CN101490023B - 治疗剂的药代动力学特性调节剂 - Google Patents
治疗剂的药代动力学特性调节剂 Download PDFInfo
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- CN101490023B CN101490023B CN2007800256073A CN200780025607A CN101490023B CN 101490023 B CN101490023 B CN 101490023B CN 2007800256073 A CN2007800256073 A CN 2007800256073A CN 200780025607 A CN200780025607 A CN 200780025607A CN 101490023 B CN101490023 B CN 101490023B
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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Abstract
本申请提供了式I的化合物,
Description
发明领域
本申请一般涉及改变,例如改善了共同给药的药物的药代动力学的化合物和药物组合物,并且涉及通过共同给予所述化合物与所述药物改变,例如改善药物的药代动力学的方法。
发明背景
细胞色素P450酶的氧化代谢为药物代谢的主要机制之一。难以维持由细胞色素P450酶快速代谢的药物的治疗有效血浆水平。因此,可以通过共同给予细胞色素P450抑制剂维持或提高对细胞色素P450酶降解敏感的药物的血浆水平,由此改善药物的药代动力学。
尽管已知某些药物抑制细胞色素P450酶,但是更多和/或改进的细胞色素P450单加氧酶是需要的。特别地,需要拥有不具有非细胞色素P450抑制作用的可感觉到的生物活性的细胞色素P450单加氧酶抑制剂。这类抑制剂可以用于将不需要的生物活性,例如副作用减少至最低限度。此外,需要拥有缺乏明显或具有降低水平的蛋白酶抑制剂活性的P450单加氧酶抑制剂。这类抑制剂可以用于增强抗逆转录病毒药物的有效性,同时将引起病毒抗性,尤其是对蛋白酶抑制剂的抗性的可能性减小至最低限度。
发明概述
本申请的一个方面涉及例如通过抑制细胞色素P450单加氧酶改变,例如改善共同给药的药物的药代动力学的化合物和药物组合物。
本申请在一个实施方案中提供了具有式I结构的化合物:
式I
或其药学上可接受的盐,溶剂合物和/或酯,其中,
L1选自-C(R6)2-,-C(O)-,-S(O)2-,-N(R7)-C(O)-和-O-C(O)-;
L2为共价键,-C(R6)2-或-C(O)-;
L3各自独立为共价键,亚烷基或取代的亚烷基;
L4各自独立地选自共价键,亚烷基,取代的亚烷基,-O-,-CH2-O-和-NH-;
A各自独立地选自H,烷基,取代的烷基,芳基,取代的芳基,杂环基和取代的杂环基,
条件是当A为H时,p为0;
Z1和Z2各自独立为-O-或-N(R7)-;
Y和X独立地选自杂环基和杂环基烷基;
Ar各自独立地选自芳基,取代的芳基,杂芳基和取代的杂芳基;
R1,R3和R5各自独立地选自H,烷基,取代的烷基,芳基烷基和取代的芳基烷基;
R2各自独立地选自H,烷基,取代的烷基,烷氧基烷基,羟基烷基,芳基杂烷基,取代的芳基杂烷基,芳基烷基,取代的芳基烷基,杂环基烷基,取代的杂环基烷基,氨基烷基,取代的氨基烷基,-亚烷基-C(O)-OH,-亚烷基-C(O)-O烷基,-亚烷基-C(O)氨基,-亚烷基-C(O)-烷基;
R4和R6独立地选自H,烷基,取代的烷基和杂烷基;
R7各自独立地选自H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基和取代的杂环基;
R8和R9各自为一个或多个取代基,其独立地选自H,烷基,取代的烷基,卤素,芳基,取代的芳基,杂环基,取代的杂环基和-CN;
m为1或2;
n为0或1;且
p各自独立为0或1。
本申请在另一个实施方案中提供了包含式I的化合物和药学上可接受的载体或赋形剂的药物组合物。
本申请在另一个实施方案中提供了包含式I的化合物,至少一种额外的治疗剂和药学上可接受的载体或赋形剂的药物组合物。
本申请在另一个实施方案中提供了改善药物的药代动力学的方法,包括对使用所述药物治疗的患者给予治疗有效量的式I的化合物,或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了抑制患者细胞色素P450单加氧酶的方法,包括对有此需要的患者给予有效抑制细胞色素P450单加氧酶的用量的式I的化合物,或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了治疗病毒感染,例如H I V的方法,包括对有此需要的患者给予治疗有效量的式I的化合物,或其药学上可接受的盐,溶剂合物和/或酯与治疗有效量的一种或多种额外的治疗剂的组合,所述的一种或多种额外的治疗剂被细胞色素P450单加氧酶代谢并且适合于治疗病毒感染,例如HIV。
本申请在另一个实施方案中提供了包括如下组分的联用药剂:
a)包含式I的化合物,或其药学上可接受的盐,溶剂合物和/或酯的第一种药物组合物;和
b)包含至少一种额外的被细胞色素P450单加氧酶代谢的活性剂的第二种药物组合物。
详细描述
现在涉及针对本发明某些权利要求的详细描述,其中的实例例证在附加的结构和式中。尽管会结合列出的权利要求描述本发明,但是可以理解并非指定它们将本发明限定到那些权利要求。相反,本发明意图是覆盖所有的可选择方案,变型和等效方案,它们包括在如权利要求定义的本发明范围内。
定义
除非另作陈述,否则指定本文所用的术语和措辞具有如下含义:
当在本文中使用商品名时,申请人独立地指定包括商品名的产品和该商品名产品的活性药物组分。
本文所用的″本发明的化合物″或″式(I)的化合物″意旨式(I)的化合物或其药学上可接受的盐,溶剂合物,酯或立体异构体或其生理功能衍生物。类似地,就可分离的中间体而言,措辞″式(编号)的化合物″意旨该式的化合物及其药学上可接受到盐,溶剂合物和生理功能衍生物。
“烷基”为含正,仲,叔或环碳原子的烃。例如,烷基可以具有1-20个碳原子(即C1-C20烷基),1-10个碳原子(即C1-C10烷基)或1-6个碳原子(即C1-C6烷基)。合适的烷基的实例包括,但不限于甲基(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-戊基(n-戊基,-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-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-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3和辛基(-(CH2)7CH3)。
“烷氧基”意旨具有式-O-烷基的基团,其中如上述定义的烷基通过氧原子与母体分子连接。烷氧基的烷基部分可以具有1-20个碳原子(即C1-C20烷氧基),1-12个碳原子(即C1-C12烷氧基)或1-6个碳原子(即C1-C6烷氧基)。合适的烷氧基的实例包括,但不限于甲氧基(-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”为如上述定义的烷基,其中烷基的一个或多个氢原子被卤原子取代。卤代烷基的烷基部分可以具有1-20个碳原子(即C1-C20卤代烷基),1-12个碳原子(即C1-C12卤代烷基)或1-6个碳原子(即C1-C6烷基)。合适的卤代烷基的实例包括,但不限于-CF3,-CHF2,-CFH2,-CH2CF3等。
“链烯基”为含正,仲,叔或环碳原子与至少一个不饱和位置,即碳-碳sp2双键的烃。例如,链烯基可以具有2-20个碳原子(即C2-C20链烯基),2-12个碳原子(即C2-C12链烯基)或2-6个碳原子(即C2-C6链烯基)。合适的链烯基的实例包括,但不限于乙烯基(ethylene)或乙烯基(vinyl)(-CH=CH2),烯丙基(-CH2CH=CH2),环戊烯基(-C5H7)和5-己烯基(-CH2CH2CH2CH2CH=CH2)。
“炔基”为含正,仲,叔或环碳原子与至少一个不饱和位置,即碳-碳sp三键的烃。例如,炔基可以具有2-20个碳原子(即C2-C20炔基),2-12个碳原子(即C2-C12炔)或2-6个碳原子(即C2-C6炔基)。合适的炔基的实例包括,但不限于乙炔(-C≡CH),炔丙基(-CH2C≡CH)等。
“亚烷基”意旨具有2个通过从母体烷的相同或两个不同碳原子上除去两个氢原子衍生的一价基团中心的饱和支链或直链或环状烃基。例如,亚烷基可以具有1-20个碳原子,1-10个碳原子或1-6个碳原子。典型的亚烷基包括,但不限于亚甲基(-CH 2-),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。
“亚烯基”意旨具有2个通过从母体烯的相同或两个不同碳原子上除去两个氢原子衍生的一价基团中心的不饱和支链或直链或环状烃基。例如,亚烯基可以具有1-20个碳原子,1-10个碳原子或1-6个碳原子。典型的亚烯基包括,但不限于1,2-乙基(-CH=CH-)。
“亚炔基”意旨具有2个通过从母体炔的相同或两个不同碳原子上除去两个氢原子衍生的一价基团中心的不饱和支链或直链或环状烃基。例如,亚炔基可以具有1-20个碳原子,1-10个碳原子或1-6个碳原子。典型的亚炔基包括,但不限于乙炔(-C≡C-),炔丙基(-CH2C≡C-)和4-戊炔基(-CH2CH2CH2C≡CH-)。
“氨基”意旨-NH2或-NR2基团,其中“R”基团独立为H,烷基,碳环基(取代或未取代的,包括饱和或部分不饱和的环烷基和芳基),杂环基(取代或未取代的,包括饱和或不饱和的杂环烷基和杂芳基),芳基烷基(取代或未取代的)或芳基烷基(取代或未取代的)。氨基的非限制性实例包括-NH2,-NH(烷基),-NH(碳环基),-NH(杂环基),-N(烷基)2,-N(碳环基)2,-N(杂环基)2,-N(烷基)(碳环基),-N(烷基)(杂环基),-N(碳环基)(杂环基)等,其中烷基,碳环基和杂环基可以被取代或未取代并且如本文定义和描述。“取代的”或“被保护的”氨基意旨如本文所述和定义的氨基烷基,其中氨基的H被例如酰基取代,例如常用胺保护基,诸如氨基甲酸9-芴基甲酯(“Fmoc”),氨基甲酸叔丁酯(“Boc”),氨基甲酸苄酯(“Cbz”),乙酰基,三氟乙酰基,邻苯二酰亚胺基,三苯甲基,对-甲苯磺酰基(“甲苯磺酰基”),甲基磺酰基(“甲磺酰基”)等。
“氨基烷基”意旨无环烷基,其中与碳原子,一般为末端或sp3碳原子键合的氢原子之一被如本文定义和描述的氨基取代。氨基烷基的非限制性实例包括-CH2-NH2,-CH2CH2-NH2,-CH2CH2CH2-NH2,-CH2CH2CH2CH2-NH2,-CH2CH(CH3)-NH2,-CH2CH2CH(CH3)-NH2,-CH2-NH(CH3),-CH2CH2-NH(CH3),-CH2CH2CH2-NH(CH3),-CH2CH2CH2CH2-NH(CH3),-CH2CH(CH3)-NH(CH3),-CH2CH2CH(CH3)-NH(CH3),-CH2-N(CH3)2,-CH2CH2-N(CH3)2,-CH2CH2CH2-N(CH3)2,-CH2CH2CH2CH2-N(CH3)2,-CH2CH(CH3)-N(CH3)2,-CH2CH2CH(CH3)-N(CH3)2,-CH2-NH(CH2CH3),-CH2CH2-NH(CH2CH3),-CH2CH2CH2-NH(CH2CH3),-CH2CH2CH2CH2-NH(CH2CH3),-CH2CH(CH3)-NH(CH2CH3),-CH2CH2CH(CH3)-NH(CH2CH3),-CH2-N(CH2CH3)2,-CH2CH2-N(CH2CH3)2,-CH2CH2CH2-N(CH2CH3)2,-CH2CH2CH2CH2-N(CH2CH3)2,-CH2CH(CH3)-N(CH2CH3)2,-CH2CH2CH(CH3)-N(CH2CH3)2等。“取代的”或“被保护的”氨基烷基意旨如本文所述和定义的氨基烷基,其中氨基的H被,例如酰基取代,例如常用胺保护基,诸如氨基甲酸9-芴基甲酯(“Fmoc”),氨基甲酸叔丁酯(“Boc”),氨基甲酸苄酯(“Cbz”),乙酰基,三氟乙酰基,邻苯二酰亚胺基,三苯甲基,对-甲苯磺酰基(“甲苯磺酰基”),甲基磺酰基(“甲磺酰基”)等。
“芳基”意旨通过从母体芳族环系的单一碳原子上除去一个氢原子衍生的芳族烃基。例如,芳基可以具有6-20个碳原子,6-14个碳原子或6-12个碳原子。典型的芳基包括,但不限于衍生自苯(例如苯基),取代的苯,萘,蒽,联苯的基团等。
“芳基烷基”意旨无环烷基,其中与碳原子,一般为末端或sp3碳原子键合的氢原子之一被芳基取代。典型的芳基烷基包括,但不限于苄基,2-苯乙-1-基,萘基甲基,2-萘乙-1-基,萘并苄基,2-萘并苯乙-1-基等。芳基烷基可以包含6-20个碳原子,例如烷基部分为1-6个碳原子且芳基部分为6-14个碳原子。
“芳基链烯基”意旨无环链烯基,其中与碳原子,一般为末端或sp3碳原子,而且还有sp2碳原子键合的氢原子之一被芳基取代。芳基链烯基的芳基部分可以包括,例如本文披露的任意芳基,且芳基链烯基的链烯基部分可以包括,例如本文披露的任意链烯基。芳基链烯基可以包含6-20个碳原子,例加链烯基部分为1-6个碳原子且芳基部分为6-14个碳原子。
“芳基炔基”意旨无环炔基,其中与碳原子,一般为末端或sp3碳原子,而且还有sp碳原子键合的氢原子之一被芳基取代。芳基炔基的芳基部分可以包括,例如本文披露的任意芳基,且芳基炔基的炔基部分可以包括,例如本文披露的任意炔基。芳基炔基可以包含6-20个碳原子,例如炔基部分为1-6个碳原子且芳基部分为6-14个碳原子。
涉及烷基,亚烷基,芳基,芳基烷基,杂环基,杂芳基,碳环基等的术语“取代”,例如,“取代的烷基”,“取代的亚烷基”,“取代的芳基”,“取代的芳基烷基”,“取代的杂环基”和“取代的碳环基”分别意旨烷基,亚烷基,芳基,芳基烷基,杂环基,碳环基,其中一个或多个氢原子各自独立地被非-氢取代基取代。典型的取代基包括,但不限于-X,-R,-O-,=O,-OR,-SR,-S-,-NR2,-N+R3,=NR,-CX 3,-CN,-OCN,-SCN,-N=C=O,-NCS,-NO,-NO2,=N2,-N3,-NHC(=O)R,-NHS(=O)2R,-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,-P(=O)(OR)2,-P(=O)(O-)2,-P(=O)(OH)2,-P(O)(OR)(O-),-C(=O)R,-C(=O)OR,-C(=O)X,-C(S)R,-C(O)OR,-C(O)O-,-C(S)OR,-C(O)SR,-C(S)SR,-C(O)NRR,-C(S)NRR,-C(=NR)NRR,其中X各自独立为卤素:F,Cl,Br或I;且R各自独立为H,烷基,芳基,芳基烷基,杂环或保护基或前体药物部分。亚烷基,亚烯基和亚炔基也可以类似地被取代。当对保护基指定碳原子数时,碳原子数意旨基团,而非取代基(除非另作陈述)。例如,C1-4取代的烷基意旨C1-4烷基,它可以被具有更多,例如4个碳原子的基团取代。
本文所用的术语“前体药物”意旨任意的化合物,在对生物系统给药时,作为自发化学反应,酶催化化学反应,光解和/或代谢化学反应的结果,它生成药物物质,即活性组分。前体药物由此为治疗活性化合物的共价修饰的类似物或潜伏形式。
本领域技术人员公认应选择式I化合物的取代基和其它部分以便提供足以稳定提供药学有用化合物的化合物,所述药学有用的化合物可以被配制成可接受的稳定药物组合物。预期具有这类稳定性的式I的化合物为属于本发明的范围。
“杂烷基”意旨烷基,其中一个或多个碳原子被杂原子,诸如O,N或S取代。例如,如果与母体分子连接的烷基的碳原子被杂原子(例如O,N或S)取代,那么所得杂烷基分别为烷氧基(例如-OCH3等),胺(例如-NHCH3,-N(CH3)2等)或硫代烷基(例如-SCH3)。如果不与母体分子连接的烷基的非-末端碳原子被杂原子(例如O,N或S)取代,那么所得杂烷基分别为烷基醚(例如-CH2CH2-O-CH3等),烷基胺(例如-CH2NHCH3,-CH2N(CH3)2等)或硫代烷基醚(例如-CH2-S-CH3)。如果烷基的末端碳原子被杂原子(例如O,N或S)取代,那么所得杂烷基分别为羟基烷基(例如-CH2CH2-OH),氨基烷基(例如-CH2NH2)或烷硫基(例如-CH2CH2-SH)。杂烷基可以具有例如,1-20个碳原子,1-10个碳原子或1-6个碳原子。C1-C6杂烷基意旨具有1-6个碳原子的杂烷基。
本文所用的“杂环”或“杂环基”作为实例包括,但不限于描述在下列文献中的那些杂环:Paquette,Leo A.;Principles of Modern Heterocyclic Chemistry(W.A.Benjamin,New York,1968),特别是Chapters 1,3,4,6,7和9;The Chemistry of Heterocyclic Compounds,A Series of Monographs”(John Wiley&Sons,New York,1950 to present),特别是Volumes 13,14,16,19和28;和J.Am.Chem.Soc.(1960)82:5566。在本发明的一个具体的实施方案中,“杂环”包括如本文定义的“碳环”,其中一个或多个(例如1,2,3或4)个碳原子被杂原子(例如O,N或S)取代。术语“杂环”或“杂环基”包括饱和环,部分不饱和环和芳族环(即杂芳族环)。取代的杂环基包括,例如,被本文披露的任意取代基取代的杂环包括羰基。羰基取代基的杂环基的非限制性实例为:
杂环的实例作为实例且不限于吡啶基,二羟基吡啶基,四氢吡啶基(哌啶基),噻唑基,四氢苯硫基,硫氧化的四氢苯硫基,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,噻萘基,吲哚基,indolenyl,喹啉基,异喹啉基,苯并咪唑基,哌啶基,4-哌啶酮基,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(azocinyl),三嗪基,6H-1,2,5-噻二嗪基,2H,6H-1,5,2-二噻嗪基,噻吩基,噻蒽基(thianthrenyl),吡喃基,异苯并呋喃基,色烯基,呫吨基,酚黄素基(phenoxathinyl),2H-吡咯基,异噻唑基,异噁唑基,吡嗪基,哒嗪基,吲嗪基,异吲哚基,3H-吲哚基,1H-吲唑基,嘌呤基,4H-喹嗪基,酞嗪基,萘啶基,喹喔啉基,喹唑啉基,噌啉基,蝶啶基,4aH-咔唑基,咔唑基,β-咔啉基,菲啶基,吖啶基,嘧啶基,菲咯啉基,吩嗪基,吩噻嗪基,呋咱基,吩噁嗪基,异苯并二氢吡喃基,苯并二氢吡喃基,咪唑烷基,咪唑啉基,吡唑烷基,吡唑啉基,哌嗪基,二氢吲哚基,异二氢吲哚基,奎宁环基,吗啉基,噁唑烷基,苯并三唑基,苯并异噁唑基,羟吲哚基,苯并噁唑啉基,靛红酰基(isatinoyl)和双-四氢呋喃基:
作为实例且并不限于此,碳键合的杂环键合在吡啶的2,3,4,5或6位上,哒嗪的3,4,5或6位上,嘧啶的2,4,5或6位上,吡嗪的2,3,5或6位上,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位上,噁唑,咪唑或噻唑的2,4或5位上,异噁唑,吡唑或异噻唑的3,4或5位上,氮丙啶的2或3位上,氮杂环丁烷的2,3或4位上,喹啉的2,3,4,5,6,7或8位上或异喹啉的1,3,4,5,6,7或8位上。更一般地,碳键合的杂环包括2-吡啶基,3-吡啶基,4-吡啶基,5-吡啶基,6-吡啶基,3-哒嗪基,4-哒嗪基,5-哒嗪基,6-哒嗪基,2-嘧啶基,4-嘧啶基,5-嘧啶基,6-嘧啶基,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。
作为实例且并不限于此,氮键合的杂环键合在氮丙啶,氮杂环丁烷,吡咯,吡咯烷,2-吡咯啉,3-吡咯啉,咪唑,咪唑烷,2-咪唑啉,3-咪唑啉,吡唑,吡唑啉,2-吡唑啉,3-吡唑啉,哌啶,哌嗪,吲哚,二氢吲哚,1H-吲唑的1位上,异吲哚或异二氢吲哚的2位上,吗啉的4位上和咔唑或β-咔啉的9位上。更一般地,氮键合的杂环包括1-吖啶基(1-aziridyl),1-氮杂环丁二烯基(azetedyl),1-吡咯基,1-咪唑基,1-吡唑基和1-哌啶基。
“杂环基烷基”意旨无环烷基,其中与碳原子键合的氢原子之一,一般为末端或sp3碳原子被杂环基基团取代(即杂环基-亚烷基-部分)。典型的杂环基烷基包括,但不限于杂环基-CH2-,杂环基-CH(CH3)-,杂环基-CH2CH2-,2-(杂环基)乙-1-基等,其中“杂环基”部分包括上述任意的杂环基,包括描述在Principles of Modern Heterocyclic Chemistry中的那些。本领域技术人员还可以理解杂环基可以通过碳-碳键或碳-杂原子键与杂环基烷基的烷基部分连接,只要所得基团为化学稳定的。杂环基烷基包含2-20个碳原子,例如杂环基烷基的烷基部分为1-6个碳原子且杂环基部分为1-14个碳原子。杂环基烷基的实例作为实例包括,但不限于5-元含硫,氧和/或氮杂环,诸如噻唑基甲基,2-噻唑基乙-1-基,咪唑基甲基,噁唑基甲基,噻二唑甲基等,6-元含硫,氧和/或氮杂环,诸如哌啶基甲基,哌嗪基甲基,吗啉基甲基,吡啶基甲基(pyridizylmethyl),吡啶基甲基,嘧啶基甲基,吡嗪基甲基等。
“杂环基烯基”意旨无环链烯基,其中与碳原子键合的氢原子之一,一般为末端或sp3碳原子,还有sp2碳原子被杂环基基团取代(即杂环基-亚链烯基-部分)。杂环基链烯基的杂环基部分包括本文所述的任意杂环基,包括描述在Principles of Modern Heterocyclic Chemistry中的那些;杂环基链烯基的链烯基部分包括本文披露的任意链烯基。本领域技术人员还可以理解杂环基可以通过碳-碳键或碳-杂原子键与杂环基链烯基的链烯基部分连接,只要所得基团为化学稳定的。杂环基链烯基包含3-20个碳原子,例如杂环基链烯基的链烯基部分为2-6个碳原子且杂环基部分为1-14个碳原子。
“杂环基炔基”意旨无环炔基,其中与碳原子键合的氢原子之一,一般为末端或sp3碳原子,还有s p碳原子被杂环基基团取代(即杂环基-亚炔基-部分)。杂环基炔基的杂环基部分包括本文所述的任意杂环基,包括描述在Principles of Modern Heterocyclic Chemistry中的那些,且杂环基炔基的炔基部分包括本文披露的任意炔基。本领域技术人员还可以理解杂环基可以通过碳-碳键或碳-杂原子键与杂环基炔基的炔基部分连接,只要所得基团为化学稳定的。杂环基炔基包含3-20个碳原子,例如杂环基炔基的炔基部分为2-6个碳原子且杂环基部分为1-14个碳原子。
“杂芳基”意旨在环上具有至少一个杂原子的芳族杂环基。可以在芳族环上包括的合适的杂原子的非限制性实例包括氧,硫和氮。杂芳基环的非限制性实例包括“杂环基”定义中所列的所有那些,包括吡啶基,吡咯基,噁唑基,吲哚基,异吲哚基,嘌呤基,呋喃基,噻吩基,苯并呋喃基,苯并苯硫基,咔唑基,咪唑基,噻唑基,异噁唑基,吡唑基,异噻唑基,喹啉基,异喹啉基,哒嗪基,嘧啶基,吡唑基等。
“碳环”或“碳环基”意旨具有3-7个碳原子作为单环,7-12个碳原子作为双环和约达20个碳原子作为多环的饱和(即环烷基),部分不饱和(例如环烯基,环烷二烯基等)或芳族环。单环碳环具有3-6个环原子,更一般的是5或6个环原子。双环碳环具有7-12个环原子,例如排列为双环[4,5],[5,5],[5,6]或[6,6]系统;或9或10环个原子,排列为双环[5,6]或[6,6]系统或螺-稠合环。单环碳环的非限制性实例包括环丙基,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-烯基和苯基。双环碳环的非限制性实例包括萘基。
“芳基杂烷基”意旨如本文定义的杂烷基,其中氢原子(可以与碳原子或杂原子连接)被如本文定义的芳基取代。芳基可以与杂烷基的碳原子或杂烷基的杂原子键合,只要所得芳基杂烷基提供化学上合适的部分。例如,芳基杂烷基可以具有通式-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。此外,上述通式中的任意亚烷基部分可以进一步被本文定义或例举的任意取代基取代。
“杂芳基烷基”意旨如本文定义的烷基,其中氢原子被如本文定义的杂芳基取代。杂芳基烷基的非限制性实例包括-CH2-吡啶基,-CH2-吡咯基,-CH2-噁唑基,-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-苯并苯硫基,-CH2-咔唑基,-CH2-咪唑基,-CH2-噻唑基,-CH2-异噁唑基,-CH2-吡唑基,-CH2-异噻唑基,-CH2-喹啉基,-CH2-异喹啉基,-CH2-哒嗪基(pyridazyl),-CH2-嘧啶基,-CH2-吡嗪基(pyrazyl),-CH(CH3)-吡啶基,-CH(CH3)-吡咯基,-CH(CH3)-噁唑基,-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)-苯并硫苯基,-CH(CH3)-咔唑基,-CH(CH3)-咪唑基,-CH(CH3)-噻唑基,-CH(CH3)-异噁唑基,-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(pyridazyl),-CH(CH3)-嘧啶基,-CH(CH3)-吡嗪基(pyrazyl)等。
涉及式I化合物的具体部分的术语“任选取代的”(例如任选取代的芳基)意旨具有0,1,2或多个取代基的部分。
“Ac”意旨乙酰基(-C(O)CH3)。
“Ac2O”意旨乙酐。
“DCM”意旨二氯甲烷(CH2Cl2)。
“DIBAL”意旨二异丁基氢化铝。
“DMAP”意旨二甲基氨基吡啶。
“EDC”意旨1-(3-二甲基氨基丙基)-3-乙基碳二亚胺。
“Et”意旨乙基。
“EtOAc”意旨乙酸乙酯。
“HOBt”意旨N-羟基苯并三唑。
“Me”意旨甲基(-CH3)。
“MeOH”意旨甲醇。
“MeCN”意旨乙腈。
“Pr”意旨丙基。
“i-Pr”意旨异丙基(-CH(CH3)2)。
“i-PrOH”意旨异丙醇。
“rt”意旨室温。
“TFA”意旨三氟乙酸。
“THF”意旨四氢呋喃。
术语“手性”意旨具有不能重叠的镜像的配偶体的特性的分子,而术语“非手性”意旨在其镜像配偶体上可重叠的分子。
术语“立体异构体”意旨具有相同化学组成,但在原子或基团的空间排列方面不同的化合物。
“非对映体”意旨具有两个或多个手性中心且其分子彼此为非镜像的立体异构体。非对映体具有不同的物理特性,例如熔点,沸点,光谱特性和反应性。非对映体的混合物可以在高拆分分析操作,诸如电泳和色谱法中分离。
“对映体”意旨彼此为不能重叠的镜像的化合物的两种立体异构体。
本文所用的立体化学定义和规定一般遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York;和Eliel,E.和Wilen,S.,Stereochemistry of Organic Compound(1994)John Wiley&Sons,Inc.,New York。许多有机化合物以旋光形式存在,即它们具有沿平面偏振光平面旋转的能力。在描述旋光活性化合物中,前缀D和L或R和S用于表示该分子有关其手性中心的绝对构型。前缀d和l或(+)和(-)用于表示该化合物沿平面偏振光平面旋转的标记,其中(-)或1意旨该化合物为左旋的。以(+)或d为前缀的化合物为右旋的。就指定的化学结构而言,这些立体异构体相同,除外它们彼此为镜像的情况。具体的立体异构体还可以称作对映体且这类异构体的混合物通常称作对映体混合物。对映体的50∶50混合物称作外消旋混合物或外消旋物,它们可以存在,其中在化学反应或过程中无立体选择性或立体特异性。术语“外消旋混合物”和“外消旋物”意旨两种无旋光性的对映体种类的等摩尔混合物。
保护基
在本发明的上下文中,保护基包括前体药物部分和化学保护基。
保护基为可得到的,通常已知的和使用的并且任选用于防止在合成操作,即制备本发明化合物的途径或方法过程中与被保护基团的副反应。在很大程度上,关于保护哪一个基团,何时这样做的决定和化学保护基“PG”的性质取决于被保护反应的化学(例如酸性,碱性,氧化性,还原性或其它条件)和指定的合成方向。PG基团无需相同且一般不同,只要化合物被多个PG取代。一般而言,PG用于保护官能基,诸如羧基,羟基,硫代或氨基且由此防止副反应乃至有利于合成效率。脱保护产生游离脱保护基团的顺序取决于指定的合成方向和遇到的反应条件,并且可以按照本领域技术人员确定的任意顺序进行。
可以保护本发明化合物的各种官能基。例如,-OH基团的保护基(无论是羟基,羧酸,膦酸还是其它官能基)包括“醚-或酯-形成基团”。醚-或酯-形成基团能够在如本文所述的合成方案中起化学保护基的作用。然而,某些羟基和硫代保护基既非醚-,也非酯-形成基团,正如本领域技术人员可以理解的并且包括下述酰胺类。
大量羟基保护基和酰胺形成基团和相应的化学裂解反应描述在Protective Groups in Organic Synthesis,Theodora W.Greene和Peter G.M.Wuts(John Wiley&Sons,Inc.,New York,1999,ISBN0-471-16019-9)(“Greene”)中。另外参见Kocienski,Philip J.;Protecting Groups(Georg Thieme Verlag Stuttgart,New York,1994),将这些文献完整地引入本文作为参考。特别是Chapter 1,Protecting Groups:AnOverview,1-20页,Chapter 2,HydroxylProtecting Groups,21- hapter3,Diol Protecting Groups,95-117页,Chapter 4,Carboxyl Protecting Groups,118-154页,Chapter 5,Carbonyl Protecting Groups,155-184页。就羧酸,膦酸,膦酸酯、磺酸的保护基和其它酸保护基而言,参见如下文Greene所述。这类基团作为实例包括且不限于酯类,酰胺类,酰肼类等。
醚-和酯-形成保护基
酯-形成基团包括:(1)膦酸酯-形成基团,诸如膦酸酰胺酯类(phosphonamidate esters),硫代磷酸酯类,磷酸酯类和膦酸双-酰胺化物类(phosphon-bis-amidates);(2)羧基酯-形成基团;和(3)硫酯-形成基团,诸如磺酸酯,硫酸酯和亚磺酸酯。
本发明化合物的代谢物
在本发明范围内还有本文所述化合物的体内代谢产物。这类产物可以例如因给予化合物的氧化,还原,水解,酰胺化,酯化等,主要因酶促过程而产生。因此,本发明包括通过一种方法生产的化合物,该方法包括使本发明的化合物接触哺乳动物足以产生其代谢产物的时间期限。这类产物一般通过下列步骤来鉴定:制备放射性标记的本发明(例如C14或H3)化合物,将其通过非肠道以可检测剂量(例如大于约0.5mg/kg)给予动物,诸如大鼠,小鼠,豚鼠,猴子或人,进行足以发生代谢的时间(一般约30秒-30小时)并且从尿,血或其它生物样品中分离其转化产物。易于分离这些产物,因为它们被标记(其它产物通过使用能够结合在代谢物中存留的表位的抗体分离)。按照常规方式,例如通过MS或NMR分析测定代谢物结构。一般而言,按照与本领域技术人员众所周知的常规药物代谢研究相同的方式进行代谢物分析。只要转化产物并非在体内额外发现,那么它们就在用于本发明化合物治疗给药的诊断试验中有用,即使它们自身无抗感染活性。
式I的化合物
本申请在一个实施方案中提供了如本文所述的式I的化合物。
在式I化合物的另一个实施方案中,n为1。
在式I化合物的另一个实施方案中,n为0。
在式I化合物的另一个实施方案中,n为1且L2为-CH(R6)-,其中R6选自H,烷基,取代的烷基和杂烷基。
在式I化合物的另一个实施方案中,n为1且L2为-CH2-。
在式I化合物的另一个实施方案中,n为1且L2为-C(O)-。
在式I化合物的另一个实施方案中,n为1且Y为杂环基烷基。
在式I化合物的另一个实施方案中,n为1且Y-R8为-CH2-(取代的杂芳基)。
在式I化合物的另一个实施方案中,n为1且Y-R8为
在式I化合物的另一个实施方案中,n为1且Y-R8为
其中R8为烷基,例如2-丙基。
在式I化合物的另一个实施方案中,n为1且X为杂环基烷基。
在式I化合物的另一个实施方案中,n为1且X为-CH2-杂芳基。
在式I化合物的另一个实施方案中,n为1且X-R9为
在式I化合物的另一个实施方案中,n为1且X-R9为
在式I化合物的另一个实施方案中,n为1且Z1为-N(R7)-。
在式I化合物的另一个实施方案中,n为1且Z1为-N(烷基)-或-N(碳环基)-。
在式I化合物的另一个实施方案中,n为1且Z1为-N(CH3)-或-N(环丙基)-。
在式I化合物的另一个实施方案中,n为1且Z1为-NH-。
在式I化合物的另一个实施方案中,n为1且A各自独立为芳基或取代的芳基。
在式I化合物的另一个实施方案中,n为1且A为苯基。
在式I化合物的另一个实施方案中,n为1且A各自为苯基且p各自为0。
在式I化合物的另一个实施方案中,n为1且R2为H,烷基,取代的烷基或杂烷基。
在式I化合物的另一个实施方案中,n为1且R2为2-丙基,甲基,-CH2-O-苄基,-CH(CH3)(O-t-Bu)或-CH(CH3)(OH)。
在式I化合物的另一个实施方案中,L1为-C(O)-;
A各自独立为芳基,取代的芳基,烷基或取代的烷基;
R1为H或烷基;
R2各自独立为H,烷基,取代的烷基或杂烷基;
R3,R4,R5和R6各自为H;
R7各自独立为H,烷基或碳环基;
R8为H或烷基;
R9为H;
X和Y均为杂环基烷基;
Z2为-O-;且
p为0。
在式I化合物的另一个实施方案中,A各自为苯基;
R1为H或-CH 3;
R2各自为H,甲基,乙基,2-丙基,-CH2-O-苄基,-CH(CH3)-OH或-CH(CH3)(O-t-Bu);
R7各自为H,甲基或环丙基;
R8为H或2-丙基;
X为
Y为
在另一个实施方案中,式I的化合物具有如下通式IA:
式IA。
在式IA化合物的另一个实施方案中,Z1为-N(R7)-。在一个具体的实施方案中,R7为H。在另一个具体的实施方案中,R7为烷基,例如本文披露的任意烷基。在另一个具体的实施方案中,R7为杂烷基,例如本文披露的任意杂烷基。在另一个具体的实施方案中,R7为取代或未取代的碳环基,其中例如,所述的碳环基为本文披露的任意碳环基。在另一个具体的实施方案中,R7为取代或未取代的杂环基,其中例如,所述的杂环基为本文披露的任意杂环基。
在式IA化合物的另一个实施方案中,Z1为-O-。
在式IA化合物的另一个实施方案中,L2为-C(R6)2-,其中R6各自为H。
在式IA化合物的另一个实施方案中,L2为-C(R6)2-,其中R6各自独立为H或烷基且所述的烷基包括本文披露的任意烷基。
在式IA化合物的另一个实施方案中,L2为-C(R6)2-,其中一个R6为H且另一个R6为烷基,其中所述的烷基包括本文披露的任意烷基。
在式IA化合物的另一个实施方案中,m为1且R2为H。
在式IA化合物的另一个实施方案中,m为1且R2为烷基,其中所述的烷基包括本文披露的任意烷基。
在式IA化合物的另一个实施方案中,m为1且R2为i-丙基。
在式IA化合物的另一个实施方案中,m为1且R2为i-丁基。
在式IA化合物的另一个实施方案中,m为1且R2为乙基。
在式IA化合物的另一个实施方案中,m为1且R2为甲基。
在式IA化合物的另一个实施方案中,m为2且R2各自独立地选自H和烷基。
在式IA化合物的另一个实施方案中,m为2且R2各自为H。
在另一个实施方案中,式I的化合物具有如下通式IB:
式IB。
在式IB化合物的另一个实施方案中,Z1为-N(R7)-。在一个具体的实施方案中,R7为H。在另一个具体的实施方案中,R7为烷基,例如本文披露的任意烷基。在另一个具体的实施方案中,R7为杂烷基,例如本文披露的任意杂烷基。在另一个具体的实施方案中,R7为取代或未取代的碳环基,其中,例如,所述的碳环基为本文披露的任意碳环基。在另一个具体的实施方案中,R7为取代或未取代的杂环基,其中,例如,所述的杂环基为本文披露的任意杂环基。
在式IB化合物的另一个实施方案中,Z1为-O-。
在式IB化合物的另一个实施方案中,L2为-C(R6)2-,其中R6各自为H。
在式IB化合物的另一个实施方案中,L2为-C(R6)2-,其中R6各自独立为H或烷基且所述的烷基包括本文披露的任意烷基。
在式IB化合物的另一个实施方案中,L2为-C(R6)2-,其中一个R6为H且另一个R6为烷基,其中所述的烷基包括本文披露的任意烷基。
在式IB化合物的另一个实施方案中,R8和R9均为H。
在式IB化合物的另一个实施方案中,R8和R9独立地选自H和烷基,其中所述的烷基包括本文披露的任意烷基。
在另一个实施方案中,式I的化合物具有如下结构之一:
包括其立体异构体或立体异构体混合物。本领域技术人员公认本申请化合物的立体异构体或立体异构体混合物包括对映体,非对映体和其它立体异构体。例如,就如下结构而言:
预期立体异构体至少包括:
和这些立体异构体的两种或多种混合物。
在式I化合物的另一个实施方案中,L1为-C(R6)2-,-C(O)-,-S(O2)-,-N(R7)-C(O)-或-O-C(O)-。当L1为-C(R6)2-时,R6各自独立地选自H,烷基,取代的烷基和杂烷基,其中烷基,取代的烷基和杂烷基如本文定义和例举。-C(R6)2-的非限制性实例包括-CH 2-,-CH(烷基)-,-CH(取代的烷基)-,-CH(杂烷基)-,-C(烷基)2-,-C(取代的烷基)2-,-C(杂烷基)2-,-C(烷基)(取代的烷基)-,-C(杂烷基)(取代的烷基)-和-C(烷基)(杂烷基)-,其中烷基,取代的烷基和杂烷基如本文定义和例举。当L1为-N(R7)-C(O)-时,R7为H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基,其中烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基如本文定义和例举。
在式I化合物的另一个实施方案中,L2为-C(R6)2-或-C(O)-。当L2为-C(R6)2-时,R6各自独立地选自H,烷基,取代的烷基或杂烷基,其中烷基,取代的烷基或杂烷基各自可以包括本文定义或披露的任意烷基,取代的烷基或杂烷基。-C(R6)2-的非限制性实例包括-CH2-,-CH(CH3)-,-CH(-CH2CH3)-,-CH(-CH2CH2CH3)-,-CH(-CH(CH3)2)-,-CH(-CH2CH2CH2CH3)-,-CH(-CH2CH(CH3)2)-,-CH(-CH(CH3)CH2CH3)-,-CH(-C(CH3)3)-,-C(CH3)2-,-CH(OCH3)-,-CH(CH2OH)-,-CH(CH2CH2OH)-等。
在式I化合物的另一个实施方案中,L3各自独立为共价键,亚烷基或取代的亚烷基。当任意的L3为亚烷基时,亚烷基的非限制性实例包括本文披露的任意亚烷基。当任意的L3为取代的亚烷基时,取代的亚烷基的非限制性实例包括本文定义或披露的任意取代的亚烷基。例如,取代的亚烷基包括被一个或多个-OH取代的亚烷基,被一个或多个醚基取代的亚烷基,例如-O-Bn基团,被一个或多个卤素取代的亚烷基或被两个或多个取代基(例如-OH和卤素,卤素和醚等)的组合取代的亚烷基。
在式I化合物的另一个实施方案中,L3各自相同,即L3各自为相同的亚烷基或取代的亚烷基。
在式I化合物的另一个实施方案中,L3各自不同,即一个L3为亚烷基且另一个L3为取代的亚烷基,一个L3为亚烷基且另一个L3为不同的亚烷基或一个L3为取代的亚烷基且另一个L3为不同的取代的亚烷基。
在式I化合物的另一个实施方案中,L4各自独立地选自共价键,亚烷基,取代的亚烷基,-O-,-CH2-O-和-NH-。当L4为亚烷基时,所述的亚烷基包括本文定义或例举的任意亚烷基。当L4为取代的亚烷基时,所述的取代基包括本文定义或例举的任意亚烷基,其被如本文定义的一个或多个取代基取代。
在式I化合物的另一个实施方案中,L4基团均相同,即L4均为共价键,均为-O-,均为-CH2-O-(其中CH2基团与式I的“A”部分或“Ar”部分连接),均为取代或未取代的亚烷基或均为-NH-。
在式I化合物的另一个实施方案中,L4各自不同。例如,一个L4为共价键且另一个L4为-O-,一个L4为共价键且另一个L4为-CH2-O-(其中CH2基团与式I的“A”部分或“Ar”部分连接),一个L4为共价键且另一个L4为-NH-,一个L4为-O-且另一个L4为-CH2-O-(其中CH2基团与式I的“A”部分或“Ar”部分连接),一个L4为-O-且另一个L4为-NH-,一个L4为-CH2-O-(其中CH2基团与式I的“A”部分或“Ar”部分连接)且另一个L4为-NH-,一个L4为共价键且另一个L4为取代或未取代的亚烷基,一个L4为取代的亚烷基且另一个L4为未取代的亚烷基,一个L4为取代或未取代的烯且另一个L4为-O-,一个L4为取代或未取代的亚烷基且另一个L4为-CH2-O-(其中CH2基团与式I的“A”部分或“Ar”部分连接)或一个L4为取代或未取代的亚烷基且另一个L4为-NH-。
在式I化合物的另一个实施方案中,A各自独立为H,烷基,取代的烷基,芳基,取代的芳基,杂环基或取代的杂环基,条件是当A为H时,p为0。当任意的A为烷基时,所述的烷基包括本文定义或例举的任意烷基。当任意的A为取代的烷基时,所述的烷基包括本文定义或例举的任意烷基,其被一个或多个本文定义或例举的任意取代基取代。当任意的A为芳基时,所述的芳基包括本文定义或例举的任意芳基。当任意的A为取代的芳基时,所述的芳基包括本文定义或例举的任意芳基,其被一个或多个本文定义或例举的任意取代基取代。当任意的A为杂环基时,所述的杂环基包括本文定义或例举的任意杂环基。当任意的A为取代的杂环基时,所述的杂环基为包括本文定义或例举的任意杂环基,其被一个或多个本文定义或例举的任意取代基取代。
在式I化合物的另一个实施方案中,A各自为H且p各自为0。
在式I化合物的另一个实施方案中,A各自为取代或未取代的烷基,其中烷基为本文定义或例举的任意烷基,并且如果存在,那么所述烷基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,A各自为取代或未取代的芳基,其中芳基为本文定义或例举的任意芳基,并且如果存在,那么所述芳基上的取代基包括本文定义或例举的任意取代基中的一种或多种。在一个具体的实施方案中,A为苯基。
在式I化合物的另一个实施方案中,A各自为取代或未取代的杂环基,其中杂环基为本文定义或例举的任意杂环基,并且如果存在,那么所述杂环基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,一个A为H且另一个A为取代或未取代的烷基,其中烷基为本文定义或例举的任意烷基,并且如果存在,那么所述烷基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,一个A为H且另一个A为取代或未取代的芳基,其中芳基为本文定义或例举的任意芳基,并且如果存在,那么所述芳基上的取代基包括本文定义或例举的任意取代基中的一种或多种。在一个具体的实施方案中,一个A为苯基。
在式I化合物的另一个实施方案中,一个A为H且另一个A为取代或未取代的杂环基,其中杂环基为本文定义或例举的任意杂环基,并且如果存在,那么所述杂环基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,一个A为取代或未取代的烷基且另一个A为取代或未取代的芳基,其中烷基和芳基为本文定义或例举的任意烷基或芳基,并且如果存在,那么所述烷基或芳基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,一个A为取代或未取代的烷基且另一个A为取代或未取代的杂环基,其中烷基和杂环基为本文定义或例举的任意烷基或杂环基,并且如果存在,那么所述烷基或杂环基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,一个A为取代或未取代的芳基且另一个A为取代或未取代的杂环基,其中芳基和杂环基为本文定义或例举的任意芳基或杂环基,并且如果存在,那么所述芳基或杂环基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,Z1为-O-或-N(R7)-。当Z1为-N(R7)-时,R7为H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基,其中烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基为本文定义或例举的任意烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基。
在式I化合物的另一个实施方案中,Z2为-O-或-N(R7)-。当Z2为-N(R7)-时,R7为H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基,其中烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基为本文定义或例举的任意烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基。
在式I化合物的另一个实施方案中,Z1和Z2相同,例如Z1和Z2均为-O-或Z1和Z2均为-N(R7)-,其中R7为H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基,其中烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基为本文定义或为典型的任意烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基。
在式I化合物的另一个实施方案中,Z1和Z2不同,例如Z1为-O-和Z2为-N(R7)-,Z1为-N(R7)-且Z2为-O-或Z1和Z2均为-N(R7)-,但在Z1中,R7与Z2中的R7不同。当Z2的Z1为-N(R7)-时,R7为H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基,其中烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基为本文定义或例举的任意烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基或取代的杂环基。
在式I化合物的另一个实施方案中,Y为杂环基或杂环基烷基,其中杂环基和杂环基烷基为本文定义或例举的任意杂环基或杂环基烷基。在一个具体的实施方案中,Y为杂环基烷基,例如噻唑基甲基(-CH2-噻唑基)。
在式I化合物的另一个实施方案中,X为杂环基或杂环基烷基,其中杂环基和杂环基烷基为本文定义或例举的任意杂环基或杂环基烷基。在一个具体的实施方案中,X为杂环基烷基,例如噻唑基甲基。
在式I化合物的另一个实施方案中,X和Y不同,例如X和Y为不同的杂环基,X和Y为不同的杂环基烷基,X为杂环基且Y为杂环基烷基或X为杂环基烷基且Y为杂环基,其中杂环基和杂环基烷基为本文定义或例举的任意杂环基或杂环基烷基。
在式I化合物的另一个实施方案中,X和Y相同。在一个具体的实施方案中,X和Y均为杂环基烷基,例如噻唑基甲基。
在式I化合物的另一个实施方案中,Ar各自为芳基,取代的芳基,杂芳基或取代的杂芳基,其中芳基或杂芳基为本文定义或例举的任意芳基或杂芳基,并且如果存在,那么芳基或杂芳基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,Ar各自相同,例如Ar各自为芳基,诸如苯基。
在式I化合物的另一个实施方案中,Ar各自不同,例如一个Ar为取代或未取代的芳基且另一个Ar为取代或未取代的杂芳基,Ar各自为不同的取代或未取代的芳基或Ar各自为不同的取代或未取代的杂芳基,其中芳基和杂芳基为本文定义或例举的任意芳基或杂芳基,并且如果存在,那么芳基或杂芳基上的取代基包括本文定义或例举的任意取代基中的一种或多种。
在式I化合物的另一个实施方案中,R1,R3和R5各自独立为H,烷基或取代的烷基,其中烷基和取代的烷基包括本文定义或披露的任意烷基或取代的烷基。
在式I化合物的另一个实施方案中,R1,R3和R5各自相同。在一个具体的实施方案中R1,R3和R5各自为H。在另一个具体的实施方案中R1,R3和R5各自为烷基,例如本文定义或披露的烷基之一。
在式I化合物的另一个实施方案中,R1,R3和R5各自不同。
在式I化合物的另一个实施方案中,R1,R3和R5中之一与另外两个基团不同。
在式I化合物的另一个实施方案中,n和m均为1且各自R2各自独立为H,烷基,取代的烷基,芳基杂烷基,芳基烷基或杂环基烷基,其中烷基,取代的烷基,芳基杂烷基,芳基烷基或杂环基烷基为本文定义或披露的任意烷基,取代的烷基,芳基杂烷基,芳基烷基或杂环基烷基。
在式I化合物的另一个实施方案中,n和m均为1且R2为H。
在式I化合物的另一个实施方案中,n为1,m为2且R2为H。
在式I化合物的另一个实施方案中,n和m均为1且至少一个R2为烷基。在一个具体的实施方案中,至少一个R2为甲基。在另一个具体的实施方案中,至少一个R2为乙基。在另一个具体的实施方案中,至少一个R2为i-丙基。在另一个具体的实施方案中,至少一个R2为t-丁基。在另一个具体的实施方案中,一个R2为H且另一个R2为甲基。在另一个具体的实施方案中,一个R2为H且另一个R2为乙基。在另一个具体的实施方案中,一个R2为H且另一个R2为i-丙基。在另一个具体的实施方案中,一个R2为H且另一个R2为t-丁基。
在式I化合物的另一个实施方案中,n和m均为1且R2为取代的烷基。在一个具体的实施方案中,至少一个R2为-CH(CH3)OH或-CH(CH3)O(t-Bu)。
在式I化合物的另一个实施方案中,n和m均为1且至少一个R2为芳基杂烷基。在具体的实施方案中,n和m均为1且至少一个R2选自H,甲基,乙基,苄基-O-CH2-,i-丙基,-CH(CH3)OBn,-CH2CH(CH3)-O-tBu,-CH(CH3)OH,-CH2OH,-CH2OtBu,-CH2CH2NH2,-CH2CH2NH-P(其中P为保护基,诸如Boc,Ac,甲磺酰基等),-CH2CH2-吗啉,-CH2C(O)OH,-CH2C(O)OtBu和-CH2C(O)-NH2。
在式I化合物的另一个实施方案中,n和m均为1且至少一个R2为芳基杂烷基。在具体的实施方案中,n和m均为1,一个R2为H且一个R2选自H,甲基,乙基,苄基-O-CH2-,i-丙基,-CH(CH3)OBn,-CH2CH(CH3)-O-tBu,-CH(CH3)OH,-CH2OH,-CH2OtBu,-CH2CH2NH2,-CH2CH2NH-P(其中P为保护基,诸如Boc,Ac,甲磺酰基等),-CH2CH2-吗啉,-CH2C(O)OH,-CH2C(O)OtBu和-CH2C(O)-NH2。
在式I化合物的另一个实施方案中,R4为H,烷基,取代的烷基和杂烷基,其中烷基,取代的烷基和杂烷基为本文定义或披露的任意烷基,取代的烷基或杂烷基。在一个具体的实施方案中,R4为H。
在式I化合物的另一个实施方案中,R6为H,烷基,取代的烷基和杂烷基,其中烷基,取代的烷基和杂烷基为本文定义或披露的任意烷基,取代的烷基或杂烷基。在一个具体的实施方案中,R6为H。
在式I化合物的另一个实施方案中,R8和R9各自为一个或多个取代基,其独立地选自H,烷基,取代的烷基,卤素,芳基,取代的芳基,杂环基,取代的杂环基和-CN,其中当R8或R9为烷基,取代的烷基,卤素,芳基,取代的芳基,杂环基或取代的杂环基时,所述的烷基,取代的烷基,卤素,芳基,取代的芳基,杂环基或取代的杂环基为本文定义或披露的任意这类基团。
在式I化合物的另一个实施方案中,R8和R9相同。在一个具体的实施方案中,R8和R9均为H。
在式I化合物的另一个实施方案中,R8和R9不同。在一个具体的实施方案中,R8为烷基和R9为H。在另一个具体的实施方案中,R8为i-丙基和R9为H,
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-亚烷基-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-亚烷基-杂芳基,其中所述的亚烷基,芳基和杂芳基部分为本文定义或例举的任意亚烷基,芳基和杂芳基部分,其任选在亚烷基和/或芳基和/或杂芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-亚烷基-杂芳基,其中所述的亚烷基和杂芳基部分为本文定义或例举的任意亚烷基和杂芳基部分,其任选在亚烷基和/或杂芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-亚烷基-芳基,其中所述的亚烷基,芳基和杂芳基部分为本文定义或例举的任意亚烷基,芳基和杂芳基部分,其任选在亚烷基和/或芳基和/或杂芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-O-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-CH2-O-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-OCH2-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-NH-芳基,其中所述的亚烷基和芳基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-O-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基和芳基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-CH2-O-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-OCH2-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-NH-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-杂环基-芳基-,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-O-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-CH2-O-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-OCH2-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-NH-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-O-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-CH2-O-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-OCH2-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-NH-杂环基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-芳基-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-O-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-CH2-O-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-OCH2-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-芳基-NH-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为亚烷基-杂芳基-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-O-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-CH2-O-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-OCH2-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-NH-芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-O-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂环基-CH2-O-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-OCH2-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为-亚烷基-杂芳基-NH-杂芳基,其中所述的亚烷基,芳基和杂环基部分为本文定义或例举的任意亚烷基,芳基和杂环基部分,其任选在亚烷基和/或芳基和/或杂环基上被本文定义或例举的任意取代基中的一种或多种取代。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分中的至少一个为烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为烷基,其中所述的烷基相同或不同。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基且X和Y均为-CH2-杂环基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基且Y为-CH2-杂环基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基且X为-CH2-杂环基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基且Y为-CH2-噻唑基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基且X为-CH2-噻唑基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基且X和Y均为-CH2-噻唑基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基和n和m均为1。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为C1-C6烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为C1-C6羟基烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为C2-C10烷氧基烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为C7-C14芳基烷氧基烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为C1-C6氨基烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为在含有选自酰基,烷基磺酰基,芳基磺酰基,杂环基酰基和苄基的胺保护基的氮上被取代的C1-C6氨基烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且至少一个R2为取代或未取代的杂环基烷基。
在式I化合物的另一个实施方案中,-L3-A-(L4-Ar)p部分均为-CH2-苯基,X和Y均为-CH2-噻唑基,n和m均为1且L2为-CH2-。
在式I化合物的另一个实施方案中,至少一个-L3-A-(L4-Ar)p部分为-CH2-苯基-CH2-苯基。
在式I化合物的另一个实施方案中,至少一个-L3-A-(L4-Ar)p部分为-CH2-杂芳基-CH2-苯基。
在式I化合物的另一个实施方案中,至少一个-L3-A-(L4-Ar)p部分为-CH2-苯基-CH2-杂芳基。
在式I化合物的另一个实施方案中,至少一个-L3-A-(L4-Ar)p部分为-CH2-杂芳基-CH2-杂芳基。
在式I化合物的另一个实施方案中,X和Y均为杂环基烷基。
在式I化合物的另一个实施方案中,X和Y均为杂芳基烷基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H且-L3-A-(L4-Ar)p基团均为取代或未取代的苄基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基且L2为-CH2-。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-和m和n均为1。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1且R1为H。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H和Z1为-N(烷基)-。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H和Z1为-N(CH3)-。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(烷基)-和Z2为-O-。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(CH3)-和Z2为-O-。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(烷基)-,Z2为-O-和Y为取代或未取代的-CH2-4-噻唑。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(烷基)-,Z2为-O-和R8-Y为-CH2-(2-烷基-4-噻唑)。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-和R8-Y为-CH2-(2-iPr-4-噻唑)。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(烷基)-,Z2为-O-,Y为取代或未取代的-CH2-4-噻唑和X为取代或未取代的-CH2-5-噻唑。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(烷基)-,Z2为-O-,Y为取代或未取代的-CH2-4-噻唑和X为未取代的-CH2-5-噻唑。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑)和X为未取代的-CH2-5-噻唑。
在式I化合物的另一个实施方案中,R2各自独立为H或羟基烷基。
在式I化合物的另一个实施方案中,R2各自独立为H或杂环基烷基。
在式I化合物的另一个实施方案中,R2各自独立为H或-CH2-杂环基,其中所述的杂环基为具有至少一个环氮原子的5-或6-元环。
在式I化合物的另一个实施方案中,R2各自独立为H或-CH2-杂环基,其中所述的杂环基为具有至少一个环氮原子的6-元环。
在式I化合物的另一个实施方案中,R2各自独立为H或-CH2-杂环基,其中所述的杂环基为具有至少一个环氮原子的6-元环,其中其-CH2-部分与环氮原子键合。
在式I化合物的另一个实施方案中,R2各自独立为H或-CH2-杂环基,其中所述的杂环基选自哌啶基,哌嗪基和吗啉基。
在式I化合物的另一个实施方案中,R2各自独立为H或-CH2-杂环基,其中所述的杂环基选自哌啶基(piperadyl),哌嗪基(piperazyl)和吗啉基且其-CH2-部分与杂环基的环氮原子键合。
在式I化合物的另一个实施方案中,R2各自独立为H或氨基烷基.
在式I化合物的另一个实施方案中,R2各自独立为H或被选自乙酰基,烷基磺酰基,Boc,Cbz和Fmoc的胺保护基取代的氨基烷基。
在式I化合物的另一个实施方案中,R2各自独立为H或乙基乙酰胺(-CH2CH2NHC(O)CH3)。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且R2各自独立为H或羟基烷基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且一个R2为H且另一个R2为羟基烷基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑和一个R2为H且另一个R2为羟基甲基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且R2各自独立为H或-CH2-杂环基,其中所述的杂环基为具有至少一个环氮原子的5-或6-元环。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且R2各自独立为H或-CH2-杂环基,其中所述的杂环基选自哌啶基,哌嗪基和吗啉且其-CH2-部分与杂环基的环氮原子键合。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH 2-5-噻唑且一个R2为H且另一个R2为-CH2-杂环基,其中所述的杂环基选自哌啶基,哌嗪基和吗啉且其-CH2-部分与杂环基的环氮原子键合。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且R2各自独立为H或被选自乙酰基,烷基磺酰基,Boc,Cbz和Fmoc的胺保护基取代的氨基烷基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且一个R2为H且另一个R2为被选自乙酰基,烷基磺酰基,Boc,Cbz和Fmoc的胺保护基取代的氨基烷基。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p基团均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(H)-,Z2为-O-,R8-Y为-CH2-(2-iPr-4-噻唑),X为未取代的-CH2-5-噻唑且一个R2为H且另一个R2为乙基乙酰胺(-CH2CH2NHC(O)CH3)。
在式I化合物的另一个实施方案中,L1为-C(O)-,R4为H,-L3-A-(L4-Ar)p均为取代或未取代的苄基,L2为-CH2-,m和n均为1,R1为H,Z1为-N(烷基)-,Z2为-O-和Y为取代或未取代的-CH2-噻唑。
在另一个实施方案中,式I的化合物或其药学上可接受的盐,溶剂合物,酯类或立体异构体具有式IIA中所示的结构:
式IIA
其中R11和R16各自独立为杂环基或取代的杂环基;且R12,R13,R14和R15各自独立为H,-C1-4烷基或-C1-4取代的烷基。
在式IIA化合物的另一个实施方案中,R13为H,-C1-4烷基,-(CH2)0-1CR17R18OR19,-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)-NR20R21,-(CH2)1-3C(O)R22,-(CH2)1-3S(O)2R22或-(CH2)1-3-R23;R14和R15各自独立为H,-C1-4烷基或芳基烷基;R17和R18各自独立为H或-C1-3烷基;R19为H,-C1-4烷基或芳基烷基;R20和R21各自独立为H,-C1-3烷基,-C(O)R17或-S(O)2R17;或R20和R21与连接它们的氮原子共同构成含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环;R22为H,-C1-3烷基,-OR19或-NR20R21;且R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环。
在式IIA化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)-NR20R21或-(CH2)1-3-R23,其中R20和R21构成含1-2个选自N和O的杂原子的5-6元杂环基环或R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环且5-6元杂环基任选被C1-2烷基取代。
在式IIA化合物的另一个实施方案中,R13为-(CH2)0-1CR17R18OR19。在一个具体的实施方案中,R13为C1-2羟基烷基或C1-6烷氧基烷基。
在式IIA化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR20R21。在一个具体的实施方案中,R13为C1-4亚烷基-NH2,C1-4亚烷基-NHP(其中P为保护基,诸如Boc,Fmoc,Cbz,Ac,三氟乙酰基,甲苯磺酰基,苄基等)或C1-4亚烷基-N(烷基)2。
在式IIA化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR17C(O)-NR20R21。在一个具体的实施方案中,R13为C1-4亚烷基-C(O)NH2或C1-4亚烷基-C(O)N(烷基)2。
在式IIA化合物的另一个实施方案中,R11,R12,R13,R14,R15和R16各自独立地选自下表中所示的基团:
在式IIA化合物的另一个实施方案中,R11为取代或未取代的杂环基,R12为烷基,R13为取代或未取代的杂环基烷基,R14和R15各自独立为取代或未取代的芳基烷基和R16为取代或未取代的杂环基。
在式IIA化合物的另一个实施方案中,R11为取代的杂环基,R12为烷基,R13为未取代的杂环基烷基,R14和R15均为未取代的芳基烷基和R16为未取代的杂环基。
在式IIA化合物的另一个实施方案中,R11为取代或未取代的杂环基,R12为烷基,R13为羟基烷基,R14和R15各自独立为取代或未取代的芳基烷基且R16为取代或未取代的杂环基。
在式IIA化合物的另一个实施方案中,R11为取代的杂环基,R12为烷基,R13为羟基烷基,R14和R15均为未取代的芳基烷基和R16为未取代的杂环基。
在式IIA化合物的另一个实施方案中,R11为取代或未取代的杂环基,R12为烷基,R13为保护或未保护的氨基烷基,R14和R15各自独立为取代或未取代的芳基烷基且R16为取代或未取代的杂环基。
在式IIA化合物的另一个实施方案中,R11为取代的杂环基,R12为烷基,R13为被保护的氨基烷基,R14和R15均为未取代的芳基烷基且R16为未取代的杂环基。
在式IIA化合物的另一个实施方案中,R11为取代的杂环基,R12为烷基,R13为酰化氨基烷基,R14和R15均为未取代的芳基烷基和R16为未取代的杂环基。
在另一个实施方案中,式I的化合物或其药学上可接受的盐,溶剂合物,立体异构体和/或酯类具有如下结构IIB:
式IIB
R10a和R10b各自独立为H或-C1-4烷基;R12为H或-CH3;R13为H,-C1-4烷基,-(CH2)0-1CR17R18OR19,-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)NR20R21,-(CH2)1-3C(O)R22,-(CH2)1-3S(O)2R22或-(CH2)1-3-R23;R14和R15各自独立为H,-C1-4烷基或芳基烷基;R17和R18各自独立为H或-C1-3烷基;R19为H,-C1-4烷基或芳基烷基;R20和R21各自独立为H,-C1-3烷基,-C(O)R17或-S(O)2R17;或R20和R21与连接它们的氮原子共同构成含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环;R22为H,-C1-3烷基,-OR19或-NR20R21;且R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环。
在式IIB化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)-NR20R21或-(CH2)1-3-R23,其中R20和R21构成含1-2个选自N和O的杂原子的5-6元杂环基环或R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环且5-6元杂环基环任选被C1-2烷基取代。
在另一个实施方案中,式I的化合物或其药学上可接受的盐,溶剂合物,立体异构体和/或酯类具有如下结构IIC:
式IIC
其中:R13为H,-C1-4烷基,-(CH2)0-1CR17R18OR19,-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)NR20R21,-(CH2)1-3C(O)R22或-(CH2)1-3-R23;R17和R18各自独立为H或C1-3烷基;R19为H,-C1-4烷基或芳基烷基;R20和R21各自独立为H,-C1-3烷基,-C(O)R17或-S(O)2R17;或R20和R21与连接它们的氮原子共同构成含1-2个选自N和O的杂原子的5-6元杂环基环;R22为H,-C1-3烷基,-OR19或-NR20R21;且R23为含1-2个选自N和O的杂原子的5-6元杂环基环。
在式IIC化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)-NR20R21或-(CH2)1-3-R23,其中R20和R21构成含1-2个选自N和O的杂原子的5-6元杂环基环或R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环且5-6元杂环基环任选被C1-2烷基取代。
在式IIC化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR20R21。在一个具体的实施方案中,R13为C1-4亚烷基-NH2,C1-4亚烷基-NHP(其中P为保护基,诸如Boc,Fmoc,Cbz,Ac,三氟乙酰基,甲苯磺酰基,苄基等)或C1-4亚烷基-N(烷基)2。
在式IIC化合物的另一个实施方案中,R13为-(CH2)0-3CR17R18NR17C(O)-NR20R21。在一个具体的实施方案中,R13为C1-4亚烷基-C(O)NH2基团或C1-4亚烷基-C(O)N(烷基)2基团。
在式IIC化合物的另一个实施方案中,R13为-CH2OH,-CH2CH2NHC(O)CH3或
在另一个实施方案中,本发明的化合物或其药学上可接受的盐,溶剂合物,立体异构体和/或酯类具有如下结构IID:
式IID
其中,
L1选自-C(R6)2-,-C(O)-,-S(O2)-,-N(R7)-C(O)-和-O-C(O)-;
L3各自独立为共价键,亚烷基或取代的亚烷基;
L4各自独立地选自共价键,亚烷基,取代的亚烷基,-O-,-CH2-O-和-NH-;
A各自独立地选自H,烷基,取代的烷基,芳基,取代的芳基,杂环基和取代的杂环基,
条件是当A为H时,p为0;
Z1和Z2各自独立为-O-或-N(R7)-;
Y和X独立地选自杂环基和杂环基烷基;
Ar各自独立地选自芳基,取代的芳基,杂芳基和取代的杂芳基;
R1,R3和R5各自独立地选自H,烷基,取代的烷基,芳基烷基和取代的芳基烷基;
R2各自独立地选自H,烷基,取代的烷基,烷氧基烷基,羟基烷基,芳基杂烷基,取代的芳基杂烷基,芳基烷基,取代的芳基烷基,杂环基烷基,取代的杂环基烷基,氨基烷基,取代的氨基烷基,-亚烷基-C(O)-OH,-亚烷基-C(O)-O烷基,-亚烷基-C(O)氨基,-亚烷基-C(O)-烷基;
R4和R6独立地选自H,烷基,取代的烷基和杂烷基;
R7各自独立地选自H,烷基,取代的烷基,杂烷基,碳环基,取代的碳环基,杂环基和取代的杂环基;
R8和R9各自为一个或多个取代基,其独立地选自H,烷基,取代的烷基,卤素,芳基,取代的芳基,杂环基,取代的杂环基和-CN;且
p各自独立为0或1。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-。
在式IID化合物的另一个实施方案中,L1为-CH2-。
在式IID化合物的另一个实施方案中,L3各自为亚烷基。
在式IID化合物的另一个实施方案中,L3各自为-CH2-。
在式IID化合物的另一个实施方案中,A各自为芳基或取代的芳基。
在式IID化合物的另一个实施方案中,A各自为苯基或取代的苯基。
在式IID化合物的另一个实施方案中,X为杂环基烷基。
在式IID化合物的另一个实施方案中,X为噻唑基甲基。
在式IID化合物的另一个实施方案中,Y为杂环基烷基。
在式IID化合物的另一个实施方案中,Y为噻唑基甲基。
在式IID化合物的另一个实施方案中,Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,Z1为-NH-。
在式IID化合物的另一个实施方案中,Z1为-N(烷基)-。
在式IID化合物的另一个实施方案中,Z1为-N(CH3)-。
在式IID化合物的另一个实施方案中,Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-且X和Y为杂环基烷基。
在式IID化合物的另一个实施方案中,L1为-CH2-且X和Y为杂环基烷基。
在式IID化合物的另一个实施方案中,L1为-CH2-且X和Y为噻唑基甲基。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,L1为-CH2-且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,L1为-CH2-且Z1为-NH-。
在式IID化合物的另一个实施方案中,L1为-CH2-且Z1为-N(烷基)-。
在式IID化合物的另一个实施方案中,L1为-CH2-且Z1为-N(CH3)-。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-和Z2为-O-。
在式IID化合物的另一个实施方案中,L3各自为亚烷基且A各自为芳基或取代的芳基。
在式IID化合物的另一个实施方案中,L3各自为-CH2-且A各自为芳基或取代的芳基。
在式IID化合物的另一个实施方案中,L3-A各自为苄基或取代的苄基。
在式IID化合物的另一个实施方案中,X和Y为杂环基烷基且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,X和Y为噻唑基甲基且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,X和Y为噻唑基甲基且Z1为-N(烷基)-。
在式IID化合物的另一个实施方案中,X和Y为噻唑基甲基且Z1为-N(CH3)-。
在式IID化合物的另一个实施方案中,X和Y为噻唑基甲基和Z1为-NH-。
在式IID化合物的另一个实施方案中,X和Y为杂环基烷基和Z2为-O-。
在式IID化合物的另一个实施方案中,X和Y为噻唑基甲基和Z2为-O-。
在式IID化合物的另一个实施方案中,Z1为-N(R7)-和Z2为-O-。
在式IID化合物的另一个实施方案中,Z1为-N(烷基)-和Z2为-O-。
在式IID化合物的另一个实施方案中,Z1为-N(CH3)-和Z2为-O-。
在式IID化合物的另一个实施方案中,Z1为-NH-和Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-,X和Y为杂环基烷基且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,L1为-CH2-,X和Y为杂环基烷基且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,L1为-CH2-,X和Y为噻唑基甲基且Z1为-N(R7)-。
在式IID化合物的另一个实施方案中,L1为-CH2-,X和Y为噻唑基甲基且Z1为-N(烷基)-。
在式IID化合物的另一个实施方案中,L1为-CH2-,X和Y为噻唑基甲基且Z1为-N(CH3)-。
在式IID化合物的另一个实施方案中,L1为-CH2-,X和Y为噻唑基甲基且Z1为-NH-。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-;X和Y为杂环基烷基;且Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-CH2-;X和Y为杂环基烷基;且Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-CH2-;X和Y为噻唑基甲基;且Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-C(R6)2-;L3各自为亚烷基;A各自为芳基或取代的芳基;X和Y为杂环基烷基;Z1为-N(R7)-;且Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-CH2-;L3-A各自为苄基或取代的苄基;X和Y为噻唑基甲基;Z1为-N(CH3)-;和Z2为-O-。
在式IID化合物的另一个实施方案中,L1为-CH2-;L3-A各自为苄基或取代的苄基;Z1为-N(CH3)-;Z2为-O-;X为
且
Y为
在另一个实施方案中,将式I的化合物在下表格(表6)中命名为通式II的化合物:
式II。
将通式II的化合物描述为被4个部分T1,T2,X1和X2取代的″核心″结构(Z)。将核心结构Z描述在表1中。将T1,T2,X1和X2的连接点表示在表1中所示各核心结构上。表2-5分别表示T1,T2,X1和X2部分的结构。将核心结构Z的连接点表示在T1,T2,X1和X2各结构上。表1中的各核心结构Z和各取代基T1,T2,X1和X2和表2-5由包含字母和数字的“代码”表示。可以通过合并使用下列有序排列表示各结构部分的“代码”将式II的化合物的结构各自命名在表格中:Z.T1.T2.X1.X2。因此,例如,Z1.T1A.T2B.X1A.X2A表示如下结构:
在表1-5中所示的结构中,术语“Alk”意旨取代或未取代的烷基,环烷基或亚烷基,其中术语“烷基”,“环烷基”和“亚烷基”如本文所定义。“Alk”意旨描述为一价的烷基或环烷基和描述为二价的亚烷基。“Het”为取代或未取代的杂环基或杂亚环基,其中术语“杂环基”如本文所定义且术语“杂亚环基”意旨如本文定义的杂环基,其中氢原子被开放的化合价取代(与亚烷基类似),由此确定为二价杂环基。“He t”为描述为一价的杂环基和描述为二价的杂亚环基。“Ar”为取代或未取代的芳基或亚芳基,其中术语“芳基”如本文所定义且术语“亚芳基”意旨如本文定义的芳基,其中氢原子被开放的化合价取代(与亚烷基类似),由此确定为二价芳基。“Ar”为描述为一价的芳基和描述为二价的亚芳基。当饱和时取代的“Alk”,“Het”和“Ar”可以被本文定义或例举的任意取代基取代。例如,“Alk”的取代基可以包括醚,卤素,-OH,酰胺,胺等,“Het”的取代基可以包括烷基,芳基,羰基,-OH,卤素且“Ar”的取代基可以包括烷基,芳基,-OH,卤素等,条件是所得结构为化学上稳定的并且可以提供足以配制药学上可接受的组合物的化合物。当下表中所示的结构或子结构包含一个以上“Alk”,“Het”或“Ar”基团时,这些基团独立地选择并且可以相同或不同。因此,例如,子结构T1A的“Alk”基团各自独立地选择并且可以相同或不同。
表1:核心结构
表2:T1结构
表3:T2结构
代码T2结构
T2A -O-Alk-Het
T2B -NH-Alk-Het
代码 T2结构
T2C -N(Alk)-Alk-Het
T2D -N(Alk)-Het
表4:X1结构
代码 X1结构
X1A -Alk
X1B -Alk-Ar
X1C -Alk-Het
X1D -Alk-Ar-O-Alk-Ar
X1E -Alk-Ar-O-Alk-Het
表5:X2结构
代码 X2结构
X2A -Alk
X2B -Alk-Ar
X2C -Alk-Het
X2D -Alk-Ar-O-Alk-Ar
X2E -Alk-Ar-O-Alk-Het
表6:式II化合物结构列表
Z1.T1A.T2A.X1A.X2A,Z2.T1A.T2A.X1A.X2A,Z3.T1A.T2A.X1A.X2A,Z4.T1A.T2A.X1A.X2A,Z5.T1A.T2A.X1A.X2A,Z6.T1A.T2A.X1A.X2A,
Z1.T1B.T2A.X1A.X2A,Z2.T1B.T2A.X1A.X2A,Z3.T1B.T2A.X1A.X2A,Z4.T1B.T2A.X1A.X2A,Z5.T1B.T2A.X1A.X2A,Z6.T1B.T2A.X1A.X2A,
Z1.T1C.T2A.X1A.X2A,Z2.T1C.T2A.X1A.X2A,Z3.T1C.T2A.X1A.X2A,Z4.T1C.T2A.X1A.X2A,Z5.T1C.T2A.X1A.X2A,Z6.T1C.T2A.X1A.X2A,
Z1.T1D.T2A.X1A.X2A,Z2.T1D.T2A.X1A.X2A,Z3.T1D.T2A.X1A.X2A,Z4.T1D.T2A.X1A.X2A,Z5.T1D.T2A.X1A.X2A,Z6.T1D.T2A.X1A.X2A,
Z1.T1A.T2B.X1A.X2A,Z2.T1A.T2B.X1A.X2A,Z3.T1A.T2B.X1A.X2A,Z4.T1A.T2B.X1A.X2A,Z5.T1A.T2B.X1A.X2A,Z6.T1A.T2B.X1A.X2A,
Z1.T1B.T2B.X1A.X2A,Z2.T1B.T2B.X1A.X2A,Z3.T1B.T2B.X1A.X2A,Z4.T1B.T2B.X1A.X2A,Z5.T1B.T2B.X1A.X2A,Z6.T1B.T2B.X1A.X2A,
Z1.T1C.T2B.X1A.X2A,Z2.T1C.T2B.X1A.X2A,Z3.T1C.T2B.X1A.X2A,Z4.T1C.T2B.X1A.X2A,Z5.T1C.T2B.X1A.X2A,Z6.T1C.T2B.X1A.X2A,
Z1.T1D.T2B.X1A.X2A,Z2.T1D.T2B.X1A.X2A,Z3.T1D.T2B.X1A.X2A,Z4.T1D.T2B.X1A.X2A,Z5.T1D.T2B.X1A.X2A,Z6.T1D.T2B.X1A.X2A,
Z1.T1A.T2C.X1A.X2A,Z2.T1A.T2C.X1A.X2A,Z3.T1A.T2C.X1A.X2A,Z4.T1A.T2C.X1A.X2A,Z5.T1A.T2C.X1A.X2A,Z6.T1A.T2C.X1A.X2A,
Z1.T1B.T2C.X1A.X2A,Z2.T1B.T2C.X1A.X2A,Z3.T1B.T2C.X1A.X2A,Z4.T1B.T2C.X1A.X2A,Z5.T1B.T2C.X1A.X2A,Z6.T1B.T2C.X1A.X2A,
Z1.T1C.T2C.X1A.X2A,Z2.T1C.T2C.X1A.X2A,Z3.T1C.T2C.X1A.X2A,Z4.T1C.T2C.X1A.X2A,Z5.T1C.T2C.X1A.X2A,Z6.T1C.T2C.X1A.X2A,
Z1.T1D.T2C.X1A.X2A,Z2.T1D.T2C.X1A.X2A,Z3.T1D.T2C.X1A.X2A,Z4.T1D.T2C.X1A.X2A,Z5.T1D.T2C.X1A.X2A,Z6.T1D.T2C.X1A.X2A,
Z1.T1A.T2D.X1A.X2A,Z2.T1A.T2D.X1A.X2A,Z3.T1A.T2D.X1A.X2A,Z4.T1A.T2D.X1A.X2A,Z5.T1A.T2D.X1A.X2A,Z6.T1A.T2D.X1A.X2A,
Z1.T1B.T2D.X1A.X2A,Z2.T1B.T2D.X1A.X2A,Z3.T1B.T2D.X1A.X2A,Z4.T1B.T2D.X1A.X2A,Z5.T1B.T2D.X1A.X2A,Z6.T1B.T2D.X1A.X2A,
Z1.T1C.T2D.X1A.X2A,Z2.T1C.T2D.X1A.X2A,Z3.T1C.T2D.X1A.X2A,Z4.T1C.T2D.X1A.X2A,Z5.T1C.T2D.X1A.X2A,Z6.T1C.T2D.X1A.X2A,
Z1.T1D.T2D.X1A.X2A,Z2.T1D.T2D.X1A.X2A,Z3.T1D.T2D.X1A.X2A,Z4.T1D.T2D.X1A.X2A,Z5.T1D.T2D.X1A.X2A,Z6.T1D.T2D.X1A.X2A,
Z1.T1A.T2A.X1B.X2A,Z2.T1A.T2A.X1B.X2A,Z3.T1A.T2A.X1B.X2A,Z4.T1A.T2A.X1B.X2A,Z5.T1A.T2A.X1B.X2A,Z6.T1A.T2A.X1B.X2A,
Z1.T1B.T2A.X1B.X2A,Z2.T1B.T2A.X1B.X2A,Z3.T1B.T2A.X1B.X2A,Z4.T1B.T2A.X1B.X2A,Z5.T1B.T2A.X1B.X2A,Z6.T1B.T2A.X1B.X2A,
Z1.T1C.T2A.X1B.X2A,Z2.T1C.T2A.X1B.X2A,Z3.T1C.T2A.X1B.X2A,Z4.T1C.T2A.X1B.X2A,Z5.T1C.T2A.X1B.X2A,Z6.T1C.T2A.X1B.X2A,
Z1.T1D.T2A.X1B.X2A,Z2.T1D.T2A.X1B.X2A,Z3.T1D.T2A.X1B.X2A,Z4.T1D.T2A.X1B.X2A,Z5.T1D.T2A.X1B.X2A,Z6.T1D.T2A.X1B.X2A,
Z1.T1A.T2B.X1B.X2A,Z2.T1A.T2B.X1B.X2A,Z3.T1A.T2B.X1B.X2A,Z4.T1A.T2B.X1B.X2A,Z5.T1A.T2B.X1B.X2A,Z6.T1A.T2B.X1B.X2A,
Z1.T1B.T2B.X1B.X2A,Z2.T1B.T2B.X1B.X2A,Z3.T1B.T2B.X1B.X2A,Z4.T1B.T2B.X1B.X2A,Z5.T1B.T2B.X1B.X2A,Z6.T1B.T2B.X1B.X2A,
Z1.T1C.T2B.X1B.X2A,Z2.T1C.T2B.X1B.X2A,Z3.T1C.T2B.X1B.X2A,Z4.T1C.T2B.X1B.X2A,Z5.T1C.T2B.X1B.X2A,Z6.T1C.T2B.X1B.X2A,
Z1.T1D.T2B.X1B.X2A,Z2.T1D.T2B.X1B.X2A,Z3.T1D.T2B.X1B.X2A,Z4.T1D.T2B.X1B.X2A,Z5.T1D.T2B.X1B.X2A,Z6.T1D.T2B.X1B.X2A,
Z1.T1A.T2C.X1B.X2A,Z2.T1A.T2C.X1B.X2A,Z3.T1A.T2C.X1B.X2A,Z4.T1A.T2C.X1B.X2A,Z5.T1A.T2C.X1B.X2A,Z6.T1A.T2C.X1B.X2A,
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Z1.T1D.T2C.X1C.X2E,Z2.T1D.T2C.X1C.X2E,Z3.T1D.T2C.X1C.X2E,Z4.T1D.T2C.X1C.X2E,Z5.T1D.T2C.X1C.X2E,Z6.T1D.T2C.X1C.X2E,
Z1.T1A.T2D.X1C.X2E,Z2.T1A.T2D.X1C.X2E,Z3.T1A.T2D.X1C.X2E,Z4.T1A.T2D.X1C.X2E,Z5.T1A.T2D.X1C.X2E,Z6.T1A.T2D.X1C.X2E,
Z1.T1B.T2D.X1C.X2E,Z2.T1B.T2D.X1C.X2E,Z3.T1B.T2D.X1C.X2E,Z4.T1B.T2D.X1C.X2E,Z5.T1B.T2D.X1C.X2E,Z6.T1B.T2D.X1C.X2E,
Z1.T1C.T2D.X1C.X2E,Z2.T1C.T2D.X1C.X2E,Z3.T1C.T2D.X1C.X2E,Z4.T1C.T2D.X1C.X2E,Z5.T1C.T2D.X1C.X2E,Z6.T1C.T2D.X1C.X2E,
Z1.T1D.T2D.X1C.X2E,Z2.T1D.T2D.X1C.X2E,Z3.T1D.T2D.X1C.X2E,Z4.T1D.T2D.X1C.X2E,Z5.T1D.T2D.X1C.X2E,Z6.T1D.T2D.X1C.X2E,
Z1.T1A.T2A.X1D.X2E,Z2.T1A.T2A.X1D.X2E,Z3.T1A.T2A.X1D.X2E,Z4.T1A.T2A.X1D.X2E,Z5.T1A.T2A.X1D.X2E,Z6.T1A.T2A.X1D.X2E,
Z1.T1B.T2A.X1D.X2E,Z2.T1B.T2A.X1D.X2E,Z3.T1B.T2A.X1D.X2E,Z4.T1B.T2A.X1D.X2E,Z5.T1B.T2A.X1D.X2E,Z6.T1B.T2A.X1D.X2E,
Z1.T1C.T2A.X1D.X2E,Z2.T1C.T2A.X1D.X2E,Z3.T1C.T2A.X1D.X2E,Z4.T1C.T2A.X1D.X2E,Z5.T1C.T2A.X1D.X2E,Z6.T1C.T2A.X1D.X2E,
Z1.T1D.T2A.X1D.X2E,Z2.T1D.T2A.X1D.X2E,Z3.T1D.T2A.X1D.X2E,Z4.T1D.T2A.X1D.X2E,Z5.T1D.T2A.X1D.X2E,Z6.T1D.T2A.X1D.X2E,
Z1.T1A.T2B.X1D.X2E,Z2.T1A.T2B.X1D.X2E,Z3.T1A.T2B.X1D.X2E,Z4.T1A.T2B.X1D.X2E,Z5.T1A.T2B.X1D.X2E,Z6.T1A.T2B.X1D.X2E,
Z1.T1B.T2B.X1D.X2E,Z2.T1B.T2B.X1D.X2E,Z3.T1B.T2B.X1D.X2E,Z4.T1B.T2B.X1D.X2E,Z5.T1B.T2B.X1D.X2E,Z6.T1B.T2B.X1D.X2E,
Z1.T1C.T2B.X1D.X2E,Z2.T1C.T2B.X1D.X2E,Z3.T1C.T2B.X1D.X2E,Z4.T1C.T2B.X1D.X2E,Z5.T1C.T2B.X1D.X2E,Z6.T1C.T2B.X1D.X2E,
Z1.T1D.T2B.X1D.X2E,Z2.T1D.T2B.X1D.X2E,Z3.T1D.T2B.X1D.X2E,Z4.T1D.T2B.X1D.X2E,Z5.T1D.T2B.X1D.X2E,Z6.T1D.T2B.X1D.X2E,
Z1.T1A.T2C.X1D.X2E,Z2.T1A.T2C.X1D.X2E,Z3.T1A.T2C.X1D.X2E,Z4.T1A.T2C.X1D.X2E,Z5.T1A.T2C.X1D.X2E,Z6.T1A.T2C.X1D.X2E,
Z1.T1B.T2C.X1D.X2E,Z2.T1B.T2C.X1D.X2E,Z3.T1B.T2C.X1D.X2E,Z4.T1B.T2C.X1D.X2E,Z5.T1B.T2C.X1D.X2E,Z6.T1B.T2C.X1D.X2E,
Z1.T1C.T2C.X1D.X2E,Z2.T1C.T2C.X1D.X2E,Z3.T1C.T2C.X1D.X2E,Z4.T1C.T2C.X1D.X2E,Z5.T1C.T2C.X1D.X2E,Z6.T1C.T2C.X1D.X2E,
Z1.T1D.T2C.X1D.X2E,Z2.T1D.T2C.X1D.X2E,Z3.T1D.T2C.X1D.X2E,Z4.T1D.T2C.X1D.X2E,Z5.T1D.T2C.X1D.X2E,Z6.T1D.T2C.X1D.X2E,
Z1.T1A.T2D.X1D.X2E,Z2.T1A.T2D.X1D.X2E,Z3.T1A.T2D.X1D.X2E,Z4.T1A.T2D.X1D.X2E,Z5.T1A.T2D.X1D.X2E,Z6.T1A.T2D.X1D.X2E,
Z1.T1B.T2D.X1D.X2E,Z2.T1B.T2D.X1D.X2E,Z3.T1B.T2D.X1D.X2E,Z4.T1B.T2D.X1D.X2E,Z5.T1B.T2D.X1D.X2E,Z6.T1B.T2D.X1D.X2E,
Z1.T1C.T2D.X1D.X2E,Z2.T1C.T2D.X1D.X2E,Z3.T1C.T2D.X1D.X2E,Z4.T1C.T2D.X1D.X2E,Z5.T1C.T2D.X1D.X2E,Z6.T1C.T2D.X1D.X2E,
Z1.T1D.T2D.X1D.X2E,Z2.T1D.T2D.X1D.X2E,Z3.T1D.T2D.X1D.X2E,Z4.T1D.T2D.X1D.X2E,Z5.T1D.T2D.X1D.X2E,Z6.T1D.T2D.X1D.X2E,
Z1.T1A.T2A.X1E.X2E,Z2.T1A.T2A.X1E.X2E,Z3.T1A.T2A.X1E.X2E,Z4.T1A.T2A.X1E.X2E,Z5.T1A.T2A.X1E.X2E,Z6.T1A.T2A.X1E.X2E,
Z1.T1B.T2A.X1E.X2E,Z2.T1B.T2A.X1E.X2E,Z3.T1B.T2A.X1E.X2E,Z4.T1B.T2A.X1E.X2E,Z5.T1B.T2A.X1E.X2E,Z6.T1B.T2A.X1E.X2E,
Z1.T1C.T2A.X1E.X2E,Z2.T1C.T2A.X1E.X2E,Z3.T1C.T2A.X1E.X2E,Z4.T1C.T2A.X1E.X2E,Z5.T1C.T2A.X1E.X2E,Z6.T1C.T2A.X1E.X2E,
Z1.T1D.T2A.X1E.X2E,Z2.T1D.T2A.X1E.X2E,Z3.T1D.T2A.X1E.X2E,Z4.T1D.T2A.X1E.X2E,Z5.T1D.T2A.X1E.X2E,Z6.T1D.T2A.X1E.X2E,
Z1.T1A.T2B.X1E.X2E,Z2.T1A.T2B.X1E.X2E,Z3.T1A.T2B.X1E.X2E,Z4.T1A.T2B.X1E.X2E,Z5.T1A.T2B.X1E.X2E,Z6.T1A.T2B.X1E.X2E,
Z1.T1B.T2B.X1E.X2E,Z2.T1B.T2B.X1E.X2E,Z3.T1B.T2B.X1E.X2E,Z4.T1B.T2B.X1E.X2E,Z5.T1B.T2B.X1E.X2E,Z6.T1B.T2B.X1E.X2E,
Z1.T1C.T2B.X1E.X2E,Z2.T1C.T2B.X1E.X2E,Z3.T1C.T2B.X1E.X2E,Z4.T1C.T2B.X1E.X2E,Z5.T1C.T2B.X1E.X2E,Z6.T1C.T2B.X1E.X2E,
Z1.T1D.T2B.X1E.X2E,Z2.T1D.T2B.X1E.X2E,Z3.T1D.T2B.X1E.X2E,Z4.T1D.T2B.X1E.X2E,Z5.T1D.T2B.X1E.X2E,Z6.T1D.T2B.X1E.X2E,
Z1.T1A.T2C.X1E.X2E,Z2.T1A.T2C.X1E.X2E,Z3.T1A.T2C.X1E.X2E,Z4.T1A.T2C.X1E.X2E,Z5.T1A.T2C.X1E.X2E,Z6.T1A.T2C.X1E.X2E,
Z1.T1B.T2C.X1E.X2E,Z2.T1B.T2C.X1E.X2E,Z3.T1B.T2C.X1E.X2E,Z4.T1B.T2C.X1E.X2E,Z5.T1B.T2C.X1E.X2E,Z6.T1B.T2C.X1E.X2E,
Z1.T1C.T2C.X1E.X2E,Z2.T1C.T2C.X1E.X2E,Z3.T1C.T2C.X1E.X2E,Z4.T1C.T2C.X1E.X2E,Z5.T1C.T2C.X1E.X2E,Z6.T1C.T2C.X1E.X2E,
Z1.T1D.T2C.X1E.X2E,Z2.T1D.T2C.X1E.X2E,Z3.T1D.T2C.X1E.X2E,Z4.T1D.T2C.X1E.X2E,Z5.T1D.T2C.X1E.X2E,Z6.T1D.T2C.X1E.X2E,
Z1.T1A.T2D.X1E.X2E,Z2.T1A.T2D.X1E.X2E,Z3.T1A.T2D.X1E.X2E,Z4.T1A.T2D.X1E.X2E,Z5.T1A.T2D.X1E.X2E,Z6.T1A.T2D.X1E.X2E,
Z1.T1B.T2D.X1E.X2E,Z2.T1B.T2D.X1E.X2E,Z3.T1B.T2D.X1E.X2E,Z4.T1B.T2D.X1E.X2E,Z5.T1B.T2D.X1E.X2E,Z6.T1B.T2D.X1E.X2E,
Z1.T1C.T2D.X1E.X2E,Z2.T1C.T2D.X1E.X2E,Z3.T1C.T2D.X1E.X2E,Z4.T1C.T2D.X1E.X2E,Z5.T1C.T2D.X1E.X2E,Z6.T1C.T2D.X1E.X2E,
Z1.T1D.T2D.X1E.X2E,Z2.T1D.T2D.X1E.X2E,Z3.T1D.T2D.X1E.X2E,Z4.T1D.T2D.X1E.X2E,Z5.T1D.T2D.X1E.X2E和Z6.T1D.T2D.X1E.X2E.
