CN101784532A - 新的hiv逆转录酶抑制剂 - Google Patents
新的hiv逆转录酶抑制剂 Download PDFInfo
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- CN101784532A CN101784532A CN200880022127A CN200880022127A CN101784532A CN 101784532 A CN101784532 A CN 101784532A CN 200880022127 A CN200880022127 A CN 200880022127A CN 200880022127 A CN200880022127 A CN 200880022127A CN 101784532 A CN101784532 A CN 101784532A
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- 108010078851 HIV Reverse Transcriptase Proteins 0.000 title claims description 54
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 736
- 239000000203 mixture Substances 0.000 claims abstract description 63
- 150000002148 esters Chemical class 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 239000012453 solvate Substances 0.000 claims abstract description 19
- -1 alkyl formyl radical Chemical compound 0.000 claims description 345
- 125000000217 alkyl group Chemical group 0.000 claims description 230
- 239000003112 inhibitor Substances 0.000 claims description 213
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 106
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 91
- 125000003118 aryl group Chemical group 0.000 claims description 86
- 239000003814 drug Substances 0.000 claims description 71
- 238000002360 preparation method Methods 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 40
- 239000002585 base Substances 0.000 claims description 38
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 31
- 125000003107 substituted aryl group Chemical group 0.000 claims description 30
- 125000001544 thienyl group Chemical group 0.000 claims description 28
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 27
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 27
- 125000001118 alkylidene group Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
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- 125000004076 pyridyl group Chemical group 0.000 claims description 25
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- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 claims description 24
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- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 21
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- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 21
- 229940087098 Oxidase inhibitor Drugs 0.000 claims description 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 21
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- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 17
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- 229910052760 oxygen Inorganic materials 0.000 claims description 17
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- NIDRYBLTWYFCFV-SEDUGSJDSA-N (+)-calanolide b Chemical compound C1=CC(C)(C)OC2=C1C(O[C@H](C)[C@@H](C)[C@H]1O)=C1C1=C2C(CCC)=CC(=O)O1 NIDRYBLTWYFCFV-SEDUGSJDSA-N 0.000 claims description 16
- CUFQBQOBLVLKRF-RZDMPUFOSA-N (4r)-3-[(2s,3s)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenylbutanoyl]-5,5-dimethyl-n-[(2-methylphenyl)methyl]-1,3-thiazolidine-4-carboxamide Chemical compound CC1=CC=CC=C1CNC(=O)[C@@H]1C(C)(C)SCN1C(=O)[C@@H](O)[C@@H](NC(=O)C=1C(=C(O)C=CC=1)C)CC1=CC=CC=C1 CUFQBQOBLVLKRF-RZDMPUFOSA-N 0.000 claims description 16
- BEMROAADXJFLBI-UHFFFAOYSA-N 1-(cyclopent-3-en-1-ylmethyl)-6-(3,5-dimethylbenzoyl)-5-ethylpyrimidine-2,4-dione Chemical compound C1C=CCC1CN1C(=O)NC(=O)C(CC)=C1C(=O)C1=CC(C)=CC(C)=C1 BEMROAADXJFLBI-UHFFFAOYSA-N 0.000 claims description 16
- 102100034544 Acyl-CoA 6-desaturase Human genes 0.000 claims description 16
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- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 claims description 16
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims description 16
- RYMCFYKJDVMSIR-RNFRBKRXSA-N apricitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1S[C@H](CO)OC1 RYMCFYKJDVMSIR-RNFRBKRXSA-N 0.000 claims description 16
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 claims description 16
- GIXWDMTZECRIJT-UHFFFAOYSA-N aurintricarboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=CC1=C(C=1C=C(C(O)=CC=1)C(O)=O)C1=CC=C(O)C(C(O)=O)=C1 GIXWDMTZECRIJT-UHFFFAOYSA-N 0.000 claims description 16
- NIDRYBLTWYFCFV-UHFFFAOYSA-N calanolide F Natural products C1=CC(C)(C)OC2=C1C(OC(C)C(C)C1O)=C1C1=C2C(CCC)=CC(=O)O1 NIDRYBLTWYFCFV-UHFFFAOYSA-N 0.000 claims description 16
- YDDGKXBLOXEEMN-IABMMNSOSA-N chicoric acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-IABMMNSOSA-N 0.000 claims description 16
- VZCYOOQTPOCHFL-OWOJBTEDSA-N fumaric acid group Chemical group C(\C=C\C(=O)O)(=O)O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 16
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- 229960005386 ipilimumab Drugs 0.000 claims description 16
- QAHLFXYLXBBCPS-IZEXYCQBSA-N methyl n-[(2s)-1-[[(5s)-5-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-6-hydroxyhexyl]amino]-1-oxo-3,3-diphenylpropan-2-yl]carbamate Chemical compound C=1C=CC=CC=1C([C@H](NC(=O)OC)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)C1=CC=CC=C1 QAHLFXYLXBBCPS-IZEXYCQBSA-N 0.000 claims description 16
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- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 claims description 16
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 16
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 claims description 16
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 16
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- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 claims description 15
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- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
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- NIDRYBLTWYFCFV-FMTVUPSXSA-N (+)-calanolide A Chemical compound C1=CC(C)(C)OC2=C1C(O[C@H](C)[C@@H](C)[C@@H]1O)=C1C1=C2C(CCC)=CC(=O)O1 NIDRYBLTWYFCFV-FMTVUPSXSA-N 0.000 claims description 8
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- RQDGBNLSKUOAJD-SFTDATJTSA-N (2,4-dimethyl-1-oxidopyridin-1-ium-3-yl)-[4-methyl-4-[(3s)-3-methyl-4-[(1s)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazin-1-yl]piperidin-1-yl]methanone Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(F)(F)F)([C@H](C1)C)CCN1C(CC1)(C)CCN1C(=O)C1=C(C)C=C[N+]([O-])=C1C RQDGBNLSKUOAJD-SFTDATJTSA-N 0.000 claims description 8
- DDVVRHNNOPQPGB-UHFFFAOYSA-N (2,4-dimethyl-1-oxidopyridin-1-ium-3-yl)-[4-methyl-4-[4-(n-pyridin-3-ylanilino)piperidin-1-yl]piperidin-1-yl]methanone Chemical compound CC1=CC=[N+]([O-])C(C)=C1C(=O)N1CCC(C)(N2CCC(CC2)N(C=2C=CC=CC=2)C=2C=NC=CC=2)CC1 DDVVRHNNOPQPGB-UHFFFAOYSA-N 0.000 claims description 8
- JHXLLEDIXXOJQD-WELGVCPWSA-N (2-decoxy-3-dodecylsulfanylpropyl) [(2r,3s,5r)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl hydrogen phosphate Chemical compound C1[C@H](F)[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 JHXLLEDIXXOJQD-WELGVCPWSA-N 0.000 claims description 8
- PNIFFZXGBAYVMQ-RKKDRKJOSA-N (2s)-n-[(2s,3r)-4-[(3-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]-2-[[2-[(3-fluorophenyl)methylamino]acetyl]amino]-3,3-dimethylbutanamide Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=C(N)C=CC=1)NC(=O)[C@@H](NC(=O)CNCC=1C=C(F)C=CC=1)C(C)(C)C)C1=CC=CC=C1 PNIFFZXGBAYVMQ-RKKDRKJOSA-N 0.000 claims description 8
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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Abstract
本发明涉及式(I)的化合物:
Description
相关申请的交叉引用
本申请要求享有2007年7月16日提交的美国临时申请No.60/959,676,以及2007年6月29日提交的美国临时申请No.60/937,756,的优先权,这里两者均作为参考文献整体引入。
技术领域
本发明涉及新型HIV逆转录酶(RT)抑制剂,其药物组合物,制备该新型HIV逆转录酶的方法,以及抑制和治疗HIV感染的方法。
背景技术
近年来,HIV逆转录酶(RT)抑制剂已经成为人类抑制和治疗艾滋病毒感染的一类重要药物。抑制HIV逆转录酶酶促作用的化合物抑制感染细胞中HIV的复制。此类化合物有助于预防或治疗人类HIV感染,如众所周知的RT抑制剂诸如齐多夫定、地达诺新、扎西他滨、司他夫定、拉米夫定、恩曲他滨、阿波卡伟、泰诺福韦、奈维拉平、地拉韦啶和依法韦仑,它们是迄今批准的用于治疗艾滋病的主要药物。
对于任何抗病毒药物治疗,在治疗AIDS中使用RT抑制剂,最终导致病毒对给定的药物敏感性降低。这些药物的抗药性(敏感性降低)是由于pol基因的逆转录酶片段发生突变所致。多种HIV的突变株的特征已被确定,并且已知治疗药物的抗药性被认为是由于RT基因的突变所致。因此,有效的新的HIV RT抑制剂不仅必须能有效地抗HIV野生型菌株,还必须对由于现有商用RT抑制剂而新产生的突变菌株有效。因此,这里仍然需要新的HIV RT抑制剂,例如,那些同时靶向作用于HIV野生型和突变型菌株中的HIV RT。
发明概述
根据一个实施方案,本申请提供了结构式(I)的新的HIV RT抑制剂化合物:
或其药学上可接受的盐、溶剂化物和/或酯,其中:X和Y独立地为O或S;
A是共价键、-O-、-S-、-NR5-、-C(O)-、-C(S)-、-C(NR8)-或-C(R6)2-;
D是共价键、亚烷基、亚烯基或亚炔基;
R1是H、卤素、烷基、卤烷基、环烷基、取代环烷基、杂环基、取代杂环基、-OH、烷氧基、硅氧基、烯基、取代烯基、炔基、取代炔基、CN、-C(O)-N(R7)2、-O-C(O)-N(R7)2、-N(R7)-C(O)-N(R7)2、-C(O)-O烷基、-C(O)-OH、-O-C(O)-O烷基、-N(R7)-C(O)-O烷基、硅氧基、-O-亚烷基-OH、-O-亚烷基-O-酰基,或-S(O)2-N(R7)2;
R2是卤素、硝基、氰基、烷基、卤烷基、取代烷基、羟烷基、烷氧基、烯、取代烯、炔、或取代炔、烷氧羰基、-N(R7)2、烷基甲酰、二烷基甲酰、环烷基、取代环烷基、芳基烷或取代芳基烷;
R3是芳基或杂芳基;
R4是H、烷基、取代烷基、环烷基、取代环烷基、羟烷基、烷氧基、芳基烷基或取代芳基烷基;
R5是H、烷基、取代烷基、芳基烷基、取代芳基烷基、-OH、酰基、取代酰基;
每个R6独立地为H、烷基、环烷基、取代环烷基、羟基、烷氧基、氰基或卤素;
每个R7独立地为H、烷基、芳基、取代芳基、芳基烷基、取代芳基烷基、环烷基、取代环烷基、杂芳基或取代杂芳基;
R8是H、烷基、芳基、取代芳基、羟基,或烷氧基;
每个Z独立地选自卤素、硝基、羟基、氨基、乙酰氨基、三氟乙酰氨基、叠氮基、氰基、甲酰、烷基、取代烷基、烷基酰胺、二烷基甲酰、烯、取代烯、炔、取代炔基、烷氧基、取代烷氧基、烷氧羰基、环烷基、环烷基取代、环烯基、取代环烯基、杂环基、取代杂环基、芳基、取代芳基、氧化物;以及
n是从0到4整数;
附带条件如下:
(a)当X和Y同时是O,R4是H,A是-O-、-S-、-C(O)-、-CH(OH)-或-CH2-,R3是苯基,并且D是-CH2-,
此时R1不可以是烷氧基;
(b)当X和Y同时是O,A是-S-、-O-或-C(O)-,R3是苯基,n是2,每个Z为烷基,D是-CH2-,R2是烷基,并且R4是H,
此时,R1不可以是未取代环烷基、未取代异环烷基或未取代杂芳基;
(c)当X和Y同时是O,A是-C(O)-、-O-或-NH-,D是-CH2-,R2是烷基,R3是苯基,n是2,R4是H,
此时,R1不可以是一种选自吡啶基、嘧啶基和哒嗪基的取代或未取代杂芳基;
(d)当X和Y同时是O,n是0或2,每个Z为烷基,A-R3是苄基、苯甲酰基、噻吩基或苯氧基,R4是H,并且R2为乙基或异丙基,
此时,D不可以是亚烯基或亚炔基以及-D-R1不可以是烷基、羟基烷基或-烃基-C(O)-O烷基;
(e)R4和-D-R1仅有一个为H。
在另一实施方案中,本申请提供一种用于治疗HIV感染的方法,其包括给药给需要此类治疗的病人治疗有效量的至少一种结构式(I)的化合物或其药学上可接受的盐、溶剂化物和/或酯。
在另一实施方案中,本申请提供一种用于治疗HIV感染的方法,其包括给药给需要此类治疗的病人一种治疗有效的组合物包括(a)一种或多种结构式(I)的化合物以及(b)其他的治疗药剂(例如,一种或多种选自HIV逆转录酶抑制剂以及HIV蛋白酶抑制剂的化合物)。
在另一实施方案中,本申请提供一种用于治疗HIV感染的方法,其包括给药给需要此类治疗的病人,一种治疗有效的剂量的:(a)一种结构式(I)的化合物;以及,(b)至少一种化合物选自HIV蛋白酶抑制化合物、逆转录酶的HIV非核苷抑制剂、逆转录酶的HIV核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD以及NADH-氧化酶抑制剂、CCR5抑制剂、治疗HIV的其它药物以及它们的混合物。
在另一实施方案中,本申请提供了一种试剂盒或容器,其包括一种在检测或分析中作为标准或试剂的有效剂量的结构式(I)的化合物,其用于确定潜在药物化合物抑制HIV RT和/或HIV生长能力。
发明详述
下面实施例结合结构式和分子式详细说明本发明的某些权利要求。虽然以下将结合例举的权利要求一起描述,但应理解本发明并不仅限于这些权利要求。相反地,本发明包括所有的可包含在如权利要求中定义的本发明范围中代替物、修饰物以及等同物。
除非另有说明,本文中所使用的下列术语和短语的含义如下:
当此处使用商品名时,申请人意在独立包括商品名称的产品以及该商品名称产品的活性药物成分。
按照本领域的惯例,
在此处的结构式中被用于描绘键,是指基团或取代基团与核心或骨架结构的附着点。
此处所用的“本发明的一种化合物”或“公式(I)所述的化合物”是指公式(I)所述的化合物,或其药学上可接受的盐、溶剂化物、酯或生理功能衍生物。本发明的化合物还包括其异构形式,例如此处所述的异构“烯醇”。同样地,关于可分离中间体,诸如结构式(4)所述化合物,短语“结构式(序号)所述化合物”是指一种此结构式的化合物以及其药学上可接受的盐、溶剂化物、酯和生理功能的衍生物。
“烷基”是含有正常、仲碳、叔碳或环碳原子的烃。例如,烷基包括1-20个碳原子(例如,C1-C20烷基),1-10个碳原子(例如,C1-C10烷基)或1-6个碳原子(例如,C1-C6烷基)。合适的烷基的例子包括但不仅限于:甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,n-丙基,-CH2CH2CH3)、2-丙基(i-Pr,i-丙基,-CH(CH3)2)、1-丁基(n-Bu,n-丁基,-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,i-丁基-CH2CH(CH3)2)、2-丁基(s-Bu,s-丁基,-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,t-丁基,-C(CH3)3)、1-丙基(n-丙基,-CH2CH2CH2CH2CH3)、2-丙基(-CH(CH3)CH2CH2CH3)、3-丙基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-丙基(-C(CH3)2CH2CH2CH3)、3-甲基-2-丙基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-丙基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-丙基(-C(CH3)(CH2CH3)2)、2-甲基-3-丙基(-CH(CH2CH3)CH(CH3)2)、2,3-双甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-双甲基-2-丁基(-CH(CH3)C(CH3)3,以及辛基(-(CH2)7CH3)。
“烷氧基”是指含有公式-O-烷基的基团,其中如上所述的烷基基团,通过氧原子与母体分子相连。烷氧基基团的烷基部分可以是含有1-20个碳原子(例如,C1-C20烷氧基),1-12个碳原子(例如,C1-C1 2烷氧基),或1-6个碳原子(例如,C1-C6烷氧基)。合适的烷氧基基团的例子包括,但不仅限于:甲氧基(-O-CH3或-OMe)、乙氧基(-OCH2CH3或-OEt)、t-丁氧基(-O-C(CH3)3或-OtBu)等。
“卤代烷基”是一种烷基基团,如上所定义,烷基基团的一个或多个氢原子被卤素原子所替代。一种卤代烷基基团的烷基部分可以是1-20个碳原子(例如,C1-C20卤代烷基),1-12个碳原子(例如,C1-C12卤代烷基),或1-6个碳原子(例如,C1-C6烷基)。合适的卤代烷基基团的例子包括,但不仅限于:-CF3、-CHF2、-CFH2、-CH2CF3等。
“烯基”是一种含有正常、仲碳、叔碳或环碳原子以及至少一个位点不饱和的烃,例如C-C,sp2双键。例如,一个烯基基团可以含有2-20个碳原子(例如,C2-C20烯基),2-12个碳原子(例如,C2-C12烯基),或2-6个碳原子(例如,C2-C6烯基)。合适的烯基基团的例子包括,但不仅限于:乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、环戊烯基(-C5H7)和5-己烯基(-CH2CH2CH2CH2CH=CH2)。
“炔基”是一种含有正常、仲碳、叔碳或环碳原子以及至少一个位点不饱和的烃,例如C-C,sp三键。例如,一个炔基基团可以含有2-20个碳原子(例如,C2-C20炔基),2-12个碳原子(例如,C2-C12炔基),或2-6个碳原子(例如,C2-C6炔基)。合适的炔基基团的例子包括,但不仅限于:炔基(-C≡CH),炔丙基(-CH2C≡CH),等等。
“亚烷基”是指一种饱和的,支链或直链或环状烃自由基,含有去除主链烷烃上相同或不同两个碳原子上的两个氢原子产生的两个单价的自由基中心。例如,一种烃基基团可以含有1-20个碳原子,1-10个碳原子,或1-6个碳原子。典型的烃基自由基包括,但是不仅限于:亚甲基(-CH2-),1,1-乙基(-CH(CH3)-),1,2-乙基(-CH2CH2-),1,1-丙基(-CH(CH2CH3)-),1,2-丙基(-CH2CH(CH3)-),1,3-丙基(-CH2CH2CH2-),1,4-丁基(-CH2CH2CH2CH2-),等等。
“亚烯基”是指一种非饱和的,支链或直链或环状烃基,含有去除主链烯烃上相同或不同两个碳原子上的两个氢原子产生的两个单价的自由基中心。例如,一种亚烯基基团可以含有1-20个碳原子,1-10个碳原子,或1-6个碳原子。典型的亚烯基自由基包括,但是不仅限于:1,2-乙烯(-CH=CH-)。
“亚炔基”属于一种非饱和的,支链或直链或环状烃基,含有去除主链炔上相同或不同两个碳原子上的两个氢原子产生的两个单价的自由基中心。例如,一种亚炔基基团可以含有1-20个碳原子,1-10个碳原子,或1-6个碳原子。典型的亚炔基自由基包括,但是不仅限于:乙炔基(-C≡C-),丙炔基(-CH2C≡C-),和4-戊炔基(-CH2CH2CH2C≡CH-)。
“氨基”是指-NR2,这里各个“R”独立地选自:H、烷基、取代烷基、芳基、取代芳基、芳基烷、取代芳基烷等等,其中术语烷基、取代烷基、芳基、取代芳基、芳基烷基以及取代芳基烷基如这里所定义和描述。典型的氨基基团包括,但是不仅限于:-NH2、-N(CH3)2、-NH(CH3)、-N(CH2CH3)2、-NH(CH2CH3)、-NH(取代或未取代苄基)、-NH(取代或未取代苯基),等等。
“芳基”是指一种通过去除主干芳香环上单个碳原子的一个氢原子产生的芳烃基团。例如,一种芳基基团可以含有6-20个碳原子,6-14个碳原子,或6-12个碳原子。典型的芳基基团包括,但是不仅限于:来源于苯(例如,苯基)、取代苯、取代或未取代萘、取代或未取代蒽、取代或未取代联苯,等等。
“芳烷基”是指一种无环烷基,其与碳原子(一般地为末端或sp3碳原子)结合的氢原子被芳基基团所替代。典型的芳烷基基团包括,但是不仅限于:苄基、2-苯基乙烷-1-基、萘甲基、2-萘基乙醇-1-基、萘苄基、2-萘苯基乙烷-1-基等(每个都可以是取代或未取代的)。芳烷基基团可以含有7-20个碳原子,例如,烷基团为1-6个碳原子,芳基基团为6-14个碳原子。
“芳烯基”是指一种无环烯基,其与碳原子(一般地为末端或sp3碳原子,也可以是一种sp2碳原子)结合的氢原子被芳基基团所取代。芳烯基的芳基部分可以包括,例如,这里所述的任何一种芳基基团,芳烯基的烯基部分可以包括,例如,这里所述的任何一种烯基基团。芳烯基基团可以由8-20个碳原子组成,例如,烯基基团含有2-6个碳原子,并且芳基基团含有6-14个碳原子。
“环烷基”是指一种环中只含有碳原子的饱和单环或多环。在单环中,环烷基可以含有3-7个碳原子,双环环烷基中则有7-12个碳原子,多环中可以达到大约20个碳原子。单环环烷基具有3-6环的原子,更典型的为5或6环原子。双环环烷基具有7-12个碳原子,例如,排列为[4,5],[5,5],[5,6]或[6,6]双环系统,或9或10环原子排列为[5,6]或[6,6]双环系统,或螺融环。单环环烷基的例子不限于包括环丙基、环丁基、环戊基和环己基(其中各种都可以使取代或未取代的)。
“芳炔基”是指一种无环炔基,其与碳原子(一般地为末端或sp3碳原子,也可以是一种sp碳原子)结合的其中一个氢原子被芳基基团所取代。芳炔基的芳基部分可以包括,例如,这里所述的任何一种芳基基团,芳炔基的炔基部分可以包括,例如,这里所述的任何一种炔基基团。芳炔基基团可以由8-20个碳原子组成,例如,炔基基团含有2-6个碳原子,并且芳基基团含有6-14个碳原子。
关于涉及烷基、亚烷基、芳基、芳烷基、杂环基等的术语“取代”,例如,“取代烷基”、“取代亚烷基”、“取代芳基”、“取代芳烷基”、“取代杂环基”,以及“取代碳环基”(例如,环烷基)意思分别是烷基、亚烷基、芳基、芳烷基、杂环基、碳环基(例如,环烷基)上一个或多个氢原子分别独立被非氢原子所取代。典型的取代基包括,但不仅限于:-X、-R、-O-、=O、-OR、-SR、-S-、-NR2、-N+R3、=NR、-CX3、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、=N2、-N3、-NHC(=O)R、-C(=O)R、-C(=O)NRR、-S(=O)2O-、-S(=O)2OH、-S(=O)2R、-OS(=O)2OR、-S(=O)2NR、-S(=O)R、-OP(=O)(OR)2、-N(=O)(OR)2、-N(=O)(O-)2、-N(=O)(OH)2、-N(O)(OR)(O-)、-C(=O)R、亚烷基-C(=O)R、-C(=O)X、亚烷基-C(=O)X、-C(S)R、-C(O)OR、亚烷基-C(O)OR、-C(O)O-、亚烷基-C(O)O-、-C(S)OR、-C(O)SR、-C(S)SR、-C(O)NRR、亚烷基-C(O)NRR、-C(S)NRR、-C(=NR)NRR,这里X单独地表示卤原子:F、Cl、Br或I;以及每个R单独地表示为H、烷基、芳基、芳烷基、一个杂环基、一个碳环基或一种保护基团或前药基团。亚烷基、亚烯基和亚炔基基团同样可以被类似地取代。
本领域技术人员应当理解,诸如“烷基”、“芳基”、“杂环基”等的基团被一个或多个基团取代时,其或者可被称为“亚烷基”、“亚芳基”、“亚杂环基”等等基团(例如,表明主链“烷基”、“芳基”、“杂环基”基团至少一个氢原子被表明的取代基团所替换)。当诸如此处所述的“烷基”、“芳基”、“杂环基”等基团涉及取代或概略地显示为将被取代(或选择性取代,例如,取代基团的数目范围从0到一个正整数),此时术语“烷基”、“芳基”、“杂环基”等理解为可与“亚烷基”、“亚芳基”、“亚杂环基”等互换。
这里所用的术语“前药”是指任何一种化合物,其具有当给药给一个生物系统可以产生药物底物,例如,活性成分,作为一种自发的化学反应、酶催化化学反应、光解反应和/或代谢化学反应的结果。因此,前药是一种治疗活性化合物的共价修饰类似物或潜在形式。
本领域技术人员应当理解,式(I)化合物的取代基团以及其他基团应当经筛选以提供一种有效稳定的化合物,提供一种治疗有效的化合物,其可以制成一种可接受的稳定的药物组合物。具有如此的稳定性的式(I)化合物,按照本发明的范围进行设想。
“异烷基”是指在烷基基团中,一个或多个碳原子被异原子(诸如O、N、S)所取代。例如,如果烷基基团上与主链分子相连的的碳原子被一种异原子取代(例如,O、N或S),产生的异烷基基团分别是,一种烷氧基基团(例如,-OCH3等),一种胺(例如,-NHCH3、-N(CH3)2,等),或硫基基团(例如,-SCH3)。如果烷基基团的非末端且不与主链分子相连的碳原子被异原子(例如,O、N或S)所取代,产生的异烷基基团分别是,一种烷基醚(例如,-CH2CH2-O-CH3,等等),一种烷基胺(例如,-CH2NHCH3、-CH2N(CH3)2,等等)或硫基醚(例如,-CH2-S-CH3)。如果烷基的末端碳原子被异原子(例如,O、N或S)取代,产生的异烷基基团分别是,一种羟烷基基团(例如,-CH2CH2-OH),一种氨烷基基团(例如,-CH2NH2),或一种烷基硫醇基团(例如,-CH2CH2-SH)。一种异烷基基团可以含有,例如,1-20个碳原子,1-10个碳原子,或1-6个碳原子。一种C1-C6异烷基基团是指含有1-6个碳原子的异烷基基团。
这里所述的“杂环”或“杂环基”的例子包括但不仅限于:Paquette,Leo A Principles of Modern Heterocyclic Chemistry(W.A.Benjamin,New York,1968),尤其是第1、3、4、6、7和9章;The Chemistry of Heterocyclic Compounds,A Series of Monographs”(John Wiley&Sons,New York,1950to present),尤其是第13、14、16、19和28卷:以及J.Am.Chem.Soc.(1960)82:5566。本发明“杂环”一个具体实施方式包括一个此处所定义的“碳环”,也就是一个或多个(例如,1、2、3或4)碳原子被异原子(例如,O、N或S)所取代。“杂环”或“杂环基”术语包括饱和环,部分非饱和环,以及芳香环(例如,芳香杂环)。取代杂环包括,例如,这里所述的包括羰基的任何取代基所取代的杂环。
杂环的例子包括但是不仅限于:吡啶基、二氢吡啶基、四氢吡啶基(哌啶)、噻唑基、四氢苯硫基、硫氧化四氢苯硫基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、四唑基、苯并呋喃基、硫杂萘基、吲哚基、吲哚烯基、喹啉基、异喹啉基、咪唑基、哌啶基、4哌啶基、吡咯烷基、2-吡咯烷酮基、吡咯啉基、四氢呋喃基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、八氢异喹啉基、吖辛基、三嗪基、6H-1、2、5-噻二嗪、2H、6H-1、5、2-二噻嗪、噻吩基、噻嗯基、吡喃基、异苯并呋喃基、苯并呋喃基、夹氧(杂)蒽基、吩恶噻基、2H-吡咯基、异噻唑基、异恶唑基、吡嗪基、哒嗪基、氮茚基、异吲哚基、3H-吲哚基、1H-吲唑基、嘌呤基、4-H喹基、酞嗪基、萘啶基、喹噁啉基、喹唑啉基、噌嗪基、喋啶基、4aH-咔唑基、咔唑基、β-咔啉基、菲啶基、吖啶基、嘧啶基、啡啉基、吩嗪基、吩噻嗪基、呋吖基、啡基(phenoxazinyl)、异苯并二氢哌喃基、苯并二氢哌喃基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉基、哌嗪基、吲哚啉基、异吲哚啉基、奎宁环基、吗啉基、唑烷基、苯并三唑基、苯并异唑基、氧化吲哚基、苯并恶唑基、isatinoyl以及2-四氢呋喃基,等等(各种都可以为取代或未取代的)。
碳结合杂环结合位点的例子包括但不仅限于:吡啶基的2、3、4、5或6位,哒嗪基的3、4、5或6位,嘧啶基的2、4、5或6位,吡嗪基的2、3、5或6位,呋喃、四氢呋喃、硫代呋喃、噻吩、吡咯或四氢吡咯的2、3、4或5位,恶唑、咪唑或噻唑的2、4或5位,异恶唑、吡唑或异噻唑的3、4或5位,氮丙啶的2或3位,吖丁啶的2、3或4位,喹啉的2、3、4、5、6、7或8或异喹啉的1、3、4、5、6、7或8。更典型地,碳结合杂环包括:2-吡喹、3-吡啶、4-吡啶、5-吡啶、6-吡啶、3-哒嗪、4-哒嗪、5-哒嗪、6-哒嗪、2-嘧啶、4-嘧啶、5-嘧啶、6-嘧啶、2-吡嗪基、3-吡嗪基、5-吡嗪基、6-吡嗪基、2-噻唑基、4-噻唑基或5-噻唑基(各种基团都可以为取代或未取代的)。
氮结合杂环的结合位点的例子但不仅限于:氮丙啶、吖丁啶、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑烷、3-咪唑烷、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑的第1位,异吲哚或异吲哚啉的第2位,吗啉的第4位,以及咔唑或β-咔啉的第9位(各种基团都可以为取代或未取代的)。更典型地,氮结合的杂环包括1-aziridyl、1-azetedyl、1-吡咯、1-咪唑、1-吡唑,以及1-哌啶(各种基团都可以为取代或未取代的)。
“杂环烷基”是指无环烷基,其中一个与碳原子(典型地末端或sp3碳原子)结合的氢原子被杂环基取代(例如,杂环-亚烷基-基团)。典型的杂环烷基基团包括,但是不仅限于:杂环-CH2-、2-(杂环)乙酮-1-基,等等,这里“杂环”部分包括上述任何一种杂环基团,包括那些在Principles of Modern Heterocyclic Chemistry中所述的杂环基团。本领域技术人员同样理解杂环基团可以与杂环烷基的烷基部分通过C-C结合或C-异原子结合,附带条件是产生的基团化学性质稳定。杂环烷基基团由2-20个碳原子组成,例如,芳烷基基团的烷基部分是1-6个碳原子以及杂环基团是1-14个碳原子。杂环烷基的例子包括但不仅限于:含5-元硫、氧和/或氮杂环诸如噻唑基甲基、2-羟乙基噻唑-1-yl、咪唑甲基、甲基恶唑、噻唑基甲基,等等。含6-元硫、氧和/或氮杂环诸如哌啶甲基、哌嗪甲基、吗啉甲基、吡啶甲基、pyridizylmethyl、嘧啶甲基、吡嗪甲基等等(各种基团都可以为取代或未取代的)。
“杂环烯基”是指无环烯基,其中一个与碳原子(典型地为末端或sp3碳原子,也可以是sp2碳原子)结合的氢原子被杂环基取代(例如,杂环-亚烯基-基团)。杂环烯基基团的杂环部分包括这里所述的任何一个杂环基团,包括Principles of Modern Heterocyclic Chemistry所述,杂环烯基基团的烯基部分包括这里所述的任何一个烯基基团。本领域技术人员同样理解杂环基团可以与杂环烯基的烯基部分通过C-C结合或C-异原子结合,附带条件是产生的基团化学性质稳定。杂环烯基基团由3-20个碳原子组成,例如,杂环烯基基团的烯基部分是2-6个碳原子以及杂环基团是1-14个碳原子。
“杂环炔基”是指无环炔基,其中一个与碳原子(典型地为末端或sp3碳原子,也可以是sp碳原子)结合的氢原子被杂环基取代(例如,杂环-亚炔基-基团)。杂环炔基基团的杂环部分包括这里所述的任何一个杂环基团,包括Principles of Modern Heterocyclic Chemistry所述,杂环炔基基团的炔基部分包括这里所述的任何一个炔基基团。本领域技术人员同样理解杂环基团可以与杂环炔基的炔基部分通过C-C结合或C-异原子结合,附带条件是产生的基团化学性质稳定。杂环炔基基团由3-20个碳原子组成,例如,杂环炔基基团的炔基部分是2-6个碳原子以及杂环基团是1-14个碳原子。
“杂环芳基”是环上至少含有1各异原子的芳香杂环。芳香环的合适的异原子的非限制的例子可以包括硫、氧和氮。杂环芳基环的非限制例子包括那些列表中定义为“杂环”,包括吡啶基、吡咯基、恶唑基、吲哚基、异吲哚基、嘌呤基、呋喃基、噻吩基、苯并呋喃基、苯并噻吩基、咔唑基、咪唑基、噻唑基、异恶唑基、吡唑基、异噻唑基、喹啉基、异喹啉基、哒嗪基、嘧啶基、pyrazyl等等(各种基团都可以为取代或未取代的)。
“碳环”或“碳环基”是指一种饱和的、部分饱和或芳香环,单环具有3-7个碳原子,双环具有7-12个碳原子,多环时可以达到20个碳原子。单环碳环有3-6圈的原子,甚至多达典型的5或6圈原子。双环碳环含有7-12圈原子,例如,排列为双环[4,5],[5,5],[5,6]或[6,6]系统,或9或10圈原子排列为双环[5,6]或[6,6]系统。单环和双环碳环的例子包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、苯基和萘基(各种基团都可以为取代或未取代的)。
“酰基”是指一种-C(O)-烷、-C(O)-碳环(取代或未取代的)、-C(O)-杂环(取代或未取代的),其烷基、碳环或杂环部分定义在此文。“酰基”的不限例子包括:-C(O)CH3、-C(O)CH2CH3、-C(O)CH(CH3)2、-C(O)C(CH3)3、-C(O)-苯基(取代或未取代的)、-C(O)-环丙基(取代或未取代的)、-C(O)-环丁基(取代或未取代的)、-C(O)-环戊基(取代或未取代的)、-C(O)-环己基(取代或未取代的)、-C(O)-吡啶(取代或未取代的),等等。
这里所述的“芳基杂烷基”涉及一种这里所定义的杂烷基基团,其中一个氢原子(可以与任何一个碳原子或一个异原子相连)被这里所定义的芳基基团所取代。芳基基团可以与杂烷基基团的一个碳原子,或杂烷基基团的一个异原子结合,结果这样产生的芳基杂烷基基团化学性质稳定。例如,一个芳基杂烷基基团具有一般公式:-亚烷基-O-芳基、-亚烷基-O-亚烷基-芳基、-亚烷基-NH-芳基、-亚烷基-NH-亚烷基-芳基、-亚烷基-S-芳基、-亚烷基-S-亚烷基-芳基,等等。另外,上面一般公式中的亚烷基基团中任何一种可以被所定义或这里所列举的任何一种取代基团取代。
“杂芳基烷基”涉及一种这里所定义的烷基基团,其中一个氢原子被这里所定义的杂芳基基团所取代。杂芳基烷基的非限制例子包括:-CH2-吡啶基、-CH2-吡咯基、-CH2-恶唑基、-CH2-吲哚基、-CH2-异吲哚基、-CH2-嘌呤基、-CH2-呋喃基、-CH2-噻吩基、-CH2-苯并呋喃基、-CH2-苯并噻吩基、-CH2-咔唑基、-CH2-咪唑基、-CH2-噻唑基、-CH2-异恶唑基、-CH2-吡唑基、-CH2-异噻唑基、-CH2-喹啉基、-CH2-异喹啉基、-CH2-哒嗪基、-CH2-嘧啶基、-CH2-吡唑基(-CH2-pyrazyl)、-CH(CH3)-吡啶基、-CH(CH3)-吡咯基、-CH(CH3)-恶唑基、-CH(CH3)-吲哚基、-CH(CH3)-异吲哚基、-CH(CH3)-嘌呤基、-CH(CH3)-呋喃基、-CH(CH3)-噻吩基、-CH(CH3)-苯并呋喃基、-CH(CH3)-苯并噻吩基、-CH(CH3)-咔唑基、-CH(CH3)-咪唑基、-CH(CH3)-噻唑基、-CH(CH3)-异恶唑基、-CH(CH3)-吡唑基、-CH(CH3)-异噻唑基、-CH(CH3)-喹啉基、-CH(CH3)-异喹啉基、-CH(CH3)-哒嗪基、-CH(CH3)-嘧啶基、-CH(CH3)-吡唑基(-CH(CH3)-pyrazyl),等等。
“硅氧基”是指一种-O-SiR3基团,这里R包括烷基、芳基(取代的或未取代的),以及杂芳基(取代的或未取代的),或其组合物。硅氧基基团的非限制例子包括:-O-Si(CH3)3、-O-Si(CH3)2tBu、-O-Si(tBu)2CH3、-O-Si(tBu)3、-O-Si(CH3)2苯基、-O-Si(苯基)2CH3,-O-Si(苯基)3。
术语“膦酸”和“膦酸基团”是指一种分子内的一种功能性的基团,其至少由一个P-C健,以及至少一个P-O双键组成。磷原子可以进一步由氧、硫以及氮原子取代。如这里所定义,“膦”和“膦酸基团”包括膦酸、膦酯、磷酸二酯、氨基磷酸酯、磷酸二酰胺和磷脂酸化物功能基团组成的分子。
“接头”或“连接”是指一种化学基团,其由共价键或一条链或原子基团共价地将一个膦酸或膦酸基团连接到药上。接头包含的基团诸如:烷氧基的重复单元(例如,聚乙氧烯、PEG、聚甲氧烯)以及氨烷基(例如,聚乙烯亚胺,JeffamineTM);以及包括丁二酸、丁二酰亚胺、二乙醇酸、丙二酸和己酰胺的二酸酯类和酰胺。
“可选取代”是指结构式(I)的化合物(的一种特殊基团例如,一种可选的取代芳基基团),指一个基团具有0,1,2,或更多的取代基团。
“其酯”是指化合物的任何酯类,其中分子的任一-COOH功能被-C(O)OR功能取代,或分子的-OH功能被OC(O)R功能取代,这里酯的R基团可以是形成一种稳定的酯基团的任何一种含碳基团,包含但不仅限于:烷基、烯基、炔基、环烷基、环烷基烷基、芳基、芳基烷基、杂环基、杂环烷基和它们的取代衍生物。酯类同样可以包括上面所述的酯“tautomeric enols”,例如,如下所示:
术语“其酯”包括但不仅限于其药学上可接受的酯类。
“其盐”意思是依据本发明的化合物的任何酸和/或碱添加盐;最好是一种其药学上可接受的盐。
“药学上可接受的盐”是指化合物的盐,其在合理的医疗判断范围之内适用于人类和低等动物接触的组织,无不当毒性、刺激性、过敏性反应等等,具有相称的合理利益/风险比,其通常是水或油可溶的或可分散的,并且使用有效。当结构式(I)或(II)的化合物的化学特性可适用和兼容时,该术语包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。合适的盐的列表参见于,例如,S.M.Birge等,J.Pharm.Sci.,1977,66,pp.1-19。
“疗法”或“治疗”意思是给药依据本发明的一种化合物或组合物药物以缓解或消除病人HIV疾病的症状和/或减少病毒量。术语“疗法”或“治疗”还包括在接触病毒后出现疾病症状前和/或检测血液中病毒之前给药依据本发明的一种化合物或组合物药物,目的是抑制疾病症状的出现和/或防止血液中病毒达到可探测的水平,通过在生产前给药母亲和出生前几天给药给婴儿给药依据本发明的一种化合物或组合物药物防止HIV通过母婴传播从母亲传给婴儿。
“手性”是指具有与镜像非重叠的特性的分子,术语“非手性”是指与镜像相重叠的分子。
“立体异构体”是指具有相同的化学组成,但是原子或基团在空间上的排列不同的化合物。
“非对映异构体”是指一类具有2个或多个手性中心的异构体,其分子彼此不成镜像。非对映异构体具有不同的物理特性,例如,熔点、沸点、光谱特性和反应性。非对映异构体的混合物在高分辨率分析程序下可能分离,诸如电泳和层析。
“对映体”是指一种化合物的两种异构体,一个与另一个是非重叠镜像。
这里所用的立体化学定义和公约遵循S.N.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York;and Eliel,E.and Wilen,S.,Stereochemistry of Organic Compounds(1994)John Wiley&Sons,Inc.,New York。许多有机化合物以光学活性形式存在,例如,它们具有在平面偏振光下平面旋转的能力。一种光学活性化合物的描述,前缀D和L或R和S用于说明分子其手性中心的绝对构型。前缀d和l或(+)和(-)用于指定化合物平面偏振光的旋转标志,添加(-)或1表示化合物是左旋的。考虑到化学结构,除那些镜像之外,这些异构体都是相同的。一个具体的异构体也可以是一种对映体,此类异构体的混合物常常被称为对映体混合物。对映体按照50∶50的混合物可以认为是消旋混合物或消旋体,其可能在一个化学反应或过程中,没有立体选择性或立体特异性时发生。术语“外消旋混合物”和“外消旋体”是指两种对映体的等摩尔混合物,缺乏光学活性。
保护基团
在本发明的上下文中,保护基团包括前体药物基团和化学保护基团。
保护基团是可用的,大家熟知的和惯用的,并且可选用于防止被保护的基团在合成过程中产生副反应,例如制备本发明所述化合物的途径或方法。决定的大部分是关于保护何种基团,什么时候保护,以及化学保护基团“PG”的性质主要取决于保护针对的化学反应(例如,酸性、碱性、氧化、还原或其他条件)以及合成的目的指向。如果化合物被多种PG取代,PG基团不需要,也通常不是相同的。一般地,PG将用于保护功能基团诸如羧基、羟基、硫基或氨基基团,因此防止副反应或否则有利于合成效率。基团的脱保护,脱保护基团取决于将面临的合成和反应条件的目标方向,并且可发生在本领域技术人员确定的任何条件中。
本发明化合物的多种功能基团都可以被保护。例如,-OH基团(是否羟基、羧酸、膦酸或其他功能)的保护基团包括“醚-或酯-形成基团”。醚-或酯-形成基团在这里所述的合成计划中具有能够作为化学保护基团的功能。然而,一些羟基和硫基保护基团既不是醚-也不是酯-形成基团,其包含在酰胺内,通过下面讨论将会被本领域技术人员所理解。
数量众多的羟基保护基团和氨基-形成基团以及相对应的化学裂解反应请参见Protective Groups in Organic Synthesis,Theodora W.Greene and Peter G.M.Wuts(John Wiley&Sons,Inc.,New York,1999,ISBN 0-471-16019-9)(“Greene”)所描述。同样参见Kocienski,Philip J.;Protecting Groups(Georg Thieme Verlag Stuttgart,New York,1994),其通过完整参考并入本申请。特别是第一章,保护基团:综述,1-20页,第二章,羟基保护基团,21-94页,第三章,二醇保护基团,95-117页,第四章,羧基保护基团,118-154页,第五章,羰基保护基团,155-184页。羧酸、磷酸、膦、磺酸以及其他酸保护基团参见Greene,如下文所述。此类基团包括通过举例的方式,而不是限制于酯类、酰胺、肼,等等。
醚-和酯-形成保护基团
酯形成保护基团包括:(1)磷酸酯形成基团、诸如磷酸酰胺酯、硫代磷酸酯、磷酸酯和磷酸二酰胺酯;(2)羧基酯形成基团;以及(3)硫酯-形成保护基团,诸如磺酸、硫酸和亚磺酸钠。
本发明化合物的代谢产物
同样这里所述化合物在体内的代谢产物也属于本发明的范围。此类产物可以是通过例如给药化合物的氧化、还原、水解、酰胺化、酯化等产生,其主要是由于酶作用过程。因此,本发明包括包含哺乳动物接触本发明化合物一段时间后足以产生的其代谢产物的化合物。此类产物通常通过制备一种本发明的放射标记(例如,C14或H3)化合物,经肠道外给药可检测剂量(例如,大于0.5mg/kg)给一种动物诸如大鼠、小鼠、豚鼠、猴或人,给其足够时间以便代谢产生(一般大约30秒至30小时)并从尿、血液或其他生物样品中分离转化产物进行鉴定。由于这些产物有标记(其他则通过利用抗体同代谢物上存在的表面抗原结合而分离),因此易于分离。代谢物的结构通过传统方式,例如MS或NMR分析确定。一般地,代谢物的分析与传统药物代谢研究方法相同为,已为本领域技术人员所熟知。转化产物,只要它们在体内不已其他方式发现,即使它们具有不抗感染活性,其对本发明的化合物的治疗剂量的诊断分析有用的。
式(I)化合物
在一个实施方案中,本申请提供式(I)的化合物,描述如下:
式(I)的化合物的每一个实施方案,除非另有说明或除非明显不适用(例如,实施例中一个或多个X和Y不是O),按以下有条件地应用:
(a)当X和Y同时为O,R4是H,A是-O-、-S-、-C(O)-、-CH(OH)-或-CH2-,R3是苯基,并且D是-CH2-时,
那么R1是烷氧基;
(b)当X和Y同时为O,A是-S-、-O-或-C(O)-,R3是苯基,n是2,每种Z是烷基,D是-CH2-,R2是烷基,并且R4是H时,
那么R1不是未取代环烷基、未取代杂环烷基或未取代杂芳基;
(c)当X和Y同时为O,A是-C(O)-、-O-或-NH-,D是-CH2-,R2是烷基,R3是苯基,n是2,R4是H时,
那么R1不是选自吡啶基、嘧啶基、哒嗪基基团的取代或未取代杂芳基;
(d)当X和Y同时为O,n是0或2,每种Z是烷基,A-R3是苄基、苯甲酰基、噻吩基或苯氧基,R4是H,并且R2是乙基或异丙基时,
那么D不是亚烯基或亚炔基,并且-D-R1不是烷基、羟烷基或亚烷基-C(O)-O烷基;
(e)R4和-D-R1只有一个为H。
例如,附带条件(a)不包括下述结构的化合物:
其中A’是这里所定义的-O-、-S-、-C(O)-、-CH(OH)-或-CH2-和烷基,并且Z和n如这里所定义。不包含的化合物包括那些文献介绍的特殊化合物,例如U.S.6911450,U.S.5112835,U.S.5461060,U.S.5318972,U.S.5604209,U.S.6136815,CN 101016265,WO03/057677,JP 2001-114767,JP 8-3143,FR 2779721,等等(均作为参考文献完整引述)。
例如,附带条件(b)不包含下述结构的化合物:
其中A’是-S-、-O-或-C(O)-,“环”是未取代环烷基、未取代杂环烷基或未取代杂芳基,并且烷基如这里所定义。在一些实施方案中,“环”可以包括取代环烷基、杂环烷基或杂芳基。不包含的化合物包括,例如WO 00/61563,WO 00/61564,WO 2007/091857,U.S.5922727,等等所描述的特殊化合物(均作为参考文献完整引述)。
例如,附带条件(c)不包含下述结构的化合物:
其中A’是-C(O)-、-O-或-NH-,Z和烷基如这里所定义,“pyr”是取代或未取代的吡啶基、嘧啶基、哒嗪基。不包含的化合物包括,例如WO 2008/016522所述的特殊化合物(均作为参考文献完整引述)。
例如,附带条件(d)不包含下述结构的化合物:
其中A’是-CH2-、-O-、-S-或-C(O)-,D是亚烯基或亚炔基;或其中A’是-CH2-、-O-、-S-或-C(O)-,D’-R’是烷基、羟烷基或-亚烷基-C(O)-O烷基;并且烷基、亚烷基、亚烯基和亚炔基如这里所定义。不包含的化合物包括,例如U.S.5747500和KR 1996-014106所述的特殊化合物(均作为参考文献完整引述)。
例如,附带条件(e)需要R4或D-R1只能有1个是H。换句话说,式(I)的化合物具有下面的结构式的一种:
其中,R1、R2、R3、R4、A、X、Y、Z和n如这里所定义或描述。
式(I)化合物的另一实施方案中方案中,A是-C(R6)2-。
式(I)化合物的另一实施方案中,A是-CH2-。
式(I)化合物的另一实施方案中,A是-C(卤素)2-。
式(I)化合物的另一实施方案中,A是-CF2-。
式(I)化合物的另一实施方案中,A是-CCl2-。
式(I)化合物的另一实施方案中,A是-CHF-。
式(I)化合物的另一实施方案中,A是-CHCl-。
式(I)化合物的另一实施方案中,A是-CHOH-。
式(I)化合物的另一实施方案中,A是-CH(O-烷基)-,其中烷基包括这里所描述和定义的任何一种烷基基团。
式(I)化合物的另一实施方案中,A是-C(O)-。
式(I)化合物的另一实施方案中,A是-O-。
式(I)化合物的另一实施方案中,A是-S-。
式(I)化合物的另一实施方案中,A是-NR5-。
式(I)化合物的另一实施方案中,A是-NH-。
式(I)化合物的另一实施方案中,A是-N(烷基)-,其中烷基包括这里所描述和定义的任何一种烷基基团。
式(I)化合物的另一实施方案中,A是-N(芳基烷基)-,其中芳基烷基包括这里所描述和定义的任何一种芳基烷基基团,其可以是取代或未取代的。
式(I)化合物的另一实施方案中,A是-N(苄基)-,其中苄基基团可以是取代或未取代的。
式(I)化合物的另一实施方案中,A是-N(苯烷基)-,其中苯烷基基团可以是取代或未取代的。
式(I)化合物的另一实施方案中,A是-N(苯基)-,其中苯基基团可以是取代或未取代的。
式(I)化合物的另一实施方案中,A是-N(苯丙基)-,其中苯丙基基团可以是取代或未取代的。
式(I)化合物的另一实施方案中,A是C(NR8)-,其中R8是这里所定义的。
式(I)化合物的另一实施方案中,A是-C(NH)-。
式(I)化合物的另一实施方案中,A是-C(N烷基)-。
式(I)化合物的另一实施方案中,A是-C(NCH3)-。
式(I)化合物的另一实施方案中,A是-C(NCH2CH3)-。
式(I)化合物的另一实施方案中,A是-C(NC(CH3)3)-。
式(I)化合物的另一实施方案中,A是C(N苯基)-。
式(I)化合物的另一实施方案中,A是-C(N苯基)-,其中苯基基团是取代的。
式(I)化合物的另一实施方案中,A是-C(NOH)-。
式(I)化合物的另一实施方案中,A是-C(N-O烷基)-。
式(I)化合物的另一实施方案中,A是-C(N-O烷基)-,其中所述烷基基团包括这里所描述的任何一种烷基。
式(I)化合物的另一实施方案中,A是一种共价键。
式(I)化合物的另一实施方案中,A是-CH(CN)-。
式(I)化合物的另一实施方案中,R3是芳基,其中所述芳基基团包括这里所描述或定义的任何一种芳基。
式(I)化合物的另一实施方案中,R3是苯基。
式(I)化合物的另一实施方案中,R3是萘基。
式(I)化合物的另一实施方案中,R3是杂芳基,这里所述杂芳基包括这里所描述或定义的任何一种芳基。
式(I)化合物的另一实施方案中,R3是吡啶基。
式(I)化合物的另一实施方案中,R3是2-吡啶基。
式(I)化合物的另一实施方案中,R3是3-吡啶基。
式(I)化合物的另一实施方案中,R3是4-吡啶基。
式(I)化合物的另一实施方案中,R3是吡咯基。
式(I)化合物的另一实施方案中,R3是1-吡咯基。
式(I)化合物的另一实施方案中,R3是2-吡咯基。
式(I)化合物的另一实施方案中,R3是3-吡咯基。
式(I)化合物的另一实施方案中,R3是呋喃基。
式(I)化合物的另一实施方案中,R3是2-呋喃基。
式(I)化合物的另一实施方案中,R3是3-呋喃基。
式(I)化合物的另一实施方案中,R3是噻吩基。
式(I)化合物的另一实施方案中,R3是2-噻吩基。
式(I)化合物的另一实施方案中,R3是3-噻吩基。
式(I)化合物的另一实施方案中,R3是吡唑基。
式(I)化合物的另一实施方案中,R3是咪唑基。
式(I)化合物的另一实施方案中,R3是恶唑基。
式(I)化合物的另一实施方案中,R3是异恶唑基。
式(I)化合物的另一实施方案中,R3是噻唑基。
式(I)化合物的另一实施方案中,R3是哒嗪基。
式(I)化合物的另一实施方案中,R3是嘧啶基。
式(I)化合物的另一实施方案中,R3是吡嗪基。
式(I)化合物的另一实施方案中,R3是喹啉基。
式(I)化合物的另一实施方案中,R3是苯并咪唑基。
式(I)化合物的另一实施方案中,R3是吲唑基。
式(I)化合物的另一实施方案中,R3是吲哚基。
式(I)化合物的另一实施方案中,R3是卤素。
式(I)化合物的另一实施方案中,R3是Cl。
式(I)化合物的另一实施方案中,Z是F。
中式(I)化合物的另一实施方案中,Z是独立的F或Cl。
式(I)化合物的另一实施方案中,Z是硝基。
式(I)化合物的另一实施方案中,Z是羟基。
式(I)化合物的另一实施方案中,Z是氨基。
式(I)化合物的另一实施方案中,Z是乙酰氨基。
式(I)化合物的另一实施方案中,Z是三氟乙酰胺。
式(I)化合物的另一实施方案中,Z是叠氮基。
式(I)化合物的另一实施方案中,Z是氰基。
式(I)化合物的另一实施方案中,Z是甲酰基。
式(I)化合物的另一实施方案中,Z是烷基甲酰。
式(I)化合物的另一实施方案中,Z是二烷基甲酰。
式(I)化合物的另一实施方案中,Z是烷基。
式(I)化合物的另一实施方案中,Z是-CH3。
式(I)化合物的另一实施方案中,Z是-CH2CH3。
式(I)化合物的另一实施方案中,Z是i-丙基。
式(I)化合物的另一实施方案中,Z是t-丁基。
式(I)化合物的另一实施方案中,Z是烯基。
式(I)化合物的另一实施方案中,Z是烯丙基。
式(I)化合物的另一实施方案中,Z是取代烯基。
式(I)化合物的另一实施方案中,Z是-CH=CH-CN。
式(I)化合物的另一实施方案中,Z是炔基。
式(I)化合物的另一实施方案中,Z是烷氧基。
式(I)化合物的另一实施方案中,Z是甲氧基。
式(I)化合物的另一实施方案中,Z是乙氧基。
式(I)化合物的另一实施方案中,Z是取代烷氧基。
式(I)化合物的另一实施方案中,Z是三氟甲氧基。
式(I)化合物的另一实施方案中,Z是甲氧基乙氧基。
式(I)化合物的另一实施方案中,Z是乙氧基甲氧基。
式(I)化合物的另一实施方案中,Z是烷氧羰基。
式(I)化合物的另一实施方案中,Z是-C(O)-OCH3。
式(I)化合物的另一实施方案中,Z是-C(O)-OC(CH3)3。
式(I)化合物的另一实施方案中,Z是-C(O)-OCH2CH3。
式(I)化合物的另一实施方案中,Z是取代或未取代环烷基。
式(I)化合物的另一实施方案中,Z是取代或未取代环丙基。
式(I)化合物的另一实施方案中,Z是取代或未取代丁基。
式(I)化合物的另一实施方案中,Z是取代或未取代环戊基。
式(I)化合物的另一实施方案中,Z是取代或未取代环己基。
式(I)化合物的另一实施方案中,Z是取代或未取代环烯烃基。
式(I)化合物的另一实施方案中,Z是取代或未取代环丙稀基。
式(I)化合物的另一实施方案中,Z是取代或未取代环丁烯基。
式(I)化合物的另一实施方案中,Z是取代或未取代环戊烯基。
式(I)化合物的另一实施方案中,Z是取代或未取代环己烯基。
式(I)化合物的另一实施方案中,Z是取代或未取代杂环基。
式(I)化合物的另一实施方案中,Z是取代或未取代杂芳基。
式(I)化合物的另一实施方案中,Z是取代或未取代芳基。
式(I)化合物的另一实施方案中,当R3是一种取代或未取代含N杂芳基,Z是氧化物,据此,R3-Z是一种含N取代或未取代杂芳基的N-氧化物。
式(I)化合物的上述任一实施方式中,Z是特别或一般定义,n至少是1,并且R3可以选择性地被其它未特别定义的Z基团取代。例如,在一个实施方案中,Z是卤素,R3可选地包括至少一种不是卤素的其他Z基团。或者,R3可以包括不少于一种的实施方案中定义的特别或一般的Z基团。因此,如果Z是卤素,该实施方案包括R3的单-、双-、三-等等卤素取代。
式(I)化合物的另一实施方案中方案中,n是2。
式(I)化合物的另一实施方案中,n是2,并且Z选自卤素、烷基、氰基、-CH2-CH2-CN和-CH=CH-CN。
式(I)化合物的另一实施方案中,n是2,并且Z是烷基和/或氰基。
式(I)化合物的另一实施方案中,n是2,并且Z是烷基和/或卤素。
式(I)化合物的另一实施方案中,n是2,并且Z是烷基和/或Cl。
式(I)化合物的另一实施方案中,n是2,并且Z是烷基和/或F。
式(I)化合物的另一实施方案中,n是2,并且Z是卤素和/或氰基。
式(I)化合物的另一实施方案中,n是2,并且Z是Cl和/或氰基。
式(I)化合物的另一实施方案中,n是2,并且Z是F和/或氰基。
式(I)化合物的另一实施方案中,n是2,并且式(I)化合物的另一实施方案中Z是烷基。
式(I)化合物的另一实施方案中,n是2,并且Z是卤素。
式(I)化合物的另一实施方案中,n是2,并且Z是Cl。
式(I)化合物的另一实施方案中,n是2,并且Z是F。
式(I)化合物的另一实施方案中,n是2,并且Z是Cl和F。
式(I)化合物的另一实施方案中,D是一个共价键。
式(I)化合物的另一实施方案中,D是亚烷基。
式(I)化合物的另一实施方案中,D是-CH2-。
式(I)化合物的另一实施方案中,D是-CH2CH2-。
式(I)化合物的另一实施方案中,D是-CH2CH2CH2-。
式(I)化合物的另一实施方案中,D是-CH(CH3)-。
式(I)化合物的另一实施方案中,D是-C(CH3)2-。
式(I)化合物的另一实施方案中,D是-CH2-环丙稀-CH2-。
式(I)化合物的另一实施方案中,D是亚烯基。
式(I)化合物的另一实施方案中,D是-CH=CH-。
式(I)化合物的另一实施方案中,D是-CH2CH=CH-。
式(I)化合物的另一实施方案中,D是-CH=CHCH2-。
式(I)化合物的另一实施方案中,D是-CH2CH=CHCH2-。
式(I)化合物的另一实施方案中,D是-CH=CHCH2CH2-。
式(I)化合物的另一实施方案中,D是-CH2CH2CH=CH-。
式(I)化合物的另一实施方案中,D是-CH2CH=CHCH2-。
式(I)化合物的另一实施方案中,D是-(CH3)C=CH-。
式(I)化合物的另一实施方案中,D是-CH2CH=C(CH3)-。
式(I)化合物的另一实施方案中,D是-(CH3)C=CHCH2-。
式(I)化合物的另一实施方案中,D是-CH2C(CH3)=CHCH2-。
式(I)化合物的另一实施方案中,D是-C(CH3)=CHCH2CH2-。
式(I)化合物的另一实施方案中,D是-CH2CH2C(CH3)=CH-。
式(I)化合物的另一实施方案中,D是-CH2C(CH3)=CHCH2-。
式(I)化合物的另一实施方案中,D是-CH=C(CH3)-。
式(I)化合物的另一实施方案中,D是-CH2CH=C(CH3)-。
式(I)化合物的另一实施方案中,D是-CH=C(CH3)CH2-。
式(I)化合物的另一实施方案中,D是-CH2CH=C(CH3)CH2-。
式(I)化合物的另一实施方案中,D是-CH=C(CH3)CH2CH2-。
式(I)化合物的另一实施方案中,D是-CH2C2CH=C(CH3)-。
式(I)化合物的另一实施方案中,D是-CH2CH=C(CH3)CH2-。
式(I)化合物的另一实施方案中,D是亚炔基。
式(I)化合物的另一实施方案中,D是-C≡C-。
式(I)化合物的另一实施方案中,D是-CH2C≡C-。
式(I)化合物的另一实施方案中,D是-CH2CH2C≡C-。
式(I)化合物的另一实施方案中,D是-C≡CCH2-。
式(I)化合物的另一实施方案中,D是-C≡CCH2CH2-。
式(I)化合物的另一实施方案中,D是-CH2C≡CCH2-。
式(I)化合物的另一实施方案中,D是-CH2CH2C≡CCH2-。
式(I)化合物的另一实施方案中,D是-CH2C≡CCH2CH2-。
式(I)化合物的另一实施方案中,只要D不是共价键,R1是H。
式(I)化合物的另一实施方案中,R1是烷基,其中所述烷基包括这里所定义和描述的任何一种烷基。
式(I)化合物的另一实施方案中,R1是-CH3。
式(I)化合物的另一实施方案中,R1是-CH2CH3。
式(I)化合物的另一实施方案中,R1是i-丙基。
式(I)化合物的另一实施方案中,R1是t-丁基。
式(I)化合物的另一实施方案中,R1是卤素。
式(I)化合物的另一实施方案中,R1是Cl。
式(I)化合物的另一实施方案中,R1是F。
式(I)化合物的另一实施方案中,R1是取代或未取代环烷基。
式(I)化合物的另一实施方案中,R1是取代或未取代环丙基。
式(I)化合物的另一实施方案中,R1是取代或未取代环丁基。
式(I)化合物的另一实施方案中,R1是取代或未取代环戊基。
式(I)化合物的另一实施方案中,R1是取代或未取代环己基。
式(I)化合物的另一实施方案中,R1是羟基。
式(I)化合物的另一实施方案中,R1是烷氧基。
式(I)化合物的另一实施方案中,R1是甲氧基。
式(I)化合物的另一实施方案中,R1是乙氧基。
式(I)化合物的另一实施方案中,R1是丁氧基。
式(I)化合物的另一实施方案中,R1是异丙氧基。
式(I)化合物的另一实施方案中,R1是t-丁氧基。
式(I)化合物的另一实施方案中,R1是烯基。
式(I)化合物的另一实施方案中,R1是烯丙基。
式(I)化合物的另一实施方案中,R1是炔基。
式(I)化合物的另一实施方案中,R1是炔丙基。
式(I)化合物的另一实施方案中,R1是氰基。
式(I)化合物的另一实施方案中,R1是-C(O)-N(R7)2。
式(I)化合物的另一实施方案中,R1是-C(O)-N(R7)2,其中R7是这里所定义的。
式(I)化合物的另一实施方案中,R1是-C(O)-NH2。
式(I)化合物的另一实施方案中,R1是-O-C(O)-N(R7)2。
式(I)化合物的另一实施方案中,R1是-O-C(O)-N(R7)2,其中R7是这里所定义的。
式(I)化合物的另一实施方案中,R1是-O-C(O)-NH2。
式(I)化合物的另一实施方案中,R1是杂环基。
式(I)化合物的另一实施方案中,R1是取代杂环基。
式(I)化合物的另一实施方案中,R1是四氢呋喃基。
式(I)化合物的另一实施方案中,R1是乙氧基。
式(I)化合物的另一实施方案中,R1是-C(O)-O烷基。
式(I)化合物的另一实施方案中,R1是-C(O)-O烷基,所述烷基基团包括这里所定义和描述的任何烷基。
式(I)化合物的另一实施方案中,R1是-C(O)-OH。
式(I)化合物的另一实施方案中,R1是硅氧基。
式(I)化合物的另一实施方案中,R1是-OSi(烷基)3。
式(I)化合物的另一实施方案中,R1是取代或未取代-OSi(烷基)2芳基。
式(I)化合物的另一实施方案中,R1是取代或未取代-OSi(芳基)2烷基。
式(I)化合物的另一实施方案中,R1是取代或未取代-OSi(芳基)3。
式(I)化合物的另一实施方案中,R1是-O-亚烷基-OH,其中所述烷基可以是这里所定义或描述的任一种亚烷基。
式(I)化合物的另一实施方案中,R1是-O-亚烷基-O-酰基,其中所述亚烷基可以是这里所定义或描述的任一种亚烷基,酰基是这里所定义的。
式(I)化合物的另一实施方案中,R1是-S(O)2-N(R7)2,这里的R7是这里所定义的。
式(I)化合物的另一实施方案中,R2是卤素。
式(I)化合物的另一实施方案中,R2是Cl。
式(I)化合物的另一实施方案中,R2是F。
式(I)化合物的另一实施方案中,R2是硝基。
式(I)化合物的另一实施方案中,R2是氰基。
式(I)化合物的另一实施方案中,R2是烷基。
式(I)化合物的另一实施方案中,R2是-CH3。
式(I)化合物的另一实施方案中,R2是-CH2CH3。
式(I)化合物的另一实施方案中,R2是-CH2CH2CH3。
式(I)化合物的另一实施方案中,R2是异丙基。
式(I)化合物的另一实施方案中,R2是丁基。
式(I)化合物的另一实施方案中,R2是t-丁基。
式(I)化合物的另一实施方案中,R2是取代烷基。
式(I)化合物的另一实施方案中,R2是烷氧基烷基。
式(I)化合物的另一实施方案中,R2是甲氧基乙基。
式(I)化合物的另一实施方案中,R2是乙氧基乙基。
式(I)化合物的另一实施方案中,R2是乙氧基甲基。
式(I)化合物的另一实施方案中,R2是羟烷基。
式(I)化合物的另一实施方案中,R2是烯基。
式(I)化合物的另一实施方案中,R2是烯丙基。
式(I)化合物的另一实施方案中,R2是取代烯基。
式(I)化合物的另一实施方案中,R2是卤素取代烯基。
式(I)化合物的另一实施方案中,R2是炔基。
式(I)化合物的另一实施方案中,R2是炔丙基。
式(I)化合物的另一实施方案中,R2是取代炔基。
式(I)化合物的另一实施方案中,R2是烷氧羰基。
式(I)化合物的另一实施方案中,R2是-C(O)-O-CH3。
式(I)化合物的另一实施方案中,R2是-C(O)-O-CH2CH3。
式(I)化合物的另一实施方案中,R2是-C(O)-O-C(CH3)3。
式(I)化合物的另一实施方案中,R2是-C(O)-O-CH(CH3)2。
式(I)化合物的另一实施方案中,R2是-N(R7)2,这里的R7是这里所定义的。
式(I)化合物的另一实施方案中,R2是烷基酰胺基。
式(I)化合物的另一实施方案中,R2是-O-C(O)-NH-CH3。
式(I)化合物的另一实施方案中,R2是二烷基酰胺基。
式(I)化合物的另一实施方案中,R2是-O-C(O)-N(CH3)2。
式(I)化合物的另一实施方案中,R2是环烷基。
式(I)化合物的另一实施方案中,R2是环丙基。
式(I)化合物的另一实施方案中,R2是环丁基。
式(I)化合物的另一实施方案中,R2是环戊基。
式(I)化合物的另一实施方案中,R2是环己基。
式(I)化合物的另一实施方案中,R2是取代环烷基。
式(I)化合物的另一实施方案中,R2是取代环丙基。
式(I)化合物的另一实施方案中,R2是取代环丁基。
式(I)化合物的另一实施方案中,R2是取代环戊基。
式(I)化合物的另一实施方案中,R2是环己基。
式(I)化合物的另一实施方案中,R2是芳基烷基。
式(I)化合物的另一实施方案中,R2是苄基。
式(I)化合物的另一实施方案中,R2是苯乙基。
式(I)化合物的另一实施方案中,R2是取代芳基烷基。
式(I)化合物的另一实施方案中,R2是取代苄基。
式(I)化合物的另一实施方案中,R2是取代苯乙基。
式(I)化合物的另一实施方案中,R3是芳基。
式(I)化合物的另一实施方案中,R3是苯基。
式(I)化合物的另一实施方案中,R3是杂芳基。
式(I)化合物的另一实施方案中,R3是单环杂芳基。
式(I)化合物的另一实施方案中,R3是双环杂芳基
式(I)化合物的另一实施方案中,R3是选自:
式(I)化合物的另一实施方案中,R3-(Z)n是选自:
式(I)化合物的另一实施方案中,R4是H。
式(I)化合物的另一实施方案中,R4是烷基。
式(I)化合物的另一实施方案中,R4是甲基。
式(I)化合物的另一实施方案中,R4是乙基。
式(I)化合物的另一实施方案中,R4是异丙基。
式(I)化合物的另一实施方案中,R4是丙基。
式(I)化合物的另一实施方案中,R4是丁基。
式(I)化合物的另一实施方案中,R4是仲-丁基。
式(I)化合物的另一实施方案中,R4是t-丁基。
式(I)化合物的另一实施方案中,R4是戊基。
式(I)化合物的另一实施方案中,R4是己基。
式(I)化合物的另一实施方案中,R4是取代烷基。
式(I)化合物的另一实施方案中,R4是卤烷基。
式(I)化合物的另一实施方案中,R4是环烷基。
式(I)化合物的另一实施方案中,R4是环丙基。
式(I)化合物的另一实施方案中,R4是环丁基。
式(I)化合物的另一实施方案中,R4是环戊基。
式(I)化合物的另一实施方案中,R4是环己基。
式(I)化合物的另一实施方案中,R4是取代环烷基。
式(I)化合物的另一实施方案中,R4是取代环烷基。
式(I)化合物的另一实施方案中,R4是取代环丙基。
式(I)化合物的另一实施方案中,R4是取代环丁基。
式(I)化合物的另一实施方案中,R4是取代环戊基。
式(I)化合物的另一实施方案中,R4是取代环己基。
式(I)化合物的另一实施方案中,R4是羟烷基。
式(I)化合物的另一实施方案中,R4是羟甲基。
式(I)化合物的另一实施方案中,R4是羟乙基。
式(I)化合物的另一实施方案中,R4是羟丙基。
式(I)化合物的另一实施方案中,R4是羟丁基。
式(I)化合物的另一实施方案中,R4是烷氧基烷基。
式(I)化合物的另一实施方案中,R4是甲氧基乙基。
式(I)化合物的另一实施方案中,R4是乙氧基甲基。
式(I)化合物的另一实施方案中,R4是乙氧基乙基。
式(I)化合物的另一实施方案中,R4是t-丁氧基乙基。
式(I)化合物的另一实施方案中,R4是芳基烷基。
式(I)化合物的另一实施方案中,R4是苄基。
式(I)化合物的另一实施方案中,R4是苯乙基。
式(I)化合物的另一实施方案中,R4是取代芳基烷基。
式(I)化合物的另一实施方案中,R4是取代苄基。
式(I)化合物的另一实施方案中,R4是取代苯乙基。
式(I)化合物的另一实施方案中,A是-C(O)-且R2是烷基。
式(I)化合物的另一实施方案中,A是-C(O)-且R2是甲基。
式(I)化合物的另一实施方案中,A是-C(O)-且R2是乙基。
式(I)化合物的另一实施方案中,A是-C(O)-且R2是丙基。
式(I)化合物的另一实施方案中,A是-C(O)-且R2是异丙基。
式(I)化合物的另一实施方案中,A是-C(O)-和R2是丁基。
式(I)化合物的另一实施方案中,A是-C(O)-且R2是t-丁基。
式(I)化合物的另一实施方案中,A是共价键且R2是烷基。
式(I)化合物的另一实施方案中,A是共价键且R2是甲基。
式(I)化合物的另一实施方案中,A是共价键且R2是乙基。
式(I)化合物的另一实施方案中,A是共价键且R2是丙基。
式(I)化合物的另一实施方案中,A是共价键且R2是异丙基。
式(I)化合物的另一实施方案中,A是共价键且R2是丁基。
式(I)化合物的另一实施方案中,A是共价键且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-C(O)-且R3是苯基。
式(I)化合物的另一实施方案中,A是-C(O)-和R3是苯基,并且n是2。
式(I)化合物的另一实施方案中,A是-C(O)-且R3是苯基,n是2,并且每个Z是烷基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,并且每个Z是甲基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,其中1个Z是烷基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,其中1个Z是甲基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,其中1个Z是乙基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,1个Z是丙基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-C(O)-,并且R3-Zn是3,5-二取代苯基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R2是烷基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R2是甲基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,和R2是乙基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R2是丙基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R2是异丙基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R2是丁基。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R2是t-丁基。
式(I)化合物的另一实施方案中,A是共价共价键(covalentcovalent bond),并且R3是芳基或杂芳基。
式(I)化合物的另一实施方案中,A是共价共价键,R3是芳基或杂芳基,并且n是2。
式(I)化合物的另一实施方案中,A是共价共价键,R3是芳基或杂芳基,n是2,并且每个Z是烷基。
式(I)化合物的另一实施方案中,A是共价共价键,R3是芳基或杂芳基,n是2,并且每个Z是甲基。
式(I)化合物的另一实施方案中,A是共价共价键,R3是芳基或杂芳基,n是2,其中一个Z是烷基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是共价共价键,R3是芳基或杂芳基,n是2,其中一个Z是甲基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是共价共价键,R3是芳基或杂芳基,n是2,其中一个Z是乙基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,其中一个Z是乙基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是共价键,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团。
式(I)化合物的另一实施方案中,A是共价键,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,并且每个Z独立地为烷基、氰基或卤素。
式(I)化合物的另一实施方案中,A是共价键,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,n是2,并且每个Z独立地为烷基、氰基或卤素。
式(I)化合物的另一实施方案中,A是-C(O)-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,n是2,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基、和吲哚基中的基团,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,n是2,每个Z是独立的烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-NR5-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,并且R4是H。
式(I)化合物的另一实施方案中,A是-NR5-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-NR5-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,n是2,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-S-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,并且R4是H。
式(I)化合物的另一实施方案中,A是-S-,R3是选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-S-,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,n是2,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-和R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,每个Z是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,每个Z是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,一个Z是烷基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,一个Z是甲基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,一个Z是乙基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3是苯基,n是2,一个Z是丙基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O)-,R3-Zn是3,5-二取代苯基,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,每个Z是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,每个Z是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,一个Z是烷基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,一个Z是甲基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,一个Z是乙基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,n是2,一个Z是丙基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键并且R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键并且R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是共价键,R3选自苯基、萘基、吡啶基、吡咯甲酰基、呋喃基、噻吩基、吡唑基、咪唑基、恶唑基、异恶唑基、噻唑基、哒嗪基、嘧啶基、吡嗪基、喹啉基、苯并咪唑基、吲唑基和吲哚基中的基团,n是2,每个Z独立地为烷基、氰基或卤素,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-且R2是烷基。
式(I)化合物的另一实施方案中,A是-O-且R2是甲基。
式(I)化合物的另一实施方案中,A是-O-且R2是乙基。
式(I)化合物的另一实施方案中,A是-O-且R2是丙基。
式(I)化合物的另一实施方案中,A是-O-且R2是异丙基。
式(I)化合物的另一实施方案中,A是-O-且R2是丁基。
式(I)化合物的另一实施方案中,A是-O-且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-O-且R3是苯基。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,并且n是2。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,并且每个Z是烷基。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,并且每个Z是甲基。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是烷基,并且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是甲基,并且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是乙基,并且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是丙基,并且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-O-和R3-Zn是3,5-双取代苯基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,并且R2是烷基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,并且R2是甲基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,并且R2是乙基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,并且R2是丙基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,并且R2是异丙基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,和R2是丁基。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-双取代苯基,并且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-O-,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,每个Z是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,每个Z是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是烷基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是甲基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是乙基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3是苯基,n是2,一个Z是丙基,另外一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-O-,R3-Zn是3,5-二取代苯基,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-且R2是烷基。
式(I)化合物的另一实施方案中,A是-NH-且R2是甲基。
式(I)化合物的另一实施方案中,A是-NH-且R2是乙基。
式(I)化合物的另一实施方案中,A是-NH-且R2是丙基。
式(I)化合物的另一实施方案中,A是-NH-且R2是异丙基。
式(I)化合物的另一实施方案中,A是-NH-且R2是丁基。
式(I)化合物的另一实施方案中,A是-NH-且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-NH-且R3是苯基。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,并且
n是2。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,并且每个Z是烷基。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,并且每个Z是甲基。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是烷基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是甲基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是乙基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是丙基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-NH-且R3-Zn是3,5-二取代苯基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是烷基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是甲基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是乙基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是丙基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是异丙基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是丁基。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-NH-,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,每个Z是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,每个Z是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是烷基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是甲基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是乙基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3是苯基,n是2,一个Z是丙基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-NH-,R3-Zn是3,5-二取代苯基,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-且R2是烷基。
式(I)化合物的另一实施方案中,A是-CF2-且R2是甲基。
式(I)化合物的另一实施方案中,A是-CF2-且R2是乙基。
式(I)化合物的另一实施方案中,A是-CF2-且R2是丙基。
式(I)化合物的另一实施方案中,A是-CF2-且R2是异丙基。
式(I)化合物的另一实施方案中,A是-CF2-且R2是丁基。
式(I)化合物的另一实施方案中,A是-CF2-且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-CF2-且R3是苯基。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,并且n是2。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,并且每个Z是烷基。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,并且每个Z是甲基。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是烷基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是甲基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是乙基,另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是丙基,且另一个Z是氰基。
式(I)化合物的另一实施方案中,A是-CF2-且R3-Zn是3,5-双取代苯基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是烷基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是甲基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是乙基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是丙基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是异丙基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是丁基。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-双取代苯基,并且R2是t-丁基。
式(I)化合物的另一实施方案中,A是-CF2-,R2是烷基,和R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,每个Z是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,每个Z是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是烷基,另一个Z是氰基,和R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是甲基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是乙基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3是苯基,n是2,一个Z是丙基,另一个Z是氰基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是烷基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是甲基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是乙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是异丙基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-CF2-,R3-Zn是3,5-二取代苯基,R2是t-丁基,并且R4是H。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是H。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是烷基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是卤烷基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是环烷基烷基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是羟烷基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是氰烷基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-亚烷基-C(O)-N(R7)2。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是烷氧基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是炔基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-炔基-环丙基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是羟基炔基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是烯基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是卤代烯基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,和-D-R1是取代或为取代杂环烷基。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-CH2-环丙烯基-CH2-C(O)-OCH3。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-CH2-环丙烯基-CH2-C(O)-OH。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-CH2-环丙烯基-CH2-C(O)-NH(PMB)。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-亚烷基-C(O)-N(R7)2。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-CH2-环丙烯基-CH2-C(O)-NH2。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-CH2-CH2-O-C(O)-OCH3。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-亚烷基-C(O)-N(R7)2。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-亚烯基-C(O)-OR7。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-亚烯基-C(O)-N(R7)2。
式(I)化合物的另一实施方案中,A是-C(O),R3-Zn是3,5-二取代苯基,R2是烷基,R4是H,X和Y同时为O,并且-D-R1是-CH2-CH=CH-C(O)-NH2。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,R2是烷基,R4是H,X和Y均为O,并且-D-R1是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,Z是烷基、氰基或卤素,R2是烷基,R4是H,X和Y均为O,并且-D-R1是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,Z是烷基、氰基或卤素,n是2,R2是烷基,R4是H,X和Y均为O,并且-D-R1是H。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,R2是烷基,R4是H,X和Y均为O,并且-D-R1是烷基。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,R2是烷基,R4是H,X和Y均为O,并且-D-R1是烷基。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,Z是烷基、氰基或卤代,R2是烷基,R4是H,X和Y均为O,并且-D-R1是烷基。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,R2是烷基,R4是H,X和Y均为O,并且-D-R1是卤烷基。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,Z是烷基、氰基或卤代,R2是烷基,R4是H,X和Y均为O,并且-D-R1是卤烷基。
式(I)化合物的另一实施方案中,A是共价键,R3是芳基或杂芳基,Z是烷基、氰基或卤代,n是2,R2是烷基,R4是H,X和Y均为O,并且-D-R1是卤烷基。
式(I)化合物的另一实施方案中,D是亚烷基、亚烯基或亚炔基。
在另一实施方案中,结构式(I)的化合物具有如下结构式(Ia)的结构:
其中X、Y、A、D、R2、R3、R4、R5、R6和R7都是上面式(I)所定义的,并且每个Z1独立地选自:卤代、硝基、羟基、氨基、乙酰氨基、三氟乙酰氨基、叠氮基、氰基、甲酰基、烷基、取代烷基、烷基甲酰基、二烷基甲酰基、烯基、取代烯基、炔基、取代炔基、烷氧基、取代烷氧基、烷氧羰基、环烷基、取代环烷基、环烯基、取代环烯基、杂环基、取代杂环基、芳基、取代芳基、氧化物;并且Z2独立地选自:卤代、硝基、羟基、氨基、乙酰氨基、三氟乙酰氨基、叠氮基、氰基、甲酰基、烷基甲酰基、二烷基甲酰基、烯基、取代烯基、炔基、取代炔基、烷氧基、取代烷氧基、烷氧羰基、环烷基、取代环烷基、环烯基、取代环烯基、杂环基、取代杂环基、芳基、取代芳基、氧化物;n是0-3的整数;并且只有R4和-D-R1中的一个是H。
在另一实施方案中,式(I)化合物或其药学上可接受的盐、溶剂化物和/或酯类,其结构式选自:
药物制剂
可以按照通常做法选择常规载体和辅料进行本发明化合物的制备。片剂含有辅料、助流剂、填料、粘合剂,等。液体制剂通过无菌形式制备,当用于非口服给药时通常需要等渗处理。所有制剂都选择性地含有诸如Handbook ofPharmaceutical Excipients(1986)所述的辅料,此处作为参考文献整体引入。辅料包括抗坏血酸和其它抗氧化剂,螯合剂诸如EDTA,碳水化合物诸如糊精,羟基烷基纤维素,羟基烷甲基纤维素,硬脂酸等。制剂的pH值范围从约3-11,但是通常约为7-10。
虽然可以单独给药有效成分,但最好采用药物制剂形式。可同时为兽用和人用的本发明的制剂,含有至少一种如上述定义的活性成分,连同一种或多种可接受的载体和可选其它治疗成分。载体必须是“可接受的”,在这种意义上与配方的其他成分兼容并且对其接受者生理无害。
该制剂包含那些适用于上述给药途径的形式。制剂可以方便地呈现为单位剂型并可采用在制药工艺上众所周知的方法制备。工艺和配方通常可参见Remington′s Pharmaceutical Sciences(Mack PublishingCo.,Easton,Pa.),此处作为参考文献整体引入。此类方法包括将活性成分和由一种或多种附加成分的载体相组合的步骤。通常通过一致地和详尽地将活性成分和液体载体或粉末固体载体或者这两种结合进行组合制备制剂,接着若有必要,制成产品。
本发明适合口服给药的制剂可以呈现为分散单元诸如胶囊、扁囊剂或片剂,每种都含有预定量的活性成分;呈现为粉剂或粒剂;呈现为液体或非液体的溶液或悬液;或呈现为水包油乳液或油包水乳液。活性成分还可以以丸剂、膏剂或粘贴剂形式给药。
片剂通过选择性地添加一种或多种附加成分压缩或塑形制成。压缩片剂通过合适的机器将自由流动的活性成分诸如粉末或颗粒,选择性地混合粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂压缩而制备。塑形片剂可以通过合适的机器将粉末状活性成分用惰性液体稀释剂湿润混合来塑形。片剂可以选择性地涂层或刻痕和选择性地制备成可活性成分的缓慢供给或可控释放。
给药眼部或其他外部组织(例如,嘴和皮肤),制剂优选应用为含有活性成分的局部药膏或乳剂,其含量为,例如,0.075-20%w/w(含有活性成分范围0.1%-20%,增量为0.1%w/w诸如0.6%w/w,0.7%w/w等),优选为0.2-15%w/w,最优为0.5-10%w/w。当制成药膏制剂,活性成分将与石蜡或水混容软膏基质共用。可选择地,活性成分可以用水包油乳剂制备成乳状。
如果需要,乳状基质的液相包括,例如,至少30%w/w的多元醇,例如具有两个或多个羟基基团的醇诸如丙二醇、1,3-丁二醇、甘露醇、山梨糖醇、甘油和聚乙二醇(包括PEG 400)及其混合物。外用制剂可以最好是包括增加活性成分通过皮肤或其他患部吸收或渗透的一种化合物。此类皮肤渗透促进剂的例子包括二甲基亚砜以及相关类似物。
尽管该发明稀释剂的油相可以是通过已知方式由已知成分组成。油相可以仅有乳化剂(或称为一种乳化剂)组成,它最好是包括至少一种乳化剂与脂肪或油或同时与脂肪和油的混合物构成。优选地,一种亲水性乳化剂常连同充当稳定剂的亲油性乳化剂组合在一起。其还倾向于同时包括油和脂肪。共同地,稀释剂和或不和稳定剂一起组成了所谓的乳化蜡,以及该蜡和油以及脂肪组成了所谓的软化软膏,其组成了乳剂的油分散相。
该制剂适合的油或脂肪的选择基于达到所需的美容特性。乳剂最好应是不油腻、不染色且易清洗的产品,其稠度合适,以避免从管中或其它容器中泄漏出来。直链或支链,单或二元烷基酯诸如二-异己二酸、硬脂酸异十六醇酯、椰子脂肪酸丙二醇酯,十四酸异丙酯、癸油酸、棕榈酸异丙酯、硬脂酸丁酯、二辛棕榈酸酯或被称为CrodamolCAP的支链酯类混合物可以被使用,最后三种为首选酯。依据需要的特性单独或组合使用这些酯类。或者,使用高熔点的脂类诸如白软蜡和、或液体石蜡或其它矿物油。
依据本发明的药物制剂包括本发明的一种或多种化合物连同一种或多种药学上可接受的载体或辅料以及可选的其它治疗药物。含有活性成分的药物制剂可以是适合用于拟给药方法的任何形式。当用作口服可制备成例如片剂、含片、锭剂,水或油悬液、分散粉末或颗粒、乳液、硬或软胶囊、糖浆或酏剂。用于口服的组合物可以依据本领域所知的任何制备药物组合物的方法制备,并且此类组合物可以含有一种或多种成分,包含甜味剂、香味剂、着色剂和保护剂,以提供一种可口的制备产品。含有活性成分并混合有适合片剂生产的无毒性药学上可接受辅料的片剂是可接受的。这些辅料可以是,例如,惰性稀释剂,诸如碳酸钙或碳酸钠、乳糖、乳糖水合物、交联羧甲基纤维素钠、聚维酮、磷酸钙或磷酸钠;制粒和崩解剂,诸如玉米淀粉、或海藻酸;粘合剂,诸如纤维素、微晶纤维素、淀粉、明胶或阿拉伯胶;以及润滑剂,诸如硬脂酸镁,硬脂酸或滑石粉。片剂可以是通过已知技术不包被或包被,包括微胶囊,目的是延迟其在胃肠道的解体和吸收,因而能在较长时间内提供持续作用。例如,延时材料诸如硬脂酸甘油酯或甘油硬脂酸单独或与蜡同时被使用。
口服制剂同样可以是以硬胶囊形式,其活性成分与惰性固体稀释剂(例如磷酸钙或高岭土)混合,或以软胶囊形式,其活性成分与水或油介质(诸如花生油、液体石蜡或橄榄油)混合。
本发明的水悬液含有活性成分与适合制备水悬液的辅料混合物。此类辅料包括悬浮剂,诸如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、胶黄蓍和阿拉伯胶,以及分散或润滑剂诸如一种天然磷脂(例如,卵磷脂),一种烃基与一种脂肪酸(例如,硬脂酸聚氧乙烯)氧化的压缩产物,乙烯与长链脂肪醇氧化的压缩产物(例如,heptadecaethyleneoxycetanol),乙烯与脂肪酸和己糖醇酸酐(例如,聚氧乙烯失水山梨醇单油酸酯)衍生出来的部分酯类氧化产生的压缩产物。水悬液也可以含有一种或多种防腐剂诸如乙基或丙基n-羟基苯甲酸,一种或多种着色剂,一种或多种调味剂以及一种或多种甜味剂,诸如蔗糖或糖精。
油悬液可以将活性成分悬浮于植物油中,诸如花生油、橄榄油、芝麻油或椰子油,或矿物油诸如液体石蜡。口服悬液可以含有增稠剂,诸如蜂蜡、石蜡或硬十六醇。可以添加甜味剂(诸如那些本文所阐述的)以及调味剂使其提供一种美味口服制剂。这些成分可以添加一种抗氧化剂诸如抗坏血酸来保护。
本发明的可分散粉末和颗粒适合通过添加含有活性成分的水与分散剂或润湿剂,悬浮剂和一种或多种保护剂混合制备成液体悬液。适宜的分散或润湿剂以及悬剂如上文所列举。此外还可以有其他辅料,例如甜味剂、增味剂以及着色剂。
本发明的药物组合物也可以是水包油乳液形式。油相可以是植物油(诸如橄榄油或花生油)、矿物油(诸如液体石蜡)或它们的混合物。适合的乳化剂包括天然产植物胶,诸如阿拉伯胶和黄芪胶,天然产磷脂,诸如大豆卵磷脂,脂肪酸的酯类或部分酯类衍生物和己糖醇酸酐,诸如失水山梨醇单油酸酯,以及这些部分酯类同乙烯氧化物的缩合产物,诸如聚氧乙烯失水山梨醇单油酸酯。乳剂也可以包含甜味剂和香味剂。可以添加甜味剂,诸如甘油、山梨醇或蔗糖制备糖浆和酏剂。此类制剂也可以包含缓和剂、防腐剂、香味剂或着色剂。
本发明的药物组合物可以是以无菌注射制剂形式,诸如无菌注射水或油状悬液。依据本领域已知技术利用那些合适的此文提及的分散剂或润滑剂以及悬剂制成悬液。无菌可注射制剂也可以是一种无毒肠外可接受的稀释剂或溶剂的无菌可注射溶液或悬液,诸如1,3-丁二醇溶液或制备成冻干粉。可接受的载体或溶剂可以是水、Ringer′s溶液以及等渗氯化钠溶液。此外,传统地无菌固定油可以用作溶剂或悬液介质。为此目的,可以用的任何温和固定油包括合成甘油单酯或甘油二酯。此外,诸如油酸的脂肪酸同样可以被用作注射用制剂。
与载体材料结合产生单剂型的活性成分量随着宿主治疗以及给药的特殊模式而变化。例如,用于人类口服给药的时间-释放制剂可以含有大约1-1000mg的活性材料同适当和方便量的载体材料,其占总组分的大约5-95%(质量:质量)复合而成。药物组分可以制备成可易计算给药量的形式。例如,静脉输液的水溶液每升可以含有大约3-500μg的活性成分为了使发生合适体积的输液速率为大约30mL/小时。
适合给药于眼部的制剂包括滴眼液,其中活性成分分散或悬浮于合适的载体中,尤其是活性成分的水溶剂。活性成分目前较好是浓度0.5-20%,最好为0.5-10%,尤其是大约1.5%w/w。
适合嘴局部用药的制剂包括由活性成分添加香味基质(通常是蔗糖)、阿拉伯胶以及黄蓍胶的含片;含有由诸如明胶和甘油,或蔗糖和阿拉伯胶惰性基质同活性成分组成的锭剂;以及合适液体载体中含有活性成分的漱口液。
直肠给药的制剂可以是具有合适包含例如可可脂或水杨酸的基质的栓剂形式。
适合肺部或鼻部给药的制剂具有例如0.1-500μm大小的颗粒(包括颗粒大小0.1-500μm增量,诸如0.5μm、1μm、30μm、35μm等),其通过鼻道快速吸入给药或通过嘴快速吸入给药以便到达肺泡囊。合适的制剂包括活性成分的水或油溶液。适合气溶胶或干粉给药的制剂可以依据传统方法制备,以及可以连同其它治疗试剂诸如本文所述的以前治疗或预防感染所用的化合物投递给药。
适合阴道给药的制剂可以以栓、棉球、乳剂、凝胶、膏、泡沫或喷雾形式,由活性成分添加此类本领域所熟知的载体是适当的。
适合肠外给药的制剂包括液体和非-液体无菌注射液,其可以含有抗氧化剂、缓冲液、抑菌剂以及给予制剂与接受者血液等渗的溶质;以及液体和非液体无菌悬液,其可以包括悬浮剂和增稠剂。
制剂可以以单位剂量或多剂量容器所呈现,例如密封安瓿和小瓶,以及可以储存于冷冻干燥(冻干)条件下,使用前仅需要添加无菌液体载体,例如注射用的水。临时注射液和悬液是用前面描述那种无菌粉末、颗粒以及片剂制备。首选单位剂量制剂包括那些如此文上面所述的含有活性成分每日剂量或单位每天分剂量,或其适当部分。
应该理解,考虑到制剂类型问题,除了该组分尤其是上述提及的本发明配方,其还可含有其他本领域常规试剂,例如例如那些适合口服给药的制剂可以包括香味剂。
本发明还提供由至少一种上述定义的活性成分连同兽医载体构成的兽用组合物。
兽用载体是那些对给药组分有用的材料,可以是固体、液体或气体材料,其是惰性的或兽医领域可接受的并能与活性成分相兼容。这些兽用组合物可以口服给药、肠外给药或其它所需的方式给药。
本发明的化合物同样可以是制成活性成分可调控释放以便允许用药次数的减少或促进活性成分的药动力学或毒性学。因此,本发明还提供含有一种或多种发明制备的用于维持或调控释放的化合物组分。
活性成分的有效剂量至少依赖于被治疗的天然条件、毒性、化合物是否是用于预防(低剂量)或对抗疾病或条件、投递方法以及药物制剂,其将由临床医生通过传统的剂量递增研究确定。可以预期,有效剂量约为0.0001-100mg/kg体重每日;典型地,约为0.01-10mg/kg体重每日;更典型地,约为0.01-5mg/kg体重每日;更为典型地,约为0.05-0.5mg/kg体重每日。例如,对于一个体重约为70kg成人的日候选剂量范围是1-1000mg,或位于5-500mg之间,并可以采用单剂量或多剂量形式。
另一实施方案中,本申请提供一种药物组合物,其含有治疗有效剂量的式(I)化合物或其药学上可接受的盐、溶剂化物和/或酯类,以及药学上可接受的载体。
另一实施方案中,本申请提供一种药物组合物,其含有治疗有效剂量的式(I)化合物或其药学上可接受的盐、溶剂化物和/或其酯,结合至少一种其它活性治疗试剂,以及药学上可接受的载体。
HIV联合治疗
在一个实施例中,适合组合的例子包括但不限于:本发明的一种或多种化合物与一种或多种HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力学增强剂和其它治疗HIV的药物,以及任意上述的组合。
更具体地,本发明的一种或多种化合物可以与选自以下的化合物联合:
1)HIV蛋白酶抑制剂,例如,安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
2)HIV逆转录酶非核苷抑制剂,例如,卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
3)HIV逆转录酶核苷抑制剂,例如,齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
4)逆转录酶类HIV核苷酸抑制剂,例如,富马酸泰诺福韦酯(Viread)和阿德福韦酯;
5)HIV整合酶抑制剂,例如,姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir(AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
6)gp41抑制剂,例如,恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
7)CXCR4抑制剂,例如,AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
8)侵入抑制剂,例如,SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
9)gp120抑制剂,例如,BMS-488043和其前药、BlockAide/CR、KPC-2和MNLP62;
10)G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);
11)CCR5抑制剂,例如,阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB 15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
12)CCR8抑制剂,例如,ZK-756326;
13)RNase H抑制剂,例如,ODN-93、和ODN-112;
14)成熟抑制剂,例如,贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
15)药动力学增强剂,例如,BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
16)其它用于治疗HIV的药物,例如,REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
另一实施例中,本申请提供一种药物试剂组合物,其包含:第一药物组分,其包括式(I)化合物,或其药学上可接受的盐、溶剂化物和/或酯;以及第二药物组分,其包括至少一种选自下述的其它活性试剂:HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、逆转录酶类HIV核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药物动力学增强剂、其它用于治疗HIV的药物以及它们的混合物。
给药途径
本发明的一种或多种化合物(以下简称的活性成分)依据治疗的条件选择恰当的途径给药。合适的途径包括口服、直肠、鼻部以及局部给药(口腔和舌下)、阴道和直肠外给药(包括皮下、肌肉注射、静脉注射、皮内注射、鞘内注射和硬膜外注射),等等。应当理解,优选途径将随着例如接受者条件而变化。本发明化合物的优点是口服生物可用并且可按剂量口服。
联合治疗
在一个实施方案中,式(I)化合物可以单独给药,例如不连同其它活性治疗成分或试剂。另一实施方案中,式(I)化合物可以连同其它活性治疗成分或试剂一起使用。优选地,其它活性治疗成分或试剂是HIV蛋白酶抑制剂、其它HIV逆转录酶抑制剂、HIV侵入/融合抑制剂、HIV整合酶抑制剂、HIV出芽/成熟抑制剂,或它们的组合。
式(I)化合物的组合的选择通常基于治疗的条件、成分的交叉反应以及组合的药理特性。例如,当治疗感染时(例如,HIV或HCV),本发明的成分结合抗感染试剂(诸如那些本文所描述的)一起使用。
合适的用于与式(I)化合物结合的抗感染试剂的例子包括但不限于:HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力学增强剂和其它用于治疗HIV的药物,以及它们的组合物。更具体地,本发明的一种或多种化合物可以结合一种或多种选自下述的化合物:1)HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;2)HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;3)HIV逆转录酶核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir (racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);4)逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;5)HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir(AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;6)gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;7)CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;8)侵入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;9)gp120抑制剂选自BMS-488043及其前药、BlockAide/CR、KPC-2和MNLP62;10)G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);11)CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB 15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;12)CCR8抑制剂是ZK-756326;13)RNase H抑制剂选自ODN-93和ODN-112;14)成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;其他用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
本发明的任一化合物结合一种或多种其它活性治疗试剂成单一剂型可同时或顺序给药给病人。组合治疗可以按照同时或顺序方案给药。当顺序给药时,组合物可以分两次或多次给药。
本发明的化合物同一种或多种其它活性治疗试剂联合给药通常地是指本发明的化合物同一种或多种其它活性治疗试剂同时或顺序给药,因此本发明化合物的治疗有效剂量以及一种或多种其它活性治疗试剂同时出现在病人体内。
联合给药包括在给药单位剂量的一种或多种其它活性治疗试剂之前或之后给药本发明化合物的单位剂量,例如,在给药本发明化合物的几秒钟、几分钟或几小时内给药一种或多种其它的活性治疗试剂。或者,首先给药单位剂量的一种或多种其它的治疗试剂,接着在几秒钟或几分钟内给药单位剂量的本发明的化合物。在某些情况下,需要首先给药单位剂量的本发明化合物,数小时内(例如,1-12小时),给药单位剂量的一种或多种其它活性治疗试剂。在其他情况下,需要首先给药单位剂量的一种或多种其它活性治疗试剂,接着,数小时后(例如,1-12小时),给药单位剂量的本发明的化合物。
综合疗法可以提供“协同作用”和“协同效应”,例如活性成分同时使用达到的效应比单独使用化合物的效应之和更大。实现协同效应的活性成分是:(1)共同制备和以联合制剂同时给药或投递;(2)作为独立的制剂交替或平行投递;或(3)借助其它方案。当交替疗法投递时,化合物顺序给药或投递时可以获得协同效应,例如,不同的片剂、丸剂或胶囊,或不同的注射器的不同注射液。一般来说,在交替治疗过程中,每种有效剂量的活性成分顺序给药(例如,串行),而联合治疗时,两种或多种活性成分的有效剂量同时给药。
在另一实施方案中,本发明提供一种用于抑制HIV RT的方法,其包含给药一种有效治疗剂量的式(I)化合物,或其药学上可接受的盐、溶剂化物或酯给需要此类治疗的病人。
在另一实施方案中,本发明提供一种用于治疗或预防一种HIV感染的方法,其包含:给药一种有效治疗剂量的式(I)化合物,或其药学上可接受的盐、溶剂化物或酯给需要此类治疗的病人。
在另一实施例中,本发明提供一种方法,进一步包含联合给药一种治疗剂量的至少一种添加活性试剂选自:一种或多种HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力学增强剂和其它用于治疗HIV的药物,以及它们的组合物。
另一实施方案中,本发明提供一种治疗AIDS或AIDS相关综合征(ARC)的方法,其包括给药有效治疗剂量的式(I)化合物,或其药学上可接受的盐、溶剂化物和/或酯给需要此类治疗的病人。
在另一实施方案中,本发明提供一种联合给药有效治疗剂量的式(I)化合物以及至少一种其他活性试剂选自:一种或多种HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力学增强剂和其它用于治疗HIV的药物,以及它们的组合物的方法。
在另一实施方案中,本发明提供一种抑制逆转录病毒复制的方法,其包括式(I)化合物,或其药学上可接受的盐、溶剂化物和/或酯接触所述的逆转录病毒。逆转录病毒的复制在体外或体内(例如受逆转录病毒感染的病人)都可被抑制。
在一实施方案中,本发明提供一种抑制逆转录病毒复制的方法,其包含与逆转录病毒接触的式(I)化合物以及至少一种添加活性试剂选自包含:一种或多种HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力学增强剂和其它用于治疗HIV的药物,以及它们的组合物。
在另一实施方案中,本申请提供式I或II化合物在制备治疗或预防病人HIV感染的药剂中的应用。
在另一实施方案中,本申请提供式I或II化合物在制备治疗病人AIDS或AIDS相关综合征(ARC)的药剂中的应用。
另一实施方案中,本申请提供式I化合物在制备抑制病人逆转录酶复制的药剂中的应用。
在再一实施方案中,式I的化合物作为通式II的化合物命名于下面表格(表7)中:
式II.
