CN111386279A - 用于治疗高钾血症的甘草次酸衍生物 - Google Patents
用于治疗高钾血症的甘草次酸衍生物 Download PDFInfo
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- CN111386279A CN111386279A CN201880064384.XA CN201880064384A CN111386279A CN 111386279 A CN111386279 A CN 111386279A CN 201880064384 A CN201880064384 A CN 201880064384A CN 111386279 A CN111386279 A CN 111386279A
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- Prior art keywords
- oxy
- dihydro
- inden
- methyl
- ethyl
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- 208000002682 Hyperkalemia Diseases 0.000 title claims abstract description 34
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical class C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 195
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- -1 alkoxyacyloxy Chemical group 0.000 claims description 653
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 201
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 116
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 110
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 125000000623 heterocyclic group Chemical group 0.000 claims description 89
- 125000001072 heteroaryl group Chemical group 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 101100451536 Arabidopsis thaliana HSD2 gene Proteins 0.000 claims description 38
- 241000124008 Mammalia Species 0.000 claims description 37
- 150000002367 halogens Chemical group 0.000 claims description 37
- 125000002947 alkylene group Chemical group 0.000 claims description 31
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 30
- 125000004043 oxo group Chemical group O=* 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000002837 carbocyclic group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 229960000890 hydrocortisone Drugs 0.000 claims description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 210000001072 colon Anatomy 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
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- 230000001419 dependent effect Effects 0.000 claims description 10
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 238000012217 deletion Methods 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 7
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
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- 229910001414 potassium ion Inorganic materials 0.000 claims description 7
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 claims description 6
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 claims description 6
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 201000010099 disease Diseases 0.000 claims 2
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- 239000003112 inhibitor Substances 0.000 abstract description 57
- 102000004277 11-beta-hydroxysteroid dehydrogenases Human genes 0.000 abstract description 2
- 108090000874 11-beta-hydroxysteroid dehydrogenases Proteins 0.000 abstract description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 193
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 188
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 110
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 107
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- 229910052757 nitrogen Inorganic materials 0.000 description 99
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000004202 carbamide Substances 0.000 description 95
- 229910001868 water Inorganic materials 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 102100022897 Sodium/hydrogen exchanger 10 Human genes 0.000 description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 57
- 239000012043 crude product Substances 0.000 description 57
- 239000011591 potassium Substances 0.000 description 57
- 229910052700 potassium Inorganic materials 0.000 description 56
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 56
- 238000002953 preparative HPLC Methods 0.000 description 55
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 48
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- 239000000741 silica gel Substances 0.000 description 45
- 229910002027 silica gel Inorganic materials 0.000 description 45
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 44