在另一个实施方案中,将选择的式T的化合物命在下标格(表12)中命名为通式III的化合物(如下):
式III
其中将1,2,3,4和5定义在下表7-11中。通过合并表示各自结构部分的“代码”,使用下列有序排列:1.2.3.4.5将化合物各自命名在表格中。因此,例如,1a.2a.3a.4a.5a表示如下结构:
表7:“1”结构
表8:“2”结构
表9:“3”结构
表10:“4”结构
表11:“5”结构
表12:式II化合物结构列表
1a.2a.3a.4a.5a.,1b.2a.3a.4a.5a.,1f.2a.3a.4a.5a.,
1h.2a.3a.4a.5a.,1j.2a.3a.4a.5a.,1p.2a.3a.4a.5a.,
1a.2b.3a.4a.5a.,1b.2b.3a.4a.5a.,1f.2b.3a.4a.5a.,
1h.2b.3a.4a.5a.,1j.2b.3a.4a.5a.,1p.2b.3a.4a.5a.,
1a.2e.3a.4a.5a.,1b.2e.3a.4a.5a.,1f.2e.3a.4a.5a.,
1h.2e.3a.4a.5a.,1j.2e.3a.4a.5a.,1p.2e.3a.4a.5a.,
1a.2f.3a.4a.5a.,1b.2f.3a.4a.5a.,1f.2f.3a.4a.5a.,
1h.2f.3a.4a.5a.,1j.2f.3a.4a.5a.,1p.2f.3a.4a.5a.,
1a.2i.3a.4a.5a.,1b.2i.3a.4a.5a.,1f.2i.3a.4a.5a.,
1h.2i.3a.4a.5a.,1j.2i.3a.4a.5a.,1p.2i.3a.4a.5a.,
1a.2m.3a.4a.5a.,1b.2m.3a.4a.5a.,1f.2m.3a.4a.5a.,
1h.2m.3a.4a.5a.,1j.2m.3a.4a.5a.,1p.2m.3a.4a.5a.,
1a.2o.3a.4a.5a.,1b.2o.3a.4a.5a.,1f.2o.3a.4a.5a.,
1h.2o.3a.4a.5a.,1j.2o.3a.4a.5a.,1p.2o.3a.4a.5a.,
1a.2u.3a.4a.5a.,1b.2u.3a.4a.5a.,1f.2u.3a.4a.5a.,
1h.2u.3a.4a.5a.,1j.2u.3a.4a.5a.,1p.2u.3a.4a.5a.,
1a.2y.3a.4a.5a.,1b.2y.3a.4a.5a.,1f.2y.3a.4a.5a.,
1h.2y.3a.4a.5a.,1j.2y.3a.4a.5a.,1p.2y.3a.4a.5a.,
1a.2a.3b.4a.5a.,1b.2a.3b.4a.5a.,1f.2a.3b.4a.5a.,
1h.2a.3b.4a.5a.,1j.2a.3b.4a.5a.,1p.2a.3b.4a.5a.,
1a.2b.3b.4a.5a.,1b.2b.3b.4a.5a.,1f.2b.3b.4a.5a.,
1h.2b.3b.4a.5a.,1j.2b.3b.4a.5a.,1p.2b.3b.4a.5a.,
1a.2e.3b.4a.5a.,1b.2e.3b.4a.5a.,1f.2e.3b.4a.5a.,
1h.2e.3b.4a.5a.,1j.2e.3b.4a.5a.,1p.2e.3b.4a.5a.,
1a.2f.3b.4a.5a.,1b.2f.3b.4a.5a.,1f.2f.3b.4a.5a.,
1h.2f.3b.4a.5a.,1j.2f.3b.4a.5a.,1p.2f.3b.4a.5a.,
1a.2i.3b.4a.5a.,1b.2i.3b.4a.5a.,1f.2i.3b.4a.5a.,
1h.2i.3b.4a.5a.,1j.2i.3b.4a.5a.,1p.2i.3b.4a.5a.,
1a.2m.3b.4a.5a.,1b.2m.3b.4a.5a.,1f.2m.3b.4a.5a.,
1h.2m.3b.4a.5a.,1j.2m.3b.4a.5a.,1p.2m.3b.4a.5a.,
1a.2o.3b.4a.5a.,1b.2o.3b.4a.5a.,1f.2o.3b.4a.5a.,
1h.2o.3b.4a.5a.,1j.2o.3b.4a.5a.,1p.2o.3b.4a.5a.,
1a.2u.3b.4a.5a.,1b.2u.3b.4a.5a.,1f.2u.3b.4a.5a.,
1h.2u.3b.4a.5a.,1j.2u.3b.4a.5a.,1p.2u.3b.4a.5a.,
1a.2y.3b.4a.5a.,1b.2y.3b.4a.5a.,1f.2y.3b.4a.5a.,
1h.2y.3b.4a.5a.,1j.2y.3b.4a.5a.,1p.2y.3b.4a.5a.,
1a.2a.3e.4a.5a.,1b.2a.3e.4a.5a.,1f.2a.3e.4a.5a.,
1h.2a.3e.4a.5a.,1j.2a.3e.4a.5a.,1p.2a.3e.4a.5a.,
1a.2b.3e.4a.5a.,1b.2b.3e.4a.5a.,1f.2b.3e.4a.5a.,
1h.2b.3e.4a.5a.,1j.2b.3e.4a.5a.,1p.2b.3e.4a.5a.,
1a.2e.3e.4a.5a.,1b.2e.3e.4a.5a.,1f.2e.3e.4a.5a.,
1h.2e.3e.4a.5a.,1j.2e.3e.4a.5a.,1p.2e.3e.4a.5a.,
1a.2f.3e.4a.5a.,1b.2f.3e.4a.5a.,1f.2f.3e.4a.5a.,
1h.2f.3e.4a.5a.,1j.2f.3e.4a.5a.,1p.2f.3e.4a.5a.,
1a.2i.3e.4a.5a.,1b.2i.3e.4a.5a.,1f.2i.3e.4a.5a.,
1h.2i.3e.4a.5a.,1j.2i.3e.4a.5a.,1p.2i.3e.4a.5a.,
1a.2m.3e.4a.5a.,1b.2m.3e.4a.5a.,1f.2m.3e.4a.5a.,
1h.2m.3e.4a.5a.,1j.2m.3e.4a.5a.,1p.2m.3e.4a.5a.,
1a.2o.3e.4a.5a.,1b.2o.3e.4a.5a.,1f.2o.3e.4a.5a.,
1h.2o.3e.4a.5a.,1j.2o.3e.4a.5a.,1p.2o.3e.4a.5a.,
1a.2u.3e.4a.5a.,1b.2u.3e.4a.5a.,1f.2u.3e.4a.5a.,
1h.2u.3e.4a.5a.,1j.2u.3e.4a.5a.,1p.2u.3e.4a.5a.,
1a.2y.3e.4a.5a.,1b.2y.3e.4a.5a.,1f.2y.3e.4a.5a.,
1h.2y.3e.4a.5a.,1j.2y.3e.4a.5a.,1p.2y.3e.4a.5a.,
1a.2a.3g.4a.5a.,1b.2a.3g.4a.5a.,1f.2a.3g.4a.5a.,
1h.2a.3g.4a.5a.,1j.2a.3g.4a.5a.,1p.2a.3g.4a.5a.,
1a.2b.3g.4a.5a.,1b.2b.3g.4a.5a.,1f.2b.3g.4a.5a.,
1h.2b.3g.4a.5a.,1j.2b.3g.4a.5a.,1p.2b.3g.4a.5a.,
1a.2e.3g.4a.5a.,1b.2e.3g.4a.5a.,1f.2e.3g.4a.5a.,
1h.2e.3g.4a.5a.,1j.2e.3g.4a.5a.,1p.2e.3g.4a.5a.,
1a.2f.3g.4a.5a.,1b.2f.3g.4a.5a.,1f.2f.3g.4a.5a.,
1h.2f.3g.4a.5a.,1j.2f.3g.4a.5a.,1p.2f.3g.4a.5a.,
1a.2i.3g.4a.5a.,1b.2i.3g.4a.5a.,1f.2i.3g.4a.5a.,
1h.2i.3g.4a.5a.,1j.2i.3g.4a.5a.,1p.2i.3g.4a.5a.,
1a.2m.3g.4a.5a.,1b.2m.3g.4a.5a.,1f.2m.3g.4a.5a.,
1h.2m.3g.4a.5a.,1j.2m.3g.4a.5a.,1p.2m.3g.4a.5a.,
1a.2o.3g.4a.5a.,1b.2o.3g.4a.5a.,1f.2o.3g.4a.5a.,
1h.2o.3g.4a.5a.,1j.2o.3g.4a.5a.,1p.2o.3g.4a.5a.,
1a.2u.3g.4a.5a.,1b.2u.3g.4a.5a.,1f.2u.3g.4a.5a.,
1h.2u.3g.4a.5a.,1j.2u.3g.4a.5a.,1p.2u.3g.4a.5a.,
1a.2y.3g.4a.5a.,1b.2y.3g.4a.5a.,1f.2y.3g.4a.5a.,
1h.2y.3g.4a.5a.,1j.2y.3g.4a.5a.,1p.2y.3g.4a.5a.,
1a.2a.3a.4d.5a.,1b.2a.3a.4d.5a.,1f.2a.3a.4d.5a.,
1h.2a.3a.4d.5a.,1j.2a.3a.4d.5a.,1p.2a.3a.4d.5a.,
1a.2b.3a.4d.5a.,1b.2b.3a.4d.5a.,1f.2b.3a.4d.5a.,
1h.2b.3a.4d.5a.,1j.2b.3a.4d.5a.,1p.2b.3a.4d.5a.,
1a.2e.3a.4d.5a.,1b.2e.3a.4d.5a.,1f.2e.3a.4d.5a.,
1h.2e.3a.4d.5a.,1j.2e.3a.4d.5a.,1p.2e.3a.4d.5a.,
1a.2f.3a.4d.5a.,1b.2f.3a.4d.5a.,1f.2f.3a.4d.5a.,
1h.2f.3a.4d.5a.,1j.2f.3a.4d.5a.,1p.2f.3a.4d.5a.,
1a.2i.3a.4d.5a.,1b.2i.3a.4d.5a.,1f.2i.3a.4d.5a.,
1h.2i.3a.4d.5a.,1j.2i.3a.4d.5a.,1p.2i.3a.4d.5a.,
1a.2m.3a.4d.5a.,1b.2m.3a.4d.5a.,1f.2m.3a.4d.5a.,
1h.2m.3a.4d.5a.,1j.2m.3a.4d.5a.,1p.2m.3a.4d.5a.,
1a.2o.3a.4d.5a.,1b.2o.3a.4d.5a.,1f.2o.3a.4d.5a.,
1h.2o.3a.4d.5a.,1j.2o.3a.4d.5a.,1p.2o.3a.4d.5a.,
1a.2u.3a.4d.5a.,1b.2u.3a.4d.5a.,1f.2u.3a.4d.5a.,
1h.2u.3a.4d.5a.,1j.2u.3a.4d.5a.,1p.2u.3a.4d.5a.,
1a.2y.3a.4d.5a.,1b.2y.3a.4d.5a.,1f.2y.3a.4d.5a.,
1h.2y.3a.4d.5a.,1j.2y.3a.4d.5a.,1p.2y.3a.4d.5a.,
1a.2a.3b.4d.5a.,1b.2a.3b.4d.5a.,1f.2a.3b.4d.5a.,
1h.2a.3b.4d.5a.,1j.2a.3b.4d.5a.,1p.2a.3b.4d.5a.,
1a.2b.3b.4d.5a.,1b.2b.3b.4d.5a.,1f.2b.3b.4d.5a.,
1h.2b.3b.4d.5a.,1j.2b.3b.4d.5a.,1p.2b.3b.4d.5a.,
1a.2e.3b.4d.5a.,1b.2e.3b.4d.5a.,1f.2e.3b.4d.5a.,
1h.2e.3b.4d.5a.,1j.2e.3b.4d.5a.,1p.2e.3b.4d.5a.,
1a.2f.3b.4d.5a.,1b.2f.3b.4d.5a.,1f.2f.3b.4d.5a.,
1h.2f.3b.4d.5a.,1j.2f.3b.4d.5a.,1p.2f.3b.4d.5a.,
1a.2i.3b.4d.5a.,1b.2i.3b.4d.5a.,1f.2i.3b.4d.5a.,
1h.2i.3b.4d.5a.,1j.2i.3b.4d.5a.,1p.2i.3b.4d.5a.,
1a.2m.3b.4d.5a.,1b.2m.3b.4d.5a.,1f.2m.3b.4d.5a.,
1h.2m.3b.4d.5a.,1j.2m.3b.4d.5a.,1p.2m.3b.4d.5a.,
1a.2o.3b.4d.5a.,1b.2o.3b.4d.5a.,1f.2o.3b.4d.5a.,
1h.2o.3b.4d.5a.,1j.2o.3b.4d.5a.,1p.2o.3b.4d.5a.,
1a.2u.3b.4d.5a.,1b.2u.3b.4d.5a.,1f.2u.3b.4d.5a.,
1h.2u.3b.4d.5a.,1j.2u.3b.4d.5a.,1p.2u.3b.4d.5a.,
1a.2y.3b.4d.5a.,1b.2y.3b.4d.5a.,1f.2y.3b.4d.5a.,
1h.2y.3b.4d.5a.,1j.2y.3b.4d.5a.,1p.2y.3b.4d.5a.,
1a.2a.3e.4d.5a.,1b.2a.3e.4d.5a.,1f.2a.3e.4d.5a.,
1h.2a.3e.4d.5a.,1j.2a.3e.4d.5a.,1p.2a.3e.4d.5a.,
1a.2b.3e.4d.5a.,1b.2b.3e.4d.5a.,1f.2b.3e.4d.5a.,
1h.2b.3e.4d.5a.,1j.2b.3e.4d.5a.,1p.2b.3e.4d.5a.,
1a.2e.3e.4d.5a.,1b.2e.3e.4d.5a.,1f.2e.3e.4d.5a.,
1h.2e.3e.4d.5a.,1j.2e.3e.4d.5a.,1p.2e.3e.4d.5a.,
1a.2f.3e.4d.5a.,1b.2f.3e.4d.5a.,1f.2f.3e.4d.5a.,
1h.2f.3e.4d.5a.,1j.2f.3e.4d.5a.,1p.2f.3e.4d.5a.,
1a.2i.3e.4d.5a.,1b.2i.3e.4d.5a.,1f.2i.3e.4d.5a.,
1h.2i.3e.4d.5a.,1j.2i.3e.4d.5a.,1p.2i.3e.4d.5a.,
1a.2m.3e.4d.5a.,1b.2m.3e.4d.5a.,1f.2m.3e.4d.5a.,
1h.2m.3e.4d.5a.,1j.2m.3e.4d.5a.,1p.2m.3e.4d.5a.,
1a.2o.3e.4d.5a.,1b.2o.3e.4d.5a.,1f.2o.3e.4d.5a.,
1h.2o.3e.4d.5a.,1j.2o.3e.4d.5a.,1p.2o.3e.4d.5a.,
1a.2u.3e.4d.5a.,1b.2u.3e.4d.5a.,1f.2u.3e.4d.5a.,
1h.2u.3e.4d.5a.,1j.2u.3e.4d.5a.,1p.2u.3e.4d.5a.,
1a.2y.3e.4d.5a.,1b.2y.3e.4d.5a.,1f.2y.3e.4d.5a.,
1h.2y.3e.4d.5a.,1j.2y.3e.4d.5a.,1p.2y.3e.4d.5a.,
1a.2a.3g.4d.5a.,1b.2a.3g.4d.5a.,1f.2a.3g.4d.5a.,
1h.2a.3g.4d.5a.,1j.2a.3g.4d.5a.,1p.2a.3g.4d.5a.,
1a.2b.3g.4d.5a.,1b.2b.3g.4d.5a.,1f.2b.3g.4d.5a.,
1h.2b.3g.4d.5a.,1j.2b.3g.4d.5a.,1p.2b.3g.4d.5a.,
1a.2e.3g.4d.5a.,1b.2e.3g.4d.5a.,1f.2e.3g.4d.5a.,
1h.2e.3g.4d.5a.,1j.2e.3g.4d.5a.,1p.2e.3g.4d.5a.,
1a.2f.3g.4d.5a.,1b.2f.3g.4d.5a.,1f.2f.3g.4d.5a.,
1h.2f.3g.4d.5a.,1j.2f.3g.4d.5a.,1p.2f.3g.4d.5a.,
1a.2i.3g.4d.5a.,1b.2i.3g.4d.5a.,1f.2i.3g.4d.5a.,
1h.2i.3g.4d.5a.,1j.2i.3g.4d.5a.,1p.2i.3g.4d.5a.,
1a.2m.3g.4d.5a.,1b.2m.3g.4d.5a.,1f.2m.3g.4d.5a.,
1h.2m.3g.4d.5a.,1j.2m.3g.4d.5a.,1p.2m.3g.4d.5a.,
1a.2o.3g.4d.5a.,1b.2o.3g.4d.5a.,1f.2o.3g.4d.5a.,
1h.2o.3g.4d.5a.,1j.2o.3g.4d.5a.,1p.2o.3g.4d.5a.,
1a.2u.3g.4d.5a.,1b.2u.3g.4d.5a.,1f.2u.3g.4d.5a.,
1h.2u.3g.4d.5a.,1j.2u.3g.4d.5a.,1p.2u.3g.4d.5a.,
1a.2y.3g.4d.5a.,1b.2y.3g.4d.5a.,1f.2y.3g.4d.5a.,
1h.2y.3g.4d.5a.,1j.2y.3g.4d.5a.,1p.2y.3g.4d.5a.,
1a.2a.3a.4f.5a.,1b.2a.3a.4f.5a.,1f.2a.3a.4f.5a.,
1h.2a.3a.4f.5a.,1j.2a.3a.4f.5a.,1p.2a.3a.4f.5a.,
1a.2b.3a.4f.5a.,1b.2b.3a.4f.5a.,1f.2b.3a.4f.5a.,
1h.2b.3a.4f.5a.,1j.2b.3a.4f.5a.,1p.2b.3a.4f.5a.,
1a.2e.3a.4f.5a.,1b.2e.3a.4f.5a.,1f.2e.3a.4f.5a.,
1h.2e.3a.4f.5a.,1j.2e.3a.4f.5a.,1p.2e.3a.4f.5a.,
1a.2f.3a.4f.5a.,1b.2f.3a.4f.5a.,1f.2f.3a.4f.5a.,
1h.2f.3a.4f.5a.,1j.2f.3a.4f.5a.,1p.2f.3a.4f.5a.,
1a.2i.3a.4f.5a.,1b.2i.3a.4f.5a.,1f.2i.3a.4f.5a.,
1h.2i.3a.4f.5a.,1j.2i.3a.4f.5a.,1p.2i.3a.4f.5a.,
1a.2m.3a.4f.5a.,1b.2m.3a.4f.5a.,1f.2m.3a.4f.5a.,
1h.2m.3a.4f.5a.,1j.2m.3a.4f.5a.,1p.2m.3a.4f.5a.,
1a.2o.3a.4f.5a.,1b.2o.3a.4f.5a.,1f.2o.3a.4f.5a.,
1h.2o.3a.4f.5a.,1j.2o.3a.4f.5a.,1p.2o.3a.4f.5a.,
1a.2u.3a.4f.5a.,1b.2u.3a.4f.5a.,1f.2u.3a.4f.5a.,
1h.2u.3a.4f.5a.,1j.2u.3a.4f.5a.,1p.2u.3a.4f.5a.,
1a.2y.3a.4f.5a.,1b.2y.3a.4f.5a.,1f.2y.3a.4f.5a.,
1h.2y.3a.4f.5a.,1j.2y.3a.4f.5a.,1p.2y.3a.4f.5a.,
1a.2a.3b.4f.5a.,1b.2a.3b.4f.5a.,1f.2a.3b.4f.5a.,
1h.2a.3b.4f.5a.,1j.2a.3b.4f.5a.,1p.2a.3b.4f.5a.,
1a.2b.3b.4f.5a.,1b.2b.3b.4f.5a.,1f.2b.3b.4f.5a.,
1h.2b.3b.4f.5a.,1j.2b.3b.4f.5a.,1p.2b.3b.4f.5a.,
1a.2e.3b.4f.5a.,1b.2e.3b.4f.5a.,1f.2e.3b.4f.5a.,
1h.2e.3b.4f.5a.,1j.2e.3b.4f.5a.,1p.2e.3b.4f.5a.,
1a.2f.3b.4f.5a.,1b.2f.3b.4f.5a.,1f.2f.3b.4f.5a.,
1h.2f.3b.4f.5a.,1j.2f.3b.4f.5a.,1p.2f.3b.4f.5a.,
1a.2i.3b.4f.5a.,1b.2i.3b.4f.5a.,1f.2i.3b.4f.5a.,
1h.2i.3b.4f.5a.,1j.2i.3b.4f.5a.,1p.2i.3b.4f.5a.,
1a.2m.3b.4f.5a.,1b.2m.3b.4f.5a.,1f.2m.3b.4f.5a.,
1h.2m.3b.4f.5a.,1j.2m.3b.4f.5a.,1p.2m.3b.4f.5a.,
1a.2o.3b.4f.5a.,1b.2o.3b.4f.5a.,1f.2o.3b.4f.5a.,
1h.2o.3b.4f.5a.,1j.2o.3b.4f.5a.,1p.2o.3b.4f.5a.,
1a.2u.3b.4f.5a.,1b.2u.3b.4f.5a.,1f.2u.3b.4f.5a.,
1h.2u.3b.4f.5a.,1j.2u.3b.4f.5a.,1p.2u.3b.4f.5a.,
1a.2y.3b.4f.5a.,1b.2y.3b.4f.5a.,1f.2y.3b.4f.5a.,
1h.2y.3b.4f.5a.,1j.2y.3b.4f.5a.,1p.2y.3b.4f.5a.,
1a.2a.3e.4f.5a.,1b.2a.3e.4f.5a.,1f.2a.3e.4f.5a.,
1h.2a.3e.4f.5a.,1j.2a.3e.4f.5a.,1p.2a.3e.4f.5a.,
1a.2b.3e.4f.5a.,1b.2b.3e.4f.5a.,1f.2b.3e.4f.5a.,
1h.2b.3e.4f.5a.,1j.2b.3e.4f.5a.,1p.2b.3e.4f.5a.,
1a.2e.3e.4f.5a.,1b.2e.3e.4f.5a.,1f.2e.3e.4f.5a.,
1h.2e.3e.4f.5a.,1j.2e.3e.4f.5a.,1p.2e.3e.4f.5a.,
1a.2f.3e.4f.5a.,1b.2f.3e.4f.5a.,1f.2f.3e.4f.5a.,
1h.2f.3e.4f.5a.,1j.2f.3e.4f.5a.,1p.2f.3e.4f.5a.,
1a.2i.3e.4f.5a.,1b.2i.3e.4f.5a.,1f.2i.3e.4f.5a.,
1h.2i.3e.4f.5a.,1j.2i.3e.4f.5a.,1p.2i.3e.4f.5a.,
1a.2m.3e.4f.5a.,1b.2m.3e.4f.5a.,1f.2m.3e.4f.5a.,
1h.2m.3e.4f.5a.,1j.2m.3e.4f.5a.,1p.2m.3e.4f.5a.,
1a.2o.3e.4f.5a.,1b.2o.3e.4f.5a.,1f.2o.3e.4f.5a.,
1h.2o.3e.4f.5a.,1j.2o.3e.4f.5a.,1p.2o.3e.4f.5a.,
1a.2u.3e.4f.5a.,1b.2u.3e.4f.5a.,1f.2u.3e.4f.5a.,
1h.2u.3e.4f.5a.,1j.2u.3e.4f.5a.,1p.2u.3e.4f.5a.,
1a.2y.3e.4f.5a.,1b.2y.3e.4f.5a.,1f.2y.3e.4f.5a.,
1h.2y.3e.4f.5a.,1j.2y.3e.4f.5a.,1p.2y.3e.4f.5a.,
1a.2a.3g.4f.5a.,1b.2a.3g.4f.5a.,1f.2a.3g.4f.5a.,
1h.2a.3g.4f.5a.,1j.2a.3g.4f.5a.,1p.2a.3g.4f.5a.,
1a.2b.3g.4f.5a.,1b.2b.3g.4f.5a.,1f.2b.3g.4f.5a.,
1h.2b.3g.4f.5a.,1j.2b.3g.4f.5a.,1p.2b.3g.4f.5a.,
1a.2e.3g.4f.5a.,1b.2e.3g.4f.5a.,1f.2e.3g.4f.5a.,
1h.2e.3g.4f.5a.,1j.2e.3g.4f.5a.,1p.2e.3g.4f.5a.,
1a.2f.3g.4f.5a.,1b.2f.3g.4f.5a.,1f.2f.3g.4f.5a.,
1h.2f.3g.4f.5a.,1j.2f.3g.4f.5a.,1p.2f.3g.4f.5a.,
1a.2i.3g.4f.5a.,1b.2i.3g.4f.5a.,1f.2i.3g.4f.5a.,
1h.2i.3g.4f.5a.,1j.2i.3g.4f.5a.,1p.2i.3g.4f.5a.,
1a.2m.3g.4f.5a.,1b.2m.3g.4f.5a.,1f.2m.3g.4f.5a.,
1h.2m.3g.4f.5a.,1j.2m.3g.4f.5a.,1p.2m.3g.4f.5a.,
1a.2o.3g.4f.5a.,1b.2o.3g.4f.5a.,1f.2o.3g.4f.5a.,
1h.2o.3g.4f.5a.,1j.2o.3g.4f.5a.,1p.2o.3g.4f.5a.,
1a.2u.3g.4f.5a.,1b.2u.3g.4f.5a.,1f.2u.3g.4f.5a.,
1h.2u.3g.4f.5a.,1j.2u.3g.4f.5a.,1p.2u.3g.4f.5a.,
1a.2y.3g.4f.5a.,1b.2y.3g.4f.5a.,1f.2y.3g.4f.5a.,
1h.2y.3g.4f.5a.,1j.2y.3g.4f.5a.,1p.2y.3g.4f.5a.,
1a.2a.3a.4g.5a.,1b.2a.3a.4g.5a.,1f.2a.3a.4g.5a.,
1h.2a.3a.4g.5a.,1j.2a.3a.4g.5a.,1p.2a.3a.4g.5a.,
1a.2b.3a.4g.5a.,1b.2b.3a.4g.5a.,1f.2b.3a.4g.5a.,
1h.2b.3a.4g.5a.,1j.2b.3a.4g.5a.,1p.2b.3a.4g.5a.,
1a.2e.3a.4g.5a.,1b.2e.3a.4g.5a.,1f.2e.3a.4g.5a.,
1h.2e.3a.4g.5a.,1j.2e.3a.4g.5a.,1p.2e.3a.4g.5a.,
1a.2f.3a.4g.5a.,1b.2f.3a.4g.5a.,1f.2f.3a.4g.5a.,
1h.2f.3a.4g.5a.,1j.2f.3a.4g.5a.,1p.2f.3a.4g.5a.,
1a.2i.3a.4g.5a.,1b.2i.3a.4g.5a.,1f.2i.3a.4g.5a.,
1h.2i.3a.4g.5a.,1j.2i.3a.4g.5a.,1p.2i.3a.4g.5a.,
1a.2m.3a.4g.5a.,1b.2m.3a.4g.5a.,1f.2m.3a.4g.5a.,
1h.2m.3a.4g.5a.,1j.2m.3a.4g.5a.,1p.2m.3a.4g.5a.,
1a.2o.3a.4g.5a.,1b.2o.3a.4g.5a.,1f.2o.3a.4g.5a.,
1h.2o.3a.4g.5a.,1j.2o.3a.4g.5a.,1p.2o.3a.4g.5a.,
1a.2u.3a.4g.5a.,1b.2u.3a.4g.5a.,1f.2u.3a.4g.5a.,
1h.2u.3a.4g.5a.,1j.2u.3a.4g.5a.,1p.2u.3a.4g.5a.,
1a.2y.3a.4g.5a.,1b.2y.3a.4g.5a.,1f.2y.3a.4g.5a.,
1h.2y.3a.4g.5a.,1j.2y.3a.4g.5a.,1p.2y.3a.4g.5a.,
1a.2a.3b.4g.5a.,1b.2a.3b.4g.5a.,1f.2a.3b.4g.5a.,
1h.2a.3b.4g.5a.,1j.2a.3b.4g.5a.,1p.2a.3b.4g.5a.,
1a.2b.3b.4g.5a.,1b.2b.3b.4g.5a.,1f.2b.3b.4g.5a.,
1h.2b.3b.4g.5a.,1j.2b.3b.4g.5a.,1p.2b.3b.4g.5a.,
1a.2e.3b.4g.5a.,1b.2e.3b.4g.5a.,1f.2e.3b.4g.5a.,
1h.2e.3b.4g.5a.,1j.2e.3b.4g.5a.,1p.2e.3b.4g.5a.,
1a.2f.3b.4g.5a.,1b.2f.3b.4g.5a.,1f.2f.3b.4g.5a.,
1h.2f.3b.4g.5a.,1j.2f.3b.4g.5a.,1p.2f.3b.4g.5a.,
1a.2i.3b.4g.5a.,1b.2i.3b.4g.5a.,1f.2i.3b.4g.5a.,
1h.2i.3b.4g.5a.,1j.2i.3b.4g.5a.,1p.2i.3b.4g.5a.,
1a.2m.3b.4g.5a.,1b.2m.3b.4g.5a.,1f.2m.3b.4g.5a.,
1h.2m.3b.4g.5a.,1j.2m.3b.4g.5a.,1p.2m.3b.4g.5a.,
1a.2o.3b.4g.5a.,1b.2o.3b.4g.5a.,1f.2o.3b.4g.5a.,
1h.2o.3b.4g.5a.,1j.2o.3b.4g.5a.,1p.2o.3b.4g.5a.,
1a.2u.3b.4g.5a.,1b.2u.3b.4g.5a.,1f.2u.3b.4g.5a.,
1h.2u.3b.4g.5a.,1j.2u.3b.4g.5a.,1p.2u.3b.4g.5a.,
1a.2y.3b.4g.5a.,1b.2y.3b.4g.5a.,1f.2y.3b.4g.5a.,
1h.2y.3b.4g.5a.,1j.2y.3b.4g.5a.,1p.2y.3b.4g.5a.,
1a.2a.3e.4g.5a.,1b.2a.3e.4g.5a.,1f.2a.3e.4g.5a.,
1h.2a.3e.4g.5a.,1j.2a.3e.4g.5a.,1p.2a.3e.4g.5a.,
1a.2b.3e.4g.5a.,1b.2b.3e.4g.5a.,1f.2b.3e.4g.5a.,
1h.2b.3e.4g.5a.,1j.2b.3e.4g.5a.,1p.2b.3e.4g.5a.,
1a.2e.3e.4g.5a.,1b.2e.3e.4g.5a.,1f.2e.3e.4g.5a.,
1h.2e.3e.4g.5a.,1j.2e.3e.4g.5a.,1p.2e.3e.4g.5a.,
1a.2f.3e.4g.5a.,1b.2f.3e.4g.5a.,1f.2f.3e.4g.5a.,
1h.2f.3e.4g.5a.,1j.2f.3e.4g.5a.,1p.2f.3e.4g.5a.,
1a.2i.3e.4g.5a.,1b.2i.3e.4g.5a.,1f.2i.3e.4g.5a.,
1h.2i.3e.4g.5a.,1j.2i.3e.4g.5a.,1p.2i.3e.4g.5a.,
1a.2m.3e.4g.5a.,1b.2m.3e.4g.5a.,1f.2m.3e.4g.5a.,
1h.2m.3e.4g.5a.,1j.2m.3e.4g.5a.,1p.2m.3e.4g.5a.,
1a.2o.3e.4g.5a.,1b.2o.3e.4g.5a.,1f.2o.3e.4g.5a.,
1h.2o.3e.4g.5a.,1j.2o.3e.4g.5a.,1p.2o.3e.4g.5a.,
1a.2u.3e.4g.5a.,1b.2u.3e.4g.5a.,1f.2u.3e.4g.5a.,
1h.2u.3e.4g.5a.,1j.2u.3e.4g.5a.,1p.2u.3e.4g.5a.,
1a.2y.3e.4g.5a.,1b.2y.3e.4g.5a.,1f.2y.3e.4g.5a.,
1h.2y.3e.4g.5a.,1j.2y.3e.4g.5a.,1p.2y.3e.4g.5a.,
1a.2a.3g.4g.5a.,1b.2a.3g.4g.5a.,1f.2a.3g.4g.5a.,
1h.2a.3g.4g.5a.,1j.2a.3g.4g.5a.,1p.2a.3g.4g.5a.,
1a.2b.3g.4g.5a.,1b.2b.3g.4g.5a.,1f.2b.3g.4g.5a.,
1h.2b.3g.4g.5a.,1j.2b.3g.4g.5a.,1p.2b.3g.4g.5a.,
1a.2e.3g.4g.5a.,1b.2e.3g.4g.5a.,1f.2e.3g.4g.5a.,
1h.2e.3g.4g.5a.,1j.2e.3g.4g.5a.,1p.2e.3g.4g.5a.,
1a.2f.3g.4g.5a.,1b.2f.3g.4g.5a.,1f.2f.3g.4g.5a.,
1h.2f.3g.4g.5a.,1j.2f.3g.4g.5a.,1p.2f.3g.4g.5a.,
1a.2i.3g.4g.5a.,1b.2i.3g.4g.5a.,1f.2i.3g.4g.5a.,
1h.2i.3g.4g.5a.,1j.2i.3g.4g.5a.,1p.2i.3g.4g.5a.,
1a.2m.3g.4g.5a.,1b.2m.3g.4g.5a.,1f.2m.3g.4g.5a.,
1h.2m.3g.4g.5a.,1j.2m.3g.4g.5a.,1p.2m.3g.4g.5a.,
1a.2o.3g.4g.5a.,1b.2o.3g.4g.5a.,1f.2o.3g.4g.5a.,
1h.2o.3g.4g.5a.,1j.2o.3g.4g.5a.,1p.2o.3g.4g.5a.,
1a.2u.3g.4g.5a.,1b.2u.3g.4g.5a.,1f.2u.3g.4g.5a.,
1h.2u.3g.4g.5a.,1j.2u.3g.4g.5a.,1p.2u.3g.4g.5a.,
1a.2y.3g.4g.5a.,1b.2y.3g.4g.5a.,1f.2y.3g.4g.5a.,
1h.2y.3g.4g.5a.,1j.2y.3g.4g.5a.,1p.2y.3g.4g.5a.,
1a.2a.3a.4h.5a.,1b.2a.3a.4h.5a.,1f.2a.3a.4h.5a.,
1h.2a.3a.4h.5a.,1j.2a.3a.4h.5a.,1p.2a.3a.4h.5a.,
1a.2b.3a.4h.5a.,1b.2b.3a.4h.5a.,1f.2b.3a.4h.5a.,
1h.2b.3a.4h.5a.,1j.2b.3a.4h.5a.,1p.2b.3a.4h.5a.,
1a.2e.3a.4h.5a.,1b.2e.3a.4h.5a.,1f.2e.3a.4h.5a.,
1h.2e.3a.4h.5a.,1j.2e.3a.4h.5a.,1p.2e.3a.4h.5a.,
1a.2f.3a.4h.5a.,1b.2f.3a.4h.5a.,1f.2f.3a.4h.5a.,
1h.2f.3a.4h.5a.,1j.2f.3a.4h.5a.,1p.2f.3a.4h.5a.,
1a.2i.3a.4h.5a.,1b.2i.3a.4h.5a.,1f.2i.3a.4h.5a.,
1h.2i.3a.4h.5a.,1j.2i.3a.4h.5a.,1p.2i.3a.4h.5a.,
1a.2m.3a.4h.5a.,1b.2m.3a.4h.5a.,1f.2m.3a.4h.5a.,
1h.2m.3a.4h.5a.,1j.2m.3a.4h.5a.,1p.2m.3a.4h.5a.,
1a.2o.3a.4h.5a.,1b.2o.3a.4h.5a.,1f.2o.3a.4h.5a.,
1h.2o.3a.4h.5a.,1j.2o.3a.4h.5a.,1p.2o.3a.4h.5a.,
1a.2u.3a.4h.5a.,1b.2u.3a.4h.5a.,1f.2u.3a.4h.5a.,
1h.2u.3a.4h.5a.,1j.2u.3a.4h.5a.,1p.2u.3a.4h.5a.,
1a.2y.3a.4h.5a.,1b.2y.3a.4h.5a.,1f.2y.3a.4h.5a.,
1h.2y.3a.4h.5a.,1j.2y.3a.4h.5a.,1p.2y.3a.4h.5a.,
1a.2a.3b.4h.5a.,1b.2a.3b.4h.5a.,1f.2a.3b.4h.5a.,
1h.2a.3b.4h.5a.,1j.2a.3b.4h.5a.,1p.2a.3b.4h.5a.,
1a.2b.3b.4h.5a.,1b.2b.3b.4h.5a.,1f.2b.3b.4h.5a.,
1h.2b.3b.4h.5a.,1j.2b.3b.4h.5a.,1p.2b.3b.4h.5a.,
1a.2e.3b.4h.5a.,1b.2e.3b.4h.5a.,1f.2e.3b.4h.5a.,
1h.2e.3b.4h.5a.,1j.2e.3b.4h.5a.,1p.2e.3b.4h.5a.,
1a.2f.3b.4h.5a.,1b.2f.3b.4h.5a.,1f.2f.3b.4h.5a.,
1h.2f.3b.4h.5a.,1j.2f.3b.4h.5a.,1p.2f.3b.4h.5a.,
1a.2i.3b.4h.5a.,1b.2i.3b.4h.5a.,1f.2i.3b.4h.5a.,
1h.2i.3b.4h.5a.,1j.2i.3b.4h.5a.,1p.2i.3b.4h.5a.,
1a.2m.3b.4h.5a.,1b.2m.3b.4h.5a.,1f.2m.3b.4h.5a.,
1h.2m.3b.4h.5a.,1j.2m.3b.4h.5a.,1p.2m.3b.4h.5a.,
1a.2o.3b.4h.5a.,1b.2o.3b.4h.5a.,1f.2o.3b.4h.5a.,
1h.2o.3b.4h.5a.,1j.2o.3b.4h.5a.,1p.2o.3b.4h.5a.,
1a.2u.3b.4h.5a.,1b.2u.3b.4h.5a.,1f.2u.3b.4h.5a.,
1h.2u.3b.4h.5a.,1j.2u.3b.4h.5a.,1p.2u.3b.4h.5a.,
1a.2y.3b.4h.5a.,1b.2y.3b.4h.5a.,1f.2y.3b.4h.5a.,
1h.2y.3b.4h.5a.,1j.2y.3b.4h.5a.,1p.2y.3b.4h.5a.,
1a.2a.3e.4h.5a.,1b.2a.3e.4h.5a.,1f.2a.3e.4h.5a.,
1h.2a.3e.4h.5a.,1j.2a.3e.4h.5a.,1p.2a.3e.4h.5a.,
1a.2b.3e.4h.5a.,1b.2b.3e.4h.5a.,1f.2b.3e.4h.5a.,
1h.2b.3e.4h.5a.,1j.2b.3e.4h.5a.,1p.2b.3e.4h.5a.,
1a.2e.3e.4h.5a.,1b.2e.3e.4h.5a.,1f.2e.3e.4h.5a.,
1h.2e.3e.4h.5a.,1j.2e.3e.4h.5a.,1p.2e.3e.4h.5a.,
1a.2f.3e.4h.5a.,1b.2f.3e.4h.5a.,1f.2f.3e.4h.5a.,
1h.2f.3e.4h.5a.,1j.2f.3e.4h.5a.,1p.2f.3e.4h.5a.,
1a.2i.3e.4h.5a.,1b.2i.3e.4h.5a.,1f.2i.3e.4h.5a.,
1h.2i.3e.4h.5a.,1j.2i.3e.4h.5a.,1p.2i.3e.4h.5a.,
1a.2m.3e.4h.5a.,1b.2m.3e.4h.5a.,1f.2m.3e.4h.5a.,
1h.2m.3e.4h.5a.,1j.2m.3e.4h.5a.,1p.2m.3e.4h.5a.,
1a.2o.3e.4h.5a.,1b.2o.3e.4h.5a.,1f.2o.3e.4h.5a.,
1h.2o.3e.4h.5a.,1j.2o.3e.4h.5a.,1p.2o.3e.4h.5a.,
1a.2u.3e.4h.5a.,1b.2u.3e.4h.5a.,1f.2u.3e.4h.5a.,
1h.2u.3e.4h.5a.,1j.2u.3e.4h.5a.,1p.2u.3e.4h.5a.,
1a.2y.3e.4h.5a.,1b.2y.3e.4h.5a.,1f.2y.3e.4h.5a.,
1h.2y.3e.4h.5a.,1j.2y.3e.4h.5a.,1p.2y.3e.4h.5a.,
1a.2a.3g.4h.5a.,1b.2a.3g.4h.5a.,1f.2a.3g.4h.5a.,
1h.2a.3g.4h.5a.,1j.2a.3g.4h.5a.,1p.2a.3g.4h.5a.,
1a.2b.3g.4h.5a.,1b.2b.3g.4h.5a.,1f.2b.3g.4h.5a.,
1h.2b.3g.4h.5a.,1j.2b.3g.4h.5a.,1p.2b.3g.4h.5a.,
1a.2e.3g.4h.5a.,1b.2e.3g.4h.5a.,1f.2e.3g.4h.5a.,
1h.2e.3g.4h.5a.,1j.2e.3g.4h.5a.,1p.2e.3g.4h.5a.,
1a.2f.3g.4h.5a.,1b.2f.3g.4h.5a.,1f.2f.3g.4h.5a.,
1h.2f.3g.4h.5a.,1j.2f.3g.4h.5a.,1p.2f.3g.4h.5a.,
1a.2i.3g.4h.5a.,1b.2i.3g.4h.5a.,1f.2i.3g.4h.5a.,
1h.2i.3g.4h.5a.,1j.2i.3g.4h.5a.,1p.2i.3g.4h.5a.,
1a.2m.3g.4h.5a.,1b.2m.3g.4h.5a.,1f.2m.3g.4h.5a.,
1h.2m.3g.4h.5a.,1j.2m.3g.4h.5a.,1p.2m.3g.4h.5a.,
1a.2o.3g.4h.5a.,1b.2o.3g.4h.5a.,1f.2o.3g.4h.5a.,
1h.2o.3g.4h.5a.,1j.2o.3g.4h.5a.,1p.2o.3g.4h.5a.,
1a.2u.3g.4h.5a.,1b.2u.3g.4h.5a.,1f.2u.3g.4h.5a.,
1h.2u.3g.4h.5a.,1j.2u.3g.4h.5a.,1p.2u.3g.4h.5a.,
1a.2y.3g.4h.5a.,1b.2y.3g.4h.5a.,1f.2y.3g.4h.5a.,
1h.2y.3g.4h.5a.,1j.2y.3g.4h.5a.,1p.2y.3g.4h.5a.,
1a.2a.3a.4i.5a.,1b.2a.3a.4i.5a.,1f.2a.3a.4i.5a.,
1h.2a.3a.4i.5a.,1j.2a.3a.4i.5a.,1p.2a.3a.4i.5a.,
1a.2b.3a.4i.5a.,1b.2b.3a.4i.5a.,1f.2b.3a.4i.5a.,
1h.2b.3a.4i.5a.,1j.2b.3a.4i.5a.,1p.2b.3a.4i.5a.,
1a.2e.3a.4i.5a.,1b.2e.3a.4i.5a.,1f.2e.3a.4i.5a.,
1h.2e.3a.4i.5a.,1j.2e.3a.4i.5a.,1p.2e.3a.4i.5a.,
1a.2f.3a.4i.5a.,1b.2f.3a.4i.5a.,1f.2f.3a.4i.5a.,
1h.2f.3a.4i.5a.,1j.2f.3a.4i.5a.,1p.2f.3a.4i.5a.,
1a.2i.3a.4i.5a.,1b.2i.3a.4i.5a.,1f.2i.3a.4i.5a.,
1h.2i.3a.4i.5a.,1j.2i.3a.4i.5a.,1p.2i.3a.4i.5a.,
1a.2m.3a.4i.5a.,1b.2m.3a.4i.5a.,1f.2m.3a.4i.5a.,
1h.2m.3a.4i.5a.,1j.2m.3a.4i.5a.,1p.2m.3a.4i.5a.,
1a.2o.3a.4i.5a.,1b.2o.3a.4i.5a.,1f.2o.3a.4i.5a.,
1h.2o.3a.4i.5a.,1j.2o.3a.4i.5a.,1p.2o.3a.4i.5a.,
1a.2u.3a.4i.5a.,1b.2u.3a.4i.5a.,1f.2u.3a.4i.5a.,
1h.2u.3a.4i.5a.,1j.2u.3a.4i.5a.,1p.2u.3a.4i.5a.,
1a.2y.3a.4i.5a.,1b.2y.3a.4i.5a.,1f.2y.3a.4i.5a.,
1h.2y.3a.4i.5a.,1j.2y.3a.4i.5a.,1p.2y.3a.4i.5a.,
1a.2a.3b.4i.5a.,1b.2a.3b.4i.5a.,1f.2a.3b.4i.5a.,
1h.2a.3b.4i.5a.,1j.2a.3b.4i.5a.,1p.2a.3b.4i.5a.,
1a.2b.3b.4i.5a.,1b.2b.3b.4i.5a.,1f.2b.3b.4i.5a.,
1h.2b.3b.4i.5a.,1j.2b.3b.4i.5a.,1p.2b.3b.4i.5a.,
1a.2e.3b.4i.5a.,1b.2e.3b.4i.5a.,1f.2e.3b.4i.5a.,
1h.2e.3b.4i.5a.,1j.2e.3b.4i.5a.,1p.2e.3b.4i.5a.,
1a.2f.3b.4i.5a.,1b.2f.3b.4i.5a.,1f.2f.3b.4i.5a.,
1h.2f.3b.4i.5a.,1j.2f.3b.4i.5a.,1p.2f.3b.4i.5a.,
1a.2i.3b.4i.5a.,1b.2i.3b.4i.5a.,1f.2i.3b.4i.5a.,
1h.2i.3b.4i.5a.,1j.2i.3b.4i.5a.,1p.2i.3b.4i.5a.,
1a.2m.3b.4i.5a.,1b.2m.3b.4i.5a.,1f.2m.3b.4i.5a.,
1h.2m.3b.4i.5a.,1j.2m.3b.4i.5a.,1p.2m.3b.4i.5a.,
1a.2o.3b.4i.5a.,1b.2o.3b.4i.5a.,1f.2o.3b.4i.5a.,
1h.2o.3b.4i.5a.,1j.2o.3b.4i.5a.,1p.2o.3b.4i.5a.,
1a.2u.3b.4i.5a.,1b.2u.3b.4i.5a.,1f.2u.3b.4i.5a.,
1h.2u.3b.4i.5a.,1j.2u.3b.4i.5a.,1p.2u.3b.4i.5a.,
1a.2y.3b.4i.5a.,1b.2y.3b.4i.5a.,1f.2y.3b.4i.5a.,
1h.2y.3b.4i.5a.,1j.2y.3b.4i.5a.,1p.2y.3b.4i.5a.,
1a.2a.3e.4i.5a.,1b.2a.3e.4i.5a.,1f.2a.3e.4i.5a.,
1h.2a.3e.4i.5a.,1j.2a.3e.4i.5a.,1p.2a.3e.4i.5a.,
1a.2b.3e.4i.5a.,1b.2b.3e.4i.5a.,1f.2b.3e.4i.5a.,
1h.2b.3e.4i.5a.,1j.2b.3e.4i.5a.,1p.2b.3e.4i.5a.,
1a.2e.3e.4i.5a.,1b.2e.3e.4i.5a.,1f.2e.3e.4i.5a.,
1h.2e.3e.4i.5a.,1j.2e.3e.4i.5a.,1p.2e.3e.4i.5a.,
1a.2f.3e.4i.5a.,1b.2f.3e.4i.5a.,1f.2f.3e.4i.5a.,
1h.2f.3e.4i.5a.,1j.2f.3e.4i.5a.,1p.2f.3e.4i.5a.,
1a.2i.3e.4i.5a.,1b.2i.3e.4i.5a.,1f.2i.3e.4i.5a.,
1h.2i.3e.4i.5a.,1j.2i.3e.4i.5a.,1p.2i.3e.4i.5a.,
1a.2m.3e.4i.5a.,1b.2m.3e.4i.5a.,1f.2m.3e.4i.5a.,
1h.2m.3e.4i.5a.,1j.2m.3e.4i.5a.,1p.2m.3e.4i.5a.,
1a.2o.3e.4i.5a.,1b.2o.3e.4i.5a.,1f.2o.3e.4i.5a.,
1h.2o.3e.4i.5a.,1j.2o.3e.4i.5a.,1p.2o.3e.4i.5a.,
1a.2u.3e.4i.5a.,1b.2u.3e.4i.5a.,1f.2u.3e.4i.5a.,
1h.2u.3e.4i.5a.,1j.2u.3e.4i.5a.,1p.2u.3e.4i.5a.,
1a.2y.3e.4i.5a.,1b.2y.3e.4i.5a.,1f.2y.3e.4i.5a.,
1h.2y.3e.4i.5a.,1j.2y.3e.4i.5a.,1p.2y.3e.4i.5a.,
1a.2a.3g.4i.5a.,1b.2a.3g.4i.5a.,1f.2a.3g.4i.5a.,
1h.2a.3g.4i.5a.,1j.2a.3g.4i.5a.,1p.2a.3g.4i.5a.,
1a.2b.3g.4i.5a.,1b.2b.3g.4i.5a.,1f.2b.3g.4i.5a.,
1h.2b.3g.4i.5a.,1j.2b.3g.4i.5a.,1p.2b.3g.4i.5a.,
1a.2e.3g.4i.5a.,1b.2e.3g.4i.5a.,1f.2e.3g.4i.5a.,
1h.2e.3g.4i.5a.,1j.2e.3g.4i.5a.,1p.2e.3g.4i.5a.,
1a.2f.3g.4i.5a.,1b.2f.3g.4i.5a.,1f.2f.3g.4i.5a.,
1h.2f.3g.4i.5a.,1j.2f.3g.4i.5a.,1p.2f.3g.4i.5a.,
1a.2i.3g.4i.5a.,1b.2i.3g.4i.5a.,1f.2i.3g.4i.5a.,
1h.2i.3g.4i.5a.,1j.2i.3g.4i.5a.,1p.2i.3g.4i.5a.,
1a.2m.3g.4i.5a.,1b.2m.3g.4i.5a.,1f.2m.3g.4i.5a.,
1h.2m.3g.4i.5a.,1j.2m.3g.4i.5a.,1p.2m.3g.4i.5a.,
1a.2o.3g.4i.5a.,1b.2o.3g.4i.5a.,1f.2o.3g.4i.5a.,
1h.2o.3g.4i.5a.,1j.2o.3g.4i.5a.,1p.2o.3g.4i.5a.,
1a.2u.3g.4i.5a.,1b.2u.3g.4i.5a.,1f.2u.3g.4i.5a.,
1h.2u.3g.4i.5a.,1j.2u.3g.4i.5a.,1p.2u.3g.4i.5a.,
1a.2y.3g.4i.5a.,1b.2y.3g.4i.5a.,1f.2y.3g.4i.5a.,
1h.2y.3g.4i.5a.,1j.2y.3g.4i.5a.,1p.2y.3g.4i.5a.,
1a.2a.3a.4a.5d.,1b.2a.3a.4a.5d.,1f.2a.3a.4a.5d.,
1h.2a.3a.4a.5d.,1j.2a.3a.4a.5d.,1p.2a.3a.4a.5d.,
1a.2b.3a.4a.5d.,1b.2b.3a.4a.5d.,1f.2b.3a.4a.5d.,
1h.2b.3a.4a.5d.,1j.2b.3a.4a.5d.,1p.2b.3a.4a.5d.,
1a.2e.3a.4a.5d.,1b.2e.3a.4a.5d.,1f.2e.3a.4a.5d.,
1h.2e.3a.4a.5d.,1j.2e.3a.4a.5d.,1p.2e.3a.4a.5d.,
1a.2f.3a.4a.5d.,1b.2f.3a.4a.5d.,1f.2f.3a.4a.5d.,
1h.2f.3a.4a.5d.,1j.2f.3a.4a.5d.,1p.2f.3a.4a.5d.,
1a.2i.3a.4a.5d.,1b.2i.3a.4a.5d.,1f.2i.3a.4a.5d.,
1h.2i.3a.4a.5d.,1j.2i.3a.4a.5d.,1p.2i.3a.4a.5d.,
1a.2m.3a.4a.5d.,1b.2m.3a.4a.5d.,1f.2m.3a.4a.5d.,
1h.2m.3a.4a.5d.,1j.2m.3a.4a.5d.,1p.2m.3a.4a.5d.,
1a.2o.3a.4a.5d.,1b.2o.3a.4a.5d.,1f.2o.3a.4a.5d.,
1h.2o.3a.4a.5d.,1j.2o.3a.4a.5d.,1p.2o.3a.4a.5d.,
1a.2u.3a.4a.5d.,1b.2u.3a.4a.5d.,1f.2u.3a.4a.5d.,
1h.2u.3a.4a.5d.,1j.2u.3a.4a.5d.,1p.2u.3a.4a.5d.,
1a.2y.3a.4a.5d.,1b.2y.3a.4a.5d.,1f.2y.3a.4a.5d.,
1h.2y.3a.4a.5d.,1j.2y.3a.4a.5d.,1p.2y.3a.4a.5d.,
1a.2a.3b.4a.5d.,1b.2a.3b.4a.5d.,1f.2a.3b.4a.5d.,
1h.2a.3b.4a.5d.,1j.2a.3b.4a.5d.,1p.2a.3b.4a.5d.,
1a.2b.3b.4a.5d.,1b.2b.3b.4a.5d.,1f.2b.3b.4a.5d.,
1h.2b.3b.4a.5d.,1j.2b.3b.4a.5d.,1p.2b.3b.4a.5d.,
1a.2e.3b.4a.5d.,1b.2e.3b.4a.5d.,1f.2e.3b.4a.5d.,
1h.2e.3b.4a.5d.,1j.2e.3b.4a.5d.,1p.2e.3b.4a.5d.,
1a.2f.3b.4a.5d.,1b.2f.3b.4a.5d.,1f.2f.3b.4a.5d.,
1h.2f.3b.4a.5d.,1j.2f.3b.4a.5d.,1p.2f.3b.4a.5d.,
1a.2i.3b.4a.5d.,1b.2i.3b.4a.5d.,1f.2i.3b.4a.5d.,
1h.2i.3b.4a.5d.,1j.2i.3b.4a.5d.,1p.2i.3b.4a.5d.,
1a.2m.3b.4a.5d.,1b.2m.3b.4a.5d.,1f.2m.3b.4a.5d.,
1h.2m.3b.4a.5d.,1j.2m.3b.4a.5d.,1p.2m.3b.4a.5d.,
1a.2o.3b.4a.5d.,1b.2o.3b.4a.5d.,1f.2o.3b.4a.5d.,
1h.2o.3b.4a.5d.,1j.2o.3b.4a.5d.,1p.2o.3b.4a.5d.,
1a.2u.3b.4a.5d.,1b.2u.3b.4a.5d.,1f.2u.3b.4a.5d.,
1h.2u.3b.4a.5d.,1j.2u.3b.4a.5d.,1p.2u.3b.4a.5d.,
1a.2y.3b.4a.5d.,1b.2y.3b.4a.5d.,1f.2y.3b.4a.5d.,
1h.2y.3b.4a.5d.,1j.2y.3b.4a.5d.,1p.2y.3b.4a.5d.,
1a.2a.3e.4a.5d.,1b.2a.3e.4a.5d.,1f.2a.3e.4a.5d.,
1h.2a.3e.4a.5d.,1j.2a.3e.4a.5d.,1p.2a.3e.4a.5d.,
1a.2b.3e.4a.5d.,1b.2b.3e.4a.5d.,1f.2b.3e.4a.5d.,
1h.2b.3e.4a.5d.,1j.2b.3e.4a.5d.,1p.2b.3e.4a.5d.,
1a.2e.3e.4a.5d.,1b.2e.3e.4a.5d.,1f.2e.3e.4a.5d.,
1h.2e.3e.4a.5d.,1j.2e.3e.4a.5d.,1p.2e.3e.4a.5d.,
1a.2f.3e.4a.5d.,1b.2f.3e.4a.5d.,1f.2f.3e.4a.5d.,
1h.2f.3e.4a.5d.,1j.2f.3e.4a.5d.,1p.2f.3e.4a.5d.,
1a.2i.3e.4a.5d.,1b.2i.3e.4a.5d.,1f.2i.3e.4a.5d.,
1h.2i.3e.4a.5d.,1j.2i.3e.4a.5d.,1p.2i.3e.4a.5d.,
1a.2m.3e.4a.5d.,1b.2m.3e.4a.5d.,1f.2m.3e.4a.5d.,
1h.2m.3e.4a.5d.,1j.2m.3e.4a.5d.,1p.2m.3e.4a.5d.,
1a.2o.3e.4a.5d.,1b.2o.3e.4a.5d.,1f.2o.3e.4a.5d.,
1h.2o.3e.4a.5d.,1j.2o.3e.4a.5d.,1p.2o.3e.4a.5d.,
1a.2u.3e.4a.5d.,1b.2u.3e.4a.5d.,1f.2u.3e.4a.5d.,
1h.2u.3e.4a.5d.,1j.2u.3e.4a.5d.,1p.2u.3e.4a.5d.,
1a.2y.3e.4a.5d.,1b.2y.3e.4a.5d.,1f.2y.3e.4a.5d.,
1h.2y.3e.4a.5d.,1j.2y.3e.4a.5d.,1p.2y.3e.4a.5d.,
1a.2a.3g.4a.5d.,1b.2a.3g.4a.5d.,1f.2a.3g.4a.5d.,
1h.2a.3g.4a.5d.,1j.2a.3g.4a.5d.,1p.2a.3g.4a.5d.,
1a.2b.3g.4a.5d.,1b.2b.3g.4a.5d.,1f.2b.3g.4a.5d.,
1h.2b.3g.4a.5d.,1j.2b.3g.4a.5d.,1p.2b.3g.4a.5d.,
1a.2e.3g.4a.5d.,1b.2e.3g.4a.5d.,1f.2e.3g.4a.5d.,
1h.2e.3g.4a.5d.,1j.2e.3g.4a.5d.,1p.2e.3g.4a.5d.,
1a.2f.3g.4a.5d.,1b.2f.3g.4a.5d.,1f.2f.3g.4a.5d.,
1h.2f.3g.4a.5d.,1j.2f.3g.4a.5d.,1p.2f.3g.4a.5d.,
1a.2i.3g.4a.5d.,1b.2i.3g.4a.5d.,1f.2i.3g.4a.5d.,
1h.2i.3g.4a.5d.,1j.2i.3g.4a.5d.,1p.2i.3g.4a.5d.,
1a.2m.3g.4a.5d.,1b.2m.3g.4a.5d.,1f.2m.3g.4a.5d.,
1h.2m.3g.4a.5d.,1j.2m.3g.4a.5d.,1p.2m.3g.4a.5d.,
1a.2o.3g.4a.5d.,1b.2o.3g.4a.5d.,1f.2o.3g.4a.5d.,
1h.2o.3g.4a.5d.,1j.2o.3g.4a.5d.,1p.2o.3g.4a.5d.,
1a.2u.3g.4a.5d.,1b.2u.3g.4a.5d.,1f.2u.3g.4a.5d.,
1h.2u.3g.4a.5d.,1j.2u.3g.4a.5d.,1p.2u.3g.4a.5d.,
1a.2y.3g.4a.5d.,1b.2y.3g.4a.5d.,1f.2y.3g.4a.5d.,
1h.2y.3g.4a.5d.,1j.2y.3g.4a.5d.,1p.2y.3g.4a.5d.,
1a.2a.3a.4d.5d.,1b.2a.3a.4d.5d.,1f.2a.3a.4d.5d.,
1h.2a.3a.4d.5d.,1j.2a.3a.4d.5d.,1p.2a.3a.4d.5d.,
1a.2b.3a.4d.5d.,1b.2b.3a.4d.5d.,1f.2b.3a.4d.5d.,
1h.2b.3a.4d.5d.,1j.2b.3a.4d.5d.,1p.2b.3a.4d.5d.,
1a.2e.3a.4d.5d.,1b.2e.3a.4d.5d.,1f.2e.3a.4d.5d.,
1h.2e.3a.4d.5d.,1j.2e.3a.4d.5d.,1p.2e.3a.4d.5d.,
1a.2f.3a.4d.5d.,1b.2f.3a.4d.5d.,1f.2f.3a.4d.5d.,
1h.2f.3a.4d.5d.,1j.2f.3a.4d.5d.,1p.2f.3a.4d.5d.,
1a.2i.3a.4d.5d.,1b.2i.3a.4d.5d.,1f.2i.3a.4d.5d.,
1h.2i.3a.4d.5d.,1j.2i.3a.4d.5d.,1p.2i.3a.4d.5d.,
1a.2m.3a.4d.5d.,1b.2m.3a.4d.5d.,1f.2m.3a.4d.5d.,
1h.2m.3a.4d.5d.,1j.2m.3a.4d.5d.,1p.2m.3a.4d.5d.,
1a.2o.3a.4d.5d.,1b.2o.3a.4d.5d.,1f.2o.3a.4d.5d.,
1h.2o.3a.4d.5d.,1j.2o.3a.4d.5d.,1p.2o.3a.4d.5d.,
1a.2u.3a.4d.5d.,1b.2u.3a.4d.5d.,1f.2u.3a.4d.5d.,
1h.2u.3a.4d.5d.,1j.2u.3a.4d.5d.,1p.2u.3a.4d.5d.,
1a.2y.3a.4d.5d.,1b.2y.3a.4d.5d.,1f.2y.3a.4d.5d.,
1h.2y.3a.4d.5d.,1j.2y.3a.4d.5d.,1p.2y.3a.4d.5d.,
1a.2a.3b.4d.5d.,1b.2a.3b.4d.5d.,1f.2a.3b.4d.5d.,
1h.2a.3b.4d.5d.,1j.2a.3b.4d.5d.,1p.2a.3b.4d.5d.,
1a.2b.3b.4d.5d.,1b.2b.3b.4d.5d.,1f.2b.3b.4d.5d.,
1h.2b.3b.4d.5d.,1j.2b.3b.4d.5d.,1p.2b.3b.4d.5d.,
1a.2e.3b.4d.5d.,1b.2e.3b.4d.5d.,1f.2e.3b.4d.5d.,
1h.2e.3b.4d.5d.,1j.2e.3b.4d.5d.,1p.2e.3b.4d.5d.,
1a.2f.3b.4d.5d.,1b.2f.3b.4d.5d.,1f.2f.3b.4d.5d.,
1h.2f.3b.4d.5d.,1j.2f.3b.4d.5d.,1p.2f.3b.4d.5d.,
1a.2i.3b.4d.5d.,1b.2i.3b.4d.5d.,1f.2i.3b.4d.5d.,
1h.2i.3b.4d.5d.,1j.2i.3b.4d.5d.,1p.2i.3b.4d.5d.,
1a.2m.3b.4d.5d.,1b.2m.3b.4d.5d.,1f.2m.3b.4d.5d.,
1h.2m.3b.4d.5d.,1j.2m.3b.4d.5d.,1p.2m.3b.4d.5d.,
1a.2o.3b.4d.5d.,1b.2o.3b.4d.5d.,1f.2o.3b.4d.5d.,
1h.2o.3b.4d.5d.,1j.2o.3b.4d.5d.,1p.2o.3b.4d.5d.,
1a.2u.3b.4d.5d.,1b.2u.3b.4d.5d.,1f.2u.3b.4d.5d.,
1h.2u.3b.4d.5d.,1j.2u.3b.4d.5d.,1p.2u.3b.4d.5d.,
1a.2y.3b.4d.5d.,1b.2y.3b.4d.5d.,1f.2y.3b.4d.5d.,
1h.2y.3b.4d.5d.,1j.2y.3b.4d.5d.,1p.2y.3b.4d.5d.,
1a.2a.3e.4d.5d.,1b.2a.3e.4d.5d.,1f.2a.3e.4d.5d.,
1h.2a.3e.4d.5d.,1j.2a.3e.4d.5d.,1p.2a.3e.4d.5d.,
1a.2b.3e.4d.5d.,1b.2b.3e.4d.5d.,1f.2b.3e.4d.5d.,
1h.2b.3e.4d.5d.,1j.2b.3e.4d.5d.,1p.2b.3e.4d.5d.,
1a.2e.3e.4d.5d.,1b.2e.3e.4d.5d.,1f.2e.3e.4d.5d.,
1h.2e.3e.4d.5d.,1j.2e.3e.4d.5d.,1p.2e.3e.4d.5d.,
1a.2f.3e.4d.5d.,1b.2f.3e.4d.5d.,1f.2f.3e.4d.5d.,
1h.2f.3e.4d.5d.,1j.2f.3e.4d.5d.,1p.2f.3e.4d.5d.,
1a.2i.3e.4d.5d.,1b.2i.3e.4d.5d.,1f.2i.3e.4d.5d.,
1h.2i.3e.4d.5d.,1j.2i.3e.4d.5d.,1p.2i.3e.4d.5d.,
1a.2m.3e.4d.5d.,1b.2m.3e.4d.5d.,1f.2m.3e.4d.5d.,
1h.2m.3e.4d.5d.,1j.2m.3e.4d.5d.,1p.2m.3e.4d.5d.,
1a.2o.3e.4d.5d.,1b.2o.3e.4d.5d.,1f.2o.3e.4d.5d.,
1h.2o.3e.4d.5d.,1j.2o.3e.4d.5d.,1p.2o.3e.4d.5d.,
1a.2u.3e.4d.5d.,1b.2u.3e.4d.5d.,1f.2u.3e.4d.5d.,
1h.2u.3e.4d.5d.,1j.2u.3e.4d.5d.,1p.2u.3e.4d.5d.,
1a.2y.3e.4d.5d.,1b.2y.3e.4d.5d.,1f.2y.3e.4d.5d.,
1h.2y.3e.4d.5d.,1j.2y.3e.4d.5d.,1p.2y.3e.4d.5d.,
1a.2a.3g.4d.5d.,1b.2a.3g.4d.5d.,1f.2a.3g.4d.5d.,
1h.2a.3g.4d.5d.,1j.2a.3g.4d.5d.,1p.2a.3g.4d.5d.,
1a.2b.3g.4d.5d.,1b.2b.3g.4d.5d.,1f.2b.3g.4d.5d.,
1h.2b.3g.4d.5d.,1j.2b.3g.4d.5d.,1p.2b.3g.4d.5d.,
1a.2e.3g.4d.5d.,1b.2e.3g.4d.5d.,1f.2e.3g.4d.5d.,
1h.2e.3g.4d.5d.,1j.2e.3g.4d.5d.,1p.2e.3g.4d.5d.,
1a.2f.3g.4d.5d.,1b.2f.3g.4d.5d.,1f.2f.3g.4d.5d.,
1h.2f.3g.4d.5d.,1j.2f.3g.4d.5d.,1p.2f.3g.4d.5d.,
1a.2i.3g.4d.5d.,1b.2i.3g.4d.5d.,1f.2i.3g.4d.5d.,
1h.2i.3g.4d.5d.,1j.2i.3g.4d.5d.,1p.2i.3g.4d.5d.,
1a.2m.3g.4d.5d.,1b.2m.3g.4d.5d.,1f.2m.3g.4d.5d.,
1h.2m.3g.4d.5d.,1j.2m.3g.4d.5d.,1p.2m.3g.4d.5d.,
1a.2o.3g.4d.5d.,1b.2o.3g.4d.5d.,1f.2o.3g.4d.5d.,
1h.2o.3g.4d.5d.,1j.2o.3g.4d.5d.,1p.2o.3g.4d.5d.,
1a.2u.3g.4d.5d.,1b.2u.3g.4d.5d.,1f.2u.3g.4d.5d.,
1h.2u.3g.4d.5d.,1j.2u.3g.4d.5d.,1p.2u.3g.4d.5d.,
1a.2y.3g.4d.5d.,1b.2y.3g.4d.5d.,1f.2y.3g.4d.5d.,
1h.2y.3g.4d.5d.,1j.2y.3g.4d.5d.,1p.2y.3g.4d.5d.,
1a.2a.3a.4f.5d.,1b.2a.3a.4f.5d.,1f.2a.3a.4f.5d.,
1h.2a.3a.4f.5d.,1j.2a.3a.4f.5d.,1p.2a.3a.4f.5d.,
1a.2b.3a.4f.5d.,1b.2b.3a.4f.5d.,1f.2b.3a.4f.5d.,
1h.2b.3a.4f.5d.,1j.2b.3a.4f.5d.,1p.2b.3a.4f.5d.,
1a.2e.3a.4f.5d.,1b.2e.3a.4f.5d.,1f.2e.3a.4f.5d.,
1h.2e.3a.4f.5d.,1j.2e.3a.4f.5d.,1p.2e.3a.4f.5d.,
1a.2f.3a.4f.5d.,1b.2f.3a.4f.5d.,1f.2f.3a.4f.5d.,
1h.2f.3a.4f.5d.,1j.2f.3a.4f.5d.,1p.2f.3a.4f.5d.,
1a.2i.3a.4f.5d.,1b.2i.3a.4f.5d.,1f.2i.3a.4f.5d.,
1h.2i.3a.4f.5d.,1j.2i.3a.4f.5d.,1p.2i.3a.4f.5d.,
1a.2m.3a.4f.5d.,1b.2m.3a.4f.5d.,1f.2m.3a.4f.5d.,
1h.2m.3a.4f.5d.,1j.2m.3a.4f.5d.,1p.2m.3a.4f.5d.,
1a.2o.3a.4f.5d.,1b.2o.3a.4f.5d.,1f.2o.3a.4f.5d.,
1h.2o.3a.4f.5d.,1j.2o.3a.4f.5d.,1p.2o.3a.4f.5d.,
1a.2u.3a.4f.5d.,1b.2u.3a.4f.5d.,1f.2u.3a.4f.5d.,
1h.2u.3a.4f.5d.,1j.2u.3a.4f.5d.,1p.2u.3a.4f.5d.,
1a.2y.3a.4f.5d.,1b.2y.3a.4f.5d.,1f.2y.3a.4f.5d.,
1h.2y.3a.4f.5d.,1j.2y.3a.4f.5d.,1p.2y.3a.4f.5d.,
1a.2a.3b.4f.5d.,1b.2a.3b.4f.5d.,1f.2a.3b.4f.5d.,
1h.2a.3b.4f.5d.,1j.2a.3b.4f.5d.,1p.2a.3b.4f.5d.,
1a.2b.3b.4f.5d.,1b.2b.3b.4f.5d.,1f.2b.3b.4f.5d.,
1h.2b.3b.4f.5d.,1j.2b.3b.4f.5d.,1p.2b.3b.4f.5d.,
1a.2e.3b.4f.5d.,1b.2e.3b.4f.5d.,1f.2e.3b.4f.5d.,
1h.2e.3b.4f.5d.,1j.2e.3b.4f.5d.,1p.2e.3b.4f.5d.,
1a.2f.3b.4f.5d.,1b.2f.3b.4f.5d.,1f.2f.3b.4f.5d.,
1h.2f.3b.4f.5d.,1j.2f.3b.4f.5d.,1p.2f.3b.4f.5d.,
1a.2i.3b.4f.5d.,1b.2i.3b.4f.5d.,1f.2i.3b.4f.5d.,
1h.2i.3b.4f.5d.,1j.2i.3b.4f.5d.,1p.2i.3b.4f.5d.,
1a.2m.3b.4f.5d.,1b.2m.3b.4f.5d.,1f.2m.3b.4f.5d.,
1h.2m.3b.4f.5d.,1j.2m.3b.4f.5d.,1p.2m.3b.4f.5d.,
1a.2o.3b.4f.5d.,1b.2o.3b.4f.5d.,1f.2o.3b.4f.5d.,
1h.2o.3b.4f.5d.,1j.2o.3b.4f.5d.,1p.2o.3b.4f.5d.,
1a.2u.3b.4f.5d.,1b.2u.3b.4f.5d.,1f.2u.3b.4f.5d.,
1h.2u.3b.4f.5d.,1j.2u.3b.4f.5d.,1p.2u.3b.4f.5d.,
1a.2y.3b.4f.5d.,1b.2y.3b.4f.5d.,1f.2y.3b.4f.5d.,
1h.2y.3b.4f.5d.,1j.2y.3b.4f.5d.,1p.2y.3b.4f.5d.,
1a.2a.3e.4f.5d.,1b.2a.3e.4f.5d.,1f.2a.3e.4f.5d.,
1h.2a.3e.4f.5d.,1j.2a.3e.4f.5d.,1p.2a.3e.4f.5d.,
1a.2b.3e.4f.5d.,1b.2b.3e.4f.5d.,1f.2b.3e.4f.5d.,
1h.2b.3e.4f.5d.,1j.2b.3e.4f.5d.,1p.2b.3e.4f.5d.,
1a.2e.3e.4f.5d.,1b.2e.3e.4f.5d.,1f.2e.3e.4f.5d.,
1h.2e.3e.4f.5d.,1j.2e.3e.4f.5d.,1p.2e.3e.4f.5d.,
1a.2f.3e.4f.5d.,1b.2f.3e.4f.5d.,1f.2f.3e.4f.5d.,
1h.2f.3e.4f.5d.,1j.2f.3e.4f.5d.,1p.2f.3e.4f.5d.,
1a.2i.3e.4f.5d.,1b.2i.3e.4f.5d.,1f.2i.3e.4f.5d.,
1h.2i.3e.4f.5d.,1j.2i.3e.4f.5d.,1p.2i.3e.4f.5d.,
1a.2m.3e.4f.5d.,1b.2m.3e.4f.5d.,1f.2m.3e.4f.5d.,
1h.2m.3e.4f.5d.,1j.2m.3e.4f.5d.,1p.2m.3e.4f.5d.,
1a.2o.3e.4f.5d.,1b.2o.3e.4f.5d.,1f.2o.3e.4f.5d.,
1h.2o.3e.4f.5d.,1j.2o.3e.4f.5d.,1p.2o.3e.4f.5d.,
1a.2u.3e.4f.5d.,1b.2u.3e.4f.5d.,1f.2u.3e.4f.5d.,
1h.2u.3e.4f.5d.,1j.2u.3e.4f.5d.,1p.2u.3e.4f.5d.,
1a.2y.3e.4f.5d.,1b.2y.3e.4f.5d.,1f.2y.3e.4f.5d.,
1h.2y.3e.4f.5d.,1j.2y.3e.4f.5d.,1p.2y.3e.4f.5d.,
1a.2a.3g.4f.5d.,1b.2a.3g.4f.5d.,1f.2a.3g.4f.5d.,
1h.2a.3g.4f.5d.,1j.2a.3g.4f.5d.,1p.2a.3g.4f.5d.,
1a.2b.3g.4f.5d.,1b.2b.3g.4f.5d.,1f.2b.3g.4f.5d.,
1h.2b.3g.4f.5d.,1j.2b.3g.4f.5d.,1p.2b.3g.4f.5d.,
1a.2e.3g.4f.5d.,1b.2e.3g.4f.5d.,1f.2e.3g.4f.5d.,
1h.2e.3g.4f.5d.,1j.2e.3g.4f.5d.,1p.2e.3g.4f.5d.,
1a.2f.3g.4f.5d.,1b.2f.3g.4f.5d.,1f.2f.3g.4f.5d.,
1h.2f.3g.4f.5d.,1j.2f.3g.4f.5d.,1p.2f.3g.4f.5d.,
1a.2i.3g.4f.5d.,1b.2i.3g.4f.5d.,1f.2i.3g.4f.5d.,
1h.2i.3g.4f.5d.,1j.2i.3g.4f.5d.,1p.2i.3g.4f.5d.,
1a.2m.3g.4f.5d.,1b.2m.3g.4f.5d.,1f.2m.3g.4f.5d.,
1h.2m.3g.4f.5d.,1j.2m.3g.4f.5d.,1p.2m.3g.4f.5d.,
1a.2o.3g.4f.5d.,1b.2o.3g.4f.5d.,1f.2o.3g.4f.5d.,
1h.2o.3g.4f.5d.,1j.2o.3g.4f.5d.,1p.2o.3g.4f.5d.,
1a.2u.3g.4f.5d.,1b.2u.3g.4f.5d.,1f.2u.3g.4f.5d.,
1h.2u.3g.4f.5d.,1j.2u.3g.4f.5d.,1p.2u.3g.4f.5d.,
1a.2y.3g.4f.5d.,1b.2y.3g.4f.5d.,1f.2y.3g.4f.5d.,
1h.2y.3g.4f.5d.,1j.2y.3g.4f.5d.,1p.2y.3g.4f.5d.,
1a.2a.3a.4g.5d.,1b.2a.3a.4g.5d.,1f.2a.3a.4g.5d.,
1h.2a.3a.4g.5d.,1j.2a.3a.4g.5d.,1p.2a.3a.4g.5d.,
1a.2b.3a.4g.5d.,1b.2b.3a.4g.5d.,1f.2b.3a.4g.5d.,
1h.2b.3a.4g.5d.,1j.2b.3a.4g.5d.,1p.2b.3a.4g.5d.,
1a.2e.3a.4g.5d.,1b.2e.3a.4g.5d.,1f.2e.3a.4g.5d.,
1h.2e.3a.4g.5d.,1j.2e.3a.4g.5d.,1p.2e.3a.4g.5d.,
1a.2f.3a.4g.5d.,1b.2f.3a.4g.5d.,1f.2f.3a.4g.5d.,
1h.2f.3a.4g.5d.,1j.2f.3a.4g.5d.,1p.2f.3a.4g.5d.,
1a.2i.3a.4g.5d.,1b.2i.3a.4g.5d.,1f.2i.3a.4g.5d.,
1h.2i.3a.4g.5d.,1j.2i.3a.4g.5d.,1p.2i.3a.4g.5d.,
1a.2m.3a.4g.5d.,1b.2m.3a.4g.5d.,1f.2m.3a.4g.5d.,