表1-6,分别表示“1”、“2”、“3”、“4”、“5”和“6”基团的结构。表1-6的“1”、“2”、“3”、“4”、“5”和“6”的每种取代表示为含有数字和字母的“编码”。式II的化合物的每种结构可以通过结合编码用表格形式定义,该编码利用以下句法1.2.3.4.5.6代表每种结构基团。因此,例如,1a.2a.3a.4a.5a.6a代表下面的结构:
表1:“1”结构
表2:“2”结构
表3:“3”结构
表4:“4”结构
表5:“5”结构
表6:“6”结构
表7:式(II)化合物列表
1a.2a.3a.4a.5a.6a,1a.2a.3a.4a.5a.6b,1a.2a.3a.4a.5a.6c,1a.2a.3a.4a.5a.6d,1a.2a.3a.4a.5a.6e,
1a.2a.3a.4a.5a.6f,1a.2a.3a.4a.5b.6a,1a.2a.3a.4a.5b.6b,1a.2a.3a.4a.5b.6c,1a.2a.3a.4a.5b.6d,
1a.2a.3a.4a.5b.6e,1a.2a.3a.4a.5b.6f,1a.2a.3a.4a.5c.6a,1a.2a.3a.4a.5c.6b,1a.2a.3a.4a.5c.6c,
1a.2a.3a.4a.5c.6d,1a.2a.3a.4a.5c.6e,1a.2a.3a.4a.5c.6f,1a.2a.3a.4a.5d.6a,1a.2a.3a.4a.5d.6b,
1a.2a.3a.4a.5d.6c,1a.2a.3a.4a.5d.6d,1a.2a.3a.4a.5d.6e,1a.2a.3a.4a.5d.6f,1a.2a.3a.4a.5e.6a,
1a.2a.3a.4a.5e.6b,1a.2a.3a.4a.5e.6c,1a.2a.3a.4a.5e.6d,1a.2a.3a.4a.5e.6e,1a.2a.3a.4a.5e.6f,
1a.2a.3a.4a.5f.6a,1a.2a.3a.4a.5f.6b,1a.2a.3a.4a.5f.6c,1a.2a.3a.4a.5f.6d,1a.2a.3a.4a.5f.6e,
1a.2a.3a.4a.5f.6f,1a.2a.3a.4b.5a.6a,1a.2a.3a.4b.5a.6b,1a.2a.3a.4b.5a.6c,1a.2a.3a.4b.5a.6d,
1a.2a.3a.4b.5a.6e,1a.2a.3a.4b.5a.6f,1a.2a.3a.4b.5b.6a,1a.2a.3a.4b.5b.6b,1a.2a.3a.4b.5b.6c,
1a.2a.3a.4b.5b.6d,1a.2a.3a.4b.5b.6e,1a.2a.3a.4b.5b.6f,1a.2a.3a.4b.5c.6a,1a.2a.3a.4b.5c.6b,
1a.2a.3a.4b.5c.6c,1a.2a.3a.4b.5c.6d,1a.2a.3a.4b.5c.6e,1a.2a.3a.4b.5c.6f,1a.2a.3a.4b.5d.6a,
1a.2a.3a.4b.5d.6b,1a.2a.3a.4b.5d.6c,1a.2a.3a.4b.5d.6d,1a.2a.3a.4b.5d.6e,1a.2a.3a.4b.5d.6f,
1a.2a.3a.4b.5e.6a,1a.2a.3a.4b.5e.6b,1a.2a.3a.4b.5e.6c,1a.2a.3a.4b.5e.6d,1a.2a.3a.4b.5e.6e,
1a.2a.3a.4b.5e.6f,1a.2a.3a.4b.5f.6a,1a.2a.3a.4b.5f.6b,1a.2a.3a.4b.5f.6c,1a.2a.3a.4b.5f.6d,
1a.2a.3a.4b.5f.6e,1a.2a.3a.4b.5f.6f,1a.2a.3a.4c.5a.6a,1a.2a.3a.4c.5a.6b,1a.2a.3a.4c.5a.6c,
1a.2a.3a.4c.5a.6d,1a.2a.3a.4c.5a.6e,1a.2a.3a.4c.5a.6f,1a.2a.3a.4c.5b.6a,1a.2a.3a.4c.5b.6b,
1a.2a.3a.4c.5b.6c,1a.2a.3a.4c.5b.6d,1a.2a.3a.4c.5b.6e,1a.2a.3a.4c.5b.6f,1a.2a.3a.4c.5c.6a,
1a.2a.3a.4c.5c.6b,1a.2a.3a.4c.5c.6c,1a.2a.3a.4c.5c.6d,1a.2a.3a.4c.5c.6e,1a.2a.3a.4c.5c.6f,
1a.2a.3a.4c.5d.6a,1a.2a.3a.4c.5d.6b,1a.2a.3a.4c.5d.6c,1a.2a.3a.4c.5d.6d,1a.2a.3a.4c.5d.6e,
1a.2a.3a.4c.5d.6f,1a.2a.3a.4c.5e.6a,1a.2a.3a.4c.5e.6b,1a.2a.3a.4c.5e.6c,1a.2a.3a.4c.5e.6d,
1a.2a.3a.4c.5e.6e,1a.2a.3a.4c.5e.6f,1a.2a.3a.4c.5f.6a,1a.2a.3a.4c.5f.6b,1a.2a.3a.4c.5f.6c,
1a.2a.3a.4c.5f.6d,1a.2a.3a.4c.5f.6e,1a.2a.3a.4c.5f.6f,1a.2a.3a.4d.5a.6a,1a.2a.3a.4d.5a.6b,
1a.2a.3a.4d.5a.6c,1a.2a.3a.4d.5a.6d,1a.2a.3a.4d.5a.6e,1a.2a.3a.4d.5a.6f,1a.2a.3a.4d.5b.6a,
1a.2a.3a.4d.5b.6b,1a.2a.3a.4d.5b.6c,1a.2a.3a.4d.5b.6d,1a.2a.3a.4d.5b.6e,1a.2a.3a.4d.5b.6f,
1a.2a.3a.4d.5c.6a,1a.2a.3a.4d.5c.6b,1a.2a.3a.4d.5c.6c,1a.2a.3a.4d.5c.6d,1a.2a.3a.4d.5c.6e,
1a.2a.3a.4d.5c.6f,1a.2a.3a.4d.5d.6a,1a.2a.3a.4d.5d.6b,1a.2a.3a.4d.5d.6c,1a.2a.3a.4d.5d.6d,
1a.2a.3a.4d.5d.6e,1a.2a.3a.4d.5d.6f,1a.2a.3a.4d.5e.6a,1a.2a.3a.4d.5e.6b,1a.2a.3a.4d.5e.6c,
1a.2a.3a.4d.5e.6d,1a.2a.3a.4d.5e.6e,1a.2a.3a.4d.5e.6f,1a.2a.3a.4d.5f.6a,1a.2a.3a.4d.5f.6b,
1a.2a.3a.4d.5f.6c,1a.2a.3a.4d.5f.6d,1a.2a.3a.4d.5f.6e,1a.2a.3a.4d.5f.6f,1a.2a.3a.4e.5a.6a,
1a.2a.3a.4e.5a.6b,1a.2a.3a.4e.5a.6c,1a.2a.3a.4e.5a.6d,1a.2a.3a.4e.5a.6e,1a.2a.3a.4e.5a.6f,
1a.2a.3a.4e.5b.6a,1a.2a.3a.4e.5b.6b,1a.2a.3a.4e.5b.6c,1a.2a.3a.4e.5b.6d,1a.2a.3a.4e.5b.6e,
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1a.2b.3c.4e.5c.6e,1a.2b.3c.4e.5c.6f,1a.2b.3c.4e.5d.6a,1a.2b.3c.4e.5d.6b,1a.2b.3c.4e.5d.6c,
1a.2b.3c.4e.5d.6d,1a.2b.3c.4e.5d.6e,1a.2b.3c.4e.5d.6f,1a.2b.3c.4e.5e.6a,1a.2b.3c.4e.5e.6b,
1a.2b.3c.4e.5e.6c,1a.2b.3c.4e.5e.6d,1a.2b.3c.4e.5e.6e,1a.2b.3c.4e.5e.6f,1a.2b.3c.4e.5f.6a,
1a.2b.3c.4e.5f.6b,1a.2b.3c.4e.5f.6c,1a.2b.3c.4e.5f.6d,1a.2b.3c.4e.5f.6e,1a.2b.3c.4e.5f.6f,
1a.2b.3c.4f.5a.6a,1a.2b.3c.4f.5a.6b,1a.2b.3c.4f.5a.6c,1a.2b.3c.4f.5a.6d,1a.2b.3c.4f.5a.6e,
1a.2b.3c.4f.5a.6f,1a.2b.3c.4f.5b.6a,1a.2b.3c.4f.5b.6b,1a.2b.3c.4f.5b.6c,1a.2b.3c.4f.5b.6d,
1a.2b.3c.4f.5b.6e,1a.2b.3c.4f.5b.6f,1a.2b.3c.4f.5c.6a,1a.2b.3c.4f.5c.6b,1a.2b.3c.4f.5c.6c,
1a.2b.3c.4f.5c.6d,1a.2b.3c.4f.5c.6e,1a.2b.3c.4f.5c.6f,1a.2b.3c.4f.5d.6a,1a.2b.3c.4f.5d.6b,
1a.2b.3c.4f.5d.6c,1a.2b.3c.4f.5d.6d,1a.2b.3c.4f.5d.6e,1a.2b.3c.4f.5d.6f,1a.2b.3c.4f.5e.6a,
1a.2b.3c.4f.5e.6b,1a.2b.3c.4f.5e.6c,1a.2b.3c.4f.5e.6d,1a.2b.3c.4f.5e.6e,1a.2b.3c.4f.5e.6f,
1a.2b.3c.4f.5f.6a,1a.2b.3c.4f.5f.6b,1a.2b.3c.4f.5f.6c,1a.2b.3c.4f.5f.6d,1a.2b.3c.4f.5f.6e,
1a.2b.3c.4f.5f.6f,1a.2b.3d.4a.5a.6a,1a.2b.3d.4a.5a.6b,1a.2b.3d.4a.5a.6c,1a.2b.3d.4a.5a.6d,
1a.2b.3d.4a.5a.6e,1a.2b.3d.4a.5a.6f,1a.2b.3d.4a.5b.6a,1a.2b.3d.4a.5b.6b,1a.2b.3d.4a.5b.6c,
1a.2b.3d.4a.5b.6d,1a.2b.3d.4a.5b.6e,1a.2b.3d.4a.5b.6f,1a.2b.3d.4a.5c.6a,1a.2b.3d.4a.5c.6b,
1a.2b.3d.4a.5c.6c,1a.2b.3d.4a.5c.6d,1a.2b.3d.4a.5c.6e,1a.2b.3d.4a.5c.6f,1a.2b.3d.4a.5d.6a,
1a.2b.3d.4a.5d.6b,1a.2b.3d.4a.5d.6c,1a.2b.3d.4a.5d.6d,1a.2b.3d.4a.5d.6e,1a.2b.3d.4a.5d.6f,
1a.2b.3d.4a.5e.6a,1a.2b.3d.4a.5e.6b,1a.2b.3d.4a.5e.6c,1a.2b.3d.4a.5e.6d,1a.2b.3d.4a.5e.6e,
1a.2b.3d.4a.5e.6f,1a.2b.3d.4a.5f.6a,1a.2b.3d.4a.5f.6b,1a.2b.3d.4a.5f.6c,1a.2b.3d.4a.5f.6d,
1a.2b.3d.4a.5f.6e,1a.2b.3d.4a.5f.6f,1a.2b.3d.4b.5a.6a,1a.2b.3d.4b.5a.6b,1a.2b.3d.4b.5a.6c,
1a.2b.3d.4b.5a.6d,1a.2b.3d.4b.5a.6e,1a.2b.3d.4b.5a.6f,1a.2b.3d.4b.5b.6a,1a.2b.3d.4b.5b.6b,
1a.2b.3d.4b.5b.6c,1a.2b.3d.4b.5b.6d,1a.2b.3d.4b.5b.6e,1a.2b.3d.4b.5b.6f,1a.2b.3d.4b.5c.6a,
1a.2b.3d.4b.5c.6b,1a.2b.3d.4b.5c.6c,1a.2b.3d.4b.5c.6d,1a.2b.3d.4b.5c.6e,1a.2b.3d.4b.5c.6f,
1a.2b.3d.4b.5d.6a, 1a.2b.3d.4b.5d.6b, 1a.2b.3d.4b.5d.6c, 1a.2b.3d.4b.5d.6d,
1a.2b.3d.4b.5d.6e,1a.2b.3d.4b.5d.6f,1a.2b.3d.4b.5e.6a,1a.2b.3d.4b.5e.6b,1a.2b.3d.4b.5e.6c,
1a.2b.3d.4b.5e.6d,1a.2b.3d.4b.5e.6e,1a.2b.3d.4b.5e.6f,1a.2b.3d.4b.5f.6a,1a.2b.3d.4b.5f.6b,
1a.2b.3d.4b.5f.6c,1a.2b.3d.4b.5f.6d,1a.2b.3d.4b.5f.6e,1a.2b.3d.4b.5f.6f,1a.2b.3d.4c.5a.6a,
1a.2b.3d.4c.5a.6b,1a.2b.3d.4c.5a.6c,1a.2b.3d.4c.5a.6d,1a.2b.3d.4c.5a.6e,1a.2b.3d.4c.5a.6f,
1a.2b.3d.4c.5b.6a,1a.2b.3d.4c.5b.6b,1a.2b.3d.4c.5b.6c,1a.2b.3d.4c.5b.6d,1a.2b.3d.4c.5b.6e,
1a.2b.3d.4c.5b.6f,1a.2b.3d.4c.5c.6a,1a.2b.3d.4c.5c.6b,1a.2b.3d.4c.5c.6c,1a.2b.3d.4c.5c.6d,
1a.2b.3d.4c.5c.6e,1a.2b.3d.4c.5c.6f,1a.2b.3d.4c.5d.6a,1a.2b.3d.4c.5d.6b,1a.2b.3d.4c.5d.6c,
1a.2b.3d.4c.5d.6d,1a.2b.3d.4c.5d.6e,1a.2b.3d.4c.5d.6f,1a.2b.3d.4c.5e.6a,1a.2b.3d.4c.5e.6b,
1a.2b.3d.4c.5e.6c,1a.2b.3d.4c.5e.6d,1a.2b.3d.4c.5e.6e,1a.2b.3d.4c.5e.6f,1a.2b.3d.4c.5f.6a,
1a.2b.3d.4c.5f.6b,1a.2b.3d.4c.5f.6c,1a.2b.3d.4c.5f.6d,1a.2b.3d.4c.5f.6e,1a.2b.3d.4c.5f.6f,
1a.2b.3d.4d.5a.6a, 1a.2b.3d.4d.5a.6b, 1a.2b.3d.4d.5a.6c, 1a.2b.3d.4d.5a.6d,
1a.2b.3d.4d.5a.6e, 1a.2b.3d.4d.5a.6f, 1a.2b.3d.4d.5b.6a, 1a.2b.3d.4d.5b.6b,
1a.2b.3d.4d.5b.6c, 1a.2b.3d.4d.5b.6d, 1a.2b.3d.4d.5b.6e, 1a.2b.3d.4d.5b.6f,
1a.2b.3d.4d.5c.6a,1a.2b.3d.4d.5c.6b,1a.2b.3d.4d.5c.6c,1a.2b.3d.4d.5c.6d,1a.2b.3d.4d.5c.6e,
1a.2b.3d.4d.5c.6f, 1a.2b.3d.4d.5d.6a, 1a.2b.3d.4d.5d.6b, 1a.2b.3d.4d.5d.6c,
1a.2b.3d.4d.5d.6d, 1a.2b.3d.4d.5d.6e, 1a.2b.3d.4d.5d.6f, 1a.2b.3d.4d.5e.6a,
1a.2b.3d.4d.5e.6b,1a.2b.3d.4d.5e.6c,1a.2b.3d.4d.5e.6d,1a.2b.3d.4d.5e.6e,1a.2b.3d.4d.5e.6f,
1a.2b.3d.4d.5f.6a,1a.2b.3d.4d.5f.6b,1a.2b.3d.4d.5f.6c,1a.2b.3d.4d.5f.6d,1a.2b.3d.4d.5f.6e,
1a.2b.3d.4d.5f.6f,1a.2b.3d.4e.5a.6a,1a.2b.3d.4e.5a.6b,1a.2b.3d.4e.5a.6c,1a.2b.3d.4e.5a.6d,
1a.2b.3d.4e.5a.6e,1a.2b.3d.4e.5a.6f,1a.2b.3d.4e.5b.6a,1a.2b.3d.4e.5b.6b,1a.2b.3d.4e.5b.6c,
1a.2b.3d.4e.5b.6d,1a.2b.3d.4e.5b.6e,1a.2b.3d.4e.5b.6f,1a.2b.3d.4e.5c.6a,1a.2b.3d.4e.5c.6b,
1a.2b.3d.4e.5c.6c,1a.2b.3d.4e.5c.6d,1a.2b.3d.4e.5c.6e,1a.2b.3d.4e.5c.6f,1a.2b.3d.4e.5d.6a,
1a.2b.3d.4e.5d.6b,1a.2b.3d.4e.5d.6c,1a.2b.3d.4e.5d.6d,1a.2b.3d.4e.5d.6e,1a.2b.3d.4e.5d.6f,
1a.2b.3d.4e.5e.6a,1a.2b.3d.4e.5e.6b,1a.2b.3d.4e.5e.6c,1a.2b.3d.4e.5e.6d,1a.2b.3d.4e.5e.6e,
1a.2b.3d.4e.5e.6f,1a.2b.3d.4e.5f.6a,1a.2b.3d.4e.5f.6b,1a.2b.3d.4e.5f.6c,1a.2b.3d.4e.5f.6d,
1a.2b.3d.4e.5f.6e,1a.2b.3d.4e.5f.6f,1a.2b.3d.4f.5a.6a,1a.2b.3d.4f.5a.6b,1a.2b.3d.4f.5a.6c,
1a.2b.3d.4f.5a.6d,1a.2b.3d.4f.5a.6e,1a.2b.3d.4f.5a.6f,1a.2b.3d.4f.5b.6a,1a.2b.3d.4f.5b.6b,
1a.2b.3d.4f.5b.6c,1a.2b.3d.4f.5b.6d,1a.2b.3d.4f.5b.6e,1a.2b.3d.4f.5b.6f,1a.2b.3d.4f.5c.6a,
1a.2b.3d.4f.5c.6b,1a.2b.3d.4f.5c.6c,1a.2b.3d.4f.5c.6d,1a.2b.3d.4f.5c.6e,1a.2b.3d.4f.5c.6f,
1a.2b.3d.4f.5d.6a,1a.2b.3d.4f.5d.6b,1a.2b.3d.4f.5d.6c,1a.2b.3d.4f.5d.6d,1a.2b.3d.4f.5d.6e,
1a.2b.3d.4f.5d.6f,1a.2b.3d.4f.5e.6a,1a.2b.3d.4f.5e.6b,1a.2b.3d.4f.5e.6c,1a.2b.3d.4f.5e.6d,
1a.2b.3d.4f.5e.6e,1a.2b.3d.4f.5e.6f,1a.2b.3d.4f.5f.6a,1a.2b.3d.4f.5f.6b,1a.2b.3d.4f.5f.6c,
1a.2b.3d.4f.5f.6d,1a.2b.3d.4f.5f.6e,1a.2b.3d.4f.5f.6f,1a.2b.3e.4a.5a.6a,1a.2b.3e.4a.5a.6b,
1a.2b.3e.4a.5a.6c,1a.2b.3e.4a.5a.6d,1a.2b.3e.4a.5a.6e,1a.2b.3e.4a.5a.6f,1a.2b.3e.4a.5b.6a,
1a.2b.3e.4a.5b.6b,1a.2b.3e.4a.5b.6c,1a.2b.3e.4a.5b.6d,1a.2b.3e.4a.5b.6e,1a.2b.3e.4a.5b.6f,
1a.2b.3e.4a.5c.6a,1a.2b.3e.4a.5c.6b,1a.2b.3e.4a.5c.6c,1a.2b.3e.4a.5c.6d,1a.2b.3e.4a.5c.6e,
1a.2b.3e.4a.5c.6f,1a.2b.3e.4a.5d.6a,1a.2b.3e.4a.5d.6b,1a.2b.3e.4a.5d.6c,1a.2b.3e.4a.5d.6d,
1a.2b.3e.4a.5d.6e,1a.2b.3e.4a.5d.6f,1a.2b.3e.4a.5e.6a,1a.2b.3e.4a.5e.6b,1a.2b.3e.4a.5e.6c,
1a.2b.3e.4a.5e.6d,1a.2b.3e.4a.5e.6e,1a.2b.3e.4a.5e.6f,1a.2b.3e.4a.5f.6a,1a.2b.3e.4a.5f.6b,
1a.2b.3e.4a.5f.6c,1a.2b.3e.4a.5f.6d,1a.2b.3e.4a.5f.6e,1a.2b.3e.4a.5f.6f,1a.2b.3e.4b.5a.6a,
1a.2b.3e.4b.5a.6b,1a.2b.3e.4b.5a.6c,1a.2b.3e.4b.5a.6d,1a.2b.3e.4b.5a.6e,1a.2b.3e.4b.5a.6f,
1a.2b.3e.4b.5b.6a,1a.2b.3e.4b.5b.6b,1a.2b.3e.4b.5b.6c,1a.2b.3e.4b.5b.6d,1a.2b.3e.4b.5b.6e,
1a.2b.3e.4b.5b.6f,1a.2b.3e.4b.5c.6a,1a.2b.3e.4b.5c.6b,1a.2b.3e.4b.5c.6c,1a.2b.3e.4b.5c.6d,
1a.2b.3e.4b.5c.6e,1a.2b.3e.4b.5c.6f,1a.2b.3e.4b.5d.6a,1a.2b.3e.4b.5d.6b,1a.2b.3e.4b.5d.6c,
1a.2b.3e.4b.5d.6d,1a.2b.3e.4b.5d.6e,1a.2b.3e.4b.5d.6f,1a.2b.3e.4b.5e.6a,1a.2b.3e.4b.5e.6b,
1a.2b.3e.4b.5e.6c,1a.2b.3e.4b.5e.6d,1a.2b.3e.4b.5e.6e,1a.2b.3e.4b.5e.6f,1a.2b.3e.4b.5f.6a,
1a.2b.3e.4b.5f.6b,1a.2b.3e.4b.5f.6c,1a.2b.3e.4b.5f.6d,1a.2b.3e.4b.5f.6e,1a.2b.3e.4b.5f.6f,
1a.2b.3e.4c.5a.6a,1a.2b.3e.4c.5a.6b,1a.2b.3e.4c.5a.6c,1a.2b.3e.4c.5a.6d,1a.2b.3e.4c.5a.6e,
1a.2b.3e.4c.5a.6f,1a.2b.3e.4c.5b.6a,1a.2b.3e.4c.5b.6b,1a.2b.3e.4c.5b.6c,1a.2b.3e.4c.5b.6d,
1a.2b.3e.4c.5b.6e,1a.2b.3e.4c.5b.6f,1a.2b.3e.4c.5c.6a,1a.2b.3e.4c.5c.6b,1a.2b.3e.4c.5c.6c,
1a.2b.3e.4c.5c.6d,1a.2b.3e.4c.5c.6e,1a.2b.3e.4c.5c.6f,1a.2b.3e.4c.5d.6a,1a.2b.3e.4c.5d.6b,
1a.2b.3e.4c.5d.6c,1a.2b.3e.4c.5d.6d,1a.2b.3e.4c.5d.6e,1a.2b.3e.4c.5d.6f,1a.2b.3e.4c.5e.6a,
1a.2b.3e.4c.5e.6b,1a.2b.3e.4c.5e.6c,1a.2b.3e.4c.5e.6d,1a.2b.3e.4c.5e.6e,1a.2b.3e.4c.5e.6f,
1a.2b.3e.4c.5f.6a,1a.2b.3e.4c.5f.6b,1a.2b.3e.4c.5f.6c,1a.2b.3e.4c.5f.6d,1a.2b.3e.4c.5f.6e,
1a.2b.3e.4c.5f.6f,1a.2b.3e.4d.5a.6a,1a.2b.3e.4d.5a.6b,1a.2b.3e.4d.5a.6c,1a.2b.3e.4d.5a.6d,
1a.2b.3e.4d.5a.6e,1a.2b.3e.4d.5a.6f,1a.2b.3e.4d.5b.6a,1a.2b.3e.4d.5b.6b,1a.2b.3e.4d.5b.6c,
1a.2b.3e.4d.5b.6d,1a.2b.3e.4d.5b.6e,1a.2b.3e.4d.5b.6f,1a.2b.3e.4d.5c.6a,1a.2b.3e.4d.5c.6b,
1a.2b.3e.4d.5c.6c,1a.2b.3e.4d.5c.6d,1a.2b.3e.4d.5c.6e,1a.2b.3e.4d.5c.6f,1a.2b.3e.4d.5d.6a,
1a.2b.3e.4d.5d.6b,1a.2b.3e.4d.5d.6c,1a.2b.3e.4d.5d.6d,1a.2b.3e.4d.5d.6e,1a.2b.3e.4d.5d.6f,
1a.2b.3e.4d.5e.6a,1a.2b.3e.4d.5e.6b,1a.2b.3e.4d.5e.6c,1a.2b.3e.4d.5e.6d,1a.2b.3e.4d.5e.6e,
1a.2b.3e.4d.5e.6f,1a.2b.3e.4d.5f.6a,1a.2b.3e.4d.5f.6b,1a.2b.3e.4d.5f.6c,1a.2b.3e.4d.5f.6d,
1a.2b.3e.4d.5f.6e,1a.2b.3e.4d.5f.6f,1a.2b.3e.4e.5a.6a,1a.2b.3e.4e.5a.6b,1a.2b.3e.4e.5a.6c,
1a.2b.3e.4e.5a.6d,1a.2b.3e.4e.5a.6e,1a.2b.3e.4e.5a.6f,1a.2b.3e.4e.5b.6a,1a.2b.3e.4e.5b.6b,
1a.2b.3e.4e.5b.6c,1a.2b.3e.4e.5b.6d,1a.2b.3e.4e.5b.6e,1a.2b.3e.4e.5b.6f,1a.2b.3e.4e.5c.6a,
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1a.2d.3a.4e.5e.6e,1a.2d.3a.4e.5e.6f,1a.2d.3a.4e.5f.6a,1a.2d.3a.4e.5f.6b,1a.2d.3a.4e.5f.6c,
1a.2d.3a.4e.5f.6d,1a.2d.3a.4e.5f.6e,1a.2d.3a.4e.5f.6f,1a.2d.3a.4f.5a.6a,1a.2d.3a.4f.5a.6b,
1a.2d.3a.4f.5a.6c,1a.2d.3a.4f.5a.6d,1a.2d.3a.4f.5a.6e,1a.2d.3a.4f.5a.6f,1a.2d.3a.4f.5b.6a,
1a.2d.3a.4f.5b.6b,1a.2d.3a.4f.5b.6c,1a.2d.3a.4f.5b.6d,1a.2d.3a.4f.5b.6e,1a.2d.3a.4f.5b.6f,
1a.2d.3a.4f.5c.6a,1a.2d.3a.4f.5c.6b,1a.2d.3a.4f.5c.6c,1a.2d.3a.4f.5c.6d,1a.2d.3a.4f.5c.6e,
1a.2d.3a.4f.5c.6f,1a.2d.3a.4f.5d.6a,1a.2d.3a.4f.5d.6b,1a.2d.3a.4f.5d.6c,1a.2d.3a.4f.5d.6d,
1a.2d.3a.4f.5d.6e,1a.2d.3a.4f.5d.6f,1a.2d.3a.4f.5e.6a,1a.2d.3a.4f.5e.6b,1a.2d.3a.4f.5e.6c,
1a.2d.3a.4f.5e.6d,1a.2d.3a.4f.5e.6e,1a.2d.3a.4f.5e.6f,1a.2d.3a.4f.5f.6a,1a.2d.3a.4f.5f.6b,
1a.2d.3a.4f.5f.6c,1a.2d.3a.4f.5f.6d,1a.2d.3a.4f.5f.6e,1a.2d.3a.4f.5f.6f,1a.2d.3b.4a.5a.6a,
1a.2d.3b.4a.5a.6b,1a.2d.3b.4a.5a.6c,1a.2d.3b.4a.5a.6d,1a.2d.3b.4a.5a.6e,1a.2d.3b.4a.5a.6f,
1a.2d.3b.4a.5b.6a,1a.2d.3b.4a.5b.6b,1a.2d.3b.4a.5b.6c,1a.2d.3b.4a.5b.6d,1a.2d.3b.4a.5b.6e,
1a.2d.3b.4a.5b.6f,1a.2d.3b.4a.5c.6a,1a.2d.3b.4a.5c.6b,1a.2d.3b.4a.5c.6c,1a.2d.3b.4a.5c.6d,
1a.2d.3b.4a.5c.6e,1a.2d.3b.4a.5c.6f,1a.2d.3b.4a.5d.6a,1a.2d.3b.4a.5d.6b,1a.2d.3b.4a.5d.6c,
1a.2d.3b.4a.5d.6d,1a.2d.3b.4a.5d.6e,1a.2d.3b.4a.5d.6f,1a.2d.3b.4a.5e.6a,1a.2d.3b.4a.5e.6b,
1a.2d.3b.4a.5e.6c,1a.2d.3b.4a.5e.6d,1a.2d.3b.4a.5e.6e,1a.2d.3b.4a.5e.6f,1a.2d.3b.4a.5f.6a,
1a.2d.3b.4a.5f.6b,1a.2d.3b.4a.5f.6c,1a.2d.3b.4a.5f.6d,1a.2d.3b.4a.5f.6e,1a.2d.3b.4a.5f.6f,
1a.2d.3b.4b.5a.6a,1a.2d.3b.4b.5a.6b,1a.2d.3b.4b.5a.6c,1a.2d.3b.4b.5a.6d,1a.2d.3b.4b.5a.6e,
1a.2d.3b.4b.5a.6f,1a.2d.3b.4b.5b.6a,1a.2d.3b.4b.5b.6b,1a.2d.3b.4b.5b.6c,1a.2d.3b.4b.5b.6d,
1a.2d.3b.4b.5b.6e,1a.2d.3b.4b.5b.6f,1a.2d.3b.4b.5c.6a,1a.2d.3b.4b.5c.6b,1a.2d.3b.4b.5c.6c,
1a.2d.3b.4b.5c.6d,1a.2d.3b.4b.5c.6e,1a.2d.3b.4b.5c.6f,1a.2d.3b.4b.5d.6a,1a.2d.3b.4b.5d.6b,
1a.2d.3b.4b.5d.6c, 1a.2d.3b.4b.5d.6d, 1a.2d.3b.4b.5d.6e, 1a.2d.3b.4b.5d.6f,
1a.2d.3b.4b.5e.6a,1a.2d.3b.4b.5e.6b,1a.2d.3b.4b.5e.6c,1a.2d.3b.4b.5e.6d,1a.2d.3b.4b.5e.6e,
1a.2d.3b.4b.5e.6f,1a.2d.3b.4b.5f.6a,1a.2d.3b.4b.5f.6b,1a.2d.3b.4b.5f.6c,1a.2d.3b.4b.5f.6d,
1a.2d.3b.4b.5f.6e,1a.2d.3b.4b.5f.6f,1a.2d.3b.4c.5a.6a,1a.2d.3b.4c.5a.6b,1a.2d.3b.4c.5a.6c,
1a.2d.3b.4c.5a.6d,1a.2d.3b.4c.5a.6e,1a.2d.3b.4c.5a.6f,1a.2d.3b.4c.5b.6a,1a.2d.3b.4c.5b.6b,
1a.2d.3b.4c.5b.6c,1a.2d.3b.4c.5b.6d,1a.2d.3b.4c.5b.6e,1a.2d.3b.4c.5b.6f,1a.2d.3b.4c.5c.6a,
1a.2d.3b.4c.5c.6b,1a.2d.3b.4c.5c.6c,1a.2d.3b.4c.5c.6d,1a.2d.3b.4c.5c.6e,1a.2d.3b.4c.5c.6f,
1a.2d.3b.4c.5d.6a,1a.2d.3b.4c.5d.6b,1a.2d.3b.4c.5d.6c,1a.2d.3b.4c.5d.6d,1a.2d.3b.4c.5d.6e,
1a.2d.3b.4c.5d.6f,1a.2d.3b.4c.5e.6a,1a.2d.3b.4c.5e.6b,1a.2d.3b.4c.5e.6c,1a.2d.3b.4c.5e.6d,
1a.2d.3b.4c.5e.6e,1a.2d.3b.4c.5e.6f,1a.2d.3b.4c.5f.6a,1a.2d.3b.4c.5f.6b,1a.2d.3b.4c.5f.6c,
1a.2d.3b.4c.5f.6d,1a.2d.3b.4c.5f.6e,1a.2d.3b.4c.5f.6f,1a.2d.3b.4d.5a.6a,1a.2d.3b.4d.5a.6b,
1a.2d.3b.4d.5a.6c,1a.2d.3b.4d.5a.6d,1a.2d.3b.4d.5a.6e,1a.2d.3b.4d.5a.6f,1a.2d.3b.4d.5b.6a,
1a.2d.3b.4d.5b.6b, 1a.2d.3b.4d.5b.6c, 1a.2d.3b.4d.5b.6d, 1a.2d.3b.4d.5b.6e,
1a.2d.3b.4d.5b.6f,1a.2d.3b.4d.5c.6a,1a.2d.3b.4d.5c.6b,1a.2d.3b.4d.5c.6c,1a.2d.3b.4d.5c.6d,
1a.2d.3b.4d.5c.6e, 1a.2d.3b.4d.5c.6f, 1a.2d.3b.4d.5d.6a, 1a.2d.3b.4d.5d.6b,
1a.2d.3b.4d.5d.6c, 1a.2d.3b.4d.5d.6d, 1a.2d.3b.4d.5d.6e, 1a.2d.3b.4d.5d.6f,
1a.2d.3b.4d.5e.6a, 1a.2d.3b.4d.5e.6b, 1a.2d.3b.4d.5e.6c, 1a.2d.3b.4d.5e.6d,
1a.2d.3b.4d.5e.6e,1a.2d.3b.4d.5e.6f,1a.2d.3b.4d.5f.6a,1a.2d.3b.4d.5f.6b,1a.2d.3b.4d.5f.6c,
1a.2d.3b.4d.5f.6d,1a.2d.3b.4d.5f.6e,1a.2d.3b.4d.5f.6f,1a.2d.3b.4e.5a.6a,1a.2d.3b.4e.5a.6b,
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1a.2d.3b.4e.5b.6b,1a.2d.3b.4e.5b.6c,1a.2d.3b.4e.5b.6d,1a.2d.3b.4e.5b.6e,1a.2d.3b.4e.5b.6f,
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1a.2d.3b.4e.5c.6f,1a.2d.3b.4e.5d.6a,1a.2d.3b.4e.5d.6b,1a.2d.3b.4e.5d.6c,1a.2d.3b.4e.5d.6d,
1a.2d.3b.4e.5d.6e,1a.2d.3b.4e.5d.6f,1a.2d.3b.4e.5e.6a,1a.2d.3b.4e.5e.6b,1a.2d.3b.4e.5e.6c,
1a.2d.3b.4e.5e.6d,1a.2d.3b.4e.5e.6e,1a.2d.3b.4e.5e.6f,1a.2d.3b.4e.5f.6a,1a.2d.3b.4e.5f.6b,
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1a.2d.3b.4f.5a.6b,1a.2d.3b.4f.5a.6c,1a.2d.3b.4f.5a.6d,1a.2d.3b.4f.5a.6e,1a.2d.3b.4f.5a.6f,
1a.2d.3b.4f.5b.6a,1a.2d.3b.4f.5b.6b,1a.2d.3b.4f.5b.6c,1a.2d.3b.4f.5b.6d,1a.2d.3b.4f.5b.6e,
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1a.2d.3b.4f.5c.6e,1a.2d.3b.4f.5c.6f,1a.2d.3b.4f.5d.6a,1a.2d.3b.4f.5d.6b,1a.2d.3b.4f.5d.6c,
1a.2d.3b.4f.5d.6d,1a.2d.3b.4f.5d.6e,1a.2d.3b.4f.5d.6f,1a.2d.3b.4f.5e.6a,1a.2d.3b.4f.5e.6b,
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1a.2d.3b.4f.5f.6b,1a.2d.3b.4f.5f.6c,1a.2d.3b.4f.5f.6d,1a.2d.3b.4f.5f.6e,1a.2d.3b.4f.5f.6f,
1a.2d.3c.4a.5a.6a,1a.2d.3c.4a.5a.6b,1a.2d.3c.4a.5a.6c,1a.2d.3c.4a.5a.6d,1a.2d.3c.4a.5a.6e,
1a.2d.3c.4a.5a.6f,1a.2d.3c.4a.5b.6a,1a.2d.3c.4a.5b.6b,1a.2d.3c.4a.5b.6c,1a.2d.3c.4a.5b.6d,
1a.2d.3c.4a.5b.6e,1a.2d.3c.4a.5b.6f,1a.2d.3c.4a.5c.6a,1a.2d.3c.4a.5c.6b,1a.2d.3c.4a.5c.6c,
1a.2d.3c.4a.5c.6d,1a.2d.3c.4a.5c.6e,1a.2d.3c.4a.5c.6f,1a.2d.3c.4a.5d.6a,1a.2d.3c.4a.5d.6b,
1a.2d.3c.4a.5d.6c,1a.2d.3c.4a.5d.6d,1a.2d.3c.4a.5d.6e,1a.2d.3c.4a.5d.6f,1a.2d.3c.4a.5e.6a,
1a.2d.3c.4a.5e.6b,1a.2d.3c.4a.5e.6c,1a.2d.3c.4a.5e.6d,1a.2d.3c.4a.5e.6e,1a.2d.3c.4a.5e.6f,
1a.2d.3c.4a.5f.6a,1a.2d.3c.4a.5f.6b,1a.2d.3c.4a.5f.6c,1a.2d.3c.4a.5f.6d,1a.2d.3c.4a.5f.6e,
1a.2d.3c.4a.5f.6f,1a.2d.3c.4b.5a.6a,1a.2d.3c.4b.5a.6b,1a.2d.3c.4b.5a.6c,1a.2d.3c.4b.5a.6d,
1a.2d.3c.4b.5a.6e,1a.2d.3c.4b.5a.6f,1a.2d.3c.4b.5b.6a,1a.2d.3c.4b.5b.6b,1a.2d.3c.4b.5b.6c,
1a.2d.3c.4b.5b.6d,1a.2d.3c.4b.5b.6e,1a.2d.3c.4b.5b.6f,1a.2d.3c.4b.5c.6a,1a.2d.3c.4b.5c.6b,
1a.2d.3c.4b.5c.6c,1a.2d.3c.4b.5c.6d,1a.2d.3c.4b.5c.6e,1a.2d.3c.4b.5c.6f,1a.2d.3c.4b.5d.6a,
1a.2d.3c.4b.5d.6b,1a.2d.3c.4b.5d.6c,1a.2d.3c.4b.5d.6d,1a.2d.3c.4b.5d.6e,1a.2d.3c.4b.5d.6f,
1a.2d.3c.4b.5e.6a,1a.2d.3c.4b.5e.6b,1a.2d.3c.4b.5e.6c,1a.2d.3c.4b.5e.6d,1a.2d.3c.4b.5e.6e,
1a.2d.3c.4b.5e.6f,1a.2d.3c.4b.5f.6a,1a.2d.3c.4b.5f.6b,1a.2d.3c.4b.5f.6c,1a.2d.3c.4b.5f.6d,
1a.2d.3c.4b.5f.6e,1a.2d.3c.4b.5f.6f,1a.2d.3c.4c.5a.6a,1a.2d.3c.4c.5a.6b,1a.2d.3c.4c.5a.6c,
1a.2d.3c.4c.5a.6d,1a.2d.3c.4c.5a.6e,1a.2d.3c.4c.5a.6f,1a.2d.3c.4c.5b.6a,1a.2d.3c.4c.5b.6b,
1a.2d.3c.4c.5b.6c,1a.2d.3c.4c.5b.6d,1a.2d.3c.4c.5b.6e,1a.2d.3c.4c.5b.6f,1a.2d.3c.4c.5c.6a,
1a.2d.3c.4c.5c.6b,1a.2d.3c.4c.5c.6c,1a.2d.3c.4c.5c.6d,1a.2d.3c.4c.5c.6e,1a.2d.3c.4c.5c.6f,
1a.2d.3c.4c.5d.6a,1a.2d.3c.4c.5d.6b,1a.2d.3c.4c.5d.6c,1a.2d.3c.4c.5d.6d,1a.2d.3c.4c.5d.6e,
1a.2d.3c.4c.5d.6f,1a.2d.3c.4c.5e.6a,1a.2d.3c.4c.5e.6b,1a.2d.3c.4c.5e.6c,1a.2d.3c.4c.5e.6d,
1a.2d.3c.4c.5e.6e,1a.2d.3c.4c.5e.6f,1a.2d.3c.4c.5f.6a,1a.2d.3c.4c.5f.6b,1a.2d.3c.4c.5f.6c,
1a.2d.3c.4c.5f.6d,1a.2d.3c.4c.5f.6e,1a.2d.3c.4c.5f.6f,1a.2d.3c.4d.5a.6a,1a.2d.3c.4d.5a.6b,
1a.2d.3c.4d.5a.6c,1a.2d.3c.4d.5a.6d,1a.2d.3c.4d.5a.6e,1a.2d.3c.4d.5a.6f,1a.2d.3c.4d.5b.6a,
1a.2d.3c.4d.5b.6b,1a.2d.3c.4d.5b.6c,1a.2d.3c.4d.5b.6d,1a.2d.3c.4d.5b.6e,1a.2d.3c.4d.5b.6f,
1a.2d.3c.4d.5c.6a,1a.2d.3c.4d.5c.6b,1a.2d.3c.4d.5c.6c,1a.2d.3c.4d.5c.6d,1a.2d.3c.4d.5c.6e,
1a.2d.3c.4d.5c.6f,1a.2d.3c.4d.5d.6a,1a.2d.3c.4d.5d.6b,1a.2d.3c.4d.5d.6c,1a.2d.3c.4d.5d.6d,
1a.2d.3c.4d.5d.6e,1a.2d.3c.4d.5d.6f,1a.2d.3c.4d.5e.6a,1a.2d.3c.4d.5e.6b,1a.2d.3c.4d.5e.6c,
1a.2d.3c.4d.5e.6d,1a.2d.3c.4d.5e.6e,1a.2d.3c.4d.5e.6f,1a.2d.3c.4d.5f.6a,1a.2d.3c.4d.5f.6b,
1a.2d.3c.4d.5f.6c,1a.2d.3c.4d.5f.6d,1a.2d.3c.4d.5f.6e,1a.2d.3c.4d.5f.6f,1a.2d.3c.4e.5a.6a,
1a.2d.3c.4e.5a.6b,1a.2d.3c.4e.5a.6c,1a.2d.3c.4e.5a.6d,1a.2d.3c.4e.5a.6e,1a.2d.3c.4e.5a.6f,
1a.2d.3c.4e.5b.6a,1a.2d.3c.4e.5b.6b,1a.2d.3c.4e.5b.6c,1a.2d.3c.4e.5b.6d,1a.2d.3c.4e.5b.6e,
1a.2d.3c.4e.5b.6f,1a.2d.3c.4e.5c.6a,1a.2d.3c.4e.5c.6b,1a.2d.3c.4e.5c.6c,1a.2d.3c.4e.5c.6d,
1a.2d.3c.4e.5c.6e,1a.2d.3c.4e.5c.6f,1a.2d.3c.4e.5d.6a,1a.2d.3c.4e.5d.6b,1a.2d.3c.4e.5d.6c,
1a.2d.3c.4e.5d.6d,1a.2d.3c.4e.5d.6e,1a.2d.3c.4e.5d.6f,1a.2d.3c.4e.5e.6a,1a.2d.3c.4e.5e.6b,
1a.2d.3c.4e.5e.6c,1a.2d.3c.4e.5e.6d,1a.2d.3c.4e.5e.6e,1a.2d.3c.4e.5e.6f,1a.2d.3c.4e.5f.6a,
1a.2d.3c.4e.5f.6b,1a.2d.3c.4e.5f.6c,1a.2d.3c.4e.5f.6d,1a.2d.3c.4e.5f.6e,1a.2d.3c.4e.5f.6f,
1a.2d.3c.4f.5a.6a,1a.2d.3c.4f.5a.6b,1a.2d.3c.4f.5a.6c,1a.2d.3c.4f.5a.6d,1a.2d.3c.4f.5a.6e,
1a.2d.3c.4f.5a.6f,1a.2d.3c.4f.5b.6a,1a.2d.3c.4f.5b.6b,1a.2d.3c.4f.5b.6c,1a.2d.3c.4f.5b.6d,
1a.2d.3c.4f.5b.6e,1a.2d.3c.4f.5b.6f,1a.2d.3c.4f.5c.6a,1a.2d.3c.4f.5c.6b,1a.2d.3c.4f.5c.6c,
1a.2d.3c.4f.5c.6d,1a.2d.3c.4f.5c.6e,1a.2d.3c.4f.5c.6f,1a.2d.3c.4f.5d.6a,1a.2d.3c.4f.5d.6b,
1a.2d.3c.4f.5d.6c,1a.2d.3c.4f.5d.6d,1a.2d.3c.4f.5d.6e,1a.2d.3c.4f.5d.6f,1a.2d.3c.4f.5e.6a,
1a.2d.3c.4f.5e.6b,1a.2d.3c.4f.5e.6c,1a.2d.3c.4f.5e.6d,1a.2d.3c.4f.5e.6e,1a.2d.3c.4f.5e.6f,
1a.2d.3c.4f.5f.6a,1a.2d.3c.4f.5f.6b,1a.2d.3c.4f.5f.6c,1a.2d.3c.4f.5f.6d,1a.2d.3c.4f.5f.6e,
1a.2d.3c.4f.5f.6f,1a.2d.3d.4a.5a.6a,1a.2d.3d.4a.5a.6b,1a.2d.3d.4a.5a.6c,1a.2d.3d.4a.5a.6d,
1a.2d.3d.4a.5a.6e,1a.2d.3d.4a.5a.6f,1a.2d.3d.4a.5b.6a,1a.2d.3d.4a.5b.6b,1a.2d.3d.4a.5b.6c,
1a.2d.3d.4a.5b.6d,1a.2d.3d.4a.5b.6e,1a.2d.3d.4a.5b.6f,1a.2d.3d.4a.5c.6a,1a.2d.3d.4a.5c.6b,
1a.2d.3d.4a.5c.6c,1a.2d.3d.4a.5c.6d,1a.2d.3d.4a.5c.6e,1a.2d.3d.4a.5c.6f,1a.2d.3d.4a.5d.6a,
1a.2d.3d.4a.5d.6b, 1a.2d.3d.4a.5d.6c, 1a.2d.3d.4a.5d.6d, 1a.2d.3d.4a.5d.6e,
1a.2d.3d.4a.5d.6f,1a.2d.3d.4a.5e.6a,1a.2d.3d.4a.5e.6b,1a.2d.3d.4a.5e.6c,1a.2d.3d.4a.5e.6d,
1a.2d.3d.4a.5e.6e,1a.2d.3d.4a.5e.6f,1a.2d.3d.4a.5f.6a,1a.2d.3d.4a.5f.6b,1a.2d.3d.4a.5f.6c,
1a.2d.3d.4a.5f.6d,1a.2d.3d.4a.5f.6e,1a.2d.3d.4a.5f.6f,1a.2d.3d.4b.5a.6a,1a.2d.3d.4b.5a.6b,
1a.2d.3d.4b.5a.6c,1a.2d.3d.4b.5a.6d,1a.2d.3d.4b.5a.6e,1a.2d.3d.4b.5a.6f,1a.2d.3d.4b.5b.6a,
1a.2d.3d.4b.5b.6b, 1a.2d.3d.4b.5b.6c, 1a.2d.3d.4b.5b.6d, 1a.2d.3d.4b.5b.6e,
1a.2d.3d.4b.5b.6f,1a.2d.3d.4b.5c.6a,1a.2d.3d.4b.5c.6b,1a.2d.3d.4b.5c.6c,1a.2d.3d.4b.5c.6d,
1a.2d.3d.4b.5c.6e, 1a.2d.3d.4b.5c.6f, 1a.2d.3d.4b.5d.6a, 1a.2d.3d.4b.5d.6b,
1a.2d.3d.4b.5d.6c, 1a.2d.3d.4b.5d.6d, 1a.2d.3d.4b.5d.6e, 1a.2d.3d.4b.5d.6f,
1a.2d.3d.4b.5e.6a, 1a.2d.3d.4b.5e.6b, 1a.2d.3d.4b.5e.6c, 1a.2d.3d.4b.5e.6d,
1a.2d.3d.4b.5e.6e,1a.2d.3d.4b.5e.6f,1a.2d.3d.4b.5f.6a,1a.2d.3d.4b.5f.6b,1a.2d.3d.4b.5f.6c,
1a.2d.3d.4b.5f.6d,1a.2d.3d.4b.5f.6e,1a.2d.3d.4b.5f.6f,1a.2d.3d.4c.5a.6a,1a.2d.3d.4c.5a.6b,
1a.2d.3d.4c.5a.6c,1a.2d.3d.4c.5a.6d,1a.2d.3d.4c.5a.6e,1a.2d.3d.4c.5a.6f,1a.2d.3d.4c.5b.6a,
1a.2d.3d.4c.5b.6b,1a.2d.3d.4c.5b.6c,1a.2d.3d.4c.5b.6d,1a.2d.3d.4c.5b.6e,1a.2d.3d.4c.5b.6f,
1a.2d.3d.4c.5c.6a,1a.2d.3d.4c.5c.6b,1a.2d.3d.4c.5c.6c,1a.2d.3d.4c.5c.6d,1a.2d.3d.4c.5c.6e,
1a.2d.3d.4c.5c.6f,1a.2d.3d.4c.5d.6a,1a.2d.3d.4c.5d.6b,1a.2d.3d.4c.5d.6c,1a.2d.3d.4c.5d.6d,
1a.2d.3d.4c.5d.6e,1a.2d.3d.4c.5d.6f,1a.2d.3d.4c.5e.6a,1a.2d.3d.4c.5e.6b,1a.2d.3d.4c.5e.6c,
1a.2d.3d.4c.5e.6d,1a.2d.3d.4c.5e.6e,1a.2d.3d.4c.5e.6f,1a.2d.3d.4c.5f.6a,1a.2d.3d.4c.5f.6b,
1a.2d.3d.4c.5f.6c,1a.2d.3d.4c.5f.6d,1a.2d.3d.4c.5f.6e,1a.2d.3d.4c.5f.6f,1a.2d.3d.4d.5a.6a,
1a.2d.3d.4d.5a.6b, 1a.2d.3d.4d.5a.6c, 1a.2d.3d.4d.5a.6d, 1a.2d.3d.4d.5a.6e,
1a.2d.3d.4d.5a.6f, 1a.2d.3d.4d.5b.6a, 1a.2d.3d.4d.5b.6b, 1a.2d.3d.4d.5b.6c,
1a.2d.3d.4d.5b.6d, 1a.2d.3d.4d.5b.6e, 1a.2d.3d.4d.5b.6f, 1a.2d.3d.4d.5c.6a,
1a.2d.3d.4d.5c.6b,1a.2d.3d.4d.5c.6c,1a.2d.3d.4d.5c.6d,1a.2d.3d.4d.5c.6e,1a.2d.3d.4d.5c.6f,
1a.2d.3d.4d.5d.6a, 1a.2d.3d.4d.5d.6b, 1a.2d.3d.4d.5d.6c, 1a.2d.3d.4d.5d.6d,
1a.2d.3d.4d.5d.6e, 1a.2d.3d.4d.5d.6f, 1a.2d.3d.4d.5e.6a, 1a.2d.3d.4d.5e.6b,
1a.2d.3d.4d.5e.6c,1a.2d.3d.4d.5e.6d,1a.2d.3d.4d.5e.6e,1a.2d.3d.4d.5e.6f,1a.2d.3d.4d.5f.6a,
1a.2d.3d.4d.5f.6b,1a.2d.3d.4d.5f.6c,1a.2d.3d.4d.5f.6d,1a.2d.3d.4d.5f.6e,1a.2d.3d.4d.5f.6f,
1a.2d.3d.4e.5a.6a,1a.2d.3d.4e.5a.6b,1a.2d.3d.4e.5a.6c,1a.2d.3d.4e.5a.6d,1a.2d.3d.4e.5a.6e,
1a.2d.3d.4e.5a.6f,1a.2d.3d.4e.5b.6a,1a.2d.3d.4e.5b.6b,1a.2d.3d.4e.5b.6c,1a.2d.3d.4e.5b.6d,
1a.2d.3d.4e.5b.6e,1a.2d.3d.4e.5b.6f,1a.2d.3d.4e.5c.6a,1a.2d.3d.4e.5c.6b,1a.2d.3d.4e.5c.6c,
1a.2d.3d.4e.5c.6d,1a.2d.3d.4e.5c.6e,1a.2d.3d.4e.5c.6f,1a.2d.3d.4e.5d.6a,1a.2d.3d.4e.5d.6b,
1a.2d.3d.4e.5d.6c,1a.2d.3d.4e.5d.6d,1a.2d.3d.4e.5d.6e,1a.2d.3d.4e.5d.6f,1a.2d.3d.4e.5e.6a,
1a.2d.3d.4e.5e.6b,1a.2d.3d.4e.5e.6c,1a.2d.3d.4e.5e.6d,1a.2d.3d.4e.5e.6e,1a.2d.3d.4e.5e.6f,
1a.2d.3d.4e.5f.6a,1a.2d.3d.4e.5f.6b,1a.2d.3d.4e.5f.6c,1a.2d.3d.4e.5f.6d,1a.2d.3d.4e.5f.6e,
1a.2d.3d.4e.5f.6f,1a.2d.3d.4f.5a.6a,1a.2d.3d.4f.5a.6b,1a.2d.3d.4f.5a.6c,1a.2d.3d.4f.5a.6d,
1a.2d.3d.4f.5a.6e,1a.2d.3d.4f.5a.6f,1a.2d.3d.4f.5b.6a,1a.2d.3d.4f.5b.6b,1a.2d.3d.4f.5b.6c,
1a.2d.3d.4f.5b.6d,1a.2d.3d.4f.5b.6e,1a.2d.3d.4f.5b.6f,1a.2d.3d.4f.5c.6a,1a.2d.3d.4f.5c.6b,
1a.2d.3d.4f.5c.6c,1a.2d.3d.4f.5c.6d,1a.2d.3d.4f.5c.6e,1a.2d.3d.4f.5c.6f,1a.2d.3d.4f.5d.6a,
1a.2d.3d.4f.5d.6b,1a.2d.3d.4f.5d.6c,1a.2d.3d.4f.5d.6d,1a.2d.3d.4f.5d.6e,1a.2d.3d.4f.5d.6f,
1a.2d.3d.4f.5e.6a,1a.2d.3d.4f.5e.6b,1a.2d.3d.4f.5e.6c,1a.2d.3d.4f.5e.6d,1a.2d.3d.4f.5e.6e,
1a.2d.3d.4f.5e.6f,1a.2d.3d.4f.5f.6a,1a.2d.3d.4f.5f.6b,1a.2d.3d.4f.5f.6c,1a.2d.3d.4f.5f.6d,
1a.2d.3d.4f.5f.6e,1a.2d.3d.4f.5f.6f,1a.2d.3e.4a.5a.6a,1a.2d.3e.4a.5a.6b,1a.2d.3e.4a.5a.6c,
1a.2d.3e.4a.5a.6d,1a.2d.3e.4a.5a.6e,1a.2d.3e.4a.5a.6f,1a.2d.3e.4a.5b.6a,1a.2d.3e.4a.5b.6b,
1a.2d.3e.4a.5b.6c,1a.2d.3e.4a.5b.6d,1a.2d.3e.4a.5b.6e,1a.2d.3e.4a.5b.6f,1a.2d.3e.4a.5c.6a,
1a.2d.3e.4a.5c.6b,1a.2d.3e.4a.5c.6c,1a.2d.3e.4a.5c.6d,1a.2d.3e.4a.5c.6e,1a.2d.3e.4a.5c.6f,
1a.2d.3e.4a.5d.6a,1a.2d.3e.4a.5d.6b,1a.2d.3e.4a.5d.6c,1a.2d.3e.4a.5d.6d,1a.2d.3e.4a.5d.6e,
1a.2d.3e.4a.5d.6f,1a.2d.3e.4a.5e.6a,1a.2d.3e.4a.5e.6b,1a.2d.3e.4a.5e.6c,1a.2d.3e.4a.5e.6d,
1a.2d.3e.4a.5e.6e,1a.2d.3e.4a.5e.6f,1a.2d.3e.4a.5f.6a,1a.2d.3e.4a.5f.6b,1a.2d.3e.4a.5f.6c,
1a.2d.3e.4a.5f.6d,1a.2d.3e.4a.5f.6e,1a.2d.3e.4a.5f.6f,1a.2d.3e.4b.5a.6a,1a.2d.3e.4b.5a.6b,
1a.2d.3e.4b.5a.6c,1a.2d.3e.4b.5a.6d,1a.2d.3e.4b.5a.6e,1a.2d.3e.4b.5a.6f,1a.2d.3e.4b.5b.6a,
1a.2d.3e.4b.5b.6b,1a.2d.3e.4b.5b.6c,1a.2d.3e.4b.5b.6d,1a.2d.3e.4b.5b.6e,1a.2d.3e.4b.5b.6f,
1a.2d.3e.4b.5c.6a,1a.2d.3e.4b.5c.6b,1a.2d.3e.4b.5c.6c,1a.2d.3e.4b.5c.6d,1a.2d.3e.4b.5c.6e,
1a.2d.3e.4b.5c.6f,1a.2d.3e.4b.5d.6a,1a.2d.3e.4b.5d.6b,1a.2d.3e.4b.5d.6c,1a.2d.3e.4b.5d.6d,
1a.2d.3e.4b.5d.6e,1a.2d.3e.4b.5d.6f,1a.2d.3e.4b.5e.6a,1a.2d.3e.4b.5e.6b,1a.2d.3e.4b.5e.6c,
1a.2d.3e.4b.5e.6d,1a.2d.3e.4b.5e.6e,1a.2d.3e.4b.5e.6f,1a.2d.3e.4b.5f.6a,1a.2d.3e.4b.5f.6b,
1a.2d.3e.4b.5f.6c,1a.2d.3e.4b.5f.6d,1a.2d.3e.4b.5f.6e,1a.2d.3e.4b.5f.6f,1a.2d.3e.4c.5a.6a,
1a.2d.3e.4c.5a.6b,1a.2d.3e.4c.5a.6c,1a.2d.3e.4c.5a.6d,1a.2d.3e.4c.5a.6e,1a.2d.3e.4c.5a.6f,
1a.2d.3e.4c.5b.6a,1a.2d.3e.4c.5b.6b,1a.2d.3e.4c.5b.6c,1a.2d.3e.4c.5b.6d,1a.2d.3e.4c.5b.6e,
1a.2d.3e.4c.5b.6f,1a.2d.3e.4c.5c.6a,1a.2d.3e.4c.5c.6b,1a.2d.3e.4c.5c.6c,1a.2d.3e.4c.5c.6d,
1a.2d.3e.4c.5c.6e,1a.2d.3e.4c.5c.6f,1a.2d.3e.4c.5d.6a,1a.2d.3e.4c.5d.6b,1a.2d.3e.4c.5d.6c,
1a.2d.3e.4c.5d.6d,1a.2d.3e.4c.5d.6e,1a.2d.3e.4c.5d.6f,1a.2d.3e.4c.5e.6a,1a.2d.3e.4c.5e.6b,
1a.2d.3e.4c.5e.6c,1a.2d.3e.4c.5e.6d,1a.2d.3e.4c.5e.6e,1a.2d.3e.4c.5e.6f,1a.2d.3e.4c.5f.6a,
1a.2d.3e.4c.5f.6b,1a.2d.3e.4c.5f.6c,1a.2d.3e.4c.5f.6d,1a.2d.3e.4c.5f.6e,1a.2d.3e.4c.5f.6f,
1a.2d.3e.4d.5a.6a,1a.2d.3e.4d.5a.6b,1a.2d.3e.4d.5a.6c,1a.2d.3e.4d.5a.6d,1a.2d.3e.4d.5a.6e,
1a.2d.3e.4d.5a.6f,1a.2d.3e.4d.5b.6a,1a.2d.3e.4d.5b.6b,1a.2d.3e.4d.5b.6c,1a.2d.3e.4d.5b.6d,
1a.2d.3e.4d.5b.6e,1a.2d.3e.4d.5b.6f,1a.2d.3e.4d.5c.6a,1a.2d.3e.4d.5c.6b,1a.2d.3e.4d.5c.6c,
1a.2d.3e.4d.5c.6d,1a.2d.3e.4d.5c.6e,1a.2d.3e.4d.5c.6f,1a.2d.3e.4d.5d.6a,1a.2d.3e.4d.5d.6b,
1a.2d.3e.4d.5d.6c,1a.2d.3e.4d.5d.6d,1a.2d.3e.4d.5d.6e,1a.2d.3e.4d.5d.6f,1a.2d.3e.4d.5e.6a,
1a.2d.3e.4d.5e.6b,1a.2d.3e.4d.5e.6c,1a.2d.3e.4d.5e.6d,1a.2d.3e.4d.5e.6e,1a.2d.3e.4d.5e.6f,
1a.2d.3e.4d.5f.6a,1a.2d.3e.4d.5f.6b,1a.2d.3e.4d.5f.6c,1a.2d.3e.4d.5f.6d,1a.2d.3e.4d.5f.6e,
1a.2d.3e.4d.5f.6f,1a.2d.3e.4e.5a.6a,1a.2d.3e.4e.5a.6b,1a.2d.3e.4e.5a.6c,1a.2d.3e.4e.5a.6d,
1a.2d.3e.4e.5a.6e,1a.2d.3e.4e.5a.6f,1a.2d.3e.4e.5b.6a,1a.2d.3e.4e.5b.6b,1a.2d.3e.4e.5b.6c,
1a.2d.3e.4e.5b.6d,1a.2d.3e.4e.5b.6e,1a.2d.3e.4e.5b.6f,1a.2d.3e.4e.5c.6a,1a.2d.3e.4e.5c.6b,
1a.2d.3e.4e.5c.6c,1a.2d.3e.4e.5c.6d,1a.2d.3e.4e.5c.6e,1a.2d.3e.4e.5c.6f,1a.2d.3e.4e.5d.6a,
1a.2d.3e.4e.5d.6b,1a.2d.3e.4e.5d.6c,1a.2d.3e.4e.5d.6d,1a.2d.3e.4e.5d.6e,1a.2d.3e.4e.5d.6f,
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1b.2a.3c.4f.5b.6f,1b.2a.3c.4f.5c.6a,1b.2a.3c.4f.5c.6b,1b.2a.3c.4f.5c.6c,1b.2a.3c.4f.5c.6d,
1b.2a.3c.4f.5c.6e,1b.2a.3c.4f.5c.6f,1b.2a.3c.4f.5d.6a,1b.2a.3c.4f.5d.6b,1b.2a.3c.4f.5d.6c,
1b.2a.3c.4f.5d.6d,1b.2a.3c.4f.5d.6e,1b.2a.3c.4f.5d.6f,1b.2a.3c.4f.5e.6a,1b.2a.3c.4f.5e.6b,
1b.2a.3c.4f.5e.6c,1b.2a.3c.4f.5e.6d,1b.2a.3c.4f.5e.6e,1b.2a.3c.4f.5e.6f,1b.2a.3c.4f.5f.6a,
1b.2a.3c.4f.5f.6b,1b.2a.3c.4f.5f.6c,1b.2a.3c.4f.5f.6d,1b.2a.3c.4f.5f.6e,1b.2a.3c.4f.5f.6f,
1b.2a.3d.4a.5a.6a,1b.2a.3d.4a.5a.6b,1b.2a.3d.4a.5a.6c,1b.2a.3d.4a.5a.6d,1b.2a.3d.4a.5a.6e,
1b.2a.3d.4a.5a.6f,1b.2a.3d.4a.5b.6a,1b.2a.3d.4a.5b.6b,1b.2a.3d.4a.5b.6c,1b.2a.3d.4a.5b.6d,
1b.2a.3d.4a.5b.6e,1b.2a.3d.4a.5b.6f,1b.2a.3d.4a.5c.6a,1b.2a.3d.4a.5c.6b,1b.2a.3d.4a.5c.6c,
1b.2a.3d.4a.5c.6d,1b.2a.3d.4a.5c.6e,1b.2a.3d.4a.5c.6f,1b.2a.3d.4a.5d.6a,1b.2a.3d.4a.5d.6b,
1b.2a.3d.4a.5d.6c,1b.2a.3d.4a.5d.6d,1b.2a.3d.4a.5d.6e,1b.2a.3d.4a.5d.6f,1b.2a.3d.4a.5e.6a,
1b.2a.3d.4a.5e.6b,1b.2a.3d.4a.5e.6c,1b.2a.3d.4a.5e.6d,1b.2a.3d.4a.5e.6e,1b.2a.3d.4a.5e.6f,
1b.2a.3d.4a.5f.6a,1b.2a.3d.4a.5f.6b,1b.2a.3d.4a.5f.6c,1b.2a.3d.4a.5f.6d,1b.2a.3d.4a.5f.6e,
1b.2a.3d.4a.5f.6f,1b.2a.3d.4b.5a.6a,1b.2a.3d.4b.5a.6b,1b.2a.3d.4b.5a.6c,1b.2a.3d.4b.5a.6d,
1b.2a.3d.4b.5a.6e,1b.2a.3d.4b.5a.6f,1b.2a.3d.4b.5b.6a,1b.2a.3d.4b.5b.6b,1b.2a.3d.4b.5b.6c,
1b.2a.3d.4b.5b.6d,1b.2a.3d.4b.5b.6e,1b.2a.3d.4b.5b.6f,1b.2a.3d.4b.5c.6a,1b.2a.3d.4b.5c.6b,
1b.2a.3d.4b.5c.6c,1b.2a.3d.4b.5c.6d,1b.2a.3d.4b.5c.6e,1b.2a.3d.4b.5c.6f,1b.2a.3d.4b.5d.6a,
1b.2a.3d.4b.5d.6b, 1b.2a.3d.4b.5d.6c, 1b.2a.3d.4b.5d.6d, 1b.2a.3d.4b.5d.6e,
1b.2a.3d.4b.5d.6f,1b.2a.3d.4b.5e.6a,1b.2a.3d.4b.5e.6b,1b.2a.3d.4b.5e.6c,1b.2a.3d.4b.5e.6d,
1b.2a.3d.4b.5e.6e,1b.2a.3d.4b.5e.6f,1b.2a.3d.4b.5f.6a,1b.2a.3d.4b.5f.6b,1b.2a.3d.4b.5f.6c,
1b.2a.3d.4b.5f.6d,1b.2a.3d.4b.5f.6e,1b.2a.3d.4b.5f.6f,1b.2a.3d.4c.5a.6a,1b.2a.3d.4c.5a.6b,
1b.2a.3d.4c.5a.6c,1b.2a.3d.4c.5a.6d,1b.2a.3d.4c.5a.6e,1b.2a.3d.4c.5a.6f,1b.2a.3d.4c.5b.6a,
1b.2a.3d.4c.5b.6b,1b.2a.3d.4c.5b.6c,1b.2a.3d.4c.5b.6d,1b.2a.3d.4c.5b.6e,1b.2a.3d.4c.5b.6f,
1b.2a.3d.4c.5c.6a,1b.2a.3d.4c.5c.6b,1b.2a.3d.4c.5c.6c,1b.2a.3d.4c.5c.6d,1b.2a.3d.4c.5c.6e,
1b.2a.3d.4c.5c.6f,1b.2a.3d.4c.5d.6a,1b.2a.3d.4c.5d.6b,1b.2a.3d.4c.5d.6c,1b.2a.3d.4c.5d.6d,
1b.2a.3d.4c.5d.6e,1b.2a.3d.4c.5d.6f,1b.2a.3d.4c.5e.6a,1b.2a.3d.4c.5e.6b,1b.2a.3d.4c.5e.6c,
1b.2a.3d.4c.5e.6d,1b.2a.3d.4c.5e.6e,1b.2a.3d.4c.5e.6f,1b.2a.3d.4c.5f.6a,1b.2a.3d.4c.5f.6b,
1b.2a.3d.4c.5f.6c,1b.2a.3d.4c.5f.6d,1b.2a.3d.4c.5f.6e,1b.2a.3d.4c.5f.6f,1b.2a.3d.4d.5a.6a,
1b.2a.3d.4d.5a.6b,1b.2a.3d.4d.5a.6c,1b.2a.3d.4d.5a.6d,1b.2a.3d.4d.5a.6e,1b.2a.3d.4d.5a.6f,
1b.2a.3d.4d.5b.6a, 1b.2a.3d.4d.5b.6b, 1b.2a.3d.4d.5b.6c, 1b.2a.3d.4d.5b.6d,
1b.2a.3d.4d.5b.6e,1b.2a.3d.4d.5b.6f,1b.2a.3d.4d.5c.6a,1b.2a.3d.4d.5c.6b,1b.2a.3d.4d.5c.6c,
1b.2a.3d.4d.5c.6d, 1b.2a.3d.4d.5c.6e, 1b.2a.3d.4d.5c.6f, 1b.2a.3d.4d.5d.6a,
1b.2a.3d.4d.5d.6b, 1b.2a.3d.4d.5d.6c, 1b.2a.3d.4d.5d.6d, 1b.2a.3d.4d.5d.6e,
1b.2a.3d.4d.5d.6f, 1b.2a.3d.4d.5e.6a, 1b.2a.3d.4d.5e.6b, 1b.2a.3d.4d.5e.6c,
1b.2a.3d.4d.5e.6d,1b.2a.3d.4d.5e.6e,1b.2a.3d.4d.5e.6f,1b.2a.3d.4d.5f.6a,1b.2a.3d.4d.5f.6b,
1b.2a.3d.4d.5f.6c,1b.2a.3d.4d.5f.6d,1b.2a.3d.4d.5f.6e,1b.2a.3d.4d.5f.6f,1b.2a.3d.4e.5a.6a,
1b.2a.3d.4e.5a.6b,1b.2a.3d.4e.5a.6c,1b.2a.3d.4e.5a.6d,1b.2a.3d.4e.5a.6e,1b.2a.3d.4e.5a.6f,
1b.2a.3d.4e.5b.6a,1b.2a.3d.4e.5b.6b,1b.2a.3d.4e.5b.6c,1b.2a.3d.4e.5b.6d,1b.2a.3d.4e.5b.6e,
1b.2a.3d.4e.5b.6f,1b.2a.3d.4e.5c.6a,1b.2a.3d.4e.5c.6b,1b.2a.3d.4e.5c.6c,1b.2a.3d.4e.5c.6d,
1b.2a.3d.4e.5c.6e,1b.2a.3d.4e.5c.6f,1b.2a.3d.4e.5d.6a,1b.2a.3d.4e.5d.6b,1b.2a.3d.4e.5d.6c,
1b.2a.3d.4e.5d.6d,1b.2a.3d.4e.5d.6e,1b.2a.3d.4e.5d.6f,1b.2a.3d.4e.5e.6a,1b.2a.3d.4e.5e.6b,
1b.2a.3d.4e.5e.6c,1b.2a.3d.4e.5e.6d,1b.2a.3d.4e.5e.6e,1b.2a.3d.4e.5e.6f,1b.2a.3d.4e.5f.6a,
1b.2a.3d.4e.5f.6b,1b.2a.3d.4e.5f.6c,1b.2a.3d.4e.5f.6d,1b.2a.3d.4e.5f.6e,1b.2a.3d.4e.5f.6f,
1b.2a.3d.4f.5a.6a,1b.2a.3d.4f.5a.6b,1b.2a.3d.4f.5a.6c,1b.2a.3d.4f.5a.6d,1b.2a.3d.4f.5a.6e,
1b.2a.3d.4f.5a.6f,1b.2a.3d.4f.5b.6a,1b.2a.3d.4f.5b.6b,1b.2a.3d.4f.5b.6c,1b.2a.3d.4f.5b.6d,
1b.2a.3d.4f.5b.6e,1b.2a.3d.4f.5b.6f,1b.2a.3d.4f.5c.6a,1b.2a.3d.4f.5c.6b,1b.2a.3d.4f.5c.6c,
1b.2a.3d.4f.5c.6d,1b.2a.3d.4f.5c.6e,1b.2a.3d.4f.5c.6f,1b.2a.3d.4f.5d.6a,1b.2a.3d.4f.5d.6b,
1b.2a.3d.4f.5d.6c,1b.2a.3d.4f.5d.6d,1b.2a.3d.4f.5d.6e,1b.2a.3d.4f.5d.6f,1b.2a.3d.4f.5e.6a,
1b.2a.3d.4f.5e.6b,1b.2a.3d.4f.5e.6c,1b.2a.3d.4f.5e.6d,1b.2a.3d.4f.5e.6e,1b.2a.3d.4f.5e.6f,
1b.2a.3d.4f.5f.6a,1b.2a.3d.4f.5f.6b,1b.2a.3d.4f.5f.6c,1b.2a.3d.4f.5f.6d,1b.2a.3d.4f.5f.6e,
1b.2a.3d.4f.5f.6f,1b.2a.3e.4a.5a.6a,1b.2a.3e.4a.5a.6b,1b.2a.3e.4a.5a.6c,1b.2a.3e.4a.5a.6d,
1b.2a.3e.4a.5a.6e,1b.2a.3e.4a.5a.6f,1b.2a.3e.4a.5b.6a,1b.2a.3e.4a.5b.6b,1b.2a.3e.4a.5b.6c,
1b.2a.3e.4a.5b.6d,1b.2a.3e.4a.5b.6e,1b.2a.3e.4a.5b.6f,1b.2a.3e.4a.5c.6a,1b.2a.3e.4a.5c.6b,
1b.2a.3e.4a.5c.6c,1b.2a.3e.4a.5c.6d,1b.2a.3e.4a.5c.6e,1b.2a.3e.4a.5c.6f,1b.2a.3e.4a.5d.6a,
1b.2a.3e.4a.5d.6b,1b.2a.3e.4a.5d.6c,1b.2a.3e.4a.5d.6d,1b.2a.3e.4a.5d.6e,1b.2a.3e.4a.5d.6f,
1b.2a.3e.4a.5e.6a,1b.2a.3e.4a.5e.6b,1b.2a.3e.4a.5e.6c,1b.2a.3e.4a.5e.6d,1b.2a.3e.4a.5e.6e,
1b.2a.3e.4a.5e.6f,1b.2a.3e.4a.5f.6a,1b.2a.3e.4a.5f.6b,1b.2a.3e.4a.5f.6c,1b.2a.3e.4a.5f.6d,
1b.2a.3e.4a.5f.6e,1b.2a.3e.4a.5f.6f,1b.2a.3e.4b.5a.6a,1b.2a.3e.4b.5a.6b,1b.2a.3e.4b.5a.6c,
1b.2a.3e.4b.5a.6d,1b.2a.3e.4b.5a.6e,1b.2a.3e.4b.5a.6f,1b.2a.3e.4b.5b.6a,1b.2a.3e.4b.5b.6b,
1b.2a.3e.4b.5b.6c,1b.2a.3e.4b.5b.6d,1b.2a.3e.4b.5b.6e,1b.2a.3e.4b.5b.6f,1b.2a.3e.4b.5c.6a,
1b.2a.3e.4b.5c.6b,1b.2a.3e.4b.5c.6c,1b.2a.3e.4b.5c.6d,1b.2a.3e.4b.5c.6e,1b.2a.3e.4b.5c.6f,
1b.2a.3e.4b.5d.6a,1b.2a.3e.4b.5d.6b,1b.2a.3e.4b.5d.6c,1b.2a.3e.4b.5d.6d,1b.2a.3e.4b.5d.6e,
1b.2a.3e.4b.5d.6f,1b.2a.3e.4b.5e.6a,1b.2a.3e.4b.5e.6b,1b.2a.3e.4b.5e.6c,1b.2a.3e.4b.5e.6d,
1b.2a.3e.4b.5e.6e,1b.2a.3e.4b.5e.6f,1b.2a.3e.4b.5f.6a,1b.2a.3e.4b.5f.6b,1b.2a.3e.4b.5f.6c,
1b.2a.3e.4b.5f.6d,1b.2a.3e.4b.5f.6e,1b.2a.3e.4b.5f.6f,1b.2a.3e.4c.5a.6a,1b.2a.3e.4c.5a.6b,
1b.2a.3e.4c.5a.6c,1b.2a.3e.4c.5a.6d,1b.2a.3e.4c.5a.6e,1b.2a.3e.4c.5a.6f,1b.2a.3e.4c.5b.6a,
1b.2a.3e.4c.5b.6b,1b.2a.3e.4c.5b.6c,1b.2a.3e.4c.5b.6d,1b.2a.3e.4c.5b.6e,1b.2a.3e.4c.5b.6f,
1b.2a.3e.4c.5c.6a,1b.2a.3e.4c.5c.6b,1b.2a.3e.4c.5c.6c,1b.2a.3e.4c.5c.6d,1b.2a.3e.4c.5c.6e,
1b.2a.3e.4c.5c.6f,1b.2a.3e.4c.5d.6a,1b.2a.3e.4c.5d.6b,1b.2a.3e.4c.5d.6c,1b.2a.3e.4c.5d.6d,
1b.2a.3e.4c.5d.6e,1b.2a.3e.4c.5d.6f,1b.2a.3e.4c.5e.6a,1b.2a.3e.4c.5e.6b,1b.2a.3e.4c.5e.6c,
1b.2a.3e.4c.5e.6d,1b.2a.3e.4c.5e.6e,1b.2a.3e.4c.5e.6f,1b.2a.3e.4c.5f.6a,1b.2a.3e.4c.5f.6b,
1b.2a.3e.4c.5f.6c,1b.2a.3e.4c.5f.6d,1b.2a.3e.4c.5f.6e,1b.2a.3e.4c.5f.6f,1b.2a.3e.4d.5a.6a,
1b.2a.3e.4d.5a.6b,1b.2a.3e.4d.5a.6c,1b.2a.3e.4d.5a.6d,1b.2a.3e.4d.5a.6e,1b.2a.3e.4d.5a.6f,
1b.2a.3e.4d.5b.6a,1b.2a.3e.4d.5b.6b,1b.2a.3e.4d.5b.6c,1b.2a.3e.4d.5b.6d,1b.2a.3e.4d.5b.6e,
1b.2a.3e.4d.5b.6f,1b.2a.3e.4d.5c.6a,1b.2a.3e.4d.5c.6b,1b.2a.3e.4d.5c.6c,1b.2a.3e.4d.5c.6d,
1b.2a.3e.4d.5c.6e,1b.2a.3e.4d.5c.6f,1b.2a.3e.4d.5d.6a,1b.2a.3e.4d.5d.6b,1b.2a.3e.4d.5d.6c,
1b.2a.3e.4d.5d.6d,1b.2a.3e.4d.5d.6e,1b.2a.3e.4d.5d.6f,1b.2a.3e.4d.5e.6a,1b.2a.3e.4d.5e.6b,
1b.2a.3e.4d.5e.6c,1b.2a.3e.4d.5e.6d,1b.2a.3e.4d.5e.6e,1b.2a.3e.4d.5e.6f,1b.2a.3e.4d.5f.6a,
1b.2a.3e.4d.5f.6b,1b.2a.3e.4d.5f.6c,1b.2a.3e.4d.5f.6d,1b.2a.3e.4d.5f.6e,1b.2a.3e.4d.5f.6f,
1b.2a.3e.4e.5a.6a,1b.2a.3e.4e.5a.6b,1b.2a.3e.4e.5a.6c,1b.2a.3e.4e.5a.6d,1b.2a.3e.4e.5a.6e,
1b.2a.3e.4e.5a.6f,1b.2a.3e.4e.5b.6a,1b.2a.3e.4e.5b.6b,1b.2a.3e.4e.5b.6c,1b.2a.3e.4e.5b.6d,
1b.2a.3e.4e.5b.6e,1b.2a.3e.4e.5b.6f,1b.2a.3e.4e.5c.6a,1b.2a.3e.4e.5c.6b,1b.2a.3e.4e.5c.6c,
1b.2a.3e.4e.5c.6d,1b.2a.3e.4e.5c.6e,1b.2a.3e.4e.5c.6f,1b.2a.3e.4e.5d.6a,1b.2a.3e.4e.5d.6b,
1b.2a.3e.4e.5d.6c,1b.2a.3e.4e.5d.6d,1b.2a.3e.4e.5d.6e,1b.2a.3e.4e.5d.6f,1b.2a.3e.4e.5e.6a,
1b.2a.3e.4e.5e.6b,1b.2a.3e.4e.5e.6c,1b.2a.3e.4e.5e.6d,1b.2a.3e.4e.5e.6e,1b.2a.3e.4e.5e.6f,
1b.2a.3e.4e.5f.6a,1b.2a.3e.4e.5f.6b,1b.2a.3e.4e.5f.6c,1b.2a.3e.4e.5f.6d,1b.2a.3e.4e.5f.6e,
1b.2a.3e.4e.5f.6f,1b.2a.3e.4f.5a.6a,1b.2a.3e.4f.5a.6b,1b.2a.3e.4f.5a.6c,1b.2a.3e.4f.5a.6d,
1b.2a.3e.4f.5a.6e,1b.2a.3e.4f.5a.6f,1b.2a.3e.4f.5b.6a,1b.2a.3e.4f.5b.6b,1b.2a.3e.4f.5b.6c,
1b.2a.3e.4f.5b.6d,1b.2a.3e.4f.5b.6e,1b.2a.3e.4f.5b.6f,1b.2a.3e.4f.5c.6a,1b.2a.3e.4f.5c.6b,
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1b.2a.3e.4f.5d.6b,1b.2a.3e.4f.5d.6c,1b.2a.3e.4f.5d.6d,1b.2a.3e.4f.5d.6e,1b.2a.3e.4f.5d.6f,
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1b.2b.3a.4f.5c.6e,1b.2b.3a.4f.5c.6f,1b.2b.3a.4f.5d.6a,1b.2b.3a.4f.5d.6b,1b.2b.3a.4f.5d.6c,
1b.2b.3a.4f.5d.6d,1b.2b.3a.4f.5d.6e,1b.2b.3a.4f.5d.6f,1b.2b.3a.4f.5e.6a,1b.2b.3a.4f.5e.6b,
1b.2b.3a.4f.5e.6c,1b.2b.3a.4f.5e.6d,1b.2b.3a.4f.5e.6e,1b.2b.3a.4f.5e.6f,1b.2b.3a.4f.5f.6a,
1b.2b.3a.4f.5f.6b,1b.2b.3a.4f.5f.6c,1b.2b.3a.4f.5f.6d,1b.2b.3a.4f.5f.6e,1b.2b.3a.4f.5f.6f,
1b.2b.3b.4a.5a.6a,1b.2b.3b.4a.5a.6b,1b.2b.3b.4a.5a.6c,1b.2b.3b.4a.5a.6d,1b.2b.3b.4a.5a.6e,
1b.2b.3b.4a.5a.6f,1b.2b.3b.4a.5b.6a,1b.2b.3b.4a.5b.6b,1b.2b.3b.4a.5b.6c,1b.2b.3b.4a.5b.6d,
1b.2b.3b.4a.5b.6e,1b.2b.3b.4a.5b.6f,1b.2b.3b.4a.5c.6a,1b.2b.3b.4a.5c.6b,1b.2b.3b.4a.5c.6c,
1b.2b.3b.4a.5c.6d,1b.2b.3b.4a.5c.6e,1b.2b.3b.4a.5c.6f,1b.2b.3b.4a.5d.6a,1b.2b.3b.4a.5d.6b,
1b.2b.3b.4a.5d.6c,1b.2b.3b.4a.5d.6d,1b.2b.3b.4a.5d.6e,1b.2b.3b.4a.5d.6f,1b.2b.3b.4a.5e.6a,
1b.2b.3b.4a.5e.6b,1b.2b.3b.4a.5e.6c,1b.2b.3b.4a.5e.6d,1b.2b.3b.4a.5e.6e,1b.2b.3b.4a.5e.6f,
1b.2b.3b.4a.5f.6a,1b.2b.3b.4a.5f.6b,1b.2b.3b.4a.5f.6c,1b.2b.3b.4a.5f.6d,1b.2b.3b.4a.5f.6e,
1b.2b.3b.4a.5f.6f,1b.2b.3b.4b.5a.6a,1b.2b.3b.4b.5a.6b,1b.2b.3b.4b.5a.6c,1b.2b.3b.4b.5a.6d,
1b.2b.3b.4b.5a.6e,1b.2b.3b.4b.5a.6f,1b.2b.3b.4b.5b.6a,1b.2b.3b.4b.5b.6b,1b.2b.3b.4b.5b.6c,
1b.2b.3b.4b.5b.6d,1b.2b.3b.4b.5b.6e,1b.2b.3b.4b.5b.6f,1b.2b.3b.4b.5c.6a,1b.2b.3b.4b.5c.6b,
1b.2b.3b.4b.5c.6c,1b.2b.3b.4b.5c.6d,1b.2b.3b.4b.5c.6e,1b.2b.3b.4b.5c.6f,1b.2b.3b.4b.5d.6a,
1b.2b.3b.4b.5d.6b, 1b.2b.3b.4b.5d.6c, 1b.2b.3b.4b.5d.6d, 1b.2b.3b.4b.5d.6e,
1b.2b.3b.4b.5d.6f,1b.2b.3b.4b.5e.6a,1b.2b.3b.4b.5e.6b,1b.2b.3b.4b.5e.6c,1b.2b.3b.4b.5e.6d,
1b.2b.3b.4b.5e.6e,1b.2b.3b.4b.5e.6f,1b.2b.3b.4b.5f.6a,1b.2b.3b.4b.5f.6b,1b.2b.3b.4b.5f.6c,
1b.2b.3b.4b.5f.6d,1b.2b.3b.4b.5f.6e,1b.2b.3b.4b.5f.6f,1b.2b.3b.4c.5a.6a,1b.2b.3b.4c.5a.6b,
1b.2b.3b.4c.5a.6c,1b.2b.3b.4c.5a.6d,1b.2b.3b.4c.5a.6e,1b.2b.3b.4c.5a.6f,1b.2b.3b.4c.5b.6a,
1b.2b.3b.4c.5b.6b,1b.2b.3b.4c.5b.6c,1b.2b.3b.4c.5b.6d,1b.2b.3b.4c.5b.6e,1b.2b.3b.4c.5b.6f,
1b.2b.3b.4c.5c.6a,1b.2b.3b.4c.5c.6b,1b.2b.3b.4c.5c.6c,1b.2b.3b.4c.5c.6d,1b.2b.3b.4c.5c.6e,
1b.2b.3b.4c.5c.6f,1b.2b.3b.4c.5d.6a,1b.2b.3b.4c.5d.6b,1b.2b.3b.4c.5d.6c,1b.2b.3b.4c.5d.6d,
1b.2b.3b.4c.5d.6e,1b.2b.3b.4c.5d.6f,1b.2b.3b.4c.5e.6a,1b.2b.3b.4c.5e.6b,1b.2b.3b.4c.5e.6c,
1b.2b.3b.4c.5e.6d,1b.2b.3b.4c.5e.6e,1b.2b.3b.4c.5e.6f,1b.2b.3b.4c.5f.6a,1b.2b.3b.4c.5f.6b,
1b.2b.3b.4c.5f.6c,1b.2b.3b.4c.5f.6d,1b.2b.3b.4c.5f.6e,1b.2b.3b.4c.5f.6f,1b.2b.3b.4d.5a.6a,
1b.2b.3b.4d.5a.6b,1b.2b.3b.4d.5a.6c,1b.2b.3b.4d.5a.6d,1b.2b.3b.4d.5a.6e,1b.2b.3b.4d.5a.6f,
1b.2b.3b.4d.5b.6a, 1b.2b.3b.4d.5b.6b, 1b.2b.3b.4d.5b.6c, 1b.2b.3b.4d.5b.6d,
1b.2b.3b.4d.5b.6e,1b.2b.3b.4d.5b.6f,1b.2b.3b.4d.5c.6a,1b.2b.3b.4d.5c.6b,1b.2b.3b.4d.5c.6c,
1b.2b.3b.4d.5c.6d, 1b.2b.3b.4d.5c.6e, 1b.2b.3b.4d.5c.6f, 1b.2b.3b.4d.5d.6a,
1b.2b.3b.4d.5d.6b, 1b.2b.3b.4d.5d.6c, 1b.2b.3b.4d.5d.6d, 1b.2b.3b.4d.5d.6e,
1b.2b.3b.4d.5d.6f, 1b.2b.3b.4d.5e.6a, 1b.2b.3b.4d.5e.6b, 1b.2b.3b.4d.5e.6c,
1b.2b.3b.4d.5e.6d,1b.2b.3b.4d.5e.6e,1b.2b.3b.4d.5e.6f,1b.2b.3b.4d.5f.6a,1b.2b.3b.4d.5f.6b,
1b.2b.3b.4d.5f.6c,1b.2b.3b.4d.5f.6d,1b.2b.3b.4d.5f.6e,1b.2b.3b.4d.5f.6f,1b.2b.3b.4e.5a.6a,
1b.2b.3b.4e.5a.6b,1b.2b.3b.4e.5a.6c,1b.2b.3b.4e.5a.6d,1b.2b.3b.4e.5a.6e,1b.2b.3b.4e.5a.6f,
1b.2b.3b.4e.5b.6a,1b.2b.3b.4e.5b.6b,1b.2b.3b.4e.5b.6c,1b.2b.3b.4e.5b.6d,1b.2b.3b.4e.5b.6e,
1b.2b.3b.4e.5b.6f,1b.2b.3b.4e.5c.6a,1b.2b.3b.4e.5c.6b,1b.2b.3b.4e.5c.6c,1b.2b.3b.4e.5c.6d,
1b.2b.3b.4e.5c.6e,1b.2b.3b.4e.5c.6f,1b.2b.3b.4e.5d.6a,1b.2b.3b.4e.5d.6b,1b.2b.3b.4e.5d.6c,
1b.2b.3b.4e.5d.6d,1b.2b.3b.4e.5d.6e,1b.2b.3b.4e.5d.6f,1b.2b.3b.4e.5e.6a,1b.2b.3b.4e.5e.6b,
1b.2b.3b.4e.5e.6c,1b.2b.3b.4e.5e.6d,1b.2b.3b.4e.5e.6e,1b.2b.3b.4e.5e.6f,1b.2b.3b.4e.5f.6a,
1b.2b.3b.4e.5f.6b,1b.2b.3b.4e.5f.6c,1b.2b.3b.4e.5f.6d,1b.2b.3b.4e.5f.6e,1b.2b.3b.4e.5f.6f,
1b.2b.3b.4f.5a.6a,1b.2b.3b.4f.5a.6b,1b.2b.3b.4f.5a.6c,1b.2b.3b.4f.5a.6d,1b.2b.3b.4f.5a.6e,
1b.2b.3b.4f.5a.6f,1b.2b.3b.4f.5b.6a,1b.2b.3b.4f.5b.6b,1b.2b.3b.4f.5b.6c,1b.2b.3b.4f.5b.6d,
1b.2b.3b.4f.5b.6e,1b.2b.3b.4f.5b.6f,1b.2b.3b.4f.5c.6a,1b.2b.3b.4f.5c.6b,1b.2b.3b.4f.5c.6c,
1b.2b.3b.4f.5c.6d,1b.2b.3b.4f.5c.6e,1b.2b.3b.4f.5c.6f,1b.2b.3b.4f.5d.6a,1b.2b.3b.4f.5d.6b,
1b.2b.3b.4f.5d.6c,1b.2b.3b.4f.5d.6d,1b.2b.3b.4f.5d.6e,1b.2b.3b.4f.5d.6f,1b.2b.3b.4f.5e.6a,
1b.2b.3b.4f.5e.6b,1b.2b.3b.4f.5e.6c,1b.2b.3b.4f.5e.6d,1b.2b.3b.4f.5e.6e,1b.2b.3b.4f.5e.6f,
1b.2b.3b.4f.5f.6a,1b.2b.3b.4f.5f.6b,1b.2b.3b.4f.5f.6c,1b.2b.3b.4f.5f.6d,1b.2b.3b.4f.5f.6e,
1b.2b.3b.4f.5f.6f,1b.2b.3c.4a.5a.6a,1b.2b.3c.4a.5a.6b,1b.2b.3c.4a.5a.6c,1b.2b.3c.4a.5a.6d,
1b.2b.3c.4a.5a.6e,1b.2b.3c.4a.5a.6f,1b.2b.3c.4a.5b.6a,1b.2b.3c.4a.5b.6b,1b.2b.3c.4a.5b.6c,
1b.2b.3c.4a.5b.6d,1b.2b.3c.4a.5b.6e,1b.2b.3c.4a.5b.6f,1b.2b.3c.4a.5c.6a,1b.2b.3c.4a.5c.6b,
1b.2b.3c.4a.5c.6c,1b.2b.3c.4a.5c.6d,1b.2b.3c.4a.5c.6e,1b.2b.3c.4a.5c.6f,1b.2b.3c.4a.5d.6a,
1b.2b.3c.4a.5d.6b,1b.2b.3c.4a.5d.6c,1b.2b.3c.4a.5d.6d,1b.2b.3c.4a.5d.6e,1b.2b.3c.4a.5d.6f,
1b.2b.3c.4a.5e.6a,1b.2b.3c.4a.5e.6b,1b.2b.3c.4a.5e.6c,1b.2b.3c.4a.5e.6d,1b.2b.3c.4a.5e.6e,
1b.2b.3c.4a.5e.6f,1b.2b.3c.4a.5f.6a,1b.2b.3c.4a.5f.6b,1b.2b.3c.4a.5f.6c,1b.2b.3c.4a.5f.6d,
1b.2b.3c.4a.5f.6e,1b.2b.3c.4a.5f.6f,1b.2b.3c.4b.5a.6a,1b.2b.3c.4b.5a.6b,1b.2b.3c.4b.5a.6c,
1b.2b.3c.4b.5a.6d,1b.2b.3c.4b.5a.6e,1b.2b.3c.4b.5a.6f,1b.2b.3c.4b.5b.6a,1b.2b.3c.4b.5b.6b,
1b.2b.3c.4b.5b.6c,1b.2b.3c.4b.5b.6d,1b.2b.3c.4b.5b.6e,1b.2b.3c.4b.5b.6f,1b.2b.3c.4b.5c.6a,
1b.2b.3c.4b.5c.6b,1b.2b.3c.4b.5c.6c,1b.2b.3c.4b.5c.6d,1b.2b.3c.4b.5c.6e,1b.2b.3c.4b.5c.6f,
1b.2b.3c.4b.5d.6a,1b.2b.3c.4b.5d.6b,1b.2b.3c.4b.5d.6c,1b.2b.3c.4b.5d.6d,1b.2b.3c.4b.5d.6e,
1b.2b.3c.4b.5d.6f,1b.2b.3c.4b.5e.6a,1b.2b.3c.4b.5e.6b,1b.2b.3c.4b.5e.6c,1b.2b.3c.4b.5e.6d,
1b.2b.3c.4b.5e.6e,1b.2b.3c.4b.5e.6f,1b.2b.3c.4b.5f.6a,1b.2b.3c.4b.5f.6b,1b.2b.3c.4b.5f.6c,
1b.2b.3c.4b.5f.6d,1b.2b.3c.4b.5f.6e,1b.2b.3c.4b.5f.6f,1b.2b.3c.4c.5a.6a,1b.2b.3c.4c.5a.6b,
1b.2b.3c.4c.5a.6c,1b.2b.3c.4c.5a.6d,1b.2b.3c.4c.5a.6e,1b.2b.3c.4c.5a.6f,1b.2b.3c.4c.5b.6a,
1b.2b.3c.4c.5b.6b,1b.2b.3c.4c.5b.6c,1b.2b.3c.4c.5b.6d,1b.2b.3c.4c.5b.6e,1b.2b.3c.4c.5b.6f,
1b.2b.3c.4c.5c.6a,1b.2b.3c.4c.5c.6b,1b.2b.3c.4c.5c.6c,1b.2b.3c.4c.5c.6d,1b.2b.3c.4c.5c.6e,
1b.2b.3c.4c.5c.6f,1b.2b.3c.4c.5d.6a,1b.2b.3c.4c.5d.6b,1b.2b.3c.4c.5d.6c,1b.2b.3c.4c.5d.6d,
1b.2b.3c.4c.5d.6e,1b.2b.3c.4c.5d.6f,1b.2b.3c.4c.5e.6a,1b.2b.3c.4c.5e.6b,1b.2b.3c.4c.5e.6c,
1b.2b.3c.4c.5e.6d,1b.2b.3c.4c.5e.6e,1b.2b.3c.4c.5e.6f,1b.2b.3c.4c.5f.6a,1b.2b.3c.4c.5f.6b,
1b.2b.3c.4c.5f.6c,1b.2b.3c.4c.5f.6d,1b.2b.3c.4c.5f.6e,1b.2b.3c.4c.5f.6f,1b.2b.3c.4d.5a.6a,
1b.2b.3c.4d.5a.6b,1b.2b.3c.4d.5a.6c,1b.2b.3c.4d.5a.6d,1b.2b.3c.4d.5a.6e,1b.2b.3c.4d.5a.6f,
1b.2b.3c.4d.5b.6a,1b.2b.3c.4d.5b.6b,1b.2b.3c.4d.5b.6c,1b.2b.3c.4d.5b.6d,1b.2b.3c.4d.5b.6e,
1b.2b.3c.4d.5b.6f,1b.2b.3c.4d.5c.6a,1b.2b.3c.4d.5c.6b,1b.2b.3c.4d.5c.6c,1b.2b.3c.4d.5c.6d,
1b.2b.3c.4d.5c.6e,1b.2b.3c.4d.5c.6f,1b.2b.3c.4d.5d.6a,1b.2b.3c.4d.5d.6b,1b.2b.3c.4d.5d.6c,
1b.2b.3c.4d.5d.6d,1b.2b.3c.4d.5d.6e,1b.2b.3c.4d.5d.6f,1b.2b.3c.4d.5e.6a,1b.2b.3c.4d.5e.6b,
1b.2b.3c.4d.5e.6c,1b.2b.3c.4d.5e.6d,1b.2b.3c.4d.5e.6e,1b.2b.3c.4d.5e.6f,1b.2b.3c.4d.5f.6a,
1b.2b.3c.4d.5f.6b,1b.2b.3c.4d.5f.6c,1b.2b.3c.4d.5f.6d,1b.2b.3c.4d.5f.6e,1b.2b.3c.4d.5f.6f,
1b.2b.3c.4e.5a.6a,1b.2b.3c.4e.5a.6b,1b.2b.3c.4e.5a.6c,1b.2b.3c.4e.5a.6d,1b.2b.3c.4e.5a.6e,
1b.2b.3c.4e.5a.6f,1b.2b.3c.4e.5b.6a,1b.2b.3c.4e.5b.6b,1b.2b.3c.4e.5b.6c,1b.2b.3c.4e.5b.6d,
1b.2b.3c.4e.5b.6e,1b.2b.3c.4e.5b.6f,1b.2b.3c.4e.5c.6a,1b.2b.3c.4e.5c.6b,1b.2b.3c.4e.5c.6c,
1b.2b.3c.4e.5c.6d,1b.2b.3c.4e.5c.6e,1b.2b.3c.4e.5c.6f,1b.2b.3c.4e.5d.6a,1b.2b.3c.4e.5d.6b,
1b.2b.3c.4e.5d.6c,1b.2b.3c.4e.5d.6d,1b.2b.3c.4e.5d.6e,1b.2b.3c.4e.5d.6f,1b.2b.3c.4e.5e.6a,
1b.2b.3c.4e.5e.6b,1b.2b.3c.4e.5e.6c,1b.2b.3c.4e.5e.6d,1b.2b.3c.4e.5e.6e,1b.2b.3c.4e.5e.6f,
1b.2b.3c.4e.5f.6a,1b.2b.3c.4e.5f.6b,1b.2b.3c.4e.5f.6c,1b.2b.3c.4e.5f.6d,1b.2b.3c.4e.5f.6e,
1b.2b.3c.4e.5f.6f,1b.2b.3c.4f.5a.6a,1b.2b.3c.4f.5a.6b,1b.2b.3c.4f.5a.6c,1b.2b.3c.4f.5a.6d,
1b.2b.3c.4f.5a.6e,1b.2b.3c.4f.5a.6f,1b.2b.3c.4f.5b.6a,1b.2b.3c.4f.5b.6b,1b.2b.3c.4f.5b.6c,
1b.2b.3c.4f.5b.6d,1b.2b.3c.4f.5b.6e,1b.2b.3c.4f.5b.6f,1b.2b.3c.4f.5c.6a,1b.2b.3c.4f.5c.6b,
1b.2b.3c.4f.5c.6c,1b.2b.3c.4f.5c.6d,1b.2b.3c.4f.5c.6e,1b.2b.3c.4f.5c.6f,1b.2b.3c.4f.5d.6a,
1b.2b.3c.4f.5d.6b,1b.2b.3c.4f.5d.6c,1b.2b.3c.4f.5d.6d,1b.2b.3c.4f.5d.6e,1b.2b.3c.4f.5d.6f,
1b.2b.3c.4f.5e.6a,1b.2b.3c.4f.5e.6b,1b.2b.3c.4f.5e.6c,1b.2b.3c.4f.5e.6d,1b.2b.3c.4f.5e.6e,
1b.2b.3c.4f.5e.6f,1b.2b.3c.4f.5f.6a,1b.2b.3c.4f.5f.6b,1b.2b.3c.4f.5f.6c,1b.2b.3c.4f.5f.6d,
1b.2b.3c.4f.5f.6e,1b.2b.3c.4f.5f.6f,1b.2b.3d.4a.5a.6a,1b.2b.3d.4a.5a.6b,1b.2b.3d.4a.5a.6c,
1b.2b.3d.4a.5a.6d,1b.2b.3d.4a.5a.6e,1b.2b.3d.4a.5a.6f,1b.2b.3d.4a.5b.6a,1b.2b.3d.4a.5b.6b,
1b.2b.3d.4a.5b.6c,1b.2b.3d.4a.5b.6d,1b.2b.3d.4a.5b.6e,1b.2b.3d.4a.5b.6f,1b.2b.3d.4a.5c.6a,
1b.2b.3d.4a.5c.6b,1b.2b.3d.4a.5c.6c,1b.2b.3d.4a.5c.6d,1b.2b.3d.4a.5c.6e,1b.2b.3d.4a.5c.6f,
1b.2b.3d.4a.5d.6a, 1b.2b.3d.4a.5d.6b, 1b.2b.3d.4a.5d.6c, 1b.2b.3d.4a.5d.6d,
1b.2b.3d.4a.5d.6e,1b.2b.3d.4a.5d.6f,1b.2b.3d.4a.5e.6a,1b.2b.3d.4a.5e.6b,1b.2b.3d.4a.5e.6c,
1b.2b.3d.4a.5e.6d,1b.2b.3d.4a.5e.6e,1b.2b.3d.4a.5e.6f,1b.2b.3d.4a.5f.6a,1b.2b.3d.4a.5f.6b,
1b.2b.3d.4a.5f.6c,1b.2b.3d.4a.5f.6d,1b.2b.3d.4a.5f.6e,1b.2b.3d.4a.5f.6f,1b.2b.3d.4b.5a.6a,
1b.2b.3d.4b.5a.6b,1b.2b.3d.4b.5a.6c,1b.2b.3d.4b.5a.6d,1b.2b.3d.4b.5a.6e,1b.2b.3d.4b.5a.6f,
1b.2b.3d.4b.5b.6a, 1b.2b.3d.4b.5b.6b, 1b.2b.3d.4b.5b.6c, 1b.2b.3d.4b.5b.6d,
1b.2b.3d.4b.5b.6e,1b.2b.3d.4b.5b.6f,1b.2b.3d.4b.5c.6a,1b.2b.3d.4b.5c.6b,1b.2b.3d.4b.5c.6c,
1b.2b.3d.4b.5c.6d, 1b.2b.3d.4b.5c.6e, 1b.2b.3d.4b.5c.6f, 1b.2b.3d.4b.5d.6a,
1b.2b.3d.4b.5d.6b, 1b.2b.3d.4b.5d.6c, 1b.2b.3d.4b.5d.6d, 1b.2b.3d.4b.5d.6e,
1b.2b.3d.4b.5d.6f, 1b.2b.3d.4b.5e.6a, 1b.2b.3d.4b.5e.6b, 1b.2b.3d.4b.5e.6c,
1b.2b.3d.4b.5e.6d,1b.2b.3d.4b.5e.6e,1b.2b.3d.4b.5e.6f,1b.2b.3d.4b.5f.6a,1b.2b.3d.4b.5f.6b,
1b.2b.3d.4b.5f.6c,1b.2b.3d.4b.5f.6d,1b.2b.3d.4b.5f.6e,1b.2b.3d.4b.5f.6f,1b.2b.3d.4c.5a.6a,
1b.2b.3d.4c.5a.6b,1b.2b.3d.4c.5a.6c,1b.2b.3d.4c.5a.6d,1b.2b.3d.4c.5a.6e,1b.2b.3d.4c.5a.6f,
1b.2b.3d.4c.5b.6a,1b.2b.3d.4c.5b.6b,1b.2b.3d.4c.5b.6c,1b.2b.3d.4c.5b.6d,1b.2b.3d.4c.5b.6e,
1b.2b.3d.4c.5b.6f,1b.2b.3d.4c.5c.6a,1b.2b.3d.4c.5c.6b,1b.2b.3d.4c.5c.6c,1b.2b.3d.4c.5c.6d,
1b.2b.3d.4c.5c.6e,1b.2b.3d.4c.5c.6f,1b.2b.3d.4c.5d.6a,1b.2b.3d.4c.5d.6b,1b.2b.3d.4c.5d.6c,
1b.2b.3d.4c.5d.6d,1b.2b.3d.4c.5d.6e,1b.2b.3d.4c.5d.6f,1b.2b.3d.4c.5e.6a,1b.2b.3d.4c.5e.6b,
1b.2b.3d.4c.5e.6c,1b.2b.3d.4c.5e.6d,1b.2b.3d.4c.5e.6e,1b.2b.3d.4c.5e.6f,1b.2b.3d.4c.5f.6a,
1b.2b.3d.4c.5f.6b,1b.2b.3d.4c.5f.6c,1b.2b.3d.4c.5f.6d,1b.2b.3d.4c.5f.6e,1b.2b.3d.4c.5f.6f,
1b.2b.3d.4d.5a.6a, 1b.2b.3d.4d.5a.6b, 1b.2b.3d.4d.5a.6c, 1b.2b.3d.4d.5a.6d,
1b.2b.3d.4d.5a.6e, 1b.2b.3d.4d.5a.6f, 1b.2b.3d.4d.5b.6a, 1b.2b.3d.4d.5b.6b,
1b.2b.3d.4d.5b.6c, 1b.2b.3d.4d.5b.6d, 1b.2b.3d.4d.5b.6e, 1b.2b.3d.4d.5b.6f,
1b.2b.3d.4d.5c.6a, 1b.2b.3d.4d.5c.6b, 1b.2b.3d.4d.5c.6c, 1b.2b.3d.4d.5c.6d,
1b.2b.3d.4d.5c.6e, 1b.2b.3d.4d.5c.6f, 1b.2b.3d.4d.5d.6a, 1b.2b.3d.4d.5d.6b,
1b.2b.3d.4d.5d.6c, 1b.2b.3d.4d.5d.6d, 1b.2b.3d.4d.5d.6e, 1b.2b.3d.4d.5d.6f,
1b.2b.3d.4d.5e.6a, 1b.2b.3d.4d.5e.6b, 1b.2b.3d.4d.5e.6c, 1b.2b.3d.4d.5e.6d,
1b.2b.3d.4d.5e.6e,1b.2b.3d.4d.5e.6f,1b.2b.3d.4d.5f.6a,1b.2b.3d.4d.5f.6b,1b.2b.3d.4d.5f.6c,
1b.2b.3d.4d.5f.6d,1b.2b.3d.4d.5f.6e,1b.2b.3d.4d.5f.6f,1b.2b.3d.4e.5a.6a,1b.2b.3d.4e.5a.6b,
1b.2b.3d.4e.5a.6c,1b.2b.3d.4e.5a.6d,1b.2b.3d.4e.5a.6e,1b.2b.3d.4e.5a.6f,1b.2b.3d.4e.5b.6a,
1b.2b.3d.4e.5b.6b,1b.2b.3d.4e.5b.6c,1b.2b.3d.4e.5b.6d,1b.2b.3d.4e.5b.6e,1b.2b.3d.4e.5b.6f,
1b.2b.3d.4e.5c.6a,1b.2b.3d.4e.5c.6b,1b.2b.3d.4e.5c.6c,1b.2b.3d.4e.5c.6d,1b.2b.3d.4e.5c.6e,
1b.2b.3d.4e.5c.6f, 1b.2b.3d.4e.5d.6a, 1b.2b.3d.4e.5d.6b, 1b.2b.3d.4e.5d.6c,
1b.2b.3d.4e.5d.6d,1b.2b.3d.4e.5d.6e,1b.2b.3d.4e.5d.6f,1b.2b.3d.4e.5e.6a,1b.2b.3d.4e.5e.6b,
1b.2b.3d.4e.5e.6c,1b.2b.3d.4e.5e.6d,1b.2b.3d.4e.5e.6e,1b.2b.3d.4e.5e.6f,1b.2b.3d.4e.5f.6a,
1b.2b.3d.4e.5f.6b,1b.2b.3d.4e.5f.6c,1b.2b.3d.4e.5f.6d,1b.2b.3d.4e.5f.6e,1b.2b.3d.4e.5f.6f,
1b.2b.3d.4f.5a.6a,1b.2b.3d.4f.5a.6b,1b.2b.3d.4f.5a.6c,1b.2b.3d.4f.5a.6d,1b.2b.3d.4f.5a.6e,
1b.2b.3d.4f.5a.6f,1b.2b.3d.4f.5b.6a,1b.2b.3d.4f.5b.6b,1b.2b.3d.4f.5b.6c,1b.2b.3d.4f.5b.6d,
1b.2b.3d.4f.5b.6e,1b.2b.3d.4f.5b.6f,1b.2b.3d.4f.5c.6a,1b.2b.3d.4f.5c.6b,1b.2b.3d.4f.5c.6c,
1b.2b.3d.4f.5c.6d,1b.2b.3d.4f.5c.6e,1b.2b.3d.4f.5c.6f,1b.2b.3d.4f.5d.6a,1b.2b.3d.4f.5d.6b,
1b.2b.3d.4f.5d.6c,1b.2b.3d.4f.5d.6d,1b.2b.3d.4f.5d.6e,1b.2b.3d.4f.5d.6f,1b.2b.3d.4f.5e.6a,
1b.2b.3d.4f.5e.6b,1b.2b.3d.4f.5e.6c,1b.2b.3d.4f.5e.6d,1b.2b.3d.4f.5e.6e,1b.2b.3d.4f.5e.6f,
1b.2b.3d.4f.5f.6a,1b.2b.3d.4f.5f.6b,1b.2b.3d.4f.5f.6c,1b.2b.3d.4f.5f.6d,1b.2b.3d.4f.5f.6e,
1b.2b.3d.4f.5f.6f,1b.2b.3e.4a.5a.6a,1b.2b.3e.4a.5a.6b,1b.2b.3e.4a.5a.6c,1b.2b.3e.4a.5a.6d,
1b.2b.3e.4a.5a.6e,1b.2b.3e.4a.5a.6f,1b.2b.3e.4a.5b.6a,1b.2b.3e.4a.5b.6b,1b.2b.3e.4a.5b.6c,
1b.2b.3e.4a.5b.6d,1b.2b.3e.4a.5b.6e,1b.2b.3e.4a.5b.6f,1b.2b.3e.4a.5c.6a,1b.2b.3e.4a.5c.6b,
1b.2b.3e.4a.5c.6c,1b.2b.3e.4a.5c.6d,1b.2b.3e.4a.5c.6e,1b.2b.3e.4a.5c.6f,1b.2b.3e.4a.5d.6a,
1b.2b.3e.4a.5d.6b,1b.2b.3e.4a.5d.6c,1b.2b.3e.4a.5d.6d,1b.2b.3e.4a.5d.6e,1b.2b.3e.4a.5d.6f,
1b.2b.3e.4a.5e.6a,1b.2b.3e.4a.5e.6b,1b.2b.3e.4a.5e.6c,1b.2b.3e.4a.5e.6d,1b.2b.3e.4a.5e.6e,
1b.2b.3e.4a.5e.6f,1b.2b.3e.4a.5f.6a,1b.2b.3e.4a.5f.6b,1b.2b.3e.4a.5f.6c,1b.2b.3e.4a.5f.6d,
1b.2b.3e.4a.5f.6e,1b.2b.3e.4a.5f.6f,1b.2b.3e.4b.5a.6a,1b.2b.3e.4b.5a.6b,1b.2b.3e.4b.5a.6c,
