R7^*. R3 can be -OH or OC(=O)R8; or R2 and R3 can be each an oxygen atom which are linked together by a carbonyl Îi ,“1 group; and R4 can be hydrogen or R5A ; RÎA can be selected from O, OH, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester dérivative,
O R14A
can be selected from O, OH, an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, an -O-optionally substituted heterocyclyl, an optionally substituted N-linked amino acid, an optionally substituted N-linked amino acid ester dérivative,
ZXX. M1can be an optionally substituted C|.
e alkyl or an optionally substituted Cj^ cycloalkyl; R6B and R60 can be independently selected from hydrogen, an unsubstituted C(^ alkyl, an unsubstituted alkenyl, an unsubstituted alkynyl and an unsubstituted cycloalkyl; R6D can be NHR60; R6E can be hydrogen, halogen or NHR6H; R6F can be NHR61; R60 can be selected from hydrogen, an optionally substituted C|_6 alkyl, an optionally substituted C3^ alkenyl, an optionally substituted C3^ cycloalkyl, -C(=O)RAl and -C(=O)0RA2; R6h can be selected from hydrogen, an optionally substituted Ci^ alkyl, an
optionally substituted Cm alkenyl, an optionally substituted Cm cycloalkyl, -C(=O)RA3 and C(=O)ORA4; R61 can be selected from hydrogen, an optionally substituted Cm alkyl, an optionally substituted alkenyl, an optionally substituted Cm cycloalkyl, -CfsOiR*5 and C(=O)ORA6; X* can be N (nitrogen) or -CRW, R67 can be selected from hydrogen, halogen, an
-5_ optionally. substituted _C|.$ alkyl, jui optionally substituted C2^ alkenyl and an optionally substituted Cm alkynyl; Ra1, R*2, R*3, RA4, R*3-and RAS can be independently selected from Cm alkyl, C2^ alkenyl, Cm alkynyl, C345 cycloalkyl. Cm cycloalkenyl, Ce-io aryl, heteroaryl, heterocyclyl, aryl (Cm alkyl), heteroaryl(CM alkyl) and heterocyclyl(Cm alkyl); R7A can be hydrogen or -C(=O)R12; R7B and R7C can be independently hydrogen or an optionally substituted 10 Cm alkyl; R1 and R12 can be independently an optionally substituted Cm alkyl or an optionally substituted Cm cycloalkyl; R9, R10 and Ru can be independently absent or hydrogen; R8A, R9A,
R,ia, R,2a, R*b, R98, Rub, Ri2b, Rp2, Rp3, RpS and R1*6 can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; RIOA, R,ob, Ri3a, RI3B, R14 and Rp7 can be independently selected from hydrogen, an optionally substituted 15 C|,24 alkyl, un optionally substituted aryl, an optionally substituted -O-C).24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -Omonocyclic heterocyclyl; RI4A, Rl4B, R13A, Rt3B, Rp8 and Rp9 can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; n can be 0 or 1 ; p, q, and r can be independently 1 or 2; s, t and u can be independently 3,4 or 5; Z1, Z,A, Z,B and
Zpl can be independently O (oxygen) or S (sulfur); and provided that when R4 is
and Rsa is O' or OH, then R3B is 0‘, OH,
O
II RnO—P—O
OR10
n , an optionally substituted Nlinked amino acid or an optionally substituted N-linked amino acid ester dérivative.
[0091] The substituents attached to the 2’-carbon can vary. In some embodiments, R7 can be halo. For example, R2 can be fluoro or chloro. In other embodiments, R2 can be Nj. 25 In some embodiments, R2 can be -OH. In other embodiments, R2 can be OR7A, wherein R7A can be -C(=O)R12, and R12 can be an optionally substituted Cm alkyl. Suitable alkyl groups include, but are not limited to 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 yet still other embodiments, R2 can be OR7A, wherein R7A
can be -C(=O)R12, and R12 can be an optionally substituted C3^ cycloalkyl. Suitable cycloalkyl groups include, but are not limited to optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cydohexyl. In some embodîment, R2 can be N(R7BR7C), wherein R70 and R7C can be independently hydrogen or an optionally substituted Cm —^5 — alkyl.-In some embodiments, R78 and R7C can be both hydrogen.such that R2 can be -NHi. In —.....-other embodiments, at least one of R70 ànd R7C can be-an optionally substituted Cm alkyl. In some embodiments, R78 and R7C can be both an optionally substituted Cm alkyl. In some embodiments, R78 and R7C can be the same. In other embodiments, R78 and R7C can be different [0092] Various substituents can be attached to the 3*-carbon of the pentose ring. In some embodiments, R3 can be -OH. In other embodiments, R3 can be -OC(=O)RS, wherein R® can be an optionally substituted Cm alkyl such as those described herein. In still other embodiments, R3 can be -OC(=O)R8, wherein R8 can be an optionally substituted Cj-e cycloalkyl. Examples of suitable optionally substituted Cm cycloalkyl groups are described herein.
[0093] In some embodiments, R2 and R3 can each be an oxygen atom and the oxygen atoms can be linked together by a carbonyl group. In other embodiments, R2 and R3 can be both -OH. In other embodiments, R2 can be halo and R3 can be -OH. In still other embodiments, R2 can be halo and R3 can be -OC(=O)RS.
[0094] In some embodiments, R* can be an optionally substituted Cm alkyl. In some embodiments, R* can be an unsubstituted Cm alkyl. For example, R1 can be unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted nbutyl, unsubstituted isobutyl, unsubstituted tert-butyl, unsubstituted penty! (branched and straîght-chained) or unsubstituted hexyl (branched and straight-chained). In some embodiments,
R* can be a substituted Cm alkyl. Suitable substitutions are described herein. As an example, R1 can be a halo-substituted Cm alkyl (such as -CF3 or -CH2CH3F). In other embodiments, R1 can be an optionally substituted Cm alkenyl. Suitable alkeny! groups include, but are not limited to optionally substituted variants of the following: ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, pentenyl (branched and straight-chained), hexenyl (branched and straight-chained), vinyl and allenyl. In still other embodîments, R* can be an optionally substituted Cm alkynyl. In yet still other embodiments, R1 can be an optionally substituted C« cycloalkyl, such as those described herein.
[0095] In some embodiments, both----can be each absent, Rp can be absent; R2 can be halo, Nj, -OR7A or -N(R78R7C); R3 can be -OH or -OC(=O)R8; or R2 and R3 can be each an oxygen atom which are linked together by a carbonyl group; and R4 can be hydrogen or
are absent, Formula (I) can hâve the structure:
When both ---- are absent, Formula (I) can hâve the structure:
ΛΓ V 1 a >
R R . In some embodiments, R can be hydrogen. In other embodiments, R can be RSA . In some embodiments, the compound of Formula (I) can be a monophosphate. In other embodiments, the compound of Formula (I) can be a thiomonophosphate. In some embodiments, the compound of Formula (I) can be a diphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiodiphosphate. In some embodiments, the compound of Formula (I) can be a triphosphate. In other embodiments, the compound of Formula (I) can be an alpha-thiotriphosphate. In some embodiments, R4 can be
Rsa ; Rsa can be O* or OH; and R3B can be O' or OH. In other embodiments, R4 can be
; R5A can be O’ or OH; R5B can be n ; and n can be 0. In
still other embodiments, R4 can be R3A ; R3A can be 0' or OH; R3B can be Ο Γ o n ; and n can be 1. The substituants attached to the phosphores can vary. In some embodiments, a compound of Formula (I) can be a phosphoroamidate. In other 15 embodiments, a compound of Formula (I) can be a thiophosphoroamidate. In still other embodiments, a compound of Formula (I) can be a phosphorbisamidate. In yet still other embodiments, a compound of Formula (I) can be a thiophosphorbisamidate.
[0096] In some embodiments, RSA can be an optionally substituted N-linked amino acid. Various amino acids are suitable, including those described herein. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucîne, lysine, - - 5 _ methioninetphenylalanine, threonine, tryptophan and valine. In other embodiments, RÎA can be an optionally substituted N-linked amino acid ester dérivative. Examples of N-linked amino acid ester dérivatives include, but arc not limited to, 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, 10 threonine, tryptophan and valine. Additional examples of N-linked amino acid ester dérivatives include, but are not limited to, an ester dérivative of any of the following amino acids: alphaethyl-glycine, alpha-propyl-glycîne and beta-alanine. In some embodiments, the N-linked amino acid ester dérivative can be a alkyl ester derivative, for example, an isopropyl ester of alanine. Ih other embodiments, the N-linked amino acid ester derivative can be a C36 cycloalkyl 15 ester derivative, such as a cyclohexyl ester of alanine.
[0097] In some embodiments, RSA can hâve the structure ° H wherein R13 can be selected from hydrogen, an optionally substituted C^-alkyl, an optionally substituted C3.$ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C[_6 alkyl) and an optionally substituted haloalkyl; R14 can be selected from hydrogen, an optionally substituted C|.
« alkyl, an optionally substituted C|_6 haloalkyl, an optionally substituted Cm cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cjo aryl and an optionally substituted aryl(Ci_6 alkyl); and R13 can be hydrogen or an optionally substituted Cu-alkyl; or R14 and R15 can be taken together to form an optionally substituted C3^ cycloalkyl.
[0098] When R14 is substituted, R14 can be substituted with one or more substituents 25 selected from N-anûdo, mercapto, alkylthîo, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In some embodiments, R14 can be an unsubstituted Ci.«-alkyl, such as those described herein. In some embodiments, R14 can be hydrogen. In other embodiments, R14 can be methyl. In some embodiments, R13 can be an optionally substituted C|_e alkyl. Examples of optionally substituted Ci^-alkyls include 30 optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straîght-chained) and hexyl (branched and straightchained). In some embodiments, R13 can be methyl or isopropyl. In some embodiments, R13 can
be ethyl or neopentyl. In other embodiments, R13 can be an optionally substituted C3-6 cycloalkyl. Examples of optionally substituted Cj^ cycloalkyl include optionally substituted variants of the following: çyclopropyt, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R13 can be an optionally substituted cyclohexyl. In still other embodiments, R13 —S—can.be an .optionally-substituted-aryl, such-as phenyl ·and- naphthyl. -- In yet-still other
- — — embodiments, R13 can be an optionally substituted ary!(Ci_6 alkyl ).In someembodiments, R13 can be an optionally substituted benzyl. In some embodiments, R13 can be an optionally substituted Cm haloalkyl, for example, CF3. In some embodiments, R13 can be hydrogen. In other embodiments, R13 can be an optionally substituted Cm alkyl, such as methyl, ethyl, n10 propyl, îsopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R13 can be methyl. In some embodiments, R14 and R13 can be taken together to form an optionally substituted cycloalkyl. Examples of optionally substituted C34 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R14 and R13, the carbon to which R14 and R13 are attached may be 15 a chiral center. In some embodiment, the carbon to which R14 and R13 are attached may be a (R)-chîral center. In other embodiments, the carbon to which R14 and R13 are attached may be a (S)-chirul center.
[0099]
Examples of suitable groups include the following:
and
[0100] In some embodiments, R5B can be an -O-optionally substîtuted aryl. For example, R!B can be an -O-optionally substîtuted phenyl. When the phenyl is substîtuted, the 5 ring can be substîtuted 1,2,3 or more than 3 times. Suitable mono-substîtuted phenyl groups include, ortho-substituted phenyl, meta-substituted phenyl and para-substituted phenyl. In other embodiments, R58 can be an -O-unsubstituted aryl. Altematively, R3B can be an -O-optionally substîtuted naphthyl. In other embodiments, R5B can be an -O-optionally substîtuted heteroaryl. For example, R5B can be an -O-optionally substîtuted quinolinyl. In still other embodiments, Rsb can be an -O-optionally substîtuted heterocyclyl.
[0101] In some embodiments, R50 is an optionally substîtuted N-linked amino acid, such as those described for R5A. In other embodiments, R3B is an optionally substîtuted N-linked amino acid ester dérivative, for example, those described herein. In some embodiments, R3B can hâve the structure
wherein R15 16 can be selected from hydrogen, an optionally substîtuted C^-alkyl, an optionally substîtuted cycloalkyl, an optionally substîtuted aryl, an optionally substîtuted aryl(Ci_6 alkyl) and an optionally substîtuted haloalkyl; R17 can be selected from hydrogen, an optionally substîtuted Cm alkyl, an optionally substîtuted Cm haloalkyl, an optionally substîtuted Cj^ cycloalkyl, an optionally substîtuted Ce aryl, an optionally substîtuted
Cio aryl and an optionally substîtuted aryl(CM alkyl); and R*8 can be hydrogen or an optionally substîtuted Cw-alkyl; or R17 and R18 * 20 * * * * 25 can be taken together to form an optionally substîtuted C3^ cycloalkyl.
[0102] When R17 is substîtuted, R17 can be substîtuted with one or more substitueras selected from N-amido, mercapto, alkylthio, an optionally substîtuted aryl, hydroxy, an optionally substîtuted heteroaryl, O-carboxy and amino. In some embodiments, R17 can be an unsubstituted Ci^-alkyl, such as those described herein. In some embodiments, R17 can be hydrogen. In other embodiments, R17 can be methyl. In some embodiments, R16 can be an
optionally substituted Cw alkyl. Examples of optionally substituted C|^-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 straightchained). In some embodiments, R,fi can be methyl or isopropyl. In some embodiments, R16 can 5 - be ethykor neopentyl. In other embodiments, R16 can be an optionally substituted cycloalkyl. Examples of optionally substituted Cye cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R16 can be an optionally substituted cyclohexyl. In still other embodiments, R16 can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other 10 embodiments, R16 can be an optionally substituted aryl(C|^ alkyl). In some embodiments, R,s can be an optionally substituted benzyl. In some embodiments, R16 can be an optionally substituted Ci^ haloalky], for example, CF3. In some embodiments, R” can be hydrogen. In other embodiments, R18 can be an optionally substituted CM-alkyl, such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R18 can be methyl. In 15 some embodiments, R17 and Rt8 can be taken together to form an optionally substituted C3^ cycloalkyl. Examples of optionally substituted C3^ cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that are selected for R17 and R”, the carbon to which R17 and R18 are attached may be a chiral center. In some embodiment, the carbon to which R17 and R18 are attached may be a 20 (R)-chiral center. In other embodiments, the carbon to which R17 and R18 are attached may be a (S)-chiral center.
[0104] In some embodiments, R5A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative and R!a can be an -Ooptionally substituted aryl. In other embodiments, RSA can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative and R3D can be an O-optionally substituted heteroaryl. In some embodiments, R3A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative and R3A 10 can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative.
[0105]
When RSA is
In some embodiments, R3A
rm o9A
Ao>yRMA
O , R8A and R9A can be independently selected from hydrogen, an optionally substituted C|_24 alkyl and an optionally substituted aiyl; and R,0A can be selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -Oheteroaryl and an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, Rsa and R9A can be hydrogen. In other embodiments, at least one of R8A and R9A can be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, RIOA can be hydrogen. In other embodiments, R,0A can be an optionally substituted Ci.24 alkyl. In some embodiments, R10A can be an unsubstituted Cm alkyl. In still other embodiments, RIOA can be an optionally substituted aryl. In yet still other embodiments, R,0Acan be -O-C].24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, RIOA can be an unsubstituted O-C m alkyl.
[0106]
In some embodiments, R!B can be
When R53 is dSE3
Αο>γΒ
O , Rsa and R9B can be independently selected from hydrogen, an optionally substituted Cj.» alkyl and an optionally substituted aryl; and RI0B can be selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -Oheteroaryl and an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, Rbb and R9D can be hydrogen. In other embodiments, at least one of R8B and R9B can be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, R,0B can be hydrogen. In other embodiments, R,0B can be an optionally substituted C1.24 alkyl. In some embodiments, RI0B can be an unsubstituted C « alkyl. In still other embodiments, RIOB can be an optionally substituted aryl. In yet still other embodiments, RIOB can be -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, Rl0B can be an unsubstituted O-C m alkyl.
[0107]
In some embodiments, R5A
In some embodiments, R3A can be
and R5B can be
and R,2A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; Rl3A can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl; and ZtA can be independently O (oxygen) or S (sulfur).
In some embodiments, R,lA and R,3A can be hydrogen. In other embodiments, at least one of RI,A and Rl2A can be an optionally substituted C|.24 alkyl or an optionally substituted aryl. In some embodiments, R,3A can be an optionally substituted C).j4 alkyl. In some embodiments, Ri3a can be an unsubstituted C m alkyl. In other embodiments, R,3a can be an optionally substituted aryl. In still other embodiments, RI3A can be an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, R,3a can be an unsubstituted 10 Ο-Cmalkyl. In some embodiments, Z,A can be O (oxygen). In other embodiments, Z,A can be or S (sulfur).
[0108] In some embodiments, R5B can be R13a, wherein R*IB and
R’28 can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; R,3B can be independently selected from hydrogen, an optionally 15 substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C|.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl; and ZIB can be independently O (oxygen) or S (sulfur). In some embodiments, R1,B and R128 can be hydrogen. In other embodiments, at least one of R118 and R,2B can be an optionally substituted C|.24 alkyl or an optionally substituted aryl. In 20 some embodiments, R*38 can be an optionally substituted C1.24 alkyl. In some embodiments, R'3B can be an unsubstituted C M alkyl. In other embodiments, R138 can be an optionally substituted aryl. In still other embodiments, R138 can be an optionally substituted —O-C1.24 alkyl, an optionally substituted -Ο-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, R,3B can be an unsubstituted 25 O-C m alkyl. In some embodiments, Z,B can be O (oxygen). In other embodiments, ZIB can be
or S (sulfur). In some embodiments, RSA can ollB o12B O
Ο
[0109] In some embodiments, R3A can be f .In some embodiments, R,4A can be hydrogen. In other embodiments, RI4A can be an optionally ___substituted C|.24 alkyl.. In still other embodiments, R'1a can be an optionally substituted aryl. In some embodiments, Rt4A can.be a Cu alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n5 butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, p can be 1. In other embodiments, p can be 2.
[0110] In some embodiments, R50 can be
In some embodiments, R,4B can be hydrogen. In other embodiments, RUB can be an optionally substituted C|.24 alkyl. In still other embodiments, Rl4B can be an optionally substituted aryl. In 10 some embodiments, RI4B can be a Cm alkyl, for example, methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, q can be 1. In other embodiments, q can be 2. In some embodiments, R3A can
O
O and RSB [0111] In some embodiments, R3A can can be
In some embodiments, RI3A can be hydrogen. In other embodiments, Rl3A can be an optionally substituted C|.24 alkyl. In still other embodiments, R,3A can be an optionally substituted aryl, for example, an optionally substituted phenyl. In some embodiments, Rt3A can be an optionally substituted Cm alkyl. In some embodiments, R,3A can be an unsubstituted Cm alkyl. In some 20 embodiments, s can be 3. In other embodiments, s can be 4. In still other embodiments, s can be
5.
[0112]
In some embodiments, R5B can be o
Rtsa
In some embodiments, R,ÎB can be hydrogen. In other embodiments, RIÎB can be an optionally -----substituted C1.24 alkyl.-In still other embodiments, R15? can bean optionally substituted aryl, for — —example, an optionally substituted phenyL- In some embodiments, RI3B can be an'optionally 5 substituted C|-e alkyl. In some embodiments, RI3B can be an unsubstituted alkyl. In some embodiments, t can be 3. In other embodiments, t can be 4. In still other embodiments, t can be
5.
In some embodiments, RÎA can be and RSB can be
O
Ao [0113] In some embodiments, RSA and/or RÎB can be isopropyloxycarbonyloxymethoxy (POC) group. In some embodiments, R3A and/or R3B can be pivaloyloxymethoxy (POM) group. In some embodiments, R3A and R!B can be both a isopropyloxycarbonyloxymethoxy (POC) group, and form a bis(îsopropyloxycarbonyloxymethoxy) (bisfPOC)) prodrug. In other embodiments, R3A and R33 can be both a pivaloyloxymethoxy (POM) group, and form a bisfpivaloyloxymethoxy) (bis(POM)) prodrug. In still other embodiments, R3A and R3B can be both a S-acylthioethyl (SATE)-O- group and form a SATE ester prodrug. In some embodiments, R3A and RÎB can be the same. In other embodiments, R3A and R3B can be different [0114] In some embodiments, both-----can be each a single bond; R4 can be zv*absent; R3 can be oxygen (O); and Rp can be Rp1 r* , wherein Zp can be oxygen (O) or sulfur (S) and Rpl can be selected from O’, OH, an -O-optionally substituted Cm alkyl. an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester
dérivative. When both ----are each a single bond, Formula (B can hâve the structure:
___R”’______________
----—: [0115] — In some embodiments,-Rpl_can be O'.- In other embodiments, Rpl can be OH.
In other embodiments, Rpl can be an -O-optionally substituted alkyi. For example, Rpl can 5 be a substituted or an unsubstituted version of the following: methoxy, ethoxy, π-propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched or straight chained) and hexoxy (branched or straight chained).
[0116] In some embodiments, Rpl can
O wherein Rp2 and Rp3 can be independently selected from hydrogen, an optionally substituted C1.24 alkyi and an optionally 10 substituted aryl; and R**4 can be selected from hydrogen, an optionally substituted Ci-m alkyi, an optionally substituted aryl, an optionally substituted —O-C1.24 alkyi, an optionally substituted O-aryl, an optionally substituted -Ο-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, Rpï and Rp3 can be hydrogen. In other embodiments, at least one of Rp2 and Rp3 can be an optionally substituted C1.24 alkyi or an optionally substituted 15 aryl. In some embodiments, R1* can be an optionally substituted C1.24 alkyi. In some embodiments, R1*4 can be an unsubstituted Cu alkyi. In other embodiments, R1*4 can be an optionally substituted aryl. In still other embodiments, R^can be an optionally substituted —OCj-24 alkyi, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl or an optionally substituted -O-monocyclic heterocyclyl. In some embodiments, R1*4 can be an 20 unsubstituted —O-Cm alkyi.
[0117] In some embodiments, Rpl can be
RpT wherein RpS and
R1*6 can be independently selected from hydrogen, an optionally substituted C1.24 alkyi and an optionally substituted aryl; Rp7 can be independently selected from hydrogen, an optionally substituted Cj.24 alkyi, an optionally substituted aryl, an optionally substituted —O-C1.24 alkyi, 25 an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl; and Zpl can be independently O (oxygen) or S (sulfur).
In some embodiments, Rp5 and R1* can be hydrogen. In other embodiments, at least one of Rp5
and R1* can be an optîonally substituted Ct.24 alkyl or an optîonally substituted aryl. In some embodiments, Rp7 can be an optîonally substituted C1.24 alkyl. . In some embodiments, Rp7 can be an unsubstituted Cm alkyl. In other embodiments, Rp7 can be an optîonally substituted aryl. In still other embodiments, Rp7 can be an optîonally substituted —O-Ci.24 alkyl, an optîonally
-5 . substituted -O-aryl, an optîonally substituted -O-heteroaryl or an optîonally substituted -O-mônôcyclic heterocyclyl-Insome embodiments, Rp- can·bean unsubstituted—O-CRalkyl. In some embodiments, 2?” can be O (oxygen). In other embodiments, Zpl can be or S (sulfur). In some embodiments, Rpl can be isopropyîoxycarbonyloxymethyloxy (POC) group. In some embodiments, Rpl can be pivaloyloxymethyloxy (POM) group.
O
IO [0118] In some embodiments, RpI can be r . In some embodiments, Rp8 can be hydrogen. In other embodiments, R*18 can be an optîonally substituted C|-24 alkyl. In still other embodiments, Rpa can be an optîonally substituted aryl. In some embodiments, Rpg can be a Cm alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight15 chained). In some embodiments, r can be 1. In other embodiments, r can be 2.
[0119] In some embodiments, Rp can be u .In some embodiments, R1*9 can be hydrogen. In other embodiments, R1*9 can be an optîonally substituted C|.24 alkyl. In still other embodiments, R1*9 can be an optîonally substituted aryl, for example, an optîonally substituted phenyl. In some embodiments, RP9 can be an optîonally substituted Cm 20 alkyl. In some embodiments, R1* can be an unsubstituted Cm alkyl. In some embodiments, u can be 3. In other embodiments, u can be 4. In still other embodiments, u can be 5. In some embodiments, Rpl can be a S-acylthioethy! (S ATE) group and form a SATE ester prodrug.
[0120] In some embodiments, Rpl can be an optîonally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. For example, Rpl can be 25 optionally substituted version of the followîng: alanine, asparagine, aspartate, cysteîne, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanîne, threonine, tryptophan, valine and ester dérivatives thereof. In some embodiments, RpI can be selected from N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester and N-leucine isopropyl ester. In some
embodiments, RpI can hâve the structure
wherein Rplû can be selected from hydrogen, an optionally substituted Cm-alkyl, an optionally substituted Cm cycloalkyl, an ——optionally substituted aryl, an optionally substituted aryl(CM alkyl) and anoptionally substituted haloalkyl; Rptl can be selected from hydrogen; an'optionally substituted Cm alkyl, an optionally 5 substituted Cm haloalkyl, an optionally substituted Cm cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryl(CM alkyl); and Rpt2 can be hydrogen or an optionally substituted CM-alkyl; or Rpl1 and Rpn can be taken together to form an optionally substituted C3^ cycloalkyl.
[0121] When RpU is substituted, RpU 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 embodiments, Rpl< can be an unsubstituted C^·alkyl, such as those described herein. In some embodiments, RpU can be hydrogen. In other embodiments, Rp” can be methyl. In some embodiments, Rpl° can be an optionally substituted Cm alkyl. Examples of optionally substituted Cj^-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chaîned), and hexyl (branched and straightchained). In some embodiments, Rp,° can be methyl or isopropyl. In some embodiments, Rpt0 can be ethyl or neopentyl. In other embodiments, Rp,° can be an optionally substituted Cm cycloalkyl. Examples of optionally substituted Cm cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, Rpl° can be an optionally substituted cyclohexyl. In still other embodiments, Rp,° can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, RpI° can be an optionally substituted aryl(CM alkyl). In some embodiments, Rp,° can be an optionally substituted benzyl. In some embodiments, Rpl° can be an optionally substituted Cm haloalkyl, for example, CF3. In some embodiments, Rpl2 can be hydrogen. In other embodiments, Rpl2 can be an optionally substituted CM-alkyl, such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl and tert-butyl. In some embodiments, Rpt2 can be methyl. In some embodiments, Rp” and Rpl2 can be taken together to form an optionally substituted Cm cycloalkyl. Examples of optionally substituted Cm cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for Rph and RpI2, the carbon to which RpU and RpI2 are attached may be a chiral center. In some embodiment, the carbon to which RpU and Rp12 are attached may be a (Æ)-chiral center. In other embodiments, the carbon to which Rpl1 and RpI2 are attached may be
[0123] The nucleobase can vary. In some embodiments, B1 can be uracil. In some embodiments. B1 can be an optionally substituted
O
In some embodiments, B1 can
In other embodiments. B1 canbe an optionally substituted
In some embodiments. B1 can be unsubstituted . In some embodiments, RSA can be an optionally substituted C]_6 alkyl. For example, R6A can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In other embodiments, RfiA can be an optionally substituted cycloalkyl, for example, optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
(0124] In some embodiments, B1 can be guanine. In some embodiments, B1 can be
. In other embodiments, B’ can be an optionally
an optionally substituted ~w·
wherein R68 can be selected from hydrogen, an unsubstituted C[_6 alkyl, an unsubstituted C34 alkenyl, an unsubstituted C34 alkynyl and an unsubstituted
. In some cycloalkyl. In some embodiments, B1 can be unsubstituted embodiments, R6B can be an unsubstituted alkyl. For example, R68 can be methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained). In some embodiments, R68 can be an unsubstituted C3.6 alkenyl. In other embodiments, RSB can be an unsubstituted Cm alkynyl. In stîll other embodiments, R6B can be an unsubstituted Cm cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0125] In some embodiments, B1 can be an optionally substituted
ΛΛΛΤ wherein R60 can be selected from hydrogen, an unsubstituted Cm alkyl, an
unsubstituted Cm alkenyl, an unsubstituted Cm alkynyl and an unsubstituted C3^ cycloalkyl. In c
L
NH2 some embodiments, B* can be unsubstituted . In some embodiments, R60 can be hydrogen. In some embodiments, R60 can be an unsubstituted Cm alkyl. For example, R60 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chaîned) or hexyl (branched and straight-chained). In some embodiments, R60 can be an ethyl. In some embodiments, R60 can be an unsubstituted Cm alkenyl. In other embodiments, R6C can be an unsubstituted Cm alkynyl. In other embodiments, R6C can be an unsubstituted C3.
cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0126] In some embodiments, B1 can be adenine. In some embodiments. B* can be
r6D λΑ | |
''''trV | |
an optionally substituted aX | wherein X’ can be N (nitrogen) or -CR61; RM can |
be selected from hydrogen, halogen, an optionally substituted Cm alkyl, an optionally substituted . C3.6 alkenyl and an optionally substituted Cm alkynyl; ReD can be NHR60; R6E can be hydrogen, halogen or NHR6H; R60 can be selected from hydrogen, an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl, an optionally substituted Cm cycloalkyl, -C(=O)RAl and C(=O)0RA2; R6H can be selected from hydrogen, an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl, an optionally substituted Cm cycloalkyl, -CfsOjR*3 and C(=O)ORA4j Ra1, R*2, R*3 and RA4 can be independently selected from Cm alkyl, C3^ alkenyl,
Cm alkynyl, Cm cycloalkyl, Cm cycloalkcnyl, Ce-io aryl, heteroaryl, beterocyclyl, aiyl(CM alkyl), heteroaryl(CM alkyl) and heterocycIyl(CM alkyl). In some embodiments, X1 can be N (nitrogen). In other embodiments, X* can be - CR61, wherein CR61 can be selected from hydrogen, halogen, an optionally substituted Cm alkyl, an optionally substituted C2.6 alkenyl and 5 an optionally substituted Cm alkynyl. In some embodiments, X* can be CH. In some embodiments, R6D and R6E can be both NH2. In other embodiments, at least one of R6D and R6E can be NH2. In some embodiments, R6D can be NHR60, wherein R60 can be an optionally substituted Cm alkyl. In some embodiments, R6E can be hydrogen. In other embodiments, R6E can be halogen. In still other embodiments, R6E can be NHR6H, wherein R6H can be an 10 optionally substituted Cm alkyl. In other embodiments, R6D can be NHR60, wherein R60 can be selected from an optionally substituted Cm alkenyl, an optionally substituted Cm cycloalkyl, C(=O)RA1 and -C(=O)ORA2. In other embodiments, RSE can be NHR6H, wherein RSH can be selected from an optionally substituted Cm alkenyl, an optionally substituted cycloalkyl, C(=O)RM and -C(=O)ORA4. In some embodiments, R60 and R6E can be the same. In other embodiments, R6D and R6E can be different.
[0127] In some embodiments. B1 can be cytosine. In some embodiments, B* can be o6F
an optionally substituted wherein R6F can be NHR6’; R61 can be selected hydrogen, an optionally substituted Cm alkyl» an optionally substituted Cm alkenyl, an optionally substituted Cm cycloalkyl, -C(=O)RA5 and -C(=O)ORA6; and RM and RAS are independently selected from the group conslsting of Cm alkyl. Cm alkenyl, Cm alkynyl, C3< cycloalkyl. Cm cycloalkenyl, O-io aryl, heteroaryl, heterocyclyl, aryl(CM alkyl), heteroaryl(CM alkyl) and heterocyclyl(CM alkyl). In some embodiments, R6F can be NH2. In other embodiments, R6F can be NHR61, wherein R6’ can be an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl or an optionally substituted Cm cycloalkyl. In still other embodiments, R6F can be NHR61, wherein R61 can be -€(=0^ or -C(=O)ORA6. When R6’ is -CizOjR*5 or C(=O)0RA6, R*5 and RA6 can be Cm alkyl, Cm alkenyl or Cm alkynyl. R*5 and RA6 can also be Cm cycloalkyl. Cm cycloalkenyl, Ce-m aryl or heteroaryl, heterocyclyl. Additionally, R*3 and RAfi can be aiyl(CM alkyl), heteroaryl(CM alkyl) or heterocyclyl(CM alkyl).
[0128] In some embodiments, Z1 can be O (oxygen). In other embodiments, Z1 can be S (sulfur).
[0129] In some embodiments, R2 is not halo. In some embodiments, R2 is not fluoro.
In some embodiments, RÎB is not an -O-optionally substituted aryl. In some embodiments, R3B is not an -O-unsubstituted aryl. In some embodiments, RSA is not N-alanine isopropyl ester. In some embodiments, R1 is not an optionally substituted Cm alkyl. For example, R1 is not an — 5 - - unsubstituted - Cm alkyl,- such as-methyl.-Inr some; embodiments,- B Vis not air optionally
- substituted uracil, for example, a halo-substituted uraciL In some embodiment, when both----- are each absent; Rp is absent; R3 is OH or -OC(=O)R’; R2 is F; and R1 is methyl, ethyl or ethenyl; then R4 cannot be selected from H and
wherein RSB is an -O-unsubstituted
and Z1 is oxygen. In some embodiments, R2 is not halo (such as fluoro) when B1 is uracil. In some embodiments, a compound of Formula (I) is not a compound in WO 2013/092481 (filed December 17,2012).
[0130] Example structures of a compound of Formula (I) include the following:
4l
Rp1 , or a pharmaceutically acceptable sait of the foregoing. In some embodiments of this paragraph, R3 can be OH. In some embodiments of this paragraph, R60 can be an unsubstituted Cm alkyl. such as CH2CH3. In some embodiments of this paragraph, Rpl can be -O-unsubstituted Cm alkyl. In some embodiments, of this paragraph, R* 5 can be H. In other embodiments, of this paragraph, R4 can be a phosphoroamidate group. In still other embodiments, of this paragraph, R4 can be a phosphate group (such as a mono-, di- or triphosphate). In yet still other embodiments, of this paragraph, R4 can be a thiophosphoroamidate group. In some embodiments, of this paragraph, R4 can be thiophosphate group (such as an alpha-thîomono-, alpha-thiodi- or alpha-thiotri-phosphate). In some embodiments of this 10 paragraph, Rp 1 can be -O-ethy 1, -O-isopropyl or -O-isobutyl.
[0131] Examples of compounds of Formula (I) include the following:
foregoing. .
or a pharmaceutically acceptable sait of the
[0132] Additional examples of compounds of Formula (I) include the following:
H , or a pharmaceutically acceptable sait of the foregoing.
hoJLJ-o-L
OH OH OH
pharmaceutically acceptable sait of the foregoing.
[0134] Examples of compounds of Formula (I) include the following:
[0135] Further examples of compounds of Formula (I) include the following:
foregoing.
[0136]
Further examples of compounds of Formula (I) include the following:
Ah Ah Ah , or a pharmaceutically acceptable sait of the foregoing.
P—O—P—OAh Ah A
x
[0137] Additional examples of compounds of Formula (I) include the following:
[0138] In some embodiments, a compound of Formula (I) cannot be selected from:
, or a pharmaceutically acceptable sait of the foregoing. described herein, a compound of Formula (I), or a pharmaceutically
R50— acceptable sait thereof, can hâve R4 being RÎA ; R3A being an optionally substituted Nlinked amino acid or an optionally substituted N-linked amino acid ester dérivative; and R50 being an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, an -Ooptionally substituted heterocyclyl, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. By neutralizîng the charge on the phosphate or thiophosphate, pénétration of the cell membrane may be facilitated as a resuit of 10 the increased Iipophilicity ofthe compound. Once absorbed and taken inside the cell, the groups attached to the phosphores can be easily removed by esterases, proteases and/or other enzymes.
In some embodiments, the groups attached to the phosphores can be removed by simple hydrolysis. Inside the cell, the phosphate thus released may then be metabolized by cellular enzymes to the diphosphate or the active triphosphate. Likewise, the thio-phosphate may be 15 metabolized to the alpha-thiodiphosphate or the alpha-thiotriphosphate. Furthermore, in some embodiments, varying the substituents on a compound described herein, such as compound of Formula (I), can help maintain the efficacy of such the compound by reducing undesirable effects, such as isomerization.
[0140] In some embodiments, the phosphorylation of a thio-monophosphate of a compound of Formula (I), or pharmaceutically acceptable sait thereof, can be stereoselective.
For examplc, a thio-monophosphate of a compound of Formula (I) can be phosphorylated to give an alpha-thiodiphosphate and/or an alpha-thiotriphosphate compound that can be enriched in the
5i (R) or (S) diastereomer with respect to the 5*-0-phosphonous atom. For example, one of the (Λ) and (S) configuration with respect to the 5’-0-phosphorous atom of the alpha-thiodiphosphate 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 5 to the 5’-0-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 S’-O-phosphorous atom. In 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’-O-phosphorous atom.
IO [0141] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can act as a chain terminator of HCV réplication. For example, compounds of Formula (I) can contain a moiety at the 2’-carbon position such that once the compound is incorporated into an RNA chain of HCV no further élongation is observed to occur. For example, a compound of Formula (D can contain a 2’-carbon modification wherein R1 is a non-hydrogen group selected from an optionally substituted Cu alkyl, an optionally substituted C2-c alkenyl, an optionally substituted C2^alkynyl and an optionally substituted C3^ cycloalkyl.
[0142] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve increased metabolic and/or plasma stability. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be 20 more résistant to hydrolysis and/or more résistant to enzymatic transformations. For example, a 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 is îdentical in structure but for having a hydrogen în place of the fluoro at the 4’-position. In some 25 embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve împroved properties. A non-limiting list of example properties include, but are not limited to, increased biological half-life, increased bioavailability, increase potency, a sustained in vivo response, increased dosing intervals, decreased dosing amounts, decreased cytotoxîcity, réduction in required amounts for treating disease conditions, réduction in viral load, réduction in time to séroconversion (i.e., the virus becomes undetectable în patient sérum), increased sustained viral response, a réduction of morbidity or mortality in clinical outcomes, increased subject compliance, decreased lîver conditions (such as liver fibrosis, lîver cirrhosis 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
grenier than 24 hours. In some embodîments, q compound of Formula (I), or a pharmaceutically acceptable sait thereof, can hâve a biologtcal half-life greater than a compound that is identical in structure but for having a hydrogen in place of the fluoro at the 4’-positîon. In some embodîments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can 5 hâve more potent antiviral activity (for example, a lower ECjo in an HCV replicon assay) as ----compared to the cuiront standard of care; In some embodîments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, does not significantly inhibit mitochondrial fonction of the mitochondrial RNA polymerase. For example, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, is incorporated in the human mitochondrial RNA 10 polymerase less than 10% compared to the naturel 5*-triphosphate nucléotide with the same B1.
[0143] Additionally, in some embodîments, the presence of a thîophosphoroamidate, phosphoroamidate, thiophosphorbîsamidate or phosphorbisamidate in a compound of Formula (I) can increase the stability of the compound by inhibiting its dégradation. Also, in some embodîments, the presence of a thîophosphoroamidate, phosphoroamidate, 15 thiophosphorbîsamidate or phosphorbisamidate can make the compound more résistant to cleavage in vivo and provide sustained, extended efficacy. In some embodîments, a thîophosphoroamidate, phosphoroamidate, thiophosphorbîsamidate or phosphorbisamidate can facilitate the pénétration of the cell membrane by a compound of Formula (I) by making the compound more lipophilie. In some embodîments, a thîophosphoroamidate, phosphoroamidate, 20 thiophosphorbîsamidate or phosphorbisamidate can hâve improved oral bîoavailability, improved aqueous stability and/or reduced risk of byproduct-related toxicity. In some embodîments, for comparison purposes, a compound of Formula (I) can be compared to a compound that is identical în structure but for having a hydrogen in place of the fluoro at the 4’position.
Synthesis [0144] Compounds of Formula (I) and 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 (ï) are shown in Scheme 1 and 30 2, and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to bc construed, to limit the scope of the daims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed synthèses and to devise altemate routes based on the disclosures herein; ail such modifications and altemate routes are within the scope of the daims.
[0145] Compounds of Formula (I) can be prepared using various methods known to those skilled in the art Examples of methods are shown in Schemes 1 and 2. Suitable phosphores containing precursors can be commercially obtained or prepared by synthetic methods known to those skilled in the art Examples of general structures of phosphores — 5 —containing precursors are shown inSchemes-l-and 2,-and include-phosphorochloridates and --thiophosphorochloridates? -S uîtable- phosphorochloridates and- thiophosphorochloridates are commercially available and/or can be synthetically prepared.
Scheme 1
(C) [0146] One method for forming a compound of Formula (I) is shown in Scheme 1. In Scheme 1, Rla, R1*, R3’ and Bu can be the same as R*, R2, R3 and B1 as described herein for
Formula (T)· In some embodiments, a compound of Formula (I) can be generated from a compound of Formula (A) and a compound of Formula (B) or a compound of Formula (A) and a 15 compound of Formula (C) using an organometallîc reagent such as a Grignard reagent Suitable
Grignard reagents are known to those skilled in the art and include, but are not limited to, alky(magnésium chlorides and alkylmagnesium bromides. In other embodiments, an appropriate base can be used to form a compound of Formula (I). Examples of suitable bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di- and tri20 alkylamines (e.g., triethylamîne)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole)).
[0147] When compounds of Formula (I) has Z1 beîng sulfur, the sulfur can be added în various manners. In some embodiments, the sulfur can be part of the phosphores containing S ™ Il R5B_p—ci precursor, for example, R5* . Altematively, one of the oxygens attached to the phosphores can be exchanged with a sulfur using a sulfurization reagent. Suitable sulfurization
agents are known to those skilled in the art, and include, but are not limited to, elemental sulfur, Lawesson’s reagent, cyclooctasulfiir, 3H-l,2-Benzodithiole-3-one-l,l-dioxide (Beaucage’s reagent), 3-((N,N-dimethylaminomethylidene)amino)-3H-l,2,4-dithiazo!e-5-thione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST). .
-----Scheme 2 -
[0148] A phosphorus containîng precursor can be coupled to the nucleoside, for example, a compound of Formula (A). Following the coupling of the phosphorus containîng 10 precursor, any leaving groups can be cleaved under suitable conditions, such as hydrolysis. In Scheme 2, R1’, R2*, R3’ and B*0 can be the same as R1, R2, R3 and B1 as described herein for Formula (I). Further phosphorus containîng groups can be added using methods known to those skilled in the art, for example using a pyrophosphate. If desired, one or more bases can be used during the addition of each phosphorus-containing group. Examples of suitable bases are 15 described herein.
[0149] As described herein, in some embodiments, R2 and R3 can be each an oxygen atom, wherein the oxygen atoms are linked together by a carbonyl groups. The -O-C(=O)-Ogroup can be formed using methods known to those skilled in the art For example, a compound of Formula (I), wherein R2 and R3 are both hydroxy groups, can be treated with 1,120 carbonyldiimîdazole (CDD.
[0150] In some embodiments, R2 and/or R3 can be -OC(=O)R12 and -OC(=O)R8, respeccively. The -OC(=O)R12 and -OC(=O)R8 groups can be formed at the 2’- and 3’-positions using various methods known to those skilled in the art As an example, a compound of Formula (D, wherein R2 and R3 are both hydroxy groups, can be treated with an alkyl anhydride 25 (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 417338 ► 55 dimethylaminopyridine (DMAP). Altematively, the -OC(=O)R12 and -OC(=O)R* groups can bc formed at the 2*- and 3'-positions by reactîng an alkyl acid (e.g. ace tic acid and propionic acid) in the présences of a carbodiimide or a coupling reagent. Examples of carbodiimides include, but are not limited to, NJT-dicyclohexylcarbodiimîde (DCC), Ν,Ν’-diisopropyIcarbodiimide 5 (DIC) and 1 -ethy!-3-(3-dimethylaminopropyl) carbodiimide (EDC)...
------[0151] - 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 R2 and/or R3 is/are hydroxy group(s), the hydroxy group(s) can be protected with suitable protecting groups, such as triarylmethyl and/or silyl groups. Examples of triarylmethyl groups 10 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 (4,5dichlorophthalimido) trityl (CPTr), 4,4',4-tris (levulînyloxy) trityl (TLTr), p-anisyl-1naphthylphenylmethyl, di-o-anisyl-l-naphthyl methyl, p-tolyldipheylmethyl, 3(imidazolylmethyl)-4,4'-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) 15 xanthen-9-yl (Mox), 4-decyloxytrityl, 4- hexadecyloxytrityl, 414'-dioctadecyltrityl, 9-(4octadecyloxyphcnyl) xanthen-9-yl, l,r-bis-(4-methoxyphenyl)-l'-pyreny! methyl, 4,4’,4-tris(tert-butylphenyl) methyl (TTTr) and 4,4'-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups are described herein and include trimethylsilyl (TMS), rert-butyldimethylsilyl (TBDMS), triisopropyisilyl (TIPS), tert-butyldîphenylsîlyl (TBDPS), tri-iro-propylsilyloxymethyl and [220 (trimethylsilyl)ethoxy]methyl. Altematively, R2 and/or R3 can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclîc ketal. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2oxacyclopentylidene orthoester, dimcthoxymethylene orthoester, I-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene orthoester, phthalide orthoester 1,225 dimethoxyethylidene orthoester, and alpha-methoxybenzylidene orthoester, suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3(benzyloxy)propyl acetal, benzylidene acetal, 3,4-dimethoxybenzylidene acetal and pacetoxybenzylidene acetal; and suitable cyclic ketals include l-t-butylethylidene ketal, Iphenylethylidene ketal, isopropylidene ketal, cyclopentylidcnc ketal, cyclohexylidene ketal, 30 cycloheptylidene ketal and l-(4-methoxyphenyl)ethylidene ketal.
Pharmaceutical Compositions [0152] Some embodiments described herein relates to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a
compound of Formula (I)), 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 (1), or a pharmaceutically acceptable sait thereof, (for example, a single diastereomer is présent in the - 5 — 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 diastereomer of > 50%, > 60%, > 70%, > 80%, > 90%, > 95%, or 10 > 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.
[0153] The term “pharmaceutical composition refers to a mixture of one or more compounds disclosed herein with other chemîcal components, such as diluents or carriers. The 15 pharmaceutical composition facilitâtes administration of the compound to an organisai. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, ni trie acid, phosphoric acid, mcthanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be taîlored to the spécifie intended route of 20 administration. A pharmaceutical composition is suitable for human and/or veterinary applications.
[0154] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
[0155] As used herein, a “carrier” refera 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 [0156] As used herein, a “diluent” refera to an ingrédient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or 30 désirable. For example, a diluent may be used to increase the bulk of a potent drug whose 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.
[0157] As used herein, an “excipient refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consîstency, stability, binding ability, fabrication, disintegrating ability etc., to the composition. A “diluent is a type of excipient.
- r—[0158] — The pharmaceutical compositions described herein can be administered to a ---human patient per se, or in pharmaceutical compositions wherethey-are mixed with other active ingrédients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dépendent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in 10 the art [0159] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dîssolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletîng processes. Additionally, the active ingrédients are contained in an amount effective to achieve its intended 15 purpose. Man y of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
[0160] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, toptcal, aérosol, injection and parentéral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct 20 intraventricular, intraperitoneal, intranasal and intraocular injections.
[0161] One may also adminîster 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 adminîster the compound in a targeted drug delivecy System, for example, in a liposome coated with a tîssue-specific antibody. 25 The liposomes will be targeted to and taken up selectively by the organ.
[0162] 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 dispenser may also 30 be accompanied with a notice associated with the container in form prescribed by a govemmental agency regulating 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 labeüng approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that ►
can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
-Methods of Us&—; ——----------[0163]-— Some embodiments disclosed herein relate to-amethod of treating and/or ameliorating a disease or condition that can include administering to a subject an effective amount of one or more compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a 10 compound described herein, or a pharmaceutically acceptable sait thereof. Other embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject identified as suffering from the disease or condition an effective amount of one or more compounds described herein, such as a compound of Formula (I). or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a 15 compound described herein, or a pharmaceutically acceptable sait thereof.
[0164] Some embodiments disclosed herein relates to a method of ameliorating or treating a HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein (for example, a compound of Formula (I)), or a pharmaceutical composition that includes one or more 20 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 HCV infection that can include administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds 25 described herein. 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 HCV infection by administering to a subject identified as suffering from a HCV infection an effective amount of one or more compounds described herein.
[0165] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a HCV infection that can include contacting a ccll infected with the hepatîtîs C 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 ► 59 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 HCV infection that can include contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s). Still other -5 ^embodiments described herein relate to one or more compounds described herein, or a —pharmaceutical ly-acceptab le sait - of- a · compound- described- - herein, - that- can- : be- used for ameliorating and/or treating a HCV infection by contacting a cell infected with the hepatitis C . virus with an effective amount of said compound(s).
[0166] Some embodiments disclosed herein relate to methods of inhibiting 10 réplication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C 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 15 compounds described herein, or a pharmaceutically acceptable sait of a compound described herein, in the manufacture of a médicament for inhibiting réplication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C 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 20 inhibiting réplication of a hepatitis C virus by contacting a cell infected with the hepatitis C virus with an effective amount of said compound(s).
[0167] In some embodiments, the compound can be a compound of Formula (I), or a pharmaceutical acceptable sait thereof, wherein R4 is hydrogen. In other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (D is a mono, di, 25 or triphosphate, or a pharmaceutically acceptable sait of the foregoing. In still other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (D is a thiomonophosphate, alpha-thiodi phosphate, or alpha-thiotriphosphate, or a pharmaceutically acceptable sait of the foregoing. In yet still other embodiments, the compound can be a compound of Formula (I), wherein compound of Formula (I) is phosphoroamidate or 30 phosphorbisamidate, or a pharmaceutically acceptable sait of the foregoing. In some embodiments, the compound can be a compound of Formula (1), wherein compound of Formula (I) is thiophosphoroamidate or thiophosphorbisamidate, or a pharmaceutically acceptable sait of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutical acceptable sait thereof, that can be used to ameliorating and/or treating a viral infection (for
example, a HCV infection) and/or inhibit réplication of a virus (such as a HCV virus) can be any of the embodiments provided in any of the embodiments described in paragraphs [0090]-[0138 ].
[0168] HCV is an enveloped positive strand RNA virus in the Flaviviridae famity. There are various nonsttuctural proteins of HCV, such as NS2, NS3, NS4, NS4A, NS4B, NS5A ---5 t—and NS5B.- NS5B îs believed to be an RNA-dependent RNA polymerase involved in the ~ réplication of HCV-RNA.-----'-----— ----------:--------- - [0169] Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include contacting a cell infected with hepatitis C virus with an effective amount of a compound of Formula (T), or a pharmaceutical acceptable sait thereof.
Some embodiments described herein relate to a method of inhibiting NS5B polymerase activity that can include administering to a subject infected with hepatitis C virus an effective amount of a compound of Formula (I), or a pharmaceutical acceptable sait thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can inhibit a RNA dépendent RNA polymerase, and thus, inhibit the réplication of HCV RNA. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can inhibit a HCV polymerase (for example, NS5B polymerase).
[0170] Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrhosis and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering to the subject an 20 effective amount of a compound or a pharmaceutical composition described herein (for example, a compound of Formula (I). or a pharmaceutical acceptable sait thereof), wherein the liver condition is caused by 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 compound or a pharmaceutical composition described herein 25 (for example, a compound of Formula (I), or a pharmaceutical acceptable sait thereof). Also contemplated is a method for reducing or eliminating 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 Formula (D, or a pharmaceutical acceptable sait thereof). In some embodiments, this method 30 can include slowing or halting the progression of liver dîsease. In other embodiments, the course of the dîsease can be reversed, and stasis or improvement in liver fonction is contemplated. In some embodiments, liver fibrosis, liver cirrhosis and/or liver cancer can be treated; liver fonction can be increased; virus-caused liver damage can be reduced or eliminated; progression of liver dîsease can be slowed or halted; the course of the liver dîsease can be reversed and/or liver
fonction can be improved or maintained by contacting a cell infected with hepatitis C virus with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable sait thereof.) [0171] There are a variety of génotypes of HCV, and a variety of subtypes within - =-5 --each génotype. For example,rat présent itis known that there are eieven (numbered 1 through 11) --main'génotypes of HCV,- although others hâve classified the génotypes as 6 main génotypes.
Each of these génotypes is further subdivided into subtypes (la-le; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a- 7b; 8a-8b; 9a; 10a; and 1 la). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutical acceptable sait thereof, or a pharmaceutical composition that 10 includes an effective amount of a compound of Formula (I), 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 Formula (I), 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 Formula (I), or a 15 pharmaceutical acceptable sait thereof) can be effective to treat 3 or more, 5 or more, 7 or more, or 9 or more génotypes of HCV. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable sait thereof can be more effective against a larger number of HCV génotypes than the standard of care. In some embodiments, a compound of Formula (I), or a pharmaceutical acceptable sait thereof, can be more effective against a particular HCV génotype 20 than the standard of care (such as génotype 1,2,3,4,5 and/or 6).
[0172] Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Examples 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 undetectable in patient sérum), an increase in the rate of sustained viral 25 response to therapy, a réduction of morbidity or mortality in clinical outcomes, a réduction in the rate of liver fonction decrease; stasis in liver fonction; improvement in liver fonction; réduction in one or more markers of liver dysfonction, including alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase and/or other indicator of disease response. Similarly, successfol therapy with an effective amount of a 30 compound or a pharmaceutical composition described herein (for ex ample, a compound of Formula (I), or a pharmaceutical acceptable sait thereof) can reduce the incidence of liver cancer in HCV infected subjects.
[0173] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, is an amount that is effective to reduce HCV viral
titers to undetectable levels, for example, to about 100 to about 500, to about 50 to about 100, to about 10 to about 50, or to about 15 to about 25 international units/mL sérum. In some embodiments, an effective amount of a compound of Formula (D. or a pharmaceutically acceptable sait thereof, is an amount that is effective to reduce HCV viral load compared to the - ^=r5— HCV-viral -load beforeadministratiorrof the compound af Formula (I), onr pharmaceutically --------—acceptable sait thereof;— For-example,-wherein the-HCV- viral load-is-measured before administration of the compound of Formula (I), or a pharmaceutically acceptable sait thereof, and again after complet ion of the treatment régime with the compound of Formula (I), or a pharmaceutically acceptable sait thereof (for example, 1 month after completion). In some 10 embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be an amount that is effective to reduce HCV viral load to lower than about 25 international units/mL sérum. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, is an amount that is effective to achieve a réduction in HCV viral titer in the sérum of the subject in the range of 15 about 15-log to about a 25-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), or a pharmaceutically acceptable sait thereof. For example, the HCV viral load can be measured before administration of the compound of Formula (I), or a pharmaceutically acceptable sait thereof, and again after completion of the treatment régime with the compound of 20 Formula (I), or a pharmaceutically acceptable sait thereof (for example, 1 month after completion).
[0174] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can resuit in at least a 1, 2, 3, 4,5, 10, 15, 20, 25, 50,75, 100-fold or more réduction in the réplication of the hepatitîs C virus relative to pre-treatment levels in a 25 subject, as determined after completion of the treatment régime (for example, 1 month after completion). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can resuit in a réduction of the réplication of the hepatitis C virus 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 30 Formula (I), or a pharmaceutically acceptable sait thereof, can resuit in a réduction of the hepatitis C virus réplication in the range of 1 to 15 log, 15 log to 2 log, 2 log to 25 log, 25 to 3 log, 3 log to 35 log or 35 to 4 log more réduction of the hepatitis C virus réplication compared to the réduction of the hepatitis C virus réduction achieved by pegylated interferon in combination with ribavirin, administered according to the standard of care, or may achieve the
same réduction 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.
[0175] In some embodiments, an effective amount of a compound of Formula (I), or — 5 ·=·a pharmaceutically acceptable salt thereof, is an amountthat is effective·to achieve-a sustained • -------viral response, for example,· non-dctectable or substantially ποη-detectable HCV RNA (e.g., less than about 500, less than about 200, less than about 100, less than about 25, or less than about 15 international units 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 cessation of therapy.
[0176] In some embodiments, an effective amount of a compound of Formula (1), or a pharmaceutically acceptable sait thereof, can reduce a level of a marker of liver fïbrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, ut least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 15 60%, at least about 65%, at least about 70%, at least about 75%, or at Jeast 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., enzyme-linked immunosorbent assays (ELIS A), radioimmunoassays, and the like, using antibody spécifie for a given sérum marker. A non20 limiting list of examples of markers includes measuring the levels of sérum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptîdase (GGT) and total bilirubin (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 IU/L, GGT in the range of 0-51 IU/L, TBIL in the range of 03-1.9 mg/dL is considered normal. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with what is considered a normal level.
[0177] Subjects who are clinically diagnosed with HCV infection include “naïve” 30 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 individuals who hâve faîled 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 sufïiciently reduced by a previous treatment for HCV (< 03 log lU/mL), for example, a previous IFN-alpha
monotherapy, a prevîous 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 IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and —.5—ribavirin combination therapy,-whoseHCV titer decreased, and subsequently increased).
-----[0178]—-In-some-embodiments,- a compound-of-Fonnulâ~(I),L6r '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 embodiments, a 10 compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered to a relapsed subject suffering from HCV.
[0179] 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, after treatment 15 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 (for example, an agent used in a 20 conventional standard of care). In some embodiments, development of résistant HCV strains is delayed when a subject is 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 (such as an agent used in a conventional standard of care).
[0180] In some embodiments, an effective amount of a compound of Formula (I), or 25 a pharmaceutically acceptable sait thereof, can be administered to a subject for whom other antiHCV 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 (I), or a 30 pharmaceutically acceptable sait thereof, can be provided to a subject that is hypersensitive to interferon and/or ribavirin.
[0181] 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 acceptable sait thereof, can be administered to a subject experiencing viral load rebound, or can prevent such viral load rebound when used to treat the subject.
[0182] The standard of care for treating HCV has been associated with several side -5— effeçts--(adverse±events).7mht’ some.~embodiments,-arCompound-of-Formu!a (I), or a -pharmaceutically acceptable sait thereof; can decrease the number and/or severity of sîde 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, arthraJgias, myalgias, fatigue, apathy, loss of appetîte, 10 nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritabîlity, confusion, dépréssion, severe dépréssion, suicidai idéation, anémia, tow white blood cell counts, and thinning of haîr. 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 (for 15 example, an agent used in a conventional standard of care).
[0183] Table 1 provides some embodiments of the percentage improvement obtained using a compound of Formula (I), or a pharmaceutically acceptable sait thereof, as 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 non20 responders that is 10% Jess 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 in a number of 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 25 thereof, results in 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 standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art
Table 1
Percentage ofnonresponders | Percentage of relapsers | Percentage of résistance | Percentage of viral load rebound | Number of side effects | Severity of side efTects |
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% less | 40% less |
507o‘less— | 50%1ess | 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% Jess |
about 10% to about 30% less | about 10% to about 30% less | about 10% to about 30% less | about 10% to about 30% less | about 10% to about 30% less | about 10% to about 30% less |
about 20% to about 50% less | about 20% to about 50% less | about 20% to about 50% less | about 20% to about 50% less | about 20% to about 50% less | about 20% to about 50% less |
about 30% to about 70% less | about 30% to about 70% less | about 30% to about 70% less | about 30% to about 70% less | about 30% to about 70% less | about 30% to about 70% less |
about 20% to about 80% less | about 20% to about 80% less | about 20% to about 80% less | about 20% to about 80% less | about 20% to about 80% less | about 20% to about 80% less |
[0184] As used herein, a subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and 5 invertebrates such as fish, shellfish, reptiles and, in particular, mammals. Mammal includes, without limitation, mice, rais, rabbits, guinea 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.
[0185] As used herein, the terrns “treating,” “treatment,” “therapeutic,” or therapy” 10 do not necessarily mean total cure or abolition of the disease or condition. Any alleviation 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 worsen the patient's overall feeling of welt-being or appearance.
[0186] The terrns “therapeutically effective amount” and “effective amount” are used 15 to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or médicinal response îndicated. For example, an effective amount of compound can be the amount needed to prevent, alleviate or ameJiorate symptoms of disease or prolong the survival of lhe subject being treated This response may occur in a tîssue, System, animal or human and > 67 includes alleviation of the signs or symptoms of the disease being treated. Détermination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will dépend on the route of administration, the type of animal, including human, being treated, and -5- - the physical characteristics ôf the spécifie anima! under considération. Thé dose can be tailored —^-Tto - achieve-a -desÎred effect,- but will dépend on · such : factors as' weight, diet, concurrent médication and other factors which those skilled in the medical arts will recognize.
[0187] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the âge, 10 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 methods, for example, human clinical trials and in vitro studies.
[0188] 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 dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral 20 dose of between 0.01 mg and 3000 mg of each active ingrédient, preferably between 1 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 continuons therapy, for example for a week or more, or for months or years. In some embodiments, a compound of Formula (I). or a 25 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), or a pharmaceutically acceptable sait thereof, can be administered one time per day. For example, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered one time per day to a subject suffering from a HCV infection. In 30 some embodiments, the total time of the treatment régime with a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can less compared to the total time of the treatment régime with the standard of care.
[0189] 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 newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from EDjo or ID50 values, or other appropriate values derived from m vitro or in vivo studies, as qualified by toxicity ---_ 5—studies and efficacy studies in animais. — .
;-----.---- —[0190] —In cases of-àdministration 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 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 10 aggressi vely treat particularly aggressive diseases or infections.
[0191] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maîntain lhe modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will dépend on îndividual 15 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 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 20 may not be related to plasma concentration.
[0192] 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 dysfonctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adéquate (precluding toxicity). The magnitude of an administrated 25 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, the dose and perhaps dose frequency, will also vary according to the âge, body weight, and response of the îndividual patient A program comparable to that discussed above may be used in veterinary medicine.
[0193] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chcmical 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 mode!, such as mice. rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using se vend recognized methods, such as in vitro methods.
animal models, or human clinîcal trials. When selecting a model to détermine efficacy, the ——5 ski lied artisan can be guided by the state of the art to choose an appropriate model, dose, route of
- administration-and/or regîme^rr— :: -. _ ·— — — Combination Thérapies . __, . ___[0194] In some embodiments, the compounds disclosed herein, such as a compound 10 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, can be used in combination with one or more addîtional agent(s). Examples of addïtîonal 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 15 pharmaceutically acceptable sait thereof, include, but are not limited to, agents currently used in a conventional standard of care for treating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of Formula (AA), (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (AA), or a pharmaceutically acceptable sait thereof), compounds of Formula (BB) 20 (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (BB), or a pharmaceutically acceptable sait thereof), compounds of Formula (CC) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (CC), or a pharmaceutically acceptable sait thereof), and/or combinations thereof. In some embodiments, a compound of Formula (I), or a 25 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 examplcs 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 pharmaceutically 30 acceptable sait thereof, is provided in Tables A, B, C, D and E.
[0195] 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 agent(s) currently used in a conventional standard of care therapy. For example, for the treatment of
HCV, a compound disclosed herein can be used in combination with Pegylated interferon-alphala (brand name PEGASYS®) and ribavirin, Pegylated interferon-alpha-2b (brand name PEGINTRON®) and ribavirin, Pegylated interferon-alpha-2a, Pegylated interferon-al pha-2b, or ribavirin.
— 5- ----- -.-[0196] — -In some embodiments, a compoundrof 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 substituted for an agent currently used in a conventional standard pf 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 10 includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be used in place of ribavirin.
[0197] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (D, or a pharmaceutically acceptable sait thereof, can be used in combination with an interferon, 15 such as a pegylated interferon. Examples of suitable interferons include, but are not limited to, Pegylated interferon-alpha-2a (brand name PEGASYS®), Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferon alfacon-l (brand name INFERGEN®), pegylated interferon lambda and/or a combination thereof.
[0198] In some embodiments, a compound of Formula (I), or a pharmaceutically 20 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, Π3Χ-32Ο, ACH-1625, ACH25 2684, TMC-435, ΓΓΜΝ-191 (DANOPREVIR®) and/or a combination thereof. Additîonal HCV protease inhibitors suitable for use 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 VP-19744, PSI879, VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479, R-1626, 30 R-7I82, MK-O6O8, INX-8014, INX-8018, A-848837, A-837093, BILB-194I. VCH-916, VCH716, GSK-71185, GSK-625433, XTL-2125 and those disclosed in PCT Publication No. WO 2012/142085, which is hereby incorporated by référencé for the limited purpose of its disclosure of HCV protease inhibitors, HCV polymerase inhibitors and NS5A inhibitors. A non-limiting
list of example HCV protease inhibitors includes the compounds numbered 1001-1016 in Figure
1.
[0199] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula ---5 — (D.-or a pharmaceutically acceptable, sait thereof,-. can ;be- used-in combinatiorrwith 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 non-nucleoside inhibitor. Examples of suitable nucleoside .inhibitors.include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189, PSI-352938, PSI-661, 4’-azidouridine (including known 10 prodrugs of 4*-uzidouridine), GS-6620, IDX-184, and TMC649128 and/or combinations thereof.
A non-limiting list of example nucleoside inhibitors includes compounds numbered 2001-2012 in Figure 2. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof. A non-limiting list of example non-nucleoside inhibitors 15 includes the compounds numbered 3001-3014 in Figure 3. Further HCV polymerase inhibitors suitable for use in combination with a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (1), or a pharmaceutically acceptable sait thereof, include VX-500, VX-813, VBY-376, TMC435350, EZ-058, EZ-063, GS-9132, ACH-1095, IDX-136, IDX-316, ΓΓΜΝ-8356, ΓΓΜΝ-8347, 20 ΓΓΜΝ-8096, ΓΓΜΝ-7587, VX-985, and those disclosed in PCT Publication No. WO
2012/142085.
[0200] 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 NS5A 25 inhibitor. Examples of NS5A inhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A non-limiting list of example NS5A inhibitors includes the compounds numbered 4001-4012 in Figure 4. Additional NS5A inhibitors suitable for use 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 30 pharmaceutically acceptable sait thereof, include A-832, PPI-1301 and those disclosed în PCT Publication No. WO 2012/142085.
[0201] 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 other antiviral
compounds. Examples of other antiviral compounds include, but arc not limited to, Debio-025, MIR-122, cydosporin A and/or combinations thereof. A non-limiting list of example other antiviral compounds includes the compounds numbered 5001-5012 in Figure 5.
[0202] In some embodiments, a compound of Formula (I), or a pharmaceutically —_ 5 - acceptable sait thereof, or a pharmaceutical composition that-includes a compound of Formula
----(I); or-a pharmaceutically acceptable-salt thereof,-can beused in combination with a compound of Formula (AA), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (AA), or a pharmaceutically acceptable sait thereof (see,
U.S. Publication No. 2013/016-4261, published June 27, 2013, the contents of which are incoiporated by référencé in its entirety):
S H r2a*O——O—P1M
I .. ..
riaa τ'·,**ι>η
H*)--R3*** R4M Formula (AA) wherein: B**1 can be an optionally substituted hcterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R**1 can be selected from O*, OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R**2 can be absent or selected from hydrogen, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and O
AAI H rAAÎq--p
I
,AA, wherein R**6, R**7 and R**’ can be independently absent or hydrogen, and can be 0 or 1; provided that when RAA1 is O' or OH, then R*^ is absent,
O rAA8q_ J1
OR**7
hydrogen or
OR^9 and -OC^OJR^10; R**4 can be selected from halogen, -ORAAI1 and -OC(=O)R‘ R**3 and R**4 can be both an oxygen atom which are linked together by a carbonyl group; R**3 can be selected from hydrogen, halogen, .^îor can be selected from an optionally substituted Cm alkyl, an optionally substituted C26 alkenyl, an optionally substituted Cm alkynyi and an optionally substituted Cm cycloalkyl; or R**4 and R**5 together can form -(Cm alkyl)-O- or -O-(Cm alkyl)-; RAA9 and R^11 can be 25 independently hydrogen or an optionally substituted Cm alkyl; and R**10 and R**12 can be independently an optionally substituted Cm alkyl or an optionally substituted Cm cycloalkyl. A
non-limîting list of examples of compounds of Formula (AA) includes the compounds numbered 7000-7027 in Figure 7.
[0203] In some embodîments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula -^-5-^(1), 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. Publication No. 2012/0165286, published June 28, 2012, the contents of which are incorporated by référencé in their entireties):
wherein Bbbi 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); RBBI 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) 15 and N(RBB,°); RBB2 and R8B3 can be independently selected from hydrogen, an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl, an optionally substituted C2.e alkynyl, an optionally substituted Cm haloalkyl and an optionally substituted aryl(Ci-6 alkyl); or RBB2 and RBB3 can be taken together to form a group selected from an optionally substituted Cm cycloalkyl, an optionally substituted Cm cycloalkenyl, an optionally substituted axyl and an 20 optionally substituted Cm heteroaryl; RBB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl, an optionally substituted Cm alkynyl and an optionally substituted allenyl; RBBS can be hydrogen or an optionally substituted Cm alkyl; RBBS can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted Cm alkyl, -ORBB“ and -OC(=O)RBB,Î; RBB7 can be selected 25 from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -ORDBI3 and OC(=O)RBBI4; RBBa can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -ORBBlï and -OC(=O)RDB’e; 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(CI^alkyI), an optionally substituted heteroaiyl(Ci^alkyl) and an optionally substituted heterocyclyl(Ci^alkyl); RBBt0 can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, -5— anoptionallyT substituted cycloalkyl, an-_optionally substituted-cycloalkenylr-an-optionally substituted-arylran-optionally substituted heteroaryl,- an optionally substituted heterocyclyl, an optionally substituted aryl(Ci^alkyl), an optionally substituted heteroaryl(Ci^alkyl) and an optionally substituted heterocyclyl(Ci^alkyl); RBBI1, RBB,Î and RBB1S can be independently hydrogen or an optionally substituted C|4 alkyl; and RBBl2, RBB*4 and RBBIfi can be independently an optionally substituted Cw alkyl or an optionally substituted Cm cycloalkyl. In some embodiments, at least one of RBB2 and RBB3 is not hydrogen. A non-limiting lîst of example compounds of Formula (BB) includes the compound numbered 8000-8016 in Figure 8.
[0204] 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 (CC), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes a compound of Formula (CC), or a pharmaceutically acceptable sait thereof (see, U.S. Publication No. 2012/0071434, published March 22, 2012, the contents of which are incorporated by référencé In its entirety):
rCCôrcct Formula (CC) wherein Bœi can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R001 can be selected from O', OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R002 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and
L
ORœw , Jn' , wherein
R009, and R001 can be independently absent or hydrogen, and η° can be 0 or 1 ; provided
independently selected from hydrogen, deuterium, an optionally substituted Cm alkyl, an —- ”-~optionally~substituted’Cz^alkenÿlrlüiroptionallÿ-substïtûtëd^Cïi alkynÿl,1 anJoptionally ' ~ ‘'substituted Ci5'halôalkyland arylfCi^àlkyl); or R^^and R^h can beTaken together to form 5 an optionally substituted Cm cycloalkyl; R004 can be selected from hydrogen, azido, an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl and an optionally substituted Cm alkynyl; R003 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -ORCC,° and -OC(=O)Rccl1; R0 6 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -OR002 and 10 OC(=O)Rccl3; R*07 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl, -ORœt4 and -OC^OJR0013; or R006 and RCCT can be both oxygen atoms and linked together by a carbonyl group; R008 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted Cm alkyl. -OR006 and -OC(=O)Rccl7; R6” can be selected from hydrogen, azido, cyano, an optionally substituted Cm alkyl and -OR6018; R0010, Rœl2, 15 R004, RCCIS and R008 can be independently selected from hydrogen and an optionally substituted Cm alkyl; and R001, R^13, R0013 and R007 can be independently selected from an optionally substituted Cm aJkyl and an optionally substituted Cm cycloalkyl. In some embodiments, when R00’, R005, Rœ4, Rra, R00, R008 and R009 are ail hydrogen, then R*·06 is not azido. In some embodiments, R”2 cannot be
ÔRœi9 . Jn' |CC when R003* is hydrogen, R005 is hydrogen, Rœ4 is H, R013 is OH or H, RCC6 is hydrogen, OH, or OC(=O)CH3, R007 is hydrogen, OH, OCH3 or -OC(=O)CH3, R008 is hydrogen, OH or OCH3, R009 is H and BŒI is an optionally substituted adenine, an optionally substituted guanine, an optionally substituted uracil or an optionally substituted hypoxanthine. In some embodiments,
R02 cannot be
A non-limiting list of examples of compounds of Formula (CC) includes the compounds numbered 6000-6078 in Figure 6.
[0205] Some embodiments described herein relate to a method of ameliorating or treating a HCV infection that can include contacting a cell infected with the HCV infection with
an effective amount of a compound of Formula (I), 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 (CC), or a
- - 5 pharmaceutically acceptable sait of any of the aforementioned compounds.
- [0206]---Some embodiments described herein-relate ta a method. of ameliorating or treating a HCV infection that can include administering to a subject suffering from the HCV infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more agents selected from an interferon, ribavirin, a 10 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 (CC), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
[0207] Some embodiments described herein relate to a method of inhibiting the réplication of a hepatitis C virus that can include contacting a cell infected with the hepatitis C 15 virus with an effective amount of a compound of Formula (I), 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 (CC), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
[0208] Some embodiments described herein relate to a method of inhibiting the réplication of a hepatitis C virus that can include administering to a subject infected with the hepatitis C virus an effective amount of a compound of Formula (I), 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 25 compound, a compound of Formula (AA), a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable sait of any of the aforementioned compounds.
[0209] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered with one or more additional agent(s) togelher tn a single pharmaceutical composition. In some embodiments, a compound of Formula (I), or a 30 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). 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 pharmaceutïcal composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
[0210] The dosing amount(s) and dosing schedule(s) when using a compound of -i— 5— Formula (I)< or a pharmaceutically acceptable sait thereof, or a pharmaceutïcal composition that -^includes à compound oFFormula (D, ora pharmaceutically acceptable sait thereof, and one or more additional agents are within the knowledge of those skilled in the art. For example, when performing a conventional standard of care therapy using art-recognized dosing amounts and dosing schedules, a compound of Formula (D, or a pharmaceutically acceptable sait thereof, or a 10 pharmaceutical composition that includes a compound of 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.
[0211] The order of administration of a compound of Formula (I), or a 15 pharmaceutically acceptable sait thereof, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (D, or a pharmaceutically acceptable sait thereof, can be administered prior to ail additional agents. In other embodiments, a compound of Formula (D, 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), or a pharmaceutically acceptable 20 sait thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (D, 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 Formula (I), or a pharmaceutically acceptable sait thereof, can be administered subséquent to the administration of ail additional agents.
[0212] 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 1-8 (încluding pharmaceutically acceptable salts and prodrugs thereof) can resuit in an addîtive effecL 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 1-8 (încluding pharmaceutically acceptable salts and prodrugs thereof) can resuit in a synergistic effecL In some embodiments, the combination of a compound of Formula (D, or a pharmaceutically acceptable sait thereof, în combination with one or more additional agent(s) in Figures 1-8 (încluding pharmaceutically acceptable salts and prodrugs thereof) can resuit in a strongly synergistic effect. In some embodiments, the combination of a compound of Formula > 78 (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts and prodrugs thereof) is not antagonistic.
[0213] 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 oFeach compound is-determined individualty (i.ft as a single compound). As used herein, the term “synergistic effect” means that the activity of the 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 10 herein, the term “additive 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 individually.
[0214] 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 15 Figures 1-8 (including pharmaceutically acceptable salts thereof) may be a réduction in the required amountfs) of one or more compounds of Figures 1-8 (including pharmaceutically acceptable salts 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 1-8 (including pharmaceutically acceptable salts thereof) are 20 administered without a compound of Formula (I), or a pharmaceutically acceptable sait thereof.
For example, the amount of a compound in Figures 1-8 (including a pharmaceutically acceptable sait thereof), can be less compared to the amount of the compound in Figures 1-8 (including a pharmaceutically acceptable sait thereof), needed to achieve the same viral load réduction when administered as a monotherapy. Another potential advantage of utilizing a compound of 25 Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof) is that the use of two or more compounds having different mechanîsm of actions can croate a higher barrier to the development of résistant viral strains compared to the barrier when a compound is administered as monotherapy.
[0215] 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 1-8 (including pharmaceutically acceptable salts 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 1-8 (including pharmaceutically acceptable salts
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 1-8 (including pharmaceutically acceptable salts thereof); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more -5- -additional agent(s) in Figures4-8-(including pharmaceutically acceptabltsalis thereof); little to --no significant effects on cytochrome-P450; little to no- pharmacokinetic in te radions between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) in Figures 1-8 (including pharmaceutically acceptable salts thereof); greater percentage of subjects achievîng a sustained viral response compared to when a compound is 10 administered as monotherapy and/or a decrease in treatment time to achieve a sustained viral response compared to when a compound is administered as monotherapy.