1h.2m.3a.4g.5d.,1j.2m.3a.4g.5d.,1p.2m.3a.4g.5d.,
1a.2o.3a.4g.5d.,1b.2o.3a.4g.5d.,1f.2o.3a.4g.5d.,
1h.2o.3a.4g.5d.,1j.2o.3a.4g.5d.,1p.2o.3a.4g.5d.,
1a.2u.3a.4g.5d.,1b.2u.3a.4g.5d.,1f.2u.3a.4g.5d.,
1h.2u.3a.4g.5d.,1j.2u.3a.4g.5d.,1p.2u.3a.4g.5d.,
1a.2y.3a.4g.5d.,1b.2y.3a.4g.5d.,1f.2y.3a.4g.5d.,
1h.2y.3a.4g.5d.,1j.2y.3a.4g.5d.,1p.2y.3a.4g.5d.,
1a.2a.3b.4g.5d.,1b.2a.3b.4g.5d.,1f.2a.3b.4g.5d.,
1h.2a.3b.4g.5d.,1j.2a.3b.4g.5d.,1p.2a.3b.4g.5d.,
1a.2b.3b.4g.5d.,1b.2b.3b.4g.5d.,1f.2b.3b.4g.5d.,
1h.2b.3b.4g.5d.,1j.2b.3b.4g.5d.,1p.2b.3b.4g.5d.,
1a.2e.3b.4g.5d.,1b.2e.3b.4g.5d.,1f.2e.3b.4g.5d.,
1h.2e.3b.4g.5d.,1j.2e.3b.4g.5d.,1p.2e.3b.4g.5d.,
1a.2f.3b.4g.5d.,1b.2f.3b.4g.5d.,1f.2f.3b.4g.5d.,
1h.2f.3b.4g.5d.,1j.2f.3b.4g.5d.,1p.2f.3b.4g.5d.,
1a.2i.3b.4g.5d.,1b.2i.3b.4g.5d.,1f.2i.3b.4g.5d.,
1h.2i.3b.4g.5d.,1j.2i.3b.4g.5d.,1p.2i.3b.4g.5d.,
1a.2m.3b.4g.5d.,1b.2m.3b.4g.5d.,1f.2m.3b.4g.5d.,
1h.2m.3b.4g.5d.,1j.2m.3b.4g.5d.,1p.2m.3b.4g.5d.,
1a.2o.3b.4g.5d.,1b.2o.3b.4g.5d.,1f.2o.3b.4g.5d.,
1h.2o.3b.4g.5d.,1j.2o.3b.4g.5d.,1p.2o.3b.4g.5d.,
1a.2u.3b.4g.5d.,1b.2u.3b.4g.5d.,1f.2u.3b.4g.5d.,
1h.2u.3b.4g.5d.,1j.2u.3b.4g.5d.,1p.2u.3b.4g.5d.,
1a.2y.3b.4g.5d.,1b.2y.3b.4g.5d.,1f.2y.3b.4g.5d.,
1h.2y.3b.4g.5d.,1j.2y.3b.4g.5d.,1p.2y.3b.4g.5d.,
1a.2a.3e.4g.5d.,1b.2a.3e.4g.5d.,1f.2a.3e.4g.5d.,
1h.2a.3e.4g.5d.,1j.2a.3e.4g.5d.,1p.2a.3e.4g.5d.,
1a.2b.3e.4g.5d.,1b.2b.3e.4g.5d.,1f.2b.3e.4g.5d.,
1h.2b.3e.4g.5d.,1j.2b.3e.4g.5d.,1p.2b.3e.4g.5d.,
1a.2e.3e.4g.5d.,1b.2e.3e.4g.5d.,1f.2e.3e.4g.5d.,
1h.2e.3e.4g.5d.,1j.2e.3e.4g.5d.,1p.2e.3e.4g.5d.,
1a.2f.3e.4g.5d.,1b.2f.3e.4g.5d.,1f.2f.3e.4g.5d.,
1h.2f.3e.4g.5d.,1j.2f.3e.4g.5d.,1p.2f.3e.4g.5d.,
1a.2i.3e.4g.5d.,1b.2i.3e.4g.5d.,1f.2i.3e.4g.5d.,
1h.2i.3e.4g.5d.,1j.2i.3e.4g.5d.,1p.2i.3e.4g.5d.,
1a.2m.3e.4g.5d.,1b.2m.3e.4g.5d.,1f.2m.3e.4g.5d.,
1h.2m.3e.4g.5d.,1j.2m.3e.4g.5d.,1p.2m.3e.4g.5d.,
1a.2o.3e.4g.5d.,1b.2o.3e.4g.5d.,1f.2o.3e.4g.5d.,
1h.2o.3e.4g.5d.,1j.2o.3e.4g.5d.,1p.2o.3e.4g.5d.,
1a.2u.3e.4g.5d.,1b.2u.3e.4g.5d.,1f.2u.3e.4g.5d.,
1h.2u.3e.4g.5d.,1j.2u.3e.4g.5d.,1p.2u.3e.4g.5d.,
1a.2y.3e.4g.5d.,1b.2y.3e.4g.5d.,1f.2y.3e.4g.5d.,
1h.2y.3e.4g.5d.,1j.2y.3e.4g.5d.,1p.2y.3e.4g.5d.,
1a.2a.3g.4g.5d.,1b.2a.3g.4g.5d.,1f.2a.3g.4g.5d.,
1h.2a.3g.4g.5d.,1j.2a.3g.4g.5d.,1p.2a.3g.4g.5d.,
1a.2b.3g.4g.5d.,1b.2b.3g.4g.5d.,1f.2b.3g.4g.5d.,
1h.2b.3g.4g.5d.,1j.2b.3g.4g.5d.,1p.2b.3g.4g.5d.,
1a.2e.3g.4g.5d.,1b.2e.3g.4g.5d.,1f.2e.3g.4g.5d.,
1h.2e.3g.4g.5d.,1j.2e.3g.4g.5d.,1p.2e.3g.4g.5d.,
1a.2f.3g.4g.5d.,1b.2f.3g.4g.5d.,1f.2f.3g.4g.5d.,
1h.2f.3g.4g.5d.,1j.2f.3g.4g.5d.,1p.2f.3g.4g.5d.,
1a.2i.3g.4g.5d.,1b.2i.3g.4g.5d.,1f.2i.3g.4g.5d.,
1h.2i.3g.4g.5d.,1j.2i.3g.4g.5d.,1p.2i.3g.4g.5d.,
1a.2m.3g.4g.5d.,1b.2m.3g.4g.5d.,1f.2m.3g.4g.5d.,
1h.2m.3g.4g.5d.,1j.2m.3g.4g.5d.,1p.2m.3g.4g.5d.,
1a.2o.3g.4g.5d.,1b.2o.3g.4g.5d.,1f.2o.3g.4g.5d.,
1h.2o.3g.4g.5d.,1j.2o.3g.4g.5d.,1p.2o.3g.4g.5d.,
1a.2u.3g.4g.5d.,1b.2u.3g.4g.5d.,1f.2u.3g.4g.5d.,
1h.2u.3g.4g.5d.,1j.2u.3g.4g.5d.,1p.2u.3g.4g.5d.,
1a.2y.3g.4g.5d.,1b.2y.3g.4g.5d.,1f.2y.3g.4g.5d.,
1h.2y.3g.4g.5d.,1j.2y.3g.4g.5d.,1p.2y.3g.4g.5d.,
1a.2a.3a.4h.5d.,1b.2a.3a.4h.5d.,1f.2a.3a.4h.5d.,
1h.2a.3a.4h.5d.,1j.2a.3a.4h.5d.,1p.2a.3a.4h.5d.,
1a.2b.3a.4h.5d.,1b.2b.3a.4h.5d.,1f.2b.3a.4h.5d.,
1h.2b.3a.4h.5d.,1j.2b.3a.4h.5d.,1p.2b.3a.4h.5d.,
1a.2e.3a.4h.5d.,1b.2e.3a.4h.5d.,1f.2e.3a.4h.5d.,
1h.2e.3a.4h.5d.,1j.2e.3a.4h.5d.,1p.2e.3a.4h.5d.,
1a.2f.3a.4h.5d.,1b.2f.3a.4h.5d.,1f.2f.3a.4h.5d.,
1h.2f.3a.4h.5d.,1j.2f.3a.4h.5d.,1p.2f.3a.4h.5d.,
1a.2i.3a.4h.5d.,1b.2i.3a.4h.5d.,1f.2i.3a.4h.5d.,
1h.2i.3a.4h.5d.,1j.2i.3a.4h.5d.,1p.2i.3a.4h.5d.,
1a.2m.3a.4h.5d.,1b.2m.3a.4h.5d.,1f.2m.3a.4h.5d.,
1h.2m.3a.4h.5d.,1j.2m.3a.4h.5d.,1p.2m.3a.4h.5d.,
1a.2o.3a.4h.5d.,1b.2o.3a.4h.5d.,1f.2o.3a.4h.5d.,
1h.2o.3a.4h.5d.,1j.2o.3a.4h.5d.,1p.2o.3a.4h.5d.,
1a.2u.3a.4h.5d.,1b.2u.3a.4h.5d.,1f.2u.3a.4h.5d.,
1h.2u.3a.4h.5d.,1j.2u.3a.4h.5d.,1p.2u.3a.4h.5d.,
1a.2y.3a.4h.5d.,1b.2y.3a.4h.5d.,1f.2y.3a.4h.5d.,
1h.2y.3a.4h.5d.,1j.2y.3a.4h.5d.,1p.2y.3a.4h.5d.,
1a.2a.3b.4h.5d.,1b.2a.3b.4h.5d.,1f.2a.3b.4h.5d.,
1h.2a.3b.4h.5d.,1j.2a.3b.4h.5d.,1p.2a.3b.4h.5d.,
1a.2b.3b.4h.5d.,1b.2b.3b.4h.5d.,1f.2b.3b.4h.5d.,
1h.2b.3b.4h.5d.,1j.2b.3b.4h.5d.,1p.2b.3b.4h.5d.,
1a.2e.3b.4h.5d.,1b.2e.3b.4h.5d.,1f.2e.3b.4h.5d.,
1h.2e.3b.4h.5d.,1j.2e.3b.4h.5d.,1p.2e.3b.4h.5d.,
1a.2f.3b.4h.5d.,1b.2f.3b.4h.5d.,1f.2f.3b.4h.5d.,
1h.2f.3b.4h.5d.,1j.2f.3b.4h.5d.,1p.2f.3b.4h.5d.,
1a.2i.3b.4h.5d.,1b.2i.3b.4h.5d.,1f.2i.3b.4h.5d.,
1h.2i.3b.4h.5d.,1j.2i.3b.4h.5d.,1p.2i.3b.4h.5d.,
1a.2m.3b.4h.5d.,1b.2m.3b.4h.5d.,1f.2m.3b.4h.5d.,
1h.2m.3b.4h.5d.,1j.2m.3b.4h.5d.,1p.2m.3b.4h.5d.,
1a.2o.3b.4h.5d.,1b.2o.3b.4h.5d.,1f.2o.3b.4h.5d.,
1h.2o.3b.4h.5d.,1j.2o.3b.4h.5d.,1p.2o.3b.4h.5d.,
1a.2u.3b.4h.5d.,1b.2u.3b.4h.5d.,1f.2u.3b.4h.5d.,
1h.2u.3b.4h.5d.,1j.2u.3b.4h.5d.,1p.2u.3b.4h.5d.,
1a.2y.3b.4h.5d.,1b.2y.3b.4h.5d.,1f.2y.3b.4h.5d.,
1h.2y.3b.4h.5d.,1j.2y.3b.4h.5d.,1p.2y.3b.4h.5d.,
1a.2a.3e.4h.5d.,1b.2a.3e.4h.5d.,1f.2a.3e.4h.5d.,
1h.2a.3e.4h.5d.,1j.2a.3e.4h.5d.,1p.2a.3e.4h.5d.,
1a.2b.3e.4h.5d.,1b.2b.3e.4h.5d.,1f.2b.3e.4h.5d.,
1h.2b.3e.4h.5d.,1j.2b.3e.4h.5d.,1p.2b.3e.4h.5d.,
1a.2e.3e.4h.5d.,1b.2e.3e.4h.5d.,1f.2e.3e.4h.5d.,
1h.2e.3e.4h.5d.,1j.2e.3e.4h.5d.,1p.2e.3e.4h.5d.,
1a.2f.3e.4h.5d.,1b.2f.3e.4h.5d.,1f.2f.3e.4h.5d.,
1h.2f.3e.4h.5d.,1j.2f.3e.4h.5d.,1p.2f.3e.4h.5d.,
1a.2i.3e.4h.5d.,1b.2i.3e.4h.5d.,1f.2i.3e.4h.5d.,
1h.2i.3e.4h.5d.,1j.2i.3e.4h.5d.,1p.2i.3e.4h.5d.,
1a.2m.3e.4h.5d.,1b.2m.3e.4h.5d.,1f.2m.3e.4h.5d.,
1h.2m.3e.4h.5d.,1j.2m.3e.4h.5d.,1p.2m.3e.4h.5d.,
1a.2o.3e.4h.5d.,1b.2o.3e.4h.5d.,1f.2o.3e.4h.5d.,
1h.2o.3e.4h.5d.,1j.2o.3e.4h.5d.,1p.2o.3e.4h.5d.,
1a.2u.3e.4h.5d.,1b.2u.3e.4h.5d.,1f.2u.3e.4h.5d.,
1h.2u.3e.4h.5d.,1j.2u.3e.4h.5d.,1p.2u.3e.4h.5d.,
1a.2y.3e.4h.5d.,1b.2y.3e.4h.5d.,1f.2y.3e.4h.5d.,
1h.2y.3e.4h.5d.,1j.2y.3e.4h.5d.,1p.2y.3e.4h.5d.,
1a.2a.3g.4h.5d.,1b.2a.3g.4h.5d.,1f.2a.3g.4h.5d.,
1h.2a.3g.4h.5d.,1j.2a.3g.4h.5d.,1p.2a.3g.4h.5d.,
1a.2b.3g.4h.5d.,1b.2b.3g.4h.5d.,1f.2b.3g.4h.5d.,
1h.2b.3g.4h.5d.,1j.2b.3g.4h.5d.,1p.2b.3g.4h.5d.,
1a.2e.3g.4h.5d.,1b.2e.3g.4h.5d.,1f.2e.3g.4h.5d.,
1h.2e.3g.4h.5d.,1j.2e.3g.4h.5d.,1p.2e.3g.4h.5d.,
1a.2f.3g.4h.5d.,1b.2f.3g.4h.5d.,1f.2f.3g.4h.5d.,
1h.2f.3g.4h.5d.,1j.2f.3g.4h.5d.,1p.2f.3g.4h.5d.,
1a.2i.3g.4h.5d.,1b.2i.3g.4h.5d.,1f.2i.3g.4h.5d.,
1h.2i.3g.4h.5d.,1j.2i.3g.4h.5d.,1p.2i.3g.4h.5d.,
1a.2m.3g.4h.5d.,1b.2m.3g.4h.5d.,1f.2m.3g.4h.5d.,
1h.2m.3g.4h.5d.,1j.2m.3g.4h.5d.,1p.2m.3g.4h.5d.,
1a.2o.3g.4h.5d.,1b.2o.3g.4h.5d.,1f.2o.3g.4h.5d.,
1h.2o.3g.4h.5d.,1j.2o.3g.4h.5d.,1p.2o.3g.4h.5d.,
1a.2u.3g.4h.5d.,1b.2u.3g.4h.5d.,1f.2u.3g.4h.5d.,
1h.2u.3g.4h.5d.,1j.2u.3g.4h.5d.,1p.2u.3g.4h.5d.,
1a.2y.3g.4h.5d.,1b.2y.3g.4h.5d.,1f.2y.3g.4h.5d.,
1h.2y.3g.4h.5d.,1j.2y.3g.4h.5d.,1p.2y.3g.4h.5d.,
1a.2a.3a.4i.5d.,1b.2a.3a.4i.5d.,1f.2a.3a.4i.5d.,
1h.2a.3a.4i.5d.,1j.2a.3a.4i.5d.,1p.2a.3a.4i.5d.,
1a.2b.3a.4i.5d.,1b.2b.3a.4i.5d.,1f.2b.3a.4i.5d.,
1h.2b.3a.4i.5d.,1j.2b.3a.4i.5d.,1p.2b.3a.4i.5d.,
1a.2e.3a.4i.5d.,1b.2e.3a.4i.5d.,1f.2e.3a.4i.5d.,
1h.2e.3a.4i.5d.,1j.2e.3a.4i.5d.,1p.2e.3a.4i.5d.,
1a.2f.3a.4i.5d.,1b.2f.3a.4i.5d.,1f.2f.3a.4i.5d.,
1h.2f.3a.4i.5d.,1j.2f.3a.4i.5d.,1p.2f.3a.4i.5d.,
1a.2i.3a.4i.5d.,1b.2i.3a.4i.5d.,1f.2i.3a.4i.5d.,
1h.2i.3a.4i.5d.,1j.2i.3a.4i.5d.,1p.2i.3a.4i.5d.,
1a.2m.3a.4i.5d.,1b.2m.3a.4i.5d.,1f.2m.3a.4i.5d.,
1h.2m.3a.4i.5d.,1j.2m.3a.4i.5d.,1p.2m.3a.4i.5d.,
1a.2o.3a.4i.5d.,1b.2o.3a.4i.5d.,1f.2o.3a.4i.5d.,
1h.2o.3a.4i.5d.,1j.2o.3a.4i.5d.,1p.2o.3a.4i.5d.,
1a.2u.3a.4i.5d.,1b.2u.3a.4i.5d.,1f.2u.3a.4i.5d.,
1h.2u.3a.4i.5d.,1j.2u.3a.4i.5d.,1p.2u.3a.4i.5d.,
1a.2y.3a.4i.5d.,1b.2y.3a.4i.5d.,1f.2y.3a.4i.5d.,
1h.2y.3a.4i.5d.,1j.2y.3a.4i.5d.,1p.2y.3a.4i.5d.,
1a.2a.3b.4i.5d.,1b.2a.3b.4i.5d.,1f.2a.3b.4i.5d.,
1h.2a.3b.4i.5d.,1j.2a.3b.4i.5d.,1p.2a.3b.4i.5d.,
1a.2b.3b.4i.5d.,1b.2b.3b.4i.5d.,1f.2b.3b.4i.5d.,
1h.2b.3b.4i.5d.,1j.2b.3b.4i.5d.,1p.2b.3b.4i.5d.,
1a.2e.3b.4i.5d.,1b.2e.3b.4i.5d.,1f.2e.3b.4i.5d.,
1h.2e.3b.4i.5d.,1j.2e.3b.4i.5d.,1p.2e.3b.4i.5d.,
1a.2f.3b.4i.5d.,1b.2f.3b.4i.5d.,1f.2f.3b.4i.5d.,
1h.2f.3b.4i.5d.,1j.2f.3b.4i.5d.,1p.2f.3b.4i.5d.,
1a.2i.3b.4i.5d.,1b.2i.3b.4i.5d.,1f.2i.3b.4i.5d.,
1h.2i.3b.4i.5d.,1j.2i.3b.4i.5d.,1p.2i.3b.4i.5d.,
1a.2m.3b.4i.5d.,1b.2m.3b.4i.5d.,1f.2m.3b.4i.5d.,
1h.2m.3b.4i.5d.,1j.2m.3b.4i.5d.,1p.2m.3b.4i.5d.,
1a.2o.3b.4i.5d.,1b.2o.3b.4i.5d.,1f.2o.3b.4i.5d.,
1h.2o.3b.4i.5d.,1j.2o.3b.4i.5d.,1p.2o.3b.4i.5d.,
1a.2u.3b.4i.5d.,1b.2u.3b.4i.5d.,1f.2u.3b.4i.5d.,
1h.2u.3b.4i.5d.,1j.2u.3b.4i.5d.,1p.2u.3b.4i.5d.,
1a.2y.3b.4i.5d.,1b.2y.3b.4i.5d.,1f.2y.3b.4i.5d.,
1h.2y.3b.4i.5d.,1j.2y.3b.4i.5d.,1p.2y.3b.4i.5d.,
1a.2a.3e.4i.5d.,1b.2a.3e.4i.5d.,1f.2a.3e.4i.5d.,
1h.2a.3e.4i.5d.,1j.2a.3e.4i.5d.,1p.2a.3e.4i.5d.,
1a.2b.3e.4i.5d.,1b.2b.3e.4i.5d.,1f.2b.3e.4i.5d.,
1h.2b.3e.4i.5d.,1j.2b.3e.4i.5d.,1p.2b.3e.4i.5d.,
1a.2e.3e.4i.5d.,1b.2e.3e.4i.5d.,1f.2e.3e.4i.5d.,
1h.2e.3e.4i.5d.,1j.2e.3e.4i.5d.,1p.2e.3e.4i.5d.,
1a.2f.3e.4i.5d.,1b.2f.3e.4i.5d.,1f.2f.3e.4i.5d.,
1h.2f.3e.4i.5d.,1j.2f.3e.4i.5d.,1p.2f.3e.4i.5d.,
1a.2i.3e.4i.5d.,1b.2i.3e.4i.5d.,1f.2i.3e.4i.5d.,
1h.2i.3e.4i.5d.,1j.2i.3e.4i.5d.,1p.2i.3e.4i.5d.,
1a.2m.3e.4i.5d.,1b.2m.3e.4i.5d.,1f.2m.3e.4i.5d.,
1h.2m.3e.4i.5d.,1j.2m.3e.4i.5d.,1p.2m.3e.4i.5d.,
1a.2o.3e.4i.5d.,1b.2o.3e.4i.5d.,1f.2o.3e.4i.5d.,
1h.2o.3e.4i.5d.,1j.2o.3e.4i.5d.,1p.2o.3e.4i.5d.,
1a.2u.3e.4i.5d.,1b.2u.3e.4i.5d.,1f.2u.3e.4i.5d.,
1h.2u.3e.4i.5d.,1j.2u.3e.4i.5d.,1p.2u.3e.4i.5d.,
1a.2y.3e.4i.5d.,1b.2y.3e.4i.5d.,1f.2y.3e.4i.5d.,
1h.2y.3e.4i.5d.,1j.2y.3e.4i.5d.,1p.2y.3e.4i.5d.,
1a.2a.3g.4i.5d.,1b.2a.3g.4i.5d.,1f.2a.3g.4i.5d.,
1h.2a.3g.4i.5d.,1j.2a.3g.4i.5d.,1p.2a.3g.4i.5d.,
1a.2b.3g.4i.5d.,1b.2b.3g.4i.5d.,1f.2b.3g.4i.5d.,
1h.2b.3g.4i.5d.,1j.2b.3g.4i.5d.,1p.2b.3g.4i.5d.,
1a.2e.3g.4i.5d.,1b.2e.3g.4i.5d.,1f.2e.3g.4i.5d.,
1h.2e.3g.4i.5d.,1j.2e.3g.4i.5d.,1p.2e.3g.4i.5d.,
1a.2f.3g.4i.5d.,1b.2f.3g.4i.5d.,1f.2f.3g.4i.5d.,
1h.2f.3g.4i.5d.,1j.2f.3g.4i.5d.,1p.2f.3g.4i.5d.,
1a.2i.3g.4i.5d.,1b.2i.3g.4i.5d.,1f.2i.3g.4i.5d.,
1h.2i.3g.4i.5d.,1j.2i.3g.4i.5d.,1p.2i.3g.4i.5d.,
1a.2m.3g.4i.5d.,1b.2m.3g.4i.5d.,1f.2m.3g.4i.5d.,
1h.2m.3g.4i.5d.,1j.2m.3g.4i.5d.,1p.2m.3g.4i.5d.,
1a.2o.3g.4i.5d.,1b.2o.3g.4i.5d.,1f.2o.3g.4i.5d.,
1h.2o.3g.4i.5d.,1j.2o.3g.4i.5d.,1p.2o.3g.4i.5d.,
1a.2u.3g.4i.5d.,1b.2u.3g.4i.5d.,1f.2u.3g.4i.5d.,
1h.2u.3g.4i.5d.,1j.2u.3g.4i.5d.,1p.2u.3g.4i.5d.,
1a.2y.3g.4i.5d.,1b.2y.3g.4i.5d.,1f.2y.3g.4i.5d.,
1h.2y.3g.4i.5d.,1j.2y.3g.4i.5d.,1p.2y.3g.4i.5d.,
1a.2a.3a.4a.5f.,1b.2a.3a.4a.5f.,1f.2a.3a.4a.5f.,
1h.2a.3a.4a.5f.,1j.2a.3a.4a.5f.,1p.2a.3a.4a.5f.,
1a.2b.3a.4a.5f.,1b.2b.3a.4a.5f.,1f.2b.3a.4a.5f.,
1h.2b.3a.4a.5f.,1j.2b.3a.4a.5f.,1p.2b.3a.4a.5f.,
1a.2e.3a.4a.5f.,1b.2e.3a.4a.5f.,1f.2e.3a.4a.5f.,
1h.2e.3a.4a.5f.,1j.2e.3a.4a.5f.,1p.2e.3a.4a.5f.,
1a.2f.3a.4a.5f.,1b.2f.3a.4a.5f.,1f.2f.3a.4a.5f.,
1h.2f.3a.4a.5f.,1j.2f.3a.4a.5f.,1p.2f.3a.4a.5f.,
1a.2i.3a.4a.5f.,1b.2i.3a.4a.5f.,1f.2i.3a.4a.5f.,
1h.2i.3a.4a.5f.,1j.2i.3a.4a.5f.,1p.2i.3a.4a.5f.,
1a.2m.3a.4a.5f.,1b.2m.3a.4a.5f.,1f.2m.3a.4a.5f.,
1h.2m.3a.4a.5f.,1j.2m.3a.4a.5f.,1p.2m.3a.4a.5f.,
1a.2o.3a.4a.5f.,1b.2o.3a.4a.5f.,1f.2o.3a.4a.5f.,
1h.2o.3a.4a.5f.,1j.2o.3a.4a.5f.,1p.2o.3a.4a.5f.,
1a.2u.3a.4a.5f.,1b.2u.3a.4a.5f.,1f.2u.3a.4a.5f.,
1h.2u.3a.4a.5f.,1j.2u.3a.4a.5f.,1p.2u.3a.4a.5f.,
1a.2y.3a.4a.5f.,1b.2y.3a.4a.5f.,1f.2y.3a.4a.5f.,
1h.2y.3a.4a.5f.,1j.2y.3a.4a.5f.,1p.2y.3a.4a.5f.,
1a.2a.3b.4a.5f.,1b.2a.3b.4a.5f.,1f.2a.3b.4a.5f.,
1h.2a.3b.4a.5f.,1j.2a.3b.4a.5f.,1p.2a.3b.4a.5f.,
1a.2b.3b.4a.5f.,1b.2b.3b.4a.5f.,1f.2b.3b.4a.5f.,
1h.2b.3b.4a.5f.,1j.2b.3b.4a.5f.,1p.2b.3b.4a.5f.,
1a.2e.3b.4a.5f.,1b.2e.3b.4a.5f.,1f.2e.3b.4a.5f.,
1h.2e.3b.4a.5f.,1j.2e.3b.4a.5f.,1p.2e.3b.4a.5f.,
1a.2f.3b.4a.5f.,1b.2f.3b.4a.5f.,1f.2f.3b.4a.5f.,
1h.2f.3b.4a.5f.,1j.2f.3b.4a.5f.,1p.2f.3b.4a.5f.,
1a.2i.3b.4a.5f.,1b.2i.3b.4a.5f.,1f.2i.3b.4a.5f.,
1h.2i.3b.4a.5f.,1j.2i.3b.4a.5f.,1p.2i.3b.4a.5f.,
1a.2m.3b.4a.5f.,1b.2m.3b.4a.5f.,1f.2m.3b.4a.5f.,
1h.2m.3b.4a.5f.,1j.2m.3b.4a.5f.,1p.2m.3b.4a.5f.,
1a.2o.3b.4a.5f.,1b.2o.3b.4a.5f.,1f.2o.3b.4a.5f.,
1h.2o.3b.4a.5f.,1j.2o.3b.4a.5f.,1p.2o.3b.4a.5f.,
1a.2u.3b.4a.5f.,1b.2u.3b.4a.5f.,1f.2u.3b.4a.5f.,
1h.2u.3b.4a.5f.,1j.2u.3b.4a.5f.,1p.2u.3b.4a.5f.,
1a.2y.3b.4a.5f.,1b.2y.3b.4a.5f.,1f.2y.3b.4a.5f.,
1h.2y.3b.4a.5f.,1j.2y.3b.4a.5f.,1p.2y.3b.4a.5f.,
1a.2a.3e.4a.5f.,1b.2a.3e.4a.5f.,1f.2a.3e.4a.5f.,
1h.2a.3e.4a.5f.,1j.2a.3e.4a.5f.,1p.2a.3e.4a.5f.,
1a.2b.3e.4a.5f.,1b.2b.3e.4a.5f.,1f.2b.3e.4a.5f.,
1h.2b.3e.4a.5f.,1j.2b.3e.4a.5f.,1p.2b.3e.4a.5f.,
1a.2e.3e.4a.5f.,1b.2e.3e.4a.5f.,1f.2e.3e.4a.5f.,
1h.2e.3e.4a.5f.,1j.2e.3e.4a.5f.,1p.2e.3e.4a.5f.,
1a.2f.3e.4a.5f.,1b.2f.3e.4a.5f.,1f.2f.3e.4a.5f.,
1h.2f.3e.4a.5f.,1j.2f.3e.4a.5f.,1p.2f.3e.4a.5f.,
1a.2i.3e.4a.5f.,1b.2i.3e.4a.5f.,1f.2i.3e.4a.5f.,
1h.2i.3e.4a.5f.,1j.2i.3e.4a.5f.,1p.2i.3e.4a.5f.,
1a.2m.3e.4a.5f.,1b.2m.3e.4a.5f.,1f.2m.3e.4a.5f.,
1h.2m.3e.4a.5f.,1j.2m.3e.4a.5f.,1p.2m.3e.4a.5f.,
1a.2o.3e.4a.5f.,1b.2o.3e.4a.5f.,1f.2o.3e.4a.5f.,
1h.2o.3e.4a.5f.,1j.2o.3e.4a.5f.,1p.2o.3e.4a.5f.,
1a.2u.3e.4a.5f.,1b.2u.3e.4a.5f.,1f.2u.3e.4a.5f.,
1h.2u.3e.4a.5f.,1j.2u.3e.4a.5f.,1p.2u.3e.4a.5f.,
1a.2y.3e.4a.5f.,1b.2y.3e.4a.5f.,1f.2y.3e.4a.5f.,
1h.2y.3e.4a.5f.,1j.2y.3e.4a.5f.,1p.2y.3e.4a.5f.,
1a.2a.3g.4a.5f.,1b.2a.3g.4a.5f.,1f.2a.3g.4a.5f.,
1h.2a.3g.4a.5f.,1j.2a.3g.4a.5f.,1p.2a.3g.4a.5f.,
1a.2b.3g.4a.5f.,1b.2b.3g.4a.5f.,1f.2b.3g.4a.5f.,
1h.2b.3g.4a.5f.,1j.2b.3g.4a.5f.,1p.2b.3g.4a.5f.,
1a.2e.3g.4a.5f.,1b.2e.3g.4a.5f.,1f.2e.3g.4a.5f.,
1h.2e.3g.4a.5f.,1j.2e.3g.4a.5f.,1p.2e.3g.4a.5f.,
1a.2f.3g.4a.5f.,1b.2f.3g.4a.5f.,1f.2f.3g.4a.5f.,
1h.2f.3g.4a.5f.,1j.2f.3g.4a.5f.,1p.2f.3g.4a.5f.,
1a.2i.3g.4a.5f.,1b.2i.3g.4a.5f.,1f.2i.3g.4a.5f.,
1h.2i.3g.4a.5f.,1j.2i.3g.4a.5f.,1p.2i.3g.4a.5f.,
1a.2m.3g.4a.5f.,1b.2m.3g.4a.5f.,1f.2m.3g.4a.5f.,
1h.2m.3g.4a.5f.,1j.2m.3g.4a.5f.,1p.2m.3g.4a.5f.,
1a.2o.3g.4a.5f.,1b.2o.3g.4a.5f.,1f.2o.3g.4a.5f.,
1h.2o.3g.4a.5f.,1j.2o.3g.4a.5f.,1p.2o.3g.4a.5f.,
1a.2u.3g.4a.5f.,1b.2u.3g.4a.5f.,1f.2u.3g.4a.5f.,
1h.2u.3g.4a.5f.,1j.2u.3g.4a.5f.,1p.2u.3g.4a.5f.,
1a.2y.3g.4a.5f.,1b.2y.3g.4a.5f.,1f.2y.3g.4a.5f.,
1h.2y.3g.4a.5f.,1j.2y.3g.4a.5f.,1p.2y.3g.4a.5f.,
1a.2a.3a.4d.5f.,1b.2a.3a.4d.5f.,1f.2a.3a.4d.5f.,
1h.2a.3a.4d.5f.,1j.2a.3a.4d.5f.,1p.2a.3a.4d.5f.,
1a.2b.3a.4d.5f.,1b.2b.3a.4d.5f.,1f.2b.3a.4d.5f.,
1h.2b.3a.4d.5f.,1j.2b.3a.4d.5f.,1p.2b.3a.4d.5f.,
1a.2e.3a.4d.5f.,1b.2e.3a.4d.5f.,1f.2e.3a.4d.5f.,
1h.2e.3a.4d.5f.,1j.2e.3a.4d.5f.,1p.2e.3a.4d.5f.,
1a.2f.3a.4d.5f.,1b.2f.3a.4d.5f.,1f.2f.3a.4d.5f.,
1h.2f.3a.4d.5f.,1j.2f.3a.4d.5f.,1p.2f.3a.4d.5f.,
1a.2i.3a.4d.5f.,1b.2i.3a.4d.5f.,1f.2i.3a.4d.5f.,
1h.2i.3a.4d.5f.,1j.2i.3a.4d.5f.,1p.2i.3a.4d.5f.,
1a.2m.3a.4d.5f.,1b.2m.3a.4d.5f.,1f.2m.3a.4d.5f.,
1h.2m.3a.4d.5f.,1j.2m.3a.4d.5f.,1p.2m.3a.4d.5f.,
1a.2o.3a.4d.5f.,1b.2o.3a.4d.5f.,1f.2o.3a.4d.5f.,
1h.2o.3a.4d.5f.,1j.2o.3a.4d.5f.,1p.2o.3a.4d.5f.,
1a.2u.3a.4d.5f.,1b.2u.3a.4d.5f.,1f.2u.3a.4d.5f.,
1h.2u.3a.4d.5f.,1j.2u.3a.4d.5f.,1p.2u.3a.4d.5f.,
1a.2y.3a.4d.5f.,1b.2y.3a.4d.5f.,1f.2y.3a.4d.5f.,
1h.2y.3a.4d.5f.,1j.2y.3a.4d.5f.,1p.2y.3a.4d.5f.,
1a.2a.3b.4d.5f.,1b.2a.3b.4d.5f.,1f.2a.3b.4d.5f.,
1h.2a.3b.4d.5f.,1j.2a.3b.4d.5f.,1p.2a.3b.4d.5f.,
1a.2b.3b.4d.5f.,1b.2b.3b.4d.5f.,1f.2b.3b.4d.5f.,
1h.2b.3b.4d.5f.,1j.2b.3b.4d.5f.,1p.2b.3b.4d.5f.,
1a.2e.3b.4d.5f.,1b.2e.3b.4d.5f.,1f.2e.3b.4d.5f.,
1h.2e.3b.4d.5f.,1j.2e.3b.4d.5f.,1p.2e.3b.4d.5f.,
1a.2f.3b.4d.5f.,1b.2f.3b.4d.5f.,1f.2f.3b.4d.5f.,
1h.2f.3b.4d.5f.,1j.2f.3b.4d.5f.,1p.2f.3b.4d.5f.,
1a.2i.3b.4d.5f.,1b.2i.3b.4d.5f.,1f.2i.3b.4d.5f.,
1h.2i.3b.4d.5f.,1j.2i.3b.4d.5f.,1p.2i.3b.4d.5f.,
1a.2m.3b.4d.5f.,1b.2m.3b.4d.5f.,1f.2m.3b.4d.5f.,
1h.2m.3b.4d.5f.,1j.2m.3b.4d.5f.,1p.2m.3b.4d.5f.,
1a.2o.3b.4d.5f.,1b.2o.3b.4d.5f.,1f.2o.3b.4d.5f.,
1h.2o.3b.4d.5f.,1j.2o.3b.4d.5f.,1p.2o.3b.4d.5f.,
1a.2u.3b.4d.5f.,1b.2u.3b.4d.5f.,1f.2u.3b.4d.5f.,
1h.2u.3b.4d.5f.,1j.2u.3b.4d.5f.,1p.2u.3b.4d.5f.,
1a.2y.3b.4d.5f.,1b.2y.3b.4d.5f.,1f.2y.3b.4d.5f.,
1h.2y.3b.4d.5f.,1j.2y.3b.4d.5f.,1p.2y.3b.4d.5f.,
1a.2a.3e.4d.5f.,1b.2a.3e.4d.5f.,1f.2a.3e.4d.5f.,
1h.2a.3e.4d.5f.,1j.2a.3e.4d.5f.,1p.2a.3e.4d.5f.,
1a.2b.3e.4d.5f.,1b.2b.3e.4d.5f.,1f.2b.3e.4d.5f.,
1h.2b.3e.4d.5f.,1j.2b.3e.4d.5f.,1p.2b.3e.4d.5f.,
1a.2e.3e.4d.5f.,1b.2e.3e.4d.5f.,1f.2e.3e.4d.5f.,
1h.2e.3e.4d.5f.,1j.2e.3e.4d.5f.,1p.2e.3e.4d.5f.,
1a.2f.3e.4d.5f.,1b.2f.3e.4d.5f.,1f.2f.3e.4d.5f.,
1h.2f.3e.4d.5f.,1j.2f.3e.4d.5f.,1p.2f.3e.4d.5f.,
1a.2i.3e.4d.5f.,1b.2i.3e.4d.5f.,1f.2i.3e.4d.5f.,
1h.2i.3e.4d.5f.,1j.2i.3e.4d.5f.,1p.2i.3e.4d.5f.,
1a.2m.3e.4d.5f.,1b.2m.3e.4d.5f.,1f.2m.3e.4d.5f.,
1h.2m.3e.4d.5f.,1j.2m.3e.4d.5f.,1p.2m.3e.4d.5f.,
1a.2o.3e.4d.5f.,1b.2o.3e.4d.5f.,1f.2o.3e.4d.5f.,
1h.2o.3e.4d.5f.,1j.2o.3e.4d.5f.,1p.2o.3e.4d.5f.,
1a.2u.3e.4d.5f.,1b.2u.3e.4d.5f.,1f.2u.3e.4d.5f.,
1h.2u.3e.4d.5f.,1j.2u.3e.4d.5f.,1p.2u.3e.4d.5f.,
1a.2y.3e.4d.5f.,1b.2y.3e.4d.5f.,1f.2y.3e.4d.5f.,
1h.2y.3e.4d.5f.,1j.2y.3e.4d.5f.,1p.2y.3e.4d.5f.,
1a.2a.3g.4d.5f.,1b.2a.3g.4d.5f.,1f.2a.3g.4d.5f.,
1h.2a.3g.4d.5f.,1j.2a.3g.4d.5f.,1p.2a.3g.4d.5f.,
1a.2b.3g.4d.5f.,1b.2b.3g.4d.5f.,1f.2b.3g.4d.5f.,
1h.2b.3g.4d.5f.,1j.2b.3g.4d.5f.,1p.2b.3g.4d.5f.,
1a.2e.3g.4d.5f.,1b.2e.3g.4d.5f.,1f.2e.3g.4d.5f.,
1h.2e.3g.4d.5f.,1j.2e.3g.4d.5f.,1p.2e.3g.4d.5f.,
1a.2f.3g.4d.5f.,1b.2f.3g.4d.5f.,1f.2f.3g.4d.5f.,
1h.2f.3g.4d.5f.,1j.2f.3g.4d.5f.,1p.2f.3g.4d.5f.,
1a.2i.3g.4d.5f.,1b.2i.3g.4d.5f.,1f.2i.3g.4d.5f.,
1h.2i.3g.4d.5f.,1j.2i.3g.4d.5f.,1p.2i.3g.4d.5f.,
1a.2m.3g.4d.5f.,1b.2m.3g.4d.5f.,1f.2m.3g.4d.5f.,
1h.2m.3g.4d.5f.,1j.2m.3g.4d.5f.,1p.2m.3g.4d.5f.,
1a.2o.3g.4d.5f.,1b.2o.3g.4d.5f.,1f.2o.3g.4d.5f.,
1h.2o.3g.4d.5f.,1j.2o.3g.4d.5f.,1p.2o.3g.4d.5f.,
1a.2u.3g.4d.5f.,1b.2u.3g.4d.5f.,1f.2u.3g.4d.5f.,
1h.2u.3g.4d.5f.,1j.2u.3g.4d.5f.,1p.2u.3g.4d.5f.,
1a.2y.3g.4d.5f.,1b.2y.3g.4d.5f.,1f.2y.3g.4d.5f.,
1h.2y.3g.4d.5f.,1j.2y.3g.4d.5f.,1p.2y.3g.4d.5f.,
1a.2a.3a.4f.5f.,1b.2a.3a.4f.5f.,1f.2a.3a.4f.5f.,
1h.2a.3a.4f.5f.,1j.2a.3a.4f.5f.,1p.2a.3a.4f.5f.,
1a.2b.3a.4f.5f.,1b.2b.3a.4f.5f.,1f.2b.3a.4f.5f.,
1h.2b.3a.4f.5f.,1j.2b.3a.4f.5f.,1p.2b.3a.4f.5f.,
1a.2e.3a.4f.5f.,1b.2e.3a.4f.5f.,1f.2e.3a.4f.5f.,
1h.2e.3a.4f.5f.,1j.2e.3a.4f.5f.,1p.2e.3a.4f.5f.,
1a.2f.3a.4f.5f.,1b.2f.3a.4f.5f.,1f.2f.3a.4f.5f.,
1h.2f.3a.4f.5f.,1j.2f.3a.4f.5f.,1p.2f.3a.4f.5f.,
1a.2i.3a.4f.5f.,1b.2i.3a.4f.5f.,1f.2i.3a.4f.5f.,
1h.2i.3a.4f.5f.,1j.2i.3a.4f.5f.,1p.2i.3a.4f.5f.,
1a.2m.3a.4f.5f.,1b.2m.3a.4f.5f.,1f.2m.3a.4f.5f.,
1h.2m.3a.4f.5f.,1j.2m.3a.4f.5f.,1p.2m.3a.4f.5f.,
1a.2o.3a.4f.5f.,1b.2o.3a.4f.5f.,1f.2o.3a.4f.5f.,
1h.2o.3a.4f.5f.,1j.2o.3a.4f.5f.,1p.2o.3a.4f.5f.,
1a.2u.3a.4f.5f.,1b.2u.3a.4f.5f.,1f.2u.3a.4f.5f.,
1h.2u.3a.4f.5f.,1j.2u.3a.4f.5f.,1p.2u.3a.4f.5f.,
1a.2y.3a.4f.5f.,1b.2y.3a.4f.5f.,1f.2y.3a.4f.5f.,
1h.2y.3a.4f.5f.,1j.2y.3a.4f.5f.,1p.2y.3a.4f.5f.,
1a.2a.3b.4f.5f.,1b.2a.3b.4f.5f.,1f.2a.3b.4f.5f.,
1h.2a.3b.4f.5f.,1j.2a.3b.4f.5f.,1p.2a.3b.4f.5f.,
1a.2b.3b.4f.5f.,1b.2b.3b.4f.5f.,1f.2b.3b.4f.5f.,
1h.2b.3b.4f.5f.,1j.2b.3b.4f.5f.,1p.2b.3b.4f.5f.,
1a.2e.3b.4f.5f.,1b.2e.3b.4f.5f.,1f.2e.3b.4f.5f.,
1h.2e.3b.4f.5f.,1j.2e.3b.4f.5f.,1p.2e.3b.4f.5f.,
1a.2f.3b.4f.5f.,1b.2f.3b.4f.5f.,1f.2f.3b.4f.5f.,
1h.2f.3b.4f.5f.,1j.2f.3b.4f.5f.,1p.2f.3b.4f.5f.,
1a.2i.3b.4f.5f.,1b.2i.3b.4f.5f.,1f.2i.3b.4f.5f.,
1h.2i.3b.4f.5f.,1j.2i.3b.4f.5f.,1p.2i.3b.4f.5f.,
1a.2m.3b.4f.5f.,1b.2m.3b.4f.5f.,1f.2m.3b.4f.5f.,
1h.2m.3b.4f.5f.,1j.2m.3b.4f.5f.,1p.2m.3b.4f.5f.,
1a.2o.3b.4f.5f.,1b.2o.3b.4f.5f.,1f.2o.3b.4f.5f.,
1h.2o.3b.4f.5f.,1j.2o.3b.4f.5f.,1p.2o.3b.4f.5f.,
1a.2u.3b.4f.5f.,1b.2u.3b.4f.5f.,1f.2u.3b.4f.5f.,
1h.2u.3b.4f.5f.,1j.2u.3b.4f.5f.,1p.2u.3b.4f.5f.,
1a.2y.3b.4f.5f.,1b.2y.3b.4f.5f.,1f.2y.3b.4f.5f.,
1h.2y.3b.4f.5f.,1j.2y.3b.4f.5f.,1p.2y.3b.4f.5f.,
1a.2a.3e.4f.5f.,1b.2a.3e.4f.5f.,1f.2a.3e.4f.5f.,
1h.2a.3e.4f.5f.,1j.2a.3e.4f.5f.,1p.2a.3e.4f.5f.,
1a.2b.3e.4f.5f.,1b.2b.3e.4f.5f.,1f.2b.3e.4f.5f.,
1h.2b.3e.4f.5f.,1j.2b.3e.4f.5f.,1p.2b.3e.4f.5f.,
1a.2e.3e.4f.5f.,1b.2e.3e.4f.5f.,1f.2e.3e.4f.5f.,
1h.2e.3e.4f.5f.,1j.2e.3e.4f.5f.,1p.2e.3e.4f.5f.,
1a.2f.3e.4f.5f.,1b.2f.3e.4f.5f.,1f.2f.3e.4f.5f.,
1h.2f.3e.4f.5f.,1j.2f.3e.4f.5f.,1p.2f.3e.4f.5f.,
1a.2i.3e.4f.5f.,1b.2i.3e.4f.5f.,1f.2i.3e.4f.5f.,
1h.2i.3e.4f.5f.,1j.2i.3e.4f.5f.,1p.2i.3e.4f.5f.,
1a.2m.3e.4f.5f.,1b.2m.3e.4f.5f.,1f.2m.3e.4f.5f.,
1h.2m.3e.4f.5f.,1j.2m.3e.4f.5f.,1p.2m.3e.4f.5f.,
1a.2o.3e.4f.5f.,1b.2o.3e.4f.5f.,1f.2o.3e.4f.5f.,
1h.2o.3e.4f.5f.,1j.2o.3e.4f.5f.,1p.2o.3e.4f.5f.,
1a.2u.3e.4f.5f.,1b.2u.3e.4f.5f.,1f.2u.3e.4f.5f.,
1h.2u.3e.4f.5f.,1j.2u.3e.4f.5f.,1p.2u.3e.4f.5f.,
1a.2y.3e.4f.5f.,1b.2y.3e.4f.5f.,1f.2y.3e.4f.5f.,
1h.2y.3e.4f.5f.,1j.2y.3e.4f.5f.,1p.2y.3e.4f.5f.,
1a.2a.3g.4f.5f.,1b.2a.3g.4f.5f.,1f.2a.3g.4f.5f.,
1h.2a.3g.4f.5f.,1j.2a.3g.4f.5f.,1p.2a.3g.4f.5f.,
1a.2b.3g.4f.5f.,1b.2b.3g.4f.5f.,1f.2b.3g.4f.5f.,
1h.2b.3g.4f.5f.,1j.2b.3g.4f.5f.,1p.2b.3g.4f.5f.,
1a.2e.3g.4f.5f.,1b.2e.3g.4f.5f.,1f.2e.3g.4f.5f.,
1h.2e.3g.4f.5f.,1j.2e.3g.4f.5f.,1p.2e.3g.4f.5f.,
1a.2f.3g.4f.5f.,1b.2f.3g.4f.5f.,1f.2f.3g.4f.5f.,
1h.2f.3g.4f.5f.,1j.2f.3g.4f.5f.,1p.2f.3g.4f.5f.,
1a.2i.3g.4f.5f.,1b.2i.3g.4f.5f.,1f.2i.3g.4f.5f.,
1h.2i.3g.4f.5f.,1j.2i.3g.4f.5f.,1p.2i.3g.4f.5f.,
1a.2m.3g.4f.5f.,1b.2m.3g.4f.5f.,1f.2m.3g.4f.5f.,
1h.2m.3g.4f.5f.,1j.2m.3g.4f.5f.,1p.2m.3g.4f.5f.,
1a.2o.3g.4f.5f.,1b.2o.3g.4f.5f.,1f.2o.3g.4f.5f.,
1h.2o.3g.4f.5f.,1j.2o.3g.4f.5f.,1p.2o.3g.4f.5f.,
1a.2u.3g.4f.5f.,1b.2u.3g.4f.5f.,1f.2u.3g.4f.5f.,
1h.2u.3g.4f.5f.,1j.2u.3g.4f.5f.,1p.2u.3g.4f.5f.,
1a.2y.3g.4f.5f.,1b.2y.3g.4f.5f.,1f.2y.3g.4f.5f.,
1h.2y.3g.4f.5f.,1j.2y.3g.4f.5f.,1p.2y.3g.4f.5f.,
1a.2a.3a.4g.5f.,1b.2a.3a.4g.5f.,1f.2a.3a.4g.5f.,
1h.2a.3a.4g.5f.,1j.2a.3a.4g.5f.,1p.2a.3a.4g.5f.,
1a.2b.3a.4g.5f.,1b.2b.3a.4g.5f.,1f.2b.3a.4g.5f.,
1h.2b.3a.4g.5f.,1j.2b.3a.4g.5f.,1p.2b.3a.4g.5f.,
1a.2e.3a.4g.5f.,1b.2e.3a.4g.5f.,1f.2e.3a.4g.5f.,
1h.2e.3a.4g.5f.,1j.2e.3a.4g.5f.,1p.2e.3a.4g.5f.,
1a.2f.3a.4g.5f.,1b.2f.3a.4g.5f.,1f.2f.3a.4g.5f.,
1h.2f.3a.4g.5f.,1j.2f.3a.4g.5f.,1p.2f.3a.4g.5f.,
1a.2i.3a.4g.5f.,1b.2i.3a.4g.5f.,1f.2i.3a.4g.5f.,
1h.2i.3a.4g.5f.,1j.2i.3a.4g.5f.,1p.2i.3a.4g.5f.,
1a.2m.3a.4g.5f.,1b.2m.3a.4g.5f.,1f.2m.3a.4g.5f.,
1h.2m.3a.4g.5f.,1j.2m.3a.4g.5f.,1p.2m.3a.4g.5f.,
1a.2o.3a.4g.5f.,1b.2o.3a.4g.5f.,1f.2o.3a.4g.5f.,
1h.2o.3a.4g.5f.,1j.2o.3a.4g.5f.,1p.2o.3a.4g.5f.,
1a.2u.3a.4g.5f.,1b.2u.3a.4g.5f.,1f.2u.3a.4g.5f.,
1h.2u.3a.4g.5f.,1j.2u.3a.4g.5f.,1p.2u.3a.4g.5f.,
1a.2y.3a.4g.5f.,1b.2y.3a.4g.5f.,1f.2y.3a.4g.5f.,
1h.2y.3a.4g.5f.,1j.2y.3a.4g.5f.,1p.2y.3a.4g.5f.,
1a.2a.3b.4g.5f.,1b.2a.3b.4g.5f.,1f.2a.3b.4g.5f.,
1h.2a.3b.4g.5f.,1j.2a.3b.4g.5f.,1p.2a.3b.4g.5f.,
1a.2b.3b.4g.5f.,1b.2b.3b.4g.5f.,1f.2b.3b.4g.5f.,
1h.2b.3b.4g.5f.,1j.2b.3b.4g.5f.,1p.2b.3b.4g.5f.,
1a.2e.3b.4g.5f.,1b.2e.3b.4g.5f.,1f.2e.3b.4g.5f.,
1h.2e.3b.4g.5f.,1j.2e.3b.4g.5f.,1p.2e.3b.4g.5f.,
1a.2f.3b.4g.5f.,1b.2f.3b.4g.5f.,1f.2f.3b.4g.5f.,
1h.2f.3b.4g.5f.,1j.2f.3b.4g.5f.,1p.2f.3b.4g.5f.,
1a.2i.3b.4g.5f.,1b.2i.3b.4g.5f.,1f.2i.3b.4g.5f.,
1h.2i.3b.4g.5f.,1j.2i.3b.4g.5f.,1p.2i.3b.4g.5f.,
1a.2m.3b.4g.5f.,1b.2m.3b.4g.5f.,1f.2m.3b.4g.5f.,
1h.2m.3b.4g.5f.,1j.2m.3b.4g.5f.,1p.2m.3b.4g.5f.,
1a.2o.3b.4g.5f.,1b.2o.3b.4g.5f.,1f.2o.3b.4g.5f.,
1h.2o.3b.4g.5f.,1j.2o.3b.4g.5f.,1p.2o.3b.4g.5f.,
1a.2u.3b.4g.5f.,1b.2u.3b.4g.5f.,1f.2u.3b.4g.5f.,
1h.2u.3b.4g.5f.,1j.2u.3b.4g.5f.,1p.2u.3b.4g.5f.,
1a.2y.3b.4g.5f.,1b.2y.3b.4g.5f.,1f.2y.3b.4g.5f.,
1h.2y.3b.4g.5f.,1j.2y.3b.4g.5f.,1p.2y.3b.4g.5f.,
1a.2a.3e.4g.5f.,1b.2a.3e.4g.5f.,1f.2a.3e.4g.5f.,
1h.2a.3e.4g.5f.,1j.2a.3e.4g.5f.,1p.2a.3e.4g.5f.,
1a.2b.3e.4g.5f.,1b.2b.3e.4g.5f.,1f.2b.3e.4g.5f.,
1h.2b.3e.4g.5f.,1j.2b.3e.4g.5f.,1p.2b.3e.4g.5f.,
1a.2e.3e.4g.5f.,1b.2e.3e.4g.5f.,1f.2e.3e.4g.5f.,
1h.2e.3e.4g.5f.,1j.2e.3e.4g.5f.,1p.2e.3e.4g.5f.,
1a.2f.3e.4g.5f.,1b.2f.3e.4g.5f.,1f.2f.3e.4g.5f.,
1h.2f.3e.4g.5f.,1j.2f.3e.4g.5f.,1p.2f.3e.4g.5f.,
1a.2i.3e.4g.5f.,1b.2i.3e.4g.5f.,1f.2i.3e.4g.5f.,
1h.2i.3e.4g.5f.,1j.2i.3e.4g.5f.,1p.2i.3e.4g.5f.,
1a.2m.3e.4g.5f.,1b.2m.3e.4g.5f.,1f.2m.3e.4g.5f.,
1h.2m.3e.4g.5f.,1j.2m.3e.4g.5f.,1p.2m.3e.4g.5f.,
1a.2o.3e.4g.5f.,1b.2o.3e.4g.5f.,1f.2o.3e.4g.5f.,
1h.2o.3e.4g.5f.,1j.2o.3e.4g.5f.,1p.2o.3e.4g.5f.,
1a.2u.3e.4g.5f.,1b.2u.3e.4g.5f.,1f.2u.3e.4g.5f.,
1h.2u.3e.4g.5f.,1j.2u.3e.4g.5f.,1p.2u.3e.4g.5f.,
1a.2y.3e.4g.5f.,1b.2y.3e.4g.5f.,1f.2y.3e.4g.5f.,
1h.2y.3e.4g.5f.,1j.2y.3e.4g.5f.,1p.2y.3e.4g.5f.,
1a.2a.3g.4g.5f.,1b.2a.3g.4g.5f.,1f.2a.3g.4g.5f.,
1h.2a.3g.4g.5f.,1j.2a.3g.4g.5f.,1p.2a.3g.4g.5f.,
1a.2b.3g.4g.5f.,1b.2b.3g.4g.5f.,1f.2b.3g.4g.5f.,
1h.2b.3g.4g.5f.,1j.2b.3g.4g.5f.,1p.2b.3g.4g.5f.,
1a.2e.3g.4g.5f.,1b.2e.3g.4g.5f.,1f.2e.3g.4g.5f.,
1h.2e.3g.4g.5f.,1j.2e.3g.4g.5f.,1p.2e.3g.4g.5f.,
1a.2f.3g.4g.5f.,1b.2f.3g.4g.5f.,1f.2f.3g.4g.5f.,
1h.2f.3g.4g.5f.,1j.2f.3g.4g.5f.,1p.2f.3g.4g.5f.,
1a.2i.3g.4g.5f.,1b.2i.3g.4g.5f.,1f.2i.3g.4g.5f.,
1h.2i.3g.4g.5f.,1j.2i.3g.4g.5f.,1p.2i.3g.4g.5f.,
1a.2m.3g.4g.5f.,1b.2m.3g.4g.5f.,1f.2m.3g.4g.5f.,
1h.2m.3g.4g.5f.,1j.2m.3g.4g.5f.,1p.2m.3g.4g.5f.,
1a.2o.3g.4g.5f.,1b.2o.3g.4g.5f.,1f.2o.3g.4g.5f.,
1h.2o.3g.4g.5f.,1j.2o.3g.4g.5f.,1p.2o.3g.4g.5f.,
1a.2u.3g.4g.5f.,1b.2u.3g.4g.5f.,1f.2u.3g.4g.5f.,
1h.2u.3g.4g.5f.,1j.2u.3g.4g.5f.,1p.2u.3g.4g.5f.,
1a.2y.3g.4g.5f.,1b.2y.3g.4g.5f.,1f.2y.3g.4g.5f.,
1h.2y.3g.4g.5f.,1j.2y.3g.4g.5f.,1p.2y.3g.4g.5f.,
1a.2a.3a.4h.5f.,1b.2a.3a.4h.5f.,1f.2a.3a.4h.5f.,
1h.2a.3a.4h.5f.,1j.2a.3a.4h.5f.,1p.2a.3a.4h.5f.,
1a.2b.3a.4h.5f.,1b.2b.3a.4h.5f.,1f.2b.3a.4h.5f.,
1h.2b.3a.4h.5f.,1j.2b.3a.4h.5f.,1p.2b.3a.4h.5f.,
1a.2e.3a.4h.5f.,1b.2e.3a.4h.5f.,1f.2e.3a.4h.5f.,
1h.2e.3a.4h.5f.,1j.2e.3a.4h.5f.,1p.2e.3a.4h.5f.,
1a.2f.3a.4h.5f.,1b.2f.3a.4h.5f.,1f.2f.3a.4h.5f.,
1h.2f.3a.4h.5f.,1j.2f.3a.4h.5f.,1p.2f.3a.4h.5f.,
1a.2i.3a.4h.5f.,1b.2i.3a.4h.5f.,1f.2i.3a.4h.5f.,
1h.2i.3a.4h.5f.,1j.2i.3a.4h.5f.,1p.2i.3a.4h.5f.,
1a.2m.3a.4h.5f.,1b.2m.3a.4h.5f.,1f.2m.3a.4h.5f.,
1h.2m.3a.4h.5f.,1j.2m.3a.4h.5f.,1p.2m.3a.4h.5f.,
1a.2o.3a.4h.5f.,1b.2o.3a.4h.5f.,1f.2o.3a.4h.5f.,
1h.2o.3a.4h.5f.,1j.2o.3a.4h.5f.,1p.2o.3a.4h.5f.,
1a.2u.3a.4h.5f.,1b.2u.3a.4h.5f.,1f.2u.3a.4h.5f.,
1h.2u.3a.4h.5f.,1j.2u.3a.4h.5f.,1p.2u.3a.4h.5f.,
1a.2y.3a.4h.5f.,1b.2y.3a.4h.5f.,1f.2y.3a.4h.5f.,
1h.2y.3a.4h.5f.,1j.2y.3a.4h.5f.,1p.2y.3a.4h.5f.,
1a.2a.3b.4h.5f.,1b.2a.3b.4h.5f.,1f.2a.3b.4h.5f.,
1h.2a.3b.4h.5f.,1j.2a.3b.4h.5f.,1p.2a.3b.4h.5f.,
1a.2b.3b.4h.5f.,1b.2b.3b.4h.5f.,1f.2b.3b.4h.5f.,
1h.2b.3b.4h.5f.,1j.2b.3b.4h.5f.,1p.2b.3b.4h.5f.,
1a.2e.3b.4h.5f.,1b.2e.3b.4h.5f.,1f.2e.3b.4h.5f.,
1h.2e.3b.4h.5f.,1j.2e.3b.4h.5f.,1p.2e.3b.4h.5f.,
1a.2f.3b.4h.5f.,1b.2f.3b.4h.5f.,1f.2f.3b.4h.5f.,
1h.2f.3b.4h.5f.,1j.2f.3b.4h.5f.,1p.2f.3b.4h.5f.,
1a.2i.3b.4h.5f.,1b.2i.3b.4h.5f.,1f.2i.3b.4h.5f.,
1h.2i.3b.4h.5f.,1j.2i.3b.4h.5f.,1p.2i.3b.4h.5f.,
1a.2m.3b.4h.5f.,1b.2m.3b.4h.5f.,1f.2m.3b.4h.5f.,
1h.2m.3b.4h.5f.,1j.2m.3b.4h.5f.,1p.2m.3b.4h.5f.,
1a.2o.3b.4h.5f.,1b.2o.3b.4h.5f.,1f.2o.3b.4h.5f.,
1h.2o.3b.4h.5f.,1j.2o.3b.4h.5f.,1p.2o.3b.4h.5f.,
1a.2u.3b.4h.5f.,1b.2u.3b.4h.5f.,1f.2u.3b.4h.5f.,
1h.2u.3b.4h.5f.,1j.2u.3b.4h.5f.,1p.2u.3b.4h.5f.,
1a.2y.3b.4h.5f.,1b.2y.3b.4h.5f.,1f.2y.3b.4h.5f.,
1h.2y.3b.4h.5f.,1j.2y.3b.4h.5f.,1p.2y.3b.4h.5f.,
1a.2a.3e.4h.5f.,1b.2a.3e.4h.5f.,1f.2a.3e.4h.5f.,
1h.2a.3e.4h.5f.,1j.2a.3e.4h.5f.,1p.2a.3e.4h.5f.,
1a.2b.3e.4h.5f.,1b.2b.3e.4h.5f.,1f.2b.3e.4h.5f.,
1h.2b.3e.4h.5f.,1j.2b.3e.4h.5f.,1p.2b.3e.4h.5f.,
1a.2e.3e.4h.5f.,1b.2e.3e.4h.5f.,1f.2e.3e.4h.5f.,
1h.2e.3e.4h.5f.,1j.2e.3e.4h.5f.,1p.2e.3e.4h.5f.,
1a.2f.3e.4h.5f.,1b.2f.3e.4h.5f.,1f.2f.3e.4h.5f.,
1h.2f.3e.4h.5f.,1j.2f.3e.4h.5f.,1p.2f.3e.4h.5f.,
1a.2i.3e.4h.5f.,1b.2i.3e.4h.5f.,1f.2i.3e.4h.5f.,
1h.2i.3e.4h.5f.,1j.2i.3e.4h.5f.,1p.2i.3e.4h.5f.,
1a.2m.3e.4h.5f.,1b.2m.3e.4h.5f.,1f.2m.3e.4h.5f.,
1h.2m.3e.4h.5f.,1j.2m.3e.4h.5f.,1p.2m.3e.4h.5f.,
1a.2o.3e.4h.5f.,1b.2o.3e.4h.5f.,1f.2o.3e.4h.5f.,
1h.2o.3e.4h.5f.,1j.2o.3e.4h.5f.,1p.2o.3e.4h.5f.,
1a.2u.3e.4h.5f.,1b.2u.3e.4h.5f.,1f.2u.3e.4h.5f.,
1h.2u.3e.4h.5f.,1j.2u.3e.4h.5f.,1p.2u.3e.4h.5f.,
1a.2y.3e.4h.5f.,1b.2y.3e.4h.5f.,1f.2y.3e.4h.5f.,
1h.2y.3e.4h.5f.,1j.2y.3e.4h.5f.,1p.2y.3e.4h.5f.,
1a.2a.3g.4h.5f.,1b.2a.3g.4h.5f.,1f.2a.3g.4h.5f.,
1h.2a.3g.4h.5f.,1j.2a.3g.4h.5f.,1p.2a.3g.4h.5f.,
1a.2b.3g.4h.5f.,1b.2b.3g.4h.5f.,1f.2b.3g.4h.5f.,
1h.2b.3g.4h.5f.,1j.2b.3g.4h.5f.,1p.2b.3g.4h.5f.,
1a.2e.3g.4h.5f.,1b.2e.3g.4h.5f.,1f.2e.3g.4h.5f.,
1h.2e.3g.4h.5f.,1j.2e.3g.4h.5f.,1p.2e.3g.4h.5f.,
1a.2f.3g.4h.5f.,1b.2f.3g.4h.5f.,1f.2f.3g.4h.5f.,
1h.2f.3g.4h.5f.,1j.2f.3g.4h.5f.,1p.2f.3g.4h.5f.,
1a.2i.3g.4h.5f.,1b.2i.3g.4h.5f.,1f.2i.3g.4h.5f.,
1h.2i.3g.4h.5f.,1j.2i.3g.4h.5f.,1p.2i.3g.4h.5f.,
1a.2m.3g.4h.5f.,1b.2m.3g.4h.5f.,1f.2m.3g.4h.5f.,
1h.2m.3g.4h.5f.,1j.2m.3g.4h.5f.,1p.2m.3g.4h.5f.,
1a.2o.3g.4h.5f.,1b.2o.3g.4h.5f.,1f.2o.3g.4h.5f.,
1h.2o.3g.4h.5f.,1j.2o.3g.4h.5f.,1p.2o.3g.4h.5f.,
1a.2u.3g.4h.5f.,1b.2u.3g.4h.5f.,1f.2u.3g.4h.5f.,
1h.2u.3g.4h.5f.,1j.2u.3g.4h.5f.,1p.2u.3g.4h.5f.,
1a.2y.3g.4h.5f.,1b.2y.3g.4h.5f.,1f.2y.3g.4h.5f.,
1h.2y.3g.4h.5f.,1j.2y.3g.4h.5f.,1p.2y.3g.4h.5f.,
1a.2a.3a.4i.5f.,1b.2a.3a.4i.5f.,1f.2a.3a.4i.5f.,
1h.2a.3a.4i.5f.,1j.2a.3a.4i.5f.,1p.2a.3a.4i.5f.,
1a.2b.3a.4i.5f.,1b.2b.3a.4i.5f.,1f.2b.3a.4i.5f.,
1h.2b.3a.4i.5f.,1j.2b.3a.4i.5f.,1p.2b.3a.4i.5f.,
1a.2e.3a.4i.5f.,1b.2e.3a.4i.5f.,1f.2e.3a.4i.5f.,
1h.2e.3a.4i.5f.,1j.2e.3a.4i.5f.,1p.2e.3a.4i.5f.,
1a.2f.3a.4i.5f.,1b.2f.3a.4i.5f.,1f.2f.3a.4i.5f.,
1h.2f.3a.4i.5f.,1j.2f.3a.4i.5f.,1p.2f.3a.4i.5f.,
1a.2i.3a.4i.5f.,1b.2i.3a.4i.5f.,1f.2i.3a.4i.5f.,
1h.2i.3a.4i.5f.,1j.2i.3a.4i.5f.,1p.2i.3a.4i.5f.,
1a.2m.3a.4i.5f.,1b.2m.3a.4i.5f.,1f.2m.3a.4i.5f.,
1h.2m.3a.4i.5f.,1j.2m.3a.4i.5f.,1p.2m.3a.4i.5f.,
1a.2o.3a.4i.5f.,1b.2o.3a.4i.5f.,1f.2o.3a.4i.5f.,
1h.2o.3a.4i.5f.,1j.2o.3a.4i.5f.,1p.2o.3a.4i.5f.,
1a.2u.3a.4i.5f.,1b.2u.3a.4i.5f.,1f.2u.3a.4i.5f.,
1h.2u.3a.4i.5f.,1j.2u.3a.4i.5f.,1p.2u.3a.4i.5f.,
1a.2y.3a.4i.5f.,1b.2y.3a.4i.5f.,1f.2y.3a.4i.5f.,
1h.2y.3a.4i.5f.,1j.2y.3a.4i.5f.,1p.2y.3a.4i.5f.,
1a.2a.3b.4i.5f.,1b.2a.3b.4i.5f.,1f.2a.3b.4i.5f.,
1h.2a.3b.4i.5f.,1j.2a.3b.4i.5f.,1p.2a.3b.4i.5f.,
1a.2b.3b.4i.5f.,1b.2b.3b.4i.5f.,1f.2b.3b.4i.5f.,
1h.2b.3b.4i.5f.,1j.2b.3b.4i.5f.,1p.2b.3b.4i.5f.,
1a.2e.3b.4i.5f.,1b.2e.3b.4i.5f.,1f.2e.3b.4i.5f.,
1h.2e.3b.4i.5f.,1j.2e.3b.4i.5f.,1p.2e.3b.4i.5f.,
1a.2f.3b.4i.5f.,1b.2f.3b.4i.5f.,1f.2f.3b.4i.5f.,
1h.2f.3b.4i.5f.,1j.2f.3b.4i.5f.,1p.2f.3b.4i.5f.,
1a.2i.3b.4i.5f.,1b.2i.3b.4i.5f.,1f.2i.3b.4i.5f.,
1h.2i.3b.4i.5f.,1j.2i.3b.4i.5f.,1p.2i.3b.4i.5f.,
1a.2m.3b.4i.5f.,1b.2m.3b.4i.5f.,1f.2m.3b.4i.5f.,
1h.2m.3b.4i.5f.,1j.2m.3b.4i.5f.,1p.2m.3b.4i.5f.,
1a.2o.3b.4i.5f.,1b.2o.3b.4i.5f.,1f.2o.3b.4i.5f.,
1h.2o.3b.4i.5f.,1j.2o.3b.4i.5f.,1p.2o.3b.4i.5f.,
1a.2u.3b.4i.5f.,1b.2u.3b.4i.5f.,1f.2u.3b.4i.5f.,
1h.2u.3b.4i.5f.,1j.2u.3b.4i.5f.,1p.2u.3b.4i.5f.,
1a.2y.3b.4i.5f.,1b.2y.3b.4i.5f.,1f.2y.3b.4i.5f.,
1h.2y.3b.4i.5f.,1j.2y.3b.4i.5f.,1p.2y.3b.4i.5f.,
1a.2a.3e.4i.5f.,1b.2a.3e.4i.5f.,1f.2a.3e.4i.5f.,
1h.2a.3e.4i.5f.,1j.2a.3e.4i.5f.,1p.2a.3e.4i.5f.,
1a.2b.3e.4i.5f.,1b.2b.3e.4i.5f.,1f.2b.3e.4i.5f.,
1h.2b.3e.4i.5f.,1j.2b.3e.4i.5f.,1p.2b.3e.4i.5f.,
1a.2e.3e.4i.5f.,1b.2e.3e.4i.5f.,1f.2e.3e.4i.5f.,
1h.2e.3e.4i.5f.,1j.2e.3e.4i.5f.,1p.2e.3e.4i.5f.,
1a.2f.3e.4i.5f.,1b.2f.3e.4i.5f.,1f.2f.3e.4i.5f.,
1h.2f.3e.4i.5f.,1j.2f.3e.4i.5f.,1p.2f.3e.4i.5f.,
1a.2i.3e.4i.5f.,1b.2i.3e.4i.5f.,1f.2i.3e.4i.5f.,
1h.2i.3e.4i.5f.,1j.2i.3e.4i.5f.,1p.2i.3e.4i.5f.,
1a.2m.3e.4i.5f.,1b.2m.3e.4i.5f.,1f.2m.3e.4i.5f.,
1h.2m.3e.4i.5f.,1j.2m.3e.4i.5f.,1p.2m.3e.4i.5f.,
1a.2o.3e.4i.5f.,1b.2o.3e.4i.5f.,1f.2o.3e.4i.5f.,
1h.2o.3e.4i.5f.,1j.2o.3e.4i.5f.,1p.2o.3e.4i.5f.,
1a.2u.3e.4i.5f.,1b.2u.3e.4i.5f.,1f.2u.3e.4i.5f.,
1h.2u.3e.4i.5f.,1j.2u.3e.4i.5f.,1p.2u.3e.4i.5f.,
1a.2y.3e.4i.5f.,1b.2y.3e.4i.5f.,1f.2y.3e.4i.5f.,
1h.2y.3e.4i.5f.,1j.2y.3e.4i.5f.,1p.2y.3e.4i.5f.,
1a.2a.3g.4i.5f.,1b.2a.3g.4i.5f.,1f.2a.3g.4i.5f.,
1h.2a.3g.4i.5f.,1j.2a.3g.4i.5f.,1p.2a.3g.4i.5f.,
1a.2b.3g.4i.5f.,1b.2b.3g.4i.5f.,1f.2b.3g.4i.5f.,
1h.2b.3g.4i.5f.,1j.2b.3g.4i.5f.,1p.2b.3g.4i.5f.,
1a.2e.3g.4i.5f.,1b.2e.3g.4i.5f.,1f.2e.3g.4i.5f.,
1h.2e.3g.4i.5f.,1j.2e.3g.4i.5f.,1p.2e.3g.4i.5f.,
1a.2f.3g.4i.5f.,1b.2f.3g.4i.5f.,1f.2f.3g.4i.5f.,
1h.2f.3g.4i.5f.,1j.2f.3g.4i.5f.,1p.2f.3g.4i.5f.,
1a.2i.3g.4i.5f.,1b.2i.3g.4i.5f.,1f.2i.3g.4i.5f.,
1h.2i.3g.4i.5f.,1j.2i.3g.4i.5f.,1p.2i.3g.4i.5f.,
1a.2m.3g.4i.5f.,1b.2m.3g.4i.5f.,1f.2m.3g.4i.5f.,
1h.2m.3g.4i.5f.,1j.2m.3g.4i.5f.,1p.2m.3g.4i.5f.,
1a.2o.3g.4i.5f.,1b.2o.3g.4i.5f.,1f.2o.3g.4i.5f.,
1h.2o.3g.4i.5f.,1j.2o.3g.4i.5f.,1p.2o.3g.4i.5f.,
1a.2u.3g.4i.5f.,1b.2u.3g.4i.5f.,1f.2u.3g.4i.5f.,
1h.2u.3g.4i.5f.,1j.2u.3g.4i.5f.,1p.2u.3g.4i.5f.,
1a.2y.3g.4i.5f.,1b.2y.3g.4i.5f.,1f.2y.3g.4i.5f.,
1h.2y.3g.4i.5f.,1j.2y.3g.4i.5f.,1p.2y.3g.4i.5f.,
1a.2a.3a.4a.5g.,1b.2a.3a.4a.5g.,1f.2a.3a.4a.5g.,
1h.2a.3a.4a.5g.,1j.2a.3a.4a.5g.,1p.2a.3a.4a.5g.,
1a.2b.3a.4a.5g.,1b.2b.3a.4a.5g.,1f.2b.3a.4a.5g.,
1h.2b.3a.4a.5g.,1j.2b.3a.4a.5g.,1p.2b.3a.4a.5g.,
1a.2e.3a.4a.5g.,1b.2e.3a.4a.5g.,1f.2e.3a.4a.5g.,
1h.2e.3a.4a.5g.,1j.2e.3a.4a.5g.,1p.2e.3a.4a.5g.,
1a.2f.3a.4a.5g.,1b.2f.3a.4a.5g.,1f.2f.3a.4a.5g.,
1h.2f.3a.4a.5g.,1j.2f.3a.4a.5g.,1p.2f.3a.4a.5g.,
1a.2i.3a.4a.5g.,1b.2i.3a.4a.5g.,1f.2i.3a.4a.5g.,
1h.2i.3a.4a.5g.,1j.2i.3a.4a.5g.,1p.2i.3a.4a.5g.,
1a.2m.3a.4a.5g.,1b.2m.3a.4a.5g.,1f.2m.3a.4a.5g.,
1h.2m.3a.4a.5g.,1j.2m.3a.4a.5g.,1p.2m.3a.4a.5g.,
1a.2o.3a.4a.5g.,1b.2o.3a.4a.5g.,1f.2o.3a.4a.5g.,
1h.2o.3a.4a.5g.,1j.2o.3a.4a.5g.,1p.2o.3a.4a.5g.,
1a.2u.3a.4a.5g.,1b.2u.3a.4a.5g.,1f.2u.3a.4a.5g.,
1h.2u.3a.4a.5g.,1j.2u.3a.4a.5g.,1p.2u.3a.4a.5g.,
1a.2y.3a.4a.5g.,1b.2y.3a.4a.5g.,1f.2y.3a.4a.5g.,
1h.2y.3a.4a.5g.,1j.2y.3a.4a.5g.,1p.2y.3a.4a.5g.,
1a.2a.3b.4a.5g.,1b.2a.3b.4a.5g.,1f.2a.3b.4a.5g.,
1h.2a.3b.4a.5g.,1j.2a.3b.4a.5g.,1p.2a.3b.4a.5g.,
1a.2b.3b.4a.5g.,1b.2b.3b.4a.5g.,1f.2b.3b.4a.5g.,
1h.2b.3b.4a.5g.,1j.2b.3b.4a.5g.,1p.2b.3b.4a.5g.,
1a.2e.3b.4a.5g.,1b.2e.3b.4a.5g.,1f.2e.3b.4a.5g.,
1h.2e.3b.4a.5g.,1j.2e.3b.4a.5g.,1p.2e.3b.4a.5g.,
1a.2f.3b.4a.5g.,1b.2f.3b.4a.5g.,1f.2f.3b.4a.5g.,
1h.2f.3b.4a.5g.,1j.2f.3b.4a.5g.,1p.2f.3b.4a.5g.,
1a.2i.3b.4a.5g.,1b.2i.3b.4a.5g.,1f.2i.3b.4a.5g.,