1b.2b.3e.4b.5a.6d,1b.2b.3e.4b.5a.6e,1b.2b.3e.4b.5a.6f,1b.2b.3e.4b.5b.6a,1b.2b.3e.4b.5b.6b,
1b.2b.3e.4b.5b.6c,1b.2b.3e.4b.5b.6d,1b.2b.3e.4b.5b.6e,1b.2b.3e.4b.5b.6f,1b.2b.3e.4b.5c.6a,
1b.2b.3e.4b.5c.6b,1b.2b.3e.4b.5c.6c,1b.2b.3e.4b.5c.6d,1b.2b.3e.4b.5c.6e,1b.2b.3e.4b.5c.6f,
1b.2b.3e.4b.5d.6a, 1b.2b.3e.4b.5d.6b, 1b.2b.3e.4b.5d.6c, 1b.2b.3e.4b.5d.6d,
1b.2b.3e.4b.5d.6e,1b.2b.3e.4b.5d.6f,1b.2b.3e.4b.5e.6a,1b.2b.3e.4b.5e.6b,1b.2b.3e.4b.5e.6c,
1b.2b.3e.4b.5e.6d,1b.2b.3e.4b.5e.6e,1b.2b.3e.4b.5e.6f,1b.2b.3e.4b.5f.6a,1b.2b.3e.4b.5f.6b,
1b.2b.3e.4b.5f.6c,1b.2b.3e.4b.5f.6d,1b.2b.3e.4b.5f.6e,1b.2b.3e.4b.5f.6f,1b.2b.3e.4c.5a.6a,
1b.2b.3e.4c.5a.6b,1b.2b.3e.4c.5a.6c,1b.2b.3e.4c.5a.6d,1b.2b.3e.4c.5a.6e,1b.2b.3e.4c.5a.6f,
1b.2b.3e.4c.5b.6a,1b.2b.3e.4c.5b.6b,1b.2b.3e.4c.5b.6c,1b.2b.3e.4c.5b.6d,1b.2b.3e.4c.5b.6e,
1b.2b.3e.4c.5b.6f,1b.2b.3e.4c.5c.6a,1b.2b.3e.4c.5c.6b,1b.2b.3e.4c.5c.6c,1b.2b.3e.4c.5c.6d,
1b.2b.3e.4c.5c.6e,1b.2b.3e.4c.5c.6f,1b.2b.3e.4c.5d.6a,1b.2b.3e.4c.5d.6b,1b.2b.3e.4c.5d.6c,
1b.2b.3e.4c.5d.6d,1b.2b.3e.4c.5d.6e,1b.2b.3e.4c.5d.6f,1b.2b.3e.4c.5e.6a,1b.2b.3e.4c.5e.6b,
1b.2b.3e.4c.5e.6c,1b.2b.3e.4c.5e.6d,1b.2b.3e.4c.5e.6e,1b.2b.3e.4c.5e.6f,1b.2b.3e.4c.5f.6a,
1b.2b.3e.4c.5f.6b,1b.2b.3e.4c.5f.6c,1b.2b.3e.4c.5f.6d,1b.2b.3e.4c.5f.6e,1b.2b.3e.4c.5f.6f,
1b.2b.3e.4d.5a.6a,1b.2b.3e.4d.5a.6b,1b.2b.3e.4d.5a.6c,1b.2b.3e.4d.5a.6d,1b.2b.3e.4d.5a.6e,
1b.2b.3e.4d.5a.6f,1b.2b.3e.4d.5b.6a,1b.2b.3e.4d.5b.6b,1b.2b.3e.4d.5b.6c,1b.2b.3e.4d.5b.6d,
1b.2b.3e.4d.5b.6e,1b.2b.3e.4d.5b.6f,1b.2b.3e.4d.5c.6a,1b.2b.3e.4d.5c.6b,1b.2b.3e.4d.5c.6c,
1b.2b.3e.4d.5c.6d,1b.2b.3e.4d.5c.6e,1b.2b.3e.4d.5c.6f,1b.2b.3e.4d.5d.6a,1b.2b.3e.4d.5d.6b,
1b.2b.3e.4d.5d.6c,1b.2b.3e.4d.5d.6d,1b.2b.3e.4d.5d.6e,1b.2b.3e.4d.5d.6f,1b.2b.3e.4d.5e.6a,
1b.2b.3e.4d.5e.6b,1b.2b.3e.4d.5e.6c,1b.2b.3e.4d.5e.6d,1b.2b.3e.4d.5e.6e,1b.2b.3e.4d.5e.6f,
1b.2b.3e.4d.5f.6a,1b.2b.3e.4d.5f.6b,1b.2b.3e.4d.5f.6c,1b.2b.3e.4d.5f.6d,1b.2b.3e.4d.5f.6e,
1b.2b.3e.4d.5f.6f,1b.2b.3e.4e.5a.6a,1b.2b.3e.4e.5a.6b,1b.2b.3e.4e.5a.6c,1b.2b.3e.4e.5a.6d,
1b.2b.3e.4e.5a.6e,1b.2b.3e.4e.5a.6f,1b.2b.3e.4e.5b.6a,1b.2b.3e.4e.5b.6b,1b.2b.3e.4e.5b.6c,
1b.2b.3e.4e.5b.6d,1b.2b.3e.4e.5b.6e,1b.2b.3e.4e.5b.6f,1b.2b.3e.4e.5c.6a,1b.2b.3e.4e.5c.6b,
1b.2b.3e.4e.5c.6c,1b.2b.3e.4e.5c.6d,1b.2b.3e.4e.5c.6e,1b.2b.3e.4e.5c.6f,1b.2b.3e.4e.5d.6a,
1b.2b.3e.4e.5d.6b,1b.2b.3e.4e.5d.6c,1b.2b.3e.4e.5d.6d,1b.2b.3e.4e.5d.6e,1b.2b.3e.4e.5d.6f,
1b.2b.3e.4e.5e.6a,1b.2b.3e.4e.5e.6b,1b.2b.3e.4e.5e.6c,1b.2b.3e.4e.5e.6d,1b.2b.3e.4e.5e.6e,
1b.2b.3e.4e.5e.6f,1b.2b.3e.4e.5f.6a,1b.2b.3e.4e.5f.6b,1b.2b.3e.4e.5f.6c,1b.2b.3e.4e.5f.6d,
1b.2b.3e.4e.5f.6e,1b.2b.3e.4e.5f.6f,1b.2b.3e.4f.5a.6a,1b.2b.3e.4f.5a.6b,1b.2b.3e.4f.5a.6c,
1b.2b.3e.4f.5a.6d,1b.2b.3e.4f.5a.6e,1b.2b.3e.4f.5a.6f,1b.2b.3e.4f.5b.6a,1b.2b.3e.4f.5b.6b,
1b.2b.3e.4f.5b.6c,1b.2b.3e.4f.5b.6d,1b.2b.3e.4f.5b.6e,1b.2b.3e.4f.5b.6f,1b.2b.3e.4f.5c.6a,
1b.2b.3e.4f.5c.6b,1b.2b.3e.4f.5c.6c,1b.2b.3e.4f.5c.6d,1b.2b.3e.4f.5c.6e,1b.2b.3e.4f.5c.6f,
1b.2b.3e.4f.5d.6a,1b.2b.3e.4f.5d.6b,1b.2b.3e.4f.5d.6c,1b.2b.3e.4f.5d.6d,1b.2b.3e.4f.5d.6e,
1b.2b.3e.4f.5d.6f,1b.2b.3e.4f.5e.6a,1b.2b.3e.4f.5e.6b,1b.2b.3e.4f.5e.6c,1b.2b.3e.4f.5e.6d,
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1b.2c.3f.4a.5a.6a,1b.2c.3f.4a.5a.6b,1b.2c.3f.4a.5a.6c,1b.2c.3f.4a.5a.6d,1b.2c.3f.4a.5a.6e,
1b.2c.3f.4a.5a.6f,1b.2c.3f.4a.5b.6a,1b.2c.3f.4a.5b.6b,1b.2c.3f.4a.5b.6c,1b.2c.3f.4a.5b.6d,
1b.2c.3f.4a.5b.6e,1b.2c.3f.4a.5b.6f,1b.2c.3f.4a.5c.6a,1b.2c.3f.4a.5c.6b,1b.2c.3f.4a.5c.6c,
1b.2c.3f.4a.5c.6d,1b.2c.3f.4a.5c.6e,1b.2c.3f.4a.5c.6f,1b.2c.3f.4a.5d.6a,1b.2c.3f.4a.5d.6b,
1b.2c.3f.4a.5d.6c,1b.2c.3f.4a.5d.6d,1b.2c.3f.4a.5d.6e,1b.2c.3f.4a.5d.6f,1b.2c.3f.4a.5e.6a,
1b.2c.3f.4a.5e.6b,1b.2c.3f.4a.5e.6c,1b.2c.3f.4a.5e.6d,1b.2c.3f.4a.5e.6e,1b.2c.3f.4a.5e.6f,
1b.2c.3f.4a.5f.6a,1b.2c.3f.4a.5f.6b,1b.2c.3f.4a.5f.6c,1b.2c.3f.4a.5f.6d,1b.2c.3f.4a.5f.6e,
1b.2c.3f.4a.5f.6f,1b.2c.3f.4b.5a.6a,1b.2c.3f.4b.5a.6b,1b.2c.3f.4b.5a.6c,1b.2c.3f.4b.5a.6d,
1b.2c.3f.4b.5a.6e,1b.2c.3f.4b.5a.6f,1b.2c.3f.4b.5b.6a,1b.2c.3f.4b.5b.6b,1b.2c.3f.4b.5b.6c,
1b.2c.3f.4b.5b.6d,1b.2c.3f.4b.5b.6e,1b.2c.3f.4b.5b.6f,1b.2c.3f.4b.5c.6a,1b.2c.3f.4b.5c.6b,
1b.2c.3f.4b.5c.6c,1b.2c.3f.4b.5c.6d,1b.2c.3f.4b.5c.6e,1b.2c.3f.4b.5c.6f,1b.2c.3f.4b.5d.6a,
1b.2c.3f.4b.5d.6b,1b.2c.3f.4b.5d.6c,1b.2c.3f.4b.5d.6d,1b.2c.3f.4b.5d.6e,1b.2c.3f.4b.5d.6f,
1b.2c.3f.4b.5e.6a,1b.2c.3f.4b.5e.6b,1b.2c.3f.4b.5e.6c,1b.2c.3f.4b.5e.6d,1b.2c.3f.4b.5e.6e,
1b.2c.3f.4b.5e.6f,1b.2c.3f.4b.5f.6a,1b.2c.3f.4b.5f.6b,1b.2c.3f.4b.5f.6c,1b.2c.3f.4b.5f.6d,
1b.2c.3f.4b.5f.6e,1b.2c.3f.4b.5f.6f,1b.2c.3f.4c.5a.6a,1b.2c.3f.4c.5a.6b,1b.2c.3f.4c.5a.6c,
1b.2c.3f.4c.5a.6d,1b.2c.3f.4c.5a.6e,1b.2c.3f.4c.5a.6f,1b.2c.3f.4c.5b.6a,1b.2c.3f.4c.5b.6b,
1b.2c.3f.4c.5b.6c,1b.2c.3f.4c.5b.6d,1b.2c.3f.4c.5b.6e,1b.2c.3f.4c.5b.6f,1b.2c.3f.4c.5c.6a,
1b.2c.3f.4c.5c.6b,1b.2c.3f.4c.5c.6c,1b.2c.3f.4c.5c.6d,1b.2c.3f.4c.5c.6e,1b.2c.3f.4c.5c.6f,
1b.2c.3f.4c.5d.6a,1b.2c.3f.4c.5d.6b,1b.2c.3f.4c.5d.6c,1b.2c.3f.4c.5d.6d,1b.2c.3f.4e.5d.6e,
1b.2c.3f.4c.5d.6f,1b.2c.3f.4c.5e.6a,1b.2c.3f.4c.5e.6b,1b.2c.3f.4c.5e.6c,1b.2c.3f.4c.5e.6d,
1b.2c.3f.4c.5e.6e,1b.2c.3f.4c.5e.6f,1b.2c.3f.4c.5f.6a,1b.2c.3f.4c.5f.6b,1b.2c.3f.4c.5f.6c,
1b.2c.3f.4c.5f.6d,1b.2c.3f.4c.5f.6e,1b.2c.3f.4c.5f.6f,1b.2c.3f.4d.5a.6a,1b.2c.3f.4d.5a.6b,
1b.2c.3f.4d.5a.6c,1b.2c.3f.4d.5a.6d,1b.2c.3f.4d.5a.6e,1b.2c.3f.4d.5a.6f,1b.2c.3f.4d.5b.6a,
1b.2c.3f.4d.5b.6b,1b.2c.3f.4d.5b.6c,1b.2c.3f.4d.5b.6d,1b.2c.3f.4d.5b.6e,1b.2c.3f.4d.5b.6f,
1b.2c.3f.4d.5c.6a,1b.2c.3f.4d.5c.6b,1b.2c.3f.4d.5c.6c,1b.2c.3f.4d.5c.6d,1b.2c.3f.4d.5c.6e,
1b.2c.3f.4d.5c.6f,1b.2c.3f.4d.5d.6a,1b.2c.3f.4d.5d.6b,1b.2c.3f.4d.5d.6c,1b.2c.3f.4d.5d.6d,
1b.2c.3f.4d.5d.6e,1b.2c.3f.4d.5d.6f,1b.2c.3f.4d.5e.6a,1b.2c.3f.4d.5e.6b,1b.2c.3f.4d.5e.6c,
1b.2c.3f.4d.5e.6d,1b.2c.3f.4d.5e.6e,1b.2c.3f.4d.5e.6f,1b.2c.3f.4d.5f.6a,1b.2c.3f.4d.5f.6b,
1b.2c.3f.4d.5f.6c,1b.2c.3f.4d.5f.6d,1b.2c.3f.4d.5f.6e,1b.2c.3f.4d.5f.6f,1b.2c.3f.4e.5a.6a,
1b.2c.3f.4e.5a.6b,1b.2c.3f.4e.5a.6c,1b.2c.3f.4e.5a.6d,1b.2c.3f.4e.5a.6e,1b.2c.3f.4e.5a.6f,
1b.2c.3f.4e.5b.6a,1b.2c.3f.4e.5b.6b,1b.2c.3f.4e.5b.6c,1b.2c.3f.4e.5b.6d,1b.2c.3f.4e.5b.6e,
1b.2c.3f.4e.5b.6f,1b.2c.3f.4e.5c.6a,1b.2c.3f.4e.5c.6b,1b.2c.3f.4e.5c.6c,1b.2c.3f.4e.5c.6d,
1b.2c.3f.4e.5c.6e,1b.2c.3f.4e.5c.6f,1b.2c.3f.4e.5d.6a,1b.2c.3f.4e.5d.6b,1b.2c.3f.4e.5d.6c,
1b.2c.3f.4e.5d.6d,1b.2c.3f.4e.5d.6e,1b.2c.3f.4e.5d.6f,1b.2c.3f.4e.5e.6a,1b.2c.3f.4e.5e.6b,
1b.2c.3f.4e.5e.6c,1b.2c.3f.4e.5e.6d,1b.2c.3f.4e.5e.6e,1b.2c.3f.4e.5e.6f,1b.2c.3f.4e.5f.6a,
1b.2c.3f.4e.5f.6b,1b.2c.3f.4e.5f.6c,1b.2c.3f.4e.5f.6d,1b.2c.3f.4e.5f.6e,1b.2c.3f.4e.5f.6f,
1b.2c.3f.4f.5a.6a,1b.2c.3f.4f.5a.6b,1b.2c.3f.4f.5a.6c,1b.2c.3f.4f.5a.6d,1b.2c.3f.4f.5a.6e,
1b.2c.3f.4f.5a.6f,1b.2c.3f.4f.5b.6a,1b.2c.3f.4f.5b.6b,1b.2c.3f.4f.5b.6c,1b.2c.3f.4f.5b.6d,
1b.2c.3f.4f.5b.6e,1b.2c.3f.4f.5b.6f,1b.2c.3f.4f.5c.6a,1b.2c.3f.4f.5c.6b,1b.2c.3f.4f.5c.6c,
1b.2c.3f.4f.5c.6d,1b.2c.3f.4f.5c.6e,1b.2c.3f.4f.5c.6f,1b.2c.3f.4f.5d.6a,1b.2c.3f.4f.5d.6b,
1b.2c.3f.4f.5d.6c,1b.2c.3f.4f.5d.6d,1b.2c.3f.4f.5d.6e,1b.2c.3f.4f.5d.6f,1b.2c.3f.4f.5e.6a,
1b.2c.3f.4f.5e.6b,1b.2c.3f.4f.5e.6c,1b.2c.3f.4f.5e.6d,1b.2c.3f.4f.5e.6e,1b.2c.3f.4f.5e.6f,
1b.2c.3f.4f.5f.6a,1b.2c.3f.4f.5f.6b,1b.2c.3f.4f.5f.6c,1b.2c.3f.4f.5f.6d,1b.2c.3f.4f.5f.6e,
1b.2c.3f.4f.5f.6f,1b.2d.3a.4a.5a.6a,1b.2d.3a.4a.5a.6b,1b.2d.3a.4a.5a.6c,1b.2d.3a.4a.5a.6d,
1b.2d.3a.4a.5a.6e,1b.2d.3a.4a.5a.6f,1b.2d.3a.4a.5b.6a,1b.2d.3a.4a.5b.6b,1b.2d.3a.4a.5b.6c,
1b.2d.3a.4a.5b.6d,1b.2d.3a.4a.5b.6e,1b.2d.3a.4a.5b.6f,1b.2d.3a.4a.5c.6a,1b.2d.3a.4a.5c.6b,
1b.2d.3a.4a.5c.6c,1b.2d.3a.4a.5c.6d,1b.2d.3a.4a.5c.6e,1b.2d.3a.4a.5c.6f,1b.2d.3a.4a.5d.6a,
1b.2d.3a.4a.5d.6b,1b.2d.3a.4a.5d.6c,1b.2d.3a.4a.5d.6d,1b.2d.3a.4a.5d.6e,1b.2d.3a.4a.5d.6f,
1b.2d.3a.4a.5e.6a,1b.2d.3a.4a.5e.6b,1b.2d.3a.4a.5e.6c,1b.2d.3a.4a.5e.6d,1b.2d.3a.4a.5e.6e,
1b.2d.3a.4a.5e.6f,1b.2d.3a.4a.5f.6a,1b.2d.3a.4a.5f.6b,1b.2d.3a.4a.5f.6c,1b.2d.3a.4a.5f.6d,
1b.2d.3a.4a.5f.6e,1b.2d.3a.4a.5f.6f,1b.2d.3a.4b.5a.6a,1b.2d.3a.4b.5a.6b,1b.2d.3a.4b.5a.6c,
1b.2d.3a.4b.5a.6d,1b.2d.3a.4b.5a.6e,1b.2d.3a.4b.5a.6f,1b.2d.3a.4b.5b.6a,1b.2d.3a.4b.5b.6b,
1b.2d.3a.4b.5b.6c,1b.2d.3a.4b.5b.6d,1b.2d.3a.4b.5b.6e,1b.2d.3a.4b.5b.6f,1b.2d.3a.4b.5c.6a,
1b.2d.3a.4b.5c.6b,1b.2d.3a.4b.5c.6c,1b.2d.3a.4b.5c.6d,1b.2d.3a.4b.5c.6e,1b.2d.3a.4b.5c.6f,
1b.2d.3a.4b.5d.6a, 1b.2d.3a.4b.5d.6b, 1b.2d.3a.4b.5d.6c, 1b.2d.3a.4b.5d.6d,
1b.2d.3a.4b.5d.6e,1b.2d.3a.4b.5d.6f,1b.2d.3a.4b.5e.6a,1b.2d.3a.4b.5e.6b,1b.2d.3a.4b.5e.6c,
1b.2d.3a.4b.5e.6d,1b.2d.3a.4b.5e.6e,1b.2d.3a.4b.5e.6f,1b.2d.3a.4b.5f.6a,1b.2d.3a.4b.5f.6b,
1b.2d.3a.4b.5f.6c,1b.2d.3a.4b.5f.6d,1b.2d.3a.4b.5f.6e,1b.2d.3a.4b.5f.6f,1b.2d.3a.4c.5a.6a,
1b.2d.3a.4c.5a.6b,1b.2d.3a.4c.5a.6c,1b.2d.3a.4c.5a.6d,1b.2d.3a.4c.5a.6e,1b.2d.3a.4c.5a.6f,
1b.2d.3a.4c.5b.6a,1b.2d.3a.4c.5b.6b,1b.2d.3a.4c.5b.6c,1b.2d.3a.4c.5b.6d,1b.2d.3a.4c.5b.6e,
1b.2d.3a.4c.5b.6f,1b.2d.3a.4c.5c.6a,1b.2d.3a.4c.5c.6b,1b.2d.3a.4c.5c.6c,1b.2d.3a.4c.5c.6d,
1b.2d.3a.4c.5c.6e,1b.2d.3a.4c.5c.6f,1b.2d.3a.4c.5d.6a,1b.2d.3a.4c.5d.6b,1b.2d.3a.4c.5d.6c,
1b.2d.3a.4c.5d.6d,1b.2d.3a.4c.5d.6e,1b.2d.3a.4c.5d.6f,1b.2d.3a.4c.5e.6a,1b.2d.3a.4c.5e.6b,
1b.2d.3a.4c.5e.6c,1b.2d.3a.4c.5e.6d,1b.2d.3a.4c.5e.6e,1b.2d.3a.4c.5e.6f,1b.2d.3a.4c.5f.6a,
1b.2d.3a.4c.5f.6b,1b.2d.3a.4c.5f.6c,1b.2d.3a.4c.5f.6d,1b.2d.3a.4c.5f.6e,1b.2d.3a.4c.5f.6f,
1b.2d.3a.4d.5a.6a, 1b.2d.3a.4d.5a.6b, 1b.2d.3a.4d.5a.6c, 1b.2d.3a.4d.5a.6d,
1b.2d.3a.4d.5a.6e, 1b.2d.3a.4d.5a.6f, 1b.2d.3a.4d.5b.6a, 1b.2d.3a.4d.5b.6b,
1b.2d.3a.4d.5b.6c, 1b.2d.3a.4d.5b.6d, 1b.2d.3a.4d.5b.6e, 1b.2d.3a.4d.5b.6f,
1b.2d.3a.4d.5c.6a,1b.2d.3a.4d.5c.6b,1b.2d.3a.4d.5c.6c,1b.2d.3a.4d.5c.6d,1b.2d.3a.4d.5c.6e,
1b.2d.3a.4d.5c.6f, 1b.2d.3a.4d.5d.6a, 1b.2d.3a.4d.5d.6b, 1b.2d.3a.4d.5d.6c,
1b.2d.3a.4d.5d.6d, 1b.2d.3a.4d.5d.6e, 1b.2d.3a.4d.5d.6f, 1b.2d.3a.4d.5e.6a,
1b.2d.3a.4d.5e.6b,1b.2d.3a.4d.5e.6c,1b.2d.3a.4d.5e.6d,1b.2d.3a.4d.5e.6e,1b.2d.3a.4d.5e.6f,
1b.2d.3a.4d.5f.6a,1b.2d.3a.4d.5f.6b,1b.2d.3a.4d.5f.6c,1b.2d.3a.4d.5f.6d,1b.2d.3a.4d.5f.6e,
1b.2d.3a.4d.5f.6f,1b.2d.3a.4e.5a.6a,1b.2d.3a.4e.5a.6b,1b.2d.3a.4e.5a.6c,1b.2d.3a.4e.5a.6d,
1b.2d.3a.4e.5a.6e,1b.2d.3a.4e.5a.6f,1b.2d.3a.4e.5b.6a,1b.2d.3a.4e.5b.6b,1b.2d.3a.4e.5b.6c,
1b.2d.3a.4e.5b.6d,1b.2d.3a.4e.5b.6e,1b.2d.3a.4e.5b.6f,1b.2d.3a.4e.5c.6a,1b.2d.3a.4e.5c.6b,
1b.2d.3a.4e.5c.6c,1b.2d.3a.4e.5c.6d,1b.2d.3a.4e.5c.6e,1b.2d.3a.4e.5c.6f,1b.2d.3a.4e.5d.6a,
1b.2d.3a.4e.5d.6b,1b.2d.3a.4e.5d.6c,1b.2d.3a.4e.5d.6d,1b.2d.3a.4e.5d.6e,1b.2d.3a.4e.5d.6f,
1b.2d.3a.4e.5e.6a,1b.2d.3a.4e.5e.6b,1b.2d.3a.4e.5e.6c,1b.2d.3a.4e.5e.6d,1b.2d.3a.4e.5e.6e,
1b.2d.3a.4e.5e.6f,1b.2d.3a.4e.5f.6a,1b.2d.3a.4e.5f.6b,1b.2d.3a.4e.5f.6c,1b.2d.3a.4e.5f.6d,
1b.2d.3a.4e.5f.6e,1b.2d.3a.4e.5f.6f,1b.2d.3a.4f.5a.6a,1b.2d.3a.4f.5a.6b,1b.2d.3a.4f.5a.6c,
1b.2d.3a.4f.5a.6d,1b.2d.3a.4f.5a.6e,1b.2d.3a.4f.5a.6f,1b.2d.3a.4f.5b.6a,1b.2d.3a.4f.5b.6b,
1b.2d.3a.4f.5b.6c,1b.2d.3a.4f.5b.6d,1b.2d.3a.4f.5b.6e,1b.2d.3a.4f.5b.6f,1b.2d.3a.4f.5c.6a,
1b.2d.3a.4f.5c.6b,1b.2d.3a.4f.5c.6c,1b.2d.3a.4f.5c.6d,1b.2d.3a.4f.5c.6e,1b.2d.3a.4f.5c.6f,
1b.2d.3a.4f.5d.6a,1b.2d.3a.4f.5d.6b,1b.2d.3a.4f.5d.6c,1b.2d.3a.4f.5d.6d,1b.2d.3a.4f.5d.6e,
1b.2d.3a.4f.5d.6f,1b.2d.3a.4f.5e.6a,1b.2d.3a.4f.5e.6b,1b.2d.3a.4f.5e.6c,1b.2d.3a.4f.5e.6d,
1b.2d.3a.4f.5e.6e,1b.2d.3a.4f.5e.6f,1b.2d.3a.4f.5f.6a,1b.2d.3a.4f.5f.6b,1b.2d.3a.4f.5f.6c,
1b.2d.3a.4f.5f.6d,1b.2d.3a.4f.5f.6e,1b.2d.3a.4f.5f.6f,1b.2d.3b.4a.5a.6a,1b.2d.3b.4a.5a.6b,
1b.2d.3b.4a.5a.6c,1b.2d.3b.4a.5a.6d,1b.2d.3b.4a.5a.6e,1b.2d.3b.4a.5a.6f,1b.2d.3b.4a.5b.6a,
1b.2d.3b.4a.5b.6b,1b.2d.3b.4a.5b.6c,1b.2d.3b.4a.5b.6d,1b.2d.3b.4a.5b.6e,1b.2d.3b.4a.5b.6f,
1b.2d.3b.4a.5c.6a,1b.2d.3b.4a.5c.6b,1b.2d.3b.4a.5c.6c,1b.2d.3b.4a.5c.6d,1b.2d.3b.4a.5c.6e,
1b.2d.3b.4a.5c.6f, 1b.2d.3b.4a.5d.6a, 1b.2d.3b.4a.5d.6b, 1b.2d.3b.4a.5d.6c,
1b.2d.3b.4a.5d.6d, 1b.2d.3b.4a.5d.6e, 1b.2d.3b.4a.5d.6f, 1b.2d.3b.4a.5e.6a,
1b.2d.3b.4a.5e.6b,1b.2d.3b.4a.5e.6c,1b.2d.3b.4a.5e.6d,1b.2d.3b.4a.5e.6e,1b.2d.3b.4a.5e.6f,
1b.2d.3b.4a.5f.6a,1b.2d.3b.4a.5f.6b,1b.2d.3b.4a.5f.6c,1b.2d.3b.4a.5f.6d,1b.2d.3b.4a.5f.6e,
1b.2d.3b.4a.5f.6f,1b.2d.3b.4b.5a.6a,1b.2d.3b.4b.5a.6b,1b.2d.3b.4b.5a.6c,1b.2d.3b.4b.5a.6d,
1b.2d.3b.4b.5a.6e, 1b.2d.3b.4b.5a.6f, 1b.2d.3b.4b.5b.6a, 1b.2d.3b.4b.5b.6b,
1b.2d.3b.4b.5b.6c, 1b.2d.3b.4b.5b.6d, 1b.2d.3b.4b.5b.6e, 1b.2d.3b.4b.5b.6f,
1b.2d.3b.4b.5c.6a,1b.2d.3b.4b.5c.6b,1b.2d.3b.4b.5c.6c,1b.2d.3b.4b.5c.6d,1b.2d.3b.4b.5c.6e,
1b.2d.3b.4b.5c.6f, 1b.2d.3b.4b.5d.6a, 1b.2d.3b.4b.5d.6b, 1b.2d.3b.4b.5d.6c,
1b.2d.3b.4b.5d.6d, 1b.2d.3b.4b.5d.6e, 1b.2d.3b.4b.5d.6f, 1b.2d.3b.4b.5e.6a,
1b.2d.3b.4b.5e.6b,1b.2d.3b.4b.5e.6c,1b.2d.3b.4b.5e.6d,1b.2d.3b.4b.5e.6e,1b.2d.3b.4b.5e.6f,
1b.2d.3b.4b.5f.6a,1b.2d.3b.4b.5f.6b,1b.2d.3b.4b.5f.6c,1b.2d.3b.4b.5f.6d,1b.2d.3b.4b.5f.6e,
1b.2d.3b.4b.5f.6f,1b.2d.3b.4c.5a.6a,1b.2d.3b.4c.5a.6b,1b.2d.3b.4c.5a.6c,1b.2d.3b.4c.5a.6d,
1b.2d.3b.4c.5a.6e,1b.2d.3b.4c.5a.6f,1b.2d.3b.4c.5b.6a,1b.2d.3b.4c.5b.6b,1b.2d.3b.4c.5b.6c,
1b.2d.3b.4c.5b.6d,1b.2d.3b.4c.5b.6e,1b.2d.3b.4c.5b.6f,1b.2d.3b.4c.5c.6a,1b.2d.3b.4c.5c.6b,
1b.2d.3b.4c.5c.6c,1b.2d.3b.4c.5c.6d,1b.2d.3b.4c.5c.6e,1b.2d.3b.4c.5c.6f,1b.2d.3b.4c.5d.6a,
1b.2d.3b.4c.5d.6b,1b.2d.3b.4c.5d.6c,1b.2d.3b.4c.5d.6d,1b.2d.3b.4c.5d.6e,1b.2d.3b.4c.5d.6f,
1b.2d.3b.4c.5e.6a,1b.2d.3b.4c.5e.6b,1b.2d.3b.4c.5e.6c,1b.2d.3b.4c.5e.6d,1b.2d.3b.4c.5e.6e,
1b.2d.3b.4c.5e.6f,1b.2d.3b.4c.5f.6a,1b.2d.3b.4c.5f.6b,1b.2d.3b.4c.5f.6c,1b.2d.3b.4c.5f.6d,
1b.2d.3b.4c.5f.6e,1b.2d.3b.4c.5f.6f,1b.2d.3b.4d.5a.6a,1b.2d.3b.4d.5a.6b,1b.2d.3b.4d.5a.6c,
1b.2d.3b.4d.5a.6d, 1b.2d.3b.4d.5a.6e, 1b.2d.3b.4d.5a.6f, 1b.2d.3b.4d.5b.6a,
1b.2d.3b.4d.5b.6b, 1b.2d.3b.4d.5b.6c, 1b.2d.3b.4d.5b.6d, 1b.2d.3b.4d.5b.6e,
1b.2d.3b.4d.5b.6f, 1b.2d.3b.4d.5c.6a, 1b.2d.3b.4d.5c.6b, 1b.2d.3b.4d.5c.6c,
1b.2d.3b.4d.5c.6d, 1b.2d.3b.4d.5c.6e, 1b.2d.3b.4d.5c.6f, 1b.2d.3b.4d.5d.6a,
1b.2d.3b.4d.5d.6b, 1b.2d.3b.4d.5d.6c, 1b.2d.3b.4d.5d.6d, 1b.2d.3b.4d.5d.6e,
1b.2d.3b.4d.5d.6f, 1b.2d.3b.4d.5e.6a, 1b.2d.3b.4d.5e.6b, 1b.2d.3b.4d.5e.6c,
1b.2d.3b.4d.5e.6d,1b.2d.3b.4d.5e.6e,1b.2d.3b.4d.5e.6f,1b.2d.3b.4d.5f.6a,1b.2d.3b.4d.5f.6b,
1b.2d.3b.4d.5f.6c,1b.2d.3b.4d.5f.6d,1b.2d.3b.4d.5f.6e,1b.2d.3b.4d.5f.6f,1b.2d.3b.4e.5a.6a,
1b.2d.3b.4e.5a.6b,1b.2d.3b.4e.5a.6c,1b.2d.3b.4e.5a.6d,1b.2d.3b.4e.5a.6e,1b.2d.3b.4e.5a.6f,
1b.2d.3b.4e.5b.6a, 1b.2d.3b.4e.5b.6b, 1b.2d.3b.4e.5b.6c, 1b.2d.3b.4e.5b.6d,
1b.2d.3b.4e.5b.6e,1b.2d.3b.4e.5b.6f,1b.2d.3b.4e.5c.6a,1b.2d.3b.4e.5c.6b,1b.2d.3b.4e.5c.6c,
1b.2d.3b.4e.5c.6d,1b.2d.3b.4e.5c.6e,1b.2d.3b.4e.5c.6f,1b.2d.3b.4e.5d.6a,1b.2d.3b.4e.5d.6b,
1b.2d.3b.4e.5d.6c,1b.2d.3b.4e.5d.6d,1b.2d.3b.4e.5d.6e,1b.2d.3b.4e.5d.6f,1b.2d.3b.4e.5e.6a,
1b.2d.3b.4e.5e.6b,1b.2d.3b.4e.5e.6c,1b.2d.3b.4e.5e.6d,1b.2d.3b.4e.5e.6e,1b.2d.3b.4e.5e.6f,
1b.2d.3b.4e.5f.6a,1b.2d.3b.4e.5f.6b,1b.2d.3b.4e.5f.6c,1b.2d.3b.4e.5f.6d,1b.2d.3b.4e.5f.6e,
1b.2d.3b.4e.5f.6f,1b.2d.3b.4f.5a.6a,1b.2d.3b.4f.5a.6b,1b.2d.3b.4f.5a.6c,1b.2d.3b.4f.5a.6d,
1b.2d.3b.4f.5a.6e,1b.2d.3b.4f.5a.6f,1b.2d.3b.4f.5b.6a,1b.2d.3b.4f.5b.6b,1b.2d.3b.4f.5b.6c,
1b.2d.3b.4f.5b.6d,1b.2d.3b.4f.5b.6e,1b.2d.3b.4f.5b.6f,1b.2d.3b.4f.5c.6a,1b.2d.3b.4f.5c.6b,
1b.2d.3b.4f.5c.6c,1b.2d.3b.4f.5c.6d,1b.2d.3b.4f.5c.6e,1b.2d.3b.4f.5c.6f,1b.2d.3b.4f.5d.6a,
1b.2d.3b.4f.5d.6b,1b.2d.3b.4f.5d.6c,1b.2d.3b.4f.5d.6d,1b.2d.3b.4f.5d.6e,1b.2d.3b.4f.5d.6f,
1b.2d.3b.4f.5e.6a,1b.2d.3b.4f.5e.6b,1b.2d.3b.4f.5e.6c,1b.2d.3b.4f.5e.6d,1b.2d.3b.4f.5e.6e,
1b.2d.3b.4f.5e.6f,1b.2d.3b.4f.5f.6a,1b.2d.3b.4f.5f.6b,1b.2d.3b.4f.5f.6c,1b.2d.3b.4f.5f.6d,
1b.2d.3b.4f.5f.6e,1b.2d.3b.4f.5f.6f,1b.2d.3c.4a.5a.6a,1b.2d.3c.4a.5a.6b,1b.2d.3c.4a.5a.6c,
1b.2d.3c.4a.5a.6d,1b.2d.3c.4a.5a.6e,1b.2d.3c.4a.5a.6f,1b.2d.3c.4a.5b.6a,1b.2d.3c.4a.5b.6b,
1b.2d.3c.4a.5b.6c,1b.2d.3c.4a.5b.6d,1b.2d.3c.4a.5b.6e,1b.2d.3c.4a.5b.6f,1b.2d.3c.4a.5c.6a,
1b.2d.3c.4a.5c.6b,1b.2d.3c.4a.5c.6c,1b.2d.3c.4a.5c.6d,1b.2d.3c.4a.5c.6e,1b.2d.3c.4a.5c.6f,
1b.2d.3c.4a.5d.6a,1b.2d.3c.4a.5d.6b,1b.2d.3c.4a.5d.6c,1b.2d.3c.4a.5d.6d,1b.2d.3c.4a.5d.6e,
1b.2d.3c.4a.5d.6f,1b.2d.3c.4a.5e.6a,1b.2d.3c.4a.5e.6b,1b.2d.3c.4a.5e.6c,1b.2d.3c.4a.5e.6d,
1b.2d.3c.4a.5e.6e,1b.2d.3c.4a.5e.6f,1b.2d.3c.4a.5f.6a,1b.2d.3c.4a.5f.6b,1b.2d.3c.4a.5f.6c,
1b.2d.3c.4a.5f.6d,1b.2d.3c.4a.5f.6e,1b.2d.3c.4a.5f.6f,1b.2d.3c.4b.5a.6a,1b.2d.3c.4b.5a.6b,
1b.2d.3c.4b.5a.6c,1b.2d.3c.4b.5a.6d,1b.2d.3c.4b.5a.6e,1b.2d.3c.4b.5a.6f,1b.2d.3c.4b.5b.6a,
1b.2d.3c.4b.5b.6b,1b.2d.3c.4b.5b.6c,1b.2d.3c.4b.5b.6d,1b.2d.3c.4b.5b.6e,1b.2d.3c.4b.5b.6f,
1b.2d.3c.4b.5c.6a,1b.2d.3c.4b.5c.6b,1b.2d.3c.4b.5c.6c,1b.2d.3c.4b.5c.6d,1b.2d.3c.4b.5c.6e,
1b.2d.3c.4b.5c.6f,1b.2d.3c.4b.5d.6a,1b.2d.3c.4b.5d.6b,1b.2d.3c.4b.5d.6c,1b.2d.3c.4b.5d.6d,
1b.2d.3c.4b.5d.6e,1b.2d.3c.4b.5d.6f,1b.2d.3c.4b.5e.6a,1b.2d.3c.4b.5e.6b,1b.2d.3c.4b.5e.6c,
1b.2d.3c.4b.5e.6d,1b.2d.3c.4b.5e.6e,1b.2d.3c.4b.5e.6f,1b.2d.3c.4b.5f.6a,1b.2d.3c.4b.5f.6b,
1b.2d.3c.4b.5f.6c,1b.2d.3c.4b.5f.6d,1b.2d.3c.4b.5f.6e,1b.2d.3c.4b.5f.6f,1b.2d.3c.4c.5a.6a,
1b.2d.3c.4c.5a.6b,1b.2d.3c.4c.5a.6c,1b.2d.3c.4c.5a.6d,1b.2d.3c.4c.5a.6e,1b.2d.3c.4c.5a.6f,
1b.2d.3c.4c.5b.6a,1b.2d.3c.4c.5b.6b,1b.2d.3c.4c.5b.6c,1b.2d.3c.4c.5b.6d,1b.2d.3c.4c.5b.6e,
1b.2d.3c.4c.5b.6f,1b.2d.3c.4c.5c.6a,1b.2d.3c.4c.5c.6b,1b.2d.3c.4c.5c.6c,1b.2d.3c.4c.5c.6d,
1b.2d.3c.4c.5c.6e,1b.2d.3c.4c.5c.6f,1b.2d.3c.4c.5d.6a,1b.2d.3c.4c.5d.6b,1b.2d.3c.4c.5d.6c,
1b.2d.3c.4c.5d.6d,1b.2d.3c.4c.5d.6e,1b.2d.3c.4c.5d.6f,1b.2d.3c.4c.5e.6a,1b.2d.3c.4c.5e.6b,
1b.2d.3c.4c.5e.6c,1b.2d.3c.4c.5e.6d,1b.2d.3c.4c.5e.6e,1b.2d.3c.4c.5e.6f,1b.2d.3c.4c.5f.6a,
1b.2d.3c.4c.5f.6b,1b.2d.3c.4c.5f.6c,1b.2d.3c.4c.5f.6d,1b.2d.3c.4c.5f.6e,1b.2d.3c.4c.5f.6f,
1b.2d.3c.4d.5a.6a,1b.2d.3c.4d.5a.6b,1b.2d.3c.4d.5a.6c,1b.2d.3c.4d.5a.6d,1b.2d.3c.4d.5a.6e,
1b.2d.3c.4d.5a.6f,1b.2d.3c.4d.5b.6a,1b.2d.3c.4d.5b.6b,1b.2d.3c.4d.5b.6c,1b.2d.3c.4d.5b.6d,
1b.2d.3c.4d.5b.6e,1b.2d.3c.4d.5b.6f,1b.2d.3c.4d.5c.6a,1b.2d.3c.4d.5c.6b,1b.2d.3c.4d.5c.6c,
1b.2d.3c.4d.5c.6d,1b.2d.3c.4d.5c.6e,1b.2d.3c.4d.5c.6f,1b.2d.3c.4d.5d.6a,1b.2d.3c.4d.5d.6b,
1b.2d.3c.4d.5d.6c, 1b.2d.3c.4d.5d.6d, 1b.2d.3c.4d.5d.6e, 1b.2d.3c.4d.5d.6f,
1b.2d.3c.4d.5e.6a,1b.2d.3c.4d.5e.6b,1b.2d.3c.4d.5e.6c,1b.2d.3c.4d.5e.6d,1b.2d.3c.4d.5e.6e,
1b.2d.3c.4d.5e.6f,1b.2d.3c.4d.5f.6a,1b.2d.3c.4d.5f.6b,1b.2d.3c.4d.5f.6c,1b.2d.3c.4d.5f.6d,
1b.2d.3c.4d.5f.6e,1b.2d.3c.4d.5f.6f,1b.2d.3c.4e.5a.6a,1b.2d.3c.4e.5a.6b,1b.2d.3c.4e.5a.6c,
1b.2d.3c.4e.5a.6d,1b.2d.3c.4e.5a.6e,1b.2d.3c.4e.5a.6f,1b.2d.3c.4e.5b.6a,1b.2d.3c.4e.5b.6b,
1b.2d.3c.4e.5b.6c,1b.2d.3c.4e.5b.6d,1b.2d.3c.4e.5b.6e,1b.2d.3c.4e.5b.6f,1b.2d.3c.4e.5c.6a,
1b.2d.3c.4e.5c.6b,1b.2d.3c.4e.5c.6c,1b.2d.3c.4e.5c.6d,1b.2d.3c.4e.5c.6e,1b.2d.3c.4e.5c.6f,
1b.2d.3c.4e.5d.6a,1b.2d.3c.4e.5d.6b,1b.2d.3c.4e.5d.6c,1b.2d.3c.4e.5d.6d,1b.2d.3c.4e.5d.6e,
1b.2d.3c.4e.5d.6f,1b.2d.3c.4e.5e.6a,1b.2d.3c.4e.5e.6b,1b.2d.3c.4e.5e.6c,1b.2d.3c.4e.5e.6d,
1b.2d.3c.4e.5e.6e,1b.2d.3c.4e.5e.6f,1b.2d.3c.4e.5f.6a,1b.2d.3c.4e.5f.6b,1b.2d.3c.4e.5f.6c,
1b.2d.3c.4e.5f.6d,1b.2d.3c.4e.5f.6e,1b.2d.3c.4e.5f.6f,1b.2d.3c.4f.5a.6a,1b.2d.3c.4f.5a.6b,
1b.2d.3c.4f.5a.6c,1b.2d.3c.4f.5a.6d,1b.2d.3c.4f.5a.6e,1b.2d.3c.4f.5a.6f,1b.2d.3c.4f.5b.6a,
1b.2d.3c.4f.5b.6b,1b.2d.3c.4f.5b.6c,1b.2d.3c.4f.5b.6d,1b.2d.3c.4f.5b.6e,1b.2d.3c.4f.5b.6f,
1b.2d.3c.4f.5c.6a,1b.2d.3c.4f.5c.6b,1b.2d.3c.4f.5c.6c,1b.2d.3c.4f.5c.6d,1b.2d.3c.4f.5c.6e,
1b.2d.3c.4f.5c.6f,1b.2d.3c.4f.5d.6a,1b.2d.3c.4f.5d.6b,1b.2d.3c.4f.5d.6c,1b.2d.3c.4f.5d.6d,
1b.2d.3c.4f.5d.6e,1b.2d.3c.4f.5d.6f,1b.2d.3c.4f.5e.6a,1b.2d.3c.4f.5e.6b,1b.2d.3c.4f.5e.6c,
1b.2d.3c.4f.5e.6d,1b.2d.3c.4f.5e.6e,1b.2d.3c.4f.5e.6f,1b.2d.3c.4f.5f.6a,1b.2d.3c.4f.5f.6b,
1b.2d.3c.4f.5f.6c,1b.2d.3c.4f.5f.6d,1b.2d.3c.4f.5f.6e,1b.2d.3c.4f.5f.6f,1b.2d.3d.4a.5a.6a,
1b.2d.3d.4a.5a.6b,1b.2d.3d.4a.5a.6c,1b.2d.3d.4a.5a.6d,1b.2d.3d.4a.5a.6e,1b.2d.3d.4a.5a.6f,
1b.2d.3d.4a.5b.6a, 1b.2d.3d.4a.5b.6b, 1b.2d.3d.4a.5b.6c, 1b.2d.3d.4a.5b.6d,
1b.2d.3d.4a.5b.6e,1b.2d.3d.4a.5b.6f,1b.2d.3d.4a.5c.6a,1b.2d.3d.4a.5c.6b,1b.2d.3d.4a.5c.6c,
1b.2d.3d.4a.5c.6d, 1b.2d.3d.4a.5c.6e, 1b.2d.3d.4a.5c.6f, 1b.2d.3d.4a.5d.6a,
1b.2d.3d.4a.5d.6b, 1b.2d.3d.4a.5d.6c, 1b.2d.3d.4a.5d.6d, 1b.2d.3d.4a.5d.6e,
1b.2d.3d.4a.5d.6f, 1b.2d.3d.4a.5e.6a, 1b.2d.3d.4a.5e.6b, 1b.2d.3d.4a.5e.6c,
1b.2d.3d.4a.5e.6d,1b.2d.3d.4a.5e.6e,1b.2d.3d.4a.5e.6f,1b.2d.3d.4a.5f.6a,1b.2d.3d.4a.5f.6b,
1b.2d.3d.4a.5f.6c,1b.2d.3d.4a.5f.6d,1b.2d.3d.4a.5f.6e,1b.2d.3d.4a.5f.6f,1b.2d.3d.4b.5a.6a,
1b.2d.3d.4b.5a.6b, 1b.2d.3d.4b.5a.6c, 1b.2d.3d.4b.5a.6d, 1b.2d.3d.4b.5a.6e,
1b.2d.3d.4b.5a.6f, 1b.2d.3d.4b.5b.6a, 1b.2d.3d.4b.5b.6b, 1b.2d.3d.4b.5b.6c,
1b.2d.3d.4b.5b.6d, 1b.2d.3d.4b.5b.6e, 1b.2d.3d.4b.5b.6f, 1b.2d.3d.4b.5c.6a,
1b.2d.3d.4b.5c.6b,1b.2d.3d.4b.5c.6c,1b.2d.3d.4b.5c.6d,1b.2d.3d.4b.5c.6e,1b.2d.3d.4b.5c.6f,
1b.2d.3d.4b.5d.6a, 1b.2d.3d.4b.5d.6b, 1b.2d.3d.4b.5d.6c, 1b.2d.3d.4b.5d.6d,
1b.2d.3d.4b.5d.6e, 1b.2d.3d.4b.5d.6f, 1b.2d.3d.4b.5e.6a, 1b.2d.3d.4b.5e.6b,
1b.2d.3d.4b.5e.6c,1b.2d.3d.4b.5e.6d,1b.2d.3d.4b.5e.6e,1b.2d.3d.4b.5e.6f,1b.2d.3d.4b.5f.6a,
1b.2d.3d.4b.5f.6b,1b.2d.3d.4b.5f.6c,1b.2d.3d.4b.5f.6d,1b.2d.3d.4b.5f.6e,1b.2d.3d.4b.5f.6f,
1b.2d.3d.4c.5a.6a,1b.2d.3d.4c.5a.6b,1b.2d.3d.4c.5a.6c,1b.2d.3d.4c.5a.6d,1b.2d.3d.4c.5a.6e,
1b.2d.3d.4c.5a.6f,1b.2d.3d.4c.5b.6a,1b.2d.3d.4c.5b.6b,1b.2d.3d.4c.5b.6c,1b.2d.3d.4c.5b.6d,
1b.2d.3d.4c.5b.6e,1b.2d.3d.4c.5b.6f,1b.2d.3d.4c.5c.6a,1b.2d.3d.4c.5c.6b,1b.2d.3d.4c.5c.6c,
1b.2d.3d.4c.5c.6d,1b.2d.3d.4c.5c.6e,1b.2d.3d.4c.5c.6f,1b.2d.3d.4c.5d.6a,1b.2d.3d.4c.5d.6b,
1b.2d.3d.4c.5d.6c, 1b.2d.3d.4c.5d.6d, 1b.2d.3d.4c.5d.6e, 1b.2d.3d.4c.5d.6f,
1b.2d.3d.4c.5e.6a,1b.2d.3d.4c.5e.6b,1b.2d.3d.4c.5e.6c,1b.2d.3d.4c.5e.6d,1b.2d.3d.4c.5e.6e,
1b.2d.3d.4c.5e.6f,1b.2d.3d.4c.5f.6a,1b.2d.3d.4c.5f.6b,1b.2d.3d.4c.5f.6c,1b.2d.3d.4c.5f.6d,
1b.2d.3d.4c.5f.6e,1b.2d.3d.4c.5f.6f,1b.2d.3d.4d.5a.6a,1b.2d.3d.4d.5a.6b,1b.2d.3d.4d.5a.6c,
1b.2d.3d.4d.5a.6d, 1b.2d.3d.4d.5a.6e, 1b.2d.3d.4d.5a.6f, 1b.2d.3d.4d.5b.6a,
1b.2d.3d.4d.5b.6b, 1b.2d.3d.4d.5b.6c, 1b.2d.3d.4d.5b.6d, 1b.2d.3d.4d.5b.6e,
1b.2d.3d.4d.5b.6f, 1b.2d.3d.4d.5c.6a, 1b.2d.3d.4d.5c.6b, 1b.2d.3d.4d.5c.6c,
1b.2d.3d.4d.5c.6d, 1b.2d.3d.4d.5c.6e, 1b.2d.3d.4d.5c.6f, 1b.2d.3d.4d.5d.6a,
1b.2d.3d.4d.5d.6b, 1b.2d.3d.4d.5d.6c, 1b.2d.3d.4d.5d.6d, 1b.2d.3d.4d.5d.6e,
1b.2d.3d.4d.5d.6f, 1b.2d.3d.4d.5e.6a, 1b.2d.3d.4d.5e.6b, 1b.2d.3d.4d.5e.6c,
1b.2d.3d.4d.5e.6d, 1b.2d.3d.4d.5e.6e, 1b.2d.3d.4d.5e.6f, 1b.2d.3d.4d.5f.6a,
1b.2d.3d.4d.5f.6b,1b.2d.3d.4d.5f.6c,1b.2d.3d.4d.5f.6d,1b.2d.3d.4d.5f.6e,1b.2d.3d.4d.5f.6f,
1b.2d.3d.4e.5a.6a, 1b.2d.3d.4e.5a.6b, 1b.2d.3d.4e.5a.6c, 1b.2d.3d.4e.5a.6d,
1b.2d.3d.4e.5a.6e,1b.2d.3d.4e.5a.6f,1b.2d.3d.4e.5b.6a,1b.2d.3d.4e.5b.6b,1b.2d.3d.4e.5b.6c,
1b.2d.3d.4e.5b.6d,1b.2d.3d.4e.5b.6e,1b.2d.3d.4e.5b.6f,1b.2d.3d.4e.5c.6a,1b.2d.3d.4e.5c.6b,
1b.2d.3d.4e.5c.6c,1b.2d.3d.4e.5c.6d,1b.2d.3d.4e.5c.6e,1b.2d.3d.4e.5c.6f,1b.2d.3d.4e.5d.6a,
1b.2d.3d.4e.5d.6b, 1b.2d.3d.4e.5d.6c, 1b.2d.3d.4e.5d.6d, 1b.2d.3d.4e.5d.6e,
1b.2d.3d.4e.5d.6f,1b.2d.3d.4e.5e.6a,1b.2d.3d.4e.5e.6b,1b.2d.3d.4e.5e.6c,1b.2d.3d.4e.5e.6d,
1b.2d.3d.4e.5e.6e,1b.2d.3d.4e.5e.6f,1b.2d.3d.4e.5f.6a,1b.2d.3d.4e.5f.6b,1b.2d.3d.4e.5f.6c,
1b.2d.3d.4e.5f.6d,1b.2d.3d.4e.5f.6e,1b.2d.3d.4e.5f.6f,1b.2d.3d.4f.5a.6a,1b.2d.3d.4f.5a.6b,
1b.2d.3d.4f.5a.6c,1b.2d.3d.4f.5a.6d,1b.2d.3d.4f.5a.6e,1b.2d.3d.4f.5a.6f,1b.2d.3d.4f.5b.6a,
1b.2d.3d.4f.5b.6b,1b.2d.3d.4f.5b.6c,1b.2d.3d.4f.5b.6d,1b.2d.3d.4f.5b.6e,1b.2d.3d.4f.5b.6f,
1b.2d.3d.4f.5c.6a,1b.2d.3d.4f.5c.6b,1b.2d.3d.4f.5c.6c,1b.2d.3d.4f.5c.6d,1b.2d.3d.4f.5c.6e,
1b.2d.3d.4f.5c.6f,1b.2d.3d.4f.5d.6a,1b.2d.3d.4f.5d.6b,1b.2d.3d.4f.5d.6c,1b.2d.3d.4f.5d.6d,
1b.2d.3d.4f.5d.6e,1b.2d.3d.4f.5d.6f,1b.2d.3d.4f.5e.6a,1b.2d.3d.4f.5e.6b,1b.2d.3d.4f.5e.6c,
1b.2d.3d.4f.5e.6d,1b.2d.3d.4f.5e.6e,1b.2d.3d.4f.5e.6f,1b.2d.3d.4f.5f.6a,1b.2d.3d.4f.5f.6b,
1b.2d.3d.4f.5f.6c,1b.2d.3d.4f.5f.6d,1b.2d.3d.4f.5f.6e,1b.2d.3d.4f.5f.6f,1b.2d.3e.4a.5a.6a,
1b.2d.3e.4a.5a.6b,1b.2d.3e.4a.5a.6c,1b.2d.3e.4a.5a.6d,1b.2d.3e.4a.5a.6e,1b.2d.3e.4a.5a.6f,
1b.2d.3e.4a.5b.6a,1b.2d.3e.4a.5b.6b,1b.2d.3e.4a.5b.6c,1b.2d.3e.4a.5b.6d,1b.2d.3e.4a.5b.6e,
1b.2d.3e.4a.5b.6f,1b.2d.3e.4a.5c.6a,1b.2d.3e.4a.5c.6b,1b.2d.3e.4a.5c.6c,1b.2d.3e.4a.5c.6d,
1b.2d.3e.4a.5c.6e,1b.2d.3e.4a.5c.6f,1b.2d.3e.4a.5d.6a,1b.2d.3e.4a.5d.6b,1b.2d.3e.4a.5d.6c,
1b.2d.3e.4a.5d.6d,1b.2d.3e.4a.5d.6e,1b.2d.3e.4a.5d.6f,1b.2d.3e.4a.5e.6a,1b.2d.3e.4a.5e.6b,
1b.2d.3e.4a.5e.6c,1b.2d.3e.4a.5e.6d,1b.2d.3e.4a.5e.6e,1b.2d.3e.4a.5e.6f,1b.2d.3e.4a.5f.6a,
1b.2d.3e.4a.5f.6b,1b.2d.3e.4a.5f.6c,1b.2d.3e.4a.5f.6d,1b.2d.3e.4a.5f.6e,1b.2d.3e.4a.5f.6f,
1b.2d.3e.4b.5a.6a,1b.2d.3e.4b.5a.6b,1b.2d.3e.4b.5a.6c,1b.2d.3e.4b.5a.6d,1b.2d.3e.4b.5a.6e,
1b.2d.3e.4b.5a.6f,1b.2d.3e.4b.5b.6a,1b.2d.3e.4b.5b.6b,1b.2d.3e.4b.5b.6c,1b.2d.3e.4b.5b.6d,
1b.2d.3e.4b.5b.6e,1b.2d.3e.4b.5b.6f,1b.2d.3e.4b.5c.6a,1b.2d.3e.4b.5c.6b,1b.2d.3e.4b.5c.6c,
1b.2d.3e.4b.5c.6d,1b.2d.3e.4b.5c.6e,1b.2d.3e.4b.5c.6f,1b.2d.3e.4b.5d.6a,1b.2d.3e.4b.5d.6b,
1b.2d.3e.4b.5d.6c,1b.2d.3e.4b.5d.6d,1b.2d.3e.4b.5d.6e,1b.2d.3e.4b.5d.6f,1b.2d.3e.4b.5e.6a,
1b.2d.3e.4b.5e.6b,1b.2d.3e.4b.5e.6c,1b.2d.3e.4b.5e.6d,1b.2d.3e.4b.5e.6e,1b.2d.3e.4b.5e.6f,
1b.2d.3e.4b.5f.6a,1b.2d.3e.4b.5f.6b,1b.2d.3e.4b.5f.6c,1b.2d.3e.4b.5f.6d,1b.2d.3e.4b.5f.6e,
1b.2d.3e.4b.5f.6f,1b.2d.3e.4c.5a.6a,1b.2d.3e.4c.5a.6b,1b.2d.3e.4c.5a.6c,1b.2d.3e.4c.5a.6d,
1b.2d.3e.4c.5a.6e,1b.2d.3e.4c.5a.6f,1b.2d.3e.4c.5b.6a,1b.2d.3e.4c.5b.6b,1b.2d.3e.4c.5b.6c,
1b.2d.3e.4c.5b.6d,1b.2d.3e.4c.5b.6e,1b.2d.3e.4c.5b.6f,1b.2d.3e.4c.5c.6a,1b.2d.3e.4c.5c.6b,
1b.2d.3e.4c.5c.6c,1b.2d.3e.4c.5c.6d,1b.2d.3e.4c.5c.6e,1b.2d.3e.4c.5c.6f,1b.2d.3e.4c.5d.6a,
1b.2d.3e.4c.5d.6b,1b.2d.3e.4c.5d.6c,1b.2d.3e.4c.5d.6d,1b.2d.3e.4c.5d.6e,1b.2d.3e.4c.5d.6f,
1b.2d.3e.4c.5e.6a,1b.2d.3e.4c.5e.6b,1b.2d.3e.4c.5e.6c,1b.2d.3e.4c.5e.6d,1b.2d.3e.4c.5e.6e,
1b.2d.3e.4c.5e.6f,1b.2d.3e.4c.5f.6a,1b.2d.3e.4c.5f.6b,1b.2d.3e.4c.5f.6c,1b.2d.3e.4c.5f.6d,
1b.2d.3e.4c.5f.6e,1b.2d.3e.4c.5f.6f,1b.2d.3e.4d.5a.6a,1b.2d.3e.4d.5a.6b,1b.2d.3e.4d.5a.6c,
1b.2d.3e.4d.5a.6d, 1b.2d.3e.4d.5a.6e, 1b.2d.3e.4d.5a.6f, 1b.2d.3e.4d.5b.6a,
1b.2d.3e.4d.5b.6b, 1b.2d.3e.4d.5b.6c, 1b.2d.3e.4d.5b.6d, 1b.2d.3e.4d.5b.6e,
1b.2d.3e.4d.5b.6f,1b.2d.3e.4d.5c.6a,1b.2d.3e.4d.5c.6b,1b.2d.3e.4d.5c.6c,1b.2d.3e.4d.5c.6d,
1b.2d.3e.4d.5c.6e,1b.2d.3e.4d.5c.6f,1b.2d.3e.4d.5d.6a,1b.2d.3e.4d.5d.6b,1b.2d.3e.4d.5d.6c,
1b.2d.3e.4d.5d.6d, 1b.2d.3e.4d.5d.6e, 1b.2d.3e.4d.5d.6f, 1b.2d.3e.4d.5e.6a,
1b.2d.3e.4d.5e.6b,1b.2d.3e.4d.5e.6c,1b.2d.3e.4d.5e.6d,1b.2d.3e.4d.5e.6e,1b.2d.3e.4d.5e.6f,
1b.2d.3e.4d.5f.6a,1b.2d.3e.4d.5f.6b,1b.2d.3e.4d.5f.6c,1b.2d.3e.4d.5f.6d,1b.2d.3e.4d.5f.6e,
1b.2d.3e.4d.5f.6f,1b.2d.3e.4e.5a.6a,1b.2d.3e.4e.5a.6b,1b.2d.3e.4e.5a.6c,1b.2d.3e.4e.5a.6d,
1b.2d.3e.4e.5a.6e,1b.2d.3e.4e.5a.6f,1b.2d.3e.4e.5b.6a,1b.2d.3e.4e.5b.6b,1b.2d.3e.4e.5b.6c,
1b.2d.3e.4e.5b.6d,1b.2d.3e.4e.5b.6e,1b.2d.3e.4e.5b.6f,1b.2d.3e.4e.5c.6a,1b.2d.3e.4e.5c.6b,
1b.2d.3e.4e.5c.6c,1b.2d.3e.4e.5c.6d,1b.2d.3e.4e.5c.6e,1b.2d.3e.4e.5c.6f,1b.2d.3e.4e.5d.6a,
1b.2d.3e.4e.5d.6b,1b.2d.3e.4e.5d.6c,1b.2d.3e.4e.5d.6d,1b.2d.3e.4e.5d.6e,1b.2d.3e.4e.5d.6f,
1b.2d.3e.4e.5e.6a,1b.2d.3e.4e.5e.6b,1b.2d.3e.4e.5e.6c,1b.2d.3e.4e.5e.6d,1b.2d.3e.4e.5e.6e,
1b.2d.3e.4e.5e.6f,1b.2d.3e.4e.5f.6a,1b.2d.3e.4e.5f.6b,1b.2d.3e.4e.5f.6c,1b.2d.3e.4e.5f.6d,
1b.2d.3e.4e.5f.6e,1b.2d.3e.4e.5f.6f,1b.2d.3e.4f.5a.6a,1b.2d.3e.4f.5a.6b,1b.2d.3e.4f.5a.6c,
1b.2d.3e.4f.5a.6d,1b.2d.3e.4f.5a.6e,1b.2d.3e.4f.5a.6f,1b.2d.3e.4f.5b.6a,1b.2d.3e.4f.5b.6b,
1b.2d.3e.4f.5b.6c,1b.2d.3e.4f.5b.6d,1b.2d.3e.4f.5b.6e,1b.2d.3e.4f.5b.6f,1b.2d.3e.4f.5c.6a,
1b.2d.3e.4f.5c.6b,1b.2d.3e.4f.5c.6c,1b.2d.3e.4f.5c.6d,1b.2d.3e.4f.5c.6e,1b.2d.3e.4f.5c.6f,
1b.2d.3e.4f.5d.6a,1b.2d.3e.4f.5d.6b,1b.2d.3e.4f.5d.6c,1b.2d.3e.4f.5d.6d,1b.2d.3e.4f.5d.6e,
1b.2d.3e.4f.5d.6f,1b.2d.3e.4f.5e.6a,1b.2d.3e.4f.5e.6b,1b.2d.3e.4f.5e.6c,1b.2d.3e.4f.5e.6d,
1b.2d.3e.4f.5e.6e,1b.2d.3e.4f.5e.6f,1b.2d.3e.4f.5f.6a,1b.2d.3e.4f.5f.6b,1b.2d.3e.4f.5f.6c,
1b.2d.3e.4f.5f.6d,1b.2d.3e.4f.5f.6e,1b.2d.3e.4f.5f.6f,1b.2d.3f.4a.5a.6a,1b.2d.3f.4a.5a.6b,
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1b.2e.3d.4a.5b.6a,1b.2e.3d.4a.5b.6b,1b.2e.3d.4a.5b.6c,1b.2e.3d.4a.5b.6d,1b.2e.3d.4a.5b.6e,
1b.2e.3d.4a.5b.6f,1b.2e.3d.4a.5c.6a,1b.2e.3d.4a.5c.6b,1b.2e.3d.4a.5c.6c,1b.2e.3d.4a.5c.6d,
1b.2e.3d.4a.5c.6e,1b.2e.3d.4a.5c.6f,1b.2e.3d.4a.5d.6a,1b.2e.3d.4a.5d.6b,1b.2e.3d.4a.5d.6c,
1b.2e.3d.4a.5d.6d,1b.2e.3d.4a.5d.6e,1b.2e.3d.4a.5d.6f,1b.2e.3d.4a.5e.6a,1b.2e.3d.4a.5e.6b,
1b.2e.3d.4a.5e.6c,1b.2e.3d.4a.5e.6d,1b.2e.3d.4a.5e.6e,1b.2e.3d.4a.5e.6f,1b.2e.3d.4a.5f.6a,
1b.2e.3d.4a.5f.6b,1b.2e.3d.4a.5f.6c,1b.2e.3d.4a.5f.6d,1b.2e.3d.4a.5f.6e,1b.2e.3d.4a.5f.6f,
1b.2e.3d.4b.5a.6a,1b.2e.3d.4b.5a.6b,1b.2e.3d.4b.5a.6c,1b.2e.3d.4b.5a.6d,1b.2e.3d.4b.5a.6e,
1b.2e.3d.4b.5a.6f,1b.2e.3d.4b.5b.6a,1b.2e.3d.4b.5b.6b,1b.2e.3d.4b.5b.6c,1b.2e.3d.4b.5b.6d,
1b.2e.3d.4b.5b.6e,1b.2e.3d.4b.5b.6f,1b.2e.3d.4b.5c.6a,1b.2e.3d.4b.5c.6b,1b.2e.3d.4b.5c.6c,
1b.2e.3d.4b.5c.6d,1b.2e.3d.4b.5c.6e,1b.2e.3d.4b.5c.6f,1b.2e.3d.4b.5d.6a,1b.2e.3d.4b.5d.6b,
1b.2e.3d.4b.5d.6c,1b.2e.3d.4b.5d.6d,1b.2e.3d.4b.5d.6e,1b.2e.3d.4b.5d.6f,1b.2e.3d.4b.5e.6a,
1b.2e.3d.4b.5e.6b,1b.2e.3d.4b.5e.6c,1b.2e.3d.4b.5e.6d,1b.2e.3d.4b.5e.6e,1b.2e.3d.4b.5e.6f,
1b.2e.3d.4b.5f.6a,1b.2e.3d.4b.5f.6b,1b.2e.3d.4b.5f.6c,1b.2e.3d.4b.5f.6d,1b.2e.3d.4b.5f.6e,
1b.2e.3d.4b.5f.6f,1b.2e.3d.4c.5a.6a,1b.2e.3d.4c.5a.6b,1b.2e.3d.4c.5a.6c,1b.2e.3d.4c.5a.6d,
1b.2e.3d.4c.5a.6e,1b.2e.3d.4c.5a.6f,1b.2e.3d.4c.5b.6a,1b.2e.3d.4c.5b.6b,1b.2e.3d.4c.5b.6c,
1b.2e.3d.4c.5b.6d,1b.2e.3d.4c.5b.6e,1b.2e.3d.4c.5b.6f,1b.2e.3d.4c.5c.6a,1b.2e.3d.4c.5c.6b,
1b.2e.3d.4c.5c.6c,1b.2e.3d.4c.5c.6d,1b.2e.3d.4c.5c.6e,1b.2e.3d.4c.5c.6f,1b.2e.3d.4c.5d.6a,
1b.2e.3d.4c.5d.6b,1b.2e.3d.4c.5d.6c,1b.2e.3d.4c.5d.6d,1b.2e.3d.4c.5d.6e,1b.2e.3d.4c.5d.6f,
1b.2e.3d.4c.5e.6a,1b.2e.3d.4c.5e.6b,1b.2e.3d.4c.5e.6c,1b.2e.3d.4c.5e.6d,1b.2e.3d.4c.5e.6e,
1b.2e.3d.4c.5e.6f,1b.2e.3d.4c.5f.6a,1b.2e.3d.4c.5f.6b,1b.2e.3d.4c.5f.6c,1b.2e.3d.4c.5f.6d,
1b.2e.3d.4c.5f.6e,1b.2e.3d.4c.5f.6f,1b.2e.3d.4d.5a.6a,1b.2e.3d.4d.5a.6b,1b.2e.3d.4d.5a.6c,
1b.2e.3d.4d.5a.6d, 1b.2e.3d.4d.5a.6e, 1b.2e.3d.4d.5a.6f, 1b.2e.3d.4d.5b.6a,
1b.2e.3d.4d.5b.6b, 1b.2e.3d.4d.5b.6c, 1b.2e.3d.4d.5b.6d, 1b.2e.3d.4d.5b.6e,
1b.2e.3d.4d.5b.6f,1b.2e.3d.4d.5c.6a,1b.2e.3d.4d.5c.6b,1b.2e.3d.4d.5c.6c,1b.2e.3d.4d.5c.6d,
1b.2e.3d.4d.5c.6e,1b.2e.3d.4d.5c.6f,1b.2e.3d.4d.5d.6a,1b.2e.3d.4d.5d.6b,1b.2e.3d.4d.5d.6c,
1b.2e.3d.4d.5d.6d, 1b.2e.3d.4d.5d.6e, 1b.2e.3d.4d.5d.6f, 1b.2e.3d.4d.5e.6a,
1b.2e.3d.4d.5e.6b,1b.2e.3d.4d.5e.6c,1b.2e.3d.4d.5e.6d,1b.2e.3d.4d.5e.6e,1b.2e.3d.4d.5e.6f,
1b.2e.3d.4d.5f.6a,1b.2e.3d.4d.5f.6b,1b.2e.3d.4d.5f.6c,1b.2e.3d.4d.5f.6d,1b.2e.3d.4d.5f.6e,
1b.2e.3d.4d.5f.6f,1b.2e.3d.4e.5a.6a,1b.2e.3d.4e.5a.6b,1b.2e.3d.4e.5a.6c,1b.2e.3d.4e.5a.6d,
1b.2e.3d.4e.5a.6e,1b.2e.3d.4e.5a.6f,1b.2e.3d.4e.5b.6a,1b.2e.3d.4e.5b.6b,1b.2e.3d.4e.5b.6c,
1b.2e.3d.4e.5b.6d,1b.2e.3d.4e.5b.6e,1b.2e.3d.4e.5b.6f,1b.2e.3d.4e.5c.6a,1b.2e.3d.4e.5c.6b,
1b.2e.3d.4e.5c.6c,1b.2e.3d.4e.5c.6d,1b.2e.3d.4e.5c.6e,1b.2e.3d.4e.5c.6f,1b.2e.3d.4e.5d.6a,
1b.2e.3d.4e.5d.6b,1b.2e.3d.4e.5d.6c,1b.2e.3d.4e.5d.6d,1b.2e.3d.4e.5d.6e,1b.2e.3d.4e.5d.6f,
1b.2e.3d.4e.5e.6a,1b.2e.3d.4e.5e.6b,1b.2e.3d.4e.5e.6c,1b.2e.3d.4e.5e.6d,1b.2e.3d.4e.5e.6e,
1b.2e.3d.4e.5e.6f,1b.2e.3d.4e.5f.6a,1b.2e.3d.4e.5f.6b,1b.2e.3d.4e.5f.6c,1b.2e.3d.4e.5f.6d,
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1b.2e.3d.4f.5a.6d,1b.2e.3d.4f.5a.6e,1b.2e.3d.4f.5a.6f,1b.2e.3d.4f.5b.6a,1b.2e.3d.4f.5b.6b,
1b.2e.3d.4f.5b.6c,1b.2e.3d.4f.5b.6d,1b.2e.3d.4f.5b.6e,1b.2e.3d.4f.5b.6f,1b.2e.3d.4f.5c.6a,
1b.2e.3d.4f.5c.6b,1b.2e.3d.4f.5c.6c,1b.2e.3d.4f.5c.6d,1b.2e.3d.4f.5c.6e,1b.2e.3d.4f.5c.6f,
1b.2e.3d.4f.5d.6a,1b.2e.3d.4f.5d.6b,1b.2e.3d.4f.5d.6c,1b.2e.3d.4f.5d.6d,1b.2e.3d.4f.5d.6e,
1b.2e.3d.4f.5d.6f,1b.2e.3d.4f.5e.6a,1b.2e.3d.4f.5e.6b,1b.2e.3d.4f.5e.6c,1b.2e.3d.4f.5e.6d,
1b.2e.3d.4f.5e.6e,1b.2e.3d.4f.5e.6f,1b.2e.3d.4f.5f.6a,1b.2e.3d.4f.5f.6b,1b.2e.3d.4f.5f.6c,
1b.2e.3d.4f.5f.6d,1b.2e.3d.4f.5f.6e,1b.2e.3d.4f.5f.6f,1b.2e.3e.4a.5a.6a,1b.2e.3e.4a.5a.6b,
1b.2e.3e.4a.5a.6c,1b.2e.3e.4a.5a.6d,1b.2e.3e.4a.5a.6e,1b.2e.3e.4a.5a.6f,1b.2e.3e.4a.5b.6a,
1b.2e.3e.4a.5b.6b,1b.2e.3e.4a.5b.6c,1b.2e.3e.4a.5b.6d,1b.2e.3e.4a.5b.6e,1b.2e.3e.4a.5b.6f,
1b.2e.3e.4a.5c.6a,1b.2e.3e.4a.5c.6b,1b.2e.3e.4a.5c.6c,1b.2e.3e.4a.5c.6d,1b.2e.3e.4a.5c.6e,
1b.2e.3e.4a.5c.6f,1b.2e.3e.4a.5d.6a,1b.2e.3e.4a.5d.6b,1b.2e.3e.4a.5d.6c,1b.2e.3e.4a.5d.6d,
1b.2e.3e.4a.5d.6e,1b.2e.3e.4a.5d.6f,1b.2e.3e.4a.5e.6a,1b.2e.3e.4a.5e.6b,1b.2e.3e.4a.5e.6c,
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1b.2e.3e.4b.5a.6b,1b.2e.3e.4b.5a.6c,1b.2e.3e.4b.5a.6d,1b.2e.3e.4b.5a.6e,1b.2e.3e.4b.5a.6f,
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1b.2e.3e.4b.5b.6f,1b.2e.3e.4b.5c.6a,1b.2e.3e.4b.5c.6b,1b.2e.3e.4b.5c.6c,1b.2e.3e.4b.5c.6d,
1b.2e.3e.4b.5c.6e,1b.2e.3e.4b.5c.6f,1b.2e.3e.4b.5d.6a,1b.2e.3e.4b.5d.6b,1b.2e.3e.4b.5d.6c,
1b.2e.3e.4b.5d.6d,1b.2e.3e.4b.5d.6e,1b.2e.3e.4b.5d.6f,1b.2e.3e.4b.5e.6a,1b.2e.3e.4b.5e.6b,
1b.2e.3e.4b.5e.6c,1b.2e.3e.4b.5e.6d,1b.2e.3e.4b.5e.6e,1b.2e.3e.4b.5e.6f,1b.2e.3e.4b.5f.6a,
1b.2e.3e.4b.5f.6b,1b.2e.3e.4b.5f.6c,1b.2e.3e.4b.5f.6d,1b.2e.3e.4b.5f.6e,1b.2e.3e.4b.5f.6f,
1b.2e.3e.4c.5a.6a,1b.2e.3e.4c.5a.6b,1b.2e.3e.4c.5a.6c,1b.2e.3e.4c.5a.6d,1b.2e.3e.4c.5a.6e,
1b.2e.3e.4c.5a.6f,1b.2e.3e.4c.5b.6a,1b.2e.3e.4c.5b.6b,1b.2e.3e.4c.5b.6c,1b.2e.3e.4c.5b.6d,
1b.2e.3e.4c.5b.6e,1b.2e.3e.4c.5b.6f,1b.2e.3e.4c.5c.6a,1b.2e.3e.4c.5c.6b,1b.2e.3e.4c.5c.6c,
1b.2e.3e.4c.5c.6d,1b.2e.3e.4c.5c.6e,1b.2e.3e.4c.5c.6f,1b.2e.3e.4c.5d.6a,1b.2e.3e.4c.5d.6b,
1b.2e.3e.4c.5d.6c,1b.2e.3e.4c.5d.6d,1b.2e.3e.4c.5d.6e,1b.2e.3e.4c.5d.6f,1b.2e.3e.4c.5e.6a,
1b.2e.3e.4c.5e.6b,1b.2e.3e.4c.5e.6c,1b.2e.3e.4c.5e.6d,1b.2e.3e.4c.5e.6e,1b.2e.3e.4c.5e.6f,
1b.2e.3e.4c.5f.6a,1b.2e.3e.4c.5f.6b,1b.2e.3e.4c.5f.6c,1b.2e.3e.4c.5f.6d,1b.2e.3e.4c.5f.6e,
1b.2e.3e.4c.5f.6f,1b.2e.3e.4d.5a.6a,1b.2e.3e.4d.5a.6b,1b.2e.3e.4d.5a.6c,1b.2e.3e.4d.5a.6d,
1b.2e.3e.4d.5a.6e,1b.2e.3e.4d.5a.6f,1b.2e.3e.4d.5b.6a,1b.2e.3e.4d.5b.6b,1b.2e.3e.4d.5b.6c,
1b.2e.3e.4d.5b.6d,1b.2e.3e.4d.5b.6e,1b.2e.3e.4d.5b.6f,1b.2e.3e.4d.5c.6a,1b.2e.3e.4d.5c.6b,
1b.2e.3e.4d.5c.6c,1b.2e.3e.4d.5c.6d,1b.2e.3e.4d.5c.6e,1b.2e.3e.4d.5c.6f,1b.2e.3e.4d.5d.6a,
1b.2e.3e.4d.5d.6b,1b.2e.3e.4d.5d.6c,1b.2e.3e.4d.5d.6d,1b.2e.3e.4d.5d.6e,1b.2e.3e.4d.5d.6f,
1b.2e.3e.4d.5e.6a,1b.2e.3e.4d.5e.6b,1b.2e.3e.4d.5e.6c,1b.2e.3e.4d.5e.6d,1b.2e.3e.4d.5e.6e,
1b.2e.3e.4d.5e.6f,1b.2e.3e.4d.5f.6a,1b.2e.3e.4d.5f.6b,1b.2e.3e.4d.5f.6c,1b.2e.3e.4d.5f.6d,
1b.2e.3e.4d.5f.6e,1b.2e.3e.4d.5f.6f,1b.2e.3e.4e.5a.6a,1b.2e.3e.4e.5a.6b,1b.2e.3e.4e.5a.6c,
1b.2e.3e.4e.5a.6d,1b.2e.3e.4e.5a.6e,1b.2e.3e.4e.5a.6f,1b.2e.3e.4e.5b.6a,1b.2e.3e.4e.5b.6b,
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1b.2e.3e.4e.5c.6b,1b.2e.3e.4e.5c.6c,1b.2e.3e.4e.5c.6d,1b.2e.3e.4e.5c.6e,1b.2e.3e.4e.5c.6f,
1b.2e.3e.4e.5d.6a,1b.2e.3e.4e.5d.6b,1b.2e.3e.4e.5d.6c,1b.2e.3e.4e.5d.6d,1b.2e.3e.4e.5d.6e,
1b.2e.3e.4e.5d.6f,1b.2e.3e.4e.5e.6a,1b.2e.3e.4e.5e.6b,1b.2e.3e.4e.5e.6c,1b.2e.3e.4e.5e.6d,
1b.2e.3e.4e.5e.6e,1b.2e.3e.4e.5e.6f,1b.2e.3e.4e.5f.6a,1b.2e.3e.4e.5f.6b,1b.2e.3e.4e.5f.6c,
1b.2e.3e.4e.5f.6d,1b.2e.3e.4e.5f.6e,1b.2e.3e.4e.5f.6f,1b.2e.3e.4f.5a.6a,1b.2e.3e.4f.5a.6b,
1b.2e.3e.4f.5a.6c,1b.2e.3e.4f.5a.6d,1b.2e.3e.4f.5a.6e,1b.2e.3e.4f.5a.6f,1b.2e.3e.4f.5b.6a,
1b.2e.3e.4f.5b.6b,1b.2e.3e.4f.5b.6c,1b.2e.3e.4f.5b.6d,1b.2e.3e.4f.5b.6e,1b.2e.3e.4f.5b.6f,
1b.2e.3e.4f.5c.6a,1b.2e.3e.4f.5c.6b,1b.2e.3e.4f.5c.6c,1b.2e.3e.4f.5c.6d,1b.2e.3e.4f.5c.6e,
1b.2e.3e.4f.5c.6f,1b.2e.3e.4f.5d.6a,1b.2e.3e.4f.5d.6b,1b.2e.3e.4f.5d.6c,1b.2e.3e.4f.5d.6d,
1b.2e.3e.4f.5d.6e,1b.2e.3e.4f.5d.6f,1b.2e.3e.4f.5e.6a,1b.2e.3e.4f.5e.6b,1b.2e.3e.4f.5e.6c,
1b.2e.3e.4f.5e.6d,1b.2e.3e.4f.5e.6e,1b.2e.3e.4f.5e.6f,1b.2e.3e.4f.5f.6a,1b.2e.3e.4f.5f.6b,
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1c.2a.3a.4c.5b.6b,1c.2a.3a.4c.5b.6c,1c.2a.3a.4c.5b.6d,1c.2a.3a.4c.5b.6e,1c.2a.3a.4c.5b.6f,
1c.2a.3a.4c.5c.6a,1c.2a.3a.4c.5c.6b,1c.2a.3a.4c.5c.6c,1c.2a.3a.4c.5c.6d,1c.2a.3a.4c.5c.6e,
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1c.2a.3a.4c.5d.6e,1c.2a.3a.4c.5d.6f,1c.2a.3a.4c.5e.6a,1c.2a.3a.4c.5e.6b,1c.2a.3a.4c.5e.6c,
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1c.2a.3a.4d.5c.6e,1c.2a.3a.4d.5c.6f,1c.2a.3a.4d.5d.6a,1c.2a.3a.4d.5d.6b,1c.2a.3a.4d.5d.6c,
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1c.2a.3a.4e.5f.6f,1c.2a.3a.4f.5a.6a,1c.2a.3a.4f.5a.6b,1c.2a.3a.4f.5a.6c,1c.2a.3a.4f.5a.6d,
1c.2a.3a.4f.5a.6e,1c.2a.3a.4f.5a.6f,1c.2a.3a.4f.5b.6a,1c.2a.3a.4f.5b.6b,1c.2a.3a.4f.5b.6c,
1c.2a.3a.4f.5b.6d,1c.2a.3a.4f.5b.6e,1c.2a.3a.4f.5b.6f,1c.2a.3a.4f.5c.6a,1c.2a.3a.4f.5c.6b,
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1c.2a.3a.4f.5d.6b,1c.2a.3a.4f.5d.6c,1c.2a.3a.4f.5d.6d,1c.2a.3a.4f.5d.6e,1c.2a.3a.4f.5d.6f,
1c.2a.3a.4f.5e.6a,1c.2a.3a.4f.5e.6b,1c.2a.3a.4f.5e.6c,1c.2a.3a.4f.5e.6d,1c.2a.3a.4f.5e.6e,
1c.2a.3a.4f.5e.6f,1c.2a.3a.4f.5f.6a,1c.2a.3a.4f.5f.6b,1c.2a.3a.4f.5f.6c,1c.2a.3a.4f.5f.6d,
1c.2a.3a.4f.5f.6e,1c.2a.3a.4f.5f.6f,1c.2a.3b.4a.5a.6a,1c.2a.3b.4a.5a.6b,1c.2a.3b.4a.5a.6c,
1c.2a.3b.4a.5a.6d,1c.2a.3b.4a.5a.6e,1c.2a.3b.4a.5a.6f,1c.2a.3b.4a.5b.6a,1c.2a.3b.4a.5b.6b,
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1c.2b.3b.4a.5c.6e,1c.2b.3b.4a.5c.6f,1c.2b.3b.4a.5d.6a,1c.2b.3b.4a.5d.6b,1c.2b.3b.4a.5d.6c,
1c.2b.3b.4a.5d.6d,1c.2b.3b.4a.5d.6e,1c.2b.3b.4a.5d.6f,1c.2b.3b.4a.5e.6a,1c.2b.3b.4a.5e.6b,
1c.2b.3b.4a.5e.6c,1c.2b.3b.4a.5e.6d,1c.2b.3b.4a.5e.6e,1c.2b.3b.4a.5e.6f,1c.2b.3b.4a.5f.6a,
1c.2b.3b.4a.5f.6b,1c.2b.3b.4a.5f.6c,1c.2b.3b.4a.5f.6d,1c.2b.3b.4a.5f.6e,1c.2b.3b.4a.5f.6f,
1c.2b.3b.4b.5a.6a,1c.2b.3b.4b.5a.6b,1c.2b.3b.4b.5a.6c,1c.2b.3b.4b.5a.6d,1c.2b.3b.4b.5a.6e,
1c.2b.3b.4b.5a.6f,1c.2b.3b.4b.5b.6a,1c.2b.3b.4b.5b.6b,1c.2b.3b.4b.5b.6c,1c.2b.3b.4b.5b.6d,
1c.2b.3b.4b.5b.6e,1c.2b.3b.4b.5b.6f,1c.2b.3b.4b.5c.6a,1c.2b.3b.4b.5c.6b,1c.2b.3b.4b.5c.6c,
1c.2b.3b.4b.5c.6d,1c.2b.3b.4b.5c.6e,1c.2b.3b.4b.5c.6f,1c.2b.3b.4b.5d.6a,1c.2b.3b.4b.5d.6b,
1c.2b.3b.4b.5d.6c,1c.2b.3b.4b.5d.6d,1c.2b.3b.4b.5d.6e,1c.2b.3b.4b.5d.6f,1c.2b.3b.4b.5e.6a,
1c.2b.3b.4b.5e.6b,1c.2b.3b.4b.5e.6c,1c.2b.3b.4b.5e.6d,1c.2b.3b.4b.5e.6e,1c.2b.3b.4b.5e.6f,
1c.2b.3b.4b.5f.6a,1c.2b.3b.4b.5f.6b,1c.2b.3b.4b.5f.6c,1c.2b.3b.4b.5f.6d,1c.2b.3b.4b.5f.6e,
1c.2b.3b.4b.5f.6f,1c.2b.3b.4c.5a.6a,1c.2b.3b.4c.5a.6b,1c.2b.3b.4c.5a.6c,1c.2b.3b.4c.5a.6d,
1c.2b.3b.4c.5a.6e,1c.2b.3b.4c.5a.6f,1c.2b.3b.4c.5b.6a,1c.2b.3b.4c.5b.6b,1c.2b.3b.4c.5b.6c,
1c.2b.3b.4c.5b.6d,1c.2b.3b.4c.5b.6e,1c.2b.3b.4c.5b.6f,1c.2b.3b.4c.5c.6a,1c.2b.3b.4c.5c.6b,
1c.2b.3b.4c.5c.6c,1c.2b.3b.4c.5c.6d,1c.2b.3b.4c.5c.6e,1c.2b.3b.4c.5c.6f,1c.2b.3b.4c.5d.6a,
1c.2b.3b.4c.5d.6b,1c.2b.3b.4c.5d.6c,1c.2b.3b.4c.5d.6d,1c.2b.3b.4c.5d.6e,1c.2b.3b.4c.5d.6f,
1c.2b.3b.4c.5e.6a,1c.2b.3b.4c.5e.6b,1c.2b.3b.4c.5e.6c,1c.2b.3b.4c.5e.6d,1c.2b.3b.4c.5e.6e,
1c.2b.3b.4c.5e.6f,1c.2b.3b.4c.5f.6a,1c.2b.3b.4c.5f.6b,1c.2b.3b.4c.5f.6c,1c.2b.3b.4c.5f.6d,
1c.2b.3b.4c.5f.6e,1c.2b.3b.4c.5f.6f,1c.2b.3b.4d.5a.6a,1c.2b.3b.4d.5a.6b,1c.2b.3b.4d.5a.6c,
1c.2b.3b.4d.5a.6d,1c.2b.3b.4d.5a.6e,1c.2b.3b.4d.5a.6f,1c.2b.3b.4d.5b.6a,1c.2b.3b.4d.5b.6b,
1c.2b.3b.4d.5b.6c,1c.2b.3b.4d.5b.6d,1c.2b.3b.4d.5b.6e,1c.2b.3b.4d.5b.6f,1c.2b.3b.4d.5c.6a,
1c.2b.3b.4d.5c.6b,1c.2b.3b.4d.5c.6c,1c.2b.3b.4d.5c.6d,1c.2b.3b.4d.5c.6e,1c.2b.3b.4d.5c.6f,
1c.2b.3b.4d.5d.6a, 1c.2b.3b.4d.5d.6b, 1c.2b.3b.4d.5d.6c, 1c.2b.3b.4d.5d.6d,
1c.2b.3b.4d.5d.6e,1c.2b.3b.4d.5d.6f,1c.2b.3b.4d.5e.6a,1c.2b.3b.4d.5e.6b,1c.2b.3b.4d.5e.6c,
1c.2b.3b.4d.5e.6d,1c.2b.3b.4d.5e.6e,1c.2b.3b.4d.5e.6f,1c.2b.3b.4d.5f.6a,1c.2b.3b.4d.5f.6b,
1c.2b.3b.4d.5f.6c,1c.2b.3b.4d.5f.6d,1c.2b.3b.4d.5f.6e,1c.2b.3b.4d.5f.6f,1c.2b.3b.4e.5a.6a,
1c.2b.3b.4e.5a.6b,1c.2b.3b.4e.5a.6c,1c.2b.3b.4e.5a.6d,1c.2b.3b.4e.5a.6e,1c.2b.3b.4e.5a.6f,
1c.2b.3b.4e.5b.6a,1c.2b.3b.4e.5b.6b,1c.2b.3b.4e.5b.6c,1c.2b.3b.4e.5b.6d,1c.2b.3b.4e.5b.6e,
1c.2b.3b.4e.5b.6f,1c.2b.3b.4e.5c.6a,1c.2b.3b.4e.5c.6b,1c.2b.3b.4e.5c.6c,1c.2b.3b.4e.5c.6d,
1c.2b.3b.4e.5c.6e,1c.2b.3b.4e.5c.6f,1c.2b.3b.4e.5d.6a,1c.2b.3b.4e.5d.6b,1c.2b.3b.4e.5d.6c,
1c.2b.3b.4e.5d.6d,1c.2b.3b.4e.5d.6e,1c.2b.3b.4e.5d.6f,1c.2b.3b.4e.5e.6a,1c.2b.3b.4e.5e.6b,
1c.2b.3b.4e.5e.6c,1c.2b.3b.4e.5e.6d,1c.2b.3b.4e.5e.6e,1c.2b.3b.4e.5e.6f,1c.2b.3b.4e.5f.6a,
1c.2b.3b.4e.5f.6b,1c.2b.3b.4e.5f.6c,1c.2b.3b.4e.5f.6d,1c.2b.3b.4e.5f.6e,1c.2b.3b.4e.5f.6f,
1c.2b.3b.4f.5a.6a,1c.2b.3b.4f.5a.6b,1c.2b.3b.4f.5a.6c,1c.2b.3b.4f.5a.6d,1c.2b.3b.4f.5a.6e,
1c.2b.3b.4f.5a.6f,1c.2b.3b.4f.5b.6a,1c.2b.3b.4f.5b.6b,1c.2b.3b.4f.5b.6c,1c.2b.3b.4f.5b.6d,
1c.2b.3b.4f.5b.6e,1c.2b.3b.4f.5b.6f,1c.2b.3b.4f.5c.6a,1c.2b.3b.4f.5c.6b,1c.2b.3b.4f.5c.6c,
1c.2b.3b.4f.5c.6d,1c.2b.3b.4f.5c.6e,1c.2b.3b.4f.5c.6f,1c.2b.3b.4f.5d.6a,1c.2b.3b.4f.5d.6b,
1c.2b.3b.4f.5d.6c,1c.2b.3b.4f.5d.6d,1c.2b.3b.4f.5d.6e,1c.2b.3b.4f.5d.6f,1c.2b.3b.4f.5e.6a,
1c.2b.3b.4f.5e.6b,1c.2b.3b.4f.5e.6c,1c.2b.3b.4f.5e.6d,1c.2b.3b.4f.5e.6e,1c.2b.3b.4f.5e.6f,
1c.2b.3b.4f.5f.6a,1c.2b.3b.4f.5f.6b,1c.2b.3b.4f.5f.6c,1c.2b.3b.4f.5f.6d,1c.2b.3b.4f.5f.6e,
1c.2b.3b.4f.5f.6f,1c.2b.3c.4a.5a.6a,1c.2b.3c.4a.5a.6b,1c.2b.3c.4a.5a.6c,1c.2b.3c.4a.5a.6d,
1c.2b.3c.4a.5a.6e,1c.2b.3c.4a.5a.6f,1c.2b.3c.4a.5b.6a,1c.2b.3c.4a.5b.6b,1c.2b.3c.4a.5b.6c,
1c.2b.3c.4a.5b.6d,1c.2b.3c.4a.5b.6e,1c.2b.3c.4a.5b.6f,1c.2b.3c.4a.5c.6a,1c.2b.3c.4a.5c.6b,
1c.2b.3c.4a.5c.6c,1c.2b.3c.4a.5c.6d,1c.2b.3c.4a.5c.6e,1c.2b.3c.4a.5c.6f,1c.2b.3c.4a.5d.6a,
1c.2b.3c.4a.5d.6b,1c.2b.3c.4a.5d.6c,1c.2b.3c.4a.5d.6d,1c.2b.3c.4a.5d.6e,1c.2b.3c.4a.5d.6f,
1c.2b.3c.4a.5e.6a,1c.2b.3c.4a.5e.6b,1c.2b.3c.4a.5e.6c,1c.2b.3c.4a.5e.6d,1c.2b.3c.4a.5e.6e,
1c.2b.3c.4a.5e.6f,1c.2b.3c.4a.5f.6a,1c.2b.3c.4a.5f.6b,1c.2b.3c.4a.5f.6c,1c.2b.3c.4a.5f.6d,
1c.2b.3c.4a.5f.6e,1c.2b.3c.4a.5f.6f,1c.2b.3c.4b.5a.6a,1c.2b.3c.4b.5a.6b,1c.2b.3c.4b.5a.6c,
1c.2b.3c.4b.5a.6d,1c.2b.3c.4b.5a.6e,1c.2b.3c.4b.5a.6f,1c.2b.3c.4b.5b.6a,1c.2b.3c.4b.5b.6b,
1c.2b.3c.4b.5b.6c,1c.2b.3c.4b.5b.6d,1c.2b.3c.4b.5b.6e,1c.2b.3c.4b.5b.6f,1c.2b.3c.4b.5c.6a,
1c.2b.3c.4b.5c.6b,1c.2b.3c.4b.5c.6c,1c.2b.3c.4b.5c.6d,1c.2b.3c.4b.5c.6e,1c.2b.3c.4b.5c.6f,
1c.2b.3c.4b.5d.6a,1c.2b.3c.4b.5d.6b,1c.2b.3c.4b.5d.6c,1c.2b.3c.4b.5d.6d,1c.2b.3c.4b.5d.6e,
1c.2b.3c.4b.5d.6f,1c.2b.3c.4b.5e.6a,1c.2b.3c.4b.5e.6b,1c.2b.3c.4b.5e.6c,1c.2b.3c.4b.5e.6d,
1c.2b.3c.4b.5e.6e,1c.2b.3c.4b.5e.6f,1c.2b.3c.4b.5f.6a,1c.2b.3c.4b.5f.6b,1c.2b.3c.4b.5f.6c,
1c.2b.3c.4b.5f.6d,1c.2b.3c.4b.5f.6e,1c.2b.3c.4b.5f.6f,1c.2b.3c.4c.5a.6a,1c.2b.3c.4c.5a.6b,
1c.2b.3c.4c.5a.6c,1c.2b.3c.4c.5a.6d,1c.2b.3c.4c.5a.6e,1c.2b.3c.4c.5a.6f,1c.2b.3c.4c.5b.6a,
1c.2b.3c.4c.5b.6b,1c.2b.3c.4c.5b.6c,1c.2b.3c.4c.5b.6d,1c.2b.3c.4c.5b.6e,1c.2b.3c.4c.5b.6f,
1c.2b.3c.4c.5c.6a,1c.2b.3c.4c.5c.6b,1c.2b.3c.4c.5c.6c,1c.2b.3c.4c.5c.6d,1c.2b.3c.4c.5c.6e,
1c.2b.3c.4c.5c.6f,1c.2b.3c.4c.5d.6a,1c.2b.3c.4c.5d.6b,1c.2b.3c.4c.5d.6c,1c.2b.3c.4c.5d.6d,
1c.2b.3c.4c.5d.6e,1c.2b.3c.4c.5d.6f,1c.2b.3c.4c.5e.6a,1c.2b.3c.4c.5e.6b,1c.2b.3c.4c.5e.6c,
1c.2b.3c.4c.5e.6d,1c.2b.3c.4c.5e.6e,1c.2b.3c.4c.5e.6f,1c.2b.3c.4c.5f.6a,1c.2b.3c.4c.5f.6b,
1c.2b.3c.4c.5f.6c,1c.2b.3c.4c.5f.6d,1c.2b.3c.4c.5f.6e,1c.2b.3c.4c.5f.6f,1c.2b.3c.4d.5a.6a,
1c.2b.3c.4d.5a.6b,1c.2b.3c.4d.5a.6c,1c.2b.3c.4d.5a.6d,1c.2b.3c.4d.5a.6e,1c.2b.3c.4d.5a.6f,
1c.2b.3c.4d.5b.6a,1c.2b.3c.4d.5b.6b,1c.2b.3c.4d.5b.6c,1c.2b.3c.4d.5b.6d,1c.2b.3c.4d.5b.6e,
1c.2b.3c.4d.5b.6f,1c.2b.3c.4d.5c.6a,1c.2b.3c.4d.5c.6b,1c.2b.3c.4d.5c.6c,1c.2b.3c.4d.5c.6d,
1c.2b.3c.4d.5c.6e,1c.2b.3c.4d.5c.6f,1c.2b.3c.4d.5d.6a,1c.2b.3c.4d.5d.6b,1c.2b.3c.4d.5d.6c,
1c.2b.3c.4d.5d.6d,1c.2b.3c.4d.5d.6e,1c.2b.3c.4d.5d.6f,1c.2b.3c.4d.5e.6a,1c.2b.3c.4d.5e.6b,
1c.2b.3c.4d.5e.6c,1c.2b.3c.4d.5e.6d,1c.2b.3c.4d.5e.6e,1c.2b.3c.4d.5e.6f,1c.2b.3c.4d.5f.6a,
1c.2b.3c.4d.5f.6b,1c.2b.3c.4d.5f.6c,1c.2b.3c.4d.5f.6d,1c.2b.3c.4d.5f.6e,1c.2b.3c.4d.5f.6f,
1c.2b.3c.4e.5a.6a,1c.2b.3c.4e.5a.6b,1c.2b.3c.4e.5a.6c,1c.2b.3c.4e.5a.6d,1c.2b.3c.4e.5a.6e,
1c.2b.3c.4e.5a.6f,1c.2b.3c.4e.5b.6a,1c.2b.3c.4e.5b.6b,1c.2b.3c.4e.5b.6c,1c.2b.3c.4e.5b.6d,
1c.2b.3c.4e.5b.6e,1c.2b.3c.4e.5b.6f,1c.2b.3c.4e.5c.6a,1c.2b.3c.4e.5c.6b,1c.2b.3c.4e.5c.6c,
1c.2b.3c.4e.5c.6d,1c.2b.3c.4e.5c.6e,1c.2b.3c.4e.5c.6f,1c.2b.3c.4e.5d.6a,1c.2b.3c.4e.5d.6b,
1c.2b.3c.4e.5d.6c,1c.2b.3c.4e.5d.6d,1c.2b.3c.4e.5d.6e,1c.2b.3c.4e.5d.6f,1c.2b.3c.4e.5e.6a,
1c.2b.3c.4e.5e.6b,1c.2b.3c.4e.5e.6c,1c.2b.3c.4e.5e.6d,1c.2b.3c.4e.5e.6e,1c.2b.3c.4e.5e.6f,
1c.2b.3c.4e.5f.6a,1c.2b.3c.4e.5f.6b,1c.2b.3c.4e.5f.6c,1c.2b.3c.4e.5f.6d,1c.2b.3c.4e.5f.6e,
1c.2b.3c.4e.5f.6f,1c.2b.3c.4f.5a.6a,1c.2b.3c.4f.5a.6b,1c.2b.3c.4f.5a.6c,1c.2b.3c.4f.5a.6d,
1c.2b.3c.4f.5a.6e,1c.2b.3c.4f.5a.6f,1c.2b.3c.4f.5b.6a,1c.2b.3c.4f.5b.6b,1c.2b.3c.4f.5b.6c,
1c.2b.3c.4f.5b.6d,1c.2b.3c.4f.5b.6e,1c.2b.3c.4f.5b.6f,1c.2b.3c.4f.5c.6a,1c.2b.3c.4f.5c.6b,
1c.2b.3c.4f.5c.6c,1c.2b.3c.4f.5c.6d,1c.2b.3c.4f.5c.6e,1c.2b.3c.4f.5c.6f,1c.2b.3c.4f.5d.6a,
1c.2b.3c.4f.5d.6b,1c.2b.3c.4f.5d.6c,1c.2b.3c.4f.5d.6d,1c.2b.3c.4f.5d.6e,1c.2b.3c.4f.5d.6f,
1c.2b.3c.4f.5e.6a,1c.2b.3c.4f.5e.6b,1c.2b.3c.4f.5e.6c,1c.2b.3c.4f.5e.6d,1c.2b.3c.4f.5e.6e,
1c.2b.3c.4f.5e.6f,1c.2b.3c.4f.5f.6a,1c.2b.3c.4f.5f.6b,1c.2b.3c.4f.5f.6c,1c.2b.3c.4f.5f.6d,
1c.2b.3c.4f.5f.6e,1c.2b.3c.4f.5f.6f,1c.2b.3d.4a.5a.6a,1c.2b.3d.4a.5a.6b,1c.2b.3d.4a.5a.6c,
1c.2b.3d.4a.5a.6d,1c.2b.3d.4a.5a.6e,1c.2b.3d.4a.5a.6f,1c.2b.3d.4a.5b.6a,1c.2b.3d.4a.5b.6b,
1c.2b.3d.4a.5b.6c,1c.2b.3d.4a.5b.6d,1c.2b.3d.4a.5b.6e,1c.2b.3d.4a.5b.6f,1c.2b.3d.4a.5c.6a,
1c.2b.3d.4a.5c.6b,1c.2b.3d.4a.5c.6c,1c.2b.3d.4a.5c.6d,1c.2b.3d.4a.5c.6e,1c.2b.3d.4a.5c.6f,
1c.2b.3d.4a.5d.6a,1c.2b.3d.4a.5d.6b,1c.2b.3d.4a.5d.6c,1c.2b.3d.4a.5d.6d,1c.2b.3d.4a.5d.6e,
1c.2b.3d.4a.5d.6f,1c.2b.3d.4a.5e.6a,1c.2b.3d.4a.5e.6b,1c.2b.3d.4a.5e.6c,1c.2b.3d.4a.5e.6d,
1c.2b.3d.4a.5e.6e,1c.2b.3d.4a.5e.6f,1c.2b.3d.4a.5f.6a,1c.2b.3d.4a.5f.6b,1c.2b.3d.4a.5f.6c,
1c.2b.3d.4a.5f.6d,1c.2b.3d.4a.5f.6e,1c.2b.3d.4a.5f.6f,1c.2b.3d.4b.5a.6a,1c.2b.3d.4b.5a.6b,
1c.2b.3d.4b.5a.6c,1c.2b.3d.4b.5a.6d,1c.2b.3d.4b.5a.6e,1c.2b.3d.4b.5a.6f,1c.2b.3d.4b.5b.6a,
1c.2b.3d.4b.5b.6b,1c.2b.3d.4b.5b.6c,1c.2b.3d.4b.5b.6d,1c.2b.3d.4b.5b.6e,1c.2b.3d.4b.5b.6f,
1c.2b.3d.4b.5c.6a,1c.2b.3d.4b.5c.6b,1c.2b.3d.4b.5c.6c,1c.2b.3d.4b.5c.6d,1c.2b.3d.4b.5c.6e,
1c.2b.3d.4b.5c.6f,1c.2b.3d.4b.5d.6a,1c.2b.3d.4b.5d.6b,1c.2b.3d.4b.5d.6c,1c.2b.3d.4b.5d.6d,
1c.2b.3d.4b.5d.6e,1c.2b.3d.4b.5d.6f,1c.2b.3d.4b.5e.6a,1c.2b.3d.4b.5e.6b,1c.2b.3d.4b.5e.6c,
1c.2b.3d.4b.5e.6d,1c.2b.3d.4b.5e.6e,1c.2b.3d.4b.5e.6f,1c.2b.3d.4b.5f.6a,1c.2b.3d.4b.5f.6b,
1c.2b.3d.4b.5f.6c,1c.2b.3d.4b.5f.6d,1c.2b.3d.4b.5f.6e,1c.2b.3d.4b.5f.6f,1c.2b.3d.4c.5a.6a,
1c.2b.3d.4c.5a.6b,1c.2b.3d.4c.5a.6c,1c.2b.3d.4c.5a.6d,1c.2b.3d.4c.5a.6e,1c.2b.3d.4c.5a.6f,
1c.2b.3d.4c.5b.6a,1c.2b.3d.4c.5b.6b,1c.2b.3d.4c.5b.6c,1c.2b.3d.4c.5b.6d,1c.2b.3d.4c.5b.6e,
1c.2b.3d.4c.5b.6f,1c.2b.3d.4c.5c.6a,1c.2b.3d.4c.5c.6b,1c.2b.3d.4c.5c.6c,1c.2b.3d.4c.5c.6d,
1c.2b.3d.4c.5c.6e,1c.2b.3d.4c.5c.6f,1c.2b.3d.4c.5d.6a,1c.2b.3d.4c.5d.6b,1c.2b.3d.4c.5d.6c,
1c.2b.3d.4c.5d.6d,1c.2b.3d.4c.5d.6e,1c.2b.3d.4c.5d.6f,1c.2b.3d.4c.5e.6a,1c.2b.3d.4c.5e.6b,
1c.2b.3d.4c.5e.6c,1c.2b.3d.4c.5e.6d,1c.2b.3d.4c.5e.6e,1c.2b.3d.4c.5e.6f,1c.2b.3d.4c.5f.6a,
1c.2b.3d.4c.5f.6b,1c.2b.3d.4c.5f.6c,1c.2b.3d.4c.5f.6d,1c.2b.3d.4c.5f.6e,1c.2b.3d.4c.5f.6f,
1c.2b.3d.4d.5a.6a,1c.2b.3d.4d.5a.6b,1c.2b.3d.4d.5a.6c,1c.2b.3d.4d.5a.6d,1c.2b.3d.4d.5a.6e,
1c.2b.3d.4d.5a.6f,1c.2b.3d.4d.5b.6a,1c.2b.3d.4d.5b.6b,1c.2b.3d.4d.5b.6c,1c.2b.3d.4d.5b.6d,
1c.2b.3d.4d.5b.6e,1c.2b.3d.4d.5b.6f,1c.2b.3d.4d.5c.6a,1c.2b.3d.4d.5c.6b,1c.2b.3d.4d.5c.6c,
1c.2b.3d.4d.5c.6d,1c.2b.3d.4d.5c.6e,1c.2b.3d.4d.5c.6f,1c.2b.3d.4d.5d.6a,1c.2b.3d.4d.5d.6b,
1c.2b.3d.4d.5d.6c, 1c.2b.3d.4d.5d.6d, 1c.2b.3d.4d.5d.6e, 1c.2b.3d.4d.5d.6f,
1c.2b.3d.4d.5e.6a,1c.2b.3d.4d.5e.6b,1c.2b.3d.4d.5e.6c,1c.2b.3d.4d.5e.6d,1c.2b.3d.4d.5e.6e,
1c.2b.3d.4d.5e.6f,1c.2b.3d.4d.5f.6a,1c.2b.3d.4d.5f.6b,1c.2b.3d.4d.5f.6c,1c.2b.3d.4d.5f.6d,
1c.2b.3d.4d.5f.6e,1c.2b.3d.4d.5f.6f,1c.2b.3d.4e.5a.6a,1c.2b.3d.4e.5a.6b,1c.2b.3d.4e.5a.6c,
1c.2b.3d.4e.5a.6d,1c.2b.3d.4e.5a.6e,1c.2b.3d.4e.5a.6f,1c.2b.3d.4e.5b.6a,1c.2b.3d.4e.5b.6b,
1c.2b.3d.4e.5b.6c,1c.2b.3d.4e.5b.6d,1c.2b.3d.4e.5b.6e,1c.2b.3d.4e.5b.6f,1c.2b.3d.4e.5c.6a,
1c.2b.3d.4e.5c.6b,1c.2b.3d.4e.5c.6c,1c.2b.3d.4e.5c.6d,1c.2b.3d.4e.5c.6e,1c.2b.3d.4e.5c.6f,
1c.2b.3d.4e.5d.6a,1c.2b.3d.4e.5d.6b,1c.2b.3d.4e.5d.6c,1c.2b.3d.4e.5d.6d,1c.2b.3d.4e.5d.6e,
1c.2b.3d.4e.5d.6f,1c.2b.3d.4e.5e.6a,1c.2b.3d.4e.5e.6b,1c.2b.3d.4e.5e.6c,1c.2b.3d.4e.5e.6d,
1c.2b.3d.4e.5e.6e,1c.2b.3d.4e.5e.6f,1c.2b.3d.4e.5f.6a,1c.2b.3d.4e.5f.6b,1c.2b.3d.4e.5f.6c,
1c.2b.3d.4e.5f.6d,1c.2b.3d.4e.5f.6e,1c.2b.3d.4e.5f.6f,1c.2b.3d.4f.5a.6a,1c.2b.3d.4f.5a.6b,
1c.2b.3d.4f.5a.6c,1c.2b.3d.4f.5a.6d,1c.2b.3d.4f.5a.6e,1c.2b.3d.4f.5a.6f,1c.2b.3d.4f.5b.6a,
1c.2b.3d.4f.5b.6b,1c.2b.3d.4f.5b.6c,1c.2b.3d.4f.5b.6d,1c.2b.3d.4f.5b.6e,1c.2b.3d.4f.5b.6f,
1c.2b.3d.4f.5c.6a,1c.2b.3d.4f.5c.6b,1c.2b.3d.4f.5c.6c,1c.2b.3d.4f.5c.6d,1c.2b.3d.4f.5c.6e,
1c.2b.3d.4f.5c.6f,1c.2b.3d.4f.5d.6a,1c.2b.3d.4f.5d.6b,1c.2b.3d.4f.5d.6c,1c.2b.3d.4f.5d.6d,
1c.2b.3d.4f.5d.6e,1c.2b.3d.4f.5d.6f,1c.2b.3d.4f.5e.6a,1c.2b.3d.4f.5e.6b,1c.2b.3d.4f.5e.6c,
1c.2b.3d.4f.5e.6d,1c.2b.3d.4f.5e.6e,1c.2b.3d.4f.5e.6f,1c.2b.3d.4f.5f.6a,1c.2b.3d.4f.5f.6b,
1c.2b.3d.4f.5f.6c,1c.2b.3d.4f.5f.6d,1c.2b.3d.4f.5f.6e,1c.2b.3d.4f.5f.6f,1c.2b.3e.4a.5a.6a,
1c.2b.3e.4a.5a.6b,1c.2b.3e.4a.5a.6c,1c.2b.3e.4a.5a.6d,1c.2b.3e.4a.5a.6e,1c.2b.3e.4a.5a.6f,
1c.2b.3e.4a.5b.6a,1c.2b.3e.4a.5b.6b,1c.2b.3e.4a.5b.6c,1c.2b.3e.4a.5b.6d,1c.2b.3e.4a.5b.6e,
1c.2b.3e.4a.5b.6f,1c.2b.3e.4a.5c.6a,1c.2b.3e.4a.5c.6b,1c.2b.3e.4a.5c.6c,1c.2b.3e.4a.5c.6d,
1c.2b.3e.4a.5c.6e,1c.2b.3e.4a.5c.6f,1c.2b.3e.4a.5d.6a,1c.2b.3e.4a.5d.6b,1c.2b.3e.4a.5d.6c,