- 150000003384 small molecules Chemical class 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- 239000012298 atmosphere Substances 0.000 description 36
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 33
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 32
- 239000003208 petroleum Substances 0.000 description 32
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 150000002431 hydrogen Chemical group 0.000 description 26
- PEDPVHYNSCOTLR-UAOJZALGSA-N (3R)-1-[(1S,2S)-4,6-dichloro-1-phenoxy-2,3-dihydro-1H-inden-2-yl]piperidin-3-amine Chemical compound N[C@H]1CN(CCC1)[C@@H]1[C@H](C2=CC(=CC(=C2C1)Cl)Cl)OC1=CC=CC=C1 PEDPVHYNSCOTLR-UAOJZALGSA-N 0.000 description 24
- 150000003254 radicals Chemical class 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 150000002148 esters Chemical group 0.000 description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 21
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 19
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 19
- WNWOGOMGWXFMIZ-WMZOPIPTSA-N (1S,2S)-4,6-dichloro-N,N-dimethyl-1-(2-methylphenoxy)-2,3-dihydro-1H-inden-2-amine Chemical compound ClC1=C2C[C@@H]([C@H](C2=CC(=C1)Cl)OC1=C(C=CC=C1)C)N(C)C WNWOGOMGWXFMIZ-WMZOPIPTSA-N 0.000 description 18
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- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 17
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- YSERCIHBCXZJHY-HKUYNNGSSA-N (1S,2S)-6-chloro-2-(dimethylamino)-1-(2-methylphenoxy)-2,3-dihydro-1H-indene-4-carbonitrile Chemical compound ClC1=CC(=C2C[C@@H]([C@H](C2=C1)OC1=C(C=CC=C1)C)N(C)C)C#N YSERCIHBCXZJHY-HKUYNNGSSA-N 0.000 description 16
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Abstract
Description
相关申请的交叉引用
本申请根据35U.S.C.119(e)要求2017年8月4日提交的美国临时申请62/541,095的优先权的权益,该申请的内容特此以引用的方式全文并入。
发明领域
本发明涉及抑制11β-HSD2的化合物以及使用这些化合物从胃肠道中排除钾的方法,包括治疗高钾血症的方法。
发明背景
钾是细胞内液中最丰富的阳离子,并且在正常的人体生理中、特别是在神经和肌肉细胞中的动作电位激发方面起着重要作用。人体钾的总含量为约50mmol/kg体重,相当于70kg成人体内有大约3500mmol钾。全身钾的大部分在细胞内(~98%),仅有大约70mmol(~2%)在细胞外空间中。细胞内钾(~120-140mmol/L)与细胞外钾(~4mmol/L)之间的这种大的差异在很大程度上决定了细胞的静息膜电位。因此,细胞外钾浓度的非常小的绝对变化将会对这一比率产生重大影响,并从而对可兴奋组织(肌肉和神经)的功能产生重大影响。因此细胞外钾水平要受到严格的调控。
两个独立且协作的***参与钾体内平衡调控,一个调控外部钾平衡(钾摄入与钾消除的身体对等),而另一个调控内部钾平衡(细胞内液室与细胞外液室之间的分布。细胞内/细胞外平衡对血清钾的变化提供短期控制,并且主要由Na+、K+-ATP酶“泵”的作用生理地驱动,所述泵利用ATP水解的能量逆着Na+和K+的浓度梯度泵送它们。几乎所有的细胞都拥有Na+、K+-ATP酶。身体对等是通过经由肾脏和胃肠道的消除机制控制的:在健康的肾脏中,每日钾负荷的90-95%通过肾脏***,余者在粪便中消除。
由于细胞内/细胞外钾比率(Ki:Ke比率)是细胞的静息膜电位的主要决定因素,因此Ke(即,血清[K])的小的变化会对电活性组织(如肌肉和神经)的功能产生深刻影响。钾和钠离子通过主动穿过细胞膜并变动膜电位来驱动神经和肌肉细胞中的动作电位,膜电位是细胞的外部与内部之间的电位差。除了主动转运之外,K+还可以在细胞外室与细胞内室之间被动移动。由较高的血钾水平引起的被动K+转运超负荷在没有刺激的情况下使膜去极化。血清钾过量被称为高钾血症,其可破坏心肌细胞中调控心室传导和收缩的膜电位。在临床上,高钾血症对心脏电生理的影响是最令人担忧的,因为其可导致心律失常和死亡。由于身体大部分对等是通过肾***维持的,因此可以预期随着肾脏功能下降,控制全身钾的能力会受到损害。
高钾血症的定义为血清钾水平高于正常范围,通常>5.0mmol/L。据报道中度高钾血症(血清钾高于6.0mEq/L)的1天死亡率高达血清钾低于5.5mEq/L的患者的30倍。重度高钾血症(血清K+为至少6.5mmol/L)是潜在危及生命的电解质紊乱,据报道在所有住院患者中有1%至10%的患者出现电解质紊乱,并且构成了需要立即进行治疗的紧急医疗情况。高钾血症由钾***不足引起,并且由于肾脏是钾排除的主要机制,因此高钾血症通常会影响患有肾脏疾病如慢性肾脏疾病(CKD)或晚期肾病(ESRD)的患者。然而,肾脏功能正常的患者也有可能出现高钾血症发作,这种情况下其仍然是危及生命的疾患。例如,在住院患者中,高钾血症与患有或没有CKD的患者的死亡率增加相关。虽然CKD是高钾血症最常见的诱因疾患,但驱动高钾血症的机制通常涉及多种因素的组合,如膳食钾摄入量增加、细胞内室与细胞外室之间的钾分布紊乱以及钾***异常。可通过因果关系在CKD之外的多种因素调节这些机制。这些包括其它合并症的存在,如2型糖尿病(T2DM)、心血管疾病(CVD),或者使用了作为副作用可能破坏钾体内平衡的联合用药,例如用血管紧张素转化酶(ACE)抑制剂和血管紧张素受体阻滞剂(ARB)阻滞了肾素-血管紧张素-醛固酮***(RAAS)。
可通过两种一般的机制来降低血清钾:第一种是通过使用诸如胰岛素、沙丁胺醇或碳酸氢钠之类的药剂在细胞内转移钾。第二种是采用以下4种途径之一将其从体内***出来:粪便,使用K结合树脂,如聚苯乙烯磺酸钠(Na PSS);尿液,使用利尿剂;血液,利用血液透析;或腹膜液,利用腹膜透析。除了Na PSS之外,治疗高钾血症的用药如胰岛素、利尿剂、β激动剂和碳酸氢钠仅仅是作为副作用引起低钾血,作为长期治疗并不合适。确定的疗法需要从体内排除钾。研究已证实降低高钾血症患者的血清钾水平实际上降低了死亡风险,从而进一步坐实了过量钾在死亡风险中的作用。虽然Na PSS是美国目前用于减少钾的护理治疗标准,但在世界的其它地区也普遍使用PSS的钙盐(Ca PSS),包括在欧洲(例如,Resonium)和日本。
Kayexalate/Na PSS耐受性差,导致GI副作用的发生率高,包括恶心、呕吐、便秘和腹泻。此外,Kayexalate是研磨产品,由尺寸为约1-150μm不等的不规则形状的颗粒组成,并且在人的口腔中具有像沙子一样的特性:摄入时其在上颚产生强烈的异物感,并且这种感觉对患者的依从性不利。总的来说,Kayexalate的物理特性及相关的副作用导致依从性不良,并且使药物对于长期使用而言是次优的。由于这些特性原因,长期以来一直需要提供长期使用的最佳药物。
盐皮质激素受体(或MR,MLR,MCR)也被称为醛固酮受体或核受体亚家族3组C成员2(NR3C2),其是在人类中由位于染色体4q31.1-31.2上的NR3C2基因编码的蛋白质。MR是对盐皮质激素和糖皮质激素(包括皮质醇)具有同等亲和力的受体。其属于核受体家族,其中配体扩散进入细胞,与受体相互作用,并导致影响细胞核中特定基因表达的信号转导。MR在许多组织中表达,如肾脏、结肠、心脏、中枢神经***(海马体)、棕色脂肪组织和汗腺。配体醛固酮和皮质醇在上皮组织中激活盐皮质激素受体促进了钾的***。在完整动物中,通过酶11β-羟基类固醇脱氢酶2(在本文中称为HSD2)的共定位“保护”MR免受皮质醇浓度较高(100-1000倍)的影响。所述酶将皮质醇氧化为无活性的代谢物皮质酮。因此HSD2阻止MR激活,并因此抑制钾的***。
因此,例如在高钾血症的治疗中,抑制HSD2以阻止MR的皮质醇激活的失活是很有前途的促进钾***的机制。
发明内容
在本发明的一方面提供了式I的化合物或其盐:
其中,