1h.2i.3b.4a.5g.,1j.2i.3b.4a.5g.,1p.2i.3b.4a.5g.,
1a.2m.3b.4a.5g.,1b.2m.3b.4a.5g.,1f.2m.3b.4a.5g.,
1h.2m.3b.4a.5g.,1j.2m.3b.4a.5g.,1p.2m.3b.4a.5g.,
1a.2o.3b.4a.5g.,1b.2o.3b.4a.5g.,1f.2o.3b.4a.5g.,
1h.2o.3b.4a.5g.,1j.2o.3b.4a.5g.,1p.2o.3b.4a.5g.,
1a.2u.3b.4a.5g.,1b.2u.3b.4a.5g.,1f.2u.3b.4a.5g.,
1h.2u.3b.4a.5g.,1j.2u.3b.4a.5g.,1p.2u.3b.4a.5g.,
1a.2y.3b.4a.5g.,1b.2y.3b.4a.5g.,1f.2y.3b.4a.5g.,
1h.2y.3b.4a.5g.,1j.2y.3b.4a.5g.,1p.2y.3b.4a.5g.,
1a.2a.3e.4a.5g.,1b.2a.3e.4a.5g.,1f.2a.3e.4a.5g.,
1h.2a.3e.4a.5g.,1j.2a.3e.4a.5g.,1p.2a.3e.4a.5g.,
1a.2b.3e.4a.5g.,1b.2b.3e.4a.5g.,1f.2b.3e.4a.5g.,
1h.2b.3e.4a.5g.,1j.2b.3e.4a.5g.,1p.2b.3e.4a.5g.,
1a.2e.3e.4a.5g.,1b.2e.3e.4a.5g.,1f.2e.3e.4a.5g.,
1h.2e.3e.4a.5g.,1j.2e.3e.4a.5g.,1p.2e.3e.4a.5g.,
1a.2f.3e.4a.5g.,1b.2f.3e.4a.5g.,1f.2f.3e.4a.5g.,
1h.2f.3e.4a.5g.,1j.2f.3e.4a.5g.,1p.2f.3e.4a.5g.,
1a.2i.3e.4a.5g.,1b.2i.3e.4a.5g.,1f.2i.3e.4a.5g.,
1h.2i.3e.4a.5g.,1j.2i.3e.4a.5g.,1p.2i.3e.4a.5g.,
1a.2m.3e.4a.5g.,1b.2m.3e.4a.5g.,1f.2m.3e.4a.5g.,
1h.2m.3e.4a.5g.,1j.2m.3e.4a.5g.,1p.2m.3e.4a.5g.,
1a.2o.3e.4a.5g.,1b.2o.3e.4a.5g.,1f.2o.3e.4a.5g.,
1h.2o.3e.4a.5g.,1j.2o.3e.4a.5g.,1p.2o.3e.4a.5g.,
1a.2u.3e.4a.5g.,1b.2u.3e.4a.5g.,1f.2u.3e.4a.5g.,
1h.2u.3e.4a.5g.,1j.2u.3e.4a.5g.,1p.2u.3e.4a.5g.,
1a.2y.3e.4a.5g.,1b.2y.3e.4a.5g.,1f.2y.3e.4a.5g.,
1h.2y.3e.4a.5g.,1j.2y.3e.4a.5g.,1p.2y.3e.4a.5g.,
1a.2a.3g.4a.5g.,1b.2a.3g.4a.5g.,1f.2a.3g.4a.5g.,
1h.2a.3g.4a.5g.,1j.2a.3g.4a.5g.,1p.2a.3g.4a.5g.,
1a.2b.3g.4a.5g.,1b.2b.3g.4a.5g.,1f.2b.3g.4a.5g.,
1h.2b.3g.4a.5g.,1j.2b.3g.4a.5g.,1p.2b.3g.4a.5g.,
1a.2e.3g.4a.5g.,1b.2e.3g.4a.5g.,1f.2e.3g.4a.5g.,
1h.2e.3g.4a.5g.,1j.2e.3g.4a.5g.,1p.2e.3g.4a.5g.,
1a.2f.3g.4a.5g.,1b.2f.3g.4a.5g.,1f.2f.3g.4a.5g.,
1h.2f.3g.4a.5g.,1j.2f.3g.4a.5g.,1p.2f.3g.4a.5g.,
1a.2i.3g.4a.5g.,1b.2i.3g.4a.5g.,1f.2i.3g.4a.5g.,
1h.2i.3g.4a.5g.,1j.2i.3g.4a.5g.,1p.2i.3g.4a.5g.,
1a.2m.3g.4a.5g.,1b.2m.3g.4a.5g.,1f.2m.3g.4a.5g.,
1h.2m.3g.4a.5g.,1j.2m.3g.4a.5g.,1p.2m.3g.4a.5g.,
1a.2o.3g.4a.5g.,1b.2o.3g.4a.5g.,1f.2o.3g.4a.5g.,
1h.2o.3g.4a.5g.,1j.2o.3g.4a.5g.,1p.2o.3g.4a.5g.,
1a.2u.3g.4a.5g.,1b.2u.3g.4a.5g.,1f.2u.3g.4a.5g.,
1h.2u.3g.4a.5g.,1j.2u.3g.4a.5g.,1p.2u.3g.4a.5g.,
1a.2y.3g.4a.5g.,1b.2y.3g.4a.5g.,1f.2y.3g.4a.5g.,
1h.2y.3g.4a.5g.,1j.2y.3g.4a.5g.,1p.2y.3g.4a.5g.,
1a.2a.3a.4d.5g.,1b.2a.3a.4d.5g.,1f.2a.3a.4d.5g.,
1h.2a.3a.4d.5g.,1j.2a.3a.4d.5g.,1p.2a.3a.4d.5g.,
1a.2b.3a.4d.5g.,1b.2b.3a.4d.5g.,1f.2b.3a.4d.5g.,
1h.2b.3a.4d.5g.,1j.2b.3a.4d.5g.,1p.2b.3a.4d.5g.,
1a.2e.3a.4d.5g.,1b.2e.3a.4d.5g.,1f.2e.3a.4d.5g.,
1h.2e.3a.4d.5g.,1j.2e.3a.4d.5g.,1p.2e.3a.4d.5g.,
1a.2f.3a.4d.5g.,1b.2f.3a.4d.5g.,1f.2f.3a.4d.5g.,
1h.2f.3a.4d.5g.,1j.2f.3a.4d.5g.,1p.2f.3a.4d.5g.,
1a.2i.3a.4d.5g.,1b.2i.3a.4d.5g.,1f.2i.3a.4d.5g.,
1h.2i.3a.4d.5g.,1j.2i.3a.4d.5g.,1p.2i.3a.4d.5g.,
1a.2m.3a.4d.5g.,1b.2m.3a.4d.5g.,1f.2m.3a.4d.5g.,
1h.2m.3a.4d.5g.,1j.2m.3a.4d.5g.,1p.2m.3a.4d.5g.,
1a.2o.3a.4d.5g.,1b.2o.3a.4d.5g.,1f.2o.3a.4d.5g.,
1h.2o.3a.4d.5g.,1j.2o.3a.4d.5g.,1p.2o.3a.4d.5g.,
1a.2u.3a.4d.5g.,1b.2u.3a.4d.5g.,1f.2u.3a.4d.5g.,
1h.2u.3a.4d.5g.,1j.2u.3a.4d.5g.,1p.2u.3a.4d.5g.,
1a.2y.3a.4d.5g.,1b.2y.3a.4d.5g.,1f.2y.3a.4d.5g.,
1h.2y.3a.4d.5g.,1j.2y.3a.4d.5g.,1p.2y.3a.4d.5g.,
1a.2a.3b.4d.5g.,1b.2a.3b.4d.5g.,1f.2a.3b.4d.5g.,
1h.2a.3b.4d.5g.,1j.2a.3b.4d.5g.,1p.2a.3b.4d.5g.,
1a.2b.3b.4d.5g.,1b.2b.3b.4d.5g.,1f.2b.3b.4d.5g.,
1h.2b.3b.4d.5g.,1j.2b.3b.4d.5g.,1p.2b.3b.4d.5g.,
1a.2e.3b.4d.5g.,1b.2e.3b.4d.5g.,1f.2e.3b.4d.5g.,
1h.2e.3b.4d.5g.,1j.2e.3b.4d.5g.,1p.2e.3b.4d.5g.,
1a.2f.3b.4d.5g.,1b.2f.3b.4d.5g.,1f.2f.3b.4d.5g.,
1h.2f.3b.4d.5g.,1j.2f.3b.4d.5g.,1p.2f.3b.4d.5g.,
1a.2i.3b.4d.5g.,1b.2i.3b.4d.5g.,1f.2i.3b.4d.5g.,
1h.2i.3b.4d.5g.,1j.2i.3b.4d.5g.,1p.2i.3b.4d.5g.,
1a.2m.3b.4d.5g.,1b.2m.3b.4d.5g.,1f.2m.3b.4d.5g.,
1h.2m.3b.4d.5g.,1j.2m.3b.4d.5g.,1p.2m.3b.4d.5g.,
1a.2o.3b.4d.5g.,1b.2o.3b.4d.5g.,1f.2o.3b.4d.5g.,
1h.2o.3b.4d.5g.,1j.2o.3b.4d.5g.,1p.2o.3b.4d.5g.,
1a.2u.3b.4d.5g.,1b.2u.3b.4d.5g.,1f.2u.3b.4d.5g.,
1h.2u.3b.4d.5g.,1j.2u.3b.4d.5g.,1p.2u.3b.4d.5g.,
1a.2y.3b.4d.5g.,1b.2y.3b.4d.5g.,1f.2y.3b.4d.5g.,
1h.2y.3b.4d.5g.,1j.2y.3b.4d.5g.,1p.2y.3b.4d.5g.,
1a.2a.3e.4d.5g.,1b.2a.3e.4d.5g.,1f.2a.3e.4d.5g.,
1h.2a.3e.4d.5g.,1j.2a.3e.4d.5g.,1p.2a.3e.4d.5g.,
1a.2b.3e.4d.5g.,1b.2b.3e.4d.5g.,1f.2b.3e.4d.5g.,
1h.2b.3e.4d.5g.,1j.2b.3e.4d.5g.,1p.2b.3e.4d.5g.,
1a.2e.3e.4d.5g.,1b.2e.3e.4d.5g.,1f.2e.3e.4d.5g.,
1h.2e.3e.4d.5g.,1j.2e.3e.4d.5g.,1p.2e.3e.4d.5g.,
1a.2f.3e.4d.5g.,1b.2f.3e.4d.5g.,1f.2f.3e.4d.5g.,
1h.2f.3e.4d.5g.,1j.2f.3e.4d.5g.,1p.2f.3e.4d.5g.,
1a.2i.3e.4d.5g.,1b.2i.3e.4d.5g.,1f.2i.3e.4d.5g.,
1h.2i.3e.4d.5g.,1j.2i.3e.4d.5g.,1p.2i.3e.4d.5g.,
1a.2m.3e.4d.5g.,1b.2m.3e.4d.5g.,1f.2m.3e.4d.5g.,
1h.2m.3e.4d.5g.,1j.2m.3e.4d.5g.,1p.2m.3e.4d.5g.,
1a.2o.3e.4d.5g.,1b.2o.3e.4d.5g.,1f.2o.3e.4d.5g.,
1h.2o.3e.4d.5g.,1j.2o.3e.4d.5g.,1p.2o.3e.4d.5g.,
1a.2u.3e.4d.5g.,1b.2u.3e.4d.5g.,1f.2u.3e.4d.5g.,
1h.2u.3e.4d.5g.,1j.2u.3e.4d.5g.,1p.2u.3e.4d.5g.,
1a.2y.3e.4d.5g.,1b.2y.3e.4d.5g.,1f.2y.3e.4d.5g.,
1h.2y.3e.4d.5g.,1j.2y.3e.4d.5g.,1p.2y.3e.4d.5g.,
1a.2a.3g.4d.5g.,1b.2a.3g.4d.5g.,1f.2a.3g.4d.5g.,
1h.2a.3g.4d.5g.,1j.2a.3g.4d.5g.,1p.2a.3g.4d.5g.,
1a.2b.3g.4d.5g.,1b.2b.3g.4d.5g.,1f.2b.3g.4d.5g.,
1h.2b.3g.4d.5g.,1j.2b.3g.4d.5g.,1p.2b.3g.4d.5g.,
1a.2e.3g.4d.5g.,1b.2e.3g.4d.5g.,1f.2e.3g.4d.5g.,
1h.2e.3g.4d.5g.,1j.2e.3g.4d.5g.,1p.2e.3g.4d.5g.,
1a.2f.3g.4d.5g.,1b.2f.3g.4d.5g.,1f.2f.3g.4d.5g.,
1h.2f.3g.4d.5g.,1j.2f.3g.4d.5g.,1p.2f.3g.4d.5g.,
1a.2i.3g.4d.5g.,1b.2i.3g.4d.5g.,1f.2i.3g.4d.5g.,
1h.2i.3g.4d.5g.,1j.2i.3g.4d.5g.,1p.2i.3g.4d.5g.,
1a.2m.3g.4d.5g.,1b.2m.3g.4d.5g.,1f.2m.3g.4d.5g.,
1h.2m.3g.4d.5g.,1j.2m.3g.4d.5g.,1p.2m.3g.4d.5g.,
1a.2o.3g.4d.5g.,1b.2o.3g.4d.5g.,1f.2o.3g.4d.5g.,
1h.2o.3g.4d.5g.,1j.2o.3g.4d.5g.,1p.2o.3g.4d.5g.,
1a.2u.3g.4d.5g.,1b.2u.3g.4d.5g.,1f.2u.3g.4d.5g.,
1h.2u.3g.4d.5g.,1j.2u.3g.4d.5g.,1p.2u.3g.4d.5g.,
1a.2y.3g.4d.5g.,1b.2y.3g.4d.5g.,1f.2y.3g.4d.5g.,
1h.2y.3g.4d.5g.,1j.2y.3g.4d.5g.,1p.2y.3g.4d.5g.,
1a.2a.3a.4f.5g.,1b.2a.3a.4f.5g.,1f.2a.3a.4f.5g.,
1h.2a.3a.4f.5g.,1j.2a.3a.4f.5g.,1p.2a.3a.4f.5g.,
1a.2b.3a.4f.5g.,1b.2b.3a.4f.5g.,1f.2b.3a.4f.5g.,
1h.2b.3a.4f.5g.,1j.2b.3a.4f.5g.,1p.2b.3a.4f.5g.,
1a.2e.3a.4f.5g.,1b.2e.3a.4f.5g.,1f.2e.3a.4f.5g.,
1h.2e.3a.4f.5g.,1j.2e.3a.4f.5g.,1p.2e.3a.4f.5g.,
1a.2f.3a.4f.5g.,1b.2f.3a.4f.5g.,1f.2f.3a.4f.5g.,
1h.2f.3a.4f.5g.,1j.2f.3a.4f.5g.,1p.2f.3a.4f.5g.,
1a.2i.3a.4f.5g.,1b.2i.3a.4f.5g.,1f.2i.3a.4f.5g.,
1h.2i.3a.4f.5g.,1j.2i.3a.4f.5g.,1p.2i.3a.4f.5g.,
1a.2m.3a.4f.5g.,1b.2m.3a.4f.5g.,1f.2m.3a.4f.5g.,
1h.2m.3a.4f.5g.,1j.2m.3a.4f.5g.,1p.2m.3a.4f.5g.,
1a.2o.3a.4f.5g.,1b.2o.3a.4f.5g.,1f.2o.3a.4f.5g.,
1h.2o.3a.4f.5g.,1j.2o.3a.4f.5g.,1p.2o.3a.4f.5g.,
1a.2u.3a.4f.5g.,1b.2u.3a.4f.5g.,1f.2u.3a.4f.5g.,
1h.2u.3a.4f.5g.,1j.2u.3a.4f.5g.,1p.2u.3a.4f.5g.,
1a.2y.3a.4f.5g.,1b.2y.3a.4f.5g.,1f.2y.3a.4f.5g.,
1h.2y.3a.4f.5g.,1j.2y.3a.4f.5g.,1p.2y.3a.4f.5g.,
1a.2a.3b.4f.5g.,1b.2a.3b.4f.5g.,1f.2a.3b.4f.5g.,
1h.2a.3b.4f.5g.,1j.2a.3b.4f.5g.,1p.2a.3b.4f.5g.,
1a.2b.3b.4f.5g.,1b.2b.3b.4f.5g.,1f.2b.3b.4f.5g.,
1h.2b.3b.4f.5g.,1j.2b.3b.4f.5g.,1p.2b.3b.4f.5g.,
1a.2e.3b.4f.5g.,1b.2e.3b.4f.5g.,1f.2e.3b.4f.5g.,
1h.2e.3b.4f.5g.,1j.2e.3b.4f.5g.,1p.2e.3b.4f.5g.,
1a.2f.3b.4f.5g.,1b.2f.3b.4f.5g.,1f.2f.3b.4f.5g.,
1h.2f.3b.4f.5g.,1j.2f.3b.4f.5g.,1p.2f.3b.4f.5g.,
1a.2i.3b.4f.5g.,1b.2i.3b.4f.5g.,1f.2i.3b.4f.5g.,
1h.2i.3b.4f.5g.,1j.2i.3b.4f.5g.,1p.2i.3b.4f.5g.,
1a.2m.3b.4f.5g.,1b.2m.3b.4f.5g.,1f.2m.3b.4f.5g.,
1h.2m.3b.4f.5g.,1j.2m.3b.4f.5g.,1p.2m.3b.4f.5g.,
1a.2o.3b.4f.5g.,1b.2o.3b.4f.5g.,1f.2o.3b.4f.5g.,
1h.2o.3b.4f.5g.,1j.2o.3b.4f.5g.,1p.2o.3b.4f.5g.,
1a.2u.3b.4f.5g.,1b.2u.3b.4f.5g.,1f.2u.3b.4f.5g.,
1h.2u.3b.4f.5g.,1j.2u.3b.4f.5g.,1p.2u.3b.4f.5g.,
1a.2y.3b.4f.5g.,1b.2y.3b.4f.5g.,1f.2y.3b.4f.5g.,
1h.2y.3b.4f.5g.,1j.2y.3b.4f.5g.,1p.2y.3b.4f.5g.,
1a.2a.3e.4f.5g.,1b.2a.3e.4f.5g.,1f.2a.3e.4f.5g.,
1h.2a.3e.4f.5g.,1j.2a.3e.4f.5g.,1p.2a.3e.4f.5g.,
1a.2b.3e.4f.5g.,1b.2b.3e.4f.5g.,1f.2b.3e.4f.5g.,
1h.2b.3e.4f.5g.,1j.2b.3e.4f.5g.,1p.2b.3e.4f.5g.,
1a.2e.3e.4f.5g.,1b.2e.3e.4f.5g.,1f.2e.3e.4f.5g.,
1h.2e.3e.4f.5g.,1j.2e.3e.4f.5g.,1p.2e.3e.4f.5g.,
1a.2f.3e.4f.5g.,1b.2f.3e.4f.5g.,1f.2f.3e.4f.5g.,
1h.2f.3e.4f.5g.,1j.2f.3e.4f.5g.,1p.2f.3e.4f.5g.,
1a.2i.3e.4f.5g.,1b.2i.3e.4f.5g.,1f.2i.3e.4f.5g.,
1h.2i.3e.4f.5g.,1j.2i.3e.4f.5g.,1p.2i.3e.4f.5g.,
1a.2m.3e.4f.5g.,1b.2m.3e.4f.5g.,1f.2m.3e.4f.5g.,
1h.2m.3e.4f.5g.,1j.2m.3e.4f.5g.,1p.2m.3e.4f.5g.,
1a.2o.3e.4f.5g.,1b.2o.3e.4f.5g.,1f.2o.3e.4f.5g.,
1h.2o.3e.4f.5g.,1j.2o.3e.4f.5g.,1p.2o.3e.4f.5g.,
1a.2u.3e.4f.5g.,1b.2u.3e.4f.5g.,1f.2u.3e.4f.5g.,
1h.2u.3e.4f.5g.,1j.2u.3e.4f.5g.,1p.2u.3e.4f.5g.,
1a.2y.3e.4f.5g.,1b.2y.3e.4f.5g.,1f.2y.3e.4f.5g.,
1h.2y.3e.4f.5g.,1j.2y.3e.4f.5g.,1p.2y.3e.4f.5g.,
1a.2a.3g.4f.5g.,1b.2a.3g.4f.5g.,1f.2a.3g.4f.5g.,
1h.2a.3g.4f.5g.,1j.2a.3g.4f.5g.,1p.2a.3g.4f.5g.,
1a.2b.3g.4f.5g.,1b.2b.3g.4f.5g.,1f.2b.3g.4f.5g.,
1h.2b.3g.4f.5g.,1j.2b.3g.4f.5g.,1p.2b.3g.4f.5g.,
1a.2e.3g.4f.5g.,1b.2e.3g.4f.5g.,1f.2e.3g.4f.5g.,
1h.2e.3g.4f.5g.,1j.2e.3g.4f.5g.,1p.2e.3g.4f.5g.,
1a.2f.3g.4f.5g.,1b.2f.3g.4f.5g.,1f.2f.3g.4f.5g.,
1h.2f.3g.4f.5g.,1j.2f.3g.4f.5g.,1p.2f.3g.4f.5g.,
1a.2i.3g.4f.5g.,1b.2i.3g.4f.5g.,1f.2i.3g.4f.5g.,
1h.2i.3g.4f.5g.,1j.2i.3g.4f.5g.,1p.2i.3g.4f.5g.,
1a.2m.3g.4f.5g.,1b.2m.3g.4f.5g.,1f.2m.3g.4f.5g.,
1h.2m.3g.4f.5g.,1j.2m.3g.4f.5g.,1p.2m.3g.4f.5g.,
1a.2o.3g.4f.5g.,1b.2o.3g.4f.5g.,1f.2o.3g.4f.5g.,
1h.2o.3g.4f.5g.,1j.2o.3g.4f.5g.,1p.2o.3g.4f.5g.,
1a.2u.3g.4f.5g.,1b.2u.3g.4f.5g.,1f.2u.3g.4f.5g.,
1h.2u.3g.4f.5g.,1j.2u.3g.4f.5g.,1p.2u.3g.4f.5g.,
1a.2y.3g.4f.5g.,1b.2y.3g.4f.5g.,1f.2y.3g.4f.5g.,
1h.2y.3g.4f.5g.,1j.2y.3g.4f.5g.,1p.2y.3g.4f.5g.,
1a.2a.3a.4g.5g.,1b.2a.3a.4g.5g.,1f.2a.3a.4g.5g.,
1h.2a.3a.4g.5g.,1j.2a.3a.4g.5g.,1p.2a.3a.4g.5g.,
1a.2b.3a.4g.5g.,1b.2b.3a.4g.5g.,1f.2b.3a.4g.5g.,
1h.2b.3a.4g.5g.,1j.2b.3a.4g.5g.,1p.2b.3a.4g.5g.,
1a.2e.3a.4g.5g.,1b.2e.3a.4g.5g.,1f.2e.3a.4g.5g.,
1h.2e.3a.4g.5g.,1j.2e.3a.4g.5g.,1p.2e.3a.4g.5g.,
1a.2f.3a.4g.5g.,1b.2f.3a.4g.5g.,1f.2f.3a.4g.5g.,
1h.2f.3a.4g.5g.,1j.2f.3a.4g.5g.,1p.2f.3a.4g.5g.,
1a.2i.3a.4g.5g.,1b.2i.3a.4g.5g.,1f.2i.3a.4g.5g.,
1h.2i.3a.4g.5g.,1j.2i.3a.4g.5g.,1p.2i.3a.4g.5g.,
1a.2m.3a.4g.5g.,1b.2m.3a.4g.5g.,1f.2m.3a.4g.5g.,
1h.2m.3a.4g.5g.,1j.2m.3a.4g.5g.,1p.2m.3a.4g.5g.,
1a.2o.3a.4g.5g.,1b.2o.3a.4g.5g.,1f.2o.3a.4g.5g.,
1h.2o.3a.4g.5g.,1j.2o.3a.4g.5g.,1p.2o.3a.4g.5g.,
1a.2u.3a.4g.5g.,1b.2u.3a.4g.5g.,1f.2u.3a.4g.5g.,
1h.2u.3a.4g.5g.,1j.2u.3a.4g.5g.,1p.2u.3a.4g.5g.,
1a.2y.3a.4g.5g.,1b.2y.3a.4g.5g.,1f.2y.3a.4g.5g.,
1h.2y.3a.4g.5g.,1j.2y.3a.4g.5g.,1p.2y.3a.4g.5g.,
1a.2a.3b.4g.5g.,1b.2a.3b.4g.5g.,1f.2a.3b.4g.5g.,
1h.2a.3b.4g.5g.,1j.2a.3b.4g.5g.,1p.2a.3b.4g.5g.,
1a.2b.3b.4g.5g.,1b.2b.3b.4g.5g.,1f.2b.3b.4g.5g.,
1h.2b.3b.4g.5g.,1j.2b.3b.4g.5g.,1p.2b.3b.4g.5g.,
1a.2e.3b.4g.5g.,1b.2e.3b.4g.5g.,1f.2e.3b.4g.5g.,
1h.2e.3b.4g.5g.,1j.2e.3b.4g.5g.,1p.2e.3b.4g.5g.,
1a.2f.3b.4g.5g.,1b.2f.3b.4g.5g.,1f.2f.3b.4g.5g.,
1h.2f.3b.4g.5g.,1j.2f.3b.4g.5g.,1p.2f.3b.4g.5g.,
1a.2i.3b.4g.5g.,1b.2i.3b.4g.5g.,1f.2i.3b.4g.5g.,
1h.2i.3b.4g.5g.,1j.2i.3b.4g.5g.,1p.2i.3b.4g.5g.,
1a.2m.3b.4g.5g.,1b.2m.3b.4g.5g.,1f.2m.3b.4g.5g.,
1h.2m.3b.4g.5g.,1j.2m.3b.4g.5g.,1p.2m.3b.4g.5g.,
1a.2o.3b.4g.5g.,1b.2o.3b.4g.5g.,1f.2o.3b.4g.5g.,
1h.2o.3b.4g.5g.,1j.2o.3b.4g.5g.,1p.2o.3b.4g.5g.,
1a.2u.3b.4g.5g.,1b.2u.3b.4g.5g.,1f.2u.3b.4g.5g.,
1h.2u.3b.4g.5g.,1j.2u.3b.4g.5g.,1p.2u.3b.4g.5g.,
1a.2y.3b.4g.5g.,1b.2y.3b.4g.5g.,1f.2y.3b.4g.5g.,
1h.2y.3b.4g.5g.,1j.2y.3b.4g.5g.,1p.2y.3b.4g.5g.,
1a.2a.3e.4g.5g.,1b.2a.3e.4g.5g.,1f.2a.3e.4g.5g.,
1h.2a.3e.4g.5g.,1j.2a.3e.4g.5g.,1p.2a.3e.4g.5g.,
1a.2b.3e.4g.5g.,1b.2b.3e.4g.5g.,1f.2b.3e.4g.5g.,
1h.2b.3e.4g.5g.,1j.2b.3e.4g.5g.,1p.2b.3e.4g.5g.,
1a.2e.3e.4g.5g.,1b.2e.3e.4g.5g.,1f.2e.3e.4g.5g.,
1h.2e.3e.4g.5g.,1j.2e.3e.4g.5g.,1p.2e.3e.4g.5g.,
1a.2f.3e.4g.5g.,1b.2f.3e.4g.5g.,1f.2f.3e.4g.5g.,
1h.2f.3e.4g.5g.,1j.2f.3e.4g.5g.,1p.2f.3e.4g.5g.,
1a.2i.3e.4g.5g.,1b.2i.3e.4g.5g.,1f.2i.3e.4g.5g.,
1h.2i.3e.4g.5g.,1j.2i.3e.4g.5g.,1p.2i.3e.4g.5g.,
1a.2m.3e.4g.5g.,1b.2m.3e.4g.5g.,1f.2m.3e.4g.5g.,
1h.2m.3e.4g.5g.,1j.2m.3e.4g.5g.,1p.2m.3e.4g.5g.,
1a.2o.3e.4g.5g.,1b.2o.3e.4g.5g.,1f.2o.3e.4g.5g.,
1h.2o.3e.4g.5g.,1j.2o.3e.4g.5g.,1p.2o.3e.4g.5g.,
1a.2u.3e.4g.5g.,1b.2u.3e.4g.5g.,1f.2u.3e.4g.5g.,
1h.2u.3e.4g.5g.,1j.2u.3e.4g.5g.,1p.2u.3e.4g.5g.,
1a.2y.3e.4g.5g.,1b.2y.3e.4g.5g.,1f.2y.3e.4g.5g.,
1h.2y.3e.4g.5g.,1j.2y.3e.4g.5g.,1p.2y.3e.4g.5g.,
1a.2a.3g.4g.5g.,1b.2a.3g.4g.5g.,1f.2a.3g.4g.5g.,
1h.2a.3g.4g.5g.,1j.2a.3g.4g.5g.,1p.2a.3g.4g.5g.,
1a.2b.3g.4g.5g.,1b.2b.3g.4g.5g.,1f.2b.3g.4g.5g.,
1h.2b.3g.4g.5g.,1j.2b.3g.4g.5g.,1p.2b.3g.4g.5g.,
1a.2e.3g.4g.5g.,1b.2e.3g.4g.5g.,1f.2e.3g.4g.5g.,
1h.2e.3g.4g.5g.,1j.2e.3g.4g.5g.,1p.2e.3g.4g.5g.,
1a.2f.3g.4g.5g.,1b.2f.3g.4g.5g.,1f.2f.3g.4g.5g.,
1h.2f.3g.4g.5g.,1j.2f.3g.4g.5g.,1p.2f.3g.4g.5g.,
1a.2i.3g.4g.5g.,1b.2i.3g.4g.5g.,1f.2i.3g.4g.5g.,
1h.2i.3g.4g.5g.,1j.2i.3g.4g.5g.,1p.2i.3g.4g.5g.,
1a.2m.3g.4g.5g.,1b.2m.3g.4g.5g.,1f.2m.3g.4g.5g.,
1h.2m.3g.4g.5g.,1j.2m.3g.4g.5g.,1p.2m.3g.4g.5g.,
1a.2o.3g.4g.5g.,1b.2o.3g.4g.5g.,1f.2o.3g.4g.5g.,
1h.2o.3g.4g.5g.,1j.2o.3g.4g.5g.,1p.2o.3g.4g.5g.,
1a.2u.3g.4g.5g.,1b.2u.3g.4g.5g.,1f.2u.3g.4g.5g.,
1h.2u.3g.4g.5g.,1j.2u.3g.4g.5g.,1p.2u.3g.4g.5g.,
1a.2y.3g.4g.5g.,1b.2y.3g.4g.5g.,1f.2y.3g.4g.5g.,
1h.2y.3g.4g.5g.,1j.2y.3g.4g.5g.,1p.2y.3g.4g.5g.,
1a.2a.3a.4h.5g.,1b.2a.3a.4h.5g.,1f.2a.3a.4h.5g.,
1h.2a.3a.4h.5g.,1j.2a.3a.4h.5g.,1p.2a.3a.4h.5g.,
1a.2b.3a.4h.5g.,1b.2b.3a.4h.5g.,1f.2b.3a.4h.5g.,
1h.2b.3a.4h.5g.,1j.2b.3a.4h.5g.,1p.2b.3a.4h.5g.,
1a.2e.3a.4h.5g.,1b.2e.3a.4h.5g.,1f.2e.3a.4h.5g.,
1h.2e.3a.4h.5g.,1j.2e.3a.4h.5g.,1p.2e.3a.4h.5g.,
1a.2f.3a.4h.5g.,1b.2f.3a.4h.5g.,1f.2f.3a.4h.5g.,
1h.2f.3a.4h.5g.,1j.2f.3a.4h.5g.,1p.2f.3a.4h.5g.,
1a.2i.3a.4h.5g.,1b.2i.3a.4h.5g.,1f.2i.3a.4h.5g.,
1h.2i.3a.4h.5g.,1j.2i.3a.4h.5g.,1p.2i.3a.4h.5g.,
1a.2m.3a.4h.5g.,1b.2m.3a.4h.5g.,1f.2m.3a.4h.5g.,
1h.2m.3a.4h.5g.,1j.2m.3a.4h.5g.,1p.2m.3a.4h.5g.,
1a.2o.3a.4h.5g.,1b.2o.3a.4h.5g.,1f.2o.3a.4h.5g.,
1h.2o.3a.4h.5g.,1j.2o.3a.4h.5g.,1p.2o.3a.4h.5g.,
1a.2u.3a.4h.5g.,1b.2u.3a.4h.5g.,1f.2u.3a.4h.5g.,
1h.2u.3a.4h.5g.,1j.2u.3a.4h.5g.,1p.2u.3a.4h.5g.,
1a.2y.3a.4h.5g.,1b.2y.3a.4h.5g.,1f.2y.3a.4h.5g.,
1h.2y.3a.4h.5g.,1j.2y.3a.4h.5g.,1p.2y.3a.4h.5g.,
1a.2a.3b.4h.5g.,1b.2a.3b.4h.5g.,1f.2a.3b.4h.5g.,
1h.2a.3b.4h.5g.,1j.2a.3b.4h.5g.,1p.2a.3b.4h.5g.,
1a.2b.3b.4h.5g.,1b.2b.3b.4h.5g.,1f.2b.3b.4h.5g.,
1h.2b.3b.4h.5g.,1j.2b.3b.4h.5g.,1p.2b.3b.4h.5g.,
1a.2e.3b.4h.5g.,1b.2e.3b.4h.5g.,1f.2e.3b.4h.5g.,
1h.2e.3b.4h.5g.,1j.2e.3b.4h.5g.,1p.2e.3b.4h.5g.,
1a.2f.3b.4h.5g.,1b.2f.3b.4h.5g.,1f.2f.3b.4h.5g.,
1h.2f.3b.4h.5g.,1j.2f.3b.4h.5g.,1p.2f.3b.4h.5g.,
1a.2i.3b.4h.5g.,1b.2i.3b.4h.5g.,1f.2i.3b.4h.5g.,
1h.2i.3b.4h.5g.,1j.2i.3b.4h.5g.,1p.2i.3b.4h.5g.,
1a.2m.3b.4h.5g.,1b.2m.3b.4h.5g.,1f.2m.3b.4h.5g.,
1h.2m.3b.4h.5g.,1j.2m.3b.4h.5g.,1p.2m.3b.4h.5g.,
1a.2o.3b.4h.5g.,1b.2o.3b.4h.5g.,1f.2o.3b.4h.5g.,
1h.2o.3b.4h.5g.,1j.2o.3b.4h.5g.,1p.2o.3b.4h.5g.,
1a.2u.3b.4h.5g.,1b.2u.3b.4h.5g.,1f.2u.3b.4h.5g.,
1h.2u.3b.4h.5g.,1j.2u.3b.4h.5g.,1p.2u.3b.4h.5g.,
1a.2y.3b.4h.5g.,1b.2y.3b.4h.5g.,1f.2y.3b.4h.5g.,
1h.2y.3b.4h.5g.,1j.2y.3b.4h.5g.,1p.2y.3b.4h.5g.,
1a.2a.3e.4h.5g.,1b.2a.3e.4h.5g.,1f.2a.3e.4h.5g.,
1h.2a.3e.4h.5g.,1j.2a.3e.4h.5g.,1p.2a.3e.4h.5g.,
1a.2b.3e.4h.5g.,1b.2b.3e.4h.5g.,1f.2b.3e.4h.5g.,
1h.2b.3e.4h.5g.,1j.2b.3e.4h.5g.,1p.2b.3e.4h.5g.,
1a.2e.3e.4h.5g.,1b.2e.3e.4h.5g.,1f.2e.3e.4h.5g.,
1h.2e.3e.4h.5g.,1j.2e.3e.4h.5g.,1p.2e.3e.4h.5g.,
1a.2f.3e.4h.5g.,1b.2f.3e.4h.5g.,1f.2f.3e.4h.5g.,
1h.2f.3e.4h.5g.,1j.2f.3e.4h.5g.,1p.2f.3e.4h.5g.,
1a.2i.3e.4h.5g.,1b.2i.3e.4h.5g.,1f.2i.3e.4h.5g.,
1h.2i.3e.4h.5g.,1j.2i.3e.4h.5g.,1p.2i.3e.4h.5g.,
1a.2m.3e.4h.5g.,1b.2m.3e.4h.5g.,1f.2m.3e.4h.5g.,
1h.2m.3e.4h.5g.,1j.2m.3e.4h.5g.,1p.2m.3e.4h.5g.,
1a.2o.3e.4h.5g.,1b.2o.3e.4h.5g.,1f.2o.3e.4h.5g.,
1h.2o.3e.4h.5g.,1j.2o.3e.4h.5g.,1p.2o.3e.4h.5g.,
1a.2u.3e.4h.5g.,1b.2u.3e.4h.5g.,1f.2u.3e.4h.5g.,
1h.2u.3e.4h.5g.,1j.2u.3e.4h.5g.,1p.2u.3e.4h.5g.,
1a.2y.3e.4h.5g.,1b.2y.3e.4h.5g.,1f.2y.3e.4h.5g.,
1h.2y.3e.4h.5g.,1j.2y.3e.4h.5g.,1p.2y.3e.4h.5g.,
1a.2a.3g.4h.5g.,1b.2a.3g.4h.5g.,1f.2a.3g.4h.5g.,
1h.2a.3g.4h.5g.,1j.2a.3g.4h.5g.,1p.2a.3g.4h.5g.,
1a.2b.3g.4h.5g.,1b.2b.3g.4h.5g.,1f.2b.3g.4h.5g.,
1h.2b.3g.4h.5g.,1j.2b.3g.4h.5g.,1p.2b.3g.4h.5g.,
1a.2e.3g.4h.5g.,1b.2e.3g.4h.5g.,1f.2e.3g.4h.5g.,
1h.2e.3g.4h.5g.,1j.2e.3g.4h.5g.,1p.2e.3g.4h.5g.,
1a.2f.3g.4h.5g.,1b.2f.3g.4h.5g.,1f.2f.3g.4h.5g.,
1h.2f.3g.4h.5g.,1j.2f.3g.4h.5g.,1p.2f.3g.4h.5g.,
1a.2i.3g.4h.5g.,1b.2i.3g.4h.5g.,1f.2i.3g.4h.5g.,
1h.2i.3g.4h.5g.,1j.2i.3g.4h.5g.,1p.2i.3g.4h.5g.,
1a.2m.3g.4h.5g.,1b.2m.3g.4h.5g.,1f.2m.3g.4h.5g.,
1h.2m.3g.4h.5g.,1j.2m.3g.4h.5g.,1p.2m.3g.4h.5g.,
1a.2o.3g.4h.5g.,1b.2o.3g.4h.5g.,1f.2o.3g.4h.5g.,
1h.2o.3g.4h.5g.,1j.2o.3g.4h.5g.,1p.2o.3g.4h.5g.,
1a.2u.3g.4h.5g.,1b.2u.3g.4h.5g.,1f.2u.3g.4h.5g.,
1h.2u.3g.4h.5g.,1j.2u.3g.4h.5g.,1p.2u.3g.4h.5g.,
1a.2y.3g.4h.5g.,1b.2y.3g.4h.5g.,1f.2y.3g.4h.5g.,
1h.2y.3g.4h.5g.,1j.2y.3g.4h.5g.,1p.2y.3g.4h.5g.,
1a.2a.3a.4i.5g.,1b.2a.3a.4i.5g.,1f.2a.3a.4i.5g.,
1h.2a.3a.4i.5g.,1j.2a.3a.4i.5g.,1p.2a.3a.4i.5g.,
1a.2b.3a.4i.5g.,1b.2b.3a.4i.5g.,1f.2b.3a.4i.5g.,
1h.2b.3a.4i.5g.,1j.2b.3a.4i.5g.,1p.2b.3a.4i.5g.,
1a.2e.3a.4i.5g.,1b.2e.3a.4i.5g.,1f.2e.3a.4i.5g.,
1h.2e.3a.4i.5g.,1j.2e.3a.4i.5g.,1p.2e.3a.4i.5g.,
1a.2f.3a.4i.5g.,1b.2f.3a.4i.5g.,1f.2f.3a.4i.5g.,
1h.2f.3a.4i.5g.,1j.2f.3a.4i.5g.,1p.2f.3a.4i.5g.,
1a.2i.3a.4i.5g.,1b.2i.3a.4i.5g.,1f.2i.3a.4i.5g.,
1h.2i.3a.4i.5g.,1j.2i.3a.4i.5g.,1p.2i.3a.4i.5g.,
1a.2m.3a.4i.5g.,1b.2m.3a.4i.5g.,1f.2m.3a.4i.5g.,
1h.2m.3a.4i.5g.,1j.2m.3a.4i.5g.,1p.2m.3a.4i.5g.,
1a.2o.3a.4i.5g.,1b.2o.3a.4i.5g.,1f.2o.3a.4i.5g.,
1h.2o.3a.4i.5g.,1j.2o.3a.4i.5g.,1p.2o.3a.4i.5g.,
1a.2u.3a.4i.5g.,1b.2u.3a.4i.5g.,1f.2u.3a.4i.5g.,
1h.2u.3a.4i.5g.,1j.2u.3a.4i.5g.,1p.2u.3a.4i.5g.,
1a.2y.3a.4i.5g.,1b.2y.3a.4i.5g.,1f.2y.3a.4i.5g.,
1h.2y.3a.4i.5g.,1j.2y.3a.4i.5g.,1p.2y.3a.4i.5g.,
1a.2a.3b.4i.5g.,1b.2a.3b.4i.5g.,1f.2a.3b.4i.5g.,
1h.2a.3b.4i.5g.,1j.2a.3b.4i.5g.,1p.2a.3b.4i.5g.,
1a.2b.3b.4i.5g.,1b.2b.3b.4i.5g.,1f.2b.3b.4i.5g.,
1h.2b.3b.4i.5g.,1j.2b.3b.4i.5g.,1p.2b.3b.4i.5g.,
1a.2e.3b.4i.5g.,1b.2e.3b.4i.5g.,1f.2e.3b.4i.5g.,
1h.2e.3b.4i.5g.,1j.2e.3b.4i.5g.,1p.2e.3b.4i.5g.,
1a.2f.3b.4i.5g.,1b.2f.3b.4i.5g.,1f.2f.3b.4i.5g.,
1h.2f.3b.4i.5g.,1j.2f.3b.4i.5g.,1p.2f.3b.4i.5g.,
1a.2i.3b.4i.5g.,1b.2i.3b.4i.5g.,1f.2i.3b.4i.5g.,
1h.2i.3b.4i.5g.,1j.2i.3b.4i.5g.,1p.2i.3b.4i.5g.,
1a.2m.3b.4i.5g.,1b.2m.3b.4i.5g.,1f.2m.3b.4i.5g.,
1h.2m.3b.4i.5g.,1j.2m.3b.4i.5g.,1p.2m.3b.4i.5g.,
1a.2o.3b.4i.5g.,1b.2o.3b.4i.5g.,1f.2o.3b.4i.5g.,
1h.2o.3b.4i.5g.,1j.2o.3b.4i.5g.,1p.2o.3b.4i.5g.,
1a.2u.3b.4i.5g.,1b.2u.3b.4i.5g.,1f.2u.3b.4i.5g.,
1h.2u.3b.4i.5g.,1j.2u.3b.4i.5g.,1p.2u.3b.4i.5g.,
1a.2y.3b.4i.5g.,1b.2y.3b.4i.5g.,1f.2y.3b.4i.5g.,
1h.2y.3b.4i.5g.,1j.2y.3b.4i.5g.,1p.2y.3b.4i.5g.,
1a.2a.3e.4i.5g.,1b.2a.3e.4i.5g.,1f.2a.3e.4i.5g.,
1h.2a.3e.4i.5g.,1j.2a.3e.4i.5g.,1p.2a.3e.4i.5g.,
1a.2b.3e.4i.5g.,1b.2b.3e.4i.5g.,1f.2b.3e.4i.5g.,
1h.2b.3e.4i.5g.,1j.2b.3e.4i.5g.,1p.2b.3e.4i.5g.,
1a.2e.3e.4i.5g.,1b.2e.3e.4i.5g.,1f.2e.3e.4i.5g.,
1h.2e.3e.4i.5g.,1j.2e.3e.4i.5g.,1p.2e.3e.4i.5g.,
1a.2f.3e.4i.5g.,1b.2f.3e.4i.5g.,1f.2f.3e.4i.5g.,
1h.2f.3e.4i.5g.,1j.2f.3e.4i.5g.,1p.2f.3e.4i.5g.,
1a.2i.3e.4i.5g.,1b.2i.3e.4i.5g.,1f.2i.3e.4i.5g.,
1h.2i.3e.4i.5g.,1j.2i.3e.4i.5g.,1p.2i.3e.4i.5g.,
1a.2m.3e.4i.5g.,1b.2m.3e.4i.5g.,1f.2m.3e.4i.5g.,
1h.2m.3e.4i.5g.,1j.2m.3e.4i.5g.,1p.2m.3e.4i.5g.,
1a.2o.3e.4i.5g.,1b.2o.3e.4i.5g.,1f.2o.3e.4i.5g.,
1h.2o.3e.4i.5g.,1j.2o.3e.4i.5g.,1p.2o.3e.4i.5g.,
1a.2u.3e.4i.5g.,1b.2u.3e.4i.5g.,1f.2u.3e.4i.5g.,
1h.2u.3e.4i.5g.,1j.2u.3e.4i.5g.,1p.2u.3e.4i.5g.,
1a.2y.3e.4i.5g.,1b.2y.3e.4i.5g.,1f.2y.3e.4i.5g.,
1h.2y.3e.4i.5g.,1j.2y.3e.4i.5g.,1p.2y.3e.4i.5g.,
1a.2a.3g.4i.5g.,1b.2a.3g.4i.5g.,1f.2a.3g.4i.5g.,
1h.2a.3g.4i.5g.,1j.2a.3g.4i.5g.,1p.2a.3g.4i.5g.,
1a.2b.3g.4i.5g.,1b.2b.3g.4i.5g.,1f.2b.3g.4i.5g.,
1h.2b.3g.4i.5g.,1j.2b.3g.4i.5g.,1p.2b.3g.4i.5g.,
1a.2e.3g.4i.5g.,1b.2e.3g.4i.5g.,1f.2e.3g.4i.5g.,
1h.2e.3g.4i.5g.,1j.2e.3g.4i.5g.,1p.2e.3g.4i.5g.,
1a.2f.3g.4i.5g.,1b.2f.3g.4i.5g.,1f.2f.3g.4i.5g.,
1h.2f.3g.4i.5g.,1j.2f.3g.4i.5g.,1p.2f.3g.4i.5g.,
1a.2i.3g.4i.5g.,1b.2i.3g.4i.5g.,1f.2i.3g.4i.5g.,
1h.2i.3g.4i.5g.,1j.2i.3g.4i.5g.,1p.2i.3g.4i.5g.,
1a.2m.3g.4i.5g.,1b.2m.3g.4i.5g.,1f.2m.3g.4i.5g.,
1h.2m.3g.4i.5g.,1j.2m.3g.4i.5g.,1p.2m.3g.4i.5g.,
1a.2o.3g.4i.5g.,1b.2o.3g.4i.5g.,1f.2o.3g.4i.5g.,
1h.2o.3g.4i.5g.,1j.2o.3g.4i.5g.,1p.2o.3g.4i.5g.,
1a.2u.3g.4i.5g.,1b.2u.3g.4i.5g.,1f.2u.3g.4i.5g.,
1h.2u.3g.4i.5g.,1j.2u.3g.4i.5g.,1p.2u.3g.4i.5g.,
1a.2y.3g.4i.5g.,1b.2y.3g.4i.5g.,1f.2y.3g.4i.5g.,
1h.2y.3g.4i.5g.,1j.2y.3g.4i.5g.,1p.2y.3g.4i.5g.,
1a.2a.3a.4a.5h.,1b.2a.3a.4a.5h.,1f.2a.3a.4a.5h.,
1h.2a.3a.4a.5h.,1j.2a.3a.4a.5h.,1p.2a.3a.4a.5h.,
1a.2b.3a.4a.5h.,1b.2b.3a.4a.5h.,1f.2b.3a.4a.5h.,
1h.2b.3a.4a.5h.,1j.2b.3a.4a.5h.,1p.2b.3a.4a.5h.,
1a.2e.3a.4a.5h.,1b.2e.3a.4a.5h.,1f.2e.3a.4a.5h.,
1h.2e.3a.4a.5h.,1j.2e.3a.4a.5h.,1p.2e.3a.4a.5h.,
1a.2f.3a.4a.5h.,1b.2f.3a.4a.5h.,1f.2f.3a.4a.5h.,
1h.2f.3a.4a.5h.,1j.2f.3a.4a.5h.,1p.2f.3a.4a.5h.,
1a.2i.3a.4a.5h.,1b.2i.3a.4a.5h.,1f.2i.3a.4a.5h.,
1h.2i.3a.4a.5h.,1j.2i.3a.4a.5h.,1p.2i.3a.4a.5h.,
1a.2m.3a.4a.5h.,1b.2m.3a.4a.5h.,1f.2m.3a.4a.5h.,
1h.2m.3a.4a.5h.,1j.2m.3a.4a.5h.,1p.2m.3a.4a.5h.,
1a.2o.3a.4a.5h.,1b.2o.3a.4a.5h.,1f.2o.3a.4a.5h.,
1h.2o.3a.4a.5h.,1j.2o.3a.4a.5h.,1p.2o.3a.4a.5h.,
1a.2u.3a.4a.5h.,1b.2u.3a.4a.5h.,1f.2u.3a.4a.5h.,
1h.2u.3a.4a.5h.,1j.2u.3a.4a.5h.,1p.2u.3a.4a.5h.,
1a.2y.3a.4a.5h.,1b.2y.3a.4a.5h.,1f.2y.3a.4a.5h.,
1h.2y.3a.4a.5h.,1j.2y.3a.4a.5h.,1p.2y.3a.4a.5h.,
1a.2a.3b.4a.5h.,1b.2a.3b.4a.5h.,1f.2a.3b.4a.5h.,
1h.2a.3b.4a.5h.,1j.2a.3b.4a.5h.,1p.2a.3b.4a.5h.,
1a.2b.3b.4a.5h.,1b.2b.3b.4a.5h.,1f.2b.3b.4a.5h.,
1h.2b.3b.4a.5h.,1j.2b.3b.4a.5h.,1p.2b.3b.4a.5h.,
1a.2e.3b.4a.5h.,1b.2e.3b.4a.5h.,1f.2e.3b.4a.5h.,
1h.2e.3b.4a.5h.,1j.2e.3b.4a.5h.,1p.2e.3b.4a.5h.,
1a.2f.3b.4a.5h.,1b.2f.3b.4a.5h.,1f.2f.3b.4a.5h.,
1h.2f.3b.4a.5h.,1j.2f.3b.4a.5h.,1p.2f.3b.4a.5h.,
1a.2i.3b.4a.5h.,1b.2i.3b.4a.5h.,1f.2i.3b.4a.5h.,
1h.2i.3b.4a.5h.,1j.2i.3b.4a.5h.,1p.2i.3b.4a.5h.,
1a.2m.3b.4a.5h.,1b.2m.3b.4a.5h.,1f.2m.3b.4a.5h.,
1h.2m.3b.4a.5h.,1j.2m.3b.4a.5h.,1p.2m.3b.4a.5h.,
1a.2o.3b.4a.5h.,1b.2o.3b.4a.5h.,1f.2o.3b.4a.5h.,
1h.2o.3b.4a.5h.,1j.2o.3b.4a.5h.,1p.2o.3b.4a.5h.,
1a.2u.3b.4a.5h.,1b.2u.3b.4a.5h.,1f.2u.3b.4a.5h.,
1h.2u.3b.4a.5h.,1j.2u.3b.4a.5h.,1p.2u.3b.4a.5h.,
1a.2y.3b.4a.5h.,1b.2y.3b.4a.5h.,1f.2y.3b.4a.5h.,
1h.2y.3b.4a.5h.,1j.2y.3b.4a.5h.,1p.2y.3b.4a.5h.,
1a.2a.3e.4a.5h.,1b.2a.3e.4a.5h.,1f.2a.3e.4a.5h.,
1h.2a.3e.4a.5h.,1j.2a.3e.4a.5h.,1p.2a.3e.4a.5h.,
1a.2b.3e.4a.5h.,1b.2b.3e.4a.5h.,1f.2b.3e.4a.5h.,
1h.2b.3e.4a.5h.,1j.2b.3e.4a.5h.,1p.2b.3e.4a.5h.,
1a.2e.3e.4a.5h.,1b.2e.3e.4a.5h.,1f.2e.3e.4a.5h.,
1h.2e.3e.4a.5h.,1j.2e.3e.4a.5h.,1p.2e.3e.4a.5h.,
1a.2f.3e.4a.5h.,1b.2f.3e.4a.5h.,1f.2f.3e.4a.5h.,
1h.2f.3e.4a.5h.,1j.2f.3e.4a.5h.,1p.2f.3e.4a.5h.,
1a.2i.3e.4a.5h.,1b.2i.3e.4a.5h.,1f.2i.3e.4a.5h.,
1h.2i.3e.4a.5h.,1j.2i.3e.4a.5h.,1p.2i.3e.4a.5h.,
1a.2m.3e.4a.5h.,1b.2m.3e.4a.5h.,1f.2m.3e.4a.5h.,
1h.2m.3e.4a.5h.,1j.2m.3e.4a.5h.,1p.2m.3e.4a.5h.,
1a.2o.3e.4a.5h.,1b.2o.3e.4a.5h.,1f.2o.3e.4a.5h.,
1h.2o.3e.4a.5h.,1j.2o.3e.4a.5h.,1p.2o.3e.4a.5h.,
1a.2u.3e.4a.5h.,1b.2u.3e.4a.5h.,1f.2u.3e.4a.5h.,
1h.2u.3e.4a.5h.,1j.2u.3e.4a.5h.,1p.2u.3e.4a.5h.,
1a.2y.3e.4a.5h.,1b.2y.3e.4a.5h.,1f.2y.3e.4a.5h.,
1h.2y.3e.4a.5h.,1j.2y.3e.4a.5h.,1p.2y.3e.4a.5h.,
1a.2a.3g.4a.5h.,1b.2a.3g.4a.5h.,1f.2a.3g.4a.5h.,
1h.2a.3g.4a.5h.,1j.2a.3g.4a.5h.,1p.2a.3g.4a.5h.,
1a.2b.3g.4a.5h.,1b.2b.3g.4a.5h.,1f.2b.3g.4a.5h.,
1h.2b.3g.4a.5h.,1j.2b.3g.4a.5h.,1p.2b.3g.4a.5h.,
1a.2e.3g.4a.5h.,1b.2e.3g.4a.5h.,1f.2e.3g.4a.5h.,
1h.2e.3g.4a.5h.,1j.2e.3g.4a.5h.,1p.2e.3g.4a.5h.,
1a.2f.3g.4a.5h.,1b.2f.3g.4a.5h.,1f.2f.3g.4a.5h.,
1h.2f.3g.4a.5h.,1j.2f.3g.4a.5h.,1p.2f.3g.4a.5h.,
1a.2i.3g.4a.5h.,1b.2i.3g.4a.5h.,1f.2i.3g.4a.5h.,
1h.2i.3g.4a.5h.,1j.2i.3g.4a.5h.,1p.2i.3g.4a.5h.,
1a.2m.3g.4a.5h.,1b.2m.3g.4a.5h.,1f.2m.3g.4a.5h.,
1h.2m.3g.4a.5h.,1j.2m.3g.4a.5h.,1p.2m.3g.4a.5h.,
1a.2o.3g.4a.5h.,1b.2o.3g.4a.5h.,1f.2o.3g.4a.5h.,
1h.2o.3g.4a.5h.,1j.2o.3g.4a.5h.,1p.2o.3g.4a.5h.,
1a.2u.3g.4a.5h.,1b.2u.3g.4a.5h.,1f.2u.3g.4a.5h.,
1h.2u.3g.4a.5h.,1j.2u.3g.4a.5h.,1p.2u.3g.4a.5h.,
1a.2y.3g.4a.5h.,1b.2y.3g.4a.5h.,1f.2y.3g.4a.5h.,
1h.2y.3g.4a.5h.,1j.2y.3g.4a.5h.,1p.2y.3g.4a.5h.,
1a.2a.3a.4d.5h.,1b.2a.3a.4d.5h.,1f.2a.3a.4d.5h.,
1h.2a.3a.4d.5h.,1j.2a.3a.4d.5h.,1p.2a.3a.4d.5h.,
1a.2b.3a.4d.5h.,1b.2b.3a.4d.5h.,1f.2b.3a.4d.5h.,
1h.2b.3a.4d.5h.,1j.2b.3a.4d.5h.,1p.2b.3a.4d.5h.,
1a.2e.3a.4d.5h.,1b.2e.3a.4d.5h.,1f.2e.3a.4d.5h.,
1h.2e.3a.4d.5h.,1j.2e.3a.4d.5h.,1p.2e.3a.4d.5h.,
1a.2f.3a.4d.5h.,1b.2f.3a.4d.5h.,1f.2f.3a.4d.5h.,
1h.2f.3a.4d.5h.,1j.2f.3a.4d.5h.,1p.2f.3a.4d.5h.,
1a.2i.3a.4d.5h.,1b.2i.3a.4d.5h.,1f.2i.3a.4d.5h.,
1h.2i.3a.4d.5h.,1j.2i.3a.4d.5h.,1p.2i.3a.4d.5h.,
1a.2m.3a.4d.5h.,1b.2m.3a.4d.5h.,1f.2m.3a.4d.5h.,
1h.2m.3a.4d.5h.,1j.2m.3a.4d.5h.,1p.2m.3a.4d.5h.,
1a.2o.3a.4d.5h.,1b.2o.3a.4d.5h.,1f.2o.3a.4d.5h.,
1h.2o.3a.4d.5h.,1j.2o.3a.4d.5h.,1p.2o.3a.4d.5h.,
1a.2u.3a.4d.5h.,1b.2u.3a.4d.5h.,1f.2u.3a.4d.5h.,
1h.2u.3a.4d.5h.,1j.2u.3a.4d.5h.,1p.2u.3a.4d.5h.,
1a.2y.3a.4d.5h.,1b.2y.3a.4d.5h.,1f.2y.3a.4d.5h.,
1h.2y.3a.4d.5h.,1j.2y.3a.4d.5h.,1p.2y.3a.4d.5h.,
1a.2a.3b.4d.5h.,1b.2a.3b.4d.5h.,1f.2a.3b.4d.5h.,
1h.2a.3b.4d.5h.,1j.2a.3b.4d.5h.,1p.2a.3b.4d.5h.,
1a.2b.3b.4d.5h.,1b.2b.3b.4d.5h.,1f.2b.3b.4d.5h.,
1h.2b.3b.4d.5h.,1j.2b.3b.4d.5h.,1p.2b.3b.4d.5h.,
1a.2e.3b.4d.5h.,1b.2e.3b.4d.5h.,1f.2e.3b.4d.5h.,
1h.2e.3b.4d.5h.,1j.2e.3b.4d.5h.,1p.2e.3b.4d.5h.,
1a.2f.3b.4d.5h.,1b.2f.3b.4d.5h.,1f.2f.3b.4d.5h.,
1h.2f.3b.4d.5h.,1j.2f.3b.4d.5h.,1p.2f.3b.4d.5h.,
1a.2i.3b.4d.5h.,1b.2i.3b.4d.5h.,1f.2i.3b.4d.5h.,
1h.2i.3b.4d.5h.,1j.2i.3b.4d.5h.,1p.2i.3b.4d.5h.,
1a.2m.3b.4d.5h.,1b.2m.3b.4d.5h.,1f.2m.3b.4d.5h.,
1h.2m.3b.4d.5h.,1j.2m.3b.4d.5h.,1p.2m.3b.4d.5h.,
1a.2o.3b.4d.5h.,1b.2o.3b.4d.5h.,1f.2o.3b.4d.5h.,
1h.2o.3b.4d.5h.,1j.2o.3b.4d.5h.,1p.2o.3b.4d.5h.,
1a.2u.3b.4d.5h.,1b.2u.3b.4d.5h.,1f.2u.3b.4d.5h.,
1h.2u.3b.4d.5h.,1j.2u.3b.4d.5h.,1p.2u.3b.4d.5h.,
1a.2y.3b.4d.5h.,1b.2y.3b.4d.5h.,1f.2y.3b.4d.5h.,
1h.2y.3b.4d.5h.,1j.2y.3b.4d.5h.,1p.2y.3b.4d.5h.,
1a.2a.3e.4d.5h.,1b.2a.3e.4d.5h.,1f.2a.3e.4d.5h.,
1h.2a.3e.4d.5h.,1j.2a.3e.4d.5h.,1p.2a.3e.4d.5h.,
1a.2b.3e.4d.5h.,1b.2b.3e.4d.5h.,1f.2b.3e.4d.5h.,
1h.2b.3e.4d.5h.,1j.2b.3e.4d.5h.,1p.2b.3e.4d.5h.,
1a.2e.3e.4d.5h.,1b.2e.3e.4d.5h.,1f.2e.3e.4d.5h.,
1h.2e.3e.4d.5h.,1j.2e.3e.4d.5h.,1p.2e.3e.4d.5h.,
1a.2f.3e.4d.5h.,1b.2f.3e.4d.5h.,1f.2f.3e.4d.5h.,
1h.2f.3e.4d.5h.,1j.2f.3e.4d.5h.,1p.2f.3e.4d.5h.,
1a.2i.3e.4d.5h.,1b.2i.3e.4d.5h.,1f.2i.3e.4d.5h.,
1h.2i.3e.4d.5h.,1j.2i.3e.4d.5h.,1p.2i.3e.4d.5h.,
1a.2m.3e.4d.5h.,1b.2m.3e.4d.5h.,1f.2m.3e.4d.5h.,
1h.2m.3e.4d.5h.,1j.2m.3e.4d.5h.,1p.2m.3e.4d.5h.,
1a.2o.3e.4d.5h.,1b.2o.3e.4d.5h.,1f.2o.3e.4d.5h.,
1h.2o.3e.4d.5h.,1j.2o.3e.4d.5h.,1p.2o.3e.4d.5h.,
1a.2u.3e.4d.5h.,1b.2u.3e.4d.5h.,1f.2u.3e.4d.5h.,
1h.2u.3e.4d.5h.,1j.2u.3e.4d.5h.,1p.2u.3e.4d.5h.,
1a.2y.3e.4d.5h.,1b.2y.3e.4d.5h.,1f.2y.3e.4d.5h.,
1h.2y.3e.4d.5h.,1j.2y.3e.4d.5h.,1p.2y.3e.4d.5h.,
1a.2a.3g.4d.5h.,1b.2a.3g.4d.5h.,1f.2a.3g.4d.5h.,
1h.2a.3g.4d.5h.,1j.2a.3g.4d.5h.,1p.2a.3g.4d.5h.,
1a.2b.3g.4d.5h.,1b.2b.3g.4d.5h.,1f.2b.3g.4d.5h.,
1h.2b.3g.4d.5h.,1j.2b.3g.4d.5h.,1p.2b.3g.4d.5h.,
1a.2e.3g.4d.5h.,1b.2e.3g.4d.5h.,1f.2e.3g.4d.5h.,
1h.2e.3g.4d.5h.,1j.2e.3g.4d.5h.,1p.2e.3g.4d.5h.,
1a.2f.3g.4d.5h.,1b.2f.3g.4d.5h.,1f.2f.3g.4d.5h.,
1h.2f.3g.4d.5h.,1j.2f.3g.4d.5h.,1p.2f.3g.4d.5h.,
1a.2i.3g.4d.5h.,1b.2i.3g.4d.5h.,1f.2i.3g.4d.5h.,
1h.2i.3g.4d.5h.,1j.2i.3g.4d.5h.,1p.2i.3g.4d.5h.,
1a.2m.3g.4d.5h.,1b.2m.3g.4d.5h.,1f.2m.3g.4d.5h.,
1h.2m.3g.4d.5h.,1j.2m.3g.4d.5h.,1p.2m.3g.4d.5h.,
1a.2o.3g.4d.5h.,1b.2o.3g.4d.5h.,1f.2o.3g.4d.5h.,
1h.2o.3g.4d.5h.,1j.2o.3g.4d.5h.,1p.2o.3g.4d.5h.,
1a.2u.3g.4d.5h.,1b.2u.3g.4d.5h.,1f.2u.3g.4d.5h.,
1h.2u.3g.4d.5h.,1j.2u.3g.4d.5h.,1p.2u.3g.4d.5h.,
1a.2y.3g.4d.5h.,1b.2y.3g.4d.5h.,1f.2y.3g.4d.5h.,
1h.2y.3g.4d.5h.,1j.2y.3g.4d.5h.,1p.2y.3g.4d.5h.,
1a.2a.3a.4f.5h.,1b.2a.3a.4f.5h.,1f.2a.3a.4f.5h.,
1h.2a.3a.4f.5h.,1j.2a.3a.4f.5h.,1p.2a.3a.4f.5h.,
1a.2b.3a.4f.5h.,1b.2b.3a.4f.5h.,1f.2b.3a.4f.5h.,
1h.2b.3a.4f.5h.,1j.2b.3a.4f.5h.,1p.2b.3a.4f.5h.,
1a.2e.3a.4f.5h.,1b.2e.3a.4f.5h.,1f.2e.3a.4f.5h.,
1h.2e.3a.4f.5h.,1j.2e.3a.4f.5h.,1p.2e.3a.4f.5h.,
1a.2f.3a.4f.5h.,1b.2f.3a.4f.5h.,1f.2f.3a.4f.5h.,
1h.2f.3a.4f.5h.,1j.2f.3a.4f.5h.,1p.2f.3a.4f.5h.,
1a.2i.3a.4f.5h.,1b.2i.3a.4f.5h.,1f.2i.3a.4f.5h.,
1h.2i.3a.4f.5h.,1j.2i.3a.4f.5h.,1p.2i.3a.4f.5h.,
1a.2m.3a.4f.5h.,1b.2m.3a.4f.5h.,1f.2m.3a.4f.5h.,
1h.2m.3a.4f.5h.,1j.2m.3a.4f.5h.,1p.2m.3a.4f.5h.,
1a.2o.3a.4f.5h.,1b.2o.3a.4f.5h.,1f.2o.3a.4f.5h.,
1h.2o.3a.4f.5h.,1j.2o.3a.4f.5h.,1p.2o.3a.4f.5h.,
1a.2u.3a.4f.5h.,1b.2u.3a.4f.5h.,1f.2u.3a.4f.5h.,
1h.2u.3a.4f.5h.,1j.2u.3a.4f.5h.,1p.2u.3a.4f.5h.,
1a.2y.3a.4f.5h.,1b.2y.3a.4f.5h.,1f.2y.3a.4f.5h.,
1h.2y.3a.4f.5h.,1j.2y.3a.4f.5h.,1p.2y.3a.4f.5h.,
1a.2a.3b.4f.5h.,1b.2a.3b.4f.5h.,1f.2a.3b.4f.5h.,
1h.2a.3b.4f.5h.,1j.2a.3b.4f.5h.,1p.2a.3b.4f.5h.,
1a.2b.3b.4f.5h.,1b.2b.3b.4f.5h.,1f.2b.3b.4f.5h.,
1h.2b.3b.4f.5h.,1j.2b.3b.4f.5h.,1p.2b.3b.4f.5h.,
1a.2e.3b.4f.5h.,1b.2e.3b.4f.5h.,1f.2e.3b.4f.5h.,
1h.2e.3b.4f.5h.,1j.2e.3b.4f.5h.,1p.2e.3b.4f.5h.,
1a.2f.3b.4f.5h.,1b.2f.3b.4f.5h.,1f.2f.3b.4f.5h.,
1h.2f.3b.4f.5h.,1j.2f.3b.4f.5h.,1p.2f.3b.4f.5h.,
1a.2i.3b.4f.5h.,1b.2i.3b.4f.5h.,1f.2i.3b.4f.5h.,
1h.2i.3b.4f.5h.,1j.2i.3b.4f.5h.,1p.2i.3b.4f.5h.,
1a.2m.3b.4f.5h.,1b.2m.3b.4f.5h.,1f.2m.3b.4f.5h.,
1h.2m.3b.4f.5h.,1j.2m.3b.4f.5h.,1p.2m.3b.4f.5h.,
1a.2o.3b.4f.5h.,1b.2o.3b.4f.5h.,1f.2o.3b.4f.5h.,
1h.2o.3b.4f.5h.,1j.2o.3b.4f.5h.,1p.2o.3b.4f.5h.,
1a.2u.3b.4f.5h.,1b.2u.3b.4f.5h.,1f.2u.3b.4f.5h.,
1h.2u.3b.4f.5h.,1j.2u.3b.4f.5h.,1p.2u.3b.4f.5h.,
1a.2y.3b.4f.5h.,1b.2y.3b.4f.5h.,1f.2y.3b.4f.5h.,
1h.2y.3b.4f.5h.,1j.2y.3b.4f.5h.,1p.2y.3b.4f.5h.,
1a.2a.3e.4f.5h.,1b.2a.3e.4f.5h.,1f.2a.3e.4f.5h.,
1h.2a.3e.4f.5h.,1j.2a.3e.4f.5h.,1p.2a.3e.4f.5h.,
1a.2b.3e.4f.5h.,1b.2b.3e.4f.5h.,1f.2b.3e.4f.5h.,
1h.2b.3e.4f.5h.,1j.2b.3e.4f.5h.,1p.2b.3e.4f.5h.,
1a.2e.3e.4f.5h.,1b.2e.3e.4f.5h.,1f.2e.3e.4f.5h.,
1h.2e.3e.4f.5h.,1j.2e.3e.4f.5h.,1p.2e.3e.4f.5h.,
1a.2f.3e.4f.5h.,1b.2f.3e.4f.5h.,1f.2f.3e.4f.5h.,
1h.2f.3e.4f.5h.,1j.2f.3e.4f.5h.,1p.2f.3e.4f.5h.,
1a.2i.3e.4f.5h.,1b.2i.3e.4f.5h.,1f.2i.3e.4f.5h.,
1h.2i.3e.4f.5h.,1j.2i.3e.4f.5h.,1p.2i.3e.4f.5h.,
1a.2m.3e.4f.5h.,1b.2m.3e.4f.5h.,1f.2m.3e.4f.5h.,
1h.2m.3e.4f.5h.,1j.2m.3e.4f.5h.,1p.2m.3e.4f.5h.,
1a.2o.3e.4f.5h.,1b.2o.3e.4f.5h.,1f.2o.3e.4f.5h.,
1h.2o.3e.4f.5h.,1j.2o.3e.4f.5h.,1p.2o.3e.4f.5h.,
1a.2u.3e.4f.5h.,1b.2u.3e.4f.5h.,1f.2u.3e.4f.5h.,
1h.2u.3e.4f.5h.,1j.2u.3e.4f.5h.,1p.2u.3e.4f.5h.,
1a.2y.3e.4f.5h.,1b.2y.3e.4f.5h.,1f.2y.3e.4f.5h.,
1h.2y.3e.4f.5h.,1j.2y.3e.4f.5h.,1p.2y.3e.4f.5h.,
1a.2a.3g.4f.5h.,1b.2a.3g.4f.5h.,1f.2a.3g.4f.5h.,
1h.2a.3g.4f.5h.,1j.2a.3g.4f.5h.,1p.2a.3g.4f.5h.,
1a.2b.3g.4f.5h.,1b.2b.3g.4f.5h.,1f.2b.3g.4f.5h.,
1h.2b.3g.4f.5h.,1j.2b.3g.4f.5h.,1p.2b.3g.4f.5h.,
1a.2e.3g.4f.5h.,1b.2e.3g.4f.5h.,1f.2e.3g.4f.5h.,
1h.2e.3g.4f.5h.,1j.2e.3g.4f.5h.,1p.2e.3g.4f.5h.,
1a.2f.3g.4f.5h.,1b.2f.3g.4f.5h.,1f.2f.3g.4f.5h.,
1h.2f.3g.4f.5h.,1j.2f.3g.4f.5h.,1p.2f.3g.4f.5h.,
1a.2i.3g.4f.5h.,1b.2i.3g.4f.5h.,1f.2i.3g.4f.5h.,
1h.2i.3g.4f.5h.,1j.2i.3g.4f.5h.,1p.2i.3g.4f.5h.,
1a.2m.3g.4f.5h.,1b.2m.3g.4f.5h.,1f.2m.3g.4f.5h.,
1h.2m.3g.4f.5h.,1j.2m.3g.4f.5h.,1p.2m.3g.4f.5h.,
1a.2o.3g.4f.5h.,1b.2o.3g.4f.5h.,1f.2o.3g.4f.5h.,
1h.2o.3g.4f.5h.,1j.2o.3g.4f.5h.,1p.2o.3g.4f.5h.,
1a.2u.3g.4f.5h.,1b.2u.3g.4f.5h.,1f.2u.3g.4f.5h.,
1h.2u.3g.4f.5h.,1j.2u.3g.4f.5h.,1p.2u.3g.4f.5h.,
1a.2y.3g.4f.5h.,1b.2y.3g.4f.5h.,1f.2y.3g.4f.5h.,
1h.2y.3g.4f.5h.,1j.2y.3g.4f.5h.,1p.2y.3g.4f.5h.,
1a.2a.3a.4g.5h.,1b.2a.3a.4g.5h.,1f.2a.3a.4g.5h.,
1h.2a.3a.4g.5h.,1j.2a.3a.4g.5h.,1p.2a.3a.4g.5h.,
1a.2b.3a.4g.5h.,1b.2b.3a.4g.5h.,1f.2b.3a.4g.5h.,
1h.2b.3a.4g.5h.,1j.2b.3a.4g.5h.,1p.2b.3a.4g.5h.,
1a.2e.3a.4g.5h.,1b.2e.3a.4g.5h.,1f.2e.3a.4g.5h.,
1h.2e.3a.4g.5h.,1j.2e.3a.4g.5h.,1p.2e.3a.4g.5h.,
1a.2f.3a.4g.5h.,1b.2f.3a.4g.5h.,1f.2f.3a.4g.5h.,
1h.2f.3a.4g.5h.,1j.2f.3a.4g.5h.,1p.2f.3a.4g.5h.,
1a.2i.3a.4g.5h.,1b.2i.3a.4g.5h.,1f.2i.3a.4g.5h.,
1h.2i.3a.4g.5h.,1j.2i.3a.4g.5h.,1p.2i.3a.4g.5h.,
1a.2m.3a.4g.5h.,1b.2m.3a.4g.5h.,1f.2m.3a.4g.5h.,
1h.2m.3a.4g.5h.,1j.2m.3a.4g.5h.,1p.2m.3a.4g.5h.,
1a.2o.3a.4g.5h.,1b.2o.3a.4g.5h.,1f.2o.3a.4g.5h.,
1h.2o.3a.4g.5h.,1j.2o.3a.4g.5h.,1p.2o.3a.4g.5h.,
1a.2u.3a.4g.5h.,1b.2u.3a.4g.5h.,1f.2u.3a.4g.5h.,
1h.2u.3a.4g.5h.,1j.2u.3a.4g.5h.,1p.2u.3a.4g.5h.,
1a.2y.3a.4g.5h.,1b.2y.3a.4g.5h.,1f.2y.3a.4g.5h.,
1h.2y.3a.4g.5h.,1j.2y.3a.4g.5h.,1p.2y.3a.4g.5h.,
1a.2a.3b.4g.5h.,1b.2a.3b.4g.5h.,1f.2a.3b.4g.5h.,
1h.2a.3b.4g.5h.,1j.2a.3b.4g.5h.,1p.2a.3b.4g.5h.,
1a.2b.3b.4g.5h.,1b.2b.3b.4g.5h.,1f.2b.3b.4g.5h.,
1h.2b.3b.4g.5h.,1j.2b.3b.4g.5h.,1p.2b.3b.4g.5h.,
1a.2e.3b.4g.5h.,1b.2e.3b.4g.5h.,1f.2e.3b.4g.5h.,
1h.2e.3b.4g.5h.,1j.2e.3b.4g.5h.,1p.2e.3b.4g.5h.,
1a.2f.3b.4g.5h.,1b.2f.3b.4g.5h.,1f.2f.3b.4g.5h.,
1h.2f.3b.4g.5h.,1j.2f.3b.4g.5h.,1p.2f.3b.4g.5h.,
1a.2i.3b.4g.5h.,1b.2i.3b.4g.5h.,1f.2i.3b.4g.5h.,
1h.2i.3b.4g.5h.,1j.2i.3b.4g.5h.,1p.2i.3b.4g.5h.,
1a.2m.3b.4g.5h.,1b.2m.3b.4g.5h.,1f.2m.3b.4g.5h.,
1h.2m.3b.4g.5h.,1j.2m.3b.4g.5h.,1p.2m.3b.4g.5h.,
1a.2o.3b.4g.5h.,1b.2o.3b.4g.5h.,1f.2o.3b.4g.5h.,
1h.2o.3b.4g.5h.,1j.2o.3b.4g.5h.,1p.2o.3b.4g.5h.,
1a.2u.3b.4g.5h.,1b.2u.3b.4g.5h.,1f.2u.3b.4g.5h.,
1h.2u.3b.4g.5h.,1j.2u.3b.4g.5h.,1p.2u.3b.4g.5h.,
1a.2y.3b.4g.5h.,1b.2y.3b.4g.5h.,1f.2y.3b.4g.5h.,
1h.2y.3b.4g.5h.,1j.2y.3b.4g.5h.,1p.2y.3b.4g.5h.,
1a.2a.3e.4g.5h.,1b.2a.3e.4g.5h.,1f.2a.3e.4g.5h.,
1h.2a.3e.4g.5h.,1j.2a.3e.4g.5h.,1p.2a.3e.4g.5h.,
1a.2b.3e.4g.5h.,1b.2b.3e.4g.5h.,1f.2b.3e.4g.5h.,
1h.2b.3e.4g.5h.,1j.2b.3e.4g.5h.,1p.2b.3e.4g.5h.,
1a.2e.3e.4g.5h.,1b.2e.3e.4g.5h.,1f.2e.3e.4g.5h.,
1h.2e.3e.4g.5h.,1j.2e.3e.4g.5h.,1p.2e.3e.4g.5h.,