1c.2b.3e.4a.5d.6d,1c.2b.3e.4a.5d.6e,1c.2b.3e.4a.5d.6f,1c.2b.3e.4a.5e.6a,1c.2b.3e.4a.5e.6b,
1c.2b.3e.4a.5e.6c,1c.2b.3e.4a.5e.6d,1c.2b.3e.4a.5e.6e,1c.2b.3e.4a.5e.6f,1c.2b.3e.4a.5f.6a,
1c.2b.3e.4a.5f.6b,1c.2b.3e.4a.5f.6c,1c.2b.3e.4a.5f.6d,1c.2b.3e.4a.5f.6e,1c.2b.3e.4a.5f.6f,
1c.2b.3e.4b.5a.6a,1c.2b.3e.4b.5a.6b,1c.2b.3e.4b.5a.6c,1c.2b.3e.4b.5a.6d,1c.2b.3e.4b.5a.6e,
1c.2b.3e.4b.5a.6f,1c.2b.3e.4b.5b.6a,1c.2b.3e.4b.5b.6b,1c.2b.3e.4b.5b.6c,1c.2b.3e.4b.5b.6d,
1c.2b.3e.4b.5b.6e,1c.2b.3e.4b.5b.6f,1c.2b.3e.4b.5c.6a,1c.2b.3e.4b.5c.6b,1c.2b.3e.4b.5c.6c,
1c.2b.3e.4b.5c.6d,1c.2b.3e.4b.5c.6e,1c.2b.3e.4b.5c.6f,1c.2b.3e.4b.5d.6a,1c.2b.3e.4b.5d.6b,
1c.2b.3e.4b.5d.6c,1c.2b.3e.4b.5d.6d,1c.2b.3e.4b.5d.6e,1c.2b.3e.4b.5d.6f,1c.2b.3e.4b.5e.6a,
1c.2b.3e.4b.5e.6b,1c.2b.3e.4b.5e.6c,1c.2b.3e.4b.5e.6d,1c.2b.3e.4b.5e.6e,1c.2b.3e.4b.5e.6f,
1c.2b.3e.4b.5f.6a,1c.2b.3e.4b.5f.6b,1c.2b.3e.4b.5f.6c,1c.2b.3e.4b.5f.6d,1c.2b.3e.4b.5f.6e,
1c.2b.3e.4b.5f.6f,1c.2b.3e.4c.5a.6a,1c.2b.3e.4c.5a.6b,1c.2b.3e.4c.5a.6c,1c.2b.3e.4c.5a.6d,
1c.2b.3e.4c.5a.6e,1c.2b.3e.4c.5a.6f,1c.2b.3e.4c.5b.6a,1c.2b.3e.4c.5b.6b,1c.2b.3e.4c.5b.6c,
1c.2b.3e.4c.5b.6d,1c.2b.3e.4c.5b.6e,1c.2b.3e.4c.5b.6f,1c.2b.3e.4c.5c.6a,1c.2b.3e.4c.5c.6b,
1c.2b.3e.4c.5c.6c,1c.2b.3e.4c.5c.6d,1c.2b.3e.4c.5c.6e,1c.2b.3e.4c.5c.6f,1c.2b.3e.4c.5d.6a,
1c.2b.3e.4c.5d.6b,1c.2b.3e.4c.5d.6c,1c.2b.3e.4c.5d.6d,1c.2b.3e.4c.5d.6e,1c.2b.3e.4c.5d.6f,
1c.2b.3e.4c.5e.6a,1c.2b.3e.4c.5e.6b,1c.2b.3e.4c.5e.6c,1c.2b.3e.4c.5e.6d,1c.2b.3e.4c.5e.6e,
1c.2b.3e.4c.5e.6f,1c.2b.3e.4c.5f.6a,1c.2b.3e.4c.5f.6b,1c.2b.3e.4c.5f.6c,1c.2b.3e.4c.5f.6d,
1c.2b.3e.4c.5f.6e,1c.2b.3e.4c.5f.6f,1c.2b.3e.4d.5a.6a,1c.2b.3e.4d.5a.6b,1c.2b.3e.4d.5a.6c,
1c.2b.3e.4d.5a.6d,1c.2b.3e.4d.5a.6e,1c.2b.3e.4d.5a.6f,1c.2b.3e.4d.5b.6a,1c.2b.3e.4d.5b.6b,
1c.2b.3e.4d.5b.6c,1c.2b.3e.4d.5b.6d,1c.2b.3e.4d.5b.6e,1c.2b.3e.4d.5b.6f,1c.2b.3e.4d.5c.6a,
1c.2b.3e.4d.5c.6b,1c.2b.3e.4d.5c.6c,1c.2b.3e.4d.5c.6d,1c.2b.3e.4d.5c.6e,1c.2b.3e.4d.5c.6f,
1c.2b.3e.4d.5d.6a,1c.2b.3e.4d.5d.6b,1c.2b.3e.4d.5d.6c,1c.2b.3e.4d.5d.6d,1c.2b.3e.4d.5d.6e,
1c.2b.3e.4d.5d.6f,1c.2b.3e.4d.5e.6a,1c.2b.3e.4d.5e.6b,1c.2b.3e.4d.5e.6c,1c.2b.3e.4d.5e.6d,
1c.2b.3e.4d.5e.6e,1c.2b.3e.4d.5e.6f,1c.2b.3e.4d.5f.6a,1c.2b.3e.4d.5f.6b,1c.2b.3e.4d.5f.6c,
1c.2b.3e.4d.5f.6d,1c.2b.3e.4d.5f.6e,1c.2b.3e.4d.5f.6f,1c.2b.3e.4e.5a.6a,1c.2b.3e.4e.5a.6b,
1c.2b.3e.4e.5a.6c,1c.2b.3e.4e.5a.6d,1c.2b.3e.4e.5a.6e,1c.2b.3e.4e.5a.6f,1c.2b.3e.4e.5b.6a,
1c.2b.3e.4e.5b.6b,1c.2b.3e.4e.5b.6c,1c.2b.3e.4e.5b.6d,1c.2b.3e.4e.5b.6e,1c.2b.3e.4e.5b.6f,
1c.2b.3e.4e.5c.6a,1c.2b.3e.4e.5c.6b,1c.2b.3e.4e.5c.6c,1c.2b.3e.4e.5c.6d,1c.2b.3e.4e.5c.6e,
1c.2b.3e.4e.5c.6f,1c.2b.3e.4e.5d.6a,1c.2b.3e.4e.5d.6b,1c.2b.3e.4e.5d.6c,1c.2b.3e.4e.5d.6d,
1c.2b.3e.4e.5d.6e,1c.2b.3e.4e.5d.6f,1c.2b.3e.4e.5e.6a,1c.2b.3e.4e.5e.6b,1c.2b.3e.4e.5e.6c,
1c.2b.3e.4e.5e.6d,1c.2b.3e.4e.5e.6e,1c.2b.3e.4e.5e.6f,1c.2b.3e.4e.5f.6a,1c.2b.3e.4e.5f.6b,
1c.2b.3e.4e.5f.6c,1c.2b.3e.4e.5f.6d,1c.2b.3e.4e.5f.6e,1c.2b.3e.4e.5f.6f,1c.2b.3e.4f.5a.6a,
1c.2b.3e.4f.5a.6b,1c.2b.3e.4f.5a.6c,1c.2b.3e.4f.5a.6d,1c.2b.3e.4f.5a.6e,1c.2b.3e.4f.5a.6f,
1c.2b.3e.4f.5b.6a,1c.2b.3e.4f.5b.6b,1c.2b.3e.4f.5b.6c,1c.2b.3e.4f.5b.6d,1c.2b.3e.4f.5b.6e,
1c.2b.3e.4f.5b.6f,1c.2b.3e.4f.5c.6a,1c.2b.3e.4f.5c.6b,1c.2b.3e.4f.5c.6c,1c.2b.3e.4f.5c.6d,
1c.2b.3e.4f.5c.6e,1c.2b.3e.4f.5c.6f,1c.2b.3e.4f.5d.6a,1c.2b.3e.4f.5d.6b,1c.2b.3e.4f.5d.6c,
1c.2b.3e.4f.5d.6d,1c.2b.3e.4f.5d.6e,1c.2b.3e.4f.5d.6f,1c.2b.3e.4f.5e.6a,1c.2b.3e.4f.5e.6b,
1c.2b.3e.4f.5e.6c,1c.2b.3e.4f.5e.6d,1c.2b.3e.4f.5e.6e,1c.2b.3e.4f.5e.6f,1c.2b.3e.4f.5f.6a,
1c.2b.3e.4f.5f.6b,1c.2b.3e.4f.5f.6c,1c.2b.3e.4f.5f.6d,1c.2b.3e.4f.5f.6e,1c.2b.3e.4f.5f.6f,
1c.2b.3f.4a.5a.6a,1c.2b.3f.4a.5a.6b,1c.2b.3f.4a.5a.6c,1c.2b.3f.4a.5a.6d,1c.2b.3f.4a.5a.6e,
1c.2b.3f.4a.5a.6f,1c.2b.3f.4a.5b.6a,1c.2b.3f.4a.5b.6b,1c.2b.3f.4a.5b.6c,1c.2b.3f.4a.5b.6d,
1c.2b.3f.4a.5b.6e,1c.2b.3f.4a.5b.6f,1c.2b.3f.4a.5c.6a,1c.2b.3f.4a.5c.6b,1c.2b.3f.4a.5c.6c,
1c.2b.3f.4a.5c.6d,1c.2b.3f.4a.5c.6e,1c.2b.3f.4a.5c.6f,1c.2b.3f.4a.5d.6a,1c.2b.3f.4a.5d.6b,
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1c.2b.3f.4a.5e.6b,1c.2b.3f.4a.5e.6c,1c.2b.3f.4a.5e.6d,1c.2b.3f.4a.5e.6e,1c.2b.3f.4a.5e.6f,
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1c.2c.3d.4a.5a.6b,1c.2c.3d.4a.5a.6c,1c.2c.3d.4a.5a.6d,1c.2c.3d.4a.5a.6e,1c.2c.3d.4a.5a.6f,
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1c.2c.3d.4a.5b.6f,1c.2c.3d.4a.5c.6a,1c.2c.3d.4a.5c.6b,1c.2c.3d.4a.5c.6c,1c.2c.3d.4a.5c.6d,
1c.2c.3d.4a.5c.6e,1c.2c.3d.4a.5c.6f,1c.2c.3d.4a.5d.6a,1c.2c.3d.4a.5d.6b,1c.2c.3d.4a.5d.6c,
1c.2c.3d.4a.5d.6d,1c.2c.3d.4a.5d.6e,1c.2c.3d.4a.5d.6f,1c.2c.3d.4a.5e.6a,1c.2c.3d.4a.5e.6b,
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1c.2c.3f.4a.5c.6c,1c.2c.3f.4a.5c.6d,1c.2c.3f.4a.5c.6e,1c.2c.3f.4a.5c.6f,1c.2c.3f.4a.5d.6a,
1c.2c.3f.4a.5d.6b,1c.2c.3f.4a.5d.6c,1c.2c.3f.4a.5d.6d,1c.2c.3f.4a.5d.6e,1c.2c.3f.4a.5d.6f,
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1c.2d.3b.4a.5c.6f,1c.2d.3b.4a.5d.6a,1c.2d.3b.4a.5d.6b,1c.2d.3b.4a.5d.6c,1c.2d.3b.4a.5d.6d,
1c.2d.3b.4a.5d.6e,1c.2d.3b.4a.5d.6f,1c.2d.3b.4a.5e.6a,1c.2d.3b.4a.5e.6b,1c.2d.3b.4a.5e.6c,
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1c.2d.3b.4b.5a.6b,1c.2d.3b.4b.5a.6c,1c.2d.3b.4b.5a.6d,1c.2d.3b.4b.5a.6e,1c.2d.3b.4b.5a.6f,
1c.2d.3b.4b.5b.6a,1c.2d.3b.4b.5b.6b,1c.2d.3b.4b.5b.6c,1c.2d.3b.4b.5b.6d,1c.2d.3b.4b.5b.6e,
1c.2d.3b.4b.5b.6f,1c.2d.3b.4b.5c.6a,1c.2d.3b.4b.5c.6b,1c.2d.3b.4b.5c.6c,1c.2d.3b.4b.5c.6d,
1c.2d.3b.4b.5c.6e,1c.2d.3b.4b.5c.6f,1c.2d.3b.4b.5d.6a,1c.2d.3b.4b.5d.6b,1c.2d.3b.4b.5d.6c,
1c.2d.3b.4b.5d.6d,1c.2d.3b.4b.5d.6e,1c.2d.3b.4b.5d.6f,1c.2d.3b.4b.5e.6a,1c.2d.3b.4b.5e.6b,
1c.2d.3b.4b.5e.6c,1c.2d.3b.4b.5e.6d,1c.2d.3b.4b.5e.6e,1c.2d.3b.4b.5e.6f,1c.2d.3b.4b.5f.6a,
1c.2d.3b.4b.5f.6b,1c.2d.3b.4b.5f.6c,1c.2d.3b.4b.5f.6d,1c.2d.3b.4b.5f.6e,1c.2d.3b.4b.5f.6f,
1c.2d.3b.4c.5a.6a,1c.2d.3b.4c.5a.6b,1c.2d.3b.4c.5a.6c,1c.2d.3b.4c.5a.6d,1c.2d.3b.4c.5a.6e,
1c.2d.3b.4c.5a.6f,1c.2d.3b.4c.5b.6a,1c.2d.3b.4c.5b.6b,1c.2d.3b.4c.5b.6c,1c.2d.3b.4c.5b.6d,
1c.2d.3b.4c.5b.6e,1c.2d.3b.4c.5b.6f,1c.2d.3b.4c.5c.6a,1c.2d.3b.4c.5c.6b,1c.2d.3b.4c.5c.6c,
1c.2d.3b.4c.5c.6d,1c.2d.3b.4c.5c.6e,1c.2d.3b.4c.5c.6f,1c.2d.3b.4c.5d.6a,1c.2d.3b.4c.5d.6b,
1c.2d.3b.4c.5d.6c,1c.2d.3b.4c.5d.6d,1c.2d.3b.4c.5d.6e,1c.2d.3b.4c.5d.6f,1c.2d.3b.4c.5e.6a,
1c.2d.3b.4c.5e.6b,1c.2d.3b.4c.5e.6c,1c.2d.3b.4c.5e.6d,1c.2d.3b.4c.5e.6e,1c.2d.3b.4c.5e.6f,
1c.2d.3b.4c.5f.6a,1c.2d.3b.4c.5f.6b,1c.2d.3b.4c.5f.6c,1c.2d.3b.4c.5f.6d,1c.2d.3b.4c.5f.6e,
1c.2d.3b.4c.5f.6f,1c.2d.3b.4d.5a.6a,1c.2d.3b.4d.5a.6b,1c.2d.3b.4d.5a.6c,1c.2d.3b.4d.5a.6d,
1c.2d.3b.4d.5a.6e,1c.2d.3b.4d.5a.6f,1c.2d.3b.4d.5b.6a,1c.2d.3b.4d.5b.6b,1c.2d.3b.4d.5b.6c,
1c.2d.3b.4d.5b.6d,1c.2d.3b.4d.5b.6e,1c.2d.3b.4d.5b.6f,1c.2d.3b.4d.5c.6a,1c.2d.3b.4d.5c.6b,
1c.2d.3b.4d.5c.6c,1c.2d.3b.4d.5c.6d,1c.2d.3b.4d.5c.6e,1c.2d.3b.4d.5c.6f,1c.2d.3b.4d.5d.6a,
1c.2d.3b.4d.5d.6b, 1c.2d.3b.4d.5d.6c, 1c.2d.3b.4d.5d.6d, 1c.2d.3b.4d.5d.6e,
1c.2d.3b.4d.5d.6f,1c.2d.3b.4d.5e.6a,1c.2d.3b.4d.5e.6b,1c.2d.3b.4d.5e.6c,1c.2d.3b.4d.5e.6d,
1c.2d.3b.4d.5e.6e,1c.2d.3b.4d.5e.6f,1c.2d.3b.4d.5f.6a,1c.2d.3b.4d.5f.6b,1c.2d.3b.4d.5f.6c,
1c.2d.3b.4d.5f.6d,1c.2d.3b.4d.5f.6e,1c.2d.3b.4d.5f.6f,1c.2d.3b.4e.5a.6a,1c.2d.3b.4e.5a.6b,
1c.2d.3b.4e.5a.6c,1c.2d.3b.4e.5a.6d,1c.2d.3b.4e.5a.6e,1c.2d.3b.4e.5a.6f,1c.2d.3b.4e.5b.6a,
1c.2d.3b.4e.5b.6b,1c.2d.3b.4e.5b.6c,1c.2d.3b.4e.5b.6d,1c.2d.3b.4e.5b.6e,1c.2d.3b.4e.5b.6f,
1c.2d.3b.4e.5c.6a,1c.2d.3b.4e.5c.6b,1c.2d.3b.4e.5c.6c,1c.2d.3b.4e.5c.6d,1c.2d.3b.4e.5c.6e,
1c.2d.3b.4e.5c.6f,1c.2d.3b.4e.5d.6a,1c.2d.3b.4e.5d.6b,1c.2d.3b.4e.5d.6c,1c.2d.3b.4e.5d.6d,
1c.2d.3b.4e.5d.6e,1c.2d.3b.4e.5d.6f,1c.2d.3b.4e.5e.6a,1c.2d.3b.4e.5e.6b,1c.2d.3b.4e.5e.6c,
1c.2d.3b.4e.5e.6d,1c.2d.3b.4e.5e.6e,1c.2d.3b.4e.5e.6f,1c.2d.3b.4e.5f.6a,1c.2d.3b.4e.5f.6b,
1c.2d.3b.4e.5f.6c,1c.2d.3b.4e.5f.6d,1c.2d.3b.4e.5f.6e,1c.2d.3b.4e.5f.6f,1c.2d.3b.4f.5a.6a,
1c.2d.3b.4f.5a.6b,1c.2d.3b.4f.5a.6c,1c.2d.3b.4f.5a.6d,1c.2d.3b.4f.5a.6e,1c.2d.3b.4f.5a.6f,
1c.2d.3b.4f.5b.6a,1c.2d.3b.4f.5b.6b,1c.2d.3b.4f.5b.6c,1c.2d.3b.4f.5b.6d,1c.2d.3b.4f.5b.6e,
1c.2d.3b.4f.5b.6f,1c.2d.3b.4f.5c.6a,1c.2d.3b.4f.5c.6b,1c.2d.3b.4f.5c.6c,1c.2d.3b.4f.5c.6d,
1c.2d.3b.4f.5c.6e,1c.2d.3b.4f.5c.6f,1c.2d.3b.4f.5d.6a,1c.2d.3b.4f.5d.6b,1c.2d.3b.4f.5d.6c,
1c.2d.3b.4f.5d.6d,1c.2d.3b.4f.5d.6e,1c.2d.3b.4f.5d.6f,1c.2d.3b.4f.5e.6a,1c.2d.3b.4f.5e.6b,
1c.2d.3b.4f.5e.6c,1c.2d.3b.4f.5e.6d,1c.2d.3b.4f.5e.6e,1c.2d.3b.4f.5e.6f,1c.2d.3b.4f.5f.6a,
1c.2d.3b.4f.5f.6b,1c.2d.3b.4f.5f.6c,1c.2d.3b.4f.5f.6d,1c.2d.3b.4f.5f.6e,1c.2d.3b.4f.5f.6f,
1c.2d.3c.4a.5a.6a,1c.2d.3c.4a.5a.6b,1c.2d.3c.4a.5a.6c,1c.2d.3c.4a.5a.6d,1c.2d.3c.4a.5a.6e,
1c.2d.3c.4a.5a.6f,1c.2d.3c.4a.5b.6a,1c.2d.3c.4a.5b.6b,1c.2d.3c.4a.5b.6c,1c.2d.3c.4a.5b.6d,
1c.2d.3c.4a.5b.6e,1c.2d.3c.4a.5b.6f,1c.2d.3c.4a.5c.6a,1c.2d.3c.4a.5c.6b,1c.2d.3c.4a.5c.6c,
1c.2d.3c.4a.5c.6d,1c.2d.3c.4a.5c.6e,1c.2d.3c.4a.5c.6f,1c.2d.3c.4a.5d.6a,1c.2d.3c.4a.5d.6b,
1c.2d.3c.4a.5d.6c,1c.2d.3c.4a.5d.6d,1c.2d.3c.4a.5d.6e,1c.2d.3c.4a.5d.6f,1c.2d.3c.4a.5e.6a,
1c.2d.3c.4a.5e.6b,1c.2d.3c.4a.5e.6c,1c.2d.3c.4a.5e.6d,1c.2d.3c.4a.5e.6e,1c.2d.3c.4a.5e.6f,
1c.2d.3c.4a.5f.6a,1c.2d.3c.4a.5f.6b,1c.2d.3c.4a.5f.6c,1c.2d.3c.4a.5f.6d,1c.2d.3c.4a.5f.6e,
1c.2d.3c.4a.5f.6f,1c.2d.3c.4b.5a.6a,1c.2d.3c.4b.5a.6b,1c.2d.3c.4b.5a.6c,1c.2d.3c.4b.5a.6d,
1c.2d.3c.4b.5a.6e,1c.2d.3c.4b.5a.6f,1c.2d.3c.4b.5b.6a,1c.2d.3c.4b.5b.6b,1c.2d.3c.4b.5b.6c,
1c.2d.3c.4b.5b.6d,1c.2d.3c.4b.5b.6e,1c.2d.3c.4b.5b.6f,1c.2d.3c.4b.5c.6a,1c.2d.3c.4b.5c.6b,
1c.2d.3c.4b.5c.6c,1c.2d.3c.4b.5c.6d,1c.2d.3c.4b.5c.6e,1c.2d.3c.4b.5c.6f,1c.2d.3c.4b.5d.6a,
1c.2d.3c.4b.5d.6b,1c.2d.3c.4b.5d.6c,1c.2d.3c.4b.5d.6d,1c.2d.3c.4b.5d.6e,1c.2d.3c.4b.5d.6f,
1c.2d.3c.4b.5e.6a,1c.2d.3c.4b.5e.6b,1c.2d.3c.4b.5e.6c,1c.2d.3c.4b.5e.6d,1c.2d.3c.4b.5e.6e,
1c.2d.3c.4b.5e.6f,1c.2d.3c.4b.5f.6a,1c.2d.3c.4b.5f.6b,1c.2d.3c.4b.5f.6c,1c.2d.3c.4b.5f.6d,
1c.2d.3c.4b.5f.6e,1c.2d.3c.4b.5f.6f,1c.2d.3c.4c.5a.6a,1c.2d.3c.4c.5a.6b,1c.2d.3c.4c.5a.6c,
1c.2d.3c.4c.5a.6d,1c.2d.3c.4c.5a.6e,1c.2d.3c.4c.5a.6f,1c.2d.3c.4c.5b.6a,1c.2d.3c.4c.5b.6b,
1c.2d.3c.4c.5b.6c,1c.2d.3c.4c.5b.6d,1c.2d.3c.4c.5b.6e,1c.2d.3c.4c.5b.6f,1c.2d.3c.4c.5c.6a,
1c.2d.3c.4c.5c.6b,1c.2d.3c.4c.5c.6c,1c.2d.3c.4c.5c.6d,1c.2d.3c.4c.5c.6e,1c.2d.3c.4c.5c.6f,
1c.2d.3c.4c.5d.6a,1c.2d.3c.4c.5d.6b,1c.2d.3c.4c.5d.6c,1c.2d.3c.4c.5d.6d,1c.2d.3c.4c.5d.6e,
1c.2d.3c.4c.5d.6f,1c.2d.3c.4c.5e.6a,1c.2d.3c.4c.5e.6b,1c.2d.3c.4c.5e.6c,1c.2d.3c.4c.5e.6d,
1c.2d.3c.4c.5e.6e,1c.2d.3c.4c.5e.6f,1c.2d.3c.4c.5f.6a,1c.2d.3c.4c.5f.6b,1c.2d.3c.4c.5f.6c,
1c.2d.3c.4c.5f.6d,1c.2d.3c.4c.5f.6e,1c.2d.3c.4c.5f.6f,1c.2d.3c.4d.5a.6a,1c.2d.3c.4d.5a.6b,
1c.2d.3c.4d.5a.6c,1c.2d.3c.4d.5a.6d,1c.2d.3c.4d.5a.6e,1c.2d.3c.4d.5a.6f,1c.2d.3c.4d.5b.6a,
1c.2d.3c.4d.5b.6b,1c.2d.3c.4d.5b.6c,1c.2d.3c.4d.5b.6d,1c.2d.3c.4d.5b.6e,1c.2d.3c.4d.5b.6f,
1c.2d.3c.4d.5c.6a,1c.2d.3c.4d.5c.6b,1c.2d.3c.4d.5c.6c,1c.2d.3c.4d.5c.6d,1c.2d.3c.4d.5c.6e,
1c.2d.3c.4d.5c.6f,1c.2d.3c.4d.5d.6a,1c.2d.3c.4d.5d.6b,1c.2d.3c.4d.5d.6c,1c.2d.3c.4d.5d.6d,
1c.2d.3c.4d.5d.6e,1c.2d.3c.4d.5d.6f,1c.2d.3c.4d.5e.6a,1c.2d.3c.4d.5e.6b,1c.2d.3c.4d.5e.6c,
1c.2d.3c.4d.5e.6d,1c.2d.3c.4d.5e.6e,1c.2d.3c.4d.5e.6f,1c.2d.3c.4d.5f.6a,1c.2d.3c.4d.5f.6b,
1c.2d.3c.4d.5f.6c,1c.2d.3c.4d.5f.6d,1c.2d.3c.4d.5f.6e,1c.2d.3c.4d.5f.6f,1c.2d.3c.4e.5a.6a,
1c.2d.3c.4e.5a.6b,1c.2d.3c.4e.5a.6c,1c.2d.3c.4e.5a.6d,1c.2d.3c.4e.5a.6e,1c.2d.3c.4e.5a.6f,
1c.2d.3c.4e.5b.6a,1c.2d.3c.4e.5b.6b,1c.2d.3c.4e.5b.6c,1c.2d.3c.4e.5b.6d,1c.2d.3c.4e.5b.6e,
1c.2d.3c.4e.5b.6f,1c.2d.3c.4e.5c.6a,1c.2d.3c.4e.5c.6b,1c.2d.3c.4e.5c.6c,1c.2d.3c.4e.5c.6d,
1c.2d.3c.4e.5c.6e,1c.2d.3c.4e.5c.6f,1c.2d.3c.4e.5d.6a,1c.2d.3c.4e.5d.6b,1c.2d.3c.4e.5d.6c,
1c.2d.3c.4e.5d.6d,1c.2d.3c.4e.5d.6e,1c.2d.3c.4e.5d.6f,1c.2d.3c.4e.5e.6a,1c.2d.3c.4e.5e.6b,
1c.2d.3c.4e.5e.6c,1c.2d.3c.4e.5e.6d,1c.2d.3c.4e.5e.6e,1c.2d.3c.4e.5e.6f,1c.2d.3c.4e.5f.6a,
1c.2d.3c.4e.5f.6b,1c.2d.3c.4e.5f.6c,1c.2d.3c.4e.5f.6d,1c.2d.3c.4e.5f.6e,1c.2d.3c.4e.5f.6f,
1c.2d.3c.4f.5a.6a,1c.2d.3c.4f.5a.6b,1c.2d.3c.4f.5a.6c,1c.2d.3c.4f.5a.6d,1c.2d.3c.4f.5a.6e,
1c.2d.3c.4f.5a.6f,1c.2d.3c.4f.5b.6a,1c.2d.3c.4f.5b.6b,1c.2d.3c.4f.5b.6c,1c.2d.3c.4f.5b.6d,
1c.2d.3c.4f.5b.6e,1c.2d.3c.4f.5b.6f,1c.2d.3c.4f.5c.6a,1c.2d.3c.4f.5c.6b,1c.2d.3c.4f.5c.6c,
1c.2d.3c.4f.5c.6d,1c.2d.3c.4f.5c.6e,1c.2d.3c.4f.5c.6f,1c.2d.3c.4f.5d.6a,1c.2d.3c.4f.5d.6b,
1c.2d.3c.4f.5d.6c,1c.2d.3c.4f.5d.6d,1c.2d.3c.4f.5d.6e,1c.2d.3c.4f.5d.6f,1c.2d.3c.4f.5e.6a,
1c.2d.3c.4f.5e.6b,1c.2d.3c.4f.5e.6c,1c.2d.3c.4f.5e.6d,1c.2d.3c.4f.5e.6e,1c.2d.3c.4f.5e.6f,
1c.2d.3c.4f.5f.6a,1c.2d.3c.4f.5f.6b,1c.2d.3c.4f.5f.6c,1c.2d.3c.4f.5f.6d,1c.2d.3c.4f.5f.6e,
1c.2d.3c.4f.5f.6f,1c.2d.3d.4a.5a.6a,1c.2d.3d.4a.5a.6b,1c.2d.3d.4a.5a.6c,1c.2d.3d.4a.5a.6d,
1c.2d.3d.4a.5a.6e,1c.2d.3d.4a.5a.6f,1c.2d.3d.4a.5b.6a,1c.2d.3d.4a.5b.6b,1c.2d.3d.4a.5b.6c,
1c.2d.3d.4a.5b.6d,1c.2d.3d.4a.5b.6e,1c.2d.3d.4a.5b.6f,1c.2d.3d.4a.5c.6a,1c.2d.3d.4a.5c.6b,
1c.2d.3d.4a.5c.6c,1c.2d.3d.4a.5c.6d,1c.2d.3d.4a.5c.6e,1c.2d.3d.4a.5c.6f,1c.2d.3d.4a.5d.6a,
1c.2d.3d.4a.5d.6b,1c.2d.3d.4a.5d.6c,1c.2d.3d.4a.5d.6d,1c.2d.3d.4a.5d.6e,1c.2d.3d.4a.5d.6f,
1c.2d.3d.4a.5e.6a,1c.2d.3d.4a.5e.6b,1c.2d.3d.4a.5e.6c,1c.2d.3d.4a.5e.6d,1c.2d.3d.4a.5e.6e,
1c.2d.3d.4a.5e.6f,1c.2d.3d.4a.5f.6a,1c.2d.3d.4a.5f.6b,1c.2d.3d.4a.5f.6c,1c.2d.3d.4a.5f.6d,
1c.2d.3d.4a.5f.6e,1c.2d.3d.4a.5f.6f,1c.2d.3d.4b.5a.6a,1c.2d.3d.4b.5a.6b,1c.2d.3d.4b.5a.6c,
1c.2d.3d.4b.5a.6d,1c.2d.3d.4b.5a.6e,1c.2d.3d.4b.5a.6f,1c.2d.3d.4b.5b.6a,1c.2d.3d.4b.5b.6b,
1c.2d.3d.4b.5b.6c,1c.2d.3d.4b.5b.6d,1c.2d.3d.4b.5b.6e,1c.2d.3d.4b.5b.6f,1c.2d.3d.4b.5c.6a,
1c.2d.3d.4b.5c.6b,1c.2d.3d.4b.5c.6c,1c.2d.3d.4b.5c.6d,1c.2d.3d.4b.5c.6e,1c.2d.3d.4b.5c.6f,
1c.2d.3d.4b.5d.6a, 1c.2d.3d.4b.5d.6b, 1c.2d.3d.4b.5d.6c, 1c.2d.3d.4b.5d.6d,
1c.2d.3d.4b.5d.6e,1c.2d.3d.4b.5d.6f,1c.2d.3d.4b.5e.6a,1c.2d.3d.4b.5e.6b,1c.2d.3d.4b.5e.6c,
1c.2d.3d.4b.5e.6d,1c.2d.3d.4b.5e.6e,1c.2d.3d.4b.5e.6f,1c.2d.3d.4b.5f.6a,1c.2d.3d.4b.5f.6b,
1c.2d.3d.4b.5f.6c,1c.2d.3d.4b.5f.6d,1c.2d.3d.4b.5f.6e,1c.2d.3d.4b.5f.6f,1c.2d.3d.4c.5a.6a,
1c.2d.3d.4c.5a.6b,1c.2d.3d.4c.5a.6c,1c.2d.3d.4c.5a.6d,1c.2d.3d.4c.5a.6e,1c.2d.3d.4c.5a.6f,
1c.2d.3d.4c.5b.6a,1c.2d.3d.4c.5b.6b,1c.2d.3d.4c.5b.6c,1c.2d.3d.4c.5b.6d,1c.2d.3d.4c.5b.6e,
1c.2d.3d.4c.5b.6f,1c.2d.3d.4c.5c.6a,1c.2d.3d.4c.5c.6b,1c.2d.3d.4c.5c.6c,1c.2d.3d.4c.5c.6d,
1c.2d.3d.4c.5c.6e,1c.2d.3d.4c.5c.6f,1c.2d.3d.4c.5d.6a,1c.2d.3d.4c.5d.6b,1c.2d.3d.4c.5d.6c,
1c.2d.3d.4c.5d.6d,1c.2d.3d.4c.5d.6e,1c.2d.3d.4c.5d.6f,1c.2d.3d.4c.5e.6a,1c.2d.3d.4c.5e.6b,
1c.2d.3d.4c.5e.6c,1c.2d.3d.4c.5e.6d,1c.2d.3d.4c.5e.6e,1c.2d.3d.4c.5e.6f,1c.2d.3d.4c.5f.6a,
1c.2d.3d.4c.5f.6b,1c.2d.3d.4c.5f.6c,1c.2d.3d.4c.5f.6d,1c.2d.3d.4c.5f.6e,1c.2d.3d.4c.5f.6f,
1c.2d.3d.4d.5a.6a, 1c.2d.3d.4d.5a.6b, 1c.2d.3d.4d.5a.6c, 1c.2d.3d.4d.5a.6d,
1c.2d.3d.4d.5a.6e, 1c.2d.3d.4d.5a.6f, 1c.2d.3d.4d.5b.6a, 1c.2d.3d.4d.5b.6b,
1c.2d.3d.4d.5b.6c, 1c.2d.3d.4d.5b.6d, 1c.2d.3d.4d.5b.6e, 1c.2d.3d.4d.5b.6f,
1c.2d.3d.4d.5c.6a,1c.2d.3d.4d.5c.6b,1c.2d.3d.4d.5c.6c,1c.2d.3d.4d.5c.6d,1c.2d.3d.4d.5c.6e,
1c.2d.3d.4d.5c.6f, 1c.2d.3d.4d.5d.6a, 1c.2d.3d.4d.5d.6b, 1c.2d.3d.4d.5d.6c,
1c.2d.3d.4d.5d.6d, 1c.2d.3d.4d.5d.6e, 1c.2d.3d.4d.5d.6f, 1c.2d.3d.4d.5e.6a,
1c.2d.3d.4d.5e.6b,1c.2d.3d.4d.5e.6c,1c.2d.3d.4d.5e.6d,1c.2d.3d.4d.5e.6e,1c.2d.3d.4d.5e.6f,
1c.2d.3d.4d.5f.6a,1c.2d.3d.4d.5f.6b,1c.2d.3d.4d.5f.6c,1c.2d.3d.4d.5f.6d,1c.2d.3d.4d.5f.6e,
1c.2d.3d.4d.5f.6f,1c.2d.3d.4e.5a.6a,1c.2d.3d.4e.5a.6b,1c.2d.3d.4e.5a.6c,1c.2d.3d.4e.5a.6d,
1c.2d.3d.4e.5a.6e,1c.2d.3d.4e.5a.6f,1c.2d.3d.4e.5b.6a,1c.2d.3d.4e.5b.6b,1c.2d.3d.4e.5b.6c,
1c.2d.3d.4e.5b.6d,1c.2d.3d.4e.5b.6e,1c.2d.3d.4e.5b.6f,1c.2d.3d.4e.5c.6a,1c.2d.3d.4e.5c.6b,
1c.2d.3d.4e.5c.6c,1c.2d.3d.4e.5c.6d,1c.2d.3d.4e.5c.6e,1c.2d.3d.4e.5c.6f,1c.2d.3d.4e.5d.6a,
1c.2d.3d.4e.5d.6b,1c.2d.3d.4e.5d.6c,1c.2d.3d.4e.5d.6d,1c.2d.3d.4e.5d.6e,1c.2d.3d.4e.5d.6f,
1c.2d.3d.4e.5e.6a,1c.2d.3d.4e.5e.6b,1c.2d.3d.4e.5e.6c,1c.2d.3d.4e.5e.6d,1c.2d.3d.4e.5e.6e,
1c.2d.3d.4e.5e.6f,1c.2d.3d.4e.5f.6a,1c.2d.3d.4e.5f.6b,1c.2d.3d.4e.5f.6c,1c.2d.3d.4e.5f.6d,
1c.2d.3d.4e.5f.6e,1c.2d.3d.4e.5f.6f,1c.2d.3d.4f.5a.6a,1c.2d.3d.4f.5a.6b,1c.2d.3d.4f.5a.6c,
1c.2d.3d.4f.5a.6d,1c.2d.3d.4f.5a.6e,1c.2d.3d.4f.5a.6f,1c.2d.3d.4f.5b.6a,1c.2d.3d.4f.5b.6b,
1c.2d.3d.4f.5b.6c,1c.2d.3d.4f.5b.6d,1c.2d.3d.4f.5b.6e,1c.2d.3d.4f.5b.6f,1c.2d.3d.4f.5c.6a,
1c.2d.3d.4f.5c.6b,1c.2d.3d.4f.5c.6c,1c.2d.3d.4f.5c.6d,1c.2d.3d.4f.5c.6e,1c.2d.3d.4f.5c.6f,
1c.2d.3d.4f.5d.6a,1c.2d.3d.4f.5d.6b,1c.2d.3d.4f.5d.6c,1c.2d.3d.4f.5d.6d,1c.2d.3d.4f.5d.6e,
1c.2d.3d.4f.5d.6f,1c.2d.3d.4f.5e.6a,1c.2d.3d.4f.5e.6b,1c.2d.3d.4f.5e.6c,1c.2d.3d.4f.5e.6d,
1c.2d.3d.4f.5e.6e,1c.2d.3d.4f.5e.6f,1c.2d.3d.4f.5f.6a,1c.2d.3d.4f.5f.6b,1c.2d.3d.4f.5f.6c,
1c.2d.3d.4f.5f.6d,1c.2d.3d.4f.5f.6e,1c.2d.3d.4f.5f.6f,1c.2d.3e.4a.5a.6a,1c.2d.3e.4a.5a.6b,
1c.2d.3e.4a.5a.6c,1c.2d.3e.4a.5a.6d,1c.2d.3e.4a.5a.6e,1c.2d.3e.4a.5a.6f,1c.2d.3e.4a.5b.6a,
1c.2d.3e.4a.5b.6b,1c.2d.3e.4a.5b.6c,1c.2d.3e.4a.5b.6d,1c.2d.3e.4a.5b.6e,1c.2d.3e.4a.5b.6f,
1c.2d.3e.4a.5c.6a,1c.2d.3e.4a.5c.6b,1c.2d.3e.4a.5c.6c,1c.2d.3e.4a.5c.6d,1c.2d.3e.4a.5c.6e,
1c.2d.3e.4a.5c.6f,1c.2d.3e.4a.5d.6a,1c.2d.3e.4a.5d.6b,1c.2d.3e.4a.5d.6c,1c.2d.3e.4a.5d.6d,
1c.2d.3e.4a.5d.6e,1c.2d.3e.4a.5d.6f,1c.2d.3e.4a.5e.6a,1c.2d.3e.4a.5e.6b,1c.2d.3e.4a.5e.6c,
1c.2d.3e.4a.5e.6d,1c.2d.3e.4a.5e.6e,1c.2d.3e.4a.5e.6f,1c.2d.3e.4a.5f.6a,1c.2d.3e.4a.5f.6b,
1c.2d.3e.4a.5f.6c,1c.2d.3e.4a.5f.6d,1c.2d.3e.4a.5f.6e,1c.2d.3e.4a.5f.6f,1c.2d.3e.4b.5a.6a,
1c.2d.3e.4b.5a.6b,1c.2d.3e.4b.5a.6c,1c.2d.3e.4b.5a.6d,1c.2d.3e.4b.5a.6e,1c.2d.3e.4b.5a.6f,
1c.2d.3e.4b.5b.6a,1c.2d.3e.4b.5b.6b,1c.2d.3e.4b.5b.6c,1c.2d.3e.4b.5b.6d,1c.2d.3e.4b.5b.6e,
1c.2d.3e.4b.5b.6f,1c.2d.3e.4b.5c.6a,1c.2d.3e.4b.5c.6b,1c.2d.3e.4b.5c.6c,1c.2d.3e.4b.5c.6d,
1c.2d.3e.4b.5c.6e,1c.2d.3e.4b.5c.6f,1c.2d.3e.4b.5d.6a,1c.2d.3e.4b.5d.6b,1c.2d.3e.4b.5d.6c,
1c.2d.3e.4b.5d.6d,1c.2d.3e.4b.5d.6e,1c.2d.3e.4b.5d.6f,1c.2d.3e.4b.5e.6a,1c.2d.3e.4b.5e.6b,
1c.2d.3e.4b.5e.6c,1c.2d.3e.4b.5e.6d,1c.2d.3e.4b.5e.6e,1c.2d.3e.4b.5e.6f,1c.2d.3e.4b.5f.6a,
1c.2d.3e.4b.5f.6b,1c.2d.3e.4b.5f.6c,1c.2d.3e.4b.5f.6d,1c.2d.3e.4b.5f.6e,1c.2d.3e.4b.5f.6f,
1c.2d.3e.4c.5a.6a,1c.2d.3e.4c.5a.6b,1c.2d.3e.4c.5a.6c,1c.2d.3e.4c.5a.6d,1c.2d.3e.4c.5a.6e,
1c.2d.3e.4c.5a.6f,1c.2d.3e.4c.5b.6a,1c.2d.3e.4c.5b.6b,1c.2d.3e.4c.5b.6c,1c.2d.3e.4c.5b.6d,
1c.2d.3e.4c.5b.6e,1c.2d.3e.4c.5b.6f,1c.2d.3e.4c.5c.6a,1c.2d.3e.4c.5c.6b,1c.2d.3e.4c.5c.6c,
1c.2d.3e.4c.5c.6d,1c.2d.3e.4c.5c.6e,1c.2d.3e.4c.5c.6f,1c.2d.3e.4c.5d.6a,1c.2d.3e.4c.5d.6b,
1c.2d.3e.4c.5d.6c,1c.2d.3e.4c.5d.6d,1c.2d.3e.4c.5d.6e,1c.2d.3e.4c.5d.6f,1c.2d.3e.4c.5e.6a,
1c.2d.3e.4c.5e.6b,1c.2d.3e.4c.5e.6c,1c.2d.3e.4c.5e.6d,1c.2d.3e.4c.5e.6e,1c.2d.3e.4c.5e.6f,
1c.2d.3e.4c.5f.6a,1c.2d.3e.4c.5f.6b,1c.2d.3e.4c.5f.6c,1c.2d.3e.4c.5f.6d,1c.2d.3e.4c.5f.6e,
1c.2d.3e.4c.5f.6f,1c.2d.3e.4d.5a.6a,1c.2d.3e.4d.5a.6b,1c.2d.3e.4d.5a.6c,1c.2d.3e.4d.5a.6d,
1c.2d.3e.4d.5a.6e,1c.2d.3e.4d.5a.6f,1c.2d.3e.4d.5b.6a,1c.2d.3e.4d.5b.6b,1c.2d.3e.4d.5b.6c,
1c.2d.3e.4d.5b.6d,1c.2d.3e.4d.5b.6e,1c.2d.3e.4d.5b.6f,1c.2d.3e.4d.5c.6a,1c.2d.3e.4d.5c.6b,
1c.2d.3e.4d.5c.6c,1c.2d.3e.4d.5c.6d,1c.2d.3e.4d.5c.6e,1c.2d.3e.4d.5c.6f,1c.2d.3e.4d.5d.6a,
1c.2d.3e.4d.5d.6b,1c.2d.3e.4d.5d.6c,1c.2d.3e.4d.5d.6d,1c.2d.3e.4d.5d.6e,1c.2d.3e.4d.5d.6f,
1c.2d.3e.4d.5e.6a,1c.2d.3e.4d.5e.6b,1c.2d.3e.4d.5e.6c,1c.2d.3e.4d.5e.6d,1c.2d.3e.4d.5e.6e,
1c.2d.3e.4d.5e.6f,1c.2d.3e.4d.5f.6a,1c.2d.3e.4d.5f.6b,1c.2d.3e.4d.5f.6c,1c.2d.3e.4d.5f.6d,
1c.2d.3e.4d.5f.6e,1c.2d.3e.4d.5f.6f,1c.2d.3e.4e.5a.6a,1c.2d.3e.4e.5a.6b,1c.2d.3e.4e.5a.6c,
1c.2d.3e.4e.5a.6d,1c.2d.3e.4e.5a.6e,1c.2d.3e.4e.5a.6f,1c.2d.3e.4e.5b.6a,1c.2d.3e.4e.5b.6b,
1c.2d.3e.4e.5b.6c,1c.2d.3e.4e.5b.6d,1c.2d.3e.4e.5b.6e,1c.2d.3e.4e.5b.6f,1c.2d.3e.4e.5c.6a,
1c.2d.3e.4e.5c.6b,1c.2d.3e.4e.5c.6c,1c.2d.3e.4e.5c.6d,1c.2d.3e.4e.5c.6e,1c.2d.3e.4e.5c.6f,
1c.2d.3e.4e.5d.6a,1c.2d.3e.4e.5d.6b,1c.2d.3e.4e.5d.6c,1c.2d.3e.4e.5d.6d,1c.2d.3e.4e.5d.6e,
1c.2d.3e.4e.5d.6f,1c.2d.3e.4e.5e.6a,1c.2d.3e.4e.5e.6b,1c.2d.3e.4e.5e.6c,1c.2d.3e.4e.5e.6d,
1c.2d.3e.4e.5e.6e,1c.2d.3e.4e.5e.6f,1c.2d.3e.4e.5f.6a,1c.2d.3e.4e.5f.6b,1c.2d.3e.4e.5f.6c,
1c.2d.3e.4e.5f.6d,1c.2d.3e.4e.5f.6e,1c.2d.3e.4e.5f.6f,1c.2d.3e.4f.5a.6a,1c.2d.3e.4f.5a.6b,
1c.2d.3e.4f.5a.6c,1c.2d.3e.4f.5a.6d,1c.2d.3e.4f.5a.6e,1c.2d.3e.4f.5a.6f,1c.2d.3e.4f.5b.6a,
1c.2d.3e.4f.5b.6b,1c.2d.3e.4f.5b.6c,1c.2d.3e.4f.5b.6d,1c.2d.3e.4f.5b.6e,1c.2d.3e.4f.5b.6f,
1c.2d.3e.4f.5c.6a,1c.2d.3e.4f.5c.6b,1c.2d.3e.4f.5c.6c,1c.2d.3e.4f.5c.6d,1c.2d.3e.4f.5c.6e,
1c.2d.3e.4f.5c.6f,1c.2d.3e.4f.5d.6a,1c.2d.3e.4f.5d.6b,1c.2d.3e.4f.5d.6c,1c.2d.3e.4f.5d.6d,
1c.2d.3e.4f.5d.6e,1c.2d.3e.4f.5d.6f,1c.2d.3e.4f.5e.6a,1c.2d.3e.4f.5e.6b,1c.2d.3e.4f.5e.6c,
1c.2d.3e.4f.5e.6d,1c.2d.3e.4f.5e.6e,1c.2d.3e.4f.5e.6f,1c.2d.3e.4f.5f.6a,1c.2d.3e.4f.5f.6b,
1c.2d.3e.4f.5f.6c,1c.2d.3e.4f.5f.6d,1c.2d.3e.4f.5f.6e,1c.2d.3e.4f.5f.6f,1c.2d.3f.4a.5a.6a,
1c.2d.3f.4a.5a.6b,1c.2d.3f.4a.5a.6c,1c.2d.3f.4a.5a.6d,1c.2d.3f.4a.5a.6e,1c.2d.3f.4a.5a.6f,
1c.2d.3f.4a.5b.6a,1c.2d.3f.4a.5b.6b,1c.2d.3f.4a.5b.6c,1c.2d.3f.4a.5b.6d,1c.2d.3f.4a.5b.6e,
1c.2d.3f.4a.5b.6f,1c.2d.3f.4a.5c.6a,1c.2d.3f.4a.5c.6b,1c.2d.3f.4a.5c.6c,1c.2d.3f.4a.5c.6d,
1c.2d.3f.4a.5c.6e,1c.2d.3f.4a.5c.6f,1c.2d.3f.4a.5d.6a,1c.2d.3f.4a.5d.6b,1c.2d.3f.4a.5d.6c,
1c.2d.3f.4a.5d.6d,1c.2d.3f.4a.5d.6e,1c.2d.3f.4a.5d.6f,1c.2d.3f.4a.5e.6a,1c.2d.3f.4a.5e.6b,
1c.2d.3f.4a.5e.6c,1c.2d.3f.4a.5e.6d,1c.2d.3f.4a.5e.6e,1c.2d.3f.4a.5e.6f,1c.2d.3f.4a.5f.6a,
1c.2d.3f.4a.5f.6b,1c.2d.3f.4a.5f.6c,1c.2d.3f.4a.5f.6d,1c.2d.3f.4a.5f.6e,1c.2d.3f.4a.5f.6f,
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1c.2d.3f.4b.5a.6f,1c.2d.3f.4b.5b.6a,1c.2d.3f.4b.5b.6b,1c.2d.3f.4b.5b.6c,1c.2d.3f.4b.5b.6d,
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1c.2f.3c.4c.5f.6f,1c.2f.3c.4d.5a.6a,1c.2f.3c.4d.5a.6b,1c.2f.3c.4d.5a.6c,1c.2f.3c.4d.5a.6d,
1c.2f.3c.4d.5a.6e,1c.2f.3c.4d.5a.6f,1c.2f.3c.4d.5b.6a,1c.2f.3c.4d.5b.6b,1c.2f.3c.4d.5b.6c,
1c.2f.3c.4d.5b.6d,1c.2f.3c.4d.5b.6e,1c.2f.3c.4d.5b.6f,1c.2f.3c.4d.5c.6a,1c.2f.3c.4d.5c.6b,
1c.2f.3c.4d.5c.6c,1c.2f.3c.4d.5c.6d,1c.2f.3c.4d.5c.6e,1c.2f.3c.4d.5c.6f,1c.2f.3c.4d.5d.6a,
1c.2f.3c.4d.5d.6b,1c.2f.3c.4d.5d.6c,1c.2f.3c.4d.5d.6d,1c.2f.3c.4d.5d.6e,1c.2f.3c.4d.5d.6f,
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1c.2f.3c.4d.5e.6f,1c.2f.3c.4d.5f.6a,1c.2f.3c.4d.5f.6b,1c.2f.3c.4d.5f.6c,1c.2f.3c.4d.5f.6d,
1c.2f.3c.4d.5f.6e,1c.2f.3c.4d.5f.6f,1c.2f.3c.4e.5a.6a,1c.2f.3c.4e.5a.6b,1c.2f.3c.4e.5a.6c,
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1c.2f.3c.4e.5c.6b,1c.2f.3c.4e.5c.6c,1c.2f.3c.4e.5c.6d,1c.2f.3c.4e.5c.6e,1c.2f.3c.4e.5c.6f,
1c.2f.3c.4e.5d.6a,1c.2f.3c.4e.5d.6b,1c.2f.3c.4e.5d.6c,1c.2f.3c.4e.5d.6d,1c.2f.3c.4e.5d.6e,
1c.2f.3c.4e.5d.6f,1c.2f.3c.4e.5e.6a,1c.2f.3c.4e.5e.6b,1c.2f.3c.4e.5e.6c,1c.2f.3c.4e.5e.6d,
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1c.2f.3c.4f.5a.6c,1c.2f.3c.4f.5a.6d,1c.2f.3c.4f.5a.6e,1c.2f.3c.4f.5a.6f,1c.2f.3c.4f.5b.6a,
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1c.2f.3c.4f.5c.6f,1c.2f.3c.4f.5d.6a,1c.2f.3c.4f.5d.6b,1c.2f.3c.4f.5d.6c,1c.2f.3c.4f.5d.6d,
1c.2f.3c.4f.5d.6e,1c.2f.3c.4f.5d.6f,1c.2f.3c.4f.5e.6a,1c.2f.3c.4f.5e.6b,1c.2f.3c.4f.5e.6c,
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1c.2f.3c.4f.5f.6c,1c.2f.3c.4f.5f.6d,1c.2f.3c.4f.5f.6e,1c.2f.3c.4f.5f.6f,1c.2f.3d.4a.5a.6a,
1c.2f.3d.4a.5a.6b,1c.2f.3d.4a.5a.6c,1c.2f.3d.4a.5a.6d,1c.2f.3d.4a.5a.6e,1c.2f.3d.4a.5a.6f,
1c.2f.3d.4a.5b.6a,1c.2f.3d.4a.5b.6b,1c.2f.3d.4a.5b.6c,1c.2f.3d.4a.5b.6d,1c.2f.3d.4a.5b.6e,
1c.2f.3d.4a.5b.6f,1c.2f.3d.4a.5c.6a,1c.2f.3d.4a.5c.6b,1c.2f.3d.4a.5c.6c,1c.2f.3d.4a.5c.6d,
1c.2f.3d.4a.5c.6e,1c.2f.3d.4a.5c.6f,1c.2f.3d.4a.5d.6a,1c.2f.3d.4a.5d.6b,1c.2f.3d.4a.5d.6c,
1c.2f.3d.4a.5d.6d,1c.2f.3d.4a.5d.6e,1c.2f.3d.4a.5d.6f,1c.2f.3d.4a.5e.6a,1c.2f.3d.4a.5e.6b,
1c.2f.3d.4a.5e.6c,1c.2f.3d.4a.5e.6d,1c.2f.3d.4a.5e.6e,1c.2f.3d.4a.5e.6f,1c.2f.3d.4a.5f.6a,
1c.2f.3d.4a.5f.6b,1c.2f.3d.4a.5f.6c,1c.2f.3d.4a.5f.6d,1c.2f.3d.4a.5f.6e,1c.2f.3d.4a.5f.6f,
1c.2f.3d.4b.5a.6a,1c.2f.3d.4b.5a.6b,1c.2f.3d.4b.5a.6c,1c.2f.3d.4b.5a.6d,1c.2f.3d.4b.5a.6e,
1c.2f.3d.4b.5a.6f,1c.2f.3d.4b.5b.6a,1c.2f.3d.4b.5b.6b,1c.2f.3d.4b.5b.6c,1c.2f.3d.4b.5b.6d,
1c.2f.3d.4b.5b.6e,1c.2f.3d.4b.5b.6f,1c.2f.3d.4b.5c.6a,1c.2f.3d.4b.5c.6b,1c.2f.3d.4b.5c.6c,
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1c.2f.3f.4b.5a.6d,1c.2f.3f.4b.5a.6e,1c.2f.3f.4b.5a.6f,1c.2f.3f.4b.5b.6a,1c.2f.3f.4b.5b.6b,
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1c.2f.3f.4b.5d.6a,1c.2f.3f.4b.5d.6b,1c.2f.3f.4b.5d.6c,1c.2f.3f.4b.5d.6d,1c.2f.3f.4b.5d.6e,
1c.2f.3f.4b.5d.6f,1c.2f.3f.4b.5e.6a,1c.2f.3f.4b.5e.6b,1c.2f.3f.4b.5e.6c,1c.2f.3f.4b.5e.6d,
1c.2f.3f.4b.5e.6e,1c.2f.3f.4b.5e.6f,1c.2f.3f.4b.5f.6a,1c.2f.3f.4b.5f.6b,1c.2f.3f.4b.5f.6c,
1c.2f.3f.4b.5f.6d,1c.2f.3f.4b.5f.6e,1c.2f.3f.4b.5f.6f,1c.2f.3f.4c.5a.6a,1c.2f.3f.4c.5a.6b,
1c.2f.3f.4c.5a.6c,1c.2f.3f.4c.5a.6d,1c.2f.3f.4c.5a.6e,1c.2f.3f.4c.5a.6f,1c.2f.3f.4c.5b.6a,
1c.2f.3f.4c.5b.6b,1c.2f.3f.4c.5b.6c,1c.2f.3f.4c.5b.6d,1c.2f.3f.4c.5b.6e,1c.2f.3f.4c.5b.6f,
1c.2f.3f.4c.5c.6a,1c.2f.3f.4c.5c.6b,1c.2f.3f.4c.5c.6c,1c.2f.3f.4c.5c.6d,1c.2f.3f.4c.5c.6e,
1c.2f.3f.4c.5c.6f,1c.2f.3f.4c.5d.6a,1c.2f.3f.4c.5d.6b,1c.2f.3f.4c.5d.6c,1c.2f.3f.4c.5d.6d,
1c.2f.3f.4c.5d.6e,1c.2f.3f.4c.5d.6f,1c.2f.3f.4c.5e.6a,1c.2f.3f.4c.5e.6b,1c.2f.3f.4c.5e.6c,
1c.2f.3f.4c.5e.6d,1c.2f.3f.4c.5e.6e,1c.2f.3f.4c.5e.6f,1c.2f.3f.4c.5f.6a,1c.2f.3f.4c.5f.6b,
1c.2f.3f.4c.5f.6c,1c.2f.3f.4c.5f.6d,1c.2f.3f.4c.5f.6e,1c.2f.3f.4c.5f.6f,1c.2f.3f.4d.5a.6a,
1c.2f.3f.4d.5a.6b,1c.2f.3f.4d.5a.6c,1c.2f.3f.4d.5a.6d,1c.2f.3f.4d.5a.6e,1c.2f.3f.4d.5a.6f,
1c.2f.3f.4d.5b.6a,1c.2f.3f.4d.5b.6b,1c.2f.3f.4d.5b.6c,1c.2f.3f.4d.5b.6d,1c.2f.3f.4d.5b.6e,
1c.2f.3f.4d.5b.6f,1c.2f.3f.4d.5c.6a,1c.2f.3f.4d.5c.6b,1c.2f.3f.4d.5c.6c,1c.2f.3f.4d.5c.6d,
1c.2f.3f.4d.5c.6e,1c.2f.3f.4d.5c.6f,1c.2f.3f.4d.5d.6a,1c.2f.3f.4d.5d.6b,1c.2f.3f.4d.5d.6c,
1c.2f.3f.4d.5d.6d,1c.2f.3f.4d.5d.6e,1c.2f.3f.4d.5d.6f,1c.2f.3f.4d.5e.6a,1c.2f.3f.4d.5e.6b,
1c.2f.3f.4d.5e.6c,1c.2f.3f.4d.5e.6d,1c.2f.3f.4d.5e.6e,1c.2f.3f.4d.5e.6f,1c.2f.3f.4d.5f.6a,
1c.2f.3f.4d.5f.6b,1c.2f.3f.4d.5f.6c,1c.2f.3f.4d.5f.6d,1c.2f.3f.4d.5f.6e,1c.2f.3f.4d.5f.6f,
1c.2f.3f.4e.5a.6a,1c.2f.3f.4e.5a.6b,1c.2f.3f.4e.5a.6c,1c.2f.3f.4e.5a.6d,1c.2f.3f.4e.5a.6e,
1c.2f.3f.4e.5a.6f,1c.2f.3f.4e.5b.6a,1c.2f.3f.4e.5b.6b,1c.2f.3f.4e.5b.6c,1c.2f.3f.4e.5b.6d,
1c.2f.3f.4e.5b.6e,1c.2f.3f.4e.5b.6f,1c.2f.3f.4e.5c.6a,1c.2f.3f.4e.5c.6b,1c.2f.3f.4e.5c.6c,
1c.2f.3f.4e.5c.6d,1c.2f.3f.4e.5c.6e,1c.2f.3f.4e.5c.6f,1c.2f.3f.4e.5d.6a,1c.2f.3f.4e.5d.6b,
1c.2f.3f.4e.5d.6c,1c.2f.3f.4e.5d.6d,1c.2f.3f.4e.5d.6e,1c.2f.3f.4e.5d.6f,1c.2f.3f.4e.5e.6a,
1c.2f.3f.4e.5e.6b,1c.2f.3f.4e.5e.6c,1c.2f.3f.4e.5e.6d,1c.2f.3f.4e.5e.6e,1c.2f.3f.4e.5e.6f,
1c.2f.3f.4e.5f.6a,1c.2f.3f.4e.5f.6b,1c.2f.3f.4e.5f.6c,1c.2f.3f.4e.5f.6d,1c.2f.3f.4e.5f.6e,
1c.2f.3f.4e.5f.6f,1c.2f.3f.4f.5a.6a,1c.2f.3f.4f.5a.6b,1c.2f.3f.4f.5a.6c,1c.2f.3f.4f.5a.6d,
1c.2f.3f.4f.5a.6e,1c.2f.3f.4f.5a.6f,1c.2f.3f.4f.5b.6a,1c.2f.3f.4f.5b.6b,1c.2f.3f.4f.5b.6c,
1c.2f.3f.4f.5b.6d,1c.2f.3f.4f.5b.6e,1c.2f.3f.4f.5b.6f,1c.2f.3f.4f.5c.6a,1c.2f.3f.4f.5c.6b,
1c.2f.3f.4f.5c.6c,1c.2f.3f.4f.5c.6d,1c.2f.3f.4f.5c.6e,1c.2f.3f.4f.5c.6f,1c.2f.3f.4f.5d.6a,
1c.2f.3f.4f.5d.6b,1c.2f.3f.4f.5d.6c,1c.2f.3f.4f.5d.6d,1c.2f.3f.4f.5d.6e,1c.2f.3f.4f.5d.6f,
1c.2f.3f.4f.5e.6a,1c.2f.3f.4f.5e.6b,1c.2f.3f.4f.5e.6c,1c.2f.3f.4f.5e.6d,1c.2f.3f.4f.5e.6e,
1c.2f.3f.4f.5e.6f,1c.2f.3f.4f.5f.6a,1c.2f.3f.4f.5f.6b,1c.2f.3f.4f.5f.6c,1c.2f.3f.4f.5f.6d,
1c.2f.3f.4f.5f.6e,1c.2f.3f.4f.5f.6f,1d.2a.3a.4a.5a.6a,1d.2a.3a.4a.5a.6b,1d.2a.3a.4a.5a.6c,
1d.2a.3a.4a.5a.6d,1d.2a.3a.4a.5a.6e,1d.2a.3a.4a.5a.6f,1d.2a.3a.4a.5b.6a,1d.2a.3a.4a.5b.6b,
1d.2a.3a.4a.5b.6c,1d.2a.3a.4a.5b.6d,1d.2a.3a.4a.5b.6e,1d.2a.3a.4a.5b.6f,1d.2a.3a.4a.5c.6a,
1d.2a.3a.4a.5c.6b,1d.2a.3a.4a.5c.6c,1d.2a.3a.4a.5c.6d,1d.2a.3a.4a.5c.6e,1d.2a.3a.4a.5c.6f,
1d.2a.3a.4a.5d.6a,1d.2a.3a.4a.5d.6b,1d.2a.3a.4a.5d.6c,1d.2a.3a.4a.5d.6d,1d.2a.3a.4a.5d.6e,
1d.2a.3a.4a.5d.6f,1d.2a.3a.4a.5e.6a,1d.2a.3a.4a.5e.6b,1d.2a.3a.4a.5e.6c,1d.2a.3a.4a.5e.6d,
1d.2a.3a.4a.5e.6e,1d.2a.3a.4a.5e.6f,1d.2a.3a.4a.5f.6a,1d.2a.3a.4a.5f.6b,1d.2a.3a.4a.5f.6c,
1d.2a.3a.4a.5f.6d,1d.2a.3a.4a.5f.6e,1d.2a.3a.4a.5f.6f,1d.2a.3a.4b.5a.6a,1d.2a.3a.4b.5a.6b,
1d.2a.3a.4b.5a.6c,1d.2a.3a.4b.5a.6d,1d.2a.3a.4b.5a.6e,1d.2a.3a.4b.5a.6f,1d.2a.3a.4b.5b.6a,
1d.2a.3a.4b.5b.6b,1d.2a.3a.4b.5b.6c,1d.2a.3a.4b.5b.6d,1d.2a.3a.4b.5b.6e,1d.2a.3a.4b.5b.6f,
1d.2a.3a.4b.5c.6a,1d.2a.3a.4b.5c.6b,1d.2a.3a.4b.5c.6c,1d.2a.3a.4b.5c.6d,1d.2a.3a.4b.5c.6e,
1d.2a.3a.4b.5c.6f,1d.2a.3a.4b.5d.6a,1d.2a.3a.4b.5d.6b,1d.2a.3a.4b.5d.6c,1d.2a.3a.4b.5d.6d,
1d.2a.3a.4b.5d.6e,1d.2a.3a.4b.5d.6f,1d.2a.3a.4b.5e.6a,1d.2a.3a.4b.5e.6b,1d.2a.3a.4b.5e.6c,
1d.2a.3a.4b.5e.6d,1d.2a.3a.4b.5e.6e,1d.2a.3a.4b.5e.6f,1d.2a.3a.4b.5f.6a,1d.2a.3a.4b.5f.6b,
1d.2a.3a.4b.5f.6c,1d.2a.3a.4b.5f.6d,1d.2a.3a.4b.5f.6e,1d.2a.3a.4b.5f.6f,1d.2a.3a.4c.5a.6a,
1d.2a.3a.4c.5a.6b,1d.2a.3a.4c.5a.6c,1d.2a.3a.4c.5a.6d,1d.2a.3a.4c.5a.6e,1d.2a.3a.4c.5a.6f,
1d.2a.3a.4c.5b.6a,1d.2a.3a.4c.5b.6b,1d.2a.3a.4c.5b.6c,1d.2a.3a.4c.5b.6d,1d.2a.3a.4c.5b.6e,
1d.2a.3a.4c.5b.6f,1d.2a.3a.4c.5c.6a,1d.2a.3a.4c.5c.6b,1d.2a.3a.4c.5c.6c,1d.2a.3a.4c.5c.6d,
1d.2a.3a.4c.5c.6e,1d.2a.3a.4c.5c.6f,1d.2a.3a.4c.5d.6a,1d.2a.3a.4c.5d.6b,1d.2a.3a.4c.5d.6c,
1d.2a.3a.4c.5d.6d,1d.2a.3a.4c.5d.6e,1d.2a.3a.4c.5d.6f,1d.2a.3a.4c.5e.6a,1d.2a.3a.4c.5e.6b,
1d.2a.3a.4c.5e.6c,1d.2a.3a.4c.5e.6d,1d.2a.3a.4c.5e.6e,1d.2a.3a.4c.5e.6f,1d.2a.3a.4c.5f.6a,
1d.2a.3a.4c.5f.6b,1d.2a.3a.4c.5f.6c,1d.2a.3a.4c.5f.6d,1d.2a.3a.4c.5f.6e,1d.2a.3a.4c.5f.6f,
1d.2a.3a.4d.5a.6a,1d.2a.3a.4d.5a.6b,1d.2a.3a.4d.5a.6c,1d.2a.3a.4d.5a.6d,1d.2a.3a.4d.5a.6e,
1d.2a.3a.4d.5a.6f,1d.2a.3a.4d.5b.6a,1d.2a.3a.4d.5b.6b,1d.2a.3a.4d.5b.6c,1d.2a.3a.4d.5b.6d,
1d.2a.3a.4d.5b.6e,1d.2a.3a.4d.5b.6f,1d.2a.3a.4d.5c.6a,1d.2a.3a.4d.5c.6b,1d.2a.3a.4d.5c.6c,
1d.2a.3a.4d.5c.6d,1d.2a.3a.4d.5c.6e,1d.2a.3a.4d.5c.6f,1d.2a.3a.4d.5d.6a,1d.2a.3a.4d.5d.6b,
1d.2a.3a.4d.5d.6c, 1d.2a.3a.4d.5d.6d, 1d.2a.3a.4d.5d.6e, 1d.2a.3a.4d.5d.6f,
1d.2a.3a.4d.5e.6a,1d.2a.3a.4d.5e.6b,1d.2a.3a.4d.5e.6c,1d.2a.3a.4d.5e.6d,1d.2a.3a.4d.5e.6e,
1d.2a.3a.4d.5e.6f,1d.2a.3a.4d.5f.6a,1d.2a.3a.4d.5f.6b,1d.2a.3a.4d.5f.6c,1d.2a.3a.4d.5f.6d,
1d.2a.3a.4d.5f.6e,1d.2a.3a.4d.5f.6f,1d.2a.3a.4e.5a.6a,1d.2a.3a.4e.5a.6b,1d.2a.3a.4e.5a.6c,
1d.2a.3a.4e.5a.6d,1d.2a.3a.4e.5a.6e,1d.2a.3a.4e.5a.6f,1d.2a.3a.4e.5b.6a,1d.2a.3a.4e.5b.6b,
1d.2a.3a.4e.5b.6c,1d.2a.3a.4e.5b.6d,1d.2a.3a.4e.5b.6e,1d.2a.3a.4e.5b.6f,1d.2a.3a.4e.5c.6a,
1d.2a.3a.4e.5c.6b,1d.2a.3a.4e.5c.6c,1d.2a.3a.4e.5c.6d,1d.2a.3a.4e.5c.6e,1d.2a.3a.4e.5c.6f,
1d.2a.3a.4e.5d.6a,1d.2a.3a.4e.5d.6b,1d.2a.3a.4e.5d.6c,1d.2a.3a.4e.5d.6d,1d.2a.3a.4e.5d.6e,
1d.2a.3a.4e.5d.6f,1d.2a.3a.4e.5e.6a,1d.2a.3a.4e.5e.6b,1d.2a.3a.4e.5e.6c,1d.2a.3a.4e.5e.6d,
1d.2a.3a.4e.5e.6e,1d.2a.3a.4e.5e.6f,1d.2a.3a.4e.5f.6a,1d.2a.3a.4e.5f.6b,1d.2a.3a.4e.5f.6c,
1d.2a.3a.4e.5f.6d,1d.2a.3a.4e.5f.6e,1d.2a.3a.4e.5f.6f,1d.2a.3a.4f.5a.6a,1d.2a.3a.4f.5a.6b,
1d.2a.3a.4f.5a.6c,1d.2a.3a.4f.5a.6d,1d.2a.3a.4f.5a.6e,1d.2a.3a.4f.5a.6f,1d.2a.3a.4f.5b.6a,
1d.2a.3a.4f.5b.6b,1d.2a.3a.4f.5b.6c,1d.2a.3a.4f.5b.6d,1d.2a.3a.4f.5b.6e,1d.2a.3a.4f.5b.6f,
1d.2a.3a.4f.5c.6a,1d.2a.3a.4f.5c.6b,1d.2a.3a.4f.5c.6c,1d.2a.3a.4f.5c.6d,1d.2a.3a.4f.5c.6e,
1d.2a.3a.4f.5c.6f,1d.2a.3a.4f.5d.6a,1d.2a.3a.4f.5d.6b,1d.2a.3a.4f.5d.6c,1d.2a.3a.4f.5d.6d,
1d.2a.3a.4f.5d.6e,1d.2a.3a.4f.5d.6f,1d.2a.3a.4f.5e.6a,1d.2a.3a.4f.5e.6b,1d.2a.3a.4f.5e.6c,
1d.2a.3a.4f.5e.6d,1d.2a.3a.4f.5e.6e,1d.2a.3a.4f.5e.6f,1d.2a.3a.4f.5f.6a,1d.2a.3a.4f.5f.6b,
1d.2a.3a.4f.5f.6c,1d.2a.3a.4f.5f.6d,1d.2a.3a.4f.5f.6e,1d.2a.3a.4f.5f.6f,1d.2a.3b.4a.5a.6a,
1d.2a.3b.4a.5a.6b,1d.2a.3b.4a.5a.6c,1d.2a.3b.4a.5a.6d,1d.2a.3b.4a.5a.6e,1d.2a.3b.4a.5a.6f,
1d.2a.3b.4a.5b.6a,1d.2a.3b.4a.5b.6b,1d.2a.3b.4a.5b.6c,1d.2a.3b.4a.5b.6d,1d.2a.3b.4a.5b.6e,
1d.2a.3b.4a.5b.6f,1d.2a.3b.4a.5c.6a,1d.2a.3b.4a.5c.6b,1d.2a.3b.4a.5c.6c,1d.2a.3b.4a.5c.6d,
1d.2a.3b.4a.5c.6e,1d.2a.3b.4a.5c.6f,1d.2a.3b.4a.5d.6a,1d.2a.3b.4a.5d.6b,1d.2a.3b.4a.5d.6c,
1d.2a.3b.4a.5d.6d,1d.2a.3b.4a.5d.6e,1d.2a.3b.4a.5d.6f,1d.2a.3b.4a.5e.6a,1d.2a.3b.4a.5e.6b,
1d.2a.3b.4a.5e.6c,1d.2a.3b.4a.5e.6d,1d.2a.3b.4a.5e.6e,1d.2a.3b.4a.5e.6f,1d.2a.3b.4a.5f.6a,
1d.2a.3b.4a.5f.6b,1d.2a.3b.4a.5f.6c,1d.2a.3b.4a.5f.6d,1d.2a.3b.4a.5f.6e,1d.2a.3b.4a.5f.6f,
1d.2a.3b.4b.5a.6a,1d.2a.3b.4b.5a.6b,1d.2a.3b.4b.5a.6c,1d.2a.3b.4b.5a.6d,1d.2a.3b.4b.5a.6e,
1d.2a.3b.4b.5a.6f,1d.2a.3b.4b.5b.6a,1d.2a.3b.4b.5b.6b,1d.2a.3b.4b.5b.6c,1d.2a.3b.4b.5b.6d,
1d.2a.3b.4b.5b.6e,1d.2a.3b.4b.5b.6f,1d.2a.3b.4b.5c.6a,1d.2a.3b.4b.5c.6b,1d.2a.3b.4b.5c.6c,
1d.2a.3b.4b.5c.6d,1d.2a.3b.4b.5c.6e,1d.2a.3b.4b.5c.6f,1d.2a.3b.4b.5d.6a,1d.2a.3b.4b.5d.6b,
1d.2a.3b.4b.5d.6c, 1d.2a.3b.4b.5d.6d, 1d.2a.3b.4b.5d.6e, 1d.2a.3b.4b.5d.6f,
1d.2a.3b.4b.5e.6a,1d.2a.3b.4b.5e.6b,1d.2a.3b.4b.5e.6c,1d.2a.3b.4b.5e.6d,1d.2a.3b.4b.5e.6e,
1d.2a.3b.4b.5e.6f,1d.2a.3b.4b.5f.6a,1d.2a.3b.4b.5f.6b,1d.2a.3b.4b.5f.6c,1d.2a.3b.4b.5f.6d,
1d.2a.3b.4b.5f.6e,1d.2a.3b.4b.5f.6f,1d.2a.3b.4c.5a.6a,1d.2a.3b.4c.5a.6b,1d.2a.3b.4c.5a.6c,
1d.2a.3b.4c.5a.6d,1d.2a.3b.4c.5a.6e,1d.2a.3b.4c.5a.6f,1d.2a.3b.4c.5b.6a,1d.2a.3b.4c.5b.6b,
1d.2a.3b.4c.5b.6c,1d.2a.3b.4c.5b.6d,1d.2a.3b.4c.5b.6e,1d.2a.3b.4c.5b.6f,1d.2a.3b.4c.5c.6a,
1d.2a.3b.4c.5c.6b,1d.2a.3b.4c.5c.6c,1d.2a.3b.4c.5c.6d,1d.2a.3b.4c.5c.6e,1d.2a.3b.4c.5c.6f,
1d.2a.3b.4c.5d.6a,1d.2a.3b.4c.5d.6b,1d.2a.3b.4c.5d.6c,1d.2a.3b.4c.5d.6d,1d.2a.3b.4c.5d.6e,
1d.2a.3b.4c.5d.6f,1d.2a.3b.4c.5e.6a,1d.2a.3b.4c.5e.6b,1d.2a.3b.4c.5e.6c,1d.2a.3b.4c.5e.6d,
1d.2a.3b.4c.5e.6e,1d.2a.3b.4c.5e.6f,1d.2a.3b.4c.5f.6a,1d.2a.3b.4c.5f.6b,1d.2a.3b.4c.5f.6c,
1d.2a.3b.4c.5f.6d,1d.2a.3b.4c.5f.6e,1d.2a.3b.4c.5f.6f,1d.2a.3b.4d.5a.6a,1d.2a.3b.4d.5a.6b,
1d.2a.3b.4d.5a.6c,1d.2a.3b.4d.5a.6d,1d.2a.3b.4d.5a.6e,1d.2a.3b.4d.5a.6f,1d.2a.3b.4d.5b.6a,
1d.2a.3b.4d.5b.6b, 1d.2a.3b.4d.5b.6c, 1d.2a.3b.4d.5b.6d, 1d.2a.3b.4d.5b.6e,
1d.2a.3b.4d.5b.6f,1d.2a.3b.4d.5c.6a,1d.2a.3b.4d.5c.6b,1d.2a.3b.4d.5c.6c,1d.2a.3b.4d.5c.6d,
1d.2a.3b.4d.5c.6e, 1d.2a.3b.4d.5c.6f, 1d.2a.3b.4d.5d.6a, 1d.2a.3b.4d.5d.6b,
1d.2a.3b.4d.5d.6c, 1d.2a.3b.4d.5d.6d, 1d.2a.3b.4d.5d.6e, 1d.2a.3b.4d.5d.6f,
1d.2a.3b.4d.5e.6a, 1d.2a.3b.4d.5e.6b, 1d.2a.3b.4d.5e.6c, 1d.2a.3b.4d.5e.6d,
1d.2a.3b.4d.5e.6e,1d.2a.3b.4d.5e.6f,1d.2a.3b.4d.5f.6a,1d.2a.3b.4d.5f.6b,1d.2a.3b.4d.5f.6c,
1d.2a.3b.4d.5f.6d,1d.2a.3b.4d.5f.6e,1d.2a.3b.4d.5f.6f,1d.2a.3b.4e.5a.6a,1d.2a.3b.4e.5a.6b,
1d.2a.3b.4e.5a.6c,1d.2a.3b.4e.5a.6d,1d.2a.3b.4e.5a.6e,1d.2a.3b.4e.5a.6f,1d.2a.3b.4e.5b.6a,
1d.2a.3b.4e.5b.6b,1d.2a.3b.4e.5b.6c,1d.2a.3b.4e.5b.6d,1d.2a.3b.4e.5b.6e,1d.2a.3b.4e.5b.6f,
1d.2a.3b.4e.5c.6a,1d.2a.3b.4e.5c.6b,1d.2a.3b.4e.5c.6c,1d.2a.3b.4e.5c.6d,1d.2a.3b.4e.5c.6e,
1d.2a.3b.4e.5c.6f,1d.2a.3b.4e.5d.6a,1d.2a.3b.4e.5d.6b,1d.2a.3b.4e.5d.6c,1d.2a.3b.4e.5d.6d,
1d.2a.3b.4e.5d.6e,1d.2a.3b.4e.5d.6f,1d.2a.3b.4e.5e.6a,1d.2a.3b.4e.5e.6b,1d.2a.3b.4e.5e.6c,
1d.2a.3b.4e.5e.6d,1d.2a.3b.4e.5e.6e,1d.2a.3b.4e.5e.6f,1d.2a.3b.4e.5f.6a,1d.2a.3b.4e.5f.6b,
1d.2a.3b.4e.5f.6c,1d.2a.3b.4e.5f.6d,1d.2a.3b.4e.5f.6e,1d.2a.3b.4e.5f.6f,1d.2a.3b.4f.5a.6a,
1d.2a.3b.4f.5a.6b,1d.2a.3b.4f.5a.6c,1d.2a.3b.4f.5a.6d,1d.2a.3b.4f.5a.6e,1d.2a.3b.4f.5a.6f,
1d.2a.3b.4f.5b.6a,1d.2a.3b.4f.5b.6b,1d.2a.3b.4f.5b.6c,1d.2a.3b.4f.5b.6d,1d.2a.3b.4f.5b.6e,
1d.2a.3b.4f.5b.6f,1d.2a.3b.4f.5c.6a,1d.2a.3b.4f.5c.6b,1d.2a.3b.4f.5c.6c,1d.2a.3b.4f.5c.6d,
1d.2a.3b.4f.5c.6e,1d.2a.3b.4f.5c.6f,1d.2a.3b.4f.5d.6a,1d.2a.3b.4f.5d.6b,1d.2a.3b.4f.5d.6c,
1d.2a.3b.4f.5d.6d,1d.2a.3b.4f.5d.6e,1d.2a.3b.4f.5d.6f,1d.2a.3b.4f.5e.6a,1d.2a.3b.4f.5e.6b,
1d.2a.3b.4f.5e.6c,1d.2a.3b.4f.5e.6d,1d.2a.3b.4f.5e.6e,1d.2a.3b.4f.5e.6f,1d.2a.3b.4f.5f.6a,
1d.2a.3b.4f.5f.6b,1d.2a.3b.4f.5f.6c,1d.2a.3b.4f.5f.6d,1d.2a.3b.4f.5f.6e,1d.2a.3b.4f.5f.6f,
1d.2a.3c.4a.5a.6a,1d.2a.3c.4a.5a.6b,1d.2a.3c.4a.5a.6c,1d.2a.3c.4a.5a.6d,1d.2a.3c.4a.5a.6e,
1d.2a.3c.4a.5a.6f,1d.2a.3c.4a.5b.6a,1d.2a.3c.4a.5b.6b,1d.2a.3c.4a.5b.6c,1d.2a.3c.4a.5b.6d,
1d.2a.3c.4a.5b.6e,1d.2a.3c.4a.5b.6f,1d.2a.3c.4a.5c.6a,1d.2a.3c.4a.5c.6b,1d.2a.3c.4a.5c.6c,
1d.2a.3c.4a.5c.6d,1d.2a.3c.4a.5c.6e,1d.2a.3c.4a.5c.6f,1d.2a.3c.4a.5d.6a,1d.2a.3c.4a.5d.6b,
1d.2a.3c.4a.5d.6c,1d.2a.3c.4a.5d.6d,1d.2a.3c.4a.5d.6e,1d.2a.3c.4a.5d.6f,1d.2a.3c.4a.5e.6a,
1d.2a.3c.4a.5e.6b,1d.2a.3c.4a.5e.6c,1d.2a.3c.4a.5e.6d,1d.2a.3c.4a.5e.6e,1d.2a.3c.4a.5e.6f,
1d.2a.3c.4a.5f.6a,1d.2a.3c.4a.5f.6b,1d.2a.3c.4a.5f.6c,1d.2a.3c.4a.5f.6d,1d.2a.3c.4a.5f.6e,
1d.2a.3c.4a.5f.6f,1d.2a.3c.4b.5a.6a,1d.2a.3c.4b.5a.6b,1d.2a.3c.4b.5a.6c,1d.2a.3c.4b.5a.6d,
1d.2a.3c.4b.5a.6e,1d.2a.3c.4b.5a.6f,1d.2a.3c.4b.5b.6a,1d.2a.3c.4b.5b.6b,1d.2a.3c.4b.5b.6c,
1d.2a.3c.4b.5b.6d,1d.2a.3c.4b.5b.6e,1d.2a.3c.4b.5b.6f,1d.2a.3c.4b.5c.6a,1d.2a.3c.4b.5c.6b,
1d.2a.3c.4b.5c.6c,1d.2a.3c.4b.5c.6d,1d.2a.3c.4b.5c.6e,1d.2a.3c.4b.5c.6f,1d.2a.3c.4b.5d.6a,
1d.2a.3c.4b.5d.6b,1d.2a.3c.4b.5d.6c,1d.2a.3c.4b.5d.6d,1d.2a.3c.4b.5d.6e,1d.2a.3c.4b.5d.6f,
1d.2a.3c.4b.5e.6a,1d.2a.3c.4b.5e.6b,1d.2a.3c.4b.5e.6c,1d.2a.3c.4b.5e.6d,1d.2a.3c.4b.5e.6e,
1d.2a.3c.4b.5e.6f,1d.2a.3c.4b.5f.6a,1d.2a.3c.4b.5f.6b,1d.2a.3c.4b.5f.6c,1d.2a.3c.4b.5f.6d,
1d.2a.3c.4b.5f.6e,1d.2a.3c.4b.5f.6f,1d.2a.3c.4c.5a.6a,1d.2a.3c.4c.5a.6b,1d.2a.3c.4c.5a.6c,
1d.2a.3c.4c.5a.6d,1d.2a.3c.4c.5a.6e,1d.2a.3c.4c.5a.6f,1d.2a.3c.4c.5b.6a,1d.2a.3c.4c.5b.6b,
1d.2a.3c.4c.5b.6c,1d.2a.3c.4c.5b.6d,1d.2a.3c.4c.5b.6e,1d.2a.3c.4c.5b.6f,1d.2a.3c.4c.5c.6a,
1d.2a.3c.4c.5c.6b,1d.2a.3c.4c.5c.6c,1d.2a.3c.4c.5c.6d,1d.2a.3c.4c.5c.6e,1d.2a.3c.4c.5c.6f,
1d.2a.3c.4c.5d.6a,1d.2a.3c.4c.5d.6b,1d.2a.3c.4c.5d.6c,1d.2a.3c.4c.5d.6d,1d.2a.3c.4c.5d.6e,
1d.2a.3c.4c.5d.6f,1d.2a.3c.4c.5e.6a,1d.2a.3c.4c.5e.6b,1d.2a.3c.4c.5e.6c,1d.2a.3c.4c.5e.6d,
1d.2a.3c.4c.5e.6e,1d.2a.3c.4c.5e.6f,1d.2a.3c.4c.5f.6a,1d.2a.3c.4c.5f.6b,1d.2a.3c.4c.5f.6c,
1d.2a.3c.4c.5f.6d,1d.2a.3c.4c.5f.6e,1d.2a.3c.4c.5f.6f,1d.2a.3c.4d.5a.6a,1d.2a.3c.4d.5a.6b,
1d.2a.3c.4d.5a.6c,1d.2a.3c.4d.5a.6d,1d.2a.3c.4d.5a.6e,1d.2a.3c.4d.5a.6f,1d.2a.3c.4d.5b.6a,
1d.2a.3c.4d.5b.6b,1d.2a.3c.4d.5b.6c,1d.2a.3c.4d.5b.6d,1d.2a.3c.4d.5b.6e,1d.2a.3c.4d.5b.6f,
1d.2a.3c.4d.5c.6a,1d.2a.3c.4d.5c.6b,1d.2a.3c.4d.5c.6c,1d.2a.3c.4d.5c.6d,1d.2a.3c.4d.5c.6e,
1d.2a.3c.4d.5c.6f,1d.2a.3c.4d.5d.6a,1d.2a.3c.4d.5d.6b,1d.2a.3c.4d.5d.6c,1d.2a.3c.4d.5d.6d,
1d.2a.3c.4d.5d.6e,1d.2a.3c.4d.5d.6f,1d.2a.3c.4d.5e.6a,1d.2a.3c.4d.5e.6b,1d.2a.3c.4d.5e.6c,
1d.2a.3c.4d.5e.6d,1d.2a.3c.4d.5e.6e,1d.2a.3c.4d.5e.6f,1d.2a.3c.4d.5f.6a,1d.2a.3c.4d.5f.6b,
1d.2a.3c.4d.5f.6c,1d.2a.3c.4d.5f.6d,1d.2a.3c.4d.5f.6e,1d.2a.3c.4d.5f.6f,1d.2a.3c.4e.5a.6a,
1d.2a.3c.4e.5a.6b,1d.2a.3c.4e.5a.6c,1d.2a.3c.4e.5a.6d,1d.2a.3c.4e.5a.6e,1d.2a.3c.4e.5a.6f,
1d.2a.3c.4e.5b.6a,1d.2a.3c.4e.5b.6b,1d.2a.3c.4e.5b.6c,1d.2a.3c.4e.5b.6d,1d.2a.3c.4e.5b.6e,
1d.2a.3c.4e.5b.6f,1d.2a.3c.4e.5c.6a,1d.2a.3c.4e.5c.6b,1d.2a.3c.4e.5c.6c,1d.2a.3c.4e.5c.6d,
1d.2a.3c.4e.5c.6e,1d.2a.3c.4e.5c.6f,1d.2a.3c.4e.5d.6a,1d.2a.3c.4e.5d.6b,1d.2a.3c.4e.5d.6c,
1d.2a.3c.4e.5d.6d,1d.2a.3c.4e.5d.6e,1d.2a.3c.4e.5d.6f,1d.2a.3c.4e.5e.6a,1d.2a.3c.4e.5e.6b,
1d.2a.3c.4e.5e.6c,1d.2a.3c.4e.5e.6d,1d.2a.3c.4e.5e.6e,1d.2a.3c.4e.5e.6f,1d.2a.3c.4e.5f.6a,
1d.2a.3c.4e.5f.6b,1d.2a.3c.4e.5f.6c,1d.2a.3c.4e.5f.6d,1d.2a.3c.4e.5f.6e,1d.2a.3c.4e.5f.6f,
1d.2a.3c.4f.5a.6a,1d.2a.3c.4f.5a.6b,1d.2a.3c.4f.5a.6c,1d.2a.3c.4f.5a.6d,1d.2a.3c.4f.5a.6e,
1d.2a.3c.4f.5a.6f,1d.2a.3c.4f.5b.6a,1d.2a.3c.4f.5b.6b,1d.2a.3c.4f.5b.6c,1d.2a.3c.4f.5b.6d,
1d.2a.3c.4f.5b.6e,1d.2a.3c.4f.5b.6f,1d.2a.3c.4f.5c.6a,1d.2a.3c.4f.5c.6b,1d.2a.3c.4f.5c.6c,
1d.2a.3c.4f.5c.6d,1d.2a.3c.4f.5c.6e,1d.2a.3c.4f.5c.6f,1d.2a.3c.4f.5d.6a,1d.2a.3c.4f.5d.6b,
1d.2a.3c.4f.5d.6c,1d.2a.3c.4f.5d.6d,1d.2a.3c.4f.5d.6e,1d.2a.3c.4f.5d.6f,1d.2a.3c.4f.5e.6a,
1d.2a.3c.4f.5e.6b,1d.2a.3c.4f.5e.6c,1d.2a.3c.4f.5e.6d,1d.2a.3c.4f.5e.6e,1d.2a.3c.4f.5e.6f,
1d.2a.3c.4f.5f.6a,1d.2a.3c.4f.5f.6b,1d.2a.3c.4f.5f.6c,1d.2a.3c.4f.5f.6d,1d.2a.3c.4f.5f.6e,
1d.2a.3c.4f.5f.6f,1d.2a.3d.4a.5a.6a,1d.2a.3d.4a.5a.6b,1d.2a.3d.4a.5a.6c,1d.2a.3d.4a.5a.6d,
1d.2a.3d.4a.5a.6e,1d.2a.3d.4a.5a.6f,1d.2a.3d.4a.5b.6a,1d.2a.3d.4a.5b.6b,1d.2a.3d.4a.5b.6c,
1d.2a.3d.4a.5b.6d,1d.2a.3d.4a.5b.6e,1d.2a.3d.4a.5b.6f,1d.2a.3d.4a.5c.6a,1d.2a.3d.4a.5c.6b,
1d.2a.3d.4a.5c.6c,1d.2a.3d.4a.5c.6d,1d.2a.3d.4a.5c.6e,1d.2a.3d.4a.5c.6f,1d.2a.3d.4a.5d.6a,
1d.2a.3d.4a.5d.6b, 1d.2a.3d.4a.5d.6c, 1d.2a.3d.4a.5d.6d, 1d.2a.3d.4a.5d.6e,
1d.2a.3d.4a.5d.6f,1d.2a.3d.4a.5e.6a,1d.2a.3d.4a.5e.6b,1d.2a.3d.4a.5e.6c,1d.2a.3d.4a.5e.6d,
1d.2a.3d.4a.5e.6e,1d.2a.3d.4a.5e.6f,1d.2a.3d.4a.5f.6a,1d.2a.3d.4a.5f.6b,1d.2a.3d.4a.5f.6c,
1d.2a.3d.4a.5f.6d,1d.2a.3d.4a.5f.6e,1d.2a.3d.4a.5f.6f,1d.2a.3d.4b.5a.6a,1d.2a.3d.4b.5a.6b,
1d.2a.3d.4b.5a.6c,1d.2a.3d.4b.5a.6d,1d.2a.3d.4b.5a.6e,1d.2a.3d.4b.5a.6f,1d.2a.3d.4b.5b.6a,
1d.2a.3d.4b.5b.6b, 1d.2a.3d.4b.5b.6c, 1d.2a.3d.4b.5b.6d, 1d.2a.3d.4b.5b.6e,
1d.2a.3d.4b.5b.6f,1d.2a.3d.4b.5c.6a,1d.2a.3d.4b.5c.6b,1d.2a.3d.4b.5c.6c,1d.2a.3d.4b.5c.6d,
1d.2a.3d.4b.5c.6e, 1d.2a.3d.4b.5c.6f, 1d.2a.3d.4b.5d.6a, 1d.2a.3d.4b.5d.6b,
1d.2a.3d.4b.5d.6c, 1d.2a.3d.4b.5d.6d, 1d.2a.3d.4b.5d.6e, 1d.2a.3d.4b.5d.6f,
1d.2a.3d.4b.5e.6a, 1d.2a.3d.4b.5e.6b, 1d.2a.3d.4b.5e.6c, 1d.2a.3d.4b.5e.6d,
1d.2a.3d.4b.5e.6e,1d.2a.3d.4b.5e.6f,1d.2a.3d.4b.5f.6a,1d.2a.3d.4b.5f.6b,1d.2a.3d.4b.5f.6c,
1d.2a.3d.4b.5f.6d,1d.2a.3d.4b.5f.6e,1d.2a.3d.4b.5f.6f,1d.2a.3d.4c.5a.6a,1d.2a.3d.4c.5a.6b,
1d.2a.3d.4c.5a.6c,1d.2a.3d.4c.5a.6d,1d.2a.3d.4c.5a.6e,1d.2a.3d.4c.5a.6f,1d.2a.3d.4c.5b.6a,
1d.2a.3d.4c.5b.6b,1d.2a.3d.4c.5b.6c,1d.2a.3d.4c.5b.6d,1d.2a.3d.4c.5b.6e,1d.2a.3d.4c.5b.6f,
1d.2a.3d.4c.5c.6a,1d.2a.3d.4c.5c.6b,1d.2a.3d.4c.5c.6c,1d.2a.3d.4c.5c.6d,1d.2a.3d.4c.5c.6e,
1d.2a.3d.4c.5c.6f,1d.2a.3d.4c.5d.6a,1d.2a.3d.4c.5d.6b,1d.2a.3d.4c.5d.6c,1d.2a.3d.4c.5d.6d,
1d.2a.3d.4c.5d.6e,1d.2a.3d.4c.5d.6f,1d.2a.3d.4c.5e.6a,1d.2a.3d.4c.5e.6b,1d.2a.3d.4c.5e.6c,
1d.2a.3d.4c.5e.6d,1d.2a.3d.4c.5e.6e,1d.2a.3d.4c.5e.6f,1d.2a.3d.4c.5f.6a,1d.2a.3d.4c.5f.6b,
1d.2a.3d.4c.5f.6c,1d.2a.3d.4c.5f.6d,1d.2a.3d.4c.5f.6e,1d.2a.3d.4c.5f.6f,1d.2a.3d.4d.5a.6a,
1d.2a.3d.4d.5a.6b, 1d.2a.3d.4d.5a.6c, 1d.2a.3d.4d.5a.6d, 1d.2a.3d.4d.5a.6e,
1d.2a.3d.4d.5a.6f, 1d.2a.3d.4d.5b.6a, 1d.2a.3d.4d.5b.6b, 1d.2a.3d.4d.5b.6c,
1d.2a.3d.4d.5b.6d, 1d.2a.3d.4d.5b.6e, 1d.2a.3d.4d.5b.6f, 1d.2a.3d.4d.5c.6a,
1d.2a.3d.4d.5c.6b,1d.2a.3d.4d.5c.6c,1d.2a.3d.4d.5c.6d,1d.2a.3d.4d.5c.6e,1d.2a.3d.4d.5c.6f,
1d.2a.3d.4d.5d.6a, 1d.2a.3d.4d.5d.6b, 1d.2a.3d.4d.5d.6c, 1d.2a.3d.4d.5d.6d,
1d.2a.3d.4d.5d.6e, 1d.2a.3d.4d.5d.6f, 1d.2a.3d.4d.5e.6a, 1d.2a.3d.4d.5e.6b,
1d.2a.3d.4d.5e.6c,1d.2a.3d.4d.5e.6d,1d.2a.3d.4d.5e.6e,1d.2a.3d.4d.5e.6f,1d.2a.3d.4d.5f.6a,
1d.2a.3d.4d.5f.6b,1d.2a.3d.4d.5f.6c,1d.2a.3d.4d.5f.6d,1d.2a.3d.4d.5f.6e,1d.2a.3d.4d.5f.6f,
1d.2a.3d.4e.5a.6a,1d.2a.3d.4e.5a.6b,1d.2a.3d.4e.5a.6c,1d.2a.3d.4e.5a.6d,1d.2a.3d.4e.5a.6e,
1d.2a.3d.4e.5a.6f,1d.2a.3d.4e.5b.6a,1d.2a.3d.4e.5b.6b,1d.2a.3d.4e.5b.6c,1d.2a.3d.4e.5b.6d,
1d.2a.3d.4e.5b.6e,1d.2a.3d.4e.5b.6f,1d.2a.3d.4e.5c.6a,1d.2a.3d.4e.5c.6b,1d.2a.3d.4e.5c.6c,
1d.2a.3d.4e.5c.6d,1d.2a.3d.4e.5v.6e,1d.2a.3d.4e.5c.6f,1d.2a.3d.4e.5d.6a,1d.2a.3d.4e.5d.6b,
1d.2a.3d.4e.5d.6c,1d.2a.3d.4e.5d.6d,1d.2a.3d.4e.5d.6e,1d.2a.3d.4e.5d.6f,1d.2a.3d.4e.5e.6a,
1d.2a.3d.4e.5e.6b,1d.2a.3d.4e.5e.6c,1d.2a.3d.4e.5e.6d,1d.2a.3d.4e.5e.6e,1d.2a.3d.4e.5e.6f,
1d.2a.3d.4e.5f.6a,1d.2a.3d.4e.5f.6b,1d.2a.3d.4e.5f.6c,1d.2a.3d.4e.5f.6d,1d.2a.3d.4e.5f.6e,
1d.2a.3d.4e.5f.6f,1d.2a.3d.4f.5a.6a,1d.2a.3d.4f.5a.6b,1d.2a.3d.4f.5a.6c,1d.2a.3d.4f.5a.6d,
1d.2a.3d.4f.5a.6e,1d.2a.3d.4f.5a.6f,1d.2a.3d.4f.5b.6a,1d.2a.3d.4f.5b.6b,1d.2a.3d.4f.5b.6c,
1d.2a.3d.4f.5b.6d,1d.2a.3d.4f.5b.6e,1d.2a.3d.4f.5b.6f,1d.2a.3d.4f.5c.6a,1d.2a.3d.4f.5c.6b,
1d.2a.3d.4f.5c.6c,1d.2a.3d.4f.5c.6d,1d.2a.3d.4f.5c.6e,1d.2a.3d.4f.5c.6f,1d.2a.3d.4f.5d.6a,
1d.2a.3d.4f.5d.6b,1d.2a.3d.4f.5d.6c,1d.2a.3d.4f.5d.6d,1d.2a.3d.4f.5d.6e,1d.2a.3d.4f.5d.6f,
1d.2a.3d.4f.5e.6a,1d.2a.3d.4f.5e.6b,1d.2a.3d.4f.5e.6c,1d.2a.3d.4f.5e.6d,1d.2a.3d.4f.5e.6e,
1d.2a.3d.4f.5e.6f,1d.2a.3d.4f.5f.6a,1d.2a.3d.4f.5f.6b,1d.2a.3d.4f.5f.6c,1d.2a.3d.4f.5f.6d,
1d.2a.3d.4f.5f.6e,1d.2a.3d.4f.5f.6f,1d.2a.3e.4a.5a.6a,1d.2a.3e.4a.5a.6b,1d.2a.3e.4a.5a.6c,
1d.2a.3e.4a.5a.6d,1d.2a.3e.4a.5a.6e,1d.2a.3e.4a.5a.6f,1d.2a.3e.4a.5b.6a,1d.2a.3e.4a.5b.6b,
1d.2a.3e.4a.5b.6c,1d.2a.3e.4a.5b.6d,1d.2a.3e.4a.5b.6e,1d.2a.3e.4a.5b.6f,1d.2a.3e.4a.5c.6a,
1d.2a.3e.4a.5c.6b,1d.2a.3e.4a.5c.6c,1d.2a.3e.4a.5c.6d,1d.2a.3e.4a.5c.6e,1d.2a.3e.4a.5c.6f,
1d.2a.3e.4a.5d.6a,1d.2a.3e.4a.5d.6b,1d.2a.3e.4a.5d.6c,1d.2a.3e.4a.5d.6d,1d.2a.3e.4a.5d.6e,
1d.2a.3e.4a.5d.6f,1d.2a.3e.4a.5e.6a,1d.2a.3e.4a.5e.6b,1d.2a.3e.4a.5e.6c,1d.2a.3e.4a.5e.6d,
1d.2a.3e.4a.5e.6e,1d.2a.3e.4a.5e.6f,1d.2a.3e.4a.5f.6a,1d.2a.3e.4a.5f.6b,1d.2a.3e.4a.5f.6c,
1d.2a.3e.4a.5f.6d,1d.2a.3e.4a.5f.6e,1d.2a.3e.4a.5f.6f,1d.2a.3e.4b.5a.6a,1d.2a.3e.4b.5a.6b,
1d.2a.3e.4b.5a.6c,1d.2a.3e.4b.5a.6d,1d.2a.3e.4b.5a.6e,1d.2a.3e.4b.5a.6f,1d.2a.3e.4b.5b.6a,
1d.2a.3e.4b.5b.6b,1d.2a.3e.4b.5b.6c,1d.2a.3e.4b.5b.6d,1d.2a.3e.4b.5b.6e,1d.2a.3e.4b.5b.6f,
1d.2a.3e.4b.5c.6a,1d.2a.3e.4b.5c.6b,1d.2a.3e.4b.5c.6c,1d.2a.3e.4b.5c.6d,1d.2a.3e.4b.5c.6e,
1d.2a.3e.4b.5c.6f,1d.2a.3e.4b.5d.6a,1d.2a.3e.4b.5d.6b,1d.2a.3e.4b.5d.6c,1d.2a.3e.4b.5d.6d,
1d.2a.3e.4b.5d.6e,1d.2a.3e.4b.5d.6f,1d.2a.3e.4b.5e.6a,1d.2a.3e.4b.5e.6b,1d.2a.3e.4b.5e.6c,
1d.2a.3e.4b.5e.6d,1d.2a.3e.4b.5e.6e,1d.2a.3e.4b.5e.6f,1d.2a.3e.4b.5f.6a,1d.2a.3e.4b.5f.6b,
1d.2a.3e.4b.5f.6c,1d.2a.3e.4b.5f.6d,1d.2a.3e.4b.5f.6e,1d.2a.3e.4b.5f.6f,1d.2a.3e.4c.5a.6a,
1d.2a.3e.4c.5a.6b,1d.2a.3e.4c.5a.6c,1d.2a.3e.4c.5a.6d,1d.2a.3e.4c.5a.6e,1d.2a.3e.4c.5a.6f,
1d.2a.3e.4c.5b.6a,1d.2a.3e.4c.5b.6b,1d.2a.3e.4c.5b.6c,1d.2a.3e.4c.5b.6d,1d.2a.3e.4c.5b.6e,
1d.2a.3e.4c.5b.6f,1d.2a.3e.4c.5c.6a,1d.2a.3e.4c.5c.6b,1d.2a.3e.4c.5c.6c,1d.2a.3e.4c.5c.6d,
1d.2a.3e.4c.5c.6e,1d.2a.3e.4c.5c.6f,1d.2a.3e.4c.5d.6a,1d.2a.3e.4c.5d.6b,1d.2a.3e.4c.5d.6c,
1d.2a.3e.4c.5d.6d,1d.2a.3e.4c.5d.6e,1d.2a.3e.4c.5d.6f,1d.2a.3e.4c.5e.6a,1d.2a.3e.4c.5e.6b,
1d.2a.3e.4c.5e.6c,1d.2a.3e.4c.5e.6d,1d.2a.3e.4c.5e.6e,1d.2a.3e.4c.5e.6f,1d.2a.3e.4c.5f.6a,
1d.2a.3e.4c.5f.6b,1d.2a.3e.4c.5f.6c,1d.2a.3e.4c.5f.6d,1d.2a.3e.4c.5f.6e,1d.2a.3e.4c.5f.6f,
1d.2a.3e.4d.5a.6a,1d.2a.3e.4d.5a.6b,1d.2a.3e.4d.5a.6c,1d.2a.3e.4d.5a.6d,1d.2a.3e.4d.5a.6e,
1d.2a.3e.4d.5a.6f,1d.2a.3e.4d.5b.6a,1d.2a.3e.4d.5b.6b,1d.2a.3e.4d.5b.6c,1d.2a.3e.4d.5b.6d,
1d.2a.3e.4d.5b.6e,1d.2a.3e.4d.5b.6f,1d.2a.3e.4d.5c.6a,1d.2a.3e.4d.5c.6b,1d.2a.3e.4d.5c.6c,
1d.2a.3e.4d.5c.6d,1d.2a.3e.4d.5c.6e,1d.2a.3e.4d.5c.6f,1d.2a.3e.4d.5d.6a,1d.2a.3e.4d.5d.6b,
1d.2a.3e.4d.5d.6c,1d.2a.3e.4d.5d.6d,1d.2a.3e.4d.5d.6e,1d.2a.3e.4d.5d.6f,1d.2a.3e.4d.5e.6a,
1d.2a.3e.4d.5e.6b,1d.2a.3e.4d.5e.6c,1d.2a.3e.4d.5e.6d,1d.2a.3e.4d.5e.6e,1d.2a.3e.4d.5e.6f,
1d.2a.3e.4d.5f.6a,1d.2a.3e.4d.5f.6b,1d.2a.3e.4d.5f.6c,1d.2a.3e.4d.5f.6d,1d.2a.3e.4d.5f.6e,
1d.2a.3e.4d.5f.6f,1d.2a.3e.4e.5a.6a,1d.2a.3e.4e.5a.6b,1d.2a.3e.4e.5a.6c,1d.2a.3e.4e.5a.6d,
1d.2a.3e.4e.5a.6e,1d.2a.3e.4e.5a.6f,1d.2a.3e.4e.5b.6a,1d.2a.3e.4e.5b.6b,1d.2a.3e.4e.5b.6c,
1d.2a.3e.4e.5b.6d,1d.2a.3e.4e.5b.6e,1d.2a.3e.4e.5b.6f,1d.2a.3e.4e.5c.6a,1d.2a.3e.4e.5c.6b,
1d.2a.3e.4e.5c.6c,1d.2a.3e.4e.5c.6d,1d.2a.3e.4e.5c.6e,1d.2a.3e.4e.5c.6f,1d.2a.3e.4e.5d.6a,
1d.2a.3e.4e.5d.6b,1d.2a.3e.4e.5d.6c,1d.2a.3e.4e.5d.6d,1d.2a.3e.4e.5d.6e,1d.2a.3e.4e.5d.6f,
1d.2a.3e.4e.5e.6a,1d.2a.3e.4e.5e.6b,1d.2a.3e.4e.5e.6c,1d.2a.3e.4e.5e.6d,1d.2a.3e.4e.5e.6e,
1d.2a.3e.4e.5e.6f,1d.2a.3e.4e.5f.6a,1d.2a.3e.4e.5f.6b,1d.2a.3e.4e.5f.6c,1d.2a.3e.4e.5f.6d,
1d.2a.3e.4e.5f.6e,1d.2a.3e.4e.5f.6f,1d.2a.3e.4f.5a.6a,1d.2a.3e.4f.5a.6b,1d.2a.3e.4f.5a.6c,
1d.2a.3e.4f.5a.6d,1d.2a.3e.4f.5a.6e,1d.2a.3e.4f.5a.6f,1d.2a.3e.4f.5b.6a,1d.2a.3e.4f.5b.6b,
1d.2a.3e.4f.5b.6c,1d.2a.3e.4f.5b.6d,1d.2a.3e.4f.5b.6e,1d.2a.3e.4f.5b.6f,1d.2a.3e.4f.5c.6a,
1d.2a.3e.4f.5c.6b,1d.2a.3e.4f.5c.6c,1d.2a.3e.4f.5c.6d,1d.2a.3e.4f.5c.6e,1d.2a.3e.4f.5c.6f,
1d.2a.3e.4f.5d.6a,1d.2a.3e.4f.5d.6b,1d.2a.3e.4f.5d.6c,1d.2a.3e.4f.5d.6d,1d.2a.3e.4f.5d.6e,
1d.2a.3e.4f.5d.6f,1d.2a.3e.4f.5e.6a,1d.2a.3e.4f.5e.6b,1d.2a.3e.4f.5e.6c,1d.2a.3e.4f.5e.6d,
1d.2a.3e.4f.5e.6e,1d.2a.3e.4f.5e.6f,1d.2a.3e.4f.5f.6a,1d.2a.3e.4f.5f.6b,1d.2a.3e.4f.5f.6c,
1d.2a.3e.4f.5f.6d,1d.2a.3e.4f.5f.6e,1d.2a.3e.4f.5f.6f,1d.2a.3f.4a.5a.6a,1d.2a.3f.4a.5a.6b,
1d.2a.3f.4a.5a.6c,1d.2a.3f.4a.5a.6d,1d.2a.3f.4a.5a.6e,1d.2a.3f.4a.5a.6f,1d.2a.3f.4a.5b.6a,
1d.2a.3f.4a.5b.6b,1d.2a.3f.4a.5b.6c,1d.2a.3f.4a.5b.6d,1d.2a.3f.4a.5b.6e,1d.2a.3f.4a.5b.6f,
1d.2a.3f.4a.5c.6a,1d.2a.3f.4a.5c.6b,1d.2a.3f.4a.5c.6c,1d.2a.3f.4a.5c.6d,1d.2a.3f.4a.5c.6e,
1d.2a.3f.4a.5c.6f,1d.2a.3f.4a.5d.6a,1d.2a.3f.4a.5d.6b,1d.2a.3f.4a.5d.6c,1d.2a.3f.4a.5d.6d,
1d.2a.3f.4a.5d.6e,1d.2a.3f.4a.5d.6f,1d.2a.3f.4a.5e.6a,1d.2a.3f.4a.5e.6b,1d.2a.3f.4a.5e.6c,
1d.2a.3f.4a.5e.6d,1d.2a.3f.4a.5e.6e,1d.2a.3f.4a.5e.6f,1d.2a.3f.4a.5f.6a,1d.2a.3f.4a.5f.6b,
1d.2a.3f.4a.5f.6c,1d.2a.3f.4a.5f.6d,1d.2a.3f.4a.5f.6e,1d.2a.3f.4a.5f.6f,1d.2a.3f.4b.5a.6a,
1d.2a.3f.4b.5a.6b,1d.2a.3f.4b.5a.6c,1d.2a.3f.4b.5a.6d,1d.2a.3f.4b.5a.6e,1d.2a.3f.4b.5a.6f,
1d.2a.3f.4b.5b.6a,1d.2a.3f.4b.5b.6b,1d.2a.3f.4b.5b.6c,1d.2a.3f.4b.5b.6d,1d.2a.3f.4b.5b.6e,
1d.2a.3f.4b.5b.6f,1d.2a.3f.4b.5c.6a,1d.2a.3f.4b.5c.6b,1d.2a.3f.4b.5c.6c,1d.2a.3f.4b.5c.6d,
1d.2a.3f.4b.5c.6e,1d.2a.3f.4b.5c.6f,1d.2a.3f.4b.5d.6a,1d.2a.3f.4b.5d.6b,1d.2a.3f.4b.5d.6c,
1d.2a.3f.4b.5d.6d,1d.2a.3f.4b.5d.6e,1d.2a.3f.4b.5d.6f,1d.2a.3f.4b.5e.6a,1d.2a.3f.4b.5e.6b,
1d.2a.3f.4b.5e.6c,1d.2a.3f.4b.5e.6d,1d.2a.3f.4b.5e.6e,1d.2a.3f.4b.5e.6f,1d.2a.3f.4b.5f.6a,
1d.2a.3f.4b.5f.6b,1d.2a.3f.4b.5f.6c,1d.2a.3f.4b.5f.6d,1d.2a.3f.4b.5f.6e,1d.2a.3f.4b.5f.6f,
1d.2a.3f.4c.5a.6a,1d.2a.3f.4c.5a.6b,1d.2a.3f.4c.5a.6c,1d.2a.3f.4c.5a.6d,1d.2a.3f.4c.5a.6e,