X是键、-O-、-C(O)-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;
V是-C(O)O-、-C(O)N(R5)-、-C(O)N(R5)O-、-NH-C(O)-N(R5)-或NH-S(O)n-;
L是键、亚烷基,其中所述亚烷基的一个或多个非相邻的亚甲基被-O-置换;二价芳基或二价杂芳基;或者L是亚烷基-Y-亚烷基,其中Y是O、NRx、S、SO、SO2或二价杂环;其中所述亚烷基任选被OH、-C(O)O-R1、烷基或被OH或-C(O)O-R1取代的烷基取代;且其中所述亚烷基的碳和Rx任选一起形成杂环;条件是当X不是键时,则L不是键;
R1是任选被卤素、OH、氨基、氧代基、羧基、酰氧基、烷氧基羰基、烷氧基酰氧基、烷氧基羰氧基、氨基羰基取代的烷基,任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环,和任选被烷基、氧代基、氨基和卤素取代的杂环;以及任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环或杂环;其中任何前述烷基中的一个或多个非相邻的亚甲基被O置换;
R2是H或R1;
R3缺失、是Me;条件是当-X-L-C(O)O-R1取决于R3所依赖的碳时,则R3缺失;或者R3是-Z-L-C(O)O-R1,其中Z是键、-O-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;且
R4缺失、是H或OH;条件是当-X-L-C(O)O-R1取决于R4所依赖的碳时,则R4是H或缺失;
R5是H或烷基;
Rx是H、-C(O)O-R1或任选被-C(O)O-R1取代的烷基;且
n是1或2。
在本发明的另一方面提供了包含式I的化合物和载体、稀释剂或赋形剂的组合物。
在本发明的另一方面提供了抑制皮质醇通过HSD2向皮质酮转化的方法,包括使HSD2与式I的化合物接触。
在本发明的另一方面提供了在哺乳动物中促进激活MR的方法,包括对所述哺乳动物施用有效量的式I的化合物。
在本发明的另一方面提供了降低哺乳动物血浆中的钾水平的方法,包括对所述哺乳动物施用有效量的式I的化合物。
在本发明的另一方面提供了促进钾离子向哺乳动物的结肠腔中分泌的方法,包括对所述哺乳动物施用有效量的式I的化合物。
在本发明的另一方面提供了治疗哺乳动物的高钾血症的方法,包括对所述哺乳动物施用有效量的式I的化合物。
在本发明的另一方面提供了治疗或预防哺乳动物的高钾血症的方法,包括将式I的化合物与肾素-血管紧张素-醛固酮***(RAAS)的抑制剂共同施用。
附图说明
图1示出组合施用HSD2抑制剂与NHE3抑制剂对粪便中的钾***的协同效应。
图2示出上皮细胞中的11-β-羟基类固醇脱氢酶2(HSD2)抑制使皮质醇激活盐皮质激素受体(MR),这促进了钾向管腔里的***。
图3描述带有碳原子编号的甘草次酸结构。
具体实施方式
甘草甜素(或甘草酸,glycyrrhizic acid/glycyrrhizinic acid)是名为甘草的植物的提取物,甘草的名称源于古希腊词语‘glykos’(意指甜)和‘rhiza’(意指根)。许多先知和法老都沉迷于甘草。欧亚甘草提取物已在战地和沙漠中使用,士兵和旅行者在长途跋涉时饮用其来抑制渴感。欧亚甘草中的活性代谢物甘草次酸抑制HSD2,从而导致皮质醇诱导的盐皮质激素效应和钾水平降低的趋势。虽然甘草次酸降低钾水平,但其与心律异常、高血压、水肿、嗜睡、充血性心力衰竭、低钾血症和横纹肌溶解症相关。因此,期望提供一种能像甘草次酸一样促进罹患高钾血症的患者的钾***而没有不良副作用的化合物。
本发明提供式I的化合物或其盐:
其中,
X是键、-O-、-C(O)-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;
V是-C(O)O-、-C(O)N(R5)-、-C(O)N(R5)O-、-NH-C(O)-N(R5)-或NH-S(O)n-;
L是键、亚烷基,其中所述亚烷基的一个或多个非相邻的亚甲基被-O-置换;二价芳基或二价杂芳基;或者L是亚烷基-Y-亚烷基,其中Y是O、NRx、S、SO、SO2或二价杂环;其中所述亚烷基任选被OH、-C(O)O-R1、烷基或被OH或-C(O)O-R1取代的烷基取代;且其中所述亚烷基的碳和Rx任选一起形成杂环;条件是当X不是键时,则L不是键;
R1是任选被卤素、OH、氨基、氧代基、羧基、酰氧基、烷氧基羰基、烷氧基酰氧基、烷氧基羰氧基、氨基羰基取代的烷基,任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环,和任选被烷基、氧代基、氨基和卤素取代的杂环;以及任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环或杂环;其中任何前述烷基中的一个或多个非相邻的亚甲基被O置换;
R2是H或R1;
R3缺失、是Me;条件是当-X-L-C(O)O-R1取决于R3所依赖的碳时,则R3缺失;或者R3是-Z-L-C(O)O-R1,其中Z是键、-O-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;且
R4缺失、是H或OH;条件是当-X-L-C(O)O-R1取决于R4所依赖的碳时,则R4是H或缺失;
R5是H或烷基;
Rx是H、-C(O)O-R1或任选被-C(O)O-R1取代的烷基;且
n是1或2。
在特定的实施方案中,本发明的化合物含有悬于稠环体系的3-、23-和/或24-位的酯部分。在一实施方案中,在对受试者施用本发明的化合物之后,酯部分在血浆或肝脏中代谢为活性较低的酸形式。在另一实施方案中,本发明的化合物具有等于或高于甘草次酸的HSD2抑制活性。在另一实施方案中,本发明的化合物具有高于甘草次酸的HSD2抑制活性。
“酰基”意指由式-C(O)-R表示的含有羰基的取代基,其中R是H、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。酰基包括烷酰基(例如,乙酰基)、芳酰基(例如,苯甲酰基)和杂芳酰基。
除另有规定外,“烷基”意指具有多达12个碳原子的支链或无支链的饱和或不饱和(即烯基、炔基)脂族烃基团。当用作另一术语的一部分时,例如“烷基氨基”、“环烷基”、“亚烷基”等,烷基部分可以是饱和烃链,但也包括不饱和烃碳链,如“烯基氨基”和“炔基氨基。特定烷基的实例有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、2-甲基戊基、2,2-二甲基丁基、正庚基、3-庚基、2-甲基己基等。术语“低级烷基”“C1-C4烷基”和“1至4个碳原子的烷基”是同义词并且可互换使用,意指甲基、乙基、1-丙基、异丙基、环丙基、1-丁基、仲丁基或叔丁基。除有规定外,取代的烷基可含有例如一个、两个、三个或四个可以是相同或不同的取代基。除另有定义外,取代基的实例有卤素、氨基、羟基、被保护的羟基、巯基、羧基、烷氧基、硝基、氰基、脒基、胍基、脲、磺酰基、亚磺酰基、氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、氨基羰基、酰基氨基、烷氧基、酰基、酰氧基、碳环和杂环。上述取代的烷基的实例包括但不限于:氰甲基、硝基甲基、羟甲基、三苯甲基氧基甲基、丙酰氧基甲基、氨基甲基、羧甲基、羧乙基、羧丙基、烷氧基羰基甲基、烯丙氧基羰基氨基甲基、氨基甲酰氧基甲基、甲氧基甲基、乙氧基甲基、叔丁氧基甲基、乙酰氧基甲基、氯甲基、溴甲基、碘甲基、三氟甲基、6-羟己基、2,4-二氯(正丁基)、2-氨基(异丙基)、2-氨基甲酰氧基乙基等。烷基也可以被碳环基团取代。实例包括环丙基甲基、环丁基甲基、环戊基甲基和环己基甲基,以及相应的-乙基、-丙基、-丁基、-戊基、-己基等。取代的烷基包括取代的甲基,例如被与“取代的Cn-Cm烷基”相同的取代基取代的甲基。取代的甲基的实例包括诸如羟甲基、被保护的羟甲基(例如,四氢吡喃氧基甲基)、乙酰氧基甲基、氨基甲酰氧基甲基、三氟甲基、氯甲基、羧甲基、溴甲基和碘甲基的基团。在一实施方案中,烷基是饱和的。在一实施方案中,烷基是不饱和的。在一实施方案中,烷基是部分不饱和的。
“脒”意指基团-C(NH)-NHR,其中R是H、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。一种特定的脒是-NH-C(NH)-NH2。
“氨基”意指伯胺(即-NH2)、仲胺(即-NRH)和叔胺(即-NRR),其中R是H、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。特定的仲胺和叔胺有烷基胺、二烷基胺、芳基胺、二芳基胺、芳烷基胺和二芳烷基胺,其中烷基如本文所定义并且任选被取代。特定的仲胺和叔胺有甲胺、乙胺、丙胺、异丙胺、苯胺、苄胺二甲胺、二乙胺、二丙胺和二异丙胺。
如本文所用的“氨基保护基团”是指当在化合物上的其它官能团上进行反应时通常用来封闭或保护氨基的基团的衍生物。这类保护基团的实例包括氨基甲酸酯、酰胺、烷基和芳基、亚胺以及可以被去掉以重新产生所需胺基团的许多N-杂原子衍生物。合适的氨基保护基团(NH-Pg)包括乙酰基、三氟乙酰基、叔丁氧基羰基(“Boc”)、苄氧基羰基(“CBz”)和9-芴基亚甲基氧基羰基(“Fmoc”)。这些基团进一步的实例见于Wuts.Greene's Protective Groups in Organic Synthesis.第5版.New York:John Wiley&Sons,Inc.,2014。术语“被保护的氨基”是指被上述氨基保护基团之一取代的氨基。