1a.2f.3e.4g.5h.,1b.2f.3e.4g.5h.,1f.2f.3e.4g.5h.,
1h.2f.3e.4g.5h.,1j.2f.3e.4g.5h.,1p.2f.3e.4g.5h.,
1a.2i.3e.4g.5h.,1b.2i.3e.4g.5h.,1f.2i.3e.4g.5h.,
1h.2i.3e.4g.5h.,1j.2i.3e.4g.5h.,1p.2i.3e.4g.5h.,
1a.2m.3e.4g.5h.,1b.2m.3e.4g.5h.,1f.2m.3e.4g.5h.,
1h.2m.3e.4g.5h.,1j.2m.3e.4g.5h.,1p.2m.3e.4g.5h.,
1a.2o.3e.4g.5h.,1b.2o.3e.4g.5h.,1f.2o.3e.4g.5h.,
1h.2o.3e.4g.5h.,1j.2o.3e.4g.5h.,1p.2o.3e.4g.5h.,
1a.2u.3e.4g.5h.,1b.2u.3e.4g.5h.,1f.2u.3e.4g.5h.,
1h.2u.3e.4g.5h.,1j.2u.3e.4g.5h.,1p.2u.3e.4g.5h.,
1a.2y.3e.4g.5h.,1b.2y.3e.4g.5h.,1f.2y.3e.4g.5h.,
1h.2y.3e.4g.5h.,1j.2y.3e.4g.5h.,1p.2y.3e.4g.5h.,
1a.2a.3g.4g.5h.,1b.2a.3g.4g.5h.,1f.2a.3g.4g.5h.,
1h.2a.3g.4g.5h.,1j.2a.3g.4g.5h.,1p.2a.3g.4g.5h.,
1a.2b.3g.4g.5h.,1b.2b.3g.4g.5h.,1f.2b.3g.4g.5h.,
1h.2b.3g.4g.5h.,1j.2b.3g.4g.5h.,1p.2b.3g.4g.5h.,
1a.2e.3g.4g.5h.,1b.2e.3g.4g.5h.,1f.2e.3g.4g.5h.,
1h.2e.3g.4g.5h.,1j.2e.3g.4g.5h.,1p.2e.3g.4g.5h.,
1a.2f.3g.4g.5h.,1b.2f.3g.4g.5h.,1f.2f.3g.4g.5h.,
1h.2f.3g.4g.5h.,1j.2f.3g.4g.5h.,1p.2f.3g.4g.5h.,
1a.2i.3g.4g.5h.,1b.2i.3g.4g.5h.,1f.2i.3g.4g.5h.,
1h.2i.3g.4g.5h.,1j.2i.3g.4g.5h.,1p.2i.3g.4g.5h.,
1a.2m.3g.4g.5h.,1b.2m.3g.4g.5h.,1f.2m.3g.4g.5h.,
1h.2m.3g.4g.5h.,1j.2m.3g.4g.5h.,1p.2m.3g.4g.5h.,
1a.2o.3g.4g.5h.,1b.2o.3g.4g.5h.,1f.2o.3g.4g.5h.,
1h.2o.3g.4g.5h.,1j.2o.3g.4g.5h.,1p.2o.3g.4g.5h.,
1a.2u.3g.4g.5h.,1b.2u.3g.4g.5h.,1f.2u.3g.4g.5h.,
1h.2u.3g.4g.5h.,1j.2u.3g.4g.5h.,1p.2u.3g.4g.5h.,
1a.2y.3g.4g.5h.,1b.2y.3g.4g.5h.,1f.2y.3g.4g.5h.,
1h.2y.3g.4g.5h.,1j.2y.3g.4g.5h.,1p.2y.3g.4g.5h.,
1a.2a.3a.4h.5h.,1b.2a.3a.4h.5h.,1f.2a.3a.4h.5h.,
1h.2a.3a.4h.5h.,1j.2a.3a.4h.5h.,1p.2a.3a.4h.5h.,
1a.2b.3a.4h.5h.,1b.2b.3a.4h.5h.,1f.2b.3a.4h.5h.,
1h.2b.3a.4h.5h.,1j.2b.3a.4h.5h.,1p.2b.3a.4h.5h.,
1a.2e.3a.4h.5h.,1b.2e.3a.4h.5h.,1f.2e.3a.4h.5h.,
1h.2e.3a.4h.5h.,1j.2e.3a.4h.5h.,1p.2e.3a.4h.5h.,
1a.2f.3a.4h.5h.,1b.2f.3a.4h.5h.,1f.2f.3a.4h.5h.,
1h.2f.3a.4h.5h.,1j.2f.3a.4h.5h.,1p.2f.3a.4h.5h.,
1a.2i.3a.4h.5h.,1b.2i.3a.4h.5h.,1f.2i.3a.4h.5h.,
1h.2i.3a.4h.5h.,1j.2i.3a.4h.5h.,1p.2i.3a.4h.5h.,
1a.2m.3a.4h.5h.,1b.2m.3a.4h.5h.,1f.2m.3a.4h.5h.,
1h.2m.3a.4h.5h.,1j.2m.3a.4h.5h.,1p.2m.3a.4h.5h.,
1a.2o.3a.4h.5h.,1b.2o.3a.4h.5h.,1f.2o.3a.4h.5h.,
1h.2o.3a.4h.5h.,1j.2o.3a.4h.5h.,1p.2o.3a.4h.5h.,
1a.2u.3a.4h.5h.,1b.2u.3a.4h.5h.,1f.2u.3a.4h.5h.,
1h.2u.3a.4h.5h.,1j.2u.3a.4h.5h.,1p.2u.3a.4h.5h.,
1a.2y.3a.4h.5h.,1b.2y.3a.4h.5h.,1f.2y.3a.4h.5h.,
1h.2y.3a.4h.5h.,1j.2y.3a.4h.5h.,1p.2y.3a.4h.5h.,
1a.2a.3b.4h.5h.,1b.2a.3b.4h.5h.,1f.2a.3b.4h.5h.,
1h.2a.3b.4h.5h.,1j.2a.3b.4h.5h.,1p.2a.3b.4h.5h.,
1a.2b.3b.4h.5h.,1b.2b.3b.4h.5h.,1f.2b.3b.4h.5h.,
1h.2b.3b.4h.5h.,1j.2b.3b.4h.5h.,1p.2b.3b.4h.5h.,
1a.2e.3b.4h.5h.,1b.2e.3b.4h.5h.,1f.2e.3b.4h.5h.,
1h.2e.3b.4h.5h.,1j.2e.3b.4h.5h.,1p.2e.3b.4h.5h.,
1a.2f.3b.4h.5h.,1b.2f.3b.4h.5h.,1f.2f.3b.4h.5h.,
1h.2f.3b.4h.5h.,1j.2f.3b.4h.5h.,1p.2f.3b.4h.5h.,
1a.2i.3b.4h.5h.,1b.2i.3b.4h.5h.,1f.2i.3b.4h.5h.,
1h.2i.3b.4h.5h.,1j.2i.3b.4h.5h.,1p.2i.3b.4h.5h.,
1a.2m.3b.4h.5h.,1b.2m.3b.4h.5h.,1f.2m.3b.4h.5h.,
1h.2m.3b.4h.5h.,1j.2m.3b.4h.5h.,1p.2m.3b.4h.5h.,
1a.2o.3b.4h.5h.,1b.2o.3b.4h.5h.,1f.2o.3b.4h.5h.,
1h.2o.3b.4h.5h.,1j.2o.3b.4h.5h.,1p.2o.3b.4h.5h.,
1a.2u.3b.4h.5h.,1b.2u.3b.4h.5h.,1f.2u.3b.4h.5h.,
1h.2u.3b.4h.5h.,1j.2u.3b.4h.5h.,1p.2u.3b.4h.5h.,
1a.2y.3b.4h.5h.,1b.2y.3b.4h.5h.,1f.2y.3b.4h.5h.,
1h.2y.3b.4h.5h.,1j.2y.3b.4h.5h.,1p.2y.3b.4h.5h.,
1a.2a.3e.4h.5h.,1b.2a.3e.4h.5h.,1f.2a.3e.4h.5h.,
1h.2a.3e.4h.5h.,1j.2a.3e.4h.5h.,1p.2a.3e.4h.5h.,
1a.2b.3e.4h.5h.,1b.2b.3e.4h.5h.,1f.2b.3e.4h.5h.,
1h.2b.3e.4h.5h.,1j.2b.3e.4h.5h.,1p.2b.3e.4h.5h.,
1a.2e.3e.4h.5h.,1b.2e.3e.4h.5h.,1f.2e.3e.4h.5h.,
1h.2e.3e.4h.5h.,1j.2e.3e.4h.5h.,1p.2e.3e.4h.5h.,
1a.2f.3e.4h.5h.,1b.2f.3e.4h.5h.,1f.2f.3e.4h.5h.,
1h.2f.3e.4h.5h.,1j.2f.3e.4h.5h.,1p.2f.3e.4h.5h.,
1a.2i.3e.4h.5h.,1b.2i.3e.4h.5h.,1f.2i.3e.4h.5h.,
1h.2i.3e.4h.5h.,1j.2i.3e.4h.5h.,1p.2i.3e.4h.5h.,
1a.2m.3e.4h.5h.,1b.2m.3e.4h.5h.,1f.2m.3e.4h.5h.,
1h.2m.3e.4h.5h.,1j.2m.3e.4h.5h.,1p.2m.3e.4h.5h.,
1a.2o.3e.4h.5h.,1b.2o.3e.4h.5h.,1f.2o.3e.4h.5h.,
1h.2o.3e.4h.5h.,1j.2o.3e.4h.5h.,1p.2o.3e.4h.5h.,
1a.2u.3e.4h.5h.,1b.2u.3e.4h.5h.,1f.2u.3e.4h.5h.,
1h.2u.3e.4h.5h.,1j.2u.3e.4h.5h.,1p.2u.3e.4h.5h.,
1a.2y.3e.4h.5h.,1b.2y.3e.4h.5h.,1f.2y.3e.4h.5h.,
1h.2y.3e.4h.5h.,1j.2y.3e.4h.5h.,1p.2y.3e.4h.5h.,
1a.2a.3g.4h.5h.,1b.2a.3g.4h.5h.,1f.2a.3g.4h.5h.,
1h.2a.3g.4h.5h.,1j.2a.3g.4h.5h.,1p.2a.3g.4h.5h.,
1a.2b.3g.4h.5h.,1b.2b.3g.4h.5h.,1f.2b.3g.4h.5h.,
1h.2b.3g.4h.5h.,1j.2b.3g.4h.5h.,1p.2b.3g.4h.5h.,
1a.2e.3g.4h.5h.,1b.2e.3g.4h.5h.,1f.2e.3g.4h.5h.,
1h.2e.3g.4h.5h.,1j.2e.3g.4h.5h.,1p.2e.3g.4h.5h.,
1a.2f.3g.4h.5h.,1b.2f.3g.4h.5h.,1f.2f.3g.4h.5h.,
1h.2f.3g.4h.5h.,1j.2f.3g.4h.5h.,1p.2f.3g.4h.5h.,
1a.2i.3g.4h.5h.,1b.2i.3g.4h.5h.,1f.2i.3g.4h.5h.,
1h.2i.3g.4h.5h.,1j.2i.3g.4h.5h.,1p.2i.3g.4h.5h.,
1a.2m.3g.4h.5h.,1b.2m.3g.4h.5h.,1f.2m.3g.4h.5h.,
1h.2m.3g.4h.5h.,1j.2m.3g.4h.5h.,1p.2m.3g.4h.5h.,
1a.2o.3g.4h.5h.,1b.2o.3g.4h.5h.,1f.2o.3g.4h.5h.,
1h.2o.3g.4h.5h.,1j.2o.3g.4h.5h.,1p.2o.3g.4h.5h.,
1a.2u.3g.4h.5h.,1b.2u.3g.4h.5h.,1f.2u.3g.4h.5h.,
1h.2u.3g.4h.5h.,1j.2u.3g.4h.5h.,1p.2u.3g.4h.5h.,
1a.2y.3g.4h.5h.,1b.2y.3g.4h.5h.,1f.2y.3g.4h.5h.,
1h.2y.3g.4h.5h.,1j.2y.3g.4h.5h.,1p.2y.3g.4h.5h.,
1a.2a.3a.4i.5h.,1b.2a.3a.4i.5h.,1f.2a.3a.4i.5h.,
1h.2a.3a.4i.5h.,1j.2a.3a.4i.5h.,1p.2a.3a.4i.5h.,
1a.2b.3a.4i.5h.,1b.2b.3a.4i.5h.,1f.2b.3a.4i.5h.,
1h.2b.3a.4i.5h.,1j.2b.3a.4i.5h.,1p.2b.3a.4i.5h.,
1a.2e.3a.4i.5h.,1b.2e.3a.4i.5h.,1f.2e.3a.4i.5h.,
1h.2e.3a.4i.5h.,1j.2e.3a.4i.5h.,1p.2e.3a.4i.5h.,
1a.2f.3a.4i.5h.,1b.2f.3a.4i.5h.,1f.2f.3a.4i.5h.,
1h.2f.3a.4i.5h.,1j.2f.3a.4i.5h.,1p.2f.3a.4i.5h.,
1a.2i.3a.4i.5h.,1b.2i.3a.4i.5h.,1f.2i.3a.4i.5h.,
1h.2i.3a.4i.5h.,1j.2i.3a.4i.5h.,1p.2i.3a.4i.5h.,
1a.2m.3a.4i.5h.,1b.2m.3a.4i.5h.,1f.2m.3a.4i.5h.,
1h.2m.3a.4i.5h.,1j.2m.3a.4i.5h.,1p.2m.3a.4i.5h.,
1a.2o.3a.4i.5h.,1b.2o.3a.4i.5h.,1f.2o.3a.4i.5h.,
1h.2o.3a.4i.5h.,1j.2o.3a.4i.5h.,1p.2o.3a.4i.5h.,
1a.2u.3a.4i.5h.,1b.2u.3a.4i.5h.,1f.2u.3a.4i.5h.,
1h.2u.3a.4i.5h.,1j.2u.3a.4i.5h.,1p.2u.3a.4i.5h.,
1a.2y.3a.4i.5h.,1b.2y.3a.4i.5h.,1f.2y.3a.4i.5h.,
1h.2y.3a.4i.5h.,1j.2y.3a.4i.5h.,1p.2y.3a.4i.5h.,
1a.2a.3b.4i.5h.,1b.2a.3b.4i.5h.,1f.2a.3b.4i.5h.,
1h.2a.3b.4i.5h.,1j.2a.3b.4i.5h.,1p.2a.3b.4i.5h.,
1a.2b.3b.4i.5h.,1b.2b.3b.4i.5h.,1f.2b.3b.4i.5h.,
1h.2b.3b.4i.5h.,1j.2b.3b.4i.5h.,1p.2b.3b.4i.5h.,
1a.2e.3b.4i.5h.,1b.2e.3b.4i.5h.,1f.2e.3b.4i.5h.,
1h.2e.3b.4i.5h.,1j.2e.3b.4i.5h.,1p.2e.3b.4i.5h.,
1a.2f.3b.4i.5h.,1b.2f.3b.4i.5h.,1f.2f.3b.4i.5h.,
1h.2f.3b.4i.5h.,1j.2f.3b.4i.5h.,1p.2f.3b.4i.5h.,
1a.2i.3b.4i.5h.,1b.2i.3b.4i.5h.,1f.2i.3b.4i.5h.,
1h.2i.3b.4i.5h.,1j.2i.3b.4i.5h.,1p.2i.3b.4i.5h.,
1a.2m.3b.4i.5h.,1b.2m.3b.4i.5h.,1f.2m.3b.4i.5h.,
1h.2m.3b.4i.5h.,1j.2m.3b.4i.5h.,1p.2m.3b.4i.5h.,
1a.2o.3b.4i.5h.,1b.2o.3b.4i.5h.,1f.2o.3b.4i.5h.,
1h.2o.3b.4i.5h.,1j.2o.3b.4i.5h.,1p.2o.3b.4i.5h.,
1a.2u.3b.4i.5h.,1b.2u.3b.4i.5h.,1f.2u.3b.4i.5h.,
1h.2u.3b.4i.5h.,1j.2u.3b.4i.5h.,1p.2u.3b.4i.5h.,
1a.2y.3b.4i.5h.,1b.2y.3b.4i.5h.,1f.2y.3b.4i.5h.,
1h.2y.3b.4i.5h.,1j.2y.3b.4i.5h.,1p.2y.3b.4i.5h.,
1a.2a.3e.4i.5h.,1b.2a.3e.4i.5h.,1f.2a.3e.4i.5h.,
1h.2a.3e.4i.5h.,1j.2a.3e.4i.5h.,1p.2a.3e.4i.5h.,
1a.2b.3e.4i.5h.,1b.2b.3e.4i.5h.,1f.2b.3e.4i.5h.,
1h.2b.3e.4i.5h.,1j.2b.3e.4i.5h.,1p.2b.3e.4i.5h.,
1a.2e.3e.4i.5h.,1b.2e.3e.4i.5h.,1f.2e.3e.4i.5h.,
1h.2e.3e.4i.5h.,1j.2e.3e.4i.5h.,1p.2e.3e.4i.5h.,
1a.2f.3e.4i.5h.,1b.2f.3e.4i.5h.,1f.2f.3e.4i.5h.,
1h.2f.3e.4i.5h.,1j.2f.3e.4i.5h.,1p.2f.3e.4i.5h.,
1a.2i.3e.4i.5h.,1b.2i.3e.4i.5h.,1f.2i.3e.4i.5h.,
1h.2i.3e.4i.5h.,1j.2i.3e.4i.5h.,1p.2i.3e.4i.5h.,
1a.2m.3e.4i.5h.,1b.2m.3e.4i.5h.,1f.2m.3e.4i.5h.,
1h.2m.3e.4i.5h.,1j.2m.3e.4i.5h.,1p.2m.3e.4i.5h.,
1a.2o.3e.4i.5h.,1b.2o.3e.4i.5h.,1f.2o.3e.4i.5h.,
1h.2o.3e.4i.5h.,1j.2o.3e.4i.5h.,1p.2o.3e.4i.5h.,
1a.2u.3e.4i.5h.,1b.2u.3e.4i.5h.,1f.2u.3e.4i.5h.,
1h.2u.3e.4i.5h.,1j.2u.3e.4i.5h.,1p.2u.3e.4i.5h.,
1a.2y.3e.4i.5h.,1b.2y.3e.4i.5h.,1f.2y.3e.4i.5h.,
1h.2y.3e.4i.5h.,1j.2y.3e.4i.5h.,1p.2y.3e.4i.5h.,
1a.2a.3g.4i.5h.,1b.2a.3g.4i.5h.,1f.2a.3g.4i.5h.,
1h.2a.3g.4i.5h.,1j.2a.3g.4i.5h.,1p.2a.3g.4i.5h.,
1a.2b.3g.4i.5h.,1b.2b.3g.4i.5h.,1f.2b.3g.4i.5h.,
1h.2b.3g.4i.5h.,1j.2b.3g.4i.5h.,1p.2b.3g.4i.5h.,
1a.2e.3g.4i.5h.,1b.2e.3g.4i.5h.,1f.2e.3g.4i.5h.,
1h.2e.3g.4i.5h.,1j.2e.3g.4i.5h.,1p.2e.3g.4i.5h.,
1a.2f.3g.4i.5h.,1b.2f.3g.4i.5h.,1f.2f.3g.4i.5h.,
1h.2f.3g.4i.5h.,1j.2f.3g.4i.5h.,1p.2f.3g.4i.5h.,
1a.2i.3g.4i.5h.,1b.2i.3g.4i.5h.,1f.2i.3g.4i.5h.,
1h.2i.3g.4i.5h.,1j.2i.3g.4i.5h.,1p.2i.3g.4i.5h.,
1a.2m.3g.4i.5h.,1b.2m.3g.4i.5h.,1f.2m.3g.4i.5h.,
1h.2m.3g.4i.5h.,1j.2m.3g.4i.5h.,1p.2m.3g.4i.5h.,
1a.2o.3g.4i.5h.,1b.2o.3g.4i.5h.,1f.2o.3g.4i.5h.,
1h.2o.3g.4i.5h.,1j.2o.3g.4i.5h.,1p.2o.3g.4i.5h.,
1a.2u.3g.4i.5h.,1b.2u.3g.4i.5h.,1f.2u.3g.4i.5h.,
1h.2u.3g.4i.5h.,1j.2u.3g.4i.5h.,1p.2u.3g.4i.5h.,
1a.2y.3g.4i.5h.,1b.2y.3g.4i.5h.,1f.2y.3g.4i.5h.,
1h.2y.3g.4i.5h.,1j.2y.3g.4i.5h.,1p.2y.3g.4i.5h.,
1a.2a.3a.4a.5i.,1b.2a.3a.4a.5i.,1f.2a.3a.4a.5i.,
1h.2a.3a.4a.5i.,1j.2a.3a.4a.5i.,1p.2a.3a.4a.5i.,
1a.2b.3a.4a.5i.,1b.2b.3a.4a.5i.,1f.2b.3a.4a.5i.,
1h.2b.3a.4a.5i.,1j.2b.3a.4a.5i.,1p.2b.3a.4a.5i.,
1a.2e.3a.4a.5i.,1b.2e.3a.4a.5i.,1f.2e.3a.4a.5i.,
1h.2e.3a.4a.5i.,1j.2e.3a.4a.5i.,1p.2e.3a.4a.5i.,
1a.2f.3a.4a.5i.,1b.2f.3a.4a.5i.,1f.2f.3a.4a.5i.,
1h.2f.3a.4a.5i.,1j.2f.3a.4a.5i.,1p.2f.3a.4a.5i.,
1a.2i.3a.4a.5i.,1b.2i.3a.4a.5i.,1f.2i.3a.4a.5i.,
1h.2i.3a.4a.5i.,1j.2i.3a.4a.5i.,1p.2i.3a.4a.5i.,
1a.2m.3a.4a.5i.,1b.2m.3a.4a.5i.,1f.2m.3a.4a.5i.,
1h.2m.3a.4a.5i.,1j.2m.3a.4a.5i.,1p.2m.3a.4a.5i.,
1a.2o.3a.4a.5i.,1b.2o.3a.4a.5i.,1f.2o.3a.4a.5i.,
1h.2o.3a.4a.5i.,1j.2o.3a.4a.5i.,1p.2o.3a.4a.5i.,
1a.2u.3a.4a.5i.,1b.2u.3a.4a.5i.,1f.2u.3a.4a.5i.,
1h.2u.3a.4a.5i.,1j.2u.3a.4a.5i.,1p.2u.3a.4a.5i.,
1a.2y.3a.4a.5i.,1b.2y.3a.4a.5i.,1f.2y.3a.4a.5i.,
1h.2y.3a.4a.5i.,1j.2y.3a.4a.5i.,1p.2y.3a.4a.5i.,
1a.2a.3b.4a.5i.,1b.2a.3b.4a.5i.,1f.2a.3b.4a.5i.,
1h.2a.3b.4a.5i.,1j.2a.3b.4a.5i.,1p.2a.3b.4a.5i.,
1a.2b.3b.4a.5i.,1b.2b.3b.4a.5i.,1f.2b.3b.4a.5i.,
1h.2b.3b.4a.5i.,1j.2b.3b.4a.5i.,1p.2b.3b.4a.5i.,
1a.2e.3b.4a.5i.,1b.2e.3b.4a.5i.,1f.2e.3b.4a.5i.,
1h.2e.3b.4a.5i.,1j.2e.3b.4a.5i.,1p.2e.3b.4a.5i.,
1a.2f.3b.4a.5i.,1b.2f.3b.4a.5i.,1f.2f.3b.4a.5i.,
1h.2f.3b.4a.5i.,1j.2f.3b.4a.5i.,1p.2f.3b.4a.5i.,
1a.2i.3b.4a.5i.,1b.2i.3b.4a.5i.,1f.2i.3b.4a.5i.,
1h.2i.3b.4a.5i.,1j.2i.3b.4a.5i.,1p.2i.3b.4a.5i.,
1a.2m.3b.4a.5i.,1b.2m.3b.4a.5i.,1f.2m.3b.4a.5i.,
1h.2m.3b.4a.5i.,1j.2m.3b.4a.5i.,1p.2m.3b.4a.5i.,
1a.2o.3b.4a.5i.,1b.2o.3b.4a.5i.,1f.2o.3b.4a.5i.,
1h.2o.3b.4a.5i.,1j.2o.3b.4a.5i.,1p.2o.3b.4a.5i.,
1a.2u.3b.4a.5i.,1b.2u.3b.4a.5i.,1f.2u.3b.4a.5i.,
1h.2u.3b.4a.5i.,1j.2u.3b.4a.5i.,1p.2u.3b.4a.5i.,
1a.2y.3b.4a.5i.,1b.2y.3b.4a.5i.,1f.2y.3b.4a.5i.,
1h.2y.3b.4a.5i.,1j.2y.3b.4a.5i.,1p.2y.3b.4a.5i.,
1a.2a.3e.4a.5i.,1b.2a.3e.4a.5i.,1f.2a.3e.4a.5i.,
1h.2a.3e.4a.5i.,1j.2a.3e.4a.5i.,1p.2a.3e.4a.5i.,
1a.2b.3e.4a.5i.,1b.2b.3e.4a.5i.,1f.2b.3e.4a.5i.,
1h.2b.3e.4a.5i.,1j.2b.3e.4a.5i.,1p.2b.3e.4a.5i.,
1a.2e.3e.4a.5i.,1b.2e.3e.4a.5i.,1f.2e.3e.4a.5i.,
1h.2e.3e.4a.5i.,1j.2e.3e.4a.5i.,1p.2e.3e.4a.5i.,
1a.2f.3e.4a.5i.,1b.2f.3e.4a.5i.,1f.2f.3e.4a.5i.,
1h.2f.3e.4a.5i.,1j.2f.3e.4a.5i.,1p.2f.3e.4a.5i.,
1a.2i.3e.4a.5i.,1b.2i.3e.4a.5i.,1f.2i.3e.4a.5i.,
1h.2i.3e.4a.5i.,1j.2i.3e.4a.5i.,1p.2i.3e.4a.5i.,
1a.2m.3e.4a.5i.,1b.2m.3e.4a.5i.,1f.2m.3e.4a.5i.,
1h.2m.3e.4a.5i.,1j.2m.3e.4a.5i.,1p.2m.3e.4a.5i.,
1a.2o.3e.4a.5i.,1b.2o.3e.4a.5i.,1f.2o.3e.4a.5i.,
1h.2o.3e.4a.5i.,1j.2o.3e.4a.5i.,1p.2o.3e.4a.5i.,
1a.2u.3e.4a.5i.,1b.2u.3e.4a.5i.,1f.2u.3e.4a.5i.,
1h.2u.3e.4a.5i.,1j.2u.3e.4a.5i.,1p.2u.3e.4a.5i.,
1a.2y.3e.4a.5i.,1b.2y.3e.4a.5i.,1f.2y.3e.4a.5i.,
1h.2y.3e.4a.5i.,1j.2y.3e.4a.5i.,1p.2y.3e.4a.5i.,
1a.2a.3g.4a.5i.,1b.2a.3g.4a.5i.,1f.2a.3g.4a.5i.,
1h.2a.3g.4a.5i.,1j.2a.3g.4a.5i.,1p.2a.3g.4a.5i.,
1a.2b.3g.4a.5i.,1b.2b.3g.4a.5i.,1f.2b.3g.4a.5i.,
1h.2b.3g.4a.5i.,1j.2b.3g.4a.5i.,1p.2b.3g.4a.5i.,
1a.2e.3g.4a.5i.,1b.2e.3g.4a.5i.,1f.2e.3g.4a.5i.,
1h.2e.3g.4a.5i.,1j.2e.3g.4a.5i.,1p.2e.3g.4a.5i.,
1a.2f.3g.4a.5i.,1b.2f.3g.4a.5i.,1f.2f.3g.4a.5i.,
1h.2f.3g.4a.5i.,1j.2f.3g.4a.5i.,1p.2f.3g.4a.5i.,
1a.2i.3g.4a.5i.,1b.2i.3g.4a.5i.,1f.2i.3g.4a.5i.,
1h.2i.3g.4a.5i.,1j.2i.3g.4a.5i.,1p.2i.3g.4a.5i.,
1a.2m.3g.4a.5i.,1b.2m.3g.4a.5i.,1f.2m.3g.4a.5i.,
1h.2m.3g.4a.5i.,1j.2m.3g.4a.5i.,1p.2m.3g.4a.5i.,
1a.2o.3g.4a.5i.,1b.2o.3g.4a.5i.,1f.2o.3g.4a.5i.,
1h.2o.3g.4a.5i.,1j.2o.3g.4a.5i.,1p.2o.3g.4a.5i.,
1a.2u.3g.4a.5i.,1b.2u.3g.4a.5i.,1f.2u.3g.4a.5i.,
1h.2u.3g.4a.5i.,1j.2u.3g.4a.5i.,1p.2u.3g.4a.5i.,
1a.2y.3g.4a.5i.,1b.2y.3g.4a.5i.,1f.2y.3g.4a.5i.,
1h.2y.3g.4a.5i.,1j.2y.3g.4a.5i.,1p.2y.3g.4a.5i.,
1a.2a.3a.4d.5i.,1b.2a.3a.4d.5i.,1f.2a.3a.4d.5i.,
1h.2a.3a.4d.5i.,1j.2a.3a.4d.5i.,1p.2a.3a.4d.5i.,
1a.2b.3a.4d.5i.,1b.2b.3a.4d.5i.,1f.2b.3a.4d.5i.,
1h.2b.3a.4d.5i.,1j.2b.3a.4d.5i.,1p.2b.3a.4d.5i.,
1a.2e.3a.4d.5i.,1b.2e.3a.4d.5i.,1f.2e.3a.4d.5i.,
1h.2e.3a.4d.5i.,1j.2e.3a.4d.5i.,1p.2e.3a.4d.5i.,
1a.2f.3a.4d.5i.,1b.2f.3a.4d.5i.,1f.2f.3a.4d.5i.,
1h.2f.3a.4d.5i.,1j.2f.3a.4d.5i.,1p.2f.3a.4d.5i.,
1a.2i.3a.4d.5i.,1b.2i.3a.4d.5i.,1f.2i.3a.4d.5i.,
1h.2i.3a.4d.5i.,1j.2i.3a.4d.5i.,1p.2i.3a.4d.5i.,
1a.2m.3a.4d.5i.,1b.2m.3a.4d.5i.,1f.2m.3a.4d.5i.,
1h.2m.3a.4d.5i.,1j.2m.3a.4d.5i.,1p.2m.3a.4d.5i.,
1a.2o.3a.4d.5i.,1b.2o.3a.4d.5i.,1f.2o.3a.4d.5i.,
1h.2o.3a.4d.5i.,1j.2o.3a.4d.5i.,1p.2o.3a.4d.5i.,
1a.2u.3a.4d.5i.,1b.2u.3a.4d.5i.,1f.2u.3a.4d.5i.,
1h.2u.3a.4d.5i.,1j.2u.3a.4d.5i.,1p.2u.3a.4d.5i.,
1a.2y.3a.4d.5i.,1b.2y.3a.4d.5i.,1f.2y.3a.4d.5i.,
1h.2y.3a.4d.5i.,1j.2y.3a.4d.5i.,1p.2y.3a.4d.5i.,
1a.2a.3b.4d.5i.,1b.2a.3b.4d.5i.,1f.2a.3b.4d.5i.,
1h.2a.3b.4d.5i.,1j.2a.3b.4d.5i.,1p.2a.3b.4d.5i.,
1a.2b.3b.4d.5i.,1b.2b.3b.4d.5i.,1f.2b.3b.4d.5i.,
1h.2b.3b.4d.5i.,1j.2b.3b.4d.5i.,1p.2b.3b.4d.5i.,
1a.2e.3b.4d.5i.,1b.2e.3b.4d.5i.,1f.2e.3b.4d.5i.,
1h.2e.3b.4d.5i.,1j.2e.3b.4d.5i.,1p.2e.3b.4d.5i.,
1a.2f.3b.4d.5i.,1b.2f.3b.4d.5i.,1f.2f.3b.4d.5i.,
1h.2f.3b.4d.5i.,1j.2f.3b.4d.5i.,1p.2f.3b.4d.5i.,
1a.2i.3b.4d.5i.,1b.2i.3b.4d.5i.,1f.2i.3b.4d.5i.,
1h.2i.3b.4d.5i.,1j.2i.3b.4d.5i.,1p.2i.3b.4d.5i.,
1a.2m.3b.4d.5i.,1b.2m.3b.4d.5i.,1f.2m.3b.4d.5i.,
1h.2m.3b.4d.5i.,1j.2m.3b.4d.5i.,1p.2m.3b.4d.5i.,
1a.2o.3b.4d.5i.,1b.2o.3b.4d.5i.,1f.2o.3b.4d.5i.,
1h.2o.3b.4d.5i.,1j.2o.3b.4d.5i.,1p.2o.3b.4d.5i.,
1a.2u.3b.4d.5i.,1b.2u.3b.4d.5i.,1f.2u.3b.4d.5i.,
1h.2u.3b.4d.5i.,1j.2u.3b.4d.5i.,1p.2u.3b.4d.5i.,
1a.2y.3b.4d.5i.,1b.2y.3b.4d.5i.,1f.2y.3b.4d.5i.,
1h.2y.3b.4d.5i.,1j.2y.3b.4d.5i.,1p.2y.3b.4d.5i.,
1a.2a.3e.4d.5i.,1b.2a.3e.4d.5i.,1f.2a.3e.4d.5i.,
1h.2a.3e.4d.5i.,1j.2a.3e.4d.5i.,1p.2a.3e.4d.5i.,
1a.2b.3e.4d.5i.,1b.2b.3e.4d.5i.,1f.2b.3e.4d.5i.,
1h.2b.3e.4d.5i.,1j.2b.3e.4d.5i.,1p.2b.3e.4d.5i.,
1a.2e.3e.4d.5i.,1b.2e.3e.4d.5i.,1f.2e.3e.4d.5i.,
1h.2e.3e.4d.5i.,1j.2e.3e.4d.5i.,1p.2e.3e.4d.5i.,
1a.2f.3e.4d.5i.,1b.2f.3e.4d.5i.,1f.2f.3e.4d.5i.,
1h.2f.3e.4d.5i.,1j.2f.3e.4d.5i.,1p.2f.3e.4d.5i.,
1a.2i.3e.4d.5i.,1b.2i.3e.4d.5i.,1f.2i.3e.4d.5i.,
1h.2i.3e.4d.5i.,1j.2i.3e.4d.5i.,1p.2i.3e.4d.5i.,
1a.2m.3e.4d.5i.,1b.2m.3e.4d.5i.,1f.2m.3e.4d.5i.,
1h.2m.3e.4d.5i.,1j.2m.3e.4d.5i.,1p.2m.3e.4d.5i.,
1a.2o.3e.4d.5i.,1b.2o.3e.4d.5i.,1f.2o.3e.4d.5i.,
1h.2o.3e.4d.5i.,1j.2o.3e.4d.5i.,1p.2o.3e.4d.5i.,
1a.2u.3e.4d.5i.,1b.2u.3e.4d.5i.,1f.2u.3e.4d.5i.,
1h.2u.3e.4d.5i.,1j.2u.3e.4d.5i.,1p.2u.3e.4d.5i.,
1a.2y.3e.4d.5i.,1b.2y.3e.4d.5i.,1f.2y.3e.4d.5i.,
1h.2y.3e.4d.5i.,1j.2y.3e.4d.5i.,1p.2y.3e.4d.5i.,
1a.2a.3g.4d.5i.,1b.2a.3g.4d.5i.,1f.2a.3g.4d.5i.,
1h.2a.3g.4d.5i.,1j.2a.3g.4d.5i.,1p.2a.3g.4d.5i.,
1a.2b.3g.4d.5i.,1b.2b.3g.4d.5i.,1f.2b.3g.4d.5i.,
1h.2b.3g.4d.5i.,1j.2b.3g.4d.5i.,1p.2b.3g.4d.5i.,
1a.2e.3g.4d.5i.,1b.2e.3g.4d.5i.,1f.2e.3g.4d.5i.,
1h.2e.3g.4d.5i.,1j.2e.3g.4d.5i.,1p.2e.3g.4d.5i.,
1a.2f.3g.4d.5i.,1b.2f.3g.4d.5i.,1f.2f.3g.4d.5i.,
1h.2f.3g.4d.5i.,1j.2f.3g.4d.5i.,1p.2f.3g.4d.5i.,
1a.2i.3g.4d.5i.,1b.2i.3g.4d.5i.,1f.2i.3g.4d.5i.,
1h.2i.3g.4d.5i.,1j.2i.3g.4d.5i.,1p.2i.3g.4d.5i.,
1a.2m.3g.4d.5i.,1b.2m.3g.4d.5i.,1f.2m.3g.4d.5i.,
1h.2m.3g.4d.5i.,1j.2m.3g.4d.5i.,1p.2m.3g.4d.5i.,
1a.2o.3g.4d.5i.,1b.2o.3g.4d.5i.,1f.2o.3g.4d.5i.,
1h.2o.3g.4d.5i.,1j.2o.3g.4d.5i.,1p.2o.3g.4d.5i.,
1a.2u.3g.4d.5i.,1b.2u.3g.4d.5i.,1f.2u.3g.4d.5i.,
1h.2u.3g.4d.5i.,1j.2u.3g.4d.5i.,1p.2u.3g.4d.5i.,
1a.2y.3g.4d.5i.,1b.2y.3g.4d.5i.,1f.2y.3g.4d.5i.,
1h.2y.3g.4d.5i.,1j.2y.3g.4d.5i.,1p.2y.3g.4d.5i.,
1a.2a.3a.4f.5i.,1b.2a.3a.4f.5i.,1f.2a.3a.4f.5i.,
1h.2a.3a.4f.5i.,1j.2a.3a.4f.5i.,1p.2a.3a.4f.5i.,
1a.2b.3a.4f.5i.,1b.2b.3a.4f.5i.,1f.2b.3a.4f.5i.,
1h.2b.3a.4f.5i.,1j.2b.3a.4f.5i.,1p.2b.3a.4f.5i.,
1a.2e.3a.4f.5i.,1b.2e.3a.4f.5i.,1f.2e.3a.4f.5i.,
1h.2e.3a.4f.5i.,1j.2e.3a.4f.5i.,1p.2e.3a.4f.5i.,
1a.2f.3a.4f.5i.,1b.2f.3a.4f.5i.,1f.2f.3a.4f.5i.,
1h.2f.3a.4f.5i.,1j.2f.3a.4f.5i.,1p.2f.3a.4f.5i.,
1a.2i.3a.4f.5i.,1b.2i.3a.4f.5i.,1f.2i.3a.4f.5i.,
1h.2i.3a.4f.5i.,1j.2i.3a.4f.5i.,1p.2i.3a.4f.5i.,
1a.2m.3a.4f.5i.,1b.2m.3a.4f.5i.,1f.2m.3a.4f.5i.,
1h.2m.3a.4f.5i.,1j.2m.3a.4f.5i.,1p.2m.3a.4f.5i.,
1a.2o.3a.4f.5i.,1b.2o.3a.4f.5i.,1f.2o.3a.4f.5i.,
1h.2o.3a.4f.5i.,1j.2o.3a.4f.5i.,1p.2o.3a.4f.5i.,
1a.2u.3a.4f.5i.,1b.2u.3a.4f.5i.,1f.2u.3a.4f.5i.,
1h.2u.3a.4f.5i.,1j.2u.3a.4f.5i.,1p.2u.3a.4f.5i.,
1a.2y.3a.4f.5i.,1b.2y.3a.4f.5i.,1f.2y.3a.4f.5i.,
1h.2y.3a.4f.5i.,1j.2y.3a.4f.5i.,1p.2y.3a.4f.5i.,
1a.2a.3b.4f.5i.,1b.2a.3b.4f.5i.,1f.2a.3b.4f.5i.,
1h.2a.3b.4f.5i.,1j.2a.3b.4f.5i.,1p.2a.3b.4f.5i.,
1a.2b.3b.4f.5i.,1b.2b.3b.4f.5i.,1f.2b.3b.4f.5i.,
1h.2b.3b.4f.5i.,1j.2b.3b.4f.5i.,1p.2b.3b.4f.5i.,
1a.2e.3b.4f.5i.,1b.2e.3b.4f.5i.,1f.2e.3b.4f.5i.,
1h.2e.3b.4f.5i.,1j.2e.3b.4f.5i.,1p.2e.3b.4f.5i.,
1a.2f.3b.4f.5i.,1b.2f.3b.4f.5i.,1f.2f.3b.4f.5i.,
1h.2f.3b.4f.5i.,1j.2f.3b.4f.5i.,1p.2f.3b.4f.5i.,
1a.2i.3b.4f.5i.,1b.2i.3b.4f.5i.,1f.2i.3b.4f.5i.,
1h.2i.3b.4f.5i.,1j.2i.3b.4f.5i.,1p.2i.3b.4f.5i.,
1a.2m.3b.4f.5i.,1b.2m.3b.4f.5i.,1f.2m.3b.4f.5i.,
1h.2m.3b.4f.5i.,1j.2m.3b.4f.5i.,1p.2m.3b.4f.5i.,
1a.2o.3b.4f.5i.,1b.2o.3b.4f.5i.,1f.2o.3b.4f.5i.,
1h.2o.3b.4f.5i.,1j.2o.3b.4f.5i.,1p.2o.3b.4f.5i.,
1a.2u.3b.4f.5i.,1b.2u.3b.4f.5i.,1f.2u.3b.4f.5i.,
1h.2u.3b.4f.5i.,1j.2u.3b.4f.5i.,1p.2u.3b.4f.5i.,
1a.2y.3b.4f.5i.,1b.2y.3b.4f.5i.,1f.2y.3b.4f.5i.,
1h.2y.3b.4f.5i.,1j.2y.3b.4f.5i.,1p.2y.3b.4f.5i.,
1a.2a.3e.4f.5i.,1b.2a.3e.4f.5i.,1f.2a.3e.4f.5i.,
1h.2a.3e.4f.5i.,1j.2a.3e.4f.5i.,1p.2a.3e.4f.5i.,
1a.2b.3e.4f.5i.,1b.2b.3e.4f.5i.,1f.2b.3e.4f.5i.,
1h.2b.3e.4f.5i.,1j.2b.3e.4f.5i.,1p.2b.3e.4f.5i.,
1a.2e.3e.4f.5i.,1b.2e.3e.4f.5i.,1f.2e.3e.4f.5i.,
1h.2e.3e.4f.5i.,1j.2e.3e.4f.5i.,1p.2e.3e.4f.5i.,
1a.2f.3e.4f.5i.,1b.2f.3e.4f.5i.,1f.2f.3e.4f.5i.,
1h.2f.3e.4f.5i.,1j.2f.3e.4f.5i.,1p.2f.3e.4f.5i.,
1a.2i.3e.4f.5i.,1b.2i.3e.4f.5i.,1f.2i.3e.4f.5i.,
1h.2i.3e.4f.5i.,1j.2i.3e.4f.5i.,1p.2i.3e.4f.5i.,
1a.2m.3e.4f.5i.,1b.2m.3e.4f.5i.,1f.2m.3e.4f.5i.,
1h.2m.3e.4f.5i.,1j.2m.3e.4f.5i.,1p.2m.3e.4f.5i.,
1a.2o.3e.4f.5i.,1b.2o.3e.4f.5i.,1f.2o.3e.4f.5i.,
1h.2o.3e.4f.5i.,1j.2o.3e.4f.5i.,1p.2o.3e.4f.5i.,
1a.2u.3e.4f.5i.,1b.2u.3e.4f.5i.,1f.2u.3e.4f.5i.,
1h.2u.3e.4f.5i.,1j.2u.3e.4f.5i.,1p.2u.3e.4f.5i.,
1a.2y.3e.4f.5i.,1b.2y.3e.4f.5i.,1f.2y.3e.4f.5i.,
1h.2y.3e.4f.5i.,1j.2y.3e.4f.5i.,1p.2y.3e.4f.5i.,
1a.2a.3g.4f.5i.,1b.2a.3g.4f.5i.,1f.2a.3g.4f.5i.,
1h.2a.3g.4f.5i.,1j.2a.3g.4f.5i.,1p.2a.3g.4f.5i.,
1a.2b.3g.4f.5i.,1b.2b.3g.4f.5i.,1f.2b.3g.4f.5i.,
1h.2b.3g.4f.5i.,1j.2b.3g.4f.5i.,1p.2b.3g.4f.5i.,
1a.2e.3g.4f.5i.,1b.2e.3g.4f.5i.,1f.2e.3g.4f.5i.,
1h.2e.3g.4f.5i.,1j.2e.3g.4f.5i.,1p.2e.3g.4f.5i.,
1a.2f.3g.4f.5i.,1b.2f.3g.4f.5i.,1f.2f.3g.4f.5i.,
1h.2f.3g.4f.5i.,1j.2f.3g.4f.5i.,1p.2f.3g.4f.5i.,
1a.2i.3g.4f.5i.,1b.2i.3g.4f.5i.,1f.2i.3g.4f.5i.,
1h.2i.3g.4f.5i.,1j.2i.3g.4f.5i.,1p.2i.3g.4f.5i.,
1a.2m.3g.4f.5i.,1b.2m.3g.4f.5i.,1f.2m.3g.4f.5i.,
1h.2m.3g.4f.5i.,1j.2m.3g.4f.5i.,1p.2m.3g.4f.5i.,
1a.2o.3g.4f.5i.,1b.2o.3g.4f.5i.,1f.2o.3g.4f.5i.,
1h.2o.3g.4f.5i.,1j.2o.3g.4f.5i.,1p.2o.3g.4f.5i.,
1a.2u.3g.4f.5i.,1b.2u.3g.4f.5i.,1f.2u.3g.4f.5i.,
1h.2u.3g.4f.5i.,1j.2u.3g.4f.5i.,1p.2u.3g.4f.5i.,
1a.2y.3g.4f.5i.,1b.2y.3g.4f.5i.,1f.2y.3g.4f.5i.,
1h.2y.3g.4f.5i.,1j.2y.3g.4f.5i.,1p.2y.3g.4f.5i.,
1a.2a.3a.4g.5i.,1b.2a.3a.4g.5i.,1f.2a.3a.4g.5i.,
1h.2a.3a.4g.5i.,1j.2a.3a.4g.5i.,1p.2a.3a.4g.5i.,
1a.2b.3a.4g.5i.,1b.2b.3a.4g.5i.,1f.2b.3a.4g.5i.,
1h.2b.3a.4g.5i.,1j.2b.3a.4g.5i.,1p.2b.3a.4g.5i.,
1a.2e.3a.4g.5i.,1b.2e.3a.4g.5i.,1f.2e.3a.4g.5i.,
1h.2e.3a.4g.5i.,1j.2e.3a.4g.5i.,1p.2e.3a.4g.5i.,
1a.2f.3a.4g.5i.,1b.2f.3a.4g.5i.,1f.2f.3a.4g.5i.,
1h.2f.3a.4g.5i.,1j.2f.3a.4g.5i.,1p.2f.3a.4g.5i.,
1a.2i.3a.4g.5i.,1b.2i.3a.4g.5i.,1f.2i.3a.4g.5i.,
1h.2i.3a.4g.5i.,1j.2i.3a.4g.5i.,1p.2i.3a.4g.5i.,
1a.2m.3a.4g.5i.,1b.2m.3a.4g.5i.,1f.2m.3a.4g.5i.,
1h.2m.3a.4g.5i.,1j.2m.3a.4g.5i.,1p.2m.3a.4g.5i.,
1a.2o.3a.4g.5i.,1b.2o.3a.4g.5i.,1f.2o.3a.4g.5i.,
1h.2o.3a.4g.5i.,1j.2o.3a.4g.5i.,1p.2o.3a.4g.5i.,
1a.2u.3a.4g.5i.,1b.2u.3a.4g.5i.,1f.2u.3a.4g.5i.,
1h.2u.3a.4g.5i.,1j.2u.3a.4g.5i.,1p.2u.3a.4g.5i.,
1a.2y.3a.4g.5i.,1b.2y.3a.4g.5i.,1f.2y.3a.4g.5i.,
1h.2y.3a.4g.5i.,1j.2y.3a.4g.5i.,1p.2y.3a.4g.5i.,
1a.2a.3b.4g.5i.,1b.2a.3b.4g.5i.,1f.2a.3b.4g.5i.,
1h.2a.3b.4g.5i.,1j.2a.3b.4g.5i.,1p.2a.3b.4g.5i.,
1a.2b.3b.4g.5i.,1b.2b.3b.4g.5i.,1f.2b.3b.4g.5i.,
1h.2b.3b.4g.5i.,1j.2b.3b.4g.5i.,1p.2b.3b.4g.5i.,
1a.2e.3b.4g.5i.,1b.2e.3b.4g.5i.,1f.2e.3b.4g.5i.,
1h.2e.3b.4g.5i.,1j.2e.3b.4g.5i.,1p.2e.3b.4g.5i.,
1a.2f.3b.4g.5i.,1b.2f.3b.4g.5i.,1f.2f.3b.4g.5i.,
1h.2f.3b.4g.5i.,1j.2f.3b.4g.5i.,1p.2f.3b.4g.5i.,
1a.2i.3b.4g.5i.,1b.2i.3b.4g.5i.,1f.2i.3b.4g.5i.,
1h.2i.3b.4g.5i.,1j.2i.3b.4g.5i.,1p.2i.3b.4g.5i.,
1a.2m.3b.4g.5i.,1b.2m.3b.4g.5i.,1f.2m.3b.4g.5i.,
1h.2m.3b.4g.5i.,1j.2m.3b.4g.5i.,1p.2m.3b.4g.5i.,
1a.2o.3b.4g.5i.,1b.2o.3b.4g.5i.,1f.2o.3b.4g.5i.,
1h.2o.3b.4g.5i.,1j.2o.3b.4g.5i.,1p.2o.3b.4g.5i.,
1a.2u.3b.4g.5i.,1b.2u.3b.4g.5i.,1f.2u.3b.4g.5i.,
1h.2u.3b.4g.5i.,1j.2u.3b.4g.5i.,1p.2u.3b.4g.5i.,
1a.2y.3b.4g.5i.,1b.2y.3b.4g.5i.,1f.2y.3b.4g.5i.,
1h.2y.3b.4g.5i.,1j.2y.3b.4g.5i.,1p.2y.3b.4g.5i.,
1a.2a.3e.4g.5i.,1b.2a.3e.4g.5i.,1f.2a.3e.4g.5i.,
1h.2a.3e.4g.5i.,1j.2a.3e.4g.5i.,1p.2a.3e.4g.5i.,
1a.2b.3e.4g.5i.,1b.2b.3e.4g.5i.,1f.2b.3e.4g.5i.,
1h.2b.3e.4g.5i.,1j.2b.3e.4g.5i.,1p.2b.3e.4g.5i.,
1a.2e.3e.4g.5i.,1b.2e.3e.4g.5i.,1f.2e.3e.4g.5i.,
1h.2e.3e.4g.5i.,1j.2e.3e.4g.5i.,1p.2e.3e.4g.5i.,
1a.2f.3e.4g.5i.,1b.2f.3e.4g.5i.,1f.2f.3e.4g.5i.,
1h.2f.3e.4g.5i.,1j.2f.3e.4g.5i.,1p.2f.3e.4g.5i.,
1a.2i.3e.4g.5i.,1b.2i.3e.4g.5i.,1f.2i.3e.4g.5i.,
1h.2i.3e.4g.5i.,1j.2i.3e.4g.5i.,1p.2i.3e.4g.5i.,
1a.2m.3e.4g.5i.,1b.2m.3e.4g.5i.,1f.2m.3e.4g.5i.,
1h.2m.3e.4g.5i.,1j.2m.3e.4g.5i.,1p.2m.3e.4g.5i.,
1a.2o.3e.4g.5i.,1b.2o.3e.4g.5i.,1f.2o.3e.4g.5i.,
1h.2o.3e.4g.5i.,1j.2o.3e.4g.5i.,1p.2o.3e.4g.5i.,
1a.2u.3e.4g.5i.,1b.2u.3e.4g.5i.,1f.2u.3e.4g.5i.,
1h.2u.3e.4g.5i.,1j.2u.3e.4g.5i.,1p.2u.3e.4g.5i.,
1a.2y.3e.4g.5i.,1b.2y.3e.4g.5i.,1f.2y.3e.4g.5i.,
1h.2y.3e.4g.5i.,1j.2y.3e.4g.5i.,1p.2y.3e.4g.5i.,
1a.2a.3g.4g.5i.,1b.2a.3g.4g.5i.,1f.2a.3g.4g.5i.,
1h.2a.3g.4g.5i.,1j.2a.3g.4g.5i.,1p.2a.3g.4g.5i.,
1a.2b.3g.4g.5i.,1b.2b.3g.4g.5i.,1f.2b.3g.4g.5i.,
1h.2b.3g.4g.5i.,1j.2b.3g.4g.5i.,1p.2b.3g.4g.5i.,
1a.2e.3g.4g.5i.,1b.2e.3g.4g.5i.,1f.2e.3g.4g.5i.,
1h.2e.3g.4g.5i.,1j.2e.3g.4g.5i.,1p.2e.3g.4g.5i.,
1a.2f.3g.4g.5i.,1b.2f.3g.4g.5i.,1f.2f.3g.4g.5i.,
1h.2f.3g.4g.5i.,1j.2f.3g.4g.5i.,1p.2f.3g.4g.5i.,
1a.2i.3g.4g.5i.,1b.2i.3g.4g.5i.,1f.2i.3g.4g.5i.,
1h.2i.3g.4g.5i.,1j.2i.3g.4g.5i.,1p.2i.3g.4g.5i.,
1a.2m.3g.4g.5i.,1b.2m.3g.4g.5i.,1f.2m.3g.4g.5i.,
1h.2m.3g.4g.5i.,1j.2m.3g.4g.5i.,1p.2m.3g.4g.5i.,
1a.2o.3g.4g.5i.,1b.2o.3g.4g.5i.,1f.2o.3g.4g.5i.,
1h.2o.3g.4g.5i.,1j.2o.3g.4g.5i.,1p.2o.3g.4g.5i.,
1a.2u.3g.4g.5i.,1b.2u.3g.4g.5i.,1f.2u.3g.4g.5i.,
1h.2u.3g.4g.5i.,1j.2u.3g.4g.5i.,1p.2u.3g.4g.5i.,
1a.2y.3g.4g.5i.,1b.2y.3g.4g.5i.,1f.2y.3g.4g.5i.,
1h.2y.3g.4g.5i.,1j.2y.3g.4g.5i.,1p.2y.3g.4g.5i.,
1a.2a.3a.4h.5i.,1b.2a.3a.4h.5i.,1f.2a.3a.4h.5i.,
1h.2a.3a.4h.5i.,1j.2a.3a.4h.5i.,1p.2a.3a.4h.5i.,
1a.2b.3a.4h.5i.,1b.2b.3a.4h.5i.,1f.2b.3a.4h.5i.,
1h.2b.3a.4h.5i.,1j.2b.3a.4h.5i.,1p.2b.3a.4h.5i.,
1a.2e.3a.4h.5i.,1b.2e.3a.4h.5i.,1f.2e.3a.4h.5i.,
1h.2e.3a.4h.5i.,1j.2e.3a.4h.5i.,1p.2e.3a.4h.5i.,
1a.2f.3a.4h.5i.,1b.2f.3a.4h.5i.,1f.2f.3a.4h.5i.,
1h.2f.3a.4h.5i.,1j.2f.3a.4h.5i.,1p.2f.3a.4h.5i.,
1a.2i.3a.4h.5i.,1b.2i.3a.4h.5i.,1f.2i.3a.4h.5i.,
1h.2i.3a.4h.5i.,1j.2i.3a.4h.5i.,1p.2i.3a.4h.5i.,
1a.2m.3a.4h.5i.,1b.2m.3a.4h.5i.,1f.2m.3a.4h.5i.,
1h.2m.3a.4h.5i.,1j.2m.3a.4h.5i.,1p.2m.3a.4h.5i.,
1a.2o.3a.4h.5i.,1b.2o.3a.4h.5i.,1f.2o.3a.4h.5i.,
1h.2o.3a.4h.5i.,1j.2o.3a.4h.5i.,1p.2o.3a.4h.5i.,
1a.2u.3a.4h.5i.,1b.2u.3a.4h.5i.,1f.2u.3a.4h.5i.,
1h.2u.3a.4h.5i.,1j.2u.3a.4h.5i.,1p.2u.3a.4h.5i.,
1a.2y.3a.4h.5i.,1b.2y.3a.4h.5i.,1f.2y.3a.4h.5i.,
1h.2y.3a.4h.5i.,1j.2y.3a.4h.5i.,1p.2y.3a.4h.5i.,
1a.2a.3b.4h.5i.,1b.2a.3b.4h.5i.,1f.2a.3b.4h.5i.,
1h.2a.3b.4h.5i.,1j.2a.3b.4h.5i.,1p.2a.3b.4h.5i.,
1a.2b.3b.4h.5i.,1b.2b.3b.4h.5i.,1f.2b.3b.4h.5i.,
1h.2b.3b.4h.5i.,1j.2b.3b.4h.5i.,1p.2b.3b.4h.5i.,
1a.2e.3b.4h.5i.,1b.2e.3b.4h.5i.,1f.2e.3b.4h.5i.,
1h.2e.3b.4h.5i.,1j.2e.3b.4h.5i.,1p.2e.3b.4h.5i.,
1a.2f.3b.4h.5i.,1b.2f.3b.4h.5i.,1f.2f.3b.4h.5i.,
1h.2f.3b.4h.5i.,1j.2f.3b.4h.5i.,1p.2f.3b.4h.5i.,
1a.2i.3b.4h.5i.,1b.2i.3b.4h.5i.,1f.2i.3b.4h.5i.,
1h.2i.3b.4h.5i.,1j.2i.3b.4h.5i.,1p.2i.3b.4h.5i.,
1a.2m.3b.4h.5i.,1b.2m.3b.4h.5i.,1f.2m.3b.4h.5i.,
1h.2m.3b.4h.5i.,1j.2m.3b.4h.5i.,1p.2m.3b.4h.5i.,
1a.2o.3b.4h.5i.,1b.2o.3b.4h.5i.,1f.2o.3b.4h.5i.,
1h.2o.3b.4h.5i.,1j.2o.3b.4h.5i.,1p.2o.3b.4h.5i.,
1a.2u.3b.4h.5i.,1b.2u.3b.4h.5i.,1f.2u.3b.4h.5i.,
1h.2u.3b.4h.5i.,1j.2u.3b.4h.5i.,1p.2u.3b.4h.5i.,
1a.2y.3b.4h.5i.,1b.2y.3b.4h.5i.,1f.2y.3b.4h.5i.,
1h.2y.3b.4h.5i.,1j.2y.3b.4h.5i.,1p.2y.3b.4h.5i.,
1a.2a.3e.4h.5i.,1b.2a.3e.4h.5i.,1f.2a.3e.4h.5i.,
1h.2a.3e.4h.5i.,1j.2a.3e.4h.5i.,1p.2a.3e.4h.5i.,
1a.2b.3e.4h.5i.,1b.2b.3e.4h.5i.,1f.2b.3e.4h.5i.,
1h.2b.3e.4h.5i.,1j.2b.3e.4h.5i.,1p.2b.3e.4h.5i.,
1a.2e.3e.4h.5i.,1b.2e.3e.4h.5i.,1f.2e.3e.4h.5i.,
1h.2e.3e.4h.5i.,1j.2e.3e.4h.5i.,1p.2e.3e.4h.5i.,
1a.2f.3e.4h.5i.,1b.2f.3e.4h.5i.,1f.2f.3e.4h.5i.,
1h.2f.3e.4h.5i.,1j.2f.3e.4h.5i.,1p.2f.3e.4h.5i.,
1a.2i.3e.4h.5i.,1b.2i.3e.4h.5i.,1f.2i.3e.4h.5i.,
1h.2i.3e.4h.5i.,1j.2i.3e.4h.5i.,1p.2i.3e.4h.5i.,
1a.2m.3e.4h.5i.,1b.2m.3e.4h.5i.,1f.2m.3e.4h.5i.,
1h.2m.3e.4h.5i.,1j.2m.3e.4h.5i.,1p.2m.3e.4h.5i.,
1a.2o.3e.4h.5i.,1b.2o.3e.4h.5i.,1f.2o.3e.4h.5i.,
1h.2o.3e.4h.5i.,1j.2o.3e.4h.5i.,1p.2o.3e.4h.5i.,
1a.2u.3e.4h.5i.,1b.2u.3e.4h.5i.,1f.2u.3e.4h.5i.,
1h.2u.3e.4h.5i.,1j.2u.3e.4h.5i.,1p.2u.3e.4h.5i.,
1a.2y.3e.4h.5i.,1b.2y.3e.4h.5i.,1f.2y.3e.4h.5i.,
1h.2y.3e.4h.5i.,1j.2y.3e.4h.5i.,1p.2y.3e.4h.5i.,
1a.2a.3g.4h.5i.,1b.2a.3g.4h.5i.,1f.2a.3g.4h.5i.,
1h.2a.3g.4h.5i.,1j.2a.3g.4h.5i.,1p.2a.3g.4h.5i.,
1a.2b.3g.4h.5i.,1b.2b.3g.4h.5i.,1f.2b.3g.4h.5i.,
1h.2b.3g.4h.5i.,1j.2b.3g.4h.5i.,1p.2b.3g.4h.5i.,
1a.2e.3g.4h.5i.,1b.2e.3g.4h.5i.,1f.2e.3g.4h.5i.,
1h.2e.3g.4h.5i.,1j.2e.3g.4h.5i.,1p.2e.3g.4h.5i.,
1a.2f.3g.4h.5i.,1b.2f.3g.4h.5i.,1f.2f.3g.4h.5i.,
1h.2f.3g.4h.5i.,1j.2f.3g.4h.5i.,1p.2f.3g.4h.5i.,
1a.2i.3g.4h.5i.,1b.2i.3g.4h.5i.,1f.2i.3g.4h.5i.,
1h.2i.3g.4h.5i.,1j.2i.3g.4h.5i.,1p.2i.3g.4h.5i.,
1a.2m.3g.4h.5i.,1b.2m.3g.4h.5i.,1f.2m.3g.4h.5i.,
1h.2m.3g.4h.5i.,1j.2m.3g.4h.5i.,1p.2m.3g.4h.5i.,
1a.2o.3g.4h.5i.,1b.2o.3g.4h.5i.,1f.2o.3g.4h.5i.,
1h.2o.3g.4h.5i.,1j.2o.3g.4h.5i.,1p.2o.3g.4h.5i.,
1a.2u.3g.4h.5i.,1b.2u.3g.4h.5i.,1f.2u.3g.4h.5i.,
1h.2u.3g.4h.5i.,1j.2u.3g.4h.5i.,1p.2u.3g.4h.5i.,
1a.2y.3g.4h.5i.,1b.2y.3g.4h.5i.,1f.2y.3g.4h.5i.,
1h.2y.3g.4h.5i.,1j.2y.3g.4h.5i.,1p.2y.3g.4h.5i.,
1a.2a.3a.4i.5i.,1b.2a.3a.4i.5i.,1f.2a.3a.4i.5i.,
1h.2a.3a.4i.5i.,1j.2a.3a.4i.5i.,1p.2a.3a.4i.5i.,
1a.2b.3a.4i.5i.,1b.2b.3a.4i.5i.,1f.2b.3a.4i.5i.,
1h.2b.3a.4i.5i.,1j.2b.3a.4i.5i.,1p.2b.3a.4i.5i.,
1a.2e.3a.4i.5i.,1b.2e.3a.4i.5i.,1f.2e.3a.4i.5i.,
1h.2e.3a.4i.5i.,1j.2e.3a.4i.5i.,1p.2e.3a.4i.5i.,
1a.2f.3a.4i.5i.,1b.2f.3a.4i.5i.,1f.2f.3a.4i.5i.,
1h.2f.3a.4i.5i.,1j.2f.3a.4i.5i.,1p.2f.3a.4i.5i.,
1a.2i.3a.4i.5i.,1b.2i.3a.4i.5i.,1f.2i.3a.4i.5i.,
1h.2i.3a.4i.5i.,1j.2i.3a.4i.5i.,1p.2i.3a.4i.5i.,
1a.2m.3a.4i.5i.,1b.2m.3a.4i.5i.,1f.2m.3a.4i.5i.,
1h.2m.3a.4i.5i.,1j.2m.3a.4i.5i.,1p.2m.3a.4i.5i.,
1a.2o.3a.4i.5i.,1b.2o.3a.4i.5i.,1f.2o.3a.4i.5i.,
1h.2o.3a.4i.5i.,1j.2o.3a.4i.5i.,1p.2o.3a.4i.5i.,
1a.2u.3a.4i.5i.,1b.2u.3a.4i.5i.,1f.2u.3a.4i.5i.,
1h.2u.3a.4i.5i.,1j.2u.3a.4i.5i.,1p.2u.3a.4i.5i.,
1a.2y.3a.4i.5i.,1b.2y.3a.4i.5i.,1f.2y.3a.4i.5i.,
1h.2y.3a.4i.5i.,1j.2y.3a.4i.5i.,1p.2y.3a.4i.5i.,
1a.2a.3b.4i.5i.,1b.2a.3b.4i.5i.,1f.2a.3b.4i.5i.,
1h.2a.3b.4i.5i.,1j.2a.3b.4i.5i.,1p.2a.3b.4i.5i.,
1a.2b.3b.4i.5i.,1b.2b.3b.4i.5i.,1f.2b.3b.4i.5i.,
1h.2b.3b.4i.5i.,1j.2b.3b.4i.5i.,1p.2b.3b.4i.5i.,
1a.2e.3b.4i.5i.,1b.2e.3b.4i.5i.,1f.2e.3b.4i.5i.,
1h.2e.3b.4i.5i.,1j.2e.3b.4i.5i.,1p.2e.3b.4i.5i.,
1a.2f.3b.4i.5i.,1b.2f.3b.4i.5i.,1f.2f.3b.4i.5i.,
1h.2f.3b.4i.5i.,1j.2f.3b.4i.5i.,1p.2f.3b.4i.5i.,
1a.2i.3b.4i.5i.,1b.2i.3b.4i.5i.,1f.2i.3b.4i.5i.,
1h.2i.3b.4i.5i.,1j.2i.3b.4i.5i.,1p.2i.3b.4i.5i.,
1a.2m.3b.4i.5i.,1b.2m.3b.4i.5i.,1f.2m.3b.4i.5i.,
1h.2m.3b.4i.5i.,1j.2m.3b.4i.5i.,1p.2m.3b.4i.5i.,
1a.2o.3b.4i.5i.,1b.2o.3b.4i.5i.,1f.2o.3b.4i.5i.,
1h.2o.3b.4i.5i.,1j.2o.3b.4i.5i.,1p.2o.3b.4i.5i.,
1a.2u.3b.4i.5i.,1b.2u.3b.4i.5i.,1f.2u.3b.4i.5i.,
1h.2u.3b.4i.5i.,1j.2u.3b.4i.5i.,1p.2u.3b.4i.5i.,
1a.2y.3b.4i.5i.,1b.2y.3b.4i.5i.,1f.2y.3b.4i.5i.,
1h.2y.3b.4i.5i.,1j.2y.3b.4i.5i.,1p.2y.3b.4i.5i.,
1a.2a.3e.4i.5i.,1b.2a.3e.4i.5i.,1f.2a.3e.4i.5i.,
1h.2a.3e.4i.5i.,1j.2a.3e.4i.5i.,1p.2a.3e.4i.5i.,
1a.2b.3e.4i.5i.,1b.2b.3e.4i.5i.,1f.2b.3e.4i.5i.,
1h.2b.3e.4i.5i.,1j.2b.3e.4i.5i.,1p.2b.3e.4i.5i.,
1a.2e.3e.4i.5i.,1b.2e.3e.4i.5i.,1f.2e.3e.4i.5i.,
1h.2e.3e.4i.5i.,1j.2e.3e.4i.5i.,1p.2e.3e.4i.5i.,
1a.2f.3e.4i.5i.,1b.2f.3e.4i.5i.,1f.2f.3e.4i.5i.,
1h.2f.3e.4i.5i.,1j.2f.3e.4i.5i.,1p.2f.3e.4i.5i.,
1a.2i.3e.4i.5i.,1b.2i.3e.4i.5i.,1f.2i.3e.4i.5i.,
1h.2i.3e.4i.5i.,1j.2i.3e.4i.5i.,1p.2i.3e.4i.5i.,
1a.2m.3e.4i.5i.,1b.2m.3e.4i.5i.,1f.2m.3e.4i.5i.,
1h.2m.3e.4i.5i.,1j.2m.3e.4i.5i.,1p.2m.3e.4i.5i.,
1a.2o.3e.4i.5i.,1b.2o.3e.4i.5i.,1f.2o.3e.4i.5i.,
1h.2o.3e.4i.5i.,1j.2o.3e.4i.5i.,1p.2o.3e.4i.5i.,
1a.2u.3e.4i.5i.,1b.2u.3e.4i.5i.,1f.2u.3e.4i.5i.,
1h.2u.3e.4i.5i.,1j.2u.3e.4i.5i.,1p.2u.3e.4i.5i.,
1a.2y.3e.4i.5i.,1b.2y.3e.4i.5i.,1f.2y.3e.4i.5i.,
1h.2y.3e.4i.5i.,1j.2y.3e.4i.5i.,1p.2y.3e.4i.5i.,
1a.2a.3g.4i.5i.,1b.2a.3g.4i.5i.,1f.2a.3g.4i.5i.,
1h.2a.3g.4i.5i.,1j.2a.3g.4i.5i.,1p.2a.3g.4i.5i.,
1a.2b.3g.4i.5i.,1b.2b.3g.4i.5i.,1f.2b.3g.4i.5i.,
1h.2b.3g.4i.5i.,1j.2b.3g.4i.5i.,1p.2b.3g.4i.5i.,
1a.2e.3g.4i.5i.,1b.2e.3g.4i.5i.,1f.2e.3g.4i.5i.,
1h.2e.3g.4i.5i.,1j.2e.3g.4i.5i.,1p.2e.3g.4i.5i.,
1a.2f.3g.4i.5i.,1b.2f.3g.4i.5i.,1f.2f.3g.4i.5i.,
1h.2f.3g.4i.5i.,1j.2f.3g.4i.5i.,1p.2f.3g.4i.5i.,
1a.2i.3g.4i.5i.,1b.2i.3g.4i.5i.,1f.2i.3g.4i.5i.,
1h.2i.3g.4i.5i.,1j.2i.3g.4i.5i.,1p.2i.3g.4i.5i.,
1a.2m.3g.4i.5i.,1b.2m.3g.4i.5i.,1f.2m.3g.4i.5i.,
1h.2m.3g.4i.5i.,1j.2m.3g.4i.5i.,1p.2m.3g.4i.5i.,
1a.2o.3g.4i.5i.,1b.2o.3g.4i.5i.,1f.2o.3g.4i.5i.,
1h.2o.3g.4i.5i.,1j.2o.3g.4i.5i.,1p.2o.3g.4i.5i.,
1a.2u.3g.4i.5i.,1b.2u.3g.4i.5i.,1f.2u.3g.4i.5i.,
1h.2u.3g.4i.5i.,1j.2u.3g.4i.5i.,1p.2u.3g.4i.5i.,
1a.2y.3g.4i.5i.,1b.2y.3g.4i.5i.,1f.2y.3g.4i.5i.,
1h.2y.3g.4i.5i.,1j.2y.3g.4i.5i.和1p.2y.3g.4i.5i.。
在另一个实施方案中,本发明的化合物对P450的抑制活性水平等于或优于由IC50表示的化合物的抑制活性,即低于约2000nM,低于约1500nM,低于约1000nM,低于约900nM,低于约800nM,低于约700nM,低于约650nM,低于约600nM,低于约550nM,低于约500nM,低于约400nM,低于约350nM,低于约300nM,低于约250nM,低于约200nM,低于约100nM或低于约50nM。
在另一个实施方案中,本发明的化合物对P450同工酶,例如3A的抑制活性在IC50表示的范围,即约2000nM-约100nM,约1000nM-约100nM,约900nM-约200nM,约800nM-约300nM,约700nM-约200nM,约600nM-约200nM,约500nM-约200nM,约700nM-约300nM,约600nM-约300nM,约700nM-约400nM,约600nM-约400nM,约400nM-约100nM,约300nM-约100nM或约600nM-约150nM。
在另一个实施方案中,本发明的化合物对P450的抑制活性水平等于或优于由IC50表示的化合物的抑制活性,即低于约2000nM,低于约1500nM,低于约1000nM,低于约900nM,低于约800nM,低于约700nM,低于约650nM,低于约600nM,低于约550nM,低于约500nM,低于约400nM,低于约350nM,低于约300nM,低于约250nM,低于约200nM,低于约100nM或低于约50nM,只要这类化合物还基本上不表现出非其对P450的抑制活性的生物活性。例如,本发明的化合物可以具有降低或不明显的蛋白酶抑制活性,包括,但不限于由HIV EC50表示的蛋白酶抑制水平,即大于约1000nM,大于约900nM,大于约800nM,大于约700nM,大于约600nM,大于约500nM,大于约400nM,大于约300nM,大于约200nM,大于约100nM,大于约50nM,大于约40nM,大于约30nM,大于约20nM,大于约10nM,大于约5nM或大于约1nM。
在另一个实施方案中,本发明的化合物特别对P450的一种或多种同工酶具有抑制活性,包括,但不限于1A2,2B6,2C8,2C19,2C9,2D6,2E1和3A4,5,7等。
在另一个实施方案中,本发明的化合物特别对P450的同工酶具有抑制活性,这些同工酶涉及代谢抗病毒药物,例如茚地那韦,奈非那韦,利托那韦,沙奎那韦等。
在另一个实施方案中,本发明的化合物特别对P450的一种或多种同工酶,但不限于其它具有抑制活性。例如,本发明的化合物特别对P4503A具有抑制活性,但对P450的另一种同工酶,例如P450 2C9具有降低,无或最低限度的抑制活性。
药物制剂
可以使用根据常规实践选择的常用载体和赋形剂配制本发明的化合物。表中包含赋形剂,助流剂,填充剂,粘合剂等。制备无菌形式的含水制剂并且在指定通过非口服给药的递送时一般为等渗的。所有制剂任选包含赋形剂,诸如在Handbook of PharmaceuticalExcipients(1986)中所列的那些,将该文献完整地引入本文作为参考。赋形剂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,羟基烷基甲基纤维素,硬脂酸等。制剂的pH在约3-约11,但通常在约7-10。
尽管能够将活性组分单独给药,但是优选将它们制成药物制剂。本发明的制剂,无论是用于兽类还是人类应用,均包含至少一种活性组分,例如本发明的化合物与一种或多种可接受的载体和任选的其它治疗组分。载体必须是″可接受的″,其含义是与制剂中的其它组分相容并且在生理上对其接受者而言无害。
制剂包括适合于上述给药途径的那些。可以将制剂便利地制成单位剂型并且可以通过制药领域众所周知的任意方法制成制备。技术和制剂一般可以在Remington′s Pharmaceutical Sciences(MackPublishing Co.,Easton,Pa.)中找到,将该文献完整地引入本文作为参考。这类方法包括将活性组分与构成一种或多种辅助组分的载体混合的步骤。一般而言,通过均匀和紧密混合活性组分与液体载体或固体载体细粉或它们两者且然后如果必要使产物成形制备制剂。
可以将适合于口服给药的本发明制剂制成分散单位,诸如各自包含预定量活性组分的胶囊,扁囊剂或片剂;粉末或颗粒;在水性或非水性液体中的溶液或混悬液;或水包油型液体乳剂或油包水型液体乳剂。还可以将活性组分作为丸剂,药糖剂或糊剂给药。
通过任选使用一种或多种辅助组分压制或模制制备片剂。可以通过在合适的机器中压制自由流动形式的任选混合了粘合剂,润滑剂,惰性稀释剂,防腐剂,表面活性剂分散剂的活性组分,诸如粉末或颗粒制备压制片。可以通过在合适的机器中模制使用经惰性液体稀释剂湿润的粉状活性组分混合物制备模制片。可以任选给片剂包衣或刻痕并且任选配制以提供活性组分缓慢或受控释放。
就对眼或其它外部组织,诸如口腔和皮肤给药而言,优选将制剂作为局部用软膏剂或霜剂施用,其含例如,0.075-20%w/w的用量(包括活性组分),范围在0.1%-20%以0.1%w/w递增,诸如0.6%w/w,0.7%w/w等),优选0.2-15%w/w且最优选0.5-10%w/w。当配制成软膏剂时,可以将活性组分与石蜡或与水易混溶的软膏剂基质一起使用。可选择地,可以使用水包油型霜剂基质将活性组分配制成霜剂。
如果需要,霜剂基质的水相可以包括,例如,至少30%w/w的多元醇,即具有两个或多个羟基的醇,诸如丙二醇,丁1,3-二醇,甘露糖醇,山梨醇,甘油和聚乙二醇(包括PEG400)及其混合物。局部用制剂可以理想地包括促进活性组分通过皮肤或其它受侵害区域吸收或渗透的化合物。这类透皮促进剂的实例包括二甲亚砜和相关类似物。
本发明乳剂的油相可以由已知组分按照已知方式构成。尽管该相可以仅包含乳化剂(也称作利泄剂),但是理想的是包含至少一种乳化剂与脂肪或油或与脂肪和油的混合物。优选包括亲水性乳化剂与作为稳定剂起作用的亲脂性乳化剂。还优选包括油和脂肪。乳化剂与或不与稳定剂共同构成所谓的乳化蜡并且该蜡与油和脂肪共同构成所谓的乳化软膏剂基质,该基质形成霜剂的油分散相。
用于制剂的合适的油或脂肪的选择基于实现所需的化妆品特性。霜剂应优选为具有合适的稠度的非油腻性的无染色和可洗涤的产品,以避免从管或其它容器中渗漏。可以使用直链或支链一-或二元烷基酯类,诸如二-异己二酸酯,硬脂酸异鲸蜡酯,椰子油脂肪酸丙二醇二酯,肉豆蔻酸异丙酯,油酸癸酯,棕榈酸异丙酯,硬脂酸丁酯,棕榈酸2-乙基己酯或称作Crodamol CAP的支链酯类的掺合物,最后三种为优选的酯类。可以单独或以组合方式使用它们,这取决于所需的特性。可选择地,使用高熔点脂质,诸如白软石蜡和/或液体石蜡或其它矿物油。