[0216] A non-lîmiting 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, 15 D and E. Each numbered X and Y compound in Tables A, B, C, D and E has a correspondîng name and/or structure provided in Figures 1-8. The numbered compounds in Tables A, B, C, D and E includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions containing the compounds or a pharmaceutically acceptable sait thereof. For example, 1001 includes the compound correspondîng to 1001, pharmaceutically acceptable salts 20 thereof, and pharmaceutical compositions that include compound 1001 and/or a pharmaceutically acceptable sait thereof. The combinations exemplifïed in Tables A, B, C, D and E 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 1001:9004 in Table A represents a combination of compound 1001 with compound 9004, including pharmaceutically acceptable 25 salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including pharmaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004). Thus, the combination designated as
1001:9004 in Table A represents the combination of Telaprevîr (compound 1001, as shown in
(compound 9004, as shown in Figure 9),
so including pharmaceutically acceptable salts of compound 1001 and/or 9004, and pharmaceutical compositions including compound 1001 and 9004 (including phannaceutical compositions that include pharmaceutically acceptable salts of compound 1001 and/or compound 9004). Each of the combinations provided in Tables A, B, C, D and E can be used with one, two, three or more . — 5 — additional agents, described. herein; In some-embodimentrriescribed hereinr-the combination of
-agents can be used to treat-,amé!iorateand/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 |
1001 | 9000 | 1001:9001 | 1001:9002 | 1001 | 9003 | 1001:9004 | 1001 | 9005 |
1002 | 9000 | 1002 : 9001 | 1002 : 9002 | 1002 | 9003 | 1002:9004 | 1002 | 9005 |
1003 | 9000 | 1003:9001 | 1003 : 9002 | 1003 | 9003 | 1003:9004 | 1003 | 9005 |
1004 | 9000 | 1004:9001 | 1004:9002 | 1004 | 9003 | 1004:9004 | 1004 | 9005 |
1005 | 9000 | 1005 : 9001 | 1005:9002 | 1005 | 9003 | 1005 : 9004 | 1005 | 9005 |
1006 | 9000 | 1006:9001 | 1006:9002 | 1006 | 9003 | 1006:9004 | 1006 | 9005 |
1007 | 9000 | 1007 : 9001 | 1007:9002 | 1007 | 9003 | 1007:9004 | 1007 | 9005 |
1008 | 9000 | 1008:9001 | 1008:9002 | 1008 | 9003 | 1008:9004 | 1008 | 9005 |
1009 | 9000 | 1009:9001 | 1009:9002 | 1009 | 9003 | 1009:9004 | 1009 | 9005 |
1010 | 9000 | 1010:9001 | 1010:9002 | 1010 | 9003 | 1010:9004 | 1010 | 9005 |
1011 | 9000 | 1011:9001 | 1011:9002 | 1011 | 9003 | 1011:9004 | 1011 | 9005 |
1012 | 9000 | 1012 : 9001 | 1012:9002 | 1012 | 9003 | 1012:9004 | 1012 | 9005 |
1013 | 9000 | 1013 : 9001 | 1013:9002 | 1013 | 9003 | 1013:9004 | 1013 | 9005 |
1014 | 9000 | 1014 : 9001 | 1014:9002 | 1014 | 9003 | 1014:9004 | 1014 | 9005 |
1015 | 9000 | 1015:9001 | 1015:9002 | 1015 | 9003 | 1015:9004 | 1015 | 9005 |
1016 | 9000 | 1016:9001 | 1016:9002 | 1016 | 9003 | 1016:9004 | 1016 | 9005 |
2001 | 9000 | 2001 :9001 | 2001:9002 | 2001 | 9003 | 2001:9004 | 2001 | 9005 |
2002 | 9000 | 2002 : 9001 | 2002:9002 | 2002 | 9003 | 2002:9004 | 2002 | 9005 |
2003 | 9000 | 2003 : 9001 | 2003:9002 | 2003 | 9003 | 2003:9004 | 2003 | 9005 |
2004 | 9000 | 2004:9001 | 2004:9002 | 2004 | 9003 | 2004:9004 | 2004 | 9005 |
2005 | 9000 | 2005:9001 | 2005:9002 | 2005 | 9003 | 2005:9004 | 2005 | 9005 |
2006 | 9000 | 2006:9001 | 2006:9002 | 2006 | 9003 | 2006:9004 | 2006 | 9005 |
2007 | 9000 | 2007:9001 | 2007:9002 | 2007 | 9003 | 2007:9004 | 2007 | 9005 |
2008 | 9000 | 2008 : 9001 | 2008:9002 | 2008 | 9003 | 2008:9004 | 2008 | 9005 |
2009 | 9000 | 2009 : 9001 | 2009:9002 | 2009 | 9003 | 2009:9004 | 2009 | 9005 |
2010 | 9000 | 2010:9001 | 2010:9002 | 2010 | 9003 | 2010:9004 | 2010 | 9005 |
2011 | 9000 | 2011:9001 | 2011:9002 | 2011 | 9003 | 2011:9004 | 2011 | 9005 |
2012 | 9000 | 2012:9001 | 2012:9002 | 2012 | 9003 | 2012:9004 | 2012 | 9005 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | ||
1001:9006 1002:9006 1003:9006 1004:9006 Ίθ03 7'9006: -1006:90061007:9006 1008:9006 1009:9006 1010:9006 1011:9006 1012:9006 1013:9006 1014:9006 1015 : 9006 1016:9006 2001:9006 2002:9006 2003 : 9006 2004:9006 2005 : 9006 2006:9006 2007:9006 2008:9006 2009:9006 2010:9006 2011:9006 2012:9006 | 1001:9007 1002:9007 1003 : 9007 1004:9007 ΊΓ005:9007 Ί006τ9007 1007:9007 1008 : 9007 1009:9007 1010:9007 1011:9007 1012:9007 1013 : 9007 1014 : 9007 1015 : 9007 1016:9007 2001:9007 2002:9007 2003 : 9007 2004:9007 2005:9007 2006:9007 2007:9007 2008:9007 2009:9007 2010:9007 2011:9007 2012:9007 | 1001:9008 1002:9008 1003:9008 1004:9008, ίθΟ5:9008 -1006-:-90081007:9008 1008 : 9008 1009:9008 1010:9008 1011:9008 1012 : 9008 1013 : 9008 1014:9008 1015:9008 1016:9008 2001:9008 2002:9008 2003:9008 2004:9008 2005:9008 2006:9008 2007:9008 2008:9008 2009 : 9008 2010 : 9008 2011:9008 2012 : 9008 | 1001:9009 1002:9009 1003 : 9009 1004:9009 100579009 -1006-: 9009 1007 ^ 9009 1008 : 9009 1009 : 9009 1010:9009 1011:9009 1012 : 9009 1013 : 9009 1014 : 9009 1015 : 9009 1016 : 9009 2001:9009 2002:9009 2003:9009 2004 : 9009 2005 : 9009 2006 : 9009 2007 : 9009 2008 : 9009 2009 : 9009 2010:9009 2011:9009 2012:9009 | 1001 1002 1003 1004 Ί(Χ)5~ -1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 | 9010 9010 9010 9010 '9010' -9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 9010 | 1001 1002 1003 1004 1005 -1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 | 9011 9011 9011 9011 '9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 9011 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ |
1001:9012 1002:9012 1003 : 9012 -1004:9012 1005 : 9012 -1006:9012 1007 : 9012 1008:9012 1009:9012 1010:9012 1011:9012 1012:9012 1013:9012 1014:9012 1015:9012 1016:9012 2001:9012 2002:9012 2003 : 9012 2004 : 9012 2005 : 9012 2006 : 9012 2007 : 9012 2008 : 9012 2009 : 9012 2010:9012 2011:9012 2012 : 9012 | 1001:9013 1002:9013 1003 : 9013 1004:9013 1005 : 9013 -1006:9013’ 1007 : 9013 1008 : 9013- 1009 : 9013 1010:9013 1011:9013 1012:9013 1013:9013 1014:9013 1015:9013 1016:9013 2001:9013 2002 : 9013 2003 : 9013 2004:9013 2005 : 9013 2006 : 9013 2007:9013 2008:9013 2009 : 9013 2010:9013 2011:9013 2012:9013 | 1001:9014 1002:9014 1003:9014 1004:9014 1005:9014 -1006 ^9014 1007 : 9014 1008:9014 1009 : 9014 1010:9014 1011:9014 1012:9014 1013:9014 1014:9014 1015:9014 1016:9014 2001:9014 2002:9014 2003:9014 2004 : 9014 2005:9014 2006 : 9014 2007:9014 2008 : 9014 2009:9014 2010:9014 2011:9014 2012:9014 | 1001:9015 1002:9015 1003 : 9015 1004:9015 1005:9015 -1006:9015 1007 : 9015 1008:9015 1009 : 9015 1010:9015 1011:9015 1012:9015 1013:9015 1014:9015 1015:9015 1016:9015 2001:9015 2002:9015 2003:9015 2004:9015 2005 : 9015 2006:9015 2007 : 9015 2008:9015 2009:9015 2010:9015 2011:9015 2012:9015 | 1001:9016 1002:9016 1003:9016 1004:9016 1005 : 9016 -1006:9016 1007:9016 1008:9016 1009:9016 1010:9016 1011:9016 1012:9016 1013:9016 1014:9016 1015:9016 1016:9016 2001:9016 2002:9016 2003 : 9016 2004 : 9016 2005:9016 2006:9016 2007:9016 2008:9016 2009:9016 2010:9016 2011:9016 2012:9016 | 1001:9017 1002:9017 1003 : 9017 1004:9017 1005 : 9017 -1006:9017 1007:9017 1008:9017 1009:9017 1010:9017 1011:9017 1012:9017 1013:9017 1014:9017 1015:9017 1016:9017 2001:9017 2002:9017 2003 : 9017 2004:9017 2005 : 9017 2006:9017 2007:9017 2008:9017 2009:9017 2010:9017 2011:9017 2012:9017 |
X | :Y | X | :Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | |
1001 | 9018 | 1001 | 9019 | 1001:9020 | 1001:9021 | 1001:9022 | 1001:9023 | |
1002 | 9018 | 1002 | 9019 | 1002:9020 | 1002:9021 | 1002:9022 | 1002:9023 | |
1003 | 9018 | 1003 | 9019 | 1003:9020 | 1003 : 9021 | 1003:9022 | 1003:9023 | |
— | -1004 | 9018 | 1004 | 9019 | 1004:9020 | 1004:9021 | 1004:9022 | 1004:9023 |
---_ - _ | cl005 | 9018 | 1005 | 9019 | .1005 : 9020 | 1005:9021 | .1005:9022 | 1005 : 9023 |
-- - ----— | -1006 | 9018- | 1006 | 5019 | ίΐ006 :-9020 | -lOOfr: 9021 | -1006-: 9022 | -1006:9023 |
1007 | 9018 | 1007 | 9019 | 1007 : 9020 | 1007:9021 | 1007:9022 | 1007:9023 | |
1008 | 9018 | 1008 | 9019 | 1008:9020 | 1008:9021 | 1008:9022 | 1008:9023 | |
* | 1009 | 9018 | 1009 | 9019 | 1009:9020 | 1009:9021 | 1009:9022 | 1009:9023 |
1010 | 9018 | 1010 | 9019 | 1010:9020 | 1010 : 9021 | 1010 : 9022 | 1010:9023 | |
1011 | 9018 | 1011 | 9019 | 1011:9020 | 1011:9021 | 1011:9022 | 1011:9023 | |
1012 | 9018 | 1012 | 9019 | 1012:9020 | 1012:9021 | 1012:9022 | 1012:9023 | |
1013 | 9018 | 1013 | 9019 | 1013 : 9020 | 1013 : 9021 | 1013:9022 | 1013 : 9023 | |
1014 | 9018 | 1014 | 9019 | 1014:9020 | 1014:9021 | 1014:9022 | 1014:9023 | |
1015 | 9018 | 1015 | 9019 | 1015:9020 | 1015 : 9021 | 1015:9022 | 1015 : 9023 | |
1016 | 9018 | 1016 | 9019 | 1016:9020 | 1016 : 9021 | 1016:9022 | 1016:9023 | |
2001 | 9018 | 2001 | 9019 | 2001:9020 | 2001:9021 | 2001:9022 | 2001:9023 | |
2002 | 9018 | 2002 | 9019 | 2002:9020 | 2002:9021 | 2002 : 9022 | 2002:9023 | |
2003 | 9018 | 2003 | 9019 | 2003:9020 | 2003 : 9021 | 2003 : 9022 | 2003 : 9023 | |
2004 | 9018 | 2004 | 9019 | 2004:9020 | 2004:9021 | 2004:9022 | 2004:9023 | |
2005 | 9018 | 2005 | 9019 | 2005:9020 | 2005:9021 | 2005:9022 | 2005:9023 | |
2006 | 9018 | 2006 | 9019 | 2006 : 9020 | 2006:9021 | 2006:9022 | 2006 : 9023 | |
2007 | 9018 | 2007 | 9019 | 2007 : 9020 | 2007:9021 | 2007:9022 | 2007:9023 | |
2008 | 9018 | 2008 | 9019 | 2008:9020 | 2008:9021 | 2008:9022 | 2008:9023 | |
2009 | 9018 | 2009 | 9019 | 2009:9020 | 2009:9021 | 2009 : 9022 | 2009:9023 | |
2010 | 9018 | 2010 | 9019 | 2010 : 9020 | 2010:9021 | 2010:9022 | 2010:9023 | |
2011 | 9018 | 2011 | 9019 | 2011:9020 | 2011:9021 | 2011:9022 | 2011:9023 | |
2012 | 9018 | 2012 | 9019 | 2012:9020 | 2012:9021 | 2012:9022 | 2012:9023 |
:Y :9024 :9024 :9024 :9024 :9024 r9024* :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024 :9024
Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ |
1001:9025 | 1001:9026 | 1001:9027 | 1001:9028 | 1001:9029 |
1002 : 9025 | 1002:9026 | 1002 : 9027 | 1002:9028 | 1002:9029 |
1003 : 9025 | 1003:9026 | 1003 : 9027 | 1003 : 9028 | 1003:9029 |
1004:9025 | 1004:9026 | 1004:9027 | 1004:9028 | 1004:9029 |
1005 : 9025 | 1005 Τ9026 | 1005:9027 | '1005:9028 | -1005:9029 |
• 1006τ9025- | -.1006^9026- | 1006t9027 | *1006 Γ9028 | /1006:9029 |
1007 : 9025 | 1007 : 9026 | 1007 : 9027 | 1007 : 9028 | 1007 : 9029 |
1008:9025 | 1008:9026 | 1008:9027 | 1008:9028 | 1008:9029 |
1009:9025 | 1009:9026 | 1009:9027 | 1009 : 9028 | 1009:9029 |
1010 : 9025 | 1010:9026 | 1010:9027 | 1010 : 9028 | 1010:9029 |
1011:9025 | 1011:9026 | 1011:9027 | 1011:9028 | 1011:9029 |
1012:9025 | 1012:9026 | 1012:9027 | 1012 : 9028 | 1012:9029 |
1013:9025 | 1013:9026 | 1013 : 9027 | 1013:9028 | 1013:9029 |
1014:9025 | 1014:9026 | 1014:9027 | 1014 : 9028 | 1014:9029 |
1015:9025 | 1015 : 9026 | 1015:9027 | 1015:9028 | 1015:9029 |
1016 : 9025 | 1016:9026 | 1016:9027 | 1016:9028 | 1016:9029 |
2001 :9025 | 2001:9026 | 2001:9027 | 2001:9028 | 2001 :9029 |
2002:9025 | 2002:9026 | 2002 : 9027 | 2002 : 9028 | 2002:9029 |
2003 : 9025 | 2003 : 9026 | 2003 : 9027 | 2003:9028 | 2003:9029 |
2004:9025 | 2004:9026 | 2004 : 9027 | 2004:9028 | 2004:9029 |
2005:9025 | 2005 : 9026 | 2005:9027 | 2005 : 9028 | 2005:9029 |
2006:9025 | 2006:9026 | 2006 : 9027 | 2006:9028 | 2006 : 9029 |
2007:9025 | 2007 : 9026 | 2007:9027 | 2007 : 9028 | 2007:9029 |
2008:9025 | 2008:9026 | 2008:9027 | 2008 : 9028 | 2008:9029 |
2009 : 9025 | 2009 : 9026 | 2009 : 9027 | 2009 : 9028 | 2009:9029 |
2010:9025 | 2010:9026 | 2010:9027 | 2010:9028 | 2010:9029 |
2011:9025 | 2011 :9026 | 2011 :9027 | 2011:9028 | 2011:9029 |
2012:9025 | 2012:9026 | 2012:9027 | 2012:9028 | 2012:9029 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X | :Υ |
1001:9030 | 1001:9031 | 1001 :9032 | 1001:9033 | 1001:9034 | 1001 | 9035 |
1002:9030 | 1002:9031 | 1002 : 9032 | 1002:9033 | 1002:9034 | 1002 | 9035 |
1003 : 9030 | 1003 : 9031 | 1003 : 9032 | 1003 : 9033 | 1003:9034 | 1003 | 9035 |
-1004:9030 | 1004:9031 | 1004 : 9032 | 1004:9033 | 1004:9034 | 1004 | 9035 |
Τ1ΟΟ5Γ9Ο3Ο' | '1005 903 Γ | •1005 : 9032 | 1005 : 9033 | 1005:9034 | 1005 | 9035 |
-1006:9030- | 1006r903l· | -1006^9032- | Π006τ9033· | -1006:9034 | -1006 | 9035 |
1007:9030 | 1007 : 9031 | 1007 : 9032 | 1007:9033 | 1007:9034 | 1007 | 9035 |
1008:9030 | 1008 : 9031 | 1008 : 9032 | 1008:9033 | 1008:9034 | 1008 | 9035 |
1009:9030 | 1009 : 9031 | 1009 : 9032 | 1009:9033 | 1009:9034 | Ί009 | 9035 |
1010:9030 | 1010 : 9031 | 1010:9032 | 1010:9033 | 1010:9034 | 1010 | 9035 |
1011:9030 | 1011:9031 | 1011:9032 | 1011:9033 | 1011:9034 | 1011 | 9035 |
1012:9030 | 1012 : 9031 | 1012:9032 | 1012:9033 | 1012:9034 | 1012 | 9035 |
1013:9030 | 1013 : 9031 | 1013:9032 | 1013:9033 | 1013:9034 | 1013 | 9035 |
1014:9030 | 1014 : 9031 | 1014:9032 | 1014:9033 | 1014:9034 | 1014 | 9035 |
1015:9030 | 1015 : 9031 | 1015:9032 | 1015:9033 | 1015:9034 | 1015 | 9035 |
1016:9030 | 1016:9031 | 1016:9032 | 1016:9033 | 1016 : 9034 | 1016 | 9035 |
2001:9030 | 2001:9031 | 2001 :9032 | 2001:9033 | 2001:9034 | 2001 | 9035 |
2002:9030 | 2002:9031 | 2002 : 9032 | 2002:9033 | 2002:9034 | 2002 | 9035 |
2003:9030 | 2003 : 9031 | 2003 : 9032 | 2003:9033 | 2003 : 9034 | 2003 | 9035 |
2004:9030 | 2004 : 9031 | 2004 : 9032 | 2004:9033 | 2004:9034 | 2004 | 9035 |
2005:9030 | 2005 : 9031 | 2005 : 9032 | 2005:9033 | 2005 : 9034 | 2005 | 9035 |
2006:9030 | 2006:9031 | 2006 : 9032 | 2006 : 9033 | 2006 : 9034 | 2006 | 9035 |
2007:9030 | 2007 : 9031 | 2007 : 9032 | 2007:9033 | 2007:9034 | 2007 | 9035 |
2008:9030 | 2008:9031 | 2008:9032 | 2008:9033 | 2008:9034 | 2008 | 9035 |
2009 : 9030 | 2009:9031 | 2009 : 9032 | 2009:9033 | 2009:9034 | 2009 | 9035 |
2010 : 9030 | 2010:9031 | 2010:9032 | 2010:9033 | 2010:9034 | 2010 | 9035 |
2011:9030 | 2011:9031 | 2011:9032 | 2011:9033 | 2011:9034 | 2011 | 9035 |
2012 : 9030 | 2012:9031 | 2012:9032 | 2012:9033 | 2012:9034 | 2012 | 9035 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ |
1001:9036 1002 : 9036 1003:9036 1004:90361005 : 9036-1006:9036’- 1007 : 9036 1008:9036 1009 : 9036 1010:9036 1011:9036 1012:9036 1013:9036 1014:9036 1015:9036 1016:9036 2001:9036 2002:9036 2003 : 9036 2004:9036 2005:9036 2006 : 9036 2007 : 9036 2008:9036 2009:9036 2010:9036 2011:9036 2012:9036 | 1001:9037 1002 : 9037 1003:9037 1004 : 90371005-: 9037 -1006 F9037·- 1007 : 9037 1008 : 9037 1009:9037 1010:9037 1011:9037 1012:9037 1013 : 9037 1014 : 9037 1015 : 9037 1016 : 9037 2001:9037 2002:9037 2003:9037 2004 : 9037 2005 : 9037 2006:9037 2007:9037 2008 : 9037 2009:9037 2010:9037 2011:9037 2012:9037 | 1001:9038 1002 : 9038 1003 : 9038 1004:9038 1005 : 9038 -1006:9038’ 1007 : 9038 1008:9038 1009 : 9038 1010 : 9038 1011:9038 1012:9038 1013 : 9038 1014:9038 1015 : 9038 1016:9038 2001:9038 2002 : 9038 2003 : 9038 2004 : 9038 2005:9038 2006:9038 2007 : 9038 2008:9038 2009:9038 2010 : 9038 2011:9038 2012:9038 | 1001:9039 1002:9039 1003:9039 1004:9039 1005:9039 -1006:9039 1007 : 9039 1008 : 9039 1009 : 9039 1010:9039 1011:9039 1012:9039 1013:9039 1014:9039 1015:9039 1016:9039 2001:9039 2002:9039 2003:9039 2004:9039 2005 : 9039 2006:9039 2007 : 9039 2008 : 9039 2009:9039 2010:9039 2011:9039 2012:9039 | 1001:9040 1002:9040 1003:9040 1004:9040 1005:9040 -700679040 1007:9040 1008:9040 1009:9040 1010:9040 1011:9040 1012 : 9040 1013:9040 1014 : 9040 1015:9040 1016:9040 2001:9040 2002 : 9040 2003 : 9040 2004:9040 2005:9040 2006 : 9040 2007 : 9040 2008:9040 2009:9040 2010:9040 2011:9040 2012:9040 | 1001:9041 1002:9041 1003:9041 1004:9041 1005 : 9041 “1006:9041 1007:9041 1008:9041 1009:9041 1010:9041 1011:9041 1012:9041 1013:9041 1014:9041 1015:9041 1016:9041 2001:9041 2002:9041 2003:9041 2004:9041 2005:9041 2006:9041 2007 : 9041 2008:9041 2009:9041 2010:9041 2011:9041 2012:9041 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | X: Y | Χ:Υ | |
1001:9042 | 1001 | 9043 | 1001:9044 | 1001:9045 | 1001:9046 | 1001:9047 |
1002:9042 | 1002 | 9043 | 1002:9044 | 1002 : 9045 | 1002 : 9046 | 1002:9047 |
1003:9042 | 1003 | 9043 | 1003 : 9044 | 1003 : 9045 | 1003 : 9046 | 1003 : 9047 |
1004:9042- | 1004 | 9043 | 1004 : 9044 | 1004:9045 | 1004:9046 | 1004:9047 |
1005:9042 | 1005 | 9043 | 1005:9044 | 1005:9045 | -1005 : 9046 | 1005:9047 |
-1006.-9042- | -1006' | -9043“ | -1006 79044- | -1006 τ 9045- | -1006 r9046- | -1006:9047 |
1007:9042 | 1007 | 9043 | 1007 : 9044 | 1007 : 9045 | 1007:9046 | 1007:9047 |
1008:9042 | 1008 | 9043 | 1008 : 9044 | 1008:9045 | 1008 : 9046 | 1008 : 9047 |
1009 : 9042 | 1009 | 9043 | 1009 : 9044 | 1009:9045 | 1009 : 9046 | 1009:9047 |
1010:9042 | 1010 | 9043 | 1010 : 9044 | 1010:9045 | 1010 : 9046 | 1010:9047 |
1011:9042 | 1011 | 9043 | 1011:9044 | 1011:9045 | 1011:9046 | 1011:9047 |
1012 : 9042 | 1012 | 9043 | 1012:9044 | 1012:9045 | 1012 : 9046 | 1012:9017 |
1013:9042 | 1013 | 9043 | 1013 : 9044 | 1013 : 9045 | 1013 : 9046 | 1013 : 9047 |
1014:9042 | 1014 | 9043 | 1014:9044 | 1014:9045 | 1014:9046 | 1014:9047 |
1015:9042 | 1015 | 9043 | 1015 : 9044 | 1015 : 9045 | 1015:9046 | 1015:9047 |
1016:9042 | 1016 | 9043 | 1016 : 9044 | 1016 : 9045 | 1016:9046 | 1016 : 9047 |
2001:9042 | 2001 | 9043 | 2001:9044 | 2001:9045 | 2001:9046 | 2001:9047 |
2002:9042 | 2002 | 9043 | 2002:9044 | 2002 : 9045 | 2002:9046 | 2002:9047 |
2003 : 9042 | 2003 | 9043 | 2003 : 9044 | 2003 : 9045 | 2003 : 9046 | 2003:9047 |
2004:9042 | 2004 | 9043 | 2004 : 9044 | 2004:9045 | 2004 : 9046 | 2004:9047 |
2005:9042 | 2005 | 9043 | 2005 : 9044 | 2005 : 9045 | 2005:9046 | 2005:9047 |
2006:9042 | 2006 | 9043 | 2006:9044 | 2006 : 9045 | 2006:9046 | 2006:9047 |
2007:9042 | 2007 | 9043 | 2007 : 9044 | 2007 : 9045 | 2007:9046 | 2007:9047 |
2008:9042 | 2008 | 9043 | 2008 : 9044 | 2008 : 9045 | 2008 : 9046 | 2008:9047 |
2009:9042 | 2009 | 9043 | 2009:9044 | 2009 : 9045 | 2009:9046 | 2009 : 9047 |
2010:9042 | 2010 | 9043 | 2010:9044 | 2010:9045 | 2010:9046 | 2010:9047 |
2011:9042 | 2011 | 9043 | 2011:9044 | 2011:9045 | 2011:9046 | 2011:9047 |
2012:9042 | 2012 | 9043 | 2012 : 9044 | 2012:9045 | 2012:9046 | 2012:9047 |
X: Y | X:Y | Χ:Υ | X: Y | Χ:Υ | Χ:Υ | |
1001:9048 | 1001:9049 | 1001:9050 | 1001:9051 | 1001:9052 | 1001 | 9053 |
1002 : 9048 | 1002:9049 | 1002:9050 | 1002:9051 | 1002:9052 | 1002 | 9053 |
1003:9048 | 1003 : 9049 | 1003 : 9050 | 1003:9051 | 1003 : 9052 | 1003 | 9053 |
1004:9048 | 1004:9049 | 1004 : 9050 | 1004:9051 | 1004:9052 | 1004 | 9053 |
-1005:9048 | -1005:9049 | -1005:9050 | -1005:9051 | -1005 : 9052 | 4005 | 9053 |
-Ι00άτ9048- | -1006Τ9049- | '100frr9050- | -1006-:^9051- | -1006?9052- | -1006 | 9053 |
1007 : 9048 | 1007 : 9049 | 1007 : 9050 | 1007:9051 | 1007 : 9052 | 1007 | 9053 |
1008:9048 | 1008:9049 | 1008:9050 | 1008 : 9051 | 1008:9052 | 1008 | 9053 |
1009:9048 | 1009:9049 | 1009:9050 | 1009 : 9051 | 1009:9052 | 1009 | 9053 |
1010:9048 | 1010:9049 | 1010 : 9050 | 1010:9051 | 1010:9052 | 1010 | 9053 |
1011:9048 | 1011:9049 | 1011:9050 | 1011:9051 | 1011:9052 | 1011 | 9053 |
1012:9048 | 1012 : 9049 | 1012 : 9050 | 1012:9051 | 1012:9052 | 1012 | 9053 |
1013 : 9048 | 1013:9049 | 1013 : 9050 | 1013 : 9051 | 1013:9052 | 1013 | 9053 |
1014:9048 | 1014:9049 | 1014 : 9050 | 1014:9051 | 1014 : 9052 | 1014 | 9053 |
1015:9048 | 1015 : 9049 | 1015 : 9050 | 1015:9051 | 1015 : 9052 | 1015 | 9053 |
1016:9048 | 1016 : 9049 | 1016:9050 | 1016:9051 | 1016:9052 | 1016 | 9053 |
2001:9048 | 2001:9049 | 2001:9050 | 2001:9051 | 2001:9052 | 2001 | 9053 |
2002 : 9048 | 2002:9049 | 2002 : 9050 | 2002:9051 | 2002:9052 | 2002 | 9053 |
2003:9048 | 2003:9049 | 2003:9050 | 2003:9051 | 2003:9052 | 2003 | 9053 |
2004:9048 | 2004:9049 | 2004:9050 | 2004:9051 | 2004:9052 | 2004 | 9053 |
2005:9048 | 2005:9049 | 2005 : 9050 | 2005:9051 | 2005 : 9052 | 2005 | 9053 |
2006:9048 | 2006:9049 | 2006:9050 | 2006:9051 | 2006:9052 | 2006 | 9053 |
2007:9048 | 2007 : 9049 | 2007:9050 | 2007:9051 | 2007:9052 | 2007 | 9053 |
2008:9048 | 2008:9049 | 2008:9050 | 2008:9051 | 2008 : 9052 | 2008 | 9053 |
2009:9048 | 2009:9049 | 2009:9050 | 2009:9051 | 2009 : 9052 | 2009 | 9053 |
2010:9048 | 2010:9049 | 2010 : 9050 | 2010:9051 | 2010:9052 | 2010 | 9053 |
2011:9048 | 2011:9049 | 2011:9050 | 2011:9051 | 2011:9052 | 2011 | 9053 |
2012:9048 | 2012:9049 | 2012:9050 | 2012:9051 | 2012 : 9052 | 2012 | 9053 |
X:Y | Χ:Υ | Χ:Υ |
1001:9054 | 1001:9055 | 1001:9056 |
1002:9054 | 1002:9055 | 1002:9056 |
1003 : 9054 | 1003 : 9055 | 1003 : 9056 |
•1004:9054 | 1004 : 9055 | 1004:9056 |
1005:9054 | 1005 : 9055 | 1005 : 9056- |
-1006:9054 | -1006 r9055 | -1006:9056; |
1007 : 9054 | 1007 : 9055 | 1007 : 9056 |
1008:9054 | 1008 : 9055 | 1008:9056 |
1009:9054 | 1009:9055 | 1009 : 9056 |
1010:9054 | 1010:9055 | 1010:9056 |
1011:9054 | 1011:9055 | 1011:9056 |
1012:9054 | 1012:9055 | 1012 : 9056 |
1013:9054 | 1013 : 9055 | 1013 : 9056 |
1014:9054 | 1014:9055 | 1014:9056 |
1015:9054 | 1015:9055 | 1015 : 9056 |
1016 : 9054 | 1016:9055 | 1016:9056 |
2001:9054 | 2001:9055 | 2001 :9056 |
2002:9054 | 2002:9055 | 2002 : 9056 |
2003 :9054 | 2003:9055 | 2003:9056 |
2004 : 9054 | 2004:9055 | 2004:9056 |
2005:9054 | 2005:9055 | 2005:9056 |
2006:9054 | 2006:9055 | 2006:9056 |
2007:9054 | 2007:9055 | 2007 : 9056 |
2008:9054 | 2008:9055 | 2008 : 9056 |
2009:9054 | 2009:9055 | 2009 : 9056 |
2010:9054 | 2010 : 9055 | 2010:9056 |
2011:9054 | 2011:9055 | 2011 :9056 |
2012:9054 | 2012:9055 | 2012:9056 |
Χ:Υ | Χ:Υ | X: Y |
1001:9057 | 1001:9058 | 1001:9059 |
1002:9057 | 1002:9058 | 1002:9059 |
1003:9057 | 1003:9058 | 1003:9059 |
'1004:9057 | 1004:9058 | 1004:9059 |
1005:9057 | 1005:9058 | '1005 : 9059 |
1006:9057L | -1006:9058 | -1006:9059 |
1007:9057 | 1007 : 9058 | 1007:9059 |
1008 : 9057 | 1008 : 9058 | 1008:9059 |
1009:9057 | 1009:9058 | 1009 : 9059 |
1010:9057 | 1010:9058 | 1010:9059 |
1011:9057 | 1011:9058 | 1011:9059 |
1012:9057 | 1012 : 9058 | 1012:9059 |
1013:9057 | 1013 : 9058 | 1013:9059 |
1014 : 9057 | 1014:9058 | 1014:9059 |
1015 : 9057 | 1015 : 9058 | 1015 : 9059 |
1016:9057 | 1016:9058 | 1016 : 9059 |
2001:9057 | 2001:9058 | 2001 :9059 |
2002:9057 | 2002 : 9058 | 2002:9059 |
2003 : 9057 | 2003 : 9058 | 2003 : 9059 |
2004:9057 | 2004:9058 | 2004:9059 |
2005:9057 | 2005:9058 | 2005:9059 |
2006:9057 | 2006:9058 | 2006:9059 |
2007:9057 | 2007:9058 | 2007:9059 |
2008:9057 | 2008:9058 | 2008:9059 |
2009:9057 | 2009:9058 | 2009:9059 |
2010:9057 | 2010:9058 | 2010:9059 |
2011:9057 | 2011:9058 | 2011:9059 |
2012:9057 | 2012:9058 | 2012:9059 |
X:Y | Χ:Υ | X: Y | Χ:Υ | Χ:Υ | Χ:Υ |
1001:9060 1002:9060 1003 : 9060 1004 : 9060 1005:9060 *1006^9060 1007:9060 1008:9060 1009:9060 1010:9060 1011:9060 1012:9060 1013:9060 1014:9060 1015:9060 1016:9060 2001:9060 2002 : 9060 2003:9060 2004:9060 2005:9060 2006:9060 2007:9060 2003:9060 2009 : 9060 2010 : 9060 2011:9060 2012:9060 | 1001:9061 1002 : 9061 1003 : 906! 1004:9061 1005:9061 -1006-:9061 1007:9061 1008:9061 1009:9061 1010:9061 1011:9061 1012:9061 1013:9061 1014:9061 1015:9061 1016:9061 2001:9061 2002:906! 2003:9061 2004:9061 2005:9061 2006:9061 2007:9061 2008:9061 2009:9061 2010:9061 2011:9061 2012:9061 | 1001:9062 1002:9062 1003:9062 1004:9062 1005 : 9062 -1006 : 9062' 1007:9062 1008:9062 1009:9062 1010:9062 1011:9062 1012:9062 1013:9062 1014:9062 1015:9062 1016:9062 2001:9062 2002:9062 2003:9062 2004:9062 2005:9062 2006:9062 2007:9062 2008:9062 2009:9062 2010:9062 2011 :9062 2012:9062 | 1001 :9063 1002:9063 1003:9063 1004:9063 1005 : 9063 -100&:9063 1007:9063 1008:9063 1009:9063 1010:9063 1011:9063 1012:9063 1013:9063 1014 : 9063 1015:9063 1016:9063 2001 :9063 2002:9063 2003 : 9063 2004:9063 2005 : 9063 2006 : 9063 2007 : 9063 2008 : 9063 2009:9063 2010:9063 2011 :9063 2012 : 9063 | 1001:9064 1002 : 9064 1003 : 9064 1004:9064 1005 : 9064 -1006:9064 1007:9064 1008:9064 1009:9064 1010:9064 1011:9064 1012:9064 1013:9064 1014:9064 1015:9064 1016:9064 2001 :9064 2002:9064 2003:9064 2004:9064 2005:9064 2006 : 9064 2007:9064 2008:9064 2009 : 9064 2010 : 9064 2011:9064 2012 : 9064 | 1001:9065 1002:9065 1003:9065 1004:9065 1005:9065 -1006 : 9065 1007:9065 1008:9065 1009 : 9065 1010:9065 1011:9065 1012 : 9065 1013 : 9065 1014:9065 1015 : 9065 1016:9065 2001:9065 2002:9065 2003 : 9065 2004:9065 2005 : 9065 2006:9065 2007:9065 2008:9065 2009:9065 2010:9065 2011:9065 2012:9065 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X: Y | |
1001:9066 | 1001:9067 | 1001:9068 | 1001:9069 | 1001:9070 | 1001 | 9071 |
1002:9066 | 1002 : 9067 | 1002:9068 | 1002:9069 | 1002:9070 | 1002 | 9071 |
1003:9066 | 1003 : 9067 | 1003 : 9068 | 1003 : 9069 | 1003:9070 | 1003 | 9071 |
1004:9066 | 1004:9067 | 1004:9068 | 1004:9069 | -1004:9070 | 1004 | 9071 |
'1005:9066- | 1005 : 9067 | 1005:9068 = | =1005:9069 | 4005:9070 | 1005 | 9071 |
-1006^9066- | -1006 : 9067 | -1006-:9068- | 1006:9069 | -1006t9070 | -1006 | 9071 |
1007 : 9066 | 1007:9067 | 1007:9068 | 1007:9069 | 1007:9070 | 1007 | 9071 |
1008:9066 | 1008:9067 | 1008:9068 | 1008:9069 | 1008 : 9070 | 1008 | 9071 |
1009:9066 | 1009 : 9067 | 1009:9068 | 1009 : 9069 | 1009 : 9070 | 1009 | 9071 |
1010:9066 | 1010:9067 | 1010:9068 | 1010:9069 | 1010:9070 | 1010 | 9071 |
1011 :9066 | 1011:9067 | 1011:9068 | 1011:9069 | 1011:9070 | 1011 | 9071 |
1012:9066 | 1012:9067 | 1012:9068 | 1012:9069 | 1012 : 9070 | 1012 | 9071 |
1013:9066 | 1013:9067 | 1013 : 9068 | 1013 : 9069 | 1013:9070 | 1013 | 9071 |
1014:9066 | 1014:9067 | 1014:9068 | 1014 : 9069 | 1014 : 9070 | 1014 | 9071 |
1015 : 9066 | 1015:9067 | 1015 : 9068 | 1015 : 9069 | 1015:9070 | 1015 | 9071 |
1016:9066 | 1016:9067 | 1016:9068 | 1016 : 9069 | 1016:9070 | 1016 | 9071 |
2001:9066 | 2001 :9067 | 2001 :9068 | 2001 :9069 | 2001:9070 | 2001 | 9071 |
2002:9066 | 2002:9067 | 2002 : 9068 | 2002 : 9069 | 2002 : 9070 | 2002 | 9071 |
2003 : 9066 | 2003 : 9067 | 2003:9068 | 2003 :9069 | 2003 : 9070 | 2003 | 9071 |
2004:9066 | 2004:9067 | 2004:9068 | 2004:9069 | 2004 : 9070 | 2004 | 9071 |
2005 : 9066 | 2005 : 9067 | 2005:9068 | 2005:9069 | 2005 : 9070 | 2005 | 9071 |
2006:9066 | 2006 : 9067 | 2006:9068 | 2006 : 9069 | 2006 : 9070 | 2006 | 9071 |
2007:9066 | 2007 : 9067 | 2007 : 9068 | 2007:9069 | 2007 : 9070 | 2007 | 9071 |
2008:9066 | 2008:9067 | 2008:9068 | 2008:9069 | 2008:9070 | 2008 | 9071 |
2009:9066 | 2009 : 9067 | 2009 : 9068 | 2009 : 9069 | 2009 : 9070 | 2009 | 9071 |
2010:9066 | 2010 : 9067 | 2010:9068 | 2010:9069 | 2010 : 9070 | 2010 | 9071 |
2011:9066 | 2011:9067 | 2011:9068 | 2011:9069 | 2011:9070 | 2011 | 9071 |
2012:9066 | 2012 : 9067 | 2012:9068 | 2012 : 9069 | 2012 : 9070 | 2012 | 9071 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | X | Y | Χ:Υ |
1001:9072 1002:9072 1003:9072 1004:9072 -1005:9072 -1006τ9072- 1007:9072 1008:9072 1009:9072 1010:9072 1011 :9072 1012:9072 1013 : 9072 1014:9072 1015:9072 1016 : 9072 2001:9072 2002 : 9072 2003 : 9072 2004:9072 2005 : 9072 2006 : 9072 2007 : 9072 2008 : 9072 2009 : 9072 2010 : 9072 2011:9072 2012:9072 | 1001:9073 1002:9073 1003:9073 1004:9073 .1005 : 9073 -1006—9073- 1007:9073 1008:9073 1009 : 9073 1010:9073 1011:9073 1012:9073 1013:9073 1014 : 9073 1015 : 9073 1016:9073 2001 :9073 2002:9073 2003 : 9073 2004 : 9073 2005:9073 2006 : 9073 2007:9073 2008:9073 2009:9073 2010:9073 2011:9073 2012 : 9073 | 1001:9074 1002:9074 1003 : 9074 1004:9074-1005:9074 -1006-79074- 1007 : 9074 1008:9074 1009:9074 1010:9074 1011:9074 1012:9074 1013:9074 1014:9074 1015 : 9074 1016 : 9074 2001 :9074 2002 : 9074 2003:9074 2004 : 9074 2005 : 9074 2006:9074 2007:9074 2008:9074 2009 : 9074 2010:9074 2011 :9074 2012:9074 | 1001:9075 1002:9075 1003 : 9075 1004:9075 1005:9075 -1006-Τ9075- 1007:9075 1008 : 9075 1009 : 9075 1010:9075 1011:9075 1012 : 9075 1013 : 9075 1014:9075 1015 : 9075 1016:9075 2001:9075 2002 : 9075 2003:9075 2004:9075 2005 : 9075 2006 : 9075 2007 : 9075 2008 : 9075 2009 : 9075 2010 : 9075 2011 :9075 2012 : 9075 | 1001 1002 1003 1004 -1005 -1006- 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 | 9076 9076 9076 9076 9076 “9076- 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 9076 | 1001:9077 1002:9077 1003 : 9077 1004:9077 1005:9077 -1006 : 9077 1007 : 9077 1008:9077 1009:9077 1010:9077 1011:9077 1012:9077 1013:9077 1014:9077 1015:9077 1016:9077 2001 :9077 2002 : 9077 2003 : 9077 2004:9077 2005:9077 2006 : 9077 2007:9077 2008:9077 2009 : 9077 2010:9077 2011:9077 2012 : 9077 |
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X: Y |
1001:9078 1002:9078 1003:9078 1004:9078 :1005 : 9078 -1006:9078 ~ 1007:9078 1008:9078 1009:9078 1010:9078 1011:9078 1012:9078 1013:9078 1014:9078 1015 : 9078 1016 : 9078 2001:9078 2002:9078 2003:9078 2004 : 9078 2005 : 9078 2006:9078 2007:9078 2008:9078 2009:9078 2010:9078 2011 :9078 2012:9078 | 1001:9079 1002 : 9079 1003 : 9079 1004:9079 10051'9079 -1006^9079 1007:9079 1008 : 9079 1009:9079 1010 : 9079 1011:9079 1012:9079 1013 : 9079 1014:9079 1015 : 9079 1016 : 9079 2001:9079 2002 : 9079 2003 : 9079 2004 : 9079 2005 : 9079 2006:9079 2007:9079 2008:9079 2009:9079 2010:9079 2011:9079 2012:9079 | 1001 :9080 1002:9080 1003:9080 1004 : 9080 -1005 :-9080 -1006^:9080' 1007:9080 1008 : 9080 1009:9080 1010:9080 1011:9080 1012:9080 1013 : 9080 1014:9080 1015:9080 1016:9080 2001:9080 2002:9080 2003:9080 2004:9080 2005 : 9080 2006 : 9080 2007 : 9080 2008 : 9080 2009:9080 2010:9080 2011 :9080 2012:9080 | 1001:9081 1002:9081 1003:9081 1004:9081 1005 : 9081 -1006 :9081- 1007 : 9081 1008 : 9081 1009 : 9081 1010:9081 1011:9081 1012 : 9081 1013:9081 1014:9081 1015 : 9081 1016 : 9081 2001:9081 2002:9081 2003 : 9081 2004 : 9081 2005:9081 2006:9081 2007:9081 2008 : 9081 2009 : 9081 2010:9081 2011:9081 2012:9081 | 1001:9082 1002:9082 1003:9082 1004:9082 1005:9082 -1006:9082- 1007 : 9082 1008:9082 1009:9082 1010:9082 1011:9082 1012:9082 1013:9082 1014:9082 1015 : 9082 1016:9082 2001:9082 2002:9082 2003:9082 2004:9082 2005:9082 2006:9082 2007:9082 2008 : 9082 2009 : 9082 2010:9082 2011:9082 2012:9082 | 1001:9083 1002:9083 1003:9083 1004:9083 '1005 : 9083 1006:9083 1007:9083 1008:9083 1009:9083 1010:9083 1011:9083 1012 : 9083 1013:9083 1014:9083 1015:9083 1016:9083 2001 :9083 2002:9083 2003 : 9083 2004:9083 2005:9083 2006:9083 2007:9083 2008:9083 2009 : 9083 2010:9083 2011:9083 2012:9083 |
X | :Y | Χ:Υ | Χ:Υ | Χ:Υ | X: | Y | X | :Υ |
1001 | 9084 | 1001:9085 | 1001 :9086 | 1001:9087 | 1001 | 9088 | 1001 | 9089 |
1002 | 9084 | 1002:9085 | 1002:9086 | 1002:9087 | 1002 | 9088 | 1002 | 9089 |
1003 | 9084 | 1003:9085 | 1003 : 9086 | 1003:9087 | 1003 | 9088 | 1003 | 9089 |
40(M | 9084 | 1004:9085 | 1004:9086 | 1004:9087 | 1004 | 9088 | 1004 | 9089 |
1005 | 9084 | 1005:9085 | : 1005:9086 | 1005:9087 | 1005 | 9088 | 4005 | 9089 |
-1006 | 9084- | 4006:9085 | 4006:9086- | 4006:9087 | 4006 | 9088 | -1006 | 9089 |
1007 | 9084 | 1007:9085 | 1007:9086 | 1007:9087 | 1007 | 9088 | 1007 | 9089 |
1008 | 9084 | 1008:9085 | 1008:9086 | 1008 : 9087 | 1008 | 9088 | 1008 | 9089 |
1009 | 9084 | 1009:9085 | 1009:9086 | 1009 : 9087 | 1009 | 9088 | 1009 | 9089 |
1010 | 9084 | 1010:9085 | 1010 : 9086 | 1010:9087 | 1010 | 9088 | 1010 | 9089 |
1011 | 9084 | 1011:9085 | 1011:9086 | 1011:9087 | 1011 | 9088 | 1011 | 9089 |
1012 | 9084 | 1012:9085 | 1012 : 9086 | 1012 : 9087 | 1012 | 9088 | 1012 | 9089 |
1013 | 9084 | 1013:9085 | 1013:9086 | 1013:9087 | 1013 | 9088 | 1013 | 9089 |
1014 | 9084 | 1014:9085 | 1014 : 9086 | 1014 : 9087 | 1014 | 9088 | 1014 | 9089 |
1015 | 9084 | 1015:9085 | 1015:9086 | 1015:9087 | 1015 | 9088 | 1015 | 9089 |
1016 | 9084 | 1016:9085 | 1016:9086 | 1016:9087 | 1016 | 9088 | 1016 | 9089 |
2001 | 9084 | 2001:9085 | 2001 :9086 | 2001:9087 | 2001 | 9088 | 2001 | 9089 |
2002 | 9084 | 2002:9085 | 2002:9086 | 2002:9087 | 2002 | 9088 | 2002 | 9089 |
2003 | 9084 | 2003 : 9085 | 2003 : 9086 | 2003 : 9087 | 2003 | 9088 | 2003 | 9089 |
2004 | 9084 | 2004:9085 | 2004:9086 | 2004:9087 | 2004 | 9088 | 2004 | 9089 |
2005 | 9084 | 2005 : 9085 | 2005:9086 | 2005 : 9087 | 2005 | 9088 | 2005 | 9089 |
2006 | 9084 | 2006:9085 | 2006:9086 | 2006:9087 | 2006 | 9088 | 2006 | 9089 |
2007 | 9084 | 2007:9085 | 2007:9086 | 2007 : 9087 | 2007 | 9088 | 2007 | 9089 |
2008 | 9084 | 2008:9085 | 2008:9086 | 2008 : 9087 | 2008 | 9088 | 2008 | 9089 |
2009 | 9084 | 2009:9085 | 2009:9086 | 2009 : 9087 | 2009 | 9088 | 2009 | 9089 |
2010 | 9084 | 2010:9085 | 2010:9086 | 2010:9087 | 2010 | 9088 | 2010 | 9089 |
2011 | 9084 | 2011:9085 | 2011:9086 | 2011:9087 | 2011 | 9088 | 2011 | 9089 |
2012 | 9084 | 2012:9085 | 2012:9086 | 2012 : 9087 | 2012 | 9088 | 2012 | 9089 |
X: Y | X:Y | Χ:Ύ | X:Y | X:Y | X:Y |
I001:9090 | 1001:9091 | 1001:9092 | 1001:9093 | 1001:9094 | 1001:9095 |
1002:9090 | 1002:9091 | 1002:9092 | 1002 : 9093 | 1002:9094 | 1002 : 9095 |
1003:9090 | 1003:9091 | 1003:9092 | 1003:9093 | 1003:9094 | 1003 : 9095 |
-1004:9090 | 1004:9091 | 1004:9092 | 1004:9093 | 1004 :.9094 | 1004:9095 |
Ί005:9090: | .1005:9091’ | 1005:90921 | 1005:9093 | 1005:9094 | 1005:9095 |
-1006T9090- | -1006-9091- | -1006^-9092- | ’1006f9093- | -1006^9094 | -1006:9095 |
1007:9090 | 1007:9091 | 1007 : 9092 | 1007:9093 | 1007 : 9094 | 1007 : 9095 |
1008:9090 | 1008:9091 | 1008:9092 | 1008:9093 | 1008:9094 | 1008:9095 |
1009:9090 | 1009 : 9091 | '1009 : 9092 | 1009:9093 | 1009:9094 | 1009 : 9095 |
1010:9090 | 1010:9091 | 1010:9092 | 1010:9093 | 1010:9094 | 1010:9095 |
1011:9090 | 1011:9091 | 1011:9092 | 1011:9093 | 1011:9094 | 1011:9095 |
1012:9090 | 1012:9091 | 1012:9092 | 1012:9093 | 1012:9094 | 1012:9095 |
1013 : 9090 | 1013:9091 | 1013 : 9092 | 1013 : 9093 | 1013:9094 | 1013 : 9095 |
1014:9090 | 1014:9091 | 1014 : 9092 | 1014 : 9093 | 1014:9094 | 1014:9095 |
1015:9090 | 1015:9091 | 1015:9092 | 1015:9093 | 1015 : 9094 | 1015:9095 |
1016:9090 | 1016:9091 | 1016:9092 | 1016:9093 | 1016 : 9094 | 1016:9095 |
2001:9090 | 2001:9091 | 2001:9092 | 2001:9093 | 2001:9094 | 2001:9095 |
2002 : 9090 | 2002:9091 | 2002:9092 | 2002:9093 | 2002 : 9094 | 2002 : 9095 |
2003 : 9090 | 2003:9091 | 2003 : 9092 | 2003 : 9093 | 2003 : 9094 | 2003 : 9095 |
2004:9090 | 2004:9091 | 2004:9092 | 2004:9093 | 2004:9094 | 2004:9095 |
2005 : 9090 | 2005:9091 | 2005 : 9092 | 2005 : 9093 | 2005 : 9094 | 2005:9095 |
2006:9090 | 2006:9091 | 2006 : 9092 | 2006 : 9093 | 2006 : 9094 | 2006 : 9095 |
2007:9090 | 2007:9091 | 2007 : 9092 | 2007 : 9093 | 2007 : 9094 | 2007:9095 |
2008 : 9090 | 2008:9091 | 2008:9092 | 2008 : 9093 | 2008 : 9094 | 2008:9095 |
2009 : 9090 | 2009 : 9091 | 2009:9092 | 2009 : 9093 | 2009 : 9094 | 2009:9095 |
2010:9090 | 2010:9091 | 2010:9092 | 2010:9093 | 2010:9094 | 2010:9095 |
2011 :9090 | 2011:9091 | 2011:9092 | 2011:9093 | 2011:9094 | 2011:9095 |
2012:9090 | 2012:9091 | 2012 : 9092 | 2012:9093 | 2012:9094 | 2012:9095 |
X:Y | Χ:Υ | Χ:Υ |
1001:9096 | 1001:9097 | 1001:9098 |
1002:9096 | 1002:9097 | 1002:9098 |
1003:9096 | 1003 : 9097 | 1003:9098 |
1004:9096 | 1004 : 9097 | 1004:9098 |
. 1005:9096 | 1005 : 9097 | 1005:9098 |
-1006 r9096- | 1006:9097- | .1006:9098- |
1007:9096 | 1007 : 9097 | 1007:9098 |
1008:9096 | 1008 : 9097 | 1008 : 9098 |
1009:9096 | 1009:9097 | 1009:9098 |
1010:9096 | 1010:9097 | 1010:9098 |
1011:9096 | 1011 :9097 | 1011:9098 |
1012 : 9096 | 1012:9097 | 1012:9098 |
1013:9096 | 1013:9097 | 1013:9098 |
1014:9096 | 1014 : 9097 | 1014:9098 |
1015:9096 | 1015 : 9097 | 1015 : 9098 |
1016 : 9096 | 1016 : 9097 | 1016:9098 |
2001:9096 | 2001 :9097 | 2001:9098 |
2002:9096 | 2002 : 9097 | 2002:9098 |
2003:9096 | 2003 : 9097 | 2003:9098 |
2004:9096 | 2004:9097 | 2004:9098 |
2005:9096 | 2005 : 9097 | 2005:9098 |
2006 : 9096 | 2006 : 9097 | 2006:9098 |
2007 : 9096 | 2007:9097 | 2007:9098 |
2008:9096 | 2008 : 9097 | 2008:9098 |
2009:9096 | 2009 : 9097 | 2009:9098 |
2010:9096 | 2010:9097 | 2010:9098 |
2011 :9096 | 2011:9097 | 2011:9098 |
2012:9096 | 2012:9097 | 2012:9098 |
X: Y | Χ:Υ | Χ:Υ |
1001:9099 | 1001:9100 | 1001:9101 |
1002:9099 | 1002 : 9100 | 1002:9101 |
1003 : 9099 | 1003:9100 | 1003:9101 |
1004:9099 | 1004:9100- | '1004:9101 |
1005 : 9099 | 1005:9100 | 1005:9101 |
-1006:9099- | -1006:9100 | -1006:9101 |
1007:9099 | 1007:9100 | 1007:9101 |
1008:9099 | 1008 : 9100 | 1008:9101 |
1009 : 9099 | 1009:9100 | 1009:910! |
1010:9099 | 1010:9100 | 1010:9101 |
1011:9099 | 1011:9100 | 1011:9101 |
1012 : 9099 | 1012:9100 | 1012:9101 |
1013 : 9099 | 1013:9100 | 1013:9101 |
1014 : 9099 | 1014:9100 | 1014:9101 |
1015 : 9099 | 1015:9100 | 1015:9101 |
1016 : 9099 | 1016:9100 | 1016:9101 |
2001:9099 | 2001:9100 | 2001:9101 |
2002:9099 | 2002 : 9100 | 2002 : 9101 |
2003:9099 | 2003 : 9100 | 2003:9101 |
2004:9099 | 2004 : 9100 | 2004:9101 |
2005 : 9099 | 2005 : 9100 | 2005:9101 |
2006 : 9099 | 2006:9100 | 2006:9101 |
2007 : 9099 | 2007 : 9100 | 2007 : 9101 |
2008:9099 | 2008 : 9100 | 2008:9101 |
2009:9099 | 2009 : 9100 | 2009 : 9101 |
2010 : 9099 | 2010:9100 | 2010:9101 |
2011:9099 | 2011:9100 | 2011:9101 |
2012:9099 | 2012:9100 | 2012:9101 |
X:Y | Χ:Υ | Χ:Υ | X: Y | X: Y | Χ:Υ |
1001:9102 1002:9102 1003:9102 1004:9102 1005:9102 -100fr:9102 1007:9102 1008:9102 1009:9102 1010:9102 1011:9102 1012:9102 1013:9102 1014:9102 1015:9102 1016:9102 2001:9102 2002:9102 2003:9102 2004:9102 2005:9102 2006:9102 2007:9102 2008:9102 2009:9102 2010:9102 2011:9102 2012:9102 | 1001:9103 1002 : 9103 1003 : 9103 1004:9103 1005:9103 -1006-:^103 1007:9103 1008:9103 1009:9103 1010:9103 1011:9103 1012:9103 1013:9103 1014:9103 1015:9103 1016:9103 2001:9103 2002:9103 2003:9103 2004:9103 2005:9103 2006:9103 2007:9103 2008:9103 2009:9103 2010:9103 2011:9103 2012:9103 | 1001:9104 1002:9104 1003 : 9104 1004:9104 1005 : 9104 -Ι006 τ9104Ξ 1007:9104 1008:9104 1009 : 9104 1010:9104 1011:9104 1012:9104 1013:9104 1014:9104 1015:9104 1016:9104 2001:9104 2002:9104 2003 : 9104 2004:9104 2005 : 9104 2006:9104 2007:9104 2008:9104 2009:9104 2010:9104 2011:9104 2012:9104 | 1001:9105 1002:9105 1003:9105 1004:9105 1005 : 9105 -1006r9I05- 1007 : 9105 1008:9105 1009:9105 1010:9105 1011:9105 1012:9105 1013:9105 1014:9105 1015:9105 1016:9105 2001:9105 2002:9105 2003 : 9105 2004:9105 2005 : 9105 2006:9105 2007:9105 2008:9105 2009 : 9105 2010:9105 2011:9105 2012:9105 | — | — |
Table B: Example combinations of a compound X with a compound Y.
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9000 | 3001 | 9001 | 3001 | 9002 | 3001 | 9003 | 3001 | 9004 | 3001 | 9005 |
3002 | 9000 | 3002 | 9001 | 3002 | 9002 | 3002 | 9003 | 3002 | 9004 | 3002 | 9005 |
3003 | 9000 | 3003 | 9001 | 3003 | 9002 | 3003 | 9003 | 3003 | 9004 | 3003 | 9005 |
3004 | 9000 | 3004 | 9001 | 3004 | 9002 | 3004 | 9003 | 3004 | 9004 | 3004 | 9005 |
3005 | 9000 | 3005 | 9001 | 3005 | 9002 | 3005 | 9003 | 3005 | 9004 | 3005 | 9005 |
-3004 | '9000- | 3006- | 900F | 3006' | '9002 | -3006 | 9003 | 3006 | 9004 | 3006 | 9005 |
3007 | 9000 | 3007 | 9001 | 3007 | 9002 | 3007 | 9003 | 3007 | 9004 | 3007 | 9005 |
3008 | 9000 | 3008 | 9001 | 3008 | 9002 | 3008 | 9003 | 3008 | 9004 | 3008 | 9005 |
3009 | 9000 | 3009 | 9001 | 3009 | 9002 | 3009 | 9003 | 3009 | 9004 | 3009 | 9005 |
3010 | 9000 | 3010 | 9001 | 3010 | 9002 | 3010 | 9003 | 3010 | 9004 | 3010 | 9005 |
3011 | 9000 | 3011 | 9001 | 3011 | 9002 | 3011 | 9003 | 3011 | 9001 | 3011 | 9005 |
3012 | 9000 | 3012 | 9001 | 3012 | 9002 | 3012 | 9003 | 3012 | 9004 | 3012 | 9005 |
3013 | 9000 | 3013 | 9001 | 3013 | 9002 | 3013 | 9003 | 3013 | 9004 | 3013 | 9005 |
3014 | 9000 | 3014 | 9001 | 3014 | 9002 | 3014 | 9003 | 3014 | 9004 | 3014 | 9005 |
4001 | 9000 | 4001 | 9001 | 4001 | 9002 | 4001 | 9003 | 4001 | 9004 | 4001 | 9005 |
4002 | 9000 | 4002 | 9001 | 4002 | 9002 | 4002 | 9003 | 4002 | 9004 | 4002 | 9005 |
4003 | 9000 | 4003 | 9001 | 4003 | 9002 | 4003 | 9003 | 4003 | 9004 | 4003 | 9005 |
4004 | 9000 | 4004 | 9001 | 4004 | 9002 | 4004 | 9003 | 4004 | 9004 | 4004 | 9005 |
4005 | 9000 | 4005 | 9001 | 4005 | 9002 | 4005 | 9003 | 4005 | 9004 | 4005 | 9005 |
4006 | 9000 | 4006 | 9001 | 4006 | 9002 | 4006 | 9003 | 4006 | 9004 | 4006 | 9005 |
4007 | 9000 | 4007 | 9001 | 4007 | 9002 | 4007 | 9003 | 4007 | 9004 | 4007 | 9005 |
4008 | 9000 | 4008 | 9001 | 4008 | 9002 | 4008 | 9003 | 4008 | 9004 | 4008 | 9005 |
4009 | 9000 | 4009 | 9001 | 4009 | 9002 | 4009 | 9003 | 4009 | 9004 | 4009 | 9005 |
4010 | 9000 | 4010 | 9001 | 4010 | 9002 | 4010 | 9003 | 4010 | 9004 | 4010 | 9005 |
4011 | 9000 | 4011 | 9001 | 4011 | 9002 | 4011 | 9003 | 4011 | 9004 | 4011 | 9005 |
4012 | 9000 | 4012 | 9001 | 4012 | 9002 | 4012 | 9003 | 4012 | 9004 | 4012 | 9005 |
5001 | 9000 | 5001 | 9001 | 5001 | 9002 | 5001 | 9003 | 5001 | 9004 | 5001 | 9005 |
5002 | 9000 | 5002 | 9001 | 5002 | 9002 | 5002 | 9003 | 5002 | 9004 | 5002 | 9005 |
5003 | 9000 | 5003 | 9001 | 5003 | 9002 | 5003 | 9003 | 5003 | 9004 | 5003 | 9005 |
5004 | 9000 | 5004 | 9001 | 5004 | 9002 | 5004 | 9003 | 5004 | 9004 | 5004 | 9005 |
5005 | 9000 | 5005 | 9001 | 5005 | 9002 | 5005 | 9003 | 5005 | 9004 | 5005 | 9005 |
5006 | 9000 | 5006 | 9001 | 5006 | 9002 | 5006 | 9003 | 5006 | 9004 | 5006 | 9005 |
5007 | 9000 | 5007 | 9001 | 5007 | 9002 | 5007 | 9003 | 5007 | 9004 | 5007 | 9005 |
5008 | 9000 | 5008 | 9001 | 5008 | 9002 | 5008 | 9003 | 5008 | 9004 | 5008 | 9005 |
5009 | 9000 | 5009 | 9001 | 5009 | 9002 | 5009 | 9003 | 5009 | 9004 | 5009 | 9005 |
5010 | 9000 | 5010 | 9001 | 5010 | 9002 | 5010 | 9003 | 5010 | 9004 | 5010 | 9005 |
5011 | 9000 | 5011 | 9001 | 5011 | 9002 | 5011 | 9003 | 5011 | 9004 | 5011 | 9005 |
5012 | 9000 | 5012 | 9001 | 5012 | 9002 | 5012 | 9003 | 5012 | 9004 | 5012 | 9005 |
X | Y | X | Y | X:Y | X | Y | X | Y | X | Y |
3001 | 9006 | 3001 | 9007 | 3001:9008 | 3001 | 9009 | 3001 | 9010 | 3001 | 9011 |
3002 | 9006 | 3002 | 9007 | 3002:9008 | 3002 | 9009 | 3002 | 9010 | 3002 | 9011 |
3003 | 9006 | 3003 | 9007 | 3003:9008 | 3003 | 9009 | 3003 | 9010 | 3003 | 9011 |
3004 | 9006 | 3004 | 9007 | 3004:9008 | 3004 | 9009 | 3004 | 9010 | 3004 | 9011 |
3005 | 9006 | 3005 | 9007 | 3005:9008 | 3005 | 9009 | 3005 | 9010 | 3005 | 9011 |
3006 | 9006 | 3006 | 9007 | 3006:9008 | 3006 | 9009 | 3006 | 9010 | 3006 | 9011 |
3007 | 9006 | 3007 | 9007 | 3007 : 9008 | 3007 | 9009 | 3007 | 9010 | 3007 | 9011 |
3008 | 9006 | 3008 | 9007 | 3008:9008 | 3008 | 9009 | 3008 | 9010 | 3008 | 9011 |
3009 | 9006 | 3009 | 9007 | 3009:9008 | 3009 | 9009 | 3009 | 9010 | 3009 | 9011 |
3010 | 9006 | 3010 | 9007 | 3010:9008 | 3010 | 9009 | 3010 | 9010 | 3010 | 9011 |
3011 | 9006 | 3011 | 9007 | 3011 :9008 | 3011 | 9009 | 3011 | 9010 | 3011 | 9011 |
3012 | 9006 | 3012 | 9007 | 3012 : 9008 | 3012 | 9009 | 3012 | 9010 | 3012 | 9011 |
3013 | 9006 | 3013 | 9007 | 3013:9008 | 3013 | 9009 | 3013 | 9010 | 3013 | 9011 |
3014 | 9006 | 3014 | 9007 | 3014:9008 | 3014 | 9009 | 3014 | 9010 | 3014 | 9011 |
4001 | 9006 | 4001 | 9007 | 4001:9008 | 4001 | 9009 | 4001 | 9010 | 4001 | 9011 |
4002 | 9006 | 4002 | 9007 | 4002:9008 | 4002 | 9009 | 4002 | 9010 | 4002 | 9011 |
4003 | 9006 | 4003 | 9007 | 4003 : 9008 | 4003 | 9009 | 4003 | 9010 | 4003 | 9011 |
4004 | 9006 | 4004 | 9007 | 4004:9008 | 4004 | 9009 | 4004 | 9010 | 4004 | 9011 |
4005 | 9006 | 4005 | 9007 | 4005:9008 | 4005 | 9009 | 4005 | 9010 | 4005 | 9011 |
4006 | 9006 | 4006 | 9007 | 4006:9008 | 4006 | 9009 | 4006 | 9010 | 4006 | 9011 |
4007 | 9006 | 4007 | 9007 | 4007 : 9008 | 4007 | 9009 | 4007 | 9010 | 4007 | 9011 |
4008 | 9006 | 4008 | 9007 | 4008:9008 | 4008 | 9009 | 4008 | 9010 | 4008 | 9011 |
4009 | 9006 | 4009 | 9007 | 4009:9008 | 4009 | 9009 | 4009 | 9010 | 4009 | 9011 |
4010 | 9006 | 4010 | 9007 | 4010:9008 | 4010 | 9009 | 4010 | 9010 | 4010 | 9011 |
4011 | 9006 | 4011 | 9007 | 4011:9008 | 4011 | 9009 | 4011 | 9010 | 4011 | 9011 |
4012 | 9006 | 4012 | 9007 | 4012:9008 | 4012 | 9009 | 4012 | 9010 | 4012 | 9011 |
5001 | 9006 | 5001 | 9007 | 5001:9008 | 5001 | 9009 | 5001 | 9010 | 5001 | 9011 |
5002 | 9006 | 5002 | 9007 | 5002:9008 | 5002 | 9009 | 5002 | 9010 | 5002 | 9011 |
5003 | 9006 | 5003 | 9007 | 5003 : 9008 | 5003 | 9009 | 5003 | 9010 | 5003 | 9011 |
5004 | 9006 | 5004 | 9007 | 5004:9008 | 5004 | 9009 | 5004 | 9010 | 5004 | 9011 |
5005 | 9006 | 5005 | 9007 | 5005 : 9008 | 5005 | 9009 | 5005 | 9010 | 5005 | 9011 |
5006 | 9006 | 5006 | 9007 | 5006 : 9008 | 5006 | 9009 | 5006 | 9010 | 5006 | 9011 |
5007 | 9006 | 5007 | 9007 | 5007:9008 | 5007 | 9009 | 5007 | 9010 | 5007 | 9011 |
5008 | 9006 | 5008 | 9007 | 5008:9008 | 5008 | 9009 | 5008 | 9010 | 5008 | 9011 |
5009 | 9006 | 5009 | 9007 | 5009:9008 | 5009 | 9009 | 5009 | 9010 | 5009 | 9011 |
5010 | 9006 | 5010 | 9007 | 5010 : 9008 | 5010 | 9009 | 5010 | 9010 | 5010 | 9011 |
5011 | 9006 | 5011 | 9007 | 5011:9008 | 5011 | 9009 | 5011 | 9010 | 5011 | 9011 |
5012 | 9006 | 5012 | 9007 | 5012:9008 | 5012 | 9009 | 5012 | 9010 | 5012 | 9011 |
ΙΟΟ
X | Y | Χ:Υ | X | Y | X | Y | X | Y | X | Y | |
3001 | 9012 | 3001:9013 | 3001 | 9014 | 3001 | 9015 | 3001 | 9016 | 3001 | 9017 | |
3002 | 9012 | 3002:9013 | 3002 | 9014 | 3002 | 9015 | 3002 | 9016 | 3002 | 9017 | |
3003 | 9012 | 3003:9013 | 3003 | 9014 | 3003 | 9015 | 3003 | 9016 | 3003 | 9017 | |
3004 | 9012 | 3004:9013 | 3004 | 9014 | 3004 | 9015 | 3004 | 9016 | 3004 | 9017 | |
3005 | 9012 | 3005 : 9013 | 3005 | 9014 | 3005 | 9015 | 3005 | 9016 | 3005 | 9017 | |
--: | 3006 | 9012 | 3006:9013 | 3006 | 9014 | 3006 | 9015 | 3006 | 9016 | 3006 | 9017 |
3007 | .9012 | 3007^9013 | 3007 | 9014 | 3007 | 9015 | 3007 | .9016 | 3007 | 9017 | |
3008 | 9012 | 3008:9013 | 3008 | 9014 | 3008 | 9015 | 3008 | 9016 | 3008 | 9017 | |
3009 | 9012 | 3009:9013 | 3009 | 9014 | 3009 | 9015 | 3009 | 9016 | 3009 | 9017 | |
3010 | 9012 | 3010:9013 | 3010 | 9014 | 3010 | 9015 | 3010 | 9016 | 3010 | 9017 | |
3011 | 9012 | 3011:9013 | 3011 | 9014 | 3011 | 9015 | 3011 | 9016 | 3011 | 9017 | |
3012 | 9012 | 3012:9013 | 3012 | 9014 | 3012 | 9015 | 3012 | 9016 | 3012 | 9017 | |
3013 | 9012 | 3013:9013 | 3013 | 9014 | 3013 | 9015 | 3013 | 9016 | 3013 | 9017 | |
3014 | 9012 | 3014:9013 | 3014 | 9014 | 3014 | 9015 | 3014 | 9016 | 3014 | 9017 | |
4001 | 9012 | 4001:9013 | 4001 | 9014 | 4001 | 9015 | 4001 | 9016 | 4001 | 9017 | |
4002 | 9012 | 4002:9013 | 4002 | 9014 | 4002 | 9015 | 4002 | 9016 | 4002 | 9017 | |
4003 | 9012 | 4003:9013 | 4003 | 9014 | 4003 | 9015 | 4003 | 9016 | 4003 | 9017 | |
4004 | 9012 | 4004:9013 | 4004 | 9014 | 4004 | 9015 | 4004 | 9016 | 4004 | 9017 | |
4005 | 9012 | 4005 : 9013 | 4005 | 9014 | 4005 | 9015 | 4005 | 9016 | 4005 | 9017 | |
4006 | 9012 | 4006:9013 | 4006 | 9014 | 4006 | 9015 | 4006 | 9016 | 4006 | 9017 | |
4007 | 9012 | 4007 : 9013 | 4007 | 9014 | 4007 | 9015 | 4007 | 9016 | 4007 | 9017 | |
4008 | 9012 | 4008 : 9013 | 4008 | 9014 | 4008 | 9015 | 4008 | 9016 | 4008 | 9017 | |
4009 | 9012 | 4009:9013 | 4009 | 9014 | 4009 | 9015 | 4009 | 9016 | 4009 | 9017 | |
4010 | 9012 | 4010:9013 | 4010 | 9014 | 4010 | 9015 | 4010 | 9016 | 4010 | 9017 | |
4011 | 9012 | 4011:9013 | 4011 | 9014 | 4011 | 9015 | 4011 | 9016 | 4011 | 9017 | |
4012 | 9012 | 4012:9013 | 4012 | 9014 | 4012 | 9015 | 4012 | 9016 | 4012 | 9017 | |
5001 | 9012 | 5001:9013 | 5001 | 9014 | 5001 | 9015 | 5001 | 9016 | 5001 | 9017 | |
5002 | 9012 | 5002:9013 | 5002 | 9014 | 5002 | 9015 | 5002 | 9016 | 5002 | 9017 | |
5003 | 9012 | 5003:9013 | 5003 | 9014 | 5003 | 9015 | 5003 | 9016 | 5003 | 9017 | |
5004 | 9012 | 5004 : 9013 | 5004 | 9014 | 5004 | 9015 | 5004 | 9016 | 5004 | 9017 | |
5005 | 9012 | 5005 : 9013 | 5005 | 9014 | 5005 | 9015 | 5005 | 9016 | 5005 | 9017 | |
5006 | 9012 | 5006 : 9013 | 5006 | 9014 | 5006 | 9015 | 5006 | 9016 | 5006 | 9017 | |
5007 | 9012 | 5007 : 9013 | 5007 | 9014 | 5007 | 9015 | 5007 | 9016 | 5007 | 9017 | |
5008 | 9012 | 5008 : 9013 | 5008 | 9014 | 5008 | 9015 | 5008 | 9016 | 5008 | 9017 | |
5009 | 9012 | 5009:9013 | 5009 | 9014 | 5009 | 9015 | 5009 | 9016 | 5009 | 9017 | |
5010 | 9012 | 5010 : 9013 | 5010 | 9014 | 5010 | 9015 | 5010 | 9016 | 5010 | 9017 | |
5011 | 9012 | 5011:9013 | 5011 | 9014 | 5011 | 9015 | 5011 | 9016 | 5011 | 9017 | |
5012 | 9012 | 5012:9013 | 5012 | 9014 | 5012 | 9015 | 5012 | 9016 | 5012 | 9017 |
ΙΟΙ
X: Y | Χ:Υ | Χ:Υ | Χ:Υ | X | Y | X | Y |
3001:9018 | 3001:9019 | 3001:9020 | 3001:9021 | 3001 | 9022 | 3001 | 9023 |
3002:9018 | 3002:9019 | 3002:9020 | 3002:9021 | 3002 | 9022 | 3002 | 9023 |
3003:9018 | 3003:9019 | 3003:9020 | 3003:9021 | 3003 | 9022 | 3003 | 9023 |
3004:9018 | 3004:9019 | 3004:9020 | 3004:9021 | 3004 | 9022 | 3004 | 9023 |
3005:9018 | 3005:9019 | 3005 : 9020 | 3005:9021 | 3005 | 9022 | 3005 | 9023 |
3006:9018 | -3006:9019 | 3006:9020 | 3006:9021 | 3006 | 9022 | 3006 | 9023 |
-3007: 9018 | 3007-9019 | -3007:9020 | 3007:9021 | 3007 | .9022 | 3007 | 9023 |
3008:9018 | 3008:9019 | 3008:9020 | 3008:9021 | 3008 | 9022 | 3008 | 9023 |
3009:9018 | 3009:9019 | 3009 : 9020 | 3009:9021 | 3009 | 9022 | 3009 | 9023 |
3010:9018 | 3010:9019 | 3010:9020 | 3010:9021 | 3010 | 9022 | 3010 | 9023 |
3011:9018 | 3011:9019 | 3011:9020 | 3011:9021 | 3011 | 9022 | 3011 | 9023 |
3012:9018 | 3012:9019 | 3012:9020 | 3012:9021 | 30Î2 | 9022 | 3012 | 9023 |
3013:9018 | 3013:9019 | 3013:9020 | 3013:9021 | 3013 | 9022 | 3013 | 9023 |
3014:9018 | 3014 : 9019 | 3014:9020 | 3014:9021 | 3014 | 9022 | 3014 | 9023 |
4001:9018 | 4001:9019 | 4001:9020 | 4001:9021 | 4001 | 9022 | 4001 | 9023 |
4002:9018 | 4002:9019 | 4002:9020 | 4002:9021 | 4002 | 9022 | 4002 | 9023 |
4003 : 9018 | 4003 : 9019 | 4003:9020 | 4003:9021 | 4003 | 9022 | 4003 | 9023 |
4004:9018 | 4004:9019 | 4004:9020 | 4004:9021 | 4004 | 9022 | 4004 | 9023 |
4005:9018 | 4005:9019 | 4005:9020 | 4005:9021 | 4005 | 9022 | 4005 | 9023 |
4006:9018 | 4006:9019 | 4006:9020 | 4006:9021 | 4006 | 9022 | 4006 | 9023 |
4007:9018 | 4007:9019 | 4007:9020 | 4007:9021 | 4007 | 9022 | 4007 | 9023 |
4008:9018 | 4008:9019 | 4008:9020 | 4008:9021 | 4008 | 9022 | 4008 | 9023 |
4009 : 9018 | 4009:9019 | 4009:9020 | 4009:9021 | 4009 | 9022 | 4009 | 9023 |
4010:9018 | 4010:9019 | 4010 : 9020 | 4010:9021 | 4010 | 9022 | 4010 | 9023 |
4011:9018 | 4011:9019 | 4011:9020 | 4011:9021 | 4011 | 9022 | 4011 | 9023 |
4012:9018 | 4012:9019 | 4012:9020 | 4012:9021 | 4012 | 9022 | 4012 | 9023 |
5001:9018 | 5001:9019 | 5001:9020 | 5001:9021 | 5001 | 9022 | 5001 | 9023 |
5002:9018 | 5002:9019 | 5002:9020 | 5002:9021 | 5002 | 9022 | 5002 | 9023 |
5003:9018 | 5003:9019 | 5003:9020 | 5003:9021 | 5003 | 9022 | 5003 | 9023 |
5004:9018 | 5004:9019 | 5004:9020 | 5004:9021 | 5004 | 9022 | 5004 | 9023 |
5005:9018 | 5005 : 9019 | 5005:9020 | 5005:9021 | 5005 | 9022 | 5005 | 9023 |
5006:9018 | 5006:9019 | 5006:9020 | 5006:9021 | 5006 | 9022 | 5006 | 9023 |
5007:9018 | 5007:9019 | 5007 : 9020 | 5007 : 9021 | 5007 | 9022 | 5007 | 9023 |
5008:9018 | 5008:9019 | 5008:9020 | 5008:9021 | 5008 | 9022 | 5008 | 9023 |
5009:9018 | 5009:9019 | 5009:9020 | 5009 : 9021 | 5009 | 9022 | 5009 | 9023 |
5010:9018 | 5010:9019 | 5010 : 9020 | 5010:9021 | 5010 | 9022 | 5010 | 9023 |
5011 :9018 | 5011:9019 | 5011:9020 | 5011:9021 | 5011 | 9022 | 5011 | 9023 |
5012:9018 | 5012:9019 | 5012:9020 | 5012:9021 | 5012 | 9022 | 5012 | 9023 |
102
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X | Y |
3001:9024 | 3001:9025 | 3001:9026 | 3001:9027 | 3001:9028 | 3001 | 9029 |
3002:9024 | 3002 : 9025 | 3002:9026 | 3002:9027 | 3002:9028 | 3002 | 9029 |
3003 : 9024 | 3003:9025 | 3003:9026 | 3003 : 9027 | 3003 : 9028 | 3003 | 9029 |
3004:9024 | 3004:9025 | 3004:9026 | 3004:9027 | 3004:9028 | 3004 | 9029 |
3005 : 9024 | 3005:9025 | 3005:9026 | 3005:9027 | 3005:9028 | 3005 | 9029 |
3006 τ9024- | 3006^9025- | 3006:9026 | 3006 :9027 | 3006 :9028 | 3006 | 9029 |
3007-:.9024. | 3007:9025 | 3007.:9026 | 3007j 9027-. | 3007:9028 | 3007 | 9029 |
3008 : 9024 | 3008:9025 | 3008:9026 | 3008 : 9027 | 3008 : 9028 | 3008 | 9029 |
3009 : 9024 | 3009:9025 | 3009 : 9026 | 3009 : 9027 | 3009:9028 | 3009 | 9029 |
3010:9024 | 3010:9025 | 3010 : 9026 | 3010:9027 | 3010:9028 | 3010 | 9029 |
3011:9024 | 3011:9025 | 3011:9026 | 3011:9027 | 3011:9028 | 3011 | 9029 |
3012 : 9024 | 3012:9025 | 3012:9026 | 3012:9027 | 3012:9028 | 3012 | 9029 |
3013:9024 | 3013:9025 | 3013:9026 | 3013 : 9027 | 3013:9028 | 3013 | 9029 |
3014:9024 | 3014:9025 | 30(4:9026 | 3014:9027 | 3014:9028 | 3014 | 9029 |
4001:9024 | 4001 :9025 | 4001:9026 | 4001:9027 | 4001:9028 | 4001 | 9029 |
4002 : 9024 | 4002:9025 | 4002:9026 | 4002:9027 | 4002:9028 | 4002 | 9029 |
4003 : 9024 | 4003 : 9025 | 4003:9026 | 4003 : 9027 | 4003 : 9028 | 4003 | 9029 |
4004:9024 | 4004:9025 | 4004:9026 | 4004:9027 | 4004:9028 | 4004 | 9029 |
4005 : 9024 | 4005:9025 | 4005 : 9026 | 4005 : 9027 | 4005:9028 | 4005 | 9029 |
4006 : 9024 | 4006:9025 | 4006:9026 | 4006:9027 | 4006 : 9028 | 4006 | 9029 |
4007 : 9024 | 4007:9025 | 4007:9026 | 4007:9027 | 4007:9028 | 4007 | 9029 |
4008 : 9024 | 4008:9025 | 4008:9026 | 4008 : 9027 | 4008 : 9028 | 4008 | 9029 |
4009 : 9024 | 4009:9025 | 4009:9026 | 4009:9027 | 4009 : 9028 | 4009 | 9029 |
4010 : 9024 | 4010:9025 | 4010:9026 | 4010:9027 | 4010:9028 | 4010 | 9029 |
4011:9024 | 4011:9025 | 4011:9026 | 4011:9027 | 4011:9028 | 4011 | 9029 |
4012 : 9024 | 4012:9025 | 4012:9026 | 4012:9027 | 4012 : 9028 | 4012 | 9029 |
5001:9024 | 5001:9025 | 5001:9026 | 5001:9027 | 5001:9028 | 5001 | 9029 |
5002 : 9024 | 5002:9025 | 5002:9026 | 5002:9027 | 5002:9028 | 5002 | 9029 |
5003 : 9024 | 5003 : 9025 | 5003:9026 | 5003:9027 | 5003:9028 | 5003 | 9029 |
5004 : 9024 | 5004:9025 | 5004:9026 | 5004:9027 | 5004 : 9028 | 5004 | 9029 |
5005 : 9024 | 5005:9025 | 5005 : 9026 | 5005:9027 | 5005:9028 | 5005 | 9029 |
5006 : 9024 | 5006:9025 | 5006:9026 | 5006 : 9027 | 5006:9028 | 5006 | 9029 |
5007:9024 | 5007:9025 | 5007 : 9026 | 5007:9027 | 5007:9028 | 5007 | 9029 |
5008:9024 | 5008:9025 | 5008:9026 | 5008 : 9027 | 5008 : 9028 | 5008 | 9029 |
5009:9024 | 5009:9025 | 5009:9026 | 5009 : 9027 | 5009:9028 | 5009 | 9029 |
5010:9024 | 5010:9025 | 5010:9026 | 5010:9027 | 5010:9028 | 5010 | 9029 |
5011:9024 | 5011:9025 | 5011:9026 | 5011:9027 | 5011:9028 | 5011 | 9029 |
5012 : 9024 | 5012:9025 | 5012:9026 | 5012:9027 | 5012 : 9028 | 5012 | 9029 |
103
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9030 | 3001 | 9031 | 3001 | 9032 | 3001 | 9033 | 3001 | 9034 | 3001 | 9035 |
3002 | 9030 | 3002 | 9031 | 3002 | 9032 | 3002 | 9033 | 3002 | 9034 | 3002 | 9035 |
3003 | 9030 | 3003 | 9031 | 3003 | 9032 | 3003 | 9033 | 3003 | 9034 | 3003 | 9035 |
3004 | 9030 | 3004 | 9031 | 3004 | 9032 | 3004 | 9033 | 3004 | 9034 | 3004 | 9035 |
3005 | 9030 | 3005 | 9031 | 3005 | 9032 | 3005 | 9033 | 3005 | 9034 | 3005 | 9035 |
3006 | 9030 | 3006 | •9031- | 3006 | 903£ | 3006 | .9033 | 3006 | 9034 | 3006 | 9035 |
3007' | -9030 | -3007 | ^031- | 3007 | 9032 | 3007. | -9033- | 3007- | 9034 | 3007 | 9035 |
3008 | 9030 | 3008 | 9031 | 3008 | 9032 | 3008 | 9033 | 3008 | 9034 | 3008 | 9035 |
3009 | 9030 | 3009 | 9031 | 3009 | 9032 | 3009 | 9033 | 3009 | 9034 | 3009 | 9035 |
3010 | 9030 | 3010 | 9031 | 3010 | 9032 | 3010 | 9033 | 3010 | 9034 | 3010 | 9035 |
3011 | 9030 | 3011 | 9031 | 3011 | 9032 | 3011 | 9033 | 3011 | 9034 | 3011 | 9035 |
3012 | 9030 | 3012 | 9031 | 3012 | 9032 | 3012 | 9033 | 3012 | 9034 | 3012 | 9035 |
3013 | 9030 | 3013 | 9031 | 3013 | 9032 | 3013 | 9033 | 3013 | 9034 | 3013 | 9035 |
3014 | 9030 | 3014 | 9031 | 3014 | 9032 | 3014 | 9033 | 3014 | 9034 | 3014 | 9035 |
4001 | 9030 | 4001 | 9031 | 4001 | 9032 | 4001 | 9033 | 4001 | 9034 | 4001 | 9035 |
4002 | 9030 | 4002 | 9031 | 4002 | 9032 | 4002 | 9033 | 4002 | 9034 | 4002 | 9035 |
4003 | 9030 | 4003 | 9031 | 4003 | 9032 | 4003 | 9033 | 4003 | 9034 | 4003 | 9035 |
4004 | 9030 | 4004 | 9031 | 4004 | 9032 | 4004 | 9033 | 4004 | 9034 | 4004 | 9035 |
4005 | 9030 | 4005 | 9031 | 4005 | 9032 | 4005 | 9033 | 4005 | 9034 | 4005 | 9035 |
4006 | 9030 | 4006 | 9031 | 4006 | 9032 | 4006 | 9033 | 4006 | 9034 | 4006 | 9035 |
4007 | 9030 | 4007 | 9031 | 4007 | 9032 | 4007 | 9033 | 4007 | 9034 | 4007 | 9035 |
4008 | 9030 | 4008 | 9031 | 4008 | 9032 | 4008 | 9033 | 4008 | 9034 | 4008 | 9035 |
4009 | 9030 | 4009 | 9031 | 4009 | 9032 | 4009 | 9033 | 4009 | 9034 | 4009 | 9035 |
4010 | 9030 | 4010 | 9031 | 4010 | 9032 | 4010 | 9033 | 4010 | 9034 | 4010 | 9035 |
4011 | 9030 | 4011 | 9031 | 4011 | 9032 | 4011 | 9033 | 4011 | 9034 | 4011 | 9035 |
4012 | 9030 | 4012 | 9031 | 4012 | 9032 | 4012 | 9033 | 4012 | 9034 | 4012 | 9035 |
5001 | 9030 | 5001 | 9031 | 5001 | 9032 | 5001 | 9033 | 5001 | 9034 | 5001 | 9035 |
5002 | 9030 | 5002 | 9031 | 5002 | 9032 | 5002 | 9033 | 5002 | 9034 | 5002 | 9035 |
5003 | 9030 | 5003 | 9031 | 5003 | 9032 | 5003 | 9033 | 5003 | 9034 | 5003 | 9035 |
5004 | 9030 | 5004 | 9031 | 5004 | 9032 | 5004 | 9033 | 5004 | 9034 | 5004 | 9035 |
5005 | 9030 | 5005 | 9031 | 5005 | 9032 | 5005 | 9033 | 5005 | 9034 | 5005 | 9035 |
5006 | 9030 | 5006 | 9031 | 5006 | 9032 | 5006 | 9033 | 5006 | 9034 | 5006 | 9035 |
5007 | 9030 | 5007 | 9031 | 5007 | 9032 | 5007 | 9033 | 5007 | 9034 | 5007 | 9035 |
5008 | 9030 | 5008 | 9031 | 5008 | 9032 | 5008 | 9033 | 5008 | 9034 | 5008 | 9035 |
5009 | 9030 | 5009 | 9031 | 5009 | 9032 | 5009 | 9033 | 5009 | 9034 | 5009 | 9035 |
5010 | 9030 | 5010 | 9031 | 5010 | 9032 | 5010 | 9033 | 5010 | 9034 | 5010 | 9035 |
5011 | 9030 | 5011 | 9031 | 5011 | 9032 | 5011 | 9033 | 5011 | 9034 | 5011 | 9035 |
5012 | 9030 | 5012 | 9031 | 5012 | 9032 | 5012 | 9033 | 5012 | 9034 | 5012 | 9035 |
104
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9036 | 3001 | 9037 | 3001 | 9038 | 3001 | 9039 | 3001 | 9040 | 3001 | 9041 |
3002 | 9036 | 3002 | 9037 | 3002 | 9038 | 3002 | 9039 | 3002 | 9040 | 3002 | 9041 |
3003 | 9036 | 3003 | 9037 | 3003 | 9038 | 3003 | 9039 | 3003 | 9040 | 3003 | 9041 |
3004 | 9036 | 3004 | 9037 | 3004 | 9038 | 3004 | 9039 | 3004 | 9040 | 3004 | 9041 |
3005 | 9036 | 3005 | 9037 | 3005 | 9038 | 3005 | 9039 | 3005 | 9040 | 3005 | 9041 |
3006 | 9036 | 3006 | 9037 | 3006 | 9038 | 30064 | 9039 | •3006 | -9040 | -3006 | 9041 |
3007 | 9036- | 3007 | 9037- | -3007 | 9038 | -3007. | 9039 | -3007:9040 | -3007 | 9041 | |
3008 | 9036 | 3008 | 9037 | 3008 | 9038 | 3008 | 9039 | 3008 | 9040 | 3008 | 9041 |
3009 | 9036 | 3009 | 9037 | 3009 | 9038 | 3009 | 9039 | 3009 | 9040 | 3009 | 9041 |
3010 | 9036 | 3010 | 9037 | 3010 | 9038 | 3010 | 9039 | 3010 | 9040 | 3010 | 9041 |
3011 | 9036 | 3011 | 9037 | 3011 | 9038 | 3011 | 9039 | 3011 | 9040 | 3011 | 9041 |
3012 | 9036 | 3012 | 9037 | 3012 | 9038 | 3012 | 9039 | 3012 | 9040 | 3012 | 9041 |
3013 | 9036 | 3013 | 9037 | 3013 | 9038 | 3013 | 9039 | 3013 | 9040 | 3013 | 9041 |
3014 | 9036 | 3014 | 9037 | 3014 | 9038 | 3014 | 9039 | 3014 | 9040 | 3014 | 9041 |
4001 | 9036 | 4001 | 9037 | 4001 | 9038 | 4001 | 9039 | 4001 | 9040 | 4001 | 9041 |
4002 | 9036 | 4002 | 9037 | 4002 | 9038 | 4002 | 9039 | 4002 | 9040 | 4002 | 9041 |
4003 | 9036 | 4003 | 9037 | 4003 | 9038 | 4003 | 9039 | 4003 | 9040 | 4003 | 9041 |
4004 | 9036 | 4004 | 9037 | 4004 | 9038 | 4004 | 9039 | 4004 | 9040 | 4004 | 9041 |
4005 | 9036 | 4005 | 9037 | 4005 | 9038 | 4005 | 9039 | 4005 | 9040 | 4005 | 9041 |
4006 | 9036 | 4006 | 9037 | 4006 | 9038 | 4006 | 9039 | 4006 | 9040 | 4006 | 9041 |
4007 | 9036 | 4007 | 9037 | 4007 | 9038 | 4007 | 9039 | 4007 | 9040 | 4007 | 9041 |
4008 | 9036 | 4008 | 9037 | 4008 | 9038 | 4008 | 9039 | 4008 | 9040 | 4008 | 9041 |
4009 | 9036 | 4009 | 9037 | 4009 | 9038 | 4009 | 9039 | 4009 | 9040 | 4009 | 9041 |
4010 | 9036 | 4010 | 9037 | 4010 | 9038 | 4010 | 9039 | 4010 | 9040 | 4010 | 9041 |
4011 | 9036 | 4011 | 9037 | 4011 | 9038 | 4011 | 9039 | 4011 | 9040 | 4011 | 9041 |
4012 | 9036 | 4012 | 9037 | 4012 | 9038 | 4012 | 9039 | 4012 | 9040 | 4012 | 9041 |
5001 | 9036 | 5001 | 9037 | 5001 | 9038 | 5001 | 9039 | 5001 | 9040 | 5001 | 9041 |
5002 | 9036 | 5002 | 9037 | 5002 | 9038 | 5002 | 9039 | 5002 | 9040 | 5002 | 9041 |
5003 | 9036 | 5003 | 9037 | 5003 | 9038 | 5003 | 9039 | 5003 | 9040 | 5003 | 9041 |
5004 | 9036 | 5004 | 9037 | 5004 | 9038 | 5004 | 9039 | 5004 | 9040 | 5004 | 9041 |
5005 | 9036 | 5005 | 9037 | 5005 | 9038 | 5005 | 9039 | 5005 | 9040 | 5005 | 9041 |
5006 | 9036 | 5006 | 9037 | 5006 | 9038 | 5006 | 9039 | 5006 | 9040 | 5006 | 9041 |
5007 | 9036 | 5007 | 9037 | 5007 | 9038 | 5007 | 9039 | 5007 | 9040 | 5007 | 9041 |
5008 | 9036 | 5008 | 9037 | 5008 | 9038 | 5008 | 9039 | 5008 | 9040 | 5008 | 9041 |
5009 | 9036 | 5009 | 9037 | 5009 | 9038 | 5009 | 9039 | 5009 | 9040 | 5009 | 9041 |
5010 | 9036 | 5010 | 9037 | 5010 | 9038 | 5010 | 9039 | 5010 | 9040 | 5010 | 9041 |
5011 | 9036 | 5011 | 9037 | 5011 | 9038 | 5011 | 9039 | 5011 | 9040 | 5011 | 9041 |
5012 | 9036 | 5012 | 9037 | 5012 | 9038 | 5012 | 9039 | 5012 | 9040 | 5012 | 9041 |
ÎOS
X:Y | X: Y | X:Y | X: Y | X:Y | X | Y |
3001:9042 | 3001:9043 | 3001:9044 | 3001:9045 | 3001 :9046 | 3001 | 9047 |
3002:9042 | 3002:9043 | 3002:9044 | 3002:9045 | 3002 : 9046 | 3002 | 9047 |
3003 : 9042 | 3003 : 9043 | 3003 : 9044 | 3003 : 9045 | 3003:9046 | 3003 | 9047 |
3004 : 9042 | 3004:9043 | 3004:9044 | 3004:9045 | 3004:9046 | 3004 | 9047 |
3005:9042 | 3005 : 9043 | 3005 : 9044 | 3005 : 9045 | 3005 : 9046 | 3005 | 9047 |
3006^9042- | 3006 r9O43- | 3006:9044 | 3006:9045 | 3006r9046 | 3006 | 9047 |
3007:9042- | 3007-9013- | 3007::9044- | -3007:9045 | •3007Î9046- | 3007 | 9047 |
3008:9042 | 3008:9045 | 3008:9044 | 3008 : 9045 | 3008:9046 | 3008 | 9047 |
3009:9042 | 3009 : 9043 | 3009:9044 | 3009 : 9045 | 3009 : 9046 | 3009 | 9047 |
3010:9042 | 3010 : 9043 | 3010 : 9044 | 3010:9045 | 3010:9046 | 3010 | 9047 |
3011:9042 | 3011:9043 | 3011:9044 | 3011:9045 | 3011:9046 | 3011 | 9047 |
3012:9042 | 3012:9043 | 3012 : 9044 | 3012:9045 | 3012:9046 | 3012 | 9047 |
3013 : 9042 | 3013:9043 | 3013 : 9044 | 3013 : 9045 | 3013:9046 | 3013 | 9047 |
3014:9042 | 3014 : 9043 | 3014:9044 | 3014:9045 | 3014 : 9046 | 3014 | 9047 |
4001:9042 | 4001:9043 | 4001:9044 | 4001:9045 | 4001:9046 | 4001 | 9047 |
4002:9042 | 4002:9043 | 4002:9044 | 4002:9045 | 4002:9046 | 4002 | 9047 |
4003:9042 | 4003:9043 | 4003 : 9044 | 4003:9045 | 4003 : 9046 | 4003 | 9047 |
4004:9042 | 4004:9043 | 4004:9044 | 4004:9045 | 4004 : 9046 | 4004 | 9047 |
4005 : 9042 | 4005 : 9043 | 4005 : 9044 | 4005 : 9045 | 4005 : 9046 | 4005 | 9047 |
4006:9042 | 4006 : 9043 | 4006:9044 | 4006:9045 | 4006 : 9046 | 4006 | 9047 |
4007:9042 | 4007:9043 | 4007:9044 | 4007:9045 | 4007 : 9046 | 4007 | 9047 |
4008 : 9042 | 4008:9043 | 4008:9044 | 4008:9045 | 4008:9046 | 4008 | 9047 |
4009:9042 | 4009:9043 | 4009:9044 | 4009:9045 | 4009:9046 | 4009 | 9047 |
4010:9042 | 4010 : 9043 | 4010:9044 | 4010:9045 | 4010:9046 | 4010 | 9047 |
4011:9042 | 4011:9043 | 4011:9044 | 4011:9045 | 4011 :9046 | 4011 | 9047 |
4012:9042 | 4012:9043 | 4012:9044 | 4012:9045 | 4012 : 9046 | 4012 | 9047 |
5001:9042 | 5001:9043 | 5001:9044 | 5001:9045 | 5001:9046 | 5001 | 9047 |
5002:9042 | 5002:9043 | 5002 : 9044 | 5002:9045 | 5002:9046 | 5002 | 9047 |
5003:9042 | 5003:9043 | 5003 : 9044 | 5003 :9045 | 5003 : 9046 | 5003 | 9047 |
5004:9042 | 5004 : 9043 | 5004:9044 | 5004:9045 | 5004 : 9046 | 5004 | 9047 |
5005:9042 | 5005:9043 | 5005:9044 | 5005 : 9045 | 5005 : 9046 | 5005 | 9047 |
5006 : 9042 | 5006 : 9043 | 5006 : 9044 | 5006:9045 | 5006:9046 | 5006 | 9047 |
5007:9042 | 5007 : 9043 | 5007:9044 | 5007:9045 | 5007 : 9046 | 5007 | 9047 |
5008 : 9042 | 5008:9043 | 5008 : 9044 | 5008:9045 | 5008:9046 | 5008 | 9047 |
5009 : 9042 | 5009:9043 | 5009:9044 | 5009 : 9045 | 5009 : 9046 | 5009 | 9047 |
5010 : 9042 | 5010:9043 | 5010:9044 | 5010:9045 | 5010:9046 | 5010 | 9047 |
5011:9042 | 5011 :9043 | 5011:9044 | 5011:9045 | 5011:9046 | 5011 | 9047 |
5012:9042 | 5012:9043 | 5012:9044 | 5012:9045 | 5012 : 9046 | 5012 | 9047 |
106
X: Y | X:Y | X | Y | X:Y | X:Y | X | Y |
3001:9048 | 3001:9049 | 3001 | 9050 | 3001:9051 | 3001:9052 | 3001 | 9053 |
3002:9048 | 3002:9049 | 3002 | 9050 | 3002:9051 | 3002:9052 | 3002 | 9053 |
3003:9048 | 3003:9049 | 3003 | 9050 | 3003:9051 | 3003:9052 | 3003 | 9053 |
3004:9048 | 3004:9049 | 3004 | 9050 | 3004:9051 | 3004:9052 | 3004 | 9053 |
3005:9048 | 3005 : 9049 | 3005 | 9050 | 3005:9051 | 3005:9052 | 3005 | 9053 |
-3006:.9048 | 3006-9049 | 3006 | 9050 | 3006:9051- | .3006:9052 | 3006 | 9053 |
-3007-9048- | -3007—9049? | -3007 | 9050 | -3007^9051- | 3007:9052 | -3007 | 9053 |
3008:9048 | 3008 : 9049 | 3008 | 9050 | 3008:9051 | 3008:9052 | 3008 | 9053 |
3009:9048 | 3009:9049 | 3009 | 9050 | 3009:9051 | 3009:9052 | 3009 | 9053 |
3010:9048 | 3010:9049 | 3010 | 9050 | 3010:9051 | 3010 : 9052 | 3010 | 9053 |
3011:9048 | 3011:9049 | 3011 | 9050 | 3011:9051 | 3011:9052 | 3011 | 9053 |
3012:9048 | 3012:9049 | 3012 | 9050 | 3012:9051 | 3012 : 9052 | 3012 | 9053 |
3013:9048 | 3013:9049 | 3013 | 9050 | 3013 : 9051 | 3013:9052 | 3013 | 9053 |
3014:9048 | 3014 : 9049 | 3014 | 9050 | 3014 : 9051 | 3014 : 9052 | 3014 | 9053 |
4001:9048 | 4001:9049 | 4001 | 9050 | 4001:9051 | 4001:9052 | 4001 | 9053 |
4002:9048 | 4002:9049 | 4002 | 9050 | 4002:9051 | 4002:9052 | 4002 | 9053 |
4003 : 9048 | 4003 :9049 | 4003 | 9050 | 4003:9051 | 4003 : 9052 | 4003 | 9053 |
4004:9048 | 4004:9049 | 4004 | 9050 | 4004 : 9051 | 4004 : 9052 | 4004 | 9053 |
4005 : 9048 | 4005:9049 | 4005 | 9050 | 4005 : 9051 | 4005:9052 | 4005 | 9053 |
4006:9048 | 4006:9049 | 4006 | 9050 | 4006:9051 | 4006 : 9052 | 4006 | 9053 |
4007:9048 | 4007:9049 | 4007 | 9050 | 4007:9051 | 4007 : 9052 | 4007 | 9053 |
4008:9048 | 4008:9049 | 4008 | 9050 | 4008:9051 | 4008 : 9052 | 4008 | 9053 |
4009:9048 | 4009 : 9049 | 4009 | 9050 | 4009 : 9051 | 4009 : 9052 | 4009 | 9053 |
4010:9048 | 4010 : 9049 | 4010 | 9050 | 4010 : 9051 | 4010 : 9052 | 4010 | 9053 |
4011:9048 | 4011:9049 | 4011 | 9050 | 4011:9051 | 4011:9052 | 4011 | 9053 |
4012 : 9048 | 4012:9049 | 4012 | 9050 | 4012:9051 | 4012 : 9052 | 4012 | 9053 |
5001:9048 | 5001:9049 | 5001 | 9050 | 5001:9051 | 5001 :9052 | 5001 | 9053 |
5002 : 9048 | 5002:9049 | 5002 | 9050 | 5002 : 9051 | 5002 : 9052 | 5002 | 9053 |
5003 : 9048 | 5003:9049 | 5003 | 9050 | 5003:9051 | 5003 :9052 | 5003 | 9053 |
5004:9048 | 5004:9049 | 5004 | 9050 | 5004:9051 | 5004:9052 | 5004 | 9053 |
5005:9048 | 5005:9049 | 5005 | 9050 | 5005:9051 | 5005 : 9052 | 5005 | 9053 |
5006 : 9048 | 5006:9049 | 5006 | 9050 | 5006 : 9051 | 5006 : 9052 | 5006 | 9053 |
5007:9048 | 5007:9049 | 5007 | 9050 | 5007:9051 | 5007 : 9052 | 5007 | 9053 |
5008 : 9048 | 5008:9049 | 5008 | 9050 | 5008:9051 | 5008:9052 | 5008 | 9053 |
5009:9048 | 5009:9049 | 5009 | 9050 | 5009:9051 | 5009:9052 | 5009 | 9053 |
5010 : 9048 | 5010:9049 | 5010 | 9050 | 5010:9051 | 5010:9052 | 5010 | 9053 |
5011:9048 | 5011:9049 | 5011 | 9050 | 5011:9051 | 5011:9052 | 5011 | 9053 |
5012:9048 | 5012 : 9049 | 5012 | 9050 | 5012:9051 | 5012:9051 | 5012 | 9053 |
I07
X | Y | X | Y | X | Y | X | Y | X | :Y | X | Y |
3001 | 9054 | 3001 | 9055 | 3001 | 9056 | 3001 | 9057 | 3001 | :9058 | 3001 | 9059 |
3002 | 9054 | 3002 | 9055 | 3002 | 9056 | 3002 | 9057 | 3002 | :9058 | 3002 | 9059 |
3003 | 9054 | 3003 | 9055 | 3003 | 9056 | 3003 | 9057 | 3003 | .9058 | 3003 | 9059 |
3004 | 9054 | 3004 | 9055 | 3004 | 9056 | 3004 | 9057 | 3004 | :9058 | 3004 | 9059 |
3005 | 9054 | 3005 | 9055 | 3005 | 9056 | 3005 | 9057 | 3005 | :9058 | 3005 | 9059 |
3006 | .9054 | -3006 | 9055 | 3006- | 9056 | 3006 | ,9057 | 3006 | :9058 | 3006 | 9059 |
-3007; | ^9054- | -3007' | 9055- | 3007 | 9056- | 3007- | 9057- | -3007^9058 | 3007 | 9059 | |
3008’ | 9054’ | 3008 | 9055 | 3008 | 9056 | 3008 | '9057 | 3008 | 9058 | 3008 | 9059 |