“芳基”当单独使用或作为另一术语的一部分使用时意指碳环芳族基团,无论是否是稠合的,其具有指定的碳原子数,或者如果未指定碳原子数,则具有最多14个碳原子。特定的芳基有苯基、萘基、联苯基、并四苯基等(参见例如,Dean,J.A.编.Lange's Handbook of Chemistry.第13版.New York:McGraw-Hill,1985,表7-2)。特定的芳基有苯基。取代的苯基或取代的芳基意指被一个、两个、三个、四个或五个取代基取代的苯基或芳基,例如被1-2、1-3或1-4个取代基取代,所述取代基除另有规定外选自卤素(F、Cl、Br、I)、羟基、被保护的羟基、氰基、硝基、烷基(例如C1-C6烷基)、烷氧基(例如C1-C6烷氧基)、苄氧基、羧基、被保护的羧基、羧甲基、被保护的羧甲基、羟甲基、被保护的羟甲基、氨基甲基、被保护的氨基甲基、三氟甲基、烷基磺酰基氨基、烷基磺酰基氨基烷基、芳基磺酰基氨基、芳基磺酰基氨基烷基、杂环基磺酰基氨基、杂环基磺酰基氨基烷基、杂环基、芳基或其它指定的基团。这些取代基中的一个或多个次甲基(CH)和/或亚甲基(CH2)又可被与上述基团类似的基团取代。术语“取代的苯基”的实例包括但不限于单或二(卤代)苯基,如2-氯苯基、2-溴苯基、4-氯苯基、2,6-二氯苯基、2,5-二氯苯基、3,4-二氯苯基、3-氯苯基、3-溴苯基、4-溴苯基、3,4-二溴苯基、3-氯-4-氟苯基、2-氟苯基等;单或二(羟基)苯基,如4-羟基苯基、3-羟基苯基、2,4-二羟基苯基、其被保护的羟基衍生物等;硝基苯基,如3-或4-硝基苯基;氰基苯基,例如4-氰基苯基;单或二(低级烷基)苯基,如4-甲基苯基、2,4-二甲基苯基、2-甲基苯基、4-(异丙基)苯基、4-乙基苯基、3-(正丙基)苯基等;单或二(烷氧基)苯基,例如3,4-二甲氧基苯基、3-甲氧基-4-苄氧基苯基、3-甲氧基-4-(1-氯甲基)苄氧基-苯基、3-乙氧基苯基、4-(异丙氧基)苯基、4-(叔丁氧基)苯基、3-乙氧基-4-甲氧基苯基等;3-或4-三氟甲基苯基;单或二羧基苯基或(被保护的羧基)苯基,如4-羧基苯基;单或二(羟甲基)苯基或(被保护的羟甲基)苯基,如3-(被保护的羟甲基)苯基或3,4-二(羟甲基)苯基;单或二(氨基甲基)苯基或(被保护的氨基甲基)苯基,如2-(氨基甲基)苯基或2,4-(被保护的氨基甲基)苯基;单或二(N-(甲基磺酰基氨基))苯基,如3-(N-甲基磺酰基氨基))苯基;二取代的苯基,如3-甲基-4-羟基苯基、3-氯-4-羟基苯基、2-甲氧基-4-溴苯基、4-乙基-2-羟基苯基、3-羟基-4-硝基苯基、2-羟基-4-氯苯基;三取代的苯基,如3-甲氧基-4-苄氧基-6-甲基磺酰氨基、3-甲氧基-4-苄氧基-6-苯基磺酰氨基;和四取代的苯基,如3-甲氧基-4-苄氧基-5-甲基-6-苯基磺酰氨基。特定的取代苯基包括2-氯苯基、2-氨基苯基、2-溴苯基、3-甲氧基苯基、3-乙氧基-苯基、4-苄氧基苯基、4-甲氧基苯基、3-乙氧基-4-苄氧基苯基、3,4-二乙氧基苯基、3-甲氧基-4-苄氧基苯基、3-甲氧基-4-(1-氯甲基)苄氧基-苯基、3-甲氧基-4-(1-氯甲基)苄氧基-6-甲基磺酰基氨基苯基。稠合的芳基环也可按与取代的烷基相同的方式被本文中指定的任何取代基例如1、2或3个取代基取代。
“碳环基”、“碳环(carbocyclic/carbocycle/carbocyclo)”单独及用作诸如碳环烷基之类的复杂基团中的部分时是指具有3至14个碳原子的单环、双环或三环脂族环,例如具有3至7个碳原子或3至6个碳原子,其可以是饱和的或不饱和的、芳族的或非芳族的。特定的饱和碳环基团有环丙基、环丁基、环戊基和环己基。一种特定的饱和碳环是环丙基。另一特定的饱和碳环是环己基。特定的不饱和碳环是芳族的,例如先前所定义的芳基,例如苯基。术语“取代的碳环基”、“碳环”意指被与“取代的烷基”相同的取代基取代的这些基团。
如本文所用的“羧基保护基团”是指羧酸基团的酯衍生物之一,其通常用来当在化合物上的其它官能团上进行反应时封闭或保护羧酸基团。这类羧酸保护基团的实例包括4-硝基苄基、4-甲氧基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基、2,4,6-三甲氧基苄基、2,4,6-三甲基苄基、五甲基苄基、3,4-亚甲基二氧基苄基、二苯甲基(benzhydryl)、4,4'-二甲氧基二苯甲基、2,2',4,4'-四甲氧基二苯甲基,烷基如叔丁基或叔戊基、三苯甲基、4-甲氧基三苯甲基、4,4'-二甲氧基三苯甲基、4,4',4”-三甲氧基三苯甲基、2-苯基丙-2-基、三甲基甲硅烷基、叔丁基二甲基甲硅烷基、苯甲酰甲基、2,2,2-三氯乙基、β-(三甲基甲硅烷基)乙基、β-(二(正丁基)甲基甲硅烷基)乙基、对甲苯磺酰基乙基、4-硝基苄基磺酰基乙基、烯丙基、肉桂基、1-(三甲基甲硅烷基甲基)丙-1-烯-3-基等部分。所用的羧基保护基团的种类不是关键的,只要衍生化羧酸对分子的其它位置上的后续反应的条件是稳定的,并且可以在适当的时机去掉而不会破坏分子的其余部分即可。特别地,重要的是不要使羧基保护分子经受强亲核碱如氢氧化锂或NaOH,或采用高度活化的金属氢化物如LiAlH4的还原条件。当去除下面讨论的氨基保护基团和羟基保护基团时也要避免这类苛刻的去除条件。特定的羧酸保护基团有烷基(例如,甲基、乙基、叔丁基)、烯丙基、苄基和对硝基苄基。头孢菌素、青霉素和肽领域中使用的类似的羧基保护基团也可用于保护羧基取代基。这些基团的进一步实例见于Greene,T.W.和P.G.M.Wuts.Protective Groups in Organic Synthesis.第2版.New York:John Wiley&Sons,Inc.1991,第5章;Haslam,E.Protective Groups in Organic Chemistry.New York:Plenum Press 1973,第5章;和Greene,T.W.Protective Groups in Organic Synthesis.New York:John Wiley&Sons,Inc.1981,第5章。术语“被保护的羧基”是指被上述羧基保护基团之一取代的羧基。
“烷氧基羰基”意指基团-C(=O)OR,其中R是烷基。一种特定的基团是C1-C6烷氧基羰基,其中R基团是C1-C6烷基。
“胍”意指基团-NH-C(NH)-NHR,其中R是氢、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。一种特定的胍是基团-NH-C(NH)-NH2。
如本文所用的“羟基保护基团”是指当在化合物上的其它官能团上进行反应时通常用来封闭或保护羟基的羟基的衍生物。这类保护基团的实例包括四氢吡喃氧基、苯甲酰基、乙酰氧基、氨基甲酰氧基、苄基和甲硅烷基醚(例如,TBS、TBDPS)。这些基团进一步的实例见于Greene,T.W.和P.G.M.Wuts.Protective Groups in Organic Synthesis.第2版.New York:John Wiley&Sons,Inc.1991,第2-3章;Haslam,E.Protective Groups in Organic Chemistry.New York:Plenum Press 1973,第5章;和Greene,T.W.Protective Groups in Organic Synthesis.New York:John Wiley&Sons,Inc.1981。术语“被保护的羟基”是指被上述羟基保护基团之一取代的羟基。
“杂环基团”、“杂环基”或“杂环(heterocyclic/heterocycle/heterocyclo)”单独及用作诸如杂环烷基之类的复杂基团中的部分时可互换使用,并且是指具有指定原子数的任何单环、双环或三环饱和或不饱和的芳族(杂芳基)或非芳族环,通常具有5至约14个环原子,其中环原子是碳和至少一个杂原子(氮、硫或氧),例如1至4个杂原子。杂环基团包括四至七元环状基团,所述环状基团含有一个、两个或三个选自由氮、氧和硫组成的组的杂原子。通常,5元环具有0至2个双键,且6或7元环具有0至3个双键。氮或硫杂原子可任选被氧化(例如,SO、SO2),并且任何氮杂原子可任选被季铵化。特定的非芳族杂环有吗啉基(吗啉代)、吡咯烷基、环氧乙烷基(oxiranyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、2,3-二氢呋喃基、2H-吡喃基、四氢吡喃基、环硫乙烷基(thiiranyl)、硫杂环丁烷基(thietanyl)、四氢硫杂环丁烷基、氮杂环丙烷基(aziridinyl)、杂氮环丁烷基(azetidinyl)、1-甲基-2-吡咯基、哌嗪基和哌啶基。“杂环烷基”是如上所定义的杂环基团,其与如上所定义的烷基共价键合。含有硫或氧原子和一至三个氮原子的特定5元杂环有噻唑基,特别是噻唑-2-基和噻唑-2-基N-氧化物,噻二唑基,特别是1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基,噁唑基,例如噁唑-2-基,和噁二唑基,如1,3,4-噁二唑-5-基和1,2,4-噁二唑-5-基。含有2至4个氮原子的特定5元环杂环包括咪唑基,如咪唑-2-基;***基,如1,3,4-***-5-基;1,2,3-***-5-基、1,2,4-***-5-基,和四唑基,如1H-四唑-5-基。特定的苯并稠合5元杂环有苯并噁唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。特定的6元杂环含有一至三个氮原子和任选硫或氧原子,例如吡啶基,如吡啶-2-基、吡啶-3-基和吡啶-4-基;嘧啶基,如嘧啶-2-基和嘧啶-4-基;三嗪基,如1,3,4--三嗪-2-基和1,3,5-三嗪-4-基;哒嗪基,特别是哒嗪-3-基,和吡嗪基。吡啶N-氧化物和哒嗪N-氧化物以及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基是特定的基团。“任选取代的杂环”的取代基以及上面讨论的5和6元环体系的进一步的实例可见于W.Druckheimer等人的第4,278,793号美国专利。在特定的实施方案中,这类任选取代的杂环基团是被羟基、烷基、烷氧基、酰基、卤素、巯基、氧代基、羧基、酰基、卤取代烷基、氨基、氰基、硝基、脒基和胍基取代的。