本发明的药物制剂包含本发明的一种或多种化合物与一种或多种药学上可接受的载体或赋形剂和任选的其它治疗剂。含有活性组分的药物制剂可以适合于指定给药方法的任意形式。当用于口服应用时,例如,可以制备片剂,药片,锭剂,水或油混悬液,可分散粉末或颗粒,乳剂,硬或软胶囊,糖浆剂或酏剂。可以按照制备药物组合物领域公知的任意方法制备指定用于口服应用的组合物,并且这类组合物可以包含一种或多种试剂,包括甜味剂,矫味剂,着色剂和防腐剂,以便提供适口的制剂。包含活性组分与适合于制备片剂的无毒性药学上可接受赋形剂的片剂为接受的。这些赋形剂可以为,例如,惰性稀释剂,诸如碳酸钙或碳酸钠,乳糖,乳糖一水合物,交联羧甲基纤维素钠,聚维酮,磷酸钙或磷酸钠;制粒剂和崩解剂,诸如玉米淀粉或藻酸;粘合剂,诸如纤维素,微晶纤维素,淀粉,明胶或阿拉伯胶;和润滑剂,诸如硬脂酸镁,硬脂酸或滑石粉。可以给片剂不包衣或通过公知技术,包括微囊化包衣以便延缓在胃肠道中崩解和吸收且由此在延长时间期限内提供持续作用。例如,可以使用延时材料,诸如单独或与蜡混合的单硬脂酸甘油酯或二硬脂酸甘油酯。
还可以将口服使用的制剂制成硬胶囊,其中将活性组分与惰性固体稀释剂混合,例如磷酸钙或高岭土或软胶囊,其中将活性组分与水或油介质混合,诸如花生油,液体石蜡或橄榄油。
本发明的含水混悬液包含活性物质与适合于制备含水混悬液的赋形剂的混合物。这类赋形剂包括悬浮剂,诸如羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,藻酸钠,聚乙烯吡咯烷酮,黄蓍树胶和阿拉伯树胶和分散或湿润剂,诸如天然存在的磷脂(例如卵磷脂),环氧乙烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯),环氧乙烷与长链脂族醇的缩合产物(例如十七乙烯氧基鲸蜡醇(hoptadecaethyleneoxycetanol)),环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚氧乙烯失水山梨醇单油酸酯)。含水混悬液还可以包含一种或多种防腐剂,诸如对-羟基-苯甲酸乙酯或对-羟基-苯甲酸正-丙酯,一种或多种着色剂,一种或多种矫味剂和一种或多种甜味剂,诸如蔗糖或糖精。
可以通过将活性组分悬浮于植物油中配制油混悬液,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。口服混悬液可以包含增稠剂,诸如蜂蜡,硬石蜡或鲸蜡醇。可以加入甜味剂,诸如本文所述的那些和矫味剂以便提供适口的口服制剂。可以通过添加抗氧化剂,诸如抗坏血酸对这些组合物防腐。
适合于通过添加水制备含水混悬液的本发明的可分散粉末和颗粒提供了活性组分与分散剂或湿润剂,悬浮剂和一种或多种防腐剂的混合物。通过以上述披露例举那些合适的分散剂或湿润剂和悬浮剂。还可以存在其它赋形剂,例如甜味剂,矫味剂和着色剂。
本发明的药物组合物还可以为水包油型乳剂的形式。油相可以为植物油,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。合适的乳化剂包括天然存在的树胶,诸如阿拉伯树胶和黄蓍树胶,天然存在的磷脂类,诸如大豆卵磷脂,衍生自脂肪酸和己糖醇酐的酯类或偏酯类,诸如失水山梨糖醇单油酸酯和这些偏酯与环氧乙烷的缩合产物,诸如聚氧乙烯失水山梨醇单油酸酯。该乳剂还可以包含甜味剂和矫味剂。可以使用甜味剂,诸如甘油,山梨醇或蔗糖配制糖浆剂和酏剂。这类制剂还可以包含缓和剂,防腐剂,矫味剂或着色剂。
本发明的药物组合物可以为无菌可注射制剂形式,诸如无菌可注射的水或油混悬液。可以按照公知技术,使用本文所述的合适的分散剂或湿润剂和悬浮剂配制该混悬液。无菌可注射制剂还可以为在无毒性非肠道可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,诸如在1,3-丁-二醇中的溶液或制备成冻干粉末。在可以使用的可接受的媒介物和溶剂中有水,林格液和等渗氯化钠溶液。此外,无菌固定油常用作溶剂或悬浮介质。为了这一目的,可以使用任意温和的固定油,包括合成的一-或二甘油酯类。此外,脂肪酸,诸如油酸同样可以用于制备可注射制剂。
可以与载体物质合并产生单一剂型的活性组分的量根据所治疗宿主和特定给药方式的不同而改变。例如,指定用于对人体口服给药的定时释放制剂可以包含混合了适当和适宜用量的载体物质的约1-1000mg活性组分,所述的载体物质的适当和适宜用量可以占总组合物的约5-约95%(重量:重量)。可以制备该药物组合物以便提供易于给药的可测定用量。例如,指定用于静脉内输注的水溶液可以包含约3-500μg活性组分/毫升溶液,以便可以约30mL/hr的速率输注适当的体积。
适合于对眼部给药的制剂包括滴眼剂,其中将活性组分溶于或悬浮于合适的载体,尤其是用于活性组分的含水溶剂中。活性组分优选以0.5-20%,有利的是0.5-10%,特别是约1.5%w/w的浓度存在于这类制剂中。
适合于在口腔中局部给药的制剂包括包含在矫味基质,通常为蔗糖和阿拉伯胶或黄蓍胶中的活性组分的锭剂;包括在惰性基质,诸如明胶和甘油或蔗糖和阿拉伯胶中的活性组分的软锭剂;和包括在合适的液体载体中的活性组分的漱口药。
可以将用于直肠给药的制剂制成含合适的基质的栓剂,所述的合适的基质例如为可可脂或水杨酸酯。
适合于肺内或鼻部给药的制剂具有例如0.1-500μm的粒度(包括0.1-500μm的粒度,以诸如0.5μm,1μm,30μm,35μm等递增),通过经鼻道快速吸入或通过经口腔吸入给药,以便达到肺泡囊。合适的制剂包括活性组分的水或油溶液。可以按照常规方法制备适合于气雾剂或干粉给药的制剂并且可以使其与其它治疗剂一起递送,诸如上文所用治疗或预防本文所述感染的化合物。
可以将适合于阴道给药的制剂制成阴道栓剂,棉塞,霜剂,凝胶剂,糊剂,泡沫剂或喷雾剂,其除包含活性组分外还包含诸如本领域公知的合适的这类载体。
适合于非肠道给药的制剂包括:水性和非水性的无菌注射溶液,其可以包含抗氧化剂,缓冲剂,制菌剂和赋予制剂与指定接受者血液等渗的溶质;和可以包括悬浮剂和增稠剂的水和非水的无菌混悬液。
将制剂提供在单位剂量或多剂量容器中,例如密封安瓿和小瓶并且可以将其储存在仅需要在使用前即刻添加无菌液体载体,例如注射用水的冷冻干燥(冻干)条件下。由上述类型的无菌粉末,颗粒和片制备临时注射溶液和混悬液。优选的单位剂量制剂为包含如上文所述活性组分的每日剂量或单位每日亚剂量或其适当部分的那些。
应理解除本发明提供的组分外,本发明的制剂可以包括本领域中有关所讨论制剂类型的其它试剂,例如适合于口服给药的那些可以包括矫味剂。
本发明进一步提供了兽用组合物,其包含至少一种活性组分,例如本发明的化合物与兽用载体。
兽用载体为用于给予组合物目的的物质并且可以为固体,液体或气态物质,另外其为惰性的或兽药领域中可接受的。可以通过口服,非肠道或通过任意其它所需途径给予这些兽用组合物。
还可以将本发明的化合物配制成可提供活性组分控释,以使给药频率较少或改善活性组分的药代动力学或毒性特性。因此,本发明还提供了包括本发明一种或多种化合物的配制成可缓释或控释的组合物。
活性组分的有效剂量至少取决于所治疗疾患的性质,毒性,无论是以预防方式使用化合物(较低剂量)还是针对活动型疾病或疾患,递送方法和药物制剂,并且由临床医师使用常规剂量按比例上升研究确定。可以预计有效剂量约为0.0001-约100mg/kg体重/天。一般而言,约0.01-约10mg/kg体重/天。更一般地,约0.01-约5mg/kg体重/天。更一般地,约0.05-约0.5mg/kg体重/天。例如,约70kg体重的成年人的每日候选剂量在1mg-1000mg或5mg-500mg并且可以采用单剂量或多剂量形式。
本申请在另一个实施方案中披露了药物组合物,其包含本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯和药学上可接受的载体或赋形剂。
本申请在另一个实施方案中披露了药物组合物,其包含本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯与至少一种额外的治疗剂和药学上可接受的载体或赋形剂。
按照本发明,与本发明化合物联用的治疗剂可以在与本发明化合物联用时具有治疗作用的任意活性剂。例如,与本发明化合物联用的治疗剂可以为易于被细胞色素P450酶,尤其是细胞色素P450单加氧酶,例如1A2,2B6,2C8,2C19,2C9,2D6,2E1,3A4,5,7等氧化代谢的任意活性剂。
在另一个实例中,用于本发明化合物组合的治疗剂可以为任意的抗病毒药,例如抗-HIV,抗-HCV等,抗菌药,抗真菌药,免疫调节剂,例如免疫抑制剂,抗肿瘤药,化疗剂,用于心血管疾患,神经疾患的活性剂等。
在另一个实例中,用于本发明化合物组合的治疗剂可以为任意的质子泵抑制剂,抗癫痫药,NSAID,口服降血糖药,血管紧张素II,磺酰脲类,β阻滞剂,抗抑郁药,抗精神病药或麻醉药或其组合。
在另一个实例中,用于本发明化合物组合的治疗剂可以为任意的:1)大环内酯抗生素类,例如克拉霉素,红霉素,泰利霉素,2)抗心律不齐药,例如奎尼丁=>3-OH,3)苯二氮类,例如阿普唑仑,地西泮=>3OH,咪达唑仑,三唑仑,4)免疫调节剂,例如环孢菌素,他克莫司(FK506),5)HIV抗病毒药,例如茚地那韦,奈非那韦,利托那韦,沙奎那韦,6)促运动药,例如西沙必利,7)抗组胺药,例如阿司咪唑,氯苯那敏,非索芬那定(terfenidine),8)钙通道阻滞剂,例如氨氯地平,地尔硫卓,非洛地平,乐卡地平,硝苯地平,尼索地平,尼群地平,维拉帕米,9)HMG CoA还原酶抑制剂,例如阿托伐他汀,西立伐他汀,洛伐他汀,辛伐他汀或10)类固醇6β-OH,例如雌二醇,氢化可的松,孕酮,睾酮。
在另一个实例中,用于本发明化合物组合的治疗剂可以为任意的四唑芬太尼(alfentanyl),阿瑞匹坦,阿立哌唑,丁螺环酮,咖啡角(cafergil),咖啡因,TMU,西洛他唑,可卡因,可待因-N-去甲 基化,氨苯砜,右美沙芬,多西他赛,多潘立酮,依普利酮,芬太尼,非那雄胺,格列卫,氟哌啶醇,伊立替康,LAAM,利多卡因,美沙酮,那格列奈,昂丹司琼,匹莫齐特,普萘洛尔,喹硫平,奎宁,沙美特罗,西地那非,西罗莫司,他莫昔芬,泰素(taxol),特非那定,曲唑酮,长春新碱,扎来普隆或唑吡坦或其组合。
本申请在另一个实施方案中披露了药物组合物,其包含本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯与至少一种额外的治疗剂和药学上可接受的载体或赋形剂,所述额外的治疗剂选自抑制HIV蛋白酶的化合物,逆转录酶的HIV非核苷抑制剂,逆转录酶的HIV核苷抑制剂,逆转录酶的HIV核苷酸抑制剂,HIV整合酶抑制剂,HCV的非-核苷抑制剂,CCR5抑制剂及其组合。
本申请在另一个实施方案中披露了药物组合物,其包含本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯与至少一种额外的治疗剂和药学上可接受的载体或赋形剂,所述额外的治疗剂选自氨普那韦,阿扎那韦,呋山那韦,茚地那韦,洛匹那韦,利托那韦,奈非那韦,沙奎那韦,替拉那韦,贝卡那韦(brecanavir),地瑞那韦(darunavir),TMC-126,TMC-114,莫折那韦(mozenavir)(DMP-450),JE-2147(AG1776),L-756423,RO0334649,KNI-272,DPC-681,DPC-684,GW640385X,卡普韦林,乙米韦林(emivirine),地拉韦定(delaviridine),依法韦仑,奈韦拉平,右旋胡桐素A((+)calanolideA),依曲韦林(etravirine),GW5634,DPC-083,DPC-961,DPC-963,MIV-150,TMC-120,齐多夫定,恩曲他滨,去羟肌苷,司他夫定,扎西他滨,拉米夫定,阿巴卡韦,氨多索韦(amdoxovir),艾夫他滨(elvucitabine),阿洛夫定,MIV-210,Racivir(±-FTC),D-d4FC,AVX754,富马酸替诺福韦酯,阿德福韦,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,酪氨酸磷酸化抑制剂(tyrphostin)(tyrphostin),酪氨酸磷酸化抑制剂(tyrphostin)衍生物,槲皮素,槲皮素衍生物,S-1360,zintevir(AR-177),L-870812,L-870810,苯并咪唑衍生物,苯并-1,2,4-噻二嗪衍生物,苯丙氨酸衍生物,阿拉韦罗,vicriviroc和马拉韦罗,阿德福韦,FK-506,雷帕霉素,泰素,泰素帝,克拉霉素,A-77003,A-80987,MK-639,沙奎那韦,VX-478,AG1343,DMP-323,XM-450,BILA 2011BS,BILA 1096BS,BILA 2185BS,BMS 186,318,LB71262,SC-52151,SC-629(N,N-二甲基甘氨酰基-N-(2-羟基-3-(((4-甲氧基苯基)磺酰基)(2-甲基丙基)氨基)-1-(苯基甲基)丙基)-3-甲基-L-缬氨酰胺),KNI-272,CGP 53437,CGP 57813和U-103017。
本申请在另一个实施方案中提供了组合,包括:
a)第一种药物组合物,其包括本发明的化合物或其药学上可接受的盐,溶剂化物或酯;和
b)第二种药物组合物,其包括至少一种额外的治疗剂,该治疗剂选自抑制HIV蛋白酶的化合物,逆转录酶的HIV非核苷抑制剂,逆转录酶的HIV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,CCR5抑制剂,干扰素,利巴韦林类似物,NS3蛋白酶抑制剂,α-糖苷酶1抑制剂,肝保护剂,HCV的非-核苷抑制剂和治疗HCV的其它药物及其组合。
给药途径
通过适合于所治疗疾患的任意途径给予本发明的一种或多种化合物(本文称作活性组分)。合适的途径包括口服,直肠,鼻部,局部(包括口含和舌下),阴道和非肠道(包括皮下,肌内,静脉内,真皮内,鞘内和硬膜外)等。可以理解优选的途径可以根据例如接受者疾患的不同而改变。本发明化合物的优点在于它们为口服生物可利用的并且可以通过口服给药。
联合疗法
在一个实施方案中,可以单独使用本发明的化合物,例如用于抑制细胞色素P450单加氧酶。在另一个实施方案中,可以将本发明的化合物与其它治疗组分或活性剂联用。优选其它的活性治疗组分或活性剂易于被细胞色素P450酶,例如单加氧酶,诸如1A2,2B6,2C8,2C19,2C9,2D6,2E1,3A4,5,7等氧化代谢。
一般基于所治疗的疾患,组分的交叉反应性和组合中的药物特性选择本发明化合物的组合。例如,当治疗感染(例如HIV或HCV)时,本发明的组合物与抗感染药(诸如本文所述的那些)联用。
在一个实施方案中,合适的组合的非限制性实例包括本发明的一种或多种化合物与一种或多种抗病毒药的组合,例如抗-HIV,抗-HCV等,抗菌药,抗真菌药,免疫调节剂,例如免疫抑制剂,抗肿瘤药,化疗剂,用于心血管疾患,神经疾患的活性剂等。
在另一个实施方案中,合适的组合的非限制性实例包括本发明的一种或多种化合物与一种或多种质子泵抑制剂,抗癫痫药,NSAID,口服降血糖药,血管紧张素II,磺酰脲类,β阻滞剂,抗抑郁药,抗精神病药或麻醉药或其组合的组合。
在另一个实施方案中,合适的组合的非限制性实例包括本发明的一种或多种化合物与一种或多种如下药物的组合:1)大环内酯抗生素类,例如克拉霉素,红霉素,泰利霉素,2)抗心律不齐药,例如奎尼丁=>3-OH,3)苯二氮卓类,例如阿普唑仑,地西泮=>3OH,咪达唑仑,三唑仑,4)免疫调节剂,例如环孢菌素,他克莫司(FK506),5)HIV抗病毒药,例如茚地那韦,奈非那韦,利托那韦,沙奎那韦,6)促运动药,例如西沙必利,7)抗组胺药,例如阿司咪唑,氯苯那敏,非索芬那定(terfenidine),8)钙通道阻滞剂,例如氨氯地平,地尔硫卓,非洛地平,乐卡地平,硝苯地平,尼索地平,尼群地平,维拉帕米,9)HMG CoA还原酶抑制剂,例如阿托伐他汀,西立伐他汀,洛伐他汀,辛伐他汀或10)类固醇6β-OH,例如雌二醇,氢化可的松,孕酮,睾酮。
在另一个实施方案中,合适的组合的非限制性实例包括本发明的一种或多种化合物与一种或多种选自如下化合物的组合:四唑芬太尼,阿瑞匹坦,阿立哌唑,丁螺环酮,咖啡角,咖啡因=>TMU,西洛他唑,可卡因,可待因-N-去甲基化,氨苯砜,右美沙芬,多西他赛,多潘立酮,依普利酮,芬太尼,非那雄胺,格列卫,氟哌啶醇,伊立替康,LAAM,利多卡因,美沙酮,那格列奈,昂丹司琼,匹莫齐特,普萘洛尔,喹硫平,奎宁,沙美特罗,西地那非,西罗莫司,他莫昔芬,泰素,特非那定,曲唑酮,长春新碱,扎来普隆或唑吡坦或其组合。
在另一个实施方案中,合适的组合的非限制性实例包括本发明的一种或多种化合物与一种或多种HIV如下化合物:逆转录酶的HIV非核苷抑制剂,逆转录酶的HIV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,CCR5抑制剂和治疗HIV的其它药物,干扰素,利巴韦林类似物,HCV NS3蛋白酶抑制剂,α-糖苷酶1抑制剂,肝保护剂,HCV的核苷或核苷酸抑制剂,HCV的非-核苷抑制剂和治疗HCV的其它药物。
更具体地说,可以将本发明的化合物与一种或多种选自如下的化合物联用:1)氨普那韦,阿扎那韦,呋山那韦,茚地那韦,洛匹那韦,利托那韦,奈非那韦,沙奎那韦,替拉那韦,贝卡那韦,地瑞那韦,TMC-126,TMC-114,莫折那韦(DMP-450),JE-2147(AG1776),L-756423,RO0334649,KNI-272,DPC-681,DPC-684,GW640385X,DG17,GS-8374,PPL-100,DG 35和AG 1859,2)逆转录酶的HIV非-核苷抑制剂,例如卡普韦林,卡普韦林,地拉韦定,依法韦仑,奈韦拉平,右旋胡桐素A,依曲韦林,GW5634,DPC-083,DPC-961,DPC-963,MIV-150和TMC-120,TMC-278(rilpivirene),依法韦仑,BILR355BS,VRX840773,UK-453061和RDEA806,3)逆转录酶的HIV核苷抑制剂,例如齐多夫定,恩曲他滨,去羟肌苷,司他夫定,扎西他滨,拉米夫定,阿巴卡韦,氨多索韦,艾夫他滨,阿洛夫定,MIV-210,racivir(±-FTC),D-d4FC,恩曲他滨,叠氮膦(phosphazide),福齐夫定替酯(fozivudine tidoxil),阿立他滨(apricitibine)(AVX754),GS-7340,KP-1461和磷夫定酯(fosalvudine tidoxil)(上述HDP 99.0003),4)逆转录酶的HIV核苷酸抑制剂,例如替诺福韦和阿德福韦,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,酪氨酸磷酸化抑制剂(tyrphostin),酪氨酸磷酸化抑制剂(tyrphostin)衍生物,槲皮素,槲皮素衍生物,S-1360,zintevir(AR-177),elvitegravir,L-870812和L-870810,MK-0518雷特格韦(raltegravir),BMS-538158,GSK364735C,BMS-707035,MK-2048和BA 011,6)gp41抑制剂,例如恩夫韦地,西夫韦肽(sifuvirtide),FB006M和TRI-1144,7)CXCR4抑制剂,例如AMD-070,8)进入抑制剂,例如SP01A,9)gp120抑制剂,例如BMS-488043或BlockAide/CR,10)G6PD和NADH-氧化酶抑制剂,例如immunitin,11)CCR5抑制剂,例如阿拉韦罗,vicriviroc,马拉韦罗,PRO-140,INCB15050,PF-232798(Pfizer)和CCR5mAb004,12)治疗HIV的其它药物,例如BAS-100,SPI-452,REP9,SP-01A,TNX-355,DES6,ODN-93,ODN-112,VGV-1,PA-457(bevirimat),聚肌胞,HRG214,Cytolin,VGX-410,KD-247,AMZ0026,CYT99007A-221HIV,DEBIO-025,BAY50-4798,MDX010(ipilimumab),PBS119,ALG889和PA-1050040(PA-040),13)干扰素,例如聚乙二醇化的rIFN-α2b,聚乙二醇化的rIFN-α2a,rIFN-α2b,rIFN-α2a,共有IFNα(干复津),β-干扰素,reaferon,intermaxα,r-IFN-β,干复津+干扰素γ-1b,IFN-ω与DUROS,α-干扰素白蛋白(albuferon),locteron,α-干扰素白蛋白(Albuferon),利比,口服干扰素α,IFNα-2bXL,AVI-005,PEG-干复津和聚乙二醇化的IFN-β,14)利巴韦林类似物,例如rebetol,copegus,viramidine(taribavirin),15)NS5b聚合酶抑制剂,例如NM-283,valopicitabine,R1626,PSI-6130(R1656),HCV-796,BILB1941,XTL-2125,MK-0608,NM-107,R7128(R4048),VCH-759,PF-868554和GSK625433,16)NS3蛋白酶抑制剂,例如SCH-503034(SCH-7),VX-950(telaprevir),BILN-2065,BMS-605339和ITMN-191,17)α-糖苷酶1抑制剂,例如MX-3253(西戈斯韦),UT-231B,18)肝保护剂,例如IDN-6556,ME3738,LB-84451和MitoQ,19)HCV的非核苷抑制剂,例如苯并咪唑衍生物,苯并-1,2,4-噻二嗪衍生物,苯丙氨酸衍生物,A-831,GS-9190和A-689;和20)治疗HCV的其它药物,例如日达仙,硝唑尼特(alinea),BIVN-401(virostat),PYN-17(altirex),KPE02003002,actilon(CPG-10101),KRN-7000,civacir,GI-5005,ANA-975,XTL-6865,ANA971,NOV-205,tarvacin,EHC-18,NIM811,DEBIO-025,VGX-410C,EMZ-702,AVI4065,巴维昔单抗(Bavituximab),Oglufanide和VX-497(merimepodib)。
还可以预期本发明的化合物可以与任意其它明显被细胞色素P450单加氧酶酶,例如细胞色素P450单加氧酶3A代谢的活性治疗剂或组分联用,由此降低被代谢的其它活性治疗剂或组分的量或速率,从而改善其它活性治疗剂或组分的药代动力学。这类改善可以包括升高其它治疗剂或组分的血浆水平或在治疗上维持比未与本发明化合物联合给药的其它治疗活性剂或组分的血浆水平更有效的其它治疗活性剂或组分的血浆水平。
还能将本发明的任意化合物与一种或多种其它活性治疗剂合并在单位剂型中可同时或依次对患者给药。可以将该联合疗法作为同时或依次方案给予。当依次给予时,可以将该组合以两次或多次给药形式给予。
本发明化合物与一种或多种其它活性治疗剂的共同给药一般意旨同时或依次给予本发明的化合物与一种或多种其它活性治疗剂,使得本发明化合物和一种或多种其它活性治疗剂的治疗有效量均存在于患者体内。
共同给药包括在给予一种或多种其它活性治疗剂之前或之后给予单位剂量的本发明的化合物,例如,在给予一种或多种其它活性治疗剂的数秒,数分钟或数小时内给予本发明的化合物。例如,可以通过在给予单位剂量的一种或多种活性治疗剂的数秒或数分钟内,首先给予单位剂量的本发明的化合物。可选择地,可以在首先给予单位剂量的一种或多种其它治疗剂,随后在数秒或数分钟内给予单位剂量的本发明的化合物。在某些情况中,可能需要在给予单位剂量的一种或多种其它活性治疗剂的数小时(例如1-12小时)前,首先给予单位剂量的本发明的化合物。在其它情况中,可能需要在给予单位剂量的本发明的化合物的数小时(例如1-12小时)前,首先给予单位剂量的一种或多种其它活性治疗剂。
联合疗法可以提供″协同作用″和″协同效应″,即在共同使用活性组分时获得的作用大于因单独使用所述化合物获得的作用总和。可以获得协同效应,此时活性组分:(1)以合并制剂同时共同配制和给药或递送;(2)作为单独制剂交替或平行递送;或(3)通过某些其它方案。当以交替疗法递送时,协同作用在依次给予或递送化合物,例如在单独的片剂,丸剂或胶囊中时或用在单独的系统中的不同注射剂获得。一般而言,在交替疗法过程中,依次,即按顺序给予有效剂量的各活性组分,而在联合疗法中,共同给予有效剂量的两种或多种活性组分。
本申请在另一个实施方案中提供了改善被细胞色素P450单加氧酶代谢的药物的药代动力学的方法,包括对使用所述药物治疗的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了改善被细胞色素P450单加氧酶代谢的药物的药代动力学的方法,包括对使用所述药物治疗的患者给予治疗有效量组合,该组合包括所述的药物和本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了改善被细胞色素P450单加氧酶3A代谢的药物的药代动力学的方法,包括对使用所述药物治疗的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了增加被细胞色素P450单加氧酶代谢的药物的血浆水平的方法,包括对使用所述药物治疗的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了增加被细胞色素P450单加氧酶代谢的药物的血浆水平的方法,包括对使用所述药物治疗的患者给予治疗有效量的组合,该组合包括所述的药物和本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了增加被细胞色素P450单加氧酶3A代谢的药物的血浆水平的方法,包括对使用所述药物治疗的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了改善被细胞色素P450单加氧酶代谢的药物的药代动力学的方法,包括对使用所述药物治疗的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯,并且其中以有效抑制细胞色素P450单加氧酶的用量给予本发明的化合物。
本申请在另一个实施方案中提供了抑制患者细胞色素P450单加氧酶的方法,包括对有此需要的患者给予有效抑制细胞色素P450单加氧酶的用量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了抑制患者细胞色素P450单加氧酶3A的方法,包括对有此需要的患者给予有效抑制细胞色素P450单加氧酶3A的用量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了抑制细胞色素P450单加氧酶的方法,包括使细胞色素P450单加氧酶接触有效抑制细胞色素P450单加氧酶的用量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了抑制细胞色素P450单加氧酶3A的方法,包括使细胞色素P450单加氧酶3A接触有效抑制细胞色素P450单加氧酶3A的用量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯。
本申请在另一个实施方案中提供了治疗HIV感染的方法,包括对有此需要的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯与治疗有效量的一种或多种额外的治疗剂的组合,所述的一种或多种额外的治疗剂选自抑制HIV蛋白酶的化合物,逆转录酶的HIV非核苷抑制剂,逆转录酶的HIV核苷抑制剂,逆转录酶的HIV核苷酸抑制剂,HIV整合酶抑制剂和CCR5抑制剂。
本申请在另一个实施方案中提供了治疗HIV感染的方法,包括对有此需要的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯与治疗有效量的一种或多种额外的治疗剂的组合,所述的一种或多种额外的治疗剂选自氨普那韦,阿扎那韦,呋山那韦,茚地那韦,洛匹那韦,利托那韦,奈非那韦,沙奎那韦,替拉那韦,贝卡那韦,地瑞那韦,TMC-126,TMC-114,莫折那韦(DMP-450),JE-2147(AG1776),L-756423,RO0334649,KNI-272,DPC-681,DPC-684和GW640385X,DG17,PPL-100,DG35,AG1859,卡普韦林,乙米韦林,地拉韦定,依法韦仑,奈韦拉平,右旋胡桐素A,依曲韦林,GW5634,DPC-083,DPC-961,DPC-963,MIV-150和TMC-120,TMC-278(rilpivirene),依法韦仑,BILR355BS,VRX840773,UK-453061,RDEA806,如齐多夫定,恩曲他滨,去羟肌苷,司他夫定,扎西他滨,拉米夫定,阿巴卡韦,氨多索韦,艾夫他宾,阿洛夫定,MIV-210,racivir(±-FTC),D-d4FC,恩曲他滨,叠氮膦,福齐夫定替酯,阿立他滨(AVX754),氨多索韦(amdoxovir),KP-1461,磷夫定酯(以前称为HDP99.0003),替诺福韦、阿德福韦,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,酪氨酸磷酸化抑制剂(tyrphostin),酪氨酸磷酸化抑制剂(tyrphostin)衍生物,槲皮素,槲皮素衍生物,S-1360,zintevir(AR-177),L-870812,L-870810,MK-0518(雷特格韦),BMS-538158,GSK364735C,BMS-707035,MK-2048和BA011,恩夫韦地,西夫韦肽,FB006M和TRI-1144,AMD-070,进入抑制剂,SP01A,BMS-488043,BlockAide/CR,G6PD和NADH-氧化酶抑制剂,immunitin,阿拉韦罗,vicriviroc,马拉韦罗,马拉韦罗,PRO-140,INCB15050,PF-232798(Pfizer),CCR5mAb004,BAS-100,SPI-452,REP9,SP-01A,TNX-355,DES6,ODN-93,ODN-112,VGV-1,PA-457(bevirimat),聚肌胞,HRG214,Cytolin,VGX-410,KD-247,AMZ0026,CYT99007A-221HIV,DEBIO-025,BAY50-4798,MDX010(ipilimumab),PBS119,ALG889和PA-1050040(PA-040)。
本申请在另一个实施方案中提供了治疗HCV感染的方法,包括对有此需要的患者给予治疗有效量的本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯与治疗有效量的一种或多种额外的治疗剂的组合,所述的一种或多种额外的治疗剂选自聚乙二醇化的rIFN-α2b,聚乙二醇化的rIFN-α2a,rIFN-α2b,rIFN-α2a,共有IFNα(干复津)(consensus IFN alfa(infergen)),β-干扰素,reaferon,intermaxα,r-IFN-β,(infergen+actimmune)干复津+干扰素γ-1b,IFN-ω与DUROS,locteron,α-干扰素白蛋白(albuferon),利比,口服干扰素α,IFNα-2bXL,AVI-005,PEG-干复津和聚乙二醇化的IFN-β,rebetol,copegus,viramidine(taribavirin),NM-283,valopicitabine,R1626,PSI-6130(R1656),HCV-796,BILB1941,XTL-2125,MK-0608,NM-107,R7128(R4048),VCH-759,PF-868554,GSK625433,SCH-503034(SCH-7),VX-950(telaprevir),BILN-2065,BMS-605339,ITMN-191,MX-3253(西戈斯韦),UT-231B,IDN-6556,ME3738,LB-84451,MitoQ,苯并咪唑衍生物,苯并-1,2,4-噻二嗪衍生物,苯丙氨酸衍生物,A-831,A-689,日达仙,硝唑尼特(alinea),BIVN-401(virostat),PYN-17(altirex),KPE02003002,actilon(CPG-10101),KRN-7000,civacir,GI-5005,ANA-975,XTL-6865,ANA971,NOV-205,巴维昔单抗(tarvacin),EHC-18,NIM811,DEBIO-025,VGX-410C,EMZ-702,AVI4065,巴维昔单抗(Bavituximab),Oglufanide和VX-497(merimepodib)。
本申请在另一个实施方案中提供了本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯在制备抑制患者细胞色素P450单加氧酶的药剂中的应用。
本申请在另一个实施方案中提供了本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯在制备治疗HIV感染的药剂中的应用。
本申请在另一个实施方案中提供了本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯在制备增加细胞色素P450单加氧酶代谢的药物的血浆水平的药剂中的应用。
本申请在另一个实施方案中提供了本发明的化合物或其药学上可接受的盐,溶剂合物和/或酯在制备改善细胞色素P450单加氧酶代谢的药物的药代动力学的药剂中的应用。
实施例
实施例A的制备
方案1
化合物2
向化合物1(利托那韦)(1.8g,2.5mmol)在1,2-二氯乙烷(15mL)中的溶液中加入1,1’-硫代羰基二咪唑(890mg,5.0mmol)。将该混合物在75℃下加热6小时并且冷却至25℃。在减压下蒸发而得到白色固体。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:EtOAc)而得到化合物2(1.6g)。m/z:831.1(M+H)+。
实施例A
在30分钟内向氢化三丁基锡(0.78mL,2.9mmol)在甲苯(130mL)中的回流溶液中加入化合物2(1.6g,1.9mmol)和2,2’-偶氮二异丁腈(31mg,0.19mmol)在甲苯(30mL)中的溶液。将该混合物在115℃下加热6小时并且冷却至25℃。在减压下除去甲苯。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:己烷/EtOAc=1/10)而得到实施例A(560mg)。m/z:705.2(M+H)+.1H-NMR(CDCl3)δ8.79(1H,s),7.82(1H,s),7.26-7.05(10H,m),6.98(1H,s),6.28(1H,m),6.03(1H,m),5.27(1H,m),5.23(2H,s),4.45-4.22(2H,m),4.17(1H,m),3.98(1H,m),3.75(1H,m),3.25(1H,m),2.91(3H,s),2.67(4H,m),2.36(1H,m),1.6-1.2(10H,m),0.85(6H,m)。
实施例B的制备
方案2
实施例B
向化合物1(利托那韦)(98mg,0.136mmol)在二氯甲烷(4mL)中的溶液中加入戴斯-马丁氧化剂(Dess-Martin periodinane)(61mg,0.143mmol)。将该混合物在室温下搅拌6小时。然后使该混合物分配在二氯甲烷与盐水之间,分离二氯甲烷层,干燥并且蒸发干。使用CombiFlash纯化(固定相:硅胶;洗脱剂:40-80%EtOAc/己烷梯度)而得到实施例B,为白色固体。通过与MeOH/己烷一起研磨进一步纯化实施例B而得到83mg白色固体。m/z:719(M+H)+。
实施例C的制备
方案3
化合物3
按照J.Med.Chem.1998,41,602的操作制备化合物3,为了所有目的而将该文献完整地引入本文作为参考。
化合物4
在室温下给烧瓶中添加环丙胺(8.2mL,117.8mmol)。在5分钟内滴加化合物3(1g,4.71mmol)在MeCN(8.5mL)中的溶液以便产生澄清黄色溶液,使其在室温下稳定过夜。在真空中除去挥发性物质并且通过硅胶色谱法纯化所得残余物(梯度洗脱,0-50%EtOAc/己烷)而得到0.65g(70%)4,为黄色液体(LC/MSm/z197(M+H)+;218(M+Na)+)。
方案4
化合物5
化合物5购自Aldrich或可选择地按照J.Org.Chem.1994,59,1937的操作制备,为了所有目的而将该文献完整地引入本文作为参考。
化合物6
向室温下化合物4在DCM(3mL)中的溶液中加入5(0.1mL,0.695mmol)。使所得溶液在室温下稳定2h。在真空中除去溶剂并且使用硅胶色谱法直接对残余物进行色谱(梯度洗脱,0-50%EtOAc/己烷)而得到0.218g(89%)6(LC/MSm/z354(M+H)+;729(2M+Na)+),为无色玻璃状物。
化合物7
在室温下将化合物6溶于THF(5mL)并且加入LiOH(在H2O中1M)。然后将所得反应混合物剧烈搅拌1.5h。用1M HCl将该反应混合物酸化至pH为3(使用pH试纸监测)。然后用EtOAc将酸化的反应混合物萃取几次。用盐水洗涤合并的有机相,用无水Na2SO4干燥并且在真空中浓缩至得到0.20g(定量产量)7(LC/MSm/z340(M+H)+),为无色薄膜状物。不经进一步纯化使用该物质。
方案5
实施例C
在室温下用THF(2mL)稀释化合物7(0.034g,0.100mmol)和8(0.034g,0.083mmol)。向所得溶液中加入,N,N-二异丙基乙胺(0.022mL,0.125mmol),EDC(0.018mL,0.099mmol)和HOBt(0.013g,0.099mmol)。然后使该溶液在室温下稳定过夜。在真空中除去溶剂并且将残余物溶于MeCN(0.5mL)且通过Acrodisc LC13PVDF滤膜(0.45μM),此后通过制备型HPLC纯化而得到0.043g(71%)实施例C,为松散白色固体(1H-NMR(300MHz,CDCl3)δ8.79(s,1H);7.82(s,1H);7.27-7.02(m,10H);6.81(s,1H);5.97(brd,J=8.7Hz,1H);5.76(brd,J=7.2Hz,1H);5.21(dt,J=7.5,12.6Hz,2H);5.02,brd,J=8.4Hz,1H);4.58(s,2H);4.16(m,1H);3.99(br t,J=6.6Hz,1H);3.79(m,1H);3.27(五重峰,J=6.6Hz,1H);2.85-2.50(m,3H);2.23(m,1H);1.82(brs,2H);1.60-1.22(m,4H);1.36(d,J=6.6Hz,6H);0.91(d,J=6.6Hz,3H);0.90-0.7(m,4H);0.80(d,J=6.6Hz,3H);LC/MSm/z731(M+))。
实施例D-I的制备
方案6
化合物9
按照J.Med.Chem.1998,41,602的操作制备化合物9。
化合物10
按照J.Med.Chem.1998,41,602的操作制备化合物10的结构。
化合物11
化合物11的结构购自Aldrich或按照J.Org.Chem.1994,59,1937的操作制备。
化合物12
方法1:向化合物9(0.8mmol)在THF(2mL)中的溶液中加入化合物10的氨基甲酸酯(0.6mmol),随后加入DMAP(16mg)和三乙胺(0.25mL)。将所得混合物在70℃下加热2小时并且用EtOAc稀释。分离有机相并且依次用饱和Na2CO3水溶液,水和盐水洗涤,然后在减压下浓缩。通过快速柱色谱法纯化残余物(硅胶,1/1-1/3己烷/EtOAc梯度)而得到化合物12的结构。
方法2:向化合物9(2.4mmol)在CH2Cl2(2mL)中的溶液中加入化合物11的异氰酸酯(2mmol)。将所得混合物搅拌4小时并且浓缩。通过快速柱色谱法纯化残余物(硅胶,己烷/EtOAc1/1-1/3)而得到化合物12的结构。
化合物13
向化合物12的结构(1.8mmol)在二噁烷(8mL)和水(8mL)中的溶液中加入氢氧化钠(3.6mmol)。将所得反应混合物搅拌1小时并且用在二噁烷中的HCl(3.6mmol)酸化。用EtOAc萃取该反应混合物并且用无水MgSO4干燥有机相。浓缩干燥的有机相而得到化合物13的结构。
方案7
化合物16
向化合物15(购自Molekula)(17mmol)在DCM(40mL)中的溶液中加入化合物14(19mmol),随后加入三乙胺(26mmol)。将所得反应混合物搅拌12小时并且在减压下浓缩。用EtOAc稀释该反应混合物并且依次用水溶液Na2CO3,水和盐水洗涤。在减压下除去溶剂。通过快速柱色谱法纯化残余物(硅胶,洗脱剂:己烷/EtOAc=1/1)而得到化合物16(4.7g)。
方案8
化合物17
按照Tetrahedron1997,53,4769的操作制备化合物17,为了所有目的而将该文献完整地引入本文作为参考。
化合物18
按照J.Org.Chem.1987,52,3759的操作制备化合物18,为了所有目的而将该文献完整地引入本文作为参考。
化合物19
在回流状态下加热化合物18(7.4mmol)在THF(200mL)中的混悬液,直到获得澄清溶液。将该溶液冷却至-78℃并且滴加正-丁基锂(14.8mmol)而得到砜18的二价离子溶液。
向在0℃下DIBAL-H的溶液(7.8mmol)中加入MeOH(7.8mmol)在THF(5mL)中的溶液。将该混合物搅拌5分钟并且冷却至-78℃。将化合物17(6.6mmol)在THF(5mL)中的溶液加入到上述DIBAL-H/MeOH溶液中并且将所得反应混合物再搅拌5分钟。将所得醛复合物的溶液转移至砜18的二价阴离子溶液中。将所得混合物在-78℃下搅拌30分钟,用NH4Cl水溶液淬灭并且温至25℃。然后用EtOAc萃取该混合物并且浓缩而得到化合物19,为非对映体混合物。(m/z 737.3(M+Na)+。
实施例20
向化合物19在DCM(20mL)中的溶液中加入Ac2O(1.5mL),随后加入吡啶(3mL)。将所得混合物搅拌12小时并且浓缩。将浓缩物溶于MeOH(30mL)并且冷却至0℃。将NaH2PO4(4.9g)加入到该溶液中,随后加入新近制备的Na-Hg(6%,6g)。将所得混合物温至25℃并且搅拌12小时。然后加入水(50mL)并且过滤和浓缩该混合物。用EtOAc稀释浓缩物并且用盐水洗涤。浓缩有机相。通过快速柱色谱法纯化(硅胶,洗脱剂:己烷/EtOAc=10/1)而得到化合物20(1.4g)。
化合物21
向在-33℃下的液氨(25mL)中加入化合物20(1.4g)在THF(2.5mL)中的溶液。缓慢加入钠,直到溶液蓝色持续为止。将所得混合物搅拌1小时。然后缓慢加入固体NH4Cl(6g),将该混合物温至25℃并且蒸发氨。用EtOAc稀释该混合物并且用水和盐水依次洗涤。在减压下除去溶剂。通过快速柱色谱法纯化所得残余物(硅胶,洗脱剂:己烷/EtOAc=5/1)而得到化合物21(1.15g)。
化合物22
将化合物21(1.15g)和10%Pd/C(160mg)在MeOH(20mL)中的混合物氢化12小时。加入CELITE并且将所得混合物搅拌5分钟。然后过滤该混合物并且浓缩而得到中间体(1g)。将该中间体(700mg)溶于DCM(20mL)和TFA(4mL)并且将所得混合物搅拌4小时,然后在减压下浓缩。用EtOAc稀释浓缩的混合物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。浓缩洗涤的EtOAc混合物而得到化合物22(420mg)。
化合物8
向化合物22(1.57mmol)在CH3CN(16mL)中的溶液中加入化合物16(1.57mmol),随后加入二异丙基乙胺(3.14mmol)。将所得混合物搅拌12小时。然后用EtOAc稀释该混合物并且依次与饱和Na2CO3水溶液,水和盐水洗涤。通过反相HPLC纯化(Phenomenex SynergiComb-HTS柱,洗脱剂:在水中25%-100%CH3CN)纯化而得到化合物8(460mg)。
实施例D
向化合物13a(R=H;0.08mmol)和化合物8(0.06mmol)在THF(1mL)中的溶液中加入HOBt(15mg),EDC(26mg)和二异丙基乙胺(0.25mL)。将该混合物搅拌12小时并且浓缩。通过反相HPLC纯化(PhenomenexSynergiComb-HTS柱,洗脱剂:在水中25%-100%CH3CN)而得到实施例D(27mg)。m/z 663.1(M+H)+.1H-NMR(CDCl3)δ8.79(1H,s),7.83(1H,s),7.25-7.04(10H,m),6.98(1H,s),6.25(1H,m),5.25(3H,m),4.40(2H,s),4.12(1H,m),3.8(3H,m),3.22(1H,m),2.95(3H,s),2.70(4H,m),1.60(4H,m),1.26(6H,d,J=7Hz)。
实施例E
按照例如D的操作制备实施例E(30mg),但使用化合物13b而不是化合物13a。m/z677.1(M+H)+。
实施例F
按照例如D的操作制备化合物F(40mg),但使用化合物13c而不是化合物13a。m/z691.2(M+H)+。1H-NMR(CDCl3)δ8.80(1H,s),7.83(1H,s),7.25-7.06(10H,m),6.98(1H,s),6.35(1H,m),6.23(1H,m),5.24(2H,s),5.12(1H,m),4.34(2H,s),4.10(2H,m),3.78(1H,m),3.23(1H,m),2.90(3H,s),2.68(4H,m),1.90(2H,m),1.7-1.4(4H,m),1.36(6H,d,J=7.0Hz),0.90(3H,t,J=7.3Hz)
实施例G
按照例如D的操作制备实施例G(84mg),但使用化合物13d而不是化合物13a。m/z 783.2(M+H)+。
实施例H
按照例如D的操作制备实施例H(90mg),但使用化合物13e而不是化合物13a。m/z 763.2(M+H)+。
实施例I
将实施例H(24mg)溶于TFA(2mL)并且将该混合物搅拌12小时,然后浓缩,通过反相HPLC纯化(Phenomenex SynergiComb-HTS柱,洗脱剂:在水中25%-100%CH3CN)而得到实施例I(14mg)。m/z707.2(M+H)+。1H-NMR(CDCl3)δ8.82(1H,s),7.85(1H,s),7.26-7.04(10H,m),7.0(1H,s),5.25(2H,s),4.86(1H,m),4.56(1H,m),4.37(2H,m),4.13(1H,m),4.06(1H,m),3.86(1H,m),3.32(1H,m),2.99(3H,s),2.8-2.6(4H,m),1.6-1.4(4H,m),1.37(6H,m),1.15(3H,m)。
实施例J的制备
方案9
实施例J
按照化合物13的操作制备化合物23,但使用3-异氰酸丙酸甲酯而不是化合物11。
按照例如D的操作制备实施例J(37mg),但使用化合物23而不是化合物13a。m/z677.2(M+H)+。
实施例K的制备
方案10
实施例K
化合物5a
按照文献Synthesis823,1976的操作制备化合物5a,为了所有目的而将该文献完整地引入本文作为参考。
化合物5b
向化合物5a(700mg,3.9mmol)在THF(10mL)中的溶液中加入水(69μL,3.9mmol),随后加入三苯膦(1.06g,4.0mmol)。将该混合物搅拌12小时。除去溶剂并且干燥该混合物而得到化合物5b,将其不经进一步纯化用于下一步。
化合物5c
在30分钟期限内向在0C下三光气(110mg,0.37mmol)在CH2Cl2(2mL)中的溶液中加入化合物5b(1mmol)和iPrNEt2(0.38mL,2.2mmol)在CH2Cl2(3.5mL)中的溶液。将该混合物搅拌30分钟并且加入氨基N-甲基亮氨酸甲酯HCl盐(182mg,1mmol)和iPrNEt2(0.34mL,2.2mmol)在CH2Cl2(2mL)中的溶液。将该混合物搅拌12小时并且用EtOAc稀释。用饱和Na2CO3(2x),水(2x)和盐水洗涤该溶液并且用Na2SO4干燥。浓缩并且使用硅胶快速柱进行纯化而得到化合物5c(300mg)。
化合物5d
按照化合物13的操作制备化合物5d,但使用化合物5c而不是化合物12。
实施例K
按照例如D的操作制备实施例K(7mg),但使用化合物5d而不是化合物13a。m/z705.2(M+H)+。1H-NMR(CDCl3)δ8.8(1H,m),7.86(1H,s),7.26-6.8(11H,m),6.10(1H,m),5.5-5.10(4H,m),4.46(2H,m),4.2-3.75(3H,m),3.25(1H,m),2.82/2.4(3H),2.8-2.5(4H,m),2.17(1H,m),1.7-1.2(10H,m),0.8(6H,m)。
实施例L的制备
方案11
实施例L
向化合物22(1.57mmol)在CH 3CN(16mL)中的溶液中加入化合物16(3.14mmol),随后加入三乙胺(4.71mmol)。将所得混合物搅拌12小时。用EtOAc稀释该反应混合物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。在减压下除去溶剂。通过快速柱色谱法纯化残余物(硅胶,洗脱剂:己烷/EtOAc=1/1)而得到实施例L(460mg)。m/z 551.2(M+H)+。1H-NMR(CDCl3)δ8.81(2H,s),7.85(2H,s),7.26-7.0(10H,m),5.24(4H,s),4.50(2H,m),3.87(2H,m),2.73(4H,m),1.4-1.2(4H,m)。
可选择的化合物22的制备
方案12
化合物25
按照J.Org.Chem.1996,61,444中所述的操作制备化合物25(将该文献完整地引入本文作为参考),但使用L-异构体而不是D-异构体制备。
化合物26
将化合物25(7.4g)和1,1’-硫代羰基二咪唑(4.5g)在THF(260mL)中的混合物在65℃下加热54小时。在减压下从混合物中除去溶剂。通过快速柱色谱法纯化(硅胶,己烷/EtOAc=1/1)而得到化合物26(7.33g)。
化合物27
将化合物26(7.3g)和三乙基亚磷酸酯(100mL)的混合物在160℃下加热4小时。在减压下除去过量试剂。通过快速柱色谱法纯化(硅胶,己烷/EtOAc=3/1)而得到化合物27(5g)。
化合物22
在有10%Pd/C(75mg)存在下将化合物27(250mg)在i-PrOH/EtOAc(5mL/5mL)中的混合物氢化14小时。向该混合物中加入CELITE并且将该混合物搅拌5分钟。过滤并且蒸发溶剂而得到化合物22(116mg)。
本领域技术人员公认方案12中概括的操作可以用于制备各种与化合物22类似的1,4-取代的1,4-二胺类。例如,可以制备与化合物25类似的胺-被保护的2,3-二羟基-1,4-二胺:
化合物25的类似物
其中L3,A,Ar和P如本文所定义并且保护基“P”为描述在Protective Groups in Organic Synthesis,Theodora W.Greene和Peter G.M.Wuts(John Wiley&Sons,Inc.,New York,1999,ISBN 0-471-16019-9)中的任意胺保护基,为了所有目的而将该文献完整地引入本文作为参考。然后可以按照方案12中概括的方法将化合物25的类似物转化成化合物26的类似物:
化合物26的类似物;
化合物27的类似物:
化合物27的类似物;和
化合物22的类似物:
化合物22的类似物。
实施例M和N的制备
方案13
化合物29
按照与用于制备化合物6类似的操作(描述在方案4中)制备化合物28,但使用化合物9而不是化合物4。
向在室温下化合物28(0.757g,2.31mmol)在THF(9mL)中的溶液中加入新近制备的1M LiOH(4.6mL,4.6mmol)。在1.5h后,加入1MHCl(7mL,7mmol)并且使用EtOAc(5×15mL)充分萃取该反应混合物。用无水Na2SO4干燥合并的有机层并且在真空中除去挥发性物质而得到0.677g(93%)化合物29,为无色玻璃状固体(LC/MSm/z314.0(M+H)+),将其不经进一步纯化用于随后的操作。
方案14
化合物30
化合物30购自Aldrich Chemical Co.并且不经进一步纯化使用。
化合物31
向化合物30(8.25g,80mmol)在MeOH(50mL)中的溶液中加入苯甲醛(8.1mL,80mmol)并且将所得溶液在室温下搅拌。2h后,将该反应混合物冷却至0℃并且分部分加入NaBH4(3.33g,88mmol)。在2h内使该反应混合物温至室温后,加入冰醋酸(2mL)。在真空中浓缩所得粘性溶液。加入EtOAc和H2O(每个50mL)并且用EtOAc萃取水相。用饱和NaHCO3,盐水洗涤有机相并且在真空中浓缩。在室温下将所得物质溶于THF(25mL)和H2O(25mL)并且加入Boc2O(15.1g,69.2mmol)以便产生不透明的混悬液,将其在室温下剧烈搅拌2h。在真空中除去THF并且用EtOAc萃取水层。用盐水洗涤合并的有机层并且用无水MgSO4干燥且在真空中浓缩。使用SiO2(3/1Hex/EtOAC)进行色谱而得到18.5g(79%)化合物31,为无色油状物(LC/MSm/z293.9(M+H)+。
化合物32
用DMSO(65mL)稀释化合物31(5.95g,20.3mmol)和Et3N(9.9mL,71mmol)并且使其在室温下放置30min,此后冷却至0℃。一次加入吡啶·SO3并且将该反应混合物维持在5℃下以防止冷冻。45min后,将该反应混合物倾入冰水并且用EtOAc萃取。用饱和NaHCO3,H2O洗涤合并的有机层并且用无水MgSO4干燥,此后在真空中浓缩(浴温25℃)而得到4.39g(74%)化合物32,为澄清黄色油状物,将其不经进一步纯化使用。1H-NMR(CDCl3,300MHz)δ(主要旋转异构体)9.36(brs,1H);5.01(d,J=15Hz,1H);4.12(d,J=15Hz,1H);3.45(m,1H);2.04-1.88(m,1H);1.80-1.58(m,1H);1.54-1.20(m,2H);1.47(s,9H);0.91(t,J=7.2Hz,3H)。(次要旋转异构体)9.46(br s,1H);4.71(d,J=15Hz,1H);4.20(d,J=15Hz,1H);3.78(m,1H);2.04-1.88(m,1H);1.80-1.58(m,1H);1.54-1.20(m,2H);1.47(s,9H);0.91(t,J=7.2Hz,3H)
化合物34
在回流状态下加热化合物33(6.23g,16.6mmol)在THF(500mL)中的混悬液,直到获得均匀溶液为止。将该溶液冷却至-78℃并且导入1.6Mn-BuLi(19.7mL,31.5mmol)而产生澄清黄色溶液。同时通过用THF(8mL)稀释DIBAL-H(在己烷中1M,18.1mL,18.1mmol)并且在添加MeOH(0.73mL,18.1mmol)前冷却至0℃制备DIBAL-OMe。使该溶液放置,同时用THF(15mL)稀释化合物32(4.39g,15.1mmol)并且冷却至-78℃。用套管将DIBAL-OMe溶液导入化合物32的溶液并且放置5min,此后将套管插入硫的二价阴离子溶液。使所得澄清黄色溶液在-78℃下放置1h。通过在-78℃下添加饱和NH 4Cl(100mL)使反应淬灭并且温至室温。加入水,直到沉淀的固体溶解并且各层分离。在真空中浓缩THF层,同时用EtOAc萃取水层。用盐水洗涤重新合并的有机层并且用固体NaOH处理所得乳浊液,直到产生均匀双层为止。用EtOAc萃取水层并且用无水Na2SO4干燥合并的有机层。在真空中浓缩而得到9.57g(95%)化合物34,为非晶形白色固体(LC/MSm/z:689.3(M+Na)+),将其不经进一步纯化用于随后的操作。
化合物35
将粗的化合物34悬浮于CH2Cl2(65mL)中,随后添加吡啶(6.7mL,83mmol)和乙酐(3.5mL,36.5mmol)。使所得溶液在室温下放置过夜。加入MeOH(6mL)并且在10min后,将该反应体系倾入盐水。添加水产生双层,分离它们并且用CH2Cl2反复萃取水相。用无水MgSO4干燥合并的有机层并且在真空中浓缩而得到8.95g(88%)白色固体,将其即刻溶于MeOH(100mL)。加入Na2HPO4(11.4g,80.3mmol)并且将所得淤浆冷却至0℃,此后分部分添加Na-Hg(6%,14.5g,37.8mmol)。在室温下放置过夜后,加入H2O(30mL)并且通过硅藻土垫过滤该反应体系。在真空中除去MeOH并且用EtOAc萃取含水残余物。用盐水洗涤合并的有机层,用无水MgSO4干燥并且在真空浓缩而得到黄色油状物,将其在SiO2上通过色谱法(0-15%EtOAc/己烷)纯化而得到2.14g(34%)化合物35,为无色油状物(LC/MSm/z:531.2(M+Na)+)。
化合物36
用MeOH(7.5mL)稀释化合物35(1.73g,3.4mmol)并且加入10%Pd/C(0.36g,0.34mmol)。用H2气囊取代气体并且将该反应混合物在室温下放置。2h后,将该反应混合物通过硅藻土垫过滤,用MeOH将滤液洗涤几次并且在真空中浓缩合并的有机层而得到1.45g(83%)化合物36,为无色油状物(LC/MSm/z:533.2(M+Na)+),将其不经进一步纯化用于随后的操作。
化合物37
用THF(3mL)稀释化合物36(0.528g,1.03mmol)并且在-35℃下加入到液氨(约20mL)中.加入小片Na,直到蓝色持续为止。1.5h后,分部分加入固体NH4Cl,直到破坏剩余的Na为止并且使氨在环境温度下脱离。加入水和EtOAc(各20mL)用EtOAc萃取水层。用盐水洗涤合并的有机层,用Na2SO4干燥并且在真空中浓缩而得到0.395g(91%)化合物37,为非晶形白色固体,将其不经进一步纯化用于随后的操作(LC/MSm/z:421.1(M+H)+;443.2(M+Na)+)。
化合物38
用CH2Cl2(3.2mL)稀释化合物37(0.362g,0.861mmol)。加入三氟乙酸(0.8mL)并且将澄清溶液放置过夜。在真空中浓缩后,将残余物与甲苯一起共沸几次以便除去残留的TFA。收集0.382g(99%)化合物38的双-三氟乙酸盐,为无色油状物,将其不经进一步纯化使用(LC/MSm/z:221.1(M+H)+)。
方案15
化合物39和40
用MeCN(10mL)稀释化合物38(0.382g,0.852mmol)并且加入N,N-二异丙基乙胺(0.60mL,3.41mmol),随后加入化合物16在MeCN(1.5mL)中的溶液。将澄清的黄色溶液在室温下放置4h并且在真空中除去挥发性物质。将残余物溶于3/1 CHCl3/IPA(v/v,13mL)并且用饱和Na2CO3(3mL)处理。用H2O(3mL)稀释所得混悬液并且用3/1 CHCl3/IPA充分萃取水相。用3/2(w/w)无水Na2SO4/无水Na2CO3的混合物干燥合并的有机层并且在真空中浓缩。进行SiO2色谱(0-20%MeOH/CH2Cl2)而得到:0.043g(14%)化合物39,为无色薄膜状物(LC/MSm/z:362.1(M+H)+);和0.105g(34%)化合物40,为无色薄膜状物(LC/MSm/z:362.1(M+H)+)。
实施例M
给烧瓶添加作为0.2M在THF(0.8mL,0.160mmol)中的溶液的化合物39(0.048g,0.133mmol)和化合物29。加入THF(1mL),随后加入DIPEA(0.026mL,0.145mmol),HOBt(0.022g,0.160mmol)且最终加入EDC(0.028mL,0.160mmol)。将澄清的无色溶液放置过夜。在真空中除去挥发性物质并且对残余物进行SiO2色谱(0-20%MeOH/CH2Cl2)。在真空中浓缩含所需化合物的级分并且进行制备型LC/MS纯化而得到0.018g(20%)实施例M,为无色薄膜状物,LC/MSm/z:657.2(M+H)+;1H-NMR(CDCl3,300MHz)δ8.95(s,1H);7.88(brs,1H);7.27-7.04(m,5H);7.04(s,1H);6.60-6.20(m,2H);5.22(m,2H);5.12(d,J=9.3Hz,1H);4.50(m,2H);4.01(br s,1H);3.83(m,2H);3.38(m,1H);3.10-2.94(m,3H);2.74(m,2H);2.23(m,1H);1.64-1.15(m,8H);1.40(d,J=6.9Hz,6H);0.96(m,6H);0.83(t,J=6.9Hz,3H)。
实施例N
使用与制备实施例M类似的操作,使用如下试剂制备实施例N:化合物40(0.055g,0.152mmol);化合物29(0.92mL的0.2M THF溶液,0.183mmol);THF(1mL);DIPEA(0.040mL,0.228mmol);HOBt(0.025g,0.182mmol);EDC(0.032mL,0.182mmol)。分离0.087g(87%)实施例N,为无色薄膜状物(LC/MSm/z:657.2(M+H)+;1H-NMRCDCl3,300MHz)δ8.84(s,1H);7.86(s,1H);7.27-7.04(m,5H);7.04(s,1H);6.28(brs,1H);6.12(brs,1H);5.25(m,2H);5.11(d,J=9.0Hz,1H);4.62-4.32(m,2H);4.19(m,1H);4.01(brs,1H);3.53(m,1H);3.10-2.90(m,3H);2.72(d,J=6.0Hz,2H);2.29(m,1H);1.65-1.18(m,8H);1.39(d,J=6.9Hz,6H);1.00-0.78(m,9H)。
实施例O和P的制备
方案16
化合物41
按照J.Org.Chem.1996,61,444-450中所述的操作制备化合物41。
化合物42
将化合物41(1.73g,3mmol)和1,1’-硫代羰基二咪唑(1.14g,6.1mmol)在THF(60mL)中的混合物在65℃下加热72小时。在减压下除去溶剂。用EtOAc稀释该混合物并且依次用1N HCl,水和盐水洗涤且用MgSO4干燥。通过快速柱色谱法纯化(硅胶,己烷/EtOAc=1/1)而得到化合物42(980mg)。m/z:611.1(M+H)+。
化合物43
将化合物42(980mg)和亚磷酸三乙酯(10mL)的混合物在160℃下加热14小时。在减压下除去过量试剂。从己烷(11mL)和EtOAc(3.6mL)的混合物中重结晶而得到化合物57(580mg)。m/z:557.3(M+Na)+。
化合物44
在有存在10%Pd/C(200mg)下化合物43(580mg)在i-PrOH/EtOAc(12mL/12mL)中的混合物在高压(100psi)下氢化24小时。加入硅藻土并且将该混合物搅拌5分钟。过滤并且蒸发而得到化合物44(285mg)。m/z:269.1(M+H)+。
本领域技术人员公认方案16中概括的操作可以用于制备与化合物44类似的各种1,4-取代的1,4-二胺类。例如,可以制备与化合物41类似的胺-被保护的2,3-二羟基-1,4-二胺:
化合物41的类似物
其中L3,A,Ar和P如本文所定义并且保护基“P”为描述在Protective Groups in Organic Synthesis,Theodora W.Greene和Peter G.M.Wuts(John Wiley&Sons,Inc.,New York,1999,ISBN0-471-16019-9)中的任意胺保护基。然后可以按照方案16中概括的方法将化合物41的类似物转化成化合物42的类似物:
化合物42的类似物;
化合物43的类似物:
化合物43的类似物;和
化合物44的类似物:
化合物44的类似物。
还公认可以通过选择具有在手性中心上具有合适的立体化学构型的化合物41的类似物制备非所示的那些的立体化学构型(即对映体或非对映体)。
方案17
化合物46
向在0℃下化合物45(950mg,3.5mmol)在CH3CN(36mL)中的溶液中加入化合物16(892mg,3.2mmol),随后加入二异丙基乙胺(1.2mL,7mmol)。将该混合物在25℃下搅拌12小时。用EtOAc稀释该混合物并且依次用饱和Na2CO3,水和盐水洗涤。通过快速柱色谱法纯化(硅胶,100%EtOAc-CH2Cl2/MeOH=4/1)而得到化合物46(770mg)。m/z:410.1(M+H)+。
本领域技术人员公认方案17中概括的操作可以用于制备与化合物46类似的各种化合物。例如,可以如上所述制备与化合物44类似的1,4-二胺类:
化合物44的类似物。
可以使化合物44的类似物与化合物16的类似物反应:
化合物16的类似物,
(其中Z2,X和R9如本文所定义)而形成化合物46的类似物:
还公认可以通过选择具有在手性中心上具有合适的立体化学构型的化合物44的类似物制备非所示的那些的立体化学构型(即对映体或非对映体)。
方案18
化合物47
化合物47商购自TCI。
化合物48
向化合物9(500mg,3mmol)在CH2Cl2(3mL)中的溶液中加入化合物47(500mg,2.5mmol)。将该混合物搅拌14小时。通过快速柱色谱法纯化(己烷/EtOAc=1/1.5)而得到化合物48(242mg)。m/z:372.1(M+H)+。
化合物49
向化合物48(240mg,0.65mmol)在二噁烷(4mL)和水(4mL)中的溶液中加入氢氧化钠(40mg,1mmol)。将该混合物搅拌1小时并且用在二噁烷中的4NHCl(0.25mL,1mmol)酸化。用EtOAc萃取该混合物并且用MgSO4干燥有机相。浓缩而得到化合物49(200mg)。m/z:356.2(M-H)+。
实施例O
向相应的酸49(30mg,0.08mmol)和化合物46(22mg,0.05mmol)在THF(1mL)中的溶液中加入HOBt(15mg,0.11mmol),EDC(20μL,0.11mmol)和二异丙基乙胺(0.2mL)。将该混合物搅拌12小时并且浓缩。通过快速柱色谱法纯化(己烷/EtOAc=1/5-0/100)而得到实施例O(17mg)。m/z:749.3(M+H)+。
实施例P
向实施例O(17mg)中加入TFA(2mL)。将该混合物搅拌3小时并且浓缩。用THF(2mL)稀释该混合物并且加入1.0NNaOH溶液,直到pH11。将该混合物搅拌10分钟并且用EtOAc萃取。用水和盐水洗涤有机相。通过快速柱色谱法纯化(EtOAc)而得到实施例P(12mg)。1H-NMR(CDCl3)δ8.76(1H,s),7.79(1H,s),7.25-6.9(11H,m),6.51(1H,宽峰),5.42(1H,m),5.18(2H,m),4.42(2H,m),4.22(1H,m),4.10(1H,m),3.95(1H,m),3.79(1H,m),3.58(1H,m),3.23(1H,m),2.93(3H,s),2.9-2.5(4H,m),1.6-1.2(10H,m);m/z:693.2(M+H)+。
实施例Q,R和S的制备
方案19
化合物50
化合物50商购自Chem Impex International并且不经进一步纯化使用。
化合物51
将化合物50(7.0g,26.0mmol)溶于CH2Cl2(330mL)并且加入1,1-羰基二咪唑(4.22g,26.0mmol),随后加入i-Pr2NEt(19mL,104mmol)。将该溶液在25℃下搅拌12小时。将化合物9(4.44g,26.0mmol)溶于20mL CH2Cl2并且加入到该反应混合物中。将该溶液在25℃下搅拌7小时。在真空中除去溶剂并且用乙酸乙酯稀释残余物且用水和盐水洗涤。干燥有机层(Na2SO4),过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:66-100%EtOAc/己烷梯度)而得到化合物51(7.34g)。m/z:429.0(M+H)+。
化合物52
将化合物51(7.34g,17.13mmol)溶于THF(90mL)并且加入1MLiOH水溶液(35mL)。将该混合物在25℃下搅拌0.5小时。用1MHCl(51mL)使反应淬灭并且将该混合物调整至pH2。用乙酸乙酯萃取该混合物。用Na2SO4干燥有机层,过滤并且蒸发至得到化合物52(7.00g)。将回收的化合物52不经进一步纯化用于下一步。m/z:415.0(M+H)+。
本领域技术人员公认方案19中概括的操作可以用于制备与化合物51和52类似的各种化合物。例如,可以使与化合物9类似的胺类与和化合物50类似的合适的氨基酯反应:
从而形成与化合物51类似的化合物,使其进一步反应而形成与化合物52类似的化合物:
其中R1,R2,R7,R8和Y如本文所定义。
还公认可以通过选择在手性中心上具有合适的立体化学构型的化合物50的类似物制备非所示的那些的立体化学构型(即对映体或非对映体)。
实施例Q
将化合物52(2.57g,6.21mmol)溶于THF(67mL)。加入化合物8(2.10g,5.13mmol),随后加入HOBt(1.04g,7.70mmol),i-Pr2NEt(3.67mL,20.52mmol)和EDC(1.82mL,10.26mmol)。将该混合物在25℃下搅拌12小时。在减压下除去溶剂。用乙酸乙酯稀释残余物并且依次用饱和水溶液Na2CO3,水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:5%iPrOH/CH2Cl2)而得到实施例Q(3.02g)。m/z:806.2(M+H)+。
实施例R
将实施例Q(3.02g,3.74mmol)悬浮于4.0NHCl/二噁烷溶液(30mL)中并且在25℃下搅拌3小时。在减压下除去溶剂并且将Et2O倾入该反应混合物。将所得混悬液剧烈搅拌1.5小时。使固体沉降并且倾析醚层。用Et2O反复洗涤沉淀两次以上。在真空中干燥产物而得到白色固体(3.18g,定量产量)。在搅拌下向上述固体(3.18g)中加入饱和Na2CO3水溶液,直到固体消失。用乙酸乙酯萃取该水溶液。用Na2SO4干燥有机相,过滤并且蒸发而得到实施例R,为黄色泡沫(2.44g,81%)。将回收的实施例R不经进一步纯化用于下一步。m/z:706.1(M+H)+。
实施例S
方法I:
将实施例R(1.00g,1.42mmol)溶于DMF(20mL)并且滴加溴乙醚(196μL,1.56mmol),随后滴加NaHCO3(0.239g,2.84mmol)。将该反应混合物在25℃下搅拌2小时。将该溶液加热至65℃并且搅拌12小时。在减压下除去溶剂。用EtOAc稀释残余物并且依次用水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过反相HPLC纯化(Phenomenex SynergiComb-HTS柱,洗脱剂:5-95%CH3CN/水)而得到化合物70(580mg,53%)。1HNMR(CDCl3)δ8.98(s,1H);7.90(s,1H);7.75(m,1H);7.40-7.00(m,11H),6.55(brs,1H);5.58(m,1H);5.28,5.19(dAB,J=14Hz,2H);4.70-4.37(m,3H);3.99(m,5H);3.76(brs,1H);3.65-3.30(m,3H);2.97(m,5H);2.90-2.60(m,6H);2.28(brs,1H);1.91(brs,1H);1.60-1.30(m,10H)。m/z:776.2(M+H)+
方法II:
方案20
化合物54
按照J.Med.Chem.1993,36,1384中所述的操作制备化合物54(为了所有目的而将该文献完整地引入本文作为参考)。
向在0℃下化合物53(0.550g,5.28mmol)(Sigma-Aldrich)在H2O(8.8mL)中的溶液中加入NaIO4(1.016g,4.75mmol)。将该混合物缓慢温至25℃并且搅拌12小时。向该反应混合物中加入固体NaHCO3,直到pH7。加入CHCl3(16mL)并且将该混合物搅拌5分钟。过滤该混合物并且用CHCl3(6mL)洗涤固体。将合并的H2O/CHCl3溶液不经进一步纯化直接用于下一步。
方案21
实施例S
向实施例R(70mg,0.1mmol)在CH3CN(5mL)中的溶液中加入在水(5mL)中的氰基硼氢化钠(50mg)。向上述混合物中加入二醛化合物54(0.6mmol)在CHCl3/H2O)(4mL/1mL)中的溶液。将该混合物搅拌12小时并且用饱和Na2CO3溶液碱化。用EtOAc萃取该混合物并且用水和盐水洗涤有机相且用Na2SO4干燥。通过反相HPLC纯化(PhenomenexSynergiComb-HTS柱)而得到实施例S(57mg)。
方法III
方案22
化合物54
胺化合物8
化合物55
将化合物51(0.28g,0.66mmol)溶于CH2Cl2(4mL)并且滴加TFA(1mL)。将该反应体系在25℃下搅拌1小时。在减压下除去溶剂而得到化合物55(0.39g)。m/z:329.0(M+H)+。
化合物56
向化合物55(0.39g,0.89mmol)在CH3CN(45mL)中的溶液中加入NaBH3CN(0.45g,7.12mmol)和H2O(45mL)。加入化合物54(0.55g,5.34mmol)在CHCl3/H2O(40mL)中的溶液。将该混合物在25℃下搅拌12小时。用饱和Na2CO3水溶液碱化该反应混合物并且依次用乙酸乙酯和二氯甲烷萃取。依次用H2O和盐水洗涤合并的有机层,用Na2SO4干燥,过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:0-10%MeOH/CH2Cl2梯度)而得到化合物56(0.17g)。m/z:399.1(M+H)+。
化合物57
将化合物56(377mg,0.95mmol)溶于THF(4mL)并且加入1MLiOH水溶液(1.90mL)。将该混合物在25℃下搅拌1小时。用1MHCl中和该反应体系。在减压下除去THF并且冻干该水溶液而得到化合物57(365mg)。将该物质不经进一步纯化直接用于下一步。m/z:385.1(M+H)+。
实施例S
按照与例如Q相同的操作制备实施例S(185mg,57%),但使用化合物57(160mg,0.42mmol)而不是化合物52。质量m/z:776.2(M+H)+。
本领域技术人员公认方案22中概括的操作可以用于制备与化合物55-57类似的各种化合物:
其中R7,R8和Y如本文所定义。
还公认可以通过选择具有在手性中心上具有合适的立体化学构型的化合物51的类似物制备非所示的那些的立体化学构型(即对映体或非对映体)。
方法IV
方案23
化合物59