1d.2a.3f.4c.5a.6f,1d.2a.3f.4c.5b.6a,1d.2a.3f.4c.5b.6b,1d.2a.3f.4c.5b.6c,1d.2a.3f.4c.5b.6d,
1d.2a.3f.4c.5b.6e,1d.2a.3f.4c.5b.6f,1d.2a.3f.4c.5c.6a,1d.2a.3f.4c.5c.6b,1d.2a.3f.4c.5c.6c,
1d.2a.3f.4c.5c.6d,1d.2a.3f.4c.5c.6e,1d.2a.3f.4c.5c.6f,1d.2a.3f.4c.5d.6a,1d.2a.3f.4c.5d.6b,
1d.2a.3f.4c.5d.6c,1d.2a.3f.4c.5d.6d,1d.2a.3f.4c.5d.6e,1d.2a.3f.4c.5d.6f,1d.2a.3f.4c.5e.6a,
1d.2a.3f.4c.5e.6b,1d.2a.3f.4c.5e.6c,1d.2a.3f.4c.5e.6d,1d.2a.3f.4c.5e.6e,1d.2a.3f.4c.5e.6f,
1d.2a.3f.4c.5f.6a,1d.2a.3f.4c.5f.6b,1d.2a.3f.4c.5f.6c,1d.2a.3f.4c.5f.6d,1d.2a.3f.4c.5f.6e,
1d.2a.3f.4c.5f.6f,1d.2a.3f.4d.5a.6a,1d.2a.3f.4d.5a.6b,1d.2a.3f.4d.5a.6c,1d.2a.3f.4d.5a.6d,
1d.2a.3f.4d.5a.6e,1d.2a.3f.4d.5a.6f,1d.2a.3f.4d.5b.6a,1d.2a.3f.4d.5b.6b,1d.2a.3f.4d.5b.6c,
1d.2a.3f.4d.5b.6d,1d.2a.3f.4d.5b.6e,1d.2a.3f.4d.5b.6f,1d.2a.3f.4d.5c.6a,1d.2a.3f.4d.5c.6b,
1d.2a.3f.4d.5c.6c,1d.2a.3f.4d.5c.6d,1d.2a.3f.4d.5c.6e,1d.2a.3f.4d.5c.6f,1d.2a.3f.4d.5d.6a,
1d.2a.3f.4d.5d.6b,1d.2a.3f.4d.5d.6c,1d.2a.3f.4d.5d.6d,1d.2a.3f.4d.5d.6e,1d.2a.3f.4d.5d.6f,
1d.2a.3f.4d.5e.6a,1d.2a.3f.4d.5e.6b,1d.2a.3f.4d.5e.6c,1d.2a.3f.4d.5e.6d,1d.2a.3f.4d.5e.6e,
1d.2a.3f.4d.5e.6f,1d.2a.3f.4d.5f.6a,1d.2a.3f.4d.5f.6b,1d.2a.3f.4d.5f.6c,1d.2a.3f.4d.5f.6d,
1d.2a.3f.4d.5f.6e,1d.2a.3f.4d.5f.6f,1d.2a.3f.4e.5a.6a,1d.2a.3f.4e.5a.6b,1d.2a.3f.4e.5a.6c,
1d.2a.3f.4e.5a.6d,1d.2a.3f.4e.5a.6e,1d.2a.3f.4e.5a.6f,1d.2a.3f.4e.5b.6a,1d.2a.3f.4e.5b.6b,
1d.2a.3f.4e.5b.6c,1d.2a.3f.4e.5b.6d,1d.2a.3f.4e.5b.6e,1d.2a.3f.4e.5b.6f,1d.2a.3f.4e.5c.6a,
1d.2a.3f.4e.5c.6b,1d.2a.3f.4e.5c.6c,1d.2a.3f.4e.5c.6d,1d.2a.3f.4e.5c.6e,1d.2a.3f.4e.5c.6f,
1d.2a.3f.4e.5d.6a,1d.2a.3f.4e.5d.6b,1d.2a.3f.4e.5d.6c,1d.2a.3f.4e.5d.6d,1d.2a.3f.4e.5d.6e,
1d.2a.3f.4e.5d.6f,1d.2a.3f.4e.5e.6a,1d.2a.3f.4e.5e.6b,1d.2a.3f.4e.5e.6c,1d.2a.3f.4e.5e.6d,
1d.2a.3f.4e.5e.6e,1d.2a.3f.4e.5e.6f,1d.2a.3f.4e.5f.6a,1d.2a.3f.4e.5f.6b,1d.2a.3f.4e.5f.6c,
1d.2a.3f.4e.5f.6d,1d.2a.3f.4e.5f.6e,1d.2a.3f.4e.5f.6f,1d.2a.3f.4f.5a.6a,1d.2a.3f.4f.5a.6b,
1d.2a.3f.4f.5a.6c,1d.2a.3f.4f.5a.6d,1d.2a.3f.4f.5a.6e,1d.2a.3f.4f.5a.6f,1d.2a.3f.4f.5b.6a,
1d.2a.3f.4f.5b.6b,1d.2a.3f.4f.5b.6c,1d.2a.3f.4f.5b.6d,1d.2a.3f.4f.5b.6e,1d.2a.3f.4f.5b.6f,
1d.2a.3f.4f.5c.6a,1d.2a.3f.4f.5c.6b,1d.2a.3f.4f.5c.6c,1d.2a.3f.4f.5c.6d,1d.2a.3f.4f.5c.6e,
1d.2a.3f.4f.5c.6f,1d.2a.3f.4f.5d.6a,1d.2a.3f.4f.5d.6b,1d.2a.3f.4f.5d.6c,1d.2a.3f.4f.5d.6d,
1d.2a.3f.4f.5d.6e,1d.2a.3f.4f.5d.6f,1d.2a.3f.4f.5e.6a,1d.2a.3f.4f.5e.6b,1d.2a.3f.4f.5e.6c,
1d.2a.3f.4f.5e.6d,1d.2a.3f.4f.5e.6e,1d.2a.3f.4f.5e.6f,1d.2a.3f.4f.5f.6a,1d.2a.3f.4f.5f.6b,
1d.2a.3f.4f.5f.6c,1d.2a.3f.4f.5f.6d,1d.2a.3f.4f.5f.6e,1d.2a.3f.4f.5f.6f,1d.2b.3a.4a.5a.6a,
1d.2b.3a.4a.5a.6b,1d.2b.3a.4a.5a.6c,1d.2b.3a.4a.5a.6d,1d.2b.3a.4a.5a.6e,1d.2b.3a.4a.5a.6f,
1d.2b.3a.4a.5b.6a,1d.2b.3a.4a.5b.6b,1d.2b.3a.4a.5b.6c,1d.2b.3a.4a.5b.6d,1d.2b.3a.4a.5b.6e,
1d.2b.3a.4a.5b.6f,1d.2b.3a.4a.5c.6a,1d.2b.3a.4a.5c.6b,1d.2b.3a.4a.5c.6c,1d.2b.3a.4a.5c.6d,
1d.2b.3a.4a.5c.6e,1d.2b.3a.4a.5c.6f,1d.2b.3a.4a.5d.6a,1d.2b.3a.4a.5d.6b,1d.2b.3a.4a.5d.6c,
1d.2b.3a.4a.5d.6d,1d.2b.3a.4a.5d.6e,1d.2b.3a.4a.5d.6f,1d.2b.3a.4a.5e.6a,1d.2b.3a.4a.5e.6b,
1d.2b.3a.4a.5e.6c,1d.2b.3a.4a.5e.6d,1d.2b.3a.4a.5e.6e,1d.2b.3a.4a.5e.6f,1d.2b.3a.4a.5f.6a,
1d.2b.3a.4a.5f.6b,1d.2b.3a.4a.5f.6c,1d.2b.3a.4a.5f.6d,1d.2b.3a.4a.5f.6e,1d.2b.3a.4a.5f.6f,
1d.2b.3a.4b.5a.6a,1d.2b.3a.4b.5a.6b,1d.2b.3a.4b.5a.6c,1d.2b.3a.4b.5a.6d,1d.2b.3a.4b.5a.6e,
1d.2b.3a.4b.5a.6f,1d.2b.3a.4b.5b.6a,1d.2b.3a.4b.5b.6b,1d.2b.3a.4b.5b.6c,1d.2b.3a.4b.5b.6d,
1d.2b.3a.4b.5b.6e,1d.2b.3a.4b.5b.6f,1d.2b.3a.4b.5c.6a,1d.2b.3a.4b.5c.6b,1d.2b.3a.4b.5c.6c,
1d.2b.3a.4b.5c.6d,1d.2b.3a.4b.5c.6e,1d.2b.3a.4b.5c.6f,1d.2b.3a.4b.5d.6a,1d.2b.3a.4b.5d.6b,
1d.2b.3a.4b.5d.6c, 1d.2b.3a.4b.5d.6d, 1d.2b.3a.4b.5d.6e, 1d.2b.3a.4b.5d.6f,
1d.2b.3a.4b.5e.6a,1d.2b.3a.4b.5e.6b,1d.2b.3a.4b.5e.6c,1d.2b.3a.4b.5e.6d,1d.2b.3a.4b.5e.6e,
1d.2b.3a.4b.5e.6f,1d.2b.3a.4b.5f.6a,1d.2b.3a.4b.5f.6b,1d.2b.3a.4b.5f.6c,1d.2b.3a.4b.5f.6d,
1d.2b.3a.4b.5f.6e,1d.2b.3a.4b.5f.6f,1d.2b.3a.4c.5a.6a,1d.2b.3a.4c.5a.6b,1d.2b.3a.4c.5a.6c,
1d.2b.3a.4c.5a.6d,1d.2b.3a.4c.5a.6e,1d.2b.3a.4c.5a.6f,1d.2b.3a.4c.5b.6a,1d.2b.3a.4c.5b.6b,
1d.2b.3a.4c.5b.6c,1d.2b.3a.4c.5b.6d,1d.2b.3a.4c.5b.6e,1d.2b.3a.4c.5b.6f,1d.2b.3a.4c.5c.6a,
1d.2b.3a.4c.5c.6b,1d.2b.3a.4c.5c.6c,1d.2b.3a.4c.5c.6d,1d.2b.3a.4c.5c.6e,1d.2b.3a.4c.5c.6f,
1d.2b.3a.4c.5d.6a,1d.2b.3a.4c.5d.6b,1d.2b.3a.4c.5d.6c,1d.2b.3a.4c.5d.6d,1d.2b.3a.4c.5d.6e,
1d.2b.3a.4c.5d.6f,1d.2b.3a.4c.5e.6a,1d.2b.3a.4c.5e.6b,1d.2b.3a.4c.5e.6c,1d.2b.3a.4c.5e.6d,
1d.2b.3a.4c.5e.6e,1d.2b.3a.4c.5e.6f,1d.2b.3a.4c.5f.6a,1d.2b.3a.4c.5f.6b,1d.2b.3a.4c.5f.6c,
1d.2b.3a.4c.5f.6d,1d.2b.3a.4c.5f.6e,1d.2b.3a.4c.5f.6f,1d.2b.3a.4d.5a.6a,1d.2b.3a.4d.5a.6b,
1d.2b.3a.4d.5a.6c,1d.2b.3a.4d.5a.6d,1d.2b.3a.4d.5a.6e,1d.2b.3a.4d.5a.6f,1d.2b.3a.4d.5b.6a,
1d.2b.3a.4d.5b.6b, 1d.2b.3a.4d.5b.6c, 1d.2b.3a.4d.5b.6d, 1d.2b.3a.4d.5b.6e,
1d.2b.3a.4d.5b.6f,1d.2b.3a.4d.5c.6a,1d.2b.3a.4d.5c.6b,1d.2b.3a.4d.5c.6c,1d.2b.3a.4d.5c.6d,
1d.2b.3a.4d.5c.6e, 1d.2b.3a.4d.5c.6f, 1d.2b.3a.4d.5d.6a, 1d.2b.3a.4d.5d.6b,
1d.2b.3a.4d.5d.6c, 1d.2b.3a.4d.5d.6d, 1d.2b.3a.4d.5d.6e, 1d.2b.3a.4d.5d.6f,
1d.2b.3a.4d.5e.6a, 1d.2b.3a.4d.5e.6b, 1d.2b.3a.4d.5e.6c, 1d.2b.3a.4d.5e.6d,
1d.2b.3a.4d.5e.6e,1d.2b.3a.4d.5e.6f,1d.2b.3a.4d.5f.6a,1d.2b.3a.4d.5f.6b,1d.2b.3a.4d.5f.6c,
1d.2b.3a.4d.5f.6d,1d.2b.3a.4d.5f.6e,1d.2b.3a.4d.5f.6f,1d.2b.3a.4e.5a.6a,1d.2b.3a.4e.5a.6b,
1d.2b.3a.4e.5a.6c,1d.2b.3a.4e.5a.6d,1d.2b.3a.4e.5a.6e,1d.2b.3a.4e.5a.6f,1d.2b.3a.4e.5b.6a,
1d.2b.3a.4e.5b.6b,1d.2b.3a.4e.5b.6c,1d.2b.3a.4e.5b.6d,1d.2b.3a.4e.5b.6e,1d.2b.3a.4e.5b.6f,
1d.2b.3a.4e.5c.6a,1d.2b.3a.4e.5c.6b,1d.2b.3a.4e.5c.6c,1d.2b.3a.4e.5c.6d,1d.2b.3a.4e.5c.6e,
1d.2b.3a.4e.5c.6f,1d.2b.3a.4e.5d.6a,1d.2b.3a.4e.5d.6b,1d.2b.3a.4e.5d.6c,1d.2b.3a.4e.5d.6d,
1d.2b.3a.4e.5d.6e,1d.2b.3a.4e.5d.6f,1d.2b.3a.4e.5e.6a,1d.2b.3a.4e.5e.6b,1d.2b.3a.4e.5e.6c,
1d.2b.3a.4e.5e.6d,1d.2b.3a.4e.5e.6e,1d.2b.3a.4e.5e.6f,1d.2b.3a.4e.5f.6a,1d.2b.3a.4e.5f.6b,
1d.2b.3a.4e.5f.6c,1d.2b.3a.4e.5f.6d,1d.2b.3a.4e.5f.6e,1d.2b.3a.4e.5f.6f,1d.2b.3a.4f.5a.6a,
1d.2b.3a.4f.5a.6b,1d.2b.3a.4f.5a.6c,1d.2b.3a.4f.5a.6d,1d.2b.3a.4f.5a.6e,1d.2b.3a.4f.5a.6f,
1d.2b.3a.4f.5b.6a,1d.2b.3a.4f.5b.6b,1d.2b.3a.4f.5b.6c,1d.2b.3a.4f.5b.6d,1d.2b.3a.4f.5b.6e,
1d.2b.3a.4f.5b.6f,1d.2b.3a.4f.5c.6a,1d.2b.3a.4f.5c.6b,1d.2b.3a.4f.5c.6c,1d.2b.3a.4f.5c.6d,
1d.2b.3a.4f.5c.6e,1d.2b.3a.4f.5c.6f,1d.2b.3a.4f.5d.6a,1d.2b.3a.4f.5d.6b,1d.2b.3a.4f.5d.6c,
1d.2b.3a.4f.5d.6d,1d.2b.3a.4f.5d.6e,1d.2b.3a.4f.5d.6f,1d.2b.3a.4f.5e.6a,1d.2b.3a.4f.5e.6b,
1d.2b.3a.4f.5e.6c,1d.2b.3a.4f.5e.6d,1d.2b.3a.4f.5e.6e,1d.2b.3a.4f.5e.6f,1d.2b.3a.4f.5f.6a,
1d.2b.3a.4f.5f.6b,1d.2b.3a.4f.5f.6c,1d.2b.3a.4f.5f.6d,1d.2b.3a.4f.5f.6e,1d.2b.3a.4f.5f.6f,
1d.2b.3b.4a.5a.6a,1d.2b.3b.4a.5a.6b,1d.2b.3b.4a.5a.6c,1d.2b.3b.4a.5a.6d,1d.2b.3b.4a.5a.6e,
1d.2b.3b.4a.5a.6f,1d.2b.3b.4a.5b.6a,1d.2b.3b.4a.5b.6b,1d.2b.3b.4a.5b.6c,1d.2b.3b.4a.5b.6d,
1d.2b.3b.4a.5b.6e,1d.2b.3b.4a.5b.6f,1d.2b.3b.4a.5c.6a,1d.2b.3b.4a.5c.6b,1d.2b.3b.4a.5c.6c,
1d.2b.3b.4a.5c.6d,1d.2b.3b.4a.5c.6e,1d.2b.3b.4a.5c.6f,1d.2b.3b.4a.5d.6a,1d.2b.3b.4a.5d.6b,
1d.2b.3b.4a.5d.6c, 1d.2b.3b.4a.5d.6d, 1d.2b.3b.4a.5d.6e, 1d.2b.3b.4a.5d.6f,
1d.2b.3b.4a.5e.6a,1d.2b.3b.4a.5e.6b,1d.2b.3b.4a.5e.6c,1d.2b.3b.4a.5e.6d,1d.2b.3b.4a.5e.6e,
1d.2b.3b.4a.5e.6f,1d.2b.3b.4a.5f.6a,1d.2b.3b.4a.5f.6b,1d.2b.3b.4a.5f.6c,1d.2b.3b.4a.5f.6d,
1d.2b.3b.4a.5f.6e,1d.2b.3b.4a.5f.6f,1d.2b.3b.4b.5a.6a,1d.2b.3b.4b.5a.6b,1d.2b.3b.4b.5a.6c,
1d.2b.3b.4b.5a.6d, 1d.2b.3b.4b.5a.6e, 1d.2b.3b.4b.5a.6f, 1d.2b.3b.4b.5b.6a,
1d.2b.3b.4b.5b.6b, 1d.2b.3b.4b.5b.6c, 1d.2b.3b.4b.5b.6d, 1d.2b.3b.4b.5b.6e,
1d.2b.3b.4b.5b.6f,1d.2b.3b.4b.5c.6a,1d.2b.3b.4b.5c.6b,1d.2b.3b.4b.5c.6c,1d.2b.3b.4b.5c.6d,
1d.2b.3b.4b.5c.6e, 1d.2b.3b.4b.5c.6f, 1d.2b.3b.4b.5d.6a, 1d.2b.3b.4b.5d.6b,
1d.2b.3b.4b.5d.6c, 1d.2b.3b.4b.5d.6d, 1d.2b.3b.4b.5d.6e, 1d.2b.3b.4b.5d.6f,
1d.2b.3b.4b.5e.6a, 1d.2b.3b.4b.5e.6b, 1d.2b.3b.4b.5e.6c, 1d.2b.3b.4b.5e.6d,
1d.2b.3b.4b.5e.6e,1d.2b.3b.4b.5e.6f,1d.2b.3b.4b.5f.6a,1d.2b.3b.4b.5f.6b,1d.2b.3b.4b.5f.6c,
1d.2b.3b.4b.5f.6d,1d.2b.3b.4b.5f.6e,1d.2b.3b.4b.5f.6f,1d.2b.3b.4c.5a.6a,1d.2b.3b.4c.5a.6b,
1d.2b.3b.4c.5a.6c,1d.2b.3b.4c.5a.6d,1d.2b.3b.4c.5a.6e,1d.2b.3b.4c.5a.6f,1d.2b.3b.4c.5b.6a,
1d.2b.3b.4c.5b.6b,1d.2b.3b.4c.5b.6c,1d.2b.3b.4c.5b.6d,1d.2b.3b.4c.5b.6e,1d.2b.3b.4c.5b.6f,
1d.2b.3b.4c.5c.6a,1d.2b.3b.4c.5c.6b,1d.2b.3b.4c.5c.6c,1d.2b.3b.4c.5c.6d,1d.2b.3b.4c.5c.6e,
1d.2b.3b.4c.5c.6f,1d.2b.3b.4c.5d.6a,1d.2b.3b.4c.5d.6b,1d.2b.3b.4c.5d.6c,1d.2b.3b.4c.5d.6d,
1d.2b.3b.4c.5d.6e,1d.2b.3b.4c.5d.6f,1d.2b.3b.4c.5e.6a,1d.2b.3b.4c.5e.6b,1d.2b.3b.4c.5e.6c,
1d.2b.3b.4c.5e.6d,1d.2b.3b.4c.5e.6e,1d.2b.3b.4c.5e.6f,1d.2b.3b.4c.5f.6a,1d.2b.3b.4c.5f.6b,
1d.2b.3b.4c.5f.6c,1d.2b.3b.4c.5f.6d,1d.2b.3b.4c.5f.6e,1d.2b.3b.4c.5f.6f,1d.2b.3b.4d.5a.6a,
1d.2b.3b.4d.5a.6b, 1d.2b.3b.4d.5a.6c, 1d.2b.3b.4d.5a.6d, 1d.2b.3b.4d.5a.6e,
1d.2b.3b.4d.5a.6f, 1d.2b.3b.4d.5b.6a, 1d.2b.3b.4d.5b.6b, 1d.2b.3b.4d.5b.6c,
1d.2b.3b.4d.5b.6d, 1d.2b.3b.4d.5b.6e, 1d.2b.3b.4d.5b.6f, 1d.2b.3b.4d.5c.6a,
1d.2b.3b.4d.5c.6b,1d.2b.3b.4d.5c.6c,1d.2b.3b.4d.5c.6d,1d.2b.3b.4d.5c.6e,1d.2b.3b.4d.5c.6f,
1d.2b.3b.4d.5d.6a, 1d.2b.3b.4d.5d.6b, 1d.2b.3b.4d.5d.6c, 1d.2b.3b.4d.5d.6d,
1d.2b.3b.4d.5d.6e, 1d.2b.3b.4d.5d.6f, 1d.2b.3b.4d.5e.6a, 1d.2b.3b.4d.5e.6b,
1d.2b.3b.4d.5e.6c,1d.2b.3b.4d.5e.6d,1d.2b.3b.4d.5e.6e,1d.2b.3b.4d.5e.6f,1d.2b.3b.4d.5f.6a,
1d.2b.3b.4d.5f.6b,1d.2b.3b.4d.5f.6c,1d.2b.3b.4d.5f.6d,1d.2b.3b.4d.5f.6e,1d.2b.3b.4d.5f.6f,
1d.2b.3b.4e.5a.6a,1d.2b.3b.4e.5a.6b,1d.2b.3b.4e.5a.6c,1d.2b.3b.4e.5a.6d,1d.2b.3b.4e.5a.6e,
1d.2b.3b.4e.5a.6f,1d.2b.3b.4e.5b.6a,1d.2b.3b.4e.5b.6b,1d.2b.3b.4e.5b.6c,1d.2b.3b.4e.5b.6d,
1d.2b.3b.4e.5b.6e,1d.2b.3b.4e.5b.6f,1d.2b.3b.4e.5c.6a,1d.2b.3b.4e.5c.6b,1d.2b.3b.4e.5c.6c,
1d.2b.3b.4e.5c.6d,1d.2b.3b.4e.5c.6e,1d.2b.3b.4e.5c.6f,1d.2b.3b.4e.5d.6a,1d.2b.3b.4e.5d.6b,
1d.2b.3b.4e.5d.6c,1d.2b.3b.4e.5d.6d,1d.2b.3b.4e.5d.6e,1d.2b.3b.4e.5d.6f,1d.2b.3b.4e.5e.6a,
1d.2b.3b.4e.5e.6b,1d.2b.3b.4e.5e.6c,1d.2b.3b.4e.5e.6d,1d.2b.3b.4e.5e.6e,1d.2b.3b.4e.5e.6f,
1d.2b.3b.4e.5f.6a,1d.2b.3b.4e.5f.6b,1d.2b.3b.4e.5f.6c,1d.2b.3b.4e.5f.6d,1d.2b.3b.4e.5f.6e,
1d.2b.3b.4e.5f.6f,1d.2b.3b.4f.5a.6a,1d.2b.3b.4f.5a.6b,1d.2b.3b.4f.5a.6c,1d.2b.3b.4f.5a.6d,
1d.2b.3b.4f.5a.6e,1d.2b.3b.4f.5a.6f,1d.2b.3b.4f.5b.6a,1d.2b.3b.4f.5b.6b,1d.2b.3b.4f.5b.6c,
1d.2b.3b.4f.5b.6d,1d.2b.3b.4f.5b.6e,1d.2b.3b.4f.5b.6f,1d.2b.3b.4f.5c.6a,1d.2b.3b.4f.5c.6b,
1d.2b.3b.4f.5c.6c,1d.2b.3b.4f.5c.6d,1d.2b.3b.4f.5c.6e,1d.2b.3b.4f.5c.6f,1d.2b.3b.4f.5d.6a,
1d.2b.3b.4f.5d.6b,1d.2b.3b.4f.5d.6c,1d.2b.3b.4f.5d.6d,1d.2b.3b.4f.5d.6e,1d.2b.3b.4f.5d.6f,
1d.2b.3b.4f.5e.6a,1d.2b.3b.4f.5e.6b,1d.2b.3b.4f.5e.6c,1d.2b.3b.4f.5e.6d,1d.2b.3b.4f.5e.6e,
1d.2b.3b.4f.5e.6f,1d.2b.3b.4f.5f.6a,1d.2b.3b.4f.5f.6b,1d.2b.3b.4f.5f.6c,1d.2b.3b.4f.5f.6d,
1d.2b.3b.4f.5f.6e,1d.2b.3b.4f.5f.6f,1d.2b.3c.4a.5a.6a,1d.2b.3c.4a.5a.6b,1d.2b.3c.4a.5a.6c,
1d.2b.3c.4a.5a.6d,1d.2b.3c.4a.5a.6e,1d.2b.3c.4a.5a.6f,1d.2b.3c.4a.5b.6a,1d.2b.3c.4a.5b.6b,
1d.2b.3c.4a.5b.6c,1d.2b.3c.4a.5b.6d,1d.2b.3c.4a.5b.6e,1d.2b.3c.4a.5b.6f,1d.2b.3c.4a.5c.6a,
1d.2b.3c.4a.5c.6b,1d.2b.3c.4a.5c.6c,1d.2b.3c.4a.5c.6d,1d.2b.3c.4a.5c.6e,1d.2b.3c.4a.5c.6f,
1d.2b.3c.4a.5d.6a,1d.2b.3c.4a.5d.6b,1d.2b.3c.4a.5d.6c,1d.2b.3c.4a.5d.6d,1d.2b.3c.4a.5d.6e,
1d.2b.3c.4a.5d.6f,1d.2b.3c.4a.5e.6a,1d.2b.3c.4a.5e.6b,1d.2b.3c.4a.5e.6c,1d.2b.3c.4a.5e.6d,
1d.2b.3c.4a.5e.6e,1d.2b.3c.4a.5e.6f,1d.2b.3c.4a.5f.6a,1d.2b.3c.4a.5f.6b,1d.2b.3c.4a.5f.6c,
1d.2b.3c.4a.5f.6d,1d.2b.3c.4a.5f.6e,1d.2b.3c.4a.5f.6f,1d.2b.3c.4b.5a.6a,1d.2b.3c.4b.5a.6b,
1d.2b.3c.4b.5a.6c,1d.2b.3c.4b.5a.6d,1d.2b.3c.4b.5a.6e,1d.2b.3c.4b.5a.6f,1d.2b.3c.4b.5b.6a,
1d.2b.3c.4b.5b.6b,1d.2b.3c.4b.5b.6c,1d.2b.3c.4b.5b.6d,1d.2b.3c.4b.5b.6e,1d.2b.3c.4b.5b.6f,
1d.2b.3c.4b.5c.6a,1d.2b.3c.4b.5c.6b,1d.2b.3c.4b.5c.6c,1d.2b.3c.4b.5c.6d,1d.2b.3c.4b.5c.6e,
1d.2b.3c.4b.5c.6f,1d.2b.3c.4b.5d.6a,1d.2b.3c.4b.5d.6b,1d.2b.3c.4b.5d.6c,1d.2b.3c.4b.5d.6d,
1d.2b.3c.4b.5d.6e,1d.2b.3c.4b.5d.6f,1d.2b.3c.4b.5e.6a,1d.2b.3c.4b.5e.6b,1d.2b.3c.4b.5e.6c,
1d.2b.3c.4b.5e.6d,1d.2b.3c.4b.5e.6e,1d.2b.3c.4b.5e.6f,1d.2b.3c.4b.5f.6a,1d.2b.3c.4b.5f.6b,
1d.2b.3c.4b.5f.6c,1d.2b.3c.4b.5f.6d,1d.2b.3c.4b.5f.6e,1d.2b.3c.4b.5f.6f,1d.2b.3c.4c.5a.6a,
1d.2b.3c.4c.5a.6b,1d.2b.3c.4c.5a.6c,1d.2b.3c.4c.5a.6d,1d.2b.3c.4c.5a.6e,1d.2b.3c.4c.5a.6f,
1d.2b.3c.4c.5b.6a,1d.2b.3c.4c.5b.6b,1d.2b.3c.4c.5b.6c,1d.2b.3c.4c.5b.6d,1d.2b.3c.4c.5b.6e,
1d.2b.3c.4c.5b.6f,1d.2b.3c.4c.5c.6a,1d.2b.3c.4c.5c.6b,1d.2b.3c.4c.5c.6c,1d.2b.3c.4c.5c.6d,
1d.2b.3c.4c.5c.6e,1d.2b.3c.4c.5c.6f,1d.2b.3c.4c.5d.6a,1d.2b.3c.4c.5d.6b,1d.2b.3c.4c.5d.6c,
1d.2b.3c.4c.5d.6d,1d.2b.3c.4c.5d.6e,1d.2b.3c.4c.5d.6f,1d.2b.3c.4c.5e.6a,1d.2b.3c.4c.5e.6b,
1d.2b.3c.4c.5e.6c,1d.2b.3c.4c.5e.6d,1d.2b.3c.4c.5e.6e,1d.2b.3c.4c.5e.6f,1d.2b.3c.4c.5f.6a,
1d.2b.3c.4c.5f.6b,1d.2b.3c.4c.5f.6c,1d.2b.3c.4c.5f.6d,1d.2b.3c.4c.5f.6e,1d.2b.3c.4c.5f.6f,
1d.2b.3c.4d.5a.6a,1d.2b.3c.4d.5a.6b,1d.2b.3c.4d.5a.6c,1d.2b.3c.4d.5a.6d,1d.2b.3c.4d.5a.6e,
1d.2b.3c.4d.5a.6f,1d.2b.3c.4d.5b.6a,1d.2b.3c.4d.5b.6b,1d.2b.3c.4d.5b.6c,1d.2b.3c.4d.5b.6d,
1d.2b.3c.4d.5b.6e,1d.2b.3c.4d.5b.6f,1d.2b.3c.4d.5c.6a,1d.2b.3c.4d.5c.6b,1d.2b.3c.4d.5c.6c,
1d.2b.3c.4d.5c.6d,1d.2b.3c.4d.5c.6e,1d.2b.3c.4d.5c.6f,1d.2b.3c.4d.5d.6a,1d.2b.3c.4d.5d.6b,
1d.2b.3c.4d.5d.6c, 1d.2b.3c.4d.5d.6d, 1d.2b.3c.4d.5d.6e, 1d.2b.3c.4d.5d.6f,
1d.2b.3c.4d.5e.6a,1d.2b.3c.4d.5e.6b,1d.2b.3c.4d.5e.6c,1d.2b.3c.4d.5e.6d,1d.2b.3c.4d.5e.6e,
1d.2b.3c.4d.5e.6f,1d.2b.3c.4d.5f.6a,1d.2b.3c.4d.5f.6b,1d.2b.3c.4d.5f.6c,1d.2b.3c.4d.5f.6d,
1d.2b.3c.4d.5f.6e,1d.2b.3c.4d.5f.6f,1d.2b.3c.4e.5a.6a,1d.2b.3c.4e.5a.6b,1d.2b.3c.4e.5a.6c,
1d.2b.3c.4e.5a.6d,1d.2b.3c.4e.5a.6e,1d.2b.3c.4e.5a.6f,1d.2b.3c.4e.5b.6a,1d.2b.3c.4e.5b.6b,
1d.2b.3c.4e.5b.6c,1d.2b.3c.4e.5b.6d,1d.2b.3c.4e.5b.6e,1d.2b.3c.4e.5b.6f,1d.2b.3c.4e.5c.6a,
1d.2b.3c.4e.5c.6b,1d.2b.3c.4e.5c.6c,1d.2b.3c.4e.5c.6d,1d.2b.3c.4e.5c.6e,1d.2b.3c.4e.5c.6f,
1d.2b.3c.4e.5d.6a,1d.2b.3c.4e.5d.6b,1d.2b.3c.4e.5d.6c,1d.2b.3c.4e.5d.6d,1d.2b.3c.4e.5d.6e,
1d.2b.3c.4e.5d.6f,1d.2b.3c.4e.5e.6a,1d.2b.3c.4e.5e.6b,1d.2b.3c.4e.5e.6c,1d.2b.3c.4e.5e.6d,
1d.2b.3c.4e.5e.6e,1d.2b.3c.4e.5e.6f,1d.2b.3c.4e.5f.6a,1d.2b.3c.4e.5f.6b,1d.2b.3c.4e.5f.6c,
1d.2b.3c.4e.5f.6d,1d.2b.3c.4e.5f.6e,1d.2b.3c.4e.5f.6f,1d.2b.3c.4f.5a.6a,1d.2b.3c.4f.5a.6b,
1d.2b.3c.4f.5a.6c,1d.2b.3c.4f.5a.6d,1d.2b.3c.4f.5a.6e,1d.2b.3c.4f.5a.6f,1d.2b.3c.4f.5b.6a,
1d.2b.3c.4f.5b.6b,1d.2b.3c.4f.5b.6c,1d.2b.3c.4f.5b.6d,1d.2b.3c.4f.5b.6e,1d.2b.3c.4f.5b.6f,
1d.2b.3c.4f.5c.6a,1d.2b.3c.4f.5c.6b,1d.2b.3c.4f.5c.6c,1d.2b.3c.4f.5c.6d,1d.2b.3c.4f.5c.6e,
1d.2b.3c.4f.5c.6f,1d.2b.3c.4f.5d.6a,1d.2b.3c.4f.5d.6b,1d.2b.3c.4f.5d.6c,1d.2b.3c.4f.5d.6d,
1d.2b.3c.4f.5d.6e,1d.2b.3c.4f.5d.6f,1d.2b.3c.4f.5e.6a,1d.2b.3c.4f.5e.6b,1d.2b.3c.4f.5e.6c,
1d.2b.3c.4f.5e.6d,1d.2b.3c.4f.5e.6e,1d.2b.3c.4f.5e.6f,1d.2b.3c.4f.5f.6a,1d.2b.3c.4f.5f.6b,
1d.2b.3c.4f.5f.6c,1d.2b.3c.4f.5f.6d,1d.2b.3c.4f.5f.6e,1d.2b.3c.4f.5f.6f,1d.2b.3d.4a.5a.6a,
1d.2b.3d.4a.5a.6b,1d.2b.3d.4a.5a.6c,1d.2b.3d.4a.5a.6d,1d.2b.3d.4a.5a.6e,1d.2b.3d.4a.5a.6f,
1d.2b.3d.4a.5b.6a, 1d.2b.3d.4a.5b.6b, 1d.2b.3d.4a.5b.6c, 1d.2b.3d.4a.5b.6d,
1d.2b.3d.4a.5b.6e,1d.2b.3d.4a.5b.6f,1d.2b.3d.4a.5c.6a,1d.2b.3d.4a.5c.6b,1d.2b.3d.4a.5c.6c,
1d.2b.3d.4a.5c.6d, 1d.2b.3d.4a.5c.6e, 1d.2b.3d.4a.5c.6f, 1d.2b.3d.4a.5d.6a,
1d.2b.3d.4a.5d.6b, 1d.2b.3d.4a.5d.6c, 1d.2b.3d.4a.5d.6d, 1d.2b.3d.4a.5d.6e,
1d.2b.3d.4a.5d.6f, 1d.2b.3d.4a.5e.6a, 1d.2b.3d.4a.5e.6b, 1d.2b.3d.4a.5e.6c,
1d.2b.3d.4a.5e.6d,1d.2b.3d.4a.5e.6e,1d.2b.3d.4a.5e.6f,1d.2b.3d.4a.5f.6a,1d.2b.3d.4a.5f.6b,
1d.2b.3d.4a.5f.6c,1d.2b.3d.4a.5f.6d,1d.2b.3d.4a.5f.6e,1d.2b.3d.4a.5f.6f,1d.2b.3d.4b.5a.6a,
1d.2b.3d.4b.5a.6b, 1d.2b.3d.4b.5a.6c, 1d.2b.3d.4b.5a.6d, 1d.2b.3d.4b.5a.6e,
1d.2b.3d.4b.5a.6f, 1d.2b.3d.4b.5b.6a, 1d.2b.3d.4b.5b.6b, 1d.2b.3d.4b.5b.6c,
1d.2b.3d.4b.5b.6d, 1d.2b.3d.4b.5b.6e, 1d.2b.3d.4b.5b.6f, 1d.2b.3d.4b.5c.6a,
1d.2b.3d.4b.5c.6b,1d.2b.3d.4b.5c.6c,1d.2b.3d.4b.5c.6d,1d.2b.3d.4b.5c.6e,1d.2b.3d.4b.5c.6f,
1d.2b.3d.4b.5d.6a, 1d.2b.3d.4b.5d.6b, 1d.2b.3d.4b.5d.6c, 1d.2b.3d.4b.5d.6d,
1d.2b.3d.4b.5d.6e, 1d.2b.3d.4b.5d.6f, 1d.2b.3d.4b.5e.6a, 1d.2b.3d.4b.5e.6b,
1d.2b.3d.4b.5e.6c,1d.2b.3d.4b.5e.6d,1d.2b.3d.4b.5e.6e,1d.2b.3d.4b.5e.6f,1d.2b.3d.4b.5f.6a,
1d.2b.3d.4b.5f.6b,1d.2b.3d.4b.5f.6c,1d.2b.3d.4b.5f.6d,1d.2b.3d.4b.5f.6e,1d.2b.3d.4b.5f.6f,
1d.2b.3d.4c.5a.6a,1d.2b.3d.4c.5a.6b,1d.2b.3d.4c.5a.6c,1d.2b.3d.4c.5a.6d,1d.2b.3d.4c.5a.6e,
1d.2b.3d.4c.5a.6f,1d.2b.3d.4c.5b.6a,1d.2b.3d.4c.5b.6b,1d.2b.3d.4c.5b.6c,1d.2b.3d.4c.5b.6d,
1d.2b.3d.4c.5b.6e,1d.2b.3d.4c.5b.6f,1d.2b.3d.4c.5c.6a,1d.2b.3d.4c.5c.6b,1d.2b.3d.4c.5c.6c,
1d.2b.3d.4c.5c.6d,1d.2b.3d.4c.5c.6e,1d.2b.3d.4c.5c.6f,1d.2b.3d.4c.5d.6a,1d.2b.3d.4c.5d.6b,
1d.2b.3d.4c.5d.6c, 1d.2b.3d.4c.5d.6d, 1d.2b.3d.4c.5d.6e, 1d.2b.3d.4c.5d.6f,
1d.2b.3d.4c.5e.6a,1d.2b.3d.4c.5e.6b,1d.2b.3d.4c.5e.6c,1d.2b.3d.4c.5e.6d,1d.2b.3d.4c.5e.6e,
1d.2b.3d.4c.5e.6f,1d.2b.3d.4c.5f.6a,1d.2b.3d.4c.5f.6b,1d.2b.3d.4c.5f.6c,1d.2b.3d.4c.5f.6d,
1d.2b.3d.4c.5f.6e,1d.2b.3d.4c.5f.6f,1d.2b.3d.4d.5a.6a,1d.2b.3d.4d.5a.6b,1d.2b.3d.4d.5a.6c,
1d.2b.3d.4d.5a.6d, 1d.2b.3d.4d.5a.6e, 1d.2b.3d.4d.5a.6f, 1d.2b.3d.4d.5b.6a,
1d.2b.3d.4d.5b.6b, 1d.2b.3d.4d.5b.6c, 1d.2b.3d.4d.5b.6d, 1d.2b.3d.4d.5b.6e,
1d.2b.3d.4d.5b.6f, 1d.2b.3d.4d.5c.6a, 1d.2b.3d.4d.5c.6b, 1d.2b.3d.4d.5c.6c,
1d.2b.3d.4d.5c.6d, 1d.2b.3d.4d.5c.6e, 1d.2b.3d.4d.5c.6f, 1d.2b.3d.4d.5d.6a,
1d.2b.3d.4d.5d.6b, 1d.2b.3d.4d.5d.6c, 1d.2b.3d.4d.5d.6d, 1d.2b.3d.4d.5d.6e,
1d.2b.3d.4d.5d.6f, 1d.2b.3d.4d.5e.6a, 1d.2b.3d.4d.5e.6b, 1d.2b.3d.4d.5e.6c,
1d.2b.3d.4d.5e.6d, 1d.2b.3d.4d.5e.6e, 1d.2b.3d.4d.5e.6f, 1d.2b.3d.4d.5f.6a,
1d.2b.3d.4d.5f.6b,1d.2b.3d.4d.5f.6c,1d.2b.3d.4d.5f.6d,1d.2b.3d.4d.5f.6e,1d.2b.3d.4d.5f.6f,
1d.2b.3d.4e.5a.6a, 1d.2b.3d.4e.5a.6b, 1d.2b.3d.4e.5a.6c, 1d.2b.3d.4e.5a.6d,
1d.2b.3d.4e.5a.6e,1d.2b.3d.4e.5a.6f,1d.2b.3d.4e.5b.6a,1d.2b.3d.4e.5b.6b,1d.2b.3d.4e.5b.6c,
1d.2b.3d.4e.5b.6d,1d.2b.3d.4e.5b.6e,1d.2b.3d.4e.5b.6f,1d.2b.3d.4e.5c.6a,1d.2b.3d.4e.5c.6b,
1d.2b.3d.4e.5c.6c,1d.2b.3d.4e.5c.6d,1d.2b.3d.4e.5c.6e,1d.2b.3d.4e.5c.6f,1d.2b.3d.4e.5d.6a,
1d.2b.3d.4e.5d.6b, 1d.2b.3d.4e.5d.6c, 1d.2b.3d.4e.5d.6d, 1d.2b.3d.4e.5d.6e,
1d.2b.3d.4e.5d.6f,1d.2b.3d.4e.5e.6a,1d.2b.3d.4e.5e.6b,1d.2b.3d.4e.5e.6c,1d.2b.3d.4e.5e.6d,
1d.2b.3d.4e.5e.6e,1d.2b.3d.4e.5e.6f,1d.2b.3d.4e.5f.6a,1d.2b.3d.4e.5f.6b,1d.2b.3d.4e.5f.6c,
1d.2b.3d.4e.5f.6d,1d.2b.3d.4e.5f.6e,1d.2b.3d.4e.5f.6f,1d.2b.3d.4f.5a.6a,1d.2b.3d.4f.5a.6b,
1d.2b.3d.4f.5a.6c,1d.2b.3d.4f.5a.6d,1d.2b.3d.4f.5a.6e,1d.2b.3d.4f.5a.6f,1d.2b.3d.4f.5b.6a,
1d.2b.3d.4f.5b.6b,1d.2b.3d.4f.5b.6c,1d.2b.3d.4f.5b.6d,1d.2b.3d.4f.5b.6e,1d.2b.3d.4f.5b.6f,
1d.2b.3d.4f.5c.6a,1d.2b.3d.4f.5c.6b,1d.2b.3d.4f.5c.6c,1d.2b.3d.4f.5c.6d,1d.2b.3d.4f.5c.6e,
1d.2b.3d.4f.5c.6f,1d.2b.3d.4f.5d.6a,1d.2b.3d.4f.5d.6b,1d.2b.3d.4f.5d.6c,1d.2b.3d.4f.5d.6d,
1d.2b.3d.4f.5d.6e,1d.2b.3d.4f.5d.6f,1d.2b.3d.4f.5e.6a,1d.2b.3d.4f.5e.6b,1d.2b.3d.4f.5e.6c,
1d.2b.3d.4f.5e.6d,1d.2b.3d.4f.5e.6e,1d.2b.3d.4f.5e.6f,1d.2b.3d.4f.5f.6a,1d.2b.3d.4f.5f.6b,
1d.2b.3d.4f.5f.6c,1d.2b.3d.4f.5f.6d,1d.2b.3d.4f.5f.6e,1d.2b.3d.4f.5f.6f,1d.2b.3e.4a.5a.6a,
1d.2b.3e.4a.5a.6b,1d.2b.3e.4a.5a.6c,1d.2b.3e.4a.5a.6d,1d.2b.3e.4a.5a.6e,1d.2b.3e.4a.5a.6f,
1d.2b.3e.4a.5b.6a,1d.2b.3e.4a.5b.6b,1d.2b.3e.4a.5b.6c,1d.2b.3e.4a.5b.6d,1d.2b.3e.4a.5b.6e,
1d.2b.3e.4a.5b.6f,1d.2b.3e.4a.5c.6a,1d.2b.3e.4a.5c.6b,1d.2b.3e.4a.5c.6c,1d.2b.3e.4a.5c.6d,
1d.2b.3e.4a.5c.6e,1d.2b.3e.4a.5c.6f,1d.2b.3e.4a.5d.6a,1d.2b.3e.4a.5d.6b,1d.2b.3e.4a.5d.6c,
1d.2b.3e.4a.5d.6d,1d.2b.3e.4a.5d.6e,1d.2b.3e.4a.5d.6f,1d.2b.3e.4a.5e.6a,1d.2b.3e.4a.5e.6b,
1d.2b.3e.4a.5e.6c,1d.2b.3e.4a.5e.6d,1d.2b.3e.4a.5e.6e,1d.2b.3e.4a.5e.6f,1d.2b.3e.4a.5f.6a,
1d.2b.3e.4a.5f.6b,1d.2b.3e.4a.5f.6c,1d.2b.3e.4a.5f.6d,1d.2b.3e.4a.5f.6e,1d.2b.3e.4a.5f.6f,
1d.2b.3e.4b.5a.6a,1d.2b.3e.4b.5a.6b,1d.2b.3e.4b.5a.6c,1d.2b.3e.4b.5a.6d,1d.2b.3e.4b.5a.6e,
1d.2b.3e.4b.5a.6f,1d.2b.3e.4b.5b.6a,1d.2b.3e.4b.5b.6b,1d.2b.3e.4b.5b.6c,1d.2b.3e.4b.5b.6d,
1d.2b.3e.4b.5b.6e,1d.2b.3e.4b.5b.6f,1d.2b.3e.4b.5c.6a,1d.2b.3e.4b.5c.6b,1d.2b.3e.4b.5c.6c,
1d.2b.3e.4b.5c.6d,1d.2b.3e.4b.5c.6e,1d.2b.3e.4b.5c.6f,1d.2b.3e.4b.5d.6a,1d.2b.3e.4b.5d.6b,
1d.2b.3e.4b.5d.6c,1d.2b.3e.4b.5d.6d,1d.2b.3e.4b.5d.6e,1d.2b.3e.4b.5d.6f,1d.2b.3e.4b.5e.6a,
1d.2b.3e.4b.5e.6b,1d.2b.3e.4b.5e.6c,1d.2b.3e.4b.5e.6d,1d.2b.3e.4b.5e.6e,1d.2b.3e.4b.5e.6f,
1d.2b.3e.4b.5f.6a,1d.2b.3e.4b.5f.6b,1d.2b.3e.4b.5f.6c,1d.2b.3e.4b.5f.6d,1d.2b.3e.4b.5f.6e,
1d.2b.3e.4b.5f.6f,1d.2b.3e.4c.5a.6a,1d.2b.3e.4c.5a.6b,1d.2b.3e.4c.5a.6c,1d.2b.3e.4c.5a.6d,
1d.2b.3e.4c.5a.6e,1d.2b.3e.4c.5a.6f,1d.2b.3e.4c.5b.6a,1d.2b.3e.4c.5b.6b,1d.2b.3e.4c.5b.6c,
1d.2b.3e.4c.5b.6d,1d.2b.3e.4c.5b.6e,1d.2b.3e.4c.5b.6f,1d.2b.3e.4c.5c.6a,1d.2b.3e.4c.5c.6b,
1d.2b.3e.4c.5c.6c,1d.2b.3e.4c.5c.6d,1d.2b.3e.4c.5c.6e,1d.2b.3e.4c.5c.6f,1d.2b.3e.4c.5d.6a,
1d.2b.3e.4c.5d.6b,1d.2b.3e.4c.5d.6c,1d.2b.3e.4c.5d.6d,1d.2b.3e.4c.5d.6e,1d.2b.3e.4c.5d.6f,
1d.2b.3e.4c.5e.6a,1d.2b.3e.4c.5e.6b,1d.2b.3e.4c.5e.6c,1d.2b.3e.4c.5e.6d,1d.2b.3e.4c.5e.6e,
1d.2b.3e.4c.5e.6f,1d.2b.3e.4c.5f.6a,1d.2b.3e.4c.5f.6b,1d.2b.3e.4c.5f.6c,1d.2b.3e.4c.5f.6d,
1d.2b.3e.4c.5f.6e,1d.2b.3e.4c.5f.6f,1d.2b.3e.4d.5a.6a,1d.2b.3e.4d.5a.6b,1d.2b.3e.4d.5a.6c,
1d.2b.3e.4d.5a.6d, 1d.2b.3e.4d.5a.6e, 1d.2b.3e.4d.5a.6f, 1d.2b.3e.4d.5b.6a,
1d.2b.3e.4d.5b.6b, 1d.2b.3e.4d.5b.6c, 1d.2b.3e.4d.5b.6d, 1d.2b.3e.4d.5b.6e,
1d.2b.3e.4d.5b.6f,1d.2b.3e.4d.5c.6a,1d.2b.3e.4d.5c.6b,1d.2b.3e.4d.5c.6c,1d.2b.3e.4d.5c.6d,
1d.2b.3e.4d.5c.6e,1d.2b.3e.4d.5c.6f,1d.2b.3e.4d.5d.6a,1d.2b.3e.4d.5d.6b,1d.2b.3e.4d.5d.6c,
1d.2b.3e.4d.5d.6d, 1d.2b.3e.4d.5d.6e, 1d.2b.3e.4d.5d.6f, 1d.2b.3e.4d.5e.6a,
1d.2b.3e.4d.5e.6b,1d.2b.3e.4d.5e.6c,1d.2b.3e.4d.5e.6d,1d.2b.3e.4d.5e.6e,1d.2b.3e.4d.5e.6f,
1d.2b.3e.4d.5f.6a,1d.2b.3e.4d.5f.6b,1d.2b.3e.4d.5f.6c,1d.2b.3e.4d.5f.6d,1d.2b.3e.4d.5f.6e,
1d.2b.3e.4d.5f.6f,1d.2b.3e.4e.5a.6a,1d.2b.3e.4e.5a.6b,1d.2b.3e.4e.5a.6c,1d.2b.3e.4e.5a.6d,
1d.2b.3e.4e.5a.6e,1d.2b.3e.4e.5a.6f,1d.2b.3e.4e.5b.6a,1d.2b.3e.4e.5b.6b,1d.2b.3e.4e.5b.6c,
1d.2b.3e.4e.5b.6d,1d.2b.3e.4e.5b.6e,1d.2b.3e.4e.5b.6f,1d.2b.3e.4e.5c.6a,1d.2b.3e.4e.5c.6b,
1d.2b.3e.4e.5c.6c,1d.2b.3e.4e.5c.6d,1d.2b.3e.4e.5c.6e,1d.2b.3e.4e.5c.6f,1d.2b.3e.4e.5d.6a,
1d.2b.3e.4e.5d.6b,1d.2b.3e.4e.5d.6c,1d.2b.3e.4e.5d.6d,1d.2b.3e.4e.5d.6e,1d.2b.3e.4e.5d.6f,
1d.2b.3e.4e.5e.6a,1d.2b.3e.4e.5e.6b,1d.2b.3e.4e.5e.6c,1d.2b.3e.4e.5e.6d,1d.2b.3e.4e.5e.6e,
1d.2b.3e.4e.5e.6f,1d.2b.3e.4e.5f.6a,1d.2b.3e.4e.5f.6b,1d.2b.3e.4e.5f.6c,1d.2b.3e.4e.5f.6d,
1d.2b.3e.4e.5f.6e,1d.2b.3e.4e.5f.6f,1d.2b.3e.4f.5a.6a,1d.2b.3e.4f.5a.6b,1d.2b.3e.4f.5a.6c,
1d.2b.3e.4f.5a.6d,1d.2b.3e.4f.5a.6e,1d.2b.3e.4f.5a.6f,1d.2b.3e.4f.5b.6a,1d.2b.3e.4f.5b.6b,
1d.2b.3e.4f.5b.6c,1d.2b.3e.4f.5b.6d,1d.2b.3e.4f.5b.6e,1d.2b.3e.4f.5b.6f,1d.2b.3e.4f.5c.6a,
1d.2b.3e.4f.5c.6b,1d.2b.3e.4f.5c.6c,1d.2b.3e.4f.5c.6d,1d.2b.3e.4f.5c.6e,1d.2b.3e.4f.5c.6f,
1d.2b.3e.4f.5d.6a,1d.2b.3e.4f.5d.6b,1d.2b.3e.4f.5d.6c,1d.2b.3e.4f.5d.6d,1d.2b.3e.4f.5d.6e,
1d.2b.3e.4f.5d.6f,1d.2b.3e.4f.5e.6a,1d.2b.3e.4f.5e.6b,1d.2b.3e.4f.5e.6c,1d.2b.3e.4f.5e.6d,
1d.2b.3e.4f.5e.6e,1d.2b.3e.4f.5e.6f,1d.2b.3e.4f.5f.6a,1d.2b.3e.4f.5f.6b,1d.2b.3e.4f.5f.6c,
1d.2b.3e.4f.5f.6d,1d.2b.3e.4f.5f.6e,1d.2b.3e.4f.5f.6f,1d.2b.3f.4a.5a.6a,1d.2b.3f.4a.5a.6b,
1d.2b.3f.4a.5a.6c,1d.2b.3f.4a.5a.6d,1d.2b.3f.4a.5a.6e,1d.2b.3f.4a.5a.6f,1d.2b.3f.4a.5b.6a,
1d.2b.3f.4a.5b.6b,1d.2b.3f.4a.5b.6c,1d.2b.3f.4a.5b.6d,1d.2b.3f.4a.5b.6e,1d.2b.3f.4a.5b.6f,
1d.2b.3f.4a.5c.6a,1d.2b.3f.4a.5c.6b,1d.2b.3f.4a.5c.6c,1d.2b.3f.4a.5c.6d,1d.2b.3f.4a.5c.6e,
1d.2b.3f.4a.5c.6f,1d.2b.3f.4a.5d.6a,1d.2b.3f.4a.5d.6b,1d.2b.3f.4a.5d.6c,1d.2b.3f.4a.5d.6d,
1d.2b.3f.4a.5d.6e,1d.2b.3f.4a.5d.6f,1d.2b.3f.4a.5e.6a,1d.2b.3f.4a.5e.6b,1d.2b.3f.4a.5e.6c,
1d.2b.3f.4a.5e.6d,1d.2b.3f.4a.5e.6e,1d.2b.3f.4a.5e.6f,1d.2b.3f.4a.5f.6a,1d.2b.3f.4a.5f.6b,
1d.2b.3f.4a.5f.6c,1d.2b.3f.4a.5f.6d,1d.2b.3f.4a.5f.6e,1d.2b.3f.4a.5f.6f,1d.2b.3f.4b.5a.6a,
1d.2b.3f.4b.5a.6b,1d.2b.3f.4b.5a.6c,1d.2b.3f.4b.5a.6d,1d.2b.3f.4b.5a.6e,1d.2b.3f.4b.5a.6f,
1d.2b.3f.4b.5b.6a,1d.2b.3f.4b.5b.6b,1d.2b.3f.4b.5b.6c,1d.2b.3f.4b.5b.6d,1d.2b.3f.4b.5b.6e,
1d.2b.3f.4b.5b.6f,1d.2b.3f.4b.5c.6a,1d.2b.3f.4b.5c.6b,1d.2b.3f.4b.5c.6c,1d.2b.3f.4b.5c.6d,
1d.2b.3f.4b.5c.6e,1d.2b.3f.4b.5c.6f,1d.2b.3f.4b.5d.6a,1d.2b.3f.4b.5d.6b,1d.2b.3f.4b.5d.6c,
1d.2b.3f.4b.5d.6d,1d.2b.3f.4b.5d.6e,1d.2b.3f.4b.5d.6f,1d.2b.3f.4b.5e.6a,1d.2b.3f.4b.5e.6b,
1d.2b.3f.4b.5e.6c,1d.2b.3f.4b.5e.6d,1d.2b.3f.4b.5e.6e,1d.2b.3f.4b.5e.6f,1d.2b.3f.4b.5f.6a,
1d.2b.3f.4b.5f.6b,1d.2b.3f.4b.5f.6c,1d.2b.3f.4b.5f.6d,1d.2b.3f.4b.5f.6e,1d.2b.3f.4b.5f.6f,
1d.2b.3f.4c.5a.6a,1d.2b.3f.4c.5a.6b,1d.2b.3f.4c.5a.6c,1d.2b.3f.4c.5a.6d,1d.2b.3f.4c.5a.6e,
1d.2b.3f.4c.5a.6f,1d.2b.3f.4c.5b.6a,1d.2b.3f.4c.5b.6b,1d.2b.3f.4c.5b.6c,1d.2b.3f.4c.5b.6d,
1d.2b.3f.4c.5b.6e,1d.2b.3f.4c.5b.6f,1d.2b.3f.4c.5c.6a,1d.2b.3f.4c.5c.6b,1d.2b.3f.4c.5c.6c,
1d.2b.3f.4c.5c.6d,1d.2b.3f.4c.5c.6e,1d.2b.3f.4c.5c.6f,1d.2b.3f.4c.5d.6a,1d.2b.3f.4c.5d.6b,
1d.2b.3f.4c.5d.6c,1d.2b.3f.4c.5d.6d,1d.2b.3f.4c.5d.6e,1d.2b.3f.4c.5d.6f,1d.2b.3f.4c.5e.6a,
1d.2b.3f.4c.5e.6b,1d.2b.3f.4c.5e.6c,1d.2b.3f.4c.5e.6d,1d.2b.3f.4c.5e.6e,1d.2b.3f.4c.5e.6f,
1d.2b.3f.4c.5f.6a,1d.2b.3f.4c.5f.6b,1d.2b.3f.4c.5f.6c,1d.2b.3f.4c.5f.6d,1d.2b.3f.4c.5f.6e,
1d.2b.3f.4c.5f.6f,1d.2b.3f.4d.5a.6a,1d.2b.3f.4d.5a.6b,1d.2b.3f.4d.5a.6c,1d.2b.3f.4d.5a.6d,
1d.2b.3f.4d.5a.6e,1d.2b.3f.4d.5a.6f,1d.2b.3f.4d.5b.6a,1d.2b.3f.4d.5b.6b,1d.2b.3f.4d.5b.6c,
1d.2b.3f.4d.5b.6d,1d.2b.3f.4d.5b.6e,1d.2b.3f.4d.5b.6f,1d.2b.3f.4d.5c.6a,1d.2b.3f.4d.5c.6b,
1d.2b.3f.4d.5c.6c,1d.2b.3f.4d.5c.6d,1d.2b.3f.4d.5c.6e,1d.2b.3f.4d.5c.6f,1d.2b.3f.4d.5d.6a,
1d.2b.3f.4d.5d.6b,1d.2b.3f.4d.5d.6c,1d.2b.3f.4d.5d.6d,1d.2b.3f.4d.5d.6e,1d.2b.3f.4d.5d.6f,
1d.2b.3f.4d.5e.6a,1d.2b.3f.4d.5e.6b,1d.2b.3f.4d.5e.6c,1d.2b.3f.4d.5e.6d,1d.2b.3f.4d.5e.6e,
1d.2b.3f.4d.5e.6f,1d.2b.3f.4d.5f.6a,1d.2b.3f.4d.5f.6b,1d.2b.3f.4d.5f.6c,1d.2b.3f.4d.5f.6d,
1d.2b.3f.4d.5f.6e,1d.2b.3f.4d.5f.6f,1d.2b.3f.4e.5a.6a,1d.2b.3f.4e.5a.6b,1d.2b.3f.4e.5a.6c,
1d.2b.3f.4e.5a.6d,1d.2b.3f.4e.5a.6e,1d.2b.3f.4e.5a.6f,1d.2b.3f.4e.5b.6a,1d.2b.3f.4e.5b.6b,
1d.2b.3f.4e.5b.6c,1d.2b.3f.4e.5b.6d,1d.2b.3f.4e.5b.6e,1d.2b.3f.4e.5b.6f,1d.2b.3f.4e.5c.6a,
1d.2b.3f.4e.5c.6b,1d.2b.3f.4e.5c.6c,1d.2b.3f.4e.5c.6d,1d.2b.3f.4e.5c.6e,1d.2b.3f.4e.5c.6f,
1d.2b.3f.4e.5d.6a,1d.2b.3f.4e.5d.6b,1d.2b.3f.4e.5d.6c,1d.2b.3f.4e.5d.6d,1d.2b.3f.4e.5d.6e,
1d.2b.3f.4e.5d.6f,1d.2b.3f.4e.5e.6a,1d.2b.3f.4e.5e.6b,1d.2b.3f.4e.5e.6c,1d.2b.3f.4e.5e.6d,
1d.2b.3f.4e.5e.6e,1d.2b.3f.4e.5e.6f,1d.2b.3f.4e.5f.6a,1d.2b.3f.4e.5f.6b,1d.2b.3f.4e.5f.6c,
1d.2b.3f.4e.5f.6d,1d.2b.3f.4e.5f.6e,1d.2b.3f.4e.5f.6f,1d.2b.3f.4f.5a.6a,1d.2b.3f.4f.5a.6b,
1d.2b.3f.4f.5a.6c,1d.2b.3f.4f.5a.6d,1d.2b.3f.4f.5a.6e,1d.2b.3f.4f.5a.6f,1d.2b.3f.4f.5b.6a,
1d.2b.3f.4f.5b.6b,1d.2b.3f.4f.5b.6c,1d.2b.3f.4f.5b.6d,1d.2b.3f.4f.5b.6e,1d.2b.3f.4f.5b.6f,
1d.2b.3f.4f.5c.6a,1d.2b.3f.4f.5c.6b,1d.2b.3f.4f.5c.6c,1d.2b.3f.4f.5c.6d,1d.2b.3f.4f.5c.6e,
1d.2b.3f.4f.5c.6f,1d.2b.3f.4f.5d.6a,1d.2b.3f.4f.5d.6b,1d.2b.3f.4f.5d.6c,1d.2b.3f.4f.5d.6d,
1d.2b.3f.4f.5d.6e,1d.2b.3f.4f.5d.6f,1d.2b.3f.4f.5e.6a,1d.2b.3f.4f.5e.6b,1d.2b.3f.4f.5e.6c,
1d.2b.3f.4f.5e.6d,1d.2b.3f.4f.5e.6e,1d.2b.3f.4f.5e.6f,1d.2b.3f.4f.5f.6a,1d.2b.3f.4f.5f.6b,
1d.2b.3f.4f.5f.6c,1d.2b.3f.4f.5f.6d,1d.2b.3f.4f.5f.6e,1d.2b.3f.4f.5f.6f,1d.2c.3a.4a.5a.6a,
1d.2c.3a.4a.5a.6b,1d.2c.3a.4a.5a.6c,1d.2c.3a.4a.5a.6d,1d.2c.3a.4a.5a.6e,1d.2c.3a.4a.5a.6f,
1d.2c.3a.4a.5b.6a,1d.2c.3a.4a.5b.6b,1d.2c.3a.4a.5b.6c,1d.2c.3a.4a.5b.6d,1d.2c.3a.4a.5b.6e,
1d.2c.3a.4a.5b.6f,1d.2c.3a.4a.5c.6a,1d.2c.3a.4a.5c.6b,1d.2c.3a.4a.5c.6c,1d.2c.3a.4a.5c.6d,
1d.2c.3a.4a.5c.6e,1d.2c.3a.4a.5c.6f,1d.2c.3a.4a.5d.6a,1d.2c.3a.4a.5d.6b,1d.2c.3a.4a.5d.6c,
1d.2c.3a.4a.5d.6d,1d.2c.3a.4a.5d.6e,1d.2c.3a.4a.5d.6f,1d.2c.3a.4a.5e.6a,1d.2c.3a.4a.5e.6b,
1d.2c.3a.4a.5e.6c,1d.2c.3a.4a.5e.6d,1d.2c.3a.4a.5e.6e,1d.2c.3a.4a.5e.6f,1d.2c.3a.4a.5f.6a,
1d.2c.3a.4a.5f.6b,1d.2c.3a.4a.5f.6c,1d.2c.3a.4a.5f.6d,1d.2c.3a.4a.5f.6e,1d.2c.3a.4a.5f.6f,
1d.2c.3a.4b.5a.6a,1d.2c.3a.4b.5a.6b,1d.2c.3a.4b.5a.6c,1d.2c.3a.4b.5a.6d,1d.2c.3a.4b.5a.6e,
1d.2c.3a.4b.5a.6f,1d.2c.3a.4b.5b.6a,1d.2c.3a.4b.5b.6b,1d.2c.3a.4b.5b.6c,1d.2c.3a.4b.5b.6d,
1d.2c.3a.4b.5b.6e,1d.2c.3a.4b.5b.6f,1d.2c.3a.4b.5c.6a,1d.2c.3a.4b.5c.6b,1d.2c.3a.4b.5c.6c,
1d.2c.3a.4b.5c.6d,1d.2c.3a.4b.5c.6e,1d.2c.3a.4b.5c.6f,1d.2c.3a.4b.5d.6a,1d.2c.3a.4b.5d.6b,
1d.2c.3a.4b.5d.6c,1d.2c.3a.4b.5d.6d,1d.2c.3a.4b.5d.6e,1d.2c.3a.4b.5d.6f,1d.2c.3a.4b.5e.6a,
1d.2c.3a.4b.5e.6b,1d.2c.3a.4b.5e.6c,1d.2c.3a.4b.5e.6d,1d.2c.3a.4b.5e.6e,1d.2c.3a.4b.5e.6f,
1d.2c.3a.4b.5f.6a,1d.2c.3a.4b.5f.6b,1d.2c.3a.4b.5f.6c,1d.2c.3a.4b.5f.6d,1d.2c.3a.4b.5f.6e,
1d.2c.3a.4b.5f.6f,1d.2c.3a.4c.5a.6a,1d.2c.3a.4c.5a.6b,1d.2c.3a.4c.5a.6c,1d.2c.3a.4c.5a.6d,
1d.2c.3a.4c.5a.6e,1d.2c.3a.4c.5a.6f,1d.2c.3a.4c.5b.6a,1d.2c.3a.4c.5b.6b,1d.2c.3a.4c.5b.6c,
1d.2c.3a.4c.5b.6d,1d.2c.3a.4c.5b.6e,1d.2c.3a.4c.5b.6f,1d.2c.3a.4c.5c.6a,1d.2c.3a.4c.5c.6b,
1d.2c.3a.4c.5c.6c,1d.2c.3a.4c.5c.6d,1d.2c.3a.4c.5c.6e,1d.2c.3a.4c.5c.6f,1d.2c.3a.4c.5d.6a,
1d.2c.3a.4c.5d.6b,1d.2c.3a.4c.5d.6c,1d.2c.3a.4c.5d.6d,1d.2c.3a.4c.5d.6e,1d.2c.3a.4c.5d.6f,
1d.2c.3a.4c.5e.6a,1d.2c.3a.4c.5e.6b,1d.2c.3a.4c.5e.6c,1d.2c.3a.4c.5e.6d,1d.2c.3a.4c.5e.6e,
1d.2c.3a.4c.5e.6f,1d.2c.3a.4c.5f.6a,1d.2c.3a.4c.5f.6b,1d.2c.3a.4c.5f.6c,1d.2c.3a.4c.5f.6d,
1d.2c.3a.4c.5f.6e,1d.2c.3a.4c.5f.6f,1d.2c.3a.4d.5a.6a,1d.2c.3a.4d.5a.6b,1d.2c.3a.4d.5a.6c,
1d.2c.3a.4d.5a.6d,1d.2c.3a.4d.5a.6e,1d.2c.3a.4d.5a.6f,1d.2c.3a.4d.5b.6a,1d.2c.3a.4d.5b.6b,
1d.2c.3a.4d.5b.6c,1d.2c.3a.4d.5b.6d,1d.2c.3a.4d.5b.6e,1d.2c.3a.4d.5b.6f,1d.2c.3a.4d.5c.6a,
1d.2c.3a.4d.5c.6b,1d.2c.3a.4d.5c.6c,1d.2c.3a.4d.5c.6d,1d.2c.3a.4d.5c.6e,1d.2c.3a.4d.5c.6f,
1d.2c.3a.4d.5d.6a, 1d.2c.3a.4d.5d.6b, 1d.2c.3a.4d.5d.6c, 1d.2c.3a.4d.5d.6d,
1d.2c.3a.4d.5d.6e,1d.2c.3a.4d.5d.6f,1d.2c.3a.4d.5e.6a,1d.2c.3a.4d.5e.6b,1d.2c.3a.4d.5e.6c,
1d.2c.3a.4d.5e.6d,1d.2c.3a.4d.5e.6e,1d.2c.3a.4d.5e.6f,1d.2c.3a.4d.5f.6a,1d.2c.3a.4d.5f.6b,
1d.2c.3a.4d.5f.6c,1d.2c.3a.4d.5f.6d,1d.2c.3a.4d.5f.6e,1d.2c.3a.4d.5f.6f,1d.2c.3a.4e.5a.6a,
1d.2c.3a.4e.5a.6b,1d.2c.3a.4e.5a.6c,1d.2c.3a.4e.5a.6d,1d.2c.3a.4e.5a.6e,1d.2c.3a.4e.5a.6f,
1d.2c.3a.4e.5b.6a,1d.2c.3a.4e.5b.6b,1d.2c.3a.4e.5b.6c,1d.2c.3a.4e.5b.6d,1d.2c.3a.4e.5b.6e,
1d.2c.3a.4e.5b.6f,1d.2c.3a.4e.5c.6a,1d.2c.3a.4e.5c.6b,1d.2c.3a.4e.5c.6c,1d.2c.3a.4e.5c.6d,
1d.2c.3a.4e.5c.6e,1d.2c.3a.4e.5c.6f,1d.2c.3a.4e.5d.6a,1d.2c.3a.4e.5d.6b,1d.2c.3a.4e.5d.6c,
1d.2c.3a.4e.5d.6d,1d.2c.3a.4e.5d.6e,1d.2c.3a.4e.5d.6f,1d.2c.3a.4e.5e.6a,1d.2c.3a.4e.5e.6b,
1d.2c.3a.4e.5e.6c,1d.2c.3a.4e.5e.6d,1d.2c.3a.4e.5e.6e,1d.2c.3a.4e.5e.6f,1d.2c.3a.4e.5f.6a,
1d.2c.3a.4e.5f.6b,1d.2c.3a.4e.5f.6c,1d.2c.3a.4e.5f.6d,1d.2c.3a.4e.5f.6e,1d.2c.3a.4e.5f.6f,
1d.2c.3a.4f.5a.6a,1d.2c.3a.4f.5a.6b,1d.2c.3a.4f.5a.6c,1d.2c.3a.4f.5a.6d,1d.2c.3a.4f.5a.6e,
1d.2c.3a.4f.5a.6f,1d.2c.3a.4f.5b.6a,1d.2c.3a.4f.5b.6b,1d.2c.3a.4f.5b.6c,1d.2c.3a.4f.5b.6d,
1d.2c.3a.4f.5b.6e,1d.2c.3a.4f.5b.6f,1d.2c.3a.4f.5c.6a,1d.2c.3a.4f.5c.6b,1d.2c.3a.4f.5c.6c,
1d.2c.3a.4f.5c.6d,1d.2c.3a.4f.5c.6e,1d.2c.3a.4f.5c.6f,1d.2c.3a.4f.5d.6a,1d.2c.3a.4f.5d.6b,
1d.2c.3a.4f.5d.6c,1d.2c.3a.4f.5d.6d,1d.2c.3a.4f.5d.6e,1d.2c.3a.4f.5d.6f,1d.2c.3a.4f.5e.6a,
1d.2c.3a.4f.5e.6b,1d.2c.3a.4f.5e.6c,1d.2c.3a.4f.5e.6d,1d.2c.3a.4f.5e.6e,1d.2c.3a.4f.5e.6f,
1d.2c.3a.4f.5f.6a,1d.2c.3a.4f.5f.6b,1d.2c.3a.4f.5f.6c,1d.2c.3a.4f.5f.6d,1d.2c.3a.4f.5f.6e,
1d.2c.3a.4f.5f.6f,1d.2c.3b.4a.5a.6a,1d.2c.3b.4a.5a.6b,1d.2c.3b.4a.5a.6c,1d.2c.3b.4a.5a.6d,
1d.2c.3b.4a.5a.6e,1d.2c.3b.4a.5a.6f,1d.2c.3b.4a.5b.6a,1d.2c.3b.4a.5b.6b,1d.2c.3b.4a.5b.6c,
1d.2c.3b.4a.5b.6d,1d.2c.3b.4a.5b.6e,1d.2c.3b.4a.5b.6f,1d.2c.3b.4a.5c.6a,1d.2c.3b.4a.5c.6b,
1d.2c.3b.4a.5c.6c,1d.2c.3b.4a.5c.6d,1d.2c.3b.4a.5c.6e,1d.2c.3b.4a.5c.6f,1d.2c.3b.4a.5d.6a,
1d.2c.3b.4a.5d.6b,1d.2c.3b.4a.5d.6c,1d.2c.3b.4a.5d.6d,1d.2c.3b.4a.5d.6e,1d.2c.3b.4a.5d.6f,
1d.2c.3b.4a.5e.6a,1d.2c.3b.4a.5e.6b,1d.2c.3b.4a.5e.6c,1d.2c.3b.4a.5e.6d,1d.2c.3b.4a.5e.6e,
1d.2c.3b.4a.5e.6f,1d.2c.3b.4a.5f.6a,1d.2c.3b.4a.5f.6b,1d.2c.3b.4a.5f.6c,1d.2c.3b.4a.5f.6d,
1d.2c.3b.4a.5f.6e,1d.2c.3b.4a.5f.6f,1d.2c.3b.4b.5a.6a,1d.2c.3b.4b.5a.6b,1d.2c.3b.4b.5a.6c,
1d.2c.3b.4b.5a.6d,1d.2c.3b.4b.5a.6e,1d.2c.3b.4b.5a.6f,1d.2c.3b.4b.5b.6a,1d.2c.3b.4b.5b.6b,
1d.2c.3b.4b.5b.6c,1d.2c.3b.4b.5b.6d,1d.2c.3b.4b.5b.6e,1d.2c.3b.4b.5b.6f,1d.2c.3b.4b.5c.6a,
1d.2c.3b.4b.5c.6b,1d.2c.3b.4b.5c.6c,1d.2c.3b.4b.5c.6d,1d.2c.3b.4b.5c.6e,1d.2c.3b.4b.5c.6f,
1d.2c.3b.4b.5d.6a, 1d.2c.3b.4b.5d.6b, 1d.2c.3b.4b.5d.6c, 1d.2c.3b.4b.5d.6d,
1d.2c.3b.4b.5d.6e,1d.2c.3b.4b.5d.6f,1d.2c.3b.4b.5e.6a,1d.2c.3b.4b.5e.6b,1d.2c.3b.4b.5e.6c,
1d.2c.3b.4b.5e.6d,1d.2c.3b.4b.5e.6e,1d.2c.3b.4b.5e.6f,1d.2c.3b.4b.5f.6a,1d.2c.3b.4b.5f.6b,
1d.2c.3b.4b.5f.6c,1d.2c.3b.4b.5f.6d,1d.2c.3b.4b.5f.6e,1d.2c.3b.4b.5f.6f,1d.2c.3b.4c.5a.6a,
1d.2c.3b.4c.5a.6b,1d.2c.3b.4c.5a.6c,1d.2c.3b.4c.5a.6d,1d.2c.3b.4c.5a.6e,1d.2c.3b.4c.5a.6f,
1d.2c.3b.4c.5b.6a,1d.2c.3b.4c.5b.6b,1d.2c.3b.4c.5b.6c,1d.2c.3b.4c.5b.6d,1d.2c.3b.4c.5b.6e,
1d.2c.3b.4c.5b.6f,1d.2c.3b.4c.5c.6a,1d.2c.3b.4c.5c.6b,1d.2c.3b.4c.5c.6c,1d.2c.3b.4c.5c.6d,
1d.2c.3b.4c.5c.6e,1d.2c.3b.4c.5c.6f,1d.2c.3b.4c.5d.6a,1d.2c.3b.4c.5d.6b,1d.2c.3b.4c.5d.6c,
1d.2c.3b.4c.5d.6d,1d.2c.3b.4c.5d.6e,1d.2c.3b.4c.5d.6f,1d.2c.3b.4c.5e.6a,1d.2c.3b.4c.5e.6b,
1d.2c.3b.4c.5e.6c,1d.2c.3b.4c.5e.6d,1d.2c.3b.4c.5e.6e,1d.2c.3b.4c.5e.6f,1d.2c.3b.4c.5f.6a,
1d.2c.3b.4c.5f.6b,1d.2c.3b.4c.5f.6c,1d.2c.3b.4c.5f.6d,1d.2c.3b.4c.5f.6e,1d.2c.3b.4c.5f.6f,
1d.2c.3b.4d.5a.6a,1d.2c.3b.4d.5a.6b,1d.2c.3b.4d.5a.6c,1d.2c.3b.4d.5a.6d,1d.2c.3b.4d.5a.6e,
1d.2c.3b.4d.5a.6f,1d.2c.3b.4d.5b.6a,1d.2c.3b.4d.5b.6b,1d.2c.3b.4d.5b.6c,1d.2c.3b.4d.5b.6d,
1d.2c.3b.4d.5b.6e,1d.2c.3b.4d.5b.6f,1d.2c.3b.4d.5c.6a,1d.2c.3b.4d.5c.6b,1d.2c.3b.4d.5c.6c,
1d.2c.3b.4d.5c.6d,1d.2c.3b.4d.5c.6e,1d.2c.3b.4d.5c.6f,1d.2c.3b.4d.5d.6a,1d.2c.3b.4d.5d.6b,
1d.2c.3b.4d.5d.6c, 1d.2c.3b.4d.5d.6d, 1d.2c.3b.4d.5d.6e, 1d.2c.3b.4d.5d.6f,
1d.2c.3b.4d.5e.6a,1d.2c.3b.4d.5e.6b,1d.2c.3b.4d.5e.6c,1d.2c.3b.4d.5e.6d,1d.2c.3b.4d.5e.6e,
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1d.2c.3b.4d.5f.6e,1d.2c.3b.4d.5f.6f,1d.2c.3b.4e.5a.6a,1d.2c.3b.4e.5a.6b,1d.2c.3b.4e.5a.6c,
1d.2c.3b.4e.5a.6d,1d.2c.3b.4e.5a.6e,1d.2c.3b.4e.5a.6f,1d.2c.3b.4e.5b.6a,1d.2c.3b.4e.5b.6b,
1d.2c.3b.4e.5b.6c,1d.2c.3b.4e.5b.6d,1d.2c.3b.4e.5b.6e,1d.2c.3b.4e.5b.6f,1d.2c.3b.4e.5c.6a,
1d.2c.3b.4e.5c.6b,1d.2c.3b.4e.5c.6c,1d.2c.3b.4e.5c.6d,1d.2c.3b.4e.5c.6e,1d.2c.3b.4e.5c.6f,
1d.2c.3b.4e.5d.6a,1d.2c.3b.4e.5d.6b,1d.2c.3b.4e.5d.6c,1d.2c.3b.4e.5d.6d,1d.2c.3b.4e.5d.6e,
1d.2c.3b.4e.5d.6f,1d.2c.3b.4e.5e.6a,1d.2c.3b.4e.5e.6b,1d.2c.3b.4e.5e.6c,1d.2c.3b.4e.5e.6d,
1d.2c.3b.4e.5e.6e,1d.2c.3b.4e.5e.6f,1d.2c.3b.4e.5f.6a,1d.2c.3b.4e.5f.6b,1d.2c.3b.4e.5f.6c,
1d.2c.3b.4e.5f.6d,1d.2c.3b.4e.5f.6e,1d.2c.3b.4e.5f.6f,1d.2c.3b.4f.5a.6a,1d.2c.3b.4f.5a.6b,
1d.2c.3b.4f.5a.6c,1d.2c.3b.4f.5a.6d,1d.2c.3b.4f.5a.6e,1d.2c.3b.4f.5a.6f,1d.2c.3b.4f.5b.6a,
1d.2c.3b.4f.5b.6b,1d.2c.3b.4f.5b.6c,1d.2c.3b.4f.5b.6d,1d.2c.3b.4f.5b.6e,1d.2c.3b.4f.5b.6f,
1d.2c.3b.4f.5c.6a,1d.2c.3b.4f.5c.6b,1d.2c.3b.4f.5c.6c,1d.2c.3b.4f.5c.6d,1d.2c.3b.4f.5c.6e,
1d.2c.3b.4f.5c.6f,1d.2c.3b.4f.5d.6a,1d.2c.3b.4f.5d.6b,1d.2c.3b.4f.5d.6c,1d.2c.3b.4f.5d.6d,
1d.2c.3b.4f.5d.6e,1d.2c.3b.4f.5d.6f,1d.2c.3b.4f.5e.6a,1d.2c.3b.4f.5e.6b,1d.2c.3b.4f.5e.6c,
1d.2c.3b.4f.5e.6d,1d.2c.3b.4f.5e.6e,1d.2c.3b.4f.5e.6f,1d.2c.3b.4f.5f.6a,1d.2c.3b.4f.5f.6b,
1d.2c.3b.4f.5f.6c,1d.2c.3b.4f.5f.6d,1d.2c.3b.4f.5f.6e,1d.2c.3b.4f.5f.6f,1d.2c.3c.4a.5a.6a,
1d.2c.3c.4a.5a.6b,1d.2c.3c.4a.5a.6c,1d.2c.3c.4a.5a.6d,1d.2c.3c.4a.5a.6e,1d.2c.3c.4a.5a.6f,
1d.2c.3c.4a.5b.6a,1d.2c.3c.4a.5b.6b,1d.2c.3c.4a.5b.6c,1d.2c.3c.4a.5b.6d,1d.2c.3c.4a.5b.6e,
1d.2c.3c.4a.5b.6f,1d.2c.3c.4a.5c.6a,1d.2c.3c.4a.5c.6b,1d.2c.3c.4a.5c.6c,1d.2c.3c.4a.5c.6d,
1d.2c.3c.4a.5c.6e,1d.2c.3c.4a.5c.6f,1d.2c.3c.4a.5d.6a,1d.2c.3c.4a.5d.6b,1d.2c.3c.4a.5d.6c,
1d.2c.3c.4a.5d.6d,1d.2c.3c.4a.5d.6e,1d.2c.3c.4a.5d.6f,1d.2c.3c.4a.5e.6a,1d.2c.3c.4a.5e.6b,
1d.2c.3c.4a.5e.6c,1d.2c.3c.4a.5e.6d,1d.2c.3c.4a.5e.6e,1d.2c.3c.4a.5e.6f,1d.2c.3c.4a.5f.6a,
1d.2c.3c.4a.5f.6b,1d.2c.3c.4a.5f.6c,1d.2c.3c.4a.5f.6d,1d.2c.3c.4a.5f.6e,1d.2c.3c.4a.5f.6f,
1d.2c.3c.4b.5a.6a,1d.2c.3c.4b.5a.6b,1d.2c.3c.4b.5a.6c,1d.2c.3c.4b.5a.6d,1d.2c.3c.4b.5a.6e,
1d.2c.3c.4b.5a.6f,1d.2c.3c.4b.5b.6a,1d.2c.3c.4b.5b.6b,1d.2c.3c.4b.5b.6c,1d.2c.3c.4b.5b.6d,
1d.2c.3c.4b.5b.6e,1d.2c.3c.4b.5b.6f,1d.2c.3c.4b.5c.6a,1d.2c.3c.4b.5c.6b,1d.2c.3c.4b.5c.6c,
1d.2c.3c.4b.5c.6d,1d.2c.3c.4b.5c.6e,1d.2c.3c.4b.5c.6f,1d.2c.3c.4b.5d.6a,1d.2c.3c.4b.5d.6b,
1d.2c.3c.4b.5d.6c,1d.2c.3c.4b.5d.6d,1d.2c.3c.4b.5d.6e,1d.2c.3c.4b.5d.6f,1d.2c.3c.4b.5e.6a,
1d.2c.3c.4b.5e.6b,1d.2c.3c.4b.5e.6c,1d.2c.3c.4b.5e.6d,1d.2c.3c.4b.5e.6e,1d.2c.3c.4b.5e.6f,
1d.2c.3c.4b.5f.6a,1d.2c.3c.4b.5f.6b,1d.2c.3c.4b.5f.6c,1d.2c.3c.4b.5f.6d,1d.2c.3c.4b.5f.6e,
1d.2c.3c.4b.5f.6f,1d.2c.3c.4c.5a.6a,1d.2c.3c.4c.5a.6b,1d.2c.3c.4c.5a.6c,1d.2c.3c.4c.5a.6d,
1d.2c.3c.4c.5a.6e,1d.2c.3c.4c.5a.6f,1d.2c.3c.4c.5b.6a,1d.2c.3c.4c.5b.6b,1d.2c.3c.4c.5b.6c,
1d.2c.3c.4c.5b.6d,1d.2c.3c.4c.5b.6e,1d.2c.3c.4c.5b.6f,1d.2c.3c.4c.5c.6a,1d.2c.3c.4c.5c.6b,
1d.2c.3c.4c.5c.6c,1d.2c.3c.4c.5c.6d,1d.2c.3c.4c.5c.6e,1d.2c.3c.4c.5c.6f,1d.2c.3c.4c.5d.6a,
1d.2c.3c.4c.5d.6b,1d.2c.3c.4c.5d.6c,1d.2c.3c.4c.5d.6d,1d.2c.3c.4c.5d.6e,1d.2c.3c.4c.5d.6f,
1d.2c.3c.4c.5e.6a,1d.2c.3c.4c.5e.6b,1d.2c.3c.4c.5e.6c,1d.2c.3c.4c.5e.6d,1d.2c.3c.4c.5e.6e,
1d.2c.3c.4c.5e.6f,1d.2c.3c.4c.5f.6a,1d.2c.3c.4c.5f.6b,1d.2c.3c.4c.5f.6c,1d.2c.3c.4c.5f.6d,
1d.2c.3c.4c.5f.6e,1d.2c.3c.4c.5f.6f,1d.2c.3c.4d.5a.6a,1d.2c.3c.4d.5a.6b,1d.2c.3c.4d.5a.6c,
1d.2c.3c.4d.5a.6d,1d.2c.3c.4d.5a.6e,1d.2c.3c.4d.5a.6f,1d.2c.3c.4d.5b.6a,1d.2c.3c.4d.5b.6b,
1d.2c.3c.4d.5b.6c,1d.2c.3c.4d.5b.6d,1d.2c.3c.4d.5b.6e,1d.2c.3c.4d.5b.6f,1d.2c.3c.4d.5c.6a,
1d.2c.3c.4d.5c.6b,1d.2c.3c.4d.5c.6c,1d.2c.3c.4d.5c.6d,1d.2c.3c.4d.5c.6e,1d.2c.3c.4d.5c.6f,
1d.2c.3c.4d.5d.6a,1d.2c.3c.4d.5d.6b,1d.2c.3c.4d.5d.6c,1d.2c.3c.4d.5d.6d,1d.2c.3c.4d.5d.6e,
1d.2c.3c.4d.5d.6f,1d.2c.3c.4d.5e.6a,1d.2c.3c.4d.5e.6b,1d.2c.3c.4d.5e.6c,1d.2c.3c.4d.5e.6d,
1d.2c.3c.4d.5e.6e,1d.2c.3c.4d.5e.6f,1d.2c.3c.4d.5f.6a,1d.2c.3c.4d.5f.6b,1d.2c.3c.4d.5f.6c,
1d.2c.3c.4d.5f.6d,1d.2c.3c.4d.5f.6e,1d.2c.3c.4d.5f.6f,1d.2c.3c.4e.5a.6a,1d.2c.3c.4e.5a.6b,
1d.2c.3c.4e.5a.6c,1d.2c.3c.4e.5a.6d,1d.2c.3c.4e.5a.6e,1d.2c.3c.4e.5a.6f,1d.2c.3c.4e.5b.6a,
1d.2c.3c.4e.5b.6b,1d.2c.3c.4e.5b.6c,1d.2c.3c.4e.5b.6d,1d.2c.3c.4e.5b.6e,1d.2c.3c.4e.5b.6f,
1d.2c.3c.4e.5c.6a,1d.2c.3c.4e.5c.6b,1d.2c.3c.4e.5c.6c,1d.2c.3c.4e.5c.6d,1d.2c.3c.4e.5c.6e,
1d.2c.3c.4e.5c.6f,1d.2c.3c.4e.5d.6a,1d.2c.3c.4e.5d.6b,1d.2c.3c.4e.5d.6c,1d.2c.3c.4e.5d.6d,
1d.2c.3c.4e.5d.6e,1d.2c.3c.4e.5d.6f,1d.2c.3c.4e.5e.6a,1d.2c.3c.4e.5e.6b,1d.2c.3c.4e.5e.6c,
1d.2c.3c.4e.5e.6d,1d.2c.3c.4e.5e.6e,1d.2c.3c.4e.5e.6f,1d.2c.3c.4e.5f.6a,1d.2c.3c.4e.5f.6b,
1d.2c.3c.4e.5f.6c,1d.2c.3c.4e.5f.6d,1d.2c.3c.4e.5f.6e,1d.2c.3c.4e.5f.6f,1d.2c.3c.4f.5a.6a,
1d.2c.3c.4f.5a.6b,1d.2c.3c.4f.5a.6c,1d.2c.3c.4f.5a.6d,1d.2c.3c.4f.5a.6e,1d.2c.3c.4f.5a.6f,
1d.2c.3c.4f.5b.6a,1d.2c.3c.4f.5b.6b,1d.2c.3c.4f.5b.6c,1d.2c.3c.4f.5b.6d,1d.2c.3c.4f.5b.6e,
1d.2c.3c.4f.5b.6f,1d.2c.3c.4f.5c.6a,1d.2c.3c.4f.5c.6b,1d.2c.3c.4f.5c.6c,1d.2c.3c.4f.5c.6d,
1d.2c.3c.4f.5c.6e,1d.2c.3c.4f.5c.6f,1d.2c.3c.4f.5d.6a,1d.2c.3c.4f.5d.6b,1d.2c.3c.4f.5d.6c,
1d.2c.3c.4f.5d.6d,1d.2c.3c.4f.5d.6e,1d.2c.3c.4f.5d.6f,1d.2c.3c.4f.5e.6a,1d.2c.3c.4f.5e.6b,
1d.2c.3c.4f.5e.6c,1d.2c.3c.4f.5e.6d,1d.2c.3c.4f.5e.6e,1d.2c.3c.4f.5e.6f,1d.2c.3c.4f.5f.6a,
1d.2c.3c.4f.5f.6b,1d.2c.3c.4f.5f.6c,1d.2c.3c.4f.5f.6d,1d.2c.3c.4f.5f.6e,1d.2c.3c.4f.5f.6f,
1d.2c.3d.4a.5a.6a,1d.2c.3d.4a.5a.6b,1d.2c.3d.4a.5a.6c,1d.2c.3d.4a.5a.6d,1d.2c.3d.4a.5a.6e,
1d.2c.3d.4a.5a.6f,1d.2c.3d.4a.5b.6a,1d.2c.3d.4a.5b.6b,1d.2c.3d.4a.5b.6c,1d.2c.3d.4a.5b.6d,
1d.2c.3d.4a.5b.6e,1d.2c.3d.4a.5b.6f,1d.2c.3d.4a.5c.6a,1d.2c.3d.4a.5c.6b,1d.2c.3d.4a.5c.6c,
1d.2c.3d.4a.5c.6d,1d.2c.3d.4a.5c.6e,1d.2c.3d.4a.5c.6f,1d.2c.3d.4a.5d.6a,1d.2c.3d.4a.5d.6b,
1d.2c.3d.4a.5d.6c,1d.2c.3d.4a.5d.6d,1d.2c.3d.4a.5d.6e,1d.2c.3d.4a.5d.6f,1d.2c.3d.4a.5e.6a,
1d.2c.3d.4a.5e.6b,1d.2c.3d.4a.5e.6c,1d.2c.3d.4a.5e.6d,1d.2c.3d.4a.5e.6e,1d.2c.3d.4a.5e.6f,
1d.2c.3d.4a.5f.6a,1d.2c.3d.4a.5f.6b,1d.2c.3d.4a.5f.6c,1d.2c.3d.4a.5f.6d,1d.2c.3d.4a.5f.6e,
1d.2c.3d.4a.5f.6f,1d.2c.3d.4b.5a.6a,1d.2c.3d.4b.5a.6b,1d.2c.3d.4b.5a.6c,1d.2c.3d.4b.5a.6d,
1d.2c.3d.4b.5a.6e,1d.2c.3d.4b.5a.6f,1d.2c.3d.4b.5b.6a,1d.2c.3d.4b.5b.6b,1d.2c.3d.4b.5b.6c,
1d.2c.3d.4b.5b.6d,1d.2c.3d.4b.5b.6e,1d.2c.3d.4b.5b.6f,1d.2c.3d.4b.5c.6a,1d.2c.3d.4b.5c.6b,
1d.2c.3d.4b.5c.6c,1d.2c.3d.4b.5c.6d,1d.2c.3d.4b.5c.6e,1d.2c.3d.4b.5c.6f,1d.2c.3d.4b.5d.6a,
1d.2c.3d.4b.5d.6b, 1d.2c.3d.4b.5d.6c, 1d.2c.3d.4b.5d.6d, 1d.2c.3d.4b.5d.6e,
1d.2c.3d.4b.5d.6f,1d.2c.3d.4b.5e.6a,1d.2c.3d.4b.5e.6b,1d.2c.3d.4b.5e.6c,1d.2c.3d.4b.5e.6d,
1d.2c.3d.4b.5e.6e,1d.2c.3d.4b.5e.6f,1d.2c.3d.4b.5f.6a,1d.2c.3d.4b.5f.6b,1d.2c.3d.4b.5f.6c,
1d.2c.3d.4b.5f.6d,1d.2c.3d.4b.5f.6e,1d.2c.3d.4b.5f.6f,1d.2c.3d.4c.5a.6a,1d.2c.3d.4c.5a.6b,
1d.2c.3d.4c.5a.6c,1d.2c.3d.4c.5a.6d,1d.2c.3d.4c.5a.6e,1d.2c.3d.4c.5a.6f,1d.2c.3d.4c.5b.6a,
1d.2c.3d.4c.5b.6b,1d.2c.3d.4c.5b.6c,1d.2c.3d.4c.5b.6d,1d.2c.3d.4c.5b.6e,1d.2c.3d.4c.5b.6f,
1d.2c.3d.4c.5c.6a,1d.2c.3d.4c.5c.6b,1d.2c.3d.4c.5c.6c,1d.2c.3d.4c.5c.6d,1d.2c.3d.4c.5c.6e,
1d.2c.3d.4c.5c.6f,1d.2c.3d.4c.5d.6a,1d.2c.3d.4c.5d.6b,1d.2c.3d.4c.5d.6c,1d.2c.3d.4c.5d.6d,
1d.2c.3d.4c.5d.6e,1d.2c.3d.4c.5d.6f,1d.2c.3d.4c.5e.6a,1d.2c.3d.4c.5e.6b,1d.2c.3d.4c.5e.6c,
1d.2c.3d.4c.5e.6d,1d.2c.3d.4c.5e.6e,1d.2c.3d.4c.5e.6f,1d.2c.3d.4c.5f.6a,1d.2c.3d.4c.5f.6b,
1d.2c.3d.4c.5f.6c,1d.2c.3d.4c.5f.6d,1d.2c.3d.4c.5f.6e,1d.2c.3d.4c.5f.6f,1d.2c.3d.4d.5a.6a,
1d.2c.3d.4d.5a.6b,1d.2c.3d.4d.5a.6c,1d.2c.3d.4d.5a.6d,1d.2c.3d.4d.5a.6e,1d.2c.3d.4d.5a.6f,
1d.2c.3d.4d.5b.6a, 1d.2c.3d.4d.5b.6b, 1d.2c.3d.4d.5b.6c, 1d.2c.3d.4d.5b.6d,
1d.2c.3d.4d.5b.6e,1d.2c.3d.4d.5b.6f,1d.2c.3d.4d.5c.6a,1d.2c.3d.4d.5c.6b,1d.2c.3d.4d.5c.6c,
1d.2c.3d.4d.5c.6d, 1d.2c.3d.4d.5c.6e, 1d.2c.3d.4d.5c.6f, 1d.2c.3d.4d.5d.6a,
1d.2c.3d.4d.5d.6b, 1d.2c.3d.4d.5d.6c, 1d.2c.3d.4d.5d.6d, 1d.2c.3d.4d.5d.6e,
1d.2c.3d.4d.5d.6f, 1d.2c.3d.4d.5e.6a, 1d.2c.3d.4d.5e.6b, 1d.2c.3d.4d.5e.6c,
1d.2c.3d.4d.5e.6d,1d.2c.3d.4d.5e.6e,1d.2c.3d.4d.5e.6f,1d.2c.3d.4d.5f.6a,1d.2c.3d.4d.5f.6b,
1d.2c.3d.4d.5f.6c,1d.2c.3d.4d.5f.6d,1d.2c.3d.4d.5f.6e,1d.2c.3d.4d.5f.6f,1d.2c.3d.4e.5a.6a,
1d.2c.3d.4e.5a.6b,1d.2c.3d.4e.5a.6c,1d.2c.3d.4e.5a.6d,1d.2c.3d.4e.5a.6e,1d.2c.3d.4e.5a.6f,
1d.2c.3d.4e.5b.6a,1d.2c.3d.4e.5b.6b,1d.2c.3d.4e.5b.6c,1d.2c.3d.4e.5b.6d,1d.2c.3d.4e.5b.6e,
1d.2c.3d.4e.5b.6f,1d.2c.3d.4e.5c.6a,1d.2c.3d.4e.5c.6b,1d.2c.3d.4e.5c.6c,1d.2c.3d.4e.5c.6d,
1d.2c.3d.4e.5c.6e,1d.2c.3d.4e.5c.6f,1d.2c.3d.4e.5d.6a,1d.2c.3d.4e.5d.6b,1d.2c.3d.4e.5d.6c,
1d.2c.3d.4e.5d.6d,1d.2c.3d.4e.5d.6e,1d.2c.3d.4e.5d.6f,1d.2c.3d.4e.5e.6a,1d.2c.3d.4e.5e.6b,
1d.2c.3d.4e.5e.6c,1d.2c.3d.4e.5e.6d,1d.2c.3d.4e.5e.6e,1d.2c.3d.4e.5e.6f,1d.2c.3d.4e.5f.6a,
1d.2c.3d.4e.5f.6b,1d.2c.3d.4e.5f.6c,1d.2c.3d.4e.5f.6d,1d.2c.3d.4e.5f.6e,1d.2c.3d.4e.5f.6f,
1d.2c.3d.4f.5a.6a,1d.2c.3d.4f.5a.6b,1d.2c.3d.4f.5a.6c,1d.2c.3d.4f.5a.6d,1d.2c.3d.4f.5a.6e,
1d.2c.3d.4f.5a.6f,1d.2c.3d.4f.5b.6a,1d.2c.3d.4f.5b.6b,1d.2c.3d.4f.5b.6c,1d.2c.3d.4f.5b.6d,
1d.2c.3d.4f.5b.6e,1d.2c.3d.4f.5b.6f,1d.2c.3d.4f.5c.6a,1d.2c.3d.4f.5c.6b,1d.2c.3d.4f.5c.6c,
1d.2c.3d.4f.5c.6d,1d.2c.3d.4f.5c.6e,1d.2c.3d.4f.5c.6f,1d.2c.3d.4f.5d.6a,1d.2c.3d.4f.5d.6b,
1d.2c.3d.4f.5d.6c,1d.2c.3d.4f.5d.6d,1d.2c.3d.4f.5d.6e,1d.2c.3d.4f.5d.6f,1d.2c.3d.4f.5e.6a,
1d.2c.3d.4f.5e.6b,1d.2c.3d.4f.5e.6c,1d.2c.3d.4f.5e.6d,1d.2c.3d.4f.5e.6e,1d.2c.3d.4f.5e.6f,
1d.2c.3d.4f.5f.6a,1d.2c.3d.4f.5f.6b,1d.2c.3d.4f.5f.6c,1d.2c.3d.4f.5f.6d,1d.2c.3d.4f.5f.6e,
1d.2c.3d.4f.5f.6f,1d.2c.3e.4a.5a.6a,1d.2c.3e.4a.5a.6b,1d.2c.3e.4a.5a.6c,1d.2c.3e.4a.5a.6d,
1d.2c.3e.4a.5a.6e,1d.2c.3e.4a.5a.6f,1d.2c.3e.4a.5b.6a,1d.2c.3e.4a.5b.6b,1d.2c.3e.4a.5b.6c,
1d.2c.3e.4a.5b.6d,1d.2c.3e.4a.5b.6e,1d.2c.3e.4a.5b.6f,1d.2c.3e.4a.5c.6a,1d.2c.3e.4a.5c.6b,
1d.2c.3e.4a.5c.6c,1d.2c.3e.4a.5c.6d,1d.2c.3e.4a.5c.6e,1d.2c.3e.4a.5c.6f,1d.2c.3e.4a.5d.6a,
1d.2c.3e.4a.5d.6b,1d.2c.3e.4a.5d.6c,1d.2c.3e.4a.5d.6d,1d.2c.3e.4a.5d.6e,1d.2c.3e.4a.5d.6f,
1d.2c.3e.4a.5e.6a,1d.2c.3e.4a.5e.6b,1d.2c.3e.4a.5e.6c,1d.2c.3e.4a.5e.6d,1d.2c.3e.4a.5e.6e,
1d.2c.3e.4a.5e.6f,1d.2c.3e.4a.5f.6a,1d.2c.3e.4a.5f.6b,1d.2c.3e.4a.5f.6c,1d.2c.3e.4a.5f.6d,
1d.2c.3e.4a.5f.6e,1d.2c.3e.4a.5f.6f,1d.2c.3e.4b.5a.6a,1d.2c.3e.4b.5a.6b,1d.2c.3e.4b.5a.6c,
1d.2c.3e.4b.5a.6d,1d.2c.3e.4b.5a.6e,1d.2c.3e.4b.5a.6f,1d.2c.3e.4b.5b.6a,1d.2c.3e.4b.5b.6b,
1d.2c.3e.4b.5b.6c,1d.2c.3e.4b.5b.6d,1d.2c.3e.4b.5b.6e,1d.2c.3e.4b.5b.6f,1d.2c.3e.4b.5c.6a,
1d.2c.3e.4b.5c.6b,1d.2c.3e.4b.5c.6c,1d.2c.3e.4b.5c.6d,1d.2c.3e.4b.5c.6e,1d.2c.3e.4b.5c.6f,
1d.2c.3e.4b.5d.6a,1d.2c.3e.4b.5d.6b,1d.2c.3e.4b.5d.6c,1d.2c.3e.4b.5d.6d,1d.2c.3e.4b.5d.6e,
1d.2c.3e.4b.5d.6f,1d.2c.3e.4b.5e.6a,1d.2c.3e.4b.5e.6b,1d.2c.3e.4b.5e.6c,1d.2c.3e.4b.5e.6d,
1d.2c.3e.4b.5e.6e,1d.2c.3e.4b.5e.6f,1d.2c.3e.4b.5f.6a,1d.2c.3e.4b.5f.6b,1d.2c.3e.4b.5f.6c,
1d.2c.3e.4b.5f.6d,1d.2c.3e.4b.5f.6e,1d.2c.3e.4b.5f.6f,1d.2c.3e.4c.5a.6a,1d.2c.3e.4c.5a.6b,
1d.2c.3e.4c.5a.6c,1d.2c.3e.4c.5a.6d,1d.2c.3e.4c.5a.6e,1d.2c.3e.4c.5a.6f,1d.2c.3e.4c.5b.6a,
1d.2c.3e.4c.5b.6b,1d.2c.3e.4c.5b.6c,1d.2c.3e.4c.5b.6d,1d.2c.3e.4c.5b.6e,1d.2c.3e.4c.5b.6f,
1d.2c.3e.4c.5c.6a,1d.2c.3e.4c.5c.6b,1d.2c.3e.4c.5c.6c,1d.2c.3e.4c.5c.6d,1d.2c.3e.4c.5c.6e,
1d.2c.3e.4c.5c.6f,1d.2c.3e.4c.5d.6a,1d.2c.3e.4c.5d.6b,1d.2c.3e.4c.5d.6c,1d.2c.3e.4c.5d.6d,
1d.2c.3e.4c.5d.6e,1d.2c.3e.4c.5d.6f,1d.2c.3e.4c.5e.6a,1d.2c.3e.4c.5e.6b,1d.2c.3e.4c.5e.6c,
1d.2c.3e.4c.5e.6d,1d.2c.3e.4c.5e.6e,1d.2c.3e.4c.5e.6f,1d.2c.3e.4c.5f.6a,1d.2c.3e.4c.5f.6b,
1d.2c.3e.4c.5f.6c,1d.2c.3e.4c.5f.6d,1d.2c.3e.4c.5f.6e,1d.2c.3e.4c.5f.6f,1d.2c.3e.4d.5a.6a,
1d.2c.3e.4d.5a.6b,1d.2c.3e.4d.5a.6c,1d.2c.3e.4d.5a.6d,1d.2c.3e.4d.5a.6e,1d.2c.3e.4d.5a.6f,
1d.2c.3e.4d.5b.6a,1d.2c.3e.4d.5b.6b,1d.2c.3e.4d.5b.6c,1d.2c.3e.4d.5b.6d,1d.2c.3e.4d.5b.6e,
1d.2c.3e.4d.5b.6f,1d.2c.3e.4d.5c.6a,1d.2c.3e.4d.5c.6b,1d.2c.3e.4d.5c.6c,1d.2c.3e.4d.5c.6d,
1d.2c.3e.4d.5c.6e,1d.2c.3e.4d.5c.6f,1d.2c.3e.4d.5d.6a,1d.2c.3e.4d.5d.6b,1d.2c.3e.4d.5d.6c,
1d.2c.3e.4d.5d.6d,1d.2c.3e.4d.5d.6e,1d.2c.3e.4d.5d.6f,1d.2c.3e.4d.5e.6a,1d.2c.3e.4d.5e.6b,
1d.2c.3e.4d.5e.6c,1d.2c.3e.4d.5e.6d,1d.2c.3e.4d.5e.6e,1d.2c.3e.4d.5e.6f,1d.2c.3e.4d.5f.6a,
1d.2c.3e.4d.5f.6b,1d.2c.3e.4d.5f.6c,1d.2c.3e.4d.5f.6d,1d.2c.3e.4d.5f.6e,1d.2c.3e.4d.5f.6f,
1d.2c.3e.4e.5a.6a,1d.2c.3e.4e.5a.6b,1d.2c.3e.4e.5a.6c,1d.2c.3e.4e.5a.6d,1d.2c.3e.4e.5a.6e,
1d.2c.3e.4e.5a.6f,1d.2c.3e.4e.5b.6a,1d.2c.3e.4e.5b.6b,1d.2c.3e.4e.5b.6c,1d.2c.3e.4e.5b.6d,
1d.2c.3e.4e.5b.6e,1d.2c.3e.4e.5b.6f,1d.2c.3e.4e.5c.6a,1d.2c.3e.4e.5c.6b,1d.2c.3e.4e.5c.6c,
1d.2c.3e.4e.5c.6d,1d.2c.3e.4e.5c.6e,1d.2c.3e.4e.5c.6f,1d.2c.3e.4e.5d.6a,1d.2c.3e.4e.5d.6b,
1d.2c.3e.4e.5d.6c,1d.2c.3e.4e.5d.6d,1d.2c.3e.4e.5d.6e,1d.2c.3e.4e.5d.6f,1d.2c.3e.4e.5e.6a,
1d.2c.3e.4e.5e.6b,1d.2c.3e.4e.5e.6c,1d.2c.3e.4e.5e.6d,1d.2c.3e.4e.5e.6e,1d.2c.3e.4e.5e.6f,
1d.2c.3e.4e.5f.6a,1d.2c.3e.4e.5f.6b,1d.2c.3e.4e.5f.6c,1d.2c.3e.4e.5f.6d,1d.2c.3e.4e.5f.6e,
1d.2c.3e.4e.5f.6f,1d.2c.3e.4f.5a.6a,1d.2c.3e.4f.5a.6b,1d.2c.3e.4f.5a.6c,1d.2c.3e.4f.5a.6d,
1d.2c.3e.4f.5a.6e,1d.2c.3e.4f.5a.6f,1d.2c.3e.4f.5b.6a,1d.2c.3e.4f.5b.6b,1d.2c.3e.4f.5b.6c,
1d.2c.3e.4f.5b.6d,1d.2c.3e.4f.5b.6e,1d.2c.3e.4f.5b.6f,1d.2c.3e.4f.5c.6a,1d.2c.3e.4f.5c.6b,
1d.2c.3e.4f.5c.6c,1d.2c.3e.4f.5c.6d,1d.2c.3e.4f.5c.6e,1d.2c.3e.4f.5c.6f,1d.2c.3e.4f.5d.6a,
1d.2c.3e.4f.5d.6b,1d.2c.3e.4f.5d.6c,1d.2c.3e.4f.5d.6d,1d.2c.3e.4f.5d.6e,1d.2c.3e.4f.5d.6f,
1d.2c.3e.4f.5e.6a,1d.2c.3e.4f.5e.6b,1d.2c.3e.4f.5e.6c,1d.2c.3e.4f.5e.6d,1d.2c.3e.4f.5e.6e,
1d.2c.3e.4f.5e.6f,1d.2c.3e.4f.5f.6a,1d.2c.3e.4f.5f.6b,1d.2c.3e.4f.5f.6c,1d.2c.3e.4f.5f.6d,
1d.2c.3e.4f.5f.6e,1d.2c.3e.4f.5f.6f,1d.2c.3f.4a.5a.6a,1d.2c.3f.4a.5a.6b,1d.2c.3f.4a.5a.6c,
1d.2c.3f.4a.5a.6d,1d.2c.3f.4a.5a.6e,1d.2c.3f.4a.5a.6f,1d.2c.3f.4a.5b.6a,1d.2c.3f.4a.5b.6b,
1d.2c.3f.4a.5b.6c,1d.2c.3f.4a.5b.6d,1d.2c.3f.4a.5b.6e,1d.2c.3f.4a.5b.6f,1d.2c.3f.4a.5c.6a,
1d.2c.3f.4a.5c.6b,1d.2c.3f.4a.5c.6c,1d.2c.3f.4a.5c.6d,1d.2c.3f.4a.5c.6e,1d.2c.3f.4a.5c.6f,
1d.2c.3f.4a.5d.6a,1d.2c.3f.4a.5d.6b,1d.2c.3f.4a.5d.6c,1d.2c.3f.4a.5d.6d,1d.2c.3f.4a.5d.6e,
1d.2c.3f.4a.5d.6f,1d.2c.3f.4a.5e.6a,1d.2c.3f.4a.5e.6b,1d.2c.3f.4a.5e.6c,1d.2c.3f.4a.5e.6d,
1d.2c.3f.4a.5e.6e,1d.2c.3f.4a.5e.6f,1d.2c.3f.4a.5f.6a,1d.2c.3f.4a.5f.6b,1d.2c.3f.4a.5f.6c,
1d.2c.3f.4a.5f.6d,1d.2c.3f.4a.5f.6e,1d.2c.3f.4a.5f.6f,1d.2c.3f.4b.5a.6a,1d.2c.3f.4b.5a.6b,
1d.2c.3f.4b.5a.6c,1d.2c.3f.4b.5a.6d,1d.2c.3f.4b.5a.6e,1d.2c.3f.4b.5a.6f,1d.2c.3f.4b.5b.6a,
1d.2c.3f.4b.5b.6b,1d.2c.3f.4b.5b.6c,1d.2c.3f.4b.5b.6d,1d.2c.3f.4b.5b.6e,1d.2c.3f.4b.5b.6f,
1d.2c.3f.4b.5c.6a,1d.2c.3f.4b.5c.6b,1d.2c.3f.4b.5c.6c,1d.2c.3f.4b.5c.6d,1d.2c.3f.4b.5c.6e,
1d.2c.3f.4b.5c.6f,1d.2c.3f.4b.5d.6a,1d.2c.3f.4b.5d.6b,1d.2c.3f.4b.5d.6c,1d.2c.3f.4b.5d.6d,
1d.2c.3f.4b.5d.6e,1d.2c.3f.4b.5d.6f,1d.2c.3f.4b.5e.6a,1d.2c.3f.4b.5e.6b,1d.2c.3f.4b.5e.6c,
1d.2c.3f.4b.5e.6d,1d.2c.3f.4b.5e.6e,1d.2c.3f.4b.5e.6f,1d.2c.3f.4b.5f.6a,1d.2c.3f.4b.5f.6b,
1d.2c.3f.4b.5f.6c,1d.2c.3f.4b.5f.6d,1d.2c.3f.4b.5f.6e,1d.2c.3f.4b.5f.6f,1d.2c.3f.4c.5a.6a,
1d.2c.3f.4c.5a.6b,1d.2c.3f.4c.5a.6c,1d.2c.3f.4c.5a.6d,1d.2c.3f.4c.5a.6e,1d.2c.3f.4c.5a.6f,
1d.2c.3f.4c.5b.6a,1d.2c.3f.4c.5b.6b,1d.2c.3f.4c.5b.6c,1d.2c.3f.4c.5b.6d,1d.2c.3f.4c.5b.6e,
1d.2c.3f.4c.5b.6f,1d.2c.3f.4c.5c.6a,1d.2c.3f.4c.5c.6b,1d.2c.3f.4c.5c.6c,1d.2c.3f.4c.5c.6d,
1d.2c.3f.4c.5c.6e,1d.2c.3f.4c.5c.6f,1d.2c.3f.4c.5d.6a,1d.2c.3f.4c.5d.6b,1d.2c.3f.4c.5d.6c,
1d.2c.3f.4c.5d.6d,1d.2c.3f.4c.5d.6e,1d.2c.3f.4c.5d.6f,1d.2c.3f.4c.5e.6a,1d.2c.3f.4c.5e.6b,