3009 | 9054 | 3009 | 9055 | 3009 | 9056 | 3009 | 9057 | 3009 | 9058 | 3009 | 9059 |
3010 | 9054 | 3010 | 9055 | 3010 | 9056 | 3010 | 9057 | 3010 | 9058 | 3010 | 9059 |
3011 | 9054 | 3011 | 9055 | 3011 | 9056 | 3011 | 9057 | 3011 | 9058 | 3011 | 9059 |
3012 | 9054 | 3012 | 9055 | 3012 | 9056 | 3012 | 9057 | 3012 | 9058 | 3012 | 9059 |
3013 | 9054 | 3013 | 9055 | 3013 | 9056 | 3013 | 9057 | 3013 | 9058 | 3013 | 9059 |
3014 | 9054 | 3014 | 9055 | 3014 | 9056 | 3014 | 9057 | 3014 | 9058 | 3014 | 9059 |
4001 | 9054 | 4001 | 9055 | 4001 | 9056 | 4001 | 9057 | 4001 | 9058 | 4001 | 9059 |
4002 | 9054 | 4002 | 9055 | 4002 | 9056 | 4002 | 9057 | 4002 | 9058 | 4002 | 9059 |
4003 | 9054 | 4003 | 9055 | 4003 | 9056 | 4003 | 9057 | 4003 | 9058 | 4003 | 9059 |
4004 | 9054 | 4004 | 9055 | 4004 | 9056 | 4004 | 9057 | 4004 | 9058 | 4004 | 9059 |
4005 | 9054 | 4005 | 9055 | 4005 | 9056 | 4005 | 9057 | 4005 | 9058 | 4005 | 9059 |
4006 | 9054 | 4006 | 9055 | 4006 | 9056 | 4006 | 9057 | 4006 | 9058 | 4006 | 9059 |
4007 | 9054 | 4007 | 9055 | 4007 | 9056 | 4007 | 9057 | 4007 | 9058 | 4007 | 9059 |
4008 | 9054 | 4008 | 9055 | 4008 | 9056 | 4008 | 9057 | 4008 | 9058 | 4008 | 9059 |
4009 | 9054 | 4009 | 9055 | 4009 | 9056 | 4009 | 9057 | 4009 | 9058 | 4009 | 9059 |
4010 | 9054 | 4010 | 9055 | 4010 | 9056 | 4010 | 9057 | 4010 | 9058 | 4010 | 9059 |
4011 | 9054 | 4011 | 9055 | 4011 | 9056 | 4011 | 9057 | 4011 | 9058 | 4011 | 9059 |
4012 | 9054 | 4012 | 9055 | 4012 | 9056 | 4012 | 9057 | 4012 | 9058 | 4012 | 9059 |
5001 | 9054 | 5001 | 9055 | 5001 | 9056 | 5001 | 9057 | 5001 | 9058 | 5001 | 9059 |
5002 | 9054 | 5002 | 9055 | 5002 | 9056 | 5002 | 9057 | 5002 | 9058 | 5002 | 9059 |
5003 | 9054 | 5003 | 9055 | 5003 | 9056 | 5003 | 9057 | 5003 | 9058 | 5003 | 9059 |
5004 | 9054 | 5004 | 9055 | 5004 | 9056 | 5004 | 9057 | 5004 | 9058 | 5004 | 9059 |
5005 | 9054 | 5005 | 9055 | 5005 | 9056 | 5005 | 9057 | 5005 | 9058 | 5005 | 9059 |
5006 | 9054 | 5006 | 9055 | 5006 | 9056 | 5006 | 9057 | 5006 | 9058 | 5006 | 9059 |
5007 | 9054 | 5007 | 9055 | 5007 | 9056 | 5007 | 9057 | 5007 | 9058 | 5007 | 9059 |
5008 | 9054 | 5008 | 9055 | 5008 | 9056 | 5008 | 9057 | 5008 | 9058 | 5008 | 9059 |
5009 | 9054 | 5009 | 9055 | 5009 | 9056 | 5009 | 9057 | 5009 | 9058 | 5009 | 9059 |
5010 | 9054 | 5010 | 9055 | 5010 | 9056 | 5010 | 9057 | 5010 | 9058 | 5010 | 9059 |
5011 | 9054 | 5011 | 9055 | 5011 | 9056 | 5011 | 9057 | 5011 | 9058 | 5011 | 9059 |
5012 | 9054 | 5012 | 9055 | 5012 | 9056 | 5012 | 9057 | 5012 | 9058 | 5012 | 9059 |
108 <
X | Y | X: | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9060 | 3001: | 9061 | 3001 | 9062 | 3001 | 9063 | 3001 | 9064 | 3001 | 9065 |
3002 | 9060 | 3002: | 9061 | 3002 | 9062 | 3002 | 9063 | 3002 | 9064 | 3002 | 9065 |
3003 | 9060 | 3003: | 9061 | 3003 | 9062 | 3003 | 9063 | 3003 | 9064 | 3003 | 9065 |
3004 | 9060 | 3004: | 9061 | 3004 | 9062 | 3004 | 9063 | 3004 | 9064 | 3004 | 9065 |
3005 | 9060 | 3005: | 9061 | 3005 | 9062 | 3005 | 9063 | 3005 | 9064 | 3005 | 9065 |
-300615060 | 300615061 | -3006J | 9062. | 3006 | .9063 | 3006 | 9064 | 3006 | 9065 | ||
3007-1-9060- | -3007 | -9061- | •3007- | 9062 | -3007 | 9063- | -3007 | 9064 | -3007 | 9065 | |
3008 | r9060 | 3008 | 9061 | 3008 | 9062 | 3008 | 9063 | 3008 | 9064 | 3008 | 9065 |
3009 | 9060 | 3009 | 9061 | 3009 | 9062 | 3009 | 9063 | 3009 | 9064 | 3009 | 9065 |
3010 | 9060 | 3010 | 9061 | 3010 | 9062 | 3010 | 9063 | 3010 | 9064 | 3010 | 9065 |
3011 | 9060 | 3011 | 9061 | 3011 | 9062 | 3011 | 9063 | 3011 | 9064 | 3011 | 9065 |
3012 | 9060 | 3012 | 9061 | 3012 | 9062 | 3012 | 9063 | 3012 | 9064 | 3012 | 9065 |
3013 | 9060 | 3013 | 9061 | 3013 | 9062 | 3013 | 9063 | 3013 | 9064 | 3013 | 9065 |
3014 | 9060 | 3014 | 9061 | 3014 | 9062 | 3014 | 9063 | 3014 | 9064 | 3014 | 9065 |
4001 | 9060 | 4001 | 9061 | 4001 | 9062 | 4001 | 9063 | 4001 | 9064 | 4001 | 9065 |
4002 | 9060 | 4002 | 9061 | 4002 | 9062 | 4002 | 9063 | 4002 | 9064 | 4002 | 9065 |
4003 | 9060 | 4003 | 9061 | 4003 | 9062 | 4003 | 9063 | 4003 | 9064 | 4003 | 9065 |
4004 | 9060 | 4004 | 9061 | 4004 | 9062 | 4004 | 9063 | 4004 | 9064 | 4004 | 9065 |
4005 | 9060 | 4005 | 9061 | 4005 | 9062 | 4005 | 9063 | 4005 | 9064 | 4005 | 9065 |
4006 | 9060 | 4006 | 9061 | 4006 | 9062 | 4006 | 9063 | 4006 | 9064 | 4006 | 9065 |
4007 | 9060 | 4007 | 9061 | 4007 | 9062 | 4007 | 9063 | 4007 | 9064 | 4007 | 9065 |
4008 | 9060 | 4008 | 9061 | 4008 | 9062 | 4008 | 9063 | 4008 | 9064 | 4008 | 9065 |
4009 | 9060 | 4009 | 9061 | 4009 | 9062 | 4009 | 9063 | 4009 | 9064 | 4009 | 9065 |
4010 | 9060 | 4010 | 9061 | 4010 | 9062 | 4010 | 9063 | 4010 | 9064 | 4010 | 9065 |
4011 | 9060 | 4011 | 9061 | 4011 | 9062 | 4011 | 9063 | 4011 | 9064 | 4011 | 9065 |
4012 | 9060 | 4012 | 9061 | 4012 | 9062 | 4012 | 9063 | 4012 | 9064 | 4012 | 9065 |
5001 | 9060 | 5001 | 9061 | 5001 | 9062 | 5001 | 9063 | 5001 | 9064 | 5001 | 9065 |
5002 | 9060 | 5002 | 9061 | 5002 | 9062 | 5002 | 9063 | 5002 | 9064 | 5002 | 9065 |
5003 | 9060 | 5003 | 9061 | 5003 | 9062 | 5003 | 9063 | 5003 | 9064 | 5003 | 9065 |
5004 | 9060 | 5004 | 9061 | 5004 | 9062 | 5004 | 9063 | 5004 | 9064 | 5004 | 9065 |
5005 | 9060 | 5005 | 9061 | 5005 | 9062 | 5005 | 9063 | 5005 | 9064 | 5005 | 9065 |
5006 | 9060 | 5006 | 9061 | 5006 | 9062 | 5006 | 9063 | 5006 | 9064 | 5006 | 9065 |
5007 | 9060 | 5007 | 9061 | 5007 | 9062 | 5007 | 9063 | 5007 | 9064 | 5007 | 9065 |
5008 | 9060 | 5008 | 9061 | 5008 | 9062 | 5008 | 9063 | 5008 | 9064 | 5008 | 9065 |
5009 | 9060 | 5009 | 9061 | 5009 | 9062 | 5009 | 9063 | 5009 | 9064 | 5009 | 9065 |
5010 | 9060 | 5010 | 9061 | 5010 | 9062 | 5010 | 9063 | 5010 | 9064 | 5010 | 9065 |
5011 | 9060 | 5011 | 9061 | 5011 | 9062 | 5011 | 9063 | 5011 | 9064 | 5011 | 9065 |
5012 | 9060 ) 5012 | 9061 | 5012 | 9062 | 5012 | 9063 | 5012 | 9064 | 5012 | 9065 |
109
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9066 | 3001 | 9067 | 3001 | 9068 | 3001 | 9069 | 3001 | 9070 | 3001 | 9071 |
3002 | 9066 | 3002 | 9067 | 3002 | 9068 | 3002 | 9069 | 3002 | 9070 | 3002 | 9071 |
3003 | 9066 | 3003 | 9067 | 3003 | 9068 | 3003 | 9069 | 3003 | 9070 | 3003 | 9071 |
3004 | 9066 | 3004 | 9067 | 3004 | 9068 | 3004 | 9069 | 3004 | 9070 | 3004 | 9071 |
3005 | 9066 | 3005 | 9067 | 3005 | 9068 | 3005 | 9069 | 3005 | 9070 | 3005 | 9071 |
-3006 | 9066 | -3006 | 9067 | 3006 | 9068 | 3006 | 9069 | 3006 | 9070 | 3006 | 9071 |
3007 | 9066 | 30074-9067- | 3007 | 9068 | 3007' | 9069 | 3007 | 9070 | 3007 | 9071 | |
'3008 | 9066 | 3008 | 9067 | 3008 | 9Ô68 | 3008 | 9069 | 3008 | 9070 | 3008 | 9071 |
3009 | 9066 | 3009 | 9067 | 3009 | 9068 | 3009 | 9069 | 3009 | 9070 | 3009 | 9071 |
3010 | 9066 | 3010 | 9067 | 3010 | 9068 | 3010 | 9069 | 3010 | 9070 | 3010 | 9071 |
3011 | 9066 | 3011 | 9067 | 3011 | 9068 | 3011 | 9069 | 3011 | 9070 | 3011 | 9071 |
3012 | 9066 | 3012 | 9067 | 3012 | 9068 | 3012 | 9069 | 3012 | 9070 | 3012 | 9071 |
3013 | 9066 | 3013 | 9067 | 3013 | 9068 | 3013 | 9069 | 3013 | 9070 | 3013 | 9071 |
3014 | 9066 | 3014 | 9067 | 3014 | 9068 | 3014 | 9069 | 3014 | 9070 | 3014 | 9071 |
4001 | 9066 | 4001 | 9067 | 4001 | 9068 | 4001 | 9069 | 4001 | 9070 | 4001 | 9071 |
4002 | 9066 | 4002 | 9067 | 4002 | 9068 | 4002 | 9069 | 4002 | 9070 | 4002 | 9071 |
4003 | 9066 | 4003 | 9067 | 4003 | 9068 | 4003 | 9069 | 4003 | 9070 | 4003 | 9071 |
4004 | 9066 | 4004 | 9067 | 4004 | 9068 | 4004 | 9069 | 4004 | 9070 | 4004 | 9071 |
4005 | 9066 | 4005 | 9067 | 4005 | 9068 | 4005 | 9069 | 4005 | 9070 | 4005 | 9071 |
4006 | 9066 | 4006 | 9067 | 4006 | 9068 | 4006 | 9069 | 4006 | 9070 | 4006 | 9071 |
4007 | 9066 | 4007 | 9067 | 4007 | 9068 | 4007 | 9069 | 4007 | 9070 | 4007 | 9071 |
4008 | 9066 | 4008 | 9067 | 4008 | 9068 | 4008 | 9069 | 4008 | 9070 | 4008 | 9071 |
4009 | 9066 | 4009 | 9067 | 4009 | 9068 | 4009 | 9069 | 4009 | 9070 | 4009 | 9071 |
4010 | 9066 | 4010 | 9067 | 4010 | 9068 | 4010 | 9069 | 4010 | 9070 | 4010 | 9071 |
4011 | 9066 | 4011 | 9067 | 4011 | 9068 | 4011 | 9069 | 4011 | 9070 | 4011 | 9071 |
4012 | 9066 | 4012 | 9067 | 4012 | 9068 | 4012 | 9069 | 4012 | 9070 | 4012 | 9071 |
5001 | 9066 | 5001 | 9067 | 5001 | 9068 | 5001 | 9069 | 5001 | 9070 | 5001 | 9071 |
5002 | 9066 | 5002 | 9067 | 5002 | 9068 | 5002 | 9069 | 5002 | 9070 | 5002 | 9071 |
5003 | 9066 | 5003 | 9067 | 5003 | 9068 | 5003 | 9069 | 5003 | 9070 | 5003 | 9071 |
5004 | 9066 | 5004 | 9067 | 5004 | 9068 | 5004 | 9069 | 5004 | 9070 | 5004 | 9071 |
5005 | 9066 | 5005 | 9067 | 5005 | 9068 | 5005 | 9069 | 5005 | 9070 | 5005 | 9071 |
5006 | 9066 | 5006 | 9067 | 5006 | 9068 | 5006 | 9069 | 5006 | 9070 | 5006 | 9071 |
5007 | 9066 | 5007 | 9067 | 5007 | 9068 | 5007 | 9069 | 5007 | 9070 | 5007 | 9071 |
5008 | 9066 | 5008 | 9067 | 5008 | 9068 | 5008 | 9069 | 5008 | 9070 | 5008 | 9071 |
5009 | 9066 | 5009 | 9067 | 5009 | 9068 | 5009 | 9069 | 5009 | 9070 | 5009 | 9071 |
5010 | 9066 | 5010 | 9067 | 5010 | 9068 | 5010 | 9069 | 5010 | 9070 | 5010 | 9071 |
5011 | 9066 | 5011 | 9067 | 5011 | 9068 | 5011 | 9069 | 5011 | 9070 | 5011 | 9071 |
5012 | 9066 | 5012 | 9067 | 5012 | 9068 | 5012 | 9069 | 5012 | 9070 | 5012 | 9071 |
110
X | Y | X | Y | X | :Y | X | :Y | X | Y | X | Y |
3001 | 9072 | 3001 | 9073 | 3001 | :9074 | 3001 | :9075 | 3001 | 9076 | 3001 | 9077 |
3002 | 9072 | 3002 | 9073 | 3002 | :9074 | 3002 | :9075 | 3002 | 9076 | 3002 | 9077 |
3003 | 9072 | 3003 | 9073 | 3003 | :9074 | 3003 | :9075 | 3003 | 9076 | 3003 | 9077 |
3004 | 9072 | 3004 | 9073 | 3004 | :9074 | 3004 | :9075 | 3004 | 9076 | 3004 | 9077 |
3005 | 9072 | 3005 | 9073 | 3005 | :9074 | 3005 | :9075 | 3005 | 9076 | 3005 | 9077 |
3006 | 9072 | 3006 | •9073 | 3006 | :9074- | 3006· | :9075 | 3006 | -9076 | 3006 | 9077 |
-3007 | -9072 | 3007 | .9073 | -3007 | :9074 | -3007 | :9075- | 3007^.9076 | 3007 | 9077 | |
3008 | 9072 | 3008 | 9073 | 3008 | 9074 | 3008 | 9075 | 3008 | 9076 | 3008 | 9077 |
3009 | 9072 | 3009 | 9073 | 3009 | 9074 | 3009 | 9075 | 3009 | 9076 | 3009 | 9077 |
3010 | 9072 | 3010 | 9073 | 3010 | 9074 | 3010 | 9075 | 3010 | 9076 | 3010 | 9077 |
3011 | 9072 | 3011 | 9073 | 3011 | 9074 | 3011 | 9075 | 3011 | 9076 | 3011 | 9077 |
3012 | 9072 | 3012 | 9073 | 3012 | 9074 | 3012 | 9075 | 3012 | 9076 | 3012 | 9077 |
3013 | 9072 | 3013 | 9073 | 3013 | 9074 | 3013 | 9075 | 3013 | 9076 | 3013 | 9077 |
3014 | 9072 | 3014 | 9073 | 3014 | 9074 | 3014 | 9075 | 3014 | 9076 | 3014 | 9077 |
4001 | 9072 | 4001 | 9073 | 4001 | 9074 | 4001 | 9075 | 4001 | 9076 | 4001 | 9077 |
4002 | 9072 | 4002 | 9073 | 4002 | 9074 | 4002 | 9075 | 4002 | 9076 | 4002 | 9077 |
4003 | 9072 | 4003 | 9073 | 4003 | 9074 | 4003 | 9075 | 4003 | 9076 | 4003 | 9077 |
4004 | 9072 | 4004 | 9073 | 4004 | 9074 | 4004 | 9075 | 4004 | 9076 | 4004 | 9077 |
4005 | 9072 | 4005 | 9073 | 4005 | 9074 | 4005 | 9075 | 4005 | 9076 | 4005 | 9077 |
4006 | 9072 | 4006 | 9073 | 4006 | 9074 | 4006 | 9075 | 4006 | 9076 | 4006 | 9077 |
4007 | 9072 | 4007 | 9073 | 4007 | 9074 | 4007 | 9075 | 4007 | 9076 | 4007 | 9077 |
4008 | 9072 | 4008 | 9073 | 4008 | 9074 | 4008 | 9075 | 4008 | 9076 | 4008 | 9077 |
4009 | 9072 | 4009 | 9073 | 4009 | 9074 | 4009 | 9075 | 4009 | 9076 | 4009 | 9077 |
4010 | 9072 | 4010 | 9073 | 4010 | 9074 | 4010 | 9075 | 4010 | 9076 | 4010 | 9077 |
4011 | 9072 | 4011 | 9073 | 4011 | 9074 | 4011 | 9075 | 4011 | 9076 | 4011 | 9077 |
4012 | 9072 | 4012 | 9073 | 4012 | 9074 | 4012 | 9075 | 4012 | 9076 | 4012 | 9077 |
5001 | 9072 | 5001 | 9073 | 5001 | 9074 | 5001 | 9075 | 5001 | 9076 | 5001 | 9077 |
5002 | 9072 | 5002 | 9073 | 5002 | 9074 | 5002 | 9075 | 5002 | 9076 | 5002 | 9077 |
5003 | 9072 | 5003 | 9073 | 5003 | 9074 | 5003 | 9075 | 5003 | 9076 | 5003 | 9077 |
5004 | 9072 | 5004 | 9073 | 5004 | 9074 | 5004 | 9075 | 5004 | 9076 | 5004 | 9077 |
5005 | 9072 | 5005 | 9073 | 5005 | 9074 | 5005 | 9075 | 5005 | 9076 | 5005 | 9077 |
5006 | 9072 | 5006 | 9073 | 5006 | 9074 | 5006 | 9075 | 5006 | 9076 | 5006 | 9077 |
5007 | 9072 | 5007 | 9073 | 5007 | 9074 | 5007 | 9075 | 5007 | 9076 | 5007 | 9077 |
5008 | 9072 | 5008 | 9073 | 5008 | 9074 | 5008 | 9075 | 5008 | 9076 | 5008 | 9077 |
5009 | 9072 | 5009 | 9073 | 5009 | 9074 | 5009 | 9075 | 5009 | 9076 | 5009 | 9077 |
5010 | 9072 | 5010 | 9073 | 5010 | 9074 | 5010 | 9075 | 5010 | 9076 | 5010 | 9077 |
5011 | 9072 | 5011 | 9073 | 5011 | 9074 | 5011 | 9075 | 5011 | 9076 | 5011 | 9077 |
5012 | 9072 | 5012 | 9073 | 5012 | 9074 | 5012 | 9075 | 5012 | 9076 | 5012 | 9077 |
III
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9078 | 3001 | 9079 | 3001 | 9080 | 3001 | 9081 | 3001 | 9082 | 3001 | 9083 |
3002 | 9078 | 3002 | 9079 | 3002 | 9080 | 3002 | 9081 | 3002 | 9082 | 3002 | 9083 |
3003 | 9078 | 3003 | 9079 | 3003 | 9080 | 3003 | 9081 | 3003 | 9082 | 3003 | 9083 |
3004 | 9078 | 3004 | 9079 | 3004 | 9080 | 3004 | 9081 | 3004 | 9082 | 3004 | 9083 |
3005 | 9078 | 3005 | 9079 | 3005 | 9080 | 3005 | 9081 | 3005 | 9082 | 3005 | 9083 |
3006 | 9078 | 3006' | 9079- | 3006 | 9080- | 3006 | 9081 | 3006 | 9082 | 3006 | 9083 |
3007 | 9078 | 3007' | 9079 | 3007- | 9080 | 3007 | .9081- | 3007 | 9082 | 3007 | 9083 |
3008 | 9078 | 3008 | 9079 | 3008 | 9080 | 3008 | 9081 | 3008 | 9082 | 3008 | 9083 |
3009 | 9078 | 3009 | 9079 | 3009 | 9080 | 3009 | 9081 | 3009 | 9082 | 3009 | 9083 |
3010 | 9078 | 3010 | 9079 | 3010 | 9080 | 3010 | 9081 | 3010 | 9082 | 3010 | 9083 |
3011 | 9078 | 3011 | 9079 | 3011 | 9080 | 3011 | 9081 | 3011 | 9082 | 3011 | 9083 |
3012 | 9078 | 3012 | 9079 | 3012 | 9080 | 3012 | 9081 | 3012 | 9082 | 3012 | 9083 |
3013 | 9078 | 3013 | 9079 | 3013 | 9080 | 3013 | 9081 | 3013 | 9082 | 3013 | 9083 |
3014 | 9078 | 3014 | 9079 | 3014 | 9080 | 3014 | 9081 | 3014 | 9082 | 3014 | 9083 |
4001 | 9078 | 4001 | 9079 | 4001 | 9080 | 4001 | 9081 | 4001 | 9082 | 4001 | 9083 |
4002 | 9078 | 4002 | 9079 | 4002 | 9080 | 4002 | 9081 | 4002 | 9082 | 4002 | 9083 |
4003 | 9078 | 4003 | 9079 | 4003 | 9080 | 4003 | 9081 | 4003 | 9082 | 4003 | 9083 |
4004 | 9078 | 4004 | 9079 | 4004 | 9080 | 4004 | 9081 | 4004 | 9082 | 4004 | 9083 |
4005 | 9078 | 4005 | 9079 | 4005 | 9080 | 4005 | 9081 | 4005 | 9082 | 4005 | 9083 |
4006 | 9078 | 4006 | 9079 | 4006 | 9080 | 4006 | 9081 | 4006 | 9082 | 4006 | 9083 |
4007 | 9078 | 4007 | 9079 | 4007 | 9080 | 4007 | 9081 | 4007 | 9082 | 4007 | 9083 |
4008 | 9078 | 4008 | 9079 | 4008 | 9080 | 4008 | 9081 | 4008 | 9082 | 4008 | 9083 |
4009 | 9078 | 4009 | 9079 | 4009 | 9080 | 4009 | 9081 | 4009 | 9082 | 4009 | 9083 |
4010 | 9078 | 4010 | 9079 | 4010 | 9080 | 4010 | 9081 | 4010 | 9082 | 4010 | 9083 |
4011 | 9078 | 4011 | 9079 | 4011 | 9080 | 4011 | 9081 | 4011 | 9082 | 4011 | 9083 |
4012 | 9078 | 4012 | 9079 | 4012 | 9080 | 4012 | 9081 | 4012 | 9082 | 4012 | 9083 |
5001 | 9078 | 5001 | 9079 | 5001 | 9080 | 5001 | 9081 | 5001 | 9082 | 5001 | 9083 |
5002 | 9078 | 5002 | 9079 | 5002 | 9080 | 5002 | 9081 | 5002 | 9082 | 5002 | 9083 |
5003 | 9078 | 5003 | 9079 | 5003 | 9080 | 5003 | 9081 | 5003 | 9082 | 5003 | 9083 |
5004 | 9078 | 5004 | 9079 | 5004 | 9080 | 5004 | 9081 | 5004 | 9082 | 5004 | 9083 |
5005 | 9078 | 5005 | 9079 | 5005 | 9080 | 5005 | 9081 | 5005 | 9082 | 5005 | 9083 |
5006 | 9078 | 5006 | 9079 | 5006 | 9080 | 5006 | 9081 | 5006 | 9082 | 5006 | 9083 |
5007 | 9078 | 5007 | 9079 | 5007 | 9080 | 5007 | 9081 | 5007 | 9082 | 5007 | 9083 |
5008 | 9078 | 5008 | 9079 | 5008 | 9080 | 5008 | 9081 | 5008 | 9082 | 5008 | 9083 |
5009 | 9078 | 5009 | 9079 | 5009 | 9080 | 5009 | 9081 | 5009 | 9082 | 5009 | 9083 |
5010 | 9078 | 5010 | 9079 | 5010 | 9080 | 5010 | 9081 | 5010 | 9082 | 5010 | 9083 |
5011 | 9078 | 5011 | 9079 | 5011 | 9080 | 5011 | 9081 | 5011 | 9082 | 5011 | 9083 |
5012 | 9078 | 5012 | 9079 | 5012 | 9080 | 5012 | 9081 | 5012 | 9082 | 5012 | 9083 |
112
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
3001 | 9084 | 3001 | 9085 | 3001 | 9086 | 3001 | 9087 | 3001 | 9088 | 3001 | 9089 |
3002 | 9084 | 3002 | 9085 | 3002 | 9086 | 3002 | 9087 | 3002 | 9088 | 3002 | 9089 |
3003 | 9084 | 3003 | 9085 | 3003 | 9086 | 3003 | 9087 | 3003 | 9088 | 3003 | 9089 |
3004 | 9084 | 3004 | 9085 | 3004 | 9086 | 3004 | 9087 | 3004 | 9088 | 3004 | 9089 |
3005 | 9084 | 3005 | 9085 | 3005 | 9086 | 3005 | 9087 | 3005 | 9088 | 3005 | 9089 |
3006 | 9084 | 3006 | 9085 | 3006 | 9086 | 3006 | 9087 | 3006 | .9088 | 3006 | 9089 |
-3007: | l9084 | -3007; | .9085 | -3007 | 9086 | -3007 | 9087 | :3007 | 9088 | 3007 | 9089 |
3008 | 9084 | 3008 | 9085 | 3008 | 9086 | 3008 | 9087 | 3008 | 9088 | 3008 | 9089 |
3009 | 9084 | 3009 | 9085 | 3009 | 9086 | 3009 | 9087 | 3009 | 9088 | 3009 | 9089 |
3010 | 9084 | 3010 | 9085 | 3010 | 9086 | 3010 | 9087 | 3010 | 9088 | 3010 | 9089 |
3011 | 9084 | 3011 | 9085 | 3011 | 9086 | 3011 | 9087 | 3011 | 9088 | 3011 | 9089 |
3012 | 9084 | 3012 | 9085 | 3012 | 9086 | 3012 | 9087 | 3012 | 9088 | 3012 | 9089 |
3013 | 9084 | 3013 | 9085 | 3013 | 9086 | 3013 | 9087 | 3013 | 9088 | 3013 | 9089 |
3014 | 9084 | 3014 | 9085 | 3014 | 9086 | 3014 | 9087 | 3014 | 9088 | 3014 | 9089 |
4001 | 9084 | 4001 | 9085 | 4001 | 9086 | 4001 | 9087 | 4001 | 9088 | 4001 | 9089 |
4002 | 9084 | 4002 | 9085 | 4002 | 9086 | 4002 | 9087 | 4002 | 9088 | 4002 | 9089 |
4003 | 9084 | 4003 | 9085 | 4003 | 9086 | 4003 | 9087 | 4003 | 9088 | 4003 | 9089 |
4004 | 9084 | 4004 | 9085 | 4004 | 9086 | 4004 | 9087 | 4004 | 9088 | 4004 | 9089 |
4005 | 9084 | 4005 | 9085 | 4005 | 9086 | 4005 | 9087 | 4005 | 9088 | 4005 | 9089 |
4006 | 9084 | 4006 | 9085 | 4006 | 9086 | 4006 | 9087 | 4006 | 9088 | 4006 | 9089 |
4007 | 9084 | 4007 | 9085 | 4007 | 9086 | 4007 | 9087 | 4007 | 9088 | 4007 | 9089 |
4008 | 9084 | 4008 | 9085 | 4008 | 9086 | 4008 | 9087 | 4008 | 9088 | 4008 | 9089 |
4009 | 9084 | 4009 | 9085 | 4009 | 9086 | 4009 | 9087 | 4009 | 9088 | 4009 | 9089 |
4010 | 9084 | 4010 | 9085 | 4010 | 9086 | 4010 | 9087 | 4010 | 9038 | 4010 | 9089 |
4011 | 9084 | 4011 | 9085 | 4011 | 9086 | 4011 | 9087 | 4011 | 9088 | 4011 | 9089 |
4012 | 9084 | 4012 | 9085 | 4012 | 9086 | 4012 | 9087 | 4012 | 9088 | 4012 | 9089 |
5001 | 9084 | 5001 | 9085 | 5001 | 9086 | 5001 | 9087 | 5001 | 9088 | 5001 | 9089 |
5002 | 9084 | 5002 | 9085 | 5002 | 9086 | 5002 | 9087 | 5002 | 9088 | 5002 | 9089 |
5003 | 9084 | 5003 | 9085 | 5003 | 9086 | 5003 | 9087 | 5003 | 9088 | 5003 | 9089 |
5004 | 9084 | 5004 | 9085 | 5004 | 9086 | 5004 | 9087 | 5004 | 9088 | 5004 | 9089 |
5005 | 9084 | 5005 | 9085 | 5005 | 9086 | 5005 | 9087 | 5005 | 9088 | 5005 | 9089 |
5006 | 9084 | 5006 | 9085 | 5006 | 9086 | 5006 | 9087 | 5006 | 9088 | 5006 | 9089 |
5007 | 9084 | 5007 | 9085 | 5007 | 9086 | 5007 | 9087 | 5007 | 9088 | 5007 | 9089 |
5008 | 9084 | 5008 | 9085 | 5008 | 9086 | 5008 | 9087 | 5008 | 9088 | 5008 | 9089 |
5009 | 9084 | 5009 | 9085 | 5009 | 9086 | 5009 | 9087 | 5009 | 9088 | 5009 | 9089 |
5010 | 9084 | 5010 | 9085 | 5010 | 9086 | 5010 | 9087 | 5010 | 9088 | 5010 | 9089 |
5011 | 9084 | 5011 | 9085 | 5011 | 9086 | 5011 | 9087 | 5011 | 9088 | 5011 | 9089 |
5012 | 9084 | 5012 | 9085 | 5012 | 9086 | 5012 | 9087 | 5012 | 9088 | 5012 | 9089 |
113
X:Y | Χ:Υ | X | Y | Χ:Υ | Χ:Υ | X | Y |
3001:9090 | 3001:9091 | 3001 | 9092 | 3001 :9093 | 3001:9094 | 3001 | 9095 |
3002:9090 | 3002:9091 | 3002 | 9092 | 3002:9093 | 3002:9094 | 3002 | 9095 |
3003:9090 | 3003:9091 | 3003 | 9092 | 3003 : 9093 | 3003:9094 | 3003 | 9095 |
3004:9090 | 3004:9091 | 3004 | 9092 | 3004:9093 | 3004:9094 | 3004 | 9095 |
3005 : 9090 | 3005 : 9091 | 3005 | 9092 | 3005:9093 | 3005:9094 | 3005 | 9095 |
3006:9090 | 3006:9091 | 3006 | ’-9092 | 3006:9093- | 3006:9094 | 3006 | 9095 |
3007-Î9090- | -3007:9091- | 3007 | -9092 | 3007’^9093 | 3007:9094 | --3007 | 9095 |
3008:9090 | 3008:9091 | 3008' | 9092 | 3008:9093 | 3008:9094 | 3008 | 9095 |
3009:9090 | 3009:9091 | 3009 | 9092 | 3009 : 9093 | 3009 : 9094 | 3009 | 9095 |
3010 : 9090 | 3010:9091 | 3010 | 9092 | 3010:9093 | 3010:9094 | 3010 | 9095 |
3011:9090 | 3011:9091 | 3011 | 9092 | 3011 :9093 | 3011 :9094 | 3011 | 9095 |
3012:9090 | 3012:9091 | 3012 | 9092 | 3012:9093 | 3012:9094 | 3012 | 9095 |
3013:9090 | 3013:9091 | 3013 | 9092 | 3013 : 9093 | 3013:9094 | 3013 | 9095 |
3014:9090 | 3014:9091 | 3014 | 9092 | 3014 : 9093 | 3014:9094 | 3014 | 9095 |
4001:9090 | 4001:9091 | 4001 | 9092 | 4001:9093 | 4001:9094 | 4001 | 9095 |
4002:9090 | 4002:9091 | 4002 | 9092 | 4002 : 9093 | 4002:9094 | 4002 | 9095 |
4003:9090 | 4003:9091 | 4003 | 9092 | 4003:9093 | 4003 : 9094 | 4003 | 9095 |
4004:9090 | 4004:9091 | 4004 | 9092 | 4004:9093 | 4004 : 9094 | 4004 | 9095 |
4005:9090 | 4005 : 9091 | 4005 | 9092 | 4005 : 9093 | 4005 : 9094 | 4005 | 9095 |
4006:9090 | 4006:9091 | 4006 | 9092 | 4006:9093 | 4006:9094 | 4006 | 9095 |
4007:9090 | 4007 : 9091 | 4007 | 9092 | 4007 : 9093 | 4007 : 9094 | 4007 | 9095 |
4008:9090 | 4008:9091 | 4008 | 9092 | 4008:9093 | 4008:9094 | 4008 | 9095 |
4009:9090 | 4009 : 9091 | 4009 | 9092 | 4009 : 9093 | 4009 : 9094 | 4009 | 9095 |
4010:9090 | 4010:9091 | 4010 | 9092 | 4010 : 9093 | 4010 : 9094 | 4010 | 9095 |
4011:9090 | 4011:9091 | 4011 | 9092 | 4011:9093 | 4011:9094 | 4011 | 9095 |
4012:9090 | 4012:9091 | 4012 | 9092 | 4012:9093 | 4012 : 9094 | 4012 | 9095 |
5001:9090 | 5001:9091 | 5001 | 9092 | 5001:9093 | 5001:9094 | 5001 | 9095 |
5002:9090 | 5002:9091 | 5002 | 9092 | 5002:9093 | 5002:9094 | 5002 | 9095 |
5003 : 9090 | 5003:9091 | 5003 | 9092 | 5003 : 9093 | 5003:9094 | 5003 | 9095 |
5004:9090 | 5004:9091 | 5004 | 9092 | 5004 : 9093 | 5004:9094 | 5004 | 9095 |
5005 : 9090 | 5005:9091 | 5005 | 9092 | 5005 : 9093 | 5005 : 9094 | 5005 | 9095 |
5006:9090 | 5006:9091 | 5006 | 9092 | 5006 : 9093 | 5006 : 9094 | 5006 | 9095 |
5007 : 9090 | 5007:9091 | 5007 | 9092 | 5007 : 9093 | 5007 : 9094 | 5007 | 9095 |
5008 : 9090 | 5008 : 9091 | 5008 | 9092 | 5008 : 9093 | 5008 : 9094 | 5008 | 9095 |
5009:9090 | 5009 : 9091 | 5009 | 9092 | 5009 : 9093 | 5009 : 9094 | 5009 | 9095 |
5010:9090 | 5010:9091 | 5010 | 9092 | 5010 : 9093 | 5010 : 9094 | 5010 | 9095 |
5011:9090 | 5011:9091 | 5011 | 9092 | 5011:9093 | 5011:9094 | 5011 | 9095 |
5012:9090 | 5012:9091 | 5012 | 9092 | 5012 : 9093 | 5012 : 9094 | 5012 | 9095 |
114
X:Y | X | Y | Χ:Υ | Χ:Υ | Χ:Υ | X | Y |
3001:9096 | 3001 | 9097 | 3001:9098 | 3001:9099 | 3001:9100 | 3001 | 9101 |
3002 : 9096 | 3002 | 9097 | 3002 : 9098 | 3002:9099 | 3002:9100 | 3002 | 9101 |
3003:9096 | 3003 | 9097 | 3003:9098 | 3003:9099 | 3003:9100 | 3003 | 9101 |
3004:9096 | 3004 | 9097 | 3004:9098 | 3004:9099 | 3004:9100 | 3004 | 9101 |
3005:9096 | 3005 | 9097 | 3005:9098 | 3005:9099 | 3005 : 9100 | 3005 | 9101. |
3006 :9096 | 3006 | -9097 | 3006:9098’ | 3006:9099 | 3006 :9100 | 3006 | 9101 |
3007:9096- | 3007 | 9097 | 3007 : 9098 | 3007 :9099- | 3007:9100 | 3007 | 9101 |
3008 : 9096 | 3008 | 9097 | 3008:9098 | 3008:9099 | 3008 : 9100 | 3008 | 9101 |
3009:9096 | 3009 | 9097 | 3009 : 9098 | 3009 : 9099 | 3009 : 9100 | 3009 | 9101 |
3010 : 9096 | 3010 | 9097 | 3010 : 9098 | 3010 : 9099 | 3010:9100 | 3010 | 9101 |
3011:9096 | 3011 | 9097 | 3011:9098 | 3011:9099 | 3011:9100 | 3011 | 9101 |
3012:9096 | 3012 | 9097 | 3012 : 9098 | 3012 : 9099 | 3012:9100 | 3012 | 9101 |
3013:9096 | 3013 | 9097 | 3013 : 9098 | 3013 : 9099 | 3013:9100 | 3013 | 9101 |
3014:9096 | 3014 | 9097 | 3014 : 9098 | 3014:9099 | 3014:9100 | 3014 | 9101 |
4001:9096 | 4001 | 9097 | 4001:9098 | 4001:9099 | 4001:9100 | 4001 | 9101 |
4002:9096 | 4002 | 9097 | 4002 : 9098 | 4002 : 9099 | 4002:9100 | 4002 | 9101 |
4003:9096 | 4003 | 9097 | 4003 : 9098 | 4003:9099 | 4003 : 9100 | 4003 | 9101 |
4004:9096 | 4004 | 9097 | 4004 : 9098 | 4004 : 9099 | 4004:9100 | 4004 | 9101 |
4005:9096 | 4005 | 9097 | 4005 : 9098 | 4005 : 9099 | 4005:9100 | 4005 | 9101 |
4006:9096 | 4006 | 9097 | 4006:9098 | 4006:9099 | 4006 : 9100 | 4006 | 9101 |
4007:9096 | 4007 | 9097 | 4007:9098 | 4007 : 9099 | 4007 : 9100 | 4007 | 9101 |
4008:9096 | 4008 | 9097 | 4008:9098 | 4008:9099 | 4008 : 9100 | 4008 | 9101 |
4009:9096 | 4009 | 9097 | 4009 : 9098 | 4009:9099 | 4009:9100 | 4009 | 9101 |
4010:9096 | 4010 | 9097 | 4010 : 9098 | 4010:9099 | 4010:9100 | 4010 | 9101 |
4011:9096 | 4011 | 9097 | 4011 :9098 | 4011:9099 | 4011:9100 | 4011 | 9101 |
4012:9096 | 4012 | 9097 | 4012:9098 | 4012:9099 | 4012:9100 | 4012 | 9101 |
5001:9096 | 5001 | 9097 | 5001:9098 | 5001:9099 | 5001:9100 | 5001 | 9101 |
5002 : 9096 | 5002 | 9097 | 5002:9098 | 5002:9099 | 5002:9100 | 5002 | 9101 |
5003:9096 | 5003 | 9097 | 5003 : 9098 | 5003 : 9099 | 5003 : 9100 | 5003 | 9101 |
5004 : 9096 | 5004 | 9097 | 5004:9098 | 5004 : 9099 | 5004 : 9100 | 5004 | 9101 |
5005:9096 | 5005 | 9097 | 5005:9098 | 5005 : 9099 | 5005:9100 | 5005 | 9101 |
5006:9096 | 5006 | 9097 | 5006:9098 | 5006:9099 | 5006:9100 | 5006 | 9101 |
5007 : 9096 | 5007 | 9097 | 5007:9098 | 5007:9099 | 5007 : 9100 | 5007 | 9101 |
5008 : 9096 | 5008 | 9097 | 5008:9098 | 5008:9099 | 5008:9100 | 5008 | 9101 |
5009:9096 | 5009 | 9097 | 5009:9098 | 5009 : 9099 | 5009:9100 | 5009 | 9101 |
5010 : 9096 | 5010 | 9097 | 5010 : 9098 | 5010:9099 | 5010:9100 | 5010 | 9101 |
5011 :9096 | 5011 | 9097 | 5011 :9098 | 5011:9099 | 5011:9100 | 5011 | 9101 |
5012:9096 | 5012 | 9097 | 5012 : 9098 | 5012:9099 | 5012:9100 | 5012 | 9101 |
115
X | Y | X | Y | X | Y | X | Y | X:Y | X:Y |
3001 | 9102 | 3001 | 9103 | 3001 | 9104 | 3001 | 9105 | ||
3002 | 9102 | 3002 | 9103 | 3002 | 9104 | 3002 | 9105 | ||
3003 | 9102 | 3003 | 9103 | 3003 | 9104 | 3003 | 9105 | ||
3004 | 9102 | 3004 | 9103 | 3004 | 9104 | 3004 | 9105 | ||
3005 | 9102 | 3005 | 9103 | 3005 | .9104 | 3005 | 9105 | ||
-3006 | :9102 | 3006 | .9103 | 3006 | :9104 | 3006 | .9105 | -- | |
3007:9102 | 3007 | ,9103- | 3007^9104- | -3007 | 9105- | — - | |||
3008 | 9102 | 3008 | 9103 | 3008 | 9104 | 3008 | 9105 | ||
3009 | 9102 | 3009 | 9103 | 3009 | 9104 | 3009 | 9105 | ||
3010 | 9102 | 3010 | 9103 | 3010 | 9104 | 3010 | 9105 | ||
3011 | 9102 | 3011 | 9103 | 3011 | 9104 | 3011 | 9105 | ||
3012 | 9102 | 3012 | 9103 | 3012 | 9104 | 3012 | 9105 | ||
3013 | 9102 | 3013 | 9103 | 3013 | 9104 | 3013 | 9105 | • | |
3014 | 9102 | 3014 | 9103 | 3014 | 9104 | 3014 | 9105 | ||
4001 | 9102 | 4001 | 9103 | 4001 | 9104 | 4001 | 9105 | ||
4002 | 9102 | 4002 | 9103 | 4002 | 9104 | 4002 | 9105 | ||
4003 | 9102 | 4003 | 9103 | 4003 | 9104 | 4003 | 9105 | ||
4004 | 9102 | 4004 | 9103 | 4004 | 9104 | 4004 | 9105 | ||
4005 | 9102 | 4005 | 9103 | 4005 | 9104 | 4005 | 9105 | ||
4006 | 9102 | 4006 | 9103 | 4006 | 9104 | 4006 | 9105 | ||
4007 | 9102 | 4007 | 9103 | 4007 | 9104 | 4007 | 9105 | ||
4008 | 9102 | 4008 | 9103 | 4008 | 9104 | 4008 | 9105 | ||
4009 | 9102 | 4009 | 9103 | 4009 | 9104 | 4009 | 9105 | ||
4010 | 9102 | 4010 | 9103 | 4010 | 9104 | 4010 | 9105 | ||
4011 | 9102 | 4011 | 9103 | 4011 | 9104 | 4011 | 9105 | ||
4012 | 9102 | 4012 | 9103 | 4012 | 9104 | 4012 | 9105 | ||
5001 | 9102 | 5001 | 9103 | 5001 | 9104 | 5001 | 9105 | ||
5002 | 9102 | 5002 | 9103 | 5002 | 9104 | 5002 | 9105 | ||
5003 | 9102 | 5003 | 9103 | 5003 | 9104 | 5003 | 9105 | ||
5004 | 9102 | 5004 | 9103 | 5004 | 9104 | 5004 | 9105 | ||
5005 | 9102 | 5005 | 9103 | 5005 | 9104 | 5005 | 9105 | ||
5006 | 9102 | 5006 | 9103 | 5006 | 9104 | 5006 | 9105 | ||
5007 | 9102 | 5007 | 9103 | 5007 | 9104 | 5007 | 9105 | ||
5008 | 9102 | 5008 | 9103 | 5008 | 9104 | 5008 | 9105 | ||
5009 | 9102 | 5009 | 9103 | 5009 | 9104 | 5009 | 9105 | ||
5010 | 9102 | 5010 | 9103 | 5010 | 9104 | 5010 | 9105 | ||
5011 | 9102 | 5011 | 9103 | 5011 | 9104 | 5011 | 9105 | ||
5012 | 9102 | 5012 | 9103 | 5012 | 9104 | 5012 | 9105 |
116
Table C: Example combinations of a compound X with a compound Y.
X | Y | X:Y | X:Y | X | Y | X:Y | X:Y | |
9000 | 7000 | 9001:7000 | 9002:7000 | 9003 | 7000 | 9004:7000 | 9005 : 7000 | |
9000 | 7001 | 9001:7001 | 9002:7001 | 9003 | 7001 | 9004:7001 | 9005:7001 | |
9000 | 7002 | 9001:7002 | 9002:7002 | 9003 | 7002 | 9004:7002 | 9005:7002 | |
9000 | 7003 | 9001:7003 | 9002:7003 | 9003 | 7003 | 9004:7003 | 9005:7003 | |
-— | 9000 | '7004 | 9001 :'7Ô04 | 9002:7004 | 9003 | 7004 | 9004:7004 | 9005:7004 |
- | 9000 | 7005 | 9001:7005 | 9002:7005 | 9003 | 7005 | 9004 : 7005 | 9005:7005 |
9000 | 7006 | 9001:7006 | 9002:7006 | 9003 | 7006 | 9004:7006 | 9005:7006 | |
9000 | 7007 | 9001:7007 | 9002:7007 | 9003 | 7007 | 9004:7007 | 9005:7007 | |
9000 | 7008 | 9001:7008 | 9002:7008 | 9003 | 7008 | 9004:7008 | 9005 : 7008 | |
9000 | 7009 | 9001:7009 | 9002:7009 | 9003 | 7009 | 9004:7009 | 9005 : 7009 | |
9000 | 7010 | 9001:7010 | 9002:7010 | 9003 | 7010 | 9004:7010 | 9005:7010 | |
9000 | 7011 | 9001:7011 | 9002:7011 | 9003 | 7011 | 9004 : 7011 | 9005:7011 | |
9000 | 7012 | 9001:7012 | 9002:7012 | 9003 | 7012 | 9004:7012 | 9005:7012 | |
9000 | 7013 | 9001:7013 | 9002:7013 | 9003 | 7013 | 9004:7013 | 9005:7013 | |
9000 | 7014 | 9001:7014 | 9002:7014 | 9003 | 7014 | 9004:7014 | 9005:7014 | |
9000 | 7015 | 9001:7015 | 9002:7015 | 9003 | 7015 | 9004 : 7015 | 9005:7015 | |
9000 | 7016 | 9001:7016 | 9002:7016 | 9003 | 7016 | 9004 : 7016 | 9005 : 7016 | |
9000 | 7017 | 9001:7017 | 9002:7017 | 9003 | 7017 | 9004 : 7017 | 9005:7017 | |
9000 | 7018 | 9001:7018 | 9002:7018 | 9003 | 7018 | 9004 : 7018 | 9005:7018 | |
9000 | 7019 | 9001:7019 | 9002:7019 | 9003 | 7019 | 9004:7019 | 9005 : 7019 | |
9000 | 7020 | 9001:7020 | 9002:7020 | 9003 | 7020 | 9004 : 7020 | 9005 : 7020 | |
9000 | 7021 | 9001:7021 | 9002:7021 | 9003 | 7021 | 9004 : 7021 | 9005 : 7021 | |
9000 | 7022 | 9001:7022 | 9002:7022 | 9003 | 7022 | 9004 : 7022 | 9005 : 7022 | |
9000 | 7023 | 9001:7023 | 9002:7023 | 9003 | 7023 | 9004 : 7023 | 9005 : 7023 | |
9000 | 7024 | 9001:7024 | 9002:7024 | 9003 | 7024 | 9004 : 7024 | 9005 : 7024 | |
9000 | 7025 | 9001:7025 | 9002:7025 | 9003 | 7025 | 9004 : 7025 | 9005 : 7025 | |
9000 | 7026 | 9001:7026 | 9002:7026 | 9003 | 7026 | 9004:7026 | 9005 : 7026 | |
9000 | 7027 | 9001:7027 | 9002:7027 | 9003 | 7027 | 9004 : 7027 | 9005 : 7027 |
117
X:Y | X | Y | X | Y | X | Y | X:Y | X | Y |
9006:7000 | 9007 | 7000 | 9008 | 7000 | 9009 | 7000 | 9010:7000 | 9011 | 7000 |
9006:7001 | 9007 | 7001 | 9008 | 7001 | 9009 | 7001 | 9010:7001 | 9011 | 7001 |
9006:7002 | 9007 | 7002 | 9008 | 7002 | 9009 | 7002 | 9010:7002 | 9011 | 7002 |
9006:7003 | 9007 | 7003 | 9008 | 7003 | 9009 | 7003 | 9010 : 7003 | 9011 | 7003 |
9006:7004 | 9007 | 7004 | 9008 | 7004 | 9009 | 7004 | 9010:7004 | 9011. | 7004 |
9006:7005 | 9007 | 7005 | 9008 | '7005 | 9009 | 7005 | 9010:7005 | 9011 | 7005 |
9006:7006 | 9007. | .7006 | 9008, | .7006 | 9009 | 7006 | 9010:7006 | 9011 | 7006 |
9006:7007 | 9007 | 7007 | 9008 | 7007 | 9009 | 7007 | 9010:7007 | 9011 | 7007 |
9006:7008 | 9007 | 7008 | 9008 | 7008 | 9009 | 7008 | 9010 : 7008 | 9011 | 7008 |
9006:7009 | 9007 | 7009 | 9008 | 7009 | 9009 | 7009 | 9010:7009 | 9011 | 7009 |
9006:7010 | 9007 | 7010 | 9008 | 7010 | 9009 | 7010 | 9010:7010 | 9011 | 7010 |
9006:7011 | 9007 | 7011 | 9008 | 7011 | 9009 | 7011 | 9010:7011 | 9011 | 7011 |
9006:7012 | 9007 | 7012 | 9008 | 7012 | 9009 | 7012 | 9010 : 7012 | 9011 | 7012 |
9006:7013 | 9007 | 7013 | 9008 | 7013 | 9009 | 7013 | 9010 : 7013 | 9011 | 7013 |
9006:7014 | 9007 | 7014 | 9008 | 7014 | 9009 | 7014 | 9010:7014 | 9011 | 7014 |
9006:7015 | 9007 | 7015 | 9008 | 7015 | 9009 | 7015 | 9010:7015 | 9011 | 7015 |
9006:7016 | 9007 | 7016 | 9008 | 7016 | 9009 | 7016 | 9010:7016 | 9011 | 7016 |
9006:7017 | 9007 | 7017 | 9008 | 7017 | 9009 | 7017 | 9010 : 7017 | 9011 | 7017 |
9006 : 7018 | 9007 | 70(8 | 9008 | 7018 | 9009 | 7018 | 9010:7018 | 9011 | 7018 |
9006:7019 | 9007 | 7019 | 9008 | 7019 | 9009 | 7019 | 9010 : 7019 | 9011 | 7019 |
9006:7020 | 9007 | 7020 | 9008 | 7020 | 9009 | 7020 | 9010 : 7020 | 9011 | 7020 |
9006:7021 | 9007 | 7021 | 9008 | 7021 | 9009 | 7021 | 9010 : 7021 | 9011 | 7021 |
9006:7022 | 9007 | 7022 | 9008 | 7022 | 9009 | 7022 | 9010:7022 | 9011 | 7022 |
9006:7023 | 9007 | 7023 | 9008 | 7023 | 9009 | 7023 | 9010 : 7023 | 9011 | 7023 |
9006:7024 | 9007 | 7024 | 9008 | 7024 | 9009 | 7024 | 9010 : 7024 | 9011 | 7024 |
9006:7025 | 9007 | 7025 | 9008 | 7025 | 9009 | 7025 | 9010 : 7025 | 9011 | 7025 |
9006:7026 | 9007 | 7026 | 9008 | 7026 | 9009 | 7026 | 9010:7026 | 9011 | 7026 |
9006:7027 | 9007 | 7027 | 9008 | 7027 | 9009 | 7027 | 9010:7027 | 9011 | 7027 |
us
X:Y | X | Y | X:Y | X | Y | X:Y | X:Y |
9012:7000 | 9013 | 7000 | 9014 : 7000 | 9015 | 7000 | 9016:7000 | 9017:7000 |
9012:7001 | 9013 | 7001 | 9014:7001 | 9015 | 7001 | 9016:7001 | 9017:7001 |
9012:7002 | 9013 | 7002 | 9014:7002 | 9015 | 7002 | 9016:7002 | 9017:7002 |
9012:7003 | 9013 | 7003 | 9014:7003 | 9015 | 7003 | 9016:7003 | 9017:7003 |
9012:7004 | 9013 | 7004 | 9014:7004 | 9015 | 7004 | 9016:7004 | 9017:7004 |
.9012 : 7005. | 9013 | 7005 | 9014:7005 | 9015 | .7005 | 9016:7005 | 9017:7005 |
9012:-7006 | 9013 | .7006 | 9014:-7006 | 9015 | -7006 | 9016:7006 | 9017:7006 |
9012:7007 | 9013 | 7007 | 9014:7007 | 9015 | 7007 | 9016 : 7007 | 9017:7007 |
9012:7008 | 9013 | 7008 | 9014:7008 | 9015 | 7008 | 9016:7008 | 9017 : 7008 |
9012:7009 | 9013 | 7009 | 9014:7009 | 9015 | 7009 | 9016:7009 | 9017:7009 |
9012:7010 | 9013 | 7010 | 9014:7010 | 9015 | 7010 | 9016:7010 | 9017:7010 |
9012:7011 | 9013 | 7011 | 9014:7011 | 9015 | 7011 | 9016:7011 | 9017:7011 |
9012:7012 | 9013 | 7012 | 9014:7012 | 9015 | 7012 | 9016:7012 | 9017:7012 |
9012:7013 | 9013 | 7013 | 9014:7013 | 9015 | 7013 | 9016 : 7013 | 9017:7013 |
9012:7014 | 9013 | 7014 | 9014:7014 | 9015 | 7014 | 9016:7014 | 9017:7014 |
9012:7015 | 9013 | 7015 | 9014:7015 | 9015 | 7015 | 9016 : 7015 | 9017 : 7015 |
9012:7016 | 9013 | 7016 | 9014:7016 | 9015 | 7016 | 9016:7016 | 9017 : 7016 |
9012 : 7017 | 9013 | 7017 | 9014:7017 | 9015 | 7017 | 9016:7017 | 9017:7017 |
9012:7018 | 9013 | 7018 | 9014:7018 | 9015 | 7018 | 9016:7018 | 9017:7018 |
9012:7019 | 9013 | 7019 | 9014:7019 | 9015 | 7019 | 9016 : 7019 | 9017:7019 |
9012 : 7020 | 9013 | 7020 | 9014 : 7020 | 9015 | 7020 | 9016 : 7020 | 9017:7020 |
9012 : 7021 | 9013 | 7021 | 9014:7021 | 9015 | 7021 | 9016 : 7021 | 9017:7021 |
9012:7022 | 9013 | 7022 | 9014:7022 | 9015 | 7022 | 9016 : 7022 | 9017:7022 |
9012 : 7023 | 9013 | 7023 | 9014:7023 | 9015 | 7023 | 9016 : 7023 | 9017:7023 |
9012 : 7024 | 9013 | 7024 | 9014:7024 | 9015 | 7024 | 9016 : 7024 | 9017:7024 |
9012 : 7025 | 9013 | 7025 | 9014:7025 | 9015 | 7025 | 9016 : 7025 | 9017:7025 |
9012 : 7026 | 9013 | 7026 | 9014:7026 | 9015 | 7026 | 9016:7026 | 9017:7026 |
9012:7027 | 9013 | 7027 | 9014:7027 | 9015 | 7027 | 9016:7027 | 9017:7027 |
119
-- | X:Y | X | Y | Χ:Υ | X: Y | Χ:Υ | Χ:Υ |
9018 : 7000 9018 : 7001 9018:7002 9018:7003 9018:7004 9018*7005 9018:7006 9018:7007 9018:7008 9018:7009 9018:7010 9018:7011 9018:7012 9018:7013 9018:7014 9018:7015 9018:7016 9018:7017 9018:7018 9018:7019 9018:7020 9018:7021 9018 : 7022 9018:7023 9018:7024 9018:7025 9018:7026 9018 : 7027 | 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 9019 | 7000 7001 7002 7003 7004 7005 17006 7007 7008 7009 7010 7011 7012 7013 7014 7015 7016 7017 7018 7019 7020 7021 7022 7023 7024 7025 7026 7027 | 9020:7000 9020:7001 9020:7002 9020:7003 9020:7004 9020:7005 9020*7006 9020 : 7007 9020:7008 9020:7009 9020:7010 9020:7011 9020:7012 9020:7013 9020:7014 9020:7015 9020:7016 9020:7017 9020:7018 9020:7019 9020:7020 9020 : 7021 9020:7022 9020:7023 9020:7024 9020:7025 9020 : 7026 9020:7027 | 9021 9021 9021 9021 9021 9021902 L·3 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 9021 | :7000 :7001 :7002 :7003 :7004 :7005 :-7006- 7007 7008 7009 7010 7011 7012 7013 7014 7015 7016 7017 7018 7019 7020 7021 7022 7023 7024 7025 7026 7027 | 9022 : 7000 9022:7001 9022 : 7002 9022:7003 9022:7004 9022:=7005 9022*7006 9022 : 7007 9022:7008 9022:7009 9022:7010 9022 : 7011 9022:7012 9022:7013 9022:7014 9022 : 7015 9022 : 7016 9022:7017 9022 : 7018 9022 : 7019 9022 : 7020 9022 : 7021 9022 : 7022 9022 : 7023 9022:7024 9022:7025 9022 : 7026 9022:7027 | 9023:7000 9023:7001 9023:7002 9023 : 7003 9023:7004 9023 : 7005 5023:7006 9023:7007 9023:7008 9023 : 7009 9023:7010 9023:7011 9023 : 7012 9023:7013 9023:7014 9023:7015 9023:7016 9023 : 7017 9023:7018 9023 : 7019 9023:7020 9023:7021 9023:7022 9023:7023 9023:7024 9023 : 7025 9023:7026 9023 : 7027 |
I20
X | Y | X: Y | X: Y | X: Y | X:Y | X:Y |
9024 | 7000 | 9025 : 7000 | 9026:7000 | 9027:7000 | 9028 : 7000 | 9029:7000 |
9024 | 700 L | 9025 : 7001 | 9026:7001 | 9027:7001 | 9028:7001 | 9029 : 7001 |
9024 | 7002 | 9025:7002 | 9026 : 7002 | 9027:7002 | 9028:7002 | 9029:7002 |
9024 | 7003 | 9025 : 7003 | 9026:7003 | 9027:7003 | 9028:7003 | 9029 : 7003 |
9024 | 7004 | 9025:7004 | 9026:7004 | 9027 : 7004 | 9028:7004 | 9029 : 7004 |
9024 | '7005 | 9025:7005 | 9026-:7005 | 9027-^7005 | 9028r7005 | 9029:7005 |
9024 | -7006 | 9025-7006 | 9026:7006 | 90274-7006- | 902847006 | 9029:7006 |
9024 | 7007 | 9025:7007 | 9026:7007 | 9027:7007 | 9028:7007 | 9029:7007 |
9024 | 7008 | 9025 : 7008 | 9026 : 7008 | 9027:7008 | 9028:7008 | 9029:7008 |
9024 | 7009 | 9025 : 7009 | 9026:7009 | 9027:7009 | 9028 : 7009 | 9029:7009 |
9024 | 7010 | 9025 : 7010 | 9026 : 7010 | 9027 : 7010 | 9028 : 7010 | 9029:7010 |
9024 | 7011 | 9025:7011 | 9026:7011 | 9027 : 7011 | 9028:7011 | 9029:7011 |
9024 | 7012 | 9025 : 7012 | 9026:7012 | 9027:7012 | 9028 : 7012 | 9029:7012 |
9024 | 7013 | 9025 : 7013 | 9026 : 7013 | 9027 : 7013 | 9028:7013 | 9029:7013 |
9024 | 7014 | 9025:7014 | 9026:7014 | 9027 : 7014 | 9028:7014 | 9029:7014 |
9024 | 7015 | 9025:7015 | 9026 : 7015 | 9027 : 7015 | 9028 : 7015 | 9029 : 7015 |
9024 | 7016 | 9025:7016 | 9026 : 7016 | 9027 : 7016 | 9028:7016 | 9029:7016 |
9024 | 7017 | 9025 : 7017 | 9026:7017 | 9027:7017 | 9028 : 7017 | 9029:7017 |
9024 | 7018 | 9025:7018 | 9026:7018 | 9027 : 7018 | 9028 : 7018 | 9029:7018 |
9024 | 7019 | 9025:7019 | 9026:7019 | 9027 : 7019 | 9028:7019 | 9029:7019 |
9024 | 7020 | 9025:7020 | 9026:7020 | 9027 : 7020 | 9028:7020 | 9029:7020 |
9024 | 7021 | 9025 : 7021 | 9026:7021 | 9027 : 7021 | 9028:7021 | 9029:7021 |
9024 | 7022 | 9025 : 7022 | 9026:7022 | 9027:7022 | 9028 : 7022 | 9029:7022 |
9024 | 7023 | 9025 : 7023 | 9026 : 7023 | 9027 : 7023 | 9028 : 7023 | 9029 : 7023 |
9024 | 7024 | 9025 : 7024 | 9026 : 7024 | 9027 : 7024 | 9028:7024 | 9029 : 7024 |
9024 | 7025 | 9025 : 7025 | 9026 : 7025 | 9027:7025 | 9028:7025 | 9029:7025 |
9024 | 7026 | 9025:7026 | 9026 : 7026 | 9027:7026 | 9028:7026 | 9029:7026 |
9024 | 7027 | 9025:7027 | 9026:7027 | 9027 : 7027 | 9028:7027 | 9029:7027 |
121
X:Y | X | Y | X:Y | X | Y | X | Y | X | Y |
9030:7000 | 9031 | 7000 | 9032 : 7000 | 9033 | 7000 | 9034 | 7000 | 9035 | 7000 |
9030:7001 | 9031 | 7001 | 9032:7001 | 9033 | 7001 | 9034 | 7001 | 9035 | 7001 |
9030:7002 | 9031 | 7002 | 9032:7002 | 9033 | 7002 | 9034 | 7002 | 9035 | 7002 |
9030:7003 | 9031 | 7003 | 9032:7003 | 9033 | 7003 | 9034 | 7003 | 9035 | 7003 |
9030:7004 | 9031 | 7004 | 9032:7004 | 9033 | 7004 | 9034 | 7004 | 9035 | 7004 |
9030:7005 | 9031- | 7005 | 9032:7005 | 9033 | 7005 | 9034 | 7005 | 9035 | 7005 |
9030:.7006 | 903 h | '7006 | 9032-7006 | 9033 | 7006 | 9034' | 7006 | 9035 | 7006 |
9030:7007 | 9031 | 7007 | 9032:7007 | 9033 | 7007 | 9034 | 7007 | 9035 | 7007 |
9030:7008 | 9031 | 7008 | 9032:7008 | 9033 | 7008 | 9034 | 7008 | 9035 | 7008 |
9030:7009 | 9031 | 7009 | 9032 : 7009 | 9033 | 7009 | 9034 | 7009 | 9035 | 7009 |
9030:7010 | 9031 | 7010 | 9032:7010 | 9033 | 7010 | 9034 | 7010 | 9035 | 7010 |
9030:7011 | 9031 | 7011 | 9032:7011 | 9033 | 7011 | 9034 | 7011 | 9035 | 7011 |
9030:7012 | 9031 | 7012 | 9032 : 7012 | 9033 | 7012 | 9034 | 7012 | 9035 | 7012 |
9030:7013 | 9031 | 7013 | 9032:7013 | 9033 | 7013 | 9034 | 7013 | 9035 | 7013 |
9030 : 7014 | 9031 | 7014 | 9032:7014 | 9033 | 7014 | 9034 | 7014 | 9035 | 7014 |
9030:7015 | 9031 | 7015 | 9032:7015 | 9033 | 70(5 | 9034 | 7015 | 9035 | 7015 |
9030:7016 | 9031 | 7016 | 9032:7016 | 9033 | 7016 | 9034 | 7016 | 9035 | 7016 |
9030 : 7017 | 9031 | 7017 | 9032:7017 | 9033 | 7017 | 9034 | 7017 | 9035 | 7017 |
9030:7018 | 9031 | 7018 | 9032:7018 | 9033 | 70(8 | 9034 | 7018 | 9035 | 7018 |
9030:7019 | 9031 | 7019 | 9032:7019 | 9033 | 7019 | 9034 | 7019 | 9035 | 7019 |
9030:7020 | 9031 | 7020 | 9032:7020 | 9033 | 7020 | 9034 | 7020 | 9035 | 7020 |
9030 : 7021 | 9031 | 7021 | 9032:7021 | 9033 | 7021 | 9034 | 7021 | 9035 | 7021 |
9030:7022 | 9031 | 7022 | 9032:7022 | 9033 | 7022 | 9034 | 7022 | 9035 | 7022 |
9030:7023 | 9031 | 7023 | 9032:7023 | 9033 | 7023 | 9034 | 7023 | 9035 | 7023 |
9030:7024 | 9031 | 7024 | 9032 : 7024 | 9033 | 7024 | 9034 | 7024 | 9035 | 7024 |
9030:7025 | 9031 | 7025 | 9032:7025 | 9033 | 7025 | 9034 | 7025 | 9035 | 7025 |
9030:7026 | 9031 | 7026 | 9032:7026 | 9033 | 7026 | 9034 | 7026 | 9035 | 7026 |
9030:7027 | 9031 | 7027 | 9032:7027 | 9033 | 7027 | 9034 | 7027 | 9035 | 7027 |
122
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X | Y |
9036:7000 | 9037 : 7000 | 9038:7000 | 9039 : 7000 | 9040:7000 | 9041 | 7000 |
9036:7001 | 9037:7001 | 9038:7001 | 9039:7001 | 9040:7001 | 9041 | 7001 |
9036:7002 | 9037 : 7002 | 9038:7002 | 9039:7002 | 9040:7002 | 9041 | 7002 |
9036:7003 | 9037:7003 | 9038:7003 | 9039:7003 | 9040 : 7003 | 9041 | 7003 |
9036:7004 | 9037:7004 | 9038 : 7004 | 9039:7004 | 9040:7004 | 9041 | 7004 |
9036:7005 | 9037 :-7005. | -9038 : 7005 | _9039 r7005 | 9040^7005 | 9041 | 7005 |
90364 7006 | 9037-7006 | 9038-7006 | 9039:7006 | 90401 7006 | 9041 | .7006 |
9036:7007 | 9037:7007 | 9038:7007 | 9039:7007 | 9040:7007 | 9041 | 7007 |
9036:7008 | 9037:7008 | 9038:7008 | 9039:7008 | 9040:7008 | 9041 | 7008 |
9036 : 7009 | 9037:7009 | 9038:7009 | 9039:7009 | 9040:7009 | 9041 | 7009 |
9036:7010 | 9037:7010 | 9038:7010 | 9039:7010 | 9040:7010 | 9041 | 7010 |
9036:7011 | 9037 : 7011 | 9038:7011 | 9039:7011 | 9040 : 7011 | 9041 | 7011 |
9036:7012 | 9037 : 7012 | 9038:7012 | 9039:7012 | 9040:7012 | 9041 | 7012 |
9036:7013 | 9037:7013 | 9038:7013 | 9039:7013 | 9040:7013 | 9041 | 7013 |
9036:7014 | 9037:7014 | 9038 : 7014 | 9039 : 7014 | 9040 : 7014 | 9041 | 7014 |
9036:7015 | 9037:7015 | 9038:7015 | 9039:7015 | 9040:7015 | 9041 | 7015 |
9036 : 7016 | 9037:7016 | 9038:7016 | 9039 : 7016 | 9040 : 7016 | 9041 | 7016 |
9036:7017 | 9037 : 7017 | 9038:7017 | 9039:7017 | 9040:7017 | 9041 | 7017 |
9036:7018 | 9037 : 7018 | 9038:7018 | 9039:7018 | 9040:7018 | 9041 | 7018 |
9036:7019 | 9037 : 7019 | 9038:7019 | 9039:7019 | 9040 : 7019 | 9041 | 7019 |
9036:7020 | 9037 : 7020 | 9038:7020 | 9039:7020 | 9040 : 7020 | 9041 | 7020 |
9036:7021 | 9037 : 7021 | 9038:7021 | 9039:7021 | 9040 : 7021 | 9041 | 7021 |
9036:7022 | 9037 : 7022 | 9038:7022 | 9039:7022 | 9040 : 7022 | 9041 | 7022 |
9036:7023 | 9037:7023 | 9038:7023 | 9039:7023 | 9040 : 7023 | 9041 | 7023 |
9036 : 7024 | 9037:7024 | 9038:7024 | 9039:7024 | 9040 : 7024 | 9041 | 7024 |
9036:7025 | 9037 : 7025 | 9038:7025 | 9039:7025 | 9040:7025 | 9041 | 7025 |
9036:7026 | 9037 : 7026 | 9038:7026 | 9039 : 7026 | 9040 : 7026 | 9041 | 7026 |
9036 : 7027 | 9037 : 7027 | 9038:7027 | 9039 : 7027 | 9040:7027 | 9041 | 7027 |
123
X:Y | Χ:Υ | Χ:Υ | X | Y | Χ:Υ | X | Y |
9042:7000 | 9043:7000 | 9044 : 7000 | 9045 | 7000 | 9046 : 7000 | 9047 | 7000 |
9042:7001 | 9043:7001 | 9044 : 7001 | 9045 | 7001 | 9046:7001 | 9047 | 7001 |
9042 : 7002 | 9043:7002 | 9044 : 7002 | 9045 | 7002 | 9046:7002 | 9047 | 7002 |
9042:7003 | 9043:7003 | 9044 : 7003 | 9045 | 7003 | 9046:7003 | 9047 | 7003 |
9012:7004 | 9043:7004 | 9044 : 7004 | 9045 | 7004 | 9046:7004 | 9047 | 7004 |
9042:7005 | 9043:7005 | 9044 : 7005 | 9045 | 7005 | 9046:7005 | 9047 | 7005 |
9042:7006 | 9043:7006 | 9044:7006 | 9045 | *-7006 | 9046:7006 | 9047 | 7006 |
9042:7007 | 9043:7007 | 9044:7007 | 9045 | 7007 | 9046:7007 | 9047 | 7007 |
9042:7008 | 9043:7008 | 9044:7008 | 9045 | 7008 | 9046:7008 | 9047 | 7008 |
9042:7009 | 9043:7009 | 9044:7009 | 9045 | 7009 | 9046:7009 | 9047 | 7009 |
9042:7010 | 9043 : 7010 | 9044:7010 | 9045 | 7010 | 9046:7010 | 9047 | 7010 |
9042:7011 | 9043:7011 | 9044 : 7011 | 9045 | 7011 | 9046 : 7011 | 9047 | 7011 |
9042:7012 | 9043 : 7012 | 9044 : 7012 | 9045 | 7012 | 9046:7012 | 9047 | 7012 |
9042:7013 | 9043:7013 | 9044 : 7013 | 9045 | 7013 | 9046:7013 | 9047 | 7013 |
9042:7014 | 9043:7014 | 9044 : 7014 | 9045 | 7014 | 9046:7014 | 9047 | 7014 |
9042:7015 | 9043 : 7015 | 9044 : 7015 | 9045 | 7015 | 9046:7015 | 9047 | 7015 |
9042 : 7016 | 9043 : 7016 | 9044 : 7016 | 9045 | 7016 | 9046:7016 | 9047 | 7016 |
9042:7017 | 9043 : 7017 | 9044:7017 | 9045 | 7017 | 9046 : 7017 | 9047 | 7017 |
9042:7018 | 9043 : 7018 | 9044 : 7018 | 9045 | 7018 | 9046 : 7018 | 9047 | 7018 |
9042 : 7019 | 9043 : 7019 | 9044:7019 | 9045 | 7019 | 9046:7019 | 9047 | 7019 |
9042:7020 | 9043 : 7020 | 9044 : 7020 | 9045 | 7020 | 9046:7020 | 9047 | 7020 |
9042:7021 | 9043 : 7021 | 9044:7021 | 9045 | 7021 | 9046 : 7021 | 9047 | 7021 |
9042:7022 | 9043:7022 | 9044 : 7022 | 9045 | 7022 | 9046:7022 | 9047 | 7022 |
9042:7023 | 9043:7023 | 9044 : 7023 | 9045 | 7023 | 9046 : 7023 | 9047 | 7023 |
9042:7024 | 9043:7024 | 9044 : 7024 | 9045 | 7024 | 9046 : 7024 | 9047 | 7024 |
9042:7025 | 9043:7025 | 9044 : 7025 | 9045 | 7025 | 9046 : 7025 | 9047 | 7025 |
9042:7026 | 9043:7026 | 9044:7026 | 9045 | 7026 | 9046:7026 | 9047 | 7026 |
9042:7027 | 9043:7027 | 9044 : 7027 | 9045 | 7027 | 9046 : 7027 | 9047 | 7027 |
124
X: Y | X:Y | X: Y | X | Y | X:Y | X:Y |
9048:7000 | 9049 : 7000 | 9050:7000 | 9051 | 7000 | 9052:7000 | 9053:7000 |
9048:7001 | 9049:7001 | 9050:7001 | 9051 | 7001 | 9052:7001 | 9053:7001 |
9048:7002 | 9049:7002 | 9050:7002 | 9051 | 7002 | 9052 : 7002 | 9053:7002 |
9048:7003 | 9049:7003 | 9050:7003 | 9051 | 7003 | 9052:7003 | 9053:7003 |
9048:7004 | 9049:7004 | 9050:7004 | 9051 | 7004 | 9052:7004 | 9053:7004 |
9048:7005 | -9049 :-7005 | 9050x7005 | 9051 | 7005 | 9051x7005- | 9053 : 7005 |
-9048-:7006 | -904^4-7006 | 9050:-7006 | 9051 | .7006 | 9052:7006 | 9053:7006 |
9048 : 7007 | 9049:7007 | 9050:7007 | 9051 | 7007 | 9052:7007 | 9053:7007 |
9048 : 7008 | 9049 : 7008 | 9050:7008 | 9051 | 7008 | 9052 : 7008 | 9053:7008 |
9048 : 7009 | 9049:7009 | 9050:7009 | 9051 | 7009 | 9052 : 7009 | 9053:7009 |
9048 : 7010 | 9049:7010 | 9050:7010 | 9051 | 7010 | 9052:7010 | 9053 : 7010 |
9048 : 7011 | 9049:7011 | 9050 : 7011 | 9051 | 7011 | 9052:7011 | 9053:7011 |
9048 : 7012 | 9049:7012 | 9050:7012 | 9051 | 7012 | 9052:7012 | 9053:7012 |
9048 : 7013 | 9049:7013 | 9050 : 7013 | 9051 | 7013 | 9052:7013 | 9053 : 7013 |
9048:7014 | 9049:7014 | 9050:7014 | 905! | 7014 | 9052 : 7014 | 9053 : 7014 |
9048:7015 | 9049 : 7015 | 9050:7015 | 9051 | 7015 | 9052 : 7015 | 9053:7015 |
9048:7016 | 9049 : 7016 | 9050:7016 | 9051 | 7016 | 9052 : 7016 | 9053:7016 |
9048 : 7017 | 9049 : 7017 | 9050 : 7017 | 905! | 7017 | 9052 : 7017 | 9053:7017 |
9048 : 7018 | 9049:7018 | 9050:7018 | 9051 | 7018 | 9052 : 7018 | 9053:7018 |
9048:7019 | 9049:7019 | 9050 : 7019 | 9051 | 7019 | 9052 : 7019 | 9053 : 7019 |
9048:7020 | 9049:7020 | 9050:7020 | 9051 | 7020 | 9052:7020 | 9053 : 7020 |
9048 : 7021 | 9049 : 7021 | 9050:7021 | 9051 | 7021 | 9052:7021 | 9053 : 7021 |
9048:7022 | 9049 : 7022 | 9050 : 7022 | 9051 | 7022 | 9052:7022 | 9053 : 7022 |
9048:7023 | 9049 : 7023 | 9050:7023 | 9051 | 7023 | 9052 : 7023 | 9053 : 7023 |
9048 : 7024 | 9049:7024 | 9050 : 7024 | 9051 | 7024 | 9052:7024 | 9053 : 7024 |
9048:7025 | 9049 : 7025 | 9050:7025 | 9051 | 7025 | 9052 : 7025 | 9053 : 7025 |
9048:7026 | 9049:7026 | 9050:7026 | 9051 | 7026 | 9052:7026 | 9053:7026 |
9048 : 7027 | 9049:7027 | 9050:7027 | 9051 | 7027 | 9052 : 7027 | 9053 : 7027 |
125
X | Y | X | Y | X:Y | X:Y | X:Y | X: Y |
9054 | 7000 | 9055 | 7000 | 9056:7000 | 9057:7000 | 9058:7000 | 9059:7000 |
9054 | 7001 | 9055 | 7001 | 9056 : 7001 | 9057:7001 | 9058:7001 | 9059:7001 |
9054 | 7002 | 9055 | 7002 | 9056:7002 | 9057:7002 | 9058:7002 | 9059:7002 |
9054 | 7003 | 9055 | 7003 | 9056:7003 | 9057:7003 | 9058:7003 | 9059:7003 |
9054 | 7004 | 9055 | 7004 | 9056:7004 | 9057:7004 | 9058:7004 | 9059:7004 |
9054 | '7005 | 9055 | 7005 | 9056:7005 | 905717005 | 9058 £7005 | 9059:7005 |
9054:-7006 | 9055 | -7006 | 9056 :-7006 | 9057 £7006 | 9058:-7006 | 9059:7006 | |
9054 | 7007 | 9055 | 7007 | 9056:7007 | 9057 : 7007 | 9058 : 7007 | 9059:7007 |
9054 | 7008 | 9055 | 7008 | 9056:7008 | 9057 : 7008 | 9058:7008 | 9059:7008 |
9054 | 7009 | 9055 | 7009 | 9056 : 7009 | 9057 : 7009 | 9058:7009 | 9059:7009 |
9054 | 7010 | 9055 | 7010 | 9056 : 7010 | 9057 : 7010 | 9058:7010 | 9059:7010 |
9054 | 7011 | 9055 | 7011 | 9056:7011 | 9057:7011 | 9058:7011 | 9059:7011 |
9054 | 7012 | 9055 | 7012 | 9056:7012 | 9057:7012 | 9058 : 7012 | 9059 : 7012 |
9054 | 7013 | 9055 | 7013 | 9056:7013 | 9057:7013 | 9058:7013 | 9059 : 7013 |
9054 | 7014 | 9055 | 7014 | 9056:7014 | 9057 : 7014 | 9058 : 7014 | 9059:7014 |
9054 | 7015 | 9055 | 7015 | 9056:7015 | 9057:7015 | 9058:7015 | 9059:7015 |
9054 | 7016 | 9055 | 7016 | 9056 : 7016 | 9057:7016 | 9058 : 7016 | 9059:7016 |
9054 | 7017 | 9055 | 7017 | 9056:7017 | 9057:7017 | 9058:7017 | 9059:7017 |
9054 | 7018 | 9055 | 7018 | 9056:7018 | 9057 : 7018 | 9058:7018 | 9059:7018 |
9054 | 7019 | 9055 | 7019 | 9056:7019 | 9057:7019 | 9058:7019 | 9059:7019 |
9054 | 7020 | 9055 | 7020 | 9056:7020 | 9057 : 7020 | 9058:7020 | 9059 : 7020 |
9054 | 7021 | 9055 | 7021 | 9056:7021 | 9057 : 7021 | 9058 : 7021 | 9059 : 7021 |
9054 | 7022 | 9055 | 7022 | 9056:7022 | 9057 : 7022 | 9058 : 7022 | 9059 : 7022 |
9054 | 7023 | 9055 | 7023 | 9056:7023 | 9057:7023 | 9058:7023 | 9059:7023 |
9054 | 7024 | 9055 | 7024 | 9056:7024 | 9057 : 7024 | 9058 : 7024 | 9059 : 7024 |
9054 | 7025 | 9055 | 7025 | 9056:7025 | 9057 : 7025 | 9058 : 7025 | 9059:7025 |
9054 | 7026 | 9055 | 7026 | 9056:7026 | 9057 : 7026 | 9058 : 7026 | 9059:7026 |
9054 | 7027 | 9055 | 7027 | 9056:7027 | 9057:7027 | 9058:7027 | 9059 : 7027 |
126
X | Y | X | Y | X:Y | X:Y | X:Y | X:Y |
9060 | 7000 | 9061 | 7000 | 9062:7000 | 9063:7000 | 9064 : 7000 | 9065:7000 |
9060 | 7001 | 9061 | 7001 | 9062:7001 | 9063 : 7001 | 9064:7001 | 9065:7001 |
9060 | 7002 | 9061 | 7002 | 9062:7002 | 9063 : 7002 | 9064:7002 | 9065:7002 |
9060 | 7003 | 9061 | 7003 | 9062:7003 | 9063 : 7003 | 9064:7003 | 9065:7003 |
9060 | 7004 | 9061 | 7004 | 9062 : 7004 | 9063:7004 | 9064:7004 | 9065:7004 |
9060 | 7005 | 9061 | 7005 | 9062:7005 | 9063<7005 | 9064:7005 | 9065:7005 |
9060 | 7006 | 9061 | -7006 | 9062:7006' | 9063:7006 | 9064::-7006 | 9065 : 7006 |
9060 | 7007 | 9061 | 7007 | 9062 : 7007 | 9063:7007 | 9064:7007 | 9065:7007 |
9060 | 7008 | 9061 | 7008 | 9062:7008 | 9063:7008 | 9064 : 7008 | 9065 : 7008 |
9060 | 7009 | 9061 | 7009 | 9062:7009 | 9063:7009 | 9064 : 7009 | 9065:7009 |
9060 | 7010 | 9061 | 7010 | 9062:7010 | 9063:7010 | 9064:7010 | 9065:7010 |
9060 | 7011 | 9061 | 7011 | 9062:7011 | 9063:7011 | 9064 : 7011 | 9065 : 7011 |
9060 | 7012 | 9061 | 7012 | 9062:7012 | 9063 : 7012 | 9064:7012 | 9065 : 7012 |
9060 | 7013 | 9061 | 7013 | 9062:7013 | 9063 : 7013 | 9064:7013 | 9065 : 7013 |
9060 | 7014 | 9061 | 7014 | 9062:7014 | 9063 : 7014 | 9064:7014 | 9065 : 7014 |
9060 | 7015 | 9061 | 7015 | 9062 : 7015 | 9063 : 7015 | 9064 : 7015 | 9065 : 7015 |
9060 | 7016 | 9061 | 7016 | 9062 : 7016 | 9063 : 7016 | 9064:7016 | 9065:7016 |
9060 | 7017 | 9061 | 7017 | 9062:7017 | 9063 : 7017 | 9064 : 7017 | 9065:7017 |
9060 | 7018 | 9061 | 7018 | 9062:70(8 | 9063:7018 | 9064 : 7018 | 9065 : 7018 |
9060 | 7019 | 9061 | 7019 | 9062:7019 | 9063:7019 | 9064 : 7019 | 9065:7019 |
9060 | 7020 | 9061 | 7020 | 9062 : 7020 | 9063 : 7020 | 9064:7020 | 9065:7020 |
9060 | 7021 | 9061 | 7021 | 9062 : 7021 | 9063:7021 | 9064:7021 | 9065:7021 |
9060 | 7022 | 9061 | 7022 | 9062:7022 | 9063:7022 | 9064:7022 | 9065 : 7022 |
9060 | 7023 | 9061 | 7023 | 9062:7023 | 9063:7023 | 9064:7023 | 9065:7023 |
9060 | 7024 | 9061 | 7024 | 9062:7024 | 9063 : 7024 | 9064 : 7024 | 9065:7024 |
9060 | 7025 | 9061 | 7025 | 9062:7025 | 9063 : 7025 | 9064 : 7025 | 9065:7025 |
9060 | 7026 | 9061 | 7026 | 9062:7026 | 9063:7026 | 9064 : 7026 | 9065 : 7026 |
9060 | 7027 | 9061 | 7027 | 9062:7027 | 9063:7027 | 9064:7027 | 9065:7027 |
127
X: Y | X:Y | X:Y | X: Y | X: Y | X | Y |
9066:7000 | 9067:7000 | 9068:7000 | 9069 : 7000 | 9070 : 7000 | 9071 | 7000 |
9066:7001 | 9067 : 7001 | 9068:7001 | 9069:7001 | 9070:7001 | 9071 | 7001 |
9066:7002 | 9067 : 7002 | 9068 : 7002 | 9069:7002 | 9070:7002 | 9071 | 7002 |
9066:7003 | 9067 : 7003 | 9068:7003 | 9069:7003 | 9070:7003 | 9071 | 7003 |
9066:7004 | 9067:7004 | 9068:7004 | 9069:7004 | 9070:7004 | 9071 | 7004 |
9066:7005 | 906717005 | 90681-7005 | 9069:7005 | 9070:7005 | 9071 | 7005 |
9066:7006 | 90674-7006 | 9068:-7006 | 9069:7006 | 9070:7006 | 9071 | 7006 |
9066:7007 | 9067:7007 | 9068:7007 | 9069:7007 | 9070:7007 | 9071 | 7007 |
9066 : 7008 | 9067 : 7008 | 9068 : 7008 | 9069:7008 | 9070 : 7008 | 9071 | 7008 |
9066 : 7009 | 9067 : 7009 | 9068:7009 | 9069:7009 | 9070 : 7009 | 9071 | 7009 |
9066:7010 | 9067 : 7010 | 9068 : 7010 | 9069:7010 | 9070 : 7010 | 9071 | 7010 |
9066:7011 | 9067:7011 | 9068:7011 | 9069:7011 | 9070 : 7011 | 9071 | 7011 |
9066:7012 | 9067 : 7012 | 9068:7012 | 9069:7012 | 9070:7012 | 9071 | 7012 |
9066:7013 | 9067 : 7013 | 9068:7013 | 9069:7013 | 9070:7013 | 9071 | 7013 |
9066:7014 | 9067:7014 | 9068:7014 | 9069:7014 | 9070 : 7014 | 9071 | 7014 |
9066:7015 | 9067:7015 | 9068:7015 | 9069:7015 | 9070:7015 | 9071 | 7015 |
9066:7016 | 9067 : 7016 | 9068 : 7016 | 9069:7016 | 9070:7016 | 9071 | 7016 |
9066:7017 | 9067 : 7017 | 9068 : 7017 | 9069:7017 | 9070:7017 | 9071 | 7017 |
9066:7018 | 9067 : 7018 | 9068 : 7018 | 9069:7018 | 9070:7018 | 9071 | 7018 |
9066:7019 | 9067 : 7019 | 9068:7019 | 9069:7019 | 9070:7019 | 9071 | 7019 |
9066:7020 | 9067:7020 | 9068:7020 | 9069 : 7020 | 9070:7020 | 9071 | 7020 |
9066:7021 | 9067:7021 | 9068:7021 | 9069:7021 | 9070:7021 | 9071 | 7021 |
9066:7022 | 9067:7022 | 9068 : 7022 | 9069:7022 | 9070 : 7022 | 9071 | 7022 |
9066:7023 | 9067:7023 | 9068:7023 | 9069:7023 | 9070:7023 | 9071 | 7023 |
9066 : 7024 | 9067:7024 | 9068:7024 | 9069 : 7024 | 9070:7024 | 9071 | 7024 |
9066:7025 | 9067:7025 | 9068:7025 | 9069:7025 | 9070:7025 | 9071 | 7025 |
9066 : 7026 | 9067 : 7026 | 9068 : 7026 | 9069:7026 | 9070 : 7026 | 9071 | 7026 |
9066:7027 | 9067:7027 | 9068 : 7027 | 9069 : 7027 | 9070:7027 | 9071 | 7027 |
12g
X: Y | X:Y | X:Y | X:Y | X:Y | X:Y |
9072:7000 | 9073:7000 | 9074 : 7000 | 9075 : 7000 | 9076 : 7000 | 9077 : 7000 |
9072:7001 | 9073:7001 | 9074:7001 | 9075 : 7001 | 9076:7001 | 9077 : 7001 |
9072:7002 | 9073:7002 | 9074:7002 | 9075:7002 | 9076 : 7002 | 9077 : 7002 |
9072:7003 | 9073 : 7003 | 9074 : 7003 | 9075:7003 | 9076 : 7003 | 9077 : 7003 |
9072:7004 | 9073:7004 | 9074:7004 | 9075:7004 | 9076:7004 | 9077 : 7004 |
9072:-7005 | 9073:-7005 | 9074:7005 | 9075 : 7005 | 9076:7005 | 9077 : 7005 |
9072 : 7006 | 9073:7006- | 9074:7006 | 9075 : 7006 | 9076:7006 | 9077:7006 |
9072:7007 | 9073 : 7007 | 9074:7007 | 9075:7007 | 9076:7007 | 9077 : 7007 |
9072 : 7008 | 9073 : 7008 | 9074:7008 | 9075:7008 | 9076 : 7008 | 9077 : 7008 |
9072 : 7009 | 9073 : 7009 | 9074:7009 | 9075:7009 | 9076 : 7009 | 9077:7009 |
9072:7010 | 9073:7010 | 9074:7010 | 9075 : 7010 | 9076:7010 | 9077:7010 |
9072:7011 | 9073:7011 | 9074:7011 | 9075 : 7011 | 9076:7011 | 9077:7011 |
9072 : 7012 | 9073:7012 | 9074:7012 | 9075:7012 | 9076:7012 | 9077 : 7012 |
9072 : 7013 | 9073 : 7013 | 9074 : 7013 | 9075:7013 | 9076 : 7013 | 9077 : 7013 |
9072:7014 | 9073 : 7014 | 9074:7014 | 9075:7014 | 9076 : 7014 | 9077:7014 |
9072:7015 | 9073 : 7015 | 9074:7015 | 9075 : 7015 | 9076 : 7015 | 9077:7015 |
9072:7016 | 9073 : 7016 | 9074:7016 | 9075:7016 | 9076:7016 | 9077:7016 |
9072:7017 | 9073 : 7017 | 9074:7017 | 9075:7017 | 9076:7017 | 9077 : 7017 |
9072 : 7018 | 9073:7018 | 9074:7018 | 9075:7018 | 9076:7018 | 9077:7018 |
9072:7019 | 9073:7019 | 9074:7019 | 9075 : 7019 | 9076:7019 | 9077:7019 |
9072:7020 | 9073:7020 | 9074:7020 | 9075 : 7020 | 9076 : 7020 | 9077:7020 |
9072:7021 | 9073 : 7021 | 9074:7021 | 9075 : 7021 | 9076 : 7021 | 9077:7021 |
9072:7022 | 9073 : 7022 | 9074:7022 | 9075:7022 | 9076:7022 | 9077 : 7022 |
9072:7023 | 9073 : 7023 | 9074 : 7023 | 9075:7023 | 9076 : 7023 | 9077:7023 |
9072 : 7024 | 9073 :7024 | 9074 : 7024 | 9075 : 7024 | 9076 : 7024 | 9077:7024 |
9072:7025 | 9073 : 7025 | 9074:7025 | 9075 : 7025 | 9076 : 7025 | 9077 : 7025 |
9072:7026 | 9073:7026 | 9074:7026 | 9075 : 7026 | 9076:7026 | 9077:7026 |
9072:7027 | 9073 : 7027 | 9074 : 7027 | 9075 : 7027 | 9076 : 7027 | 9077 : 7027 |
129
X | Y | X | Y | X:Y | X | Y | X:Y | X | Y |
9078 | 7000 | 9079 | 7000 | 9080:7000 | 9081 | 7000 | 9082 : 7000 | 9083 | 7000 |
9078 | 7001 | 9079 | 7001 | 9080:7001 | 9081 | 7001 | 9082:7001 | 9083 | 7001 |
9078 | 7002 | 9079 | 7002 | 9080:7002 | 9081 | 7002 | 9082:7002 | 9083 | 7002 |
9078 | 7003 | 9079 | 7003 | 9080:7003 | 9081 | 7003 | 9082:7003 | 9083 | 7003 |
9078 | 7004 | 9079 | 7004 | 9080:7004 | 9081 | 7004 | 9082:7004 | 9083 | 7004 |
9078 | 7005 | 9079 | 7005 | 9080:7005 | 908 L | •7005 | 9082:7005 | 9083 | 7005 |
9078 | 7006 | 9079 | -7006 | 9080:-7006 | 9081 | -7006 | 9082 :=7006 | 9083 | 7006 |
9078 | 7007 | 9079 | 7007 | 9080:7007 | 9081 | 7007 | 9082:7007 | 9083 | 7007 |
9078 | 7008 | 9079 | 7008 | 9080:7008 | 9081 | 7008 | 9082 : 7008 | 9083 | 7008 |
9078 | 7009 | 9079 | 7009 | 9080:7009 | 9081 | 7009 | 9082 : 7009 | 9083 | 7009 |
9078 | 7010 | 9079 | 7010 | 9080 : 7010 | 9081 | 7010 | 9082:7010 | 9083 | 7010 |
9078 | 7011 | 9079 | 7011 | 9080:7011 | 9081 | 7011 | 9082:7011 | 9083 | 7011 |
9078 | 7012 | 9079 | 7012 | 9080:7012 | 9081 | 7012 | 9082:7012 | 9083 | 7012 |
9078 | 7013 | 9079 | 7013 | 9080:7013 | 9081 | 7013 | 9082 : 7013 | 9083 | 7013 |
9078 | 7014 | 9079 | 7014 | 9080 : 7014 | 9081 | 7014 | 9082 : 7014 | 9083 | 7014 |
9078 | 7015 | 9079 | 7015 | 9080:7015 | 9081 | 7015 | 9082 : 7015 | 9083 | 7015 |
9078 | 7016 | 9079 | 7016 | 9080 : 7016 | 9081 | 7016 | 9082:7016 | 9083 | 7016 |
9078 | 7017 | 9079 | 7017 | 9080:7017 | 9081 | 7017 | 9082:7017 | 9083 | 7017 |
9078 | 7018 | 9079 | 7018 | 9080:7018 | 9081 | 7018 | 9082 : 7018 | 9083 | 7018 |
9078 | 7019 | 9079 | 7019 | 9080:7019 | 9081 | 7019 | 9082 : 7019 | 9083 | 7019 |
9078 | 7020 | 9079 | 7020 | 9080:7020 | 9081 | 7020 | 9082 : 7020 | 9083 | 7020 |
9078 | 7021 | 9079 | 7021 | 9080:7021 | 9081 | 7021 | 9082 : 7021 | 9083 | 7021 |
9078 | 7022 | 9079 | 7022 | 9080:7022 | 9081 | 7022 | 9082 : 7022 | 9083 | 7022 |
9078 | 7023 | 9079 | 7023 | 9080 : 7023 | 9081 | 7023 | 9082 : 7023 | 9083 | 7023 |
9078 | 7024 | 9079 | 7024 | 9080:7024 | 9081 | 7024 | 9082:7024 | 9083 | 7024 |
9078 | 7025 | 9079 | 7025 | 9080:7025 | 9081 | 7025 | 9082 : 7025 | 9083 | 7025 |
9078 | 7026 | 9079 | 7026 | 9080 : 7026 | 9081 | 7026 | 9082 : 7026 | 9083 | 7026 |
9078 | 7027 | 9079 | 7027 | 9080:7027 | 9081 | 7027 | 9082:7027 | 9083 | 7027 |
130
X: Y | Χ:Υ | Χ:Υ | X | Y | Χ:Υ | Χ:Υ | |
9084:7000 | 9085 : 7000 | 9086 : 7000 | 9087 | 7000 | 9088:7000 | 9089:7000 | |
9084:7001 | 9085 : 7001 | 9086:7001 | 9087 | 7001 | 9088:7001 | 9089:7001 | |
9084:7002 | 9085 : 7002 | 9086:7002 | 9087 | 7002 | 9088:7002 | 9089:7002 | |
9084:7003 | 9085:7003 | 9086:7003 | 9087 | 7003 | 9088:7003 | 9089:7003 | |
9084:7004 | 9085 : 7004 | 9086:7004 | 9087 | 7004 | 9088:7004 | 9089:7004 | |
----Γ_—:-- | 9084:7005 | 9085 : 7005 | 9086:-7005 | 9087 | 7005 | 9088^7005 | 9089:7005 |
.9084:7006 | -9085 :-7006 | -90861-7006 | 9087 | •7006 | 9088:7006 | 9089:7006 | |
9084:7007 | 9085:7007 | 9086:7007 | 9087 | 7007 | 9088:7007 | 9089:7007 | |
9084 : 7008 | 9085:7008 | 9086:7008 | 9087 | 7008 | 9088:7008 | 9089:7008 | |
9084:7009 | 9085 : 7009 | 9086:7009 | 9087 | 7009 | 9088:7009 | 9089:7009 | |
9084:7010 | 9085 : 7010 | 9086:7010 | 9087 | 7010 | 9088 : 7010 | 9089:7010 | |
9084:7011 | 9085 : 7011 | 9086:7011 | 9087 | 7011 | 9088:7011 | 9089:7011 | |
9084:7012 | 9085:7012 | 9086:7012 | 9087 | 7012 | 9088:7012 | 9089:7012 | |
9084:7013 | 9085:7013 | 9086:7013 | 9087 | 7013 | 9088:7013 | 9089:7013 | |
9084:7014 | 9085 : 7014 | 9086:7014 | 9087 | 7014 | 9088:7014 | 9089:7014 | |
9084:7015 | 9085 : 7015 | 9086:7015 | 9087 | 7015 | 9088:7015 | 9089:7015 | |
9084:7016 | 9085 : 7016 | 9086:7016 | 9087 | 7016 | 9088:7016 | 9089:7016 | |
9084:7017 | 9085 : 7017 | 9086:7017 | 9087 | 7017 | 9088:7017 | 9089:7017 | |
9084:7018 | 9085 : 7018 | 9086 : 7018 | 9087 | 7018 | 9088:7018 | 9089:7018 | |
9084:7019 | 9085 : 7019 | 9086:7019 | 9087 | 7019 | 9088 : 7019 | 9089:7019 | |
9084:7020 | 9085 : 7020 | 9086 : 7020 | 9087 | 7020 | 9088:7020 | 9089 : 7020 | |
9084:7021 | 9085 : 7021 | 9086:7021 | 9087 | 7021 | 9088 :7021 | 9089:7021 | |
9084 : 7022 | 9085:7022 | 9086 : 7022 | 9087 | 7022 | 9088 : 7022 | 9089:7022 | |
9084:7023 | 9085:7023 | 9086 : 7023 | 9087 | 7023 | 9088 : 7023 | 9089:7023 | |
9084 : 7024 | 9085 : 7024 | 9086:7024 | 9087 | 7024 | 9088:7024 | 9089:7024 | |
9084:7025 | 9085 : 7025 | 9086:7025 | 9087 | 7025 | 9088 : 7025 | 9089:7025 | |
9084:7026 | 9085 : 7026 | 9086:7026 | 9087 | 7026 | 9088 : 7026 | 9089:7026 | |
9084:7027 | 9085:7027 | 9086:7027 | 9087 | 7027 | 9088:7027 | 9089:7027 |
131
X | Y | X | :Y | X:Y | Χ:Υ | Χ:Υ | X: Y | |
9090 | 7000 | 9091 | :7000 | 9092:7000 | 9093:7000 | 9094:7000 | 9095:7000 | |
9090 | 7001 | 9091 | :7001 | 9092:7001 | 9093 : 7001 | 9094:7001 | 9095:7001 | |
9090 | 7002 | 9091 | :7002 | 9092:7002 | 9093:7002 | 9094:7002 | 9095:7002 | |
9090 | 7003 | 9091 | :7003 | 9092:7003 | 9093:7003 | 9094:7003 | 9095:7003 | |
9090 | 7004 | 9091 | :7004 | 9092:7004 | 9093 : 7004 | 9094:7004 | 9095:7004 | |
-- ----—— ' | -9090 | -700Γ | 9091 | :7005 | 9092:.7005 | 9093^7005 | 9094-^7005 | 9095:7005 |
9090 | -7006 | 9091 | -7006 | 9092-7006 | 909317006^ | 9094-7006 | 9095 : 7006 | |
- | 9090 | 7007 | 9091 | :7007 | 9092 : 7007 | 9093 : 7007 | 9094:7007 | 9095:7007 |
9090 | 7008 | 9091 | :7008 | 9092 : 7008 | 9093:7008 | 9094:7008 | 9095:7008 | |
9090 | 7009 | 9091 | :7009 | 9092:7009 | 9093:7009. | 9094:7009 | 9095:7009 | |
9090 | 7010 | 9091 | :7010 | 9092:7010 | 9093:7010 | 9094:7010 | 9095:7010 | |
9090 | 7011 | 9091 | :7011 | 9092:7011 | 9093:7011 | 9094:7011 | 9095:7011 | |
9090 | 7012 | 9091 | :7012 | 9092 : 7012 | 9093 : 7012 | 9094 : 7012 | 9095:7012 | |
9090 | 7013 | 9091 | :7013 | 9092:7013 | 9093:7013 | 9094 : 7013 | 9095:7013 | |
9090 | 7014 | 9091 | :7014 | 9092:7014 | 9093:7014 | 9094:7014 | 9095:7014 | |
9090 | 7015 | 9091 | :7015 | 9092:7015 | 9093:7015 | 9094:7015 | 9095:7015 | |
9090 | 7016 | 9091 | :7016 | 9092 : 7016 | 9093:7016 | 9094:7016 | 9095:7016 | |
9090 | 7017 | 9091 | :7017 | 9092 : 7017 | 9093:7017 | 9094:7017 | 9095 : 7017 | |
9090 | 7018 | 9091 | :7018 | 9092 : 7018 | 9093:7018 | 9094:7018 | 9095:7018 | |
9090 | 7019 | 9091 | :7019 | 9092 : 7019 | 9093 : 7019 | 9094:7019 | 9095:7019 | |
9090 | 7020 | 9091 | :7020 | 9092:7020 | 9093:7020 | 9094 : 7020 | 9095:7020 | |
9090 | 7021 | 9091 | :7021 | 9092:7021 | 9093:7021 | 9094:702! | 9095:7021 | |
9090 | 7022 | 9091 | :7022 | 9092:7022 | 9093 : 7022 | 9094:7022 | 9095:7022 | |
9090 | 7023 | 9091 | :7023 | 9092:7023 | 9093 : 7023 | 9094 : 7023 | 9095:7023 | |
9090 | 7024 | 9091 | :7024 | 9092:7024 | 9093:7024 | 9094 : 7024 | 9095:7024 | |
9090 | 7025 | 9091 | :7025 | 9092:7025 | 9093 : 7025 | 9094 : 7025 | 9095 : 7025 | |
9090 | 7026 | 9091 | :7026 | 9092:7026 | 9093 : 7026 | 9094:7026 | 9095:7026 | |
9090 | 7027 | 9091 | :7027 | 9092:7027 | 9093 : 7027 | 9094:7027 | 9095:7027 |
I32
X:Y | X | Y | Χ:Υ | X: Y | Χ:Υ | Χ:Υ |
9096:7000 | 9097 | 7000 | 9098:7000 | 9099:7000 | 9100:7000 | 9101:7000 |
9096:7001 | 9097 | 7001 | 9098:7001 | 9099:7001 | 9100:7001 | 9101:7001 |
9096:7002 | 9097 | 7002 | 9098:7002 | 9099 : 7002 | 9100:7002 | 9101:7002 |
9096:7003 | 9097 | 7003 | 9098:7003 | 9099 : 7003 | 9100:7003 | 9101:7003 |
9096:7004 | 9097 | 7004 | 9098:7004 | 9099:7004 | 9100:7004 | 9101:7004 |
9096:-7005 | 9097 | -7005 | 9098^7005 | 909917005 | 91001-7005 | 9101:7005 |
9096 ΐ 7006 | 9097- | .700ά | 9098 17006 | 9099-17006 | 9100-17006 | 9101:7006 |
9096:7007 | 9097 | 7007 | 9098 : 7007 | 9099:7007 | 9100:7007 | 9101:7007 |
9096:7008 | 9097 | 7008 | 9098 : 7008 | 9099:7008 | 9100:7008 | 9101:7008 |
9096:7009 | 9097 | 7009 | 9098:7009 | 9099 : 7009 | 9100:7009 | 9101:7009 |
9096:7010 | 9097 | 7010 | 9098:7010 | 9099:7010 | 9100:7010 | 9101:7010 |
9096:7011 | 9097 | 7011 | 9098:7011 | 9099:7011 | 9100:7011 | 9101:7011 |
9096:7012 | 9097 | 7012 | 9098:7012 | 9099:7012 | 9100:7012 | 9101:7012 |
9096:7013 | 9097 | 7013 | 9098:7013 | 9099:7013 | 9100:7013 | 9101:7013 |
9096:7014 | 9097 | 7014 | 9098:7014 | 9099:7014 | 9100:7014 | 9101:7014 |
9096:7015 | 9097 | 7015 | 9098:7015 | 9099 : 7015 | 9100:7015 | 9101:7015 |
9096 : 7016 | 9097 | 7016 | 9098 : 7016 | 9099 : 7016 | 9100:7016 | 9101:7016 |
9096:7017 | 9097 | 7017 | 9098:7017 | 9099 : 7017 | 9100:7017 | 9101:7017 |
9096:7018 | 9097 | 7018 | 9098:7018 | 9099:7018 | 9100:7018 | 9101:7018 |
9096 : 7019 | 9097 | 7019 | 9098:7019 | 9099 : 7019 | 9100 : 7019 | 9101:7019 |
9096:7020 | 9097 | 7020 | 9098:7020 | 9099:7020 | 9100 : 7020 | 9101:7020 |
9096:7021 | 9097 | 7021 | 9098:7021 | 9099:7021 | 9100:7021 | 9101:7021 |
9096:7022 | 9097 | 7022 | 9098:7022 | 9099 : 7022 | 9100:7022 | 9101:7022 |
9096:7023 | 9097 | 7023 | 9098:7023 | 9099 : 7023 | 9100:7023 | 9101:7023 |
9096:7024 | 9097 | 7024 | 9098 : 7024 | 9099:7024 | 9100:7024 | 9101:7024 |
9096:7025 | 9097 | 7025 | 9098:7025 | 9099:7025 | 9100 : 7025 | 9101:7025 |
9096:7026 | 9097 | 7026 | 9098:7026 | 9099 : 7026 | 9100:7026 | 9101:7026 |
9096:7027 | 9097 | 7027 | 9098:7027 | 9099 : 7027 | 9100 : 7027 | 9101:7027 |
133
X: Y | X:Y | X:Y | X:Y | Χ:Υ | X: Y |
9102:7000 | 9103:7000 | 9104:7000 | 9105 : 7000 | ||
9102:7001 | 9103:7001 | 9104:7001 | 9105:7001 | ||
9102:7002 | 9103:7002 | 9104:7002 | 9105:7002 | ||
9102:7003 | 9103 : 7003 | 9104:7003 | 9105:7003 | ||
9102:7004 | 9103 : 7004 | 9104:7004 | 9105:7004 | ||
9102:7005 | 9103t7005 | .9104^.7005 | 9105 : 7005 | .-λ— | =“Γ- - . |
9102>7006 | 9103*7006 | 9104^7006 | 9105-:7006 | — | |
9102:7007 | 9103:7007 | 9104 .'7007 | 9105 : 7007 | - | |
9102:7008 | 9103 : 7008 | 9104:7008 | 9105 : 7008 | ||
9102:7009 | 9103 : 7009 | 9104:7009 | 9105 : 7009 | ||
9102:7010 | 9103 : 7010 | 9104:7010 | 9105:7010 | ||
9102:7011 | 9103 : 7011 | 9104:7011 | 9105:7011 | ||
9102:7012 | 9103 : 7012 | 9104:7012 | 9105:7012 | ||
9102:7013 | 9103:7013 | 9104:7013 | 9105 : 7013 | ||
9102:7014 | 9103 : 7014 | 9104:7014 | 9105:7014 | ||
9102:7015 | 9103 : 7015 | 9104:7015 | 9105:7015 | ||
9102:7016 | 9103:7016 | 9104:7016 | 9105 : 7016 | ||
9102:7017 | 9103:7017 | 9104:7017 | 9105:7017 | ||
9102:7018 | 9103 : 7018 | 9104:7018 | 9105 : 7018 | ||
9102:7019 | 9103:7019 | 9104 : 7019 | 9105 : 7019 | ||
9102:7020 | 9103 : 7020 | 9104 : 7020 | 9105 : 7020 | ||
9102 : 7021 | 9103 : 7021 | 9104 : 7021 | 9105 : 7021 | ||
9102 : 7022 | 9103 : 7022 | 9104 : 7022 | 9105:7022 | ||
9102:7023 | 9103 : 7023 | 9104 : 7023 | 9105:7023 | ||
9102:7024 | 9103 : 7024 | 9104 : 7024 | 9105:7024 | ||
9102 : 7025 | 9103 : 7025 | 9104:7025 | 9105:7025 | ||
9102:7026 | 9103 : 7026 | 9104 : 7026 | 9105 : 7026 | ||
9102 : 7027 | 9103 : 7027 | 9104 : 7027 | 9105 : 7027 |
134
Table D: Exemple combinations of a compound X with a compound Y.