向在0℃下化合物122(33g,112mmol)(参见方案69)在乙醇(366mL)中的溶液中加入氢氧化钠(4.7g,117mmol)在水(62mL)中的溶液。将该化合物在25℃下搅拌1小时并且在减压下除去溶剂。将该混合物与乙醇(3x400mL)共蒸发并且在60℃下和高度真空中干燥2小时而得到白色固体。向上述在DMF中的溶液(180mL)中加入苄基溴(16.2mL,136mmol)。将该混合物在黑暗中搅拌16小时并且用水(300mL)淬灭。用EtOAc(4x300mL)萃取该混合物。用水(5x)和盐水洗涤合并的有机相并且用Na2SO4干燥。浓缩而得到化合物59(48g),将其不经进一步纯化用于下一步。
化合物60
将化合物59(33g,74mmol)在DMSO(225mL)和Et3N(36mL)中的混合物搅拌30分钟。将该混合物冷却至0-10℃,加入SO3-吡啶(45g)并且持续搅拌60分钟。加入冰(300g)并且将该混合物搅拌30分钟。加入EtOAc(300mL)并且加入饱和Na2CO3,直到pH为9~10。从水相中分离有机相并且用EtOAc(2x300ml)萃取水相。用饱和Na2CO3(2x),水(3x)和盐水洗涤合并的有机相。用Na2SO4干燥该混合物并且浓缩而得到化合物60(32g),将其不经进一步纯化直接用于下一步。
化合物61
向化合物60(32g)在CH3CN(325mL)中的溶液中加入吗啉(12.9mL,148mmol),其中在反应容器周围使用水浴,随后加入HOAc(8.9mL,148mmol)和NaBH(OAc)3(47g,222mmol)。将该混合物搅拌12小时。在减压下除去CH3CN并且用EtOAc(300mL)稀释该混合物。加入饱和Na2CO3,直到pH为9~10。从水相中分离有机相并且用EtOAc(2x300mL)萃取水相。用饱和Na2CO3(2x),水(1x)和盐水(1x)洗涤合并的有机相。用Na2SO4干燥该混合物。浓缩所得残余物并且通过硅胶柱色谱法纯化(EtOAc-DCM/iPrOH=10/1)而得到化合物61(30g)。
化合物57
向在0℃下化合物61(26.5g,56mmol)在乙醇(160mL)中的溶液中加入氢氧化钠(2.5g,62mmol)在水(30mL)中的溶液。将该混合物在25℃下搅拌1小时并且在减压下除去溶剂。用水(200mL)稀释该混合物并且用CH2Cl2(6x100mL洗涤。用12N HCl(5.2mL)酸化水相并且在减压下干燥而得到化合物57(22g)。
实施例S
使用上述方法III中所述的操作将化合物57转化成实施例S。
化合物T和U的制备
方案24
实施例T
方法I
将实施例R的盐酸盐(100mg,0.13mmol)悬浮于CH2Cl2(2mL)中并且通过添加iPr2NEt(69μL)溶解。滴加乙酰氯(11μL)并且将该混合物在25℃下搅拌4小时。在真空中除去溶剂。通过快速柱色谱法纯化残余物(固定相:硅胶;洗脱剂:8%iPrOH/CH2Cl2)而得到实施例T(39mg,40%)。m/z:748.2(M+H)+。1HNMR(CDCl3)δ8.85(s,1H);7.87(s,1H);7.73(s,1H);7.40-7.00(m,13H);6.45(brs,1H);5.70(m,1H);5.32,5.22(dAB,J=13Hz,2H);4.51(s,2H);4.20-3.90(m,4H);3.78(m,1H);3.38(m,2H);3.20-2.50(m,8H);1.95(s,4H);1.82(m,2H);1.41(m,6H)。
方法II
将饱和Na2CO3水溶液加入到实施例R的盐酸盐(3.18g,3.46mmol)中,同时搅拌至固体消失。用乙酸乙酯萃取该水溶液。用Na2SO4干燥有机相,过滤并且蒸发至得到实施例R,为黄色泡沫(2.44g,81%)。将该物质不经进一步纯化用于下一步。m/z:706.1(M+H)+。
将实施例R(300mg,0.43mmol)溶于THF(5.5mL)。加入乙酸(37μL,0.64mmol),随后加入HOBt(85mg,0.64mmol),iPr2NEt(304μL,1.70mmol)和EDC(151μL,0.85mmol)。将该反应混合物在25℃下搅拌12小时。在减压下除去溶剂。用EtOAc稀释残余物并且依次用饱和水溶液Na2CO3,水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:10%MeOH/CH2Cl2)而得到实施例T(249mg,77%)。m/z:748.2(M+H)+。
实施例U
将实施例R(100mg,0.13mmol)悬浮于CH2Cl2(2mL)中并且通过添加iPr2NEt(69μL)溶解。滴加甲磺酰氯(12μL)并且将该混合物在25℃下搅拌4小时。在真空中除去溶剂。通过快速柱色谱法纯化残余物(固定相:硅胶;洗脱剂:8%iPrOH/CH2Cl2)而得到实施例U(55mg,54%)。m/z:784.2(M+H)+。1HNMR(CDCl3)δ8.90(s,1H);7.88(s,1H);7.40-7.00(m,12H);6.54(brs,1H);6.19(brs,1H);5.25(s,2H);4.53(s,2H);4.38(m,1H);4.12(m,1H);3.79(m,1H);3.79(m,1H);3.48(m,1H);2.99(s,3H);2.90(m,3H);2.73(m,6H);2.00(m,1H);1.79(m,1H);1.60-1.18(m,10H)。
实施例V,W,X和Y的制备
方案25
实施例V
按照与制备实施例Q相同的操作制备实施例V(692mg),但使用化合物46而不是化合物8。m/z:806.2(M+H)+。
实施例W
按照例如R相同的操作制备实施例W(770mg,定量产量),但使用实施例V而不是实施例Q.m/z:706.2(M+H)+。1HNMR(CD3OD)δ9.86(s,1H);8.23(s,1H);7.66(s,1H);7.40-7.00(m,10H);5.29,5.17(dAB,J=13Hz,2H);4.80-4.60(m,2H);4.18(s,2H);4.26(m,2H);3.67(brs,1H);3.55(m,2H);3.03(m,3H);2.90-2.60(m,8H);2.53(s,2H);2.00-1.80(m,2H);1.85-1.30(m,10H)。
化合物59
方法I
按照方法I的操作,例如T制备实施例X(107mg,55%),但使用实施例W而不是实施例R。m/z:748.2(M+H)+.1HNMR(CDCl3)δ8.80(s,1H);7.85(s,1H);7.40(m,1H);7.38-7.00(m,10H),6.94(s,1H);6.30(m,2H);5.75(m,1H);5.30,5.23(dAB,J=13Hz,2H);4.54,4.46(dAB,J=8Hz,2H);4.20-3.90(m,2H);3.74(brs,1H);3.46(brs,1H);3.28(m,1H);2.98(s,3H);2.83(m,3H);2.72(m,1H);2.62(m,1H);2.05-1.20(m,15H)。
方法II
按照方法II的操作,例如T制备实施例X(205mg,65%),但使用实施例W而不是实施例R。m/z:748.2(M+H)+,
实施例Y
按照相同的操作,例如U制备实施例Y(106mg,50%),但使用实施例W而不是实施例R。m/z:784.2(M+H)+。1HNMR(CDCl3)δ8.81(s,1H);7.85(s,1H);7.40-7.05(m,10H),6.98(s,1H);6.22(brs,1H);5.78(s,1H);5.25(m,4H);4.29(m,2H);4.33(brs,1H);4.12(brs,1H);3.77(brs,1H);3.10(brs,1H);2.98(s,3H);2.90(s,3H);2.73(m,6H);2.00-1.20(m,12H)。
实施例Z-A的制备D
方案26
化合物62
2-氨基乙基氨基甲酸叔-丁酯(62)商购自Aldrich并且不经进一步纯化使用。
化合物63
向化合物62(2.0mmol)在CH3CN(15mL)中的溶液中加入化合物16(1.82mmol),随后添加N,N-二异丙基乙胺(0.61mL)。将该混合物在25℃下搅拌12小时。在真空中除去溶剂并且用乙酸乙酯稀释残余物且依次用饱和Na2CO3水溶液,水和盐水洗涤。用Na2SO4干燥有机层,过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:25-100%EtOAc/己烷梯度)而得到化合物63。m/z:301.9(M+H)+。
化合物64
向化合物63(1.05mmol)在EtOAc(3mL)中的溶液中加入4N HCl/二噁烷溶液(1.1mL)。将该混合物在25℃下搅拌12小时。在减压下除去溶剂并且获得化合物64,为白色粉末。将该物质不经进一步纯化用于下一步。m/z:216.0(M+H)+。
实施例Z
将化合物64(70mg,0.29mmol)溶于THF(2.2mL)。向反应烧瓶中加入作为1.0M在THF中的溶液的化合物29(91mg,0.29mmol),随后加入HOBt(59mg,0.44mmol),N,N-二异丙基乙胺(207μL,1.16mmol)和EDC(103μL,0.58mmol)。将该反应体系在25℃下搅拌12小时并且在减压下浓缩。用EtOAc稀释残余物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。用Na2SO4干燥有机层,过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:0-10%MeOH/CH2Cl2梯度)而得到实施例Z(54mg,38%)。m/z:497.1(M+H)+.1HNMR(CDCl3)δ8.78(s,1H);7.83(s,1H);6.99(s,1H);6.80(brs,1H);6.22(brs,1H);5.87(brs,1H);5.25(s,2H);4.43(s,2H);3.97(m,1H);3.34(m,4H);2.95(s,3H);2.22(m,2H);1.38(d,J=7Hz,6H);0.97(d,J=7Hz,6H)。
实施例AA
按照步骤I-III的操作(方案20),例如Z制备实施例AA,但使用3-氨基丙基氨基甲酸叔丁酯而不是2-氨基乙基氨基甲酸叔丁酯(化合物62)。在Combiflash纯化后,获得38mg(34%)实施例AA。m/z:511.1(M+H)+.1HNMR(CDCl3)δ8.78(s,1H);7.84(s,1H);6.96(s,2H);6.17(brs,1H);5.80(m,1H);5.26(m,2H);4.44(s,2H);4.09(m,1H);3.40-3.10(m,5H);2.97(s,3H);2.20(m,1H);1.60(m,2H);1.36(d,J=7Hz,6H);0.96(d,J=7Hz,6H)。
实施例AB
按照步骤I-III的操作(方案20),例如Z制备实施例AB,但使用1-哌嗪甲酸叔丁酯而不是2-氨基乙基氨基甲酸叔丁酯(化合物62)。在Combiflash纯化后,获得64mg(45%)实施例AB。m/z:523.1(M+H)+.1HNMR(CDCl3)δ8.82(s,1H);7.89(s,1H);6.96(s,1H);5.93(brs,1H);5.35(s,2H);4.62(m,1H);4.50(m,2H);3.80-3.40(m,8H);3.34(m,1H);3.00(s,3H);1.97(m,1H);1.40(d,J=7Hz,6H);0.96,0.93(d,J=7Hz,6H)。
实施例AC
按照步骤I-III的操作(方案20),例如Z制备实施例AC,但使用4-氨基-1-哌嗪甲酸叔丁酯而不是2-氨基乙基氨基甲酸叔丁酯(化合物62)。在Combiflash纯化后,获得60mg(44%)实施例AC。m/z:537.1(M+H)+.1HNMR(CDCl3)δ8.82(s,1H);7.87(s,1H);6.97(s,1H);5.82(brs,1H);5.30(m,3H);4.80-4.40(m,5H);4.03(m,1H);3.72(brs,1H);3.34(m,1H);3.18(m,1H);3.01(s,3H);2.79(m,1H);2.20-1.90(m,4H);1.40(d,J=7Hz,6H);0.97,0.90(d,J=7Hz,6H)。
实施例AD
按照步骤I-III的操作,例如Z制备实施例AD,但使用4-哌啶基氨基甲酸叔丁酯而不是2-氨基乙基氨基甲酸叔丁酯(化合物62)。在Combiflash纯化后,获得49mg(36%)实施例AD。m/z:537.1(M+H)+。1HNMR(CDCl3)δ8.82(s,1H);7.87(s,1H);7.01(s,1H);6.33(brs,1H);6.11(brs,1H);5.32(s,2H);4.47(s,2H);4.20-3.80(m,4H);3.35(m,1H);3.10-2.80(m,6H);2.21(m,2H);1.90(m,2H);1.40(d,J=7Hz,6H);0.97(d,J=7Hz,6H)。
实施例AE-AG的制备
方案27
化合物65
化合物65商购自Chem Impex International并且不经进一步纯化使用。
化合物66
将化合物65(956mg,4.0mmol)溶于CH2Cl2(45mL)并且加入1,1-羰基二咪唑(648mg,4.0mmol),随后加入i-Pr2NEt(2.8mL,16mmol)。将该溶液在25℃下搅拌12小时。将化合物9(679mg,4.0mmol)溶于CH2Cl2(5mL)并且加入到该反应体系中。将该混合物搅拌5小时。然后在减压下除去溶剂。用乙酸乙酯稀释残余物并且通过硅藻土过滤。然后在真空中除去乙酸乙酯。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:EtOAc)而得到化合物66(841mg)。m/z:400.0(M+H)+。
化合物67
将化合物66(841mg,2.11mmol)溶于THF(9mL)并且加入2N NaOH水溶液。将该溶液在25℃下搅拌2小时。用1N HCl将该反应体系调整至pH2。用乙酸乙酯萃取该混合物,用Na2SO4干燥,过滤并且蒸发。将化合物67(772mg)不经进一步纯化直接用于下一步。m/z:386.0(M+H)+。
实施例AE
将化合物67(569mg,1.48mmo l)溶于THF(17mL)。加入化合物8(970mg,2.37mmol),随后加入HOBt(300mg,2.22mmol),i-Pr2NEt(1.06mL,5.92mmol)和EDC(0.52mL,2.96mmol)。将该混合物在25℃下搅拌36小时。在减压下除去溶剂。用乙酸乙酯稀释所得残余物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:8%iPrOH/CH2Cl2)而得到实施例AE(3.02g)。m/z:777.2(M+H)+。
实施例AF
将实施例AE(100mg,0.13mmol)溶于净TFA(3mL)。将该混合物在25℃下搅拌2小时。在减压下除去溶剂。通过反相HPLC纯化(Phenomenex SynergiComb-HTS柱,洗脱剂:5-95%CH3CN/H2O梯度)而得到实施例AF(20mg,21%)。m/z:721.2(M+H)+。1HNMR(CDCl3)δ8.92(s,1H);7.91(s,1H);7.40-7.00(m,11H);6.41(brs,1H);6.12(brs,1H);5.40-5.00(m,3H);4.70-4.50(m,3H);4.05(brs,1H);3.81(brs,1H);3.51(brs,1H);2.97(s,3H);2.90-2.60(m,6H);1.41(d,J=7Hz,10H)。
实施例AG
将实施例AF(70mg,0.10mmol)溶于二噁烷(0.5mL)。加入DMF(83μL),吡啶(25μL,0.29mmol),二碳酸二叔丁酯(27mg,0.13mmol)和碳酸氢铵(15mg,0.19mmol)。将该混合物在25℃下搅拌48小时,然后用乙酸乙酯稀释并且依次用水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过反相HPLC纯化(PhenomenexSynergiComb-HTS柱,洗脱剂:5-95%CH3CN/H2O梯度)而得到实施例AG(35mg,50%)。1HNMR(CDCl3)δ8.80(s,1H);7.84(s,1H);7.40-7.00(m,10H);7.08(s,1H);6.83(m,1H);6.65(m,1H);5.40-5.10(m,4H);4.60-4.40(m,3H);4.06(m,1H);3.79(m,1H);3.36(m,1H);2.97(s,3H);2.90-2.60(m,6H);2.45(m,1H);1.70-1.20(m,10H)。
化合物68和69的制备
方案28
化合物15
化合物15商购自Molekula并且不经进一步纯化使用。
化合物68
将化合物15(6.81g,59.1mmol)溶于CH3CN(340mL)并且加入甲磺酰氯(7.03mL,65.1mmol),随后加入三乙胺(9.03mL,65.1mmol)。在将该混合物搅拌20mi n后,将40%wt.甲胺/水(516mL)加入到该反应混合物中。将该溶液在25℃下搅拌12小时。在减压下除去溶剂并且使残余物分配在饱和Na2CO3水溶液与CH2Cl2之间。分离有机相,用Na2SO4干燥,过滤并且蒸发。通过快速色谱法纯化(固定相:硅胶;洗脱剂:0-10%MeOH/CH2Cl2梯度)而得到化合物68(5.07g)。m/z:128.9(M+H)+。
化合物69
将化合物15(10.0g,80mmol)溶于CH3CN(500mL)并且加入甲磺酰氯(7.0mL,88mmol),随后加入三乙胺(12.3mL,88mmol)。在将该混合物搅拌2h后,将在CH3CN(500mL)中的环丙基胺(140mL,2000mmol)加入到该反应混合物中。将该溶液在25℃下搅拌36小时。在减压下除去溶剂并且使淤浆分配在饱和Na2CO3水溶液与3∶1(CH2Cl2:1-PrOH)之间。分离有机相,用Na2SO4干燥,过滤并且蒸发。将化合物69(12.81g)不经进一步纯化用于下一步。m/z:155.0(M+H)+。
实施例AH和AI的制备
方案29
化合物70
将化合物68(1.00g,7.80mmol)溶于THF(25mL)并且加入化合物10e(2.51g,7.09mmol),随后加入N,N-二甲氨基吡啶(200mg,1.63mmol)和三乙胺(4.34mL,31.2mmol)。将该化合物在60℃下搅拌6小时。在减压下除去溶剂。用乙酸乙酯稀释残余物并且依次用饱和Na2CO3水溶液,H2O和盐水洗涤。用Na2SO4干燥有机层,过滤并且蒸发。通过Combiflash纯化所得残余物(固定相:硅胶;洗脱剂:20-100%EtOAc/己烷梯度)而得到化合物70(2.14g)。m/z:343.9(M+H)+。
化合物71
将化合物70(2.14g,6.23mmol)溶于THF(25mL)并且加入1MLiOH水溶液(12.5mL)。将该混合物在25℃下搅拌2小时。用1MHCl(15mL)使反应淬灭并且将该混合物调整至pH2。用乙酸乙酯萃取该混合物。用Na2SO4干燥有机层,过滤并且蒸发而得到化合物71(1.96g)。将该物质不经进一步纯化用于下一步。m/z:330.0(M+H)+。
实施例AH
将化合物71(43mg,0.13mmol)溶于THF(1.5mL)。加入化合物8(50mg,0.12mmol),随后加入HOBt(24mg,0.18mmol),iPr2NEt(86μL,0.48mmol)和EDC(42μL,0.24mmol)。将该混合物在25℃下搅拌12小时。在减压下除去溶剂并且用乙酸乙酯稀释所得残余物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:1-10%MeOH/CH2Cl2梯度)而得到实施例AH(66mg)。m/z:721.2(M+H)+。
化合物AI
将实施例AH(66mg,0.09mmol)溶于TFA并且在25℃下搅拌3小时。在减压下除去溶剂并且用THF(3mL)稀释残余物且加入2N NaOH水溶液至pH12。将该混合物搅拌20min并且用EtOAc萃取。依次用水和盐水洗涤有机层,用Na2SO4干燥,过滤并且蒸发。通过快速色谱法纯化(固定相:硅胶;洗脱剂:0-20%i-PrOH/CH2Cl2梯度)而得到实施例AI(71mg,97%)。m/z:665.2(M+H)+。1HNMR(CDCl3)δ8.84(s,1H);8.80(s,1H);7.85(s,1H);7.79(s,1H);7.40-7.00(m,10H);6.69(m,1H);5.34(m,1H);5.24(s,2H);4.86(m,2H);4.73,4.59(dAB,J=16Hz,2H);4.30(s,1H);4.15(m,2H);3.86(brs,1H);2.88(s,3H);2.85-2.60(m,4H);2.01(s,1H);1.58(s,2H);1.44(s,2H);1.09(d,J=6Hz,3H)。
实施例AJ和AK的制备
方案30
化合物47
化合物47商购自TCI America并且不经进一步纯化使用。
化合物72
按照化合物48的操作(方法II)制备化合物72,但使用化合物68而不是化合物9。
化合物73
按照化合物49的操作制备化合物73,但使用化合物72而不是化合物48。
实施例AJ
按照用于制备实施例AH相同的操作制备实施例AJ(70mg),但使用化合物73(41mg,0.13mmol)而不是化合物71。m/z:707.2(M+H)+。
实施例AK
按照用于制备实施例AI相同的操作制备实施例AK(43mg,67%),但使用实施例AJ(70g,0.10mmol)而不是实施例AH。m/z:651.2(M+H)+。1HNMR(CDCl3)δ8.83(s,2H);7.84(s,1H);7.79(s,1H);7.40-7.00(m,10H);6.65(brs,1H);5.47(brs,1H);5.24(s,2H);4.90(m,1H);4.82-4.50(m,2H);4.30-4.00(m,3H);3.84(brs,1H);3.49(m,1H);2.87(s,3H);2.75(brs,5H);1.60-1.20(m,4H)。
实施例AL和AM的制备
方案31
化合物74
将化合物69(1.56g,10.1mmol)溶于CH2Cl2(10mL)。加入在CH2Cl2(20mL)中的化合物47(1.7g,8.5mmol),随后加入iPr2NEt(3.02mL,16.9mmol)。将该反应体系在25℃下搅拌12小时。在减压下除去溶剂。用乙酸乙酯稀释残余物并且依次用水和盐水洗涤,用Na2SO4干燥,过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:50-100%EtOAc/己烷梯度)而得到化合物74(2.92g)。m/z:356.0(M+H)+。
化合物75
将化合物74(0.97mmol)溶于THF(3mL)并且用新近制备的1MLiOH(2mmol)处理且剧烈搅拌1h。用1M HCl(2.5mmol)使反应淬灭并且用EtOAc(3×15mL)萃取。用盐水(25mL)洗涤合并的有机相,用无水Na2SO4干燥并且在真空中浓缩而得到0.331g(定量)的化合物75,为无色薄膜状物(m/z342.0(M+H)+)。
实施例AL
按照用于制备实施例AH相同的操作制备实施例AL(2.20g),但使用化合物75(2.00g,4.88mmol)而不是化合物71。m/z:733.2(M+H)+。
实施例AM
按照用于制备实施例AI相同的操作制备实施例AM(1.88g,92%),但使用实施例AL(2.20g,3.01mmol)而不是实施例AH。m/z:677.2(M+H)+.1HNMR(CDCl3)δ8.79(s,1H);8.72(s,1H);7.82(s,1H);7.77(s,1H);7.40-7.00(m,10H);6.59(m,1H);6.31(m,1H);5.23(s,2H);5.00(m,1H);4.72,4.60(dAB,J=15Hz,2H);4.18(s,2H);4.03(m,1H);3.84(brs,1H);3.48(m,1H);2.85-2.60(m,4H);2.37(brs,2H);1.58(s,2H);1.41(s,2H);0.93(m,2H);0.76(m,2H)。
方案32
化合物76
使用与用于制备化合物25(方案7中所述)类似的操作制备化合物76(m/z 117.0(M+H)+的二胺),但使用CBZ-L-丙氨醇(CBZ-L-alininol)而不是CBZ-D-苯丙氨醇(CBZ-D-phenylalininol)且使用添加的1MHCl进行步骤III。
化合物77
使用与用于制备化合物76类似的操作制备化合物77(m/z145.0(M+H)+的二胺),但使用(S)-(+)-2-CBZ-氨基-1-丁醇而不是CBZ-D-苯丙氨醇。
化合物78
将化合物76(7.93mmol)加入到冷却至0℃的NaOH(16.7mmol)在H2O(5mL)中的溶液中并且用MeCN(40mL)稀释。加入DIPEA(2.1mL,11.9mmol)。将化合物16(7.9mmol)溶于MeCN(40mL)并且通过加液漏斗在1h内滴加到反应溶液中。将所得溶液温至室温下过夜。在真空中除去溶剂并且将残余物溶于3/1(HCl3/IPA(50mL))。用饱和Na2CO3(50mL)洗涤所得溶液并且加入水,直到水层均匀。用3/1(CHCl3/IPA(3X25mL))萃取水层。用饱和Na2CO3(50mL),水(50mL)和盐水(50mL)洗涤合并的有机层并且用无水Na2SO4干燥。在真空中除去溶剂并且通过SiO2柱色谱法纯化残余物(100%EtOAc,然后0-20%MeOH/DCM)而得到0.63g(31%)78,为黄白色固体。(m/z258.0(M+H)+)。
化合物79
按照化合物78的操作制备化合物79(m/z286.1(M+H)+),但使用化合物77而不是化合物76。
方案33
实施例AN
按照用于制备实施例AH相同的操作制备实施例AN(68mg),但使用化合物49(68mg,0.19mmol)而不是化合物71且使用化合物79(50mg,0.18mmol)而不是化合物8。m/z:625.2(M+H)+。
实施例AO
按照用于制备实施例AI相同的操作制备实施例AO(66mg,76%),但使用实施例AN(43mg,0.13mmol)而不是实施例AH。m/z:569.2(M+H)+。1HNMR(CDCl3)δ8.85(s,1H);7.89(s,1H);7.08(s,1H);6.81(m,1H);5.29(s,2H);4.87(m,1H);4.63,4.48(dAB,J=16Hz,2H);4.31(m,1H);4.11(m,1H);3.76(m,2H);3.44(m,2H);3.02(m,4H);1.60-1.20(m,14H);1.00-0.70(m,6H)。
实施例AP和AQ的制备
方案34
化合物13d
按照用于制备化合物71相同的操作制备化合物13e(1.39g),但使用化合物12e(1.53g,3.97mmol)而不是化合物70m/z:372.0(M+H)+。
实施例AP
按照用于制备实施例AH相同的操作制备实施例AP(87mg),但使用化合物13e(71mg,0.19mmol)而不是化合物71且使用化合物79(50mg,0.18mmol)而不是化合物8。m/z:639.2(M+H)+。
化合物AQ
按照用于制备实施例AI相同的操作制备实施例AQ(61mg,76%),但使用实施例AP(87mg,0.14mmol)而不是实施例AH。m/z:583.2(M+H)+.1HNMR(CDCl3)δ8.81(s,1H);7.87(s,1H);7.01(s,1H);6.87(m,1H);6.52(s,1H);5.28(m,2H);4.47(m,1H);4.59,4.43(dAB,J=16Hz,2H);4.45(m,1H);4.17(brs,1H);3.75(brs,1H);3.52(brs,1H);3.35(brs,1H);3.01(m,3H);2.07(brs,1H);1.60-1.10(m,17H);1.00-0.70(m,6H)。
实施例AR的制备
方案35
化合物80
化合物80商购自Chem Impex International并且不经进一步纯化使用。
化合物81
将化合物80(2.0g,11.0mmol)溶于CH2Cl2(170mL)并且加入1,1-羰基二咪唑(1.78g,11.0mmol),随后加入iPr2NEt(7.83mL,43.8mmol)。将该溶液在25℃下搅拌12小时。将化合物9(1.86g,11.0mmol)溶于20mLCH2Cl2并且加入到该反应混合物中。将该溶液在25℃下搅拌12小时。在真空中除去溶剂并且用乙酸乙酯稀释残余物且用水和盐水洗涤。用Na2SO4干燥有机层,过滤并且蒸发。通过Combiflash纯化(固定相:硅胶;洗脱剂:66-100%EtOAc/己烷梯度)而得到化合物81(0.252mg)。m/z:343.0(M+H)+。
化合物82
将化合物82(0.252g,0.74mmol)溶于THF(4mL)并且加入1M LiOH水溶液(1.48mL)。将该混合物在25℃下搅拌3小时。用1M HCl(2mL)使反应淬灭并且将该混合物调整至pH2。用乙酸乙酯萃取该混合物。用Na2SO4干燥有机层,过滤并且蒸发至得到化合物82(0.18g)。将该物质不经进一步纯化用于下一步。m/z:329.1(M+H)+。
实施例AR
将化合物82(182mg,0.55mmol)溶于THF(7.15mL)。加入化合物46(225mg,0.55mmol),随后加入HOBt(112mg,0.83mmol),iPr2NEt(393μL,2.20mmol)和EDC(194μL,1.10mmol)。将该混合物在25℃下搅拌12小时。在减压下除去溶剂。用乙酸乙酯稀释残余物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:5-10%MeOH/CH2Cl2梯度)而得到实施例AR(208mg,53%)。m/z:720.2(M+H)+。1HNMR(CDCl3)δ8.80(s,1H);7.84(s,1H);7.40-7.00(m,10H);6.97(s,1H);6.83(m,1H);6.65(brs,1H);5.99(m,1H);5.40-5.10(m,4H);4.52(m,3H);4.06(m,1H);3.79(m,1H);3.34(m,1H);2.97(s,3H);2.90-2.60(m,5H);2.50-2.40(brs,1H);1.80-1.20(m,10H)。
实施例AS的制备
方案36
化合物85a
按照与化合物4相同的操作制备化合物85a,但使用4-氯甲基噻唑(购自TCI America)而不是化合物3并且使用甲胺而不是异丙胺。
化合物83
向在CH2Cl2(9mL)中的化合物85a(0.40g,3.12mmol)中加入N,N-二异丙基乙胺(1.04mL,5.85mmol),随后加入化合物5(280μL,1.95mmol)。将该反应混合物在25℃下搅拌3.5小时。在减压下除去溶剂。通过Combiflash纯化(固定相:硅胶;洗脱剂:90-100%EtOAc/己烷梯度)而得到化合物83(0.51g)。m/z:286.0(M+H)+。
化合物84
将化合物83(0.51g,1.77mmol)溶于THF(10mL)并且加入1M LiOH水溶液(3.54mL)。将该混合物在25℃下搅拌2小时。用1M HCl(4.8mL)使反应淬灭并且将该混合物调整至pH2。用乙酸乙酯萃取该混合物。用Na2SO4干燥有机层,过滤并且蒸发而得到化合物84(0.430g)。将该物质不经进一步纯化在下一步使用。m/z:272.0(M+H)+。
实施例AS
将化合物84(150mg,0.55mmol)溶于THF(7.15mL)。加入化合物8(225mg,0.55mmol),随后加入HOBt(112mg,0.83mmol),iPr2NEt(393μL,2.20mmol)和EDC(198μL,1.11mmol)。将该混合物在25℃下搅拌12小时。在减压下除去溶剂。用乙酸乙酯稀释残余物并且依次用饱和Na2CO3水溶液,水和盐水洗涤。用Na2SO4干燥有机相,过滤并且蒸发。通过快速柱色谱法纯化(固定相:硅胶;洗脱剂:7%i-PrOH/CH2Cl2)而得到实施例AS(219mg,60%)。m/z:663.1(M+H)+.1HNMR(CDCl3)δ8.87(s,1H);8.76(s,1H);7.84(s,1H);7.40-7.00(m,10H);6.22(brs,1H);5.73(brs,1H);5.22(m,2H);4.50(m,2H);4.16(brs,1H);4.05(brs,1H);3.75(m,1H);2.93(s,3H);2.90-2.60(m,5H);2.90(m,1H);2.31(m,1H);1.60-1.30(m,4H);1.00-0.80(m,6H)。
实施例AT的制备
方案37
化合物87
按照用于由化合物6制备化合物7相同的操作由化合物86制备化合物87(386mg),但使用化合物68而不是化合物4。m/z 286.0(M+H)+
实施例AU的制备
方案38
化合物85b
按照与化合物4相同的操作制备化合物85b,但使用4-氯甲基噻唑(获自TCI America)而不是化合物3。
化合物88
按照用于制备化合物83相同的操作制备化合物88(341mg),但使用化合物85b(300mg,1.95mmol)而不是化合物68。m/z:312.0(M+H)+。
化合物89
按照与84相同的操作制备化合物89(341mg),但使用化合物88(293mg,0.99mmol)而不是化合物83。m/z:298.0(M+H)+。
实施例AU
按照用于制备实施例AS相同的操作制备实施例AU(226mg,64%),但使用化合物89(150mg,0.51mmol)而不是化合物84。m/z:689.1(M+H)+.1HNMR(CDCl3)δ8.87(s,1H);8.74(s,1H);7.83(s,1H);7.40-7.00(m,10H);6.21(m,1H);5.73(m,1H);5.29(m,1H);5.17(m,2H);4.88(d,J=16Hz,1H);4.47(d,J=16Hz,1H);4.18(m,1H);3.75(brs,1H);2.90-2.60(m,6H);2.51(brs,1H);2.31(m,1H);1.60-1.30(m,4H);1.00-0.80(m,10H)。
实施例AV的制备
方案39
化合物90
按照用于制备化合物4的操作制备化合物90(190mg),但使用4-(氯甲基)-2-甲基噻唑而不是化合物3。m/z141.1(M-H)
化合物91
按照用于制备化合物6相同的操作制备化合物91(400mg),但使用化合物90而不是化合物4。m/z300.0(M+H)+
化合物92
按照用于制备化合物7相同的操作制备化合物92(188mg),但使用化合物91而不是化合物6。m/z284.0(M-H)-
实施例AV
按照用于制备实施例C的操作制备实施例AV(107mg),但使用化合物92而不是化合物7。1HNMR(CDCl3)δ8.76(s,1H),7.78(s,1H),7.27-7.07(m,10H),6.93(s,1H),6.25(m,2H),5.39(m,1H),5.19(m,2H),4.37-4.32(m,2H),4.06(m,1H),3.81(brs,1H),2.83(m,4H),2.65(brs,7H),2.28-2.22(m,1H),1.51-1.37(m,4H),0.82(m,6H):m/z677.2(M+H)+
实施例AW的制备
方案40
化合物93
化合物93商购自TCI并且不经进一步纯化使用。
化合物94
向化合物93(500mg,3.76mmol)在甲醇(20mL)中的溶液中滴加亚硫酰氯(0.5mL,6.6mmol)。将该混合物在60℃下搅拌20分钟并且在真空中浓缩而得到化合物94。
化合物95
向搅拌的化合物94(3.7mmol)和二异丙基乙胺(1.4mL,8.3mmol)在二氯甲烷(50mL)中的溶液中加入CDI(609mg,3.7mmol)。将该混合物搅拌12小时。加入化合物9并且将该混合物再搅拌12小时。浓缩并且通过快速柱色谱法纯化(0-100%:EtOAc/己烷)而得到化合物95(100mg)。m/z344.3(M+H)+
化合物96
按照用于制备化合物7相同的操作制备化合物96(39mg),但使用化合物95而不是化合物6。m/z328.3(M-H)-
实施例AW
按照例如C的操作制备实施例AW(107mg),但使用化合物96而不是化合物7。1HNMR(CDCl3)δ8.79(s,1H),7.82(s,1H),7.27-7.09(m,10H),6.95(s,1H),6.23(m,1H),6.14(s,1H),5.22(s,3H),4.45(m,2H),4.35-4.0(m,3H),3.8(m,1H),3.6(m,1H),3.25(s,3H),3.21(m,2H),2.95(s,3H),2.8-2.6(m,4H),2.0-1.4(m,4H),1.25(m,4H),1.05(m,4H):m/z721.3(M+H)+
实施例AX和AY的制备
方案41
实施例AX
向实施例I(650mg,1.00mmol)在DMSO(3.5mL)中的溶液中加入三乙胺(0.5mL)。将该混合物搅拌30分钟。在5℃向该混合物中加入吡啶SO3,然后搅拌60分钟。将该混合物倾倒在冰水上,然后搅拌30分钟。用EtOAc稀释该混合物并且用水,饱和NaHCO3和盐水洗涤。浓缩而得到实施例AX。m/z705.2(M+H)+
实施例AY
向实施例AX(70mg,0.099mmol)和甲胺(1.5mL,2M)在MeOH(1.5mL)中的搅拌溶液中加入AcOH(119mg,1.99mmol)。将该混合物搅拌2小时。加入NaBH(OAc)3(94mg)并且将该混合物搅拌2小时。浓缩并且通过制备型HPLC纯化而得到实施例AY(30mg)。1HNMR(CDCl3)δ8.79(s,1H),7.82(s,1H),7.27-7.09(m,10H),6.95(s,1H),6.23(m,1H),6.14(s,1H),5.22(s,2H),4.45(m,1H),4.35-4.0(m,4H),3.8(m,1H),3.6(m,1H),3.21(m,1H),2.95(s,3H),2.93(s,3H),2.8-2.6(m,4H),2.0-1.4(m,4H),1.25(m,4H),1.05(m,4H):m/z 720.3(M+H)+
实施例AZ的制备
方案42
实施例AZ
按照例如C的操作制备化合物AZ(61mg),但使用化合物87而不是化合物7和化合物79而不是化合物8。1HNMR(CDCl3)δ8.77(s,1H),8.72(s,1H),7.78(s,1H),7.71(s,1H),6.23(d,1H),5.28-5.24(m,2H),4.85(d,1H),4.71-4.57(m,2H),4.08-4.03(m,1H),3.78(brs,1H),3.51(brs,1H),2.87(s,3H),2.33(brs,1H),2.13-2.06(m,1H),1.49-1.33(m,8H),0.93-0.80(m,12H):m/z539.2(M+H)+
实施例BA和BB的制备
方案43
化合物97
化合物97商购自TCI并且作为普遍接受的使用。
化合物98
向化合物97(1g,2.2mmol)和二异丙基乙胺(1.6mL,8.9mmol)在二氯甲烷(26mL)中的搅拌溶液中加入CDI(362mg,2.2mmol)。将该混合物搅拌12小时。加入化合物9并且将该混合物再搅拌12小时。浓缩并且通过快速柱色谱法纯化(0-8%:MeOH/DCM)而得到化合物98(1.2g)。m/z608.1(M+H)+
化合物99
按照用于制备化合物67相同的操作制备化合物99(1.2g),但使用化合物98而不是化合物66。m/z592.2(M-H)-
实施例BA
按照用于制备实施例C的操作制备实施例BA(111mg),但使用化合物99而不是化合物7。m/z986.1(M+H)+
实施例BB
向实施例BA(111mg,0.113mmol)和TFA(1.4mL)的搅拌溶液中加入Et3SiH(0.1mL)。将该混合物搅拌60分钟,然后浓缩并且使用EtOAc和饱和NaHCO3分配,随后用EtOAc(2X)萃取并且用Na2SO4干燥。浓缩并且通过快速柱色谱法纯化(0-15%:MeOH/DCM)而得到实施例BB(50mg)。
1H-NMR(CDCl3)δ8.75(s,1H),7.79(s,1H),7.42(s,1H),7.22-7.12(m,9H),6.99-6.96(m,2H),6.86(s,1H),6.71(m,2H),5.51(brs,1H),5.17(m,2H),4.57-4.52(m,1H),4.39-4.35(m,2H),4.07(m,1H),3.74(brs1H),3.28-3.19(m,1H,),3.09-2.76(m,6H),3.65-2.58(m,3H),1.49(m,2H),1.36-1.20(m,8H);m/z743.2(M+H)+
实施例BC的制备
方案44
实施例BC
按照用于制备实施例C的操作制备实施例BC(95mg),但使用化合物29而不是化合物7和化合物78而不是化合物8。1HNMR(CDCl3)δ8.75(s,1H),7.80(s,1H),6.93(s,1H),6.28(d,1H),6.18(m,1H),5.26-5.21(m,3H),4.47-4.30(m,2H),4.11-4.00(m,1H),3.91(brs,1H),3.59(brs,1H),3.28(m,1H),2.97-2.90(m,3H),2.26-2.19(m,1H),1.39-1.24(m,10H),1.09-1.01(m,6H),0.94-0.86(m,6H):m/z553.1(M+H)+
实施例BD和BE的制备
方案45
实施例BD
按照用于制备实施例C的操作制备实施例BD(148mg),但使用化合物13e而不是化合物7和化合物78而不是胺8。m/z611.1(M+H)+
实施例BE
将实施例BD(148mg,0.242mmol)溶于TFA(3mL)并且在25℃下搅拌3小时。在减压下除去溶剂并且用THF(3mL)稀释残余物且加入2NNaOH水溶液至pH10。将该混合物搅拌20min并且用EtOAc萃取。依次用水和盐水洗涤有机层,用Na2SO4干燥,过滤并且蒸发。通过快速色谱法纯化(0-10%MeOH/CH2Cl2)而得到实施例BE(109mg)。1HNMR(CDCl3)δ8.75(s,1H),7.80(s,1H),6.97-6.94(d,1H),6.90(s,1H),6.32(brs,1H),5.26-5.22(m,2H),5.12(d,1H),4.51-4.39(m,3H),4.25-4.22(m,2H),3.87(brs,1H),3.62(brs,1H),3.27-3.18(m,1H),2.94(s,3H),1.41-1.31(m,10H),1.13-1.00(m,9H)。m/z:555.1(M+H)+。
实施例BF的制备
方案46
化合物100
使用制备化合物122相同的方法制备化合物100,但使用化合物9而不使用化合物8(参考方案70)。
化合物101
将化合物100(108mg,0.423mmol)溶于THF(2mL),然后加入847μl 1M LiOH/H2O。在搅拌过夜后,加入843μl 1N HCl。浓缩而得到化合物101。
实施例BF
按照用于制备实施例C的操作制备实施例BF(24mg),但使用化合物101而不是化合物7。1HNMR(CDCl3)δ8.77(s,1H),8.73(s,1H),7.80(s,1H),7.74(s,1H),7.27-7.10(m,10H),6.55-6.52(d,1H),5.84(d,1H),5.21-5.19(m,3H),4.77-4.53(m,2H),4.39(brs,1H),4.11-3.99(m,2H),3.81(brs,1H),3.58(m,2H),2.86(s,3H),2.81-1.72(m,5H),2.04(m,1H),1.85(m,1H),1.66-1.37(m,6H):m/z665.2(M+H)+
实施例BG的制备
方案47
实施例BG
将实施例R(102mg,0.137mmol)溶于THF(2mL),然后加入2mL乙基三氟乙酸酯。然后加入1.3eq MeI和过量的Cs2CO3。在搅拌1天后,使用EtOAc和饱和Na2CO3分配该混合物,用EtOAc(2X)萃取并且用Na2SO4干燥。通过快速色谱法纯化(0-20%MeOH/CH2Cl2)而得到实施例BG(6.5mg)。1HNMR(CD3OD)δ9.94(s,1H),8.27(s,1H),7.73(s,1H),7.30-7.10(m,10H),5.29,5.17(d2H),4.72(s,3H),4.29(m,1H),4.15(brs,1H),3.83(brs,1H),3.61(m,2H),3.07(s,3H),2.93(m,2H),2.82-2.70(m,4H),2.68-2.58(m,2H),2.42(s,3H),2.05(m,2H),1.70-1.40(m,10H)。m/z:720.2(M+H)+。
实施例BH的制备
方案48
实施例BH
按照用于制备实施例C的操作制备实施例BH(78mg),但使用化合物87而不是化合物7和化合物46而不是化合物8。1HNMR(CDCl3)δ8.73(s,1H),8.68(s,1H),7.76(s,1H),7.68(s,1H),7.18-7.09(m,10H),6.26(m,1H),5.76(m,1H),5.22-5.18(m,4H),4.71-4.65(d,1H),4.46-4.40(d,1H),4.11-4.04(m,2H),3.81(brs,1H),3.14(brs,1H),2.83(s,3H),2.76-2.52(m,4H),1.88(m,1H),1.51-1.37(m,2H),0.73-0.69(m,6H)m/z663.2(M+H)+
实施例BI和BJ的制备
方案49
实施例BI
按照用于制备实施例C的操作制备实施例BI(1.78g),但使用化合物99而不是化合物7和化合物46而不是化合物8。m/z 986.1(M+H)+
实施例BJ
按照用于制备实施例BB的操作制备实施例BJ(728mg),但使用实施例BI而不是实施例BA。1H-NMR(CDCl3)δ8.75(s,1H),7.79(s,1H),7.42(s,1H),7.22-7.12(m,9H),6.99-6.96(m,2H),6.86(s,1H),6.71(m,2H),5.51(brs,1H),5.17(m,2H),4.57-4.52(m,1H),4.39-4.35(m,2H),4.07(m,1H),3.74(brs1H),3.28-3.19(m,1H,),3.09-2.76(m,6H),3.65-2.58(m,3H),1.49(m,2H),1.36-1.20(m,8H);m/z743.2(M+H)+
化合物104-115的制备
方案50
化合物102
化合物102商购自Aldrich Chemical Co.并且不经进一步纯化使用。
化合物103
将化合物102(5.5mmol)悬浮于MeCN(55mL)中并且加入DIPEA(8.25mmol)。用MeCN(20mL)稀释羰基二咪唑(5.5mmol)并且在45min内将该溶液缓慢加入反应混合物中。将所得混合物放置过夜。用MeCN(10mL)稀释化合物9(5.5mmol)并且用DIPEA(8.25mmol)处理,此后加入到反应混合物中,然后放置过夜。在真空中除去挥发性物质并且将残余物溶于EtOAc(50mL)且用1M HCl(50mL)洗涤。分离各层并且用EtOAc(3×50mL)萃取水层。用饱和Na2CO3洗涤合并的有机层,直到洗涤液的pH~pH8。在盐水洗涤(30mL)后用无水MgSO4干燥。在真空中浓缩后,用SiO2(0-65%EtOAc/己烷)纯化残余物而得到0.340g(20%)化合物103,为非晶形白色固体(m/z 314.0(M+H)+)。
化合物104
用THF(5mL)稀释化合物103(1.1mmol)并且用新近制备的1MLiOH(2.2mmol)处理。将该两相反应体系剧烈搅拌2h,此后用1MHCl(3mmol)淬灭。用EtOAc(5×15mL)萃取该反应体系并且用盐水(30mL)洗涤合并的有机层,用无水Na2SO4干燥并且浓缩至得到0.282g(86%)化合物104,为非晶形白色粉末,将其不经进一步纯化使用。1H-NMR(CDCl3,300MHz):7.06(s,1H);4.37(s,1H);3.28(p,J=6.9Hz,1H);3.00(s,3H);1.62(s,6H);1.39(d,J=6.9Hz,6H)。
方案51
化合物105
化合物105商购自Aldrich Chemical Co.并且不经进一步纯化使用。
化合物106
用MeOH(100mL)稀释外消旋化合物105(12.2mmol)。加入HCl/二噁烷溶液(4M,25mmol)并且将该溶液回流过夜。在真空中除去挥发性物质而得到2.60g(97%)化合物106,为外消旋混合物。将该泡沫状白色固体不经进一步纯化使用(m/z147.0(M+H)+)。
化合物107
用MeCN(65mL)稀释化合物106(5mmol)并且用DIPEA(25mmol)处理。将所得溶液通过加液漏斗缓慢加入到CDI(5mmol)在MeCN(30mL)中的溶液中并且放置过夜。向该反应溶液中加入化合物9(5mmol)和DIPEA(3mmol),将其放置过夜。在真空中除去挥发性物质并且将残余物溶于EtOAc和饱和Na2CO3(各30mL)。用EtOAc(3X25mL)萃取水层并且用盐水(50mL)洗涤合并的有机层且用无水MgSO4干燥。在真空中浓缩后,通过SiO2柱色谱法(0-10%MeOH/DCM)纯化而得到0.36g(21%)外消旋化合物107,为黄色油状物(m/z343.1(M+H)+)。
化合物108
将化合物107(1.05mmol)溶于THF(5mL)并且用新近制备的1MLiOH溶液(2.1mmol)处理。将该溶液剧烈搅拌2h并且用1MHCl(2.1mmol)淬灭。在真空中除去挥发性物质并且将所得油状物与甲苯一起共沸,直到获得定量产率的外消旋化合物107,为非晶形白色固体,将其不经进一步纯化使用(m/z329.1(M+H)+)。
方案52
化合物109
化合物109商购自Bachem并且作为普遍接受的使用。
化合物110
用DCM(5mL)稀释化合物109(4.1mmol)并且用N-甲基吗啉(8.2mmol)处理。在0℃下将该溶液缓慢加入到氯甲酸4-硝基苯酯(4.1mmol)的DCM(5mL)溶液中。然后将该反应体系温至室温下过夜。在真空中除去挥发性物质并且将残余物溶于EtOAc和饱和Na2CO3。用EtOAc(3X10mL)萃取水层并且用盐水(30mL)洗涤合并的有机层,此后用无水Na2SO4干燥。在真空中浓缩后,通过SiO2柱色谱法纯化(0-25%EtOAc/己烷)而得到0.75g(51%)化合物110,为非晶形白色固体(m/z354.8(M+H)+)。
化合物111
用THF(3.5mL)稀释化合物110(1.1mmol)。用THF(3mL)稀释化合物9(1.4mmol),用Et3N(2.8mmol)处理并且转至反应溶液中。加入DMAP(0.11mmol)并且将该反应体系加热至70℃下保持2h。在冷却至室温后,加入EtOAc(10mL)和饱和Na2CO3。用EtOAc(3X10mL)萃取水相并且用饱和Na2CO3,H2O和盐水(各15mL)洗涤合并的有机相。在用无水MgSO4干燥后,在真空中除去挥发性物质并且通过SiO2柱色谱法(0-50%EA/己烷)纯化而得到0.346g(82%)化合物111(m/z386.0(M+H)+)。
化合物112
将化合物111(0.88mmol)溶于THF(4mL)并且用新近制备的1MLiOH(1.8mmol)处理。将该反应混合物剧烈搅拌1.5h并且用1MHCl(2.5mmol)淬灭。用EtOAc(3X10mL)萃取该反应混合物并且用盐水(30mL)洗涤合并的有机层且用无水Na2SO4干燥。在真空中浓缩而得到0.300g(92%)化合物112,为无色薄膜状物,将其不经进一步纯化使用(m/z372.0(M+H)+)。
方案53
化合物113
化合物113商购自Chem-Impex并且不经进一步纯化使用。
化合物114
用THF(15mL)稀释化合物113(3.2mmol)。缓慢加入TMSCHN2(3.2mmol),随后加入MeOH(5mL)。该溶液快速变无色并且观察到浓重气体排出。在放置过夜后,在真空中除去挥发性物质并且通过SiO2柱色谱法纯化残余物(0-50%EtOAc/己烷)而得到0.805g(52%)化合物114(m/z505.2(M+Na)+)。
化合物115
用DMF(4mL)稀释化合物114(1.7mmol)并且加入哌啶(1mL)。30min后,在真空中除去挥发性物质并且通过SiO2柱色谱法(0-5%MeOH/DCM)纯化残余物而得到0.414(94%)化合物115,为非晶形白色固体(m/z261.0(M+H)+)。
实施例BK的制备
方案54
化合物BK
在THF(7mL)中合并化合物79(0.70mmol)和化合物29(0.91mmol)。在室温下连续加入HOBt(0.91mmol),DIPEA(1.05mmol)和EDC(0.91mmol)并且将该反应体系放置过夜。在真空中除去挥发性物质并且将残余物溶于3/1(CHCl3/IPA)和饱和Na2CO3(各15mL)。用3/1(CHCl3/IPA)(3X10mL)萃取水层并且用饱和Na2CO3,水和盐水(各15mL)洗涤合并的有机层。在用无水MgSO4干燥后,在真空中除去挥发性物质并且通过SiO2柱色谱法纯化残余物(0-10%MeOH/DCM)而得到8.5mg(2%)化合物BK m/z581.2(M+H)+;1H-NMR(CDCl3,300MHz):8.91(s,1H);7.89(s,1H);7.15(s,1H);6.52-6.0(brm,2H);5.26(s,2H);5.18(brd,J=8.1Hz,1H);4.55(s,2H);4.06(brs,1H);3.79(brs,1H);3.48(m,2H);3.09(s,3H,次要旋转异构体);3.01(s,3H,主要旋转异构体);2.34(m,1H);1.60-1.30(m,8H);1.42(d,J=6.9Hz,6H);0.98(t,J=7.2Hz,6H);0.86(m,6H)。
实施例BL的制备
方案55
实施例BL
按照与实施例BK类似的方式,使用化合物104(0.26mmol)和化合物8(0.29mmol)制备实施例BL,得到0.087g(64%)实施例BL,为非晶形白色固体,m/z691.3(M+H)+;1H-NMR(CDCl3,300MHz):8.82(s,1H);7.82(s,1H);7.30-7.10(m,11H);7.06(s,1H);6.54(d,J=9.6Hz,1H);5.89(d,J=8.4Hz,1H);5.22(s,1H);5.07(m,1H);4.45(ABd,J=16.5Hz,1H);4.37(AB d,J=15.6Hz,1H);4.07(m,1H);3.68(m,1H);3.40(m,1H);3.06(s,3H,次要旋转异构体);2.89(s,3H,主要旋转异构体);2.90-2.54(m,4H);1.60-1.25(m,16H)。
实施例BMa和BMb的制备
方案56
实施例BMa和BMb
按照与实施例BK类似的方式,使用外消旋化合物108(0.36mmol)和化合物8(0.28mmol)制备实施例BMa和BMb。通过制备型HPLC分离对映体产物(Chiralcel OD-H(250X4.6mm,70∶30庚烷/IPA,30min)而得到0.008g(4%)对映体BMa(HPLC RT=11.71min)m/z720.3(M+H)+;1H-NMR(CDCl3,300MHz):8.73(s,1H);7.78(s,1H);7.41(brs,1H);7.30-7.00(m,11H);6.94(s,1H);5.40(brs,1H);5.18(brs,2H);4.56(ABd,J=15Hz,1H);4.48(ABd,J=16Hz,1H);4.39(brs,1H);4.05(brs,1H);3.73(brs,1H);3.25(s,3H,次要旋转异构体);3.23(m,1H);2.98(s,3H,主要旋转异构体);2.82-2.30(m,10H);1.60-1.20(m,6H);1.32(d,J=7Hz,6H);和0.010g(5%)对映体BMb(HPLCRT=15.41min)。(m/z720.3(M+H)+;1H-NMR(CDCl3,300MHz):8.78(s,1H);7.83(s,1H);7.38(brd,J=8Hz,1H);7.30-7.7.05(m,11H);7.02(s,1H);5.52(d,J=9Hz,1H);5.25(ABd,J=13Hz,1H);5.21(ABd,J=13Hz,1H);4.85-4.62(m,2H);4.44(d,J=16Hz,1H);3.99(brs,1H);3.78(brs,1H);3.37(brs,3H,次要旋转异构体);3.26(m,1H);3.07(s,3H,主要旋转异构体);2.77(s,6H);2.86-2.60(m,4H);1.6-1.3(m,6H);1.35(d,J=7Hz,6H)。
实施例BN和BO的制备
方案57
实施例BP
按照与实施例BK类似的方式,使用化合物112(0.78mmol)和化合物8(0.60mmol)制备实施例BN,得到0.227g(50%)化合物BN,为无色薄膜状物。(m/z763.3(M+H)+)。
实施例BO
按照与实施例AM类似的方式,使用实施例BN(0.29mmol)制备实施例BO,得到0.149g(72%)实施例BO,为非晶形白色固体。(m/z707.3(M+H)+;1H-NMR(CDCl3,300MHz):8.82(s,1H);7.84(s,1H);7.26-7.03(m,11H);6.99(s,1H);6.69(d,J=9.6,1H);6.42(brs,1H);5.47(brd,J=8.7Hz,1H);5.27(ABd,J=13Hz,1H);5.22(ABd,J=13Hz,1H);4.55(ABd,J=16Hz,1H);4.43(ABd,J=16Hz,1H);4.18(m,1H);4.00(m,2H);3.72(brs,1H);2.25(m,1H);2.99(s,3H);2.84-2.60(m,3H);2.54-2.42(m,1H);1.64-1.12(m,4H);1.37(d,J=7Hz,6H);1.11(d,J=6Hz,3H)。
实施例BP-BR的制备
方案58
实施例BP
按照与实施例BK类似的方式,使用化合物52(0.22mmol)和化合物78(0.20mmol)制备实施例BP,得到0.091g(71%)实施例BP,为无色薄膜状物(m/z654.2(M+H)+)。
实施例BQ
用在二噁烷中的4M/HCl(2mL)处理实施例BQ(0.14mmol)而在5min内得到白色沉淀。除去溶剂并且将固体溶于MeOH。在真空中浓缩而得到0.083g(99%)实施例BQ的HCl盐,为无色薄膜状物(m/z554.1(M+H)+;1H-NMR(CD3OD,300MHz):10.03(s,1H);8.41(s,1H);7.81(s,1H);5.48(s,2H,次要旋转异构体);5.35(s,2H,主要旋转异构体);4.74(s,2H);4.34(brs,1H);3.90(brs,1H);3.78-3.54(m,2H);3.20-2.98(m,5H);2.20(brs,1H);2.07(brs,1H);1.60-1.4(m,10H);1.12(m,6H)。
实施例BR
将实施例BQ(0.11mmol)溶于MeOH(1.5mL)。加入甲醛(在H2O中37%,13.4mmol)并且放置10min。加入NaHB(OAc)3(0.324mmol)并且将该反应混合物在室温下放置过夜。再加入更多甲醛(13.4mmol)和NaHB(OAc)3(0.324mmol)并且在室温下再放置6h。在真空中除去溶剂并且通过制备型HPLC分离产物而得到0.058g(77%)实施例BR的TFA盐,为非晶形固体。m/z582.3(M+H)+;1H-NMR(CD3OD,300MHz):9.07(s,1H);7.91(s,1H);7.25(s,1H);5.47(s,2H,次要旋转异构体);5.28(s,2H,主要旋转异构体);4.59(ABd,J=16Hz,1H);4.53(ABd,J=16Hz,1H);4.31(dd,J=9.2,5Hz,1H);3.88(m,1H);3.59(m,1H);3.32(m,1H);3.20(m,2H);2.98(s,3H);2.89(brs,6H);2.23(m,1H);2.00(m,1H);1.44(m,4H);1.37(d,J=7Hz,6H);1.10(m,6H)。
实施例BS和BT的制备
方案59
化合物116
按照与实施例75类似的方式,使用化合物4(0.76mmol)和化合物47(0.64mmol)制备化合物116,得到0.218g(90%)化合物116,为泡沫状白色固体(m/z384.1(M+H)+)。
实施例BS
按照与实施例BK类似的方式,使用化合物116(0.28mmol)和化合物8(0.25mmol)制备实施例BS,得到0.139g(72%)实施例BS,为无色薄膜状物(m/z775.3(M+H)+)。
实施例BT
按照与实施例AM类似的方式,使用实施例BU(0.18mmol)制备实施例BT,得到0.080g(62%)实施例BT,为非晶形白色固体。m/z719.3(M+H)+;1H-NMR(CDCl3,300MHz):8.79(s,1H);7.82(s,1H);7.27-7.0(m,10H);6.98-6.82(m,1H);6.85(s,1H);6.44(brs,1H);5.30(s,2H,次要旋转异构体);5.22(s,2H,主要旋转异构体);5.04(brs,1H);4.62(ABd,J=15Hz,1H);4.54(ABd,J=15Hz,1H);4.27(brs,1H);4.11(brs,1H);3.97(brd,J=10Hz,1H);3.82,brs,1H);3.57(brs,1H);3.40-3.10(m,2H);2.80-2.60(m,4H);2.55(m,1H);1.54(m,2H);1.46-1.30(m,2H);1.35(d,J=7Hz,6H);0.94-0.72(m,4H)。
实施例BU和BV的制备
方案60
化合物117
按照与化合物13d类似的方式制备化合物117,但将化合物4(1.5mmol)和化合物10d的L-对映体(1.15mmol)用于最终产生0.328g(88%)化合物190,为泡沫状白色固体(m/z398.1(M+H)+)。
实施例BU
按照与实施例AL类似的方式,使用化合物117(0.33mmol)和化合物8(0.30mmol)制备实施例BU,得到0.196g(84%)实施例BU,为非晶形白色固体(m/z789.3(M+H)+)。
实施例BV
按照与实施例AM类似的方式,使用实施例BU(0.29mmol)制备实施例BV,得到0.140g(77%)实施例BV,为非晶形白色固体。m/z733.3(M+H)+;1H-NMR(CDCl3,300MHz):8.80(s,1H);7.84(s,1H);7.27-7.10(m,10H);6.70-6.10(m,1H);6.86(s,1H);6.20(brd,J=7Hz,1H);5.24(s,2H);4.81(brd,J=7Hz,1H);4.82(s,2H);4.34(brd,J=7Hz,1H);4.16(brs,1H);4.07(brd,J=6Hz,1H);3.86(brs,1H);3.38(brs,1H);2.69(m,6H);1.62-1.50(m,2H);1.50-1.34(m,2H);1.38(m,6H);1.13(d,J=6Hz,3H);0.98-0.76(m,4H)。
实施例BW和BX的制备
方案61
实施例BW
按照与实施例BK类似的方式,使用化合物75(0.27mmol)和化合物46(0.24mmol)制备实施例BW,得到0.154g(86%)实施例BW,为非晶形白色固体(m/z733.3(M+H)+)。
实施例BX
按照与实施例AM类似的方式,使用实施例BW(0.21mmol)制备实施例BX,得到0.091g(98%)实施例BX的TFA盐,为非晶形白色固体。m/z677.5(M+H)+;1H-NMR(CDCl3,300MHz):8.83(s,1H);8.77(s,1H);7.84(s,1H);7.77(s,1H);7.27-7.00(m,10H);6.62(d,J=9Hz,1H);6.44(d,J=6Hz,1H);5.35(d,J=10Hz,1H);5.24(s,2H);4.69(ABd,J=15Hz,1H);4.62(ABd,J=16Hz,1H);4.14(brm,2H);3.96-3.78(m,2H);3.51(dd,J=11,4.5Hz,1H);3.38(brs,1H);2.82-2.58(m,4H);2.41(m,1H);1.70-1.24(m,4H);1.20-0.88(m,2H);0.88-0.54(m,2H)。
实施例BY和BZ的制备
方案62
化合物118
按照与化合物104类似的方式制备化合物118,但使用化合物115(0.40mmol)而不是化合物102,使其与化合物9(0.48mmol)反应而最终生成0.075g(89%)化合物118,为泡沫状白色固体(m/z443.4(M+H)+)。
实施例BY
按照与实施例BM类似的方式,使用化合物118(0.17mmol)和化合物8(0.15mmol)制备实施例BY,得到0.079g(62%)实施例BY,为非晶形白色固体(m/z834.3(M+H)+)。
实施例BZ
按照与实施例BQ类似的方式,使用实施例BY(0.095mmol)制备实施例BZ,得到0.082g(99%)实施例BZ的HCl盐,为非晶形白色固体m/z734.2(M+H)+;1H-NMR(DMSO-d6,300MHz):8.08(s,1H);7.86(brm,3H);7.58(d,J=9Hz,1H);7.25-7.00(m,11H);6.32(brs,1H);5.16(s,2H);4.99(brm,4H);4.48(ABd,J=15Hz,1H);4.43(ABd,J=15Hz,1H);4.02(m,1H);3.89(m,1H);3.63(m,1H);3.22(hep,J=7Hz,1H);2.87(s,3H);2.76-2.56(m,4H);1.58-1.15(m,10H);1.29(d,J=7Hz,6H)。
实施例CA的制备
方案63
实施例CA
用DCM(1mL)稀释实施例R(0.11mmol)并且用4-吗啉甲酰氯(0.13mmol)和DIPEA(0.16mmol)处理。2h后,在真空中除去挥发性物质并且通过SiO2柱色谱法纯化残余物(0-20%MeOH/DCM)而得到0.068g(76%)实施例CA,为非晶形白色固体m/z819.1(M+H)+;1H-NMR(CDCl3,300MHz):8.82(s,1H);7.85(s,1H);7.27-7.07(m,12H);6.94(s,1H);6.26(brs,1H);5.73(d,J=8Hz,1H);5.28(ABd,J=13Hz,1H);5.22(ABd,J=13Hz,1H);4.50(ABd,J=16Hz,1H);4.44(ABd,J=16Hz,1H);4.17(m,1H);3.98(brs,1H)3.76(brs,1H);3.68(brs,1H);3.60(m,4H);3.40(m,2H),3.32(m,4H);2.97(s,3H);2.87(dd,J=13,5Hz,2H);2.73,(m,2H);2.57(m,2H);1.79(m,2H);1.60-1.20(m,6H);1.37(d,J=7Hz,6H)。
化合物CB的制备
方案64
实施例CB
用THF(1mL)稀释实施例AF(0.15mmol)并且用吗啉(0.61mmol),HOBt(0.18mmol)且最终用EDC(0.18mmol)处理。将该反应混合物放置过夜。然后用EtOAc和饱和Na2CO3稀释该反应混合物。用EtOAc萃取水层并且用盐水洗涤合并的有机层,用无水MgSO4干燥并且在真空中浓缩。通过制备型HPLC纯化所得残余物而得到0.024g(20%)实施例CB,为非晶形白色固体。/z790.4(M+H)+;1H-NMR(CDCl3,300MHz):8.81(s,1H);7.84(s,1H);7.27-7.10(m,10H);6.96(s,1H);6.78(d,J=8Hz,1H);6.67(s,1H);5.36(d,J=9Hz,1H);5.27(ABd,J=13Hz,1H);5.20(ABd,J=13Hz,1H);4.59(s,1H);4.51(s,2H);4.02(m,1H);3.80-3.30(m,10H);2.98(s,3H);2.90-2.45(m,6H);1.52(m,2H);1.39(d,J=7Hz,6H);1.32(m,2H)。
化合物CC的制备
方案65
实施例CC
按照与实施例CB类似的方式制备实施例CC,但使用N-甲基哌嗪(0.16mmol)与化合物AF(0.10mmol)反应而不是吗啉并且加入DIPEA(0.19mmol)产生0.009g(11%)实施例CC,为非晶形白色固体m/z803.4(M+H)+;1H-NMR(CDCl3,300MHz):8.80(s,1H);7.84(s,1H);7.27-7.10(m,11H);6.91(s,1H);6.78(m,2H);5.27(ABd,J=13Hz,1H);5.21(ABd,J=13Hz,1H);4.59(m,1H);4.49(ABd,J=16Hz,4.44(ABd,J=16Hz,1H);4.01(m,1H);3.90-3.40(m,4H);3.27(hep,J=7Hz,1H);3.10-2.90(m,1H);2.97(s,3H);2.90-2.30(m,11H);1.60-1.25(m,6H);1.37(d,J=7Hz,6H)。
实施例CD的制备
方案66
实施例CD
向实施例R(30.5mg,0.043mmol)在甲醇(1.5mL)中的溶液中加入甲醛(1mL,在H2O中37%)。在搅拌10分钟后,加入NaBH(OAc)3(49mg,0.23mmol)并且将所得混合物搅拌10h。使用LC/MS监测反应。当LC/MS显示不存在原料实施例R,将该反应混合物蒸发至干并且通过棉絮塞过滤。然后通过CombiFlash纯化粗产物(10%MeOH/CH2Cl2)而得到29.7mg实施例CD。1H-NMR(CDCl3,500MHz):8.78(s,1H);7.83(s,1H);7.12-7.22(m,10H);6.85(s,1H);5.83(d,1H,J=8.5Hz),5.23(dAB,2H,J=13.1Hz);4.49(dAB,2H,J=16.5Hz);4.29(m,1H);4.15(m,1H);3.75(m,1H);3.30(m,1H);2.93(s,3H);2.87(dd,1H,J 1=5.5Hz,J 2=13.5Hz);2.72(m,2H);2.66(dd,J 1=7.3Hz,J 2=13.3Hz),2.47(brs,1H),2.36(brs,1H),2.23(s,6H),1.91(m,2H),1.56(m,2H),1.40(m,2H),1.40(d,6H,J=6.8Hz)。m/z734(M+H)+;756(M+Na)+;
实施例CE的制备
方案67
化合物119
化合物119商购自Aldrich并且作为普遍可接受的使用。
化合物120
将化合物119(200mg,0.91mmol),化合物8(373.7mg,0.91mmol),EDC(212mg,1.37mmol),HOBt(160.3mg,1.19mmol)和iPr2NEt(794.7μL,4.56mmol)在THF中的混合物在室温下搅拌10h。然后将该混合物蒸发至小体积并且通过CombiFlash纯化(用1-10%MeOH/CH2Cl2洗脱)。收集含靶化合物的级分并且通过CombiFlash再纯化(40-100%EtOAc/己烷)而得到449mg化合物120,为油状物。(m/z611.0(M+H)+)。
实施例CE
用HCl/二噁烷(3mL)处理化合物120(449mg,0.74mmol)。将所得混合物蒸发至干并且冻干至得到373.6mg白色固体。
向上述白色化合物(52.5mg,0.096mmol)在CH2Cl2(10mL)中的溶液中加入化合物9(19.8mg,0.096mmol),CDI(15.6mg,0.096mmol),随后加入iPr2NEt(33.4μL,0.192mmol)。将该混合物搅拌20h,此后将其蒸发至干。向该混合物中加入CH2Cl2,然后通过棉絮塞过滤。将滤液蒸发至干并且用CombiFlash纯化。收集含实施例CE的级分并且使用TLC再纯化而得到15.1mg实施例CE。1H-NMR(CDCl3,300MHz):8.79(s,1H);7.82(s,1H);7.09-7.27(m,10H),6.94(s,1H);6.25(d,2H,J=8.7Hz);5.23(s,2H);5.17(brs,1H);4.43(dAB,2H,J=16.5Hz);4.29(m,1H);4.13(m,1H),3.76(m,2H);3.48(m,1H);3.29(s,3H);3.25(m,1H),2.94(s,3H),2.65-2.82(m,4H),1.75(m,2H),1.54(m,2H),1.39(d,5H,J=6.9Hz)。m/z707(M+H)+;729(M+Na)+。
实施例CF的制备
方案68
实施例CF
使用与实施例CE相同的方法制备实施例CF,但使用化合物68替代化合物9。1H-NMR(CDCl3,300MHz):8.79(s,1H);8.74(s,1H),7.81(s,1H),7.73(s,1H);7.12-7.27(m,10H);6.15(d,1H,J=8.7Hz),5.39(d,1H,J=6.8Hz);5.21(s,2H),5.06(d,J=9.1Hz,1H);4.64(dAB,2H,J=15.5Hz);4.28(m,1H);4.134(m,1H),3.79(m,1H),3.70(m,1H);3.34(m,1H);3.28(s,3H);2.87(s,3H);2.72(m,4H);1.57(m,2H);1.50(m,2H)。(m/z665.2(M+H)+;687.3(M+Na)+。
化合物CG的制备
方案69
化合物121
化合物121商购自Aldrich并且作为普遍接受的使用。
化合物122
向化合物121(2.05g,11.3mmol)在CH2Cl2(40mL)中的混悬液中加入iPr2NEt(5.87mL,33.9mmol),随后加入CDI(1.86g,11.3mmol)。将所得混合物在室温下搅拌6h,然后加入化合物9(2.33g,11.3mmol)。将所得混合物再搅拌10h,此后将其蒸发至干。将该混合物再溶于CH2Cl2并且通过过滤除去固体。将滤液蒸发至干并且通过CombiFlash纯化(用20-80%EtOAc/己烷洗脱)而得到3.2g化合物207,为淡黄色油状物。m/z 298.0(M+H)+。
化合物123