“杂芳基”单独及用作诸如杂芳烷基之类的复杂基团中的部分时是指具有指定原子数的任何单环、双环或三环芳族环体系,其中至少一个环是含有一至四个选自氮、氧和硫的杂原子的5、6或7元环,并且在特定的实施方案中至少一个杂原子是氮(Lange'sHandbook of Chemistry,同上)。在一个实例中,杂芳基是含有一个、两个或三个选自氮、氧和硫的杂原子的五至六元芳族环。定义中包括其中任何上述杂芳基环与苯环稠合的任何双环基团。特定的杂芳基包含氮或氧杂原子。以下环体系是由术语“杂芳基”表示的杂芳基(无论是取代的还是未取代的)基团的实例:噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、***基、噻二唑基、噁二唑基、四唑基、噻***基、噁***基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻嗪基、噁嗪基、三嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二噁嗪基、噁噻嗪基、四嗪基、噻三嗪基、噁三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、四唑并[1,5-b]哒嗪基和嘌呤基,以及苯并稠合衍生物,例如苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并***基、苯并咪唑基和吲哚基。特定的“杂芳基”可选自:1,3-噻唑-2-基、4-(羧甲基)-5-甲基-1,3-噻唑-2-基、4-(羧甲基)-5-甲基-1,3-噻唑-2-基、1,2,4-噻二唑-5-基、3-甲基-1,2,4-噻二唑-5-基、1,3,4-***-5-基、2-甲基-1,3,4-***-5-基、2-羟基-1,3,4-***-5-基、2-羧基-4-甲基-1,3,4-***-5-基、2-羧基-4-甲基-1,3,4-***-5-基、1,3-噁唑-2-基、1,3,4-噁二唑-5-基、2-甲基-1,3,4-噁二唑-5-基、2-(羟甲基)-1,3,4-噁二唑-5-基、1,2,4-噁二唑-5-基、1,3,4-噻二唑-5-基、2-巯基-1,3,4-噻二唑-5-基、2-(甲硫基)-1,3,4-噻二唑-5-基、2-氨基-1,3,4-噻二唑-5-基、1H-四唑-5-基、1-甲基-1H-四唑-5-基、1-(1-(二甲氨基)乙-2-基)-1H-四唑-5-基、1-(羧甲基)-1H-四唑-5-基、1-(羧甲基)-1H-四唑-5-基、1-(甲基磺酸)-1H-四唑-5-基、1-(甲基磺酸)-1H-四唑-5-基、2-甲基-1H-四唑-5-基、1,2,3-***-5-基、1-甲基-1,2,3-***-5-基、2-甲基-1,2,3-***-5-基、4-甲基-1,2,3-***-5-基、吡啶-2-基N-氧化物、6-甲氧基-2-(n-氧化物)-哒嗪-3-基、6-羟基哒嗪-3-基、1-甲基吡啶-2-基、1-甲基吡啶-4-基、2-羟基嘧啶-4-基、1,4,5,6-四氢-5,6-二氧代-4-甲基-as-三嗪-3-基、1,4,5,6-四氢-4-(甲酰基甲基)-5,6-二氧代-as-三嗪-3-基、2,5-二氢-5-氧代-6-羟基-as三嗪-3-基、2,5-二氢-5-氧代-6-羟基-as-三嗪-3-基、2,5-二氢-5-氧代-6-羟基-2-甲基-as三嗪-3-基、2,5-二氢-5-氧代-6-羟基-2-甲基-as-三嗪-3-基、2,5-二氢-5-氧代-6-甲氧基-2-甲基-as-三嗪-3-基、2,5-二氢-5-氧代-as-三嗪-3-基、2,5-二氢-5-氧代-2-甲基-as-三嗪-3-基、2,5-二氢-5-氧代-2,6-二甲基-as-三嗪-3-基、四唑并[1,5-b]哒嗪-6-基和8-氨基四唑并[1,5-b]-哒嗪-6-基。“杂芳基”的替代基团包括:4-(羧甲基)-5-甲基-1,3-噻唑-2-基、4-(羧甲基)-5-甲基-1,3-噻唑-2-基、1,3,4-***-5-基、2-甲基-1,3,4-***-5-基、1H-四唑-5-基、1-甲基-1H-四唑-5-基、1-(1-(二甲氨基)乙-2-基)-1H-四唑-5-基、1-(羧甲基)-1H-四唑-5-基、1-(羧甲基)-1H-四唑-5-基、1-(甲基磺酸)-1H-四唑-5-基、1-(甲基磺酸)-1H-四唑-5-基、1,2,3-***-5-基、1,4,5,6-四氢-5,6-二氧代-4-甲基-as-三嗪-3-基、1,4,5,6-四氢-4-(2-甲酰基甲基)-5,6-二氧代-as-三嗪-3-基、2,5-二氢-5-氧代-6-羟基-2-甲基-as-三嗪-3-基、2,5-二氢-5-氧代-6-羟基-2-甲基-as-三嗪-3-基、四唑并[1,5-b]哒嗪-6-基和8-氨基四唑并[1,5-b]哒嗪-6-基。杂芳基任选如针对杂环所述的那样被取代。
“抑制剂”意指减少或阻止皮质醇通过HSD2向皮质酮酶促转化的化合物。
除另有规定外,“任选取代的”意指基团可以是未取代的,或者在化合价允许的情况下被一个或多个(例如,0、1、2、3或4个)针对该基团列出的取代基取代,其中所述取代基可以是相同的或不同的。在一个实施方案中,任选取代的基团具有1个取代基。在另一实施方案中,任选取代的基团具有2个取代基。在另一实施方案中,任选取代的基团具有3个取代基。
“药学上可接受的盐”包括酸加成盐和碱加成盐两者。“药学上可接受的酸加成盐”是指保留了游离碱的生物有效性和性质并且在生物学上或其它方面并非不可取、与无机酸及有机酸形成的那些盐,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,所述有机酸可选自脂族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类有机酸,如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸(maloneic acid)、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、扑酸(embonic acid)、苯乙酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。
“药学上可接受的碱加成盐”包括衍生自无机碱的那些,如钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。特别地,碱加成盐是铵盐、钾盐、钠盐、钙盐和镁盐。衍生自药学上可接受的有机无毒碱的盐包括以下的胺的盐:伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、氨基丁三醇(trimethamine)、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、葡甲胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、多胺树脂等。特别地,有机无毒碱是异丙胺、二乙胺、乙醇胺、氨基丁三醇、二环己胺、胆碱和咖啡因。
“硫烷基(Sulfanyl)”意指-S-R基团,其中R是烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。特定的硫烷基有烷基硫烷基(即,-SO2-烷基),例如甲基硫烷基;芳基硫烷基,例如苯基硫烷基;芳烷基硫烷基,例如苄基硫烷基。
“亚磺酰基(Sulfinyl)”意指-SO-R基团,其中R是氢、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。特定的磺酰基有烷基亚磺酰基(即,-SO-烷基),例如甲基亚磺酰基;芳基亚磺酰基,例如苯基亚磺酰基;芳烷基亚磺酰基,例如苄基亚磺酰基。
“磺酰基(Sulfonyl)”意指-SO2-R基团,其中R是氢、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中烷基、烷氧基、碳环和杂环如本文所定义。特定的磺酰基有烷基磺酰基(即-SO2-烷基),例如甲基磺酰基;芳基磺酰基,例如苯基磺酰基;芳烷基磺酰基,例如苄基磺酰基。
如本文所用的短语“及其盐和溶剂合物”意指本发明的化合物可以盐和溶剂合物中的一种的形式或盐和溶剂合物的混合物形式存在。例如本发明的化合物可呈基本上纯的一种特定的盐或溶剂合物形式,或者可以是两种或更多种盐或溶剂合物形式的混合物。
在本发明的特定实施方案中,式I的化合物具有由式Ia-Ir定义的结构:
其中X、L、R1、R2、R3和R4如本文所定义。在特定的实施方案中,所述化合物具有根据式Ia的结构。在特定的实施方案中,所述化合物具有根据式Ib的结构。在特定的实施方案中,所述化合物具有根据式Ic的结构。在特定的实施方案中,所述化合物具有根据式Id的结构。在特定的实施方案中,所述化合物具有根据式Ie的结构。在特定的实施方案中,所述化合物具有根据式If的结构。在特定的实施方案中,所述化合物具有根据式Ig的结构。在特定的实施方案中,所述化合物具有根据式Ih的结构。在特定的实施方案中,所述化合物具有根据式Ii的结构。在特定的实施方案中,所述化合物具有根据式Ij的结构。在特定的实施方案中,所述化合物具有根据式Ik的结构。在特定的实施方案中,所述化合物具有根据式Il的结构。在特定的实施方案中,所述化合物具有根据式Im的结构。在特定的实施方案中,所述化合物具有根据式In的结构。在特定的实施方案中,所述化合物具有根据式Io的结构。在特定的实施方案中,所述化合物具有根据式Ip的结构。在特定的实施方案中,所述化合物具有根据式Iq的结构。在特定的实施方案中,所述化合物具有根据式Ir的结构。
在本发明的特定实施方案中,式I的化合物具有由式Ib'、Ic'、Id'、If'、Ih'、Ij'、Ik'、Il'、Im'、In'、Io'、Ip'和Iq'定义的结构:
其中X、L、R1、R2、R3、R4和R5如本文所定义。在特定的实施方案中,所述化合物具有根据式Ib'的结构。在特定的实施方案中,所述化合物具有根据式Ic'的结构。在特定的实施方案中,所述化合物具有根据式Id'的结构。在特定的实施方案中,所述化合物具有根据式If'的结构。在特定的实施方案中,所述化合物具有根据式Ih'的结构。在特定的实施方案中,所述化合物具有根据式Ij'的结构。在特定的实施方案中,所述化合物具有根据式Ik'的结构。在特定的实施方案中,所述化合物具有根据式Il'的结构。在特定的实施方案中,所述化合物具有根据式Im'的结构。在特定的实施方案中,所述化合物具有根据式Io'的结构。在特定的实施方案中,所述化合物具有根据式Ip'的结构。在特定的实施方案中,所述化合物具有根据式Iq'的结构。
在一实施方案中,本发明的化合物的化学式为式I中的任一者
在一实施方案中,X是键、-O-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;其中Rx是H、-C(O)O-R1或任选被-C(O)O-R1取代的烷基;在一实施方案中,X是键。在一实施方案中,X是-O-。在一实施方案中,X是-N(Rx)-。在一实施方案中,X是-NH-。在一实施方案中,X是-C(O)N(Rx)-。在一实施方案中,X是-C(O)NH-。在一实施方案中,X是-N(Rx)-C(O)-。在一实施方案中,X是-NH-C(O)-。在一实施方案中,X是-S(O)n-N(Rx)-。在一实施方案中,X是-S(O)-NH-。在一实施方案中,X是-S(O)2-NH-。在一实施方案中,X是-N(Rx)-S(O)n-。在一实施方案中,X是-NH-S(O)-。在一实施方案中,X是-NH-S(O)2-。
V是-C(O)O-、-C(O)N(R5)-、-C(O)N(R5)O-、-NH-C(O)-N(R5)-或NH-S(O)n-。在一实施方案中,V是-C(O)O-。在一实施方案中,V是-C(O)O-,且R2是H。在一实施方案中,V是-C(O)O-,且R2是前药基团。在一实施方案中,V是-C(O)O-,且R2是烷基。在一实施方案中,V是-C(O)O-,且R2是甲基。在另一实施方案中,V是-C(O)O-,且R2是任选被氧代基、酰氧基、烷氧基羰基、烷氧基酰氧基、烷氧基羰氧基取代的烷基,任选被烷基和氧代基取代的碳环,和任选被烷基和氧代基取代的杂环。
在一实施方案中,V是-C(O)N(R5)-。在一实施方案中,V是-C(O)N(R5)-,且R2和R5都是H。在一实施方案中,V是-C(O)N(R5)-,且R2和R5独立地为H和任选被OH取代的烷基。在一实施方案中,V是-C(O)N(R5)-,R5是H,且R2是羟乙基。
在一实施方案中,V是-C(O)N(R5)O-。在一实施方案中,V是-C(O)N(R5)O-,且R2和R5独立地为H或烷基。在一实施方案中,V是-C(O)N(R5)O-,R2是甲基,且R5是H。
在一实施方案中,V是-NH-C(O)-N(R5)-,且R2和R5独立地为H或烷基。在一实施方案中,V是-NH-C(O)-N(R2)-,R2是甲基,且R5是H。在一实施方案中,V是-NH-C(O)-N(R5)-,且R2和R5都是H。
在一实施方案中,V是NH-S(O)n-。在一实施方案中,V是NH-S(O)2-。在一实施方案中,V是NH-S(O)2-,且R2是烷基。在一实施方案中,V是NH-S(O)2-,且R2是甲基。
L是键、亚烷基,其中所述亚烷基的一个或多个非相邻的亚甲基被-O-置换;二价芳基或二价杂芳基;或者L是亚烷基-Y-亚烷基,其中Y是O、NRx、S、SO、SO2或二价杂环;其中所述亚烷基任选被OH、-C(O)O-R1、烷基或被OH或-C(O)O-R1取代的烷基取代;且其中所述亚烷基的碳和Rx任选一起形成杂环;条件是当X不是键时,则L不是键;
在一实施方案中,L是键或亚烷基,其中所述亚烷基的一个或多个非相邻的亚甲基被-O-置换。在一实施方案中,L是键。在一实施方案中,L是亚烷基。在一实施方案中,L是亚烷基。在一实施方案中,L是亚烷基,其中所述亚烷基的一个或多个非相邻的亚甲基被-O-置换。在一实施方案中,L是-[(CH2)2-O]1-5-。在一实施方案中,L是-(CH2)2-O-。在一实施方案中,L是-[(CH2)2-O]2-。在一实施方案中,L是-[(CH2)2-O]3-。在一实施方案中,L是-[(CH2)2-O]4-。在一实施方案中,L是-[(CH2)2-O]5-。
在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是O、NRx、S、SO、SO2或二价杂环;其中所述亚烷基任选被OH、-C(O)O-R1、烷基或被OH或-C(O)O-R1取代的烷基取代;且其中所述亚烷基的碳和Rx任选一起形成杂环;条件是当X不是键时,则L不是键。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是O。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是NRx。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是NRx,其中所述亚烷基的碳和Rx一起形成杂环。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是S。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是SO。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是SO2。在一实施方案中,L是亚烷基-Y-亚烷基,其中Y是二价杂环。在一实施方案中,L是芳基。在一实施方案中,L是苯基。在一实施方案中,L是1,4-亚苯基。在一实施方案中,L是杂芳基。在一实施方案中,L是***。在一实施方案中,L是异噁唑。
R1是任选被卤素、OH、氨基、氧代基、羧基、酰氧基、烷氧基羰基、烷氧基酰氧基、烷氧基羰氧基、氨基羰基取代的烷基,任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环,和任选被烷基、氧代基、氨基和卤素取代的杂环;以及任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环或杂环;其中任何前述烷基中的一个或多个非相邻的亚甲基被O置换。在一实施方案中,R1是烷基。在一实施方案中,R1是被OH取代的烷基。在一实施方案中,R1是被氧代基取代的烷基。在一实施方案中,R1是被羧基取代的烷基。在一实施方案中,R1是被酰氧基取代的烷基。在一实施方案中,R1是被烷氧基羰基取代的烷基。在一实施方案中,R1中的任何烷基中的一个或多个非相邻的亚甲基被O置换。在一实施方案中,R1是被烷氧基酰氧基取代的烷基。在一实施方案中,R1是被烷氧基羰氧基取代的烷基。在一实施方案中,R1是被氨基羰基取代的烷基。在一实施方案中,R1是甲基。在一实施方案中,R1是丙基。在一实施方案中,R1是羟乙基。在一实施方案中,R1是2,2,2-三氟乙基。在一实施方案中,R1是1,1-三氟甲基乙基。在一实施方案中,R1是2-吗啉代乙基。在一实施方案中,R1是2-(1H-咪唑-1-基)乙基。在一实施方案中,R1是2-(吡啶-2-基)乙基。在一实施方案中,R1是-CH2-C(O)OH。
在一实施方案中,R1是-CH2-C(O)O-Me。在一实施方案中,R1是-CH2-C(O)NH2。在一实施方案中,R1是-CH2-C(O)NMe2。在一实施方案中,R1是-CH2-C(O)O-叔丁基。在一实施方案中,R1是(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基。在一实施方案中,R1是(新戊酰氧基)甲基。在一实施方案中,R1是((异丙氧基羰基)氧基)甲基。在一实施方案中,R1是(S)-1-((异丙氧基羰基)氧基)乙基。在一实施方案中,R1是(R)-1-((异丙氧基羰基)氧基)乙基。在一实施方案中,R1是2-吗啉代-2-氧代乙基。在一实施方案中,R1是2-(4-甲基哌嗪-1-基)-2-氧代乙基。在一实施方案中,R1是(R)-奎宁环-3-基。
在一实施方案中,R1是-[(CH2)2-O]p-Me,其中p是1至20。在一实施方案中,p是1至19。在一实施方案中,p是1至18。在一实施方案中,p是1至17。在一实施方案中,p是1至16。在一实施方案中,p是1至15。在一实施方案中,p是1至14。在一实施方案中,p是1至13。在一实施方案中,p是1至12。在一实施方案中,p是1至11。在一实施方案中,p是1至10。在一实施方案中,p是1至9。在一实施方案中,p是1至8。在一实施方案中,p是1至7。在一实施方案中,p是1至6。在一实施方案中,p是1至5。在一实施方案中,p是1至4。在一实施方案中,p是1至3。在一实施方案中,p是1至2。在一实施方案中,p是1至1。
在一实施方案中,R2是H或R1。在一实施方案中,R2是H。在一实施方案中,R2是R1。在一实施方案中,R2是甲基。在一实施方案中,R2是叔丁基。在一实施方案中,R2是二苯甲基。在一实施方案中,R2是苄基。
R3缺失、是Me;条件是当X取决于R3所依赖的碳时,则R3缺失;或者R3是-Z-L-C(O)O-R1,其中Z是键、-O-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-。在一实施方案中,R3是甲基。在一实施方案中,R3缺失,且X取决于R3所依赖的碳。在一实施方案中,R3是-Z-L-C(O)O-R1,其中Z是键、-O-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-。在一实施方案中,Z是-O-。在一实施方案中,Z是-N(Rx)-。在一实施方案中,Z是-NH-。在一实施方案中,R3是-C(O)N(Rx)-。在一实施方案中,R3是-C(O)NH-。在一实施方案中,R3是-N(Rx)-C(O)-。在一实施方案中,R3是-NH-C(O)-。在一实施方案中,R3是-S(O)n-N(Rx)-。在一实施方案中,R3是-S(O)-NH-。在一实施方案中,R3是-S(O)2-NH-。在一实施方案中,R3是-N(Rx)-S(O)n-。在一实施方案中,R3是-NH-S(O)1-。在一实施方案中,R3是-NH-S(O)2-。