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9000 | 6040 | 9000 | 6000 | 9001 | 6040 | 9001 | 6000 | 9002 | 6040 | 9002 |
6001 | 9000 | 6041 | 9000 | 6001 | 9001 | 6041 | 9001 | 6001 | 9002 | 6041 | 9002 |
6002 | 9000 | 6042 | 9000 | 6002 | 9001 | 6042 | 9001 | 6002 | 9002 | 6042 | 9002 |
6003 | 9000 | 6043 | 9000 | 6003 | 9001 | 6043 | 9001 | 6003 | 9002 | 6043 | 9002 |
6004 | .9000- | 6044 | 9000. | 6004 | 9001. | 6044 | 9001 | 6004 | 9002 | 6044 | 9002 |
6005 | '9000 | '6045 | 9000 | '6005 | 9001. | 6045 | 9001 | 6005 | 9002 | 6045 | 9002 |
6006 | 9000 | 6046 | 9000 | 6006 | 9001 | 6046 | 9001 | 6006 | 9002 | 6046 | 9002 |
6007 | 9000 | 6047 | 9000 | 6007 | 9001 | 6047 | 9001 | 6007 | 9002 | 6047 | 9002 |
6008 | 9000 | 6048 | 9000 | 6008 | 9001 | 6048 | 9001 | 6008 | 9002 | 6048 | 9002 |
6009 | 9000 | 6049 | 9000 | 6009 | 9001 | 6049 | 9001 | 6009 | 9002 | 6049 | 9002 |
6010 | 9000 | 6050 | 9000 | 6010 | 9001 | 6050 | 9001 | 6010 | 9002 | 6050 | 9002 |
6011 | 9000 | 6051 | 9000 | 6011 | 9001 | 6051 | 9001 | 6011 | 9002 | 6051 | 9002 |
6012 | 9000 | 6052 | 9000 | 6012 | 9001 | 6052 | 9001 | 6012 | 9002 | 6052 | 9002 |
6013 | 9000 | 6053 | 9000 | 6013 | 9001 | 6053 | 9001 | 6013 | 9002 | 6053 | 9002 |
6014 | 9000 | 6054 | 9000 | 6014 | 9001 | 6054 | 9001 | 6014 | 9002 | 6054 | 9002 |
6015 | 9000 | 6055 | 9000 | 6015 | 9001 | 6055 | 9001 | 6015 | 9002 | 6055 | 9002 |
6016 | 9000 | 6056 | 9000 | 6016 | 9001 | 6056 | 9001 | 6016 | 9002 | 6056 | 9002 |
6017 | 9000 | 6057 | 9000 | 6017 | 9001 | 6057 | 9001 | 6017 | 9002 | 6057 | 9002 |
6018 | 9000 | 6058 | 9000 | 6018 | 9001 | 6058 | 9001 | 6018 | 9002 | 6058 | 9002 |
6019 | 9000 | 6059 | 9000 | 6019 | 9001 | 6059 | 9001 | 6019 | 9002 | 6059 | 9002 |
6020 | 9000 | 6060 | 9000 | 6020 | 9001 | 6060 | 9001 | 6020 | 9002 | 6060 | 9002 |
6021 | 9000 | 6061 | 9000 | 6021 | 9001 | 6061 | 9001 | 6021 | 9002 | 6061 | 9002 |
6022 | 9000 | 6062 | 9000 | 6022 | 9001 | 6062 | 9001 | 6022 | 9002 | 6062 | 9002 |
6023 | 9000 | 6063 | 9000 | 6023 | 9001 | 6063 | 9001 | 6023 | 9002 | 6063 | 9002 |
6024 | 9000 | 6064 | 9000 | 6024 | 9001 | 6064 | 9001 | 6024 | 9002 | 6064 | 9002 |
6025 | 9000 | 6065 | 9000 | 6025 | 9001 | 6065 | 9001 | 6025 | 9002 | 6065 | 9002 |
6026 | 9000 | 6066 | 9000 | 6026 | 9001 | 6066 | 9001 | 6026 | 9002 | 6066 | 9002 |
6027 | 9000 | 6067 | 9000 | 6027 | 9001 | 6067 | 9001 | 6027 | 9002 | 6067 | 9002 |
6028 | 9000 | 6068 | 9000 | 6028 | 9001 | 6068 | 9001 | 6028 | 9002 | 6068 | 9002 |
6029 | 9000 | 6069 | 9000 | 6029 | 9001 | 6069 | 9001 | 6029 | 9002 | 6069 | 9002 |
6030 | 9000 | 6070 | 9000 | 6030 | 9001 | 6070 | 9001 | 6030 | 9002 | 6070 | 9002 |
6031 | 9000 | 6071 | 9000 | 6031 | 9001 | 6071 | 9001 | 6031 | 9002 | 6071 | 9002 |
6032 | 9000 | 6072 | 9000 | 6032 | 9001 | 6072 | 9001 | 6032 | 9002 | 6072 | 9002 |
6033 | 9000 | 6073 | 9000 | 6033 | 9001 | 6073 | 9001 | 6033 | 9002 | 6073 | 9002 |
6034 | 9000 | 6074 | 9000 | 6034 | 9001 | 6074 | 9001 | 6034 | 9002 | 6074 | 9002 |
6035 | 9000 | 6075 | 9000 | 6035 | 9001 | 6075 | 9001 | 6035 | 9002 | 6075 | 9002 |
6036 | 9000 | 6076 | 9000 | 6036 | 9001 | 6076 | 9001 | 6036 | 9002 | 6076 | 9002 |
6037 | 9000 | 6077 | 9000 | 6037 | 9001 | 6077 | 9001 | 6037 | 9002 | 6077 | 9002 |
6038 | 9000 | 6078 | 9000 | 6038 | 9001 | 6078 | 9001 | 6038 | 9002 | 6078 | 9002 |
6039 | 9000 | 6039 | 9001 | 6039 | 9002 |
135
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9003 | 6040 | 9003 | 6000 | 9004 | 6010 | 9004 | 6000 | 9005 | 6040 | 9005 |
6001 | 9003 | 6041 | 9003 | 6001 | 9004 | 6041 | 9004 | 6001 | 9005 | 6041 | 9005 |
6002 | 9003 | 6042 | 9003 | 6002 | 9004 | 6042 | 9004 | 6002 | 9005 | 6042 | 9005 |
6003 | 9003 | 6043 | 9003 | 6003 | 9004 | 6043 | 9004 | 6003 | 9005 | 6043 | 9005 |
6004 | 9003 | 6044 | 9003 | 6004 | 9004 | 6044 | 9004 | 6004 | 9005 | 6044 | 9005 |
.6005 | .9003 | 6045 | 9003 | 6005' | '9004 | 6045 | 9004 | 6005 | .9005 | .6045 | 9005 |
6006 | 9003 | 6046 | 9003 | 6006 | 9004 | 6046 | 9004 | 6006 | 9005 | 6046 | 9005 |
6007 | 9003 | 6047 | 9003 | 6007 | 9004 | 6047 | 9004 | 6007 | 9005 | 6047 | 9005 |
6008 | 9003 | 6048 | 9003 | 6008 | 9004 | 6048 | 9004 | 6008 | 9005 | 6048 | 9005 |
6009 | 9003 | 6049 | 9003 | 6009 | 9004 | 6049 | 9004 | 6009 | 9005 | 6049 | 9005 |
6010 | 9003 | 6050 | 9003 | 6010 | 9004 | 6050 | 9004 | 6010 | 9005 | 6050 | 9005 |
6011 | 9003 | 6051 | 9003 | 6011 | 9004 | 6051 | 9004 | 6011 | 9005 | 6051 | 9005 |
6012 | 9003 | 6052 | 9003 | 6012 | 9004 | 6052 | 9004 | 6012 | 9005 | 6052 | 9005 |
6013 | 9003 | 6053 | 9003 | 6013 | 9004 | 6053 | 9004 | 6013 | 9005 | 6053 | 9005 |
6014 | 9003 | 6054 | 9003 | 6014 | 9004 | 6054 | 9004 | 6014 | 9005 | 6054 | 9005 |
6015 | 9003 | 6055 | 9003 | 6015 | 9004 | 6055 | 9004 | 6015 | 9005 | 6055 | 9005 |
6016 | 9003 | 6056 | 9003 | 6016 | 9004 | 6056 | 9004 | 6016 | 9005 | 6056 | 9005 |
6017 | 9003 | 6057 | 9003 | 6017 | 9004 | 6057 | 9004 | 6017 | 9005 | 6057 | 9005 |
6018 | 9003 | 6058 | 9003 | 6018 | 9004 | 6058 | 9004 | 6018 | 9005 | 6058 | 9005 |
6019 | 9003 | 6059 | 9003 | 6019 | 9004 | 6059 | 9004 | 6019 | 9005 | 6059 | 9005 |
6020 | 9003 | 6060 | 9003 | 6020 | 9004 | 6060 | 9004 | 6020 | 9005 | 6060 | 9005 |
6021 | 9003 | 6061 | 9003 | 6021 | 9004 | 6061 | 9004 | 6021 | 9005 | 6061 | 9005 |
6022 | 9003 | 6062 | 9003 | 6022 | 9004 | 6062 | 9004 | 6022 | 9005 | 6062 | 9005 |
6023 | 9003 | 6063 | 9003 | 6023 | 9004 | 6063 | 9004 | 6023 | 9005 | 6063 | 9005 |
6024 | 9003 | 6064 | 9003 | 6024 | 9004 | 6064 | 9004 | 6024 | 9005 | 6064 | 9005 |
6025 | 9003 | 6065 | 9003 | 6025 | 9004 | 6065 | 9004 | 6025 | 9005 | 6065 | 9005 |
6026 | 9003 | 6066 | 9003 | 6026 | 9004 | 6066 | 9004 | 6026 | 9005 | 6066 | 9005 |
6027 | 9003 | 6067 | 9003 | 6027 | 9004 | 6067 | 9004 | 6027 | 9005 | 6067 | 9005 |
6028 | 9003 | 6068 | 9003 | 6028 | 9004 | 6068 | 9004 | 6028 | 9005 | 6068 | 9005 |
6029 | 9003 | 6069 | 9003 | 6029 | 9004 | 6069 | 9004 | 6029 | 9005 | 6069 | 9005 |
6030 | 9003 | 6070 | 9003 | 6030 | 9004 | 6070 | 9004 | 6030 | 9005 | 6070 | 9005 |
6031 | 9003 | 6071 | 9003 | 6031 | 9004 | 6071 | 9004 | 6031 | 9005 | 6071 | 9005 |
6032 | 9003 | 6072 | 9003 | 6032 | 9004 | 6072 | 9004 | 6032 | 9005 | 6072 | 9005 |
6033 | 9003 | 6073 | 9003 | 6033 | 9004 | 6073 | 9004 | 6033 | 9005 | 6073 | 9005 |
6034 | 9003 | 6074 | 9003 | 6034 | 9004 | 6074 | 9004 | 6034 | 9005 | 6074 | 9005 |
6035 | 9003 | 6075 | 9003 | 6035 | 9004 | 6075 | 9004 | 6035 | 9005 | 6075 | 9005 |
6036 | 9003 | 6076 | 9003 | 6036 | 9004 | 6076 | 9004 | 6036 | 9005 | 6076 | 9005 |
6037 | 9003 | 6077 | 9003 | 6037 | 9004 | 6077 | 9004 | 6037 | 9005 | 6077 | 9005 |
6038 | 9003 | 6078 | 9003 | 6038 | 9004 | 6078 | 9004 | 6038 | 9005 | 6078 | 9005 |
6039 | 9003 | 6039 | 9004 | 6039 | 9005 |
I36
X | Y | X:Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9006 | 6040:9006 | 6000 | 9007 | 6040 | 9007 | 6000 | 9008 | 6040 | 9008 |
6001 | 9006 | 6041:9006 | 6001 | 9007 | 6041 | 9007 | 6001 | 9008 | 6041 | 9008 |
6002 | 9006 | 6042:9006 | 6002 | 9007 | 6042 | 9007 | 6002 | 9008 | 6042 | 9008 |
6003 | 9006 | 6043 : 9006 | 6003 | 9007 | 6043 | 9007 | 6003 | 9008 | 6043 | 9008 |
6004 | 9006 | 6044:9006 | 6004 | 9007 | 6044 | 9007 | 6004 | 9008 | 6044 | 9008 |
-.6005 | 9006-. | 6045:9006 | 6005 | 9007. | 6045. | 9007: | 6005. | 9008. | .6045 | 9008 |
-6006 | -9006- | 6046 : 9006 | 6006 | 9007 | 6046 | 9007 | 6006 | 9008 | 6046 | 9008 |
6007 | 9006 | 6047:9006 | 6007 | 9007 | 6047 | 9007 | 6007 | 9008 | 6047 | 9008 |
6008 | 9006 | 6048 : 9006 | 6008 | 9007 | 6048 | 9007 | 6008 | 9008 | 6048 | 9008 |
6009 | 9006 | 6049:9006 | 6009 | 9007 | 6049 | 9007 | 6009 | 9008 | 6049 | 9008 |
6010 | 9006 | 6050 : 9006 | 6010 | 9007 | 6050 | 9007 | 6010 | 9008 | 6050 | 9008 |
6011 | 9006 | 6051:9006 | 6011 | 9007 | 6051 | 9007 | 6011 | 9008 | 6051 | 9008 |
6012 | 9006 | 6052:9006 | 6012 | 9007 | 6052 | 9007 | 6012 | 9008 | 6052 | 9008 |
6013 | 9006 | 6053 : 9006 | 6013 | 9007 | 6053 | 9007 | 6013 | 9008 | 6053 | 9008 |
6014 | 9006 | 6054:9006 | 6014 | 9007 | 6054 | 9007 | 6014 | 9008 | 6054 | 9008 |
6015 | 9006 | 6055:9006 | 6015 | 9007 | 6055 | 9007 | 6015 | 9008 | 6055 | 9008 |
6016 | 9006 | 6056:9006 | 6016 | 9007 | 6056 | 9007 | 6016 | 9008 | 6056 | 9008 |
6017 | 9006 | 6057:9006 | 6017 | 9007 | 6057 | 9007 | 6017 | 9008 | 6057 | 9008 |
6018 | 9006 | 6058:9006 | 6018 | 9007 | 6058 | 9007 | 6018 | 9008 | 6058 | 9008 |
6019 | 9006 | 6059:9006 | 6019 | 9007 | 6059 | 9007 | 6019 | 9008 | 6059 | 9008 |
6020 | 9006 | 6060:9006 | 6020 | 9007 | 6060 | 9007 | 6020 | 9008 | 6060 | 9008 |
6021 | 9006 | 6061 :9006 | 6021 | 9007 | 6061 | 9007 | 6021 | 9008 | 6061 | 9008 |
6022 | 9006 | 6062 : 9006 | 6022 | 9007 | 6062 | 9007 | 6022 | 9008 | 6062 | 9008 |
6023 | 9006 | 6063:9006 | 6023 | 9007 | 6063 | 9007 | 6023 | 9008 | 6063 | 9008 |
6024 | 9006 | 6064 : 9006 | 6024 | 9007 | 6064 | 9007 | 6024 | 9008 | 6064 | 9008 |
6025 | 9006 | 6065:9006 | 6025 | 9007 | 6065 | 9007 | 6025 | 9008 | 6065 | 9008 |
6026 | 9006 | 6066 : 9006 | 6026 | 9007 | 6066 | 9007 | 6026 | 9008 | 6066 | 9008 |
6027 | 9006 | 6067 : 9006 | 6027 | 9007 | 6067 | 9007 | 6027 | 9008 | 6067 | 9008 |
6028 | 9006 | 6068:9006 | 6028 | 9007 | 6068 | 9007 | 6028 | 9008 | 6068 | 9008 |
6029 | 9006 | 6069 : 9006 | 6029 | 9007 | 6069 | 9007 | 6029 | 9008 | 6069 | 9008 |
6030 | 9006 | 6070:9006 | 6030 | 9007 | 6070 | 9007 | 6030 | 9008 | 6070 | 9008 |
6031 | 9006 | 6071:9006 | 6031 | 9007 | 6071 | 9007 | 6031 | 9008 | 6071 | 9008 |
6032 | 9006 | 6072:9006 | 6032 | 9007 | 6072 | 9007 | 6032 | 9008 | 6072 | 9008 |
6033 | 9006 | 6073 : 9006 | 6033 | 9007 | 6073 | 9007 | 6033 | 9008 | 6073 | 9008 |
6034 | 9006 | 6074:9006 | 6034 | 9007 | 6074 | 9007 | 6034 | 9008 | 6074 | 9008 |
6035 | 9006 | 6075 : 9006 | 6035 | 9007 | 6075 | 9007 | 6035 | 9008 | 6075 | 9008 |
6036 | 9006 | 6076 : 9006 | 6036 | 9007 | 6076 | 9007 | 6036 | 9008 | 6076 | 9008 |
6037 | 9006 | 6077 : 9006 | 6037 | 9007 | 6077 | 9007 | 6037 | 9008 | 6077 | 9008 |
6038 | 9006 | 6078:9006 | 6038 | 9007 | 6078 | 9007 | 6038 | 9008 | 6078 | 9008 |
6039 | 9006 | 6039 | 9007 | 6039 | 9008 |
137
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9009 | 6040 | 9009 | 6000 | 9010 | 6040 | 9010 | 6000 | 9011 | 6040 | 9011 |
6001 | 9009 | 6041 | 9009 | 6001 | 9010 | 6041 | 9010 | 6001 | 9011 | 6041 | 9011 |
6002 | 9009 | 6042 | 9009 | 6002 | 9010 | 6042 | 9010 | 6002 | 9011 | 6042 | 9011 |
6003 | 9009 | 6043 | 9009 | 6003 | 9010 | 6043 | 9010 | 6003 | 9011 | 6043 | 9011 |
6004 | 9009 | 6044 | 9009 | 6004 | 9010 | 6044 | 9010 | 6004 | 9011 | 6044 | 9011 |
-6005 | 9009 | 6045 | 9009 | 6005 | .9010 | -604S | 9010 | -6005 | •P011. | 6045 | 9011 |
.6006 | 9009 | 6046 | 9009 | 6006 | 9010 | 6046 | 9010 | -6006 | 9011 | 6046 | 9011 |
6007 | 9009 | 6047 | 9009 | 6007 | 9010 | 6047 | 9010 | 6007 | 9011 | 6047 | 9011 |
6008 | 9009 | 6048 | 9009 | 6008 | 9010 | 6048 | 9010 | 6008 | 9011 | 6048 | 9011 |
6009 | 9009 | 6049 | 9009 | 6009 | 9010 | 6049 | 9010 | 6009 | 9011 | 6049 | 9011 |
6010 | 9009 | 6050 | 9009 | 6010 | 9010 | 6050 | 9010 | 6010 | 9011 | 6050 | 9011 |
6011 | 9009 | 6051 | 9009 | 6011 | 9010 | 6051 | 9010 | 6011 | 9011 | 6051 | 9011 |
6012 | 9009 | 6052 | 9009 | 6012 | 9010 | 6052 | 9010 | 6012 | 9011 | 6052 | 9011 |
6013 | 9009 | 6053 | 9009 | 6013 | 9010 | 6053 | 9010 | 6013 | 9011 | 6053 | 9011 |
6014 | 9009 | 6054 | 9009 | 6014 | 9010 | 6054 | 9010 | 6014 | 9011 | 6054 | 9011 |
6015 | 9009 | 6055 | 9009 | 6015 | 9010 | 6055 | 9010 | 6015 | 9011 | 6055 | 9011 |
6016 | 9009 | 6056 | 9009 | 6016 | 9010 | 6056 | 9010 | 6016 | 9011 | 6056 | 9011 |
6017 | 9009 | 6057 | 9009 | 6017 | 9010 | 6057 | 9010 | 6017 | 9011 | 6057 | 9011 |
6018 | 9009 | 6058 | 9009 | 6018 | 9010 | 6058 | 9010 | 6018 | 9011 | 6058 | 9011 |
6019 | 9009 | 6059 | 9009 | 6019 | 9010 | 6059 | 9010 | 6019 | 9011 | 6059 | 9011 |
6020 | 9009 | 6060 | 9009 | 6020 | 9010 | 6060 | 9010 | 6020 | 9011 | 6060 | 9011 |
6021 | 9009 | 6061 | 9009 | 6021 | 9010 | 6061 | 9010 | 6021 | 9011 | 6061 | 9011 |
6022 | 9009 | 6062 | 9009 | 6022 | 9010 | 6062 | 9010 | 6022 | 9011 | 6062 | 9011 |
6023 | 9009 | 6063 | 9009 | 6023 | 9010 | 6063 | 9010 | 6023 | 9011 | 6063 | 9011 |
6024 | 9009 | 6064 | 9009 | 6024 | 9010 | 6064 | 9010 | 6024 | 9011 | 6064 | 9011 |
6025 | 9009 | 6065 | 9009 | 6025 | 9010 | 6065 | 9010 | 6025 | 9011 | 6065 | 9011 |
6026 | 9009 | 6066 | 9009 | 6026 | 9010 | 6066 | 9010 | 6026 | 9011 | 6066 | 9011 |
6027 | 9009 | 6067 | 9009 | 6027 | 9010 | 6067 | 9010 | 6027 | 9011 | 6067 | 9011 |
6028 | 9009 | 6068 | 9009 | 6028 | 9010 | 6068 | 9010 | 6028 | 9011 | 6068 | 9011 |
6029 | 9009 | 6069 | 9009 | 6029 | 9010 | 6069 | 9010 | 6029 | 9011 | 6069 | 9011 |
6030 | 9009 | 6070 | 9009 | 6030 | 9010 | 6070 | 9010 | 6030 | 9011 | 6070 | 9011 |
6031 | 9009 | 6071 | 9009 | 6031 | 9010 | 6071 | 9010 | 6031 | 9011 | 6071 | 9011 |
6032 | 9009 | 6072 | 9009 | 6032 | 9010 | 6072 | 9010 | 6032 | 9011 | 6072 | 9011 |
6033 | 9009 | 6073 | 9009 | 6033 | 9010 | 6073 | 9010 | 6033 | 9011 | 6073 | 9011 |
6034 | 9009 | 6074 | 9009 | 6034 | 9010 | 6074 | 9010 | 6034 | 9011 | 6074 | 9011 |
6035 | 9009 | 6075 | 9009 | 6035 | 9010 | 6075 | 9010 | 6035 | 9011 | 6075 | 9011 |
6036 | 9009 | 6076 | 9009 | 6036 | 9010 | 6076 | 9010 | 6036 | 9011 | 6076 | 9011 |
6037 | 9009 | 6077 | 9009 | 6037 | 9010 | 6077 | 9010 | 6037 | 9011 | 6077 | 9011 |
6038 | 9009 | 6078 | 9009 | 6038 | 9010 | 6078 | 9010 | 6038 | 9011 | 6078 | 9011 |
6039 | 9009 | 6039 | 9010 | 6039 | 9011 |
138
X | : Y | X | Y | X | Y | X | Y | X | Y | X | Y | |
6000 | :9012 | 6040 | 9012 | 6000 | 9013 | 6040 | 9013 | 6000 | 9014 | 6040 | 9014 | |
6001 | :9012 | 6041 | 9012 | 6001 | 9013 | 6041 | 9013 | 6001 | 9014 | 6041 | 9014 | |
6002 | :9012 | 6042 | 9012 | 6002 | 9013 | 6042 | 9013 | 6002 | 9014 | 6042 | 9014 | |
6003 | :9012 | 6043 | 9012 | 6003 | 9013 | 6043 | 9013 | 6003 | 9014 | 6043 | 9014 | |
6004 | :9012 | 6044 | 9012 | 6004 | 9013 | 6044 | 9013 | 6004 | 9014 | 6044 | 9014 | |
- * - - | -6005 | t-9012- | 6045' | 9012 | 6005- | 9013 | 6045- | 9013 | 6045 | 9014 | ||
~ -~~-X | -6006 | 9012; | -6046- | 9012 | 6006 | .9013- | 6046-:9013- | 6006 | -9014 | 6046 | 9014 | |
—. . - | 6007 | 9012 | 6047 | 9012 | 6007 | 9013 | 6047 | 9013 | 6007 | 9014 | 6047 | 9014 |
6008 | 9012 | 6048 | 9012 | 6008 | 9013 | 6048 | 9013 | 6008 | 9014 | 6048 | 9014 | |
6009 | 9012 | 6049 | 9012 | 6009 | 9013 | 6049 | 9013 | 6009 | 9014 | 6049 | 9014 | |
6010 | 9012 | 6050 | 9012 | 6010 | 9013 | 6050 | 9013 | 6010 | 9014 | 6050 | 9014 | |
6011 | 9012 | 6051 | 9012 | 6011 | 9013 | 6051 | 9013 | 6011 | 9014 | 6051 | 9014 | |
6012 | 9012 | 6052 | 9012 | 6012 | 9013 | 6052 | 9013 | 6012 | 9014 | 6052 | 9014 | |
6013 | 9012 | 6053 | 9012 | 6013 | 9013 | 6053 | 9013 | 6013 | 9014 | 6053 | 9014 | |
6014 | 9012 | 6054 | 9012 | 6014 | 9013 | 6054 | 9013 | 6014 | 9014 | 6054 | 9014 | |
6015 | 9012 | 6055 | 9012 | 6015 | 9013 | 6055 | 9013 | 6015 | 9014 | 6055 | 9014 | |
6016 | 9012 | 6056 | 9012 | 6016 | 9013 | 6056 | 9013 | 6016 | 9014 | 6056 | 9014 | |
6017 | 9012 | 6057 | 9012 | 6017 | 9013 | 6057 | 9013 | 6017 | 9014 | 6057 | 9014 | |
6018 | 9012 | 6058 | 9012 | 6018 | 9013 | 6058 | 9013 | 6018 | 9014 | 6058 | 9014 | |
6019 | 9012 | 6059 | 9012 | 6019 | 9013 | 6059 | 9013 | 6019 | 9014 | 6059 | 9014 | |
6020 | 9012 | 6060 | 9012 | 6020 | 9013 | 6060 | 9013 | 6020 | 9014 | 6060 | 9014 | |
6021 | 9012 | 6061 | 9012 | 6021 | 9013 | 6061 | 9013 | 6021 | 9014 | 6061 | 9014 | |
6022 | 9012 | 6062 | 9012 | 6022 | 9013 | 6062 | 9013 | 6022 | 9014 | 6062 | 9014 | |
6023 | 9012 | 6063 | 9012 | 6023 | 9013 | 6063 | 9013 | 6023 | 9014 | 6063 | 9014 | |
6024 | 9012 | 6064 | 9012 | 6024 | 9013 | 6064 | 9013 | 6024 | 9014 | 6064 | 9014 | |
6025 | 9012 | 6065 | 9012 | 6025 | 9013 | 6065 | 9013 | 6025 | 9014 | 6065 | 9014 | |
6026 | 9012 | 6066 | 9012 | 6026 | 9013 | 6066 | 9013 | 6026 | 9014 | 6066 | 9014 | |
6027 | 9012 | 6067 | 9012 | 6027 | 9013 | 6067 | 9013 | 6027 | 9014 | 6067 | 9014 | |
6028 | 9012 | 6068 | 9012 | 6028 | 9013 | 6068 | 9013 | 6028 | 9014 | 6068 | 9014 | |
6029 | 9012 | 6069 | 9012 | 6029 | 9013 | 6069 | 9013 | 6029 | 9014 | 6069 | 9014 | |
6030 | 9012 | 6070 | 9012 | 6030 | 9013 | 6070 | 9013 | 6030 | 9014 | 6070 | 9014 | |
6031 | 9012 | 6071 | 9012 | 6031 | 9013 | 6071 | 9013 | 6031 | 9014 | 6071 | 9014 | |
6032 | 9012 | 6072 | 9012 | 6032 | 9013 | 6072 | 9013 | 6032 | 9014 | 6072 | 9014 | |
6033 | 9012 | 6073 | 9012 | 6033 | 9013 | 6073 | 9013 | 6033 | 9014 | 6073 | 9014 | |
6034 | 9012 | 6074 | 9012 | 6034 | 9013 | 6074 | 9013 | 6034 | 9014 | 6074 | 9014 | |
6035 | 9012 | 6075 | 9012 | 6035 | 9013 | 6075 | 9013 | 6035 | 9014 | 6075 | 9014 | |
6036 | 9012 | 6076 | 9012 | 6036 | 9013 | 6076 | 9013 | 6036 | 9014 | 6076 | 9014 | |
6037 | 9012 | 6077 | 9012 | 6037 | 9013 | 6077 | 9013 | 6037 | 9014 | 6077 | 9014 | |
6038 | 9012 | 6078 | 9012 | 6038 | 9013 | 6078 | 9013 | 6038 | 9014 | 6078 | 9014 | |
6039 | 9012 | 6039 | 9013 | 6039 | 9014 |
139
X | Y | X | Y | X: Y | X | Y | X | Y | X | Y |
6000 | 9015 | 6040 | 9015 | 6000 : 9016 | 6040 | 9016 | 6000 | 9017 | 6040 | 9017 |
6001 | 9015 | 6041 | 9015 | 6001:9016 | 6041 | 9016 | 6001 | 9017 | 6041 | 9017 |
6002 | 9015 | 6042 | 9015 | 6002:9016 | 6042 | 9016 | 6002 | 9017 | 6042 | 9017 |
6003 | 9015 | 6043 | 9015 | 6003:9016 | 6043 | 9016 | 6003 | 9017 | 6043 | 9017 |
6004 | 9015 | 6044 | 9015 | 6004:9016 | 6044 | 9016 | 6004 | 9017 | 6044 | 9017 |
-6005 | 9015- | 6045 | 9015 | 6005:.9016- | 6045 | 9016 | .6005x9017 | 6045 | 9017 | |
.6006 | 9015 | 6046 | 9015 | 60064 9016- | 6046 | 9016- | 6006 | 9017- | 6046 | 9017 |
6007 | 9015 | 6047 | 9015 | 6007:9016 | 6047 | 9016 | 6007 | 9017 | 6047 | 9017 |
6008 | 9015 | 6048 | 9015 | 6008:9016 | 6048 | 9016 | 6008 | 9017 | 6048 | 9017 |
6009 | 9015 | 6049 | 9015 | 6009:9016 | 6049 | 9016 | 6009 | 9017 | 6049 | 9017 |
6010 | 9015 | 6050 | 9015 | 6010:9016 | 6050 | 9016 | 6010 | 9017 | 6050 | 9017 |
6011 | 9015 | 6051 | 9015 | 6011:9016 | 6051 | 9016 | 6011 | 9017 | 6051 | 9017 |
6012 | 9015 | 6052 | 9015 | 6012 : 9016 | 6052 | 9016 | 6012 | 9017 | 6052 | 9017 |
6013 | 9015 | 6053 | 9015 | 6013 : 9016 | 6053 | 9016 | 6013 | 9017 | 6053 | 9017 |
6014 | 9015 | 6054 | 9015 | 6014:9016 | 6054 | 9016 | 6014 | 9017 | 6054 | 9017 |
6015 | 9015 | 6055 | 9015 | 6015:9016 | 6055 | 9016 | 6015 | 9017 | 6055 | 9017 |
6016 | 9015 | 6056 | 9015 | 6016:9016 | 6056 | 9016 | 6016 | 9017 | 6056 | 9017 |
6017 | 9015 | 6057 | 9015 | 6017:9016 | 6057 | 9016 | 6017 | 9017 | 6057 | 9017 |
6018 | 9015 | 6058 | 9015 | 6018:9016 | 6058 | 9016 | 6018 | 9017 | 6058 | 9017 |
6019 | 9015 | 6059 | 9015 | 6019:9016 | 6059 | 9016 | 6019 | 9017 | 6059 | 9017 |
6020 | 9015 | 6060 | 9015 | 6020:9016 | 6060 | 9016 | 6020 | 9017 | 6060 | 9017 |
6021 | 9015 | 6061 | 9015 | 6021 :9016 | 6061 | 9016 | 6021 | 9017 | 6061 | 9017 |
6022 | 9015 | 6062 | 9015 | 6022:9016 | 6062 | 9016 | 6022 | 9017 | 6062 | 9017 |
6023 | 9015 | 6063 | 9015 | 6023 : 9016 | 6063 | 9016 | 6023 | 9017 | 6063 | 9017 |
6024 | 9015 | 6064 | 9015 | 6024:9016 | 6064 | 9016 | 6024 | 9017 | 6064 | 9017 |
6025 | 9015 | 6065 | 9015 | 6025:9016 | 6065 | 9016 | 6025 | 9017 | 6065 | 9017 |
6026 | 9015 | 6066 | 9015 | 6026:9016 | 6066 | 9016 | 6026 | 9017 | 6066 | 9017 |
6027 | 9015 | 6067 | 9015 | 6027:9016 | 6067 | 9016 | 6027 | 9017 | 6067 | 9017 |
6028 | 9015 | 6068 | 9015 | 6028:9016 | 6068 | 9016 | 6028 | 9017 | 6068 | 9017 |
6029 | 9015 | 6069 | 9015 | 6029:9016 | 6069 | 9016 | 6029 | 9017 | 6069 | 9017 |
6030 | 9015 | 6070 | 9015 | 6030:9016 | 6070 | 9016 | 6030 | 9017 | 6070 | 9017 |
6031 | 9015 | 6071 | 9015 | 6031:9016 | 6071 | 9016 | 6031 | 9017 | 6071 | 9017 |
6032 | 9015 | 6072 | 9015 | 6032:9016 | 6072 | 9016 | 6032 | 9017 | 6072 | 9017 |
6033 | 9015 | 6073 | 9015 | 6033:9016 | 6073 | 9016 | 6033 | 9017 | 6073 | 9017 |
6034 | 9015 | 6074 | 9015 | 6034:9016 | 6074 | 9016 | 6034 | 9017 | 6074 | 9017 |
6035 | 9015 | 6075 | 9015 | 6035:9016 | 6075 | 9016 | 6035 | 9017 | 6075 | 9017 |
6036 | 9015 | 6076 | 9015 | 6036:9016 | 6076 | 9016 | 6036 | 9017 | 6076 | 9017 |
6037 | 9015 | 6077 | 9015 | 6037:9016 | 6077 | 9016 | 6037 | 9017 | 6077 | 9017 |
6038 | 9015 | 6078 | 9015 | 6038:9016 | 6078 | 9016 | 6038 | 9017 | 6078 | 9017 |
6039 | 9015 | 6039:9016 | 6039 | 9017 | —J |
140
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X | Y |
6000:9018 | 6040 : 9018 | 6000:9019 | 6040:9019 | 6000:9020 | 6040 | 9020 |
6001:9018 | 6041:9018 | 6001:9019 | 6041:9019 | 6001:9020 | 6041 | 9020 |
6002:9018 | 6042 : 9018 | 6002:9019 | 6042:9019 | 6002 : 9020 | 6042 | 9020 |
6003:9018 | 6043 : 9018 | 6003:9019 | 6043:9019 | 6003 : 9020 | 6043 | 9020 |
6004:9018 | 6044 : 9018 | 6004:9019 | 6044 : 9019 | 6004 : 9020 | 6044 | 9020 |
6005:9018- | -6045 : 9018 | 6005:9019 | 6045 i 9019 | 6005:9020- | 6045 | 9020 |
•6006:9018 | 6046 ^9018 | 6006:9019 | 6046:9019 | 6006:9020 | 6046 | 9020 |
6007:9018 | 6047:9018 | 6007:9019 | 6047 : 9019 | 6007:9020 | 6047 | 9020 |
6008:9018 | 6048 : 9018 | 6008:9019 | 6048:9019 | 6008 : 9020 | 6048 | 9020 |
6009 : 9018 | 6049 : 9018 | 6009:9019 | 6049 : 9019 | 6009 : 9020 | 6049 | 9020 |
6010:9018 | 6050:9018 | 6010:9019 | 6050:9019 | 6010 : 9020 | 6050 | 9020 |
6011:9018 | 6051:9018 | 6011:9019 | 6051 :9019 | 6011:9020 | 6051 | 9020 |
6012:9018 | 6052:9018 | 6012:9019 | 6052:9019 | 6012 : 9020 | 6052 | 9020 |
6013 : 9018 | 6053:9018 | 6013 : 9019 | 6053 : 9019 | 6013 : 9020 | 6053 | 9020 |
6014:9018 | 6054 : 9018 | 6014 : 9019 | 6054:9019 | 6014:9020 | 6054 | 9020 |
6015:9018 | 6055:9018 | 6015 : 9019 | 6055 : 9019 | 6015 : 9020 | 6055 | 9020 |
6016:9018 | 6056 : 9018 | 6016:9019 | 6056:9019 | 6016 : 9020 | 6056 | 9020 |
6017:9018 | 6057:9018 | 6017:9019 | 6057:9019 | 6017:9020 | 6057 | 9020 |
6018:9018 | 6058:9018 | 6018:9019 | 6058:9019 | 6018:9020 | 6058 | 9020 |
6019:9018 | 6059 : 9018 | 6019 : 9019 | 6059 : 9019 | 6019 : 9020 | 6059 | 9020 |
6020:9018 | 6060 : 9018 | 6020:9019 | 6060 : 9019 | 6020:9020 | 6060 | 9020 |
6021:9018 | 6061:9018 | 6021:9019 | 6061:9019 | 6021:9020 | 6061 | 9020 |
6022:9018 | 6062:9018 | 6022 : 9019 | 6062 : 9019 | 6022 : 9020 | 6062 | 9020 |
6023 : 9018 | 6063:9018 | 6023:9019 | 6063:9019 | 6023 : 9020 | 6063 | 9020 |
6024 : 9018 | 6064:9018 | 6024:9019 | 6064:9019 | 6024 : 9020 | 6064 | 9020 |
6025 : 9018 | 6065:9018 | 6025:9019 | 6065 : 9019 | 6025:9020 | 6065 | 9020 |
6026 : 9018 | 6066 : 9018 | 6026:9019 | 6066:9019 | 6026:9020 | 6066 | 9020 |
6027:9018 | 6067 : 9018 | 6027:9019 | 6067:9019 | 6027 : 9020 | 6067 | 9020 |
6028:9018 | 6068:9018 | 6028:9019 | 6068:9019 | 6028 : 9020 | 6068 | 9020 |
6029:9018 | 6069 : 9018 | 6029:9019 | 6069 : 9019 | 6029 : 9020 | 6069 | 9020 |
6030 : 9018 | 6070 : 9018 | 6030:9019 | 6070:9019 | 6030 : 9020 | 6070 | 9020 |
6031:9018 | 6071:9018 | 6031:9019 | 6071:9019 | 6031:9020 | 6071 | 9020 |
6032 : 9018 | 6072:9018 | 6032:9019 | 6072 : 9019 | 6032 : 9020 | 6072 | 9020 |
6033:9018 | 6073:9018 | 6033 : 9019 | 6073:9019 | 6033 : 9020 | 6073 | 9020 |
6034:9018 | 6074:9018 | 6034 : 9019 | 6074 : 9019 | 6034 : 9020 | 6074 | 9020 |
6035:9018 | 6075 : 9018 | 6035:9019 | 6075:9019 | 6035 : 9020 | 6075 | 9020 |
6036:9018 | 6076:9018 | 6036 : 9019 | 6076:9019 | 6036 : 9020 | 6076 | 9020 |
6037:9018 | 6077 : 9018 | 6037 : 9019 | 6077 : 9019 | 6037 : 9020 | 6077 | 9020 |
6038 : 9018 | 6078 : 9018 | 6038:9019 | 6078 : 9019 | 6038:9020 | 6078 | 9020 |
6039:9018 | 6039:9019 | 6039 : 9020 |
141
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9021 | 6040 | 9021 | 6000 | 9022 | 6040 | 9022 | 6000 | 9023 | 6040 | 9023 |
6001 | 9021 | 6041 | 9021 | 6001 | 9022 | 6041 | 9022 | 6001 | 9023 | 6041 | 9023 |
6002 | 9021 | 6042 | 9021 | 6002 | 9022 | 6042 | 9022 | 6002 | 9023 | 6042 | 9023 |
6003 | 9021 | 6043 | 9021 | 6003 | 9022 | 6043 | 9022 | 6003 | 9023 | 6043 | 9023 |
6004 | 9021 | 6044 | 9021 | 6004 | 9022 | 6044 | 9022 | 6004 | 9023 | 6044 | 9023 |
6005 | 9021 | 6045 | 9021 | 6005 | 9022 | 6045 | 9022 | 6005 | k9023 | 6045 | 9023 |
6006 | 9021 | 6046 | 9021 | 6006 | 9022 | 6046 | 9022 | -6006 | 9023 | 6046 | 9023 |
6007 | 9021 | 6047 | 9021 | 6007 | 9022 | 6047 | 9022 | 6007 | 9023 | 6047 | 9023 |
6008 | 9021 | 6048 | 9021 | 6008 | 9022 | 6048 | 9022 | 6008 | 9023 | 6048 | 9023 |
6009 | 9021 | 6049 | 9021 | 6009 | 9022 | 6049 | 9022 | 6009 | 9023 | 6049 | 9023 |
6010 | 9021 | 6050 | 9021 | 6010 | 9022 | 6050 | 9022 | 6010 | 9023 | 6050 | 9023 |
6011 | 9021 | 6051 | 9021 | 6011 | 9022 | 6051 | 9022 | 6011 | 9023 | 6051 | 9023 |
6012 | 9021 | 6052 | 9021 | 6012 | 9022 | 6052 | 9022 | 6012 | 9023 | 6052 | 9023 |
6013 | 9021 | 6053 | 9021 | 6013 | 9022 | 6053 | 9022 | 6013 | 9023 | 6053 | 9023 |
6014 | 9021 | 6054 | 9021 | 6014 | 9022 | 6054 | 9022 | 6014 | 9023 | 6054 | 9023 |
6015 | 9021 | 6055 | 9021 | 6015 | 9022 | 6055 | 9022 | 6015 | 9023 | 6055 | 9023 |
6016 | 9021 | 6056 | 9021 | 6016 | 9022 | 6056 | 9022 | 6016 | 9023 | 6056 | 9023 |
6017 | 9021 | 6057 | 9021 | 6017 | 9022 | 6057 | 9022 | 6017 | 9023 | 6057 | 9023 |
6018 | 9021 | 6058 | 9021 | 6018 | 9022 | 6058 | 9022 | 6018 | 9023 | 6058 | 9023 |
6019 | 9021 | 6059 | 9021 | 6019 | 9022 | 6059 | 9022 | 6019 | 9023 | 6059 | 9023 |
6020 | 9021 | 6060 | 9021 | 6020 | 9022 | 6060 | 9022 | 6020 | 9023 | 6060 | 9023 |
6021 | 9021 | 6061 | 9021 | 6021 | 9022 | 6061 | 9022 | 6021 | 9023 | 6061 | 9023 |
6022 | 9021 | 6062 | 9021 | 6022 | 9022 | 6062 | 9022 | 6022 | 9023 | 6062 | 9023 |
6023 | 9021 | 6063 | 9021 | 6023 | 9022 | 6063 | 9022 | 6023 | 9023 | 6063 | 9023 |
6024 | 9021 | 6064 | 9021 | 6024 | 9022 | 6064 | 9022 | 6024 | 9023 | 6064 | 9023 |
6025 | 9021 | 6065 | 9021 | 6025 | 9022 | 6065 | 9022 | 6025 | 9023 | 6065 | 9023 |
6026 | 9021 | 6066 | 9021 | 6026 | 9022 | 6066 | 9022 | 6026 | 9023 | 6066 | 9023 |
6027 | 9021 | 6067 | 9021 | 6027 | 9022 | 6067 | 9022 | 6027 | 9023 | 6067 | 9023 |
6028 | 9021 | 6068 | 9021 | 6028 | 9022 | 6068 | 9022 | 6028 | 9023 | 6068 | 9023 |
6029 | 9021 | 6069 | 9021 | 6029 | 9022 | 6069 | 9022 | 6029 | 9023 | 6069 | 9023 |
6030 | 9021 | 6070 | 9021 | 6030 | 9022 | 6070 | 9022 | 6030 | 9023 | 6070 | 9023 |
6031 | 9021 | 6071 | 9021 | 6031 | 9022 | 6071 | 9022 | 6031 | 9023 | 6071 | 9023 |
6032 | 9021 | 6072 | 9021 | 6032 | 9022 | 6072 | 9022 | 6032 | 9023 | 6072 | 9023 |
6033 | 9021 | 6073 | 9021 | 6033 | 9022 | 6073 | 9022 | 6033 | 9023 | 6073 | 9023 |
6034 | 9021 | 6074 | 9021 | 6034 | 9022 | 6074 | 9022 | 6034 | 9023 | 6074 | 9023 |
6035 | 9021 | 6075 | 9021 | 6035 | 9022 | 6075 | 9022 | 6035 | 9023 | 6075 | 9023 |
6036 | 9021 | 6076 | 9021 | 6036 | 9022 | 6076 | 9022 | 6036 | 9023 | 6076 | 9023 |
6037 | 9021 | 6077 | 9021 | 6037 | 9022 | 6077 | 9022 | 6037 | 9023 | 6077 | 9023 |
6038 | 9021 | 6078 | 9021 | 6038 | 9022 | 6078 | 9022 | 6038 | 9023 | 6078 | 9023 |
6039 | 9021 | 6039 | 9022 | 6039 | 9023 |
142
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X | Y |
6000:9024 | 6040 : 9024 | 6000 : 9025 | 6040:9025 | 6000:9026 | 6040 | 9026 |
6001:9024 | 6041:9024 | 6001:9025 | 6041:9025 | 6001:9026 | 6041 | 9026 |
6002:9024 | 6042:9024 | 6002:9025 | 6012:9025 | 6002:9026 | 6042 | 9026 |
6003:9024 | 6043:9024 | 6003:9025 | 6043:9025 | 6003 : 9026 | 6043 | 9026 |
6004:9024 | 6044:9024 | 6004 : 9025 | 6044:9025 | 6004 : 9026 | 6044 | 9026 |
-6005:9024- | 6045:9024 | 600519025 | 60451.9025 | 6005 : 9026 | 6045 | 9026 |
:6006:9024 | 6046 : 9024 | r6000:9025 | 6046 : 9025 | -6006 :-9026 | 6046 | 9026 |
6007 : 9024 | 6047 : 9024 | 6007 : 9025 | 6047:9025 | 6007 : 9026 | 6047 | 9026 |
6008:9024 | 6048:9024 | 6008 : 9025 | 6048:9025 | 6008:9026 | 6048 | 9026 |
6009:9024 | 6049:9024 | 6009 : 9025 | 6049:9025 | 6009:9026 | 6049 | 9026 |
6010:9024 | 6050:9024 | 6010:9025 | 6050:9025 | 6010 : 9026 | 6050 | 9026 |
6011:9024 | 6051 :9024 | 6011:9025 | 6051:9025 | 6011 :9026 | 6051 | 9026 |
6012:9024 | 6052 : 9024 | 6012:9025 | 6052:9025 | 6012:9026 | 6052 | 9026 |
6013:9024 | 6053:9024 | 6013:9025 | 6053:9025 | 6013 : 9026 | 6053 | 9026 |
6014:9024 | 6054 : 9024 | 6014:9025 | 6054 : 9025 | 6014:9026 | 6054 | 9026 |
6015:9024 | 6055 : 9024 | 6015:9025 | 6055:9025 | 6015 : 9026 | 6055 | 9026 |
6016:9024 | 6056:9024 | 6016:9025 | 6056:9025 | 6016:9026 | 6056 | 9026 |
6017:9024 | 6057:9024 | 6017 : 9025 | 6057:9025 | 6017 : 9026 | 6057 | 9026 |
6018:9024 | 6058:9024 | 6018 : 9025 | 6058:9025 | 6018:9026 | 6058 | 9026 |
6019 : 9024 | 6059:9024 | 6019 : 9025 | 6059:9025 | 6019 : 9026 | 6059 | 9026 |
6020:9024 | 6060 : 9024 | 6020:9025 | 6060 : 9025 | 6020 : 9026 | 6060 | 9026 |
6021:9024 | 6061:9024 | 6021:9025 | 6061:9025 | 6021 :9026 | 6061 | 9026 |
6022:9024 | 6062:9024 | 6022 : 9025 | 6062 : 9025 | 6022 : 9026 | 6062 | 9026 |
6023 :9024 | 6063 : 9024 | 6023:9025 | 6063 : 9025 | 6023 : 9026 | 6063 | 9026 |
6024:9024 | 6064:9024 | 6024:9025 | 6064 : 9025 | 6024:9026 | 6064 | 9026 |
6025:9024 | 6065 : 9024 | 6025 : 9025 | 6065:9025 | 6025 : 9026 | 6065 | 9026 |
6026:9024 | 6066:9024 | 6026:9025 | 6066:9025 | 6026:9026 | 6066 | 9026 |
6027:9024 | 6067:9024 | 6027:9025 | 6067:9025 | 6027 : 9026 | 6067 | 9026 |
6028:9024 | 6068 : 9024 | 6028:9025 | 6068 : 9025 | 6028 : 9026 | 6068 | 9026 |
6029 : 9024 | 6069:9024 | 6029:9025 | 6069:9025 | 6029:9026 | 6069 | 9026 |
6030 : 9024 | 6070:9024 | 6030:9025 | 6070:9025 | 6030 : 9026 | 6070 | 9026 |
6031:9024 | 6071:9024 | 6031:9025 | 6071:9025 | 6031:9026 | 6071 | 9026 |
6032:9024 | 6072:9024 | 6032:9025 | 6072:9025 | 6032:9026 | 6072 | 9026 |
6033:9024 | 6073:9024 | 6033:9025 | 6073:9025 | 6033:9026 | 6073 | 9026 |
6034:9024 | 6074:9024 | 6034 : 9025 | 6074:9025 | 6034:9026 | 6074 | 9026 |
6035 : 9024 | 6075:9024 | 6035 : 9025 | 6075:9025 | 6035 : 9026 | 6075 | 9026 |
6036:9024 | 6076:9024 | 6036:9025 | 6076:9025 | 6036 : 9026 | 6076 | 9026 |
6037:9024 | 6077 : 9024 | 6037:9025 | 6077:9025 | 6037 : 9026 | 6077 | 9026 |
6038 : 9024 | 6078:9024 | 6038:9025 | 6078 : 9025 | 6038:9026 | 6078 | 9026 |
6039:9024 | 6039 : 9025 | 6039 : 9026 |
143
X | Y | X:Y | X:Y | Χ:Υ | Χ:Υ | X | Y |
6000 | 9027 | 6040:9027 | 6000:9028 | 6040:9028 | 6000 : 9029 | 6040 | 9029 |
6001 | 9027 | 6041:9027 | 6001:9028 | 6041:9028 | 6001:9029 | 6041 | 9029 |
6002 | 9027 | 6042 : 9027 | 6002:9028 | 6042:9028 | 6002:9029 | 6042 | 9029 |
6003 | 9027 | 6043 : 9027 | 6003:9028 | 6043:9028 | 6003 : 9029 | 6043 | 9029 |
6004 | 9027 | 6044 : 9027 | 6004:9028 | 6044 : 9028 | 6004:9029 | 6044 | 9029 |
6005 | 9027- | 6045-:-9027 | 6005:9028 | 6045:9028 | 6005:9029· | 6045 | 9029 |
-6006 | 9027- | 6046 :9027 | 6006:9028 | .6046:9028- | .6006:9029 | 6046 | 9029 |
6007 | 9027’ | 6047:9027 | 6007:9028 | 6047:9028 | 6007:9029 | 6047 | 9029 |
6008 | 9027 | 6048:9027 | 6008:9028 | 6048:9028 | 6008:9029 | 6048 | 9029 |
6009 | 9027 | 6049:9027 | 6009 : 9028 | 6049 : 9028 | 6009 : 9029 | 6049 | 9029 |
6010 | 9027 | 6050 : 9027 | 6010:9028 | 6050:9028 | 6010:9029 | 6050 | 9029 |
6011 | 9027 | 6051:9027 | 6011:9028 | 6051:9028 | 6011:9029 | 6051 | 9029 |
6012 | 9027 | 6052 : 9027 | 6012:9028 | 6052:9028 | 6012 : 9029 | 6052 | 9029 |
6013 | 9027 | 6053:9027 | 6013:9028 | 6053 : 9028 | 6013 : 9029 | 6053 | 9029 |
6014 | 9027 | 6054:9027 | 6014:9028 | 6054 : 9028 | 6014 : 9029 | 6054 | 9029 |
6015 | 9027 | 6055:9027 | 6015:9028 | 6055:9028 | 6015 : 9029 | 6055 | 9029 |
6016 | 9027 | 6056:9027 | 6016:9028 | 6056:9028 | 6016 : 9029 | 6056 | 9029 |
6017 | 9027 | 6057:9027 | 6017:9028 | 6057:9028 | 6017:9029 | 6057 | 9029 |
6018 | 9027 | 6058:9027 | 6018 : 9028 | 6058:9028 | 6018:9029 | 6058 | 9029 |
6019 | 9027 | 6059 : 9027 | 6019 : 9028 | 6059 : 9028 | 6019:9029 | 6059 | 9029 |
6020 | 9027 | 6060:9027 | 6020:9028 | 6060:9028 | 6020:9029 | 6060 | 9029 |
6021 | 9027 | 6061:9027 | 6021:9028 | 6061:9028 | 6021:9029 | 6061 | 9029 |
6022 | 9027 | 6062:9027 | 6022:9028 | 6062:9028 | 6022:9029 | 6062 | 9029 |
6023 | 9027 | 6063:9027 | 6023:9028 | 6063:9028 | 6023:9029 | 6063 | 9029 |
6024 | 9027 | 6064 : 9027 | 6024 : 9028 | 6064 : 9028 | 6024:9029 | 6064 | 9029 |
6025 | 9027 | 6065 : 9027 | 6025:9028 | 6065:9028 | 6025 : 9029 | 6065 | 9029 |
6026 | 9027 | 6066 : 9027 | 6026:9028 | 6066:9028 | 6026:9029 | 6066 | 9029 |
6027 | 9027 | 6067:9027 | 6027:9028 | 6067:9028 | 6027:9029 | 6067 | 9029 |
6028 | 9027 | 6068 : 9027 | 6028:9028 | 6068:9028 | 6028:9029 | 6068 | 9029 |
6029 | 9027 | 6069 : 9027 | 6029 : 9028 | 6069:9028 | 6029:9029 | 6069 | 9029 |
6030 | 9027 | 6070:9027 | 6030 : 9028 | 6070:9028 | 6030 : 9029 | 6070 | 9029 |
6031 | 9027 | 6071:9027 | 6031:9028 | 6071 :9028 | 6031 :9029 | 6071 | 9029 |
6032 | 9027 | 6072:9027 | 6032:9028 | 6072:9028 | 6032 : 9029 | 6072 | 9029 |
6033 | 9027 | 6073:9027 | 6033:9028 | 6073 : 9028 | 6033:9029 | 6073 | 9029 |
6034 | 9027 | 6074:9027 | 6034 : 9028 | 6074 : 9028 | 6034:9029 | 6074 | 9029 |
6035 | 9027 | 6075:9027 | 6035 : 9028 | 6075 : 9028 | 6035:9029 | 6075 | 9029 |
6036 | 9027 | 6076:9027 | 6036:9028 | 6076:9028 | 6036 : 9029 | 6076 | 9029 |
6037 | 9027 | 6077 : 9027 | 6037 : 9028 | 6077:9028 | 6037:9029 | 6077 | 9029 |
6038 | 9027 | 6078:9027 | 6038 : 9028 | 6078:9028 | 6038:9029 | 6078 | 9029 |
6039 | 9027 | 6039:9028 | 6039:9029 |
I44
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9030 | 6040 | 9030 | 6000 | 9031 | 6040 | 9031 | 6000 | 9032 | 6040 | 9032 |
6001 | 9030 | 6041 | 9030 | 6001. | 9031 | 6041 | 9031 | 6001 | 9032 | 6041 | 9032 |
6002 | 9030 | 6042 | 9030 | 6002 | 9031 | 6042 | 9031 | 6002 | 9032 | 6042 | 9032 |
6003 | 9030 | 6043 | 9030 | 6003 | 9031 | 6043 | 9031 | 6003 | 9032 | 6043 | 9032 |
6004 | 9030 | 6044 | 9030 | 6004 | 9031 | 6044 | 9031 | 6004 | 9032 | 6044 | 9032 |
6005 | 9030 | 6045 | 9030 | 6005 | ‘9031- | 6045 | ‘9031 | -6005 | ‘9032 | 6045 | 9032 |
6006 | 9030 | 6046 | 9030 | 6006 | 9031 | 6046 | 9031. | -6006 | -9032 | 6046 | 9032 |
6007 | 9030 | 6047 | 9030 | 6007 | 9031 | 6047 | 9031 | 6007 | 9032 | 6047 | 9032 |
6008 | 9030 | 6048 | 9030 | 6008 | 9031 | 6048 | 9031 | 6008 | 9032 | 6048 | 9032 |
6009 | 9030 | 6049 | 9030 | 6009 | 9031 | 6049 | 9031 | 6009 | 9032 | 6049 | 9032 |
6010 | 9030 | 6050 | 9030 | 6010 | 9031 | 6050 | 9031 | 6010 | 9032 | 6050 | 9032 |
6011 | 9030 | 6051 | 9030 | 6011 | 9031 | 6051 | 9031 | 6011 | 9032 | 6051 | 9032 |
6012 | 9030 | 6052 | 9030 | 6012 | 9031 | 6052 | 9031 | 6012 | 9032 | 6052 | 9032 |
6013 | 9030 | 6053 | 9030 | 6013 | 9031 | 6053 | 9031 | 6013 | 9032 | 6053 | 9032 |
6014 | 9030 | 6054 | 9030 | 6014 | 9031 | 6054 | 9031 | 6014 | 9032 | 6054 | 9032 |
6015 | 9030 | 6055 | 9030 | 6015 | 9031 | 6055 | 9031 | 6015 | 9032 | 6055 | 9032 |
6016 | 9030 | 6056 | 9030 | 6016 | 9031 | 6056 | 9031 | 6016 | 9032 | 6056 | 9032 |
6017 | 9030 | 6057 | 9030 | 6017 | 9031 | 6057 | 9031 | 6017 | 9032 | 6057 | 9032 |
6018 | 9030 | 6058 | 9030 | 6018 | 9031 | 6058 | 9031 | 6018 | 9032 | 6058 | 9032 |
6019 | 9030 | 6059 | 9030 | 6019 | 9031 | 6059 | 9031 | 6019 | 9032 | 6059 | 9032 |
6020 | 9030 | 6060 | 9030 | 6020 | 9031 | 6060 | 9031 | 6020 | 9032 | 6060 | 9032 |
6021 | 9030 | 6061 | 9030 | 6021 | 9031 | 6061 | 9031 | 6021 | 9032 | 6061 | 9032 |
6022 | 9030 | 6062 | 9030 | 6022 | 9031 | 6062 | 9031 | 6022 | 9032 | 6062 | 9032 |
6023 | 9030 | 6063 | 9030 | 6023 | 9031 | 6063 | 9031 | 6023 | 9032 | 6063 | 9032 |
6024 | 9030 | 6064 | 9030 | 6024 | 9031 | 6064 | 9031 | 6024 | 9032 | 6064 | 9032 |
6025 | 9030 | 6065 | 9030 | 6025 | 9031 | 6065 | 9031 | 6025 | 9032 | 6065 | 9032 |
6026 | 9030 | 6066 | 9030 | 6026 | 9031 | 6066 | 9031 | 6026 | 9032 | 6066 | 9032 |
6027 | 9030 | 6067 | 9030 | 6027 | 9031 | 6067 | 9031 | 6027 | 9032 | 6067 | 9032 |
6028 | 9030 | 6068 | 9030 | 6028 | 9031 | 6068 | 9031 | 6028 | 9032 | 6068 | 9032 |
6029 | 9030 | 6069 | 9030 | 6029 | 9031 | 6069 | 9031 | 6029 | 9032 | 6069 | 9032 |
6030 | 9030 | 6070 | 9030 | 6030 | 9031 | 6070 | 9031 | 6030 | 9032 | 6070 | 9032 |
6031 | 9030 | 6071 | 9030 | 6031 | 9031 | 6071 | 9031 | 6031 | 9032 | 6071 | 9032 |
6032 | 9030 | 6072 | 9030 | 6032 | 9031 | 6072 | 9031 | 6032 | 9032 | 6072 | 9032 |
6033 | 9030 | 6073 | 9030 | 6033 | 9031 | 6073 | 9031 | 6033 | 9032 | 6073 | 9032 |
6034 | 9030 | 6074 | 9030 | 6034 | 9031 | 6074 | 9031 | 6034 | 9032 | 6074 | 9032 |
6035 | 9030 | 6075 | 9030 | 6035 | 9031 | 6075 | 9031 | 6035 | 9032 | 6075 | 9032 |
6036 | 9030 | 6076 | 9030 | 6036 | 9031 | 6076 | 9031 | 6036 | 9032 | 6076 | 9032 |
6037 | 9030 | 6077 | 9030 | 6037 | 9031 | 6077 | 9031 | 6037 | 9032 | 6077 | 9032 |
6038 | 9030 | 6078 | 9030 | 6038 | 9031 | 6078 | 9031 | 6038 | 9032 | 6078 | 9032 |
6039 | 9030 | 6039 | 9031 | 6039 | 9032 |
145
X | Y | X:Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9033 | 6040 : 9033 | 6000 | 9034 | 6040 | 9034 | 6000 | 9035 | 6040 | 9035 |
6001 | 9033 | 6041 :9033 | 6001 | 9034 | 6041 | 9034 | 6001 | 9035 | 6041 | 9035 |
6002 | 9033 | 6042:9033 | 6002 | 9034 | 6042 | 9034 | 6002 | 9035 | 6042 | 9035 |
6003 | 9033 | 6043 : 9033 | 6003 | 9034 | 6043 | 9034 | 6003 | 9035 | 6043 | 9035 |
6004 | 9033 | 6044 : 9033 | 6004 | 9034 | 6044 | 9034 | 6004 | 9035 | 6044 | 9035 |
-6005- | -9033- | 6Ο45τ9Ο33- | 6005- | -9034 | 6045 | -9034 | -6005 | -9035 | 6045 | 9035 |
-6006 | 9033- | 604frt9033- | '6006 | 9034- | 6046 | -.9034 | -6006 | ..9035 | 6046 | 9035 |
6007 | 9033' | 6047 : 9033 | 6007 | 9034 | 6047 | *9034 | '6007 | 9035 | 6047 | 9035 |
6008 | 9033 | 6048:9033 | 6008 | 9034 | 6048 | 9034 | 6008 | 9035 | 6048 | 9035 |
6009 | 9033 | 6049 : 9033 | 6009 | 9034 | 6049 | 9034 | 6009 | 9035 | 6049 | 9035 |
6010 | 9033 | 6050 : 9033 | 6010 | 9034 | 6050 | 9034 | 6010 | 9035 | 6050 | 9035 |
6011 | 9033 | 6051:9033 | 6011 | 9034 | 6051 | 9034 | 6011 | 9035 | 6051 | 9035 |
6012 | 9033 | 6052:9033 | 6012 | 9034 | 6052 | 9034 | 6012 | 9035 | 6052 | 9035 |
6013 | 9033 | 6053:9033 | 6013 | 9034 | 6053 | 9034 | 6013 | 9035 | 6053 | 9035 |
6014 | 9033 | 6054:9033 | 6014 | 9034 | 6054 | 9034 | 6014 | 9035 | 6054 | 9035 |
6015 | 9033 | 6055 : 9033 | 6015 | 9034 | 6055 | 9034 | 6015 | 9035 | 6055 | 9035 |
6016 | 9033 | 6056:9033 | 6016 | 9034 | 6056 | 9034 | 6016 | 9035 | 6056 | 9035 |
6017 | 9033 | 6057 : 9033 | 6017 | 9034 | 6057 | 9034 | 6017 | 9035 | 6057 | 9035 |
6018 | 9033 | 6058:9033 | 6018 | 9034 | 6058 | 9034 | 6018 | 9035 | 6058 | 9035 |
6019 | 9033 | 6059:9033 | 6019 | 9034 | 6059 | 9034 | 6019 | 9035 | 6059 | 9035 |
6020 | 9033 | 6060 : 9033 | 6020 | 9034 | 6060 | 9034 | 6020 | 9035 | 6060 | 9035 |
6021 | 9033 | 6061:9033 | 6021 | 9034 | 6061 | 9034 | 6021 | 9035 | 6061 | 9035 |
6022 | 9033 | 6062:9033 | 6022 | 9034 | 6062 | 9034 | 6022 | 9035 | 6062 | 9035 |
6023 | 9033 | 6063 : 9033 | 6023 | 9034 | 6063 | 9034 | 6023 | 9035 | 6063 | 9035 |
6024 | 9033 | 6064 : 9033 | 6024 | 9034 | 6064 | 9034 | 6024 | 9035 | 6064 | 9035 |
6025 | 9033 | 6065:9033 | 6025 | 9034 | 6065 | 9034 | 6025 | 9035 | 6065 | 9035 |
6026 | 9033 | 6066:9033 | 6026 | 9034 | 6066 | 9034 | 6026 | 9035 | 6066 | 9035 |
6027 | 9033 | 6067 : 9033 | 6027 | 9034 | 6067 | 9034 | 6027 | 9035 | 6067 | 9035 |
6028 | 9033 | 6068 : 9033 | 6028 | 9034 | 6068 | 9034 | 6028 | 9035 | 6068 | 9035 |
6029 | 9033 | 6069 : 9033 | 6029 | 9034 | 6069 | 9034 | 6029 | 9035 | 6069 | 9035 |
6030 | 9033 | 6070 : 9033 | 6030 | 9034 | 6070 | 9034 | 6030 | 9035 | 6070 | 9035 |
6031 | 9033 | 6071:9033 | 6031 | 9034 | 6071 | 9034 | 6031 | 9035 | 6071 | 9035 |
6032 | 9033 | 6072:9033 | 6032 | 9034 | 6072 | 9034 | 6032 | 9035 | 6072 | 9035 |
6033 | 9033 | 6073:9033 | 6033 | 9034 | 6073 | 9034 | 6033 | 9035 | 6073 | 9035 |
6034 | 9033 | 6074:9033 | 6034 | 9034 | 6074 | 9034 | 6034 | 9035 | 6074 | 9035 |
6035 | 9033 | 6075 : 9033 | 6035 | 9034 | 6075 | 9034 | 6035 | 9035 | 6075 | 9035 |
6036 | 9033 | 6076 : 9033 | 6036 | 9034 | 6076 | 9034 | 6036 | 9035 | 6076 | 9035 |
6037 | 9033 | 6077 : 9033 | 6037 | 9034 | 6077 | 9034 | 6037 | 9035 | 6077 | 9035 |
6038 6039 | 9033 9033 | 6078:9033 | 6038 6039 | 9034 9034 | 6078 | 9034 | 6038 6039 | 9035 9035 | 6078 | 9035 |
146
X | Y | X:Y | X | Y | X | Y | X | Y | X | Y | ||
6000 | 9036 | 6040 | :9036 | 6000 | 9037 | 6040 | 9037 | 6000 | 9038 | 6040 | 9038 | |
6001 | 9036 | 6041 | :9036 | 6001 | 9037 | 6041 | 9037 | 6001 | 9038 | 6041 | 9038 | |
6002 | 9036 | 6042 | :9036 | 6002 | 9037 | 6042 | 9037 | 6002 | 9038 | 6042 | 9038 | |
6003 | 9036 | 6043 | :9036 | 6003 | 9037 | 6043 | 9037 | 6003 | 9038 | 6043 | 9038 | |
6004 | 9036 | 6044 | :9036 | 6004 | 9037 | 6044 | 9037 | 6004 | 9038 | 6044 | 9038 | |
----7.- | L6005 | ,9036 | 6045 | :9036 | 6005 | 9037- | 6045 | 9037 | 6005 | 9038 | 6045 | 9038 |
— - - | 16006 | 9036- | 6046 | 19036 | 6006 | 9037’ | 6046 | 9037- | •6006 | 9038 | 6046 | 9038 |
6007 | 9036- | 6047 | 9036 | 6007 | 9037 | 6047 | 9037 | 6007 | 9038 | 6047 | 9038 | |
6008 | 9036 | 6048 | 9036 | 6008 | 9037 | 6048 | 9037 | 6008 | 9038 | 6048 | 9038 | |
6009 | 9036 | 6049 | 9036 | 6009 | 9037 | 6049 | 9037 | 6009 | 9038 | 6049 | 9038 | |
6010 | 9036 | 6050 | 9036 | 6010 | 9037 | 6050 | 9037 | 6010 | 9038 | 6050 | 9038 | |
6011 | 9036 | 6051 | 9036 | 6011 | 9037 | 6051 | 9037 | 6011 | 9038 | 6051 | 9038 | |
6012 | 9036 | 6052 | 9036 | 6012 | 9037 | 6052 | 9037 | 6012 | 9038 | 6052 | 9038 | |
6013 | 9036 | 6053 | 9036 | 6013 | 9037 | 6053 | 9037 | 6013 | 9038 | 6053 | 9038 | |
6014 | 9036 | 6054 | 9036 | 6014 | 9037 | 6054 | 9037 | 6014 | 9038 | 6054 | 9038 | |
6015 | 9036 | 6055 | 9036 | 6015 | 9037 | 6055 | 9037 | 6015 | 9038 | 6055 | 9038 | |
6016 | 9036 | 6056 | 9036 | 6016 | 9037 | 6056 | 9037 | 6016 | 9038 | 6056 | 9038 | |
6017 | 9036 | 6057 | 9036 | 6017 | 9037 | 6057 | 9037 | 6017 | 9038 | 6057 | 9038 | |
6018 | 9036 | 6058 | 9036 | 6018 | 9037 | 6058 | 9037 | 6018 | 9038 | 6058 | 9038 | |
6019 | 9036 | 6059 | 9036 | 6019 | 9037 | 6059 | 9037 | 6019 | 9038 | 6059 | 9038 | |
6020 | 9036 | 6060 | 9036 | 6020 | 9037 | 6060 | 9037 | 6020 | 9038 | 6060 | 9038 | |
6021 | 9036 | 6061 | 9036 | 6021 | 9037 | 6061 | 9037 | 6021 | 9038 | 6061 | 9038 | |
6022 | 9036 | 6062 | 9036 | 6022 | 9037 | 6062 | 9037 | 6022 | 9038 | 6062 | 9038 | |
6023 | 9036 | 6063 | 9036 | 6023 | 9037 | 6063 | 9037 | 6023 | 9038 | 6063 | 9038 | |
6024 | 9036 | 6064 | 9036 | 6024 | 9037 | 6064 | 9037 | 6024 | 9038 | 6064 | 9038 | |
6025 | 9036 | 6065 | 9036 | 6025 | 9037 | 6065 | 9037 | 6025 | 9038 | 6065 | 9038 | |
6026 | 9036 | 6066 | 9036 | 6026 | 9037 | 6066 | 9037 | 6026 | 9038 | 6066 | 9038 | |
6027 | 9036 | 6067 | 9036 | 6027 | 9037 | 6067 | 9037 | 6027 | 9038 | 6067 | 9038 | |
6028 | 9036 | 6068 | 9036 | 6028 | 9037 | 6068 | 9037 | 6028 | 9038 | 6068 | 9038 | |
6029 | 9036 | 6069 | 9036 | 6029 | 9037 | 6069 | 9037 | 6029 | 9038 | 6069 | 9038 | |
6030 | 9036 | 6070 | 9036 | 6030 | 9037 | 6070 | 9037 | 6030 | 9038 | 6070 | 9038 | |
6031 | 9036 | 6071 | 9036 | 6031 | 9037 | 6071 | 9037 | 6031 | 9038 | 6071 | 9038 | |
6032 | 9036 | 6072 | 9036 | 6032 | 9037 | 6072 | 9037 | 6032 | 9038 | 6072 | 9038 | |
6033 | 9036 | 6073 | 9036 | 6033 | 9037 | 6073 | 9037 | 6033 | 9038 | 6073 | 9038 | |
6034 | 9036 | 6074 | 9036 | 6034 | 9037 | 6074 | 9037 | 6034 | 9038 | 6074 | 9038 | |
6035 | 9036 | 6075 | 9036 | 6035 | 9037 | 6075 | 9037 | 6035 | 9038 | 6075 | 9038 | |
6036 | 9036 | 6076 | 9036 | 6036 | 9037 | 6076 | 9037 | 6036 | 9038 | 6076 | 9038 | |
6037 | 9036 | 6077 | 9036 | 6037 | 9037 | 6077 | 9037 | 6037 | 9038 | 6077 | 9038 | |
6038 6039 | 9036 9036 | 6078 | 9036 | 6038 6039 | 9037 9037 | 6078 | 9037 | 6038 6039 | 9038 9038 | 6078 | 9038 |
I47
X | Y | X | Y | X: Y | X | Y | X | Y | X | Y |
6000 | 9039 | 6040 | 9039 | 6000 : 9040 | 6040 | 9040 | 6000 | 9041 | 6040 | 9041 |
6001 | 9039 | 6041 | 9039 | 6001:9040 | 6041 | 9040 | 6001 | 9041 | 6041 | 9041 |
6002 | 9039 | 6042 | 9039 | 6002:9040 | 6042 | 9040 | 6002 | 9041 | 6042 | 9041 |
6003 | 9039 | 6043 | 9039 | 6003 : 9040 | 6043 | 9040 | 6003 | 9041 | 6043 | 9041 |
6004 | 9039 | 6044 | 9039 | 6004:9040 | 6044 | 9040 | 6004 | 9041 | 6044 | 9041 |
-6005 | 9039 | 6045 | 9039 | 6005 r9040 | 6045 | 9040 | 6005 | 9041 | 6045 | 9041 |
-6006 | 9039 | 6046 | 9039 | 6006 ^9040 | 6046 | 9040 | 6006 | 9011 | 6046 | 9041 |
‘6007 | 9039' | 6047 | 9039 | 6007:9040 | 6047 | 9040 | 6007 | 9041 | 6047 | 9041 |
6008 | 9039 | 6048 | 9039 | 6008:9040 | 6048 | 9040 | 6008 | 9041 | 6048 | 9041 |
6009 | 9039 | 6049 | 9039 | 6009:9040 | 6049 | 9040 | 6009 | 9041 | 6049 | 9041 |
6010 | 9039 | 6050 | 9039 | 6010 : 9040 | 6050 | 9040 | 6010 | 9041 | 6050 | 9041 |
6011 | 9039 | 6051 | 9039 | 6011:9040 | 6051 | 9040 | 6011 | 9041 | 6051 | 9041 |
6012 | 9039 | 6052 | 9039 | 6012 : 9040 | 6052 | 9040 | 6012 | 9041 | 6052 | 9041 |
6013 | 9039 | 6053 | 9039 | 6013 : 9040 | 6053 | 9010 | 6013 | 9041 | 6053 | 9041 |
6014 | 9039 | 6054 | 9039 | 6014:9040 | 6054 | 9040 | 6014 | 9041 | 6054 | 9041 |
6015 | 9039 | 6055 | 9039 | 6015:9040 | 6055 | 9040 | 6015 | 9041 | 6055 | 9041 |
6016 | 9039 | 6056 | 9039 | 6016 : 9040 | 6056 | 9040 | 6016 | 9041 | 6056 | 9041 |
6017 | 9039 | 6057 | 9039 | 6017 : 9040 | 6057 | 9040 | 6017 | 9041 | 6057 | 9041 |
6018 | 9039 | 6058 | 9039 | 6018 : 9040 | 6058 | 9040 | 6018 | 9041 | 6058 | 9041 |
6019 | 9039 | 6059 | 9039 | 6019 : 9040 | 6059 | 9040 | 6019 | 9041 | 6059 | 9011 |
6020 | 9039 | 6060 | 9039 | 6020:9040 | 6060 | 9040 | 6020 | 9041 | 6060 | 9041 |
6021 | 9039 | 6061 | 9039 | 6021:9040 | 6061 | 9040 | 6021 | 9041 | 6061 | 9041 |
6022 | 9039 | 6062 | 9039 | 6022:9040 | 6062 | 9040 | 6022 | 9041 | 6062 | 9041 |
6023 | 9039 | 6063 | 9039 | 6023:9040 | 6063 | 9040 | 6023 | 9041 | 6063 | 9041 |
6024 | 9039 | 6064 | 9039 | 6024 : 9040 | 6064 | 9040 | 6024 | 9041 | 6064 | 9041 |
6025 | 9039 | 6065 | 9039 | 6025 : 9040 | 6065 | 9040 | 6025 | 9041 | 6065 | 9041 |
6026 | 9039 | 6066 | 9039 | 6026 : 9040 | 6066 | 9040 | 6026 | 9041 | 6066 | 9041 |
6027 | 9039 | 6067 | 9039 | 6027 : 9040 | 6067 | 9040 | 6027 | 9041 | 6067 | 9041 |
6028 | 9039 | 6068 | 9039 | 6028 : 9040 | 6068 | 9040 | 6028 | 9041 | 6068 | 9041 |
6029 | 9039 | 6069 | 9039 | 6029:9040 | 6069 | 9040 | 6029 | 9041 | 6069 | 9041 |
6030 | 9039 | 6070 | 9039 | 6030:9040 | 6070 | 9040 | 6030 | 9041 | 6070 | 9041 |
6031 | 9039 | 6071 | 9039 | 6031 :9040 | 6071 | 9040 | 6031 | 9041 | 6071 | 9041 |
6032 | 9039 | 6072 | 9039 | 6032 : 9040 | 6072 | 9040 | 6032 | 9041 | 6072 | 9041 |
6033 | 9039 | 6073 | 9039 | 6033 : 9040 | 6073 | 9040 | 6033 | 9041 | 6073 | 9041 |
6034 | 9039 | 6074 | 9039 | 6034 : 9040 | 6074 | 9040 | 6034 | 9041 | 6074 | 9041 |
6035 | 9039 | 6075 | 9039 | 6035 : 9040 | 6075 | 9040 | 6035 | 9041 | 6075 | 9041 |
6036 | 9039 | 6076 | 9039 | 6036:9040 | 6076 | 9040 | 6036 | 9041 | 6076 | 9041 |
6037 | 9039 | 6077 | 9039 | 6037:9040 | 6077 | 9040 | 6037 | 9041 | 6077 | 9041 |
6038 | 9039 | 6078 | 9039 | 6038:9040 | 6078 | 9040 | 6038 | 9041 | 6078 | 9041 |
6039 | 9039 | 6039 : 9040 | 6039 | 9041 |
148
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9042 | 6040 | 9042 | 6000 | 9043 | 6040 | 9043 | 6000 | 9044 | 6040 | 9044 |
6001 | 9042 | 6041 | 9042 | 6001 | 9043 | 6041 | 9043 | 6001 | 9044 | 6041 | 9044 |
6002 | 9042 | 6042 | 9042 | 6002 | 9043 | 6042 | 9043 | 6002 | 9044 | 6042 | 9044 |
6003 | 9042 | 6043 | 9042 | 6003 | 9043 | 6043 | 9043 | 6003 | 9044 | 6043 | 9044 |
6004 | 9042 | 6044 | 9042 | 6001 | 9043 | 6044 | 9043 | 6004 | 9044 | 6044 | 9044 |
6005 | 9042. | 6045 | 9042 | 6005 | 9043 | 6045 | 9043 | .6005 | .9044 | 6045 | 9044 |
•6006 | 9042- | -6046 | 9042 | 6006 | 9043 | 6046 | 9043 | 6006 | 9044 | 6046 | 9044 |
6007 | 9042 | 6047 | 9042 | 6007 | 9043 | 6047 | 9043 | 6007 | 9044 | 6047 | 9044 |
6008 | 9042 | 6048 | 9042 | 6008 | 9043 | 6048 | 9043 | 6008 | 9044 | 6048 | 9044 |
6009 | 9042 | 6049 | 9042 | 6009 | 9043 | 6049 | 9043 | 6009 | 9044 | 6049 | 9044 |
6010 | 9042 | 6050 | 9042 | 6010 | 9043 | 6050 | 9043 | 6010 | 9044 | 6050 | 9044 |
6011 | 9042 | 605! | 9042 | 6011 | 9043 | 6051 | 9043 | 6011 | 9044 | 6051 | 9044 |
6012 | 9042 | 6052 | 9042 | 6012 | 9043 | 6052 | 9043 | 6012 | 9044 | 6052 | 9044 |
6013 | 9042 | 6053 | 9042 | 6013 | 9043 | 6053 | 9043 | 6013 | 9044 | 6053 | 9044 |
6014 | 9042 | 6054 | 9042 | 6014 | 9043 | 6054 | 9043 | 6014 | 9044 | 6054 | 9044 |
6015 | 9042 | 6055 | 9042 | 6015 | 9043 | 6055 | 9043 | 6015 | 9044 | 6055 | 9044 |
6016 | 9042 | 6056 | 9042 | 6016 | 9043 | 6056 | 9043 | 6016 | 9044 | 6056 | 9044 |
6017 | 9042 | 6057 | 9042 | 6017 | 9043 | 6057 | 9043 | 6017 | 9044 | 6057 | 9044 |
6018 | 9042 | 6058 | 9042 | 6018 | 9043 | 6058 | 9043 | 6018 | 9044 | 6058 | 9044 |
6019 | 9042 | 6059 | 9042 | 6019 | 9043 | 6059 | 9043 | 6019 | 9044 | 6059 | 9044 |
6020 | 9042 | 6060 | 9042 | 6020 | 9043 | 6060 | 9043 | 6020 | 9044 | 6060 | 9044 |
6021 | 9042 | 6061 | 9042 | 6021 | 9043 | 6061 | 9043 | 6021 | 9044 | 6061 | 9044 |
6022 | 9042 | 6062 | 9042 | 6022 | 9043 | 6062 | 9043 | 6022 | 9044 | 6062 | 9014 |
6023 | 9042 | 6063 | 9042 | 6023 | 9043 | 6063 | 9043 | 6023 | 9044 | 6063 | 9044 |
6024 | 9042 | 6064 | 9042 | 6024 | 9043 | 6064 | 9043 | 6024 | 9044 | 6064 | 9044 |
6025 | 9042 | 6065 | 9042 | 6025 | 9043 | 6065 | 9043 | 6025 | 9044 | 6065 | 9044 |
6026 | 9042 | 6066 | 9042 | 6026 | 9043 | 6066 | 9043 | 6026 | 9044 | 6066 | 9044 |
6027 | 9042 | 6067 | 9042 | 6027 | 9043 | 6067 | 9043 | 6027 | 9044 | 6067 | 9044 |
6028 | 9042 | 6068 | 9042 | 6028 | 9043 | 6068 | 9043 | 6028 | 9044 | 6068 | 9044 |
6029 | 9042 | 6069 | 9042 | 6029 | 9043 | 6069 | 9043 | 6029 | 9044 | 6069 | 9044 |
6030 | 9042 | 6070 | 9042 | 6030 | 9043 | 6070 | 9043 | 6030 | 9044 | 6070 | 9044 |
6031 | 9042 | 6071 | 9042 | 6031 | 9043 | 6071 | 9043 | 6031 | 9044 | 6071 | 9044 |
6032 | 9042 | 6072 | 9042 | 6032 | 9043 | 6072 | 9043 | 6032 | 9044 | 6072 | 9044 |
6033 | 9042 | 6073 | 9042 | 6033 | 9043 | 6073 | 9043 | 6033 | 9044 | 6073 | 9044 |
6034 | 9042 | 6074 | 9042 | 6034 | 9043 | 6074 | 9043 | 6034 | 9044 | 6074 | 9044 |
6035 | 9042 | 6075 | 9042 | 6035 | 9043 | 6075 | 9043 | 6035 | 9044 | 6075 | 9044 |
6036 | 9042 | 6076 | 9042 | 6036 | 9043 | 6076 | 9043 | 6036 | 9044 | 6076 | 9044 |
6037 | 9042 | 6077 | 9042 | 6037 | 9043 | 6077 | 9043 | 6037 | 9044 | 6077 | 9044 |
6038 | 9042 | 6078 | 9042 | 6038 | 9043 | 6078 | 9043 | 6038 | 9044 | 6078 | 9044 |
6039 | 9042 | 6039 | 9043 | 6039 | 9044 |
I49
X | Y | X:Y | X: | Y | X | Y | X:Y | X | Y | |
6000 | 9045 | 6040 : 9045 | 6000: | 9046 | 6040 | 9046 | 6000 | :9047 | 6040 | 9047 |
6001 | 9045 | 6041 :9045 | 6001 : | 9046 | 6041 | 9046 | 6001 | :9047 | 6041 | 9047 |
6002 | 9045 | 6042:9045 | 6002: | 9046 | 6042 | 9046 | 6002 | :9047 | 6042 | 9047 |
6003 | 9045 | 6043:9045 | 6003: | 9046 | 6043 | 9046 | 6003 | :9047 | 6043 | 9047 |
6004 | 9045 | 6044 : 9045 | 6004: | 9046 | 6044 | 9046 | 6004 | :9047 | 6044 | 9047 |
-6005 | 9045-. | 6045:9045 | 6005:9046 | 6045 | 9046 | 6005. | :9047 | 6045 | 9047 | |
-6006 | 9045- | 6046*9045 | 6006- | 9046- | 6046 | .9046 | 6006 | 9047 | 6046 | 9047 |
6007 | 9045 | 6047 : 9045 | 6007 | 9046 | 6047 | 9046 | 6007 | 9047 | 6047 | 9047 |
6008 | 9045 | 6048:9045 | 6008 | 9046 | 6048 | 9046 | 6008 | 9047 | 6048 | 9047 |
6009 | 9045 | 6049:9045 | 6009 | 9046 | 6049 | 9046 | 6009 | 9047 | 6049 | 9047 |
6010 | 9045 | 6050:9045 | 6010 | 9046 | 6050 | 9046 | 6010 | 9047 | 6050 | 9047 |
6011 | 9045 | 6051:9045 | 6011 | 9046 | 6051 | 9046 | 6011 | 9047 | 6051 | 9047 |
6012 | 9045 | 6052:9045 | 6012 | 9046 | 6052 | 9046 | 6012 | 9047 | 6052 | 9047 |
6013 | 9045 | 6053 : 9045 | 6013 | 9046 | 6053 | 9046 | 6013 | 9047 | 6053 | 9047 |
6014 | 9045 | 6054:9045 | 6014 | 9046 | 6054 | 9046 | 6014 | 9047 | 6054 | 9047 |
6015 | 9045 | 6055:9045 | 6015 | 9046 | 6055 | 9046 | 6015 | 9047 | 6055 | 9047 |
6016 | 9045 | 6056 : 9045 | 6016 | 9046 | 6056 | 9046 | 6016 | 9047 | 6056 | 9047 |
6017 | 9045 | 6057 : 9045 | 6017 | 9046 | 6057 | 9046 | 6017 | 9047 | 6057 | 9047 |
6018 | 9045 | 6058:9045 | 6018 | 9046 | 6058 | 9046 | 6018 | 9047 | 6058 | 9047 |
6019 | 9045 | 6059:9045 | 6019 | 9046 | 6059 | 9046 | 6019 | 9047 | 6059 | 9047 |
6020 | 9045 | 6060 : 9045 | 6020 | 9046 | 6060 | 9046 | 6020 | 9047 | 6060 | 9047 |
6021 | 9045 | 6061:9045 | 6021 | 9046 | 6061 | 9046 | 6021 | 9047 | 6061 | 9047 |
6022 | 9045 | 6062:9045 | 6022 | 9046 | 6062 | 9046 | 6022 | 9047 | 6062 | 9047 |
6023 | 9045 | 6063 : 9045 | 6023 | 9046 | 6063 | 9046 | 6023 | 9047 | 6063 | 9047 |
6024 | 9045 | 6064:9045 | 6024 | 9046 | 6064 | 9046 | 6024 | 9047 | 6064 | 9047 |
6025 | 9045 | 6065:9045 | 6025 | 9046 | 6065 | 9046 | 6025 | 9047 | 6065 | 9047 |
6026 | 9045 | 6066:9045 | 6026 | 9046 | 6066 | 9046 | 6026 | 9047 | 6066 | 9047 |
6027 | 9045 | 6067:9045 | 6027 | 9046 | 6067 | 9046 | 6027 | 9047 | 6067 | 9047 |
6028 | 9045 | 6068 : 9045 | 6028 | 9046 | 6068 | 9046 | 6028 | 9047 | 6068 | 9047 |
6029 | 9045 | 6069:9045 | 6029 | 9046 | 6069 | 9046 | 6029 | 9047 | 6069 | 9047 |
6030 | 9045 | 6070:9045 | 6030 | 9046 | 6070 | 9046 | 6030 | 9047 | 6070 | 9047 |
6031 | 9045 | 6071:9045 | 6031 | 9046 | 6071 | 9046 | 6031 | 9047 | 6071 | 9047 |
6032 | 9045 | 6072:9045 | 6032 | 9046 | 6072 | 9046 | 6032 | 9047 | 6072 | 9047 |
6033 | 9045 | 6073 : 9045 | 6033 | 9046 | 6073 | 9046 | 6033 | 9047 | 6073 | 9047 |
6034 | 9045 | 6074:9045 | 6034 | 9046 | 6074 | 9046 | 6034 | 9047 | 6074 | 9047 |
6035 | 9045 | 6075 : 9045 | 6035 | 9046 | 6075 | 9046 | 6035 | 9047 | 6075 | 9047 |
6036 | 9045 | 6076:9045 | 6036 | 9046 | 6076 | 9046 | 6036 | 9047 | 6076 | 9047 |
6037 | 9045 | 6077 : 9045 | 6037 | 9046 | 6077 | 9046 | 6037 | 9047 | 6077 | 9047 |
6038 | 9045 | 6078:9045 | 6038 | 9046 | 6078 | 9046 | 6038 | 9047 | 6078 | 9047 |
6039 | 9045 | 6039 | 9046 | 6039 | 9047 |
150
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | X | Y | X | Y | |
6000:9048 | 6040 : 9048 | 6000:9049 | 6040:9049 | 6000 | 9050 | 6040 | 9050 | |
6001:9048 | 6041:9048 | 6001:9049 | 6041:9049 | 6001 | 9050 | 6041 | 9050 | |
6002:9048 | 6042 : 9048 | 6002:9049 | 6042:9049 | 6002 | 9050 | 6042 | 9050 | |
6003:9048 | 6043 : 9048 | 6003:9049 | 6043 : 9049 | 6003 | 9050 | 6043 | 9050 | |
6004:9048 | 6044:9048 | 6004 : 9049 | 6044 : 9049 | 6004 | 9050 | 6044 | 9050 | |
--- . . | 6005:9048- | 6045.-9048 | 6005:9049 | 6045:9049 | -6005 | 9050 | 6045 | 9050 |
- | -6006:9048- | 6046:9048 | 6006:9049 | 6046:9049 | 6006 | 9050 | 6046 | 9050 |
6007:9048 | 6047:9048 | 6007': 9049 | 6047:9049 | ‘6007 | 9050 | 6047 | 9050 | |
6008:9048 | 6048:9048 | 6008:9049 | 6048 : 9049 | 6008 | 9050 | 6048 | 9050 | |
6009:9048 | 6049 : 9048 | 6009 : 9049 | 6049 : 9049 | 6009 | 9050 | 6049 | 9050 | |
6010:9048 | 6050 : 9048 | 6010 : 9049 | 6050:9049 | 6010 | 9050 | 6050 | 9050 | |
6011:9048 | 6051:9048 | 6011:9049 | 6051:9049 | 6011 | 9050 | 6051 | 9050 | |
6012:9048 | 6052:9048 | 6012:9049 | 6052 : 9049 | 6012 | 9050 | 6052 | 9050 | |
6013:9048 | 6053:9048 | 6013 : 9049 | 6053:9049 | 6013 | 9050 | 6053 | 9050 | |
6014 : 9048 | 6054:9048 | 6014:9049 | 6054:9049 | 6014 | 9050 | 6054 | 9050 | |
6015:9048 | 6055:9048 | 6015 : 9049 | 6055:9049 | 6015 | 9050 | 6055 | 9050 | |
6016 : 9048 | 6056 : 9048 | 6016:9049 | 6056 : 9049 | 6016 | 9050 | 6056 | 9050 | |
6017 : 9048 | 6057 : 9048 | 6017 : 9049 | 6057 : 9049 | 6017 | 9050 | 6057 | 9050 | |
6018 : 9048 | 6058:9048 | 6018:9049 | 6058 : 9049 | 6018 | 9050 | 6058 | 9050 | |
6019 : 9048 | 6059:9048 | 6019:9049 | 6059 : 9049 | 6019 | 9050 | 6059 | 9050 | |
6020:9048 | 6060:9048 | 6020:9049 | 6060:9049 | 6020 | 9050 | 6060 | 9050 | |
6021:9048 | 6061:9048 | 6021:9049 | 6061:9049 | 6021 | 9050 | 6061 | 9050 | |
6022:9048 | 6062:9048 | 6022 : 9049 | 6062 : 9049 | 6022 | 9050 | 6062 | 9050 | |
6023:9048 | 6063 : 9048 | 6023:9049 | 6063:9049 | 6023 | 9050 | 6063 | 9050 | |
6024 : 9048 | 6064 : 9048 | 6024 : 9049 | 6064:9049 | 6024 | 9050 | 6064 | 9050 | |
6025:9048 | 6065:9048 | 6025:9049 | 6065 : 9049 | 6025 | 9050 | 6065 | 9050 | |
6026:9048 | 6066:9048 | 6026:9049 | 6066 : 9049 | 6026 | 9050 | 6066 | 9050 | |
6027:9048 | 6067 : 9048 | 6027:9049 | 6067 : 9049 | 6027 | 9050 | 6067 | 9050 | |
6028:9048 | 6068 : 9048 | 6028:9049 | 6068 : 9049 | 6028 | 9050 | 6068 | 9050 | |
6029:9048 | 6069:9048 | 6029 : 9049 | 6069:9049 | 6029 | 9050 | 6069 | 9050 | |
6030:9048 | 6070:9048 | 6030 : 9049 | 6070:9049 | 6030 | 9050 | 6070 | 9050 | |
6031:9048 | 6071:9048 | 6031:9049 | 6071:9049 | 6031 | 9050 | 6071 | 9050 | |
6032:9048 | 6072 : 9048 | 6032 : 9049 | 6072 : 9049 | 6032 | 9050 | 6072 | 9050 | |
6033:9048 | 6073:9048 | 6033 : 9049 | 6073:9049 | 6033 | 9050 | 6073 | 9050 | |
6034:9048 | 6074 : 9048 | 6034 : 9049 | 6074 : 9049 | 6034 | 9050 | 6074 | 9050 | |
6035:9048 | 6075:9048 | 6035:9049 | 6075:9049 | 6035 | 9050 | 6075 | 9050 | |
6036:9048 | 6076 : 9048 | 6036 : 9049 | 6076 : 9049 | 6036 | 9050 | 6076 | 9050 | |