向化合物122(3.2g,10.8mmol)在THF(100mL)中的溶液中加入新近制备的1M LiOH(10.8mmol)。将两相反应体系在室温下剧烈搅拌16h,此后用1M HCl淬灭。将该混合物的pH调整至2.5-3且然后蒸发至小体积。使该混合物分配在CH2Cl2与盐水(50mL)之间,分离水层并且用CH2Cl2萃取两次。用无水Na2SO4干燥合并的CH2Cl2层并且浓缩而得到3.37g化合物123,为淡黄色油状物,将其不经进一步纯化使用。m/z316.0(M+H)+,338(M+Na)+;
实施例CG
按照例如C相同的操作制备实施例CG,但使用化合物123而不是化合物7。1H-NMR(CDCl3,500MHz):8.80(s,1H);7.83(s,1H),7.11-7.26(m,10H),6.96(s,1H);7.12-7.27(m,10H);6.52(br s,1H),6.40(brs,1H),5.23(s,2H),5.20(m,1H),4.44(dAB,2H,J=15.5Hz),4.39(m,1H),4.11(m,1H),3.80(m,1H),3.61(m,2H),3.28(sep,1H,J=7.0Hz);2.94(s,3H),2.79(dd,1H,J1=6.1Hz,J2=13.4Hz);2.71(m,3H),1.93(m,1H),1.71(m,1H),1.54(m,1H),1.38(d,6H,J=7.0Hz)1.37(m,1H)。(:)+;m/z707.3(M+H)+),729.2(M+Na)+。
化合物100的制备
方案70
使用用于制备化合物122相同的方法制备化合物100,但使用化合物9替代化合物68。
实施例CH的制备
方案71
化合物124和125
向化合物29(135mg,0.43mmol)和化合物22(116mg,0.43mmol)在THF(5mL)中的溶液中加入HOBt(70mg,0.52mmo l),EDC(94μL,0.52mmol)和二异丙基乙胺(150μL,0.83mmol)。将该混合物搅拌12小时并且浓缩。通过反相HPLC纯化而得到化合物124(70mg)和化合物125(120mg)。化合物124:1H-NMR(CDCl3)δ7.2-7.1(10H,m),7.0(2H,s),6.45(2H,m),6.15(2H,m),4.45(4H,s),4.1(2H,m),3.96(2H,m),3.3(2H,m),2.98(6H,s),2.7(4H,m),2.1(2H,m),1.6-1.3(16H,m),0.90(12H,m)。m/z 859.3(M+H)+;化合物125:m/z 564.3(M+H)+
化合物126
向化合物125(120mg,0.21mmol)在CH3CN(1mL)中的溶液中加入37%甲醛溶液(17μL,0.23mmol),随后加入HOAc(24μl,0.42mmol)。将该混合物搅拌2小时并且加入NaBH(OAc)3(140mg,0.63mmol)。将该混合物再搅拌2小时并且用EtOAc稀释。用饱和Na2CO3溶液,水和盐水洗涤有机相并且用Na2SO4干燥。浓缩而得到化合物126,将其不经进一步纯化使用。m/z578.3(M+H)+
实施例CH
按照用于制备实施例L的操作制备实施例CH(26mg),但使用化合物126而不是化合物22。1H-NMR(CDCl3)δ8.91(1H,m),7.82(1H,m),7.2-7.0(11H,m),6.4(1H,m),6.2(1H,m),5.23-5.05(2H,m),4.44(2H,s),4.44(1H,m),4.2(1H,m),3.95(1H,m),3.32(1H,m),2.98(3H,s),2.8-2.5(7H,m),2.15(1H,m),1.7-1.2(10H,m),0.88(6H,m)。m/z719.3(M+H)+
实施例CI的制备
方案72
化合物127
按照用于制备化合物126的操作制备化合物127(110mg),但使用化合物8而不是化合物125。m/z424.4(M+H)+
实施例CI
按照用于制备实施例C的操作制备实施例CI(7mg),但使用化合物127和29而不是化合物8和7。1H-NMR(CDCl3)δ9.0(1H,s),8.92(1H,s),7.4-7.0(11H,m),5.25(2H,m),4.6-4.0(5H,m),3.4(1H,m),3.1-2.6(10H,m),1.9(1H,m),1.8(10H,m),0.9(6H,m);m/z 719.2(M+H)+
化合物CJ的制备
方案73
化合物128
向化合物21(100mg)在二氯甲烷(5mL)中的溶液中加入TFA(1mL)。将该混合物搅拌3小时并且蒸发过量的试剂。用EtOAc稀释油状物且然后用饱和Na2CO3溶液(2x),水(2x)和盐水洗涤并且用Na2SO4干燥。浓缩而得到化合物128(46mg)。m/z267.1(M+H)+
化合物129
按照化合物8的操作制备化合物129(44mg),但使用化合物128而不是化合物22。m/z408.10(M+H)+
实施例CJ
按照例如C的操作制备实施例CJ(55mg),但使用化合物129和29而不是化合物8和7。1H-NMR(CDCl3)δ8.81(1H,s),7.85(1H,s),7.2-7.0(11H,m),6.4(1H,m),6.12(1H,m),5.44(2H,m),5.26(2H,s),4.85(1H,m),4.70(1H,m),4.4(3H,m),4.06(1H,m),3.25(1H,m),2.98(3H,s),2.78(4H,m),2.21(1H,m),1.38(6H,m),0.88(6H,m);m/z 703.2(M+H)+
化合物CK和CL的制备
方案74
实施例CK
按照用于制备实施例C的操作制备实施例CK(88mg),但使用化合物49而不是化合物7。m/z749.2(M+H)+
实施例CL
将实施例CK(85mg)和TFA(5mL)的混合物搅拌3小时。蒸发过量的TFA并且在高度真空中干燥该混合物。将该混合物溶于THF(5mL)并且加入1.0N氢氧化钠,直到pH为11。将该溶液搅拌10分钟并且用EtOAc萃取。用水,盐水洗涤有机相并且用Na2SO4干燥。
浓缩并且通过快速柱色谱法纯化(EtOAc)而得到实施例CL(66mg)。1H-NMR(CDCl3)δ8.81(1H,s),7.84(1H,s),7.30-6.96(11H,m),5.22(2H,s),4.90(1H,m),4.45(1H,m),4.35-4.0(4H,m),3.8(1H,m),3.6(1H,m),3.21(1H,m),2.95(3H,s),2.8-2.6(4H,m),2.0-1.4(4H,m),1.25(6H,m)。m/z693.2(M+H)+。
实施例CM的制备
方案75
化合物130
化合物130商购自(TCI)并且作为普遍接受的使用。
化合物131
向在0℃下化合物130(510mg,3mmol)在甲醇(12mL)中的溶液中滴加亚硫酰氯(0.5mL,6.6mmol)。将该混合物在0℃下搅拌30分钟并且使其达到回流3小时。浓缩而得到化合物131,为白色固体。
化合物132
向化合物131(3mmol)和二异丙基乙胺(2mL,12mmol)在二氯甲烷(35mL)中的搅拌溶液中加入CDI(486mg,3mmol)。将该混合物搅拌12小时。加入化合物9并且将该混合物再搅拌12小时。浓缩并且通过快速柱色谱法纯化(CH2Cl2/iPrOH=10/1)而得到化合物132(414mg)。m/z380.0(M+H)+
化合物133
按照用于制备化合物67的操作制备化合物133,但使用化合物132而不是化合物66。m/z364.0(M-H)-
实施例CM
按照例如C的操作制备实施例CM(600mg),但使用化合物133而不是化合物7。1H-NMR(CDCl3)δ9.18(1H,s),8.35(1H,s),7.95(1H,s),7.6(1H,m),7.3-7.0(11H,m),5.22(2H,m),4.70(1H,m),4.50(2H,m),4.05(1H,m),3.86(3H,s),3.80(2H,m),3.55(1H,m),3.10(1H,m),2.90(3H,s),2.70(4H,m),1.45(10H,m);m/z757.3(M+H)+
实施例O,P,CN和CO的制备
方案76
实施例O
按照例如C的操作制备实施例O(17mg)制备,但使用化合物46和49而不是化合物8和7。m/z749.3(M+H)+
实施例CN
按照用于制备实施例C的操作制备实施例CN(22mg),但使用化合物46和13e而不是化合物8和7。m/z763.2(M+H)+
实施例P
按照用于制备实施例CM的操作制备实施例P(12mg),但使用实施例O而不是实施例CL。1H-NMR(CDCl3)δ8.76(1H,s),7.79(1H,s),7.25-6.9(11H,m),6.51(1H,宽峰),5.42(1H,m),5.18(2H,m),4.42(2H,m),4.22(1H,m),4.10(1H,m),3.95(1H,m),3.79(1H,m),3.58(1H,m),3.23(1H,m),2.93(3H,s),2.9-2.5(4H,m),1.6-1.2(10H,m);m/z:693.2(M+H)+。
化合物CO
按照用于制备实施例CL的操作制备实施例CO(13mg),但使用实施例CN而不是化合物CK。1H-NMR(CDCl3)δ8.85(1H,m),7.88(1H,m),7.3-7.0(11H,m),6.55(1H,m),6.24(1H,m),5.45(1H,m),5.23(2H,m),4.6(2H,m),4.2(1H,m),4.0(2H,m),3.7(1H,m),3.5(1H,m),3.02(3H,s),2.70(4H,m),1.6-1.0(13H,m);m/z:707.3(M+H)+。
实施例CP-CS的制备
方案77
化合物134
使用对化合物76所述的操作制备化合物134,但使用CBZ-D-丙氨醇而不是CBZ-L-丙氨醇。
化合物135
按照用于制备化合物8的操作制备化合物135,但使用化合物134而不是化合物22。
实施例CP
按照用于制备实施例C的操作制备实施例CP(12mg),但使用化合物135和49而不是化合物8和7。m/z597.2(M+H)+。
实施例CQ
按照用于制备实施例C的操作制备实施例CQ(11mg),但使用化合物135和13d而不是化合物8和7。m/z611.2(M+H)+。
实施例CR
按照用于制备实施例P的操作制备实施例CR(7mg),但使用实施例CP而不是实施例O。1H-NMR(CDCl3)δ8.82(1H,s),7.88(1H,s),7.02(1H,s),6.92(1H,m),5.28(2H,s),5.10(1H,m),4.5(2H,m),4.15(2H,m),3.88(1H,m),3.8-3.5(2H,m),3.35(1H,m),3.0(3H,s),1.5-1.0(16H,m);m/z:541.1(M+H)+。
实施例CS
按照用于制备实施例CO的操作制备实施例CS(8mg),但使用实施例CQ而不是实施例CN。1H-NMR(CDCl3)δ8.83(1H,s),7.88(1H,s),6.98(1H,s),6.81(1H,m),6.58(1H,m),5.28(2H,s),5.18(1H,m),4.4-4.3(2H,m),4.03(1H,m),3.85(1H,m),3.58(2H,m),3.3(1H,m),2.99(3H,s),1.5-0.98(19H,m);m/z:555.2(M+H)+。
实施例CT-CV的制备
方案78
化合物136
化合物136a-c为商购的(Sigma-Aldrich)。
化合物137
向化合物136(20mmol)在甲醇(25mL)中的溶液中滴加苯甲醛(40mmol)。将该混合物搅拌2小时并且冷却至0℃。分部分加入硼氢化钠(44mmol)。将该混合物温至25℃并且搅拌2小时。加入乙酸(10mL)并且将该混合物搅拌10分钟。除去甲醇并且使用EtOAc和3NNaOH溶液分配该混合物。分离有机层并且用EtOAc(2x)萃取水相。用水,盐水洗涤合并的有机层并且用Na2SO4干燥。浓缩而得到化合物137。
化合物138
按照用于制备化合物8的操作制备化合物138,但使用化合物137而不是化合物22。
实施例CT
按照用于制备实施例C的操作制备实施例CT(70mg),但使用化合物29和138a而不是化合物13a和8。1H-NMR(CDCl3)δ8.79(1H,s),7.86(1H,s),6.97(1H,s),6.49(1H,m),6.15(1H,m),5.28(2H,s),5.20(1H,m),4.44(2H,m),4.05(1H,m),3.25(5H,m),3.0(3H,s),2.24(1H,m),1.8-1.45(4H,m),1.38(6H,m),0.97(6H,m);m/z:525.2(M+H)+。
实施例CU
按照用于制备实施例C的操作制备实施例CU(140mg),但使用化合物29和138b而不是化合物13a和8。1H-NMR(CDCl3)δ8.78(1H,s),7.85(1H,m),7.4-7.05(10H,m),6.93(1H,s),5.90(1H,m),5.35(2H,s),4.9-4.6(2H,m),4.6-4.4(4H,m),4.2(1H,m),3.4-3.05(5H,m),3.0(3H,s),2.0(1H,m),1.8-1.3(10H,m),0.90(6H,m);m/z:705.2(M+H)+。
实施例CV
按照用于制备实施例C的操作制备实施例CV(145mg),但使用化合物29和138c而不是化合物13a和8。1H-NMR(CDCl3)δ8.76(1H,m),7.86(1H,m),7.4-7.02(10H,m),6.97(1H,m),5.75(1H,m),5.38(2H,m),4.95-4.3(6H,m),4.15(1H,m),3.4-3.0(5H,m),3.0(3H,s),2.2-1.6(3H,m),1.4(6H,m),0.88(6H,m);m/z:691.2(M+H)+。
实施例CW的制备
可以例如通过使化合物8与具有如下结构的化合物反应制备实施例CW:
其中“LG”为离去基,诸如卤素。这类化合物可以通过使用公知方法,诸如Hunsdieker反应或Kochi反应或类似方法使相应羧酸或酯(例如化合物28或29)的一-碳降解制备。
人肝细胞色素P450的IC50测定
材料和一般方法
采集的(n≥15个供体)人肝微粒体部分获自BD-Gentest(Woburn,MA),其还提供了羟基-特非那定,4’-羟基双氯芬酸和NADPH再生系统。利托那韦由商购口服溶液(AbbottLaboratories,Abbott Park,IL)制备。其它试剂来自Sigma-Aldrich(St.Louis,MO)并且包括特非那定,非索非那定,BRL15572,双氯芬酸和甲芬那酸。
使用作为制造商描述使用的NADPH再生系统按照一式两份在pH7.4的50mM磷酸钾缓冲液中进行孵育。预先测定最终微粒体蛋白质浓度在活性的线性范围内并且在孵育过程中产生小于20%的底物消耗。所用的最终底物浓度等于在相同条件下测定的活性的表观Km值。将抑制剂溶于DMSO并且来自底物和抑制剂媒介物的DMSO终浓度为1%(v/v)。在37℃下通过振摇进行孵育并且通过添加底物启动。然后在0,7和15分钟时取出等分部分。通过用包含内标的乙腈,甲酸,水(94.8%/0.2%/5%,v/v/v)混合物处理使样品淬灭。通过以3000rpm离心10min除去沉淀的蛋白质且然后对上清液进行LC-MS分析。
LC-MS系统由Waters Acquity UPLC与二元溶剂控制器和冷却(8℃)样品收集仪和样品控制器组成,它与以电喷射离子化模式操作的Micromass QuattroPremier串联质谱仪衔接。柱为Waters AcquityUPLC BEH C182.1x50mm,1.7μm孔径。流动相由乙腈,甲酸和水的混合物组成,流动相A的组成为1%/0.2%/98.8%(v/v/v)且流动相B的组成为94.8%/0.2%/5%(v/v/v)。注射体积为5μL且流速为0.8mL/min。通过参比在与孵育相同条件下使用可靠分析物生成的标准曲线确定代谢物浓度。
通过使用GraphPad Prism4.0软件和S形模型进行非线性回归计算IC50值(将CYP3A活性降低50%的抑制剂浓度)。
CYP3A抑制测定
使用特非那定氧化酶评价作为人肝CYP3A亚族的P450细胞色素(特别是CYP3A4)抑制剂的化合物的效能,即一种充分表征的Ling,K.-H.J.等在Drug Metab.Dispos.23,631-636,(1995)和Jurima-Romet,等在Drug Metab.Dispos.22,849-857,(1994)中所述的CYP3A-选择性活性。微粒体蛋白和特非那定底物的终浓度分别为0.25mg/mL和3μM。通过用7个体积的含0.1μMBRL 15572作为内标的淬灭溶液处理终止代谢反应。再加入8个体积的水,此后离心并且取出上清液的等分部分用于LC-MS分析。
就LC-MS分析而言,通过下列步骤进行色谱洗脱:以20%B开始的一系列线性梯度并且保持0.1分钟,然后在1.5内增加至80%B,保持0.4min且然后恢复到起始条件0.05min。该系统需要再平衡至少0.25分钟,此后进行接下来的注射。以正离子模式操作质谱仪并且监测下列前体([M+H]+)/产物离子对并且用MassLynx4.0(SP4,525)软件定量:羟基-特非那定488.7/452.4,非索非那定502.7/466.4和BRL15572 407.5/209.1。根据羟基-特非那定和羧基-特非那定(非索非那定)代谢物的总和确定特非那定氧化酶活性。
CYP2C9抑制测定
使用双氯芬酸4’-羟化酶评价人肝CYP2C9抑制剂的化合物的效能,即一种如Leeman,T.等在Life Sci.52,29-34,(1992)中所述的该酶的特异性活性。微粒体蛋白和双氯芬酸底物的终浓度分别为0.08mg/mL和4μM。通过用3个体积的含1μM甲芬那酸作为内标的淬灭溶液处理终止代谢反应。再离心后,加入4个体积的水。然后取出上清液的等分部分用于LC-MS分析。
就LC-MS分析而言,通过下列步骤进行色谱洗脱:以20%B开始的一系列线性梯度并且保持0.3分钟,然后在1.2分钟内增加99%B,保持0.5分钟且然后恢复到起始条件0.25min。该系统需再平衡至少0.25分钟,此后进行接下来的注射。以负离子模式操作质谱仪并且监测下列前体([M-H]-)/产物离子对并且定量:4’-羟基-双氯芬酸312.4/294.2且甲芬那酸242.4/224.2。
用于HIV蛋白酶抑制剂表征的生物学试验
HIV-1蛋白酶测定法(Ki)
本测定法基于用HIV-1蛋白酶在最初如M.V.Toth和G.R.Marshall,Int.J.Peptide Protein Res.36,544(1990)(为了所有目的而将该文献完整地引入本文作为参考)所述的确定的反应缓冲液中对合成的六肽底物裂解进行荧光检测。
本测定法使用(2-氨基苯甲酰基)Thr-Ile-Nle-(对-硝基)Phe-Gln-Arg作为底物和在大肠杆菌(E.Coli)中表达的重组HIV-1蛋白酶作为酶。两种试剂均由Bachem California,Inc.(Torrance,CA;Cat.no.H-2992)提供。用于该反应的缓冲液为100mM乙酸铵,pH5.3,1M氯化钠,1mM乙二胺四乙酸,1mM二硫苏糖醇和10%二甲基亚砜。
为了测定抑制常数Ki,制备含相同量酶(1-2.5nM)和在反应缓冲液中不同浓度下测试的抑制剂的一系列溶液。随后将这些溶液转入白色96-孔平板(各190μl)并且在37℃下预孵育15min。使底物以800μM的浓度在100%二甲基亚砜中增溶并且将10μl 800μM底物加入到各孔中以便达到40μM的最终底物浓度。在37℃下使用Gemini96-孔平板荧光计(Molecular Devices,Sunnyvale,CA)在λ(Ex)=330nm和λ(Em)=420nm测定实时反应动力学。测定与不同抑制剂浓度反应的初速度并且通过使用EnzFitter程序(Biosoft,Cambridge,U.K.),按照Ermolieff J.,Lin X.和Tang J.,Biochemistry36,12364(1997)所述用于紧密结合竞争性抑制的算法计算Ki值(以皮摩尔浓度单位计)。
HIV-1蛋白酶测定法(IC50)
就上述Ki测定而言,IC50测定法基于使用HIV-1蛋白酶在最初如M.V.Toth和G.R.Marshall,Int.J.Peptide Protein Res.36,544(1990)所述的确定的反应缓冲液中对合成的六肽底物裂解进行荧光检测。
本测定法使用(2-氨基苯甲酰基)Thr-Ile-Nle-(对-硝基)Phe-Gln-Arg作为底物和在大肠杆菌中表达的重组HIV-1蛋白酶作为酶。两种试剂均由Bachem California,Inc.(Torrance,CA;Cat.nos.分别为H-2992和H-9040)提供。用于该反应的缓冲液为100mM乙酸铵,pH5.5,1M氯化钠,1mM乙二胺四乙酸,1mM二硫苏糖醇和10%二甲基亚砜。
为了测定IC50值,将170μL反应缓冲液转入白色96-孔微量滴定板的各孔。制备一系列测试抑制剂在DMSO中的3-倍稀释液并且将10μL所得稀释液转入微量滴定板的各孔。将10μL在反应缓冲液中20-50nM酶储备溶液加入到96-孔平板的各孔中以便提供1-2.5nM的最终酶浓度。然后将平板在37℃下预孵育10分钟。使底物以400μM的浓度在100%二甲亚砜中增溶并且将10μl 400μM底物加入到各孔中以便达到20μM的最终底物浓度。使用Gemini96-孔平板荧光计(Molecular Devices,Sunnyvale,CA)在λ(Ex)=330nm和λ(Em)=420nm测定实时反应动力学。测定与不同抑制剂浓度反应的初速度并且通过使用GraphPad PrismTM软件拟合非线性回归曲线计算IC50值(以纳摩尔浓度单位计)。
抗-HIV-1细胞培养物测定(EC50)
本测定法基于在有或没有测试抑制剂存在下通过对病毒感染细胞的存活率进行比色检测对HIV-1-关联的致细胞病变效应进行定量。使用代谢底物2,3-双(2-甲氧基-4-硝基-5-磺基苯基)-2H-四唑-5-甲酰苯胺(XTT)测定HIV-1-诱导的细胞死亡,所述的代谢底物2,3-双(2-甲氧基-4-硝基-5-磺基苯基)-2H-四唑-5-甲酰苯胺(XTT)仅由完整细胞转化成具有如Weislow OS,Kiser R,Fine DL,Bader J,ShoemakerRH和Boyd MR,J.Natl.Cancer Inst.81,577(1989)(为了所有目的而将该文献完整地引入本文作为参考)所述特异性吸收特征的产物。
在37℃下用野生型HIV-1株IIIB(Advanced Biotechnologies,Columbia,MD),使用相当于等于0.01的感染复数的病毒接种物将维持在补充了5%胎牛血清和抗生素的RPMI-1640培养基中的MT2细胞(NIH AIDS试剂程序,Cat#237)感染3小时。使在培养基中的感染细胞分布入96-孔平板(以100μl/孔的20,000个细胞)并且在37℃和一组含5-倍测试抑制剂的系列稀释液的溶液(100μl/孔)存在下孵育5天。还使未处理的感染的样品和未处理的模拟感染的对照组细胞分布入96-孔平板并且在相同条件下孵育。
为了测定所测试抑制剂的抗病毒活性,在55℃下在水浴中使在磷酸缓冲盐水pH7.4中2mg/mL浓度的底物XTT溶液(6mL/测定平板)加热5min,此后每6mL XTT溶液加入50μl N-甲基二甲基苯基吡唑酮鎓(n-methylphen azonium methasulfate)(5μg/mL)。在从测定平板的各孔中取出100μl培养基后,将100μl XTT底物溶液加入到各孔中。将细胞和XTT溶液在37℃下和CO2孵育箱中孵育45-60min。为了使病毒失活,向各孔中加入20μl 2%TritonX-100。根据在450nm处的吸收度,以分光光度法对如通过产生的XTT代谢物量确定的存活率进行定量(其中扣除在650nm处的背景吸收度)。将来自本测定的数据表示为相对于未处理对照组的百分比吸收度并且将50%有效浓度(EC50)计算为使感染的化合物处理的细胞中XTT代谢物产生百分比增加至未感染的无化合物细胞产生的50%的化合物浓度。
在40%人血清或人血清蛋白存在下的抗-HIV-1细胞培养物测定(EC
50
)
本测定法基本上与上述抗-HIV-1细胞培养物测定法相同,但在有或没有生理浓度的40%人血清(Type AB Male Cambrex 14-498E)或人血清蛋白(人α-酸糖蛋白,SigmaG-9885;人血清白蛋白,Sigma A1653,96-99%)存在下进行感染。如上所述测定HIV-1-诱导的细胞死亡,但将在96-孔平板至分布的感染细胞在80%人血清(2X浓度)或2mg/mL人α-酸糖蛋白+70mg/mL HSA(2X浓度)而非培养基中孵育。
细胞毒性细胞培养物测定(CC
50
)
本测定法基于使用如Weislow OS,Kiser R,Fine DL,Bader J,Shoemaker RH和Boyd MR,J.Natl.Cancer Inst.81,577(1989)所述的代谢底物2,3-双(2-甲氧基-4-硝基-5-磺基苯基)-2H-四唑-5-甲酰苯胺(XTT)对测试化合物进行的细胞毒性效应评价。本测定法基本上与上述测定法相同(抗-HI V-1细胞培养物测定法),但不感染细胞。如上所述测定化合物诱导的细胞死亡(或生长减少)。
将维持在补充了5%胎牛血清和抗生素的RPMI-1640培养基的MT-2细胞分布在96-孔平板(100μl/孔中的20,000个细胞)中并且在37℃和有或没有5-倍测试抑制剂系列稀释液(100μl/孔)存在下孵育5天。对照组包括未处理的感染细胞和被1μM P4405(鬼臼毒素,SigmaCat#P4405)保护的感染细胞。
为了测定细胞毒性,在55℃下和黑暗中的水浴中使在磷酸缓冲盐水pH7.4中2mg/mL浓度的XTT溶液(6mL/测定平板)加热5min,此后每6mL XTT溶液加入50μl N-甲基二甲基苯基吡唑酮鎓(5μg/mL)。在从测定平板的各孔中取出100μl培养基后,将100μl XTT底物溶液加入到各孔中。将细胞和XTT溶液在37℃下和CO2孵育箱中孵育45-60min。为了使病毒失活,向各孔中加入20μl 2%Triton X-100。根据在450nm处的吸收度,以分光光度法对如通过产生的XTT代谢物量确定的存活率进行定量(其中扣除在650nm处的背景吸收度)。将来自本测定的数据表示为相对于未处理对照组的百分比吸收度并且将50%细胞毒性浓度(EC50)计算为使化合物处理细胞中的细胞生长百分比增加至由未感染的无化合物的细胞提供的细胞生长的50%的化合物浓度。
基于有代表性的实施例A-CV的实验数据证实本发明式(I)的化合物可以具有由IC50约100nM-约4700nM表示的范围的CYP4503A4抑制活性和由IC50约100nM-约4200nM表示的范围的CYP4502C9抑制活性。
基于有代表性的实施例A-CV的实验数据证实本发明式(I)的化合物可以具有由HIVEC50约140nM-大于约1000nM表示的范围的蛋白酶抑制活性。
基于有代表性的实施例P,S和T的实验数据具有由IC50约80-150nM表示的范围的CYP450 3A4抑制活性,由IC50约1000-10,000nM表示的范围的CYP450 2C9抑制活性和由HIV EC50大于约20,000nM表示的范围的蛋白酶抑制活性。
Claims (18)
1.式IIB的化合物:
或其药学上可接受的盐,和/或立体异构体,其中:
R10a和R10b各自独立为H或-C1-4烷基;
R12为H或-CH3;
R13为H,-C1-4烷基,-(CH2)0-1CR17R18OR19,
-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)NR20R21,
-(CH2)1-3C(O)R22,-(CH2)1-3S(O)2R22或-(CH2)1-3-R23;
R14和R15各自独立为H,-C1-4烷基,或芳基烷基;
R17和R18各自独立为H或-C1-3烷基;
R19为H,-C1-4烷基或芳基烷基;
R20和R21各自独立为H,-C1-3烷基,-C(O)R17或
-S(O)2R17;或
R20和R21与连接它们的氮原子共同构成含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环;
R22为H,-C1-3烷基,-OR19或-NR20R21;且
R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环;
其中所述R20和R21构成的未被取代或取代的5-6元杂环基环和所述R23的未被取代或取代的5-6元杂环基环各自独立为未被取代或被C1-2烷基取代。
3.权利要求2的化合物,其中:
R13为-(CH2)0-3CR17R18NR20R21或-(CH2)0-3CR17R18NR17C(O)NR20R21;
4.式IIC的化合物:
或其药学上可接受的盐,和/或立体异构体,其中:
R13为H,-C1-4烷基,-(CH2)0-1CR17R18OR19,
-(CH2)0-3CR17R18NR20R21,-(CH2)0-3CR17R18NR17C(O)NR20R21,
-(CH2)1-3C(O)R22或-(CH2)1-3-R23;
R17和R18各自独立为H或C1-3烷基;
R19为H,-C1-4烷基或芳基烷基;
R20和R21各自独立为H,-C1-3烷基,-C(O)R17或
-S(O)2R17;或
R20和R21与连接它们的氮原子共同构成含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环;
R22为H,-C1-3烷基,-OR19或-NR20R21;且
R23为含1-2个选自N和O的杂原子的未被取代或取代的5-6元杂环基环;
其中所述R20和R21构成的未被取代或取代的5-6元杂环基环和所述R23的未被取代或取代的5-6元杂环基环各自独立为未被取代或被C1-2烷基取代。
6.权利要求5的化合物,其为:
或其药学上可接受的盐和/或立体异构体。
9.药物组合物,包括权利要求1至8任一项的化合物,或其药学上可接受的盐,和/或立体异构体;和药学上可接受的载体或赋形剂。
10.权利要求1至8任一项的化合物在制备药剂中的应用,所述药剂用于在有此需要的患者中抑制细胞色素P450单加氧酶。
11.权利要求1至8任一项的化合物在制备药剂中的应用,所述药剂用于在有此需要的患者中改善被细胞色素P450单加氧酶代谢的药物的药代动力学或增加被细胞色素P450单加氧酶代谢的药物的血浆水平。
12.权利要求11所述的应用,其中所述被细胞色素P450单加氧酶代谢的药物为抑制HIV蛋白酶的化合物,逆转录酶的HIV非-核苷抑制剂,逆转录酶的HIV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和NADH-氧化酶抑制剂,CCR5抑制剂,治疗HIV的其它药物,干扰素,利巴韦林类似物,NS3蛋白酶抑制剂,α-糖苷酶1抑制剂,肝保护剂,HCV的非核苷抑制剂,和治疗HCV的其它药物,或其混合物。
13.权利要求12所述的应用,其中所述的药剂为权利要求1的化合物与一种或多种额外的治疗剂的组合,所述的一种或多种额外的治疗剂选自抑制HIV蛋白酶的化合物,逆转录酶的HIV非-核苷抑制剂,逆转录酶的HIV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和NADH-氧化酶抑制剂,CCR5抑制剂,治疗HIV的其它药物,干扰素,利巴韦林类似物,NS5b聚合酶抑制剂,NS3蛋白酶抑制剂,α-糖苷酶1抑制剂,肝保护剂,HCV的非核苷抑制剂,和治疗HCV的其它药物,及其混合物。
14.权利要求13所述的应用,其中:
(1)所述的HIV蛋白酶抑制剂选自氨普那韦,阿扎那韦,呋山那韦,茚地那韦,洛匹那韦,利托那韦,奈非那韦,沙奎那韦,替拉那韦,贝卡那韦,地瑞那韦,TMC-126,TMC-114,莫折那韦(DMP-450),JE-2147(AG1776),L-756423,RO0334649,KNI-272,DPC-681,DPC-684,GW640385X,DG17,PPL-100,DG35和AG1859;
(2)所述的逆转录酶的HIV非核苷抑制剂选自卡普韦林,乙米韦林,地拉韦定,依法韦仑,奈韦拉平,右旋胡桐素A((+)calanolideA),依曲韦林,GW5634,DPC-083,DPC-961,DPC-963,MIV-150和TMC-120,TMC-278(rilpivirene),依法韦仑,BILR355BS,VRX840773,UK-453061和RDEA806;
(3)所述的逆转录酶的HIV核苷抑制剂选自齐多夫定,恩曲他滨,去羟肌苷,司他夫定,扎西他滨,拉米夫定,阿巴卡韦,氨多素韦(amdoxovir),艾夫他滨,阿洛夫定,MIV-210,racivir(±-FTC),D-d4FC,恩曲他滨,叠氮膦,福齐夫定替酯,阿立他滨(AVX754),氨多索韦(amdoxovir),KP-1461和磷夫定酯(以前称为HDP99.0003);
(4)所述的逆转录酶的HIV核苷酸抑制剂选自替诺福韦和阿德福韦;
(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,酪氨酸磷酸化抑制剂(tyrphostin),酪氨酸磷酸化抑制剂(tyrphostin)衍生物,槲皮素,槲皮素衍生物,S-1360,zintevir(AR-177),L-870812和L-870810,MK-0518(雷特格韦),BMS-538158,GSK364735C,BMS-707035,MK-2048和BA011;
(6)所述的gp41抑制剂选自恩夫韦地,西夫韦肽,FB006M和TRI-1144;
(7)所述的CXCR4抑制剂为AMD-070;
(8)所述的进入抑制剂为SP01A;
(9)所述的gp120抑制剂为BMS-488043或BlockAide/CR;
(10)所述的G6PD和NADH-氧化酶抑制剂为immunitin;
(11)所述的CCR5抑制剂选自阿拉韦罗,vicriviroc,马拉韦罗,PRO-140,INCB15050,PF-232798(Pfizer)和CCR5mAb004;
(12)所述治疗HIV的其它药物选自BAS-100,SPI-452,REP9,SP-01A,TNX-355,DES6,ODN-93,ODN-112,VGV-1,PA-457(bevirimat),聚肌胞,HRG214,Cytolin,VGX-410,KD-247,AMZ0026,CYT99007A-221HIV,DEBIO-025,BAY50-4798,MDX010(ipilimumab),PBS119,ALG889和PA-1050040(PA-040);
(13)所述的干扰素选自聚乙二醇化的rIFN-α2b,聚乙二醇化的rIFN-α2a,rIFN-α2b,rIFN-α2a,共有IFNα(干复津),β-干扰素,reaferon,intermaxα,r-IFN-β,干复津+干扰素γ-1b,IFN-ω与DUROS,albuferon,locteron,Albuferon,利比,口服干扰素α,IFNα-2bXL,AVI-005,PEG-Infergen和聚乙二醇化的IFN-β;
(14)所述的利巴韦林类似物选自rebetol,copegus和viramidine(taribavirin);
(15)所述的NS5b聚合酶抑制剂选自NM-283,valopicitabine,R1626,PSI-6130(R1656),HCV-796,BILB1941,XTL-2125,MK-0608,NM-107,R7128(R4048),VCH-759,PF-868554和GSK625433;
(16)所述的NS3蛋白酶抑制剂选自SCH-503034(SCH-7),VX-950(telaprevir),BILN-2065,BMS-605339和ITMN-191;
(17)所述的α-糖苷酶1抑制剂选自MX-3253(西戈斯韦)和UT-231B;
(18)所述的肝保护剂选自IDN-6556,ME3738,LB-84451和MitoQ;
(19)所述HCV的非-核苷抑制剂选自苯并咪唑衍生物,苯并-1,2,4-噻二嗪衍生物,苯丙氨酸衍生物,A-831和A-689;和
(20)所述治疗HCV的其它药物选自日达仙,硝唑尼特(alinea),BIVN-401(virostat),PYN-17(altirex),KPE02003002,actilon(CPG-10101),KRN-7000,civacir,GI-5005,ANA-975,XTL-6865,ANA971,NOV-205,tarvacin,EHC-18,NIM811,DEBIO-025,VGX-410C,EMZ-702,AVI4065,巴维昔单抗,Oglufanide和VX-497(merimepodib)。
15.权利要求10的应用,其中所述细胞色素P450单加氧酶是3A同工酶。
16.权利要求15的应用,其中所述细胞色素P450单加氧酶是3A4同工酶。
17.权利要求11的应用,中所述细胞色素P450单加氧酶是3A同工酶。
18.权利要求17的应用,其中所述细胞色素P450单加氧酶是3A4同工酶。
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Families Citing this family (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7786153B2 (en) | 2005-03-02 | 2010-08-31 | Abbott Laboratories Inc. | Compounds that are useful for improving pharmacokinetics |
CN103275033B (zh) | 2006-07-07 | 2015-04-29 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
EP2465855A1 (en) * | 2006-08-31 | 2012-06-20 | Abbott Laboratories | Cytochrome P450 oxidase inhibitors and uses thereof |
AU2013204817B2 (en) * | 2007-02-23 | 2015-05-07 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
AU2015204378B2 (en) * | 2007-02-23 | 2017-03-09 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
PL2487163T3 (pl) | 2007-02-23 | 2017-04-28 | Gilead Sciences, Inc. | Modulatory farmakokinetycznych właściwości środków terapeutycznych |
US9891239B2 (en) * | 2007-02-23 | 2018-02-13 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
SG182229A1 (en) * | 2007-06-29 | 2012-07-30 | Gilead Sciences Inc | Therapeutic compositions and the use thereof |
US20090093482A1 (en) * | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
CN101796040A (zh) * | 2007-07-06 | 2010-08-04 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
JP2011503231A (ja) * | 2007-11-20 | 2011-01-27 | コンサート ファーマシューティカルズ インコーポレイテッド | Hcv感染処置のためのペプチド |
AU2008346823B2 (en) * | 2008-01-04 | 2015-03-12 | Gilead Sciences, Inc. | Inhibitors of cytochrome P450 |
WO2009094190A2 (en) | 2008-01-25 | 2009-07-30 | Chimerix, Inc. | Methods of treating viral infections |
US10039718B2 (en) | 2008-05-02 | 2018-08-07 | Gilead Sciences, Inc. | Use of solid carrier particles to improve the processability of a pharmaceutical agent |
AR074897A1 (es) | 2008-12-23 | 2011-02-23 | Pharmasset Inc | Fosforamidatos de nucleosidos |
SG172361A1 (en) | 2008-12-23 | 2011-07-28 | Pharmasset Inc | Nucleoside analogs |
AU2009329872B2 (en) | 2008-12-23 | 2016-07-07 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
SG173544A1 (en) * | 2009-02-06 | 2011-09-29 | Gilead Sciences Inc | Tablets for combination therapy |
UA108738C2 (uk) | 2009-04-03 | 2015-06-10 | Спосіб одержання інгібітора цитохром р450 монооксигенази та залучені проміжні сполуки | |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
TWI583692B (zh) | 2009-05-20 | 2017-05-21 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
WO2011123672A1 (en) | 2010-03-31 | 2011-10-06 | Pharmasset, Inc. | Purine nucleoside phosphoramidate |
EP2752422B1 (en) | 2010-03-31 | 2017-08-16 | Gilead Pharmasset LLC | Stereoselective synthesis of phosphorus containing actives |
EP2418196A1 (en) * | 2010-07-29 | 2012-02-15 | IMTM GmbH | Dual alanyl-aminopeptidase and dipeptidyl-peptidase IV inhibitors |
MY158809A (en) * | 2010-09-22 | 2016-11-15 | Craun Res Sdn Bhd | Pharmaceutical compositions for calanolides, their derivatives and analogues, and process for producing the same |
WO2012045007A1 (en) | 2010-10-01 | 2012-04-05 | Gilead Sciences, Inc. | Method of preparation of (4 - {4 -acetylamino- 2 - [3- ( 2 - isopropyl - thiazol - 4 - ylmethyl) - 3 -methyl - ureido] - butyryl amino} -1 -benzyl- 5 -phenyl- pentyl) -carbamic acid thiazol - 5 - ylmethyl ester |
ES2716158T3 (es) | 2010-11-30 | 2019-06-10 | Gilead Pharmasset Llc | 2'-spiro-nucleótidos para el tratamiento de hepatitis C |
WO2012088153A1 (en) * | 2010-12-21 | 2012-06-28 | Gilead Sciences, Inc. | Inhibitors of cytochrome p450 |
US20140187771A1 (en) * | 2011-05-02 | 2014-07-03 | Gilead Sciences, Inc. | Amorphous solid salts |
CN103826616B (zh) | 2011-07-07 | 2016-08-10 | 爱尔兰詹森科学公司 | 地瑞纳韦组合配制品 |
CA2845553C (en) | 2011-08-16 | 2019-05-28 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
MD4589C1 (ro) | 2011-09-16 | 2019-03-31 | Gilead Pharmasset Llc | Compoziţie farmaceutică cu conţinut de sofosbuvir şi utilizarea acesteia în tratamentul hepatitei virale C |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
US9089574B2 (en) | 2011-11-30 | 2015-07-28 | Emory University | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US20150004239A1 (en) | 2012-01-12 | 2015-01-01 | Gilead Sciences, Inc. | Pharmaceutical compositions and methods for their preparation |
SG11201404527QA (en) | 2012-02-03 | 2014-08-28 | Gilead Sciences Inc | Methods and intermediates for preparing pharmaceutical agents |
JP2015508822A (ja) | 2012-03-01 | 2015-03-23 | ギリアード サイエンシーズ, インコーポレイテッド | 噴霧乾燥製剤 |
CN104540813A (zh) * | 2012-06-27 | 2015-04-22 | 默沙东公司 | 磺酰胺衍生物以及使用它们用于改善药物的药物动力学的方法 |
WO2014000178A1 (en) * | 2012-06-27 | 2014-01-03 | Merck Sharp & Dohme Corp. | Sulfonamide derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
CN103694196A (zh) * | 2012-09-27 | 2014-04-02 | 上海迪赛诺化学制药有限公司 | 细胞色素p450单加氧酶抑制剂中间体及其制法和用途 |
US20160200716A1 (en) * | 2012-12-26 | 2016-07-14 | Assia Chemical Industries Ltd. | Cobicistat dichlohydrate salt |
NZ625087A (en) | 2013-01-31 | 2017-05-26 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
WO2014194519A1 (en) | 2013-06-07 | 2014-12-11 | Merck Sharp & Dohme Corp. | Imidazole derivatives and methods of use thereof for improving pharmacokinetics of drug |
CN104370777A (zh) * | 2013-08-13 | 2015-02-25 | 上海迪赛诺化学制药有限公司 | 合成(2r,5r)-1,6-二苯基己烷-2,5-二胺及其盐的中间体及所述中间体的制备方法和应用 |
ES2900570T3 (es) | 2013-08-27 | 2022-03-17 | Gilead Pharmasset Llc | Formulación de combinación de dos compuestos antivirales |
WO2015070366A1 (en) | 2013-11-12 | 2015-05-21 | Merck Sharp & Dohme Corp. | Aryl linked imidazole and triazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
WO2015070367A1 (en) | 2013-11-12 | 2015-05-21 | Merck Sharp & Dohme Corp. | Piperidine or piperazine linked imidazole and triazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
WO2015079415A1 (en) | 2013-11-29 | 2015-06-04 | Mylan Laboratories Ltd. | Amorphous cobicistat solid dispersion |
DK3236972T3 (en) | 2014-12-26 | 2021-10-04 | Univ Emory | Antivirale N4-hydroxycytidin-derivativer |
CN105198829B (zh) * | 2015-08-15 | 2017-10-31 | 浙江永宁药业股份有限公司 | 一种可比司他中间体的制备方法及其中间体和用途 |
TW201728582A (zh) | 2016-01-28 | 2017-08-16 | 基利科學股份有限公司 | 結晶型 |
US10653681B2 (en) | 2016-03-16 | 2020-05-19 | Recurium Ip Holdings, Llc | Analgesic compounds |
CN105884760B (zh) * | 2016-06-13 | 2019-01-04 | 厦门市蔚嘉化学科技有限公司 | 一种可比司他中间体的制备方法 |
CN107674039A (zh) * | 2016-08-01 | 2018-02-09 | 上海朴颐化学科技有限公司 | 一种可比西他中间体的制备方法 |
JP6764017B2 (ja) * | 2016-08-04 | 2020-09-30 | ギリアード サイエンシーズ, インコーポレイテッド | がんの処置での使用のためのコビシスタット |
EP3518935A1 (en) | 2016-09-27 | 2019-08-07 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
US11185548B2 (en) | 2016-12-23 | 2021-11-30 | Helmholtz Zentrum Munchen—Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) | Inhibitors of cytochrome P450 family 7 subfamily B member 1 (CYP7B1) for use in treating diseases |
SI3661937T1 (sl) | 2017-08-01 | 2021-11-30 | Gilead Sciences, Inc. | Kristalinične oblike etil((S)-((((2R,5R)-5-(6-amino-9H-purin-9-IL)-4- fluoro-2,5-dihidrofuran-2-IL)oksi)metil)(fenoksi)fosforil)-L-alaninata (GS-9131) za zdravljenje virusnih okužb |
SG11202004403QA (en) | 2017-12-07 | 2020-06-29 | Univ Emory | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US20220010054A1 (en) * | 2018-11-26 | 2022-01-13 | Mitsubishi Gas Chemical Company, Inc. | Aqueous epoxy resin composition and cured product of same |
CN111329858B (zh) * | 2018-12-18 | 2022-09-20 | 深圳先进技术研究院 | 一种小分子抑制剂在抑制病毒沉默抑制蛋白中的应用 |
EP4121437A1 (en) | 2020-03-20 | 2023-01-25 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
TWI815194B (zh) | 2020-10-22 | 2023-09-11 | 美商基利科學股份有限公司 | 介白素2-Fc融合蛋白及使用方法 |
WO2022103758A1 (en) | 2020-11-11 | 2022-05-19 | Gilead Sciences, Inc. | METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES |
WO2023102523A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
TW202337439A (zh) | 2021-12-03 | 2023-10-01 | 美商基利科學股份有限公司 | 用於hiv病毒感染之治療性化合物 |
US20230203071A1 (en) | 2021-12-03 | 2023-06-29 | Zhimin Du | Therapeutic compounds for hiv virus infection |
TW202400165A (zh) | 2022-04-06 | 2024-01-01 | 美商基利科學股份有限公司 | 橋聯三環胺甲醯基吡啶酮化合物及其用途 |
WO2024006982A1 (en) | 2022-07-01 | 2024-01-04 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
US20240083984A1 (en) | 2022-08-26 | 2024-03-14 | Gilead Sciences, Inc. | Dosing and scheduling regimen for broadly neutralizing antibodies |
WO2024076915A1 (en) | 2022-10-04 | 2024-04-11 | Gilead Sciences, Inc. | 4'-thionucleoside analogues and their pharmaceutical use |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997001349A1 (en) * | 1995-06-29 | 1997-01-16 | Abbott Laboratories | Use of ritonavir (abt-538) for improving the pharmacokinetics of drugs metabolized by cytochrome p450 in a method of treating aids |
CN1353607A (zh) * | 1999-06-04 | 2002-06-12 | 艾博特公司 | 改进的药物制剂 |
Family Cites Families (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3354866A (en) * | 1966-04-25 | 1967-11-28 | Frank D Karkoska | Coating apparatus including means to rotate and translate a rod-substrate |
US3882114A (en) * | 1967-10-26 | 1975-05-06 | Oreal | N-(morpholinomethyl carbamyl) cysteamine and glycine |
GB1339764A (en) * | 1971-03-29 | 1973-12-05 | Ici Ltd | Pyridine derivatives |
US3957774A (en) * | 1972-04-17 | 1976-05-18 | L'oreal | N-morpholinomethyl-n-'-substituted ethyl and propylureas |
US5142056A (en) * | 1989-05-23 | 1992-08-25 | Abbott Laboratories | Retroviral protease inhibiting compounds |
HU186777B (en) | 1981-07-09 | 1985-09-30 | Magyar Tudomanyos Akademia | Process for producing complex-forming agents of crown-ether base and ionoselective membranelektrodes containing them |
DE3478684D1 (en) * | 1983-11-02 | 1989-07-20 | Magyar Tudomanyos Akademia | Crown ether derivatives |
US5362912A (en) * | 1989-05-23 | 1994-11-08 | Abbott Laboratories | Process for the preparation of a substituted diaminodiol |
US5539122A (en) * | 1989-05-23 | 1996-07-23 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5354866A (en) * | 1989-05-23 | 1994-10-11 | Abbott Laboratories | Retroviral protease inhibiting compounds |
EP0428849A3 (en) | 1989-09-28 | 1991-07-31 | Hoechst Aktiengesellschaft | Retroviral protease inhibitors |
US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
US6703396B1 (en) | 1990-02-01 | 2004-03-09 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers |
US5914331A (en) | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
IE20010533A1 (en) * | 1990-11-20 | 2003-03-05 | Abbott Lab | Intermediates for preparing retroviral protease inhibiting compounds |
JPH06127981A (ja) | 1992-03-03 | 1994-05-10 | Fuainiteii Kk | 複合複層ガラス及びそれを使用した窓 |
US5556418A (en) * | 1993-07-06 | 1996-09-17 | Pappas; Panagiotis T. | Method and apparatus for pulsed magnetic induction |
US5968942A (en) * | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
KR100360964B1 (ko) * | 1992-12-29 | 2002-11-22 | 아보트 러보러터리즈 | 레트로바이러스성 프로테아제 억제 화합물의 중간체의제조방법 |
US5567592A (en) * | 1994-02-02 | 1996-10-22 | Regents Of The University Of California | Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal |
UA49803C2 (uk) * | 1994-06-03 | 2002-10-15 | Дж.Д. Сьорль Енд Ко | Спосіб лікування ретровірусних інфекцій |
US5567823A (en) * | 1995-06-06 | 1996-10-22 | Abbott Laboratories | Process for the preparation of an HIV protease inhibiting compound |
US5763464A (en) * | 1995-11-22 | 1998-06-09 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Retroviral agents containing anthranilamide, substituted benzamide and other subunits, and methods of using same |
US5922695A (en) | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
US5935946A (en) | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
WO1999033792A2 (en) * | 1997-12-24 | 1999-07-08 | Vertex Pharmaceuticals Incorporated | Prodrugs os aspartyl protease inhibitors |
FR2773994B1 (fr) | 1998-01-23 | 2002-10-11 | Univ Nice Sophia Antipolis | Prodrogues issues d'anti-proteases inhibitrices du virus de l'immunodeficience humaine (vih) pour l'amelioration de leur biodisponibilite, de leur tropisme vers et/ou de leur delivrance dans le systeme nerveux central |
FR2779653B1 (fr) * | 1998-06-11 | 2002-12-20 | Inst Nat Sante Rech Med | Utilisation de composes modulateurs du proteasome en therapie |
NZ518580A (en) | 1999-10-06 | 2004-01-30 | Us Gov Health & Human Serv | Hexahydrofuro[2,3-B]furan-3-YL-N- {3-[1,3-benzodioxol-5-ylsulfonyl) (isobutyl) amino]-1-benzyl-2-hydroxypropyl} carbamate as retroviral protease inhibitor |
US6252336B1 (en) | 1999-11-08 | 2001-06-26 | Cts Corporation | Combined piezoelectric silent alarm/battery charger |
AU2001259817A1 (en) * | 2000-05-04 | 2001-11-12 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The National Institutes Of Health | Methods of and compounds for inhibiting calpains |
US7193065B2 (en) * | 2001-07-13 | 2007-03-20 | Roche Diagnostics Operations, Inc. | Protease inhibitor conjugates and antibodies useful in immunoassay |
US6946449B2 (en) * | 2001-07-13 | 2005-09-20 | Cv Therapeutics, Inc. | Partial and full agonists of A1 adenosine receptors |
US7285566B2 (en) | 2002-01-07 | 2007-10-23 | Erickson John W | Resistance-repellent retroviral protease inhibitors |
ES2291642T3 (es) | 2002-01-17 | 2008-03-01 | MERCK & CO., INC. | Hidroxinaftiridinoncarboxamidas utiles como inhibidores de la integrasa de vih. |
US7205413B2 (en) * | 2002-05-03 | 2007-04-17 | Transform Pharmaceuticals, Inc. | Solvates and polymorphs of ritonavir and methods of making and using the same |
DK1564210T5 (da) | 2002-11-20 | 2010-05-03 | Japan Tobacco Inc | 4-Oxoquinolinforbindelser og anvendelse deraf som HIV-integraseinhibitorer |
JP2004184681A (ja) * | 2002-12-03 | 2004-07-02 | Konica Minolta Holdings Inc | 熱現像感光材料 |
EP1923063A3 (en) | 2003-01-14 | 2009-04-08 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
TW200505441A (en) | 2003-03-24 | 2005-02-16 | Hoffmann La Roche | Non-nucleoside reverse transcriptase inhibitorsⅠ |
US7737608B2 (en) | 2003-07-30 | 2010-06-15 | The Boeing Company | Enhanced amplitude piezoelectric motor apparatus and method |
JP2005091988A (ja) * | 2003-09-19 | 2005-04-07 | Konica Minolta Medical & Graphic Inc | 熱現像感光材料及び画像形成方法 |
MXPA06004723A (es) * | 2003-10-27 | 2006-07-05 | Vertex Pharma | Combinacion para el tratamiento del hcv. |
BRPI0401742B8 (pt) | 2004-05-13 | 2021-05-25 | Cristalia Produtos Quim Farmaceuticos Ltda | composto análogo do ritonavir útil como inibidor de protease retroviral, preparação do composto análogo do ritonavir e composição farmacêutica do composto análogo do ritonavir |
MY134672A (en) | 2004-05-20 | 2007-12-31 | Japan Tobacco Inc | Stable crystal of 4-oxoquinoline compound |
JP2006003701A (ja) * | 2004-06-18 | 2006-01-05 | Konica Minolta Medical & Graphic Inc | 熱現像感光材料および画像形成方法 |
EP2336138A3 (en) * | 2004-07-06 | 2011-11-16 | Abbott Laboratories | Prodrugs of HIV protease inhibitors |
US7786153B2 (en) * | 2005-03-02 | 2010-08-31 | Abbott Laboratories Inc. | Compounds that are useful for improving pharmacokinetics |
TWI471145B (zh) | 2005-06-13 | 2015-02-01 | Bristol Myers Squibb & Gilead Sciences Llc | 單一式藥學劑量型 |
TWI375560B (en) | 2005-06-13 | 2012-11-01 | Gilead Sciences Inc | Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same |
CN103275033B (zh) | 2006-07-07 | 2015-04-29 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
EP2465855A1 (en) | 2006-08-31 | 2012-06-20 | Abbott Laboratories | Cytochrome P450 oxidase inhibitors and uses thereof |
US9891239B2 (en) * | 2007-02-23 | 2018-02-13 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
SG182229A1 (en) | 2007-06-29 | 2012-07-30 | Gilead Sciences Inc | Therapeutic compositions and the use thereof |
US20090093482A1 (en) | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
CN101796040A (zh) * | 2007-07-06 | 2010-08-04 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
EP2245456B1 (en) | 2007-12-27 | 2013-02-13 | Baxter International Inc. | Method and compositions for specifically detecting physiologically acceptable polymer molecules |
US10039718B2 (en) | 2008-05-02 | 2018-08-07 | Gilead Sciences, Inc. | Use of solid carrier particles to improve the processability of a pharmaceutical agent |
SG173544A1 (en) | 2009-02-06 | 2011-09-29 | Gilead Sciences Inc | Tablets for combination therapy |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997001349A1 (en) * | 1995-06-29 | 1997-01-16 | Abbott Laboratories | Use of ritonavir (abt-538) for improving the pharmacokinetics of drugs metabolized by cytochrome p450 in a method of treating aids |
CN1353607A (zh) * | 1999-06-04 | 2002-06-12 | 艾博特公司 | 改进的药物制剂 |
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