1d.2c.3f.4c.5e.6c,1d.2c.3f.4c.5e.6d,1d.2c.3f.4c.5e.6e,1d.2c.3f.4c.5e.6f,1d.2c.3f.4c.5f.6a,
1d.2c.3f.4c.5f.6b,1d.2c.3f.4c.5f.6c,1d.2c.3f.4c.5f.6d,1d.2c.3f.4c.5f.6e,1d.2c.3f.4c.5f.6f,
1d.2c.3f.4d.5a.6a,1d.2c.3f.4d.5a.6b,1d.2c.3f.4d.5a.6c,1d.2c.3f.4d.5a.6d,1d.2c.3f.4d.5a.6e,
1d.2c.3f.4d.5a.6f,1d.2c.3f.4d.5b.6a,1d.2c.3f.4d.5b.6b,1d.2c.3f.4d.5b.6c,1d.2c.3f.4d.5b.6d,
1d.2c.3f.4d.5b.6e,1d.2c.3f.4d.5b.6f,1d.2c.3f.4d.5c.6a,1d.2c.3f.4d.5c.6b,1d.2c.3f.4d.5c.6c,
1d.2c.3f.4d.5c.6d,1d.2c.3f.4d.5c.6e,1d.2c.3f.4d.5c.6f,1d.2c.3f.4d.5d.6a,1d.2c.3f.4d.5d.6b,
1d.2c.3f.4d.5d.6c,1d.2c.3f.4d.5d.6d,1d.2c.3f.4d.5d.6e,1d.2c.3f.4d.5d.6f,1d.2c.3f.4d.5e.6a,
1d.2c.3f.4d.5e.6b,1d.2c.3f.4d.5e.6c,1d.2c.3f.4d.5e.6d,1d.2c.3f.4d.5e.6e,1d.2c.3f.4d.5e.6f,
1d.2c.3f.4d.5f.6a,1d.2c.3f.4d.5f.6b,1d.2c.3f.4d.5f.6c,1d.2c.3f.4d.5f.6d,1d.2c.3f.4d.5f.6e,
1d.2c.3f.4d.5f.6f,1d.2c.3f.4e.5a.6a,1d.2c.3f.4e.5a.6b,1d.2c.3f.4e.5a.6c,1d.2c.3f.4e.5a.6d,
1d.2c.3f.4e.5a.6e,1d.2c.3f.4e.5a.6f,1d.2c.3f.4e.5b.6a,1d.2c.3f.4e.5b.6b,1d.2c.3f.4e.5b.6c,
1d.2c.3f.4e.5b.6d,1d.2c.3f.4e.5b.6e,1d.2c.3f.4e.5b.6f,1d.2c.3f.4e.5c.6a,1d.2c.3f.4e.5c.6b,
1d.2c.3f.4e.5c.6c,1d.2c.3f.4e.5c.6d,1d.2c.3f.4e.5c.6e,1d.2c.3f.4e.5c.6f,1d.2c.3f.4e.5d.6a,
1d.2c.3f.4e.5d.6b,1d.2c.3f.4e.5d.6c,1d.2c.3f.4e.5d.6d,1d.2c.3f.4e.5d.6e,1d.2c.3f.4e.5d.6f,
1d.2c.3f.4e.5e.6a,1d.2c.3f.4e.5e.6b,1d.2c.3f.4e.5e.6c,1d.2c.3f.4e.5e.6d,1d.2c.3f.4e.5e.6e,
1d.2c.3f.4e.5e.6f,1d.2c.3f.4e.5f.6a,1d.2c.3f.4e.5f.6b,1d.2c.3f.4e.5f.6c,1d.2c.3f.4e.5f.6d,
1d.2c.3f.4e.5f.6e,1d.2c.3f.4e.5f.6f,1d.2c.3f.4f.5a.6a,1d.2c.3f.4f.5a.6b,1d.2c.3f.4f.5a.6c,
1d.2c.3f.4f.5a.6d,1d.2c.3f.4f.5a.6e,1d.2c.3f.4f.5a.6f,1d.2c.3f.4f.5b.6a,1d.2c.3f.4f.5b.6b,
1d.2c.3f.4f.5b.6c,1d.2c.3f.4f.5b.6d,1d.2c.3f.4f.5b.6e,1d.2c.3f.4f.5b.6f,1d.2c.3f.4f.5c.6a,
1d.2c.3f.4f.5c.6b,1d.2c.3f.4f.5c.6c,1d.2c.3f.4f.5c.6d,1d.2c.3f.4f.5c.6e,1d.2c.3f.4f.5c.6f,
1d.2c.3f.4f.5d.6a,1d.2c.3f.4f.5d.6b,1d.2c.3f.4f.5d.6c,1d.2c.3f.4f.5d.6d,1d.2c.3f.4f.5d.6e,
1d.2c.3f.4f.5d.6f,1d.2c.3f.4f.5e.6a,1d.2c.3f.4f.5e.6b,1d.2c.3f.4f.5e.6c,1d.2c.3f.4f.5e.6d,
1d.2c.3f.4f.5e.6e,1d.2c.3f.4f.5e.6f,1d.2c.3f.4f.5f.6a,1d.2c.3f.4f.5f.6b,1d.2c.3f.4f.5f.6c,
1d.2c.3f.4f.5f.6d,1d.2c.3f.4f.5f.6e,1d.2c.3f.4f.5f.6f,1d.2d.3a.4a.5a.6a,1d.2d.3a.4a.5a.6b,
1d.2d.3a.4a.5a.6c,1d.2d.3a.4a.5a.6d,1d.2d.3a.4a.5a.6e,1d.2d.3a.4a.5a.6f,1d.2d.3a.4a.5b.6a,
1d.2d.3a.4a.5b.6b,1d.2d.3a.4a.5b.6c,1d.2d.3a.4a.5b.6d,1d.2d.3a.4a.5b.6e,1d.2d.3a.4a.5b.6f,
1d.2d.3a.4a.5c.6a,1d.2d.3a.4a.5c.6b,1d.2d.3a.4a.5c.6c,1d.2d.3a.4a.5c.6d,1d.2d.3a.4a.5c.6e,
1d.2d.3a.4a.5c.6f, 1d.2d.3a.4a.5d.6a, 1d.2d.3a.4a.5d.6b, 1d.2d.3a.4a.5d.6c,
1d.2d.3a.4a.5d.6d, 1d.2d.3a.4a.5d.6e, 1d.2d.3a.4a.5d.6f, 1d.2d.3a.4a.5e.6a,
1d.2d.3a.4a.5e.6b,1d.2d.3a.4a.5e.6c,1d.2d.3a.4a.5e.6d,1d.2d.3a.4a.5e.6e,1d.2d.3a.4a.5e.6f,
1d.2d.3a.4a.5f.6a,1d.2d.3a.4a.5f.6b,1d.2d.3a.4a.5f.6c,1d.2d.3a.4a.5f.6d,1d.2d.3a.4a.5f.6e,
1d.2d.3a.4a.5f.6f,1d.2d.3a.4b.5a.6a,1d.2d.3a.4b.5a.6b,1d.2d.3a.4b.5a.6c,1d.2d.3a.4b.5a.6d,
1d.2d.3a.4b.5a.6e, 1d.2d.3a.4b.5a.6f, 1d.2d.3a.4b.5b.6a, 1d.2d.3a.4b.5b.6b,
1d.2d.3a.4b.5b.6c, 1d.2d.3a.4b.5b.6d, 1d.2d.3a.4b.5b.6e, 1d.2d.3a.4b.5b.6f,
1d.2d.3a.4b.5c.6a,1d.2d.3a.4b.5c.6b,1d.2d.3a.4b.5c.6c,1d.2d.3a.4b.5c.6d,1d.2d.3a.4b.5c.6e,
1d.2d.3a.4b.5c.6f, 1d.2d.3a.4b.5d.6a, 1d.2d.3a.4b.5d.6b, 1d.2d.3a.4b.5d.6c,
1d.2d.3a.4b.5d.6d, 1d.2d.3a.4b.5d.6e, 1d.2d.3a.4b.5d.6f, 1d.2d.3a.4b.5e.6a,
1d.2d.3a.4b.5e.6b,1d.2d.3a.4b.5e.6c,1d.2d.3a.4b.5e.6d,1d.2d.3a.4b.5e.6e,1d.2d.3a.4b.5e.6f,
1d.2d.3a.4b.5f.6a,1d.2d.3a.4b.5f.6b,1d.2d.3a.4b.5f.6c,1d.2d.3a.4b.5f.6d,1d.2d.3a.4b.5f.6e,
1d.2d.3a.4b.5f.6f,1d.2d.3a.4c.5a.6a,1d.2d.3a.4c.5a.6b,1d.2d.3a.4c.5a.6c,1d.2d.3a.4c.5a.6d,
1d.2d.3a.4c.5a.6e,1d.2d.3a.4c.5a.6f,1d.2d.3a.4c.5b.6a,1d.2d.3a.4c.5b.6b,1d.2d.3a.4c.5b.6c,
1d.2d.3a.4c.5b.6d,1d.2d.3a.4c.5b.6e,1d.2d.3a.4c.5b.6f,1d.2d.3a.4c.5c.6a,1d.2d.3a.4c.5c.6b,
1d.2d.3a.4c.5c.6c,1d.2d.3a.4c.5c.6d,1d.2d.3a.4c.5c.6e,1d.2d.3a.4c.5c.6f,1d.2d.3a.4c.5d.6a,
1d.2d.3a.4c.5d.6b,1d.2d.3a.4c.5d.6c,1d.2d.3a.4c.5d.6d,1d.2d.3a.4c.5d.6e,1d.2d.3a.4c.5d.6f,
1d.2d.3a.4c.5e.6a,1d.2d.3a.4c.5e.6b,1d.2d.3a.4c.5e.6c,1d.2d.3a.4c.5e.6d,1d.2d.3a.4c.5e.6e,
1d.2d.3a.4c.5e.6f,1d.2d.3a.4c.5f.6a,1d.2d.3a.4c.5f.6b,1d.2d.3a.4c.5f.6c,1d.2d.3a.4c.5f.6d,
1d.2d.3a.4c.5f.6e,1d.2d.3a.4c.5f.6f,1d.2d.3a.4d.5a.6a,1d.2d.3a.4d.5a.6b,1d.2d.3a.4d.5a.6c,
1d.2d.3a.4d.5a.6d, 1d.2d.3a.4d.5a.6e, 1d.2d.3a.4d.5a.6f, 1d.2d.3a.4d.5b.6a,
1d.2d.3a.4d.5b.6b, 1d.2d.3a.4d.5b.6c, 1d.2d.3a.4d.5b.6d, 1d.2d.3a.4d.5b.6e,
1d.2d.3a.4d.5b.6f, 1d.2d.3a.4d.5c.6a, 1d.2d.3a.4d.5c.6b, 1d.2d.3a.4d.5c.6c,
1d.2d.3a.4d.5c.6d, 1d.2d.3a.4d.5c.6e, 1d.2d.3a.4d.5c.6f, 1d.2d.3a.4d.5d.6a,
1d.2d.3a.4d.5d.6b, 1d.2d.3a.4d.5d.6c, 1d.2d.3a.4d.5d.6d, 1d.2d.3a.4d.5d.6e,
1d.2d.3a.4d.5d.6f, 1d.2d.3a.4d.5e.6a, 1d.2d.3a.4d.5e.6b, 1d.2d.3a.4d.5e.6c,
1d.2d.3a.4d.5e.6d,1d.2d.3a.4d.5e.6e,1d.2d.3a.4d.5e.6f,1d.2d.3a.4d.5f.6a,1d.2d.3a.4d.5f.6b,
1d.2d.3a.4d.5f.6c,1d.2d.3a.4d.5f.6d,1d.2d.3a.4d.5f.6e,1d.2d.3a.4d.5f.6f,1d.2d.3a.4e.5a.6a,
1d.2d.3a.4e.5a.6b,1d.2d.3a.4e.5a.6c,1d.2d.3a.4e.5a.6d,1d.2d.3a.4e.5a.6e,1d.2d.3a.4e.5a.6f,
1d.2d.3a.4e.5b.6a, 1d.2d.3a.4e.5b.6b, 1d.2d.3a.4e.5b.6c, 1d.2d.3a.4e.5b.6d,
1d.2d.3a.4e.5b.6e,1d.2d.3a.4e.5b.6f,1d.2d.3a.4e.5c.6a,1d.2d.3a.4e.5c.6b,1d.2d.3a.4e.5c.6c,
1d.2d.3a.4e.5c.6d,1d.2d.3a.4e.5c.6e,1d.2d.3a.4e.5c.6f,1d.2d.3a.4e.5d.6a,1d.2d.3a.4e.5d.6b,
1d.2d.3a.4e.5d.6c,1d.2d.3a.4e.5d.6d,1d.2d.3a.4e.5d.6e,1d.2d.3a.4e.5d.6f,1d.2d.3a.4e.5e.6a,
1d.2d.3a.4e.5e.6b,1d.2d.3a.4e.5e.6c,1d.2d.3a.4e.5e.6d,1d.2d.3a.4e.5e.6e,1d.2d.3a.4e.5e.6f,
1d.2d.3a.4e.5f.6a,1d.2d.3a.4e.5f.6b,1d.2d.3a.4e.5f.6c,1d.2d.3a.4e.5f.6d,1d.2d.3a.4e.5f.6e,
1d.2d.3a.4e.5f.6f,1d.2d.3a.4f.5a.6a,1d.2d.3a.4f.5a.6b,1d.2d.3a.4f.5a.6c,1d.2d.3a.4f.5a.6d,
1d.2d.3a.4f.5a.6e,1d.2d.3a.4f.5a.6f,1d.2d.3a.4f.5b.6a,1d.2d.3a.4f.5b.6b,1d.2d.3a.4f.5b.6c,
1d.2d.3a.4f.5b.6d,1d.2d.3a.4f.5b.6e,1d.2d.3a.4f.5b.6f,1d.2d.3a.4f.5c.6a,1d.2d.3a.4f.5c.6b,
1d.2d.3a.4f.5c.6c,1d.2d.3a.4f.5c.6d,1d.2d.3a.4f.5c.6e,1d.2d.3a.4f.5c.6f,1d.2d.3a.4f.5d.6a,
1d.2d.3a.4f.5d.6b,1d.2d.3a.4f.5d.6c,1d.2d.3a.4f.5d.6d,1d.2d.3a.4f.5d.6e,1d.2d.3a.4f.5d.6f,
1d.2d.3a.4f.5e.6a,1d.2d.3a.4f.5e.6b,1d.2d.3a.4f.5e.6c,1d.2d.3a.4f.5e.6d,1d.2d.3a.4f.5e.6e,
1d.2d.3a.4f.5e.6f,1d.2d.3a.4f.5f.6a,1d.2d.3a.4f.5f.6b,1d.2d.3a.4f.5f.6c,1d.2d.3a.4f.5f.6d,
1d.2d.3a.4f.5f.6e,1d.2d.3a.4f.5f.6f,1d.2d.3b.4a.5a.6a,1d.2d.3b.4a.5a.6b,1d.2d.3b.4a.5a.6c,
1d.2d.3b.4a.5a.6d, 1d.2d.3b.4a.5a.6e, 1d.2d.3b.4a.5a.6f, 1d.2d.3b.4a.5b.6a,
1d.2d.3b.4a.5b.6b, 1d.2d.3b.4a.5b.6c, 1d.2d.3b.4a.5b.6d, 1d.2d.3b.4a.5b.6e,
1d.2d.3b.4a.5b.6f,1d.2d.3b.4a.5c.6a,1d.2d.3b.4a.5c.6b,1d.2d.3b.4a.5c.6c,1d.2d.3b.4a.5c.6d,
1d.2d.3b.4a.5c.6e, 1d.2d.3b.4a.5c.6f, 1d.2d.3b.4a.5d.6a, 1d.2d.3b.4a.5d.6b,
1d.2d.3b.4a.5d.6c, 1d.2d.3b.4a.5d.6d, 1d.2d.3b.4a.5d.6e, 1d.2d.3b.4a.5d.6f,
1d.2d.3b.4a.5e.6a, 1d.2d.3b.4a.5e.6b, 1d.2d.3b.4a.5e.6c, 1d.2d.3b.4a.5e.6d,
1d.2d.3b.4a.5e.6e,1d.2d.3b.4a.5e.6f,1d.2d.3b.4a.5f.6a,1d.2d.3b.4a.5f.6b,1d.2d.3b.4a.5f.6c,
1d.2d.3b.4a.5f.6d,1d.2d.3b.4a.5f.6e,1d.2d.3b.4a.5f.6f,1d.2d.3b.4b.5a.6a,1d.2d.3b.4b.5a.6b,
1d.2d.3b.4b.5a.6c, 1d.2d.3b.4b.5a.6d, 1d.2d.3b.4b.5a.6e, 1d.2d.3b.4b.5a.6f,
1d.2d.3b.4b.5b.6a, 1d.2d.3b.4b.5b.6b, 1d.2d.3b.4b.5b.6c, 1d.2d.3b.4b.5b.6d,
1d.2d.3b.4b.5b.6e, 1d.2d.3b.4b.5b.6f, 1d.2d.3b.4b.5c.6a, 1d.2d.3b.4b.5c.6b,
1d.2d.3b.4b.5c.6c, 1d.2d.3b.4b.5c.6d, 1d.2d.3b.4b.5c.6e, 1d.2d.3b.4b.5c.6f,
1d.2d.3b.4b.5d.6a, 1d.2d.3b.4b.5d.6b, 1d.2d.3b.4b.5d.6c, 1d.2d.3b.4b.5d.6d,
1d.2d.3b.4b.5d.6e, 1d.2d.3b.4b.5d.6f, 1d.2d.3b.4b.5e.6a, 1d.2d.3b.4b.5e.6b,
1d.2d.3b.4b.5e.6c,1d.2d.3b.4b.5e.6d,1d.2d.3b.4b.5e.6e,1d.2d.3b.4b.5e.6f,1d.2d.3b.4b.5f.6a,
1d.2d.3b.4b.5f.6b,1d.2d.3b.4b.5f.6c,1d.2d.3b.4b.5f.6d,1d.2d.3b.4b.5f.6e,1d.2d.3b.4b.5f.6f,
1d.2d.3b.4c.5a.6a,1d.2d.3b.4c.5a.6b,1d.2d.3b.4c.5a.6c,1d.2d.3b.4c.5a.6d,1d.2d.3b.4c.5a.6e,
1d.2d.3b.4c.5a.6f,1d.2d.3b.4c.5b.6a,1d.2d.3b.4c.5b.6b,1d.2d.3b.4c.5b.6c,1d.2d.3b.4c.5b.6d,
1d.2d.3b.4c.5b.6e,1d.2d.3b.4c.5b.6f,1d.2d.3b.4c.5c.6a,1d.2d.3b.4c.5c.6b,1d.2d.3b.4c.5c.6c,
1d.2d.3b.4c.5c.6d,1d.2d.3b.4c.5c.6e,1d.2d.3b.4c.5c.6f,1d.2d.3b.4c.5d.6a,1d.2d.3b.4c.5d.6b,
1d.2d.3b.4c.5d.6c, 1d.2d.3b.4c.5d.6d, 1d.2d.3b.4c.5d.6e, 1d.2d.3b.4c.5d.6f,
1d.2d.3b.4c.5e.6a,1d.2d.3b.4c.5e.6b,1d.2d.3b.4c.5e.6c,1d.2d.3b.4c.5e.6d,1d.2d.3b.4c.5e.6e,
1d.2d.3b.4c.5e.6f,1d.2d.3b.4c.5f.6a,1d.2d.3b.4c.5f.6b,1d.2d.3b.4c.5f.6c,1d.2d.3b.4c.5f.6d,
1d.2d.3b.4c.5f.6e,1d.2d.3b.4c.5f.6f,1d.2d.3b.4d.5a.6a,1d.2d.3b.4d.5a.6b,1d.2d.3b.4d.5a.6c,
1d.2d.3b.4d.5a.6d, 1d.2d.3b.4d.5a.6e, 1d.2d.3b.4d.5a.6f, 1d.2d.3b.4d.5b.6a,
1d.2d.3b.4d.5b.6b, 1d.2d.3b.4d.5b.6c, 1d.2d.3b.4d.5b.6d, 1d.2d.3b.4d.5b.6e,
1d.2d.3b.4d.5b.6f, 1d.2d.3b.4d.5c.6a, 1d.2d.3b.4d.5c.6b, 1d.2d.3b.4d.5c.6c,
1d.2d.3b.4d.5c.6d, 1d.2d.3b.4d.5c.6e, 1d.2d.3b.4d.5c.6f, 1d.2d.3b.4d.5d.6a,
1d.2d.3b.4d.5d.6b, 1d.2d.3b.4d.5d.6c, 1d.2d.3b.4d.5d.6d, 1d.2d.3b.4d.5d.6e,
1d.2d.3b.4d.5d.6f, 1d.2d.3b.4d.5e.6a, 1d.2d.3b.4d.5e.6b, 1d.2d.3b.4d.5e.6c,
1d.2d.3b.4d.5e.6d, 1d.2d.3b.4d.5e.6e, 1d.2d.3b.4d.5e.6f, 1d.2d.3b.4d.5f.6a,
1d.2d.3b.4d.5f.6b,1d.2d.3b.4d.5f.6c,1d.2d.3b.4d.5f.6d,1d.2d.3b.4d.5f.6e,1d.2d.3b.4d.5f.6f,
1d.2d.3b.4e.5a.6a, 1d.2d.3b.4e.5a.6b, 1d.2d.3b.4e.5a.6c, 1d.2d.3b.4e.5a.6d,
1d.2d.3b.4e.5a.6e,1d.2d.3b.4e.5a.6f,1d.2d.3b.4e.5b.6a,1d.2d.3b.4e.5b.6b,1d.2d.3b.4e.5b.6c,
1d.2d.3b.4e.5b.6d,1d.2d.3b.4e.5b.6e,1d.2d.3b.4e.5b.6f,1d.2d.3b.4e.5c.6a,1d.2d.3b.4e.5c.6b,
1d.2d.3b.4e.5c.6c,1d.2d.3b.4e.5c.6d,1d.2d.3b.4e.5c.6e,1d.2d.3b.4e.5c.6f,1d.2d.3b.4e.5d.6a,
1d.2d.3b.4e.5d.6b, 1d.2d.3b.4e.5d.6c, 1d.2d.3b.4e.5d.6d, 1d.2d.3b.4e.5d.6e,
1d.2d.3b.4e.5d.6f,1d.2d.3b.4e.5e.6a,1d.2d.3b.4e.5e.6b,1d.2d.3b.4e.5e.6c,1d.2d.3b.4e.5e.6d,
1d.2d.3b.4e.5e.6e,1d.2d.3b.4e.5e.6f,1d.2d.3b.4e.5f.6a,1d.2d.3b.4e.5f.6b,1d.2d.3b.4e.5f.6c,
1d.2d.3b.4e.5f.6d,1d.2d.3b.4e.5f.6e,1d.2d.3b.4e.5f.6f,1d.2d.3b.4f.5a.6a,1d.2d.3b.4f.5a.6b,
1d.2d.3b.4f.5a.6c,1d.2d.3b.4f.5a.6d,1d.2d.3b.4f.5a.6e,1d.2d.3b.4f.5a.6f,1d.2d.3b.4f.5b.6a,
1d.2d.3b.4f.5b.6b,1d.2d.3b.4f.5b.6c,1d.2d.3b.4f.5b.6d,1d.2d.3b.4f.5b.6e,1d.2d.3b.4f.5b.6f,
1d.2d.3b.4f.5c.6a,1d.2d.3b.4f.5c.6b,1d.2d.3b.4f.5c.6c,1d.2d.3b.4f.5c.6d,1d.2d.3b.4f.5c.6e,
1d.2d.3b.4f.5c.6f,1d.2d.3b.4f.5d.6a,1d.2d.3b.4f.5d.6b,1d.2d.3b.4f.5d.6c,1d.2d.3b.4f.5d.6d,
1d.2d.3b.4f.5d.6e,1d.2d.3b.4f.5d.6f,1d.2d.3b.4f.5e.6a,1d.2d.3b.4f.5e.6b,1d.2d.3b.4f.5e.6c,
1d.2d.3b.4f.5e.6d,1d.2d.3b.4f.5e.6e,1d.2d.3b.4f.5e.6f,1d.2d.3b.4f.5f.6a,1d.2d.3b.4f.5f.6b,
1d.2d.3b.4f.5f.6c,1d.2d.3b.4f.5f.6d,1d.2d.3b.4f.5f.6e,1d.2d.3b.4f.5f.6f,1d.2d.3c.4a.5a.6a,
1d.2d.3c.4a.5a.6b,1d.2d.3c.4a.5a.6c,1d.2d.3c.4a.5a.6d,1d.2d.3c.4a.5a.6e,1d.2d.3c.4a.5a.6f,
1d.2d.3c.4a.5b.6a,1d.2d.3c.4a.5b.6b,1d.2d.3c.4a.5b.6c,1d.2d.3c.4a.5b.6d,1d.2d.3c.4a.5b.6e,
1d.2d.3c.4a.5b.6f,1d.2d.3c.4a.5c.6a,1d.2d.3c.4a.5c.6b,1d.2d.3c.4a.5c.6c,1d.2d.3c.4a.5c.6d,
1d.2d.3c.4a.5c.6e,1d.2d.3c.4a.5c.6f,1d.2d.3c.4a.5d.6a,1d.2d.3c.4a.5d.6b,1d.2d.3c.4a.5d.6c,
1d.2d.3c.4a.5d.6d,1d.2d.3c.4a.5d.6e,1d.2d.3c.4a.5d.6f,1d.2d.3c.4a.5e.6a,1d.2d.3c.4a.5e.6b,
1d.2d.3c.4a.5e.6c,1d.2d.3c.4a.5e.6d,1d.2d.3c.4a.5e.6e,1d.2d.3c.4a.5e.6f,1d.2d.3c.4a.5f.6a,
1d.2d.3c.4a.5f.6b,1d.2d.3c.4a.5f.6c,1d.2d.3c.4a.5f.6d,1d.2d.3c.4a.5f.6e,1d.2d.3c.4a.5f.6f,
1d.2d.3c.4b.5a.6a,1d.2d.3c.4b.5a.6b,1d.2d.3c.4b.5a.6c,1d.2d.3c.4b.5a.6d,1d.2d.3c.4b.5a.6e,
1d.2d.3c.4b.5a.6f,1d.2d.3c.4b.5b.6a,1d.2d.3c.4b.5b.6b,1d.2d.3c.4b.5b.6c,1d.2d.3c.4b.5b.6d,
1d.2d.3c.4b.5b.6e,1d.2d.3c.4b.5b.6f,1d.2d.3c.4b.5c.6a,1d.2d.3c.4b.5c.6b,1d.2d.3c.4b.5c.6c,
1d.2d.3c.4b.5c.6d,1d.2d.3c.4b.5c.6e,1d.2d.3c.4b.5c.6f,1d.2d.3c.4b.5d.6a,1d.2d.3c.4b.5d.6b,
1d.2d.3c.4b.5d.6c, 1d.2d.3c.4b.5d.6d, 1d.2d.3c.4b.5d.6e, 1d.2d.3c.4b.5d.6f,
1d.2d.3c.4b.5e.6a,1d.2d.3c.4b.5e.6b,1d.2d.3c.4b.5e.6c,1d.2d.3c.4b.5e.6d,1d.2d.3c.4b.5e.6e,
1d.2d.3c.4b.5e.6f,1d.2d.3c.4b.5f.6a,1d.2d.3c.4b.5f.6b,1d.2d.3c.4b.5f.6c,1d.2d.3c.4b.5f.6d,
1d.2d.3c.4b.5f.6e,1d.2d.3c.4b.5f.6f,1d.2d.3c.4c.5a.6a,1d.2d.3c.4c.5a.6b,1d.2d.3c.4c.5a.6c,
1d.2d.3c.4c.5a.6d,1d.2d.3c.4c.5a.6e,1d.2d.3c.4c.5a.6f,1d.2d.3c.4c.5b.6a,1d.2d.3c.4c.5b.6b,
1d.2d.3c.4c.5b.6c,1d.2d.3c.4c.5b.6d,1d.2d.3c.4c.5b.6e,1d.2d.3c.4c.5b.6f,1d.2d.3c.4c.5c.6a,
1d.2d.3c.4c.5c.6b,1d.2d.3c.4c.5c.6c,1d.2d.3c.4c.5c.6d,1d.2d.3c.4c.5c.6e,1d.2d.3c.4c.5c.6f,
1d.2d.3c.4c.5d.6a,1d.2d.3c.4c.5d.6b,1d.2d.3c.4c.5d.6c,1d.2d.3c.4c.5d.6d,1d.2d.3c.4c.5d.6e,
1d.2d.3c.4c.5d.6f,1d.2d.3c.4c.5e.6a,1d.2d.3c.4c.5e.6b,1d.2d.3c.4c.5e.6c,1d.2d.3c.4c.5e.6d,
1d.2d.3c.4c.5e.6e,1d.2d.3c.4c.5e.6f,1d.2d.3c.4c.5f.6a,1d.2d.3c.4c.5f.6b,1d.2d.3c.4c.5f.6c,
1d.2d.3c.4c.5f.6d,1d.2d.3c.4c.5f.6e,1d.2d.3c.4c.5f.6f,1d.2d.3c.4d.5a.6a,1d.2d.3c.4d.5a.6b,
1d.2d.3c.4d.5a.6c,1d.2d.3c.4d.5a.6d,1d.2d.3c.4d.5a.6e,1d.2d.3c.4d.5a.6f,1d.2d.3c.4d.5b.6a,
1d.2d.3c.4d.5b.6b, 1d.2d.3c.4d.5b.6c, 1d.2d.3c.4d.5b.6d, 1d.2d.3c.4d.5b.6e,
1d.2d.3c.4d.5b.6f,1d.2d.3c.4d.5c.6a,1d.2d.3c.4d.5c.6b,1d.2d.3c.4d.5c.6c,1d.2d.3c.4d.5c.6d,
1d.2d.3c.4d.5c.6e, 1d.2d.3c.4d.5c.6f, 1d.2d.3c.4d.5d.6a, 1d.2d.3c.4d.5d.6b,
1d.2d.3c.4d.5d.6c, 1d.2d.3c.4d.5d.6d, 1d.2d.3c.4d.5d.6e, 1d.2d.3c.4d.5d.6f,
1d.2d.3c.4d.5e.6a, 1d.2d.3c.4d.5e.6b, 1d.2d.3c.4d.5e.6c, 1d.2d.3c.4d.5e.6d,
1d.2d.3c.4d.5e.6e,1d.2d.3c.4d.5e.6f,1d.2d.3c.4d.5f.6a,1d.2d.3c.4d.5f.6b,1d.2d.3c.4d.5f.6c,
1d.2d.3c.4d.5f.6d,1d.2d.3c.4d.5f.6e,1d.2d.3c.4d.5f.6f,1d.2d.3c.4e.5a.6a,1d.2d.3c.4e.5a.6b,
1d.2d.3c.4e.5a.6c,1d.2d.3c.4e.5a.6d,1d.2d.3c.4e.5a.6e,1d.2d.3c.4e.5a.6f,1d.2d.3c.4e.5b.6a,
1d.2d.3c.4e.5b.6b,1d.2d.3c.4e.5b.6c,1d.2d.3c.4e.5b.6d,1d.2d.3c.4e.5b.6e,1d.2d.3c.4e.5b.6f,
1d.2d.3c.4e.5c.6a,1d.2d.3c.4e.5c.6b,1d.2d.3c.4e.5c.6c,1d.2d.3c.4e.5c.6d,1d.2d.3c.4e.5c.6e,
1d.2d.3c.4e.5c.6f,1d.2d.3c.4e.5d.6a,1d.2d.3c.4e.5d.6b,1d.2d.3c.4e.5d.6c,1d.2d.3c.4e.5d.6d,
1d.2d.3c.4e.5d.6e,1d.2d.3c.4e.5d.6f,1d.2d.3c.4e.5e.6a,1d.2d.3c.4e.5e.6b,1d.2d.3c.4e.5e.6c,
1d.2d.3c.4e.5e.6d,1d.2d.3c.4e.5e.6e,1d.2d.3c.4e.5e.6f,1d.2d.3c.4e.5f.6a,1d.2d.3c.4e.5f.6b,
1d.2d.3c.4e.5f.6c,1d.2d.3c.4e.5f.6d,1d.2d.3c.4e.5f.6e,1d.2d.3c.4e.5f.6f,1d.2d.3c.4f.5a.6a,
1d.2d.3c.4f.5a.6b,1d.2d.3c.4f.5a.6c,1d.2d.3c.4f.5a.6d,1d.2d.3c.4f.5a.6e,1d.2d.3c.4f.5a.6f,
1d.2d.3c.4f.5b.6a,1d.2d.3c.4f.5b.6b,1d.2d.3c.4f.5b.6c,1d.2d.3c.4f.5b.6d,1d.2d.3c.4f.5b.6e,
1d.2d.3c.4f.5b.6f,1d.2d.3c.4f.5c.6a,1d.2d.3c.4f.5c.6b,1d.2d.3c.4f.5c.6c,1d.2d.3c.4f.5c.6d,
1d.2d.3c.4f.5c.6e,1d.2d.3c.4f.5c.6f,1d.2d.3c.4f.5d.6a,1d.2d.3c.4f.5d.6b,1d.2d.3c.4f.5d.6c,
1d.2d.3c.4f.5d.6d,1d.2d.3c.4f.5d.6e,1d.2d.3c.4f.5d.6f,1d.2d.3c.4f.5e.6a,1d.2d.3c.4f.5e.6b,
1d.2d.3c.4f.5e.6c,1d.2d.3c.4f.5e.6d,1d.2d.3c.4f.5e.6e,1d.2d.3c.4f.5e.6f,1d.2d.3c.4f.5f.6a,
1d.2d.3c.4f.5f.6b,1d.2d.3c.4f.5f.6c,1d.2d.3c.4f.5f.6d,1d.2d.3c.4f.5f.6e,1d.2d.3c.4f.5f.6f,
1d.2d.3d.4a.5a.6a, 1d.2d.3d.4a.5a.6b, 1d.2d.3d.4a.5a.6c, 1d.2d.3d.4a.5a.6d,
1d.2d.3d.4a.5a.6e, 1d.2d.3d.4a.5a.6f, 1d.2d.3d.4a.5b.6a, 1d.2d.3d.4a.5b.6b,
1d.2d.3d.4a.5b.6c, 1d.2d.3d.4a.5b.6d, 1d.2d.3d.4a.5b.6e, 1d.2d.3d.4a.5b.6f,
1d.2d.3d.4a.5c.6a, 1d.2d.3d.4a.5c.6b, 1d.2d.3d.4a.5c.6c, 1d.2d.3d.4a.5c.6d,
1d.2d.3d.4a.5c.6e, 1d.2d.3d.4a.5c.6f, 1d.2d.3d.4a.5d.6a, 1d.2d.3d.4a.5d.6b,
1d.2d.3d.4a.5d.6c, 1d.2d.3d.4a.5d.6d, 1d.2d.3d.4a.5d.6e, 1d.2d.3d.4a.5d.6f,
1d.2d.3d.4a.5e.6a, 1d.2d.3d.4a.5e.6b, 1d.2d.3d.4a.5e.6c, 1d.2d.3d.4a.5e.6d,
1d.2d.3d.4a.5e.6e,1d.2d.3d.4a.5e.6f,1d.2d.3d.4a.5f.6a,1d.2d.3d.4a.5f.6b,1d.2d.3d.4a.5f.6c,
1d.2d.3d.4a.5f.6d,1d.2d.3d.4a.5f.6e,1d.2d.3d.4a.5f.6f,1d.2d.3d.4b.5a.6a,1d.2d.3d.4b.5a.6b,
1d.2d.3d.4b.5a.6c, 1d.2d.3d.4b.5a.6d, 1d.2d.3d.4b.5a.6e, 1d.2d.3d.4b.5a.6f,
1d.2d.3d.4b.5b.6a, 1d.2d.3d.4b.5b.6b, 1d.2d.3d.4b.5b.6c, 1d.2d.3d.4b.5b.6d,
1d.2d.3d.4b.5b.6e, 1d.2d.3d.4b.5b.6f, 1d.2d.3d.4b.5c.6a, 1d.2d.3d.4b.5c.6b,
1d.2d.3d.4b.5c.6c, 1d.2d.3d.4b.5c.6d, 1d.2d.3d.4b.5c.6e, 1d.2d.3d.4b.5c.6f,
1d.2d.3d.4b.5d.6a, 1d.2d.3d.4b.5d.6b, 1d.2d.3d.4b.5d.6c, 1d.2d.3d.4b.5d.6d,
1d.2d.3d.4b.5d.6e, 1d.2d.3d.4b.5d.6f, 1d.2d.3d.4b.5e.6a, 1d.2d.3d.4b.5e.6b,
1d.2d.3d.4b.5e.6c, 1d.2d.3d.4b.5e.6d, 1d.2d.3d.4b.5e.6e, 1d.2d.3d.4b.5e.6f,
1d.2d.3d.4b.5f.6a,1d.2d.3d.4b.5f.6b,1d.2d.3d.4b.5f.6c,1d.2d.3d.4b.5f.6d,1d.2d.3d.4b.5f.6e,
1d.2d.3d.4b.5f.6f,1d.2d.3d.4c.5a.6a,1d.2d.3d.4c.5a.6b,1d.2d.3d.4c.5a.6c,1d.2d.3d.4c.5a.6d,
1d.2d.3d.4c.5a.6e, 1d.2d.3d.4c.5a.6f, 1d.2d.3d.4c.5b.6a, 1d.2d.3d.4c.5b.6b,
1d.2d.3d.4c.5b.6c, 1d.2d.3d.4c.5b.6d, 1d.2d.3d.4c.5b.6e, 1d.2d.3d.4c.5b.6f,
1d.2d.3d.4c.5c.6a,1d.2d.3d.4c.5c.6b,1d.2d.3d.4c.5c.6c,1d.2d.3d.4c.5c.6d,1d.2d.3d.4c.5c.6e,
1d.2d.3d.4c.5c.6f, 1d.2d.3d.4c.5d.6a, 1d.2d.3d.4c.5d.6b, 1d.2d.3d.4c.5d.6c,
1d.2d.3d.4c.5d.6d, 1d.2d.3d.4c.5d.6e, 1d.2d.3d.4c.5d.6f, 1d.2d.3d.4c.5e.6a,
1d.2d.3d.4c.5e.6b,1d.2d.3d.4c.5e.6c,1d.2d.3d.4c.5e.6d,1d.2d.3d.4c.5e.6e,1d.2d.3d.4c.5e.6f,
1d.2d.3d.4c.5f.6a,1d.2d.3d.4c.5f.6b,1d.2d.3d.4c.5f.6c,1d.2d.3d.4c.5f.6d,1d.2d.3d.4c.5f.6e,
1d.2d.3d.4c.5f.6f, 1d.2d.3d.4d.5a.6a, 1d.2d.3d.4d.5a.6b, 1d.2d.3d.4d.5a.6c,
1d.2d.3d.4d.5a.6d, 1d.2d.3d.4d.5a.6e, 1d.2d.3d.4d.5a.6f, 1d.2d.3d.4d.5b.6a,
1d.2d.3d.4d.5b.6b, 1d.2d.3d.4d.5b.6c, 1d.2d.3d.4d.5b.6d, 1d.2d.3d.4d.5b.6e,
1d.2d.3d.4d.5b.6f, 1d.2d.3d.4d.5c.6a, 1d.2d.3d.4d.5c.6b, 1d.2d.3d.4d.5c.6c,
1d.2d.3d.4d.5c.6d, 1d.2d.3d.4d.5c.6e, 1d.2d.3d.4d.5c.6f, 1d.2d.3d.4d.5d.6a,
1d.2d.3d.4d.5d.6b, 1d.2d.3d.4d.5d.6c, 1d.2d.3d.4d.5d.6d, 1d.2d.3d.4d.5d.6e,
1d.2d.3d.4d.5d.6f, 1d.2d.3d.4d.5e.6a, 1d.2d.3d.4d.5e.6b, 1d.2d.3d.4d.5e.6c,
1d.2d.3d.4d.5e.6d, 1d.2d.3d.4d.5e.6e, 1d.2d.3d.4d.5e.6f, 1d.2d.3d.4d.5f.6a,
1d.2d.3d.4d.5f.6b,1d.2d.3d.4d.5f.6c,1d.2d.3d.4d.5f.6d,1d.2d.3d.4d.5f.6e,1d.2d.3d.4d.5f.6f,
1d.2d.3d.4e.5a.6a, 1d.2d.3d.4e.5a.6b, 1d.2d.3d.4e.5a.6c, 1d.2d.3d.4e.5a.6d,
1d.2d.3d.4e.5a.6e, 1d.2d.3d.4e.5a.6f, 1d.2d.3d.4e.5b.6a, 1d.2d.3d.4e.5b.6b,
1d.2d.3d.4e.5b.6c, 1d.2d.3d.4e.5b.6d, 1d.2d.3d.4e.5b.6e, 1d.2d.3d.4e.5b.6f,
1d.2d.3d.4e.5c.6a, 1d.2d.3d.4e.5c.6b, 1d.2d.3d.4e.5c.6c, 1d.2d.3d.4e.5c.6d,
1d.2d.3d.4e.5c.6e, 1d.2d.3d.4e.5c.6f, 1d.2d.3d.4e.5d.6a, 1d.2d.3d.4e.5d.6b,
1d.2d.3d.4e.5d.6c, 1d.2d.3d.4e.5d.6d, 1d.2d.3d.4e.5d.6e, 1d.2d.3d.4e.5d.6f,
1d.2d.3d.4e.5e.6a, 1d.2d.3d.4e.5e.6b, 1d.2d.3d.4e.5e.6c, 1d.2d.3d.4e.5e.6d,
1d.2d.3d.4e.5e.6e,1d.2d.3d.4e.5e.6f,1d.2d.3d.4e.5f.6a,1d.2d.3d.4e.5f.6b,1d.2d.3d.4e.5f.6c,
1d.2d.3d.4e.5f.6d,1d.2d.3d.4e.5f.6e,1d.2d.3d.4e.5f.6f,1d.2d.3d.4f.5a.6a,1d.2d.3d.4f.5a.6b,
1d.2d.3d.4f.5a.6c,1d.2d.3d.4f.5a.6d,1d.2d.3d.4f.5a.6e,1d.2d.3d.4f.5a.6f,1d.2d.3d.4f.5b.6a,
1d.2d.3d.4f.5b.6b,1d.2d.3d.4f.5b.6c,1d.2d.3d.4f.5b.6d,1d.2d.3d.4f.5b.6e,1d.2d.3d.4f.5b.6f,
1d.2d.3d.4f.5c.6a,1d.2d.3d.4f.5c.6b,1d.2d.3d.4f.5c.6c,1d.2d.3d.4f.5c.6d,1d.2d.3d.4f.5c.6e,
1d.2d.3d.4f.5c.6f,1d.2d.3d.4f.5d.6a,1d.2d.3d.4f.5d.6b,1d.2d.3d.4f.5d.6c,1d.2d.3d.4f.5d.6d,
1d.2d.3d.4f.5d.6e,1d.2d.3d.4f.5d.6f,1d.2d.3d.4f.5e.6a,1d.2d.3d.4f.5e.6b,1d.2d.3d.4f.5e.6c,
1d.2d.3d.4f.5e.6d,1d.2d.3d.4f.5e.6e,1d.2d.3d.4f.5e.6f,1d.2d.3d.4f.5f.6a,1d.2d.3d.4f.5f.6b,
1d.2d.3d.4f.5f.6c,1d.2d.3d.4f.5f.6d,1d.2d.3d.4f.5f.6e,1d.2d.3d.4f.5f.6f,1d.2d.3e.4a.5a.6a,
1d.2d.3e.4a.5a.6b,1d.2d.3e.4a.5a.6c,1d.2d.3e.4a.5a.6d,1d.2d.3e.4a.5a.6e,1d.2d.3e.4a.5a.6f,
1d.2d.3e.4a.5b.6a, 1d.2d.3e.4a.5b.6b, 1d.2d.3e.4a.5b.6c, 1d.2d.3e.4a.5b.6d,
1d.2d.3e.4a.5b.6e,1d.2d.3e.4a.5b.6f,1d.2d.3e.4a.5c.6a,1d.2d.3e.4a.5c.6b,1d.2d.3e.4a.5c.6c,
1d.2d.3e.4a.5c.6d,1d.2d.3e.4a.5c.6e,1d.2d.3e.4a.5c.6f,1d.2d.3e.4a.5d.6a,1d.2d.3e.4a.5d.6b,
1d.2d.3e.4a.5d.6c,1d.2d.3e.4a.5d.6d,1d.2d.3e.4a.5d.6e,1d.2d.3e.4a.5d.6f,1d.2d.3e.4a.5e.6a,
1d.2d.3e.4a.5e.6b,1d.2d.3e.4a.5e.6c,1d.2d.3e.4a.5e.6d,1d.2d.3e.4a.5e.6e,1d.2d.3e.4a.5e.6f,
1d.2d.3e.4a.5f.6a,1d.2d.3e.4a.5f.6b,1d.2d.3e.4a.5f.6c,1d.2d.3e.4a.5f.6d,1d.2d.3e.4a.5f.6e,
1d.2d.3e.4a.5f.6f,1d.2d.3e.4b.5a.6a,1d.2d.3e.4b.5a.6b,1d.2d.3e.4b.5a.6c,1d.2d.3e.4b.5a.6d,
1d.2d.3e.4b.5a.6e,1d.2d.3e.4b.5a.6f,1d.2d.3e.4b.5b.6a,1d.2d.3e.4b.5b.6b,1d.2d.3e.4b.5b.6c,
1d.2d.3e.4b.5b.6d,1d.2d.3e.4b.5b.6e,1d.2d.3e.4b.5b.6f,1d.2d.3e.4b.5c.6a,1d.2d.3e.4b.5c.6b,
1d.2d.3e.4b.5c.6c,1d.2d.3e.4b.5c.6d,1d.2d.3e.4b.5c.6e,1d.2d.3e.4b.5c.6f,1d.2d.3e.4b.5d.6a,
1d.2d.3e.4b.5d.6b, 1d.2d.3e.4b.5d.6c, 1d.2d.3e.4b.5d.6d, 1d.2d.3e.4b.5d.6e,
1d.2d.3e.4b.5d.6f,1d.2d.3e.4b.5e.6a,1d.2d.3e.4b.5e.6b,1d.2d.3e.4b.5e.6c,1d.2d.3e.4b.5e.6d,
1d.2d.3e.4b.5e.6e,1d.2d.3e.4b.5e.6f,1d.2d.3e.4b.5f.6a,1d.2d.3e.4b.5f.6b,1d.2d.3e.4b.5f.6c,
1d.2d.3e.4b.5f.6d,1d.2d.3e.4b.5f.6e,1d.2d.3e.4b.5f.6f,1d.2d.3e.4c.5a.6a,1d.2d.3e.4c.5a.6b,
1d.2d.3e.4c.5a.6c,1d.2d.3e.4c.5a.6d,1d.2d.3e.4c.5a.6e,1d.2d.3e.4c.5a.6f,1d.2d.3e.4c.5b.6a,
1d.2d.3e.4c.5b.6b,1d.2d.3e.4c.5b.6c,1d.2d.3e.4c.5b.6d,1d.2d.3e.4c.5b.6e,1d.2d.3e.4c.5b.6f,
1d.2d.3e.4c.5c.6a,1d.2d.3e.4c.5c.6b,1d.2d.3e.4c.5c.6c,1d.2d.3e.4c.5c.6d,1d.2d.3e.4c.5c.6e,
1d.2d.3e.4c.5c.6f,1d.2d.3e.4c.5d.6a,1d.2d.3e.4c.5d.6b,1d.2d.3e.4c.5d.6c,1d.2d.3e.4c.5d.6d,
1d.2d.3e.4c.5d.6e,1d.2d.3e.4c.5d.6f,1d.2d.3e.4c.5e.6a,1d.2d.3e.4c.5e.6b,1d.2d.3e.4c.5e.6c,
1d.2d.3e.4c.5e.6d,1d.2d.3e.4c.5e.6e,1d.2d.3e.4c.5e.6f,1d.2d.3e.4c.5f.6a,1d.2d.3e.4c.5f.6b,
1d.2d.3e.4c.5f.6c,1d.2d.3e.4c.5f.6d,1d.2d.3e.4c.5f.6e,1d.2d.3e.4c.5f.6f,1d.2d.3e.4d.5a.6a,
1d.2d.3e.4d.5a.6b, 1d.2d.3e.4d.5a.6c, 1d.2d.3e.4d.5a.6d, 1d.2d.3e.4d.5a.6e,
1d.2d.3e.4d.5a.6f, 1d.2d.3e.4d.5b.6a, 1d.2d.3e.4d.5b.6b, 1d.2d.3e.4d.5b.6c,
1d.2d.3e.4d.5b.6d, 1d.2d.3e.4d.5b.6e, 1d.2d.3e.4d.5b.6f, 1d.2d.3e.4d.5c.6a,
1d.2d.3e.4d.5c.6b,1d.2d.3e.4d.5c.6c,1d.2d.3e.4d.5c.6d,1d.2d.3e.4d.5c.6e,1d.2d.3e.4d.5c.6f,
1d.2d.3e.4d.5d.6a, 1d.2d.3e.4d.5d.6b, 1d.2d.3e.4d.5d.6c, 1d.2d.3e.4d.5d.6d,
1d.2d.3e.4d.5d.6e, 1d.2d.3e.4d.5d.6f, 1d.2d.3e.4d.5e.6a, 1d.2d.3e.4d.5e.6b,
1d.2d.3e.4d.5e.6c,1d.2d.3e.4d.5e.6d,1d.2d.3e.4d.5e.6e,1d.2d.3e.4d.5e.6f,1d.2d.3e.4d.5f.6a,
1d.2d.3e.4d.5f.6b,1d.2d.3e.4d.5f.6c,1d.2d.3e.4d.5f.6d,1d.2d.3e.4d.5f.6e,1d.2d.3e.4d.5f.6f,
1d.2d.3e.4e.5a.6a,1d.2d.3e.4e.5a.6b,1d.2d.3e.4e.5a.6c,1d.2d.3e.4e.5a.6d,1d.2d.3e.4e.5a.6e,
1d.2d.3e.4e.5a.6f,1d.2d.3e.4e.5b.6a,1d.2d.3e.4e.5b.6b,1d.2d.3e.4e.5b.6c,1d.2d.3e.4e.5b.6d,
1d.2d.3e.4e.5b.6e,1d.2d.3e.4e.5b.6f,1d.2d.3e.4e.5c.6a,1d.2d.3e.4e.5c.6b,1d.2d.3e.4e.5c.6c,
1d.2d.3e.4e.5c.6d,1d.2d.3e.4e.5c.6e,1d.2d.3e.4e.5c.6f,1d.2d.3e.4e.5d.6a,1d.2d.3e.4e.5d.6b,
1d.2d.3e.4e.5d.6c,1d.2d.3e.4e.5d.6d,1d.2d.3e.4e.5d.6e,1d.2d.3e.4e.5d.6f,1d.2d.3e.4e.5e.6a,
1d.2d.3e.4e.5e.6b,1d.2d.3e.4e.5e.6c,1d.2d.3e.4e.5e.6d,1d.2d.3e.4e.5e.6e,1d.2d.3e.4e.5e.6f,
1d.2d.3e.4e.5f.6a,1d.2d.3e.4e.5f.6b,1d.2d.3e.4e.5f.6c,1d.2d.3e.4e.5f.6d,1d.2d.3e.4e.5f.6e,
1d.2d.3e.4e.5f.6f,1d.2d.3e.4f.5a.6a,1d.2d.3e.4f.5a.6b,1d.2d.3e.4f.5a.6c,1d.2d.3e.4f.5a.6d,
1d.2d.3e.4f.5a.6e,1d.2d.3e.4f.5a.6f,1d.2d.3e.4f.5b.6a,1d.2d.3e.4f.5b.6b,1d.2d.3e.4f.5b.6c,
1d.2d.3e.4f.5b.6d,1d.2d.3e.4f.5b.6e,1d.2d.3e.4f.5b.6f,1d.2d.3e.4f.5c.6a,1d.2d.3e.4f.5c.6b,
1d.2d.3e.4f.5c.6c,1d.2d.3e.4f.5c.6d,1d.2d.3e.4f.5c.6e,1d.2d.3e.4f.5c.6f,1d.2d.3e.4f.5d.6a,
1d.2d.3e.4f.5d.6b,1d.2d.3e.4f.5d.6c,1d.2d.3e.4f.5d.6d,1d.2d.3e.4f.5d.6e,1d.2d.3e.4f.5d.6f,
1d.2d.3e.4f.5e.6a,1d.2d.3e.4f.5e.6b,1d.2d.3e.4f.5e.6c,1d.2d.3e.4f.5e.6d,1d.2d.3e.4f.5e.6e,
1d.2d.3e.4f.5e.6f,1d.2d.3e.4f.5f.6a,1d.2d.3e.4f.5f.6b,1d.2d.3e.4f.5f.6c,1d.2d.3e.4f.5f.6d,
1d.2d.3e.4f.5f.6e,1d.2d.3e.4f.5f.6f,1d.2d.3f.4a.5a.6a,1d.2d.3f.4a.5a.6b,1d.2d.3f.4a.5a.6c,
1d.2d.3f.4a.5a.6d,1d.2d.3f.4a.5a.6e,1d.2d.3f.4a.5a.6f,1d.2d.3f.4a.5b.6a,1d.2d.3f.4a.5b.6b,
1d.2d.3f.4a.5b.6c,1d.2d.3f.4a.5b.6d,1d.2d.3f.4a.5b.6e,1d.2d.3f.4a.5b.6f,1d.2d.3f.4a.5c.6a,
1d.2d.3f.4a.5c.6b,1d.2d.3f.4a.5c.6c,1d.2d.3f.4a.5c.6d,1d.2d.3f.4a.5c.6e,1d.2d.3f.4a.5c.6f,
1d.2d.3f.4a.5d.6a,1d.2d.3f.4a.5d.6b,1d.2d.3f.4a.5d.6c,1d.2d.3f.4a.5d.6d,1d.2d.3f.4a.5d.6e,
1d.2d.3f.4a.5d.6f,1d.2d.3f.4a.5e.6a,1d.2d.3f.4a.5e.6b,1d.2d.3f.4a.5e.6c,1d.2d.3f.4a.5e.6d,
1d.2d.3f.4a.5e.6e,1d.2d.3f.4a.5e.6f,1d.2d.3f.4a.5f.6a,1d.2d.3f.4a.5f.6b,1d.2d.3f.4a.5f.6c,
1d.2d.3f.4a.5f.6d,1d.2d.3f.4a.5f.6e,1d.2d.3f.4a.5f.6f,1d.2d.3f.4b.5a.6a,1d.2d.3f.4b.5a.6b,
1d.2d.3f.4b.5a.6c,1d.2d.3f.4b.5a.6d,1d.2d.3f.4b.5a.6e,1d.2d.3f.4b.5a.6f,1d.2d.3f.4b.5b.6a,
1d.2d.3f.4b.5b.6b,1d.2d.3f.4b.5b.6c,1d.2d.3f.4b.5b.6d,1d.2d.3f.4b.5b.6e,1d.2d.3f.4b.5b.6f,
1d.2d.3f.4b.5c.6a,1d.2d.3f.4b.5c.6b,1d.2d.3f.4b.5c.6c,1d.2d.3f.4b.5c.6d,1d.2d.3f.4b.5c.6e,
1d.2d.3f.4b.5c.6f,1d.2d.3f.4b.5d.6a,1d.2d.3f.4b.5d.6b,1d.2d.3f.4b.5d.6c,1d.2d.3f.4b.5d.6d,
1d.2d.3f.4b.5d.6e,1d.2d.3f.4b.5d.6f,1d.2d.3f.4b.5e.6a,1d.2d.3f.4b.5e.6b,1d.2d.3f.4b.5e.6c,
1d.2d.3f.4b.5e.6d,1d.2d.3f.4b.5e.6e,1d.2d.3f.4b.5e.6f,1d.2d.3f.4b.5f.6a,1d.2d.3f.4b.5f.6b,
1d.2d.3f.4b.5f.6c,1d.2d.3f.4b.5f.6d,1d.2d.3f.4b.5f.6e,1d.2d.3f.4b.5f.6f,1d.2d.3f.4c.5a.6a,
1d.2d.3f.4c.5a.6b,1d.2d.3f.4c.5a.6c,1d.2d.3f.4c.5a.6d,1d.2d.3f.4c.5a.6e,1d.2d.3f.4c.5a.6f,
1d.2d.3f.4c.5b.6a,1d.2d.3f.4c.5b.6b,1d.2d.3f.4c.5b.6c,1d.2d.3f.4c.5b.6d,1d.2d.3f.4c.5b.6e,
1d.2d.3f.4c.5b.6f,1d.2d.3f.4c.5c.6a,1d.2d.3f.4c.5c.6b,1d.2d.3f.4c.5c.6c,1d.2d.3f.4c.5c.6d,
1d.2d.3f.4c.5c.6e,1d.2d.3f.4c.5c.6f,1d.2d.3f.4c.5d.6a,1d.2d.3f.4c.5d.6b,1d.2d.3f.4c.5d.6c,
1d.2d.3f.4c.5d.6d,1d.2d.3f.4c.5d.6e,1d.2d.3f.4c.5d.6f,1d.2d.3f.4c.5e.6a,1d.2d.3f.4c.5e.6b,
1d.2d.3f.4c.5e.6c,1d.2d.3f.4c.5e.6d,1d.2d.3f.4c.5e.6e,1d.2d.3f.4c.5e.6f,1d.2d.3f.4c.5f.6a,
1d.2d.3f.4c.5f.6b,1d.2d.3f.4c.5f.6c,1d.2d.3f.4c.5f.6d,1d.2d.3f.4c.5f.6e,1d.2d.3f.4c.5f.6f,
1d.2d.3f.4d.5a.6a,1d.2d.3f.4d.5a.6b,1d.2d.3f.4d.5a.6c,1d.2d.3f.4d.5a.6d,1d.2d.3f.4d.5a.6e,
1d.2d.3f.4d.5a.6f,1d.2d.3f.4d.5b.6a,1d.2d.3f.4d.5b.6b,1d.2d.3f.4d.5b.6c,1d.2d.3f.4d.5b.6d,
1d.2d.3f.4d.5b.6e,1d.2d.3f.4d.5b.6f,1d.2d.3f.4d.5c.6a,1d.2d.3f.4d.5c.6b,1d.2d.3f.4d.5c.6c,
1d.2d.3f.4d.5c.6d,1d.2d.3f.4d.5c.6e,1d.2d.3f.4d.5c.6f,1d.2d.3f.4d.5d.6a,1d.2d.3f.4d.5d.6b,
1d.2d.3f.4d.5d.6c,1d.2d.3f.4d.5d.6d,1d.2d.3f.4d.5d.6e,1d.2d.3f.4d.5d.6f,1d.2d.3f.4d.5e.6a,
1d.2d.3f.4d.5e.6b,1d.2d.3f.4d.5e.6c,1d.2d.3f.4d.5e.6d,1d.2d.3f.4d.5e.6e,1d.2d.3f.4d.5e.6f,
1d.2d.3f.4d.5f.6a,1d.2d.3f.4d.5f.6b,1d.2d.3f.4d.5f.6c,1d.2d.3f.4d.5f.6d,1d.2d.3f.4d.5f.6e,
1d.2d.3f.4d.5f.6f,1d.2d.3f.4e.5a.6a,1d.2d.3f.4e.5a.6b,1d.2d.3f.4e.5a.6c,1d.2d.3f.4e.5a.6d,
1d.2d.3f.4e.5a.6e,1d.2d.3f.4e.5a.6f,1d.2d.3f.4e.5b.6a,1d.2d.3f.4e.5b.6b,1d.2d.3f.4e.5b.6c,
1d.2d.3f.4e.5b.6d,1d.2d.3f.4e.5b.6e,1d.2d.3f.4e.5b.6f,1d.2d.3f.4e.5c.6a,1d.2d.3f.4e.5c.6b,
1d.2d.3f.4e.5c.6c,1d.2d.3f.4e.5c.6d,1d.2d.3f.4e.5c.6e,1d.2d.3f.4e.5c.6f,1d.2d.3f.4e.5d.6a,
1d.2d.3f.4e.5d.6b,1d.2d.3f.4e.5d.6c,1d.2d.3f.4e.5d.6d,1d.2d.3f.4e.5d.6e,1d.2d.3f.4e.5d.6f,
1d.2d.3f.4e.5e.6a,1d.2d.3f.4e.5e.6b,1d.2d.3f.4e.5e.6c,1d.2d.3f.4e.5e.6d,1d.2d.3f.4e.5e.6e,
1d.2d.3f.4e.5e.6f,1d.2d.3f.4e.5f.6a,1d.2d.3f.4e.5f.6b,1d.2d.3f.4e.5f.6c,1d.2d.3f.4e.5f.6d,
1d.2d.3f.4e.5f.6e,1d.2d.3f.4e.5f.6f,1d.2d.3f.4f.5a.6a,1d.2d.3f.4f.5a.6b,1d.2d.3f.4f.5a.6c,
1d.2d.3f.4f.5a.6d,1d.2d.3f.4f.5a.6e,1d.2d.3f.4f.5a.6f,1d.2d.3f.4f.5b.6a,1d.2d.3f.4f.5b.6b,
1d.2d.3f.4f.5b.6c,1d.2d.3f.4f.5b.6d,1d.2d.3f.4f.5b.6e,1d.2d.3f.4f.5b.6f,1d.2d.3f.4f.5c.6a,
1d.2d.3f.4f.5c.6b,1d.2d.3f.4f.5c.6c,1d.2d.3f.4f.5c.6d,1d.2d.3f.4f.5c.6e,1d.2d.3f.4f.5c.6f,
1d.2d.3f.4f.5d.6a,1d.2d.3f.4f.5d.6b,1d.2d.3f.4f.5d.6c,1d.2d.3f.4f.5d.6d,1d.2d.3f.4f.5d.6e,
1d.2d.3f.4f.5d.6f,1d.2d.3f.4f.5e.6a,1d.2d.3f.4f.5e.6b,1d.2d.3f.4f.5e.6c,1d.2d.3f.4f.5e.6d,
1d.2d.3f.4f.5e.6e,1d.2d.3f.4f.5e.6f,1d.2d.3f.4f.5f.6a,1d.2d.3f.4f.5f.6b,1d.2d.3f.4f.5f.6c,
1d.2d.3f.4f.5f.6d,1d.2d.3f.4f.5f.6e,1d.2d.3f.4f.5f.6f,1d.2e.3a.4a.5a.6a,1d.2e.3a.4a.5a.6b,
1d.2e.3a.4a.5a.6c,1d.2e.3a.4a.5a.6d,1d.2e.3a.4a.5a.6e,1d.2e.3a.4a.5a.6f,1d.2e.3a.4a.5b.6a,
1d.2e.3a.4a.5b.6b,1d.2e.3a.4a.5b.6c,1d.2e.3a.4a.5b.6d,1d.2e.3a.4a.5b.6e,1d.2e.3a.4a.5b.6f,
1d.2e.3a.4a.5c.6a,1d.2e.3a.4a.5c.6b,1d.2e.3a.4a.5c.6c,1d.2e.3a.4a.5c.6d,1d.2e.3a.4a.5c.6e,
1d.2e.3a.4a.5c.6f,1d.2e.3a.4a.5d.6a,1d.2e.3a.4a.5d.6b,1d.2e.3a.4a.5d.6c,1d.2e.3a.4a.5d.6d,
1d.2e.3a.4a.5d.6e,1d.2e.3a.4a.5d.6f,1d.2e.3a.4a.5e.6a,1d.2e.3a.4a.5e.6b,1d.2e.3a.4a.5e.6c,
1d.2e.3a.4a.5e.6d,1d.2e.3a.4a.5e.6e,1d.2e.3a.4a.5e.6f,1d.2e.3a.4a.5f.6a,1d.2e.3a.4a.5f.6b,
1d.2e.3a.4a.5f.6c,1d.2e.3a.4a.5f.6d,1d.2e.3a.4a.5f.6e,1d.2e.3a.4a.5f.6f,1d.2e.3a.4b.5a.6a,
1d.2e.3a.4b.5a.6b,1d.2e.3a.4b.5a.6c,1d.2e.3a.4b.5a.6d,1d.2e.3a.4b.5a.6e,1d.2e.3a.4b.5a.6f,
1d.2e.3a.4b.5b.6a,1d.2e.3a.4b.5b.6b,1d.2e.3a.4b.5b.6c,1d.2e.3a.4b.5b.6d,1d.2e.3a.4b.5b.6e,
1d.2e.3a.4b.5b.6f,1d.2e.3a.4b.5c.6a,1d.2e.3a.4b.5c.6b,1d.2e.3a.4b.5c.6c,1d.2e.3a.4b.5c.6d,
1d.2e.3a.4b.5c.6e,1d.2e.3a.4b.5c.6f,1d.2e.3a.4b.5d.6a,1d.2e.3a.4b.5d.6b,1d.2e.3a.4b.5d.6c,
1d.2e.3a.4b.5d.6d,1d.2e.3a.4b.5d.6e,1d.2e.3a.4b.5d.6f,1d.2e.3a.4b.5e.6a,1d.2e.3a.4b.5e.6b,
1d.2e.3a.4b.5e.6c,1d.2e.3a.4b.5e.6d,1d.2e.3a.4b.5e.6e,1d.2e.3a.4b.5e.6f,1d.2e.3a.4b.5f.6a,
1d.2e.3a.4b.5f.6b,1d.2e.3a.4b.5f.6c,1d.2e.3a.4b.5f.6d,1d.2e.3a.4b.5f.6e,1d.2e.3a.4b.5f.6f,
1d.2e.3a.4c.5a.6a,1d.2e.3a.4c.5a.6b,1d.2e.3a.4c.5a.6c,1d.2e.3a.4c.5a.6d,1d.2e.3a.4c.5a.6e,
1d.2e.3a.4c.5a.6f,1d.2e.3a.4c.5b.6a,1d.2e.3a.4c.5b.6b,1d.2e.3a.4c.5b.6c,1d.2e.3a.4c.5b.6d,
1d.2e.3a.4c.5b.6e,1d.2e.3a.4c.5b.6f,1d.2e.3a.4c.5c.6a,1d.2e.3a.4c.5c.6b,1d.2e.3a.4c.5c.6c,
1d.2e.3a.4c.5c.6d,1d.2e.3a.4c.5c.6e,1d.2e.3a.4c.5c.6f,1d.2e.3a.4c.5d.6a,1d.2e.3a.4c.5d.6b,
1d.2e.3a.4c.5d.6c,1d.2e.3a.4c.5d.6d,1d.2e.3a.4c.5d.6e,1d.2e.3a.4c.5d.6f,1d.2e.3a.4c.5e.6a,
1d.2e.3a.4c.5e.6b,1d.2e.3a.4c.5e.6c,1d.2e.3a.4c.5e.6d,1d.2e.3a.4c.5e.6e,1d.2e.3a.4c.5e.6f,
1d.2e.3a.4c.5f.6a,1d.2e.3a.4c.5f.6b,1d.2e.3a.4c.5f.6c,1d.2e.3a.4c.5f.6d,1d.2e.3a.4c.5f.6e,
1d.2e.3a.4c.5f.6f,1d.2e.3a.4d.5a.6a,1d.2e.3a.4d.5a.6b,1d.2e.3a.4d.5a.6c,1d.2e.3a.4d.5a.6d,
1d.2e.3a.4d.5a.6e,1d.2e.3a.4d.5a.6f,1d.2e.3a.4d.5b.6a,1d.2e.3a.4d.5b.6b,1d.2e.3a.4d.5b.6c,
1d.2e.3a.4d.5b.6d,1d.2e.3a.4d.5b.6e,1d.2e.3a.4d.5b.6f,1d.2e.3a.4d.5c.6a,1d.2e.3a.4d.5c.6b,
1d.2e.3a.4d.5c.6c,1d.2e.3a.4d.5c.6d,1d.2e.3a.4d.5c.6e,1d.2e.3a.4d.5c.6f,1d.2e.3a.4d.5d.6a,
1d.2e.3a.4d.5d.6b, 1d.2e.3a.4d.5d.6c, 1d.2e.3a.4d.5d.6d, 1d.2e.3a.4d.5d.6e,
1d.2e.3a.4d.5d.6f,1d.2e.3a.4d.5e.6a,1d.2e.3a.4d.5e.6b,1d.2e.3a.4d.5e.6c,1d.2e.3a.4d.5e.6d,
1d.2e.3a.4d.5e.6e,1d.2e.3a.4d.5e.6f,1d.2e.3a.4d.5f.6a,1d.2e.3a.4d.5f.6b,1d.2e.3a.4d.5f.6c,
1d.2e.3a.4d.5f.6d,1d.2e.3a.4d.5f.6e,1d.2e.3a.4d.5f.6f,1d.2e.3a.4e.5a.6a,1d.2e.3a.4e.5a.6b,
1d.2e.3a.4e.5a.6c,1d.2e.3a.4e.5a.6d,1d.2e.3a.4e.5a.6e,1d.2e.3a.4e.5a.6f,1d.2e.3a.4e.5b.6a,
1d.2e.3a.4e.5b.6b,1d.2e.3a.4e.5b.6c,1d.2e.3a.4e.5b.6d,1d.2e.3a.4e.5b.6e,1d.2e.3a.4e.5b.6f,
1d.2e.3a.4e.5c.6a,1d.2e.3a.4e.5c.6b,1d.2e.3a.4e.5c.6c,1d.2e.3a.4e.5c.6d,1d.2e.3a.4e.5c.6e,
1d.2e.3a.4e.5c.6f,1d.2e.3a.4e.5d.6a,1d.2e.3a.4e.5d.6b,1d.2e.3a.4e.5d.6c,1d.2e.3a.4e.5d.6d,
1d.2e.3a.4e.5d.6e,1d.2e.3a.4e.5d.6f,1d.2e.3a.4e.5e.6a,1d.2e.3a.4e.5e.6b,1d.2e.3a.4e.5e.6c,
1d.2e.3a.4e.5e.6d,1d.2e.3a.4e.5e.6e,1d.2e.3a.4e.5e.6f,1d.2e.3a.4e.5f.6a,1d.2e.3a.4e.5f.6b,
1d.2e.3a.4e.5f.6c,1d.2e.3a.4e.5f.6d,1d.2e.3a.4e.5f.6e,1d.2e.3a.4e.5f.6f,1d.2e.3a.4f.5a.6a,
1d.2e.3a.4f.5a.6b,1d.2e.3a.4f.5a.6c,1d.2e.3a.4f.5a.6d,1d.2e.3a.4f.5a.6e,1d.2e.3a.4f.5a.6f,
1d.2e.3a.4f.5b.6a,1d.2e.3a.4f.5b.6b,1d.2e.3a.4f.5b.6c,1d.2e.3a.4f.5b.6d,1d.2e.3a.4f.5b.6e,
1d.2e.3a.4f.5b.6f,1d.2e.3a.4f.5c.6a,1d.2e.3a.4f.5c.6b,1d.2e.3a.4f.5c.6c,1d.2e.3a.4f.5c.6d,
1d.2e.3a.4f.5c.6e,1d.2e.3a.4f.5c.6f,1d.2e.3a.4f.5d.6a,1d.2e.3a.4f.5d.6b,1d.2e.3a.4f.5d.6c,
1d.2e.3a.4f.5d.6d,1d.2e.3a.4f.5d.6e,1d.2e.3a.4f.5d.6f,1d.2e.3a.4f.5e.6a,1d.2e.3a.4f.5e.6b,
1d.2e.3a.4f.5e.6c,1d.2e.3a.4f.5e.6d,1d.2e.3a.4f.5e.6e,1d.2e.3a.4f.5e.6f,1d.2e.3a.4f.5f.6a,
1d.2e.3a.4f.5f.6b,1d.2e.3a.4f.5f.6c,1d.2e.3a.4f.5f.6d,1d.2e.3a.4f.5f.6e,1d.2e.3a.4f.5f.6f,
1d.2e.3b.4a.5a.6a,1d.2e.3b.4a.5a.6b,1d.2e.3b.4a.5a.6c,1d.2e.3b.4a.5a.6d,1d.2e.3b.4a.5a.6e,
1d.2e.3b.4a.5a.6f,1d.2e.3b.4a.5b.6a,1d.2e.3b.4a.5b.6b,1d.2e.3b.4a.5b.6c,1d.2e.3b.4a.5b.6d,
1d.2e.3b.4a.5b.6e,1d.2e.3b.4a.5b.6f,1d.2e.3b.4a.5c.6a,1d.2e.3b.4a.5c.6b,1d.2e.3b.4a.5c.6c,
1d.2e.3b.4a.5c.6d,1d.2e.3b.4a.5c.6e,1d.2e.3b.4a.5c.6f,1d.2e.3b.4a.5d.6a,1d.2e.3b.4a.5d.6b,
1d.2e.3b.4a.5d.6c,1d.2e.3b.4a.5d.6d,1d.2e.3b.4a.5d.6e,1d.2e.3b.4a.5d.6f,1d.2e.3b.4a.5e.6a,
1d.2e.3b.4a.5e.6b,1d.2e.3b.4a.5e.6c,1d.2e.3b.4a.5e.6d,1d.2e.3b.4a.5e.6e,1d.2e.3b.4a.5e.6f,
1d.2e.3b.4a.5f.6a,1d.2e.3b.4a.5f.6b,1d.2e.3b.4a.5f.6c,1d.2e.3b.4a.5f.6d,1d.2e.3b.4a.5f.6e,
1d.2e.3b.4a.5f.6f,1d.2e.3b.4b.5a.6a,1d.2e.3b.4b.5a.6b,1d.2e.3b.4b.5a.6c,1d.2e.3b.4b.5a.6d,
1d.2e.3b.4b.5a.6e,1d.2e.3b.4b.5a.6f,1d.2e.3b.4b.5b.6a,1d.2e.3b.4b.5b.6b,1d.2e.3b.4b.5b.6c,
1d.2e.3b.4b.5b.6d,1d.2e.3b.4b.5b.6e,1d.2e.3b.4b.5b.6f,1d.2e.3b.4b.5c.6a,1d.2e.3b.4b.5c.6b,
1d.2e.3b.4b.5c.6c,1d.2e.3b.4b.5c.6d,1d.2e.3b.4b.5c.6e,1d.2e.3b.4b.5c.6f,1d.2e.3b.4b.5d.6a,
1d.2e.3b.4b.5d.6b, 1d.2e.3b.4b.5d.6c, 1d.2e.3b.4b.5d.6d, 1d.2e.3b.4b.5d.6e,
1d.2e.3b.4b.5d.6f,1d.2e.3b.4b.5e.6a,1d.2e.3b.4b.5e.6b,1d.2e.3b.4b.5e.6c,1d.2e.3b.4b.5e.6d,
1d.2e.3b.4b.5e.6e,1d.2e.3b.4b.5e.6f,1d.2e.3b.4b.5f.6a,1d.2e.3b.4b.5f.6b,1d.2e.3b.4b.5f.6c,
1d.2e.3b.4b.5f.6d,1d.2e.3b.4b.5f.6e,1d.2e.3b.4b.5f.6f,1d.2e.3b.4c.5a.6a,1d.2e.3b.4c.5a.6b,
1d.2e.3b.4c.5a.6c,1d.2e.3b.4c.5a.6d,1d.2e.3b.4c.5a.6e,1d.2e.3b.4c.5a.6f,1d.2e.3b.4c.5b.6a,
1d.2e.3b.4c.5b.6b,1d.2e.3b.4c.5b.6c,1d.2e.3b.4c.5b.6d,1d.2e.3b.4c.5b.6e,1d.2e.3b.4c.5b.6f,
1d.2e.3b.4c.5c.6a,1d.2e.3b.4c.5c.6b,1d.2e.3b.4c.5c.6c,1d.2e.3b.4c.5c.6d,1d.2e.3b.4c.5c.6e,
1d.2e.3b.4c.5c.6f,1d.2e.3b.4c.5d.6a,1d.2e.3b.4c.5d.6b,1d.2e.3b.4c.5d.6c,1d.2e.3b.4c.5d.6d,
1d.2e.3b.4c.5d.6e,1d.2e.3b.4c.5d.6f,1d.2e.3b.4c.5e.6a,1d.2e.3b.4c.5e.6b,1d.2e.3b.4c.5e.6c,
1d.2e.3b.4c.5e.6d,1d.2e.3b.4c.5e.6e,1d.2e.3b.4c.5e.6f,1d.2e.3b.4c.5f.6a,1d.2e.3b.4c.5f.6b,
1d.2e.3b.4c.5f.6c,1d.2e.3b.4c.5f.6d,1d.2e.3b.4c.5f.6e,1d.2e.3b.4c.5f.6f,1d.2e.3b.4d.5a.6a,
1d.2e.3b.4d.5a.6b,1d.2e.3b.4d.5a.6c,1d.2e.3b.4d.5a.6d,1d.2e.3b.4d.5a.6e,1d.2e.3b.4d.5a.6f,
1d.2e.3b.4d.5b.6a, 1d.2e.3b.4d.5b.6b, 1d.2e.3b.4d.5b.6c, 1d.2e.3b.4d.5b.6d,
1d.2e.3b.4d.5b.6e,1d.2e.3b.4d.5b.6f,1d.2e.3b.4d.5c.6a,1d.2e.3b.4d.5c.6b,1d.2e.3b.4d.5c.6c,
1d.2e.3b.4d.5c.6d,1d.2e.3b.4d.5c.6e,1d.2e.3b.4d.5c.6f,1d.2e.3b.4d.5d.6a,1d.2e.3b.4d.5d.6b,
1d.2e.3b.4d.5d.6c, 1d.2e.3b.4d.5d.6d, 1d.2e.3b.4d.5d.6e, 1d.2e.3b.4d.5d.6f,
1d.2e.3b.4d.5e.6a,1d.2e.3b.4d.5e.6b,1d.2e.3b.4d.5e.6c,1d.2e.3b.4d.5e.6d,1d.2e.3b.4d.5e.6e,
1d.2e.3b.4d.5e.6f,1d.2e.3b.4d.5f.6a,1d.2e.3b.4d.5f.6b,1d.2e.3b.4d.5f.6c,1d.2e.3b.4d.5f.6d,
1d.2e.3b.4d.5f.6e,1d.2e.3b.4d.5f.6f,1d.2e.3b.4e.5a.6a,1d.2e.3b.4e.5a.6b,1d.2e.3b.4e.5a.6c,
1d.2e.3b.4e.5a.6d,1d.2e.3b.4e.5a.6e,1d.2e.3b.4e.5a.6f,1d.2e.3b.4e.5b.6a,1d.2e.3b.4e.5b.6b,
1d.2e.3b.4e.5b.6c,1d.2e.3b.4e.5b.6d,1d.2e.3b.4e.5b.6e,1d.2e.3b.4e.5b.6f,1d.2e.3b.4e.5c.6a,
1d.2e.3b.4e.5c.6b,1d.2e.3b.4e.5c.6c,1d.2e.3b.4e.5c.6d,1d.2e.3b.4e.5c.6e,1d.2e.3b.4e.5c.6f,
1d.2e.3b.4e.5d.6a,1d.2e.3b.4e.5d.6b,1d.2e.3b.4e.5d.6c,1d.2e.3b.4e.5d.6d,1d.2e.3b.4e.5d.6e,
1d.2e.3b.4e.5d.6f,1d.2e.3b.4e.5e.6a,1d.2e.3b.4e.5e.6b,1d.2e.3b.4e.5e.6c,1d.2e.3b.4e.5e.6d,
1d.2e.3b.4e.5e.6e,1d.2e.3b.4e.5e.6f,1d.2e.3b.4e.5f.6a,1d.2e.3b.4e.5f.6b,1d.2e.3b.4e.5f.6c,
1d.2e.3b.4e.5f.6d,1d.2e.3b.4e.5f.6e,1d.2e.3b.4e.5f.6f,1d.2e.3b.4f.5a.6a,1d.2e.3b.4f.5a.6b,
1d.2e.3b.4f.5a.6c,1d.2e.3b.4f.5a.6d,1d.2e.3b.4f.5a.6e,1d.2e.3b.4f.5a.6f,1d.2e.3b.4f.5b.6a,
1d.2e.3b.4f.5b.6b,1d.2e.3b.4f.5b.6c,1d.2e.3b.4f.5b.6d,1d.2e.3b.4f.5b.6e,1d.2e.3b.4f.5b.6f,
1d.2e.3b.4f.5c.6a,1d.2e.3b.4f.5c.6b,1d.2e.3b.4f.5c.6c,1d.2e.3b.4f.5c.6d,1d.2e.3b.4f.5c.6e,
1d.2e.3b.4f.5c.6f,1d.2e.3b.4f.5d.6a,1d.2e.3b.4f.5d.6b,1d.2e.3b.4f.5d.6c,1d.2e.3b.4f.5d.6d,
1d.2e.3b.4f.5d.6e,1d.2e.3b.4f.5d.6f,1d.2e.3b.4f.5e.6a,1d.2e.3b.4f.5e.6b,1d.2e.3b.4f.5e.6c,
1d.2e.3b.4f.5e.6d,1d.2e.3b.4f.5e.6e,1d.2e.3b.4f.5e.6f,1d.2e.3b.4f.5f.6a,1d.2e.3b.4f.5f.6b,
1d.2e.3b.4f.5f.6c,1d.2e.3b.4f.5f.6d,1d.2e.3b.4f.5f.6e,1d.2e.3b.4f.5f.6f,1d.2e.3c.4a.5a.6a,
1d.2e.3c.4a.5a.6b,1d.2e.3c.4a.5a.6c,1d.2e.3c.4a.5a.6d,1d.2e.3c.4a.5a.6e,1d.2e.3c.4a.5a.6f,
1d.2e.3c.4a.5b.6a,1d.2e.3c.4a.5b.6b,1d.2e.3c.4a.5b.6c,1d.2e.3c.4a.5b.6d,1d.2e.3c.4a.5b.6e,
1d.2e.3c.4a.5b.6f,1d.2e.3c.4a.5c.6a,1d.2e.3c.4a.5c.6b,1d.2e.3c.4a.5c.6c,1d.2e.3c.4a.5c.6d,
1d.2e.3c.4a.5c.6e,1d.2e.3c.4a.5c.6f,1d.2e.3c.4a.5d.6a,1d.2e.3c.4a.5d.6b,1d.2e.3c.4a.5d.6c,
1d.2e.3c.4a.5d.6d,1d.2e.3c.4a.5d.6e,1d.2e.3c.4a.5d.6f,1d.2e.3c.4a.5e.6a,1d.2e.3c.4a.5e.6b,
1d.2e.3c.4a.5e.6c,1d.2e.3c.4a.5e.6d,1d.2e.3c.4a.5e.6e,1d.2e.3c.4a.5e.6f,1d.2e.3c.4a.5f.6a,
1d.2e.3c.4a.5f.6b,1d.2e.3c.4a.5f.6c,1d.2e.3c.4a.5f.6d,1d.2e.3c.4a.5f.6e,1d.2e.3c.4a.5f.6f,
1d.2e.3c.4b.5a.6a,1d.2e.3c.4b.5a.6b,1d.2e.3c.4b.5a.6c,1d.2e.3c.4b.5a.6d,1d.2e.3c.4b.5a.6e,
1d.2e.3c.4b.5a.6f,1d.2e.3c.4b.5b.6a,1d.2e.3c.4b.5b.6b,1d.2e.3c.4b.5b.6c,1d.2e.3c.4b.5b.6d,
1d.2e.3c.4b.5b.6e,1d.2e.3c.4b.5b.6f,1d.2e.3c.4b.5c.6a,1d.2e.3c.4b.5c.6b,1d.2e.3c.4b.5c.6c,
1d.2e.3c.4b.5c.6d,1d.2e.3c.4b.5c.6e,1d.2e.3c.4b.5c.6f,1d.2e.3c.4b.5d.6a,1d.2e.3c.4b.5d.6b,
1d.2e.3c.4b.5d.6c,1d.2e.3c.4b.5d.6d,1d.2e.3c.4b.5d.6e,1d.2e.3c.4b.5d.6f,1d.2e.3c.4b.5e.6a,
1d.2e.3c.4b.5e.6b,1d.2e.3c.4b.5e.6c,1d.2e.3c.4b.5e.6d,1d.2e.3c.4b.5e.6e,1d.2e.3c.4b.5e.6f,
1d.2e.3c.4b.5f.6a,1d.2e.3c.4b.5f.6b,1d.2e.3c.4b.5f.6c,1d.2e.3c.4b.5f.6d,1d.2e.3c.4b.5f.6e,
1d.2e.3c.4b.5f.6f,1d.2e.3c.4c.5a.6a,1d.2e.3c.4c.5a.6b,1d.2e.3c.4c.5a.6c,1d.2e.3c.4c.5a.6d,
1d.2e.3c.4c.5a.6e,1d.2e.3c.4c.5a.6f,1d.2e.3c.4c.5b.6a,1d.2e.3c.4c.5b.6b,1d.2e.3c.4c.5b.6c,
1d.2e.3c.4c.5b.6d,1d.2e.3c.4c.5b.6e,1d.2e.3c.4c.5b.6f,1d.2e.3c.4c.5c.6a,1d.2e.3c.4c.5c.6b,
1d.2e.3c.4c.5c.6c,1d.2e.3c.4c.5c.6d,1d.2e.3c.4c.5c.6e,1d.2e.3c.4c.5c.6f,1d.2e.3c.4c.5d.6a,
1d.2e.3c.4c.5d.6b,1d.2e.3c.4c.5d.6c,1d.2e.3c.4c.5d.6d,1d.2e.3c.4c.5d.6e,1d.2e.3c.4c.5d.6f,
1d.2e.3c.4c.5e.6a,1d.2e.3c.4c.5e.6b,1d.2e.3c.4c.5e.6c,1d.2e.3c.4c.5e.6d,1d.2e.3c.4c.5e.6e,
1d.2e.3c.4c.5e.6f,1d.2e.3c.4c.5f.6a,1d.2e.3c.4c.5f.6b,1d.2e.3c.4c.5f.6c,1d.2e.3c.4c.5f.6d,
1d.2e.3c.4c.5f.6e,1d.2e.3c.4c.5f.6f,1d.2e.3c.4d.5a.6a,1d.2e.3c.4d.5a.6b,1d.2e.3c.4d.5a.6c,
1d.2e.3c.4d.5a.6d,1d.2e.3c.4d.5a.6e,1d.2e.3c.4d.5a.6f,1d.2e.3c.4d.5b.6a,1d.2e.3c.4d.5b.6b,
1d.2e.3c.4d.5b.6c,1d.2e.3c.4d.5b.6d,1d.2e.3c.4d.5b.6e,1d.2e.3c.4d.5b.6f,1d.2e.3c.4d.5c.6a,
1d.2e.3c.4d.5c.6b,1d.2e.3c.4d.5c.6c,1d.2e.3c.4d.5c.6d,1d.2e.3c.4d.5c.6e,1d.2e.3c.4d.5c.6f,
1d.2e.3c.4d.5d.6a, 1d.2e.3c.4d.5d.6b, 1d.2e.3c.4d.5d.6c, 1d.2e.3c.4d.5d.6d,
1d.2e.3c.4d.5d.6e,1d.2e.3c.4d.5d.6f,1d.2e.3c.4d.5e.6a,1d.2e.3c.4d.5e.6b,1d.2e.3c.4d.5e.6c,
1d.2e.3c.4d.5e.6d,1d.2e.3c.4d.5e.6e,1d.2e.3c.4d.5e.6f,1d.2e.3c.4d.5f.6a,1d.2e.3c.4d.5f.6b,
1d.2e.3c.4d.5f.6c,1d.2e.3c.4d.5f.6d,1d.2e.3c.4d.5f.6e,1d.2e.3c.4d.5f.6f,1d.2e.3c.4e.5a.6a,
1d.2e.3c.4e.5a.6b,1d.2e.3c.4e.5a.6c,1d.2e.3c.4e.5a.6d,1d.2e.3c.4e.5a.6e,1d.2e.3c.4e.5a.6f,
1d.2e.3c.4e.5b.6a,1d.2e.3c.4e.5b.6b,1d.2e.3c.4e.5b.6c,1d.2e.3c.4e.5b.6d,1d.2e.3c.4e.5b.6e,
1d.2e.3c.4e.5b.6f,1d.2e.3c.4e.5c.6a,1d.2e.3c.4e.5c.6b,1d.2e.3c.4e.5c.6c,1d.2e.3c.4e.5c.6d,
1d.2e.3c.4e.5c.6e,1d.2e.3c.4e.5c.6f,1d.2e.3c.4e.5d.6a,1d.2e.3c.4e.5d.6b,1d.2e.3c.4e.5d.6c,
1d.2e.3c.4e.5d.6d,1d.2e.3c.4e.5d.6e,1d.2e.3c.4e.5d.6f,1d.2e.3c.4e.5e.6a,1d.2e.3c.4e.5e.6b,
1d.2e.3c.4e.5e.6c,1d.2e.3c.4e.5e.6d,1d.2e.3c.4e.5e.6e,1d.2e.3c.4e.5e.6f,1d.2e.3c.4e.5f.6a,
1d.2e.3c.4e.5f.6b,1d.2e.3c.4e.5f.6c,1d.2e.3c.4e.5f.6d,1d.2e.3c.4e.5f.6e,1d.2e.3c.4e.5f.6f,
1d.2e.3c.4f.5a.6a,1d.2e.3c.4f.5a.6b,1d.2e.3c.4f.5a.6c,1d.2e.3c.4f.5a.6d,1d.2e.3c.4f.5a.6e,
1d.2e.3c.4f.5a.6f,1d.2e.3c.4f.5b.6a,1d.2e.3c.4f.5b.6b,1d.2e.3c.4f.5b.6c,1d.2e.3c.4f.5b.6d,
1d.2e.3c.4f.5b.6e,1d.2e.3c.4f.5b.6f,1d.2e.3c.4f.5c.6a,1d.2e.3c.4f.5c.6b,1d.2e.3c.4f.5c.6c,
1d.2e.3c.4f.5c.6d,1d.2e.3c.4f.5c.6e,1d.2e.3c.4f.5c.6f,1d.2e.3c.4f.5d.6a,1d.2e.3c.4f.5d.6b,
1d.2e.3c.4f.5d.6c,1d.2e.3c.4f.5d.6d,1d.2e.3c.4f.5d.6e,1d.2e.3c.4f.5d.6f,1d.2e.3c.4f.5e.6a,
1d.2e.3c.4f.5e.6b,1d.2e.3c.4f.5e.6c,1d.2e.3c.4f.5e.6d,1d.2e.3c.4f.5e.6e,1d.2e.3c.4f.5e.6f,
1d.2e.3c.4f.5f.6a,1d.2e.3c.4f.5f.6b,1d.2e.3c.4f.5f.6c,1d.2e.3c.4f.5f.6d,1d.2e.3c.4f.5f.6e,
1d.2e.3c.4f.5f.6f,1d.2e.3d.4a.5a.6a,1d.2e.3d.4a.5a.6b,1d.2e.3d.4a.5a.6c,1d.2e.3d.4a.5a.6d,
1d.2e.3d.4a.5a.6e,1d.2e.3d.4a.5a.6f,1d.2e.3d.4a.5b.6a,1d.2e.3d.4a.5b.6b,1d.2e.3d.4a.5b.6c,
1d.2e.3d.4a.5b.6d,1d.2e.3d.4a.5b.6e,1d.2e.3d.4a.5b.6f,1d.2e.3d.4a.5c.6a,1d.2e.3d.4a.5c.6b,
1d.2e.3d.4a.5c.6c,1d.2e.3d.4a.5c.6d,1d.2e.3d.4a.5c.6e,1d.2e.3d.4a.5c.6f,1d.2e.3d.4a.5d.6a,
1d.2e.3d.4a.5d.6b, 1d.2e.3d.4a.5d.6c, 1d.2e.3d.4a.5d.6d, 1d.2e.3d.4a.5d.6e,
1d.2e.3d.4a.5d.6f,1d.2e.3d.4a.5e.6a,1d.2e.3d.4a.5e.6b,1d.2e.3d.4a.5e.6c,1d.2e.3d.4a.5e.6d,
1d.2e.3d.4a.5e.6e,1d.2e.3d.4a.5e.6f,1d.2e.3d.4a.5f.6a,1d.2e.3d.4a.5f.6b,1d.2e.3d.4a.5f.6c,
1d.2e.3d.4a.5f.6d,1d.2e.3d.4a.5f.6e,1d.2e.3d.4a.5f.6f,1d.2e.3d.4b.5a.6a,1d.2e.3d.4b.5a.6b,
1d.2e.3d.4b.5a.6c,1d.2e.3d.4b.5a.6d,1d.2e.3d.4b.5a.6e,1d.2e.3d.4b.5a.6f,1d.2e.3d.4b.5b.6a,
1d.2e.3d.4b.5b.6b, 1d.2e.3d.4b.5b.6c, 1d.2e.3d.4b.5b.6d, 1d.2e.3d.4b.5b.6e,
1d.2e.3d.4b.5b.6f,1d.2e.3d.4b.5c.6a,1d.2e.3d.4b.5c.6b,1d.2e.3d.4b.5c.6c,1d.2e.3d.4b.5c.6d,
1d.2e.3d.4b.5c.6e,1d.2e.3d.4b.5c.6f,1d.2e.3d.4b.5d.6a,1d.2e.3d.4b.5d.6b,1d.2e.3d.4b.5d.6c,
1d.2e.3d.4b.5d.6d, 1d.2e.3d.4b.5d.6e, 1d.2e.3d.4b.5d.6f, 1d.2e.3d.4b.5e.6a,
1d.2e.3d.4b.5e.6b,1d.2e.3d.4b.5e.6c,1d.2e.3d.4b.5e.6d,1d.2e.3d.4b.5e.6e,1d.2e.3d.4b.5e.6f,
1d.2e.3d.4b.5f.6a,1d.2e.3d.4b.5f.6b,1d.2e.3d.4b.5f.6c,1d.2e.3d.4b.5f.6d,1d.2e.3d.4b.5f.6e,
1d.2e.3d.4b.5f.6f,1d.2e.3d.4c.5a.6a,1d.2e.3d.4c.5a.6b,1d.2e.3d.4c.5a.6c,1d.2e.3d.4c.5a.6d,
1d.2e.3d.4c.5a.6e,1d.2e.3d.4c.5a.6f,1d.2e.3d.4c.5b.6a,1d.2e.3d.4c.5b.6b,1d.2e.3d.4c.5b.6c,
1d.2e.3d.4c.5b.6d,1d.2e.3d.4c.5b.6e,1d.2e.3d.4c.5b.6f,1d.2e.3d.4c.5c.6a,1d.2e.3d.4c.5c.6b,
1d.2e.3d.4c.5c.6c,1d.2e.3d.4c.5c.6d,1d.2e.3d.4c.5c.6e,1d.2e.3d.4c.5c.6f,1d.2e.3d.4c.5d.6a,
1d.2e.3d.4c.5d.6b,1d.2e.3d.4c.5d.6c,1d.2e.3d.4c.5d.6d,1d.2e.3d.4c.5d.6e,1d.2e.3d.4c.5d.6f,
1d.2e.3d.4c.5e.6a,1d.2e.3d.4c.5e.6b,1d.2e.3d.4c.5e.6c,1d.2e.3d.4c.5e.6d,1d.2e.3d.4c.5e.6e,
1d.2e.3d.4c.5e.6f,1d.2e.3d.4c.5f.6a,1d.2e.3d.4c.5f.6b,1d.2e.3d.4c.5f.6c,1d.2e.3d.4c.5f.6d,
1d.2e.3d.4c.5f.6e,1d.2e.3d.4c.5f.6f,1d.2e.3d.4d.5a.6a,1d.2e.3d.4d.5a.6b,1d.2e.3d.4d.5a.6c,
1d.2e.3d.4d.5a.6d, 1d.2e.3d.4d.5a.6e, 1d.2e.3d.4d.5a.6f, 1d.2e.3d.4d.5b.6a,
1d.2e.3d.4d.5b.6b, 1d.2e.3d.4d.5b.6c, 1d.2e.3d.4d.5b.6d, 1d.2e.3d.4d.5b.6e,
1d.2e.3d.4d.5b.6f, 1d.2e.3d.4d.5c.6a, 1d.2e.3d.4d.5c.6b, 1d.2e.3d.4d.5c.6c,
1d.2e.3d.4d.5c.6d, 1d.2e.3d.4d.5c.6e, 1d.2e.3d.4d.5c.6f, 1d.2e.3d.4d.5d.6a,
1d.2e.3d.4d.5d.6b, 1d.2e.3d.4d.5d.6c, 1d.2e.3d.4d.5d.6d, 1d.2e.3d.4d.5d.6e,
1d.2e.3d.4d.5d.6f, 1d.2e.3d.4d.5e.6a, 1d.2e.3d.4d.5e.6b, 1d.2e.3d.4d.5e.6c,
1d.2e.3d.4d.5e.6d,1d.2e.3d.4d.5e.6e,1d.2e.3d.4d.5e.6f,1d.2e.3d.4d.5f.6a,1d.2e.3d.4d.5f.6b,
1d.2e.3d.4d.5f.6c,1d.2e.3d.4d.5f.6d,1d.2e.3d.4d.5f.6e,1d.2e.3d.4d.5f.6f,1d.2e.3d.4e.5a.6a,
1d.2e.3d.4e.5a.6b,1d.2e.3d.4e.5a.6c,1d.2e.3d.4e.5a.6d,1d.2e.3d.4e.5a.6e,1d.2e.3d.4e.5a.6f,
1d.2e.3d.4e.5b.6a,1d.2e.3d.4e.5b.6b,1d.2e.3d.4e.5b.6c,1d.2e.3d.4e.5b.6d,1d.2e.3d.4e.5b.6e,
1d.2e.3d.4e.5b.6f,1d.2e.3d.4e.5c.6a,1d.2e.3d.4e.5c.6b,1d.2e.3d.4e.5c.6c,1d.2e.3d.4e.5c.6d,
1d.2e.3d.4e.5c.6e,1d.2e.3d.4e.5c.6f,1d.2e.3d.4e.5d.6a,1d.2e.3d.4e.5d.6b,1d.2e.3d.4e.5d.6c,
1d.2e.3d.4e.5d.6d,1d.2e.3d.4e.5d.6e,1d.2e.3d.4e.5d.6f,1d.2e.3d.4e.5e.6a,1d.2e.3d.4e.5e.6b,
1d.2e.3d.4e.5e.6c,1d.2e.3d.4e.5e.6d,1d.2e.3d.4e.5e.6e,1d.2e.3d.4e.5e.6f,1d.2e.3d.4e.5f.6a,
1d.2e.3d.4e.5f.6b,1d.2e.3d.4e.5f.6c,1d.2e.3d.4e.5f.6d,1d.2e.3d.4e.5f.6e,1d.2e.3d.4e.5f.6f,
1d.2e.3d.4f.5a.6a,1d.2e.3d.4f.5a.6b,1d.2e.3d.4f.5a.6c,1d.2e.3d.4f.5a.6d,1d.2e.3d.4f.5a.6e,
1d.2e.3d.4f.5a.6f,1d.2e.3d.4f.5b.6a,1d.2e.3d.4f.5b.6b,1d.2e.3d.4f.5b.6c,1d.2e.3d.4f.5b.6d,
1d.2e.3d.4f.5b.6e,1d.2e.3d.4f.5b.6f,1d.2e.3d.4f.5c.6a,1d.2e.3d.4f.5c.6b,1d.2e.3d.4f.5c.6c,
1d.2e.3d.4f.5c.6d,1d.2e.3d.4f.5c.6e,1d.2e.3d.4f.5c.6f,1d.2e.3d.4f.5d.6a,1d.2e.3d.4f.5d.6b,
1d.2e.3d.4f.5d.6c,1d.2e.3d.4f.5d.6d,1d.2e.3d.4f.5d.6e,1d.2e.3d.4f.5d.6f,1d.2e.3d.4f.5e.6a,
1d.2e.3d.4f.5e.6b,1d.2e.3d.4f.5e.6c,1d.2e.3d.4f.5e.6d,1d.2e.3d.4f.5e.6e,1d.2e.3d.4f.5e.6f,
1d.2e.3d.4f.5f.6a,1d.2e.3d.4f.5f.6b,1d.2e.3d.4f.5f.6c,1d.2e.3d.4f.5f.6d,1d.2e.3d.4f.5f.6e,
1d.2e.3d.4f.5f.6f,1d.2e.3e.4a.5a.6a,1d.2e.3e.4a.5a.6b,1d.2e.3e.4a.5a.6c,1d.2e.3e.4a.5a.6d,
1d.2e.3e.4a.5a.6e,1d.2e.3e.4a.5a.6f,1d.2e.3e.4a.5b.6a,1d.2e.3e.4a.5b.6b,1d.2e.3e.4a.5b.6c,
1d.2e.3e.4a.5b.6d,1d.2e.3e.4a.5b.6e,1d.2e.3e.4a.5b.6f,1d.2e.3e.4a.5c.6a,1d.2e.3e.4a.5c.6b,
1d.2e.3e.4a.5c.6c,1d.2e.3e.4a.5c.6d,1d.2e.3e.4a.5c.6e,1d.2e.3e.4a.5c.6f,1d.2e.3e.4a.5d.6a,
1d.2e.3e.4a.5d.6b,1d.2e.3e.4a.5d.6c,1d.2e.3e.4a.5d.6d,1d.2e.3e.4a.5d.6e,1d.2e.3e.4a.5d.6f,
1d.2e.3e.4a.5e.6a,1d.2e.3e.4a.5e.6b,1d.2e.3e.4a.5e.6c,1d.2e.3e.4a.5e.6d,1d.2e.3e.4a.5e.6e,
1d.2e.3e.4a.5e.6f,1d.2e.3e.4a.5f.6a,1d.2e.3e.4a.5f.6b,1d.2e.3e.4a.5f.6c,1d.2e.3e.4a.5f.6d,
1d.2e.3e.4a.5f.6e,1d.2e.3e.4a.5f.6f,1d.2e.3e.4b.5a.6a,1d.2e.3e.4b.5a.6b,1d.2e.3e.4b.5a.6c,
1d.2e.3e.4b.5a.6d,1d.2e.3e.4b.5a.6e,1d.2e.3e.4b.5a.6f,1d.2e.3e.4b.5b.6a,1d.2e.3e.4b.5b.6b,
1d.2e.3e.4b.5b.6c,1d.2e.3e.4b.5b.6d,1d.2e.3e.4b.5b.6e,1d.2e.3e.4b.5b.6f,1d.2e.3e.4b.5c.6a,
1d.2e.3e.4b.5c.6b,1d.2e.3e.4b.5c.6c,1d.2e.3e.4b.5c.6d,1d.2e.3e.4b.5c.6e,1d.2e.3e.4b.5c.6f,
1d.2e.3e.4b.5d.6a,1d.2e.3e.4b.5d.6b,1d.2e.3e.4b.5d.6c,1d.2e.3e.4b.5d.6d,1d.2e.3e.4b.5d.6e,
1d.2e.3e.4b.5d.6f,1d.2e.3e.4b.5e.6a,1d.2e.3e.4b.5e.6b,1d.2e.3e.4b.5e.6c,1d.2e.3e.4b.5e.6d,
1d.2e.3e.4b.5e.6e,1d.2e.3e.4b.5e.6f,1d.2e.3e.4b.5f.6a,1d.2e.3e.4b.5f.6b,1d.2e.3e.4b.5f.6c,
1d.2e.3e.4b.5f.6d,1d.2e.3e.4b.5f.6e,1d.2e.3e.4b.5f.6f,1d.2e.3e.4c.5a.6a,1d.2e.3e.4c.5a.6b,
1d.2e.3e.4c.5a.6c,1d.2e.3e.4c.5a.6d,1d.2e.3e.4c.5a.6e,1d.2e.3e.4c.5a.6f,1d.2e.3e.4c.5b.6a,
1d.2e.3e.4c.5b.6b,1d.2e.3e.4c.5b.6c,1d.2e.3e.4c.5b.6d,1d.2e.3e.4c.5b.6e,1d.2e.3e.4c.5b.6f,
1d.2e.3e.4c.5c.6a,1d.2e.3e.4c.5c.6b,1d.2e.3e.4c.5c.6c,1d.2e.3e.4c.5c.6d,1d.2e.3e.4c.5c.6e,
1d.2e.3e.4c.5c.6f,1d.2e.3e.4c.5d.6a,1d.2e.3e.4c.5d.6b,1d.2e.3e.4c.5d.6c,1d.2e.3e.4c.5d.6d,
1d.2e.3e.4c.5d.6e,1d.2e.3e.4c.5d.6f,1d.2e.3e.4c.5e.6a,1d.2e.3e.4c.5e.6b,1d.2e.3e.4c.5e.6c,
1d.2e.3e.4c.5e.6d,1d.2e.3e.4c.5e.6e,1d.2e.3e.4c.5e.6f,1d.2e.3e.4c.5f.6a,1d.2e.3e.4c.5f.6b,
1d.2e.3e.4c.5f.6c,1d.2e.3e.4c.5f.6d,1d.2e.3e.4c.5f.6e,1d.2e.3e.4c.5f.6f,1d.2e.3e.4d.5a.6a,
1d.2e.3e.4d.5a.6b,1d.2e.3e.4d.5a.6c,1d.2e.3e.4d.5a.6d,1d.2e.3e.4d.5a.6e,1d.2e.3e.4d.5a.6f,
1d.2e.3e.4d.5b.6a,1d.2e.3e.4d.5b.6b,1d.2e.3e.4d.5b.6c,1d.2e.3e.4d.5b.6d,1d.2e.3e.4d.5b.6e,
1d.2e.3e.4d.5b.6f,1d.2e.3e.4d.5c.6a,1d.2e.3e.4d.5c.6b,1d.2e.3e.4d.5c.6c,1d.2e.3e.4d.5c.6d,
1d.2e.3e.4d.5c.6e,1d.2e.3e.4d.5c.6f,1d.2e.3e.4d.5d.6a,1d.2e.3e.4d.5d.6b,1d.2e.3e.4d.5d.6c,
1d.2e.3e.4d.5d.6d,1d.2e.3e.4d.5d.6e,1d.2e.3e.4d.5d.6f,1d.2e.3e.4d.5e.6a,1d.2e.3e.4d.5e.6b,
1d.2e.3e.4d.5e.6c,1d.2e.3e.4d.5e.6d,1d.2e.3e.4d.5e.6e,1d.2e.3e.4d.5e.6f,1d.2e.3e.4d.5f.6a,
1d.2e.3e.4d.5f.6b,1d.2e.3e.4d.5f.6c,1d.2e.3e.4d.5f.6d,1d.2e.3e.4d.5f.6e,1d.2e.3e.4d.5f.6f,
1d.2e.3e.4e.5a.6a,1d.2e.3e.4e.5a.6b,1d.2e.3e.4e.5a.6c,1d.2e.3e.4e.5a.6d,1d.2e.3e.4e.5a.6e,
1d.2e.3e.4e.5a.6f,1d.2e.3e.4e.5b.6a,1d.2e.3e.4e.5b.6b,1d.2e.3e.4e.5b.6c,1d.2e.3e.4e.5b.6d,
1d.2e.3e.4e.5b.6e,1d.2e.3e.4e.5b.6f,1d.2e.3e.4e.5c.6a,1d.2e.3e.4e.5c.6b,1d.2e.3e.4e.5c.6c,
1d.2e.3e.4e.5c.6d,1d.2e.3e.4e.5c.6e,1d.2e.3e.4e.5c.6f,1d.2e.3e.4e.5d.6a,1d.2e.3e.4e.5d.6b,
1d.2e.3e.4e.5d.6c,1d.2e.3e.4e.5d.6d,1d.2e.3e.4e.5d.6e,1d.2e.3e.4e.5d.6f,1d.2e.3e.4e.5e.6a,
1d.2e.3e.4e.5e.6b,1d.2e.3e.4e.5e.6c,1d.2e.3e.4e.5e.6d,1d.2e.3e.4e.5e.6e,1d.2e.3e.4e.5e.6f,
1d.2e.3e.4e.5f.6a,1d.2e.3e.4e.5f.6b,1d.2e.3e.4e.5f.6c,1d.2e.3e.4e.5f.6d,1d.2e.3e.4e.5f.6e,
1d.2e.3e.4e.5f.6f,1d.2e.3e.4f.5a.6a,1d.2e.3e.4f.5a.6b,1d.2e.3e.4f.5a.6c,1d.2e.3e.4f.5a.6d,
1d.2e.3e.4f.5a.6e,1d.2e.3e.4f.5a.6f,1d.2e.3e.4f.5b.6a,1d.2e.3e.4f.5b.6b,1d.2e.3e.4f.5b.6c,
1d.2e.3e.4f.5b.6d,1d.2e.3e.4f.5b.6e,1d.2e.3e.4f.5b.6f,1d.2e.3e.4f.5c.6a,1d.2e.3e.4f.5c.6b,
1d.2e.3e.4f.5c.6c,1d.2e.3e.4f.5c.6d,1d.2e.3e.4f.5c.6e,1d.2e.3e.4f.5c.6f,1d.2e.3e.4f.5d.6a,
1d.2e.3e.4f.5d.6b,1d.2e.3e.4f.5d.6c,1d.2e.3e.4f.5d.6d,1d.2e.3e.4f.5d.6e,1d.2e.3e.4f.5d.6f,
1d.2e.3e.4f.5e.6a,1d.2e.3e.4f.5e.6b,1d.2e.3e.4f.5e.6c,1d.2e.3e.4f.5e.6d,1d.2e.3e.4f.5e.6e,
1d.2e.3e.4f.5e.6f,1d.2e.3e.4f.5f.6a,1d.2e.3e.4f.5f.6b,1d.2e.3e.4f.5f.6c,1d.2e.3e.4f.5f.6d,
1d.2e.3e.4f.5f.6e,1d.2e.3e.4f.5f.6f,1d.2e.3f.4a.5a.6a,1d.2e.3f.4a.5a.6b,1d.2e.3f.4a.5a.6c,
1d.2e.3f.4a.5a.6d,1d.2e.3f.4a.5a.6e,1d.2e.3f.4a.5a.6f,1d.2e.3f.4a.5b.6a,1d.2e.3f.4a.5b.6b,
1d.2e.3f.4a.5b.6c,1d.2e.3f.4a.5b.6d,1d.2e.3f.4a.5b.6e,1d.2e.3f.4a.5b.6f,1d.2e.3f.4a.5c.6a,
1d.2e.3f.4a.5c.6b,1d.2e.3f.4a.5c.6c,1d.2e.3f.4a.5c.6d,1d.2e.3f.4a.5c.6e,1d.2e.3f.4a.5c.6f,
1d.2e.3f.4a.5d.6a,1d.2e.3f.4a.5d.6b,1d.2e.3f.4a.5d.6c,1d.2e.3f.4a.5d.6d,1d.2e.3f.4a.5d.6e,
1d.2e.3f.4a.5d.6f,1d.2e.3f.4a.5e.6a,1d.2e.3f.4a.5e.6b,1d.2e.3f.4a.5e.6c,1d.2e.3f.4a.5e.6d,
1d.2e.3f.4a.5e.6e,1d.2e.3f.4a.5e.6f,1d.2e.3f.4a.5f.6a,1d.2e.3f.4a.5f.6b,1d.2e.3f.4a.5f.6c,
1d.2e.3f.4a.5f.6d,1d.2e.3f.4a.5f.6e,1d.2e.3f.4a.5f.6f,1d.2e.3f.4b.5a.6a,1d.2e.3f.4b.5a.6b,
1d.2e.3f.4b.5a.6c,1d.2e.3f.4b.5a.6d,1d.2e.3f.4b.5a.6e,1d.2e.3f.4b.5a.6f,1d.2e.3f.4b.5b.6a,
1d.2e.3f.4b.5b.6b,1d.2e.3f.4b.5b.6c,1d.2e.3f.4b.5b.6d,1d.2e.3f.4b.5b.6e,1d.2e.3f.4b.5b.6f,
1d.2e.3f.4b.5c.6a,1d.2e.3f.4b.5c.6b,1d.2e.3f.4b.5c.6c,1d.2e.3f.4b.5c.6d,1d.2e.3f.4b.5c.6e,
1d.2e.3f.4b.5c.6f,1d.2e.3f.4b.5d.6a,1d.2e.3f.4b.5d.6b,1d.2e.3f.4b.5d.6c,1d.2e.3f.4b.5d.6d,
1d.2e.3f.4b.5d.6e,1d.2e.3f.4b.5d.6f,1d.2e.3f.4b.5e.6a,1d.2e.3f.4b.5e.6b,1d.2e.3f.4b.5e.6c,
1d.2e.3f.4b.5e.6d,1d.2e.3f.4b.5e.6e,1d.2e.3f.4b.5e.6f,1d.2e.3f.4b.5f.6a,1d.2e.3f.4b.5f.6b,
1d.2e.3f.4b.5f.6c,1d.2e.3f.4b.5f.6d,1d.2e.3f.4b.5f.6e,1d.2e.3f.4b.5f.6f,1d.2e.3f.4c.5a.6a,
1d.2e.3f.4c.5a.6b,1d.2e.3f.4c.5a.6c,1d.2e.3f.4c.5a.6d,1d.2e.3f.4c.5a.6e,1d.2e.3f.4c.5a.6f,
1d.2e.3f.4c.5b.6a,1d.2e.3f.4c.5b.6b,1d.2e.3f.4c.5b.6c,1d.2e.3f.4c.5b.6d,1d.2e.3f.4c.5b.6e,
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1d.2e.3f.4e.5a.6e,1d.2e.3f.4e.5a.6f,1d.2e.3f.4e.5b.6a,1d.2e.3f.4e.5b.6b,1d.2e.3f.4e.5b.6c,
1d.2e.3f.4e.5b.6d,1d.2e.3f.4e.5b.6e,1d.2e.3f.4e.5b.6f,1d.2e.3f.4e.5c.6a,1d.2e.3f.4e.5c.6b,
1d.2e.3f.4e.5c.6c,1d.2e.3f.4e.5c.6d,1d.2e.3f.4e.5c.6e,1d.2e.3f.4e.5c.6f,1d.2e.3f.4e.5d.6a,
1d.2e.3f.4e.5d.6b,1d.2e.3f.4e.5d.6c,1d.2e.3f.4e.5d.6d,1d.2e.3f.4e.5d.6e,1d.2e.3f.4e.5d.6f,