6037:9048 | 6077 : 9048 | 6037 : 9049 | 6077 : 9049 | 6037 | 9050 | 6077 | 9050 | |
6038:9048 | 6078:9048 | 6038 : 9049 | 6078:9049 | 6038 | 9050 | 6078 | 9050 | |
6039:9048 | 6039:9049 | 6039 | 9050 |
151
X | Y | X | Y | X | :Y | X | Y | X | Y | X | Y |
6000 | 9051 | 6040 | 9051 | 6000 | :9052 | 6040 | 9052 | 6000 | 9053 | 6040 | 9053 |
6001 | 9051 | 6041 | 9051 | 6001 | :9052 | 6041 | 9052 | 6001 | 9053 | 6041 | 9053 |
6002 | 9051 | 6042 | 9051 | 6002 | 9052 | 6042 | 9052 | 6002 | 9053 | 6042 | 9053 |
6003 | 9051 | 6043 | 9051 | 6003 | :9052 | 6043 | 9052 | 6003 | 9053 | 6043 | 9053 |
6004 | 9051 | 6044 | 9051 | 6004 | :9052 | 6044 | 9052 | 6004 | 9053 | 6044 | 9053 |
:6005 | 9051/ | 6045 | :9051 | -6005’ | :9052 | 6045 | 9052 | 6005 | .9053 | 6045 | 9053 |
-6006 | 9051- | 6046 | 9051* | 6006’ | :9052 | 6046 | .9052 | .6006 | 9053- | 6046 | 9053 |
6007 | 9051 | 6047 | 9051 | 6007 | 9052 | 6047 | 9052 | 6007 | 9053- | 6047 | 9053 |
6008 | 9051 | 6048 | 9051 | 6008 | 9052 | 6048 | 9052 | 6008 | 9053 | 6048 | 9053 |
6009 | 9051 | 6049 | 9051 | 6009 | 9052 | 6049 | 9052 | 6009 | 9053 | 6049 | 9053 |
6010 | 9051 | 6050 | 9051 | 6010 | 9052 | 6050 | 9052 | 6010 | 9053 | 6050 | 9053 |
6011 | 9051 | 6051 | 9051 | 6011 | 9052 | 6051 | 9052 | 6011 | 9053 | 6051 | 9053 |
6012 | 9051 | 6052 | 9051 | 6012 | 9052 | 6052 | 9052 | 6012 | 9053 | 6052 | 9053 |
6013 | 9051 | 6053 | 9051 | 6013 | 9052 | 6053 | 9052 | 6013 | 9053 | 6053 | 9053 |
6014 | 9051 | 6054 | 9051 | 6014 | 9052 | 6054 | 9052 | 6014 | 9053 | 6054 | 9053 |
6015 | 9051 | 6055 | 9051 | 6015 | 9052 | 6055 | 9052 | 6015 | 9053 | 6055 | 9053 |
6016 | 9051 | 6056 | 9051 | 6016 | 9052 | 6056 | 9052 | 6016 | 9053 | 6056 | 9053 |
6017 | 9051 | 6057 | 9051 | 6017 | 9052 | 6057 | 9052 | 6017 | 9053 | 6057 | 9053 |
6018 | 9051 | 6058 | 9051 | 6018 | 9052 | 6058 | 9052 | 6018 | 9053 | 6058 | 9053 |
6019 | 9051 | 6059 | 9051 | 6019 | 9052 | 6059 | 9052 | 6019 | 9053 | 6059 | 9053 |
6020 | 9051 | 6060 | 9051 | 6020 | 9052 | 6060 | 9052 | 6020 | 9053 | 6060 | 9053 |
6021 | 9051 | 6061 | 9051 | 6021 | 9052 | 6061 | 9052 | 6021 | 9053 | 6061 | 9053 |
6022 | 9051 | 6062 | 9051 | 6022 | 9052 | 6062 | 9052 | 6022 | 9053 | 6062 | 9053 |
6023 | 9051 | 6063 | 9051 | 6023 | 9052 | 6063 | 9052 | 6023 | 9053 | 6063 | 9053 |
6024 | 9051 | 6064 | 9051 | 6024 | 9052 | 6064 | 9052 | 6024 | 9053 | 6064 | 9053 |
6025 | 9051 | 6065 | 9051 | 6025 | 9052 | 6065 | 9052 | 6025 | 9053 | 6065 | 9053 |
6026 | 9051 | 6066 | 9051 | 6026 | 9052 | 6066 | 9052 | 6026 | 9053 | 6066 | 9053 |
6027 | 9051 | 6067 | 9051 | 6027 | 9052 | 6067 | 9052 | 6027 | 9053 | 6067 | 9053 |
6028 | 9051 | 6068 | 9051 | 6028 | 9052 | 6068 | 9052 | 6028 | 9053 | 6068 | 9053 |
6029 | 9051 | 6069 | 9051 | 6029 | 9052 | 6069 | 9052 | 6029 | 9053 | 6069 | 9053 |
6030 | 9051 | 6070 | 9051 | 6030 | 9052 | 6070 | 9052 | 6030 | 9053 | 6070 | 9053 |
6031 | 9051 | 6071 | 9051 | 6031 | 9052 | 6071 | 9052 | 6031 | 9053 | 6071 | 9053 |
6032 | 9051 | 6072 | 9051 | 6032 | 9052 | 6072 | 9052 | 6032 | 9053 | 6072 | 9053 |
6033 | 9051 | 6073 | 9051 | 6033 | 9052 | 6073 | 9052 | 6033 | 9053 | 6073 | 9053 |
6034 | 9051 | 6074 | 9051 | 6034 | 9052 | 6074 | 9052 | 6034 | 9053 | 6074 | 9053 |
6035 | 9051 | 6075 | 9051 | 6035 | 9052 | 6075 | 9052 | 6035 | 9053 | 6075 | 9053 |
6036 | 9051 | 6076 | 9051 | 6036 | 9052 | 6076 | 9052 | 6036 | 9053 | 6076 | 9053 |
6037 | 9051 | 6077 | 9051 | 6037 | 9052 | 6077 | 9052 | 6037 | 9053 | 6077 | 9053 |
6038 | 9051 | 6078 | 9051 | 6038 | 9052 | 6078 | 9052 | 6038 | 9053 | 6078 | 9053 |
6039 | 9051 | 6039 | 9052 | 6039 | 9053 |
152
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9054 | 6040 | 9054 | 6000 | 9055 | 6040 | 9055 | 6000 | 9056 | 6040 | 9056 |
6001 | 9054 | 6041 | 9054 | 6001 | 9055 | 6041 | 9055 | 6001 | 9056 | 6041 | 9056 |
6002 | 9054 | 6042 | 9054 | 6002 | 9055 | 6042 | 9055 | 6002 | 9056 | 6042 | 9056 |
6003 | 9054 | 6043 | 9054 | 6003 | 9055 | 6043 | 9055 | 6003 | 9056 | 6043 | 9056 |
6004 | 9054 | 6044 | 9054 | 6004 | 9055 | 6044 | 9055 | 6004 | 9056 | 6044 | 9056 |
6005 | 9054- | 6045. | -9054 | 6005 | 9055. | 6045 | 9055 | 6005 | 9056 | 6045 | 9056 |
-6006 | 9054- | 6046 | ^9054 | 6006 | -9055- | 6046 | 9055 | 6006 | .9056 | 6046 | 9056 |
6007 | 9054 | 6047 | 9054 | 6007 | 9055 | 6047 | 9055 | 6007 | 9056 | 6047 | 9056 |
6008 | 9054 | 6048 | 9054 | 6008 | 9055 | 6048 | 9055 | 6008 | 9056 | 6048 | 9056 |
6009 | 9054 | 6049 | 9054 | 6009 | 9055 | 6049 | 9055 | 6009 | 9056 | 6049 | 9056 |
6010 | 9054 | 6050 | 9054 | 6010 | 9055 | 6050 | 9055 | 6010 | 9056 | 6050 | 9056 |
6011 | 9054 | 6051 | 9054 | 6011 | 9055 | 6051 | 9055 | 6011 | 9056 | 6051 | 9056 |
6012 | 9054 | 6052 | 9054 | 6012 | 9055 | 6052 | 9055 | 6012 | 9056 | 6052 | 9056 |
6013 | 9054 | 6053 | 9054 | 6013 | 9055 | 6053 | 9055 | 6013 | 9056 | 6053 | 9056 |
6014 | 9054 | 6054 | 9054 | 6014 | 9055 | 6054 | 9055 | 6014 | 9056 | 6054 | 9056 |
6015 | 9054 | 6055 | 9054 | 6015 | 9055 | 6055 | 9055 | 6015 | 9056 | 6055 | 9056 |
6016 | 9054 | 6056 | 9054 | 6016 | 9055 | 6056 | 9055 | 6016 | 9056 | 6056 | 9056 |
6017 | 9054 | 6057 | 9054 | 6017 | 9055 | 6057 | 9055 | 6017 | 9056 | 6057 | 9056 |
6018 | 9054 | 6058 | 9054 | 6018 | 9055 | 6058 | 9055 | 6018 | 9056 | 6058 | 9056 |
6019 | 9054 | 6059 | 9054 | 6019 | 9055 | 6059 | 9055 | 6019 | 9056 | 6059 | 9056 |
6020 | 9054 | 6060 | 9054 | 6020 | 9055 | 6060 | 9055 | 6020 | 9056 | 6060 | 9056 |
6021 | 9054 | 6061 | 9054 | 6021 | 9055 | 6061 | 9055 | 6021 | 9056 | 6061 | 9056 |
6022 | 9054 | 6062 | 9054 | 6022 | 9055 | 6062 | 9055 | 6022 | 9056 | 6062 | 9056 |
6023 | 9054 | 6063 | 9054 | 6023 | 9055 | 6063 | 9055 | 6023 | 9056 | 6063 | 9056 |
6024 | 9054 | 6064 | 9054 | 6024 | 9055 | 6064 | 9055 | 6024 | 9056 | 6064 | 9056 |
6025 | 9054 | 6065 | 9054 | 6025 | 9055 | 6065 | 9055 | 6025 | 9056 | 6065 | 9056 |
6026 | 9054 | 6066 | 9054 | 6026 | 9055 | 6066 | 9055 | 6026 | 9056 | 6066 | 9056 |
6027 | 9054 | 6067 | 9054 | 6027 | 9055 | 6067 | 9055 | 6027 | 9056 | 6067 | 9056 |
6028 | 9054 | 6068 | 9054 | 6028 | 9055 | 6068 | 9055 | 6028 | 9056 | 6068 | 9056 |
6029 | 9054 | 6069 | 9054 | 6029 | 9055 | 6069 | 9055 | 6029 | 9056 | 6069 | 9056 |
6030 | 9054 | 6070 | 9054 | 6030 | 9055 | 6070 | 9055 | 6030 | 9056 | 6070 | 9056 |
6031 | 9054 | 6071 | 9054 | 6031 | 9055 | 6071 | 9055 | 6031 | 9056 | 6071 | 9056 |
6032 | 9054 | 6072 | 9054 | 6032 | 9055 | 6072 | 9055 | 6032 | 9056 | 6072 | 9056 |
6033 | 9054 | 6073 | 9054 | 6033 | 9055 | 6073 | 9055 | 6033 | 9056 | 6073 | 9056 |
6034 | 9054 | 6074 | 9054 | 6034 | 9055 | 6074 | 9055 | 6034 | 9056 | 6074 | 9056 |
6035 | 9054 | 6075 | 9054 | 6035 | 9055 | 6075 | 9055 | 6035 | 9056 | 6075 | 9056 |
6036 | 9054 | 6076 | 9054 | 6036 | 9055 | 6076 | 9055 | 6036 | 9056 | 6076 | 9056 |
6037 | 9054 | 6077 | 9054 | 6037 | 9055 | 6077 | 9055 | 6037 | 9056 | 6077 | 9056 |
6038 | 9054 | 6078 | 9054 | 6038 | 9055 | 6078 | 9055 | 6038 | 9056 | 6078 | 9056 |
6039 | 9054 | 6039 | 9055 | 6039 | 9056 |
133
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9057 | 6040 | 9057 | 6000 | 9058 | 6040 | 9058 | 6000 | 9059 | 6040 | 9059 |
6001 | 9057 | 6041 | 9057 | 6001 | 9058 | 6041 | 9058 | 6001 | 9059 | 6041 | 9059 |
6002 | 9057 | 6042 | 9057 | 6002 | 9058 | 6042 | 9058 | 6002 | 9059 | 6042 | 9059 |
6003 | 9057 | 6043 | 9057 | 6003 | 9058 | 6043 | 9058 | 6003 | 9059 | 6043 | 9059 |
6004 | 9057 | 6044 | 9057 | 6004 | 9058 | 6044 | 9058 | 6004 | 9059 | 6044 | 9059 |
-6005 | 9057- | 6045J | -9057 | 6005- | 9058- | 6045 | 9058 | 6005 | 9059 | 6045 | 9059 |
:6006 | .9057- | 6046-' | 19057 | -6006i 9058- | 6046-t9058- | 6006 | 9059- | 6046 | 9059 | ||
'6007 | '9057 | 6047' | 9057 | 6007 | 9058 | 6047 | 9058 | 6007 | 9059 | 6047 | 9059 |
6008 | 9057 | 6048 | 9057 | 6008 | 9058 | 6048 | 9058 | 6008 | 9059 | 6048 | 9059 |
6009 | 9057 | 6049 | 9057 | 6009 | 9058 | 6049 | 9058 | 6009 | 9059 | 6049 | 9059 |
6010 | 9057 | 6050 | 9057 | 6010 | 9058 | 6050 | 9058 | 6010 | 9059 | 6050 | 9059 |
6011 | 9057 | 6051 | 9057 | 6011 | 9058 | 6051 | 9058 | 6011 | 9059 | 6051 | 9059 |
6012 | 9057 | 6052 | 9057 | 6012 | 9058 | 6052 | 9058 | 6012 | 9059 | 6052 | 9059 |
6013 | 9057 | 6053 | 9057 | 6013 | 9058 | 6053 | 9058 | 6013 | 9059 | 6053 | 9059 |
6014 | 9057 | 6054 | 9057 | 6014 | 9058 | 6054 | 9058 | 6014 | 9059 | 6054 | 9059 |
6015 | 9057 | 6055 | 9057 | 6015 | 9058 | 6055 | 9058 | 6015 | 9059 | 6055 | 9059 |
6016 | 9057 | 6056 | 9057 | 6016 | 9058 | 6056 | 9058 | 6016 | 9059 | 6056 | 9059 |
6017 | 9057 | 6057 | 9057 | 6017 | 9058 | 6057 | 9058 | 6017 | 9059 | 6057 | 9059 |
6018 | 9057 | 6058 | 9057 | 6018 | 9058 | 6058 | 9058 | 6018 | 9059 | 6058 | 9059 |
6019 | 9057 | 6059 | 9057 | 6019 | 9058 | 6059 | 9058 | 6019 | 9059 | 6059 | 9059 |
6020 | 9057 | 6060 | 9057 | 6020 | 9058 | 6060 | 9058 | 6020 | 9059 | 6060 | 9059 |
6021 | 9057 | 6061 | 9057 | 6021 | 9058 | 6061 | 9058 | 6021 | 9059 | 6061 | 9059 |
6022 | 9057 | 6062 | 9057 | 6022 | 9058 | 6062 | 9058 | 6022 | 9059 | 6062 | 9059 |
6023 | 9057 | 6063 | 9057 | 6023 | 9058 | 6063 | 9058 | 6023 | 9059 | 6063 | 9059 |
6024 | 9057 | 6064 | 9057 | 6024 | 9058 | 6064 | 9058 | 6024 | 9059 | 6064 | 9059 |
6025 | 9057 | 6065 | 9057 | 6025 | 9058 | 6065 | 9058 | 6025 | 9059 | 6065 | 9059 |
6026 | 9057 | 6066 | 9057 | 6026 | 9058 | 6066 | 9058 | 6026 | 9059 | 6066 | 9059 |
6027 | 9057 | 6067 | 9057 | 6027 | 9058 | 6067 | 9058 | 6027 | 9059 | 6067 | 9059 |
6028 | 9057 | 6068 | 9057 | 6028 | 9058 | 6068 | 9058 | 6028 | 9059 | 6068 | 9059 |
6029 | 9057 | 6069 | 9057 | 6029 | 9058 | 6069 | 9058 | 6029 | 9059 | 6069 | 9059 |
6030 | 9057 | 6070 | 9057 | 6030 | 9058 | 6070 | 9058 | 6030 | 9059 | 6070 | 9059 |
6031 | 9057 | 6071 | 9057 | 6031 | 9058 | 6071 | 9058 | 6031 | 9059 | 6071 | 9059 |
6032 | 9057 | 6072 | 9057 | 6032 | 9058 | 6072 | 9058 | 6032 | 9059 | 6072 | 9059 |
6033 | 9057 | 6073 | 9057 | 6033 | 9058 | 6073 | 9058 | 6033 | 9059 | 6073 | 9059 |
6034 | 9057 | 6074 | 9057 | 6034 | 9058 | 6074 | 9058 | 6034 | 9059 | 6074 | 9059 |
6035 | 9057 | 6075 | 9057 | 6035 | 9058 | 6075 | 9058 | 6035 | 9059 | 6075 | 9059 |
6036 | 9057 | 6076 | 9057 | 6036 | 9058 | 6076 | 9058 | 6036 | 9059 | 6076 | 9059 |
6037 | 9057 | 6077 | 9057 | 6037 | 9058 | 6077 | 9058 | 6037 | 9059 | 6077 | 9059 |
6038 | 9057 | 6078 | 9057 | 6038 | 9058 | 6078 | 9058 | 6038 | 9059 | 6078 | 9059 |
6039 | 9057 | 6039 | 9058 | 6039 | 9059 |
154
X | Y | X | Y | X | Y | X: Y | X | Y | X | Y | |
6000 | 9060 | 6040 | 9060 | 6000 | 9061 | 6040 : 9061 | 6000 | 9062 | 6040 | 9062 | |
6001 | 9060 | 6041 | 9060 | 6001 | 9061 | 6041:9061 | 6001 | 9062 | 6041 | 9062 | |
6002 | 9060 | 6042 | 9060 | 6002 | 9061 | 6042:9061 | 6002 | 9062 | 6042 | 9062 | |
6003 | 9060 | 6043 | 9060 | 6003 | 9061 | 6043 : 9061 | 6003 | 9062 | 6043 | 9062 | |
__ | 6004 | 9060 | 6044 | 9060 | 6004 | 9061 | 6044 : 9061 | 6004 | 9062 | 6044 | 9062 |
—ï - | 16005 | 9060- | 6045 | 9060 | 6005 | 9061- | 6045^9061 | 6005 | 9062' | 6045 | 9062 |
-6006 | 9060- | 6046 | -9060 | 6006 | 9061- | 6046:9061- | 6006 | 9062 | 6046 | 9062 | |
- — - | 6007 | '9060 | 6047 | 9060 | 6007 | 9061 | 6047:9061 | 6007 | 9062 | 6047 | 9062 |
6008 | 9060 | 6048 | 9060 | 6008 | 9061 | 6048 : 9061 | 6008 | 9062 | 6048 | 9062 | |
6009 | 9060 | 6049 | 9060 | 6009 | 9061 | 6049 : 9061 | 6009 | 9062 | 6049 | 9062 | |
6010 | 9060 | 6050 | 9060 | 6010 | 9061 | 6050:9061 | 6010 | 9062 | 6050 | 9062 | |
6011 | 9060 | 6051 | 9060 | 6011 | 9061 | 6051:9061 | 6011 | 9062 | 6051 | 9062 | |
6012 | 9060 | 6052 | 9060 | 6012 | 9061 | 6052:9061 | 6012 | 9062 | 6052 | 9062 | |
6013 | 9060 | 6053 | 9060 | 6013 | 9061 | 6053 : 9061 | 6013 | 9062 | 6053 | 9062 | |
6014 | 9060 | 6054 | 9060 | 6014 | 9061 | 6054 : 9061 | 6014 | 9062 | 6054 | 9062 | |
6015 | 9060 | 6055 | 9060 | 6015 | 9061 | 6055 : 9061 | 6015 | 9062 | 6055 | 9062 | |
6016 | 9060 | 6056 | 9060 | 6016 | 9061 | 6056 : 9061 | 6016 | 9062 | 6056 | 9062 | |
6017 | 9060 | 6057 | 9060 | 6017 | 9061 | 6057 : 9061 | 6017 | 9062 | 6057 | 9062 | |
6018 | 9060 | 6058 | 9060 | 6018 | 9061 | 6058:9061 | 6018 | 9062 | 6058 | 9062 | |
6019 | 9060 | 6059 | 9060 | 6019 | 9061 | 6059:9061 | 6019 | 9062 | 6059 | 9062 | |
6020 | 9060 | 6060 | 9060 | 6020 | 9061 | 6060:9061 | 6020 | 9062 | 6060 | 9062 | |
6021 | 9060 | 6061 | 9060 | 6021 | 9061 | 6061:9061 | 6021 | 9062 | 6061 | 9062 | |
6022 | 9060 | 6062 | 9060 | 6022 | 9061 | 6062:9061 | 6022 | 9062 | 6062 | 9062 | |
6023 | 9060 | 6063 | 9060 | 6023 | 9061 | 6063 : 9061 | 6023 | 9062 | 6063 | 9062 | |
6024 | 9060 | 6064 | 9060 | 6024 | 9061 | 6064:9061 | 6024 | 9062 | 6064 | 9062 | |
6025 | 9060 | 6065 | 9060 | 6025 | 9061 | 6065 : 9061 | 6025 | 9062 | 6065 | 9062 | |
6026 | 9060 | 6066 | 9060 | 6026 | 9061 | 6066:9061 | 6026 | 9062 | 6066 | 9062 | |
6027 | 9060 | 6067 | 9060 | 6027 | 9061 | 6067 : 9061 | 6027 | 9062 | 6067 | 9062 | |
6028 | 9060 | 6068 | 9060 | 6028 | 9061 | 6068:9061 | 6028 | 9062 | 6068 | 9062 | |
6029 | 9060 | 6069 | 9060 | 6029 | 9061 | 6069:9061 | 6029 | 9062 | 6069 | 9062 | |
6030 | 9060 | 6070 | 9060 | 6030 | 9061 | 6070:9061 | 6030 | 9062 | 6070 | 9062 | |
6031 | 9060 | 6071 | 9060 | 6031 | 9061 | 6071:9061 | 6031 | 9062 | 6071 | 9062 | |
6032 | 9060 | 6072 | 9060 | 6032 | 9061 | 6072:9061 | 6032 | 9062 | 6072 | 9062 | |
6033 | 9060 | 6073 | 9060 | 6033 | 9061 | 6073 : 9061 | 6033 | 9062 | 6073 | 9062 | |
6034 | 9060 | 6074 | 9060 | 6034 | 9061 | 6074 : 9061 | 6034 | 9062 | 6074 | 9062 | |
6035 | 9060 | 6075 | 9060 | 6035 | 9061 | 6075 : 9061 | 6035 | 9062 | 6075 | 9062 | |
6036 | 9060 | 6076 | 9060 | 6036 | 9061 | 6076 : 9061 | 6036 | 9062 | 6076 | 9062 | |
6037 | 9060 | 6077 | 9060 | 6037 | 9061 | 6077:9061 | 6037 | 9062 | 6077 | 9062 | |
6038 | 9060 | 6078 | 9060 | 6038 | 9061 | 6078 : 9061 | 6038 | 9062 | 6078 | 9062 | |
6039 | 9060 | 6039 | 9061 | 6039 | 9062 |
155
X:Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000:9063 | 6040 | 9063 | 6000 | 9064 | 6040 | 9064 | 6000 | 9065 | 6040 | 9065 |
6001 :9063 | 6041 | 9063 | 6001 | 9064 | 6041 | 9064 | 6001 | 9065 | 6041 | 9065 |
6002:9063 | 6042 | 9063 | 6002 | 9064 | 6042 | 9064 | 6002 | 9065 | 6042 | 9065 |
6003:9063 | 6043 | 9063 | 6003 | 9064 | 6043 | 9064 | 6003 | 9065 | 6043 | 9065 |
6004:9063 | 6044 | 9063 | 6004 | 9064 | 6044 | 9064 | 6004 | 9065 | 6044 | 9065 |
•6005:9063- | 6045 | 9063 | 6005 | 9064 | 6045. | .9064 | -6005 | 9065 | 6045 | 9065 |
• 6006:9063- | 6046 | <9063 | 6006 | .9064 | •6046 | 9064 | -6006 | 9065 | 6046 | 9065 |
6007:9063 | 60471 | 9063 | 6007 | 9064 | 6047 | 9064 | 6007 | 9065 | 6047 | 9065 |
6008:9063 | 6048 | 9063 | 6008 | 9064 | 6048 | 9064 | 6008 | 9065 | 6048 | 9065 |
6009:9063 | 6049 | 9063 | 6009 | 9064 | 6049 | 9064 | 6009 | 9065 | 6049 | 9065 |
6010:9063 | 6050 | 9063 | 6010 | 9064 | 6050 | 9064 | 6010 | 9065 | 6050 | 9065 |
6011:9063 | 6051 | 9063 | 6011 | 9064 | 6051 | 9064 | 6011 | 9065 | 6051 | 9065 |
6012 : 9063 | 6052 | 9063 | 6012 | 9064 | 6052 | 9064 | 6012 | 9065 | 6052 | 9065 |
6013 : 9063 | 6053 | 9063 | 6013 | 9064 | 6053 | 9064 | 6013 | 9065 | 6053 | 9065 |
6014 : 9063 | 6054 | 9063 | 6014 | 9064 | 6054 | 9064 | 6014 | 9065 | 6054 | 9065 |
6015 : 9063 | 6055 | 9063 | 6015 | 9064 | 6055 | 9064 | 6015 | 9065 | 6055 | 9065 |
6016 : 9063 | 6056 | 9063 | 6016 | 9064 | 6056 | 9064 | 6016 | 9065 | 6056 | 9065 |
6017 : 9063 | 6057 | 9063 | 6017 | 9064 | 6057 | 9064 | 6017 | 9065 | 6057 | 9065 |
6018:9063 | 6058 | 9063 | 6018 | 9064 | 6058 | 9064 | 6018 | 9065 | 6058 | 9065 |
6019:9063 | 6059 | 9063 | 6019 | 9064 | 6059 | 9064 | 6019 | 9065 | 6059 | 9065 |
6020:9063 | 6060 | 9063 | 6020 | 9064 | 6060 | 9064 | 6020 | 9065 | 6060 | 9065 |
6021:9063 | 6061 | 9063 | 6021 | 9064 | 6061 | 9064 | 6021 | 9065 | 6061 | 9065 |
6022:9063 | 6062 | 9063 | 6022 | 9064 | 6062 | 9064 | 6022 | 9065 | 6062 | 9065 |
6023 : 9063 | 6063 | 9063 | 6023 | 9064 | 6063 | 9064 | 6023 | 9065 | 6063 | 9065 |
6024 : 9063 | 6064 | 9063 | 6024 | 9064 | 6064 | 9064 | 6024 | 9065 | 6064 | 9065 |
6025 : 9063 | 6065 | 9063 | 6025 | 9064 | 6065 | 9064 | 6025 | 9065 | 6065 | 9065 |
6026:9063 | 6066 | 9063 | 6026 | 9064 | 6066 | 9064 | 6026 | 9065 | 6066 | 9065 |
6027:9063 | 6067 | 9063 | 6027 | 9064 | 6067 | 9064 | 6027 | 9065 | 6067 | 9065 |
6028:9063 | 6068 | 9063 | 6028 | 9064 | 6068 | 9064 | 6028 | 9065 | 6068 | 9065 |
6029:9063 | 6069 | 9063 | 6029 | 9064 | 6069 | 9064 | 6029 | 9065 | 6069 | 9065 |
6030 : 9063 | 6070 | 9063 | 6030 | 9064 | 6070 | 9064 | 6030 | 9065 | 6070 | 9065 |
6031:9063 | 6071 | 9063 | 6031 | 9064 | 6071 | 9064 | 6031 | 9065 | 6071 | 9065 |
6032:9063 | 6072 | 9063 | 6032 | 9064 | 6072 | 9064 | 6032 | 9065 | 6072 | 9065 |
6033:9063 | 6073 | 9063 | 6033 | 9064 | 6073 | 9064 | 6033 | 9065 | 6073 | 9065 |
6034 : 9063 | 6074 | 9063 | 6034 | 9064 | 6074 | 9064 | 6034 | 9065 | 6074 | 9065 |
6035:9063 | 6075 | 9063 | 6035 | 9064 | 6075 | 9064 | 6035 | 9065 | 6075 | 9065 |
6036:9063 | 6076 | 9063 | 6036 | 9064 | 6076 | 9064 | 6036 | 9065 | 6076 | 9065 |
6037:9063 | 6077 | 9063 | 6037 | 9064 | 6077 | 9064 | 6037 | 9065 | 6077 | 9065 |
6038 : 9063 | 6078 | 9063 | 6038 | 9064 | 6078 | 9064 | 6038 | 9065 | 6078 | 9065 |
6039 : 9063 | 6039 | 9064 | 6039 | 9065 |
156
X | Y | X:Y | X:Y | X | Y | X | Y | X | Y |
6000 | 9066 | 6040:9066 | 6000:9067 | 6040 | 9067 | 6000 | 9068 | 6040 | 9068 |
6001 | 9066 | 6041:9066 | 6001:9067 | 6041 | 9067 | 6001 | 9068 | 6041 | 9068 |
6002 | 9066 | 6042:9066 | 6002:9067 | 6042 | 9067 | 6002 | 9068 | 6042 | 9068 |
6003 | 9066 | 6043:9066 | 6003 : 9067 | 6043 | 9067 | 6003 | 9068 | 6043 | 9068 |
6004 | 9066 | 6044 : 9066 | 6004:9067 | 6044 | 9067 | 6004 | 9068 | 6044 | 9068 |
6005 | 9066- | 6045 : 9066 | 6005 :9067 | 6045 | .9067 | 6005 | .9068 | 6045 | 9068 |
6006 | 9066 | 6046 :9066 | 6006-9067 | 6046 | 9067 | 6006 | 9068 | 6046 | 9068 |
'6007 | 9066 | 6047:9066' | 6007:9067 | 6047 | 9067 | 6007 | 9068 | 6047 | 9068 |
6008 | 9066 | 6048 : 9066 | 6008 : 9067 | 6048 | 9067 | 6008 | 9068 | 6048 | 9068 |
6009 | 9066 | 6049:9066 | 6009 : 9067 | 6049 | 9067 | 6009 | 9068 | 6049 | 9068 |
6010 | 9066 | 6050:9066 | 6010:9067 | 6050 | 9067 | 6010 | 9068 | 6050 | 9068 |
6011 | 9066 | 6051:9066 | 6011:9067 | 6051 | 9067 | 6011 | 9068 | 6051 | 9068 |
6012 | 9066 | 6052:9066 | 6012:9067 | 6052 | 9067 | 6012 | 9068 | 6052 | 9068 |
6013 | 9066 | 6053 : 9066 | 6013 : 9067 | 6053 | 9067 | 6013 | 9068 | 6053 | 9068 |
6014 | 9066 | 6054 : 9066 | 6014:9067 | 6054 | 9067 | 6014 | 9068 | 6054 | 9068 |
6015 | 9066 | 6055:9066 | 6015:9067 | 6055 | 9067 | 6015 | 9068 | 6055 | 9068 |
6016 | 9066 | 6056:9066 | 6016:9067 | 6056 | 9067 | 6016 | 9068 | 6056 | 9068 |
6017 | 9066 | 6057 : 9066 | 6017:9067 | 6057 | 9067 | 6017 | 9068 | 6057 | 9068 |
6018 | 9066 | 6058 : 9066 | 6018 : 9067 | 6058 | 9067 | 6018 | 9068 | 6058 | 9068 |
6019 | 9066 | 6059:9066 | 6019:9067 | 6059 | 9067 | 6019 | 9068 | 6059 | 9068 |
6020 | 9066 | 6060:9066 | 6020:9067 | 6060 | 9067 | 6020 | 9068 | 6060 | 9068 |
6021 | 9066 | 6061:9066 | 6021:9067 | 6061 | 9067 | 6021 | 9068 | 6061 | 9068 |
6022 | 9066 | 6062:9066 | 6022:9067 | 6062 | 9067 | 6022 | 9068 | 6062 | 9068 |
6023 | 9066 | 6063 : 9066 | 6023 : 9067 | 6063 | 9067 | 6023 | 9068 | 6063 | 9068 |
6024 | 9066 | 6064 : 9066 | 6024 : 9067 | 6064 | 9067 | 6024 | 9068 | 6064 | 9068 |
6025 | 9066 | 6065:9066 | 6025 : 9067 | 6065 | 9067 | 6025 | 9068 | 6065 | 9068 |
6026 | 9066 | 6066 : 9066 | 6026:9067 | 6066 | 9067 | 6026 | 9068 | 6066 | 9068 |
6027 | 9066 | 6067 : 9066 | 6027:9067 | 6067 | 9067 | 6027 | 9068 | 6067 | 9068 |
6028 | 9066 | 6068:9066 | 6028:9067 | 6068 | 9067 | 6028 | 9068 | 6068 | 9068 |
6029 | 9066 | 6069 : 9066 | 6029:9067 | 6069 | 9067 | 6029 | 9068 | 6069 | 9068 |
6030 | 9066 | 6070:9066 | 6030 : 9067 | 6070 | 9067 | 6030 | 9068 | 6070 | 9068 |
6031 | 9066 | 6071:9066 | 6031:9067 | 6071 | 9067 | 6031 | 9068 | 6071 | 9068 |
6032 | 9066 | 6072 : 9066 | 6032 : 9067 | 6072 | 9067 | 6032 | 9068 | 6072 | 9068 |
6033 | 9066 | 6073 : 9066 | 6033 : 9067 | 6073 | 9067 | 6033 | 9068 | 6073 | 9068 |
6034 | 9066 | 6074:9066 | 6034 : 9067 | 6074 | 9067 | 6034 | 9068 | 6074 | 9068 |
6035 | 9066 | 6075 : 9066 | 6035:9067 | 6075 | 9067 | 6035 | 9068 | 6075 | 9068 |
6036 | 9066 | 6076:9066 | 6036 : 9067 | 6076 | 9067 | 6036 | 9068 | 6076 | 9068 |
6037 | 9066 | 6077 : 9066 | 6037 : 9067 | 6077 | 9067 | 6037 | 9068 | 6077 | 9068 |
6038 | 9066 | 6078 : 9066 | 6038 : 9067 | 6078 | 9067 | 6038 | 9068 | 6078 | 9068 |
6039 | 9066 | 6039 : 9067 | 6039 | 9068 |
157
X | Y | X | :Y | X | Y | X | Y | X:Y | X | Y |
6000 | 9069 | 6040 | :9069 | 6000 | 9070 | 6040 | 9070 | 6000:9071 | 6040 | 9071 |
6001 | 9069 | 6041 | 9069 | 6001 | 9070 | 6041 | 9070 | 6001:9071 | 6041 | 9071 |
6002 | 9069 | 6042 | 9069 | 6002 | 9070 | 6042 | 9070 | 6002:9071 | 6042 | 9071 |
6003 | 9069 | 6043 | 9069 | 6003 | 9070 | 6043 | 9070 | 6003:9071 | 6043 | 9071 |
6004 | 9069 | 6044 | 9069 | 6004 | 9070 | 6044 | 9070 | 6004 : 9071 | 6044 | 9071 |
-6005 | 9069 | 6045· | :9069 | 6005 | •9070 | 6045 | 9070 | 6005 f 9071 | 6045 | 9071 |
'6006 | 9069' | 6046 | 9069- | 6006 | 9070 | .6046 | •9070 | .6006 : 9071 | 6046 | 9071 |
6007 | 9069 | 6047 | 9069 | 6007 | 9070 | 6047 | 9070 | '6007:9071 | 6047 | 9071 |
6008 | 9069 | 6048 | 9069 | 6008 | 9070 | 6048 | 9070 | 6008:9071 | 6048 | 9071 |
6009 | 9069 | 6049 | 9069 | 6009 | 9070 | 6049 | 9070 | 6009 : 9071 | 6049 | 9071 |
6010 | 9069 | 6050 | 9069 | 6010 | 9070 | 6050 | 9070 | 6010:9071 | 6050 | 9071 |
6011 | 9069 | 6051 | 9069 | 6011 | 9070 | 6051 | 9070 | 6011:9071 | 6051 | 9071 |
6012 | 9069 | 6052 | 9069 | 6012 | 9070 | 6052 | 9070 | 6012:9071 | 6052 | 9071 |
6013 | 9069 | 6053 | 9069 | 6013 | 9070 | 6053 | 9070 | 6013:9071 | 6053 | 9071 |
6014 | 9069 | 6054 | 9069 | 6014 | 9070 | 6054 | 9070 | 6014:9071 | 6054 | 9071 |
6015 | 9069 | 6055 | 9069 | 6015 | 9070 | 6055 | 9070 | 6015 : 9071 | 6055 | 9071 |
6016 | 9069 | 6056 | 9069 | 6016 | 9070 | 6056 | 9070 | 6016 : 9071 | 6056 | 9071 |
6017 | 9069 | 6057 | 9069 | 6017 | 9070 | 6057 | 9070 | 6017:9071 | 6057 | 9071 |
6018 | 9069 | 6058 | 9069 | 6018 | 9070 | 6058 | 9070 | 6018:9071 | 6058 | 9071 |
6019 | 9069 | 6059 | 9069 | 6019 | 9070 | 6059 | 9070 | 6019:9071 | 6059 | 9071 |
6020 | 9069 | 6060 | 9069 | 6020 | 9070 | 6060 | 9070 | 6020:9071 | 6060 | 9071 |
6021 | 9069 | 6061 | 9069 | 6021 | 9070 | 6061 | 9070 | 6021:9071 | 6061 | 9071 |
6022 | 9069 | 6062 | 9069 | 6022 | 9070 | 6062 | 9070 | 6022:9071 | 6062 | 9071 |
6023 | 9069 | 6063 | 9069 | 6023 | 9070 | 6063 | 9070 | 6023:9071 | 6063 | 9071 |
6024 | 9069 | 6064 | 9069 | 6024 | 9070 | 6064 | 9070 | 6024 : 9071 | 6064 | 9071 |
6025 | 9069 | 6065 | 9069 | 6025 | 9070 | 6065 | 9070 | 6025 : 9071 | 6065 | 9071 |
6026 | 9069 | 6066 | 9069 | 6026 | 9070 | 6066 | 9070 | 6026:9071 | 6066 | 9071 |
6027 | 9069 | 6067 | 9069 | 6027 | 9070 | 6067 | 9070 | 6027:9071 | 6067 | 9071 |
6028 | 9069 | 6068 | 9069 | 6028 | 9070 | 6068 | 9070 | 6028:9071 | 6068 | 9071 |
6029 | 9069 | 6069 | 9069 | 6029 | 9070 | 6069 | 9070 | 6029 : 9071 | 6069 | 9071 |
6030 | 9069 | 6070 | 9069 | 6030 | 9070 | 6070 | 9070 | 6030 : 9071 | 6070 | 9071 |
6031 | 9069 | 6071 | 9069 | 6031 | 9070 | 6071 | 9070 | 6031:9071 | 6071 | 9071 |
6032 | 9069 | 6072 | 9069 | 6032 | 9070 | 6072 | 9070 | 6032:9071 | 6072 | 9071 |
6033 | 9069 | 6073 | 9069 | 6033 | 9070 | 6073 | 9070 | 6033 : 9071 | 6073 | 9071 |
6034 | 9069 | 6074 | 9069 | 6034 | 9070 | 6074 | 9070 | 6034 : 9071 | 6074 | 9071 |
6035 | 9069 | 6075 | 9069 | 6035 | 9070 | 6075 | 9070 | 6035 : 9071 | 6075 | 9071 |
6036 | 9069 | 6076 | 9069 | 6036 | 9070 | 6076 | 9070 | 6036 : 9071 | 6076 | 9071 |
6037 | 9069 | 6077 | 9069 | 6037 | 9070 | 6077 | 9070 | 6037:9071 | 6077 | 9071 |
6038 | 9069 | 6078 | 9069 | 6038 | 9070 | 6078 | 9070 | 6038:9071 | 6078 | 9071 |
6039 | 9069 | 6039 | 9070 | 6039:9071 |
158
X | Y | X:Y | X:Y | X | Y | X | Y | X | Y | |
6000 6001 6002 6003 6004 6005 6006 6007 6008 6009 6010 6011 6012 6013 6014 6015 6016 6017 6018 6019 6020 6021 6022 6023 6024 6025 6026 6027 6028 6029 6030 6031 6032 6033 6034 6035 6036 6037 6038 6039 | 9072 9072 9072 9072 9072 -9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 9072 | 6040 : 9072 6041:9072 6042:9072 6043:9072 6044 : 9072 6045 ;9072 6046:9072 6047:9072 6048:9072 6049:9072 6050 : 9072 6051:9072 6052:9072 6053:9072 6054:9072 6055:9072 6056:9072 6057:9072 6058:9072 6059 : 9072 6060 : 9072 6061:9072 6062:9072 6063:9072 6064:9072 6065:9072 6066:9072 6067:9072 6068:9072 6069 : 9072 6070:9072 6071:9072 6072 : 9072 6073:9072 6074:9072 6075 : 9072 6076:9072 6077:9072 6078:9072 | 6000: 6001: 6002: 6003: 6004: 6005: 6006: 6007 6008 6009 6010 6011 6012 6013 6014 6015 6016 6017 6018 6019 6020 6021 6022 6023 6024 6025 6026 6027 6028 6029 6030 6031 6032 6033 6034 6035 6036 6037 6038 6039 | 9073 9073 9073 9073 9073 r9073 ^9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 | 6040 6041 6042 6043 6044 6045 6046 6047 6048 6049 6050 6051 6052 6053 6054 6055 6056 6057 6058 6059 6060 6061 6062 6063 6064 6065 6066 6067 6068 6069 6070 6071 6072 6073 6074 6075 6076 6077 6078 | 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 9073 | 6000 6001 6002 6003 6004 -6005 6006 6007 6008 6009 6010 6011 6012 6013 6014 6015 6016 6017 6018 6019 6020 6021 6022 6023 6024 6025 6026 6027 6028 6029 6030 6031 6032 6033 6034 6035 6036 6037 6038 6039 | 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 | 6040 6041 6042 6043 6044 6045 6046 6047 6048 6049 6050 6051 6052 6053 6054 6055 6056 6057 6058 6059 6060 6061 6062 6063 6064 6065 6066 6067 6068 6069 6070 6071 6072 6073 6074 6075 6076 6077 6078 | 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 9074 |
159
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9075 | 6040 | 9075 | 6000 | 9076 | 6040 | 9076 | 6000 | 9077 | 6040 | 9077 |
6001 | 9075 | 6041 | 9075 | 6001 | 9076 | 6041 | 9076 | 6001 | 9077 | 6041 | 9077 |
6002 | 9075 | 6042 | 9075 | 6002 | 9076 | 6042 | 9076 | 6002 | 9077 | 6042 | 9077 |
6003 | 9075 | 6043 | 9075 | 6003 | 9076 | 6043 | 9076 | 6003 | 9077 | 6043 | 9077 |
6004 | 9075 | 6044 | 9075 | 6004 | 9076 | 6044 | 9076 | 6004 | 9077 | 6044 | 9077 |
6005 | r9075 | 6045' | 9075 | 6005 | 9076- | 6045 | 9076 | 6005 | ‘9077 | 6045 | 9077 |
6006 | 9075; | 6046 | .9075 | 6006 | 9076 | 6046 | 9076 | -6006 | 9077 | 6046 | 9077 |
6007 | 9075 | 6047 | 9075 | 6007 | 9076 | 6047 | 9076 | 6007 | 9077 | 6047 | 9077 |
6008 | 9075 | 6048 | 9075 | 6008 | 9076 | 6048 | 9076 | 6008 | 9077 | 6048 | 9077 |
6009 | 9075 | 6049 | 9075 | 6009 | 9076 | 6049 | 9076 | 6009 | 9077 | 6049 | 9077 |
6010 | 9075 | 6050 | 9075 | 6010 | 9076 | 6050 | 9076 | 6010 | 9077 | 6050 | 9077 |
6011 | 9075 | 6051 | 9075 | 6011 | 9076 | 6051 | 9076 | 6011 | 9077 | 6051 | 9077 |
6012 | 9075 | 6052 | 9075 | 6012 | 9076 | 6052 | 9076 | 6012 | 9077 | 6052 | 9077 |
6013 | 9075 | 6053 | 9075 | 6013 | 9076 | 6053 | 9076 | 6013 | 9077 | 6053 | 9077 |
6014 | 9075 | 6054 | 9075 | 6014 | 9076 | 6054 | 9076 | 6014 | 9077 | 6054 | 9077 |
6015 | 9075 | 6055 | 9075 | 6015 | 9076 | 6055 | 9076 | 6015 | 9077 | 6055 | 9077 |
6016 | 9075 | 6056 | 9075 | 6016 | 9076 | 6056 | 9076 | 6016 | 9077 | 6056 | 9077 |
6017 | 9075 | 6057 | 9075 | 6017 | 9076 | 6057 | 9076 | 6017 | 9077 | 6057 | 9077 |
6018 | 9075 | 6058 | 9075 | 6018 | 9076 | 6058 | 9076 | 6018 | 9077 | 6058 | 9077 |
6019 | 9075 | 6059 | 9075 | 6019 | 9076 | 6059 | 9076 | 6019 | 9077 | 6059 | 9077 |
6020 | 9075 | 6060 | 9075 | 6020 | 9076 | 6060 | 9076 | 6020 | 9077 | 6060 | 9077 |
6021 | 9075 | 6061 | 9075 | 6021 | 9076 | 6061 | 9076 | 6021 | 9077 | 6061 | 9077 |
6022 | 9075 | 6062 | 9075 | 6022 | 9076 | 6062 | 9076 | 6022 | 9077 | 6062 | 9077 |
6023 | 9075 | 6063 | 9075 | 6023 | 9076 | 6063 | 9076 | 6023 | 9077 | 6063 | 9077 |
6024 | 9075 | 6064 | 9075 | 6024 | 9076 | 6064 | 9076 | 6024 | 9077 | 6064 | 9077 |
6025 | 9075 | 6065 | 9075 | 6025 | 9076 | 6065 | 9076 | 6025 | 9077 | 6065 | 9077 |
6026 | 9075 | 6066 | 9075 | 6026 | 9076 | 6066 | 9076 | 6026 | 9077 | 6066 | 9077 |
6027 | 9075 | 6067 | 9075 | 6027 | 9076 | 6067 | 9076 | 6027 | 9077 | 6067 | 9077 |
6028 | 9075 | 6068 | 9075 | 6028 | 9076 | 6068 | 9076 | 6028 | 9077 | 6068 | 9077 |
6029 | 9075 | 6069 | 9075 | 6029 | 9076 | 6069 | 9076 | 6029 | 9077 | 6069 | 9077 |
6030 | 9075 | 6070 | 9075 | 6030 | 9076 | 6070 | 9076 | 6030 | 9077 | 6070 | 9077 |
6031 | 9075 | 6071 | 9075 | 6031 | 9076 | 6071 | 9076 | 6031 | 9077 | 6071 | 9077 |
6032 | 9075 | 6072 | 9075 | 6032 | 9076 | 6072 | 9076 | 6032 | 9077 | 6072 | 9077 |
6033 | 9075 | 6073 | 9075 | 6033 | 9076 | 6073 | 9076 | 6033 | 9077 | 6073 | 9077 |
6034 | 9075 | 6074 | 9075 | 6034 | 9076 | 6074 | 9076 | 6034 | 9077 | 6074 | 9077 |
6035 | 9075 | 6075 | 9075 | 6035 | 9076 | 6075 | 9076 | 6035 | 9077 | 6075 | 9077 |
6036 | 9075 | 6076 | 9075 | 6036 | 9076 | 6076 | 9076 | 6036 | 9077 | 6076 | 9077 |
6037 | 9075 | 6077 | 9075 | 6037 | 9076 | 6077 | 9076 | 6037 | 9077 | 6077 | 9077 |
6038 | 9075 | 6078 | 9075 | 6038 | 9076 | 6078 | 9076 | 6038 | 9077 | 6078 | 9077 |
6039 | 9075 | 6039 | 9076 | 6039 | 9077 |
160
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9078 | 6040 | 9078 | 6000 | 9079 | 6040 | 9079 | 6000 | 9080 | 6040 | 9080 |
6001 | 9078 | 6041 | 9078 | 6001 | 9079 | 6041 | 9079 | 6001 | 9080 | 6041 | 9080 |
6002 | 9078 | 6042 | 9078 | 6002 | 9079 | 6042 | 9079 | 6002 | 9080 | 6042 | 9080 |
6003 | 9078 | 6043 | 9078 | 6003 | 9079 | 6043 | 9079 | 6003 | 9080 | 6043 | 9080 |
6004 | 9078 | 6044 | 9078 | 6004 | 9079 | 6044 | 9079 | 6004 | 9080 | 6044 | 9080 |
-6005 | 9078 | 6045 | 9078 | 6005 | 9079 | 6045 | 9079 | 6005 | 9080 | 6045 | 9080 |
-6006 | L9078- | 6046 | 9078- | 6006, | 9079 | 6046 | .9079- | 6006 | 9080 | 6046 | 90S0 |
6007 | 9078 | 6047 | 9078 | 6007 | 9079 | 6047 | 9079 | 6007 | 9080 | 6047 | 9080 |
6008 | 9078 | 6048 | 9078 | 6008 | 9079 | 6048 | 9079 | 6008 | 9080 | 6048 | 9080 |
6009 | 9078 | 6049 | 9078 | 6009 | 9079 | 6049 | 9079 | 6009 | 9080 | 6049 | 9080 |
6010 | 9078 | 6050 | 9078 | 6010 | 9079 | 6050 | 9079 | 6010 | 9080 | 6050 | 9080 |
6011 | 9078 | 6051 | 9078 | 6011 | 9079 | 6051 | 9079 | 6011 | 9080 | 6051 | 9080 |
6012 | 9078 | 6052 | 9078 | 6012 | 9079 | 6052 | 9079 | 6012 | 9080 | 6052 | 9080 |
6013 | 9078 | 6053 | 9078 | 6013 | 9079 | 6053 | 9079 | 6013 | 9080 | 6053 | 9080 |
6014 | 9078 | 6054 | 9078 | 6014 | 9079 | 6054 | 9079 | 6014 | 9080 | 6054 | 9080 |
6015 | 9078 | 6055 | 9078 | 6015 | 9079 | 6055 | 9079 | 6015 | 9080 | 6055 | 9080 |
6016 | 9078 | 6056 | 9078 | 6016 | 9079 | 6056 | 9079 | 6016 | 9080 | 6056 | 9080 |
6017 | 9078 | 6057 | 9078 | 6017 | 9079 | 6057 | 9079 | 6017 | 9080 | 6057 | 9080 |
6018 | 9078 | 6058 | 9078 | 6018 | 9079 | 6058 | 9079 | 6018 | 9080 | 6058 | 9080 |
6019 | 9078 | 6059 | 9078 | 6019 | 9079 | 6059 | 9079 | 6019 | 9080 | 6059 | 9080 |
6020 | 9078 | 6060 | 9078 | 6020 | 9079 | 6060 | 9079 | 6020 | 9080 | 6060 | 9080 |
6021 | 9078 | 6061 | 9078 | 6021 | 9079 | 6061 | 9079 | 6021 | 9080 | 6061 | 9080 |
6022 | 9078 | 6062 | 9078 | 6022 | 9079 | 6062 | 9079 | 6022 | 9080 | 6062 | 9080 |
6023 | 9078 | 6063 | 9078 | 6023 | 9079 | 6063 | 9079 | 6023 | 9080 | 6063 | 9080 |
6024 | 9078 | 6064 | 9078 | 6024 | 9079 | 6064 | 9079 | 6024 | 9080 | 6064 | 9080 |
6025 | 9078 | 6065 | 9078 | 6025 | 9079 | 6065 | 9079 | 6025 | 9080 | 6065 | 9080 |
6026 | 9078 | 6066 | 9078 | 6026 | 9079 | 6066 | 9079 | 6026 | 9080 | 6066 | 9080 |
6027 | 9078 | 6067 | 9078 | 6027 | 9079 | 6067 | 9079 | 6027 | 9080 | 6067 | 9080 |
6028 | 9078 | 6068 | 9078 | 6028 | 9079 | 6068 | 9079 | 6028 | 9080 | 6068 | 9080 |
6029 | 9078 | 6069 | 9078 | 6029 | 9079 | 6069 | 9079 | 6029 | 9080 | 6069 | 9080 |
6030 | 9078 | 6070 | 9078 | 6030 | 9079 | 6070 | 9079 | 6030 | 9080 | 6070 | 9080 |
6031 | 9078 | 6071 | 9078 | 6031 | 9079 | 6071 | 9079 | 6031 | 9080 | 6071 | 9080 |
6032 | 9078 | 6072 | 9078 | 6032 | 9079 | 6072 | 9079 | 6032 | 9080 | 6072 | 9080 |
6033 | 9078 | 6073 | 9078 | 6033 | 9079 | 6073 | 9079 | 6033 | 9080 | 6073 | 9080 |
6034 | 9078 | 6074 | 9078 | 6034 | 9079 | 6074 | 9079 | 6034 | 9080 | 6074 | 9080 |
6035 | 9078 | 6075 | 9078 | 6035 | 9079 | 6075 | 9079 | 6035 | 9080 | 6075 | 9080 |
6036 | 9078 | 6076 | 9078 | 6036 | 9079 | 6076 | 9079 | 6036 | 9080 | 6076 | 9080 |
6037 | 9078 | 6077 | 9078 | 6037 | 9079 | 6077 | 9079 | 6037 | 9080 | 6077 | 9080 |
6038 | 9078 | 6078 | 9078 | 6038 | 9079 | 6078 | 9079 | 6038 | 9080 | 6078 | 9080 |
6039 | 9078 | 6039 | 9079 | 6039 | 9080 |
161
X | Y | X | Y | X | Y | X | Y | X | Y | X | Y |
6000 | 9081 | 6040 | 9081 | 6000 | 9082 | 6040 | 9082 | 6000 | 9083 | 6040 | 9083 |
6001 | 9081 | 6041 | 9081 | 6001 | 9082 | 6041 | 9082 | 6001 | 9083 | 6041 | 9083 |
6002 | .9081 | 6042 | 9081 | 6002 | 9082 | 6042 | 9082 | 6002 | 9083 | 6042 | 9083 |
6003 | :9081 | 6043 | 9081 | 6003 | 9082 | 6043 | 9082 | 6003 | 9083 | 6043 | 9083 |
6004 | •9081 | 6044 | 9081 | 6004 | 9082 | 6044 | 9082 | 6004 | 9083 | 6044 | 9083 |
6005 | •9081- | 6045 | 9081- | 6005 | 9082 | 6045 | 9082 | 6005 | 9083 | 6045 | 9083 |
-6006:9081- | .6046- | '908b | 6006 | 9082- | 6046 | 9082- | ^6006 | -9083- | 6046 | 9083 | |
6007 | 9081 | 6047 | 9081 | 6007 | 9082 | 6047 | 9082 | 6007 | 9083 | 6047 | 9083 |
6008 | 9081 | 6048 | 9081 | 6008 | 9082 | 6048 | 9082 | 6008 | 9083 | 6048 | 9083 |
6009 | 9081 | 6049 | 9081 | 6009 | 9082 | 6049 | 9082 | 6009 | 9083 | 6049 | 9083 |
6010 | 9081 | 6050 | 9081 | 6010 | 9082 | 6050 | 9082 | 6010 | 9083 | 6050 | 9083 |
6011 | 9081 | 6051 | 9081 | 6011 | 9082 | 6051 | 9082 | 6011 | 9083 | 6051 | 9083 |
6012 | 9081 | 6052 | 9081 | 6012 | 9082 | 6052 | 9082 | 6012 | 9083 | 6052 | 9083 |
6013 | 9081 | 6053 | 9081 | 6013 | 9082 | 6053 | 9082 | 6013 | 9083 | 6053 | 9083 |
6014 | 9081 | 6054 | 9081 | 6014 | 9082 | 6054 | 9082 | 6014 | 9083 | 6054 | 9083 |
6015 | 9081 | 6055 | 9081 | 6015 | 9082 | 6055 | 9082 | 6015 | 9083 | 6055 | 9083 |
6016 | 9081 | 6056 | 9081 | 6016 | 9082 | 6056 | 9082 | 6016 | 9083 | 6056 | 9083 |
6017 | 9081 | 6057 | 9081 | 6017 | 9082 | 6057 | 9082 | 6017 | 9083 | 6057 | 9083 |
6018 | 9081 | 6058 | 9081 | 6018 | 9082 | 6058 | 9082 | 6018 | 9083 | 6058 | 9083 |
6019 | 9081 | 6059 | 9081 | 6019 | 9082 | 6059 | 9082 | 6019 | 9083 | 6059 | 9083 |
6020 | 9081 | 6060 | 9081 | 6020 | 9082 | 6060 | 9082 | 6020 | 9083 | 6060 | 9083 |
6021 | 9081 | 6061 | 9081 | 6021 | 9082 | 6061 | 9082 | 6021 | 9083 | 6061 | 9083 |
6022 | 9081 | 6062 | 9081 | 6022 | 9082 | 6062 | 9082 | 6022 | 9083 | 6062 | 9083 |
6023 | 9081 | 6063 | 9081 | 6023 | 9082 | 6063 | 9082 | 6023 | 9083 | 6063 | 9083 |
6024 | 9081 | 6064 | 9081 | 6024 | 9082 | 6064 | 9082 | 6024 | 9083 | 6064 | 9083 |
6025 | 9081 | 6065 | 9081 | 6025 | 9082 | 6065 | 9082 | 6025 | 9083 | 6065 | 9083 |
6026 | 9081 | 6066 | 9081 | 6026 | 9082 | 6066 | 9082 | 6026 | 9083 | 6066 | 9083 |
6027 | 9081 | 6067 | 9081 | 6027 | 9082 | 6067 | 9082 | 6027 | 9083 | 6067 | 9083 |
6028 | 9081 | 6068 | 9081 | 6028 | 9082 | 6068 | 9082 | 6028 | 9083 | 6068 | 9083 |
6029 | 9081 | 6069 | 9081 | 6029 | 9082 | 6069 | 9082 | 6029 | 9083 | 6069 | 9083 |
6030 | 9081 | 6070 | 9081 | 6030 | 9082 | 6070 | 9082 | 6030 | 9083 | 6070 | 9083 |
6031 | 9081 | 6071 | 9081 | 6031 | 9082 | 6071 | 9082 | 6031 | 9083 | 6071 | 9083 |
6032 | 9081 | 6072 | 9081 | 6032 | 9082 | 6072 | 9082 | 6032 | 9083 | 6072 | 9083 |
6033 | 9081 | 6073 | 9081 | 6033 | 9082 | 6073 | 9082 | 6033 | 9083 | 6073 | 9083 |
6034 | 9081 | 6074 | 9081 | 6034 | 9082 | 6074 | 9082 | 6034 | 9083 | 6074 | 9083 |
6035 | 9081 | 6075 | 9081 | 6035 | 9082 | 6075 | 9082 | 6035 | 9083 | 6075 | 9083 |
6036 | 9081 | 6076 | 9081 | 6036 | 9082 | 6076 | 9082 | 6036 | 9083 | 6076 | 9083 |
6037 | 9081 | 6077 | 9081 | 6037 | 9082 | 6077 | 9082 | 6037 | 9083 | 6077 | 9083 |
6038 | 9081 | 6078 | 9081 | 6038 | 9082 | 6078 | 9082 | 6038 | 9083 | 6078 | 9083 |
6039 | 9081 | 6039 | 9082 | 6039 | 9083 |
I62
X | Y | X | Y | X | Y | X | Y | X | Y | X:Y |
6000 | 9084 | 6040 | 9084 | 6000 | 9085 | 6040 | 9085 | 6000 | 9086 | 6040:9086 |
6001 | 9084 | 6041 | 9084 | 6001 | 9085 | 6041 | 9085 | 6001 | 9086 | 6041:9086 |
6002 | 9084 | 6042 | 9084 | 6002 | 9085 | 6042 | 9085 | 6002 | 9086 | 6042:9086 |
6003 | 9084 | 6043 | 9084 | 6003 | 9085 | 6043 | 9085 | 6003 | 9086 | 6043:9086 |
6004 | 9084 | 6044 | 9084 | 6004 | 9085 | 6044 | 9085 | 6004 | 9086 | 6044 : 9086 |
6005 | 9084- | 6045- | *9084 | 6005 | *9085 | 6045 | 9085 | 6005 | '9086 | 6045:9086 |
-6006 | 9084- | '6046 | 9084 | 6006 | =9085 | 6046 | .9085 | 6006 | 9086 | 6046:9086 |
6007 | 9084 | 6047 | 9084 | 6007 | 9085 | 6047 | 9085 | 6007 | 9086 | 6047:9086 |
6008 | 9084 | 6048 | 9084 | 6008 | 9085 | 6048 | 9085 | 6008 | 9086 | 6048:9086 |
6009 | 9084 | 6049 | 9084 | 6009 | 9085 | 6049 | 9085 | 6009 | 9086 | 6049:9086 |
6010 | 9084 | 6050 | 9084 | 6010 | 9085 | 6050 | 9085 | 6010 | 9086 | 6050:9086 |
6011 | 9084 | 6051 | 9084 | 6011 | 9085 | 6051 | 9085 | 6011 | 9086 | 6051:9086 |
6012 | 9084 | 6052 | 9084 | 6012 | 9085 | 6052 | 9085 | 6012 | 9086 | 6052:9086 |
6013 | 9084 | 6053 | 9084 | 6013 | 9085 | 6053 | 9085 | 6013 | 9086 | 6053 : 9086 |
6014 | 9084 | 6054 | 9084 | 6014 | 9085 | 6054 | 9085 | 6014 | 9086 | 6054:9086 |
6015 | 9084 | 6055 | 9084 | 6015 | 9085 | 6055 | 9085 | 6015 | 9086 | 6055:9086 |
6016 | 9084 | 6056 | 9084 | 6016 | 9085 | 6056 | 9085 | 6016 | 9086 | 6056:9086 |
6017 | 9084 | 6057 | 9084 | 6017 | 9085 | 6057 | 9085 | 6017 | 9086 | 6057:9086 |
6018 | 9084 | 6058 | 9084 | 6018 | 9085 | 6058 | 9085 | 6018 | 9086 | 6058:9086 |
6019 | 9084 | 6059 | 9084 | 6019 | 9085 | 6059 | 9085 | 6019 | 9086 | 6059:9086 |
6020 | 9084 | 6060 | 9084 | 6020 | 9085 | 6060 | 9085 | 6020 | 9086 | 6060 : 9086 |
6021 | 9084 | 6061 | 9084 | 6021 | 9085 | 6061 | 9085 | 6021 | 9086 | 6061 :9086 |
6022 | 9084 | 6062 | 9084 | 6022 | 9085 | 6062 | 9085 | 6022 | 9086 | 6062 : 9086 |
6023 | 9084 | 6063 | 9084 | 6023 | 9085 | 6063 | 9085 | 6023 | 9086 | 6063 : 9086 |
6024 | 9084 | 6064 | 9084 | 6024 | 9085 | 6064 | 9085 | 6024 | 9086 | 6064:9086 |
6025 | 9084 | 6065 | 9084 | 6025 | 9085 | 6065 | 9085 | 6025 | 9086 | 6065:9086 |
6026 | 9084 | 6066 | 9084 | 6026 | 9085 | 6066 | 9085 | 6026 | 9086 | 6066:9086 |
6027 | 9084 | 6067 | 9084 | 6027 | 9085 | 6067 | 9085 | 6027 | 9086 | 6067:9086 |
6028 | 9084 | 6068 | 9084 | 6028 | 9085 | 6068 | 9085 | 6028 | 9086 | 6068 : 9086 |
6029 | 9084 | 6069 | 9084 | 6029 | 9085 | 6069 | 9085 | 6029 | 9086 | 6069:9086 |
6030 | 9084 | 6070 | 9084 | 6030 | 9085 | 6070 | 9085 | 6030 | 9086 | 6070:9086 |
6031 | 9084 | 6071 | 9084 | 6031 | 9085 | 6071 | 9085 | 6031 | 9086 | 6071:9086 |
6032 | 9084 | 6072 | 9084 | 6032 | 9085 | 6072 | 9085 | 6032 | 9086 | 6072:9086 |
6033 | 9084 | 6073 | 9084 | 6033 | 9085 | 6073 | 9085 | 6033 | 9086 | 6073 : 9086 |
6034 | 9084 | 6074 | 9084 | 6034 | 9085 | 6074 | 9085 | 6034 | 9086 | 6074:9086 |
6035 | 9084 | 6075 | 9084 | 6035 | 9085 | 6075 | 9085 | 6035 | 9086 | 6075 : 9086 |
6036 | 9084 | 6076 | 9084 | 6036 | 9085 | 6076 | 9085 | 6036 | 9086 | 6076 : 9086 |
6037 | 9084 | 6077 | 9084 | 6037 | 9085 | 6077 | 9085 | 6037 | 9086 | 6077 : 9086 |
6038 6039 | 9084 9084 | 6078 | 9084 | 6038 6039 | 9085 9085 | 6078 | 9085 | 6038 6039 | 9086 9086 | 6078:9086 |
163
X:Y | Χ:Υ | X: Y | X | Y | Χ:Υ | X | Y |
6000 : 9087 | 6040:9087 | 6000:9088 | 6040 | 9088 | 6000:9089 | 6040 | 9089 |
6001 :9087 | 6041:9087 | 6001:9088 | 6041 | 9088 | 6001:9089 | 6041 | 9089 |
6002:9087 | 6042 : 9087 | 6002:9088 | 6042 | 9088 | 6002:9089 | 6042 | 9089 |
6003 : 9087 | 6043:9087 | 6003:9088 | 6043 | 9088 | 6003 : 9089 | 6043 | 9089 |
6004:9087 | 6044 : 9087 | 6004:9088 | 6044 | 9088 | 6004:9089 | 6044 | 9089 |
6005 : 9087 | 6045 : 9087 | 6005:9088= | 6045. | .9088 | 6005: 9089 | 6045 | 9089 |
6006 : 9087- | 6046:9087- | 60064 9088- | 6046 | (9088 | -6006:9089 | 6046 | 9089 |
6007:9087* | 6047:9087 | 6007:9088 | 6047 | 9088 | 6007:9089 | 6047 | 9089 |
6008:9087 | 6048:9087 | 6008 : 9088 | 6048 | 9088 | 6008:9089 | 6048 | 9089 |
6009:9087 | 6049:9087 | 6009 : 9088 | 6049 | 9088 | 6009:9089 | 6049 | 9089 |
6010:9087 | 6050:9087 | 6010:9088 | 6050 | 9088 | 6010 : 9089 | 6050 | 9089 |
6011:9087 | 6051:9087 | 6011 :9088 | 6051 | 9088 | 6011:9089 | 6051 | 9089 |
6012:9087 | 6052 : 9087 | 6012:9088 | 6052 | 9088 | 6012:9089 | 6052 | 9089 |
6013 : 9087 | 6053:9087 | 6013:9038 | 6053 | 9088 | 6013 : 9089 | 6053 | 9089 |
6014:9087 | 6054:9087 | 6014 : 9088 | 6054 | 9088 | 6014 : 9089 | 6054 | 9089 |
6015:9087 | 6055 : 9087 | 6015 : 9088 | 6055 | 9088 | 6015:9089 | 6055 | 9089 |
6016:9087 | 6056:9087 | 6016:9088 | 6056 | 9088 | 6016:9089 | 6056 | 9089 |
6017:9087 | 6057:9087 | 6017:9088 | 6057 | 9088 | 6017 : 9089 | 6057 | 9089 |
6018:9087 | 6058:9087 | 6018:9088 | 6058 | 9088 | 6018 : 9089 | 6058 | 9089 |
6019:9087 | 6059 : 9087 | 6019 : 9088 | 6059 | 9088 | 6019 : 9089 | 6059 | 9089 |
6020 : 9087 | 6060 : 9087 | 6020:9088 | 6060 | 9088 | 6020 : 9089 | 6060 | 9089 |
6021 :9087 | 6061:9087 | 6021:9088 | 6061 | 9088 | 6021:9089 | 6061 | 9089 |
6022 : 9087 | 6062:9087 | 6022:9088 | 6062 | 9088 | 6022 : 9089 | 6062 | 9089 |
6023 : 9087 | 6063 : 9087 | 6023 : 9088 | 6063 | 9088 | 6023 : 9089 | 6063 | 9089 |
6024:9087 | 6064:9087 | 6024 : 9088 | 6064 | 9088 | 6024 : 9089 | 6064 | 9089 |
6025 : 9087 | 6065:9087 | 6025:9088 | 6065 | 9088 | 6025 : 9089 | 6065 | 9089 |
6026:9087 | 6066:9087 | 6026:9088 | 6066 | 9088 | 6026 : 9089 | 6066 | 9089 |
6027:9087 | 6067:9087 | 6027:9088 | 6067 | 9088 | 6027 : 9089 | 6067 | 9089 |
6028:9087 | 6068:9087 | 6028:9088 | 6068 | 9088 | 6028:9089 | 6068 | 9089 |
6029:9087 | 6069:9087 | 6029:9088 | 6069 | 9088 | 6029 : 9089 | 6069 | 9089 |
6030:9087 | 6070:9087 | 6030:9088 | 6070 | 9088 | 6030 : 9089 | 6070 | 9089 |
6031:9087 | 6071:9087 | 6031 :9088 | 6071 | 9088 | 6031:9089 | 6071 | 9089 |
6032:9087 | 6072 : 9087 | 6032 : 9088 | 6072 | 9088 | 6032:9089 | 6072 | 9089 |
6033 : 9087 | 6073 : 9087 | 6033 : 9088 | 6073 | 9088 | 6033:9089 | 6073 | 9089 |
6034:9087 | 6074 : 9087 | 6034 : 9088 | 6074 | 9088 | 6034 : 9089 | 6074 | 9089 |
6035:9087 | 6075:9087 | 6035:9088 | 6075 | 9088 | 6035 : 9089 | 6075 | 9089 |
6036:9087 | 6076:9087 | 6036:9088 | 6076 | 9088 | 6036 : 9089 | 6076 | 9089 |
6037:9087 | 6077:9087 | 6037 : 9088 | 6077 | 9088 | 6037 : 9089 | 6077 | 9089 |
6038:9087 | 6078:9087 | 6038:9088 | 6078 | 9088 | 6038 : 9089 | 6078 | 9089 |
6039:9087 | 6039:9088 | 6039:9089 |
164
X:Y | X | Y | X | Y | X | Y | X: Y | X | Y | ||
6000 | :9090 | 6040 | 9090 | 6000 | 9091 | 6040 | 9091 | 6000 | :9092 | 6040 | 9092 |
6001 | :9090 | 6041 | 9090 | 6001 | 9091 | 6041 | 9091 | 6001 | :9092 | 6041 | 9092 |
6002 | .9090 | 6042 | 9090 | 6002 | 9091 | 6042 | 9091 | 6002 | :9092 | 6042 | 9092 |
6003 | :9090 | 6043 | 9090 | 6003 | 9091 | 6043 | 9091 | 6003 | :9092 | 6043 | 9092 |
6004 | 9090 | 6044 | 9090 | 6004 | 9091 | 6044 | 9091 | 6004 | :9092 | 6044 | 9092 |
6005: | :9090. | 6045 | 9090 | 6005 | 9091 | 6045 | 9091 | 6005 | :9092 | 6045 | 9092 |
-6006; | 9090' | 6046 | 9090 | 6006 | 9091 | 6046 | 9091- | -6006 | *9092 | 6046 | 9092 |
6007 | 9090 | 6047 | 9090 | 6007 | 9091 | 6047 | 9091 | 6007 | 9092 | 6047 | 9092 |
6008 | 9090 | 6048 | 9090 | 6008 | 9091 | 6048 | 9091 | 6008 | 9092 | 6048 | 9092 |
6009 | 9090 | 6049 | 9090 | 6009 | 9091 | 6049 | 9091 | 6009 | 9092 | 6049 | 9092 |
6010 | 9090 | 6050 | 9090 | 6010 | 9091 | 6050 | 9091 | 6010 | 9092 | 6050 | 9092 |
6011 | 9090 | 6051 | 9090 | 6011 | 9091 | 6051 | 9091 | 6011 | 9092 | 6051 | 9092 |
6012 | 9090 | 6052 | 9090 | 6012 | 9091 | 6052 | 9091 | 6012 | 9092 | 6052 | 9092 |
6013 | 9090 | 6053 | 9090 | 6013 | 9091 | 6053 | 9091 | 6013 | 9092 | 6053 | 9092 |
6014 | 9090 | 6054 | 9090 | 6014 | 9091 | 6054 | 9091 | 6014 | 9092 | 6054 | 9092 |
6015 | 9090 | 6055 | 9090 | 6015 | 9091 | 6055 | 9091 | 6015 | 9092 | 6055 | 9092 |
6016 | 9090 | 6056 | 9090 | 6016 | 9091 | 6056 | 9091 | 6016 | 9092 | 6056 | 9092 |
6017 | 9090 | 6057 | 9090 | 6017 | 9091 | 6057 | 9091 | 6017 | 9092 | 6057 | 9092 |
6018 | 9090 | 6058 | 9090 | 6018 | 9091 | 6058 | 9091 | 6018 | 9092 | 6058 | 9092 |
6019 | 9090 | 6059 | 9090 | 6019 | 9091 | 6059 | 9091 | 6019 | 9092 | 6059 | 9092 |
6020 | 9090 | 6060 | 9090 | 6020 | 9091 | 6060 | 9091 | 6020 | 9092 | 6060 | 9092 |
6021 | 9090 | 6061 | 9090 | 6021 | 9091 | 6061 | 9091 | 6021 | 9092 | 6061 | 9092 |
6022 | 9090 | 6062 | 9090 | 6022 | 9091 | 6062 | 9091 | 6022 | 9092 | 6062 | 9092 |
6023 | 9090 | 6063 | 9090 | 6023 | 9091 | 6063 | 9091 | 6023 | 9092 | 6063 | 9092 |
6024 | 9090 | 6064 | 9090 | 6024 | 9091 | 6064 | 9091 | 6024 | 9092 | 6064 | 9092 |
6025 | 9090 | 6065 | 9090 | 6025 | 9091 | 6065 | 9091 | 6025 | 9092 | 6065 | 9092 |
6026 | 9090 | 6066 | 9090 | 6026 | 9091 | 6066 | 9091 | 6026 | 9092 | 6066 | 9092 |
6027 | 9090 | 6067 | 9090 | 6027 | 9091 | 6067 | 9091 | 6027 | 9092 | 6067 | 9092 |
6028 | 9090 | 6068 | 9090 | 6028 | 9091 | 6068 | 9091 | 6028 | 9092 | 6068 | 9092 |
6029 | 9090 | 6069 | 9090 | 6029 | 9091 | 6069 | 9091 | 6029 | 9092 | 6069 | 9092 |
6030 | 9090 | 6070 | 9090 | 6030 | 9091 | 6070 | 9091 | 6030 | 9092 | 6070 | 9092 |
6031 | 9090 | 6071 | 9090 | 6031 | 9091 | 6071 | 9091 | 6031 | 9092 | 6071 | 9092 |
6032 | 9090 | 6072 | 9090 | 6032 | 9091 | 6072 | 9091 | 6032 | 9092 | 6072 | 9092 |
6033 | 9090 | 6073 | 9090 | 6033 | 9091 | 6073 | 9091 | 6033 | 9092 | 6073 | 9092 |
6034 | 9090 | 6074 | 9090 | 6034 | 9091 | 6074 | 9091 | 6034 | 9092 | 6074 | 9092 |
6035 | 9090 | 6075 | 9090 | 6035 | 9091 | 6075 | 9091 | 6035 | 9092 | 6075 | 9092 |
6036 | 9090 | 6076 | 9090 | 6036 | 9091 | 6076 | 9091 | 6036 | 9092 | 6076 | 9092 |
6037 | 9090 | 6077 | 9090 | 6037 | 9091 | 6077 | 9091 | 6037 | 9092 | 6077 | 9092 |
6038 | 9090 | 6078 | 9090 | 6038 | 9091 | 6078 | 9091 | 6038 | 9092 | 6078 | 9092 |
6039 | 9090 | 6039 | 9091 | 6039 | 9092 |
165
166
X:Y
6000:9096 6001:9096 6002:9096 6003 : 9096 6004:9096 •6005:9096-6006-90966007:9096 6008:9096 6009:9096 6010:9096 6011:9096
6012 : 9096
6013 : 9096 6014:9096
6015 : 9096
6016 : 9096
6017 : 9096 6018:9096 6019 : 9096 6020:9096 6021:9096 6022:9096 6023:9096 6024:9096 6025:9096 6026 : 9096 6027:9096 6028:9096 6029:9096 6030:9096 6031:9096 6032:9096 6033 : 9096 6034:9096 6035 : 9096 6036:9096 6037:9096 6038:9096 6039:9096
X | Y |
6040 | 9096 |
6041 | 9096 |
6042 | 9096 |
6043 | 9096 |
6044 | 9096 |
-6045 | -9096 |
6046 | 9096 |
6047 | 9096 |
6048 | 9096 |
6049 | 9096 |
6050 | 9096 |
6051 | 9096 |
6052 | 9096 |
6053 | 9096 |
6054 | 9096 |
6055 | 9096 |
6056 | 9096 |
6057 | 9096 |
6058 | 9096 |
6059 | 9096 |
6060 | 9096 |
6061 | 9096 |
6062 | 9096 |
6063 | 9096 |
6064 | 9096 |
6065 | 9096 |
6066 | 9096 |
6067 | 9096 |
6068 | 9096 |
6069 | 9096 |
6070 | 9096 |
6071 | 9096 |
6072 | 9096 |
6073 | 9096 |
6074 | 9096 |
6075 | 9096 |
6076 | 9096 |
6077 | 9096 |
6078 | 9096 |
Χ:Υ 6000:9097 6001:9097 6002:9097 6003:9097 6004:9097 6005:9097 6006:9097 6007:9097 6008:9097
6009 : 9097
6010 : 9097 6011:9097 6012 : 9097 6013:9097 6014 : 9097 6015:9097 6016:9097 6017:9097 6018:9097 6019 : 9097 6020:9097 6021:9097 6022:9097 6023:9097 6024:9097 6025 : 9097 6026:9097 6027 : 9097 6028:9097 6029:9097 6030:9097 6031:9097 6032:9097 6033 : 9097 6034:9097
6035 : 9097
6036 : 9097 6037:9097 6038:9097 6039:9097
Χ:Υ 6040:9097 6041:9097 6042:9097 6043:9097 6044:9097 6045 ^ 9097 6046:9097 6047:9097 6048:9097 6049:9097 6050 : 9097 6051:9097
6052 : 9097
6053 : 9097 6054:9097 6055:9097
6056 : 9097
6057 : 9097
6058 : 9097 6059:9097 6060 : 9097 6061:9097 6062:9097 6063:9097 6064:9097 6065:9097 6066:9097 6067 : 9097 6068:9097
6069 : 9097
6070 : 9097 6071:9097 6072:9097 6073 : 9097 6074:9097 6075 : 9097 6076:9097
6077 : 9097
6078 : 9097
Χ:Υ 6000:9098 6001:9098
6002 : 9098
6003 : 9098 6004:9098 6005:9098: 6006:90986007:9098 6008:9098 6009 : 9098 6010:9098 6011:9098 6012:9098 6013:9098
6014 : 9098
6015 : 9098
6016 : 9098
6017 : 9098 6018:9098 6019:9098 6020:9098 6021:9098
6022 : 9098
6023 : 9098
6024 : 9098 6025:9098 6026:9098 6027:9098
6028 : 9098
6029 : 9098 6030:9098
6031 :9098
6032 : 9098
6033 : 9098 6034:9098
6035 : 9098
6036 : 9098
6037 : 9098
6038 : 9098
6039 : 9098
Χ:Υ 6040:9098 6041:9098 6042:9098
6043 : 9098
6044 : 9098
6045 : 9098
6046 : 9098 6047:9098 6048 : 9098 6049:9098 6050:9098 6051:9098 6052:9098
6053 : 9098
6054 : 9098
6055 : 9098 6056:9098 6057:9098 6058:9098 6059 : 9098 6060:9098 6061:9098 6062 : 9098 6063:9098 6064:9098 6065:9098 6066:9098 6067:9098 6068 : 9098 6069:9098 6070:9098 6071:9098 6072:9098
6073 : 9098
6074 : 9098
6075 : 9098 6076:9098 6077 : 9098 6078:9098
167
X | Y | Χ:Υ | X | Y | X | Y | Χ:Υ | X | Y | ||
6000 | 9099 | 6040 | :9099 | 6000 | 9100 | 6040 | 9100 | 6000:9101 | 6040 | 9101 | |
6001 | 9099 | 6041 | :9099 | 6001 | 9100 | 6041 | 9100 | 6001:9101 | 6041 | 9101 | |
6002 | 9099 | 6042 | :9099 | 6002 | 9100 | 6042 | 9100 | 6002:9101 | 6042 | 9101 | |
6003 | 9099 | 6043 | :9099 | 6003 | 9100 | 6043 | 9100 | 6003:9101 | 6043 | 9101 | |
6004 | 9099 | 6044 | :9099 | 6004 | 9100 | 6044 | 9100 | 6004:9101 | 6044 | 9101 | |
— - - * | 6005 | 9099 | 6045 | :9099 | 6005 | 9100 | 6045 | 9100 | 6005:9101 | 6045 | 9101 |
-- | -6006 | 9099 | 6046 | ^9099- | 6006- | -9100 | 6046 | -9100 | -6006/9101 | 6046 | 9101 |
— | 6007 | 9099 | 6047 | 9099 | 6007 | 9100 | 6047 | 9100 | 6007 : 9101 | 6047 | 9101 |
6008 | 9099 | 6048 | 9099 | 6008 | 9100 | 6048 | 9100 | 6008:9101 | 6048 | 9101 | |
6009 | 9099 | 6049 | 9099 | 6009 | 9100 | 6049' | 9100 | 6009:9101 | 6049 | 9101 | |
6010 | 9099 | 6050 | 9099 | 6010 | 9100 | 6050 | 9100 | 6010:9101 | 6050 | 9101 | |
6011 | 9099 | 6051 | 9099 | 6011 | 9100 | 6051 | 9100 | 6011:9101 | 6051 | 9101 | |
6012 | 9099 | 6052 | 9099 | 6012 | 9100 | 6052 | 9100 | 6012:9101 | 6052 | 9101 | |
6013 | 9099 | 6053 | 9099 | 6013 | 9100 | 6053 | 9100 | 6013:9101 | 6053 | 9101 | |
6014 | 9099 | 6054 | 9099 | 6014 | 9100 | 6054 | 9100 | 6014:9101 | 6054 | 9101 | |
6015 | 9099 | 6055 | 9099 | 6015 | 9100 | 6055 | 9100 | 6015:9101 | 6055 | 9101 | |
6016 | 9099 | 6056 | 9099 | 6016 | 9100 | 6056 | 9100 | 6016:9101 | 6056 | 9101 | |
6017 | 9099 | 6057 | 9099 | 6017 | 9100 | 6057 | 9100 | 6017:9101 | 6057 | 9101 | |
6018 | 9099 | 6058 | 9099 | 6018 | 9100 | 6058 | 9100 | 6018:9101 | 6058 | 9101 | |
6019 | 9099 | 6059 | 9099 | 6019 | 9100 | 6059 | 9100 | 6019:9101 | 6059 | 9101 | |
6020 | 9099 | 6060 | 9099 | 6020 | 9100 | 6060 | 9100 | 6020 : 9101 | 6060 | 9101 | |
6021 | 9099 | 6061 | 9099 | 6021 | 9100 | 6061 | 9100 | 6021:9101 | 6061 | 9101 | |
6022 | 9099 | 6062 | 9099 | 6022 | 9100 | 6062 | 9100 | 6022:9101 | 6062 | 9101 | |
6023 | 9099 | 6063 | 9099 | 6023 | 9100 | 6063 | 9100 | 6023 : 9101 | 6063 | 9101 | |
6024 | 9099 | 6064 | 9099 | 6024 | 9100 | 6064 | 9100 | 6024 : 9101 | 6064 | 9101 | |
6025 | 9099 | 6065 | 9099 | 6025 | 9100 | 6065 | 9100 | 6025:9101 | 6065 | 9101 | |
6026 | 9099 | 6066 | 9099 | 6026 | 9100 | 6066 | 9100 | 6026 : 9101 | 6066 | 9101 | |
6027 | 9099 | 6067 | 9099 | 6027 | 9100 | 6067 | 9100 | 6027:9101 | 6067 | 9101 | |
6028 | 9099 | 6068 | 9099 | 6028 | 9100 | 6068 | 9100 | 6028 : 9101 | 6068 | 9101 | |
6029 | 9099 | 6069 | 9099 | 6029 | 9100 | 6069 | 9100 | 6029 : 9101 | 6069 | 9101 | |
6030 | 9099 | 6070 | 9099 | 6030 | 9100 | 6070 | 9100 | 6030 : 9101 | 6070 | 9101 | |
6031 | 9099 | 6071 | 9099 | 6031 | 9100 | 6071 | 9100 | 6031:9101 | 6071 | 9101 | |
6032 | 9099 | 6072 | 9099 | 6032 | 9100 | 6072 | 9100 | 6032 : 9101 | 6072 | 9101 | |
6033 | 9099 | 6073 | 9099 | 6033 | 9100 | 6073 | 9100 | 6033 : 9101 | 6073 | 9101 | |
6034 | 9099 | 6074 | 9099 | 6034 | 9100 | 6074 | 9100 | 6034 : 9101 | 6074 | 9101 | |
6035 | 9099 | 6075 | 9099 | 6035 | 9100 | 6075 | 9100 | 6035 : 9101 | 6075 | 9101 | |
6036 | 9099 | 6076 | 9099 | 6036 | 9100 | 6076 | 9100 | 6036 : 9101 | 6076 | 9101 | |
6037 | 9099 | 6077 | 9099 | 6037 | 9100 | 6077 | 9100 | 6037:9101 | 6077 | 9101 | |
6038 6039 | 9099 9099 | 6078 | 9099 | 6038 6039 | 9100 9100 | 6078 | 9100 | 6038 : 9101 6039 : 9101 | 6078 | 9101 |
I68
X | Y | X | Y | X | Y | X | : Y | X: Y | X | Y |
6000 | 9102 | 6040 | 9102 | 6000 | 9103 | 6040 | :9103 | 6000:9104 | 6040 | 9104 |
6001 | 9102 | 6041 | :9102 | 6001 | 9103 | 6041 | :9103 | 6001:9104 | 6041 | 9104 |
6002 | 9102 | 6042 | :9102 | 6002 | 9103 | 6042 | :9103 | 6002:9104 | 6042 | 9104 |
6003 | 9102 | 6043 | :9102 | 6003 | 9103 | 6043 | :9103 | 6003 : 9104 | 6043 | 9104 |
6004 | 9102 | 6044 | :9102 | 6004 | 9103 | 6044 | :9103 | 6004:9104 | 6044 | 9104 |
6005 | -9102- | 6045 | 9102 | 6005. | 9103 | 6045 | :9103 | 6005*9104 | 6045 | 9104 |
6006 | -9102: | 6046; | -9102 | 6006^ | 9103- | 6046*9103- | 6006*9104- | 6046 | 9104 | |
6007 | 9102 | 6047 | 9102 | 6007 | 9103 | 6047 | 9103 | 6007:9104 | 6047 | 9104 |
6008 | 9102 | 6048 | 9102 | 6008 | 9103 | 6048 | 9103 | 6008:9104 | 6048 | 9104 |
6009 | 9102 | 6049 | 9102 | 6009 | 9103 | 6049 | 9103 | 6009 : 9104 | 6049 | 9104 |
6010 | 9102 | 6050 | 9102 | 6010 | 9103 | 6050 | 9103 | 6010:9104 | 6050 | 9104 |
60 U | 9102 | 6051 | 9102 | 6011 | 9103 | 6051 | 9103 | 6011:9104 | 6051 | 9104 |
6012 | 9102 | 6052 | 9102 | 6012 | 9103 | 6052 | 9103 | 6012:9104 | 6052 | 9104 |
6013 | 9102 | 6053 | 9102 | 6013 | 9103 | 6053 | 9103 | 6013:9104 | 6053 | 9104 |
6014 | 9102 | 6054 | 9102 | 6014 | 9103 | 6054 | 9103 | 6014:9104 | 6054 | 9104 |
6015 | 9102 | 6055 | 9102 | 6015 | 9103 | 6055 | 9103 | 6015:9104 | 6055 | 9104 |
6016 | 9102 | 6056 | 9102 | 6016 | 9103 | 6056 | 9103 | 6016:9104 | 6056 | 9104 |
6017 | 9102 | 6057 | 9102 | 6017 | 9103 | 6057 | 9103 | 6017:9104 | 6057 | 9104 |
6018 | 9102 | 6058 | 9102 | 6018 | 9103 | 6058 | 9103 | 6018:9104 | 6058 | 9104 |
6019 | 9102 | 6059 | 9102 | 6019 | 9103 | 6059 | 9103 | 6019:9104 | 6059 | 9104 |
6020 | 9102 | 6060 | 9102 | 6020 | 9103 | 6060 | 9103 | 6020 : 9104 | 6060 | 9104 |
6021 | 9102 | 6061 | 9102 | 6021 | 9103 | 6061 | 9103 | 6021:9104 | 6061 | 9104 |
6022 | 9102 | 6062 | 9102 | 6022 | 9103 | 6062 | 9103 | 6022:9104 | 6062 | 9104 |
6023 | 9102 | 6063 | 9102 | 6023 | 9103 | 6063 | 9103 | 6023:9104 | 6063 | 9104 |
6024 | 9102 | 6064 | 9102 | 6024 | 9103 | 6064 | 9103 | 6024:9104 | 6064 | 9104 |
6025 | 9102 | 6065 | 9102 | 6025 | 9103 | 6065 | 9103 | 6025 : 9104 | 6065 | 9104 |
6026 | 9102 | 6066 | 9102 | 6026 | 9103 | 6066 | 9103 | 6026:9104 | 6066 | 9104 |
6027 | 9102 | 6067 | 9102 | 6027 | 9103 | 6067 | 9103 | 6027:9104 | 6067 | 9104 |
6028 | 9102 | 6068 | 9102 | 6028 | 9103 | 6068 | 9103 | 6028:9104 | 6068 | 9104 |
6029 | 9102 | 6069 | 9102 | 6029 | 9103 | 6069 | 9103 | 6029:9104 | 6069 | 9104 |
6030 | 9102 | 6070 | 9102 | 6030 | 9103 | 6070 | 9103 | 6030 : 9104 | 6070 | 9104 |
6031 | 9102 | 6071 | 9102 | 6031 | 9103 | 6071 | 9103 | 6031:9104 | 6071 | 9104 |
6032 | 9102 | 6072 | 9102 | 6032 | 9103 | 6072 | 9103 | 6032 : 9104 | 6072 | 9104 |
6033 | 9102 | 6073 | 9102 | 6033 | 9103 | 6073 | 9103 | 6033:9104 | 6073 | 9104 |
6034 | 9102 | 6074 | 9102 | 6034 | 9103 | 6074 | 9103 | 6034:9104 | 6074 | 9104 |
6035 | 9102 | 6075 | 9102 | 6035 | 9103 | 6075 | 9103 | 6035 : 9104 | 6075 | 9104 |
6036 | 9102 | 6076 | 9102 | 6036 | 9103 | 6076 | 9103 | 6036 : 9104 | 6076 | 9104 |
6037 | 9102 | 6077 | 9102 | 6037 | 9103 | 6077 | 9103 | 6037 : 9104 | 6077 | 9104 |
6038 | 9102 | 6078 | 9102 | 6038 | 9103 | 6078 | 9103 | 6038 : 9104 | 6078 | 9104 |
6039 | 9102 | 6039 | 9103 | 6039 : 9104 |
169
X | Y | X: Y | X: Y | X:Y | X:Y | Χ:Υ |
6000 | 9105 | 6040:9105 | ||||
6001 | 9105 | 6041:9105 | ||||
6002 | 9105 | 6042:9105 | ||||
6003 | 9105 | 6043:9105 | ||||
6004 | 9105 | 6044:9105 | - | |||
-6005 | 9105 | 6045 r9105 | ,W.. | ”15 - . | ||
-6006 | -9105 | 6O46S91O5 | -7·—- | |||
6007 | 9105 | 6047Ï9105 | -* - | - - . ” — | ||
6008 | 9105 | 6048:9105 | ||||
6009 | 9105 | 6049:9105 | ||||
6010 | 9105 | 6050:9105 | ||||
6011 | 9105 | 6051:9105 | ||||
6012 | 9105 | 6052:9105 | ||||
6013 | 9105 | 6053 : 9105 | ||||
6014 | 9105 | 6054:9105 | ||||
6015 | 9105 | 6055:9105 | ||||
6016 | 9105 | 6056 : 9105 | ||||
6017 | 9105 | 6057 : 9105 | ||||
6018 | 9105 | 6058:9105 | ||||
6019 | 9105 | 6059 : 9105 | ||||
6020 | 9105 | 6060 : 9105 | ||||
6021 | 9105 | 6061:9105 | ||||
6022 | 9105 | 6062:9105 | ||||
6023 | 9105 | 6063:9105 | ||||
6024 | 9105 | 6064:9105 | ||||
6025 | 9105 | 6065 : 9105 | ||||
6026 | 9105 | 6066 : 9105 | ||||
6027 | 9105 | 6067 : 9105 | ||||
6028 | 9105 | 6068 : 9105 | ||||
6029 | 9105 | 6069 : 9105 | ||||
6030 | 9105 | 6070:9105 | ||||
6031 | 9105 | 6071:9105 | ||||
6032 | 9105 | 6072:9105 | ||||
6033 | 9105 | 6073 : 9105 | ||||
6034 | 9105 | 6074 : 9105 | ||||
6035 | 9105 | 6075 : 9105 | ||||
6036 | 9105 | 6076:9105 | ||||
6037 | 9105 | 6077:9105 | ||||
6038 | 9105 | 6078:9105 | ||||
6039 | 9105 |
170
Table E: Example combinations of a compound X with a compound Y.
X:Y | X:Y | X:Y | X:Y | X:Y | X:Y |
8000:9000 | 8000 : 9001 | 8000:9002 | 8000:9003 | 8000:9004 | 8000:9005 |
8001:9000 | 8001:9001 | 8001:9002 | 8001:9003 | 8001:9004 | 8001:9005 |
8002:.9000 | 8002:9001 | 8002:9002 | 8002 : 9003 | 8002:9004 | 8002:9005 |
8003:9000 | 8003:9001 | 8003 : 9002 | 8003 : 9003 | 8003 : 9004 | 8003:9005 |
8004:9000 | 8004:9001 | 8004 : 9002 | 8004:9003 | 8004:9004 | 8004:9005 |
8005:9000 | 8005:9001 | 8005 : 9002 | 8005 : 9003 | 8005:9004 | 8005:9005 |
8006 : 9000 | 8006 : 9001 | 8006:9002 | 8006:9003 | 8006:9004 | 8006:9005 |
8007:9000 | 8007 : 9001 | 8007 : 9002 | 8007 : 9003 | 8007:9004 | 8007:9005 |
8008:9000 | 8008:9001 | 8008:9002 | 8008:9003 | 8008:9004 | 8008:9005 |
8009 : 9000 | 8009:9001 | 8009:9002 | 8009:9003 | 8009:9004 | 8009 : 9005 |
8010 : 9000 | 8010:9001 | 8010:9002 | 8010:9003 | 8010:9004 | 8010:9005 |
8011:9000 | 8011:9001 | 8011:9002 | 8011 :9003 | 8011:9004 | 8011 :9005 |
8012 : 9000 | 8012 : 9001 | 8012:9002 | 8012:9003 | 8012:9004 | 8012 : 9005 |
8013 : 9000 | 8013:9001 | 8013:9002 | 8013:9003 | 8013 : 9004 | 8013 : 9005 |
8014:9000 | 8014 : 9001 | 8014:9002 | 8014:9003 | 8014:9004 | 8014 : 9005 |
8015:9000 | 8015:9001 | 8015:9002 | 8015:9003 | 8015:9004 | 8015:9005 |
8016 : 9000 | 8016:9001 | 8016:9002 | 8016 : 9003 | 8016:9004 | 8016:9005 |
8000:9006 | 8000:9007 | 8000 : 9008 | 8000:9009 | 8000:9010 | 8000:9011 |
8001:9006 | 8001:9007 | 8001:9008 | 8001:9009 | 8001:9010 | 8001:9011 |
8002 : 9006 | 8002:9007 | 8002:9008 | 8002:9009 | 8002:9010 | 8002:9011 |
8003:9006 | 8003:9007 | 8003:9008 | 8003:9009 | 8003 : 9010 | 8003:9011 |
8004 : 9006 | 8004 : 9007 | 8004 : 9008 | 8004 : 9009 | 8004 : 9010 | 8004:9011 |
8005 : 9006 | 8005:9007 | 8005 : 9008 | 8005:9009 | 8005 : 9010 | 8005:9011 |
8006:9006 | 8006 : 9007 | 8006:9008 | 8006:9009 | 8006:9010 | 8006:9011 |
8007:9006 | 8007:9007 | 8007:9008 | 8007:9009 | 8007:9010 | 8007:9011 |
8008 : 9006 | 8008:9007 | 8008:9008 | 8008 : 9009 | 8008:9010 | 8008:9011 |
8009:9006 | 8009 : 9007 | 8009 : 9008 | 8009:9009 | 8009:9010 | 8009 : 9011 |
8010:9006 | 8010:9007 | 8010:9008 | 8010:9009 | 8010:9010 | 8010:9011 |
8011 :9006 | 8011:9007 | 8011:9008 | 8011:9009 | 8011:9010 | 8011:9011 |
8012 : 9006 | 8012:9007 | 8012:9008 | 8012:9009 | 8012:9010 | 8012:9011 |
8013 : 9006 | 8013:9007 | 8013 : 9008 | 8013:9009 | 8013:9010 | 8013:9011 |
8014:9006 | 8014 : 9007 | 8014:9008 | 8014:9009 | 8014:9010 | 8014:9011 |
8015:9006 | 8015 : 9007 | 8015:9008 | 8015:9009 | 8015:9010 | 8015:9011 |
8016:9006 | 8016 : 9007 | 8016 : 9008 | 8016 : 9009 | 8016:9010 | 8016:9011 |
171
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | |
8000:9012 | 8000:9013 | 8000:9014 | 8000:9015 | 8000 | 9016 | 8000:9017 |
8001:9012 | 8001:9013 | 8001:9014 | 8001:9015 | 8001 | 9016 | 8001:9017 |
8002:9012 | 8002:9013 | 8002:9014 | 8002:9015 | 8002 | 9016 | 8002:9017 |
8003:9012 | 8003:9013 | 8003:9014 | 8003 : 9015 | 8003 | 9016 | 8003:9017 |
'8004:9012 | 8004:9013 | 8004:9014 | 8004:9015’ | 8004 | 9016 | 8004:9017 |
8005:9012 | 8005:9013 | 8005 Γ 9014 | 8005 : 9015 | 8005 | 9016 | 8005:9017 |
8006:9012 | 8006 : 9013 | 8006 : 9014 | 8006:9015 | '8006 | 9016 | 8006:9017 |
8007:9012 | 8007 : 9013 | 8007:9014 | 8007:9015 | 8007 | 9016 | 8007:9017 |
8008:9012 | 8008:9013 | 8008:9014 | 8008:9015 | 8008 | 9016 | 8008:9017 |
8009:9012 | 8009 : 9013 | 8009:9014 | 8009:9015 | 8009 | 9016 | 8009:9017 |
8010:9012 | 8010:9013 | 8010:9014 | 8010:9015 | 8010 | 9016 | 8010:9017 |
8011:9012 | 8011:9013 | 8011:9014 | 8011 :9015 | 8011 | 9016 | 8011:9017 |
8012:9012 | 8012:9013 | 8012:9014 | 8012:9015 | 8012 | 9016 | 8012:9017 |
8013:9012 | 8013:9013 | 8013:9014 | 8013:9015 | 8013 | 9016 | 8013:9017 |
8014:9012 | 8014:9013 | 8014:9014 | 8014:9015 | 8014 | 9016 | 8014:9017 |
8015 : 9012 | 8015:9013 | 8015:9014 | 8015:9015 | 8015 | 9016 | 8015:9017 |
8016:9012 | 8016:9013 | 8016:9014 | 8016:9015 | 8016 | 9016 | 8016:9017 |
8000:9018 | 8000:9019 | 8000:9020 | 8000:9021 | 8000 | 9022 | 8000:9023 |
8001:9018 | 8001:9019 | 8001:9020 | 8001:9021 | 8001 | 9022 | 8001 :9023 |
8002:9018 | 8002:9019 | 8002 : 9020 | 8002:9021 | 8002 | 9022 | 8002:9023 |
8003:9018 | 8003:9019 | 8003 : 9020 | 8003:9021 | 8003 | 9022 | 8003:9023 |
8004:9018 | 8004:9019 | 8004:9020 | 8004 : 9021 | 8004 | 9022 | 8004 : 9023 |
8005:9018 | 8005 : 9019 | 8005 : 9020 | 8005 : 9021 | 8005 | 9022 | 8005:9023 |
8006:9018 | 8006:9019 | 8006 : 9020 | 8006 : 9021 | 8006 | 9022 | 8006:9023 |
8007:9018 | 8007:9019 | 8007:9020 | 8007:9021 | 8007 | 9022 | 8007:9023 |
8008:9018 | 8008:9019 | 8008:9020 | 8008:9021 | 8008 | 9022 | 8008:9023 |
8009 : 9018 | 8009 : 9019 | 8009 : 9020 | 8009:9021 | 8009 | 9022 | 8009 : 9023 |
8010:9018 | 8010:9019 | 8010 : 9020 | 8010:9021 | 8010 | 9022 | 8010:9023 |
8011:9018 | 8011 :9019 | 8011:9020 | 8011:9021 | 8011 | 9022 | 8011 :9023 |
8012:9018 | 8012:9019 | 8012:9020 | 8012 : 9021 | 8012 | 9022 | 8012 : 9023 |
8013:9018 | 8013:9019 | 8013:9020 | 8013 : 9021 | 8013 | 9022 | 8013:9023 |
8014:9018 | 8014 : 9019 | 8014:9020 | 8014 : 9021 | 8014 | 9022 | 8014 : 9023 |
8015:9018 | 8015:9019 | 8015:9020 | 8015 : 9021 | 8015 | 9022 | 8015:9023 |
8016:9018 | 8016:9019 | 8016:9020 | 8016 : 9021 | 8016 | 9022 | 8016:9023 |
I72
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | X: Y |
8000 : 9024 | 8000:9025 | 8000:9026 | 8000 : 9027 | 8000:9028 | 8000:9029 |
8001:9024 | 8001:9025 | 8001:9026 | 8001:9027 | 8001:9028 | 8001 :9029 |
8002:9024 | 8002:9025 | 8002 : 9026 | 8002:9027 | 8002:9028 | 8002:9029 |
8003:9024 | 8003:9025 | 8003:9026 | 8003 : 9027 | 8003 : 9028 | 8003:9029 |
8004:9024 | 8004:9025. | .8004:9026 | '800419027 | .8004 : 9028 | 8004:9029 |
8005:9024 | -8005 : 9025 | -8005:9026- | :8005 : 9027 | 8005:9028 | :8005 : 9029 |
8006:9024 | 8006:9025 | 8006:9026 | 8006 : 9027 | 8006 : 9028 | 8006:9029 |
8007 : 9024 | 8007:9025 | 8007:9026 | 8007:9027 | 8007 : 9028 | 8007:9029 |
8008 : 9024 | 8008:9025 | 8008:9026 | 8008 : 9027 | 8008:9028 | 8008:9029 |
8009:9024 | 8009:9025 | 8009:9026 | 8009:9027 | 8009 : 9028 | 8009:9029 |
8010 : 9024 | 8010:9025 | 8010:9026 | 8010:9027 | 8010:9028 | 8010:9029 |
8011:9024 | 8011:9025 | 8011:9026 | 8011:9027 | 8011:9028 | 8011:9029 |
8012 : 9024 | 8012:9025 | 8012:9026 | 8012 : 9027 | 8012:9028 | 8012 : 9029 |
8013 : 9024 | 8013:9025 | 8013 : 9026 | 8013:9027 | 8013:9028 | 8013 : 9029 |
8014 : 9024 | 8014:9025 | 8014:9026 | 8014:9027 | 8014:9028 | 8014:9029 |
8015 : 9024 | 8015 : 9025 | 8015 : 9026 | 8015:9027 | 8015:9028 | 8015:9029 |
8016:9024 | 8016 : 9025 | 8016:9026 | 8016:9027 | 8016 : 9028 | 8016:9029 |
8000:9030 | 8000:9031 | 8000:9032 | 8000 : 9033 | 8000 : 9034 | 8000:9035 |
8001 :9030 | 8001:9031 | 8001:9032 | 8001:9033 | 8001:9034 | 8001 :9035 |
8002 : 9030 | 8002:9031 | 8002:9032 | 8002:9033 | 8002 : 9034 | 8002:9035 |
8003:9030 | 8003 : 9031 | 8003:9032 | 8003 : 9033 | 8003:9034 | 8003 : 9035 |
8004:9030 | 8004:9031 | 8004:9032 | 8004:9033 | 8004:9034 | 8004:9035 |
8005 : 9030 | 8005:9031 | 8005:9032 | 8005:9033 | 8005 : 9034 | 8005:9035 |
8006 : 9030 | 8006:9031 | 8006:9032 | 8006:9033 | 8006 : 9034 | 8006:9035 |
8007:9030 | 8007:9031 | 8007:9032 | 8007 : 9033 | 8007 : 9034 | 8007:9035 |
8008:9030 | 8008:9031 | 8008:9032 | 8008 : 9033 | 8008 : 9034 | 8008:9035 |
8009:9030 | 8009:9031 | 8009:9032 | 8009 : 9033 | 8009 : 9034 | 8009 : 9035 |
8010 : 9030 | 8010:9031 | 8010:9032 | 8010 : 9033 | 8010 : 9034 | 8010:9035 |
8011 :9030 | 8011:9031 | 8011 :9032 | 8011:9033 | 8011:9034 | 8011:9035 |
8012 : 9030 | 8012:9031 | 8012 : 9032 | 8012 : 9033 | 8012:9034 | 8012 : 9035 |
8013:9030 | 8013 : 9031 | 8013:9032 | 8013:9033 | 8013:9034 | 8013:9035 |
8014 : 9030 | 8014:9031 | 8014:9032 | 8014:9033 | 8014:9034 | 8014:9035 |
8015:9030 | 8015:9031 | 8015 : 9032 | 8015 : 9033 | 8015 : 9034 | 8015:9035 |
8016 : 9030 | 8016 : 9031 | 8016:9032 | 8016:9033 | 8016:9034 | 8016:9035 |
173
X: Y | X:Y | X:Y | X:Y | X:Y | X:Y |
8000:9036 | 8000:9037 | 8000:9038 | 8000:9039 | 8000:9040 | 8000:9041 |
8001:9036 | 8001:9037 | 8001 :9038 | 8001 :9039 | 8001:9040 | 8001:9041 |
8002:9036 | 8002 : 9037 | 8002 : 9038 | 8002:9039 | 8002 : 9040 | 8002:9041 |
8003 : 9036 | 8003:9037 | 8003 : 9038 | 8003 : 9039 | 8003 : 9040 | 8003 : 9041 |
8004:9036 | 18004:9037 | .8004 :9038 | '8004 :-9039 | 28004^9040 | 8004:9041 |
8005-r9036 | -8005 :9037 - | -8005 r9038* | -8005:9039- | -8005:9040 | 8005:9041 |
8006 : 9036 | 8006:9037 | 8006:9038 | 8006:9039 | 8006:9040 | 8006 : 9041 |
8007:9036 | 8007 : 9037 | 8007 : 9038 | 8007:9039 | 8007:9040 | 8007 : 9041 |
8008 : 9036 | 8008:9037 | 8008 : 9038 | 8008:9039 | 8008 : 9040 | 8008:9041 |
8009 : 9036 | 8009:9037 | 8009 : 9038 | 8009 : 9039 | 8009 : 9040 | 8009:9041 |
8010 : 9036 | 8010:9037 | 8010:9038 | 8010:9039 | 8010 : 9040 | 8010:9041 |
8011 :9036 | 8011:9037 | 8011:9038 | 8011 :9039 | 8011:9040 | 8011:9041 |
8012 : 9036 | 8012:9037 | 8012:9038 | 8012:9039 | 8012 : 9040 | 8012:9041 |
8013 : 9036 | 8013:9037 | 8013 : 9038 | 8013:9039 | 8013:9040 | 8013:9041 |
8014:9036 | 8014:9037 | 8014:9038 | 8014 : 9039 | 8014:9040 | 8014 : 9041 |
8015 : 9036 | 8015:9037 | 8015:9038 | 8015 : 9039 | 8015:9040 | 8015:9041 |
8016:9036 | 8016 : 9037 | 8016:9038 | 8016 : 9039 | 8016:9040 | 8016 : 9041 |
8000:9042 | 8000 : 9043 | 8000:9044 | 8000:9045 | 8000:9046 | 8000:9047 |
8001:9042 | 8001:9043 | 8001:9044 | 8001 :9045 | 8001:9046 | 8001:9047 |
8002 : 9042 | 8002:9043 | 8002 : 9044 | 8002:9045 | 8002 : 9046 | 8002:9047 |
8003 : 9042 | 8003:9043 | 8003 : 9044 | 8003:9045 | 8003 : 9046 | 8003:9047 |
8004:9042 | 8004 : 9043 | 8004:9044 | 8004 : 9045 | 8004:9046 | 8004:9047 |
8005 : 9042 | 8005 : 9043 | 8005:9044 | 8005:9045 | 8005 : 9046 | 8005:9047 |
8006 : 9042 | 8006 : 9043 | 8006 : 9044 | 8006:9045 | 8006 : 9046 | 8006:9047 |
8007:9042 | 8007:9043 | 8007 : 9044 | 8007:9045 | 8007 : 9046 | 8007:9047 |
8008:9042 | 8008:9043 | 8008 : 9044 | 8008:9045 | 8008:9046 | 8008:9047 |
8009 : 9042 | 8009:9043 | 8009:9044 | 8009:9045 | 8009 : 9046 | 8009:9047 |
8010:9042 | 8010:9043 | 8010 : 9044 | 8010:9045 | 8010 : 9046 | 8010:9047 |
8011:9042 | 8011 :9043 | 8011 :9044 | 8011 :9045 | 8011 :9046 | 8011:9047 |
8012:9042 | 8012:9043 | 8012:9044 | 8012:9045 | 8012:9046 | 8012 : 9047 |
8013:9042 | 8013 : 9043 | 8013:9044 | 8013 : 9045 | 8013 : 9046 | 8013 : 9047 |
8014 : 9042 | 8014:9043 | 8014:9044 | 8014 : 9045 | 8014:9046 | 8014:9047 |
8015:9042 | 8015 : 9043 | 8015 : 9044 | 8015:9045 | 8015 : 9046 | 8015 : 9047 |
8016:9042 | 8016:9043 | 8016:9044 | 8016 : 9045 | 8016:9046 | 8016 : 9047 |
174
X: Y | X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ |
8000:9048 | 8000:9049 | 8000:9050 | 8000 : 9051 | 8000:9052 | 8000 : 9053 |
8001:9048 | 8001:9049 | 8001:9050 | 8001:9051 | 8001:9052 | 8001:9053 |
8002:9048 | 8002:9049 | 8002 : 9050 | 8002:9051 | 8002:9052 | 8002 : 9053 |
8003 : 9048 | 8003:9049 | 8003 : 9050 | 8003 : 9051 | 8003:9052 | 8003 : 9053 |
8004x9048 | : 8004x9049: | .8004 :-9050 | -8004-: 905 L· | .8004 :.9052 | -8004 : 9053 |
8005x9048 | -8005x9049- | -8005 x9050 | -8005:905 b | -8005x9052 | -8005 : 9053 |
8006:9048 | 8006:9049 | 8006:9050 | 8006:9051 | 8006:9052 | 8006:9053 |
8007 : 9048 | 8007 : 9049 | 8007:9050 | 8007:9051 | 8007:9052 | 8007 : 9053 |
8008 : 9048 | 8008:9049 | 8008:9050 | 8008:9051 | 8008 : 9052 | 8008 : 9053 |
8009 : 9048 | 8009:9049 | 8009:9050 | 8009 : 9051 | 8009:9052 | 8009 : 9053 |
8010:9048 | 8010 : 9049 | 8010 : 9050 | 8010 : 9051 | 8010:9052 | 8010:9053 |
8011:9048 | 8011:9049 | 8011:9050 | 8011 :9051 | 8011 :9052 | 8011:9053 |
8012 : 9048 | 8012:9049 | 8012 : 9050 | 8012 : 9051 | 8012 : 9052 | 8012 : 9053 |
8013:9048 | 8013:9049 | 8013:9050 | 8013:9051 | 8013 : 9052 | 8013:9053 |
8014:9048 | 8014 : 9049 | 8014:9050 | 8014 : 9051 | 8014 : 9052 | 8014 : 9053 |
8015 : 9048 | 8015:9049 | 8015 : 9050 | 8015:9051 | 8015 : 9052 | 8015 : 9053 |
8016 : 9048 | 8016:9049 | 8016:9050 | 8016:9051 | 8016 : 9052 | 8016 : 9053 |
8000 : 9054 | 8000:9055 | 8000:9056 | 8000 : 9057 | 8000:9058 | 8000 : 9059 |
8001:9054 | 8001:9055 | 8001:9056 | 8001:9057 | 8001:9058 | 8001 :9059 |
8002 : 9054 | 8002:9055 | 8002 : 9056 | 8002:9057 | 8002:9058 | 8002:9059 |
8003 : 9054 | 8003:9055 | 8003 : 9056 | 8003 : 9057 | 8003:9058 | 8003 : 9059 |
8004:9054 | 8004:9055 | 8004 : 9056 | 8004 : 9057 | 8004:9058 | 8004 : 9059 |
8005 : 9054 | 8005 : 9055 | 8005:9056 | 8005:9057 | 8005:9058 | 8005:9059 |
8006 : 9054 | 8006:9055 | 8006:9056 | 8006:9057 | 8006 : 9058 | 8006 : 9059 |
8007:9054 | 8007:9055 | 8007:9056 | 8007:9057 | 8007:9058 | 8007:9059 |
8008 : 9054 | 8008:9055 | 8008:9056 | 8008 : 9057 | 8008:9058 | 8008:9059 |
8009 : 9054 | 8009 : 9055 | 8009 : 9056 | 8009 : 9057 | 8009:9058 | 8009 : 9059 |
8010:9054 | 8010 : 9055 | 8010 : 9056 | 8010 : 9057 | 8010:9058 | 8010 : 9059 |
8011:9054 | 8011 :9055 | 8011:9056 | 8011 :9057 | 8011:9058 | 8011 :9059 |
8012 : 9054 | 8012 : 9055 | 8012 : 9056 | 8012:9057 | 8012:9058 | 8012 : 9059 |
8013:9054 | 8013 : 9055 | 8013:9056 | 8013 : 9057 | 8013:9058 | 8013:9059 |
8014:9054 | 8014:9055 | 8014:9056 | 8014 : 9057 | 8014:9058 | 8014 : 9059 |
8015:9054 | 8015 : 9055 | 8015:9056 | 8015:9057 | 8015 : 9058 | 8015:9059 |
8016 : 9054 | 8016:9055 | 8016:9056 | 8016 : 9057 | 8016:9058 | 8016:9059 |
175
X: Y | X:Y | X:Y | Χ:Υ | Χ:Υ | Χ:Υ |
8000 : 9060 | 8000:9061 | 8000 : 9062 | 8000 : 9063 | 8000:9064 | 8000:9065 |
8001:9060 | 8001:9061 | 8001:9062 | 8001:9063 | 8001:9064 | 8001 :9065 |
8002:9060 | 8002 : 9061 | 8002:9062 | 8002:9063 | 8002:9064 | 8002:9065 |
8003:9060 | 8003:9061 | 8003:.9062 | 8003:9063 | 8003:9064 | 8003 : 9065 |
8004 : 9060 | -8004:9061 | 8004:9062- | -8004:9063 | 8004:9064 | 8004:9065 |
8005-: 9060 | -8005:-9061- | 8005 τ 9062“ | -8005-Γ9063- | -8005-Τ9064- | 8005:9065 |
8006:9060 | 8006:9061 | 8006:9062 | 8006:9063 | 8006 : 9064 | 8006:9065 |
8007:9060 | 8007 : 9061 | 8007:9062 | 8007:9063 | 8007 : 9064 | 8007:9065 |
8008:9060 | 8008:9061 | 8008:9062 | 8008:9063 | 8008:9064 | 8008 : 9065 |
8009 : 9060 | 8009 : 9061 | 8009:9062 | 8009:9063 | 8009:9064 | 8009:9065 |
8010 : 9060 | 8010:9061 | 8010 : 9062 | 8010:9063 | 8010:9064 | 8010 : 9065 |
8011:9060 | 8011:9061 | 8011 :9062 | 8011 :9063 | 8011:9064 | 8011:9065 |
8012 : 9060 | 8012:9061 | 8012 : 9062 | 8012:9063 | 8012:9064 | 8012 : 9065 |
8013 : 9060 | 8013:9061 | 8013 : 9062 | 8013:9063 | 8013 : 9064 | 8013:9065 |
8014:9060 | 8014 : 9061 | 8014 : 9062 | 8014 : 9063 | 8014:9064 | 8014:9065 |
8015:9060 | 8015:9061 | 8015:9062 | 8015:9063 | 8015 : 9064 | 8015 : 9065 |
8016:9060 | 8016:9061 | 8016:9062 | 8016:9063 | 8016:9064 | 8016:9065 |
8000 : 9066 | 8000 : 9067 | 8000 : 9068 | 8000:9069 | 8000 : 9070 | 8000:9071 |
8001:9066 | 8001:9067 | 8001 :9068 | 8001:9069 | 8001:9070 | 8001 :9071 |
8002 ; 9066 | 8002:9067 | 8002:9068 | 8002:9069 | 8002:9070 | 8002:9071 |
8003:9066 | 8003:9067 | 8003:9068 | 8003:9069 | 8003 : 9070 | 8003 : 9071 |
8004:9066 | 8004:9067 | 8004 : 9068 | 8004:9069 | 8004:9070 | 8004:9071 |
8005:9066 | 8005:9067 | 8005 : 9068 | 8005:9069 | 8005 : 9070 | 8005 : 9071 |
8006 : 9066 | 8006:9067 | 8006:9068 | 8006 : 9069 | 8006 : 9070 | 8006 : 9071 |
8007:9066 | 8007:9067 | 8007:9068 | 8007:9069 | 8007 : 9070 | 8007 : 9071 |
8008:9066 | 8008 : 9067 | 8008 : 9068 | 8008 : 9069 | 8008 : 9070 | 8008:9071 |
8009:9066 | 8009:9067 | 8009 : 9068 | 8009:9069 | 8009:9070 | 8009:9071 |
8010:9066 | 8010:9067 | 8010:9068 | 8010 : 9069 | 8010 : 9070 | 8010 : 9071 |
8011 :9066 | 8011:9067 | 8011 :9068 | 8011:9069 | 8011:9070 | 8011 :9071 |
8012:9066 | 8012:9067 | 8012:9068 | 8012:9069 | 8012 : 9070 | 8012 : 9071 |
8013 : 9066 | 8013:9067 | 8013:9068 | 8013:9069 | 8013 : 9070 | 8013:9071 |
8014:9066 | 8014:9067 | 8014:9068 | 8014 : 9069 | 8014:9070 | 8014 : 9071 |
8015:9066 | 8015:9067 | 8015 : 9068 | 8015:9069 | 8015:9070 | 8015:9071 |
8016:9066 | 8016:9067 | 8016:9068 | 8016:9069 | 8016 : 9070 | 8016:9071 |
176
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ |
8000:9072 | 8000 : 9073 | 8000 : 9074 | 8000:9075 | 8000:9076 | 8000:9077 |
8001:9072 | 8001:9073 | 8001:9074 | 8001 :9075 | 8001:9076 | 8001:9077 |
8002:9072 | 8002:9073 | 8002 : 9074 | 8002:9075 | 8002:9076 | 8002:9077 |
8003:9072 | 8003 : 9073 | 8003 : 9074. | 8003 : 9075 | 8003:9076 | 8003:9077 |
8004:9072 | 8004:9073 | 8004:9074 | 8004:9075 | 8004:9076 | 8004:9077 |
- 8005-: 9072 | - 8005 r9073 - | -8005:9074 | 8005 r9075 | 8005τ9076 | -8005:9077 |
8006 : 9072 | 8006 : 9073 | 8006 : 9074 | 8006 : 9075 | 8006:9076 | 8006 : 9077 |
8007:9072 | 8007 : 9073 | 8007:9074 | 8007:9075 | 8007:9076 | 8007:9077 |
8008 : 9072 | 8008:9073 | 8008:9074 | 8008 : 9075 | 8008:9076 | 8008:9077 |
8009 : 9072 | 8009:9073 | 8009:9074 | 8009:9075 | 8009:9076 | 8009 : 9077 |
8010 : 9072 | 8010:9073 | 8010:9074 | 8010:9075 | 8010 : 9076 | 8010:9077 |
8011:9072 | 8011 :9073 | 8011:9074 | 8011:9075 | 8011:9076 | 8011:9077 |
8012:9072 | 8012 : 9073 | 8012 : 9074 | 8012 : 9075 | 8012:9076 | 8012:9077 |
8013:9072 | 8013 : 9073 | 8013 : 9074 | 8013 : 9075 | 8013 : 9076 | 8013:9077 |
8014:9072 | 8014 : 9073 | 8014:9074 | 8014 : 9075 | 8014 : 9076 | 8014:9077 |
8015 : 9072 | 8015 : 9073 | 8015:9074 | 8015:9075 | 8015:9076 | 8015:9077 |
8016 : 9072 | 8016:9073 | 8016:9074 | 8016 : 9075 | 8016 : 9076 | 8016 : 9077 |
8000 : 9078 | 8000:9079 | 8000:9080 | 8000 : 9081 | 8000:9082 | 8000:9083 |
8001 :9078 | 8001 :9079 | 8001:9080 | 8001:9081 | 8001:9082 | 8001 :9083 |
8002 : 9078 | 8002:9079 | 8002:9080 | 8002 : 9081 | 8002:9082 | 8002:9083 |
8003 : 9078 | 8003 : 9079 | 8003 : 9080 | 8003 : 9081 | 8003:9082 | 8003:9083 |
8004:9078 | 8004:9079 | 8004:9080 | 8004:9081 | 8004:9082 | 8004:9083 |
8005 : 9078 | 8005 : 9079 | 8005:9080 | 8005:9081 | 8005:9082 | 8005:9083 |
8006 : 9078 | 8006 : 9079 | 8006:9080 | 8006:9081 | 8006 : 9082 | 8006:9083 |
8007 : 9078 | 8007 : 9079 | 8007:9080 | 8007:9081 | 8007:9082 | 8007:9083 |
8008:9078 | 8008 : 9079 | 8008:9080 | 8008 : 9081 | 8008:9082 | 8008:9083 |
8009 : 9078 | 8009 : 9079 | 8009 : 9080 | 8009:9081 | 8009:9082 | 8009 : 9083 |
8010:9078 | 8010:9079 | 8010 : 9080 | 8010:9081 | 8010:9082 | 8010:9083 |
8011:9078 | 8011:9079 | 8011:9080 | 8011:9081 | 8011 :9082 | 8011:9083 |
8012:9078 | 8012:9079 | 8012 : 9080 | 8012:9081 | 8012 : 9082 | 8012:9083 |
8013:9078 | 8013 : 9079 | 8013:9080 | 8013:9081 | 8013:9082 | 8013:9083 |
8014 : 9078 | 8014:9079 | 8014:9080 | 8014:9081 | 8014 : 9082 | 8014:9083 |
8015:9078 | 8015 : 9079 | 8015 : 9080 | 8015:9081 | 8015:9082 | 8015:9083 |
8016:9078 | 8016 : 9079 | 8016:9080 | 8016:9081 | 8016:9082 | 8016:9083 |
177
X:Y | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ | Χ:Υ |
8000 : 9084 | 8000:9085 | 8000:9086 | 8000:9087 | 8000:9088 | 8000:9089 |
8001:9084 | 8001 :9085 | 8001:9086 | 8001 :9087 | 8001:9088 | 8001:9089 |
8002:9084 | 8002:9085 | 8002 : 9086 | 8002:9087 | 8002:9088 | 8002:9089 |
8003 : 9084 | 8003:9085 | 8003:9086 | 8003 : 9087 | 8003:9088 | 8003:9089 |
8004 : 9084 | 8004 :.9085 | 8004:9086 | 8004:9087 | 8004 :-9088 - | 8004:9089 |
8005 : 9084 | -80051-9085 | 8005 τ9086 | -8005:9087- | -8OO5r9O88 | -8005 : 9089 |
8006:9084 | 8006:9085 | 8006:9086 | 8006 : 9087 | 8006:9088 | 8006:9089 |
8007 : 9084 | 8007:9085 | 8007:9086 | 8007:9087 | 8007 : 9088 | 8007:9089 |
8008:9084 | 8008:9085 | 8008 : 9086 | 8008 : 9087 | 8008:9088 | 8008:9089 |
8009 : 9084 | 8009:9085 | 8009:9086 | 8009:9087 | 8009:9088 | 8009:9089 |
8010:9084 | 8010:9085 | 8010:9086 | 8010:9087 | 8010:9088 | 8010:9089 |
8011 :9084 | 8011:9085 | 8011 :9086 | 8011 :9087 | 8011:9088 | 8011:9089 |
8012 : 9084 | 8012:9085 | 8012:9086 | 8012:9087 | 8012:9088 | 8012:9089 |
8013 : 9084 | 8013:9085 | 8013:9086 | 8013:9087 | 8013:9088 | 8013 : 9089 |
8014:9084 | 8014:9085 | 8014 : 9086 | 8014:9087 | 8014:9088 | 8014:9089 |
8015 : 9084 | 8015:9085 | 8015:9086 | 8015:9087 | 8015:9088 | 8015:9089 |
8016:9084 | 8016:9085 | 8016:9086 | 8016 : 9087 | 8016:9088 | 8016:9089 |
8000 : 9090 | 8000:9091 | 8000:9092 | 8000:9093 | 8000:9094 | 8000:9095 |
8001:9090 | 8001 :9091 | 8001:9092 | 8001:9093 | 8001 :9094 | 8001:9095 |
8002 : 9090 | 8002:9091 | 8002:9092 | 8002:9093 | 8002:9094 | 8002:9095 |
8003 : 9090 | 8003:9091 | 8003 : 9092 | 8003 : 9093 | 8003:9094 | 8003:9095 |
8004:9090 | 8004:9091 | 8004 : 9092 | 8004 : 9093 | 8004 : 9094 | 8004:9095 |
8005 : 9090 | 8005 : 9091 | 8005 : 9092 | 8005 : 9093 | 8005:9094 | 8005 : 9095 |
8006:9090 | 8006:9091 | 8006:9092 | 8006 : 9093 | 8006 : 9094 | 8006:9095 |
8007 : 9090 | 8007 : 9091 | 8007:9092 | 8007 : 9093 | 8007 : 9094 | 8007:9095 |
8008 : 9090 | 8008:9091 | 8008:9092 | 8008:9093 | 8008:9094 | 8008 : 9095 |
8009 : 9090 | 8009 : 9091 | 8009 : 9092 | 8009 : 9093 | 8009 : 9094 | 8009 : 9095 |
8010:9090 | 8010:9091 | 8010 : 9092 | 8010 : 9093 | 8010:9094 | 8010:9095 |
8011 :9090 | 8011 :9091 | 8011 :9092 | 8011 :9093 | 8011:9094 | 8011:9095 |
8012 : 9090 | 8012:9091 | 8012:9092 | 8012:9093 | 8012 : 9094 | 8012:9095 |
8013:9090 | 8013:9091 | 8013 : 9092 | 8013:9093 | 8013:9094 | 8013:9095 |
8014 : 9090 | 8014:9091 | 8014:9092 | 8014:9093 | 8014:9094 | 8014:9095 |
8015:9090 | 8015:9091 | 8015:9092 | 8015 : 9093 | 8015:9094 | 8015:9095 |
8016:9090 | 8016:9091 | 8016 : 9092 | 8016 : 9093 | 8016 : 9094 | 8016:9095 |
178
X:Y | X:Y | X:Y | X:Y | X:Y | X:Y |
8000:9096 | 8000:9097 | 8000:9098 | 8000:9099 | 8000:9100 | 8000:9101 |
8001:9096 | 8001:9097 | 8001:9098 | 8001:9099 | 8001:9100 | 8001 :9101 |
8002:9096 | 8002:9097 | 8002 : 9098 | 8002:9099 | 8002:9100 | 8002 : 9101 |
8003:9096 | 8003:9097 | 8003 : 9098 | 8003:9099 | 8003 : 9100 | 8003 : 9101 |
800419096 | 8004:9097- | 8004:.9098 | 8004:9099 | 8004:5100 | 8004:9101 |
8005 19096 | -8005:9097- | -8005 : 9098- | 8005τ9099· | 8005 :^100 | 8005:9101 |
8006:9096 | 8006:9097 | 8006 : 9098 | 8006:9099 | 8006:9100 | 8006:9101 |
8007 : 9096 | 8007:9097 | 8007 : 9098 | 8007:9099 | 8007 : 9100 | 8007 : 9101 |
8008:9096 | 8008:9097 | 8008:9098 | 8008:9099 | 8008:9100 | 8008 : 9101 |
8009:9096 | 8009:9097 | 8009:9098 | 8009:9099 | 8009 : 9100 | 8009 : 9101 |
8010:9096 | 8010:9097 | 8010:9098 | 8010 : 9099 | 8010:9100 | 8010:9101 |
8011 :9096 | 8011:9097 | 8011:9098 | 8011:9099 | 8011:9100 | 8011:9101 |
8012:9096 | 8012:9097 | 8012:9098 | 8012:9099 | 8012:9100 | 8012:9101 |
8013:9096 | 8013:9097 | 8013:9098 | 8013:9099 | 8013:9100 | 8013:9101 |
8014:9096 | 8014 : 9097 | 8014:9098 | 8014:9099 | 8014:9100 | 8014:9101 |
8015 : 9096 | 8015:9097 | 8015:9098 | 8015:9099 | 8015:9100 | 8015:9101 |
8016 : 9096 | 8016:9097 | 8016 : 9098 | 8016:9099 | 8016:9100 | 8016:9101 |
8000:9102 | 8000:9103 | 8000:9104 | 8000:9105 | ||
8001:9102 | 8001:9103 | 8001:9104 | 8001:9105 | ||
8002:9102 | 8002:9103 | 8002:9104 | 8002:9105 | ||
8003 : 9102 | 8003:9103 | 8003:9104 | 8003:9105 | ||
8004:9102 | 8004:9103 | 8004 : 9104 | 8004:9105 | ||
8005 : 9102 | 8005:9103 | 8005 : 9104 | 8005:9105 | ||
8006 : 9102 | 8006:9103 | 8006 : 9104 | 8006:9105 | ||
8007:9102 | 8007:9103 | 8007 : 9104 | 8007 : 9105 | ||
8008 : 9102 | 8008:9103 | 8008:9104 | 8008:9105 | — | — |
8009:9102 | 8009:9103 | 8009:9104 | 8009 : 9105 | ||
8010:9102 | 8010:9103 | 8010:9104 | 8010:9105 | ||
8011:9102 | 8011:9103 | 8011:9104 | 8011:9105 | ||
8012:9102 | 8012:9103 | 8012:9104 | 8012:9105 | ||
8013:9102 | 8013:9103 | 8013:9101 | 8013:9105 | ||
8014:9102 | 8014:9103 | 8014:9104 | 8014:9105 | ||
8015:9102 | 8015:9103 | 8015:9104 | 8015:9105 | ||
8016:9102 | 8016:9103 | 8016:9104 | 8016:9105 |
EXAMPLES [0217] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intcnded to limit the scope of the daims.
179
EXAMPLE 1 r-C-METHYL-d’-FLUOROURIDINE 1
[0218] To a stirred suspension of 1-1 (20 g, 773 mmol), PPhj (30 g, 1143 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF (300 mL) was added a solution of Ij (25 g, 98.4 mmol) in THF (100 mL) dropwise at 0°C. The mixture was warmed to room température (R.T.) and stirred at R.T. for 10 h. The reaction was quenched by MeOH (100 mL). The solvent was removed, and the residue was re-dîssolved in a mixture ethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washed with saturated Na2S20j aq., and the aqueous phase was extracted with a mixture of EA and THF (2 L, 10:1). The organic layer was combined and concentrated to give a residue, which was purified on a silica get column (0-10% MeOH in DCM) to give 1-2 (223 g, 78.9%) as a white solid. ’H NMR: (DMSO-dj,400 MHz) δ 11.42 (s, 1H), 739 (d, J =8.4 Hz, 1H),5.82 (s, 1H), 5.63 (d, J = 8.0 Hz, lH),530(s, 1H),5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H).
[0219] To a stined solution of 1-2 (24.3 g, 66.03 mmol) in anhydrous MeOH (240 mL) was added NaOMe (10.69 g, 198.09 mmol) at R.T. under Ni The mixture was refluxed for 3 h. The solvent was removed, and the residue was re-dissolved in anhydrous pyridine (200 mL). To the mixture was added AcjO (84.9 g, 8333 mmol) at 0°C. The mixture was warmed to 60 °C and stirred for 10 h. The solvent was removed, and the residue was diluted with DCM, washed 20 with saturated NaHCOj and brine. The organic layer was concentrated and purified on a silica gel column (10-50% EA in PE) to give 1-3(15 g, 70.1%) as a white soli± *H NMR: (CDClj.400 MHz) δ 8.82 (s, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.54 (s, IH), 5.85 (s, 1H), 5.77 (dd, J - 8.0,2.0 Hz, 1H), 4.69 (d, J = 2.4 Hz, IH),4.58 (d, J = 2.8Hz, lH),2.07(d,J=5.2Hz,6H), 1.45 (s, 3H).
[0220] To an ice-cooled solution of 1-3 (15 g, 46.29 mmol) in anhydrous DCM (300 mL) was added AgF (29.39 g, 231.4 mmol). I2 (23.51 g, 9238 mmol) in anhydrous DCM (1.0
L) was added dropwise to the solution. The reaction mixture was stirred at R.T. for 5 h. The reaction was quenched with saturated Na2S20j and NaHCOj, and extracted with DCM. The
180 organic layer was separated, dried and evaporated to dryness. The residue was purified on a silica gel column (10-30% EA in PE) to give 1-4 (95 g, 43.6%) as a white solid. lH NMR: (Methano!-d4.400MHz)<57.52(d, J = 8.0 Hz, IH),6.2l (s, lH),5.80(d, J- 17.2 Hz. 1H),5.73 (d, J = 8.0 Hz, IH), 358 (s, IH), 354 (d, J = 6.8 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 158 (s,
3H). ’ „ ~
- - [0221] - To a solution of 1-4 (7.0 g; 14.89 mmol) in anhydrous DMF (400 mL) were added NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol). The réaction mixture.was stirred at 130 °C for 6 h. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel column (ΙΟΙ 0 30% EA in PE) to give 1-5 (2.8 g, 405%). *H NMR: (CDClj. 400 MHz) δ 8.84 (s, IH), 8.048.06 (m, 2H), 759 (t, J = 7.2 Hz. IH). 7.44-7.47 (m, 2H). 7.21-7.26 (m. IH), 6.21 (s, IH), 5.85 (d,J = 18Hz, IH),5.67(d.7=8.0Hz. IH), 4.59-4.72 (m,2H), 2.14 (s, 6H). 1.64(d,J =6.0Hz. 3H). ESI-MS: m/z 444.9 [M-F+H] *.
[0222] A mixture of 1-5 (4.0 g; 8.6 mmol) and liquid ammonia was kept ovemight at 15 R. T. in a hîgh-pressure stainless-steel vessel. Ammonia was then evaporated, and the residue purified on silica (50g column) with a CHiCb/MeOH solvent mixture (4-12% gradient) to yield compound 1 as a colorless foam (2.0 g; 84% yield). ESI-MS: m/z 275.1 [M-H]
EXAMPLE 2
COMPOUND 2 o
ums
2-1
OMe 2 [0223] To a solution of 1 (1.2 g; 43 mmol) in dîoxane (30 mL) were added ptoluenesulphonic acid monohydrate (820 mg; 1 eq.) and trimethyl orthoformate (14 mL; 30 eq.). The mixture was stirred ovemight at R.T. The mixture was then neutralized with methanolic
181 ammoma and the solvent evaporatcd. Purification on silica gel column with CHiCti-MeOH solvent System (4-10% gradient) yielded 2-1 (1.18 g, 87%).
[0224] To an ice cold solution of 2-1 (0.91 g; 2.9 mmol) in anhydrous THF (20 mL) was added iso-propylmagnesîum chloride (2.1 mL; 2 M in THF). The mixture was stirred at 0 °C for 20 mîns. A solution of phosphorochloridate reagent (22 g; 2.5 eq.) in THF (2 mL) was -added dropwise.— The mixture wâs-stirred ovemight atR.Tr-The 'reaction was-quenched with saturated aq. NH4CI solution and stirred at R.T. for 10 mîns. The mixture was then diluted with water and CHjCb, and the two layers were separated. The organîc layer was washed with water, half saturated aq. NaHCOj and brine, and dried with Na^SO.». The evaporated residue was purified on silica get column with CHiClî-iPrOH solvent System (4-10% gradient) to yield Rp/Sp-mixture of 2-2 ( 159 g; 93 %).
[0225] A mixture of 2-2 (1.45 g; 2.45 mmol) and 80% aq. HCOOH (7 mL) was stirred at R.T. for 1.5 h. The solvent was evaporated and coevaporated with toluene. The obtained residue was dissolved in MeOH, treated with EtjN (3 drops) and the solvent was evaporated. Purification on silica gel column with CHjClî-MeOH solvent System (4-10% gradient) yielded Rp/Sp-mixture of compound 2 (950 mg; 70%). 3,P-NMR (DMSO-de): 5 352, 3.47. MS: m/z = 544 [M-l].
EXAMPLE 3
COMPOUND 3
3-1
O
[0226] To an ice cold solution of 3-1 (80 mg; 015 mmol) in anhydrous THF (2 mL) was added îsopropylmagnesium chloride (0.22 mL; 2 M in THF). The mixture was stirred at 0 °C for 20 mins. A solution of the phosphorochloridate reagent (0.16 g; 0.45 mmol) in THF (0.5
182 mL) was added dropwise. The mixture was stirred ovemight at R.T. The reaction was quenched with saturated aq. NHjCl solution and stirred at R.T. for 10 mins. The mixture was diluted with water and CH2CI2, and the two layers were separated. The organic layer was washed with water, half saturated aq. NaHCQj and brine, and dried with Na2SO4. The evaporated residue was purified on silica gel column with.CHnCL-MeOH solvent.System (2-10%-gradient) to yield Rp/Sp-mixture of3-2 (102 mg;80%);—. T—[0227] A mixture of 3-2 (100 mg; 0.12 mmol) in EtOH (3 mL) and 10% Pd/C (10 mg) was stirred under the H2 atmosphère for 15 h. The mixture was filtered through a Celite pad, evaporated and purified on silica gel column with CH2C12-MeOH solvent System (4-10% gradient) to yield Rp/Sp-mixture of compound 3 (52 mg, 74%). 3IP-NMR (DMSO-de): δ 351, 3.48. MS: m/z = 584 [M-l]'.
EXAMPLE 4 COMPOUNDS 4 and 6
[0228] Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)j (0.750 mL ) and pyridine (05 mL). The mixture was evaporated in vacuum for 15 mins at bath température 42 °C, and then cooled down to R.T. N-Methylimidazo!e (0.009 mL, 0.11 mmol) was added followed by POCI3 (0.009 mL, 0.1 mmol). The mixture was kept at R.T. for 45 mins. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium sait of pyrophosphate (100 mg) was added. About 1 mL of dry DMF was added to get a homogeneous solution. In ! h, the reaction was quenched with 2M ammonium acetate buffer (I mL, pH = 75), diluted water (10 mL) and loaded on a column HiLoad 16/10 with Q Sepharose High Performance. The séparation was done in linear gradient of NaCl from 0 to IN in 50mM TRIS-buffer (pH7.5). The fractions eluted at 60% buffer B contained Compound 4 and at 80% buffer B contained Compound 6. The corresponding fractions were concentrated, and the residue purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elutîon. The
183 corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. Compound 4:3IP-NMR (D2O): -3.76 (s); MS: m/z 355.3 [M-H]*. Compound 6:3IPNMR (D20):-9.28(d, IH, Pa),-1231(d, 1 H, Py),-22.95(1,1H.P0); MS: m/z 515.0 [M-l]*.
EXAMPLE 5 _ _____ _________COMPOUND 5
[0229] Compound 5 was syntbesized as described for 2 on 0.1 mmol scale and with neopentyl ester of phosphorochloridate reagent. Yield was 36 mg (63%). 3IP-NMR (CDCI3): δ 257 (s), 2.43 (s). MS: 572.6 [Μ-ΙΓ.
10 | EXAMPLE 6 COMPOUND 7 | |
- ηοΈη 1 | HOoH 7 |
[0230] Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)3 (0.750 mL ) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15 mins at bath 15 température 42 °C, and then coolcd down to R.T. N-Methylimidazoie (0.009 mL, 0.11 mmol) was added followed by PSCI3 (0.01 mL, 0.1 mmol). The mixture was kept at R.T. for 1 h. Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium sait of pyrophosphate (200 mg) was added. About 1 mL of dry DMF was added to get a homogeneous solution. In 2 h, the reaction was quenched with 2M ammonium acetate buffer (1 mL, pH = 75), diluted with water 20 (10 mL) and loaded on a column HiLoad 16/10 with Q Sepharose Hîgh Performance. Séparation was done in linear gradient of NaCl from 0 to IN in 50mM TRIS-buffer (pH75). The fractions eluted at 80% buffer B contained 7 (compounds 7a and 7b). The corresponding fractions were concentrated, and the residue purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 20% in 50mM triethylammonium 25 acetate buffer (pH 75) was used for elutîon. Two peaks were collected. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer. Pcak l (more polar): 3IP-NMR (D;O): 442.68(d, IH, Pa), -9.05(d, 1H, Py), -22.95(1, 1H, P0);
184
MS 530.90 [Μ-ΙΓ. Peak2 (less polar): 3,P-NMR (D2O): +42.78(d, IH, Pa), -!0.12(bs, IH, Py),
-23.94(1, IH, Pp); and MS 530.90 [M-l]*.
EXAMPLE 7
Λ° | COMPOUND 23 | ||
Oh H0-V/n ° — HO' ’tH 23-t | Oh _'-yyX _ HCÎ 'OH 23-2 | / nh HO' Î3H 23-3 | % NH H(J bH 23-« |
Bztf bSz
Bzd tfflz Hd &H
23-5 | 23-5 | 23-7 |
rC TWS_O-· | - mNl_ TlPDS^d^o | HÔ ÔH |
2M 23-9 23 [0231] To a stirred suspension of 23-1 (20.0 g, 813 mmol), imidazole (15.9 g, 234.0 mmol), PPhj (53.5 g, 2033 mmol) and pyridîne (90 mL) in anhydrous THF (100 mL) was added a solution of I2 (413 g, 162.6 mmol) inTHF(l50 mL) dropwise at 0°C. The mixture was slowly warmed to R.T. and stirred for 14 h. The reaction was quenched with saL aq. Na2S2O2 (150 mL) and extracted with THF/EA (1/1) (100 mL x 3). The organic layer was dried over Na2SQi. and concentrated at a low pressure. The residue was recrystallized from EtOH to afford pure 23-2 (23 g, 79%) as a white solid.
[0232] To a stirred solution of 23-2 (23 g, 65 mmol) in anhydrous MeOH (200 mL) was added NaOCHj (10.5 g, 195 mmol) in MeOH (50 mL) at R.T. The mixture was stirred at 60 °C for 3 h, and quenched with dry ice. A solid precipitated and removed by filtration. The filtrate was concentrated at a low pressure. The residue was purified on column silica gel column (MeOH in DCM from 1% to 10%) to provide 23-3 (13.1 g, 92.5%) as a white foam solid.
[0233] To a stirred solution of 23-3 (12.0 g, 53 mmol) in anhydrous CHjCN was added TEA*3HF (8.5 g, 53 mmol) and NIS (10.2 g, 63.6 mmol) at 0°C. The mixture was stirred for 30 mins, and slowly warmed to R.T. The mixture was stirred for another 30 mins. The solid
185 was removed by filtration, and washed with DCM to give 23-4 (14 g, 73%) as a yellow solid. ESI-MS: m/z 373.0 [M+HJ*.
[0234] To a stirred solution of 23-4 (12.0 g, 32 mmol) and DMAP (1.2 g, 9.6 mmol) in pyridine (100 mL) was added BzîO (2L7 g, 96 mmol) at R.T. The mixture was stirred at 50 °C for 16 h.-The resulting solution was quenched with water, and concentrated to dryness at low pressure. The crude was purified on silîca gel column (50% EA in PE) to give 23-5 (15 g, 81%) as a white solid. ESI-TOF-MS: m/z 581.0 [M+H]*.
[0235] Tetra-butylammonium hydroxide (288 mL as 54-56% aqueous solution, 576 mmol) was adjusted to pH-4 by adding TFA (48 mL). The resulting solution was treated with a solution of 23-5 (14 g, 24 mmol) in DCM (200 mL). m-Cloroperbenzoic acid (30 g, 60-70%, 120 mmol) was added portion wise with vigorous stirring, and the mixture was stirred ovemighL The organic layer was separated and washed with brine. The resulting solution was dried over magnésium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 23-6 (7.5 g, 68%) [0236] Compound 23-6 (5.0 g, 10.6 mmol) was treated with 7N NHj’MeOH (100 mL), and the mixture was stirred for 5 h. The mixture was then concentrated to dryness at low pressure. The residue was washed with DCM, and the solid was filtered to give 23-7 (2.1 g, 75%) as a white foam. ESI-MS: m/z 263.0 [M+H]+.
[0237] To a solution of 23-7 (2.1 g, 8.0 mmol) in pyridine was added TIDPSC1 (2.5 g, 8.0 mmol) dropwise at 0 °C, and stirred for 12 h. at R.T. The solution was quenched with water, and concentrated to dryness at low pressure. The crude was purified by column chromatography (EA in PE from 10% to 50%) to give pure 23-8 (1.6 g, 40%) as a white foam.
[0238] A solution of 23-8 (1.5 g, 3.0 mmol) and IBX (1.69 g, 6.0 mmol) in anhydrous CHjCN (10 mL) was stirred at 80 °C for 3 h. The mixture was cooled down to R.T. and filtered. The filtrate was concentrated to dryness at low pressure. The residue was purified by column chromatography (EA in PE from 2% to 50%) to give pure 23-9 (1.2 g, 80%) as a white foam. ESI-MS: m/z 503.0 [M+HJ* [0239] Compound 23-9 (500 mg, 1 mmol) was dissolved in dry THF (8 mL). Ethynyl magnésium bromide (8 mL of 0.5M solution in cyclohexane) was added at R.T. After 30 mins, additional ethynyl magnésium bromide (8 mL) was added. The mixture was left for 30 mins, and then quenched with sat solution of ammonium chloride. The product was extracted with EA. The organic extracts were washed with brine, dried, and concentrated. The residue was purified by flash chromatography on silîca gel in EA to remove the dark color. The yellow compound was dissolved in THF (3 mL) and treated with TB AF (ImL, 2M solution in THF) for
186 mins. The solvent was evaporaîed, and the residue was subjected to silica gel chromatography on a Biotage cartridge (25g). EA saturated with water was used for ïsocratîc elution. Each fractions were analyzed by TEC in DCM-MeOH (9:1 v/v). Fractions containing only the isomer with a high Rf were concentrated to give pure compound 23 (110 mg). MS:
— 285.1 [M-l]
-EXAMPLE8 COMPOUND 22
Ht [0240] Compound 23 (57 mg, 0.2 mmol) was dissolved in CHjCN (2 mL), containing N-methylimidazole (40 uL). The phosphorochloridate (207 mg, 0.6 mmol) was added, and the mixture was kept ovemight at 40 °C. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The product was isolated by silîca gel chromatography in gradient of methanol in DCM from 0% to 15%. Compound 22 was obtaïned (46 mg, 39%). MS: m/z 593.9 [M-lf.
EXAMPLE 9
COMPOUND 51
Hl
51*1
51*2 [0241] To solution of triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.74 mmol) in THF was added 51-1 (0.16gg; 20 0.49 mmol). The mixture evaporated and rendered anhydrous by coevaporating with pyridine follow by toluene. The residue was dissolved in anhydrous THF and cooled in an ice-bath. Diisopropylethyl amine (0.34 mL) was added, followed by BOP-C1 (250 mg) and 3-nîtn>l,2,4triazole (112 mg) in THF (5 mL). The mixture was stirred at 0 °C for 90 mins, diluted with EtOAc, washed with sat. aq. NaHCOj and brine, and dried (Na^SO-i). The residue was purified 25 on silica column with 3-10% i-PrOH in DCM to give 51-2 (0.2 g, 64%).
[0242] A solution of 51-2 (0.20 g; 0.31 mmol) in 80% aq. HCOOH was stined at R.T. for 2 h, and then concentrated. The residue was coevaporated with toluene and then with
MeOH containing a small amount of EtjN (2 drops). Purification on silica gel (10 g column) with CHiCIî/MeOH (4-10% gradient) was followed by RP-HPLC purification in 5 runs on a
- 5 _ Synergi Hydro RP column 250 x 30 mm (Phenomenex P/N OOCM375-UO-AX) using HiO and
ACN both 50mM TEAA. The Gradient .was 25-75% ACN in 20 mins at 24mL/mins, 254nM détection. The compound eluted at 16.0 minutes; and the pure fractions were pooled and lyophilized. TEAA was removed by dissolving the compound in DMSO (2 mL) and using the same column and same gradient, using only HiO and ACN. Pure fractions were pooled and 10 lyophilized to give compound 51 (18 mg). MS: m/z =1197 [2M+1]+.
188
EXAMPLE 10 COMPOUND8 azd bez
ΑΛη
NHMMTr
Hd' bn
8-8
Hd bH
8-8 —m
Bzd bsz
8-9
Szt/^^U r NHMMTr Bzd* bBz
8-10 N NHMWTf
Hd bn
8-11 /*y\h
Ho' 'î)H [0243] Compound 8-1 (5.0 g. 8.5 mmol) and 2-amino-6-chloropurine (3.0 g, 17.7 5 mmol) were co-concentrated with anhydrous tolucne for 3 tîntes. To a stirred suspension of the above mixtures in anhydrous MeCN (50 mL) was added DBU (75 g, 49 mmol) at 0°C. The mixture was stirred at 0 °C for 15 mins, and then TMSOTf (15 g, 67.6 mmol) was added dropwise at 0°C. The mixture was stirred at O °C for 15 mins. The mixture was heated at 70°C ovemighL The mixture was cooled to R.T., and diluted with EA ( 100 mL). The solution was 10 washed with saL NaHCOj solution and brine. The organic layer was dried over Na2SÛ4 and concentrated at low pressure. The residue was purified by column on silica gel (PE/EA: from 15/1 to 3/1) to give 8-2 (25 g, 46.3%) as a white foam.
I89 [0244] To a solution of 8-2 ( 10 g, 15.7 mmol), AgNOj (8.0g, 47 mmol) and collidine (10 mL) in anhydrous DCM (20 mL) was added MMTrCl (145 g, 47 mmol) in small portions under N2. The mixture was stirred at R.T. ovemighL The mixture was filtered, and the filtrate was washed with sat. aq. NaHCOj and brine. The organic layer was dried over anhydrous 5 Na2SO4. and concentrated at low pressure. The residue was purified by silica gel column (PE/ME = 2Q/l to 8/l) to give' 8-3 (10 g, 70 %) as a yellow solid. [0245] To a solution of 3-hydroxy-propionitrile (3-51 g, 49.4 mmol) in anhydrous THF (100 mL) was added NaH (2.8 g, 70 mmol) at 0°C, and the mixture was stirred at R.T. for 30 mins. A solution of 8-3 (8.5 g, 935 mmol) in anhydrous THF (100 mL) at 0°C was added, 10 and the mixture was stirred at R.T. ovemight. The reaction was quenched with water, and extracted with EA (100 mL). The organic layer was dried over anhydrous Na2SO<_ and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH = 100/1 to 20/1) to give 8-4 (45 g, 83%) as a white solid.
[0246] Compound 8-4 (15g, 2.6 mmol) was co-concentrated with anhydrous 15 pyridine 3 times. To an ice-cooled solution of 8-4 in anhydrous pyridine (30 mL) was added TsCl (1.086 g, 5.7 mmol), and the mixture was stirred at O °C for 1 h. The reaction was quenched with water, and extracted with EA (80 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH « 100/1 to 15/1) to give 8-5 (1.4 g, 73%) as a white solid.
[0247] To a solution of 8-5 (422 g, 5.7 mmol) in acetone (60 mL) was added Nal (3.45 g, 23 mmol), and the mixture was refluxed ovemight. The reaction was quenched with sat. aq. Na2S2O2 and extracted with EA (100 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH = 100/1 to 15/1) to give 8-6 (4 g, 73%) as a white solid.
[0248] To a solution of 8-6 (4.0 g, 5.8 mmol) in anhydrous THF (60 mL) was added
DBU (3.67 g, 24 mmol), and the mixture was stirred at 60 °C ovemighL The mixture was diluted with EA (80 mL), and the solution was washed with brine. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH s 100/1 to 20/1) to give 8-7 (2 g, 61%) as a white solid.
[0249] To an ice-cooled solution of 8-7 (500 mg, 0.89 mmol) in anhydrous DCM (20 mL) was added AgF (618 mg, 4.9 mmol) and a solution of I2 (500 mg, 1.97 mmol) in anhydrous DCM (20 mL). The mixture was stirred at R.T. for 3 h. The reaction was quenched with sat Na2S20j and NaHCO3 aqueous, and the mixture was extracted with DCM (50 mL). The organic
layer was separated, dried over anhydrous Na2SO4. and concentrated to give the crude 8-8 (250 mg) as a yellow solid.
[0250] To a solution of crude 8-8 (900 mg, 1.28 mmol) in anhydrous DCM (50 mL) was added DMAP (1.0g, 8.2 mmol) and BzCl (795 mg, 5.66 mmol). The mixture was stirred at -5 . R.T. ovemighL- The mixture was washed withsat. aq. NaHCOj and brine. The organic layer - was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by prep-TLC (DCM/MeOH = 15:1 ) to give 8-9 (300 mg, 26%) as a white solid.
[0251] To a solution of crude 8-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL) was added NaOBz( 1.2 g, 83 mmol) and 15-crown-5 (1.8 g, 83 mmol). The mixture was stirred 10 at60°Cfor2d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na^SCL, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA = 1:1) to give crude 8-10 (550 mg, 73%) as a white solid.
[0252] The crude 8-10 (550 mg. 0.6 mmol) was dissolved in NHj/MeOH (7N, 50 mL). The mixture was stirred at R.T. ovemight. The mixture was concentrated, and the residue 15 was purified by silica gel column (DCM/MeOH from 100/1 to 20/1) to give 8-11 (62 mg, 17%) as a white solid. ESI-MS: m/z 598.0 [M+H]+ [0253] A solution of 8-11 ( 12 mg) in 80% formic acid (03 mL) stood at R.T. for 33 h and then was concentrated. The residue was co-evaporated with MeOH/toluene 4 tîmes in a vïal, and triturated with EtOAc at 40°C. The EtOAc solution removed with pippet. The 20 trituration step was repeated several times, and the remaining solid was dissolved in MeOH.
The solution was concentrated and dried to give compound 8 as off white solid (4.7 mg). ESIMS: m/z 326.6 [M+Hf.
191
EXAMPLE 11
Bzû* bat
- 8-1' ~
COMPOUNDS 34 and 35
- BzÛ--'t)BX-_ -a. _ _ _34-1 _____ oet M nd
Htf bH
34-3 a
' ô5 T'
BitJ ’-'bSz . ___ 34-2___ |'Λ“\'0>/^ί£ ^ΝΗΜΜΤΓ Hd bH
34-5 oa
Cttï ν*^νημμτγ
Hd ’bH
34-8
NHMMTr
oa νΑημμτϊ
Bzd bsz
34-9
OEt
V
192 [0254] To a stirred suspension of 8-1 (50 g, 84.8 mmol) and 2-amino-6-chloropurine (28.6 g, 169.2 mmol) in anhydrous MeCN (500 mL) was added DBU (77.8 g, 508 mmol) at 0°C. The mixture was stirred at 0 °C for 30 mins, and TMSOTf (150.5 g, 678 mmol) was added dropwise at 0°C. The mixture was stirred at R.T. for 20 mins until a clear solution was formed. The mixture was stirred at 90-110°C ovemight The mixture was cooled to R.T., and diluted with EA. The solution was washed with sat. NaHCOfsolution and brine. The organic layer was dried over Na2SO4 and then concentrated at low pressure. The residue was purified by silica gel column (PE/EA ~ 2/1) to give 34-1 (30 g. 555%) as a white solid.
[0255] To a solution of 34-1 (30 g, 47.1 mmol) in anhydrous DCM (300 mL) was added collidine (30 mL), AgNOj (24 g, 141.4 mmol) and MMTrCl (43.6 g, 141.4 mmol). The mixture was stirred at R.T. ovemight. The mixture was filtered, and the filtrate was washed with water and brine. The organic layer was dried over anhydrous Na^SO^ and concentrated at low pressure. The residue was purified by silica gel column (PE/EA= 4/1) to give 34-2 (35 g, 82%) as a white solid.
[0256] To a stirred solution of 34-2 (35 g, 383 mmol) in anhydrous EtOH (150 mL) was added a solution of EtONa in EtOH (2N, 150 mL). The mixture was stirred at R.T. ovemight, and then concentrated at low pressure. The residue was dissolved in EA (200 mL) and the solution was washed with water and brine. The organic layer was dried over NaiSQ». and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH = 100/2) to give 34-3 (19 g, 81%) as a white solid.
[0257] Compound 34-3 (19 g, 313 mmol) was co-concentrated with anhydrous pyridine for 3 times. To an ice-cooled solution of 34-3 in anhydrous pyridine (120 mL) was added a solution of TsCl (6.6 g, 34.6 mmol) in pyridine (40 mL) dropwise at 0°C. The mixture was stirred at 0 °C for 16 h. The mixture was quenched with water, and the reaction mixture was concentrated. The residue was re-dissolved in EA (200 mL). The solution was washed with sat aq. NaHCOj and brine. The organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated. The residue was purified by silica gel column (DCM/MeOH = 100/1) to give 34-4 ( 16 g, 67 %) as a yellow solid.
[0258] To a solution of 34-4 (15 g, 19.7 mmol) in acetone (100 mL) was added Nal (30 g, 197 mmol). The mixture was refluxed ovemight, and then concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH - 100/1) to give 34-5 (9 g, 63.7%) as a white solid.
[0259] To a solution of 34-5 (8 g, 11.2 mmol) in anhydrous THF (60 mL) was added DBU (5.12 g, 335 mmol), and the mixture was heated at 60°C ovemight The mixture was
193 diluted with EA, and washed with water and brine. The organic layer was dried over anhydrous NaiSO-j and filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE/acetone = 4/1) to give 34-6 (5.7 g, 86%) as a white solid. ’H-NMR (CD3OH,
- 400MHz) 6= 8.18 (s. IH), 7.17-733 (m, 12H), 6.80 (d, J = 8.8 Hz, 2H), 5.98 (s, IH), 5.40 (d, J
- 5 = 8.6 Ηζ,ΙΗ), 3.87 (m,5H), 3.75 (s,3H), 2.69 (s, IH), t.05 (s, 3H): ~ . [0260] - < - To air ïce-cooled solutiôir of34-6 (4.44 g, 73 mmol) in anhydrous MeCN (45 mL) was added TEA*3HF (1.23 g, 7.6 mmol) and NIS (2.16 g, 9.5 mmol). The mixture was stirred at R.T. for 2-3 h. The reaction was quenched with sat Na3SO3 and NaHCO3 solution. The mixture was extracted with EA (3 x 100 mL). The organic layer was separated, dried over anhydrous Na^SO.» and concentrated at low pressure. The residue was purified by silica gel column (DCM/acetone = IOQ/2) to give 34-7 (4.4 g, 79.8%) as a white solid.
[0261] To a solution of 34-7 (536 g, 73 mmol) in anhydrous DCM (50 mL) was added DMAP (3.6 g, 29.8 mmol) and BzCl (3.1 g, 22.1 mmol) at 0°C. The mixture was stirred at R.T. ovemight. The mixture was washed with sat aq. NaHCOj and brine. The organic layer 15 was concentrated, and the residue was purified by silica gel column (PE/EA= 5/1) to give34-8 (5.6 g, 813%) as a white solid.
[0262] To a solution of 34-8 (5.0 g, 53 mmol) in anhydrous DMF (150 mL) was added NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). The mixture was stirred at 90-100 °C for 48 h. The mixture was diluted with EA, and washed with water and brine. The 20 organic layer was concentrated, and the residue was purified by silica gel column (PE/EA = 5/1) to give 34-9 (3.9 g, 783%) as a white solid.
[0263] Compound 34-9 in NH3 in MeOH (7N, 60 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure. The residue was purified by silica gel column (DCM/acetone = 50/1) to give 34-10 (500 mg, 74.7%) as a white solid. ESI-MS: m/z 6263 25 [M+Hf.
[0264] To a solution of 34-10 (350 mg, 036 mmol) in anhydrous pyridine (4 mL) was added imidazole (50 mg, 0.72 mmol) and TBSC1 (108 mg, 0.72 mmol) at 0 to 5 °C, and stirred at R.T. for 15 h. The reaction was quenched with absolute EtOH (03 mL). The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA (150 mL), 30 and washed with water, sat. NaHCO3 and brine. The combined organic layers were dried over Na2SÛ4, filtered and evaporated at low pressure. The residue was purified by silica gel column (10-30% EA in hexanes) to give 34-11 (338 mg, 81.8%) as a white sotid.
[0265] To a solution of compound 34-11(328 mg, 0.44 mmol), AgNO3 (226 mg, 133 mmol) and collidine (039 mL, 4.84 mmol) in anhydrous DCM (4 mL) was added MMTrCI (410
194 mg, 1.33 mmol) under N2. The mixture was stirred at R.T. ovemight under Ni and monitored by TLC to completîon. The mixture was filtered through pre-packed Celite filter, and the filtrate was washed with water, 50% aqueous citric acid, and brine. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated at low pressure. The residue was . - 5 - purified by silica gel column (EA in hexanes from 0% to 30%) to gîve 34-12 (337 mg).
—— [0266] - z.To a solution of 34-12 (337.mg, 0.33 mmol) in-anhydroua THF (4 mL) was added 1.0 M solution of TB AF (0.66 ML, 0.66 mmol) at 0 to 5°C. The reaction was slowly _ warmed to R.T., and stirred for l h. The mixture was quenched with silica gel, and filtered. The solvents were evaporated to gïve the crude product, which was purified by silica gel column (EA 10 în hexanes from 0% to 50%) to give 34-13 (188 mg).
[0267] To a stirred solution of34-13 (180 mg, 0.16 mmol) in anhydrous CHjCN (23 mL) was added N-methylimidazolc (132 pL, 1.6 mmol) at 0-5 °C (ice/water bath) followed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (207 mg, 0.6 mmol, dissolved in 2mL of CH3CN). The solution was stirred at R.T. for 2.5 h, and the mixture was 15 diluted with EA followed by addition of water (15 mL). The solution was washed HiO, 50 % aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give 34-14 (75.8 mg) and 34-15 (108 mg) as a slower eluting isomer.
[0268] Compound 34-14 (76 mg, 0.063 mmol) was dissolved inanhydrous CHjCN (0.5 mL), and 4N HCl in dîoxane (47 pL) was added at 0 to 5 °C (ice/ water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CHjCN/ H2O, purified on a reverse-phase HPLC (Cl8) using acetonitrile and water, and lyophilized to give compound 34 (26.6 mg). ES1-LCMS: m/z = 663.3 [M+H]+.
[0269] Compound 34-15 (108 mg, 0.089 mmol) was dissolved injmhydrous CH3CN (0.7 mL), and 4N HCl in dîoxane (67 pL) was added at 0 to 5 °C (ice/ water bath). The mixture was stirred at R.T. for 60 mins, and anhydrous EtOH (200 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% 30 CH3CN/ H2O, purified on a reverse-phase HPLC (C18) using acetonitrile and water, and lyophilized to give compound 35 (40.3 mg). ESÏ-LCMS: m/z = 663.2 [M+H]*.
195
EXAMPLE 12 COMPOUND 25
25-4 25-5 25-5 25 [0270] To a solution of 25-1 (260 mg, 1 mmol), PPhj (780 mg, 3 mmol) and pyridine 5 (0.5 mL) in anhydrous THF (8 mL) were added I2 (504 mg, 2 mmol) at R.T., and the mixture was stirred at R.T. for 12 h. The mixture was diluted with EtOAc and washed with IM HCl solution. The organic layer was dried over NaiSOj, Filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 25-2 (190 mg, 85%) as a white solid.
[0271] To a solution of 25-2 (190 mg, 0.52 mmol) in THF (4 mL) was added DBU (760 mg, 5 mmol) at R.T., and the mixture was heated at 50 °C ovemight. The mixture was diluted with EtOAc, and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 25-3 (75 mg, 52%) as a white solid.
[0272] To a solution of25-3 (200 mg, 0.82 mmol) in MeCN (anhydrous, 4 mL) was added NIS (337 mg, 1.5 mmol) and TEA*3HF (213 mg, 1.25 mmol) at R.T., and the mixture was stirred at R.T. for 7 h. The reaction was quenched with sat Na2SOj solution and sat aq. NaHCOj solution. The mixture was extracted with EA. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel 20 column (20% EA in PE) to give 25-4 (300 mg, 62%) as a white solid.
[0273] To a solution of 25-4 (194 mg, 0.5 mmol) in pyridine (5 mL) was added BzCl (92 mg, 0.55 mmol) at 0C. The mixture was stirred at R.T. for 5 h, and the reaction was quenched with water. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (20% EA in PE) to give 25-5 (397 mg, 81%) as a white solid.
[0274] To a solution of 25-5 (1.05 g, 2.13 mmol) in DCM (12 mL) was added a mixture of TFA (0.5 mL) and BU4NOH (l mL), followed by addition of m-CPBA (U g, 6
196 mmol) at R.T. The mixture was stined at R.T. for 5 h. The mixture was washed with saL NaiSOî solution and aq. NaHCOj solution. The organic layer was dried over anhydrous Na^SO.!, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 25-6 (450 mg, 63%) as a white solid.
[0275] Compound 25-6 (250 mg, 0.65 mmol) was dissolved in NHj/MeOH (5 mL). The mixture was stirred at R.T. for 5 h, and then concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give compound 25 (120 mg, 66%) as a white powder. ESI-MS: m/z 279.0 [M+H]+.
EXAMPLE 13 COMPOUND 31
31 [0276] To a stirred solution of compound 25 (I00 mg, 036 mmol) in anhydrous THF (3.0 mL) was added N-methylîmidazole (236 pL, 2.87 mmol) at 0 °C (dry ice/acetone bath) followed by a solution of the phosphorochloridate (329 mg, 1.08 mmol, dissolved in 2 mL of THF). The solution was stirred at 0 °C for 1 h, the reaction température was raised up-to 10 °C during the next 1 h, and the solution was left at 10 ®C for the next 4 h. The mixture was cooled to 0 to 5 °C, diluted with EA, and water was added (15 mL). The solution was washed HiO, 50 % aqueous cîtric acid solution and brine. The organic layer was separated, dried over anhydrous MgSQi and fiîtered. The filtrate was concentrated in vacuum to give a residue, which dissolved in 25% CH3CN/ H2O. The residue was purified on a reverse-phasc HPLC (Cl8) using acetonitrile and water, followed by lyophilizatîon to give a mixture of two isomers of compound 31 (17.5 mg). MS: m/z 546.05 [M-H]'.
197
EXAMPLE 14 COMPOUND 27
.... 25 -- .... 27-1
27-2 27 [0277] To a solution of compound 25 (139 mg, 05 mmol) în pyridine (5 mL) was 5 added BzCl (92 mg, 055 mmol) at 0°C. The mixture was stirred at R.T. for 5 h, diluted with EtOAc and washed with IN HCl solution. The organic layer was dried over anhydrous Na^SOj, and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 27-1 (274 mg, 79%) as a white solid.