1d.2e.3f.4e.5e.6a,1d.2e.3f.4e.5e.6b,1d.2e.3f.4e.5e.6c,1d.2e.3f.4e.5e.6d,1d.2e.3f.4e.5e.6e,
1d.2e.3f.4e.5e.6f,1d.2e.3f.4e.5f.6a,1d.2e.3f.4e.5f.6b,1d.2e.3f.4e.5f.6c,1d.2e.3f.4e.5f.6d,
1d.2e.3f.4e.5f.6e,1d.2e.3f.4e.5f.6f,1d.2e.3f.4f.5a.6a,1d.2e.3f.4f.5a.6b,1d.2e.3f.4f.5a.6c,
1d.2e.3f.4f.5a.6d,1d.2e.3f.4f.5a.6e,1d.2e.3f.4f.5a.6f,1d.2e.3f.4f.5b.6a,1d.2e.3f.4f.5b.6b,
1d.2e.3f.4f.5b.6c,1d.2e.3f.4f.5b.6d,1d.2e.3f.4f.5b.6e,1d.2e.3f.4f.5b.6f,1d.2e.3f.4f.5c.6a,
1d.2e.3f.4f.5c.6b,1d.2e.3f.4f.5c.6c,1d.2e.3f.4f.5c.6d,1d.2e.3f.4f.5c.6e,1d.2e.3f.4f.5c.6f,
1d.2e.3f.4f.5d.6a,1d.2e.3f.4f.5d.6b,1d.2e.3f.4f.5d.6c,1d.2e.3f.4f.5d.6d,1d.2e.3f.4f.5d.6e,
1d.2e.3f.4f.5d.6f,1d.2e.3f.4f.5e.6a,1d.2e.3f.4f.5e.6b,1d.2e.3f.4f.5e.6c,1d.2e.3f.4f.5e.6d,
1d.2e.3f.4f.5e.6e,1d.2e.3f.4f.5e.6f,1d.2e.3f.4f.5f.6a,1d.2e.3f.4f.5f.6b,1d.2e.3f.4f.5f.6c,
1d.2e.3f.4f.5f.6d,1d.2e.3f.4f.5f.6e,1d.2e.3f.4f.5f.6f,1d.2f.3a.4a.5a.6a,1d.2f.3a.4a.5a.6b,
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1d.2f.3a.4a.5b.6b,1d.2f.3a.4a.5b.6c,1d.2f.3a.4a.5b.6d,1d.2f.3a.4a.5b.6e,1d.2f.3a.4a.5b.6f,
1d.2f.3a.4a.5c.6a,1d.2f.3a.4a.5c.6b,1d.2f.3a.4a.5c.6c,1d.2f.3a.4a.5c.6d,1d.2f.3a.4a.5c.6e,
1d.2f.3a.4a.5c.6f,1d.2f.3a.4a.5d.6a,1d.2f.3a.4a.5d.6b,1d.2f.3a.4a.5d.6c,1d.2f.3a.4a.5d.6d,
1d.2f.3a.4a.5d.6e,1d.2f.3a.4a.5d.6f,1d.2f.3a.4a.5e.6a,1d.2f.3a.4a.5e.6b,1d.2f.3a.4a.5e.6c,
1d.2f.3a.4a.5e.6d,1d.2f.3a.4a.5e.6e,1d.2f.3a.4a.5e.6f,1d.2f.3a.4a.5f.6a,1d.2f.3a.4a.5f.6b,
1d.2f.3a.4a.5f.6c,1d.2f.3a.4a.5f.6d,1d.2f.3a.4a.5f.6e,1d.2f.3a.4a.5f.6f,1d.2f.3a.4b.5a.6a,
1d.2f.3a.4b.5a.6b,1d.2f.3a.4b.5a.6c,1d.2f.3a.4b.5a.6d,1d.2f.3a.4b.5a.6e,1d.2f.3a.4b.5a.6f,
1d.2f.3a.4b.5b.6a,1d.2f.3a.4b.5b.6b,1d.2f.3a.4b.5b.6c,1d.2f.3a.4b.5b.6d,1d.2f.3a.4b.5b.6e,
1d.2f.3a.4b.5b.6f,1d.2f.3a.4b.5c.6a,1d.2f.3a.4b.5c.6b,1d.2f.3a.4b.5c.6c,1d.2f.3a.4b.5c.6d,
1d.2f.3a.4b.5c.6e,1d.2f.3a.4b.5c.6f,1d.2f.3a.4b.5d.6a,1d.2f.3a.4b.5d.6b,1d.2f.3a.4b.5d.6c,
1d.2f.3a.4b.5d.6d,1d.2f.3a.4b.5d.6e,1d.2f.3a.4b.5d.6f,1d.2f.3a.4b.5e.6a,1d.2f.3a.4b.5e.6b,
1d.2f.3a.4b.5e.6c,1d.2f.3a.4b.5e.6d,1d.2f.3a.4b.5e.6e,1d.2f.3a.4b.5e.6f,1d.2f.3a.4b.5f.6a,
1d.2f.3a.4b.5f.6b,1d.2f.3a.4b.5f.6c,1d.2f.3a.4b.5f.6d,1d.2f.3a.4b.5f.6e,1d.2f.3a.4b.5f.6f,
1d.2f.3a.4c.5a.6a,1d.2f.3a.4c.5a.6b,1d.2f.3a.4c.5a.6c,1d.2f.3a.4c.5a.6d,1d.2f.3a.4c.5a.6e,
1d.2f.3a.4c.5a.6f,1d.2f.3a.4c.5b.6a,1d.2f.3a.4c.5b.6b,1d.2f.3a.4c.5b.6c,1d.2f.3a.4c.5b.6d,
1d.2f.3a.4c.5b.6e,1d.2f.3a.4c.5b.6f,1d.2f.3a.4c.5c.6a,1d.2f.3a.4c.5c.6b,1d.2f.3a.4c.5c.6c,
1d.2f.3a.4c.5c.6d,1d.2f.3a.4c.5c.6e,1d.2f.3a.4c.5c.6f,1d.2f.3a.4c.5d.6a,1d.2f.3a.4c.5d.6b,
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1d.2f.3a.4c.5e.6b,1d.2f.3a.4c.5e.6c,1d.2f.3a.4c.5e.6d,1d.2f.3a.4c.5e.6e,1d.2f.3a.4c.5e.6f,
1d.2f.3a.4c.5f.6a,1d.2f.3a.4c.5f.6b,1d.2f.3a.4c.5f.6c,1d.2f.3a.4c.5f.6d,1d.2f.3a.4c.5f.6e,
1d.2f.3a.4c.5f.6f,1d.2f.3a.4d.5a.6a,1d.2f.3a.4d.5a.6b,1d.2f.3a.4d.5a.6c,1d.2f.3a.4d.5a.6d,
1d.2f.3a.4d.5a.6e,1d.2f.3a.4d.5a.6f,1d.2f.3a.4d.5b.6a,1d.2f.3a.4d.5b.6b,1d.2f.3a.4d.5b.6c,
1d.2f.3a.4d.5b.6d,1d.2f.3a.4d.5b.6e,1d.2f.3a.4d.5b.6f,1d.2f.3a.4d.5c.6a,1d.2f.3a.4d.5c.6b,
1d.2f.3a.4d.5c.6c,1d.2f.3a.4d.5c.6d,1d.2f.3a.4d.5c.6e,1d.2f.3a.4d.5c.6f,1d.2f.3a.4d.5d.6a,
1d.2f.3a.4d.5d.6b,1d.2f.3a.4d.5d.6c,1d.2f.3a.4d.5d.6d,1d.2f.3a.4d.5d.6e,1d.2f.3a.4d.5d.6f,
1d.2f.3a.4d.5e.6a,1d.2f.3a.4d.5e.6b,1d.2f.3a.4d.5e.6c,1d.2f.3a.4d.5e.6d,1d.2f.3a.4d.5e.6e,
1d.2f.3a.4d.5e.6f,1d.2f.3a.4d.5f.6a,1d.2f.3a.4d.5f.6b,1d.2f.3a.4d.5f.6c,1d.2f.3a.4d.5f.6d,
1d.2f.3a.4d.5f.6e,1d.2f.3a.4d.5f.6f,1d.2f.3a.4e.5a.6a,1d.2f.3a.4e.5a.6b,1d.2f.3a.4e.5a.6c,
1d.2f.3a.4e.5a.6d,1d.2f.3a.4e.5a.6e,1d.2f.3a.4e.5a.6f,1d.2f.3a.4e.5b.6a,1d.2f.3a.4e.5b.6b,
1d.2f.3a.4e.5b.6c,1d.2f.3a.4e.5b.6d,1d.2f.3a.4e.5b.6e,1d.2f.3a.4e.5b.6f,1d.2f.3a.4e.5c.6a,
1d.2f.3a.4e.5c.6b,1d.2f.3a.4e.5c.6c,1d.2f.3a.4e.5c.6d,1d.2f.3a.4e.5c.6e,1d.2f.3a.4e.5c.6f,
1d.2f.3a.4e.5d.6a,1d.2f.3a.4e.5d.6b,1d.2f.3a.4e.5d.6c,1d.2f.3a.4e.5d.6d,1d.2f.3a.4e.5d.6e,
1d.2f.3a.4e.5d.6f,1d.2f.3a.4e.5e.6a,1d.2f.3a.4e.5e.6b,1d.2f.3a.4e.5e.6c,1d.2f.3a.4e.5e.6d,
1d.2f.3a.4e.5e.6e,1d.2f.3a.4e.5e.6f,1d.2f.3a.4e.5f.6a,1d.2f.3a.4e.5f.6b,1d.2f.3a.4e.5f.6c,
1d.2f.3a.4e.5f.6d,1d.2f.3a.4e.5f.6e,1d.2f.3a.4e.5f.6f,1d.2f.3a.4f.5a.6a,1d.2f.3a.4f.5a.6b,
1d.2f.3a.4f.5a.6c,1d.2f.3a.4f.5a.6d,1d.2f.3a.4f.5a.6e,1d.2f.3a.4f.5a.6f,1d.2f.3a.4f.5b.6a,
1d.2f.3a.4f.5b.6b,1d.2f.3a.4f.5b.6c,1d.2f.3a.4f.5b.6d,1d.2f.3a.4f.5b.6e,1d.2f.3a.4f.5b.6f,
1d.2f.3a.4f.5c.6a,1d.2f.3a.4f.5c.6b,1d.2f.3a.4f.5c.6c,1d.2f.3a.4f.5c.6d,1d.2f.3a.4f.5c.6e,
1d.2f.3a.4f.5c.6f,1d.2f.3a.4f.5d.6a,1d.2f.3a.4f.5d.6b,1d.2f.3a.4f.5d.6c,1d.2f.3a.4f.5d.6d,
1d.2f.3a.4f.5d.6e,1d.2f.3a.4f.5d.6f,1d.2f.3a.4f.5e.6a,1d.2f.3a.4f.5e.6b,1d.2f.3a.4f.5e.6c,
1d.2f.3a.4f.5e.6d,1d.2f.3a.4f.5e.6e,1d.2f.3a.4f.5e.6f,1d.2f.3a.4f.5f.6a,1d.2f.3a.4f.5f.6b,
1d.2f.3a.4f.5f.6c,1d.2f.3a.4f.5f.6d,1d.2f.3a.4f.5f.6e,1d.2f.3a.4f.5f.6f,1d.2f.3b.4a.5a.6a,
1d.2f.3b.4a.5a.6b,1d.2f.3b.4a.5a.6c,1d.2f.3b.4a.5a.6d,1d.2f.3b.4a.5a.6e,1d.2f.3b.4a.5a.6f,
1d.2f.3b.4a.5b.6a,1d.2f.3b.4a.5b.6b,1d.2f.3b.4a.5b.6c,1d.2f.3b.4a.5b.6d,1d.2f.3b.4a.5b.6e,
1d.2f.3b.4a.5b.6f,1d.2f.3b.4a.5c.6a,1d.2f.3b.4a.5c.6b,1d.2f.3b.4a.5c.6c,1d.2f.3b.4a.5c.6d,
1d.2f.3b.4a.5c.6e,1d.2f.3b.4a.5c.6f,1d.2f.3b.4a.5d.6a,1d.2f.3b.4a.5d.6b,1d.2f.3b.4a.5d.6c,
1d.2f.3b.4a.5d.6d,1d.2f.3b.4a.5d.6e,1d.2f.3b.4a.5d.6f,1d.2f.3b.4a.5e.6a,1d.2f.3b.4a.5e.6b,
1d.2f.3b.4a.5e.6c,1d.2f.3b.4a.5e.6d,1d.2f.3b.4a.5e.6e,1d.2f.3b.4a.5e.6f,1d.2f.3b.4a.5f.6a,
1d.2f.3b.4a.5f.6b,1d.2f.3b.4a.5f.6c,1d.2f.3b.4a.5f.6d,1d.2f.3b.4a.5f.6e,1d.2f.3b.4a.5f.6f,
1d.2f.3b.4b.5a.6a,1d.2f.3b.4b.5a.6b,1d.2f.3b.4b.5a.6c,1d.2f.3b.4b.5a.6d,1d.2f.3b.4b.5a.6e,
1d.2f.3b.4b.5a.6f,1d.2f.3b.4b.5b.6a,1d.2f.3b.4b.5b.6b,1d.2f.3b.4b.5b.6c,1d.2f.3b.4b.5b.6d,
1d.2f.3b.4b.5b.6e,1d.2f.3b.4b.5b.6f,1d.2f.3b.4b.5c.6a,1d.2f.3b.4b.5c.6b,1d.2f.3b.4b.5c.6c,
1d.2f.3b.4b.5c.6d,1d.2f.3b.4b.5c.6e,1d.2f.3b.4b.5c.6f. 1d.2f.3b.4b.5d.6a,1d.2f.3b.4b.5d.6b,
1d.2f.3b.4b.5d.6c,1d.2f.3b.4b.5d.6d,1d.2f.3b.4b.5d.6e,1d.2f.3b.4b.5d.6f,1d.2f.3b.4b.5e.6a,
1d.2f.3b.4b.5e.6b,1d.2f.3b.4b.5e.6c,1d.2f.3b.4b.5e.6d,1d.2f.3b.4b.5e.6e,1d.2f.3b.4b.5e.6f,
1d.2f.3b.4b.5f.6a,1d.2f.3b.4b.5f.6b,1d.2f.3b.4b.5f.6c,1d.2f.3b.4b.5f.6d,1d.2f.3b.4b.5f.6e,
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1d.2f.3b.4c.5a.6e,1d.2f.3b.4c.5a.6f,1d.2f.3b.4c.5b.6a,1d.2f.3b.4c.5b.6b,1d.2f.3b.4c.5b.6c,
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1d.2f.3d.4b.5c.6b,1d.2f.3d.4b.5c.6c,1d.2f.3d.4b.5c.6d,1d.2f.3d.4b.5c.6e,1d.2f.3d.4b.5c.6f,
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1d.2f.3d.4b.5d.6f,1d.2f.3d.4b.5e.6a,1d.2f.3d.4b.5e.6b,1d.2f.3d.4b.5e.6c,1d.2f.3d.4b.5e.6d,
1d.2f.3d.4b.5e.6e,1d.2f.3d.4b.5e.6f,1d.2f.3d.4b.5f.6a,1d.2f.3d.4b.5f.6b,1d.2f.3d.4b.5f.6c,
1d.2f.3d.4b.5f.6d,1d.2f.3d.4b.5f.6e,1d.2f.3d.4b.5f.6f,1d.2f.3d.4c.5a.6a,1d.2f.3d.4c.5a.6b,
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1d.2f.3f.4a.5f.6c,1d.2f.3f.4a.5f.6d,1d.2f.3f.4a.5f.6e,1d.2f.3f.4a.5f.6f,1d.2f.3f.4b.5a.6a,
1d.2f.3f.4b.5a.6b,1d.2f.3f.4b.5a.6c,1d.2f.3f.4b.5a.6d,1d.2f.3f.4b.5a.6e,1d.2f.3f.4b.5a.6f,
1d.2f.3f.4b.5b.6a,1d.2f.3f.4b.5b.6b,1d.2f.3f.4b.5b.6c,1d.2f.3f.4b.5b.6d,1d.2f.3f.4b.5b.6e,
1d.2f.3f.4b.5b.6f,1d.2f.3f.4b.5c.6a,1d.2f.3f.4b.5c.6b,1d.2f.3f.4b.5c.6c,1d.2f.3f.4b.5c.6d,
1d.2f.3f.4b.5c.6e,1d.2f.3f.4b.5c.6f,1d.2f.3f.4b.5d.6a,1d.2f.3f.4b.5d.6b,1d.2f.3f.4b.5d.6c,
1d.2f.3f.4b.5d.6d,1d.2f.3f.4b.5d.6e,1d.2f.3f.4b.5d.6f,1d.2f.3f.4b.5e.6a,1d.2f.3f.4b.5e.6b,
1d.2f.3f.4b.5e.6c,1d.2f.3f.4b.5e.6d,1d.2f.3f.4b.5e.6e,1d.2f.3f.4b.5e.6f,1d.2f.3f.4b.5f.6a,
1d.2f.3f.4b.5f.6b,1d.2f.3f.4b.5f.6c,1d.2f.3f.4b.5f.6d,1d.2f.3f.4b.5f.6e,1d.2f.3f.4b.5f.6f,
1d.2f.3f.4c.5a.6a,1d.2f.3f.4c.5a.6b,1d.2f.3f.4c.5a.6c,1d.2f.3f.4c.5a.6d,1d.2f.3f.4c.5a.6e,
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1e.2d.3b.4d.5b.6a, 1e.2d.3b.4d.5b.6b, 1e.2d.3b.4d.5b.6c, 1e.2d.3b.4d.5b.6d,
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1e.2d.3c.4a.5c.6e,1e.2d.3c.4a.5c.6f,1e.2d.3c.4a.5d.6a,1e.2d.3c.4a.5d.6b,1e.2d.3c.4a.5d.6c,
1e.2d.3c.4a.5d.6d,1e.2d.3c.4a.5d.6e,1e.2d.3c.4a.5d.6f,1e.2d.3c.4a.5e.6a,1e.2d.3c.4a.5e.6b,
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1e.2d.3c.4a.5f.6b,1e.2d.3c.4a.5f.6c,1e.2d.3c.4a.5f.6d,1e.2d.3c.4a.5f.6e,1e.2d.3c.4a.5f.6f,
1e.2d.3c.4b.5a.6a,1e.2d.3c.4b.5a.6b,1e.2d.3c.4b.5a.6c,1e.2d.3c.4b.5a.6d,1e.2d.3c.4b.5a.6e,
1e.2d.3c.4b.5a.6f,1e.2d.3c.4b.5b.6a,1e.2d.3c.4b.5b.6b,1e.2d.3c.4b.5b.6c,1e.2d.3c.4b.5b.6d,
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1e.2d.3c.4b.5c.6d,1e.2d.3c.4b.5c.6e,1e.2d.3c.4b.5c.6f,1e.2d.3c.4b.5d.6a,1e.2d.3c.4b.5d.6b,
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1e.2d.3c.4c.5a.6e,1e.2d.3c.4c.5a.6f,1e.2d.3c.4c.5b.6a,1e.2d.3c.4c.5b.6b,1e.2d.3c.4c.5b.6c,
1e.2d.3c.4c.5b.6d,1e.2d.3c.4c.5b.6e,1e.2d.3c.4c.5b.6f,1e.2d.3c.4c.5c.6a,1e.2d.3c.4c.5c.6b,
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1e.2d.3c.4c.5d.6b,1e.2d.3c.4c.5d.6c,1e.2d.3c.4c.5d.6d,1e.2d.3c.4c.5d.6e,1e.2d.3c.4c.5d.6f,
1e.2d.3c.4c.5e.6a,1e.2d.3c.4c.5e.6b,1e.2d.3c.4c.5e.6c,1e.2d.3c.4c.5e.6d,1e.2d.3c.4c.5e.6e,
1e.2d.3c.4c.5e.6f,1e.2d.3c.4c.5f.6a,1e.2d.3c.4c.5f.6b,1e.2d.3c.4c.5f.6c,1e.2d.3c.4c.5f.6d,
1e.2d.3c.4c.5f.6e,1e.2d.3c.4c.5f.6f,1e.2d.3c.4d.5a.6a,1e.2d.3c.4d.5a.6b,1e.2d.3c.4d.5a.6c,
1e.2d.3c.4d.5a.6d,1e.2d.3c.4d.5a.6e,1e.2d.3c.4d.5a.6f,1e.2d.3c.4d.5b.6a,1e.2d.3c.4d.5b.6b,
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1e.2d.3c.4d.5c.6b,1e.2d.3c.4d.5c.6c,1e.2d.3c.4d.5c.6d,1e.2d.3c.4d.5c.6e,1e.2d.3c.4d.5c.6f,
1e.2d.3c.4d.5d.6a, 1e.2d.3c.4d.5d.6b, 1e.2d.3c.4d.5d.6c, 1e.2d.3c.4d.5d.6d,
1e.2d.3c.4d.5d.6e,1e.2d.3c.4d.5d.6f,1e.2d.3c.4d.5e.6a,1e.2d.3c.4d.5e.6b,1e.2d.3c.4d.5e.6c,
1e.2d.3c.4d.5e.6d,1e.2d.3c.4d.5e.6e,1e.2d.3c.4d.5e.6f,1e.2d.3c.4d.5f.6a,1e.2d.3c.4d.5f.6b,
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1e.2d.3c.4e.5a.6b,1e.2d.3c.4e.5a.6c,1e.2d.3c.4e.5a.6d,1e.2d.3c.4e.5a.6e,1e.2d.3c.4e.5a.6f,
1e.2d.3c.4e.5b.6a,1e.2d.3c.4e.5b.6b,1e.2d.3c.4e.5b.6c,1e.2d.3c.4e.5b.6d,1e.2d.3c.4e.5b.6e,
1e.2d.3c.4e.5b.6f,1e.2d.3c.4e.5c.6a,1e.2d.3c.4e.5c.6b,1e.2d.3c.4e.5c.6c,1e.2d.3c.4e.5c.6d,
1e.2d.3c.4e.5c.6e,1e.2d.3c.4e.5c.6f,1e.2d.3c.4e.5d.6a,1e.2d.3c.4e.5d.6b,1e.2d.3c.4e.5d.6c,
1e.2d.3c.4e.5d.6d,1e.2d.3c.4e.5d.6e,1e.2d.3c.4e.5d.6f,1e.2d.3c.4e.5e.6a,1e.2d.3c.4e.5e.6b,
1e.2d.3c.4e.5e.6c,1e.2d.3c.4e.5e.6d,1e.2d.3c.4e.5e.6e,1e.2d.3c.4e.5e.6f,1e.2d.3c.4e.5f.6a,
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1e.2d.3c.4f.5a.6a,1e.2d.3c.4f.5a.6b,1e.2d.3c.4f.5a.6c,1e.2d.3c.4f.5a.6d,1e.2d.3c.4f.5a.6e,
1e.2d.3c.4f.5a.6f,1e.2d.3c.4f.5b.6a,1e.2d.3c.4f.5b.6b,1e.2d.3c.4f.5b.6c,1e.2d.3c.4f.5b.6d,
1e.2d.3c.4f.5b.6e,1e.2d.3c.4f.5b.6f,1e.2d.3c.4f.5c.6a,1e.2d.3c.4f.5c.6b,1e.2d.3c.4f.5c.6c,
1e.2d.3c.4f.5c.6d,1e.2d.3c.4f.5c.6e,1e.2d.3c.4f.5c.6f,1e.2d.3c.4f.5d.6a,1e.2d.3c.4f.5d.6b,
1e.2d.3c.4f.5d.6c,1e.2d.3c.4f.5d.6d,1e.2d.3c.4f.5d.6e,1e.2d.3c.4f.5d.6f,1e.2d.3c.4f.5e.6a,
1e.2d.3c.4f.5e.6b,1e.2d.3c.4f.5e.6c,1e.2d.3c.4f.5e.6d,1e.2d.3c.4f.5e.6e,1e.2d.3c.4f.5e.6f,
1e.2d.3c.4f.5f.6a,1e.2d.3c.4f.5f.6b,1e.2d.3c.4f.5f.6c,1e.2d.3c.4f.5f.6d,1e.2d.3c.4f.5f.6e,
1e.2d.3c.4f.5f.6f,1e.2d.3d.4a.5a.6a,1e.2d.3d.4a.5a.6b,1e.2d.3d.4a.5a.6c,1e.2d.3d.4a.5a.6d,
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1e.2d.3d.4a.5b.6d,1e.2d.3d.4a.5b.6e,1e.2d.3d.4a.5b.6f,1e.2d.3d.4a.5c.6a,1e.2d.3d.4a.5c.6b,
1e.2d.3d.4a.5c.6c,1e.2d.3d.4a.5c.6d,1e.2d.3d.4a.5c.6e,1e.2d.3d.4a.5c.6f,1e.2d.3d.4a.5d.6a,
1e.2d.3d.4a.5d.6b, 1e.2d.3d.4a.5d.6c, 1e.2d.3d.4a.5d.6d, 1e.2d.3d.4a.5d.6e,
1e.2d.3d.4a.5d.6f,1e.2d.3d.4a.5e.6a,1e.2d.3d.4a.5e.6b,1e.2d.3d.4a.5e.6c,1e.2d.3d.4a.5e.6d,
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1e.2d.3d.4b.5a.6c,1e.2d.3d.4b.5a.6d,1e.2d.3d.4b.5a.6e,1e.2d.3d.4b.5a.6f,1e.2d.3d.4b.5b.6a,
1e.2d.3d.4b.5b.6b, 1e.2d.3d.4b.5b.6c, 1e.2d.3d.4b.5b.6d, 1e.2d.3d.4b.5b.6e,
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1e.2d.3d.4b.5d.6d, 1e.2d.3d.4b.5d.6e, 1e.2d.3d.4b.5d.6f, 1e.2d.3d.4b.5e.6a,
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1e.2d.3d.4b.5f.6a,1e.2d.3d.4b.5f.6b,1e.2d.3d.4b.5f.6c,1e.2d.3d.4b.5f.6d,1e.2d.3d.4b.5f.6e,
1e.2d.3d.4b.5f.6f,1e.2d.3d.4c.5a.6a,1e.2d.3d.4c.5a.6b,1e.2d.3d.4c.5a.6c,1e.2d.3d.4c.5a.6d,
1e.2d.3d.4c.5a.6e,1e.2d.3d.4c.5a.6f,1e.2d.3d.4c.5b.6a,1e.2d.3d.4c.5b.6b,1e.2d.3d.4c.5b.6c,
1e.2d.3d.4c.5b.6d,1e.2d.3d.4c.5b.6e,1e.2d.3d.4c.5b.6f,1e.2d.3d.4c.5c.6a,1e.2d.3d.4c.5c.6b,
1e.2d.3d.4c.5c.6c,1e.2d.3d.4c.5c.6d,1e.2d.3d.4c.5c.6e,1e.2d.3d.4c.5c.6f,1e.2d.3d.4c.5d.6a,
1e.2d.3d.4c.5d.6b,1e.2d.3d.4c.5d.6c,1e.2d.3d.4c.5d.6d,1e.2d.3d.4c.5d.6e,1e.2d.3d.4c.5d.6f,
1e.2d.3d.4c.5e.6a,1e.2d.3d.4c.5e.6b,1e.2d.3d.4c.5e.6c,1e.2d.3d.4c.5e.6d,1e.2d.3d.4c.5e.6e,
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1f.2f.3b.4e.5b.6e,1f.2f.3b.4e.5b.6f,1f.2f.3b.4e.5c.6a,1f.2f.3b.4e.5c.6b,1f.2f.3b.4e.5c.6c,
1f.2f.3b.4e.5c.6d,1f.2f.3b.4e.5c.6e,1f.2f.3b.4e.5c.6f,1f.2f.3b.4e.5d.6a,1f.2f.3b.4e.5d.6b,
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1f.2f.3f.4d.5e.6d,1f.2f.3f.4d.5e.6e,1f.2f.3f.4d.5e.6f,1f.2f.3f.4d.5f.6a,1f.2f.3f.4d.5f.6b,
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1f.2f.3f.4e.5b.6a,1f.2f.3f.4e.5b.6b,1f.2f.3f.4e.5b.6c,1f.2f.3f.4e.5b.6d,1f.2f.3f.4e.5b.6e,
1f.2f.3f.4e.5b.6f,1f.2f.3f.4e.5c.6a,1f.2f.3f.4e.5c.6b,1f.2f.3f.4e.5c.6c,1f.2f.3f.4e.5c.6d,
1f.2f.3f.4e.5c.6e,1f.2f.3f.4e.5c.6f,1f.2f.3f.4e.5d.6a,1f.2f.3f.4e.5d.6b,1f.2f.3f.4e.5d.6c,
1f.2f.3f.4e.5d.6d,1f.2f.3f.4e.5d.6e,1f.2f.3f.4e.5d.6f,1f.2f.3f.4e.5e.6a,1f.2f.3f.4e.5e.6b,
1f.2f.3f.4e.5e.6c,1f.2f.3f.4e.5e.6d,1f.2f.3f.4e.5e.6e,1f.2f.3f.4e.5e.6f,1f.2f.3f.4e.5f.6a,
1f.2f.3f.4e.5f.6b,1f.2f.3f.4e.5f.6c,1f.2f.3f.4e.5f.6d,1f.2f.3f.4e.5f.6e,1f.2f.3f.4e.5f.6f,
1f.2f.3f.4f.5a.6a,1f.2f.3f.4f.5a.6b,1f.2f.3f.4f.5a.6c,1f.2f.3f.4f.5a.6d,1f.2f.3f.4f.5a.6e,
1f.2f.3f.4f.5a.6f,1f.2f.3f.4f.5b.6a,1f.2f.3f.4f.5b.6b,1f.2f.3f.4f.5b.6c,1f.2f.3f.4f.5b.6d,
1f.2f.3f.4f.5b.6e,1f.2f.3f.4f.5b.6f,1f.2f.3f.4f.5c.6a,1f.2f.3f.4f.5c.6b,1f.2f.3f.4f.5c.6c,
1f.2f.3f.4f.5c.6d,1f.2f.3f.4f.5c.6e,1f.2f.3f.4f.5c.6f,1f.2f.3f.4f.5d.6a,1f.2f.3f.4f.5d.6b,
1f.2f.3f.4f.5d.6c,1f.2f.3f.4f.5d.6d,1f.2f.3f.4f.5d.6e,1f.2f.3f.4f.5d.6f,1f.2f.3f.4f.5e.6a,
1f.2f.3f.4f.5e.6b,1f.2f.3f.4f.5e.6c,1f.2f.3f.4f.5e.6d,1f.2f.3f.4f.5e.6e,1f.2f.3f.4f.5e.6f,
1f.2f.3f.4f.5f.6a,1f.2f.3f.4f.5f.6b,1f.2f.3f.4f.5f.6c,1f.2f.3f.4f.5f.6d,1f.2f.3f.4f.5f.6e,
1f.2f.3f.4f.5f.6f,
具体实施方式
方案1
试剂和条件:i.卤代烷,K2CO3,DMF或CH3CH3OCH2Cl,SnCl4,乙腈
化合物1:化合物1是用下面的一般步骤制备的:
5-异丙基巴比妥酸与磷酰氯反应产生2,4,6-三氯-5-异丙基嘧啶。接着将2,4,6-三氯-5-异丙基嘧啶与苄醇盐反应形成2,4-双(苄氧基)-6氯-5-异丙基嘧啶。接着将2,4-双(苄氧基)-6氯-5-异丙基嘧啶与3-(氰甲基)-5-甲基苯甲腈反应形成3-((2,6-双(苄氧基)-5-异丙基嘧啶-4-基)(氰基)甲基)-5-甲基苯甲腈。用NaH和O2处理3-((2,6-双(苄氧基)-5-异丙基嘧啶-4-基)(氰基)甲基)-5-甲基苯甲腈,形成酮3-((2,6-双(苄氧基)-5-异丙基嘧啶-4-基)(氰基)甲基)-5-甲基苯甲腈,接着催化加氢形成化合物1。
3-(氰甲基)-5-甲基苯甲腈中间体是由3,5-二甲基苯甲酸通过多步反应获得,首先3,5-二甲基苯甲酸用亚硫酰氯发生氯化反应形成酰氯,接着与氢氧化铵反应,形成相对应的酰胺,3,5-二甲基苯甲酰胺。相应的溴腈,3-(溴甲基)-5-甲基苯甲腈是通过3,5-二甲基苯甲酰胺同NBS和过氧化苯甲酰在紫外线照射下反应产生。接着3-(溴甲基)-5-甲基苯甲腈同KCN反应形成3-(氰甲基)-5-甲基苯甲腈。
化合物2:向碳酸锂(13.2mg,0.178)和3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物1,52.9mg,0.178mmol)的DMF(1.0mL)混合溶液中添加碘甲烷(11.1μL,0.178mmol)并将反应混合液搅拌72小时。反应混合液利用乙酸乙酯和饱和氯化铵溶液分离。去除有机层,干燥(MgSO4),浓缩并用反向HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化,经冻干后获得白色粉末(17.4mg,31%)。1H NMR(300MHz,CD3OD):8.23(s,1H),8.14(s,1H),7.93(s,1H),3.03(s,3H),2.47(s,3H),2.3-2.1(m,1H),1.15(d,J=6.6Hz,3H),1.08(d,J=6.6Hz,3H)。质谱:312.2(M+H),310.0(M-H)。
化合物3:向置于0℃的碳酸钾(0.67g,4.85mmol)和化合物1(1.44g,4.85mmol,1.0eq.)的DMF(23mL)混合溶液中添加碘乙烷(0.326mL,4.04mmol)。将反应混合液加热至室温过夜,然后浓缩。分离位于乙酸乙酯和饱和氯化铵溶液之间的残渣。去除有机层,干燥(MgSO4),浓缩并用快速柱层析(20-50%乙酸乙酯/己烷)纯化获得3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(0.900g,68%);1H NMR(300MHz,CDCl3):δ8.69(br,1H),8.02(s,1H),7.92(s,1H),7.76(s,1H),3.9-3.8(m,1H),3.2-3.1(m,1H),2.49(s,3H),2.3-2.1(m,1H),1.17(d,J=6.9Hz,3H),1.1-1.0(m,6H);质谱:326.2(M+H),324.0(M-H);以及
3-(1,3-二乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈,化合物4(0.0899g),1H NMR(300MHz,CD3OD):δ8.24(s,1H),8.16(s,1H),7.93(s,1H),4.0-3.8(m,3H),3.3-3.1(m,1H),2.48(s,3H),2.3-2.1(m,1H),1.3-1.0(m,12H)。
化合物5:向置于0℃的碳酸钾(0.046g,0.336mmol)和化合物1(0.100g,0.336mmol)的DMF(3.0mL)混合溶液中添加(溴甲基)环丙烷(22μL,0.224mmol)。反应混合液加热至室温过夜,用乙酸乙酯和饱和氯化铵溶液分离。去除有机层,干燥(MgSO4),浓缩并用快速柱层析(20-50%乙酸乙酯/己烷),冻干后产生白色粉末(0.0308g,39%);1H NMR(300MHz,CDCl3):δ9.62(br,1H),8.02(s,1H),7.91(s,1H),7.74(s,1H),3.56(dd,J=14.7,8.1Hz,1H),3.19(dd,J=14.7,5.7Hz,1H),2.47(s,3H),2.3-2.1(m,1H),1.18(d,J=6.9Hz,3H),1.07(d,J=6.9Hz,3H),0.9-0.7(m,1H),0.4-0.2(m,4H);质谱:352.1(M+H),350.0(M-H)。
化合物6:将碳酸钾(29mg,0.212mmol,1.2eq.),化合物1(76mg,0.254mmol,1.0eq.)和1-溴-2-氯-2-丁烯(36mg,0.212mmol,1.0eq,按照Kuehne等J.Org.Chem.1996,61(22),7873-7801制备)的DMF(2.0mL)混合溶液,置于0搅拌,接着加热至室温反应3小时。将反应混合液加热到室温过夜,用乙酸乙酯和饱和氯化铵溶液分离。去除有机层,干燥(MgSO4),浓缩并用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化冻干后获得白色粉末(20.6mg,25%);1H NMR(300MHz,CDCl3):δ8.67(br,1H),8.00(s,1H),7.87(s,1H),7.70(s,1H),5.4-5.35(m,1H),5.02(d,J=14.4Hz,1H),4.05(d,J=16.2Hz,1H),2.47(s,3H),2.2-2.0(m,1H),1.2-1.0(m,9H)。质谱:386.1,388.1(M+H)。
化合物7:将化合物1(95mg,0.32mmol,1.2eq.)溶于3mL的DMF中。添加碳酸钾溶液(37mg,1eq.)并将反应混合液置于室温搅拌10分钟。添加1-溴-2-甲氧基-乙烷(37mg,0.266mmol,1eq.)和碘化锂(36mg,1eq.)。将反应混合液置于室温搅拌过夜。反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷),接着用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)冻干后获得白色粉末(24.8mg,26%)。LC-MS显示356.1(M+1)。1H NMR(300MHz,CDCl3):δ9.10(br,1H),8.10(s,1H),8.01(s,1H),7.77(s,1H),3.78(m,2H),3.59(m,1H),3.36(m,1H),3.03(s,3H),2.48(s,3H),2.2(m,1H),1.20(dd,6H)。
化合物8:将化合物1(62mg,0.208mmol,1.2eq.)溶于2mL的DMF中。添加碳酸钾(24mg,1eq.)并将反应混合液置于室温搅拌10分钟。添加2-溴乙酸乙酯(29mg,0.174mmol,1eq.)和碘化锂(23mg,1eq.)。将反应混合溶液置于室温搅拌3天。反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)并用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)冻干后获得白色粉末(15mg,22%)。LC-MS显不384(M+1)。1H NMR(300MHz,CDCl3):δ9.06(br,1H),8.03(s,1H),7.96(s,1H),7.81(s,1H),4.26(m,1H),4.08(m,2H),3.40(m,1H),2.50(s,3H),2.22(m,1H),2.03(s,3H),1.20(dd,6H)。
化合物9:将化合物1(0.0953g,0.321mmol.),三甲基氯硅烷(2.0μL,0.016mmol)和1,1,1,3,3,3-六甲基二硅氮烷(1.6mL)的混合溶液加热到140℃直到形成棕色溶液(4小时)。将反应混合溶液冷却并浓缩。将反应产生的残渣溶于乙腈(1.6mL)并添加氯甲基乙醚(31μL,0.321mmol)和四氯化锡(1M in CH2Cl2,32μL,0.0321mmol)。将反应混合溶液置于室温搅拌过夜,接着用饱和碳酸氢钠溶液淬火1小时。用乙酸乙酯和水将混合液分离。去除有机层,干燥(MgSO4),浓缩并用快速柱色谱(10-40%乙酸乙酯/己烷)纯化产生泡沫。将回流甲醇重结晶获得白色固体(0.0639g,56%);1H NMR(300MHz,CD3OD):δ8.15(s,1H),8.08(s,1H),7.88(s,1H),5.40(d,J=10.5Hz,1H),4.75(d,J=10.5Hz,1H),3.5-3.2(m,2H),2.46(s,3H),2.3-2.1(m,1H),1.13(d,J=6.9Hz,3H),1.06(d,J=6.9Hz,3H),0.70(t,J=6.9Hz,3H);质谱:356.0(M+H),354.0(M-H)。
方案2
试剂和条件:i.K2CO3,MeOH
化合物10:将碳酸钾(15mg,0.108mmol,2.8eq)添加到溶有化合物8(15mg,0.039mmol)的2mL MeOH中。将反应混合溶液置于室温搅拌2小时。将反应混合溶液浓缩并用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化冻干后获得白色粉末(6.1mg,46%)。LC-MS显示342.1(M+1)。1H NMR(300MHz,CD3OD)大部分是目的化合物,少部分是环化形式:δ8.24(s,1H),8.19(s,1H),7.96(s,1H),3.82(m,1H),3.60(m,2H),3.41(m,1H),2.53(s,3H),2.22(m,1H),1.17(dd,6H)。
方案3
试剂和条件:i.n-BuLi,HCHO,THF,-78℃;ii.MsCl,TEA,DCM,0℃;化合物1,K2CO3,Lil,DMF。
3-环丙基-丙-2-yn-1-醇:在-78℃时,将n-丁基锂(1.3M己烷溶液,14.3mL,18.57mmol,1.1eq.)添加到43mL溶有乙炔环丙烷(甲苯中浓度为70%,2mL,16.88mmol)的THF溶液中。将反应混合溶液置于0℃搅拌1小时,接着冷却至-78℃。再添加多聚甲醛(633mg,21.1mmol,1.25eq.)。接着将反应混合溶液再置于-78搅拌并加热至室温过夜。然后将反应混合溶液浓缩,添加乙酸乙酯,并用盐水洗涤有机层。将有机层浓缩和纯化(硅胶,0-20%EtOAC/己烷)获得淡黄色油(900mg,56%)。1H NMR(300MHz,CDCl3):δ4.20(s,2H),1.62(s,1H),1.23(m,1H),0.75(m,6H)。
3-环丙基-丙-2炔甲基磺酸酯:在0时,将TEA(140μL,1.0mmol,2.0eq.)添加到2ml溶有3-环丙基-丙-2-yn-1-醇的DCM溶液中,接着添加MsCl(46μL,0.6mmol,1.2eq.)。将反应混合溶液置于0搅拌30分钟。将反应混合溶液浓缩。添加乙酸乙酯并用饱和NaHCO3溶液洗涤。将有机层浓缩并用无水硫酸钠干燥后获得淡黄色的油(59mg,68%),其直接用作下一步实验。
化合物11:将化合物1(121mg,0.406mmol,1.2eq.)溶于4mL的DMF中。添加碳酸钾(59mg,0.338mmol,1eq.)并将反应混合溶液置于室温搅拌10分钟。添加3-环丙基-丙-2-炔基甲基磺酸酯(59mg,0.338mmol,1eq.)和碘化锂(45mg,1eq.)。并将反应混合溶液置于室温搅拌过夜。在反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)获得灰白色粉末(88mg,69%)。LC-MS显示376.1(M+1)。1HNMR(300MHz,CDCl3):δ8.81(br,1H),8.17(s,1H),8.03(s,1H),7.81(s,1H),4.91(d,1H),3.98(d,1H),2.52(s,3H),2.22(m,1H),1.20(dd,6H),0.78(m,1H),0.73(m,2H),0.59(m,1H),0.38(m,1H)。
方案4
试剂和条件:i.Deoxoflouor,cat.EtOH,110℃;ii.AcBr,60℃;iii.K2CO3,Etl,DMF;或氯甲氧基-乙烷,K2CO3,Lil,DMF。
3-[二氟-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-甲基]-5-甲基-苯甲腈:添加Deoxoflouor(3mL,过量)到3-(5-异丙基-2,6-二甲基-嘧啶-4-羰基)-5-苯甲氰(用与制备化合1中的制备3-(2,6-双(苄氧基)-5-异丙基嘧啶-4-羰基-5-苯甲腈中间体相似的方法制备,甲醇替代苄醇除外)(779mg,2.39mmol),随后添加一滴乙醇(大约0.1mL)。将反应混合溶液置于氩气下110℃下加热9小时。接着将反应混合溶液浓缩,添加乙酸乙酯,并用盐水洗涤混合溶液。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)获得灰白色粉末(500mg,73%)。LC-MS显示348.1(M+1)。
化合物12:将乙酰溴(2mL,过量)添加到3-[二氟-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-甲基]-5-甲基-苯甲腈(500mg,1.44mmol)。将反应混合溶液置于氩气下加热至60℃过夜。接着将反应混合溶液浓缩和纯化(硅胶,0-80%EtOAC/己烷)获得灰白色固体(390mg,85%)。LC-MS显示318.1(M-1)。
化合物13:将化合物12(92mg,0.288mmol,1.2eq.)溶于1.4mL的DMF中。将碳酸钾(40mg,0.288mmol,1.2eq.)添加到反应混合溶液中置于0℃搅拌10分钟。添加碘乙烷(19.4μL,0.24mmol,1eq.)。将反应混合溶液置于0℃搅拌并加热至室温2天。向反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)获得灰白色粉末(4.5mg,6%)。LC-MS显示348.1(M+1)。1H NMR(300MHz,CD3OD):δ7.95(s,1H),7.82(s,2H),3.58(m,2H),2.50(s,3H),1.22(dd,6H)。
化合物14:将化合物12(80mg,0.25mmol,1.2eq.)溶于2mL的DMF中。添加碳酸钾(29mg,0.209mmol,1eq.)并将反应混合溶液置于0搅拌10分钟。添加氯甲氧基乙烷(19.4μL,0.209mmol,1eq.),随后添加碘化锂(28mg,1eq.)。将反应混合溶液置于0℃搅拌并加热至室温过夜。反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)以及prep TLC(2%MeOH/DCM)获得灰白色粉末(8.3mg,11%)。LC-MS显示378.0(M+1)。1H NMR(300MHz,CDCl3):δ9.03(br,1H),7.76(s,1H),7.62(s,2H),5.37(s,2H),3.40(m,2H),2.70(m,1H),2.48(s,3H),1.22(dd,6H),1.00(t,3H)。F NMR(300MHz,CDCl3):δ-77.43。
也同样分离获得了属于该反应副产物的化合物15:
方案5
试剂和条件:i.a.NBS;CCl4;b.KF,18-cr-6,CAN;ii.a.NBS;CCl4;b.KCN,EtOH/H2O;iii.4-氯-5-异丙基-2,6-二甲氧基-嘧啶,NaH,DMF;b.NaH,O2,DMF;iv.AcBr;v.Etl,K2CO3,DMF。
3-氟甲基-5-甲基-苯甲腈:向3,5-二甲基苯甲腈(25g,190mmol)的四氯化碳溶液(190mL)中添加N-溴代琥珀酰亚胺(33.9g,190mmol)和过氧苯甲酰(2.28g,9.4mmol)。将反应混合溶液在UV灯下回流3小时,冷却至室温并过滤。将滤液浓缩并用硅胶柱色谱(10%乙酸乙酯/己烷)纯化获得不纯产物。将产物从回流乙醚(100mL)和己烷(400mL)中结晶获得白色固体(19.11g,48%)。
向上述部分材料中(3.04g,14.47mmol)添加氟化钾(2.52g,43.41mmol),18-冠醚-6(0.76g,2.89mmol)和乙腈(20mL),并将反应产生的黄色混合溶液回流几天。通过过滤去除产生的白色沉淀,再将滤液浓缩并用硅胶柱色谱(0-20%乙酸乙酯/己烷)纯化获得白色固体(1.27g,59%)。1H NMR(300MHz,CDCl3):δ7.41(s,2H),7.37(s,1H),5.33(d,J=47Hz,2H),2.37(s,3H)。
3-氰甲基-5-氟甲基-苯甲腈:向3-氟甲基-5-甲基-苯甲腈(1.22g,8.18mmol)的四氯化碳溶液(8mL)中添加N-溴代琥珀酰亚胺(1.46g,8.18mmol)和过氧苯甲酰(0.099g,0.41mmol)。将反应混合溶液置于UV灯下回流3.5小时,冷却至室温并过滤。将滤液浓缩并用硅胶柱色谱(0-20%乙酸乙酯/己烷)纯化获得白色固体(0.3561g,19%)。
向上述物质(0.3561g,1.56mmol)中添加氰化钾(0.187g,2.87mmol),乙醇(1.5mL)和水(0.5mL)。将反应混合溶液回流6小时,并冷却至室温。用乙酸乙酯萃取产物,H2O洗涤,并干燥(MgSO4),浓缩并用硅胶柱色谱(0-40%乙酸乙酯/己烷)纯化获得白色固体(0.1788g,66%)。1H NMR(300MHz,CDCl3):δ7.55(s,3H),5.73(d,J=47Hz,2H),3.79(s,2H)。
3-氟甲基-5-(5-异丙基-2,6-二甲氧基-嘧啶-4-羰基)-苯甲腈:向置于0℃的3-氰甲基-5-氟甲基-苯甲腈(0.1351g,0.776mmol)和4-氯-5-异丙基-2,6-二甲氧基-嘧啶(0.176g,0.814mmol)的DMF溶剂(5.0mL)中添加60%氢氧化钠(0.062g,1.552mmol),超过30分钟产生橙色溶液。将反应混合溶液置于0℃搅拌1小时,接着置于室温搅拌4小时。将反应混合溶液用1N HCl溶液淬火,并用乙酸乙酯和饱和NH4Cl溶液分离。用饱和NH4Cl溶液洗涤有机层,干燥(MgSO4),浓缩并用硅胶柱色谱(0-30%乙酸乙酯/己烷)纯化获得白色固体(0.1714g,62%)。
将上述物质溶于DMF(5mL)中并冷却至0℃。分次添加60%的氢氧化钠(0.027g,0.686mmol),并将产生的黄色反应混合溶液置于室温搅拌30分钟。反应混合溶液中接入氧气,剧烈搅拌4小时。混合溶液用1N HCl溶液淬火,并用乙酸乙酯和饱和NH4Cl溶液分离。用水以及饱和NH4Cl溶液洗涤有机层,干燥(MgSO4),浓缩并用硅胶柱色谱(0-50%乙酸乙酯/己烷)纯化获得白色固体(0.036g,22%)。1H NMR(300MHz,CDCl3):δ8.05(s,1H),8.03(s,1H),7.83(s,1H),5.43(d,J=47Hz,2H),4.04(s,3H),3.88(s,3H),2.86-2.80(m,1H),1.15(d,J=6.9Hz,6H);质谱:343.2(M+H)。
化合物16:将3-氟甲基-5-(5-异丙基-2,6-二甲氧基-嘧啶-4-羰基)-苯甲腈(0.036g,0.105mmol)的乙酰溴溶液(2.0mL)置于60℃搅拌6小时。将反应混合溶液冷却至室温,与乙腈(3×)共蒸发获得灰白色的薄膜(0.016g,48%)。
1H NMR(300MHz,CDCl3):δ10.70(br s,1H),10.30(br s,1H),8.18(s,1H),8.09(s,1H),7.89(s,1H),5.47(d,J=47Hz,2H),3.41(s,3H),2.5-2.2(m,1H),0.95(d,J=6.6Hz,6H);质谱:316.1(M+H)。
化合物17:向0的化合物16(16mg,0.0507mmol)的DMF(0.5mL)溶液中添加碘乙烷(4.1μL,0.0507mmol)和碳酸钾(7.0mg,0.0507mmol)。将反应混合溶液加热至室温过夜,用乙酸乙酯稀释,盐水洗涤,干燥(MgSO4),以及浓缩。用硅胶柱色谱(20-50%乙酸乙酯/己烷)纯化粗产物冻干后产生白色粉末(4.6mg,26%)。1H NMR(300MHz,CD3OD):δ8.44(s,1H),8.32(s,1H),8.14(s,1H),5.52(d,J=47Hz,2H),3.9-3.7(m,1H),3.2-3.1(m,1H),2.3-2.1(m,1H),1.14(d,J=6.9Hz,3H),1.1-1.0(m,6H);质谱:344.2(M+H),342.0(M-H)。
方案6
试剂和条件:i.三氟-甲磺酸2,2,2-三氟-乙酯,NaH,THF;ii.a.尿素,乙醇钠,乙醇;b.三氯氧磷,2,6-吡啶;iii.甲醇钠,甲醇;iv.a.3-氰甲基-5-甲基-苯甲腈,NaH,DMF;b.O2;v.AcBr;vi.Etl,Li2CO3,DMF。
2-(2,2,2-三氟-乙基)-丙二酸苄酯:向置于室温下的溶有60%氢氧化钠(0.678g,16.97mmol)的THF(100mL)悬液中添加丙二酸苄酯(4.825g,16.97mmol)30分钟后产生清亮溶液。添加三氟甲磺酸2,2,2-三氟乙酯(3.52g,15.43mmol)并将反应混合溶液置于50搅拌48小时。将反应混合溶液浓缩,利用乙酸乙酯分离以及饱和氯化铵溶液洗涤并用1N HCl酸化。用乙酸乙酯(2×)萃取混合溶液,干燥(MgSO4),以及浓缩。将产生的残渣用快速柱层析(硅胶,0-0%乙酸乙酯/己烷)获得无色的油(3.844g,68%)。1H NMR(300MHz,CDCl3):δ7.4-7.2(m,10H),5.15(s,4H),3.75(t,J=6.9Hz,1H),2.9-7.7(m,2H)。
2,4,6-三氯-5-(2,2,2-三氟-乙基)-嘧啶:向置于室温的2-(2,2,2-三氟-乙基)-丙二酸苄酯(3.40g,9.29mmol)乙醇(2.0mL)溶液中添加尿素(0.558g,9.29mmol)和乙醇钠(21wt%,8.0mL,21.4mmol)。将反应混合溶液置于60℃搅拌12小时。将反应混合溶液冷却至室温,用乙醚稀释(20mL),并搅拌1小时。通过过滤收集反应的固体并真空中干燥获得灰白色的固体(1.228g,52%)。将该固体重悬于三氯氧磷(14mL)并精心添加2,6-吡啶(0.7mL)。将反应混合溶液置于140℃搅拌1小时,接着置于105℃过夜。将反应混合溶液冷却至室温,浓缩以及用甲苯共蒸发产生棕色的油。将残渣溶于乙醚并用饱和碳酸氢钠溶液洗涤。将有机层干燥(MgSO4),浓缩并用快速柱层析(硅胶,0-10%乙酸乙酯/正己烷)纯化获得白色固体(0.6331g,49%)。1H NMR(300MHz,CDCl3):δ3.75(q,J=9.3Hz,2H)。
4-氯-2,6二甲氧基-5-(2,2,2-三氟-乙基)-嘧啶:向置于0的2,4,6-三氯-5-(2,2,2-三氟-乙基)-嘧啶(0.633g,2.39mmol)甲醇(20mL)溶液中添加甲醇钠(25wt%,1.09mL,4.77mmol)。将反应混合溶液加热至室温过夜。将反应混合溶液浓缩,溶于乙醚并用水洗涤。将有机层干燥(MgSO4),浓缩并用快速柱层析(硅胶,0-10%乙酸乙酯/正己烷)纯化获得无色油(0.5531g,90%)。1H NMR(300MHz,CDCl3):δ3.87(s,3H),3.83(s,3H),3.32(q,J=10.2Hz,2H);质谱:257.1,259.1(M+H)。
3-[2,6-二甲氧基-5-(2,2,2-三氟-乙基)-嘧啶-4-羰基]-5-甲基-苯甲腈:向置于0℃的3-氰甲基-5-氟甲基-苯甲腈(0.348g,2.23mmol)和4-氯-2,6-二甲氧基-5-(2,2,2-三氟-乙基)-嘧啶(0.546g,2.13mmol)的DMF(10.0mL)溶液中添加60%的氢氧化钠(0.170g,4.26mmol)反应30分钟产生橙色溶液。将反应混合溶液置于0℃搅拌1小时,接着置于室温搅拌3小时。向反应混合溶液中通入氧气剧烈搅拌24小时。混合溶液用1N HCl溶液淬火并用乙酸乙酯和饱和NH4Cl溶液分离。用H2O,饱和NH4Cl溶液洗涤有机层,干燥(MgSO4),浓缩并用快速柱层析(硅胶,0-30%乙酸乙酯/正己烷)纯化获得白色固体(0.476g,61%)。1H NMR(300MHz,CDCl3):δ7.92(s,2H),7.63(s,1H),4.06(s,3H),3.93(s,3H),3.60(q,J=10.5Hz,2H),2.41(s,3H);质谱:366.2(M+H)。
化合物18:将3-[2,6-二甲氧基-5-(2,2,2-三氟-乙基)-嘧啶-4-羰基]-5-甲基-苯甲腈(0.4638g,1.27mmol)的乙酰溴溶液(13.0mL)置于60℃搅拌36小时。将反应混合溶液冷却至室温,并与乙腈(3×)共蒸发。用快速柱层析(硅胶,0-5%甲醇/二氯甲烷)纯化残渣获得棕色固体(0.2179g,94%)。1H NMR(300MHz,CD3OD):δ8.12(s,1H),8.03(s,1H),7.90(s,1H),3.15(q,J=10.5Hz,2H),2.46(s,3H);质谱:336.0(M-H)。
化合物19:向置于室温的化合物18(0.147g,0.436mmol)和碳酸锂(0.016g,0.218mmol)的DMF(1.0mL)悬液中添加碘乙烷(17.6μL,0.218mmol)。将反应混合溶液置于室温搅拌72小时,接着用乙酸乙酯稀释,用饱和氯化铵溶液洗涤,干燥(MgSO4),以及浓缩。用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化残渣冻干后获得白色粉末(31.3mg,39%)。1H NMR(300MHz,CD3OD):δ8.22(s,1H),8.12(s,1H),7.94(s,1H),3.9-3.8(m,1H),3.3-3.1(m,2H),2.9-2.7(m,1H),2.47(s,3H),1.08(t,J=6.6Hz,3H);质谱:366.2(M+H),363.90(M-H)。
方案7
试剂和条件:i.卤代烷,K2CO3,DMF。
化合物20:向置于室温的化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(5mL)搅拌溶液中添加3,3-二甲基烯丙基溴(149mg,1mmol)。搅拌过夜之后,将混合溶液置于真空中蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得254mg(69%)的白色固体。m.p.158-159℃1H-NMR(200MHz,CDCl3):δ1.10(3H,d,J=6.8Hz),1.20(3H,d,J=6.8Hz),1.33(6H,d,J=4.6Hz),2.20(1H,m),2.51(3H,s),4.11(1H,m),4.32(1H,m),4.90(1H,m),7.76(1H,s),7.91(1H,s),8.02(1H,s),8.96(1H,s)。
也同样分离出副产物,化合物21:
化合物22:向置于氮气下冰浴冷却的2-丁炔-1-醇(70mg,1mmol)的氯仿搅拌溶液中,添加三乙胺(210μL,1.5mmol)和小滴添加甲基磺酰氯(90μL,1.2mmol)。搅拌1.1小时后,用饱和碳酸氢钠水溶液洗涤反应混合溶液,用无水硫酸镁干燥,过滤,并置于真空蒸发。将残渣进一步于高真空中干燥大约20分钟,并与化合物1(297mg,1mmol)、粉状无水碳酸钾(138mg,1mmol),以及碘化锂(134mg,1mmol)混合。接着向混合物中添加DMF(5mL),置于室温搅拌过夜。DMF蒸发后,将残渣溶于甲醇-氯仿(1∶9)并用硅藻土滤片过滤。将滤液置于真空中蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得110mg(26%)的白色固体;m.p.116-117℃;1H-NMR(200MHz,CDCl3):δ1.14(3H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),1.44(3H,t,J=2.4Hz),2.26(1H,m),2.56(3H,s),4.00(1H,dd,J=2.4Hz,17.8Hz),4.86(1H,dd,J=2.4Hz,17.8Hz),7.79(1H,s),8.09(1H,s),8.16(1H,s),8.89(1H,s);m/z(EI)349[M+]。
化合物23:向置于室温的化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)DMF(5mL)搅拌溶液中,添加80wt.%的炔丙基溴的甲苯溶液(112μL,1mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得167mg(50%)的白色固体;m.p.209-210℃;1H-NMR(200MHz,CDCl3)δ1.15(3H,d,J=6.8Hz),1.23(3H,d,J=6.8Hz),2.10(1H,t,J=2.4Hz),2.29(1H,m),2.55(3H,s),4.16(1H,d,J=16.0Hz),4.74(1H,d,J=16.0Hz),7.83(1H,s),8.09(1H,s),8.17(1H,s),10.20(1H,s);m/z(EI)335[M+]。
化合物24:向置于室温的化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)DMF(5mL)的搅拌溶液中,添加三氟甲磺酸2,2,2-三氟酯(144μL,1mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶9))将残渣纯化获得48mg(12%)的白色固体;m.p.237-238℃;1H-NMR(200MHz,CDCl3)δ1.17(3H,d,J=5.4Hz),1.23(3H,d,J=5.4Hz),2.23(1H,m),2.53(3H,s),4.14(1H,m),4.62(1H,m),7.80(1H,s),7.98(1H,s),8.07(1H,s),9.43(1H,s);m/z(EI)379[M+]。
化合物25:将化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol),碘化锂(134mg,1mmol)以及3-溴-1-丙醇(87μL,1mmol)的DMF(5mL)混合溶液置于油浴(90-110)中搅拌过夜。冷却至室温后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(2∶1))将残渣纯化获得138mg(39%)的白色固体;m.p.166-167℃;1H-NMR(200MHz,DMSO-d6)δ1.00(3H,d,J=7.0Hz),1.09(3H,d,J=7.0Hz),1.53-1.63(2H,m),2.09(1H,m),2.47(3H,s),3.08(1H,m),3.20-3.28(2H,m),3.68(1H,m),4.38(1H,t,J=5.4Hz),8.11(1H,s),8.24(1H,s),8.49(1H,s),11.45(1H,s);m/z(EI)355[M+]。
化合物26:向置于室温的化合物1(836mg,2.81mmol)和粉状无水碳酸钾(836mg,2.81mmol)以及碘化锂(377mg,2.81mmol)DMF(5mL)搅拌混合溶液中添加溴乙酰胺(388mg,2.81mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,甲醇∶氯仿(5∶95))将残渣纯化获得370mg(37%)的白色固体;m.p.275-276℃;1H-NMR(200MHz,DMSO-d6)δ1.05(3H,d,J=7.0Hz),1.11(3H,d,J=7.0Hz),2.11(1H,m),2.45(3H,s),3.87(1H,d,J=17.0Hz),4.02(1H,d,J=17.0Hz),7.09(1H,s),7.34(1H,s),8.09(1H,s),8.19(1H,s),8.36(1H,s),11.56(1H,s);m/z(EI)354[M+]。
化合物27:向在氮气下冰浴冷却的4-甲基-3-丁烯-1-醇(100mg,1mmol)氯仿(10mL)搅拌混合溶液中添加三乙胺(210μL,1.5mmol)以及逐滴加入甲基磺酰氯(90μL,1.2mmol)。搅拌1.1小时后,用饱和含水碳酸氢钠洗涤,用无水硫酸镁干燥,过滤,并置于真空蒸发。将残渣进一步高压真空大约20分钟,并与化合物1(297mg,1mmol),粉状无水碳酸钾(138mg,1mmol)以及碘化锂(134mg,1mmol)混合。接着向混合溶液中添加DMF(5mL),室温搅拌过夜。将DMF蒸发之后,将残渣溶于甲醇-氯仿(1∶9),通过硅藻土滤片过滤。接着将滤液真空中蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶5))将残渣纯化获得118mg(31%)的白色固体;m.p.192-194℃;1H-NMR(200MHz,CDCl3)δ1.13(3H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),1.49(3H,s),1.62(3H,s),2.17-2.27(4H,m),2.52(3H,s),2.95(1H,m),3.75(1H,m),4.90(1H,m),7.79(1H,s),7.94(1H,s),8.05(1H,s),8.88(1H,s);m/z(EI)379(M+)。
方案8
2,4-双-苄氧基-6-氯-5-乙基-嘧啶:向置于水浴的苯乙醇(80mL)搅拌溶液,在氮气条件下添加金属钠(2.17g,94.6mmol)。在金属钠完全反应之后,用冰浴冷却混合溶液并分次添加2,4,6-三氯-5-乙基-嘧啶(10.5g,49.6mmol)。在冰浴中搅拌30分钟后,将反应混合溶液置于室温搅拌过夜。将过量的苯乙醇在真空中蒸发并将残渣溶于乙醚,水洗涤,无水硫酸镁干燥,过滤,并置于真空中蒸发获得浅黄色油。并用硅胶柱色谱(洗脱液,乙醚∶己烷(4∶96))将粗产物纯化获得14g(80%)的白色固体;m.p.53-54℃;1H NMR(200MHz,CDCl3)δ:1.14(3H,t,J=7.4Hz),2.70(2H,q,J=7.4Hz),5.41(2H,s),5.45(2H,s),7.34-7.53(10H,m);m/z(EI):354(M+)。
3-[(2,6-双-苄氧基-5-乙基-嘧啶-4-基)-氰基-甲基]-5-甲基-苯甲腈:向冰水浴的2,4-双-苄氧基-6-氯-5-乙基-嘧啶(9.89g,27.87mmol)和3-氰甲基-5-甲基-苯甲腈(4.15g,26.55mmol)的无水DMF(50mL)搅拌混合溶液,在氮气条件下,分次添加60%氢氧化钠(2.34g,58.4mmol)。搅拌1小时后,将混合溶液置于室温搅拌过夜。用水饱和氯化铵溶液中和反应混合溶液。用乙醚萃取粗产物,并从二氯甲烷-己烷中再结晶获得10.3g(82%)的浅黄色固体;m.p.139-141℃;1HNMR(200MHz,CDCl3)δ:1.00(3H,t,J=7.6Hz),2.37(3H,s),2.52-2.58(2H,m),5.29(1H,s),5.49(4H,s),7.27-7.50(10H,m);m/z(EI):474(M+)。
3-(2,6-双-苄氧基-5-乙基-嘧啶-4-羰基)-5-甲基-苯甲腈:在水浴的3-[2,6-双-苄氧基-5-乙基-嘧啶-4-基]氰基-甲基]-5-甲基-苯甲腈(10g,21.1mmol)的无水DMF(80mL)搅拌混合溶液,在氮气条件下分次添加60%氢氧化钠(869mg,21.7mmol)。30分钟后,向反应混合溶液中通入氧气5小时。用水饱和氯化铵溶液中和混合溶液。用乙醚萃取粗产物并从双氯甲烷-己烷中重结晶获得8g(80%)的白色固体;m.p.123-124℃;1H NMR(200MHz,CDCl3)δ:1.09(3H,t,J=7.4Hz),2.43(3H,s),2.50(2H,q,J=7.4Hz),5.35(2H,s),5.50(2H,s),7.27-7.46(10H,m),7.67(1H,s),7.87(1H,s),7.92(1H,s);m/z(EI):463(M+)。
3-(5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物28):将3-(2,6-双-苄氧基-5-乙基-嘧啶-4-羰基)-5-甲基-苯甲腈(4.5g,9.7mmol)的无水乙醇(30mL)以及THF(30mL)溶液同10%的钯碳(250mg)置于氢气下搅拌。1.5小时后,用硅土藻滤片过滤混合溶液并将滤液在真空中蒸发。用硅胶柱色谱(洗脱液,氯仿∶甲醇(95∶5))将残渣纯化获得2.3g(84%)的白色固体;m.p.253-254℃;1H NMR(200MHz,DMSO-d6)δ:0.84(3H,t,J=7.0Hz),1.96(2H,q,J=7.0Hz),2.45(3H,s),8.06(1H,s),8.11(1H,s),8.33(1H,s),11.05(1H,s),8.28(1H,s);m/z(EI):283(M+)。
方案9
试剂和条件:i.卤代烷或甲磺酸,K2CO3,DMF;ii.CH3CH2OCH2Cl,SnCl4,乙腈CH3CH2OCH2Cl,SnCl4,乙腈
化合物29:向置于室温的化合物28(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(5mL)搅拌溶液中,添加碘乙烷(161μL,1mmol)。搅拌过夜后,将混合溶液在真空中蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得134mg(43%)的白色固体;m.p.237-238℃;1H-NMR(200MHz,CDCl3):δ0.97(3H,t,J=7.4Hz),1.16(3H,t,J=7.2Hz),1.95(1H,m),2.27(1H,m),2.53(3H,s),3.22(1H,m),3.92(1H,m),7.80(1H,s),7.95(1H,s),8.05(1H,s),9.06(1H,s);m/z(EI)311[M+]。
化合物31:向置于室温的化合物30(用与U.S.6,713,486相同的步骤制备,这里作为参考文献整体引入)(327mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(5mL)搅拌溶液中,添加碘乙烷(161μL,1mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶4))将残渣纯化获得149mg(42%)的白色固体;m.p.220-221℃;1H-NMR(200MHz,CDCl3):δ1.12-1.21(9H,m),2.24(1H,m),3.20(1H,m),3.89(1H,m),7.71(1H,t,J=1.8Hz),7.81(2H,d,J=1.8Hz),8.95(1H,s);m/z(EI)354[M+]。
化合物33:向置于室温的化合物32(用与U.S.6,713,486相同的步骤制备)(313mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(5mL)搅拌溶液中,添加碘乙烷(161μL,1mmol)。搅拌过夜后,将混合溶液置于真空蒸发,并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶4))将残渣纯化获得204mg(59%)的白色固体;m.p.246-248℃;1H-NMR(200MHz,CDCl3):δ0.98(3H,t,J=7.4Hz),1.17(3H,t,J=7.0Hz),1.97(1H,m),2.28(1H,m),3.24(1H,m),3.92(1H,m),7.11(1H,t,J=2.0Hz),7.79(2H,d,J=2.0Hz),9.12(1H,s);m/z(EI)340[M+]。
化合物35:向置于室温的化合物34(用与U.S.6,713,486相同的步骤制备)(311mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(5mL)搅拌溶液中,添加碘乙烷(161μL,1mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得106mg(31%)的白色固体;m.p.287-284℃;1H-NMR(200MHz,CDCl3):δ1.10(3H,t,J=7.0Hz),1.21(9H,s),2.53(3H,s),3.01(1H,m),3.94(1H,m),7.98(1H,s),8.04(2H,br.s),8.97(1H,s);m/z(EI)339[M+]。
化合物37:向置于室温的化合物36(3-氰甲基-5-氯-苯甲腈替换3-氰甲基-5-甲基-苯甲腈除外,制备步骤与化合物28的制备步骤相似)(212mg,0.667mmol)和粉状无水碳酸钾(92mg,0.667mmol)的DMF(3.5mL)搅拌溶液中,添加碘乙烷(54μL,0.667mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得62mg(27%)的白色固体;m.p.248-249℃;1H-NMR(200MHz,CDCl3):δ1.12-1.29(9H,m),2.20(1H,m),3.15(1H,m),3.91(1H,m),7.97(1H,t,J=1.8Hz),8.12-8.15(2H,m),8.59(1H,s);m/z(EI)345[M+]。
化合物38:将化合物36(219mg,0.689mmol),1,1,1,3,3,3-六甲基二硅氮烷(5mL),以及三甲基氯硅烷(0.2mL)的混合溶液回流4小时。冷却至室温后,将混合溶液置于真空蒸发并将残渣溶于乙腈(5mL)。边搅拌边添加氯甲基乙基甲醚(64μL,0.689mmol)和1M的氯化锡二氯甲烷溶液(40μL,0.04mmol)溶液。搅拌过夜后,添加过量的碳酸氢钠并搅拌1小时。将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶3))将残渣纯化获得206mg(79%)的白色固体;m.p.162-164℃;1H-NMR(200MHz,CDCl3):δ0.79(3H,t,J=7.0Hz),1.14(2H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),2.21(1H,m),3.21-3.50(2H,m),4.68(1H,d,J=9.8Hz),5.56(1H,d,J=9.8Hz),7.92(1H,t,J=1.8Hz),8.11(2H,d,J=1.8Hz),8.47(1H,s);m/z(EI)375[M+]。
方案10
试剂和条件:i.亚硫酰氯,苯;ii.乙基-溴丁酸,LiI,K2CO3,DMF;iii.p-甲氧基苄胺;iv.CAN,乙腈。
化合物39:向化合物26(120mg,0.338mmol)的苯(15mL)搅拌溶液中,添加亚硫酰氯(1mL)以及DMF(1滴)。将混合溶液回流3小时。冷却至室温之后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得49mg(43%)的白色固体;m.p.270-271℃;1H-NMR(200MHz,DMSO-d6):δ1.05(6H,br.s),2.14(1H,m),2.46(3H,s),4.48(2H,br.d),8.12(1H,s),8.27(1H,s),8.52(1H,s),11.80(1H,s);m/z(EI)336[M+]。
化合物40:将化合物1(891mg,3mmol)和粉状无水碳酸钾(414mg,3mmol),碘化锂(402mg,3mmol),以及4-溴丁酸乙酯(432μL,3mmol)的DMF(15mL)混合溶液置于油浴下(100-115℃)搅拌过夜。冷却至室温后,将混合溶液置于真空蒸发,并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得521mg(42%)的白色糖浆;1H-NMR(200MHz,CDCl3):δ1.12(3H,d,J=7.0Hz),1.17-1.29(8H,m),1.85(1H,m),2.24(2H,t,J=6.8Hz),2.51(3H,s),3.10(1H,m),3.86(1H,m),4.12(2H,q,J=7.0Hz),7.79(1H,s),7.96(1H,s),8.06(1H,s),8.96(1H,s)。
化合物41:将化合物40(411mg,1mmol)与对甲氧基苄胺(2mL)置于油浴下中(170℃)搅拌4小时。冷却至室温后,用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将混合物纯化获得218mg(43%)的浅黄色糖浆;1H-NMR(200MHz,CDCl3):δ1.09(3H,d,J=6.8Hz),1.20(3H,d,J=6.8Hz),1.77-1.97(2H,m),2.17(2H,t,J=6.8Hz),2.50(3H,s),3.23(1H,m),3.75(3H,s),3.82(1H,m),4.27(2H,d,5.4Hz),6.50(1H,t,J=5.4Hz),6.78(2H,d,J=7.5Hz),7.14(2H,d,J=7.5Hz),7.72(1H,s),7.99(1H,s),8.06(1H,s)。
化合物42:向置于室温的化合物41(218mg,0.43mmol)的乙腈(4mL)搅拌溶液中,添加CAN(硝酸铈铵)(475mg,0.86mmol),接着添加蒸馏水(2mL)。40分钟后,用乙酸乙酯将混合溶液稀释,水洗涤,无水硫酸镁干燥,过滤,以及真空中蒸发产生棕色糖浆。用硅胶柱色谱(洗脱液,甲醇∶氯仿(3∶97))将粗产物纯化获得125mg(75%)的白色固体;m.p.261-262℃;1H-NMR(200MHz,DMSO-d6):δ1.00(3H,d,J=6.6Hz),1.08(3H,d,J=6.6Hz),1.59-1.75(2H,m),1.87-2.12(3H,m),2.46(3H,s),3.03(1H,m),3.66(1H,m),6.66(1H,s),7.16(1H,s),8.10(1H,s),8.24(1H,s),8.47(1H,s),11.45(1H,s);m/z(EI)382[M+]。
方案11
试剂和条件:i.4-(叔-丁基-二苯基-硅氧基)-2-丁炔甲磺酸酯,LiI,K2CO3,DMF;ii.TBAF,THF;iii.H2,Pd/C,乙醇/THF。
化合物43:向冰浴冷却的4-叔-丁基-二苯基硅氧基-2-丁炔-1-醇(324mg,1mmol)的氯仿(10mL)搅拌溶液中置于氮气中,添加三乙胺(210μL,1.5mmol)以及滴加甲基磺酰氯(90μL,1.2mmol)。搅拌1.1小时后,将反应混合溶液用饱和碳酸钠水溶液洗涤,无水硫酸镁干燥,过滤,并于真空中蒸发。用高真空将残渣进一步干燥20分钟,并与化合物1(297mg,1mmol),粉状无水碳酸钾(138mg,1mmol),以及碘化锂(134mg,1mmol)混合。接着在室温下,向混合物中添加DMF(5mL)并搅拌过夜。DMF蒸发之后,将残渣溶于甲醇-氯仿(1∶9)并用硅藻土滤片过滤。接着将滤液置于真空中蒸发,并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶4))将残渣纯化获得370mg(61%)的无色糖浆;1H-NMR(200MHz,CDCl3):δ0.98(9H,s),1.10(3H,d,J=6.8Hz),1.19(3H,d,J=6.8Hz),2.22(1H,m),2.37(3H,s),3.87(2H,s),4.06(1H,d,J=18.0Hz),4.83(1H,d,J=18.0Hz),7.35-7.60(11H,m),7.96(1H,s),8.06(1H,s),8.39(1H,s)。
化合物44:将化合物43(370mg,0.61mmol)溶于THF(5mL)中并在室温下与四丁基氟化铵(1M in THF;0.8mL,0.8mmol)一起搅拌1小时。将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得168mg(75%)的白色固体;m.p.181-182℃;1H-NMR(200MHz,CDCl3):δ1.13(3H,d,J=6.8Hz),1.22(3H,d,J=6.8Hz),2.03(1H,br.s),2.26(1H,m),2.54(3H,s),3.90(1H,d,J=16.6Hz),4.00(1H,d,J=16.6Hz),4.12(1H,d,J=18.2Hz),4.77(1H,d,J=18.2Hz),7.80(1H,s),8.08(1H,s),8.19(1H,s),9.22(1H,s);m/z(EI)365(M+)。
化合物45:在氢气条件下向置于室温的10%钯碳(20mg)无水乙醇(8mL)和THF(5mL)中搅拌加入化合物44(100mg,0.27mmol)。6小时后,用硅藻土滤片过滤反应混合容易并用乙醇和氯仿洗脱滤片。真空蒸发混合的滤液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得57mg(56%)的白色无色糖浆;从氯仿/乙醚/己烷中再结晶获得白色固体;m.p.119-120℃;1H-NMR(200MHz,CDCl3):δ1.11(3H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),1.37-1.58(2H,m),1.61-1.69(2H,m),2.22(1H,m),2.53(3H,s),3.20(1H,m),3.53-3.59(2H,m),3.88(1H,m),7.81(1H,s),7.98(1H,s),8.09(1H,s),10.02(1H,s);m/z(EI)369[M+]。
方案12
试剂和条件:i.H2,Pd/C,乙醇/THF。
化合物46:在氢气条件下向置于室温的10%钯碳(20mg)无水乙醇(10mL)和THF(5mL)中搅拌加入化合物23(100mg,0.298mmol)。4.5小时后,用硅藻土滤片过滤反应混合溶液并用乙醇和氯仿洗脱滤片。真空蒸发混合的滤液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶3))将残渣纯化获得81mg(80%)的白色固体;m.p.202-203℃;1H-NMR(200MHz,CDCl3):δ0.78(3H,t,J=7.4Hz),1.13(3H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),1.54-1.64(2H,m),2.24(1H,m),2.54(3H,s),3.02(1H,m),3.81(1H,m),7.82(1H,s),7.97(1H,s),8.07(1H,s),9.76(1H,s);m/z(EI)339[M+]。
化合物47:在氢气条件下向置于室温的10%钯碳(20mg)的无水乙醇(10mL)溶液中搅拌加入化合物22(140mg,0.4mmol)。5小时后,用硅藻土滤片过滤反应混合溶液并用乙醇和氯仿洗脱滤片。真空蒸发混合的滤液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得88mg(62%)的无色糖浆;从氯仿/乙醚/己烷中再结晶获得白色固体;m.p.133-134℃;1H-NMR(200MHz,DMSO-d6):δ0.71(3H,t,J=6.6Hz),0.99-1.17(8H,m),1.35-1.39(2H,m),2.09(1H,m),2.46(3H,s),2.97(1H,m),3.65(1H,m),8.11(1H,s),8.24(1H,s),8.49(1H,s),11.44(1H,s);m/z(EI)353[M+]。
方案13
化合物48:向化合物42(71mg,0.185mmol)的苯(24mL)搅拌溶液中,添加亚硫酰氯(1mL)以及DMF(3滴)。将混合溶液回流3小时。冷却至室温后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶1到2∶1))将残渣纯化获得54mg(80%)的化合物48白色固体;m.p.224-225℃;1H-NMR(200MHz,DMSO-d6):δ1.14(3H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),1.84-2.02(2H,m),2.21-2.40(3H,m),2.54(3H,s),3.19(1H,m),4.03(1H,m),7.83(1H,s),8.03(1H,s),8.08(1H,s),9.58(1H,s);m/z(EI)364(M+)。
方案14
化合物49:将化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol),碘化锂(134mg,1mmol),以及3-溴-N-(4-甲氧基-苄基)-丙酰胺(272mg,1mmol l)的DMF(5mL)混合溶液置于油浴中(90-110℃)搅拌17小时。冷却至室温后,将混合溶液置于真空蒸发,并用硅胶柱色谱(洗脱液,甲醇∶氯仿(3∶97);收集Rf=0.15部分)将残渣纯化获得73mg(15%)的白色糖浆。1H-NMR(200MHz,CDCl3):δ1.11(3H,d,J=6.8HzHz),1.18(3H,d,J=6.8Hz),2.22(1H,m),2.38-2.67(5H,m),3.42(1H,m),3.79(3H,s),4.17(1H,m),4.27(2H,d,J=5.6Hz),5.96(1H,t,J=5.6Hz),6.81-6.88(2H,m),7.14-7.225(2H,m),7.80(1H,s),8.01(1H,s),8.04(1H,s),8.83(1H,s)。
化合物50:向置于室温的化合物49(73mg,0.149mmol)的乙腈(2mL)搅拌溶液中,添加CAN(164mg,0.298mmol),接着添加蒸馏水(1mL)。1.5小时后,用乙酸乙酯稀释混合溶液,水洗涤,无水硫酸镁干燥,过滤,并置于真空中蒸发获得棕色糖浆。用硅胶柱色谱(洗脱液,甲醇∶氯仿(5∶95))将粗产物纯化获得26mg(47%)的化合物50的白色固体;m.p.253-254℃;1H-NMR(200MHz,CDCl3):δ1.10(3H,d,J=6.6Hz),1.17(3H,d,J=6.6Hz),2.20(1H,m),2.40-2.70(5H,m),3.40(1H,m),4.13(1H,m),6.12(1H,s),6.26(1H,s),7.80(1H,s),8.03(1H,s),8.11(1H,s),10.26(1H,s);m/z(EI)368(M+)。
化合物51:向化合物50(45mg,0.122mmol)的苯(10mL)搅拌溶液中,添加亚硫酰氯(1mL)以及DMF(3滴)。将混合溶液回流3小时。冷却至室温后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(2∶1))将残渣纯化获得33mg(76%)的化合物51的白色固体;m.p.195-196℃;1H-NMR(200MHz,CDCl3):δ1.13(3H,d,J=6.6Hz),1.20(3H,d,J=6.6Hz),2.23(1H,m),2.55(3H,s),2.65-2.86(2H,m),3.31(1H,m),4.20(1H,m),7.85(1H,s),8.02(1H,s),8.08(1H,s),9.14(1H,s);m/z(EI)350(M+)。
方案15
化合物52:化合物52是通过化合物3氧化制备的,例如通过在磷酸缓冲液(50mM,pH 7.4)和NADPH(Gentest)中与大鼠微粒体(体外技术,MD)孵育。
化合物53:在15mL乙醇中将盐酸羟胺(262mg,3.77mmol,20eq.)添加到的化合物1(56mg,0.188mmol)中。将反应混合溶液加热回流3天。过滤掉反应粗产物沉淀,将滤液浓缩并用反相HPLC(MeCN/水)纯化获得白色固体(19mg,32%)。LC-MS显示313.1(M+1)。1H NMR(300MHz,CD3OD):δ7.81(s,1H),7.70(s,1H),7.61(s,1H),2.44(s,3H),2.38(m,1H),1.71(d,6H)。
上面化合物54,是利用6-(3,5-二甲基苯甲酰)-5-异丙基嘧啶-2,4(1H,3H)-二酮按照U.S.6,136,815介绍的步骤制备的,这里作为参考文献整体引入。
将3-[3-(5-异丙基-2,6-二氧基-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(55)(323mg,1mmol),HMDS(5mL),以及三甲基氯硅烷(10μL)的混合溶液回流4小时。冷却至室温后,真空中蒸发混合溶液。接着将残渣溶于乙腈(5mL)。向搅拌溶液中添加氯甲基乙醚(93μL,1mmol),接着添加氯化锡(1M)三氯甲烷(100μL,0.1mmol)溶液。搅拌过夜后,将过量的碳酸氢钠添加到反应混合溶液中。搅拌30分钟,真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得170mg(44%)的无色糖浆。从乙醚/己烷中再结晶获得白色固体。1H NMR(200MHz,CDCl3):δ0.75(3H,t,J=7.0Hz),1.10(3H,d,J=6.8Hz),1.21(3H,d,J=6.8Hz),2.29(1H,m),2.47(3H,s),3.20-3.44(2H,m),4.77(1H,d,J=10.0Hz),5.48(1H,d,J=10.0Hz),5.99(1H,d,J=16.6Hz),7.43(1H,d,J=16.6Hz),7.55(1H,s),7.77(1H,s),7.86(1H,s),8.73(1H,s)。m/z(LC/Mass,EI)382(M+H+)。
如下面方案16所示,可以通过不同的方法制备3-[3-(5-异丙基-2,6-二氧基-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(55)。
方案16
1-溴-3-溴甲基-5-甲基-苯:将含有3,5-二甲基溴苯(80.25g,0.43M),NBS(77g,0.43M),以及过氧苯甲酰(5.2g,0.021M)的四氯化碳(400mL)混合溶液在500W的钨灯下回流3小时。冷却至室温后,将混合溶液过滤并将滤液置于真空中蒸发产生白色固体,再用硅胶柱色谱(洗脱液∶己烷)纯化获得82g(72%)的白色固体。m.p.46-47℃;1H NMR(200MHz,CDCl3):δ2.32(3H,s),4.38(2H,s),7.12(1H,s),7.25(1H.s),7.33(1H,s)。
(3-溴-5-甲基-苯基)-乙腈:向附带有漏斗的烧瓶中放入氰化钾(29.6g,0.45M)以及蒸馏水(30mL)。将混合溶液置于油浴中搅拌加热到70℃,并通过附带的漏斗1小时内逐滴加入1-溴-3-溴甲基-5-甲基-苯(80g,0.3M)的乙醇(150mL)溶液。添加完全后,将混合溶液回流2小时。冷却至室温,真空蒸发混合溶液并用乙醚和水分离残渣。取出乙醚层,用水洗涤,无水硫酸镁干燥,过滤,真空蒸发产生棕色残渣,再用硅胶柱色谱(洗脱液,乙醚∶己烷(1∶3))纯化获得47g(74%)的浅棕色油。1H NMR(200MHz,CDCl3):δ2.33(3H,s),3.68(2H,s),7.08(1H,s),7.28(1H.s),7.29(1H,s)。
(3-溴-5-甲基-苯基)-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-乙腈:向置于氮气下冰浴的4-氯-5-异丙基-2,6-二甲氧基-嘧啶(47.63g,0.22M)和(3-溴-5-甲基-苯基)-乙腈(42g,0.2M)无水DMF(220mL)混合溶液中分次添加60%的氢氧化钠溶液(16g,0.4M)。搅拌1小时后,再将混合溶液置于室温搅拌过夜。用水饱和氯化铵溶液中和混合溶液。用乙醚萃取粗产物并用硅胶柱色谱(洗脱液,乙醚∶己烷(1∶7))纯化获得68g(87%)的白色固体。m.p.123-124℃;1H NMR(200MHz,CDCl3):δ1.11(3H,d,J=6.9Hz),1.15(3H,D,J=6.9Hz),2.32(3H,s),2.97(1H,m),4.00(3H,s),4.01(3H,s),5.34(1H,s),7.14(1H,s),7.28(1H,s),7.31(1H,s)。
(3-溴-5-甲基-苯基)-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-甲酮:向置于氮气下的水浴(3-溴-5-甲基-苯基)-(5-异丙基-2,6-二甲氧基-嘧啶-4-基-乙腈(40g,0.1M)无水DMF(300mL)搅拌溶液中,分次添加60%的氢氧化钠(4.92g,0.12M)。30分钟后,将反应混合溶液中通入氧气2小时。用水饱和氯化铵溶液中和混合溶液。用乙醚萃取粗产物并用硅胶柱色谱(洗脱液,乙醚∶己烷(1∶9))纯化获得34.6g(89%)的白色固体。m.p.122-123℃;1H NMR(200MHz,CDCl3):δ1.17(6H,d,J=7.1Hz),2.36(3H,s),2.77(1H,m),3.92(3H,s),4.05(3H,s),7.54-7.56(2H,m),7.75(1H,m)。
3-[3-(5-异丙基-2,6-二甲氧基-嘧啶-4-羰基)-5-甲基-苯基]-乙腈:向(3-溴-5-甲基-苯基)-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-甲酮(3.79g,10mmol)的无水DMF(10mL)搅拌溶液中按顺序添加醋酸钠(902mg,1mmol),醋酸钯(224mg,1mmol),四羟甲(三苯基膦)钯(0)(1.049g,4mmol)),以及乙腈。接着将混合溶液置于90-132℃(油浴)搅拌大约23小时。冷却至室温后,向反应混合溶液中添加乙醚和乙酸乙酯(2∶1)。接着将混合溶液用水饱和碳酸钠溶液洗涤,水洗涤两次,无水硫酸镁干燥,过滤,并置于真空蒸发。用硅胶柱色谱(洗脱液:乙酸乙酯∶己烷(1∶4))纯化残渣获得595mg(17%)的白色固体。同样也获得白色固体的Z-异构体(275mg,8%)。m.p.144-145℃;1H NMR(300MHz,CDCl3):δ1.19(6H,d,J=6.9Hz),2.42(3H,s),2.83(1H,m),3.94(3H,s),4.08(3H,s),5.92(1H,d,J=16.8Hz),7.39(1H,d,J=16.8Hz),7.49(1H,s),7.69(1H,s),7.75(1H,s)。
Z异构体:1H NMR(300MHz,CDCl3):δ1.19(6H,d,J=7.2Hz),2.45(3H,s),2.84(1H,m),3.93(3H,s),4.06(3H,s),5.49(1H,d,J=12.0Hz),7.11(1H,d,J=12.0Hz),7.75(1H,s),7.90(1H,s),7.97(1H,s)。
3-[3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物55):向3-[3-(5-异丙基-2,6-二甲氧基-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(5.36g,15.27mmol)的无水THF(50mL)搅拌溶液中添加草酰氯(25mL)。接着将混合溶液剧烈搅拌回流过夜。冷却至室温后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶1到4∶1))纯化残渣获得2.7g(55%)的白色固体。m.p.233-235℃;1H NMR(300MHz,CD3OD/CDCl3):δ1.16(6H,d,J=6.9Hz),2.39-2.56(4H,m),6.12(1H,d,J=16.6Hz),7.49(1H,d,J=16.6Hz),7.66(1H,s),7.83(1H,s),7.87(1H,s);m/z(LC/Mass,EI)324(M+H+)。
化合物57:按照Tanaka等J.Med.Chem.1991,34,349-357的方法用硼氢化钠处理化合物54,接着用(二乙胺)三氟化硫(购自Aldrich)处理产生的中间体可获得化合物57。
化合物58:按照Tanaka等J.Med.Chem.1991,34,349-357的方法用硼氢化钠处理化合物54,接着用甲基磺酰氯处理产生的中间体并同碱一起在甲醇中回流可获得化合物58。
上面化合物59,是利用6-(3,5-二甲基苯甲酰)-5-异丙基嘧啶-2,4(1H,3H)-二酮按照U.S.5,747,500介绍的相似步骤制备的,这里作为参考文献整体引入。
上面化合物60,是利用6-(3,5-二甲基苯甲酰)-5-异丙基嘧啶-2,4(1H,3H)-二酮按照U.S.5,747,500介绍的相似步骤制备的。
上面化合物61,是利用6-(3,5-二甲基苯胺)-5-乙基嘧啶-2,4(1H,3H)-二酮按照U.S.6,713,486介绍的相似步骤制备的,这里作为参考文献整体引入。
上面化合物62,是利用6-(3,5-二甲基苯胺)-5-乙基嘧啶-2,4(1H,3H)-二酮按照U.S.6,713,486介绍的相似步骤制备的。
上面化合物63,是利用6-(3,5-二甲基苯胺)-5-乙基嘧啶-2,4(1H,3H)-二酮按照U.S.6,713,486介绍的相似步骤制备的。
方案17
向化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol),以及碘化锂(134mg,1mmol)的DMF(5mL)搅拌溶液中添加(2-乙酰氧基乙氧基)甲基溴(197mg,1mmol;如J.Chem.Soc.Perkin Trans.1 1993,PP.1109-1111所描述)。室温搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得264mg(63%)的白色固体化合物64。
m.p.178-179℃;1H-NMR(200MHz,CDCl3):δ1.12(3H,d,J=6.8Hz),1.21(3H,d,J=6.8Hz),2.00(3H,s),2.25(1H,m),2.51(3H,s),3.51-3.58(2H,m),3.77-3.83(2H,m),4.85(1H,d,J=10.4Hz),5.48(1H,d,J=10.4Hz),7.77(1H,s),7.97(1H,s),8.04(1H,s),8.78(1H,s)。
将化合物64(234mg,0.566mmol)与氢氧化铵(2mL)的THF(10mL)和甲醇(10mL)溶液置于室温搅拌过夜。接着将混合溶液于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶1到4∶1))将残渣纯化获得180mg(85%)的白色泡沫化合物65。从氯仿/乙醚/己烷中重结晶获得白色固体。
m.p.149-150℃;1H-NMR(200MHz,CDCl3):δ1.11(3H,d,J=7.0Hz),1.20(3H,d,J=7.0Hz),2.12(1H,br.s),2.25(1H,m),2.51(1H,s),3.44-3.59(4H,m),4.93(1H,d,J=10.6Hz),5.42(1H,d,J=10.6Hz),7.76(1H,s),8.03(1H,s),8.11(1H,s),9.31(1H,s)。
方案18
向化合物1(297mg,1mmol)和粉状无水碳酸钾(138mg,1mmol),以及碘化锂(134mg,1mmol)的DMF(5mL)搅拌溶液中添加3-溴丙烷-1-磺酸p-甲氧基苯酰胺(322mg,1mmol,按照J.Org.Chem.2006,71,6573-6578的方法制备(m.p.105-106℃,1H-NMR(200MHz,DMSO-d6),2.06-2.20(2H,m),3.03(2H,t,J=7.4Hz),3.55(2H,t,J=6.6Hz),3.74(3H,s),4.08(2H,d,J=6.2Hz),6.91(2H,d,J=8.6Hz),7.26(2H,d,J=8.6Hz),7.67(1H,t,J=6.2Hz)。m/z(EI)321(M+),323(M+2+))。室温搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,甲醇∶氯仿(3∶97))将残渣纯化获得210mg(39%)的白色固体化合物66。
m.p.170℃;1H-NMR(200MHz,CDCl3):δ1.12(3H,d,J=7.0Hz),1.20(3H,d,J=7.0Hz),1.93-2.05(2H,m),2.22(1H,m),2.52(3H,s),2.81(2H,t,J=6.8Hz),3.28(1H,m),3.80(3H,s),3.96(1H,m),4.21(2H,d,J=5.8Hz),4.90(1H,t,J=5.8Hz),6.89(2H,d,J=7.0Hz),7.27(2H,d,J=7.0Hz),7.79(1H,s),7.96(1H,s),8.03(1H,s),8.82(1H,s)。
向置于室温的化合物66(210mg,0.39mmol)的乙腈(4mL)搅拌溶液中添加CAN(427mg,0.78mmol)之后添加双蒸水(2mL)。2小时后,用乙酸乙酯稀释混合溶液,无水硫酸镁干燥,过滤,并置于真空中蒸发产生褐色糖浆。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶1到4∶1))将粗产物纯化获得120mg(73%)的白色固体化合物67。
m.p.241-242℃;1H-NMR(200MHz,DMSO-d6):δ0.99(3H,d,J=6.2Hz),1.07(3H,d,J=6.2Hz),1.80-1.87(2H,m),2.08(1H,m),2.45(3H,s),2.84-2.87(2H,m),3.14(1H,m),3.81(1H,m),6.71(2H,s),8.09(1H,s),8.24(1H,s),8.47(1H,s),11.50(1H,s);m/z(EI)418(M+)。
方案19
向5-三氟甲基尿嘧啶(1.8g,10mmol)和粉状无水碳酸钾(1.38g,10mmol)的DMF(50mL)的搅拌混合溶液中添加碘乙烷(0.8mL,10mmol)。室温搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶1))将残渣纯化获得563mg(27%)的白色固体1-乙基-5-三氟甲基尿嘧啶。m.p.259-260℃;1H-NMR(200MHz,CDCl3/CD3OD):δ1.35(3H,d,J=7.2Hz),3.87(2H,q,J=7.2Hz),7.94(1H,s);m/z(EI)208(M+)。
向置于氮气下的1-乙基-5-三氟甲基尿嘧啶(416mg,2mmol)的THF(10mL)搅拌混合溶液中按照温度不超过-70℃的速度添加2M LDA庚烷/THF/苯溶液(2.2mL,4.4mmol)。将混合溶液搅拌1小时后,添加3-氰基-5-甲基苯甲醛(435mg,3mmol)的THF(10mL)溶液,维持温度低于-70℃。将混合溶液置于低于-70℃条件下搅拌1小时,然后加热至室温。用浓HCl中和混合溶液,水稀释,并用乙酸乙酯萃取。用饱和NaHCO3溶液洗涤有机层,MgSO4干燥,过滤,并浓缩干燥。用硅胶柱色谱(洗脱液,甲醇∶氯仿(3∶97))将残渣纯化获得552mg(78%)的白色固体化合物68。m.p.260-262℃;1H-NMR(200MHz,DMSO-d6):δ0.81(3H,t,J=6.0Hz),2.37(3H,s),3.58-3.65(2H,m),6.10(1H,d,J=5.2Hz),7.45(1H,d,J=5.2Hz),7.59(1H,s),7.63(1H,s),7.66(1H,s),11.87(1H,s);m/z(EI)353(M+)。
在室温下,将化合物68(200mg,0.566mmol)与重铬酸吡啶(426mg,1.13mmol)在DMF(4mL)中搅拌。24小时后,真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得173mg(87%)的白色固体化合物69。
m.p.277-278℃;1H-NMR(200MHz,DMSO-d6):δ1.00(3H,d,J=6.8Hz),2.46(3H,s),3.13(1H,m),3.80(1H,m),8.13(1H,s),8.28(1H,s),8.54(1H,s),12.17(1H,s);m/z(EI)351(M+)。
方案20
向化合物28(283mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(50mL)搅拌混合溶液中添加1-碘丁烷(114μL,1mmol)。室温搅拌过夜后,将混合溶液真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得145mg(42%)的白色固体化合物70。
m.p.190-191℃;1H-NMR(200MHz,CDCl3):δ0.80(3H,t,J=7.4Hz),0.95(3H,t,J=7.4Hz),1.08-1.28(2H,m),1.45-1.60(2H,m),1.93(1H,m),2.26(1H,m),2.52(3H,s),3.06(1H,m),3.81(1H,m),7.79(1H,s),7.93(1H,s),8.04(1H,s),9.56(1H,s);m/z(EI)339(M+)。
方案21
向化合物36(318mg,1mmol)和粉状无水碳酸钾(138mg,1mmol)的DMF(5mL)搅拌混合溶液中添加1-碘丁烷(114μL,1mmol)。室温搅拌过夜后,将混合溶液真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得96mg(25%)的浅棕色固体化合物71。
m.p.183-184℃;1H-NMR(200MHz,CDCl3):δ0.81(3H,t,J=7.4Hz),1.07-1.28(8H,m),1.45-1.60(2H,m),2.20(1H,m),3.04(1H,m),3.81(1H,m),7.98(1H,s),8.13(2H,s),9.35(1H,s);m/z(EI)373(M+)。
方案22
3-[3-(3-环丙基甲基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物72):向置于室温的3-[3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物55)(323mg,1mmol),无水粉状碳酸钾(165mg,1.2mmol),以及碘化锂(134mg,1mmol)的DMF(5mL)搅拌溶液中添加溴甲基环丙烷(97μL,1mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶2))将残渣纯化获得320mg(84%)的白色固体3-[3-(3-环丙基甲基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(72)。将产物从氯仿-乙醚中重结晶获得白色固体。m.p.225-226℃;1H-NMR(300MHz,CDCl3):δ0.22-0.44(4H,m),0.93(1H,m),1.12(3H,d,J=6.9Hz),1.24(3H,d,J=6.9Hz),2.28(1H,m),2.50(3H,s),3.28(1H,dd,J=6.0Hz,J=15.0Hz),3.59(1H,dd,J=6.0Hz,J=15.0Hz),6.01(1H,d,J=16.8Hz),7.44(1H,d,J=16.8Hz),7.61(1H,s),7.77(1H,s),7.88(1H,s),9.00(1H,s);m/z(EI)377(M+)。
3-[3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物73):向置于室温的3-[3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物55)(323mg,1mmol),无水粉状碳酸钾(165mg,1.2mmol)的DMF搅拌溶液中添加溴甲基环丙烷(97μL,1.2mmol)。搅拌过夜后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶2))将残渣纯化获得190mg(54%)的白色固体3-[3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(73)。将产物从氯仿-乙醚中重结晶获得白色固体。m.p.174-176℃;1H-NMR(200MHz,CDCl3):δ1.12-1.30(9H,m),2.29(1H,m),2.51(3H,s),3.25(1H,m),3.90(1H,m),6.06(1H,d,J=16.8Hz),7.47(1H,d,J=16.8Hz),7.64(1H,s),7.80(1H,s),7.92(1H.s),10.08(1H,s);m/z(EI)351(M+)。