[0278] To a solution of 27-1 (490 mg, 1 mmol), DMAP (244 mg, 2 mmol) and TEA 10 (205 mg, 2.1 mmol) in MeCN (10 mL) were added TPSC1 (604 mg, 2 mmol) at 0°C. The mixture was stirred at R.T. for 2 h., and then NHjOH aq. was added at R.T. The mixture was stirred for 05 h, diluted with EtOAc and washed with sat. aq. NaHCOj and brine. The organic layer was dried over anhydrous NajSOx, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 27-2 (250 mg, 41%) as a white solid.
[0279] Compound 27-2 (250 mg, 051 mmol) was dissolved in NHa/MeOH (15 mL).
The mixture was stirred at R.T. for 5 h. and then concentrated at low pressure. The residue was purified by silica gel column (5% DCM in DCM) to give compound 27 (95 mg, 66%) us a white powder. ESI-MS: m/z 278.1 [M+H]+.
198
EXAMPLE 15 COMPOUND 29
Bztf V Bztf > Bzrf >
2M 29-2 29-3
29-10 29-11 29 [0280] To a solution of compound 29-1 (30 g, 0.08 mol) in anhydrous THF (300 mL) was added a solution of lithium tri-tert-butoxyaluminohydride (120 mL, 0.12 mol) dropwise at 78 °C under N2. The mixture was stirred at -20 °C for 1 h. The reaction was quenched with sat aq. NH4CI and then filtered. The filtrate was extracted with EA (3 x 300 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 29-2 (26 g, 86%) as a colorless oil.
[0281] To a stirred solution of PPhj (37.7 g, 0.144 mol) in DCM (100 mL) was added compound 29-2 (27 g, 0.072 mol) at -20 °C under N2. After the mixture was stirred at R.T. for 15 mins, CBq (42 g, 0.129 mol) was added while maîntaining the reaction température between -25 and -20pC under N2. The mixture was then stirred below -17 °C for 20 mins. Silica gel was added into the solution, and then purified by flash silica gel column séparation to give the crude oil product. The crude was purified by silica gel column (EA in PE from 2% to 20%) to give 29-3 (a-isomer, 17 g, 55%) as a colorless oil.
[0282] A mixture of 6-Cl-guanine ( 11.6 g, 68.8 mmol) and t-BuOK (82 g, 73 mmol) in t-BuOH (200 mL) and MeCN (150 mL) was stined at 35 °C for 30 mins, and then 29-3 (10 g, 22.9 mmol) in MeCN 100 mL) was added at R.T. The mixture was heated at 50 °C ovemight The reaction was quenched with a solution of NH4CI (5 g) in water (40 mL), and the mixture was filtered. The filtrate was evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-4 (6 g, 42%) as a yellow solid.
[0283] Το a solution of 29-4 (125 g, 23.8 mol) in DCM (50 mL) was added AgNO3 (8.1 g, 47.6 mmol), collidine (5.77 g, 47.6 mmol) andMMTrCl (l 1 g, 35.7 mmol). The mixture was stined at R.T. ovemight. The reaction was quenched with MeOH (5 mL), fîltered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH în DCM) to give the intermediate (16 g, 86%) as a yellow solid. To a solution of HOCH2CH2CN (4.7'g, 66 mmol) m THF (200 mL) \vas added NaH (3.7 g, 92'mmol) at O°C. The mixture was stirred at R.T. for 30 mins. A solution of the intermediate (10.5 g, 13 mmol) in THF (50 mL) was added, and the reaction mixture was stirred at R.T. for 12 h. The reaction was quenched with MeOH (2 mL), diluted with EA (100 mL), and washed with brine. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 29-5 (5.8 g, 77%) as a yellow solid.
[0284] To a solution of PPh3 (7.0 g, 26.6 mmol) in anhydrous pyridine (100 mL) was added I2 (6.3 g, 24.9 mmol), and stirred at R.T. for 30 mins. The mixture was treated with a solution of 29-5 (9.5 g, 16.6 mmol) in pyridine (40 mL). The mixture was stirred at R.T. ovemight. The reaction was quenched with sat. Na2S2O3 solution, and the mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 29-6 (7 g, 66%) as a yellow solid.
[0285] To a solution of 29-6 (75 g. Il mmol) in dry THF (50 raL) was added DBU (5.4 g, 33 mmol), and the mixture was heated to reflux for 4 h. The mixture was diluted with EA (3 x 100 mL), and washed with brine. The organic layer was dried over anhydrous Na2SO4. and concentrated at low pressure. The residue was purified by silica gel column (30% EA in PE) to give 29-7 (4.0 g, 67%) as a white solid.
[0286] To an ice-cooled solution of 29-7 (3.0 g, 5.4 mmol) in anhydrous MeCN (20 mL) was added TEA*3HF (0.65 g, 4.1 mmol) and NIS (153 g, 6.78 mmol) at R.T., and the reaction mixture was stirred at R.T. for 2 h. The mixture was diluted with EA (50 mL), and washed with sat. Na3S2O3 solution and NaHCO3 aq. The organic layer was dried over anhydrous NaiSCXi, and concentrated to dryness at low pressure. The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to separate the two isomers (about 1:1). NOE showed the polar one was 29-8 (0.6 g, 16%) as a white solid.
[0287] To a solution of 29-8 (0.7 g, l mmol) in dry pyridine (10 mL) was added BzCl (147 mg, 1.05 mmol) at 0°C. The mixture was stirred at R.T. for 3 h. The mixture was then diluted with EA, and washed with sat. NaHCOj aq. and brine. The organic layer was dried over
200
NajSOi, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-9 (0.65 g, 81%) as a white solid.
[0288] To a solution of 29-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was added NaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture was stirred at 100 “C . 5 for 48 h. - The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 -”r .:mL),-and-washed.'with.water-and-briné. * The organîc foyer'was dried-over Na2SO4 and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-10 (500 mg, 78%) as a white solid.
[0289] Compound 29-10 (400 mg, 03 mmol) in NHj/MeOH (7N, 100 mL) was 10 stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (5% MeOH in DCM) to give 29-11 (220 mg, 63%) as a white solid. ES1-MS: m/z 590.3 [M+Hf.
[0290] Compound 29-11 (59 mg, 0.1 mmol) was dissolved in 50% TFA in methanol (10 mL), and the mixture was kept at R.T. for 2 h. The solvent was evaporated and co15 evaporated with a methanol/toluene mixture to remove traces of the acid. The residue was suspended in CHjCN (1 mL) and centrifuged. The precipitate was washed with CHjCN (ImL) and dried. Compound 29 was obtained as a colortess solid (21 mg, 65%. MS: m/z 316.2 [M-l]’.
EXAMPLE 16
COMPOUNDS 42 AND 43
42-aand42-b
201 [0291] A freshly prepared EtONa in dry EtOH (2N, 150 mL) was added to a solution of 29-4 (13.67 g, 17.15 mmol) in EtOH (50 mL) at 0°C. The mixture was stirred at R.T. for 1 h. and then concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 42-1 (10 g, 98%) as a yellow solid.
— '5 - '= ~[0292] ~~ To a solution of PPhj (2.73 g, 10.4 mol) in anhydrous pyridine (60 mL) was -î.'- -^-àddcd Ij (2.48 g: 9.76 mmol) at R.T.~and the reaction-mixture-was stirred R.T: for 30 mins. A solution of 42-1 (3.9 g, 631 mmol) in pyridine (10 mL) was added. The mixture was stirred at R.T. ovemight. The réaction was quenched with saL Na2S20j solution and NaHCOj aq., and then extracted with EA (100 mL). The organic layer was dried over anhydrous Na2SO4, and 10 evaporated at low pressure. The residue was purified by silica get column (2% MeOH in DCM) to give 42-2 (3.0 g, 75%) as a yellowed solid.
[0293] To a solution of 42-2 in dry THF (300 mL) was added DBU (14.0 g, 91.8 mmol), and the mixture was heated to reflux for 3 h. The mixture was concentrated at low pressure. The residue was dissolved in EA (100 mL), and washed with brine. The organic layer 15 was dried over anhydrous Na2SO.i. and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 42-3 (0.6 g, 373%) as a white solid.
[0294] To an ice-cooled solution of 42-3 (2.0 g, 3.44 mmol) in anhydrous MeCN (20 mL) was added N1S (0.975 g, 43 mmol) and TEA*3HF (0.82 g, 5.16 mmol) at 0°C. The mixture was stirred at R.T. for 2 h. The reaction was quenched with saL Na2SOj and NaHCOj 20 aqueous solution, and then concentrated at low pressure. The residue was dissolved in EA (50 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 42-4 (13 g, 60%) as a white solid.
[0295] To a solution of 42-4 (l g, 137 mmol) in dry pyridine (100 mL) was added 25 BzCl (0.23 g, 1.65 mmol) at 0°C. The reaction was stirred for 30 mins and checked by LCMS.
The mixture was concentrated at low pressure, and the residue was dissolved in EA (50 mL). The solution was washed with brine. The organic layer was dried over MgSCL, and evaporated at low pressure. The residue was purified by silica gel column chromatography (10% EA in PE) to give 42-5 (0.9 g, 78%) as a white solid.
[0296] To a solution of 42-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz (3.46 g, 24 mmol) and 15-crown-5 (43 mL). The mixture was stirred at 95 °C for 72 h. The mixture was then diluted with EA (100 mL), and washed with water and brine. The organic phase was dried over MgSOj, and concentrated at low pressure. The residue was purified by silica gel column ( 15% EA in PE) to give 42-6 (1.5 g, 75%) as a white solid.
202 [0297] Compound 42-6 (135 g, 1.64 mmol) in NHî/MeOH (150 mL) was stirred at R.T. for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (5% MeOH in DCM) to give 42-7 (0.9 g, 90%) as a white solid. ESI-MS: m/z 6183 [M+HJ*.
— — - [0298] _ To a solution of 42-7 (99 mg, 0.16 mmol) in DCM (1.0 mL), triethylamine r~i-- (92.-7 pLrO.64mmol) was added arR.T;“The mixture-was-cooled-to 0 to 5°C (ice/water bath), and freshly prepared and distilled isopropyl phosphorodichloridate (36.6 pL, 0.2 mmol, prepared - according to a procedure , Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) was added to the mixture. The mixture was stirred 0 to 5°C (ice/ water bath) for 15 mins, followed by addition 10 of N-methylimidazole (26.3 pL, 032 mmol). The mixture was then stirred for 1 h at 0 to 5°C.
TLC showed absence of 42-7. EA (100 mL) was added, followed by water. The organic layer was washed H2O, saturated aqueous NHjCl solution and brine. The organic layer was separated, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 10% iPrOH/ DCM to give a mixture of 42-a 15 and 42-b (61.5 mg).
[0299] A mixture of 42-a and 42-b (61.5mg, 0.085 mmol) was dissolved in anhydrous CHjCN (05 mL), and 4N HCl in dioxane (64 pL) was added at 0 to 5 °C (ice/ water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was 20 dissolved in 50% CH3CN/H2O, was purified on a reverse-phasc HPLC (Cl8) using acetonitrile and water, followed by lyophilization to give compound 42 (1.8 mg) and compound 43 (145 mg).
[0300] Compound 42: lH NMR (CDjOD-dx, 400 MHz) δ 8.0 (s, IH), 6.69 (d, J = 16.0 Hz, 1Η)5·9-5.6 (br s, IH), 4.94-4.85 (m, 1H), 4.68-452 (m, 3H), 1.49-13 (m, 12H); ,9F 25 NMR (CDjOD-dx) δ-122.8 (s), -160.06 (s); 3,P NMR (CD3OD-d4Ï Ô-7.97 (s). ESI-LCMS: m/z = 450.1 [M+H]+; Compound 43:'H NMR (CD3OD-d4, 400 MHz) δ 7.96 (s, IH), 6.68 (s, IH), 6.69 (d, J= 16.8 Hz, IH), 6.28-6.1 (br s, IH), 4.81-45 (m, 4H), 1.45-139 (m, 12H); 3,P NMR (CD3OD-dLt) 5-5.84 (s). ESI-LCMS: m/z = 450.0 [M+H]*.
203
EXAMPLE 17 COMPOUNDS 32 AND 33
[0301] To a solution of 42-7 (0.47 g, 0,65 mol) in DCM (3 mL) was added AgNOj 5 (0.22 g, 1.29 mmol), colüdine (0.15 g, 1.29 mmol) and MMTiCl (0.3 g, 0.974 mmol) at 0°C.
The mixture was stirred at R.T. ovemight. The mixture was filtered, and the filter was washed with saL aq. NaHCOj solution and brine. The organic layer was separated, dried over anhydrous NaiSO-j and concentrated at low pressure. The residue was purified by silica gel column to give 32-1 (035,85%) as a white solid.
[0302] To a solution of 32-1 (03 g, 03 mmol) in dry DMF (10 mL) was added
NaOBz (0.72 g, 5 mmol) and l5-crown-5 (0.9 mL). The mixture was stirred at 95 °C for 72 h. The mixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO4 and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 32-2 (03 g, 60%) as a white solid.
[0303] Compound 32-2 (03 g, 03 mmol) in NHj/MeOH (30 mL) was stirred at R.T.
for 18 h. The mixture was concentrated at low pressure, and the residue was purified by silica gel column (20% EA in PE) to give 32-3 (145 mg, 56%) as a white solid. ESI-LCMS: m/z 8903 [M+H]+.
[0304] To a stirred solution of 32-3 (161 mg, 0.16 mmol) in anhydrous CH3CN (2.0 20 mL) was added N-methylimidazole (118 pL, 2.87 mmol) at 0 to 5 °C (ice/water bath) followed
by solution of32-4 (186 mg, 054 mmol, dissolved m 2mL of CH3CN). The solution was stirred at 0 to 5 °C for 4 h. The mixture was diluted with EA, and water was added (15 mL). The solution was washed H2O,50 % aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSÛ4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on silica gel with 0 to 40% EA/hexanes to give as 32-5 (82.6 mg) as the faster eluting isomer and 32-6 (106 mg) as the slowereluting isomer.
[0305] Compound 32-5 (82.6 mg, 0.07 mmol) was dissolved in.anhydrous CHjCN (05 mL), and 4N HCl in dioxane (35 pL) was added at 0 to 5°C. The mixture was stirred at R.T.
for 1 h, and anhydrous EtOH (100 pL) was added. The solvents were evaporated at R.T. and coevaporated with toluene 3 times. The residue was dissolved in 50% CH3CN/H2O, and purified on a reverse-phase HPLC (C 18) using acetonitrile and water, followed by lyophilization to give compound 32 (19.4 mg). 'H NMR (CDjOD-dj, 400 MHz) δ 7.9 (s, 1H), 732-728 (t, J = 8.0 Hz, 2H), 7.2-7.12 (m, 3H), 6.43 (d, J = 17.6 Hz, 1H), 4.70-4.63 (m. 2H), 4.55-4.4 (m, 3Η), 3.943.9 (m, 1H), 1.79-1.67 (m,4H), 1.53-1.49 (m, 1H), 1.45-122 (m, 15H);3IP NMR (CD3OD-d4) δ 4.06 (s); ESI-LCMS: m/z = 655.2 [M+H]+. 653.15 [M-H]'.
[0306] Compound 32-6 (100 mg, 0.083 mmol) was dissolved in.anhydrous CH3CN (05 mL), and 4N HCl in dioxane (50 pL) was added at 0 to 5°Q Following the procedure for obtaining compound 32, compound 33 (31.8 mg) was obtained. *H NMR (CD3OD-d4, 400 MHz) δ 7.93 (s, 1H), 733-7.29 (m, 2H). 724-7.14 (m, 3H), 6.41 (d, 17.6 Hz, 1H), 4.7(M.6O (m, 2H), 4.54-4.49 (m, 2H), 4.44-4.39 (m, 1H), 3.92-3.89 (m, 1H), 1.77-1.66 (m, 4H), 154-124 (m, 16H);3,P NMR (CD3OD-d,) <53.91 (s); ESI-LCMS: m/z = 6552 [M+Hf, 653.1 [M-H]'.
EXAMPLE 18 COMPOUND 53
OEt
t 205 [0307] Compound 53-1 (70 mg, 58%) was prepared from 32-3 (90 mg; 0.1 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.2 mmol) with DIPEA (87 gL), BopCl (44 mg), and 3-nitn>-l,2,4-triazole (29 mg) in THF (2 mL) according to a method described for compound 51-2. Purification was done with hexanes/EtOAc solvent 5 - System,20-80%gradient. - - - - - - - 7 τ
- -----[0308] -Compound 53 (25 mg, 64%) was prepared fronr53-l (70 mg) in acetonitrile (0.6 mL) and 4 N HCl/dîoxane (50 pL) according to a method described for compound 51. MS: m/z = 658[M+l]+. - —
206
EXAMPLE 19 COMPOUNDS 40 AND 41
40-8
40-10
40-9
40*12
40*13
207
40-18 40-17
40-18 «Μ’
41 [0309] To a mixture of pre-silylated 6-Cl-guanine (using HMDS and (NHDiSOj) (25.2 g, 150 mmol) In DCE (300 mL) was added 40-1 (50 g, 100 mmol) and TMSOTf (33.3 g, 150 mmol) at 0°C. The mixture was stirred at 70 °C for 16 h, and then concentrated at low 5 pressure. The residue was re-dissolved in EA, and washed with saL aq. NaHCOj and brine. The organic layer was dried over anhydrous NaiSO.», and concentrated at low pressure. The residue was purified on silica gel column (PE/EA = 2/1) to give pure 40-2 (45 g, 73%) as a white solid.
[0310] To a solution of 40-2 (45 g, 73.4 mmol) in EtOH (73 mL) was added with EtONa (IN in EtOH, 360 mL). The mixture was stirred at R.T. for 16 h. The mixture was then 10 concentrated to give a residue, which was purified by silica gel column (DCM/MeOH = 10/1 ) to give pure 40-3 (19 g, 83%) as a white solid.
[0311] To a solution of 40-3 (19 g, 61.1 mmol) in pyridine (120 mL) was added with TIPDSCh (19.2 g, 61 mmol) dropwise at 0°C. The mixture was stirred at R.T. for 16 h, and then concentrated at low pressure. The residue was re-dissolved in EA, and washed with sat. aq.
NaHCOj. The organic layer was dried over anhydrous Na^SO.», and concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH = 20/1) to give pure 40-4 (22 g, 65%) as a white solid.
[0312] To a solution of 40*4 (22 g, 39.8 mmol) in DMF/pyridine (5/1, 100 mL) was added TMSC1 (12.9 g, 119 mmol) dropwise at 0°C. The mixture was stirred at R.T. for l h and
208 then treated with isobutyryl chloride (5.4 g, 50 mmol). The mixture was stirred at R.T. for 3 h and then quenched by NH4OH. The mixture was concentrated at low pressure. The residue was dissolved in EA (200 mL). The solution was washed with sat aq. NaHCO3, and then tbe organic layer was dried and concentrated at low pressure. The residue was purified by silîca gel column (DCM/MeOH = 50/1) to give pure 40-5 ( 15 g, 60%) as a white solid.
[0313] To a solution of 40-5 (15 g, 24.1 mmol) in DCM (100 mL) was added PDC (13.5 g, 26 mmol) and Ac2O (9.8 g, 96 mmol) at 0°C. The mixture was stirred at R.T. for 16 h.
The reaction was quenched by sat. aq. NaHCOj, and then extracted with EA. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was dissolved 10 in anhydrous THF (100 mL). To a solution of TMSCCH (12 g, 112 mmol) in THF (200 mL) was added n-BuLi (2.5 N, 44 mL) at -78°C. The mixture was stirred at -78 °C for 15 mins and 0 °C for 15 mins. The mixture was treated with a solution of crude ketone in THF at -78 eC and stirred at -30 °C for 2 h. The reaction was quenched by saL aq. NH4CI, and then extracted by EA. The combined organic layer was dried over anhydrous Na2SO4, and concentrated at low 15 pressure. The residue was purified by silica gel column (PE/EA= 10/1) to give pure 40-6 (3.1 g, 18%) as a white solid.
[0314] To a solution of 40-6 (7 g, 7.5 mmol) and pyridine (1.4 g, 17 mmol) in DCM (35 mL) was added with DAST (5.6 g, 35 mmol) at -78°C. The mixture was stirred at -78 °C for 3 h. The reaction was quenched by sat aq. NaHCOj, nnd then extracted with EA. The 20 combined organic layer was dried over anhydrous, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA= 10/1) to give pure 40-7 (3.1 g, 18%) as a white solid.
[0315] Compound 40-7 (4.1 g, 5.7 mmol) in sat. NHj/MeOH ( 100 mL) was stirred at
R.T. for 16 h, and concentrated at low pressure. The residue was re-dissolved in anhydrous 25 DCM (300 mL), and was treated with AgNOj (27.0 g, 160 mmol), collidine (22 mL) and
MMTrCl (23.0 g, 75.9 mmol) in smaJl portions under N2. The mixture was stirred at R.T. for 16 h. The mixture was filtered, and the filtrate was washed with sat. NaHCO3 solution and brine.
The organic layer was separated, dried over anhydrous Na2SO4. and concentrated at low pressure. The residue was purified by silica gel column (PE/EA = 10/1) to give lhe pure 30 intermédiare. The întermediate was dissolved in a solution ofTBAF/THF (iN, 20 mL). The mixture was stirred at R.T. for 2 h and then concentrated at low pressure. The residue was purified by silica gel column (DCM/MeOH = 50/1) to give pure 40-8 (3.0 g, 86%) as a white solid.
209 [0316] To a solution of 40-8 (3.0 g, 4.9 mmol) in THF (50 mL) was added îmidazole (840 mg, 12 mmol), PPh3 (3.2 g, 12 mmol), and I2 (2.4 g, 9.2 mmol) at 0°C. The mixture was stirred at R.T. for 16 h. The reaction was quenched by sat aq. Na2S2O3, and thën extracted with EA. The combined organic layer was dried over anhydrous Na2SO4, and concentrated at low —_ 5 -r pressure. The residue was purified by silica gel column (PE/EA= 2/1) to give crude 40-9 (4.2 g, >100%, containing TPPO) as â white solid.~ ———r— ~ [0317] To a solution of crude 40-9 in anhydrous THF (30 mL) was added DBU (2.7 g, 18 mmol), and heated to 80°C. The mixture was stirred for l h and checked by LCMS. The mixture was quenched by water, and extracted with EA. The organic layer was dried over 10 anhydrous Na2SO4 and filtered, and the filtrate was concentrated at low pressure. The residue was purified by silica gel column (PE/EA= 2/1) to give 40-10 (2.0 g, 69%) as a white solid.
[0318] To an ice-cooled solution of 40-10 (2.0 g, 3-38 mmol) in anhydrous MeCN (15 mL) was added NIS (777 mg, 3.5 mmol) and NEt3«3HF (536 g, 3.3 mmol) at 0°C. The mixture was stirred at R.T. for 16 h and checked by LCMS. After completion, the mixture was 15 quenched by sat. NajSOj and sat. NaHCO3 solution, and extracted with EA The organic layer was separated, dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was purified by silica gel column chromatography (PE/EA=l0/l to 3/1) to give 40-11 (2.1 g, 84.0%) as a white solid.
[0319] To a solution of crude 40-11 (2.1 g, 2.85 mmol) in anhydrous DCM (100 mL) 20 was added DMAP (490 mg, 4 mmol), and BzCl (580 mg, 4 mmol) at 0°C. The mixture was stirred ovemight and checked by LCMS. The reaction was washed with saL NaHCQj solution. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column chromatography (PE/EA = 8/1 to 3/1) to give 40-12 (2.0 g, 83.4%) as a white solid.
[0320] To a solution of 40-12 (2.0 g, 2.4 mmol) in anhydrous DMF (60 mL) was added NaOBz (3.3 g, 23.0 mmol) and l5-crown-5 (5.11 g, 23 mmol). The mixture was stirred at 110 °C for 36 h. The reaction was quenched by water, and the mixture was extracted with EA. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column (PE/EA= 5/1 to 3/1) to give 40-13 (830 mg, 42.0%) as 30 a white solid. ESI-MS: m/z 836.11 [M+H]*.
[0321] A solution of 40-13 (831mg, 1.0 mmol) in anhydrous n-butylamine (4 mL) was stirred at R.T. for 3 h under N2 atmosphère. The reaction was monitored by TLC. The solvent was evaporated in vacuo, and the residue was purified by silica gel column (MeOH in
210
DCM from 0% to 10%) to give the crude product, which as re-purified using silica gel column to give 40-14 as a light pink solid (563 mg).
[0322] To a solution of 40-14 (560 mg, 0.89 mmol) in anhydrous pyridine (5 mL) was added imîdazole (78.6 mg, 1.16 mmol) and TBSCI (202 mg, 1.34 mmol) at 0 to 5°C. The _ 5 — mixture was stirred at R.T. for 15 h.-The reaction was quenched by adding absolute EtOH (0.3 - · ★ mL)—The solution was concentrated to dryness under reduced pressure, and co-evaporated with toluene 3 times. The residue was dissolved in EA (150 mL), and washed with water, sat NaHCOj, and brine. The combined organic layer was dried-over-NaiSOj, filtered and evaporated at low pressure. The residue was purified by silica gel column (0-20% EA in 10 hexanes) to give 40-15 (303 mg) as a white solid.
[0323] To a solution of 40-15 (303 mg, 0.41 mmol), AgNOj (208 mg, 1.23 mmol) and collidine (055 mL, 451 mmol) in anhydrous DCM (4 mL) was added MMTrCl (378 mg, 1.3 mmol) under N*. The mixture was stirred at R.T. ovemight under Νχ and monitored by TLC. The mixture was filtered through pre-packed celite filter, and the filtrate was washed with 15 water and, 50% aqueous ci trie acid, and brine. The organic layer was separated, dried over anhydrous Na^SCL, filtered and concentrated at low pressure. The residue was purified by silica gel column (EA in hexanes from 0% to 30%) to give 40-16 (374 mg, 90%).
[0324] To a solution of 40-16 (374 mg, 0.37 mmol) in anhydrous THF (4 mL) was added 1.0 M solution of TB AF (0.74 mL, 0.74 mmol) at 0 to 5°C. The mixture was stirred at 20 R.T. for 1 h. The mixture was quenched with silica gel, and filtered. The solvents were evaporated to give the crude product, which was purified by silica gel column (EA in hexanes from 0% to 50%) to give 40-17 (265 mg).
[0325] To a stirred solution of 40-17 (1875 mg, 0.16 mmol) in anhydrous CHjCN (25 mL) was added N-methyl imîdazole (136 pL, 1.66 mmol) at 0-5 °C (ice/water bath) followed 25 by solution of phenyt (cyclohexanoxy-L-alaninyl) phosphorochloridate (214 mg, 0.62 mmol, dissolved tn 05 mL of CHjCN). The solution was stirred at R.T. for 3 h, and then diluted with EA followed by the addition of water (15 mL). The solution was washed with H2O, 50 % aqueous citric acid solution and brine. The organic layer was separated, dried over anhydrous MgSQ* and filtered. The filtrate was concentrated in vacuum to give a residue, which was 30 purified on silica gel with 0 to 40% EA/hexanes to give (single isomers) of 40-18 (108 mg) Elution of the latter fraction gave (single ïsomers) of40-19 (120 mg) as glassy solid.
[0326] Compound 40-18 (t08mg, 0.089 mmol) was dissolved injanhydrous CH3CN (05 mL), and 4N HCl in dioxane (67 pL) was added at 0 to 5 °C (ice/ water bath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH (200 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene 3 times. The residue was dissolved in 50% CH3CN/H1O, was purified on a re verse-phase HPLC (Cl8) using acetonitrile and water, followed by lyophilization to give compound 40 (26.6 mg) as a white foam. ’H NMR (CD3OD~ 0,7 400 MHz) S 7.89 (5,111)77.33-7.29^0^ 2H), 7.20-7.13 (m, 3H),7.17 (m, 1H), 6.62 (d, J = -- ’-15.6 Hz, IH), 539 (t,V = 25.2 Hz? IH), 4.754.42 (m, 6H), 3.92 (t;J = 8.8 Hz.'lH); 324 (d, J 5.6 Hz, IH), 1.76-1.51 (m, 5H), 1.45-1.25 (m, 12H);3IP NMR (CDjOD-dL,) <54.04 (s); ESILCMS: m/z = 665.2 [M+H]*. ” [0327] Compound 41 (44.4 mg, single isomer) was obtained according to the 10 procedure described for compound 40 using 40-19. ’H NMR (CDjOD-dj, 400 MHz) S 7.93 (s,
IH), ), 7.32 (t, 8.0 Hz. IH), 724 (d, J = 7.6 Hz, 2H), 7.16 (t. J = 7.6 Hz, IH), 6.61 (d, J s
16.0 Hz, IH), 4.684.60 (m, 2H), 454-4.39 (m, 3H), 3.93-3.89 (m, IH), 3.24 (d, J= 5.6 Hz, IH), 1.75-15 (m, 5H), 1.48-1.23 (m, 12H); ”F NMR (CDjOD-rU) <5-122.95 (s), -155.84-155.99 (m);
3,P NMR (CDjOD-dj) <53.94 (s); ESI-LCMS: m/z = 665.15 [M+H]*.
EXAMPLE 20 COMPOUND 49
MMTÛ solution [0328] b is(isopropyl oxycarbonyloxymethy l)phosphate
MMTCJ triethylammonium prepared from 110 mg of
212 bis(POC)phosphate and 46 gL of EtjN) in THF was added 49-1 (91 mg, 0.11 mmol). The mixture evaporated and rendered anhydrous by co-evaporating with pyridine folio w by toluene.
The residue was dissolved in anhydrous THF (1.5 mL) and cooled in an ice-bath.
Dîisopropylethyl amine (0.19 mL, 10 eq.) was added, followed by BOP-C1 (0.14 g, 5 eq.), and 35~ - nitro-l,2,4-triazole (63 mg, 5 eq,). -The mixture was stirred 0 °C for 90 mins, diluted with ------ EtOAc (30 mL),-washed with saù aq: NaHCOj, brine. and dried (NaiSQ»). *The residue was purified on silica (10 g column) with QLCb/i-PrOH solvent System (2-10% gradient) to obtaîn
49-2 (13 mg, 10%) and 49-3 (95 mg, 58%).
[0329] A solution of 49-2 and 49-3 (13 mg and 95 mg, respectively) in 80% aq. HCOOH (3 mL) was stirred at R.T. for 3 h, then evaporated and co-evaporated with toluene. The residue was purified on silica (10 g column) with CHiCp/MeOH (4-10% gradient) to obtain compound 49 in (42 mg, 94%) yield. MS: m/z=628 [M+l]+.
EXAMPLE 21
COMPOUND 52
[0330] Compound 52-2 (158 mg, 50%) was from 52-1 (0.21 g; 035 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.54 mmol) with DIPEA (0.18 mL), BopCl (178 mg), and 3-nitro-l,2,4-triazole (80 mg) in THF (4 mL).
[0331] A solution of 52-2 (158 mg) in acetonitrile (1 mL) and HCl (4 N/dioxane; 85 pL) was stirred at R.T. for 30 mins. The reaction was quenched with MeOH and concentrated. The residue was purified on silica gel (10 g column) with CH1CI2 Λ-PrOH (3-10% gradient) to givecompound 52 (85 mg, 76%). MS: m/z »656 [M+l]+.
213
EXAMPLE 22 COMPOUND 11
11.1 - 11-2
[0332] A mixture of 11-1 (170 mg, 0.19 mmol) and methanolîc ammonia (7 N; 3 5 mL) was stirred at R.T. for 8 h, concentrated and purified on silica gel (10 g column) with CH2Cl2/MeOH (4-H% gradient) to give 11-2 (100 mg, 90%).
[0333] Compound 11-2 was rendered anhydrous by co-evaporating with pyridine, followed by toluene. To a solution of 11-2 (24 mg, 0.04 mmol), and N-methylimidazole (17 pL, 5 eq.) in acetonitrile (I mL) was added the phosphorochloridate (50 mg, 3.5 eq.) in 2 portions in 10 6 h intervals. The mixture was stirred at R.T. for l d and evaporated. Purification on silica (10 g column) with CHiChZMeOH (4-12% gradient) yîelded 11-3 (10 mg, 28%).
[0334] A solution of 11-3 (9 mg, 0.01 mmol) in 80% formic acid was stirred 3 h at R.T. The mixture was evaporated and purified on silica (10 g column) with CH2Cl2/MeOH (515% gradient) to give compound 11 (3 mg, 50%). MS: πί/ζ = 624[Μ-ΙΓ·
214
EXAMPLE 23 COMPOUND 14
HÛ bH
14-1
ΟΜβ
14-3 o^o ho’ &h
Y ” [0335] A mixture of 14-1 (1.2 g, 4.3 mmol), PTS A monohydrate (0.82 g, l eq.), and 5 trimethyl orthoformate (14 mL, 30 eq.) in dioxane (30 mL) was stirred ovemight at R.T. The reaction was neutralîzed with 7 N NHj/MeOH and a whîte solid removed by filtration. The residue was dissol ved in THF (10 mL) and treated with 80% aq. AcOH (5 mL). The mixture was kept at R.T, for 45 mins and then evaporated. The residue was purified on silica gel (25 g column) with CHiCli/MeOH (4-10% gradient) to give 14-2 (1.18 g, 87%).
[0336] Compound 14-3 (137 mg, 75%) was prepared from 14-2 (93 mg, 0.29 mmol) and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.44 mmol) with DIPEA (0.2 mL), BopCl (147 mg), and 3-nitro-l,2,4-triazole (66 mg) in THF (3 mL). Purification was done with CH2C12 /i-PrOH solvent System (3-10% gradient).
[0337] A solution of 14-3 (137 mg) in 80% aq. HCOOH was stirred at R.T. for 2 h, 15 and then concentrated. The residue was co-evaporated with toluene and then MeOH containing a small amount of a small amount of Et3N (2 drops). Purification on silica (25 g column) with CH2CI2/MeOH (4-10% gradient) gave compound 14 (100 mg, 77%). MS: m/z =1175 [2M-1J.
215
EXAMPLE 24 COMPOUND 16
[0338] Compound 16-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mL) was added DBU (393 g, 258.0 mmol) at 0°C. The mixture was stirred at 0 °C for 30 mins, and then TMSOTf (953 g, 430.0 mmol) was added dropwisc at 0°C. The mixture was stirred at 0 °C for 30 mins. The mixture was heated to 70 °C, and stirred ovemight The solution was cooled to R.T. and diluted with EA (100 mL). The solution was washed with sat NaHCOj solution and brine. The organîc layer was drîed over NaiSCL, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE firom 10% to 40%) to give 16-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]+.
[0339] To a solution of 16-2 (48.0 g, 76.4 mol), AgNOj (50.0 g, 294.1 mmol) and collidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCt (46.0 g, 149.2 mmol) in 15 small portions under Nj. The mixture was stirred at R.T. for 3 h under Νχ The reaction was monitored by TLC. The mixture was filtered, and the filter was washed with sat. NaHCOj
2I6 solution and brine. The organic layer was dried over anhydrous NajSOj, and concentrated at low pressure. The residue was purified by silica gel column (EA in PE from 5% to 50%) to the give crade 16-3 (68 g, 98%). ESI-MS: m/z 900.1 [M+Hf.
[0340] Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0 °C, and slowly warmed to R.T. Compound 16-3 (68.0 g, 75.6 mmol) was treated with freshly prepared NaOEt solution, and stirred ovemight at R.T. The reaction was monitored by TLC, and the *
mixture was concentrated at low pressure. The mixture was diluted with H2O (100 mL), and extracted with EA (3 x 100 mL). The organic layer was dried over anhydrous Na^SO^ and evaporated at low pressure. The residue was purified by silica gel column chromatography 10 (MeOH in DCM from 1% to 5%) to give 16-4 (34.0 g, 752%) as a yellow solid. ESI-MS: m/z
598 [M+Hf.
[0341] Compound 16-4 (32.0 g, 53.5 mmol) was coevaporated with anhydrous pyridine 3 times. To an ice-coo!ed solution of 16-4 in anhydrous pyridinc (100 mL) was added TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL) dropwise at 0°C. The mixture was stirred for 18 15 h. at 0°C. The reaction was checked by LCMS (about 70% was the desired product). The reaction was quenched with H2O, and the solution was concentrated at low pressure. The residue was dissolved in EA (100 mL), and washed with sat NaHCOj solution. The organic layer was dried over anhydrous NajSO^ and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give crade 20 16-5 (25.0 g, 622%) as a yellow solid. ESI-MS: m/z 752 [M+H]+.
[0342] To a solution of 16-5 (23.0 g, 30.6 mmol) in acétone (150 mL) was added Nal (45.9 g, 306.0 mmol) and TB AI (2.0 g), and refluxed ovemight The reaction was monitored by LCMS. After the reaction was complété, the mixture was concentrated at low pressure. The residue was dissolved in EA (100 mL), washed with brine, and dried over anhydrous Na2SO4. 25 The organic solution was evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=100:l to 20:1) to give the crude product To a solution of the crade product in diy THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and heated to 60°C. The mixture was stirred ovemight, and checked by LCMS. The reaction was quenched with sat NaHCOj. and the solution was extracted with EA ( 100 mL). The organic layer was 30 dried over anhydrous Na2SO4. and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 16-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580 [M+H]+.
[0343] To an ice-cooled solution of 16-6 (8.0 g, 13.8 mmol) in dry MeCN (lOOmL) was added NIS (3.9 g, 17.2 mmol) and TEA*3HF (33 g, 20.7 mmol) at 0°C. The mixture was
stirred at R.T. for 18 h and checked by LCMS. After the reaction was complété, the reaction was quenched with sat Na2SO3 and saL NaHCOj solution. The solution was extracted with EA. The organic layer was dried over anhydrous NajSO^, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from I0% to 50%) to give 16-7(7.2 - 5 ' g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]*. - - - ---_ -c.---[0344]· —Toa solution of crude 16-7 (7.2 g,-9.^-mmol) in dry DCM (100 mL) was added DMAP (3.6 g. 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0°C. The mixture was stirred ovemigbt, and checked by LCMS. The mixture was washed with sat. NaHCO3 solution. The organic layer was dried over anhydrous NaiSOj, and evaporated at low pressure. The residue 10 was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give 16-8 (8.0 g. 86.4%) as a solid. ESI-MS: m/z 934 [M+H]*.
[0345] To a solution of 16-8 (73 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (113 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90°C. The mixture was dîluted with H2O (100 mL), and extracted with EA (3x150 mL). The 15 organic layer was dried over anhydrous Na^SO-i, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 16-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]*.
[0346] Compound 16-9 (4.0 g. 43 mmol) was co-evaporated with anhydrous toluene 3 times, and treated with NHj/MeOH (50 mL, 4N) at R.T. The mixture was stirred for 18 h at 20 R.T. The reaction was monîtored by LCMS, and the mixture was concentrated at low pressure.
The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 16-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]*.
[0347] Compound 16-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydrous toluene 3 times, and was dissolved in MeCN (2 mL). The mixture was treated with NMI (1203 25 mg, 1.47 mmol) and lhe phosphorochloridate reagent (338.1 mg, 0.98 mmol) in MeCN ( 1 mL) at 0°C. The mixture was stirred for 18 h at R.T. The reaction was monîtored by LCMS. The mixture was diluted with 10% NaHCO3 solution, and extracted with EA. The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 16-11 (240 mg, 533%) as a solid. ESI-MS: m/z 925 [M+H]*.
[0348] Compound 16-11 (240.0 mg, 0.26 mmol) was treated with 80% AcOH (10 mL), and the mixture was stirred for 18 h at R.T. The reaction was monitored by LCMS. The mixture was concentrated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 3%) to give compound 16 (87.6 mg, 51.7%) as a solid. ESI-MS: m/z 653 [M+H]*.
218
EXAMPLE 25 COMPOUND 30
[0349] To a stirred solution of compound 25 (60 mg, 0.22 mmol) in anhydrous THF 5 (2.0 mL) was added N-methylimidazole (0.142 mL, 1.73 mmol) at 0 °C (dry ice/acetone bath) fotlowed by solution of phenyl (cyclohexanoxy-L-alaninyl) phosphorochloridate (235 mg, 0.68 mmol, dissolved in THF (2 mL). The resultîng solution was stirred at 0 °C for 1 h, and the température was raised up-to 10 °C over the next 1 h. The reaction left at 10 °C for 3 h. The mixture was cooled to 0 to 5 °C, diluted with EA, and water (5 mL) was added. The solution 10 was washed with H2O and brine. The organic layer was separated, dried over anhydrous Na2SQi and filtered. The filtrate was concentrated in vacuum to give a residue, which dissolved in 25% CHjCN/HjO. The compound was purified on a rcverse-phase HPLC (Cl8) using acetonitrile and water, followed by lyophilization gave a white foam. The produce was re-dissolved in EtOAc, washed with 50 % aqueous citric acid solution, dried over anhydrous MgSO4 and 15 filtered. The filtrate was concentrated in vacuum, and lyophilized to give two isomers (Rp/Sp) of compound 30 (6.3 mg). MS: m/z 586.05 [M-HJ‘,
219
EXAMPLE 26 COMPOUND 17
[0350] Compound 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) 5 were co-evaporated with anhydrous toluene 3 times. To a solution of 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g. 98.2 mmol) in McCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0°C. The mixture was stirred at 0 °C for 30 mins, and TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0°C. The mixture was stirred at 0 °C for 30 mins until a clear solution was observed. The mixture was heated to 70 °C, and stirred ovemighL The solution was cooled to 10 R.T., and diluted with EA (100 mL). The solution was washed with sat NaHCOj solution and brine. The organic layer was dried over NajSO^ and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 17-2 (48.0 g, 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+HJ*.
[0351] To a solution of 17-2 (48.0 g, 76.4 mol), AgNOj (50.0 g, 294.1 mmol) and 15 collidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g, 149.2 mmol) in small portions under Nj. The mixture was stirred at R.T. for 3 h under Ni Completion of the reaction was determîned by TLC. After filtration, the filtrate was washed with sat. NaHCOj solution and brine. The organic layer was dried over anhydrous Nj^SOa. and concentrated at low
220 pressure. The residue was purified by silica gel column (EA in PE from 5% to 50%) to the give crude 17-3 (68 g, 98%). ESI-MS: m/z 900.1 [M+H]*.
[0352] Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH ( 100 mL) at 0 °Ct and slowly warmed to R.T. Compound 17-3 (68.0 g, 75.6 mmol) was treated with freshly prepared NaOEt solution, and stirred ovemight at R.T. Completîon of the réaction was determined by __ —4»
TLC and LCMS. The mixture was concentrated at a low pressure, diluted with H2O (100 mL), and extracted with EA (3 x 100 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 17-4 (34.0 g, 152%) as a yellow solid. ESI-MS: m/z 598 [M+H]*.
[0353] Compound 17-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrous pyridine 3 times. To an ice-cooled solution of 17-4 (32.0 g, 53.5 mmol) in anhydrous pyridine (100 mL) was added a solution of TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL) dropwise at 0°C. The mixture was stirred for 18 h. at 0°C. The reaction was monitored by LCMS, and quenched with H2O. The solution was concentrated at low pressure, and the residue was dissolved in EA (100 mL), and washed with sat. NaHCOj solution. The organic layer was dried over anhydrous Na2SO4. and evaporated at a low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give crude 17-5 (25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]*.
[0354] To a solution of 17-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was added Nal (45.9 g, 306.0 mmol) and TBAI (2.0 g), and the mixture was refluxed ovemighL Completîon of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was dissolved in EA (100 mL). The solution was washed with brine, and dried over anhydrous Na2SO4. The organic solution was evaporated at low pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH=100:l to 20:1) to give a crude product. To a solution of the crude product în dry THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and the mixture was heated to 60 °C and stirred ovemight. The reaction was monitored by LCMS. The reaction was quenched with sat NaHCOj solution, and the solution was extracted with EA (100 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 17-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580 [M+H]*.
[0355] To an ice-cooled solution of 17-6 (8.0 g, 13.8 mmol) in anhydrous MeCN (lOOmL) was added NIS (3.9 g, 17.2 mmol) and TEA*3HF (3.3 g, 20.7 mmol) at 0°C. The
221 mixture was stirred at R.T. for 18 h, and the reaction was checked by LCMS. After the reaction was completed, the reaction was quenched with saL Na^SOi solution and sat NaHCOj solution. The solution was extracted with EA (3 x 100 mL). The organic layer was dried over anhydrous Na^SCL, and evaporated at low.pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 50%) to give 17-7 (7.2 g, 72.0%) as a solid. ESI-MS:
_ - - m/z-726 [M+H]*. ~ - ---------— —- - - - ---[0356] . To a solution of 17-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was added - DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0°C. The mixture was stirred ovemight, and checked by LCMS. The mixture was washed with sat NaHCOj solution. The 10 organic layer was dried over anhydrous Na^SOj, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give 17-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 (M+H]+.
[0357] To a solution of 17-8 (75 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (115 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 15 90°C. The mixture was diluted with H2O ( 100 mL). and extracted with EA (3 x 150 mL). The organic layer was dried over anhydrous Na^SO^, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 17-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]*.
[0358] Compound 17-9 (4.0 g, 43 mmol) was coevaporated with anhydrous toluene 20 3 times, and treated with NHj/MeOH (50 mL, 4N) at R.T. The mixture was stirred for 18 h. at
R.T. Completion of the réaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give product 17-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z616 [M+H]+.
[0359] Compound 17-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydrous 25 toluene 3 times, and was dissolved in MeCN (2 mL). The mixture was treated with NMI (1205 mg, 1.47 mmol) and the phosphorochloridate reagent (3263 mg, 0.98 mmol) in MeCN ( 1 mL) at 0°C. The mixture was stirred for 18 h at R.T. and monîtored by LCMS. The mixture was diluted with 10% NaHCOj solution, and extracted with EA (3 x 30 mL). The residue was purified by silica gel column chromatography (EA in PE from 30% to 50%) to give 17-11 (210 30 mg, 475%) as a solid. ESI-MS: m/z 913.0 [M+HJ*.
[0360] Compound 17-11 (210 mg, 0.26 mmol) was treated with 80% of AcOH (15 mL), and the mixture was stined for 18 h at R.T. Completion of the reaction was determined by LCMS. The mixture was concentrated at low pressure, and the residue was purified by silica gel
J,Ui
222 column chromatography (MeOH in DCM from 1% to 3%) to give compound 17 (71.8 mg, 48.7%) as a solid. ESI-MS: m/z 641.3 [M+Hf.
EXAMPLE 27
COMPOUNDS 9.12.15,26,28,38,44,46,50,63,64.69 and 76 _ [0361] . Compounds 9,12,15,26,28,38,44,46,50,63,64,69 and 76 were prepared _ ... jn a manner similar to method for preparing compound 6. After the addition of POClj, the mixture was kept at R.T. for 20-40 mins. The reaction was contrai led by LCMS and monitored ‘ ' r by the appearance of corresponding nucleosîde 5*-monophosphate. After completion of the réaction, tetrabutylammonîum sait of pyrophosphate (150 mg) was added, followed by DMF (0.5 10 mL) to get a homogeneous solution. After 13 h at ambient température, the reaction was diluted with water (10 mL). The triphosphate (eluted at 75-80%B) were obtaîned as described for compound 6.
223
Î]PNMR | ||||
Structure | MS [M-ir | P(a) | P(P) | PCT) |
OH OH OH jeN 0 Ht/ ¥ Λη, ‘ 28 ~ · | • 556.2 | -10.92 -11.03(d) | -23.18(t) | -11.86 -U.98(d) |
O<s^N. .NHj n4oM<rx/V OH OH OH F^X T- HO* ¥ 38 | 516.1 | -7.49 -7.61(d) | -22.42(0 | -12.17 -1230(d) |
N o ΗΟ-?-Ο-?-Ο-?-Ο'νΑ^~ζ^ΙΗ Ôh Ôh 6h n><hî HO V)H 9 | 554.0 | -10.94 -II.06(d) | -23.25(1) | -11.85 -ll.97(d) |
9 9 o OH ΗΟ-ΡΌ P OPO-\ a 61ÔH ÔH rÔQ> Ηό &H 12 | 525.2 | -833(bs) | -22.61 (bs) | -12.17 -12.29(d) |
/‘Τ^ΝΗ ΗΟ-Ρ-ΟΡΟ-Ρ-ΟρΛ /2=¾ NH* oh ôh oh jjH 15 | 564.4 | -11.05 (bs) | -23.25 (bs) | -11.96 -12.08(d) |
O 0 o II II II —J*1 HO-P-O-P-O-P-O n X» «» NH; 44 | 566.0 | -10.92 -ll.04(d) | -23.18(t) | -11.93 -l(d) |
°Π HO* S 46 | 533.3 | -10.89 -1 l.Ol(d) | -23.31(0 | -12.49 -Kd) |
0 0 O nΛΥ* ηο-ρ-ο-Ρ-ο-Ρ-τ/^χ 72 ÔH ÔHHÔ 50 | 513.8 | -8.66(bs) | -22.80(0 | -12.17 -12.29(d) |
rfH 9 9 9 ^ olVA ΗΟ-Ρ-Ο-Ρ-Ο-Ρ-Ο'^Χ*'*/ s, ÔH ÔH ÔH ρΛ /> Hc/ V 26 | 517.7 | -13.73 -13.60(d) | -25.98(0 | -15.18 -15.06(d) |
h
224
Structure | MS [Μ-1Γ | Ρ(α) | Ρ(β) | P(ï) |
NHj ο ο o ΗΟ-β-Ο-^-Ο-Ρ—Û-X^oJ^o ~ OH OH OH Ρ*Λ_2- Hcf 63 | 539.5^ | -7.42 — (bns) | -22.57(1) | -12.23 -1234(d) |
000 O HO* 64 | 513.1 | -6.36 -6.49(d) | -22.49(0 | -12.20 -12.33(d) |
o o 0 Ho-p-o-$-o-p-o-''*Y'D'yN~v0 Ah oh oh f~‘ \ h/ \ 69 | 526.8 | -10.96 -ll.08(d) | -23.33(t) | -12.41 -12.53(d) |
A™ Htf bH^ 76 | 533.4 | -10.78 (br.s) | -23.22(t) | -12.24 -12.36(d) |
[0362] The following compounds can also be prepared using a method similar to the method described in Example 27:
225
EXAMPLE 28
COMPOUND 10 ΗΟ /Ύ°Υί Ν Ν^ΝΗΜΜΤγ Τκ/ΎθΧ NHMMTr ' Htf 'tJH- -T ~ Htï bu
1(M n 1M
O >u-< - - Q * ’ N<^NHWÎr_ O o /S^NH N^NHMMTr
BzO bBz Bzd t®2
1°-· 10-7
NH ___
N^NHMMTr rW
KÔ HHUMTr
1<M
[0363] Compound 10-1 (5 g, 8.79 mmol) was co-evaporated with anhydrous pyridine. To an ice-cooled solution of 10-1 in anhydrous pyridîne (15 mL) was added TsCl (3.43 g, 1738 mmol), and stirred for l h at 0°C. The reaction was checked by LCMS and TLC. The reaction was quenched with Η2Ο, and extracted with EA. The organic phase was dried over anhydrous Na2SO4, and evaporated at low pressure. Compound 10-2 (635 g, 100%) was used for next step directly.
[0364] To a solution of 10-2 (31.77g, 43.94 mmol) in acetone (300 mL) was added Nal (65.86 g, 439.4 mmol), and heated to reflux ovemight The reaction was checked by LCMS. The reaction was quenched with sat. Na2S2O3 solution, and extracted with EA. The organic layer was dried over anhydrous Na2SO4. and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 6%) to give 10-3 (113g, 38%) as a white solid.
[0365] To a solution of 10-3 (113 g, 16.94 mmol) in dry THF (120 mL) was added DBU (12.87 g, 84.68 mmol), and heated to 60“C. The reaction was stirred ovemight and checked by LCMS. The reaction was quenched with sat. NaHCO3 solution, and extracted with EA. The organic phase was dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column chromatography (MeOH in DCM from 1% to 5%) to give 10-4 (5.5 g, 54%) as a white solid.
226 [0366] To an ice-cooled solution of 10-4 (500 mg, 0.90 mmol) in dry DCM (20ml) was added AgF (618 mg, 4.9 mmol) and a solution of h (500 mg, 1.97 mmol) in dry DCM (20 mL).’ The reaction was stirred for 3 h., and checked by LCMS. The reaction was quenched with sat NajSiOj solution and sat. NaHCQj solution, and the mixture was extracted with DCM. The organic layer was dried by anhydrous NaiSO.», and evaporated at low pressure to give crude 10-5 (420 mg, 66%).
[0367] . To a solution of crude 10-5 (250 mg, 0.36 mmol) in dry DCM (8 mL) was added DMAP (028 g, 2.33 mmol), TE A (145 mg, 1.44mmol) and BzCl (230 mg, 1.62 mmol) in a solution of DCM (2 mL). The reaction was stirred ovemight, and checked by LCMS. The 10 mixture was washed with sat NaHCOj solution and brine. The organic foyer was evaporated at low pressure. The residue was purified by prep-TLC to give crude 10-6 (150 mg, 46%).
[0368] To a solution of crude 10-6 (650 mg, 0.72 mmol) in dry HMPA (20 mL) was added NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). The reaction was stirred for 2 d at 60°C. The mixture was diluted with H2O, and extracted with EA. The organic foyer 15 was evaporated at low pressure. The residue was purified by prep-TLC to give 10-7 (210 mg, 32.4%). ESI-MS: m/z: 900.4 [M+H]+.
[0369] A mixture of 10-7 (25 mg) and BuNHj (0.8 mL) was stirred ovemight at R.T. The mixture was evaporated and purified on silica gel (10 g column) with CH2Cl2/MeOH (415% gradient) to yield 10-8 (15 mg, 91%).
[0370] A mixture of 10-8 (15 mg, 0.02 mmol) in ACN (0.25 mL) and 4 N
HCL/dîoxane (19 uL) was stirred at R.T. for 45 mins. The mixture was diluted with MeOH and evaporated. The crude residue was treated with MeCN, and the solid was filtered to yield compound 10 (7 mg). MS: m/z = 314 [M-l].
EXAMPLE 29
COMPOUNDS 36 AND 37
227
[0371] To a solution of 36-1 (150 mg, 024 mmol) in DCM (2.0 mL), triethylamine (141 pL, 2.0 mmol) was added at R.T. The mixture was cooled to 0 to 5°C (ice/water bath), and freshly prepared and distilled isopropyl phosphorodichloridate (45 pL, 026 mmol, prepared according to a procedure , Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) was added.
Thé mixture was stirred at 0 to 5°C (ice/water bath) for'15 mins, followed by N-methylimidazole (40 pL, 0.49 mmol). The mixture was stirred for I h at 0 to 5°C. TLC showed the absence of starting material 36-1. EA (100 mL) was added, followed by water. The organic layer was washed with H2O, sat aq. NHfCI solution and brine. The organic layer was separated, dried over anhydrous MgSÛ4 and filtered. The filtrate was concentrated in vacuum to give a residue, 10 which was purified on silica gel with 0 to 10% ÎPrOH/ DCM to give 36-2a (16.9 mg, faster eluting isomer) and 36-2b (72.7 mg, slower eluting isomer).
[0372] Compounds 36-2a and 36-2b were deprotected using a procedure described herein. Compound 36 (7.3 mg, single isomers from 36-2a (16.5 mg, 0.0235 mmol)) and compound 37 (29.0 mg. single isomers from 36-2b (72.7 mg, 0.1 mmol)) were obtained.
[0373] Compound 36: ’H NMR (CEhOD-dLi, 400 MHz) δ 7.94 (s, 1H), 632 (s, 1H).
6.00-5.9 (br s, 1H), 4.9-4.487 (m, 1H), 4.83-4.77 (m, IH), 4.65-4.50 (m, 3H), 1.45-1.39 (s, 9H), 12 (s, 3H),; ”F NMR (CDsOD-dj) <5-1203 (s); 3,P NMR (CDjOD-dj) <5-5.19 (s); ESI-LCMS: m/z = 448.05 [M+HJ*. Compound 37: ’H NMR (CD3OD-d4,400 MHz) <5 7.98 (s. 1H), 6.34 (s, IH), 5.78-5.64 (br s, 1H), 4.95-4.48 (m, 2H), 4.62-4.52 (m, 3H), 1.48-1.42 (s, 9H), 1.1 (s, 3H),;
,9F NMR (CD3OD-di) <5-1213 (s); 3,P NMR (CDjOD-dj) <5-7.38 (s); ESI-LCMS: m/z = 448.05 [M+HJ*.
EXAMPLE 30 COMPOUND 48
Acd t)Ac
48-2
[0374] To a solution of 48-1 (600 mg, 1.29 mmol) in anhydrous CH3CN (4 mL) was added DMAP (315 mg, 259 mmol), TEA (391 mg, 3.87 mmol) and TPSC1 (782 mg, 258 mmol). The mixture was stirred for 3 h. under N2. A solution of NH3 tn THF (2 mL) was added, and stirred for 1 h. The reaction was quenched with sat. NH4CI solution, and extracted with EA. The organic layer was dried over anhydrous Na2SO.i, and concentrated to dryness at low pressure. The residue was purified by column chromatography to provide 48-2 (370 mg, 62%) as a white foam solid.
228
[0375] Compound 48-2 (370 mg, 1.48 mmol) in methanolic ammonium was stirred at R.T. for 4 h. The solution was concentrated to dryness to give compound 48 (200 mg, 91%) as a white solid. ESI-MS: m/z 275.9 [M+Hf.
of 1O-43%ACN in H2O over 26 mins on a Synergi Hydro RP 30 x 250 m 4u particle column (Phenomcnex PN 00G-4375-U0-AX) eluted compound 19 (295 mins) and compound 18 (30.1 mins). Pure fractions were lyophilized to produce a white powder. Compound 19: 3,P-NMR (DMSO-d6) 3.448 ppm; MS: m/z: 544 [M-l]*; Compound 18: 3IP-NMR (DMSO-dâ) 3338 ppm; MS: m/z: 544 [M-l]'.
EXAMPLE 32 COMPOUNDS 20 AND 21
of 25-52%ACN in H2O over 26 mins on a Synergi Hydro RP 30x250m 4u particle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 21 (24.8 mins) and compound 20 (25.3 mins). Pure fractions were lyophilized to produce a white powder. Compound 21: 3IP-NMR 20 (DMSO-d6) 3.492 ppm; MS: m/z: 584 [M-l]’. Compound 20: 3,P-NMR (DMSO-d6) 3328 ppm; MS: m/z: 584 [M-l]*.
229
EXAMPLE 33
COMPOUND 13
2-1 [0378] Compound 2-1 (32 mg, 0.1 mmol) was dissolved in dry THF (3 mL) and 2M solution of isopropylmagnesium bromide in THF (0.1 mL) was added at 0°C. The reaction was left for 1 h at R.T., and phenyl(isopropyZ-L-alaninyl) thiophosphorochloridate was added (0.3 mmol). The mixture was left ovemight at R.T. LSMS analysis showed about 20% of unreactcd starting material. The same amount of Grignard reagent and thiophosphorochloridate were added, and the mixture was heated at 37°C for 4 h. The reaction was quenched with NH4C1. The product was extracted with EA, washed with brine, dried over Na^SO-t, and evaporated. The resulting oil was dissolved in 80% formic acid (4 mL) and in 1 h evaporated. Compound 13 was purified by RP HPLC in gradient of methanol in water from 30% to 95% on Synergy 4u HydroRP column (Phenominex) yielding a colorless solid. Compound 13 (7 mg, yield 12.5%). MS: m/z: 560.0 [M-l]’.
EXAMPLE 34 COMPOUND 39. Bis-lithium Sait
(bf»athluin Mit} [0379] Compound 39-1 was synthesized using a procedure similar for preparing compound 2 using alanine benzyl ester hydrochloride. LCMS: m/z 592 [M-1J*.
[0380] To a solution of 39-1 (1.1 g, 1.85 mmol) in dioxane (15 mL) and water (3 mL) was added aqueous triethyl ammonium acetate (2M, 2 mL, 4 mmol) followed by Pd-C (10%, 100 mg). The mixture was hydrogenated (balloon) for 2 h, and monitored by HPLC. The catalyst was fiîtered off, and the filtrate was concentrated to dryness. The residue was suspended
230 in 3% solution of lithium perchloratc in acetone (25 mL). The solid was isolated by filtration.
nnsed with acetone and dried under vacuum to give compound 39 (bis-lithium sait) (731 mg.
90%). LCMS: m/z426 [M-l]'.
EXAMPLE 35 COMPOUND 55 [0381]
r'VJx H<5* ‘t)H o
Compound 1 (40 mg, 0.14 mmol) and triethylammonium bis(pivaloyloxymethyl)phosphate (0.21 mmol, prepared from 80 mg of bis(pivaloyloxymethyl)phosphate and 30 pL of Et3N) were rendered anhydrous by coevaporating with pyridine, followed by toluene. The evaporated residue was dissolved in anhydrous THF (2 mL) and cooled in an ice-bath. Diisopropylethyl amine (73 pL, 3 eq.), BopCl (71 mg, 2 eq.), and 3-nitro-l,2,4-triazoIe (32 mg, 2 eq.) were added. The mixture was stirred at 0°C for 90 mins.
The mixture was then diluted with EtOAc, washed with sat aq. NaHCOj and brine, and dried (NazSOJ. Purification on silica gel column with CHiCli/i-PrOH solvent System (4-10% gradient) followed by RP-HPLC purification (A: water. B: MeCN) yielded compound 55 (13 mg, 16%). MS: m/z= 1167 [2M-Ï].
EXAMPLE 36 COMPOUND 45
4M
b0
4M
[0382] Compound 45-1 ( 15.0 g, 25.55 mmol) was treated with 90% HOAc (150 mL) at R.T. The mixture was stirred at 1 IO°C for 12 h, and then concentrated at a low pressure. The residue was dissolved in DCM, and the solution was washed with brine. The organic phase was
231
dried over anhydrous NaiSCh, and then concentrated at a low pressure. The residue was purified by column chromatography (5% MeOH in DCM) to give 45-2 (11.0 g, 88.9%) as a white solid.
[0383] Compound 45-2 (12.0 g, 24.79 mmol) was treated with NHj in MeOH (200 mL, 7 M) at R.T. The solution was stirred at R.T. for 12 h, and then concentrated at a low pressure. The residue was purified by column chromatography (10% MeOH in DCM) to give
45-3 (65 g, 95.0%) as a white solid.
[0384] To a stirred suspension of 45-3 (4.3 g, 1558 mmol), PPh3 (8.16 g, 31.15 mmol), imidazole (2.11 g, 31.15 mmol) and pyridine (15 mL) in anhydrous THF (45 mL) was added a solution of L· (7.91 g, 31.15 mmol) in THF (100 mL) dropwise atO°C. The mixture was 10 slowly warmed to R.T. and stirred ovemight The mixture was quenched with MeOH (100 mL). The solvent was removed at a low pressure, and the residue was re-dissolved in a mixture of EA and THF (0.2 L, 10:1). The organic phase was washed with sat Na2S2O3aq. (2x). The aqueous phase was extracled with a mixture of EA and THF (0.2 L, 10:1,2x). The concentrated organic phase was dried over anhydrous Na2SO4. The residue was purified on a silica gel column (0-10% 15 MeOH in DCM) to afford 45-4 (5.1 g, 85.0%) as a white solid.
[0385] Compound 45-4 (800 mg, 2.07 mmol) was dissolved in a mixture of DBU (4 mL) and THF (4 mL) at R.T. under Ni. The solution was stirred at R.T. for 1 h. The mixture was neutralized with HOAc, and extracted with a mixture of EA and THF (10:1,40 mL). The organic phase was washed with brine, and dried over anhydrous Na2SO4. The concentrated 20 organic phase was purified by column chromatography (0-10% MeOH in DCM) to give 45-5 (240 mg, 44.9%) as a white solid.
[0386] To an ice-cooled solution of 45-5 (1.20 g, 4.65 mmol) in anhydrous MeCN (12 mL) was added NIS (157 g, 6.97 mmol) and TEA*3HF (1.12 g, 6.97 mmol) under N2. The mixture was stirred at R.T. for 5 h. The reaction was quenched with saL NaHCOj solution, and 25 extracted with EA (3 x 100 mL). The organic phase was dried over anhydrous Na2SO4, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (0-5% MeOH în DCM) to give 45-6 (0.91 g, 48.6%) as a white solid.
[0387] To a stirred solution of 45-6 (1.2 g, 2.97 mmol) in anhydrous DCM (12 mL) was added BzCl (0.83 g, 5.94 mmol), TEA (0.6 g, 5.94 mmol) and DMAP (0.72 g, 5.94 mmol) 30 successively at R.T. The mixture was stirred at R.T. for 12 k The reaction was quenched with water, and extracted with EA (3 x 60 mL). The organic phase was concentrated at low pressure. The residue was purified by column chromatography (0-5% MeOH in DCM) to give 45-7 (1.2 g, 66.2%) as a white solid.
232 [0388] Tetra-butyl ammonium hydroxide (25.78 mL, 51.78 mmol) was ncutralized with TFA (4.3 mL) to pH=4, and the solution was added to a solution of 45-7 (1.09 g, 2.14 mmol) in DCM (30 mL). m-CPBA (1.85 g, 10.74 mmol) was added portion-wise under vigorous stirring, and the mixture was stirred for 12 h. The mixture was diluted with EA (100 mL), and t— 5 - washed with sat. sodium bicarbonate. The organic phase was concentrated at low pressure. The residue was purified by column chromatography (50% EA in PE) to give 45-8 (350 mg, 41.1%) as a white solid. . ...
[0389] Compound 45-8 (280 mg, 0.704 mmol) was treated with NH3 in MeOH (10 mL, 7 M) at R.T. The mixture was stirred at R.T, for 2 h. The mixture was concentrated at a low pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give compound 45 (110 mg, 53.1 %) as a white solid. ESÏ-LCMS: m/z 295.1 [M+H]*.
EXAMPLE 37
COMPOUND 54
[0390] To an ice-cooled solution of 54-1 (10 g, 42 mmol) in anhydrous MeCN (200 mL) was added TEA*3HF (10 g, 625 mmol) and NIS (28 g, 126 mmol). The mixture was stirred at R.T. for 15 h, and monîtored by LCMS. After the réaction was completed, the mixture was concentrated at a low pressure. The residue was purified by silica gel column chromatography (15% MeCN in DCM) to give 54-2 (12 g, 74%) as a yellow solid.
[0391] To a solution of 54-2 (22 g, 57 mmol) in anhydrous DCM (200 mL) was added DMAP (21 g, 171 mmol) and BzCl (17.6 g, 125 mol). The mixture was stirred for 5 h at R.T., and monitored by LCMS. The solution was washed with sat. NaHCQj solution, brine and extracted with EA. The organic phase was dried over anhydrous Na^SOj and filtered. The
233 filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-3 (30 g, 88%) as a white foam.
[0392] To a solution of 54-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) was added NaOBz (l 5.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at ~-5- -95°C for 48 hz The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved în EA (200 mL), and the solution was washed with sat NaHCOj solution, and brine. The organic layer was dried over anhydrous Na^SO; and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-4 (3 g crude, 46.1 %) as an oil.
[0393] Compound 54-4 (3 g, crude) was treated with NHj in MeOH (120 mL, 7 M).
The mixture was stirred for 3 h and monitored by TLC. The solution was concentrated at low pressure. The residue was purified by silica gel column chromatography (10% isopropanol in DCM) to give 54-5 (1.0 g, 67%) as a white solid. ’H-NMR (CDjOD, 400MHz) 6= 1.19(s, 3H), 3.76-3.82 (m, 2H), 4.02 (d, J = 19.8 Hz, I H), 5.70 (d, J - 8.07 Hz, 1H), 6.27 (s, 1 H), 7.89 (d, J 15 8.07 Hz, 1 H).
[0394] Compound 54-5 (100 mg, 0.36 mmol) was co-evaporated with toluène 3 times. To a stirred solution of 54-5 (100 mg, 0.36 mmol) in a mixture of MeCN (1.0 mL) and NMI (295 mg, 3.6 mmol) was added a solution of 54-C (255.6 mg, 0.72 mmol, préparation described below) in MeCN (0-5 mL) at 0 °C. The mixture was stirred at R.T. ovemight. The 20 reaction was quenched with water, and diluted with EA (20 mL). The organic layer was washed with water and brine. The organic layer was dried over anhydrous Na^SO?. The organic phase was concentrated at low pressure. The residue was purified on a silica gel column (5% i-PrOH in DCM) to give the crude product The product was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 54 (46.7 mg, 233%) as a white solid. ESI-LCMS: m/z 618 25 [M+Naf.
[0395] To a stirred solution of 54-A (2.0 g, 13.16 mmol) and naphthalen-l-ol (1.89 g, 13.16 mmol) In anhydrous DCM (100 mL) was added a solution of TEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at -78°C. After addition, the mixture was gradually warmed to R.T., and stirred for 2 h. The solution was cooled to -78°C, and (S)-isopropyl 2-aminopropanoate 30 hydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed by TEA (2.66 g, 26.29 mmol) in DCM (20 mL) dropwise. The mixture was gradually warmed to R.T., and stirred for 2 h. The organic solvent was removed at low pressure. The residue was dissolved in methyl-butyl ether. The precipitate was filtered, and the filtrate was concentrated at low
234 pressure. The residue was purified on a silica gel column (anhydrous DCM) to give 54-C (1.0 g, 24.8%) as a colorless oil.
EXAMPLE 38 COMPOUNDS 56 AND 57
[0396] To a solution of 54-5 (300 mg, 1.08 mmol) and NMI (892 mg, 10 mmol) in anhydrous MeCN (4 mL) was added a solution of 57-C (736 mg, 2 .17 mmol, préparation described below) in anhydrous MeCN (l mL) dropwise at 0°C. The mixture was stirred at R.T. ovemight. The reaction was quenched with water, and diluted with EA (30 mL). The organic 10 layer was washed with water and brine. The organic phase was dried over anhydrous NanSOj and concentrated at low pressure. The residue was purified by a silica gel column (iPrOH in DCM from I % to 5%) to give crude compound 56 (276 mg, crude). Crude compound 56 (96 mg) was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 56 (46 mg, 47.9%) as a white solid. ESI-LCMS: m/z 560 [M - Ff.
[0397] To a solution of compound 56 (180 mg, 0.31 mmol) in anhydrous pyridine (6 mL) was added acetic anhydride (158 mg, 134 mmol) dropwise at 0°C. The mixture was stirred at R.T. ovemight The solution was quenched with water and concentrated at a low pressure. The residue was dissolved in EA (10 mL), and washed with brine. The organic layer was dried over anhydrous Na2SO4 The organic phase was concentrated at low pressure. The residue was 20 purified by silica gel column (r-PrOH in DCM from 1% to 3%) to give crude compound 57 (172 mg). Crude compound 57 was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 57 (46 mg, 23.8%) as a white solid. ESI-LCMS: m/z 602.3 [M-F]*.
[0398] Compound 56-C (1.02 g, 23%, a colorless oil) was prepared using a procedure similar to the préparation of 54-C using 54-A (2.00 g, 13.16 mmol) and 425 chlorophenol (1.68 g, 13.16 mmol).
235
EXAMPLE 39 COMPOUND 61
[0399] Compound 25 (109 mg, 039 mmol) and bis(isopropyloxycaibonyloxymethyl)phosphate (0.6 mmol, prepared triethylammonium from 195 mg of bis(isopropyloxycarbonyloxymethyl)phosphate and 85 gL of EtjN) were rendered anhydrous by coevaporating with pyridinc, followed by toluene. The residue was dîssolved in anhydrous THF (3 mL) and cooled in an ice-bath. Dîisopropylethyl amine (03 mL, 3 eq.), BopCl (190 mg, 2 eq.), and 3-nitro-l,2,4-triazole (81 mg, 2 eq.) were added, and the mixture was stirred at0°C for 10 90 mins. The mixture was diluted with EtOAc, washed with saL aq. NaHCOj and brine, and dried (NazSOj). Purification on silica gel column with CHiCL/i-PrOH (4-10% gradient) followed by RP-HPLC purification (A: 0.1% HCOOH in water. B: 0.1% HCOOH in MeCN) yielded compound 61 (28 mg, 12%). 'H-NMR (CDCIj): δ 7.24 (d, 1H), 6.6 (br, 1H), 5.84 (d, 1H), 5.65-5.73 (m, 4H), 4.94 (m, 2H), 438 (m. 2H), 4.1 (b. IH), 2.88 (d, 1H), 1.47 (d, 3H), 133 15 (m, 12H).
EXAMPLE 40 COMPOUND 74
[0400] Dry nucleoside (0.05 mmol) was dîssolved in a mixture of PO(OMe)3 (0.7 20 mL) and pyridine (03 mL). The mixture was evaporated in vacuum for 15 mins. at 42°C, then cooled to R.T. N-Methylîmidazole (0.009 mL, 0.11 mmol) was added followed by POClj (0.009 mL, 0.11 mmol). The mixture was kept at R.T. for 20-40 mins and monitored for the formation of compound 74 by LCMS. The reaction was quenched with water and isolated by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 25 30% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove exccss of buffer. MS: m/z 3963 [M-IJ*.
* J
EXAMPLE 41 COMPOUND 68
[0401] .The nucleoside ( 140 mg, 0.42 mmol) was dissolved in n-butylamine (0.5 mL).
The mixture was kept for 2 h at R.T., and the amine was then evaporated. The residue was f · - dissolved in EtOAc, and the organic layer was washed twice with 10% citric acid, dried over
NaiSOj,' and evaporated. The residue purified by column chromatography on silica gel in lînear gradient of methanol in DCM from 0% to 12% over 10 column volumes. The fractions containing the product were concentrated and treated with 80% HCOOH for 1 h at R.T. The mixture was evaporated to dryness, and suspended in CHjCN. The precipitate was separated, washed with CH3CN ( 1 mL) and dried to yield compound 68 (27 mg, 50%). MS: m/z 326.5 [M1]‘.
EXAMPLE 42 COMPOUND 62
[0402] Compound 45 (30 mg, 0.1 mmol) was dissolved in a mixture of CHjCN (2 mL) and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol) was added, and the mixture was kept for 5 d at R.T. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The phosphoroamidate was isolated by silica gel chromatography in a gradient of methano! in DCM from 3% to 10%. The corresponding fractions were concentrated and re-purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lînear gradient of methanol in DCM from 3% to 95% containing 0.1% formic acid was used for elution. Compound 62 was obtaîned as a mixture Rp and Rs isomers (9 mg, 16%). MS: m/z 562.1 [M-l]'.
237
EXAMPLE 43 COMPOUND 72
[0403] Compound 47 (30 mg, 0.1 mmol) was dissolved in a mixture of CHjCN (2 mL) and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol) was added, and the mixture was kept ovemight at 40°C. The température was increased to 65°C and heated for 1 h. The mixture was distributed between water and EA. The organic layer was separated, washed with brine, dried and evaporated. The azido-phosphoramidate was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 30% to 100% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elution. The azidophosphoramidate (8 mg) was dissolved in pyridine/EtjN (3 mL, 8:1 v/v) and cooled to 0°C. H2S gas was bubbled through the solution for 10 min, and the reaction was kept for 1 h at R.T. The solvents were evaporated, and the residue isolated by RP HPLC. The corresponding fractions were combîned, concentrated and lyophilized 3 limes to remove excess of buffer, to provide compound 72 (1.2 mg) as mixture Rp and Rs isomers. MS: m/z 544.1 [M+l]*.
EXAMPLE 44 COMPOUND 65
HO F
BS [0404] To a solution of 65-1 (23.0 g, 393 mmol) in anhydrous toluene (200 mL) was added DAST (31.9 g, 198 mmol) dropwise at -78°C, and the solution was stirred at -78°C for 3
238
h. The mixture was quenched with sat. NaHCOj, extracted with EA (2 x 200 mL) and dried over with anhydrous NajSQ*. The solution was concentrated to dryness under low pressure. The residue was purified on a silica gel column (50% EA in PE) to give 65-2 (165 g, 71%) as a yellow foam.
-[0405] A mixture of 65-2 (16.0 g, 27.4 mmol) and NH4F (3.0 g, 82.2 mmol) in methanol (100 mL) was stirred at 70°C for 12 h. The reaction was cooled, and the sait was removed by filtration. The filtrate was concentrated to dryness at low pressure. The residue was purified on a silica gel column (3% MeOH in DCM) to give 65-3 (5.1 g, 69.0%) as a white foam.
[0406] To a stirred suspension of 65-3 (4.1 g, 15.2 mmol), PPhj (8.0 g, 30.4 mmol), tmidazole (2.1 g, 30.4 mmol) and pyridine (18.2 mL) in anhydrous THF (40 mL) was added dropwise a solution of h (5.8 g, 22.8 mmol) in THF (20 mL) at 0°C. The mixture was stirred at R.T. for 12 h. The reaction was quenched with MeOH (100 mL), and the solvent was removed under reduced pressure. The residue was purified on a silica gel column (4% MeOH in DCM) to give pure 65-4 (4.4 g, 77%) as a white solid. ESI-MS: m/z 381.1 [M+l]*.
[0407] To a stirred solution of 65-4 (2.5 g, 0.7 mmol) in anhydrous THF (3 mL) was added DBU (2.1 g, 14 mmol) at R.T., and the mixture was stirred at R.T. for 1 h. The reaction was quenched with HOAc, and diluted with 2-Me-tetrahydroluran. The solution was washed with brine, dried over with anhydrous Na2SO4 and concentrated to dryness at low pressure. The residue was purified on a silica gel column (MeOH 5% in DCM) to give 65-5 (l.l g, 68.9%) as a white foam.
[0408] To a stirred solution of 65-5 (800 mg, 3.17 mmol) in anhydrous CH3CN (10 mL) was added TEA*3HF (510 mg, 3.17 mmol) and NIS (785 mg, 3.49 mmol) at 0°C. The mixture was stirred for 30 mins, gradually warmed to R.T., and stirred for 1 h. The mixture was quenched with sat. NaHCOj solution and Na2S20j solution, and extracted with EA (2 x 20 mL).
The organic layer was dried over with anhydrous Na2SO.j, and concentrated to dryness at low pressure. The residue was purified on a silica gel column to give pure 65-6 (695 mg, 57.9%) as a yellow solid.
[0409] To a stirred solution of 65-6 (650 mg, 1.63 mmol) in pyridine (3 mL) was added BzCl (507 mg, 3.59 mmol) at 0°C, and stirred at R.T. for 12 h. The mixture was quenched with water, and concentrated to dryness under reducing pressure. The residue was purified on a silica gel column (EA 50% in PE) to yield 65-7 (550 mg, 67%) as a white foam.
[0410] Tetra-butylammonium hydroxide (9 mL as 54-56% aqueous solution, 72 mmol) was neutralized with TFA to pH~4 (13 mL), and the mixture was added to a solution of 65-7 (375 mg, 0.75 mmol) in DCM (9 mL). m-Chloroperbenzoîc acid (924 mg, 60-70%, 3.75
mmol) was added in portions with vigorous stirring, and the mixture was stirred ovemight The mixture was washed with brine, dried over magnésium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EA 50% in PE) to give 65-8 (230 mg, 78.8%) as a white foam. ESI-MS: m/z 393.1 [M+lf.
[0411].— Compound 65-8 (120 mg, 0.24 mmol) was treated with 7N NHj’MeOH (20 · - mL),'and stirred for 5 h. The mixture was concentrated to dryness at low pressure. -The residue was purified on a silica gel column (propan-2-ol 15% in DCM) to yield compound 65 (53 mg, 60.2%) as a white solid. ESI-MS: m/z 288.8 [M+lf.
EXAMPLE 45 COMPOUND 70
[0412] To a solution of 70-1 (3.0 g, 18.0 mmol) and POCI3 (135 g, 9.0 mmol) in DCM (80 mL) was added ΤΈΑ (3.6 g, 36.0 mmol) in DCM (20 mL) dropwise at 0°C. The mixture was stirred at 0°C for 2 h. A solution of pentafluorophenol (1.65 g, 9.0 mmol) and TEA 15 (0.9 g, 9.0 mmol) in DCM (20 mL) was added dropwise at 0°C, and the mixture was stirred at
0°C for 15 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed by TB ME and filtered. The fïltrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (20% EA in PE) to give 70-2 (2.7 g, 62.7%) as a white solid. ESI-MS: m/z 491.1 [M+lf.
[0413] To a stirred solution of l-((3aR,4R,6S,6aS)-6-fluoro-6-(hydroxymethyl)-2methoxy-3a-methyltetrahydrofuro[3,4-d] [ 1,3 ]dîoxol-4-yl)pyrimidine-2,4 ( 1 H3H)-dione ( 150 mg, 0.47 mmol) in anhydrous THF (2 mL) was added a solution of t-BuMgCl (0.46 mL, IM in THF) dropwise at 0°C. The mixture was stirred at R.T. for 40 mins, and re-cooled to 0°C. A solution of 70-2 (462 mg, 0.94 mmol) was added, and the mixture was stirred at R.T. for 4 h. The 25 mixture was quenched with H2O, and extracted with EA. The organic layer was dried over
Na2SÛ4 and concentrated under reducing pressure. The residue was purified on a silica gel column (50% EA in PE) to give 70-3 as a white foam (230 mg, 78%).
240
[0414] Compound 70-3 (230 mg, 0.37 mmol) was dissolved in 80% HCOOH aqueous solution (20 mL), and the mixture was stirred at R.T. for 24 h. The solvent was removed at low pressure. The residue was purified on a silica gel column to give the crude product, which was purified by RP HPLC (HCOOH System) to give compound 70 as a mixture 5 of two P-isomers (75 mgi33%). ESI-TOF-MS: m/z 583.0 [M+Hf. - -- ·— . . ^ EXAMPLE46 - —----------—
COMPOUND 75
7M3
75-1#
75-15
[0415] To a solution of 75-1 (120 g, 0.26 mol) in CH3CN (2.0 L) was added IBX 10 (109 g, 0.39 mol), and refluxed for 12 h. The reaction was monitored by TLC and LCMS. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated at low pressure. The crude product was used dîrectly for the next step.
[0416] Compound 75-2 (130 g, 0.26 mol) was co-evaporated with anhydrous toluene three times to remove H2O. To a solution of 75-2 in THF (300 mL) was added dropwise vinyl
241
magnésium bromide (700 mL, 0.78 mol, IN in THF) over 30 min at -78°C. The mixture was stirred for about 1 h at R.T. After the starting materia! was consumed, the mixture was poured into a sat. NHjCl solution. The organic layer was washed with brine, dried with anhydrous Na2SO4 and filtered. The solution was concentrated at low pressure to get the crude product To - - 5 ~ a solution of this crude product (170 g, 0346 mol) in anhydrous CHjCfe was added TEA (105 g,
1.04 mol) and DMAP (84 g, 0.69 mol) Beôzoyl chloride (146 g, 1.04 mo!) was added slowly at R.T. for 12 h. The mixture was diluted with CH2CI2 and then washed with sat aq. NaHCOj. The combined aq. phase was extracted with DCM (100 mL), and the combined organic phase was dried with Na2SÛ4. After filtration, the solution was evaporated to dryness under reduced 10 pressure, and the residue was purified by column chromatography to give 75-3 ( 107 g, 52%).
[0417] Uracil (44.8 g, 0.4 mol) (co-evaporated with tolucne twice) and NOBSA (81.4 g, 0.4 mol) were dissolved in CHjCN (500 mL). The mixture was refluxed for 1.5 h and then slowly cooled to R.T. The mixture was treated with 75-3 (59 g, 0.1 mot) and TMSOTf (155 g, 0.7 mol), and then warmed to 6O-7O°C for 12 h. The mixture was neutralîzed with a sat 15 NaHCOj solution, and extracted with EA (3 x 1000 mL). The solution was dried over anhydrous MgSO4, and evaporated at low pressure. The residue was purified using a silica gel column to give pure 75-4 (40 g, 69%) as a white solid.
[0418] To a solution of 75-4 (50 g, 0.086 mol) in DMF was added PMBC1 (16 g, 0.1 mol) and K2COj (17.8 g, 0.13 mol) at 0°C, and the mixture was stirred at R.T. for 12 h. The 20 mixture was quenched with water (100 mL), and extracted with EA (3 x 200 mL). The organic phase was concentrated at low pressure to give crude 75-5 (65 g) which was used in the next step without further purification.
[0419] To a solution of crude 75-5 (65 g, 0.086 mol) in MeOH/DCM (4/1) (200 mL) was added NaOMe (16.8 g, 0.3 mol), and the mixture was stirred at R.T. for 2.5 h. The reaction 25 was quenched with dry ice, and then concentrated at low pressure. The residue was dissolved in EA (200 mL) and washed with brine. The organic layer was concentrated at low pressure, and the residue was purified using a silica gel column using 1% MeOH in CH2CI2 to give 75-6 as a yellow foam (25 g, 75%).
[0420] To a solution of 75-6 (255 g, 0.065 mol) in DMF was added NaH (105 g, 30 0.26 mol) slowly at 0°C, and the mixture was stirred for 30 mins. BnBr (36.3 g, 031 mol) was added, and the mixture was stirred at R.T. for 12 h. The reaction was quenched with sat. NH4CI (aq.), and then extracted with EA (3 x 100 mL). The solution was dried over anhydrous MgSCh, and evaporated at low pressure. The residue was purified by a silica gel column using 10% EA în PE to give 75-7 (20 g, 46%) as a white solid.
242 [0421] Το α solution of 75-7 (20 g, 0.03 mol) and NMMO (7 g, 0.06 mol) in
THF:H2O (5:1) ( 100 mL) was added OsO4 (2.6 g, 0.01 mol) at R.T., and the mixture was stirred at R.T. for 24 h. The mixture was quenched with a sat. Na2S2O3 solution, and extracted with EA (3 x 100 mL). The organic layer was washed with brine, and dried over anhydrous MgSO4. The — ~5 'solution was evaporated al low pressure to give the crude compound, whichwas used in the next — - - step without' further purification.'-----— - - ---— - - - —:---- —' [0422] To a solution of the crude diol (0.03 mol) in MeOH:H2O:THF (170 mL:30 mL:50 mL) was added NaIO4 (9.6 g, 0.045 mol), and the mixture was stirred at R.T. for 2 h. After filtration, the filtrate was used directly in the next step. This solution was treated with 10 NaBH» (1.8 g, 0.048 mol) at 0°C, and the mixture was stirred at R.T. for 30 mins. The mixture was quenched with MeOH, and evaporated at low pressure. The residue was dissolved in EA (100 mL), and washed with brine. The solution was evaporated at low pressure, and the residue was purified by a silica gel column using 20% EA in EA to give 75-8 (12 g, 61% over three steps).
[0423] To a solution of 75-8 (14 g, 21 mmol) and DMAP (5.1 g, 42 mmol) in DCM (100 mL) was added MsCl (3.1 g, 27 mmol) at 0°C, and the mixture was stirred at R.T. for 40 mins. The reaction was quenched with sat NaHCOj (aq.), and washed with HCl (0.2 N) solution. The organic phase was dried over anhydrous MgSO4, and evaporated at low pressure. The residue was purified by a silica gel column using 5% EA in PE to give mysolate product (14 20 g, 90%). The MsO-product (41 g, 55 mmol) was treated with TBAF (1N in THF, 500 mL), and the mixture was stirred at 70-80°C for 3 d. The mixture was concentrated at low pressure, and the residue was dissolved in EA (200 mL). The solution was washed with brine, dried over anhydrous MgSO4 and evaporated at low pressure. The residue was purified by chromatography using 10% EA in PE to give 75-9 (9.9 g, 27%).
[0424] To a solution of 75-9 (63 g, 9.45 mmol) in CHsCN:H2O (3:1,36 mL: 12 mL) was added CAN (153 g, 283 mmol), and the mixture was stirred at R.T. ovemîght. The mixture was extracted with EA (3 x 50 mL). The solution was dried over anhydrous MgSO4, and evaporated at low pressure. The residue was purified by chromatography using 20% EA in PE to give 75-10 (3.6 g, 71%) as a white solid.
[0425] To a solution of 75-10 (2.4 g, 4.4 mmol) in anhydrous DCM (10 mL) was added slowly BCI3 (I N, 30 mL CH2C12) at -70°C, and the mixture was stirred for 2 h. at -70°C. The mixture was quenched with the slow addition of MeOH at -70°C, and the mixture was concentrated at low pressure. The residue was purified by chromatography using 50% EA in PE to give 75-11 (1,2 g, 86%) as a white solid. ESI-MS: m/z 277.1 [M+H]*.
243 [0426] To a solution of PPhj (3.37 g, 12.8 mmol) in pyridine (15 mL) was added h (3.06 g, 12 mmol) at 0°C, and the mixture was stirred at R.T. for 30-40 mins. The mixture was . cooled to 0°C, and then treated with 75-11 (2.2 g, 8 mmol) in Py. (5 mL). The mixture was stirred at R.T. under N2 for 12 h. - The mixture was quenched with saL Na2SiOj (aq.) and
- -5 · extracted with CH2C12 (3 x 50 mL). -The organic phase was dried over anhydrous MgSO4, and — - -then-concentrated at low pressure. The residue was purified by chromatography using 1-2%
MeOH in CH2C12 to yield 75-12 (1.8 g, 58%) as a white solid.
[0427] To a solution of 75-12 (1.35 g, 33 mmol) in THF:CHjCN (10 mL:5 mL) was added DBU (1.06 g, 7 mmol), and the mixture was stirred at 60-70°C for 2 h. The mixture was 10 concentrated at low pressure, and the residue was dissolved in EA (20 mL). The solution was washed with 10% HCl solution and brine. The organic phase was dried over anhydrous MgSO4 and concentrated at low pressure. The residue was purified by chromatography using 30% EA in PE to give 75-13 (03 g, 55%).
[0428] To a solution of 75-13 (670 mg, 2.6 mmol) in CH3CN (6 mL) was added NIS 15 (730 mg, 3.25 mmol) and 3HF*TEA (335 mg, 2.1 mmol) at 0°C, and the mixture was stirred at
R.T. for 2 h. The mixture was quenched with sat. NaHCOa (aq.) and Na2S2Û3 (aq.) solution. The mixture was extracted with EA (3 x 20 mL), dried over anhydrous MgSO4 and concentrated at low pressure. The residue was purified by chromatography using 1-2% MeOH in CH2C12 to give 75-14(1.2 g, 80%).
[0429] To a solution of 75-14 (1.0 g, 2.47 mmol), DMAP (0.75 g, 6.2 mmol) and
TEA (0.75 g, 7.42 mmol) in DCM (10 mL) was added BzCl (1.15 g, 8.16 mmol) in DCM (1 mL) at 0°C, and the mixture was stirred at R.T. for 12 h. The mixture was diluted with CH2C12 (10 mL), and then washed with HCl (0.1 N, 20 mL) solution and brine. The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by chromatography using 20% EA în PE to afford 75-15 (850 mg, purity-80%).
[0430] To a solution of 75-15 (600 mg, 1 mmol) in DMF (25 mL) was added BzONa (1.45 g, 10 mmol), 15-crown-5 (2.2 g, 10 mmol), and the mixture was stirred at90-100°C for 24 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (20 mL), and washed with brine. The organic phase was dried over anhydrous MgSO4, and then 30 concentrated at low pressure. The residue was purified by chromatography using 15% EA in PE to give 75-16 (275 mg, 37%) as a light yellow foam.
[0431] Compound 75-16 (250 mg, 0.41 mmol) was treated with NHj’MeOH (7 N, 5 mL), and the mixture stirred at R.T. for 15 h. The mixture was concentrated at low pressure, and
244 the residue was purified by prep-HPLC to give compound 75 (33 mg, 25%) as a white solid.
ESI-MS: m/z 295.1 [M+Hf.
EXAMPLE 47 COMPOUND 73
[0432] To a solution of IBX (13333 g, 476 mmol) in dry CH3CN (2 L) was added
73-1 (100.0 g, 216 mol) at R.T. The mixture was refluxed and stirred for 12 h. The mixture was filtered, and the fîltrate was concentrated at low pressure to give 73-2 as a yellow oil (90.0 g, 90.4%).
[0433] Compound 73-2 (50.0 g, 108.70 mmol) was coevaporated with anhydrous toluene twîce to remove H2O. Ethynyl magnésium bromide, (800 mL, 400.0 mmol) was added dropwise into a solution of 73-2 in THF (500 mL) over 20 mins at -78°C. The mixture was stirred for about 10 mins at -78°C. When the starting matcrial was consumed, the ice-acetone cooling bath was removed. The mixture was quenched with a sat. NH4C1 solution with stirring, and then warmed to R.T. The mixture was extracted with EA, filtered through Celite and washed with brine. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated at low pressure to give crude 73-3 as a deep yellow oil (48.0g, yield: 90.8%).