3-[3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物74):向置于室温的3-[3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物55)(323mg,1mmol),无水粉状碳酸钾(165mg,1.2mmol)的DMF搅拌溶液中添加碘丁烷(136μL,1.2mmol)。搅拌过夜后,将混合溶液真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得170mg(44%)的白色糖浆3-[3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(74)。将产物从乙醚-己烷中重结晶获得白色固体。m.p.164-165℃;1H-NMR(200MHz,CDCl3)δ:0.79(3H,t,J=7.2Hz),1.11-1.29(8H,m),1.46-1.57(2H,m),2.27(1H,m),2.50(3H,s),3.09(1H,m),3.77(1H,m),6.00(1H,d,J=16.8Hz),7.44(1H,d,J=16.8Hz),7.61(1H,s),7.74(1H,s),7.86(1H,s),8.75(1H,s);m/z(EI)379(M+)。
方案23
3-[3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-丙腈(化合物75):向置于室温氢气条件下的无水乙醇(10mL)中搅拌添加3-[3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物73)(190mg,0.54mmol)和10%碳钯(20mg)。17小时后,将反应混合溶液用硅藻土滤片过滤并用乙醇和氯仿洗脱滤片。真空蒸发结合的滤液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得180mg(94%)的白色泡沫3-[3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-丙腈(75)。将产物从氯仿-乙醚中重结晶获得白色固体。m.p.173-174℃;1H-NMR(300MHz,CDCl3):δ1.13-1.18(6H,m),1.23(3H,d,J=6.9Hz),2.31(1H,m),2.47(3H,s),2.70(2H,t,J=6.9Hz),3.04(2H,t,J=6.9Hz),3.25(1H,m),3.89(1H,m),7.45(1H,s),7.66(2H,s),9.17(1H,s);m/z(EI)353(M+)。
3-[3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-丙腈(化合物76):向置于室温氢气条件下的无水乙醇(10mL)中搅拌添加3-[3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯基]-乙腈(化合物74)(180mg,0.474mmol)和10%碳钯(20mg)。17小时后,将反应混合溶液用硅藻土滤片过滤并用乙醇和氯仿洗脱滤片。真空蒸馏结合的滤液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得120mg(66%)的白色泡沫3.[3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四羟基-嘧啶-4-羰基)-5-甲基-苯基]-丙腈(76)。将产物从乙醚-己烷中重结晶获得白色固体。m.p.172-173℃;1H-NMR(300MHz,CDCl3)δ:0.79(3H,t,J=7.5Hz),1.12-1.24(8H,m),1.45-1.59(2H,m),2.30(1H,m),2.46(3H,s),2.68(2H,t,J=7.2Hz),3.00-3.15(3H,m),3.79(1H,m),7.44(1H,s),7.63(2H,s),8.89(1H,s);m/z(EI)381(M+)。
方案24
3-(3,5-二异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物77):向置于室温的3-(5-异丙基-2,6-二氧-1,2,3,6-四羟基-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物1)(5.94g,20mmol),粉状无水碳酸钾(13.31g,24mmol)的DMF(40mL)搅拌溶液中添加2-碘丙烷(2mL,20mmol)。接着将混合溶液油浴(50-60℃)搅拌过夜并置于真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得700mg(10%)的白色固体3-(3,5-二异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(77)。m.p.278-280℃;1H-NMR(200MHz,CDCl3)δ:1.11(3H,d,J=7.0Hz),1.20(3H,d,J=7.0Hz),1.37(3H,d,J=6.6Hz),1.47(3H,d,J=6.6Hz),2.19(1H,m),2.54(3H,s),3.55(1H,m),7.81(1H,s),7.98(1H,s),8.07(1H,s),9.09(1H,s);m/z(EI)339(M+)。
3-(3-异丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物78):向置于室温的3-(5-异丙基-2,6-二氧-1,2,3,6-四羟基-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物1)(1.19g,4mmol),粉状无水碳酸钾(662mg,4.8mmol)的DMF(20mL)搅拌溶液中添加2-碘-2-甲基丙烷(460μL,4mmol)。接着将混合溶液油浴(50-60℃)搅拌过夜并置于真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得500mg(35%)的白色固体3-(3-异丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(78)。m.p.200-201℃;1H-NMR(200MHz,CDCl3)δ:0.80(3H,d,J=3.2Hz),0.83(3H,d,J=3.2Hz),1.12(3H,d,J=7.0Hz),1.23(3H,d),J=7.0Hz),1.90(1H,m),2.25(1H,m),2.53(3H,s),2.93(1H,dd,J=14.2Hz,J=7.4Hz),3.75(1H,dd,J=14.2Hz,J=7.4Hz),7.80(1H,s),7.92(1H,s),8.03(1H,s),9.03(1H,s);m/z(EI)353(M+)。
3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物47):向置于室温的3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲氰(化合物1)(2.97g,10mmol),粉状无水碳酸钾(1.66g,12mmol)的DMF(20mL)搅拌溶液中添加碘丁烷(1.37mL,12mmol)。接着将混合溶液油浴(50-60℃)搅拌24小时,并置于真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得1.78g(50%)的白色泡沫3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(47)。1H-NMR(200MHz,CDCl3):δ0.80(3H,d,J=3.2Hz),0.83(3H,d,J=3.2Hz),1.12(3H,d,J=7.0Hz),1.23(3H,d),J=7.0Hz),1.90(1H,m),2.25(1H,m),2.53(3H,s),2.93(1H,dd,J=14.2Hz,J=7.4Hz),3.75(1H,dd,J=14.2Hz,J=7.4Hz),7.80(1H,s),7.92(1H,s),8.03(1H,s),9.03(1H,s);m/z(EI)353(M+)。
方案25
3-(3-丁-3-烯基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物79):向冰浴冷却的3-丁烯-1-醇(216mg,3mmol)氯仿(20mL)搅拌溶液置于氮气下,添加三乙胺(630μL,4.5mmol)以及滴加甲基磺酰氯(270μL,3.6mmol)。搅拌1.1小时后,用双氯甲烷稀释反应混合溶液并用饱和水合碳酸氢钠洗涤,无水碳酸镁干燥,过滤,以及真空蒸发。将残渣进一步在高真空中干燥约20分钟,与3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物1)(891mg,3mmol),粉状无水碳酸钾(414mg,3.6mmol)以及碘化锂(402mg,3mmol)。接着向混合溶液中添加DMF(15mL)并置于油浴(40-50℃)中搅拌过夜。蒸发DMF后,将残渣溶于甲醇-氯仿(1∶9)并用硅藻土滤片过滤。再将滤液置于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得320mg(30%)的白色泡沫3-(3-丁-3-烯基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(79)。从乙醚-己烷中再结晶获得白色固体。m.p.133-134℃;1H-NMR(300MHz,CDCl3):δ1.13(3H,d,J=6.9Hz),1.22(3H,d,J=6.9Hz),2.19-2.34(3H,m),2.54(3H,s),3.15(1H,m),3.90(1H,m),4.94-5.02(2H,m),5.58(1H,m),7.82(1H,s),7.96(1H,s),8.06(1H,s),8.99(1H,s);m/z(EI)351(M+)。
3-(3-丁-2-烯基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物80):向置于室温的3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物1)(297mg,1mmol),粉状无水碳酸钾(165mg,1.2mmol)以及碘化锂(134mg,1mmol)的DMF(5mL)搅拌溶液中添加巴豆基氯(97μL,1mmol)。搅拌过夜后,将混合溶液真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得300mg(85%)的白色固体3-(3-丁-2-烯基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(80)。将产物从氯仿-乙醚-己烷重结晶获得白色固体。m.p.177-178℃;1H-NMR(300MHz,CDCl3):δ1.12(3H,d,J=6.6Hz),1.21(3H,d,J=6.6Hz),1.44(3H,d,J=5.1Hz),2.22(1H,m),2.53(3H,s),4.02-4.20(2H,m),5.19-5.43(2H,m),7.78(1H,s),7.93(1H,s),8.03(1H,s),8.95(1H,s)。m/z(EI)351(M+)。
方案26
Scheme 26
6-氯-5-异丙基-1H-嘧啶-2,4-二酮:将4-氯-5-异丙基-2,6二甲氧基-嘧啶(40g,18.47mmol)溶于150mL的浓HCl-甲醇(1∶2)并回流6小时。真空蒸发混合溶液并用硅胶柱色谱(洗脱液,氯仿∶甲醇(从95∶5到90∶10))将残渣纯化获得24.4g(70%)的白色固体6-氯-5-异丙基-1H-嘧啶-2,4-二酮。m.p.250-251℃;1H-NMR(200MHz,CDCl3):δ1.25(6H,d,J=7.1Hz),3.13(1H,m);m/z(EI)188(M+)。
6-氯-1-乙基-5-异丙基-1H-嘧啶-2,4-二酮:在室温下将6-氯-5-异丙基-1H-嘧啶-2,4-二酮(18.8g,100mmol)搅拌添加于无水粉状碳酸钾(16.56g,120mmol)的DMF(200mL)搅拌溶液中。40分钟后,添加碘乙烷(8mL,100mmol)并将混合溶液搅拌过夜。真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶4到1∶2))将残渣纯化获得13.8(63%)的白色固体6-氯-1-乙基-5-异丙基-1H-嘧啶-2,4-二酮。m.p.160-161℃;1H-NMR(200MHz,CDCl3):δ1.28-1.35(9H,m),3.22(1H,m),4.15(2H,q,J=7.2Hz);m/z(EI)216(M+)。
6-氯-1-乙基-5-异丙基-3-甲氧甲基-1H-嘧啶-2,4-二酮:向置于水浴的6-氯-1-乙基-5-异丙基-1H-嘧啶-2,4-二酮(11.5g,53mmol)的DMF(100mL)的搅拌溶液中,添加60%NaH(3.18g,79.6mmol)。搅拌40分钟后,向混合溶液中添加工业用氯甲基甲醚(7.6mL,80mmol)并置于室温搅拌过夜。真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶5))将残渣纯化获得12.6g(91%)的无色油6-氯-1-乙基-5-异丙基-3-甲氧甲基-1H-嘧啶-2,4-二酮。H-NMR(200MHz,CDCl3):δ1.26-1.34(9H,m),3.24(1H,m),3.44(3H,s),4.16(2H,q,J=7.0Hz),5.35(2H,s);m/z(EI)260(M+)。
3-[氰基-(3-乙基-5-异丙基-1-甲氧甲基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-甲基]-5-甲基-苯甲腈:向置于水浴的6-氯-1-乙基-3-甲氧甲基-1H-嘧啶-2,4-二酮(1.43g,5.48mmol)和3-氰基-5-甲基苄基腈(857mg,5.48mmol)的DMF(12mL)的搅拌溶液中,添加60%NaH(483mg,12mmol)。15分钟后,将混合溶液置于室温搅拌过夜。向混合溶液中添加过量的氯化铵并持续搅拌1小时。接着真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(从1∶4到2∶3))将残渣纯化获得1.6g(80%)的无色固体3-[氰基-(3-乙基-5-异丙基-1-甲氧甲基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-甲基]-5-甲基-苯甲腈。m.p.202-205℃;1H-NMR(200MHz,DMSO-d6):δ0.77(3H,d,J=6.8Hz),1.10(3H,t,J=6.8Hz),1.20(3H,d,J=6.8Hz),2.40(3H,s),2.55(1H,m),3.71(1H,m),4.05(1H,m),5.21(2H,dd,J=11.2Hz,J=9.4Hz),6.26(1H,s),7.60(1H,s),7.69(1H,s),7.73(1H,s);m/z(EI)380(M+)。
3-[氰基-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-甲基]-5-甲基-苯甲腈(化合物85):向置于常温的3-[氰基-(3-乙基-5-异丙基-1-甲氧基甲基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-甲基]-5-甲基-苯甲腈(190mg,0.5mmol)的二氯甲烷(5mL)搅拌溶液中添加二甲基二硫(804μL,10mmol))和三氟化硼乙醚(300μL,2.37mmol)。搅拌3天后,将混合溶液于真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得150mg(89%)的白色固体3-[氰基-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四羟基-嘧啶-4-基)-甲基]-5-甲基-苯甲腈。将产物从氯仿-甲醇-乙醚中重结晶。m.p.260-261℃;1H-NMR(200MHz,DMSO-d6)δ0.77(3H,d,J=6.6Hz),1.07(3H,t,J=7.0Hz),1.19(3H,d,J=6.6Hz),2.41(3H,s),2.49(1H,m),3.68(1H,m),4.00(1H,m),6.22(1H,s),7.59(1H,s),7.71(1H,s),7.73(1H,s),11.45(1H,s);m/z(EI)336(M+)。
方案27
(1-羟甲基-环丙基)醋酸甲酯:向置于水浴中的粗的5-乙酸基-螺旋[2.4]庚-6-酮(2.24g,ca.20mmol;按照EP 0 678 515 A1的方法制备(这里作为参考文献整体引入):不纯N,N-二甲基乙酰胺)的无水甲醇(40mL)搅拌溶液中添加甲醇钠(1.296g,24mmol)。15分钟后,添加氯化铵(2g)并将混合溶液置于室温搅拌30分钟。真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1)将残渣纯化获得5.8g(47%)的无色油(1-羟甲基-环丙基)醋酸甲酯。1H-NMR(200MHz,CDCl3)δ0.47-0.61(4H,m),2.44(2H,s),2.55(1H,t,J=5.6Hz),3.48(2H,d,J=5.6Hz),3.69(3H,s)。
(1-甲磺酰基氧甲基-环丙基)醋酸甲酯:向干冰-丙酮浴冷却(-40℃)的(1-羟甲基-环丙基)醋酸甲酯(600mg,4.16mmol)二氯甲烷(10mL)搅拌溶液中添加甲基磺酰氯(483μL,6.24mmol)。接着将混合溶液冷却至-60℃并添加三乙胺(928μL,6.66mmol)。将混合溶液在1小时内搅拌加热到0℃。将混合溶液冷却到-15℃,按顺序添加冰3N HCl溶液(0.6mL),冰盐水(2mL),以及二氯甲烷(25mL)。用冰盐水(25mL)洗涤混合溶液2次,MgSO4干燥,过滤,并置于真空蒸发获得962mg(定量)的粗(1-甲磺酰基氧甲基-环丙基)-醋酸甲酯无色油。将粗产物不进一步纯化直接用于下一反应。1H-NMR(200MHz,CDCl3)δ0.62-0.72(4H,m),2.42(2H,s),3.02(3H,s),3.70(3H,s),4.17(2H,s)。
{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-醋酸甲酯(化合物82):向置于室温的3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(962mg,4.16mmol),无水粉状碳酸钾(574mg,4.16mmol),以及碘化锂(557mg,4.16mmol)的混合物中,添加DMF(18mL)。搅拌30分钟后,添加粗(1-甲磺酰基氧甲基-环丙基)-醋酸甲酯(962mg)的DMF(2mL)溶液。接着油浴(70-80℃)加热混合溶液并搅拌ca.19小时。冷却到室温之后,真空蒸发混合溶液。将残渣溶于甲醇-二氯甲烷(5∶95)并用硅藻土滤片过滤。蒸发滤液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2)将残渣纯化获得230mg(13%)的白色泡沫{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-醋酸甲酯(82)。H-NMR(200MHz,CDCl3)δ0.36-0.65(4H,m),1.12(3H,d,J=7.0Hz),1.23(3H,d,J=7.0Hz),2.17-2.32(2H,m),2.44-2.52(4H,m),3.58(1H,d,J=15.2Hz),3.69(3H,s),3.76(1H,d,J=15.2Hz),7.79(1H,s),7.95(1H,s),8.06(1H,s),9.36(1H,s);m/z(EI)423(M+)。
{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基-甲基】-环丙基}-醋酸(化合物83):向{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-醋酸甲酯(170mg,0.4mmol)的THF(4mL)搅拌溶液中添加氢氧化锂(20mg,0.8mmol)和2滴水。接着将混合溶液回流2小时。冷却至室温后,将混合溶液置于真空蒸发并用硅胶柱色谱(洗脱液,从乙酸乙酯到含有20%甲醇的乙酸乙酯)将残渣纯化获得100mg(62%)的白色固体{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-醋酸(83)。m.p.244-245℃;1H-NMR(500MHz,DMSO-d6)δ0.21-0.26(2H,m),0.34-0.36(1H,m),0.46-0.48(1H,m),0.98(3H,d,J=6.8Hz),1.08(3H,d,J=6.8Hz),2.06-2.12(2H,m),2.23(1H,d,J=17.0Hz),2.44(3H,s),3.32(1H,d,J=15.0Hz),3.74(1H,d,J=15.0Hz),8.08(1H,s),8.19(1H,s),8.43(1H,s),11.45(1H,s),12.02(1H,br.s);m/z(EI)409(M+)。
2-{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-N-(4-甲氧基-苯甲基)-乙酰胺(化合物84):向冰浴冷却的{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-醋酸(90mg,0.22mmol)的THF(5mL)搅拌混合溶液中添加草酰氯(38μL,0.44mmol)以及一滴DMF。搅拌1小时后,将混合溶液真空蒸发。将残渣溶于THF(8mL)中并添加对甲氧基苄胺(261μL,2mmol)。搅拌1小时后,将混合溶液于真空蒸馏并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(2∶1):收集Rf=0.25部分)将残渣纯化获得97mg(83%)的白色固体2-{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-N-(4-甲氧基-苯甲酰)-乙酰胺(84)。1H-NMR(200MHz,CDCl3)δ0.40-0.46(4H,m),1.12(3H,d,J=6.6Hz),1.23(3H,d,J=6.6Hz),2.00(1H,d,J-15.4Hz),2.25(1H,m),2.48-2.55(4H,m),3.45(1H.,d,J=15.4Hz),3.80(3H,s),3.90(1H,d,J=15.4Hz),4.34-4.39(2H,m),6.69(1H,m),6.83-6.90(2H,m),7.22-7.30(2H,m),7.81(1H,s),8.01(1H,s),8.07(1H,s),9.81(1H,s)。
2-{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-乙酰胺(化合物85):向置于室温的2-{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-N-(4-甲氧基-苯甲酰)-乙酰胺(97mg,0.18mmol)的乙腈(4mL)和冰醋酸(1mL)搅拌混合溶液中按顺序添加硝酸铈铵(201mg,0.36mmol)以及水(2mL)。搅拌20分钟后,用乙酸乙酯将混合溶液稀释,水洗涤2次,MgSO4干燥,过滤,以及真空蒸发。用硅胶柱色谱(洗脱液,从乙酸乙酯到含有10%甲醇的乙酸乙酯)将残渣纯化获得59mg(78%)的白色固体2-{1-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基甲基]-环丙基}-乙酰胺(85)。m.p.283-285℃;1H-NMR(500MHz,DMSO-d6)δ0.20-0.27(2H,m),0.31-0.36(1H,m),0.43-0.47(1H,m),0.99(3H,d,J=6.8Hz),1.08(3H,d,J=6.8Hz),2.02-2.13(2H,m),2.17(1H,d,J=16.5Hz),2.44(3H,s),3.32(1H,d,J=15.1Hz),3.39-3.41(1H,m),3.46-3.51(1H,m),3.79(1H,d,J=15.1Hz),8.08(1H,s),8.19(1H,s),8.42(1H,s),11.45(1H,s);m/z(EI)408(M+)。
方案28
试剂和条件:i.1-溴甲基-4-甲氧基-苯,K2CO3,LiI,DMF;ii.K2CO3,MeOH;iii.三氯-异氰酸-甲烷,DCM;iv.DCM饱和氨溶液;CAN,乙酸,MeCN/水。
2-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-3-(4-甲氧基-苯基)-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]醋酸乙酯:将2-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]醋酸乙酯(化合物8)(126mg,0.328mmol,1.0eq.)溶于1.5mL的DMF中。添加碳酸钾(45mg,1eq.)并将反应混合溶液置于室温搅拌10分钟。添加1-溴甲基-4-甲氧基-苯(47μL,0.328mmol,1eq.)和碘化锂(44mg,1eq.)。将反应混合溶液置于室温搅拌过夜。向反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)获得白色粉末(88mg,0.175mmol,53%)。LC-MS显示504.1(M+1)。
3-[3-(2-羟基-乙基)-5-异丙基-1-(4-甲氧基-苯基)-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基]-5-甲基苯甲氰:将2-【6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-3-(4-甲氧基-苯基)-2,4-二氧-3,4-二氢-2H-嘧啶-1-基】醋酸乙酯(88mg,0.175mmol,1.2eq.)溶于15mL的MeOH中。添加碳酸钾(48mg,0.349mmol,2eq.)并将反应混合溶液置于室温搅拌20分钟。将反应混合溶液浓缩并纯化(硅胶,0-10%MeOH/DCM)获得白色粉末(76mg,94%)。LC-MS显示462.1(M+1)。
2-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-3-(4-甲氧基-苯基)-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]氨基甲酸乙酯:将三氯-异氰酸-甲烷(39uL,0.33mmol,2.0eq)添加到溶有3-[3-(2-羟基-乙基)-5-异丙基-1-(4-甲氧基-苯基)-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基]-5-甲基苯甲腈(76mg,0.165mmol)的2mL DCM中。将反应混合溶液置于室温搅拌10分钟.HPLC和LC-MS显示初始材料反应完全。向检测管中的3mL DCM中通入氨气(保持起泡5分钟)。向上述反应混合溶液中加入氨溶液。将反应混合溶液置于室温搅拌2小时。将反应混合溶液过滤、浓缩并纯化(硅胶,0-80%EtOAC/己烷)获得白色粉末(42mg,51%)。LC-MS显示505.0(M+1)。
2-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]氨基甲酸乙酯(化合物86):将硝酸铈铵(156mg,0.189mmol,3eq.)添加到2-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-3-(4-甲氧基-苯基)-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]氨基甲酸乙酯(32mg,0.063mmol,1.0eq)的MeCN(1mL),醋酸(0.4mL)和水(0.2mL)混合溶液中。将反应混合溶液置于室温搅拌10分钟。将反应混合溶液浓缩。添加乙酸乙酯并用盐水洗涤混合溶液。将有机层浓缩和纯化(硅胶,20-80%EtOAC/己烷)获得白色固体(13.6mg,56%)。1HNMR(300MHz,d6DMSO):δ11.52(s,1H),8.43(s,1H),8.22(s,1H),8.09(s,1H),3.92(m,1H),3.81(m,2H),3.22(m,1H),2.44(s,3H),2.08(m,1H),1.04(dd,6H)。
方案29
试剂和条件:i.4-溴-丁-2-烯酸乙酯,K2CO3,LiI,DMF;ii.NH4OH水溶液,MeOH,微波120℃。
4-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]-丁-2-烯酸乙酯(化合物87):将3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物1)(412mg,1.386mmol,1.0eq.)溶于8mL的DMF中。添加碳酸钾(191mg,1eq.)并将反应混合溶液置于室温搅拌10分钟。添加4-溴-丁-2-烯酸乙酯(0.24mL,1eq.)和碘化锂(186mg,1eq.)。将反应混合溶液置于室温搅拌过夜。向反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩并纯化(硅胶,0-80%EtOAC/己烷)获得淡黄色泡沫(384mg,68%)。LC-MS显示410.4(M+1)。
4-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]-丁-2-烯酸酰胺(化合物88):在一个5mL的微波反应管中,添加4-[6-(3-氰基-5-甲基-苯甲酰)-5-异丙基-2,4-二氧-3,4-二氢-2H-嘧啶-1-基]-丁-2-烯酸乙酯(69mg,0.168mmol)和0.5mL MeOH,接着添加0.7mL NH4OH(30%溶于水,过量)。将反应混合溶液用微波加热120℃,30分钟。将反应混合溶液浓缩并用反相prep HPLC纯化(MeCN/水)获得白色粉末(4.2mg,6.6%)。1H NMR(300MHz,CD3OD):δ8.8(d,1H),7.64(m,2H),7.4-7.28(m,2H),3.19(dd,1H),2.52(m,1H),0.95(d,3H),0.65(dd,3H)。LC-MS显示381.0(M+1)。
方案30
试剂和条件:i.6-甲基-1H-吲哚-4-腈,NaH,DMF,加热;ii.AcBr,加热;iii.EtI,K2CO3,DMF。
1-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-6-甲基-1H-吲哚-4-腈:将NaH(148mg,1.1eq.)添加到6-甲基-1H-吲哚-4-腈的20mL DMF中。5分钟后,将4-氯-5-异丙基-2,6-二甲氧基-嘧啶添加到反应混合溶液。将反应混合溶液50℃加热5小时。将混合溶液用EtOAc稀释以及用盐水洗涤。将有机层浓缩和纯化(硅胶,0-80%EtOAC/己烷)获得白色固体(470mg,42%)。LC-MS显示337.2(M+1)。
1-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-6-甲基-1H-吲哚-4-腈(化合物89):将AcBr(3mL)添加到6-甲基-1-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-1H-吲哚-4-腈(470mg,1.40mmol)。将反应混合溶液置于70℃加热6小时。接着将反应混合溶液冷却至室温并浓缩。纯化(硅胶,0-80%EtOAC/己烷)反应粗产物获得白色固体(280mg,65%)。LC-MS显示307.1(M-1)。
1-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-6-甲基-1H-吲哚-4-腈(化合物90):将6-氯-1-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-1H-吲哚-4-腈(35mg,0.113mmol,1.0eq.)溶于0.5mL DMF中。添加碳酸钾(16mg,1eq.)并将反应混合溶液置于室温搅拌10分钟。添加EtI(9.1μL,1eq.)。将反应混合溶液置于室温搅拌2小时。将乙酸乙酯添加到反应混合溶液中,接着用盐水洗涤。将有机层浓缩并纯化(硅胶,0-80%EtOAC/己烷)获得白色粉末(14mg,37%)。LC-MS显示335.0(M-1)。1H NMR(300MHz,CDCl3):δ9.37(br,1H),8.05(s,1H),7.08(m,2H),6.80(d,1H),3.58(m,1H),3.17(m,1H),2.62(s,3H),1.88(m,1H),1.17(dd,6H),1.02(t,3H)。
6-咪唑-1-基1-乙基-5-异丙基-1H-嘧啶-2,4-二酮(化合物91):该化合物是用与制备1-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-6-甲基-1H-吲哚-4-腈(90)相似的步骤制备的,用咪唑替代6-氯-1H-吲哚-4-腈除外。LC-MS显示299.1(M+1)。1H NMR(300MHz,CDCl3):δ9.32(br,1H),7.97(m,2H),7.43(m,2H),7.30(m,1H),3.60(m,1H),3.20(m,1H),1.98(m,1H),1.10(m,9H)。
1-乙基-6-吲唑-1-基-5-异丙基-1H-嘧啶-2,4-二酮(化合物92):该化合物的制备步骤与制备6-氯-1-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-1H-吲哚-4-腈(90)步骤相似,吲唑用于替代6-氯-1H-吲哚-4-腈除外。LC-MS显示299.1(M+1)。1H NMR(300MHz,CDCl3):δ8.97(br,1H),8.31(s,1H),7.83(d,2H),7.54(m,1H),7.36(m,2H),3.42(m,1H),3.20(m,1H),1.90(m,1H),1.15(dd,6H),1.00(t,3H)。
1-乙基-6-吲哚-1-基-5-异丙基-1H-嘧啶-2,4-二酮(化合物93):该化合物的制备步骤与制备6-氯-1-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-1H-吲哚-4-腈(90)步骤相似,1H-吲哚用于替代6-氯-1H-吲哚-4-腈除外。LC-MS显示298.2(M+1)。1H NMR(300MHz,CDCl3):δ8.32(br,1H),7.72(d,1H),7.25(m,2H),7.19(m,1H),6.80(m,1H),3.50(m,1H),3.18(m,1H),1.97(m,1H),1.17(dd,6H),1.03(t,3H)。
1-乙基-6-咪唑-1-基-5-异丙基-1H-嘧啶-2,4-二酮(化合物94):该化合物的制备步骤与制备6-氯-1-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-1H-吲哚-4-腈(90)步骤相似,咪唑用于替代6-氯-1H-吲哚-4-腈除外。LC-MS显示249.1(M+1)。1H NMR(300MHz,CDCl3):δ9.03(br,1H),7.60(m,1H),7.32(m,1H),7.00(m,1H),3.40(m,2H),2.08(m,1H),1.19(m,9H)。
1-乙基-5-异丙基-6-吡唑-1-基-1H-嘧啶-2,4-二酮(化合物95):该化合物的制备步骤与制备6-氯-1-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-1H-吲哚-4-腈(90)步骤相似,吡唑用于替代6-氯-1H-吲哚-4-腈除外。LC-MS显示249.1(M+1)。1H NMR(300MHz,CDCl3):δ9.36(br,1H),7.81(m,1H),7.58(m,1H),6.54(m,1H),3.38(m,2H),2.04(m,1H),1.17(m,9H)。
方案31
试剂和条件:i.a)BnOH,NaH,DMF;b)H2,10%Pd/C;
ii.N-苯三氟甲烷磺酰胺,Cs2CO3,DCM。
iii.3-喹啉硼酸,Pd(dppf)2Cl2,2M aq.Na2CO3,DME,微波;
iv.AcBr,加热;v.EtI,K2CO3,DMF。
5-异丙基-2,6-二甲氧基-嘧啶-4-醇:在0℃下,向10mL DMF的4-氯-5-异丙基-2,6-二甲氧基-嘧啶(1.4g,6.51mmol,1eq)和苯甲醇(704mg,1.0eq.)混合溶液中添加NaH(60%溶于矿物油,273mg,1.05eq.)。将反应混合溶液置于0℃下搅拌,接着加热至室温。LC-MS显示目的产物形成。接着用乙酸乙酯稀释反应混合溶液,水洗涤2次,无水硫酸镁干燥,过滤,以及真空蒸发获得粗产物。
向上述粗产物(大约1.7g)的9mL EtOH以及36mL EtOAc的混合溶液中添加10%的碳钯(340mg),并用一个氢气球。将反应混合溶液置于室温搅拌1小时。并通过硅藻土滤片过滤混合溶液并浓缩。用硅胶柱色谱(洗脱液:EtOAc/己烷(20-80%))将粗产物纯化获得440mg(对于这两步是34%)的白色固体5-异丙基-2,6-二甲氧基-嘧啶-4-醇。1H NMR(300MHz,CDCl3)1.20(6H,d),3.25(1H,m),3.95(6H,d),12.9(1H,br)。LC-MS(M+1:199.1,M-1:197.0)。
3-氟-甲磺酸5-异丙基-2,6-二甲氧基-嘧啶-4-基酯:向5-异丙基-2,6-二甲氧基-嘧啶-4-醇(64mg,0.322mmol)以及N-苯基三氟甲烷磺酰胺(127mg,1.1eq)的3mL DCM混合溶液中添加Cs2CO3(116mg,1.1eq.)。将反应混合溶液置于室温搅拌90分钟。将反应混合溶液浓缩并纯化(硅胶,0-80%EtOAC/己烷)获得白色固体(74mg,69%)。LC-MS显示330.9(M+1)。
3-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)喹啉:在一个5mL的微波反应管中,将三氟-甲磺酸5-异丙基-2,6-二甲氧基-嘧啶-4-基酯(30mg,0.091mmol),3-喹啉硼酸(19mg,1.2eq.)以及Pd(dppf)2Cl2(7.4mg,10%)与2mL DME和0.18mL 2M水合Na2CO3(4eq.)混合。将反应混合溶液微波130℃加热40分钟。将反应混合溶液浓缩并用反相prep HPLC(MeCN/水)纯化获得白色粉末(14mg,50%)。LC-MS显示310.2(M+1)。
5-异丙基-6-喹啉-3-基-1H-嘧啶-2,4-二酮(化合物96):在一个10mL的圆底烧瓶中,向3-(5-异丙基-2,6-二甲氧基-嘧啶-4-基)-喹啉(14mg,0.045mmol)中添加1mL AcBr。将反应混合溶液在70℃加热2小时。浓缩反应混合溶液并用反相prep HPLC(MeCN/水)纯化获得白色粉末(6mg,47%)。LC-MS显示280.3(M-1)。
1-乙基-5-异丙基-6-喹啉-3-基-1H-嘧啶-2,4-二酮(化合物97):将5-异丙基-6-喹啉-3-基-1H-嘧啶-2,4-二酮(6mg,0.021mmol,1.0eq.)溶于0.5mL DMF中。添加碳酸钾(3mg,1eq.)并将反应混合溶液置于室温搅拌10分钟。添加EtI(1.7μL,1eq.)。将反应混合溶液置于室温反应过夜。未观察到任何反应。添加更多的碳酸钾(6mg)。2小时后,反应混合溶液反应完成。将反应粗产物过滤并用反相HPLC纯化获得白色粉末(1.5mg,23%)。LC-MS显示310.2(M+1)。1H-NMR(300MHz,CDCl3):δ8.83(s,1H),8.40(m,1H),8.22(m,1H),7.96(m,2H),7.78(m,1H),3.58(m,2H),2.10(m,1H),1.90(dd,6H),1.04(t,3H)。
方案32
试剂和条件:i.tBuNO2,CuCl2,ACN,89%;ii.NBS,CCl4,68%;iii.KCN,EtOH/H2O,39%;iv.a.4-氯-5-异丙基-2,6-二甲氧基-嘧啶,NaH,DMF;b.O2,11%(2步);v.AcBr,95%;vi.碘乙烷,K2CO3,DMF,30%。
4-氯-3,5-二甲基-苯甲腈:向置于0℃的氯化铜(II)(1.10g,8.21mmol)的乙腈(27mL)混合溶液中添加亚硝酸叔丁酯(1.35g,110.26mmol)。在5分钟内向这个棕色混合溶液中分批添加4-氨基-3,5-二甲基-苯甲腈(1.0g,6.84mmol)并将反应混合溶液置于室温搅拌18小时。将反应混合溶液浓缩,用1N HCl稀释并用乙醚萃取。将有机层干燥(MgSO4),浓缩并用快速柱色谱(硅胶,0-20%乙酸乙酯/己烷)纯化获得白色固体(1.011g,89%)。1H NMR(300MHz,CDCl3):7.30(s,2H),2.33(s,6H);13C NMR(75MHz,CDCl3):139.9,137.8,131.5,118.3,109.9,20.6。
4-氯-3-氰甲基-5-甲基-苯甲腈:将4-氯-3,5-二甲基-苯甲腈(1.011g,6.10mmol),N-溴代琥珀酰亚胺(1.087g,6.10mmol)以及过氧化苯甲酰(0.074g,0.305mmol)的四氯化碳(30mL)混合溶液加热回流4小时。将反应混合溶液冷却至室温并过滤。用快速柱色谱(硅胶,0-30%乙酸乙酯/己烷)将滤液纯化获得不纯白色固体3-溴甲基-4-氯-5-甲基-苯甲腈(0.9938g,66%),其未纯化产物直接用于下一步操作。
将3-溴甲基-4-氯-5-甲基-苯甲腈(0.9938g,4.06mmol),氰化钾(0.529g,8.12mmol)的乙醇(5.0mL)和水(2.5mL)溶液置于85℃加热3小时。将反应混合溶液冷却,用乙酸乙酯稀释,盐水洗涤,干燥(MgSO4),浓缩并用快速柱色谱(硅胶,0-30%乙酸乙酯/己烷)纯化获得白色固体4-氯-3-氰甲基-5-甲基-苯甲腈(0.3707g,48%)。1H NMR(300MHz,CDCl3):7.61(s,1H),7.51(s,1H),3.83(s,2H),2.40(s,3H)。
4-氯-3-(5-异丙基-2,6-二甲氧基-嘧啶-4-羰基)-5-甲基-苯甲腈:向置于0℃的4-氯-5-异丙基-2,6-二甲氧基-嘧啶(0.442g,2.04mmol)和4-氯-3-氰甲基-5-甲基-苯甲腈(0.3707g,1.94mmol)的DMF搅拌混合溶液中在15分钟内分批加入NaH产生橙色-红色反应混合溶液。搅拌24小时后,向反应混合溶液中通入O236小时。反应混合物用饱和氯化铵溶液和甲醇淬火,以及用乙酸乙酯稀释。用饱和氯化铵溶液,水,饱和氯化铵溶液洗涤有机层并干燥(MgSO4)接着浓缩和用快速柱色谱(硅胶,5-50%乙酸乙酯/己烷)纯化获得标题化合物(0.0767g,11%)。1H NMR(300MHz,CDCl3):7.67(s,1H),7.59(s,1H),4.00(s,3H),3.75(s,3H),3.3-3.2(m,1H),2.37(s,3H),1.25(s,3H),1.23(s,3H);13C NMR(75MHz,CDCl3):192.8,171.1,162.2,160.2,139.1,138.9,137.3,135.9,132.3,119.9,117.4,110.8,54.7,54.2,26.5,20.2,20.2;质谱:360.2,362.1(M+H)。
4-氯-3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物98):将4-氯-3-(5-异丙基-2,6-二甲氧基-嘧啶-4-羰基)-5-甲基-苯甲腈(0.0767g,0.213mmol)的乙酰溴溶液(3.5mL)置于65℃加热18小时,冷却至室温并浓缩。用快速柱色谱(硅胶,20-100%乙酸乙酯/己烷)纯化最终残渣获得化合物102的灰白色固体(0.067g,95%)。1H NMR(300MHz,CD3OD):8.05(s,1H),7.96(s,1H),2.47(s,3H),2.5-2.4(m,1H),1.09(s,3H),1.07(s,3H);质谱:332.2(M+H)。
4-氯-3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(化合物99):向化合物98(0.067g,0.202mmol)和碳酸钾(0.0279g,0.202mmol)的DMF(1.0mL)的混合溶液中添加碘乙烷(14μL,0.168mmol)并将反应混合溶液置于室温搅拌过夜。反应混合溶液用饱和氯化铵溶液淬火并用乙酸乙酯萃取,干燥(MgSO4)和浓缩。用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化残渣冻干后获得白色粉末(20.5mg,28%)。1H NMR(300MHz,CD3CN):9.15(s,1H),8.16(s,1H),7.96(s,1H),3.52(br s,2H),2.47(s,3H),2.3-2.2(m,1H),1.1-1.0(s,9H);质谱:360.2,362.2(M+H)。
方案33
试剂和条件:i.NaBH4,EtOH,44%;ii.DASTA,68%;iii.a.MsCl,Et3N,THF;b.KCN,EtOH/H2O,39%。
3-[(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-羟基-甲基]-5-甲基-苯甲腈(化合物100):向置于0℃的3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-羰基)-5-甲基-苯甲腈(3)(0.700g,2.15mmol)乙醇(61mL)溶液中添加硼氢化钠(0.081g,2.15mmol)并将反应混合溶液置于0℃搅拌2小时,接着置于室温搅拌过夜。接着添加更多的硼氢化钠(0.081g,2.15mmol),将混合溶液搅拌24小时。再一次添加更多的硼氢化钠(0.081g,2.15mmol),并继续搅拌6小时。将反应混合溶液浓缩并用饱和NH4Cl溶液淬火,用1N HCl酸化并接着用乙酸乙酯(2×)萃取。将结合的有机层干燥(MgSO4),浓缩并用快速柱色谱(硅胶,30-60%乙酸乙酯/己烷)纯化获得不纯产物。将不纯产物再一次用快速柱色谱(硅胶,0-5%甲醇/二氯甲烷)纯化,接着用快速柱色谱(硅胶,40-60%乙酸乙酯/己烷)纯化获得白色固体(0.31g,44%)。1H NMR(300MHz,CD3OD):7.55(s,1H),7.47(s,1H),7.43(s,1H),6.18(s,1H),3.73(q,J=6.9Hz,2H),3.12-3.07(m,1H),2.37(s,3H),1.30(d,J=7.2Hz,3H),1.11(d,J=6.6Hz,3H),0.92-0.84(m,3H);质谱:328.1(M+H)。
3-[(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-氟-甲基]-5-甲基-苯甲腈(化合物101):向置于0℃的3-[(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-羟基-甲基]-5-甲基-苯甲腈(100)(55.7mg,0.17mmol)的二氯甲烷(2.0mL)搅拌混合溶液中添加(二乙氨基)三氟化硫(33μL,0.255mmol)并将反应混合溶液搅拌1小时。将混合溶液用饱和NaHCO3溶液淬火并用乙酸乙酯(2×)萃取。将结合的有机层干燥(MgSO4),浓缩并用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化冻干后获得白色粉末(45mg,80%)。1H NMR(300MHz,CD3OD):7.60(s,1H),7.55(s,1H),7.46(s,1H),7.04(d,J=45.9Hz,1H),3.75-3.57(m,2H),2.94-2.89(m,1H),2.40(s,3H),1.24(d,J=6.9Hz,3H),1.1-1.0(s,6H);%)。19F NMR(CD3OD):-180.5;质谱:330.1(M+H)。
3-[乙氧基-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-甲基]-5-甲基-苯甲腈(化合物102):向3-[(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-羟基-甲基]-5-甲基-苯甲腈(100)(69mg,0.211mmol)和三乙胺(353μL,2.53mmol)的THF(4.0mL)溶液中添加甲烷磺酰氯(166μL,2.11mmol)。将反应混合溶液置于0℃搅拌2小时,接着置于室温搅拌48小时。用乙酸乙酯稀释反应混合溶液并用1N HCl,饱和NaHCO3溶液洗涤,干燥(MgSO4),浓缩和纯化获得不纯产物(80mg)。将产生的残渣溶于乙醇(1.5mL)和水(0.5mL)中并添加氰化钾(21mg,0.32mmol)。将反应混合溶液回流2小时,冷却并用乙酸乙酯稀释以及用饱和氯化铵溶液洗涤,干燥(MgSO4)和浓缩。将产生的残渣用反相HPLC(Phenomenexcolumn,5-100%乙腈/H2O)纯化冻干后获得白色粉末(14mg,22%)。1H NMR(300MHz,CD3OD):7.52(s,1H),7.50(s,1H),7.39(s,1H),5.98(s,1H),3.75-3.57(m,4H),3.12-3.07(m,1H),2.37(s,3H),1.37-1.30(m,6H),1.15(d,J=6.3Hz,3H),0.92-0.87(m,3H);质谱:356.2(M+H)。
方案34
试剂和条件:i.Br,AcOH,MeOH,0℃→室温;ii.NaNO2,AcOH,HCl,H2O,H3PO2,0℃→室温;iii.Zn(CN)2,Pd(PPh3)4,DMF,90℃;iv.BCl3,Bu4Nl,DCM,-78℃→室温;v.NaH,DMF;vi.BnOH,NaH,DMF;vii.K2CO3,DMF,R-l。
4-溴-2-甲氧基-6-甲基-苯胺:在一个100mL的圆底烧瓶中,将2-甲氧基-6-甲基-苯胺(4.54g,33.16mmol)溶于15mL MeOH和5mL醋酸中。将烧瓶冷却至0℃。将溴(1.7mL,33.16mmol)的5mL醋酸溶液添加到滴加反应(30分钟内)。将反应混合溶液置于0℃搅拌2小时,接着加热到室温1小时。将反应混合溶液浓缩。在0℃下添加1N NaOH中和反应。添加乙酸乙酯萃取反应混合溶液。将有机层在无水硫酸钠干燥后进行浓缩获得暗棕色固体(5.8g,81%)。LC-MS显示218.0(M+1)。1H NMR(300MHz,CDCl3):δ6.88(s,1H),6.81(s,1H),3.84(s,3H),2.11(s,3H)。
1-溴-3-甲氧基-5-甲基-苯:在一个250mL的圆底烧瓶中,将4-溴-2-甲氧基-6-甲基-苯胺(5.8g,26.84mmol)溶于醋酸(49mL)以及浓HCl(5.6mL)。在0℃下,将溶于7mL水的亚硝酸钠(2.19g,31.78mmol)逐滴添加到混合溶液中。将反应混合溶液置于0℃搅拌30分钟。在0℃下添加50%的次磷酸(56.5mL)。将反应混合溶液置于0℃搅拌,并加热到室温过夜。接着添加乙酸乙酯,随后用饱和NaHCO3溶液洗涤。将有机层浓缩和纯化(硅胶,100%己烷)获得苍白的液体(5.12g,95%)。1H NMR(300MHz,CDCl3):δ6.97(s,1H),6.87(s,1H),6.64(s,1H),3.80(s,3H),2.36(s,3H)。
3-甲氧基-5-甲基-苯甲腈:在100mL圆底烧瓶中,将1-溴-3-甲氧基-5-甲基-苯(2.17g,10.79mmol),Zn(CN)2(1.9g,16.19mmol,1.5eq.)和Pd(PPh3)4(1.24g,1.08mmol,0.1eq.)溶于DMF(20mL)中。在氩气下将反应混合溶液90℃加热7小时。添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-50%EtOAC/己烷)获得白色固体(1.31g,83%)。1H NMR(300MHz,CDCl3):δ7.05(s,1H),6.97(s,2H),3.81(s,3H),2.39(s,3H)。
3-羟基-5-甲基-苯甲腈:在100mL圆底烧瓶中,将3-甲氧基-5-甲基-苯甲腈(500mg,3.39mmol)溶于15mL的干DCM中,并添加四丁基碘化铵(1.38g,3.73mmol,3.5eq.)。将烧瓶冷却到-78℃。添加BCl3(1M溶于DCM,11.87mL,33.16mmol)滴加反应。将反应混合溶液置于-78℃搅拌并加热到室温过夜。用冰终止反应混合溶液并用饱和NaHCO3溶液中和反应。添加DCM萃取反应混合溶液。将有机层浓缩并纯化(硅胶,0-10%MeOH/DCM)获得浅黄色固体(408g,90%)。LC-MS显示132.0(M-1)。1H NMR(300MHz,CDCl3):δ7.20(s,1H),6.96(s,1H),6.91(s,1H),2.37(s,3H)。
3-(2,6-二氯-5-异丙基-嘧啶-4-氧基)-5-甲基-苯甲腈:在0℃下,将NaH(60%,125mg,3.06mmol,1.0eq.)添加到3-羟基-5-甲基-苯甲腈(408mg,3.06mmol)的10mL DMF溶液中。将反应混合溶液置于0℃搅拌5分钟。接着添加2,4,6-三氯-5-异丙基-嘧啶(691mg,3.06mmol)。将反应混合溶液置于0℃搅拌30分钟。将乙酸乙酯添加到反应混合溶液,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-50%EtOAc/己烷)获得白色固体(868mg,88%)。LC-MS显示322.1(M+1)。1H NMR(300MHz,CDCl3):δ7.41(s,1H),7.26(s,1H),7.19(s,1H),3.60(m,1H),2.42(s,3H),1.42(d,6H)。
3-(2,6-双-苄氧基-5-异丙基-嘧啶-4-氧基)-5-甲基-苯甲腈:在0℃下,将NaH(60%,118mg,2.88mmol,2.2eq.)添加到苯甲醇(298μL,2.88mmol)的5mL THF溶液中。将反应混合溶液置于0℃搅拌5分钟。添加3-(2,6-二氯-5-异丙基-嘧啶-4-氧基)-5-甲基-苯甲腈(422mg,1.31mmol)。将反应混合溶液置于0℃搅拌15分钟,接着加热到室温搅拌90分钟。将乙酸乙酯添加到反应混合溶液,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,0-50%EtOAc/己烷)获得白色固体(372mg,HPLC纯化为65%,40%)。LC-MS显示466.1(M+1)。
3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-氧基)-5-甲基-苯甲腈(化合物103):将3-(2,6-双-苄氧基-5-异丙基-嘧啶-4-氧基)-5-甲基-苯甲腈(372mg,纯度65%,0.52mmol)溶于20mL的EtOAc和5mL的EtOH中。添加10%的Pd/C(75mg)并应用一个氢气球。将反应混合溶液置于室温反应1小时。将Pd/C通过硅藻土过滤,并将滤液浓缩和用硅胶纯化(EtOAc/己烷)获得白色固体(100mg,29%)。LC-MS显示286.0(M+1)。
3-(3-乙基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-氧基)-5-甲基-苯甲腈(化合物104):将碳酸钾(24mg,0.172mmol,1.0eq.)添加到3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-氧基)-5-甲基-苯甲腈(103)(59mg,0.207mmol,1.2eq.)的2.0mL DMF溶液中。将反应混合溶液置于室温搅拌10分钟,接着添加碘乙烷(14μL,0.172mmol)。将反应混合溶液置于室温搅拌过夜。向反应混合溶液中添加乙酸乙酯,接着用盐水洗涤。将有机层浓缩和纯化(硅胶,20-80%EtOAc/己烷),随后用反相HPLC(MeCN/水)纯化获得白色粉末(15mg,28%)。LC-MS显示314.1(M+1)。1H NMR(300MHz,CDCl3):δ9.17(br,1H),7.25(s,1H),7.08(s,1H),7.00(s,1H),3.77(t,2H),2.69(m,1H),2.42(s,3H),1.2(m,9H)。
3-(3-丁基-5-异丙基-2,6-二氧-1,2,3,6四氢-嘧啶-4-氧基)-5-甲基-苯甲腈(化合物105):将碳酸钾(9.3mg,0.0067mmol,1.0eq.)添加到3-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-氧基)-5-甲基-苯甲腈(103)(23mg,0.0.08mmol,1.2eq.)的1.0mL DMF溶液中。将反应混合溶液置于室温搅拌10分钟,接着添加碘代正丁烷(7.6μL,0.0.067mmol)。将反应混合溶液过滤并用反相HPLC(MeCN/水)纯化获得白色粉末(3.8mg,17%)。LC-MS显示342.1(M+1)。1H NMR(300MHz,CDCl3):δ8.37(br,1H),7.28(s,1H),7.08(s,1H),6.98(s,1H),3.42(t,2H),2.71(m,1H),2.42(s,3H),1.60(m,2H),1.28(m,2H),1.17(d,6H),0.88(t,3H)。
方案35
N-(3-丁-2-烯基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-N-(3,5-二甲基-苯基)-乙酰胺(化合物107):向N-(3,5-二甲基-苯基)-N-(5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-乙酰胺(106)(与下面方案36的化合物109的制备方法类似,用2,4,6-三氯-5-异丙基-嘧啶替代2,4,6-三氯-5-乙基-嘧啶除外)(600mg,1.9mmol),无水粉状K2CO3(262mg,1.9mmol),以及碘化锂(254mg,1.9mmo1)的DMF(7mL)搅拌溶液中,添加1-甲基磺酰-反式-2-丁烯(269μL,2.28mmol)。搅拌13小时后,用乙醚稀释反应混合溶液,水洗涤,MgSO4干燥,并置于真空干燥。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得382mg(54%)的白色固体。m.p.103-105℃;m/z(EI)369(M+)。
1-丁-2-烯基-6-(3,5-二甲基-苯胺)-5-异丙基-1H-嘧啶-2,4-二酮(化合物108):向N-(3-丁-2-烯基-5-异丙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-N-(3,5-二甲基-苯基)-乙酰胺(107)(100mg,0.27mmol)的甲醇(3mL)搅拌溶液中添加甲醇钠(73mg,1.35mmol)。4小时后,用过量的NH4Cl中和混合溶液并真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得62mg(70%)的白色固体。m.p.186-187℃;1H-NMR(200MHz,CDCl3)δ1.17(6H,d,J=6.9Hz),1.64-1.67(3H,m),2.24(6H,s),2.86(1H.m),4.25-4.30(2H,m),5.33(1H,s),5.48-5.54(2H,m),6.32(2H,s),6.60(1H,s),8.42(1H,s);m/z(EI)327(M+)。
方案36
N-(2,6-二氯-5-乙基-嘧啶-4-基)-N-(3,5-甲基-苯基)-甲酰胺:向冰浴冷却的置于氮气下的N-(3,5-二甲基苯基)甲酰苯胺(8.94g,60mmol)的DMF(60mL)搅拌溶液中,分次加入60%的氢氧化钠(2.88g,72mmol)。10分钟后,添加2,4,6-三氯-5-乙基-嘧啶(15.2g,72mmol)。搅拌10分钟后,将混合溶液置于室温搅拌24小时。用乙醚稀释混合溶液,水洗涤三次,MgSO4干燥,过滤,真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶10))将残渣纯化获得8.6g(44%)的白色固体。m.p.124-125℃;m/z(EI)323(M+)。
(3,5-二甲基-苯基)-(5-乙基-2,6-二甲氧基-嘧啶-4-基)-胺:在室温下将金属钠(2.3g,0.1M)与甲醇(80mL)反应。接着添加N-(2,6-二氯-5-乙基-嘧啶-4-yl)-N-(3,5-二甲基-苯基)-甲酰胺(6.48g,20mmol)并将混合溶液回流4小时。冷却至室温后,将反应混合溶液用过量NH4Cl中和。真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶15))将残渣纯化获得5g(88%)的白色固体。m.p.113-114℃;1H-NMR(200MHz,CDCl3)δ1.12(3H,t,J=7.5Hz),2.31(6H,s),2.38(2H,q,J=7.5Hz),3.94(6H,s),6.32(1H,s),6.70(1H,s),7.25(2H,s);m/z(EI)287(M+)。
N-(3,5-二甲基-苯基)-N-(5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-乙酰胺(化合物109):将(3,5-二甲基-苯基)-(5-乙基-2,6-二甲氧-嘧啶-4-基)-胺(5g,17.4mmol)与乙酰溴(50mL)一起回流18小时。冷却至室温之后,将混合溶液真空蒸发并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(2∶1))将残渣纯化获得4.5g(86%)的白色固体。m.p.238-239℃;1H-NMR(200MHz,CDCl3)δ0.93(3H,t,J=7.5Hz),2.05-2.15(3H,m),2.24-2.40(8H,m),6.94-6.99(3H,m);m/z(EI)301(M+)。
N-(3-丁-2-烯基-5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-N-(3,5-二甲基-苯基)-乙酰胺(化合物110):向N-(3,5-二甲基-苯基)-N-(5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-乙酰胺(109)(602mg,2mmol),无水粉状K2CO3(276mg,2mmol),以及碘化锂(268mg,2mmol)的DMF(6mL)搅拌混合溶液中添加1-甲基磺酰-反式-2-丁烯(283μL,2.4mmol)。搅拌13小时后,用乙醚稀释反应混合溶液,水洗涤,MgSO4干燥,过滤,并真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得291mg(40%)的白色固体。m.p.218-220℃;m/z(EI)355(M+)。
1-丁-2-烯基-6-(3,5-二甲基-苯胺)-5-乙基-1H-嘧啶-2,4-二酮(化合物111):向N-(3-丁-2-烯基-5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-N-(3,5-二甲基-苯基)-乙酰胺(110)(90mg,0.25mmol)的甲醇(3mL)搅拌混合溶液中,添加甲醇钠(73mg,1.35mmol)。4小时后,将反应混合溶液用过量NH4Cl中和并真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得57mg(72%)的白色固体。m.p.190-192℃;1H-NMR(200MHz,CDCl3)δ1.00(3H,t,J=7.5Hz),1.68-1.70(3H,m),2.28-2.37(8H,m),4.31-4.33(2H,m),5.44(1H,s),5.51-5.58(2H,m),6.39(2H,s),6.66(1H,s),8.72(1H,s);m/z(EI)313(M+)。
N-(3,5-二甲基-苯基)-N-(3-乙氧基甲基-5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-乙酰胺(化合物112):将N-(3,5-二甲基-苯基)-N-(5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-乙酰胺(109)(301mg,1mmol),六甲基二硅氮烷(5mL),以及三甲基氯硅烷(5滴)的混合溶液回流4小时。冷却至室温之后,真空蒸馏混合溶液。将残渣溶于乙腈(5mL)。添加氯甲基乙醚(110μL,1.2mmol)和SnCl4(1M二氯甲烷,100μL,0.1mmol)。将混合溶液至于室温搅拌16小时。接着添加过量的碳酸钠并将混合溶液搅拌1小时。真空蒸发混合溶液并用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶1))将残渣纯化获得162mg(45%)的白色固体。m.p.182-183℃;HRMS(EI)Calcd.359.184507;Found 359.183174。
6-(3,5-二甲基-苯基胺)-1-乙氧基甲基-5-乙基-1H-嘧啶-2,4-二酮(化合物113):向N-(3,5-二甲基-苯基)-N-(3-乙氧基甲基-5-乙基-2,6-二氧-1,2,3,6-四氢-嘧啶-4-基)-乙酰胺(112)(93mg,0.26mmol)的甲醇(5mL)搅拌溶液中,添加甲醇钠(73mg,1.35mmol)。4小时后,将反应混合溶液用过量NH4Cl中和并真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得58mg(70%)的白色固体。m.p.175-176℃;1H-NMR(200MHz,CDCl3)δ0.93(3H,t,J=7.5Hz),1.26(3H,t,J=7.1Hz),2.19(2H,q,J=7.5Hz),2.27(6H,s),3.70(2H,q,J=7.1Hz),5.34(2H,s),6.42(1H,s),6.46(2H,s),6.65(1H,s),8.64(1H,s);m/z(EI)317(M+)。
方案37
1-丁-2-烯基-6-(3,5-二甲基-苯氧基)-5-异丙基-1H-嘧啶-2,4-二酮(化合物115):向6-(3,5-二甲基-苯氧基)-5-异丙基-1H-嘧啶-2,4-二酮(114)(用WO9518109的方法制备,这里作为参考文献整体引入;274mg,1mmo),无水粉状K2CO3(138mg,1mmol),以及碘化锂(134mg,1mmol)的DMF(5mL)搅拌混合溶液中,添加1-甲基磺酰-反式-2-丁烯(141μL,1.2mmol)。搅拌15小时后,用乙醚稀释反应混合溶液,水洗涤,MgSO4干燥,过滤,并真空蒸发。用硅胶柱色谱(洗脱液,乙醚∶二氯甲烷∶己烷(1∶1∶2))将残渣纯化获得247mg(75%)的白色固体。m.p.141-143℃;1H-NMR(200MHz,CDCl3)δ1.13(6H,d,J=7.0Hz),1.59(3H,d,J=6.0Hz),2.29(6H,s),2.72(1H,m),4.20(2H,d,J=5.5Hz),5.34-5.61(2H,m),6.51(2H,s),6.75(1H,s),9.00(1H,s);m/z(EI)328(M+)。
方案38
1-丁-3-炔基-6-(3,5-二甲基-苯氧基)-5-异丙基-1H-嘧啶-2,4-二酮(化合物116):向6-(3,5-二甲基-苯氧基)-5-异丙基-1H-嘧啶-2,4-二酮(114)(548mg,2mmol),无水粉状K2CO3(276mg,2mmol),以及碘化锂(268mg,2mmol)的DMF(10mL)搅拌混合溶液中,添加1-甲基磺酰-2-丙炔(247μL,2.1mmol)。17小时后,用乙醚稀释反应混合溶液,水洗涤,MgSO4干燥,过滤,以及真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得546mg(84%)的白色固体。m.p.158-160℃;1H-NMR(200MHz,CDCl3)δ1.15(6H,d,J=7.0Hz),1.69(3H,t,J=2.2Hz),2,32(6H,s),2.80(1H,m),4.43(2H,q,J=2.2Hz),6.60(2H,s),6.78(1H,s),8.55(1H,s);m/z(EI)326(M+)。
1-丁-2-炔基-6-(3,5-二甲基-苯氧基)-5-异丙基-1H-嘧啶-2,4-二酮(化合物117):在氢气下,将1-丁-3-炔基-6-(3,5-二甲基-苯氧基)-5-异丙基-1H-嘧啶-2,4-二酮(116)(50mg,0.15mmol)在钯存在的情况下在含硫酸钡(15mg)的甲醇(5mL)中搅拌。15分钟后,将混合溶液通过硅藻土plug过滤并将滤液真空蒸发。用硅胶柱色谱(洗脱液,乙酸乙酯∶己烷(1∶2))将残渣纯化获得50mg(100%)的白色固体。m.p.141-142℃;1H-NMR(200MHz,CDCl3)δ1.13(6H,d,J=7.0Hz),1.61(3H,dd,J=6.9Hz,1.4Hz),2,31(6H,s),2.79(1H,m),4.35(2H,d,J=6.8Hz),5.38(1H,m),5.60(1H,m),6.54(2H,s),6.77(1H,s);m/z(EI)328(M+)。
在MT2和MT4细胞中的抗病毒以及细胞毒性试验
对于用MT-2细胞的抗病毒试验,将50μL用10%FBS的培养基稀释的2X检测浓度的5-倍系列稀释化合物添加到96孔板(9个浓度),重复三次。用感染复数(m.o.i)为0.01的HIV-IIIb感染MT-2细胞3小时。接着向50微升的含有10%FBS培养基的感染细胞悬液(~1.5x104细胞)每孔中添加50μL的稀释化合物。接着将板子置于37℃培养5天。对于用MT-4细胞的抗病毒试验,将20μL用10%FBS的培养基稀释的2X检测浓度的5-倍系列稀释化合物添加到384孔板(7个浓度),重复三次。MT-4细胞接着与m.o.i.为0.1的HIV-IIIb混合,并立即将20μL的病毒/细胞混合溶液(约2000个细胞)添加的含有20μL稀释化合物的每孔中。接着将板子置于37℃培养5天。培养5天后,向含有MT-2细胞的每孔中添加100μL的CellTiter-GloTM试剂(catalog#G7571,Promega Biosciences,Inc.,Madison,WI)以及含有MT-4细胞的每孔中添加40μL。将细胞裂解液室温孵育10分钟并用化学发光读数。
对于MT-2细胞中的化合物细胞毒性试验,其操作步骤与MT-2细胞的抗病毒试验一样,所用的未感染细胞以及化合物3-倍顺序稀释除外。对于MT-4细胞中的细胞毒性试验,其操作步骤与MT-4细胞的抗病毒试验一样,未加病毒除外。
本发明的化合物具有的抗病毒EC50值(nM)范围大约是0.1-1000,或大约0.1-500,或大约0.1-300,或大约0.1-200,或大约0.1-100,或大约0.1-50,或少于500,或少于400,或少于300,或200,或少于100,或少于50,或少于20,或少于10。化合物3、5、6、9、13、14、17、25、38、46、47、54、56、57、60、70、72、73、74、76、80、86和115的EC50值少于大约10。
Claims (45)
1.一种式(I)化合物:
或其药学上可接受的盐、溶剂化物和/或酯;其中:
X和Y独立地为O或S;
A是共价键、-O-、-S-、-NR5-、-C(O)-、-C(S)-、-C(NR8)-或-C(R6)2-;
D是共价键,亚烷基、亚烯基或亚炔基;
R1是H、卤素、烷基、卤代烷基、环烷基、取代环烷基、杂环基、取代杂环基、-OH、烷氧基、-O-酰基、硫烷基、硅氧基、烯基、取代烯基、炔基、取代炔基、CN、-C(O)-N(R7)2、-O-C(O)-N(R7)2、-N(R7)-C(O)-N(R7)2、-C(O)-O烷基、-C(O)-OH、-O-C(O)-O烷基、N(R7)-C(O)-O烷基、硅氧基、-O-亚烷基-OH、-O-亚烷基-O-酰基或-S(O)2-N(R7)2;
R2是卤素、硝基、氰基、烷基、卤代烷基、取代烷基、羟烷基、烷氧基、烯基、取代烯基、炔基、或取代炔基、烷氧羰基、N(R7)2、烷基甲酰基、二烷基甲酰基、环烷基、取代环烷基、芳基烷基或取代芳基烷基;
R3是芳基或杂芳基;
R4是H、烷基、取代烷基、环烷基、取代环烷基、羟烷基、氧烷基、芳基烷基或取代芳基烷基;
R5是H、烷基、取代烷基、芳基烷基、取代芳基烷基、-OH、酰基、取代酰基;
每个R6独立地为H、烷基、环烷基、取代环烷基、羟基、烷氧基、氰基或卤素;
每个R7独立地为H、烷基、芳基、取代芳基、芳基烷基、取代芳基烷基、取代环烷基、杂芳基或取代杂芳基;
R8是H、烷基、芳基、取代芳基、OH或烷氧基;
每个Z独立地选自:卤素、硝基、羟基、氨基、乙酰氨基、三氟乙酰氨基、叠氮基、氰基、甲酰、烷基、取代烷基、烷基甲酰、二烷基甲酰、烯基、取代烯基、炔基、取代炔基、烷氧基、取代烷氧基、烷氧羰基、环烷基、取代环烷基、环烯基、取代环烯基、杂环基、取代杂环基、芳基、取代芳基、氧化物;并且
n是从0到4的整数;
附加条件如下:
(a)当X和Y同时是O,R4是H,A是-O-、-S-、-C(O)-、-CH(OH)-或-CH2-,R3是苯基,并且D是-CH2-时,那么R1不可以是烷氧基;
(b)当X和Y同时是O,A是-S-,-O-,或-C(O)-,R3是苯基,n是2,每个Z为烷基,D是-CH2-,R2是烷基,并且R4是H,
此时,R1不可以是未取代环烷基、未取代杂环烷基或未取代杂芳基;
(c)当X和Y 同时是O,A是-C(O)-,-O-或-NH-,D是-CH2-,R2是烷基,R3是苯基,n是2,R4是H,此时,R1不可以是选自吡啶基、嘧啶基和哒嗪基的取代或未取代杂芳基;
(d)当X和Y同时是O,n是0或2,每个Z为烷基,A-R3是苄基、苯甲酰基、噻吩基或苯氧基,R4是H,并且R2为乙基或异丙基,
此时,D不可以是亚烯基或亚炔基,-D-R1不可以是烷基、羟基烷基或-烃基-C(O)-O烷基;
(e)R4和-D-R1仅有一个为H。
2.式(Ia)的化合物:
或其药学上可接受的盐、溶剂化物和/或酯;其中:X和Y独立地为O或S;
A是共价键,-O-、-S-、-NR5-、-C(O)-、-C(S)-、-C(NR8)-或-C(R6)2-;
D是共价键,亚烷基、亚烯基或亚炔基;
R1是H、卤素、烷基、卤代烷基、取代环烷基、取代杂环基、-OH、-O-酰基、硫烷基、硅氧基、烯基、取代烯基、炔基、取代炔基、CN、-C(O)-N(R7)2、-O-C(O)-N(R7)2、-N(R7)-C(O)-N(R7)2、-C(O)-O烷基、-C(O)-OH、-O-C(O)-O烷基、-N(R7)-C(O)-O烷基、硅氧基、-O-亚烷基-OH、-O-亚烷基-O-酰基或-S(O)2-N(R7)2;
R2是卤素、硝基、氰基、烷基、卤代烷基、取代烷基、羟烷基、烷氧基、烯基、取代烯基、炔基或取代炔基、烷氧羰基、N(R7)2、烷基甲酰基、二烷基甲酰基、环烷基、取代环烷基、芳基烷基或取代芳基烷基;
R3是芳基或杂芳基;
R4是H、烷基、取代烷基、环烷基、取代环烷基、羟烷基、氧烷基、芳基烷基或取代芳基烷基;
R5是H、烷基、取代烷基、芳基烷基、取代芳基烷基、-OH、酰基、取代酰基;
每个R6独立地为H、烷基、环烷基、取代环烷基、羟基、烷氧基、氰基或卤素;
每个R7独立地为H、烷基、芳基、取代芳基、芳基烷基、取代芳基烷基、环烷基、取代环烷基、杂芳基或取代杂芳基;
R8是H、烷基、芳基、取代芳基、OH或烷氧基;
每个Z1独立地选自下列基团:卤素、硝基、羟基、氨基、乙酰氨基、三氟乙酰氨基、叠氮基、氰基、甲酰、烷基、取代烷基、烷基甲酰、二烷基甲酰、烯基、取代烯基、炔基、取代炔基、烷氧基、取代烷氧基、烷氧羰基、环烷基、取代环烷基、环烯基、取代环烯基、杂环基、取代杂环基、芳基、取代芳基、氧化物;
每个Z2独立地选自:卤素、硝基、羟基、氨基、乙酰氨基、三氟乙酰氨基、叠氮基、氰基、甲酰、烷基甲酰、二烷基甲酰、烯基、取代烯基、炔基、取代炔基、烷氧基、取代烷氧基、烷氧羰基、环烷基、取代环烷基、环烯基、取代环烯基、杂环基、取代杂环基、芳基、取代芳基、氧化物;
n是从0到3的整数;且R4和-D-R1只有一个是H。
3.根据权利要求1所述的化合物,其中A是-C(R6)2-。
4.根据权利要求3所述的化合物,其中A是-C(O)-。
5.根据权利要求1-4任一项所述的化合物,其中R2是烷基或卤代烷基。
6.根据权利要求1-5任一项所述的化合物,其中D是共价键或亚烷基。
7.根据权利要求1或3-6任一项所述的化合物,R1是H、烷基、卤代烷基、环烷基或取代环烷基。
8.根据权利要求1-7任一项所述的化合物,其中n至少是1,并且Z、Z1或Z2至少一个是-CN。
9.根据权利要求1-6任一项所述的化合物,其中:
D是亚烷基,亚烯基或亚炔基;并且
R1是H、卤素、烷基、取代烷基、环烷基或取代环烷基、-OH、烷氧基、-CN、-C(O)-N(R7)2、-O-亚烷基-OH、-O-亚烷基-O-酰基、-S(O)2-N(R7)2、-O-C(O)-N(R7)2、-C(O)-O烷基或-C(O)-OH。
10.根据权利要求1-9任一项所述的化合物,其中:
A是共价键、-C(NR8)-、-O-或-NR5-;
D是共价键或亚烷基;并且R2是烷基。
11.根据权利要求1-10任一项所述的化合物,其中R1是H或烷基。
12.根据权利要求1所述的化合物,其中:
X和Y同时是O;
R3是苯基;
每个Z独立地选自:-CH3、-CN、-CH=CH-CN、-CH2-CH2-CN和Cl。
n是2;
A选自-C(O)-、-C(N-OH)-、-CF2-、-CHF-、-CH(OCH3)-、-CH(CN)-、-O-和-NH-;以及
D-R1选自H、烷基、卤代烷基、环烷烷基、取代环烷烷基、羟烷基、氰烷基、-亚烷基-C(O)-N(R7)2、亚烷基-S(O2)-N(R7)2、-亚烷基-O-C(O)-N(R7)2、-亚烷基-C(O)-O烷基、-亚烷基-C(O)-OH、-亚烷基-C(O)-O烷基、-亚烷基-C(O)-N(R7)2、烷氧基、烯基、卤代烯基、炔基、环烷基炔基、取代环烷基炔基、环烷基烯基和取代环烷基烯基。
14.根据权利要求12所述的化合物,其中D-R1选自:H、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CF3、环丙基-CH2-、-CH2CH2-OH、-CH2CH2CH2-OH、-CH2CH2CH2CH2-OH、-CH2CN、-CH2CH2CN、-CH2CH2CN、-CH2C(O)NH2、-CH2CH2C(O)NH2、-CH2CH2CH2C(O)NH2、-CH2-O-CH2CH3、-CH2CH2-O-CH2CH3、-CH2CH2CH2-O-CH2CH3、-CH2CH2CH2CH2-O-CH2CH3、-CH2-O-CH3、-CH2CH2-O-CH3、-CH2CH2CH2-O-CH3、-CH2CH2CH2CH2-O-CH3、-CH2-C≡CH、-CH2-C≡C-CH3、-CH2-C≡C-环丙基、-CH2-C≡C-CH2-OH、顺式-CH2CH=CH-CH3、反式-CH2CH=CH-CH3、-CH2CH=C(CH3)2、-CH2CH2CH=C(CH3)2、-CH2CH2C(CH3)=CH2、-CH2CCl=CH(CH3)、-CH(CH3)2、-CH2CH2CH=CH2、-CH2-环丙烯基-CH2-C(O)-OCH3、-CH2-环丙烯基-CH2-C(O)-OH、-CH2-环丙烯基-CH2-C(O)-NH(PMB)、-CH2-环丙烯基-CH2-C(O)-NH2、-CH2-CH2-O-C(O)-OCH3、-CH2-CH=CH-C(O)-OCH2CH3和-CH2-CH=CH-C(O)-NH2。
15.根据权利要求13所述的化合物,其中D-R1选自:H、-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CF3、环丙基-CH2-、-CH2CH2-OH、-CH2CH2CH2-OH、-CH2CH2CH2CH2-OH、-CH2CN、-CH2CH2CN、-CH2C(O)NH2、-CH2CH2C(O)NH2、-CH2CH2CH2C(O)NH2、-CH2-O-CH2CH3、-CH2CH2-O-CH2CH3、-CH2CH2CH2-O-CH2CH3、-CH2CH2CH2CH2-O-CH2CH3、-CH2-O-CH3、-CH2CH2-O-CH3、-CH2CH2CH2-O-CH3、-CH2CH2CH2CH2-O-CH3、-CH2-C≡CH、-CH2-C≡C-CH3、-CH2-C≡C-环丙基、-CH2-C≡C-CH2-OH、顺式-CH2CH=CH-CH3、反式-CH2CH=CH-CH3、-CH2CH=C(CH3)2、-CH2CH2CH=C(CH3)2、-CH2CH2C(CH3)=CH2、-CH2CCl=CH(CH3)、-CH(CH3)2、-CH2CH2CH=CH2、-CH2-环丙烯基-CH2-C(O)-OCH3、-CH2-环丙烯基-CH2-C(O)-OH、-CH2-环丙烯基-CH2-C(O)-NH(PMB)、-CH2-环丙烯基-CH2-C(O)-NH2、-CH2-CH2-O-C(O)-OCH3、-CH2-CH=CH-C(O)-OCH2CH3和-CH2-CH=CH-C(O)-NH2。
16.根据权利要求1所述化合物,其中:
X和Y同时是O;
A是共价键;
每个Z独立地选自:-CH3、-CN和Cl;
n是2;以及
D-R1是H或烷基。
18.根据权利要求17所述的化合物,其中D-R1选自:H、-CH3、
-CH2CH3、-CH(CH3)2、-CH2CH2CH3和-CH2CH2CH2CH3。
21.一种药物组合物,其含有治疗有效剂量的权利要求1-20任一化合物以及药学上可接受的载体。
22.根据权利要求21所述的药物组合物,其还含有一种或多种其它活性药剂。
23.根据权利要求22所述的药物组合物,其中:
所述的一种或多种其它活性药剂选自HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD以及NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力增强剂、治疗HIV的其他药物以及它们的混合物。
24.根据权利要求23所述的药物组合物,其中:
(1)所述的HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
(2)所述的HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
(3)所述HIV逆转录酶核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
(4)所述逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;
(5)所述的HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir (AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
(6)所述gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
(7)所述CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
(8)所述侵入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
(9)所述gp120抑制剂选自BMS-488043及其前药、BlockAide/CR、KPC-2和MNLP62;
(10)所述G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);
(11)所述CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB 15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
(12)所述CCR8抑制剂是ZK-756326;
(13)所述RNase H抑制剂选自ODN-93和ODN-112;
(14)所述成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
(15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
(16)所述其它用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
25.一种组合药物试剂,其包含:
第一药物组分,其包括权利要求1-20任一所述的化合物,或其药学上可接受的盐、溶剂化物和/或酯;以及
第二药物组分,其包括至少一种选自下述的其它活性试剂:HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、逆转录酶类HIV核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药物动力学增强剂、其它用于治疗HIV的药物以及它们的混合物。
26.根据权利要求25所述的组合药物试剂,其中:
(1)所述的HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
(2)所述的HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355B S、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
(3)所述HIV逆转录酶核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
(4)所述逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;
(5)所述的HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir(AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elVitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
(6)所述gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
(7)所述CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
(8)所述倾入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
(9)所述gp120抑制剂选自BMS-488043和其前药、BlockAide/CR、KPC-2和MNLP62;
(10)所述G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);
(11)所述CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB 15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
(12)所述CCR8抑制剂是ZK-756326;
(13)所述RNase H抑制剂选自ODN-93和ODN-112;
(14)所述成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
(15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
(16)所述其它用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
27.一种抑制逆转录病毒复制的方法包括:用权利要求1-20任一所述的化合物,或其药学上可接受的盐、溶剂化物和/或酯接触所述逆转录病毒。
28.根据权利要求27所述的方法,其还包括:
用至少一种选自下组的其它活性药剂接触逆转录病毒:一种或多种HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、逆转录酶类HIV核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD和NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药物动力学增强剂、其他用于治疗HIV的药物以及它们的混合物。
29.根据权利要求28所述的方法,其中:
(1)所述的HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
(2)所述的HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
(3)所述HIV逆转录酶核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
(4)所述逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;
(5)所述的HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir(AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
(6)所述gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
(7)所述CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
(8)所述侵入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
(9)所述gp120抑制剂选自BMS-488043和其前药、BlockAide/CR、KPC-2和MNLP62;
(10)所述G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);
(11)所述CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
(12)所述CCR8抑制剂是ZK-756326;
(13)所述RNase H抑制剂选自ODN-93和ODN-112;
(14)所述成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
(15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
(16)所述其它用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
30.实质上如在这里所描述的一种新化合物。
31.实质上如在这里所描述和解释的权利要求1-20任一项所述的化合物。
32.实质上如在这里所描述的一种新的药物组合物或其在制备药物中的应用。
33.权利要求1-20任一项作为治疗物质的化合物。
34.权利要求1-20任一项所述的化合物在制备用于抑制病人HIV逆转录酶的药物中的应用。
35.权利要求1-20任一项所述的化合物在制备用于治疗或预防病人HIV感染的药物中的应用。
36.权利要求1-20任一项所述的化合物在制备用于治疗病人AIDS或AIDS相关综合征(ARC)的药物中的应用。
37.根据权利要求34所述的应用,其中所述药物还包含至少一种或多种其它活性药剂。
38.根据权利要求35所述的应用,其中所述的药物还包含至少一种或多种其它活性药剂。
39.根据权利要求36所述的应用,其中所述的药物还包含至少一种或多种其它活性药剂。
40.根据权利要求37所述的应用,其中所述一种或多种其它活性药剂选自:HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD以及NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力增强剂、治疗HIV的其他药物以及它们的混合物。
41.根据权利要求38所述的应用,其中所述一种或多种其它活性药剂选自:HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD以及NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力增强剂、治疗HIV的其他药物以及它们的混合物。
42.根据权利要求39所述的应用,其中所述一种或多种其它活性药剂选自:HIV蛋白酶抑制剂、HIV逆转录酶非核苷抑制剂、HIV逆转录酶核苷抑制剂、HIV逆转录酶核苷酸抑制剂、HIV整合酶抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、G6PD以及NADH-氧化酶抑制剂、CCR5抑制剂、CCR8抑制剂、侵入抑制剂、RNase H抑制剂、成熟抑制剂、药动力增强剂、治疗HIV的其他药物以及它们的混合物。
43.根据权利要求40所述的应用,其中:
(1)所述的HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
(2)所述的HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
(3)所述HIV逆转录酶核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
(4)所述逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;
(5)所述的HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir (AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir (GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
(6)所述gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
(7)所述CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
(8)所述侵入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
(9)所述gp120抑制剂选自BMS-488043和其前药、BlockAide/CR、KPC-2和MNLP62;
(10)所述G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);
(11)所述CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
(12)所述CCR8抑制剂是ZK-756326;
(13)所述RNase H抑制剂选自ODN-93、和ODN-112;
(14)所述成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
(15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
(16)所述其它用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
44.根据权利要求41所述的应用,其中:
(1)所述的HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
(2)所述的HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
(3)所述逆转录酶HIV核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
(4)所述逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;
(5)所述的HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir (AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
(6)所述gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
(7)所述CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
(8)所述侵入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
(9)所述gp120抑制剂选自BMS-488043和其前药、BlockAide/CR、KPC-2和MNLP62;
(10)所述G6PD和NADH-氧化酶抑制剂,例如,免疫素(immunitin);
(11)所述CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
(12)所述CCR8抑制剂是ZK-756326;
(13)所述RNase H抑制剂选自ODN-93和ODN-112;
(14)所述成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
(15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
(16)所述其它用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
45.根据权利要求42所述的应用,其中:
(1)所述的HIV蛋白酶抑制剂选自:安普那韦(Agenerase)、阿扎那韦(Reyataz)、夫沙那韦(Lexiva)、英迪纳瓦(Crixivan)、洛匹那韦、利托那韦(norvir)、奈非那韦(Viracept)、沙奎那韦(Invirase)、替拉那韦(Aptivus)、贝卡那韦、地瑞那韦(Prezista)、TMC-126、TMC-114、莫折那韦(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、DG17、GS-8374、MK-8122(PPL-100)、DG35和AG 1859、SPI-256、TMC 52390、PL-337、SM-322377、SM-309515、GRL-02031、CRS-074、CRS-075、KB-98和A-790742;
(2)所述的HIV逆转录酶非核苷抑制剂选自:卡普韦林、乙米韦林、地拉韦定(Rescriptor)、依发韦仑(Sustiva)、奈维拉平(Viramune)、(+)-calanolide A、calanolide B、依曲韦林(Intelence)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、MIV-160、MIV-170、dapivirine(TMC-120)、rilpivirine(TMC-278)、BILR 355BS、VRX 840773、UK-453061、和RDEA806、RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1206、LOC-dd、IQP-0410(SJ-3366)、YM-215389、YM-228855、CMX-052和CMX-182;
(3)所述HIV逆转录酶核苷抑制剂选自齐多夫定(Retrovir)、恩曲他滨(Emtriva)、地达诺新(Videx)、司他夫定(Zerit)、扎西他滨(Hivid)、拉米夫定(Epivir)、阿波卡伟(Ziagen)、amdoxovir、艾夫他滨(ACH 126443)、阿洛夫定(MIV-310)、MIV-210、racivir(racemic FTC,PSI-5004)、D-d4FC、叠氮膦、福齐夫定替酯、阿立他滨(AVX754,SPD-754)、GS-7340、KP-1461、AVX756、OBP-601、二氧胸腺嘧啶、TMC-254072、INK-20、PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108以及磷夫定酯(HDP 99.0003);
(4)所述逆转录酶类HIV核苷酸抑制剂选自富马酸泰诺福韦酯(Viread)和阿德福韦酯;
(5)所述的HIV整合酶抑制剂选自姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、tyrphostin、tyrphostin衍生物、槲皮素、槲皮素衍生物、S-1360、zintevir (AR-177)、L-870812、和L-870810、雷特格韦(Raltegravir)(Isentress,MK-0518)、elvitegravir(GS-9137)、BMS-538158、GSK364735C、BMS-707035、MK-2048、GSK-349572(S-349572)、GSK-265744(S-265744)、GSK-247303(S-247303)、S-1360(GW810871)、1,5-DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001、BFX-1002、BFX-1003、RSC-1838、BCH-33040和BA 011;
(6)所述gp41抑制剂选自恩夫韦地(Fuzeon)、西夫韦肽、MPI-451936、FB006M、A-329029和TRI-1144;
(7)所述CXCR4抑制剂选自AMD-070、KRH-3955(CS-3955)、AMD-9370、AMD-3451、RPI-MN、MSX-122和POL-2438;
(8)所述侵入抑制剂选自SP01A、PA-161、SPC3、TNX-355、DES6、SP-10、SP-03、CT-319和CT-326;
(9)所述gp120抑制剂选自BMS-488043及其前药、BlockAide/CR、KPC-2和MNLP62;
(10)所述G6PD和NADH-氧化酶抑制剂,例如,免疫素;
(11)所述CCR5抑制剂选自阿普韦罗、尼非韦罗、维克韦罗(SCH-417690)、马拉韦罗(Selzentry)、PRO-140、PRO-542、INCB15050、INCB9471、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO-1752、ZM-688523、AMD-887、YM-370749、NIBR-1282、SCH-350634、ZM-688523和CCR5mAb004;
(12)所述CCR8抑制剂是ZK-756326;
(13)所述RNase H抑制剂选自ODN-93和ODN-112;
(14)所述成熟抑制剂选自贝韦立马(PA-457)、PA-040、MPC-9055(vicecon,MPI-49839)、ACH-100703、ACH-100706;
(15)所述药动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629和罗红霉素;以及
(16)所述其它用于治疗HIV的药物选自REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、Ampligen、HRG214、Cytolin、VGX-410、VGX-820、KD-247、AMZ 0026、CYT 99007、A-221HIV、HPH-116、DEBIO-025、BAY 50-4798、MDX010(ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-367、AFX-400、BL-1050、GRN-139951、GRN-140665、AX-38679、RGB-340638、PPI-367和ALG 889。
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US93775607P | 2007-06-29 | 2007-06-29 | |
US60/937,756 | 2007-06-29 | ||
US95967607P | 2007-07-16 | 2007-07-16 | |
US60/959,676 | 2007-07-16 | ||
PCT/US2008/007925 WO2009005674A2 (en) | 2007-06-29 | 2008-06-26 | Novel hiv reverse transcriptase inhibitors |
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CN101784532A true CN101784532A (zh) | 2010-07-21 |
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US (2) | US8334295B2 (zh) |
EP (1) | EP2167476B1 (zh) |
JP (1) | JP2010532350A (zh) |
KR (1) | KR101551238B1 (zh) |
CN (1) | CN101784532B (zh) |
AR (1) | AR067181A1 (zh) |
AU (1) | AU2008271114A1 (zh) |
BR (1) | BRPI0813269A2 (zh) |
CA (1) | CA2692460A1 (zh) |
EA (1) | EA200971115A1 (zh) |
ES (1) | ES2533863T3 (zh) |
MX (1) | MX2009013804A (zh) |
TW (1) | TW200918507A (zh) |
WO (1) | WO2009005674A2 (zh) |
ZA (1) | ZA201000023B (zh) |
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- 2008-06-26 KR KR1020107002073A patent/KR101551238B1/ko active IP Right Grant
- 2008-06-26 US US12/215,450 patent/US8334295B2/en active Active
- 2008-06-26 AR ARP080102755A patent/AR067181A1/es not_active Application Discontinuation
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- 2008-06-26 TW TW097123922A patent/TW200918507A/zh unknown
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BRPI0813269A2 (pt) | 2014-12-30 |
JP2010532350A (ja) | 2010-10-07 |
EP2167476A2 (en) | 2010-03-31 |
CA2692460A1 (en) | 2009-01-08 |
EA200971115A1 (ru) | 2010-04-30 |
KR101551238B1 (ko) | 2015-09-09 |
EP2167476B1 (en) | 2015-02-25 |
WO2009005674A3 (en) | 2009-09-24 |
ES2533863T3 (es) | 2015-04-15 |
US20110076276A1 (en) | 2011-03-31 |
MX2009013804A (es) | 2010-02-03 |
CN101784532B (zh) | 2014-10-22 |
WO2009005674A2 (en) | 2009-01-08 |
KR20100041799A (ko) | 2010-04-22 |
AR067181A1 (es) | 2009-09-30 |
ZA201000023B (en) | 2011-04-28 |
AU2008271114A1 (en) | 2009-01-08 |
US20130078256A1 (en) | 2013-03-28 |
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