CSESeSM
245 [0434] Compound 73-3 (200.0 g, 41132 mmol) was dissolved in anhydrous CH2CI2 (2000 mL) and then DMAP (100.41 g, 823.05 mmol) and EtjN (124.94 g, 1.23 mol) were added at R.T. The mixture was treated with benzoyl chloride (173.46 g, 1.23 mol) at 0°C. After stining for 12 h at R.T., the reaction was quenched with H2O. The combined aq. phase was extracted with DCM. The combined organic phase was dried over anhydrous NajSO.», fiîtered and evaporated to dryness under reduced pressure to give a black oil, The oil was purified by column chromatography using 7%-20% EA in PE as the eluent to give a yellow oil. The residue triturated with CHjOH and fiîtered. Thè filtercake was concentrated in vacuo to give 73-4 as a white solid (30.0 g, 36.4%).
[0435] Uracil (34.17 g, 305.08 mmol) were coevaporated with anhydrous toluene twice to remove HiO. To a stirred suspension of uracil in anhydrous MeCN (150 mL) was added N.O-BSA (123.86 g, 610.17 mmol) at R.T. The mixture was refluxed for 1.5 h and then cooled to R.T. Compound 73-4 (90 g, 15234 mmol, which were coevaporated with anhydrous toluene twice to remove H2O) was added. TMSOTf (237.05 g, 1.07 mol) was then added at R.T.
The mixture was heated to 70°C, and then stirred overnight and then monitored by LCMS. The mixture was cooled to R.T., and quenched with a sat. NaHCOj solution. The solution was extracted with EA. The organic layer was dried over Na^SO.», and then concentrated at low pressure. The residue was purified using a silica gel column eluted with I0%-50% EA in PE to give 73-5 as a white solid (45 g, 50.9%).
[0436] Compound 73-5 (50 g, 86.21 mmol) was treated with NHj in MeOH (1 L) at
R.T., and then stirred for 48 h. The mixture was concentrated at low pressure, and the residue was purified by column chromatography ( 10% MeOH in DCM) to give 73-6 (12.6 g, 5435%) as a white solid.
[0437] To a solution of cyclopentanone (100 g, 1.189 mmol) and trimethyl 25 orthoformate (150 mL) in MeOH (600 mL) was added TsOH-HjO (1.13 g, 5.9 mmol), and the mixture was stirred at R.T. for 30 mins. The reaction was quenched with NaOMe (0.32 g, 5.9 mmol) and H2O, and the solution was extracted by n-hexane. The organic layer was dried over anhydrous NajSO.». and then concentrated at low pressure. The cyclopentyl dimethoxy acetal and 73-6 (20 g, 74.63 mmol) was dissolved in DCE (200 mL), and then treated with TsOH*H2O 30 (0.71 g, 3.73 mmol). The mixture was stirred at 50“C for 12 h, and then concentrated at low pressure. The residue was purified by silica gel column chromatography (1-10% MeOH in DCM) to give 73-7 ( 15.4 g, 61.8% ) as a white solid.
[0438] Compound 73-7 (20.0 g, 0.06 mol) was coevaporated with anhydrous pyridine three times to remove H2O. To an ice-cold solution of 73-7 in anhydrous pyridine (100 ml) was
246 added TsCl (22.8 g, 0.12 mol) at 0°C, and the mixture was stined ovemight and monitored by LCMS and TLC. The reaction was quenched with H2O and extracted wîth EA. The organic phase was dried over anhydrous NaSO4 and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM: MeOH= 100:1 to 15:1) to give 78-8 (20.0
-;5 .·, g, 69.0%) as a white solid.- - [0439] To a solution of 73-8 (20.0 g, 0.04 mol) in âcetone (200 ml)' was-added Nal (31.0 g, 0.2 mol) and heated to reflux ovemight and monitored by LCMS. The mixture was quenched with a sat Na2S2O3 solution, and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and evaporated at low pressure. The residue was purified by silica gel 10 column chromatography (DCM: MeOH=100:l to 15:1) to give 73-9 (15.0 g, 83.3%) as a white solid.
[0440] To 73-9 (30.0 g, 0.068 mol) in dioxane (60 mL) in sealed tube was added CuBr (4.9 g, 0.034 mol), r-Pr2NH(13.6 g, 0.135 mol) and (CH2O)0(5.1 g, 0.17 mol) under N2. The mixture was heated at reflux for 16 h. The mixture was diluted with EtOAc, and washed 15 with a sat NH4CI solution and brine. The solution was dried over anhydrous MgSÛ4, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH=100:l to 15:1) to give 73-10 (10.0 g, 32.3%) as a white solid.
[0441] Compound 73-10 (10 g, 21.83 mmol) was treated with HCOOH (80%) in HiO at R.T. The solution was stirred at 60°C for 2 h, and then concentrated at a low pressure.
The residue was purified by column chromatography (I %-10% MeOH in DCM) to give 73-11 (5.1 g, 5855%) as a white solid.
[0442] Compound 73-11 (5 g, 12.79 mmol) was dissolved in anhydrous MeOH (100 mL) and treated with NaOMe (4.83 g, 895 mmol) at R.T.. The solution was stirred at 60°C for 36 h. The mixture was quenched with CO2 and then concentrated at low pressure. The residue 25 was purified by column chromatography (0-10% MeOH in DCM) to give 73-12 (23 g, 68.05%) as a yellow solid. ’H-NMR (CDCI2,400MHz) J = 7.29 (d, /= 8 Hz 1H), 6.10 (s, 1H), 5.71 (d, J = 8.0 Hz 1H), 5.18(t,/= 6.4 Hz, 1 H), 4.79-4.84 (m, 1H),4.61 (d,/=8.0 Hz, 2H), 4.39 (s, 1H), 3.45 (s, 1H).
[0443] To an ice-cold solution of 73-12 (15 g, 5.68 mmol) in anhydrous MeCN (15 30 mL) was added NIS (1.66 g, 7.39 mmol) and TEA· 3HF (0.73 g, 455 mmol) under N2. The mixture was stirred at R.T. for 1 h. The reaction was quenched with sat. NaHCOj and sat. Na2SOj solution, and extracted with EA (3 x 100 mL). The organic phase was dried over anhydrous Na2SO4, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (0-5% MeOH in DCM) to give 73-13 ( 1.08 g, 46.2%) as a yellow solid.
247 [0444] To a stirred solution of 73-13 (1 g, 2.44 mmol) in anhydrous DCM (10 mL) was added DMAP (0.60 g, 4.88 mmol) and Et3N (0.74g, 7.32 mmol) at R.T. The mixture was treated with benzoyl chloridc (0.79 g, 5.61 mmol) at 0°C and then stirred at R.T. for 3 h. The reaction was quenched with water, and extracted with EA (3 x 60 mL). The oiganic phase was
- - ~5 n concentrated at low pressure, and the residue was purified by column chromatography (0-10% ‘ MeOH in DCM) to give 73Π4 (0.9 g, 59.6%) as a white solid. ; ~----- - ’ r [0445] BujNOH (55% in H2O, 13.74 mL) was treated with TFA (to adjust pH=3-4). The mixture was cooled to R.T. To a solution of 73-14 (0.9 g, 1.46 mmol) in DCM (9 mL) was added m-CPBA (80%, 1.57 g, 7.28 mmol) at R.T. The mixture was stirred at 25°C for 48 h. The 10 mixture was washed with saL aq. NaHCO3. The organic layer was passed through an anhydrous A12O3 column, and the solution was concentrated at low pressure. The residue was purified by a silica gel column (30% EA in PE) to give 73-15 (0.26 g, 35.1%) as a yellow solid.
[0446] Compound 73-15 (0.25 g, 0.49 mmol) was dissolved in NHj/MeOH (5 mL, 7 M), and the mixture was stirred at R.T. for 24 h under N2. The mixture was concentrated at low 15 pressure at R.T., and the residue was purified by a silica gel column (5% MeOH in DCM) to give 73-16 (100 g, 67.75%) as a white solid. 'H-NMR (CD3OD, 400 MHz) δ - 7.83 (d, J = 8 Hz 1H), 6.29 (s. 1H), 5.67 (d, J= 6.0 Hz 1H), 5.12 (t,/= 6.8 Hz, 1H), 4.99-5.01 (m, 1H), 438 (d, J = 19.6 Hz 1H), 3.74-3.81 (m, 2H), 335 (s, 1H).
[0447] Compound 73-16 (100 mg, 033 mmol) was co-evaporated with toluene three 20 limes to remove H2O. To a stirred solution of 73-16 (100 mg, 033 mmol) in a mixture of MeCN (1.0 mL) and NMI (271 mg, 33 mmol) was added a solution of 73-C (2163 mg, 0.66 mmol) in MeCN (03 mL) at 0 °C The mixture was stined at R.T. ovemight and then reaction was quenched with water. The mixture was diluted with EA (20 mL), and the organic layer was washed with water and brine, and dried over anhydrous Na^SO^. The organic phase was 25 concentrated at low pressure, and the residue was purified on a silica gel column (5% i-PrOH in DCM) to give the crude product. The crude product was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 73 (35.6 mg, 19.0%) as a white solid. ESI-LCMS: m/z 592 [M+Na]*.
[0448] To a stirred solution of 73-A (2.0 g, 13.16 mmol) and phénol (1.22 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (133 g, 13.16 mmol) in DCM (20 mL) dropwise at -78°C. The mixture was warmed gradually to R.T., and then stirred for 2 h. The solution was re-cooled to -78°C, and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g, 13.16 mmol) tn DCM (20 mL) was added, followed by the dropwise addition of TEA (2.66 g, 26.29 mmol) in DCM (20 mL). The mixture was warmed gradually to R.T., and then stirred for
248
h. The organic solvent was removed at low pressure, and the residue was dissolved in methylbutyl ether. The precipitate was filtered, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (anhydrous DCM) to give 73-C (0.9 g, 22.3%) as a colorless oil. = - EXAMPLE 48 —
COMPOUND 66
Htf ¥ BztJ ¥ Bztf· ¥ (β-7 6M «M
Bzrf ¥
B5-10
[0449] Compound 66-2 (2648 g, 7.3 mol) was dissolved in anhydrous dichloromethane (I0 L), and the solution was cooled to -40 °C with stirring under N2. 10 Compound 66-1 (1 kg, 7.69 mol) was dissolved in anhydrous CH2C12 (3 L) and added to the solution of 66-2 over 30 mins at -40 °C. The stirred mixture was allowed to warm to R.T. ovemight. The mixture was concentrated under reduced pressure to dryness, and the residue was suspended in TMBE (6 L). The suspension was filtered to remove PhjPO, and the filtrate was concentrated under reduced pressure to afford crude 66-3 (1230 g, 78.6%). ’H NMR (400 Hz) 15 (CDClj): δ 6.65 (dt.J-7.6 Hz, 1 H), 4.82 (dd, J = 14.8,7.6 Hz, lH),4.204.10(m,3H),3.59(t, J = 8.0 Hz, 1 H), 1.86 (d, J = 1.2 Hz, 3H), 1.41 (s, 3H), 137 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H).
249 [0450] Crude 66-3 (1230 g, 5.74 mol) was dissolved in acetone (30 L) at 0-5 °C.
KMnQj (1107 g, 5.17 mol) was added m one portion. After being stirred at 0-5°C for 5 h, the reaction was quenched with sat aq. sodium sulfite (20 L). After 30 mins, a colorless suspension was formed. The solid was removed by filtration and washed with EA (6 L). The filtrate was extracted with EA (3 x 2 L). - The-combined extracts were dried over NaiSCh, filtered, and concentrated under reduced pressure to'give'a white solid residue. The residue was dissolved in EA, and PE was added to give a precipitate. The solid was collected by filtration and recrystallization was 3 limes to give 66-4 (770 g, 53.6%) as a white solid.
[0451] To a stirred solution of 66-4 (770 g, 3.1 mol) in anhydrous DCM (5 L) and triethylamine (1.1 L, 8.05 mol) at 0°C was added slowly sulfuryl chloride (300 mL, 3.6 mmol). The mixture was stined at R.T. for 2 h, diluted with DCM (3 L), and washed with sat. NaHCOj aq. and brine. The organic phase was dried over anhydrous NajSOj, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column using PE:EA = 1:0 to 10:1 as the eluent to give 66-5 (490 g, 50.6%) as an oil.
[0452] Tetraethylammonium fluoride hydrate (650 g, 3.7 mol) was added into a solution of 66-5 (490 g, 1.6 mol) in anhydrous dioxane (3 L), and the mixture was heated to 120°C for 16 h. The mixture was then cooled to ambient température. 2,2-Dimethoxypropane (3 L) was added followed by conc. aq hydrochloric acid (200 mL). The mixture was stirred for 3 h at ambient température. The solvent was concentrated to % of the original volume, and then diluted with EA (3 L). The mixture was washed with cold sat. aq. sodium bicarbonate and brine. The combined aqueous layer was back-extracted with EA (1 L). The combined organic layer was dried over anhydrous NazSO^ filtered, and concentrated at low pressure to give crude 66-6 (220 g, 70.8%).
[0453] Crude 66-6 (220 g, 0.89mol) was dissolved in éthanol (2 L) and conc. aq. HCl (60 mL). The solution was stined at ambient température for 48 h. and then concentrated under reduced pressure followed by co-evaporations with toluene 3 times to give 66-7 as a pale yellow solid (110 g).
[0454] Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoy! chloride (200 mL, 1.67 mol) was added slowly at 0-5°C. The mixture was stirred at ambient température for 45 mins. The reaction was quenched with ice and MeOH to form a precipitate. After filtration, the filtrate was washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.
[0455] To a solution of 66-8 (100 g, 269 mmol) in anhydrous THF (1000 ml) was added dropwise a solution of lithium tri-tert-butoxyaluminohydride (400 ml, IM, 0.4 mol) at 78°C under Ni for 30 mins. The solution was stined at -20°C for 1 h, and TLC (PE: EA= 3:1)
250 showed that the reaction was complété. The mixture was quenched with saLNHiCl, and diluted with EA. After filtration, the Citrate was extracted with EA. The combined layers were dried over Na2SO4, and concentrated at low pressure. The residue was purified by a silica column gel (PE: EA=20:1) to give 66-9 ( 100 g, 100%) as a colorless oil.
-•5 [0456] ToastirredsolutionofPPhj(140g,382mol)inCHiClj(1000ml) wasadded
-—66-9 (loo g,-269 mmol) at -20 °C under N2.- After stirring fbr-15 mins·, CBr4 (177g, 382 mol) was added dropwise while maintaîning the température between -25 and -20 °C under N2. The mixture was stirred below -17 °C for 20 mins. Silica gel was added to the mixture. The mixture was filtered through cold silica column gel and wàshed with PE: EA (50:1 to 4:1). The combined 10 filtrâtes were concentrated under reduced pressure at R.T. to give the crude oîl product The residue was purified by a silica column gel a second time (PE EA=50:l to 4:1) to give 66-10 (aisomer, 64 g, yield: 55%) as a colorless oïl.
[0457] A mixture of 6-chloro-guanine (55.8 g, 316.5 mol) and t-BuOK (39.5 g, 352.7 mmol) in t-BuOH (500 mL) and MeCN (280 mL) was stirred for 30 mins. Compound 66-10 (48 15 g, 105.5 mmol) was added at R.T., and the mixture was heated to 50 °C and stirred ovemight.
The reaction was monitored by TLC (PE:EA=2:1). The mixture was quenched with solid NH4CI. After stirring for 1 h, the mixture was filtered and washed with MeCN. The fîltrate was evaporated at low pressure, and the residue was purified by a silica gel column to give 66-11 (33 g, 57%).
[0458] To a solution of 66-11 (49 g, 93.1 mol) in CECb (200 mL) was added
AgNOj (31.7 g. 186 mmol), collidine (225 g, 186 mmol) and MMTrCl (43 g, 140 mmol) in small portions under N2 at 0°C. The mixture was stirred at R.T., and monitored by TLC (PE:EA=4:I). After filtration, the organic phase was washed with NaHCO3 aqueous and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was purified by a silica gel column (PE:ME= 20:1 to 1:1) to give 66-12 (70 g, 94.2%). [0459] Sodium (10.1 g, 439 mmol) was dissolved in dry EtOH (600 mL) at 70°C and then cooled to 0 °C. To a solution of 66-12 (70 g, 87.7 mmol) was added a freshly prepared NaOEt solution in portions at 0°C, and the mixture was stirred for 1 h. at R.T. After TLC and LCMS showed the reaction was completed, the reaction was quenched with carbon dioxide. The mixture was evaporated at low pressure, and the residue was purified using silica gel column chromatography (DCM: MeOH=100:1 to 20:1) to give 66-13 (50 g, yield 5%) as a yellow solid.
[0460] A mixture of PPh3 (35 g, 1335 mol) and 12 (31.75 g. 125 mmol) in anhydrous pyridine (600 mL) was stirred for 30 mins, and then a solution of 66-13 (50 g, 833 mmol) in pyridine (100 mL) was added at 0°C. The mixture was stirred ovemight at R.T. and monitored
251 by TLC (DCM:MeOH=50:l). The reaction was quenched with a saL NaHCOj solution, and extracted with DCM (3 x 50 mL). The organic phase was dried over anhydrous MgSOj, and evaporated at low pressure. The residue was purified using silica gel column chromatography (DCM: MeOH=200:l to 50:l) togive 66-14 (50 g, 84.7%).
- [0461] .-To a solution of 66-14 (37-g, 52.1 mmol) in dry THF (400 mL) was added _-----DBU (16 g; 105 mmol).-The mixture was heated to reflux and stirred for 3 h.-The reaction was monitored by LCMS. The reaction was quenched with a saL NaHCOj solution, and extracted with EA. The combined organic layers were dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified using silica gel column chromatography (PE:EA=10:l to 10 5:1) to give 66-15 (25 g, 61.1%) as a white solid.
[0462] To an ice-cold solution of 66-15 (26 g, 44.6 mmol) in dry MeCN (300 mL) was added NIS (12.68 g, 56 mmol) and NEtj · 3HF (10.6 g, 67 mmol) at 0 °C. The reaction was stirred at R.T. for 2 h. and monitored by LCMS. After the reaction was completed, the reaction was quenched with a sat NajSOj and sat. NaHCOj solution, and extracted with EA. The organic 15 layer was separated, dried over anhydrous NaiSO*, and evaporated at low pressure. The residue was purified using silica gel column chromatography (PE: EA=8:1 to 1:1) to give 66-16 (21 g, 64.4%) as a white solid.
[0463] To a solution of 66-16 (21 g, 28.8 mol) in CH2CI2 (150 mL) was added AgNOj (9.8 g, 59.6 mmol) and collidine (7 g, 59.8 mmol) and MMTrCI (13.1 g. 425 mmol) in 20 small portions under N2 at 0eC. The mixture was stirred at R.T., and the reaction was monitored by TLC (PE:EA=2:1 ). After filtration, the solution was washed with sat. aq. NaHCQj and brine. The organic layer was separated, dried over anhydrous Na2SOi and concentrated at low pressure. The residue was purified by a silica gel column to give 66-17 (25 g, yield 86.5%).
[0464] To a solution of 66-17 (22 g, 22 mmol) in dry DMF (500 mL) was added 25 NaOBz (31.9 g, 220 mmol) and 15-crown-5 (48.4 g, 220 mmol), and the mixture was stirred for 72 h. at 95eC. The mixture was diluted with EA, washed with water and brine, and dried over MgSO*. The organic layer was evaporated at low pressure, and the residue was purified using a silica gel column chromatography to give 66-18 (15 g, 68.8%) as a white solid.
[0465] Compound 66-18 (15.2 g, 153 mmol) was co-evaporated with anhydrous 30 toluene 3 times to remove H2O. The compound was treated with NHj in MeOH (7 N, 200 mL) at R.T. The mixture was stirred for 18 h at R.T., and the reaction was monitored by LCMS. The residue was concentrated at low pressure, and purified using silica gel column chromatography togive 66-19 (Il g,81%)as a whitesolid.
252 [0466] To a stirred solution of 66-20 (14 g, 15.73 mmol) in anhydrous CHjCN (150 mL) was added N-methytimidazole (233 g, 283.9 mmol) at 0 to 5°C (ice/water bath) followed by a solution of phenyl(cyclohexanoxy-L-aIaninyl)phosphorochloridate (16.33 g, 47.2 mmol, dissolved in 50 mL of CHjCN). The solution was stirred at 0 to 5°C for 12 h and then diluted with EA. The solution was-washed 50 % aqueous citric acid, solution and brine.-The organic - -layer was separated, dried over anhydrous MgSO4 and filtered. -The filüaîe-was concentrated at low pressure, and the residue was purified on silica gel with PE: EA=5:1 as the eluent to give 66-20 (17.62 g, 93.4%) as a white solid.
[0467] Compound 66-20 (17.62 g, 14.7 mmol) was dissolved in 80% AcOH (200 10 mL), and the mixture was stirred overnight at R.T. After removal of the solvents, the résidé was purified on silica gel using PE:EA=2:1 to eluent to give the crude product, which was purified on via reverse-phase HPLC using acetonitrile and water to give compound 66 (5.25 g, yield 66%) as a white solid. ESI-LCMS: m/z 655 [M+H]*.
HÔ bH
EXAMPLE 49 COMPOUND 67
h<5 'bH [0468] To a solution of the nuclcoside (300 mg, 1.09 mmol) and proton-sponge (467 mg, 2.18 mmol) in anhydrous CHjCN (5 mL) at 0°C under N2 was added dropwise a solution of phosphores oxychloride (330 mg, 2.18 mmol) in anhydrous CH3CN (1 mL). The mixture was 20 stirred at 0°C for 30 mins, and the hydrogen chloride sait of (S)-ethyl 2-aminopropanoate (998 mg, 632 mmol) and triethylamine (13 mL, 10.87 mmol) at (FC were added. The mixture was stirred overnight at 30°C. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The organic layer was concentrated at low pressure, and the residue was purified by reverse phase HPLC to give compound 67 (20 mg, 3%) as a white solid. ESI-LCMS: m/z 535 25 [M-Ff.
253
EXAMPLE 50 COMPOUND 59
[0469] To a solution of sodium hydrosulfîde (4.26 g, 76.0 mmol) in EtOH (100 mL) was added t-butyiyl chloride (76.2 mmol; 9.35 mL) dropwise at 0 °Ct and the mixture was stirred at R.T. for 1 h. A solution of 2-(2-chloroethoxy)eihanol (57 mmol; 6.0 mL) and TEA (21 mL, 120 mmol) was added, and the mixture was heated at reflux for 60 h. The mixture was filtered, and then concentrated to a small volume. The residue was dissolved in EA, and then washed with water, sat. aq. NaHCOj and brine. The organic phase was dried over Na^SO^, filtered and concentrated in vacuo. The crude product (10.0 g) was îsolated and 5 grams were purified by silica gel flash column chromatography using a gradient of 0 to 100% EA in hexane to give 59-3 (43 g, 22 mmol) as a clear, colorless oil. ’H-NMR ( CDCJj): 3.70-3.74 (m, 2H), 33-3.65 (m,4H), 3.1 (t, 2H), 1.25 (s, 9H).
[0470] A solution 59-3 (43 g; 21.8 mmol) and triethylamine (6.7 mL, 872 mmol) in tetrahydrofuran (50 mL) was added dropwise over 1 h to a stirred solution of N,Ndiisopropylphosphorodichloridite (2.0 mL, 10.9 mmol) in THF (50 mL) under argon at -78°C. The mixture was stirred at R.T. for 2 h, and then diluted with EA (200 mL). The mixture was
254 washed with saL aq. NaCl and dried over NajSOj. After filtration, the filtrate was evaporated under reduced pressure to give a pale yellow oil. Purification by flash column chromatography using a gradient of EA (0-5%) in hexane containing 5% triethylamine afforded 59-4 (2.5 g, 4.25 mmol) as a clear, colorless oil. -*H-NMR (CDC13): 3.70-3.82 (m, 4H), 3.57-3.65 (m, 10H), 3.1 (t,4H), 1.25 (s, 18H), 1.17 (t, 12H); 3,P-NMR (CDC13): 148.0 ppm.
— [0471]-—: Compound 59-5’ (285 mg, 0.9 mmol) and DCI (175 mg, U mmol) were coevaporated twice with ACN and then dissolved in ACN (5 mL). Compound 594 (790 mg, 1.35 mmol) in ACN (4 mL) was added, and the reaction was monitored by TEC. After 15 mins, tert-butylhydroperoxide (02 mL of 5.5M solution in decane) was added, and the mixture was stirred for 10 mins. The mixture was diluted with EA (25 mL), washed with sat. aq. NaHCO3 and sat. aq. NaCl solution, dried over Na3SO4, filtered and concentrated. Purification by flash column chromatography using a gradient of EA (0-100%) in hexane afforded 59-6 (0.17 g, 0.22 mmol) as a white solid. Compound 59-6 was dissolved in 80% aq. HCOOH (5 mL). After 30 mins at R.T., the solvent was removed and coevaporated twice with toluene. The residue was dissolved in methanol (10 mL) and TEA (0.2 mL) was added. After 2 mins at R.T., the solvent was removed tn vacuo. Purification by flash column chromatography using a gradient of methanol (0-15%) în DCM afforded compound 59 (90 mg). *H-NMR (CDC13): 7.40 (d, 1H), 6.1 (s, 1H). 5.83 (d, 1H), 4.3 (t, 2H), 4.14.2 (m, 6H), 3.70-3.82 (m, 4H), 327-3.65 (m, 4H), 3.1 (t, 4H) 1.61 (s, 8H), 12 (s, 3H), 1.23 (s, 18H). 3,P-NMR (CDClj): -125 ppm.
EXAMPLE 51 COMPOUND 60
60-3 [0472] Compound 60-1 (6.0 g, 31.6 mmol) was prepared using a similar procedure to the one used to prepared 59-3 using 4-chlorobutanol. Compound 60-1 was obtained as a clear.
colorless oil. Ή-NMR (CDCl3): 3.67 (s, 2H), 2.86 (m, 2H), 1.65 (m, 4H), 125 (s, 9H).
255 [0473] Compound 60-2 (2.14 g, 4.0 mmol) was prepared using a similar procedure to the one used to prepared 59-4. Compound 60-2 was obtained as a clear, colorless oil. Ή-NMR (CDCIj): 3.67 (m, 6H), 2.86 (t, 4H), 1.65 (m, 8H), 1.25 (s, 18H), 1.17 (t, 12H). 3IP-NMR (CDCIj): 143.7 ppm.
[0474] - Compound 60-3 (0.23 g, 0.22 mmol) was prepared using a similar procedure tolhê one-used to prepared 59-6 using 59-5 and 60-2. Compound 60-3 was obtained as a white solicL Using a similar procedure to the one used to prepared compound 59, 60-3 was used to prépare compound 60 (170 mg). *H-NMR (CDCIj): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 43 (t, 2H), 4.1-4.2 (m, 6H), 2.8 (t, 4H), 1.78 (m, 4H), 1.69 (s, 8H), 1.3 (s, 3H), 133 (s, 18H). 3IPNMR (CDCI3): -1.56 ppm.
EXAMPLE 52 COMPOUND 58 [0475] Compound 58-1 was prepared according to the procedure described în Lefebre et al. J. Med. Chem. (1995) 38:3941-3950, which is hereby incorporated by référencé for the limited purpose of its description of the préparation of 58-1.
[0476] Compound 58-2 (033 g, 0.5 mmol) was prepared using a similar procedure to the one used to prepared 59-6 using 59-5 and 58-1. Compound 58-2 was obtained as a white solid. Using a similar procedure to the one used to prepared compound 59, 58-2 was used to prépare compound 58 (130 mg). *H-NMR (CDCIj): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 43 (t, 2H), 4.1-43 (m, 6H), 33 (t, 4H), 1.69 (s, 4H), 13 (s, 3H), 133 (s, 18H); 3,P-NMR (CDCIj):
256
EXAMPLE 53 COMPOUND 47
[0477] Compound 47-1 (1.0 g, 3.53 mmol) was coevaporated with anhydrous 5 pyridine 3 times to remove H2O. To an îce-cold solution of 47-1 in anhydrous pyridine (9 mL) was added TsCl (808 mg, 4.24 mmol) in pyridine (3 mL) drop-wise at 0°C, and the mixture was stirred for 18 h. at 0°C. The reaction was monitored by LCMS, and then quenched with H2O. After concentration at low pressure, the residue was dissolved in EA (50 mL). The solution was washed with sat. NaHCOj solution and brine. The organic layer was dried over anhydrous 10 Na2SO4 and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-2 (980 mg, 63 %) as a white solid.
[0478] To a solution of47-2 (980 mg, 2.24 mmol) in acetone (10 mL) was added Nal (1.01 g, 6.73 mmol), and the mixture was heated to reflux ovemight. The reaction was 15 monitored by LCMS. After the reaction was completed, the mixture was concentrated at low pressure. The residue was dissolved in EA (50 mL). The solution was washed with brine, and dried over anhydrous Na2SO4. The solution was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-3 (700 mg, 79 %) as a solid.
[0479] To a solution of 47-3 (700 mg, 1.78 mmol) in dry THF (9 mL) was added
DBU (817 mg, 534 mmol), and the mixture was heated to 60°C. The mixture was stirred
257 ovemight, and monitored by LCMS. The reaction was quenched with sat. NaHCCh and extracted with EA (3 x 50 mL). The organic phase was dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 47-4 (250 mg, 53 %) as a white solid.
[0480] To an ice-clod solution of47-4 (250 mg, 0.94 mmol) in dry MeCN (5mL) was added-NEtj*3HF (151 mg, 0.94 mmol) and NIS (255 mg,-1.13 mmol). The mixture was stirred at R.T., for 3 h., and checked by LCMS. The réaction was quenched with sat NaiSiCh and sat NaHCOj solution, and extracted with EA (3 x 50 mL). The organic layer was separated, dried over anhydrous NüiSOj, and evaporated at low pressure. The residue was purified by silica gel 10 column chromatography (2% acetone in DCM) to give 47-5 (170 mg, 44 %).
[0481] To a solution of 47-5 (270 mg, 0.65 mmol) in dry DCM (4 mL) was added
DMAP (158.6 mg, 13 mmol), and BzCI (137 mg, 0.98 mmol). The mixture was stined for 4-5
h. at R.T., and checked by LCMS. The mixture was diluted with CHiClj, and washed with sat.
NaHCOj solution and brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-6 (290 mg, 86 %) as a solid.
[0482] To a solution of 47-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (25 g, 17.4 mmol) and 15-crown-5 (45 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100°C. The mixture was diluted with EA (100 mL), and washed with brine. The organic 20 layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-7 (500 mg, 56 %) as a solid.
[0483] To a solution of 47-7 (500 mg, 0.98 mmol) in anhydrous CHjCN (5 mL) was added TPSC1 (741 mg, 2.45 mmol), DMAP (299.6 mg, 2.45 mmol) and NEt3 (248 mg, 2.45 mmol) at R.T., and the mixture was stirred ovemight The mixture was then treated with NH3 in 25 THF (5 mL) and then stirred for another 30 mins. The mixture was diluted with EA (100 mL).
The solution was washed with 05% AcOH solution. The organic solvent was dried over anhydrous MgSO4, and concentrated at low pressure. The crude product was purified by silica gel column chromatography (2% Acetone in DCM) to give 47-8 (257 mg, 51.6 %) as a white solid. ESI-MS: m/z 509 [M+Hf.
[0484] Compound 47-8 (80 mg, 0.16 mmol) was dissolved in n-butylamine (3 mL).
The mixture was kept ovemight at R.T. and evaporated. The residue was crystallized from methanol lo give compound 47 (30 mg). The mother liquor was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50mM triethylammonium acetate buffer (pH 75) was used for elution. The
258 correspondîng fractions were combined, concentrated and lyophilized 3 limes to remove excess of buffer to yield additional compound 47 (13 mg). Compound 47 (total yield 43 mgt 73%).
MS: m/z 299.7 [M-l]\ q α-β-α ci
EXAMPLE 54
«
HMMTr
[0485] To a stirred solution of POCI3 (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added 1-naphthol (1.88 g, 13 mmol) at -70°C, and TEA (131 g, 13 mmol) in DCM (3 mL) dropwise at -70°C. The mixture was gradually warmed to R.T. and stirTed for 1 h. Crude 83-1 was obtained.
[0486] To a stirred solution of (S)-isopropyl 2-aminopropanoate hydrochloride (2.17 g, 13 mmol) in DCM (10 mL) was added crude 83-1 at -70°C. TEA (2.63 g, 26 mmol) was added to the stirred solution dropwise at -70°C. The mixture was gradually warmed to R.T. and stirred for 2 h. The reaction was monitored by LCMS and quenched with n-propylamine. The mixture was concentrated at low pressure, and the residue was purified by a silica gel column (PE:MTBE = 5:1-1:1) to give pure 83-2 (1.6 g, 35%).
[0487] To a solution of 83-(A) (300 mg, 0337 mmol) and NMI (276 mg, 337 mmol) in anhydrous CH3CN (4 mL) was added 83-2 (240 mg, 0.674 mol, in DCM (5 mL)) at 0°C. The mixture was stirred at R.T. for 10 h. The reaction was monitored by LCMS. The reaction was quenched with water, and extracted with CHiCl· (3 x 20 mL). The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by sil-gel (PE:EA = 5:1-2:1) to give 83-3 (380 mg, 93%).
[0488] Compound 83-3 (380 mg, 0.314 mmol) was dissolved in CHjCOOH (80%, 8 mL), and stirred at 40-50°C for 2.5 h. The reaction was monitored by LCMS. The mixture was concentrated at low pressure, and the residue was purified by chromatography (PE:EA t r
665.1 [M+H]+.
259 l: I-EA) to give crude compound 83. The crude product was purified by prep-HPLC (neutrai system, NH4HCO3) to give pure compound 83 (70 mg, 80%) as a white solid. ESI-MS: m/z
73-1
EXAMPLE 55 COMPOUND 79
[0489] A solution of 79-1 (16.70 g, 0363 mol) and TEA (36.66 g. 0363 mol) in CHiClj (150 mL) was added dropwise to a stirred solution of POCI3 (55.65 g, 0363 mol) in DCM (100 mL) over 25 mins at -78eC. After the mixture was stirred for 2 h. at R.T., the 10 triethylamine hydrochloride sait was filtered, and washed with CH2CI2 (100 mL). The filtrate was concentrated at low pressure, and the residue was distîlled under high vacuum (-10 mm Hg) with a cow-head fraction collecter. The product was collected between 45°C (distillation head température) as a colorless lîquid (30.5 g, 50% yield). ’H-NMR (400 MHz, CDC13) δ = 4.44 (dq, 7=10.85,7.17 Hz, 2 H), 1.44 - 137 (m, 3 H); 3,P-NMR (162 MHz, CDCI3) δ = 6.75 (br. s., 15 1 P).
[0490] To a stirred suspension of 83-A (93 mg, 0.15 mmol) in CH2CI2 (1 mL) was added TEA (61 mg, 0.15 mmol) at R.T. The mixture was cooled to -20 °C, and then was treated with a 79-2 (35 mg, 0.21 mmol) solution dropwise over a period of 10 mins. The mixture was stirred at this température for 15 min., and then was treated with NMI (27 mg, 033 mmol). The 20 mixture was stirred at -20°C, and then slowly warmed to R.T. The mixture was stirred ovemighL The mixture was suspended in EA (15 mL), washed with brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated at low pressure, and the residue was purified by chromatography (DCM: MeOH=100:l) to give 79-3 (60 mg, yield: 56%) as a solid.
[0491] A solution of 79-3 (60 mg, 0.085 mmol) in 80% AcOH aqueous (2 mL) was stirred at R.T. for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column eluting DCM/MeOH = 50/1 and prep-HPLC to give compound 79 (23 mg, 62%) as a white solid. ESI-MS: m/z 4363 [M+Hf.
i
260
EXAMPLE 56
[0492] Compound 80-2 was prepared using a similar procedure as for the préparation of 79-2 using a solution of iso-butanol (23.9 g, 322.98 mmol) and POCl3 (49.5 g, 322.98 mmol). Compound 80-2 (26 g, 42% yield) was obtained as a colorless liquid. *H-NMR (400 MHz, CDCb) 6 = 4.10 (dd. 7=9.04,6.39 Hz, 2 H), 2.09 (dq, 7=13.24,6.67,6.67,6.67,6.67 Hz, 1 H), 1.01 (d, 7=6.62 Hz, 6 H); 3,P-NMR (162 MHz, CDCI3) δ ~ 7.06 (br. s., 1 P).
[0493] To a stirred suspension of 83-A (310 mg, 03 mmol) in CHjCb (3 mL) was added TEA (202 mg, 2 mmol) at R.T. The mixture was cooled to -20 °C, and then was treated with 80-2 (134 mg, 0.7 mmol). The mixture was stirred at this température for 15 mins and then was treated with NMI (90 mg, 1.1 mmol). The mixture was stirred at -20°C for 1 h., and then slowly warmed to R.T. ovemight. The mixture was suspended in EA (15 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated at low pressure, and the residue was purified by silica column gel (DCM: MeOH= 100:1) to give 80-3 (310 mg, yield: 84%) as a solid.
[0494] A solution of 80-3 (310 mg, 0.43 mmol) in 80% AcOH aqueous (4 mL) was stirred at R.T. for 2 h. The mixture was concentrated at low pressure, and the residue was purified by a silica gel column eluting DCM/MeOH = 50/1 and prep-HPLC to give compound 80 (79 mg, 50%) as a white solid. ESI-MS: m/z 464.0 [M+H]*.
EXAMPLE 57
COMPOUND 81
[0495] Compound 81-2 was prepared using a similar procedure as for the préparation of 79-2 using a solution of isopropyl alcohol (21 g, 350 mmol) and POC13 (53.6 g, 350 mmol). Compound 81-2 (40.5 g, 65% yield) was obtained as a colorless liquid. ’H-NMR (400 MHz,
26!
CDClj) δ = 4.94 - 5.10 (m, 1 H), 1.48 (d, .7=6.17 Hz, 6 H); 3IP- NMR (162 MHz, CDClj) δ =
538 (br. s., I P).
[0496] Compound 81*3 was prepared using a similar procedure as for the préparation of 80-3 using 81-2 (124 mg, 0.7 mmol) and 83-A (310 mg, 03 mmol). Compound 81-3 (300 5 mg, 83%) was obtained as a solid.
[0497] Compound 81 was prepared using a similar procedure as for the préparation of compound 80 using 81-3 (300 mg, 0.41 mmol) in 80% AcOH aqueous (4 mL). Compound 81 (80 mg, 43%) was obtained as a white solid. ESI-MS: m/z 450.0 [M+H]+.
EXAMPLE 58 COMPOUND 82
Hi
Hl
[0498] To on ice cooled solution of 82-1 (50 g, 204.9 mmol) in dry Py (400 mL) was added TIPDSCt (70.78 g, 225.4 mmol) dropwise. The mixture was stirred at R.T. for 16 h. and then concentrated at low pressure. The residue was purified by chromatography using 20% EA 5 in PE to generale 82-2 ( 1113 g, 100%) as a white solid.
[0499] To a solution of 82-2 (50 g, 103 mmol) in anhydrous CH3CN (400 mL) was added IBX (43 g, 153 mmol) at R.T. The mixture was refluxed ovemight and monitored by TLC (PE:EA=1:1). The prccipîtate was fiîtered off, and the filtrate was concentrated to give the crude 82-3 (50 g, 99%) as a white solid.
[0500] To a solution of trimethylsilylacetylcnc (20 g, 200 mmol) in anhydrous THF (400 mL) was added dropwise n-BuLi (80 mL, 200 mL) at -78°C. The mixture was stirred at 78°C for 30 mins, and then warmed to R.T for 10 mins. Compound 82-3 (30 g, 60 mmol) in THF (100 mL) was added to the mixture dropwise at -78°C. The mixture was stirred at -78°C for 1 h and then slowly warmed to R.T. The mixture was stirred for 20 mins, and then the reaction was quenched with a sat NH4CI solution at -78°C. The mixture was diluted with EA. The organic phase was washed with brine, dried over anhydrous Na^SO», and concentrated at low pressure. The residue was purified by silica gel column chromatography (15% EA in PE) to give 82^4 as a white solid ( 14 g, 50 %).
[0501] Compound 82-4 (14 g, 24 mmol) was dissolved in anhydrous toluene (100 20 mL) under Ni and cooled to -78°C. DAST ( 19 g, 120 mmol) was added dropwise at -78°C and stirring was continued for 13 h. The mixture was diluted with EA and poured into a sat NaHCOj solution. The organic layer was washed with brine, dried over anhydrous Na^SOj, and concentrated at low pressure. The residue was purified by silica gel chromatography (20% EA in PE) to give 82-5 as a white solid (12 g, 81 %).
[0502] A mixture of82-5 (12 g, 20 mmol)andNH4F(Il g, 30mmol) in MeOH (150 mL) was refluxed for 2 h. After cooling to R.T, the mixture was concentrated at low pressure,
263 and the residue was purified by silica gel column chromatography (5% MeOH în DCM) to give 82-6 (3.1 g, 58%) as a white solid.
[0503] To a solution of 82-6 (3.1 g, Π.6 mmol) în dry Py (50 mL) was added imidazole (3.1 g, 46.4 mmol) and TBSC1 (5.2 g, 34.8 mmol). The mixture was stirred at 505 60°C for 3 h. The mixture was concentrated at low pressure, and the residue was dissolved în
EA (100 mL). -The solution was washed with brine, dried over anhydrous Na^SOj, and concentrated at low pressure. The residue was purified by silica gel chromatography (20% EA in PE) to give 82-7 as a white solid (5 g, 86%).
[0504] To a solution of 82-7 (4.5 g, 9 mmol) in 1,4-dioxane (45 mL) was added CuBr 10 (643 mg, 4.5 mmol), dicyclohexylamîne (33 g, 18 mmol) and paraformaldéhyde (675 mg, 22.5 mmol). The mixture was refluxed for 24 h and then cooled to R.T. The reaction was quenched with a sat. NH4CI solution. The mixture was extracted with EA (3 x 100 mL). The organic layer was washed with brine, dried over anhydrous Na^SOj, and concentrated at low pressure. The residue was purified by silica gel column chromatography (15% EA in PE) to give 82-8 as a 15 white solid (2.0 g, 43%).
[0505] A mixture of 82-8 (2 g, 4 mmol) and NH4F (2.2 g, 60 mmol) in MeOH (20 mL) was refluxed overnight. After cooling to R.T., the mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% MeOH in DCM) to give 82-9 (946 mg, 83%) as a white solid.
[0506] To a stirred suspension of 82-9 (946 mg, 333 mmol), PPhj (13 g, 5 mmol), imidazole (453 mg, 6.66 mmol) and pyridine (3 mL) in anhydrous THF (12 mL) was added a solution of I2 (1 g, 433 mmol) in THF (4 mL) dropwise at 0°C. The mixture was warmed to R.T. and stirTed for 16 h. The reaction was quenched with a saL NaîSjOj aq. solution and extracted with EA (3 x 60 mL). The organic layer was dried over NajSO* and concentrated at 25 low pressure. The residue was purified on a silica gel column (2% MeOH in DCM to 5% MeOH in DCM) to afford 82-10 (2.1 g, crude) as a white solid.
[0507] To a solution of 82-10 (2.1 g, 53 mmol) in THF (15 mL) was added DBU (15 g, 100 mmol) and the mixture stirred for 30 mins. The mixture was diluted with EA and neutralized with acetic acid. The solution was washed with brine, dried over anhydrous NajSO^ 30 and concentrated at low pressure. The residue was purified by silica gel column chromatography (13% MeOH in DCM) to give 82-11 as a white solid (800 mg, 90%).
[0508] To an ice-coolcd solution of 82-11 (800 mg, 3 mmol) in dry MeCN ( 13 mL) was added NEtj· 3HF (484 mg, 3 mmol) and NIS (1.68 g, 73 mmol). The mixture was stirred
264 at R.T. for 30 mins., and the reaction was monitored by LC MS. The réaction was quenched with saL NaxSiOj and sat NaHCOj solution, and extracted with EA (3 x 50 mL). The organic layer was dried over anhydrous Na2SO.i, and concentrated at low pressure. The residue was purified by a silica gel column (25% EA in PE) to afford 82-12 (850 mg, 68%) as a white solid.
- 5 - [0509] - To a solution of 82-12 (850 mg, 2 mmol) in dry DCM (10 mL) was added . ·£ DMAP (488 mg, 4 mmol) and BzCl (422 mg, 3 mot). The mixture was stirred Tor 4-5 h at R.T., and the reaction was monitored by LCMS. The mixture, was diluted with CH2CI2 (40 mL), and washed with a sat NaHCOj solution. The organîc layer was dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated at low pressure, and the residue was purified by silica gel 10 column chromatography (20% EA in PE) to give 82-13 (900 mg, 87%) as a white foam.
[0510] Tetra-butylammonium hydroxide (21 mL as 54-56% aqueous solution, - 42 mmol, 24 eq.) was adjusted with TFA to pH - 4 (- 3.5 mL), and the solution was treated with a solution of 82-13 (900 mg, 1.7 mmol) in DCM (21 mL). m-Cloroperbenzoîc acid (2.1 g, 6070%, - 8.75 mmol, - 5 eq.) was added portionwise under vigorous stirring, and the mixture was 15 stirred ovemight The mixture was diluted with CH2CI2 (30 mL), and washed with a saturated NaHCOj solution. The organic layer was washed with brine, dried over anhydrous magnésium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography in (40-70% EA in PE) to give 82-14 as an oil. The residue was purified by TLC (50% EA in PE) to give pure 82-14 (350 mg 50%).
[0511] Compound 82-14 (350 mg, 0.86 mg) was treated with 7N NH3 in MeOH ( 15 mL). The mixture was stirred for 2-3 h and monitored by TLC. The mixture was concentrated at low pressure, and the residue was purified by silica gel column chromatography (5% isopropanol in DCM) to give 82-15 (250 mg, 96%) as a white solid. ’H NMR (CD3OD, 400 M Hz) δ = 7.75 (d, J = 7.9 Hz, !H), 6.60-6.35 (m, 1H), 5.72 (d, J = 8.2 Hz, 1H), 5.37-5.25 (m,
1H), 5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 439-4.29 (m, 1H), 3.87-3.70 (m, 2H).
[0512] To a stirred solution of 82-16 (3.79 g, 18 mmol) and 82-17 (3 g, 18 mmol) in anhydrous DCM (60 mL) was added with a solution of TEA (4 g, 39 mmol) in DCM (40 mL) dropwise at -78°C, and the mixture was stirred for 2 h. The mixture was concentrated at low pressure, and the residue was dissolved in methyl-butyl ether. The precipitate was removed by 30 filtration, and the filtrate was concentrated to give the crude product. The residue was purified by dry column chromatography (anhydrous DCM) to give pure 82-18 as a colorless oil (3 g, 54 %).
[0513] Compound 82-15 (200 mg, 0.66 mmol) was coevaporated with toluene 3 times to remove HjO. Compound 82-15 was treated with MeCN (13 mL) and NMI (541 mg, 6.6 mmol). The mixture was stirred at R.T., and then 82-18 (403 mg, 132 mmol) in MeCN (03
265 mL) was added. The residue was purified by a silica gel column (5% iPrOH in DCM) to give the crude product, which was purified by HPLC (0.1% HCOOH in water and MeCN) to give compound 82 (33 mg, 9%). ESI-LCMS: m/z 594 [M+Na]+.
EXAMPLE 59
[0514] To a stirred solution of POCI3 (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added l-naphthol (1.88 g, 13 mmol) at -70°C and TEA (1.31 g, 13 mmol) in DCM (3 mL) dropwise at -70°C The mixture was gradually warmed to R.T., and stirred for 1 h. A crude 10 solution of 84-1 was obtained.
[0515] To a stirred solution of (S)-isobutyl 2-aminopropanoate hydrochloride (235 g, mmol) in DCM (20 mL) was added TEA (2.63 g, 26 mmol) and a crude solution of 84-1 at 70°C. The mixture was gradually warmed to R.T., and stirred for 2 h. The reaction was monitored by LCMS and quenched with n-propylamine. The solvent was evaporated at low 15 pressure, and the residue was purified by chromatography (PEiMTBE » 5:1-1:1) to give pure 84-2(1.8 g, 37%).
[0516] To a solution of 83-A (300 mg, 0337 mmol) and NMI (276 mg, 337 mmol) in anhydrous CHjCN (4 mL) was added 84-2 (249 mg, 0.674 mol, in DCM (5 mL)) at 0°C. The mixture was stirred at R.T. for 10 h. The reaction was monitored by LCMS, and then quenched 20 with HiO. The mixture was extracted with CH2CI2 (3 x 20 mL). The organic phase was dried over anhydrous MgSO4, and concentrated at low pressure. The residue was purified by chromatography using PE:EA - 5:1-2:1 as the eluent to give 84-3 (360 mg, 87%).
[0517] Compound 84-3 (360 mg, 0.294 mmol) was dissolved in CH3COOH (80%, 8 mL), and stirred at 40-50°C for 2.5 h. The reaction was monitored by LCMS and then quenched 25 with MeO. The mixture was concentrated at low pressure, and the residue was purified by chromatography using PE:EA = 1:1 as the eluent to generale crude compound 84. The product
266 purified by prep-HPLC (neutre! System, NHtHCOj) to givc compound 84 (70 mg, 75%) as a white solid. ESI-MS: m/z 679.2
EXAMPLE 60 COMPOUND 85 □ Oc - Qo
CI-P-C1------Χθ-β-ci------► I OO*P-CI 83^4
Cl 6t •Μ I 85-2
85-3 [0518] To a stirred solution of POClj (2.0 g, 13 mmol) in anhydrous DCM (10 mL) was added phénol (1.22 g, 13 mmol) at -70°C and ΊΈΑ (1.31 g, 13 mmol) in DCM (3 mL) dropwise at -70°C. The mixture was gradually warmed to R.T., and stirred for 1 h. A crude solution of 85-1 was obtained.
[0519] Compound 85 was prepared using a similar procedure as for the préparation of compound 84 using 85-2 (205 mg, 0.674 mol, in DCM (5 mL) obtained from (S)-isopropyl 2aminopropanoate hydrochloride and 85-1) and 83-A (300 mg, 0337 mmol). Compound 85 (50 mg, 74%) was obtained as a white solid. ESI-MS: m/z 615.2 [M+H]+.
EXAMPLE 61 COMPOUND 86
86-1 | 1 86-2
[0520] Compound 86 was prepared using a similar procedure as for the préparation of compound 84 using 86-2 (214 mg, 0.674 mol, în DCM (5 mL) obtained from (S)-isobutyl 2aminopropanoate hydrochloride and 86-1) and 83-A (300 mg, 0337 mmol). Compound 86 (70 mg, 87%) was obtained as a white solid. ESI-MS: m/z 629.2 [M+H]*.
267
EXAMPLE 62 COMPOUND 87
87-1 a
MMTrÔ 'F
87-3
[0521] Compound 87 was prepared using a similar procedure as for the préparation 5 of compound 84 using 87-2 (223 mg, 0.674 mol, DCM (5 mL) obtained from (S)-cyclopentyl 2aminopropanoate hydrochloride and 87-1) and 83-A (300 mg, 0337 mmol). Compound 87 (62 mg, 71%) was obtained as a white solid. ESI-MS: m/z 641.2 [M+H]*.
EXAMPLE 63 COMPOUND 88
88-3 88 [0522] Compound 88 was prepared using a similar procedure as for the préparation of compound 84 using 88-2 (223 mg, 0.674 mol, DCM (5 mL), obtained from (S)-3-pentyl 2aminopropanoate hydrochloride and 88-1) and 83-A (300 mg, 0337 mmol). Compound 88 (42 mg, 60%) was obtained as a white solid. ESI-MS: m/z 643.2 [M+H]+.
268
EXAMPLE 64
COMPOUND 89
[0523] A stirred solution of phosphoryl trichloride (1.00 g, 6.58 mmol) and 5quînoline (955 mg, 658 mmol) in anhydrous DCM (50 mL) was treated with a solution of TEA (665 mg, 658 mmol) in DCM (10 mL) at -78°C. The mixture was gradually warmed to R.T., and stined for 2 h. The solution was cooled to -78°C and then treated with (S)-neopentyl 2aminopropanoate hydrochloride (1.28 g, 658 mmol). TEA (133 g, 13.16 mmol) was added dropwise at -78°C. The mixture was gradually warmed to R.T., and stÎTred for 2 h. The mixture was concentrated at low pressure, and the residue was dissol ved in methyl-butyl ether. The precipitate was filtered ofï, and the filtrate was concentrated at low pressure. The residue was purified by a silica gel column (pure AcOEt) to give 89-1 as colorless oil (500 mg, 20%).
[0524] To a solution of 89-2 (300 mg, O.337mmol) and NMI (276.6 mg, 337 mmol) in anhydrous CHjCN (0.9 mL) was added 89-1 (388 mg, 1.011 mmol) in CH3CN (03 mL) dropwise at 0°C. The mixture was stined at R.T. ovemight. The reaction was quenched with water, and extracted with AcOEt. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by silica gel column (33% EA in PE) to give 89-3 as a yellow powder (300 mg, 71.9%).
[0525] Compound 89-3 (300 mg, 0.243 mmol) was dissolved in 80% CHjCOOH (3 mL), and the mixture was stined at 60°C for 25 h. The mixture was partitioned between AcOEt and water. The organic layer phase was washed by brine, dried over sodium sulfate and concentrated at low pressure. The residue was purified by silica gel column (50% EA in PE) to give compound 89 as a yellow powder (81 mg, crude product). The crude product (81 mg) was purified by RP HPLC to give compound 89 as a white solid. (28.7 mg, 17.1%). ESI-LCMS: m/z 694.1 [M+H]*.
269
EXAMPLE 65
COMPOUND 90
MMTrÔ
90-3
[0526] Compound 90-1 was prepared using a similar procedure as for the préparation of compound 89-1 using phosphoryl trichloride (2.00 g, 13.16 mmol), 1-naphthol (1.882 g, 13.16 mmol) and (S)-neopentyl 2-aminopropanoate hydrochloride (2.549 g, 13.16 mmol). Compound 90-1 (600 mg, 12%) was obtained as a colorless oil.
[0527] A solution of 90-2 (230 mg 0.26 mmol) and NMI (212 mg 2.60 mmol) in anhydrous CH3CN (1 mL) was treated with a solution of 90-1 (300 mg 0.78 mmol) in anhydrous CH3CN (05 mL) at R.T. The mixture was stincd at R.T. overnight The reaction was quenched with water, and extracted with EA (3 x 20 mL). The organic layer was washed with brine, dried by anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by a silica gel column (CH3OH in CHiClj from 1% to 5%) to give 90-3 (300 mg, 93%) as a white solid.
[0528] Compound 90-3 (300 mg, 0.24 mmol) was dissolved in CH3COOH (80%, 5 mL). The mixture was stirred at 60°C for 25 h. The mixture was diluted with EA (30 mL) and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by a silica gel column (CH3OH in CH2CI2 from 1% to 5%) to give crude compound 90 (105 mg). The crude product was purified by HPLC (0.1% NlLHCQj in water and CH3CN) to give compound 90 (45 mg, 26%) as a white solid. ESI-LCMS: m/z 693.2 [M+HJ*.
<.
270
EXAMPLE 66 COMPOUND 91
[0529] A stirred solution of 91-1 (2.00 g, 13.99 mmol) and 91-2 (2.00 g, 13.99 5 mmol) in anhydrous DCM (8 mL) was treated with a solution of TEA (3.11 g, 30.8 mmol) in DCM (20 mL) dropwise at -78°C. The mixture was stirred for 2 h. at -78 °C and then gradually warmed to R.T. The organic solvent was removed at low pressure, and the residue was dissolved in methyl-butyl ether. The precipîtate was filtered off, and the filtrate was concentrated at low pressure. The residue was purified on a silica gel column (dry DCM) to give 10 91-3 as colorless oil (1 g, 20.96%).
[0530] Compound 91-4 (260 mg, 029 mmol) was coevaporated with toluene 3 times to remove H2O. Dried 91-4 was treated with MeCN (0.8 mL) and NMI (240 mg, 2.9 mmol) and then stirred for 10 mins. The mixture was treated with a solution of 91-3 (291 mg, 0.87 mmol) in MeCN (0.4 mL), and then concentrated at low pressure. The residue was purified on a silica 15 gel column (75% EA in PE)) to give 91-5 (300 mg, 86%) as a white solid.
[0531] Compound 91-5 (300 mg, 0.25 mmol) was treated with CH3COOH (5 mL, 80%), and stirred at 50 °C for 3 h. The mixture was diluted with EA. The solution was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by silica gel column chromatography (67% EA in PE) to give crude compound 91, 20 which was purified by HPLC. The product was dried by lyophilization to give compound 91 (30 mg, 18.5%) as a white solid. ESI-LCMS: m/z 643 [M+H]+.
271
EXAMPLE 67 COMPOUND 77
[0532] To a solution of 1,1-dimethoxycyclopentane (193 g, 148.52 mmol) and 77-1 5 (10.0 g, 37.13 mmol) in DCE (100 mL) was added TsOHH2O (0.7 g, 3.71 mmol). The mixture was stirred at 50°C for 12 h. The mixture was neutralized with Et3N, and concentrated at low pressure. The residue was purified by silica gel column chromatography (1-10% MeOH in DCM) to give 77-2 (8.7 g, 70.1 % ) as a white solid.
[0533] Compound 77-2 (20.0 g, 0.06 mol) was coevaporated with anhydrous pyridine 10 3 times to remove HjO. To an ice-cold solution of 77-2 in anhydrous pyridine (100 mL) was added TsCl (22.8 g, 0.12 mol) at 0°C, and the mixture was stirred ovemîghL The reaction was monitored by LCMS and TLC The reaction was quenched with H2O, and the mixture extracted with EA (3 x 200 mL). The solution was dried over anhydrous Na2SO.j and evaporated at low pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=100:l 15 to 15:1) to give 77-3 (20.0 g, 69.0%) as a white solid.
[0534] To a solution of 77-3 (20.0 g, 0.04 mol) in acetone (200 mL) was added Naï (31.0 g, 0.2 mol), and the mixture was heated to reflux ovemight The reaction was monitored by LCMS. The reaction was quenched with a saL Na2S2O3 solution. The solution was extracted with EA (3 x 200 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated at
272 low pressure. The residue was purified by silica gel column chromatography (DCM: MeOH= 100:1 to 15:1) to give 77-4 (15.0 g, 833%) as a white solid.
(0535] Compound 77-4 (13.4 g, 30.16 mmol) was treated with HCOOH (80%) in H2O at R.T. The solution was stirred at 60 °C for 2 h. The mixture was concentrated at low pressure. The residue was purified by column chromatography (l%-10% MeOH in DCM) to give 77-5- (9.1 g, 80.0%) as a white solid.
[0536] To a solution of 77-5 (5.0 g, 13.22 mmol) in anhydrous CHjCN/THF (50 mL, 1:1, v:v) was added DBU (6.0 g, 39.66 mmol) at R.T., The solution was stirred at 50°C for 15 h. The reaction was quenched with HCOOH at 0°C, and then concentrated at low pressure. The 10 residue was purified by column chromatography (50%-70% EA in PE) to give 77-6 (33 g, 48.1 %) as a white solid.
[0537] To an ice-cold solution of 77-6 (2.1 g, 839 mmol) in anhydrous MeCN (21 mL) was added NIS (2.4 g, 10.49 mmol) and TEA*3HF (1.0 g, 6.29 mmol) under N2. The mixture was stirred at R.T. for 1 h. The reaction was quenched with saL NaHCOj and sat 15 Na2SOj solution, and extracted with EA (3 x 100 mL). The organic phase was dried over anhydrous Na2SO4, and evaporated to dryness at low pressure. The residue was purified on a silica gel column (30%-50% EA in PE) to give 77-7 (13 g, 393%) as a light yellow solid.
[0538] To a stirred solution of 77-7 (3.2 g, 8.08 mmol) in anhydrous DCM (32 mL) was added DMAP (2.5 g, 20.20 mmol) and Et3N (25 g, 24.24 mmol) at R.T. The mixture was 20 treated with BzCl (3.7 g, 26.66 mmol) at 0°C and then stirred at R.T. ovemighL The reaction was quenched with water, and extracted with EA (3 x 60 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography (20%30% EA in PE) to give 77-8 (1.8 g, 31.6 %) as a white solid.
[0539] B114NOH (8.0 g, 13.74 mL, 55% in H2O) was adjusted to pH=3-4 with TFA, 25 and then cooled to R.T. To a solution of77-8 (600 mg, 0.85 mmol) in DCM ( 10 mL) was added the B114NOH solution and m-CPBA (917 mg, 4.25 mmol, 80%) at R.T. The mixture was stirred at 25 °C for 48 h and then washed with a sat. NaHCOj solution. The organic layer was directly passed through basic A12O2 column, and the solvent was concentrated at low pressure. The residue was purified by a silica gel column (20%-30% EA in PE) to give 77-9 (123 mg, 243%) 30 as a white solid.
[0540] To a solution of 77-9 (300 mg, 0.50 mmol) in EA/hexane (20 mL, 1:1, v:v) was added Lindlar catalyst (200 mg) under N2. The mixture was stirred under H2 (40 Psi) at 2 °C for 1.5 h. The suspension was filtered, and the filtrate was treated with Lindlar catalyst (200 mg)
273 under N2, and stined under H2 (40 Psi) at 25 °C for 15 h. The mixture was filtered, and the filtrate was concentrated at low pressure to give crude 77-10 (287 mg) as a white solid.
[0541] Compound 77-10 (287 mg, 0.48 mmol) was dissolved in NHj/MeOH (30 mL,
M). The mixture was stined at R.T. for 24 h under N2 and then concentrated at low pressure.
τ 5 - The residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give 77-11 (50 mg, 34.7% over two steps) as a white solid. ’H-NMR (CD3OD, 400 MHz) â = 7.86 (d, J = 8.0
Hz 1H), 6.26 (s, 1H), 5.62-5.86 (m. 1H), 5.49 (d, J= 17.1 Hz, 1 H), 530 (d, J= 105 Hz, IH), 4.41 (d, J= 19.3 Hz, 1 H),'3.71-3.86 (m, 1H).
[0542] Compound 77-11 (113 mg, 039 mmol) was co-evaporated with toluene 3
ÎO times to rcmove HjO. To a stined solution of 77-11 (113 mg, 039 mmol) in a mixture of
MeCN (0.5 mL) and NMI (320 mg, 3.90 mmol) was added a solution of 73-C (256 mg, 0.66 mmol) in MeCN (05 mL) at 0°C The mixture was stined at RT. ovemight and then concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in
DCM) to give crude compound 77, which purified by prep-HPLC (0.1% HCOOH in water and
MeCN) to give compound 77 (45 mg, 20.1%) us a white solid. ESI-MS: m/z 538.2 [M-F]* ESIMS: m/z 580.2 [M+Na]+.
274
EXAMPLE 68 COMPOUND 78
[0543] To a solution of 77-9 (300 mg, 050 mmol) in MeOH (30 mL) was added wet
Pd/C (300 mg, 10%) under N2. The mixture was stirred under H2(l atm) at 25°C for L5 h. The suspension was filtered, and then concentrated at low pressure to give crude 78-1 (307 mg) as a white solid.
[0544] Compound 78-1 (307 mg, 0.48 mmol) was dissolved in NHj/MeOH (30 mL, · 7 M). The mixture was stirred at R.T. for 24 h under N2 then concentrated at low pressure. The 10 residue was purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give 78-2 (30 mg, 21 % over two steps) as a white solid.
[0545] Compound 78-2 (91 mg, 0.31 mmol) was co-evaporated with toluene 3 times to remove H2O. To a stirred solution of 78-2 (91 mg, 0.31 mmol) in a mixture of MeCN (0.5 mL) and NM1 (254 mg, 3.90 mmol) was added a solution 73-C (203 mg, 0.66 mmol) în MeCN 15 (05 mL) at 0°C. The mixture was stirred at R.T. ovemight and then concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to the crude compound 78, which purified by prep-HPLC (0.1% HCOOH in water and MeCN) to give compound 78 (30 mg, 17%) as a white solid. ESI-MS: m/z 540.1 [M-F]+.
1BJUJ
275
EXAMPLE 69
ADDITIONAL COMPOUNDS OF FORMULA (D [0546] The foregoïng synthèses are exemplary and can be used as a starting point to prépare a large number of additional compounds. Examples of compounds of Formula (I) that can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to recognize modifications of the disclosed synthèses and to devise routes based on the disclosures herein; ail such modifications and altemate routes are within the scope of the daims.
EXAMPLE 70 HCV Replicon Assav
Cells [0547] Huh-7 cells containing the self-replicating, subgenomic HCV replicon with a stable luciferase (LUC) reporter were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 2mM L-glutamine and supplemented with 10% heat-inactivated fêtai bovine sérum (FBS), 1% penicillin-streptomyocin, 1% nonessentîal amino acids, and 05 mg/mL G418.
Détermination of antî-HCV activity [0548] Détermination of 50% inhibitory concentration (EC») of compounds in 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-weIl plate. On the following day, test compounds were solubilized in 100% DMSO to lOOx the desired final testing concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. Compounds in 100% DMSO are reduced to 10% DMSO by diluting 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 incubated at 37 °C for 72 h. At 72 h, cells were processed when the cells are still subconfluent. Compounds that reduce the LUC signal are determined by Bright-Glo Luciferase Assay (Promega, Madison,
276
WI). % Inhibition was determined for each compound concentration in relation to the control cells (untreated HCV replicon) to calculate the ECm.
[0549] Compounds of Formula (I) are active in the replicon assay. The antiviral activity of exemplary compounds is shown in Table 2, where ‘A* indicates an ECjo < 1 μΜ, *B’ 5 ' indicates an ECsq> 1 μΜ and <10 μΜ, and ‘C’ indicates an ÉCjo> 10 μΜ and <100 μΜ.
Table 2
277
Compound # | EC„ |
2 | A |
3 | A |
5 | A |
II | A |
13 | B |
14 | A |
16.. ^ t | - A' ‘ |
17 | A |
18 | A |
19 | A |
20 | A |
21 | A |
22 | A |
27 | C |
28 | A |
29 | C |
30 | A |
31 | A |
32 | A |
33 | A |
34 | A |
35 | A |
36 | A |
37 | A |
40 | B |
41 | B |
42 | A |
43 | A |
49 | A |
51 | B |
52 | A |
53 | A |
54 | A |
55 | A |
56 | A |
57 | A |
58 | A |
59 | C |
60 | C |
61 | A |
62 | A |
66 | A |
67 | B |
70 | B |
73 | B |
77 | B |
79 | A |
80 | B |
81 | A |
83 | A |
84 | A |
85 | A |
86 | A |
87 | A |
88 | A |
89 | A |
90 | A |
Componnd # | EC«, |
91 | A |
EXAMPLE 71
NS5B Inhibition Assay [0550] 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, correspondîng to 377 nucléotides from the 3end of HCV (-) strand RNA of the Con-1 strain, with abase content of21% 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 Qîagen RNeasy maxi kit HCV polymerase reactions 10 contained 50 nM NS5B570-Conl, 50 nM cIRES RNA, about 0.5 pCi tritiated NTP, 1 μΜ of competing cold NTP, 20 mM NaCI, 40 mM Tris-HCl (pH 8.0), 4 mM dithiothreitol, and 4 mM MgCl2. Standard reactions were incubated for 2 h at 37°C, in the presence of increasîng 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 15 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-catalyzcd rate was reduced by 50% (IC50) was calculated by fitting the data to a non-linear régression (sigmoidal). The ICjq values were derived from the mean of several independent experiments and are shown in Table 3. Compounds of Formula (I) 20 showed activity in this assay. A value of ‘A’ in the table beJow indicates an IC50 of < 1 μΜ, a value of *B* indicates an IC30 > 1 μΜ and < 10 μΜ, and a value of ‘C* indicates an IC50 value of > 10 μΜ and < 100 μΜ.
Table 3
279
Compound # | ICs® |
6 | A |
7a | A |
7b | B |
9 | A |
. 12 | -A- |
15 | A |
26 | A’ |
28 | A |
38 | A |
44 | A |
46 | A |
50 | A |
63 | A |
64 | A |
69 | A |
76 | A |
EXAMPLE 72
Assessment of inhibition of mitochondrial fonction [0551] Drug-associated dysfonction of mîtochondria is believed to play a rôle in the etiology of the various adverse symptoms that occur in patients treated with antiviral nucleoside/nucteotîdes. For this reason, évaluation of compounds for their potential to inhibit mitochondrial fonction is usefol. To assess the potential for nucleotide/nudeoside analogs to interfère with normal mitochondrial fonctions and exhibit mitochondrial toxicity, the following 10 were measured: (1) the ability of nucléotides to be incorporated by human mitochondrial RNA polymerase in vitro and (2) the cellular inhibition of the synthesis of the mitochondrial DNA (mtDNA)-encoded protein, cytochrome c oxidase (COX-I), relative to the nuclear DNA (nDNA)-encoded mitochondrial protein succinatc dehydrogenase subunit A (SDH-A) in HepG2 cells. Control compounds and compounds of Formula (D were studied in these assays.
Biochemical assay [0552] Arnold et al. “Sensitivity of Mitochondrial Transcription and Résistance of RNA Polymerase Π Dépendent Nuclear Transcription to Antiviral Ribonucleosides PLoS Pathog (2012) 8(11): e!003030. doi:10.1371/joumal.ppat.l003030, which is hereby incorporated by reference in its entirety.
280
Assessment of incorporation of nucléotides by human mitochondrial RNA polymerase (HMRP)
DdRp assav with human mitochondrial RNA polymerase [0553] The DdRp assay with human mitochondrial RNA polymerase was performed 5 under single turnover conditions where enzyme concentration is in excess of the primer/template. The 33P-RNA/DNA primer/template was used at a concentration of 100 nM, together with 320 nM enzyme. The standard 10-pL reactions were canied out at 30*C for 1 minute with 100 μΜ of each nucléotide 5’-triphosphate (NTP), 10 mM MgCl2. 50 mM NaCl, 40 mM Tris, pH 75, and 1 mM DTT. The reaction was stopped by adding 20 pL of formamide 10 loading dye containing 50 mM EDTA. RNA products were resolved by electrophoresis on 22.5% TBE Urea polyaciylamide sequencing gels that were scanned using a TYPHOON Phosphorlmager.
Results [0554] As shown in both Figures 10 and 11, the appropriate naturel nucléotides were 15 shown to be good substrates for incorporation by HMRP in each template. The template in
Figure 10 was designed to measure incorporation of UTP analogs. Primer/Template: (SEQ ID NO: 1) UUUUGCCGCGCC and (SEQ ID NO: 2) GGGAATGCTAGGCGCGGC. In the contre! water lanes, wherein no nucléotides were added, no incorporation was observed as indîcated by the lack of product band. As shown in Figure 10, UTP and 3’-deoxy-UTP were efficient 20 substrates for incorporation as indîcated by the prominent product band. The potential for mîsincorporation was assessed using the contrat nudeotide CTP. As provided in Figure 10, CTP was incorporated to a Jesser extent relative to UTP. In contrast to UTP and 3’-deoxy-UTP, compounds of Formula (I) and 2’-Me-2’-F-UTP were not efficient substrates for incorporation by HMRP as demonstrated by the lack of product band.
[0555] The template strand shown in Figure 11 was designed to measure the incorporation of GTP analogs. Primer/Template: (SEQ ID NO: 3) UUUUGCCGCGCC and (SEQ ID NO: 4) GGGAATGCACGGCGCGGC. In the contre! water lanes, no incorporation was observed as indîcated by the lack of product band. GTP and 3’-deoxy-GTP were found to be efficient substrates for incorporation as demonstrated by lhe significant product bands. The 30 potential for mîsincorporation was assessed using the control nucleotîde ATP. As shown by the lack of product band in Figure 11, control ATP was a poor substrate for incorporation.
Nudeotide analog 2’-Me-GTP (the nudeotide métabolite of monophosphate prodrug INX0189/BMS-986094) was tested and found to be a good substrate for incorporation by HMRP as indîcated by the product band. Nudeotide analog 2’-Me-2'-F-GTP (nudeotide métabolite of
281 monophosphate prodrug GS-938) was tested and also found to be incorporated by HMRP. In contrast, compounds of Formula (I) were not efficient substrates for incorporation into the template strand by HMRP as indicated by the lack of product bands in Figure 11.
Assessment of inhibition of mitochondrial protein synthesis Cell Based Assav
Assav Princîple * [0556]’ ' MitoBiogenêsisnrIri Cell ELISA kits (Cat. #MS643) were obtained from
Mitosciences, OR, USA. The MitoBiogenesis™ In Cell ELISA kit is a duplexïng 96 well assay that ratios both an mtDNA and an nDNÀ encoded mitochondrial protein. Cells were seeded in microplates and after exposure to compounds for several cell doublings, the levels of the two 10 mitochondrial proteins were measured simultaneously in each well. The two proteins assayed were each subunîts of different oxidative phosphorylation enzyme complexes, one protein being subunit I of Complex IV (cytochrome c oxidase; COX I) that is mtDNA encoded and the other being the 70 kDa subunit of Complex Π (succinate dehydrogenase subunit A; SDH A) that is nDNA encoded. Complex IV includes several proteîns that are encoded by the mtDNA while 15 the proteins of Complex H are entircly encoded by nDNA. To control for the density of cells présent at the end of the culture period, the number of cells were assessed by staining with Janus Green and the levels of COX I/SDH A normalized to the final cell density.
Well Plate Assav Format for HepG2 Cells [0557] On the first day, 1000 HepG2 cells per well were plated in a 96 well plate. 20 On the following day, compounds to be tested were solubilized in 100% DMSO to 100 x the desired final testing concentration. Each compound was scrially diluted (1:3) up to 9 distinct concentrations. Compounds in 100% DMSO were reduced to 10% (v/v) DMSO by dîlutîng 1:10 in cell culture media. A 10 pL aliquot of the compounds diluted to 10% (v/v) DMSO with cell culture media was used to dose the cells in duplicate. The final DMSO concentration was 1% 25 (v/v). Untreated cells and wells containing no cells were included on the plate to serve as controls. Cells were then incubated with compounds and observed for 8 days at 37°C and 5% CO2. Plates were processed as described below in the assay procedure.
Batch Assav Format for Het>G2 Cells [0558] An altemate cell culture procedure was employed to test the potential to 30 médiate mitochondrial toxicity at higher concentrations than achievable in the 96 well plate format. HepG2 cells were grown either in media/DMSO alone or in a sériés of compound concentrations in 15 cm2 dishes or 6 well plates at an initial cell seeding density of 5 x 106 and 5 x 104 cells/mL, respectively. Cells were then incubated and observed for 8 days at 37°C and 5% CO2. After 8 days, the cells were harvested by trypsînîzation, counted, and seeded in 96 well
282 plates at a density of 25,000 cells/well in 16 replicate wells. Cells were allowed to adhéré ovemight and then the plates were processed as described below în the assay procedure.
Assay Procedure [0559] The assay was performed according to the manufactureras instructions.
5— Briefly, after the end of the culture period the cell culture media was gently aspîrated from the wells of thé plate and replaced with 100' pL of 4% (v/v) paraformaldéhyde solution in phosphate buffered saline (PBS, Electron Microscopy Sciences Cat #15713). After a20 mins incubation at R.T., the solution was removed and the wells washed 3 x with 300 pL of PBS. After the final wash, the PBS was removed and the wells overlayed with 100 pL PBS. The plates were then 10 sealed and stored at 4'C until used. To perform the assay, the PBS overlay was removed by blotting on a paper towel and 100 pL of 0.5% (v/v) acetic acid added to each well to block endogenous alkaline phosphatase activity. After a 5 mins incubation at R.T., the acetic acid solution was removed and the cells washed once with 200 pL PBS. Then, 100 pL of pcrmeabilization buffer (0.1% (v/v) Triton X 100) was added to each well. After 30 mins 15 incubation at R.T., the permeabilization buffer was removed and each well was blocked with
200 pL of 2 x blocking solution for 2 h at R.T. The 2 x blocking solution was then removed and 100 pL of primary antibody solution contaîning anti COX I and anti SDH A antibodies in 1 x blocking solution was added to each well. Plates were then sealed and incubated ovemight at 4’C. The primary antibody/blocking solution was removed and the plate washed 3 x with 250 20 pL 0.05% (v/v) Tween 20 in PBS. Then, 100 pL of secondary antibody solution contaîning alkaline phosphatase (AP) labeled anti SDH A antibody and horseradish peroxidase (HRP) tabeled anti COX I antibody was added and incubated for 1 h at R.T. The plate was then washed 4 x with 250 pL 0.05% (v/v) Tween 20 in PBS. After blotting the plate dry 100 pL of AP détection reagent was added to each well, and the plate incubated in the dark for 30 mins at R.T.
The optical density of each well was then measured at 405 nm. The AP détection reagent was then removed and replaced with 100 pL of HRP détection reagent, and the plate incubated in the dark for a further 30 mins at R.T. The optical density of each well was then measured at 600 nm. The HRP détection reagent was then removed and each well was then staîned with 50 pL of I x Janus Green Stain for 5 mins at R.T. After removal of the dye, the plates were washed 5 x in ultrapure water to remove any remaining dye. The Janus Green stain was then solubilized by the addition of 100 pL of 0.5 M HCl and incubated for 10 mins. The optical density of each well was then measured at 595 nm.
Data Analysis
283 [0560] The average of al! replicate background measurements from each experimental condition was calculated and subtracted from the experimental values of the same condition. The SDH A and COX I signais were then plotted as a ratio (COX I/SDH A) and
- - 5 normalized to the Janus Green staining întensity to correct for différences In cell density.
- Results - - ·-- - - ----------------- [0561] Control compound d4T was tested and found not to inhibit mitochondrial protein synthesis at concentrations up to 100 μΜ as shown in Figures 12A-D. Control compound ddC was tested and found to strongly inhibit mitochondrial protein synthesis. See 10 Figures 12A-D. As demonstrated in Figure 12A, nucleoside monophosphate prodrug INX08189/BMS-986094 (which delivers 2’-Me-GTP) was tested in the assay and found to strongly inhibit mitochondrial protein synthesis. In contrast, compounds of Formula (I) were tested and found to not inhibit mitochondrial protein synthesis at concentrations up to 100 μΜ as shown in Figures 12B-D.
EXAMPLE 73
Combination of Compounds
Combination Testing [0562] 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) 20 reporter. Cells were cultured under standard conditions in Dulbecco’s modified Eagle’s medium (DMEM; Mediatech Inc, Herndon, VA) containing 10% heat-inaclivated 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-weIl 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 25 containing either no compound as a control, the test compounds serially diluted in the presence of 2% FBS and 05% DMSO, or a combination of compound 18 with one or more test compounds serially diluted in the presence of 2% FBS and 05% 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 30 examined using a luciferase (LUC) based reporter as determincd by the Bright-GIo Luciferase Assay (Promega, Madison, WI). Dose-response curves were determined for indîvidual compounds and fixed ratio combinations of two or more test compounds.
[0563] The method ut ilized for evaluating combination effects used a program called MacSynergy Π. MacSynergy H software was kindly provided by Dr. M. Prichard (Unîversity of
284
Michigan). The Prichard Model allows for a three-dimensional examination of drug interactions and a calculation of the synergy volume (units: μΜ2%) 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 =*-5 ---orrantagonism per change in the concentrations of the twodrugs.- Synergy and antagonism - ? volumes are defined based on the Bliss independence model. In this model, synergy volumes of less than -25 îndicate antagonistic interactions, volumes in the -25 - 25 range indicate additive behavior, volumes in the 25 -100 range indicate synergistic behavior and volumes >100 indicate strong synergistic behavior. Détermination of in vitro additive, synergistîc and strongly 10 synergistic behavior for combinations of compounds can be of utility in predicting therapeutic benefits for administering the combinations of compounds in vivo to infected patients.
[0564] The synergy volume results for the combinations are provided in Table 4.
Table 4
Combination Compound | Synergy Volume (UM2%) | Détermination |
ANA-598 (3002) | 29.46 | Synergistic |
HCV-796 (3004) | 81.72 | Synergistic |
Ribavirin (5012) | 6.77 | Additive |
Filibuvir (3007) | 2351 | Additive |
VX-222 (3003) | 3235 | Synergistic |
BMS-790052 (4001) | 38.01 | Synergistic |
VX-950 (1001) | 32.28 | Synergistic |
TMC-435 (1013) | 97.17 | Synergistic |
[0565] 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 cleariy understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the présent 20 disclosure, but rather to also cover ail modification and alternatives coming with the true scope and spirit of the invention.
Claims (30)
- , 1 o or 1 oThe compound of uny one of Claims 20 or 33-35, wherein RÎB is i9B29452. The compound of any one of Claims 20 or 33-35, wherein RÎB is is53. The compound of any one of Claims 20 or 33-35, wherein RÎB55.56.o ro—J.The compound of any one of Claims 20-35 or 54, wherein R5B is O or OH.The compound of Claim 20, wherein R5A is O' or OH; RÏB O isOR’ L Jn ; and n is 0.The compound of Claim 20, wherein R5A is O‘ or OH; RÎB Γ Ο ΊII-p—o—OR’ is58.59.60.bond.L Jn ;andnis l.The compound of any one of Claims 1-57, wherein Z1 is O.The compound of any one of Claims 1 -57, wherein Z1 is S.The compound of any one of Claims 1-14, wherein both----are each a single61. The compound of Claim 60, wherein Z1* is O.62. The compound of Claim 60, wherein Zp is S.63. The compound of any one of Claims 60-62, wherein Rpl is O* or OH.64. The compound of any one of Claims 60-62, wherein Rpl is an -O-optîonally substituted Cm alkyl.65. The compound of Claim 64, wherein Rpl is an -O-unsubstituted Cm alkyl.29566. The compound of any one of Claims 60-62, wherein Rpl is an substituted N-linked amino acid or an optionally substituted N-linked amino optionally acid ester dérivative.
- 2. The compound of Claîm 1, wherein R2 is halo.
- 3. The compound of Claim 1, wherein R2 is -OR7A.
- 4. The compound of Claîm 3, wherein R7A is hydrogen.
- 5 sait thereof, or a pharmaceutical composition of Claim 75 for preparing a médicament for ameliorating or treating a HCV infection.77. Use of a compound of any one of Claims 1-74, or a pharmaceutically acceptable sait thereof, for preparing a médicament for inhibiting NS5B polymerase activity of a hepatitis C virus.5 67. The compound of any one of Claims 1-66, wherein B1 is an optionally substitutedO68. The compound of any one of Claims 1-66, wherein B1 is an optionally substituted69. The compound of any one of Claims 1-66, wherein B1 is an optionally substituted29670. The compound of any one of Claims 1-66, wherein B1 is an optionally substituted .r8F71. The compound of any one of Claims 1-66, wherein B1 is an optionally substitutedWW*HOF , or a pharmaceutically acceptable sait of the foregoing.303 άΗ CH or a pharmaceutically acceptable sait of the foregoing., or a pharmaceutically acceptable sait of the foregoing.-IEESSæSœsa»B0BSS î ' .30475. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims l-74, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.76. Use of a compound of any one of Claims 1-74, or a pharmaceutically acceptable.5 -45. The compound ofClaim 43, wherein R17 is an optionally substituted Cm alkyl.46. The compound of any one of Claims 43-45, wherein R18 is hydrogen.47. The compound of any one of Claims 43-45, wherein R18 is an optionally substituted Cm alkyl.48. The compound of any one of Claims 43-47, wherein RIS is an optionally 10 substituted C i alkyl.49. The compound of any one of Claims 43-47, wherein R16 is an optionally substituted Cm cycloalkyl.O HN—;50. The compound of Claim 43, wherein51.5. The compound of Claim 3, wherein R7A is -C(=O)R12.5 R6B and R60 are independently selected from the group consisting of hydrogen, an unsubstituted C|_<5 alkyl, an unsubstituted C34 alkenyl, an unsubstituted C» alkynyl and an unsubstituted Cm cycloalkyl;R^isNHR60;R6e is hydrogen, halogen or NHR6H;
- 6. The compound of Claim 1, wherein R2 is Nj.
- 7. The compound of Claim 1, wherein R2 is -N(R7BR7C).
- 8. The compound of Claîm 7, wherein R2 is -NH2.
- 9. The compound of Claim 7, wherein at least one of R70 and R7C is an optionally substituted Cu alkyl.
- 10 78. Use of a compound of any one of Claims 1-74, or a pharmaceutically acceptable sait thereof, for preparing a médicament for inhibiting réplication of a hepatitis C virus.79. Use of a compound of any one of Claims 1-74, or a pharmaceutically acceptable sait thereof, for preparing a médicament for contacting a cell infected with a hepatitis C virus, whereby ameliorating or treating the HCV infection.10. The compound of Claim 7, wherein R7B and R7C are both an optionally10 R6FisNHR61;Rm is selected from the group consisting of hydrogen, an optionally substituted Cm alkyl, an optionally substituted C3_6 alkenyl, an optionally substituted Cm cycloalkyl, -C(=O)Rai and -C^JOR*2;r6H is selected from the group consisting of hydrogen, an optionally substituted
- 11. The compound of any one of Claims 1-10, wherein R1 is an optionally substituted Cm alkyl.
- 12. The compound of any one of Claims 1-10, wherein R1 is an optionally substituted C2^ alkenyl.
- 13. The compound of any one of Claims 1-10, wherein R1 is an optionally substituted Cm alkynyl.
- 14. The compound of any one of Claims 1-10, wherein R1 is an optionally substitutedCm cycloalkyl.
- 15 80. Use of a compound of any one of Claims 1-74 in the préparation of a médicament for ameliorating or treating a HCV infection, wherein the médicament is manufactured for use in combination with one or more agents selected from the group consîsting of 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 20 Formula (CC), or a pharmaceutically acceptable sait any of the aforementîoned compounds.81. Use of a compound of any one of Claims 1-74 in the préparation of a médicament for contacting a cell infected with a hepatitis C virus, wherein the médicament is manufactured for use in combination with one or more agents selected from the group consîsting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor,15 4L The compound of any one of Claims 20-32, wherein R50 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, valîne and ester dérivatives thereof.42. The compound of any one of Claims 20-32, wherein RS0 is selected from the15. The compound of any one of Claims 1-14, wherein both are each absent15 substituted Cm alkyl.29015 Cm alkyl, an optionally substituted C34 alkenyl, an optionally substituted C34 cycloalkyl,-CÎ^JR*3 and-C(=O)ORA4;R61 is selected from the group consisting of hydrogen, an optionally substituted Cm alkyl, an optionally substituted C3^ alkenyl, an optionally substituted Cm cycloalkyl, -C(=O)R and-C(=O)ORa6;
- 16. The compound of any one of Claims 1-15, wherein R3 is -OH.
- 17. The compound of any one of Claims 1-15, wherein R3 is -OC(=O)RS.
- 18. The compound of Claim l or 15, R3 and R3 are both oxygen atoms and linked together by a carbonyl group.The compound of any one of Claims 1-18, wherein R4 is hydrogen.R58-^-1
- 19.
- 20 group consisting of alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valîne isopropyl ester, isoleucine isopropyl ester, methîonîne isopropyl ester and leucine isopropyl ester.43. The compound of any one of Claims 20-32, wherein R10 has the structure , wherein R16 is selected from the group consisting of hydrogen, an optionally substituted Ci-e-alkyl, an optionally substituted C« cycloalkyl, an optionally substituted aryl, an optionally substituted aryl (Cm alkyl) and an optionally substituted haloalkyl; R17 is selected from the group consisting of hydrogen, an optionally substituted Cm alkyl, an optionally substituted Cm haloalkyl, substituted an optionally substituted Cj e cycloalkyl, an optionally293 substituted Q aryl, an optionally C)0 aryl and an optionally substituted aryl(CM alkyl); and R18 is hydrogen or an optionally substituted Cu-alkyh or R17 and R18 is taken together to form an optionally substituted Cm cycloalkyl.44. The compound of Claim 43, wherein R17 is hydrogen.20.20 X1 is N or-CR61,Rw is selected from the group consisting of hydrogen, halogen, an optionally substituted Cm alkyl, an optionally substituted Cm alkenyl or an optionally substituted C2.6 alkynyl;Rai, R*2, R*3, RA4, R*3 and RA6 are independently selected from the group 25 consisting of Cm alkyl. Cm alkenyl. Cm alkynyl, Cm cycloalkyl, Cm cycloalkenyl, Ce_ 1(j aryl, heteroaryl, heterocyclyl, aryl(CM alkyl), heteroaryl(CM alkyl) and heterocyclyl (Cm alkyl);R7A is hydrogen or-C(=O)R12;R7B and R7C are independently hydrogen or an optionally substituted Cm alkyl;28SR8 and R12 are independently an optionally substituted C|_6 alkyl or an optionally substituted Cj_6cycloalkyl;R9, R10 and R11 are independently absent or hydrogen;R8A, R9a, Rua, R12a, R8B. R9B, R,1b, R12b, Rp2, Rp3, Rps and R”6 are independently selected from the group consisting of hydrogen, an optionally substituted Ct.24 alkyl and an optionally substituted aiyl; - - —- Rt0A, Rl0B, R13a, R’3B, R1*4 and Rp7 are independently selected from the group consisting of hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ct.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl;r!4a, rI4b. rua. ri« Rpe rp? independently selected from the group consisting of hydrogen, an optionally substituted Cjh alkyl and an optionally substituted aryl;n isOor 1;p, q, and r are independently 1 or 2;s, t and u are independently 3,4 or 5;Z1, ZIA, ZIB and Zp,are independently O or S; and or provided that when R* is , an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative; and provided that the compound is not selected from the group consisting of:
- 21. amino acid.The compound of any one of Claims 1-18, wherein R4 is RÎA .The compound of Claim 20, wherein R3A is an optionally substituted N-linked
- 22.The compound of Claim 20, wherein R3A is an optionally substituted N-linked amino acid ester derivative.20
- 23. The compound of Claim 20, wherein RSA is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, praline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan, valine and ester dérivatives thereof.
- 24. The compound of Claim 20, wherein RJA is selected from the group consisting of
- 25 an antiviral compound, a compound of Formula (AA) , a compound of Formula (BB) and a compound of Formula (CC), or a pharmaceutically acceptable sait any of the aforementioned compounds.82. The use of any one of Claim 80-81, wherein the one or more agents are selected from the group consîsting of Compounds 1001-1016,2001-2012,3001-3014,4001-4012,5001-25. The compound of Claim 20, wherein R3A has the structure wherein R13 is selected from the group consisting of hydrogen, an optionally substituted Cmalkyi, an optionally substituted Cm cycloalkyl, an optionally substituted aryl, an optionally291 substîtuted aryl(Ct^ alkyl) and an optionally substîtuted haloalkyl; R14 is selected from the group consisting of hydrogen, an optionally substîtuted Cm alkyl, an optionally substîtuted Cm haloalkyl, an optionally substîtuted Cm cycloalkyl, an optionally substîtuted Ce aryl, an optionally substîtuted Cio aryl and an optionally substîtuted aryl(CM alkyl); and Rts is hydrogen or an optionally-substîtuted Ci .«-alkyl;. or R14 and R13- is taken together to form an optionally substîtuted Cm cycloalkyl.25 alanine isopropyl ester, alanine cyclohexy! ester, alanine neopentyl ester, valine isopropyl ester, isoleucine isopropyl ester, méthionine isopropyl ester and leucine isopropyl ester.R13
- 26. The compound of Claim 25, wherein R14 is hydrogen.
- 27. The compound of Claim 25, wherein R14 is an optionally substîtuted CM-alkyl.
- 28. The compound of any one of Claims 25-27, wherein R13 is hydrogen.
- 29. The compound of any one of Claims 25-27, wherein R,s is an optionally substîtuted Cm alkyl.30. The compound of any one of Claims 25-29, wherein R13 is an optionally substîtuted Cm alkyl.31. The compound of any one of Claims 25-29, wherein R13 is an optionally substîtuted Cm cycloalkyl.32.The compound of Claim 25, wherein R8A r9AA>Y”“33. The compound of any one of Claims 20-32, wherein R3Ais O29234. The compound of any one of Claims 20-32, wherein RSA isRî3A.35. The compound of any one of Claims 20-32, wherein R5A is r15A536. The compound of any one of Claims 20-32, wherein R5® is an -O-optionally substituted aryl.37. The compound of any one of Claims 20-32, wherein R50 is an -O-optionally substituted heteroaryl.38. The compound of any one of Claims 20-32, wherein R5B is an -O-optionally 10 substituted heterocyclyl.39. The compound of any one of Claims 20-32, wherein R50 is an optionally substituted N-linked amino acid.40. The compound of any one of Claims 20-32, wherein RÎB is, an optionally substituted N-linked amino acid ester dérivative.
- 30 5012,6001-6078,7000-7027 and 8000-8016, or a pharmaceutically acceptable sait of any of the aforementioned compounds.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61/745,466 | 2012-12-21 | ||
US61/890,125 | 2013-10-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA17338A true OA17338A (en) | 2016-05-25 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018203337B2 (en) | Substituted nucleosides, nucleotides and analogs thereof | |
CA2894541A1 (en) | Substituted nucleosides, nucleotides and analogs thereof | |
OA17338A (en) | Substituted nucleosides, nucleotides and analogs thereof. |