R4缺失、是H或OH;条件是当-X-L-C(O)O-R1取决于R4所依赖的碳时,则R4是H或缺失;在一实施方案中,R4是H。在一实施方案中,R4是H,且其所取决的碳是双键的一部分。在一实施方案中,R4是H,且其所取决的碳不是双键的一部分。在一实施方案中,R4是OH。在一实施方案中,R4缺失,且X依赖-X-L-C(O)O-R1取决于R4所依赖的碳,并且所述碳是双键的一部分。
R5是H或任选被碳环或杂环取代的烷基,其中所述碳环和杂环任选被氧代基和烷基取代。在一实施方案中,R5是H。在一实施方案中,R5是烷基。在一实施方案中,R5是甲基。在一实施方案中,R5是
在一实施方案中,Rx是H。在一实施方案中,Rx是-C(O)O-R1。在一实施方案中,Rx是烷基。在一实施方案中,Rx是任选被-C(O)O-R1取代的烷基。
在一实施方案中,‘n’是1。在另一实施方案中,‘n’是2。
在一实施方案中,本发明的化合物是以下化合物之一:
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(甲氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(异丙氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-六氟-2-甲基丙烷-2-基)氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-羟基乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2,2,2-三氟乙氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-咪唑-1-基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-吗啉代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((((R)-奎宁环-3-基)氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-(吡啶-2-基)乙氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-氨基-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((羧甲氧基)羰基)-,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(叔丁氧基)-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-10-(甲氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-十八氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((羧甲基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)(甲基)-氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(甲氧基羰基)吡咯烷-1-羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-二甲氧基-1,5-二氧代戊烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-二甲氧基-1,4-二氧代丁烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-羟基-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-咪唑-1-基)乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-羟基乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(2-吗啉代乙氧基)-2-氧代乙基)氨基甲酰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(((新戊酰氧基)甲氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((异丙氧基羰基)氧基)甲氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((异丙氧基羰基)氧基)-乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((异丙氧基羰基)氧基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(二乙氨基)-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-吗啉代-2-氧代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(4-甲基哌嗪-1-基)-2-氧代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(双(2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氮烷二基)二乙酸二苄酯;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-2,2-二甲基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-甲氧基-4-氧代丁-2-烯酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-3,3-二甲基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-3,3-二甲基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-甲氧基-3-氧代丙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-甲氧基-2-氧代乙氧基)乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-甲氧基-2-氧代乙基)-1H-1,2,3-***-4-基)甲氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-二甲氧基-1,3-二氧代丙烷-2-基)氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(乙氧基羰基)哌啶-1-基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((3-氧代-2,6,9,12-四氧杂十四烷-14-基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((12-氧代-2,5,8,11-四氧杂十四烷)磺酰氨基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(4-氧代-2,8,11,14-四氧杂-5-氮杂十五烷酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-羟基-9-(甲氧基羰基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-氧代-2-(((R)-奎宁环-3-基)氧基)乙基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸。
在另一实施方案中,本发明的化合物是以下化合物之一:
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((12-氧代-2,5,8,11-四氧杂十三烷-13-基)氧基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((10-甲基-12-氧代-2,5,8,11-四氧杂十三烷-13-基)氧基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2,5,9,12-四氧杂十三烷-7-基氧基)-2-氧代乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-乙氧基-2-氧代乙氧基)乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-(2-甲氧基乙氧基)-2-氧代乙氧基)乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-((1-甲氧基丙烷-2-基)氧基)-2-氧代乙氧基)乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(双(2-(2-(2-甲氧基乙氧基)乙氧基)-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(2,5,8,11-四氧杂十二烷-1-酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(4-氧代-2,5,8,11,14-五氧杂十五烷-1-酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-(5-甲基-4-氧代-2,8,11,14-四氧杂-5-氮杂十五烷-1-酰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-(3-甲基-4-氧代-2,8,11,14-四氧杂-5-氮杂十五烷-1-酰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(3,5-二甲基-4-氧代-2,8,11,14-四氧杂-5-氮杂十五烷-1-酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(2,5,8,11,14-五氧杂十五烷-1-酰基)哌啶-1-基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-羟基-9-(甲氧基羰基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,5,8,11-四氧杂十四烷-14-酰基氧基)-9-(甲氧基羰基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-{3-[4,4-双(甲氧基羰基)哌啶-1-基]-2-羟基丙氧基}-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-{[(2-甲氧基-2-氧代乙基)氨基甲酰基]氧基}-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(乙酰基氧基)-9-[(乙基硫烷基)羰基]-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-[3-(叔丁氧基)-3-氧代丙氧基]-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸;
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(3R)-3-(甲氧基羰基)吡咯烷-1-基]-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,9-二羧酸;和
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[4-(甲氧基羰基)哌啶-1-基]-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,9-二羧酸。
在实施例59中描述的测定法中测试了以上列出的许多化合物(超过50%),以通过在接触细胞裂解物(人和大鼠)或来源于人结肠组织的结肠单层器官样物质之前和之后测量皮质醇的量来确定它们抑制HSD2的活性。本发明的化合物的HSD2抑制作用以在8.9至7.7(人裂解物)和8.9至7.5(大鼠裂解物)以及>8至5.9(人器官样物质)范围内的pIC50表示。作为参考,在相同的HSD2测定中测试甘草次酸:8.5(人裂解物)、6.4(人器官样物质)。本发明的化合物与它们的相应酸化合物之间的pIC50差在2.2至0.4(人裂解物)、1.3至0.8(人器官样物质)范围内,例外的是测试的一种化合物在两种裂解物中的pIC50差是负的(较小的HSD2抑制活性),但在人器官样物质中为1.3。正差表明与相应的酸化合物相比,本发明的化合物的HSD2抑制活性更强。
本发明的化合物可含有一个或多个不对称或手性中心。因此,所述化合物可作为非对映体、对映体或其混合物存在。化合物的合成可采用外消旋体、非对映体或对映体作为起始物或中间体。可通过色谱法或结晶法分离非对映体化合物。类似地,可采用相同的技术或本领域中已知的其它技术来分离对映体混合物。除有规定外,每个不对称中心可呈R或S构型,并且这两种构型都在本发明的范围内。本文所述的化合物的所有立体异构形式,包括但不限于非对映体、对映体和阻转异构体,以及它们的混合物,如外消旋混合物,都旨在为本发明化合物的一部分。
还将要理解的是,某些式I的化合物可用作进一步的式I的化合物的中间体。进一步要理解的是,本文所述的化合物可按非溶剂化的形式存在,以及按与药学上可接受的溶剂如水、乙醇等溶剂化的形式存在,并且所述化合物旨在包括溶剂化和非溶剂化形式两者。
采用标准有机合成技术由市售的起始物和试剂制备本发明的化合物。将要理解的是,制备本发明的化合物所采用的合成程序将取决于化合物中存在的特定取代基,并且可能需要在有机合成中为标准的各种保护和脱保护步骤,但这些在以下一般方案中可能未示出。起始物通常可得自商业来源,或者采用本领域技术人员熟知的方法很容易地制备。作为说明的目的,本文的方案显示出制备本发明的化合物以及关键中间体的一般方法。本领域技术人员将要理解的是,可采用其它合成路线来合成所述化合物。虽然在方案中描述了并且在下面讨论了具体的起始物和试剂,但可以很容易地替换其它起始物和试剂以提供各种衍生物和/或反应条件。此外,根据本公开内容,采用本领域技术人员熟知的常规化学方法可对通过下述方法制备的许多化合物进行进一步的改性。一般来说,可根据方案1制备本发明的化合物,以甘草次酸的羧酸衍生物(i)开始,其例如通过由二甲基甲酰胺催化用草酰氯转化成相应的酰卤,例如酰氯中间体(ii)。然后中间体(ii)与醇中间体(iii)反应,得到最终式I的酯化合物。
方案1
在制备式I的化合物时,可能有必要保护中间体的远端官能团(例如,伯胺或仲胺等)。对这种保护的需求将根据远端官能团的性质和制备方法的条件而有所不同。本领域技术人员很容易确定对这种保护的需求。关于保护基团及其用途的一般描述,请参阅Greene,T.W.和P.G.M.Wuts.Greene's Protective Groups in Organic Synthesis.第4版.NewYork:Wiley-Interscience,2006。
可能有利的是将反应产物彼此分离和/或与起始物分离。通过本领域中常见的技术将每一步骤或系列步骤的所需产物分离和/或纯化(下文中分离)至所需的均匀度。通常这类分离涉及多相萃取、从溶剂或溶剂混合物中结晶、蒸馏、升华或色谱法。色谱法可涉及许多方法,包括例如:反相和正相;尺寸排阻;离子交换;高、中和低压液相色谱方法和装置;小规模分析;模拟移动床(“SMB”)和制备型薄层或厚层色谱法,以及小规模薄层和快速色谱法技术。本领域技术人员将会应用最有可能实现所需分离的技术。
可通过本领域技术人员熟知的方法(如通过色谱法和/或分级结晶),将非对映体和对映体混合物根据它们的物理化学差异分离成它们单独的立体异构体。可通过如下方式分离对映体,即通过与适当的光学活性化合物(例如,手性助剂如手性醇或Mosher酰氯)反应将对映体混合物转化成非对映体混合物,分离非对映体,并将单独的非对映体转化(例如,水解)为相应的纯对映体。也可通过使用手性HPLC柱来分离对映体。
本发明还包括含有本发明的化合物和治疗惰性载体、稀释剂或赋形剂的药物组合物或药剂,以及使用本发明的化合物制备这类组合物和药剂的方法。通常,通过在环境温度和适当的pH及所需的纯度下与生理学上可接受的载体(即,在所用剂量和浓度下对接受者无毒的载体)混合来配制用在本发明方法中的式I的化合物。制剂的pH主要取决于化合物的具体用途和浓度,但可以是约3至约8范围内的任何值。在pH 5的乙酸盐缓冲液中的制剂是一个合适的实施方案。在一个实施方案中,包含本发明的化合物的制剂是无菌的。通常将以固体组合物的形式储存所述化合物,尽管冻干制剂或水溶液也是可以接受的。
包含本发明的化合物的组合物将以符合良好医疗操作规程的方式进行配制、给药和施用。这种情况下需要考虑的因素包括所治疗的具体病症、所治疗的具体哺乳动物、个体患者的临床疾患、病症的原因、施用部位、施用方法、施用日程安排及执业医师已知的其它因素。要施用的化合物的“有效量”将由这类考虑因素决定,并且是抑制皮质醇通过HSD2向皮质酮转化所必需的最低量。这种量可低于对正常细胞或整个哺乳动物有毒的量。
可通过任意合适的方式施用本发明的化合物。在特定的实施方案中,口服施用所述化合物。在特定的实施方案中,经直肠施用所述化合物。
一般地,每剂肠胃外施用的本发明的化合物的初始药学有效量将在约0.01-1,000mg/kg/天的范围内,例如每天约0.1至100mg/kg患者体重,化合物的典型初始用量范围是0.5至50mg/kg/天。口服单位剂型如片剂和胶囊可含有约25至约1000mg本发明的化合物。在特定的实施方案中,有效量是本发明的化合物足以使结肠钾分泌增加约15mmol/天的量。在特定的实施方案中,有效量是本发明的化合物足以使结肠钾分泌增加约1mmol/天的量。在特定的实施方案中,有效量是本发明的化合物足以使结肠钾分泌增加约5mmol/天的量。在特定的实施方案中,有效量是本发明的化合物足以使结肠钾分泌增加约10mmol/天的量。在特定的实施方案中,有效量是本发明的化合物足以使结肠钾分泌增加约15mmol/天的量。在特定的实施方案中,有效量是本发明的化合物足以使结肠钾分泌增加约20mmol/天的量。
可按任意方便的施用形式(例如片剂、胶囊、溶液、分散体、混悬液、糖浆、栓剂、凝胶、乳液等)施用所述化合物。合适口服剂型的一个实例是含有约25mg、50mg、100mg、250mg或500mg本发明的化合物与约90-30mg无水乳糖、约5-40mg交联羧甲纤维素钠、约5-30mg聚乙烯吡咯烷酮(“PVP”)K30和约1-10mg硬脂酸镁混配的片剂。首先将粉末成分混合在一起,然后与PVP的溶液混合。可使用常规设备将所得组合物干燥、制粒、与硬脂酸镁混合并压制成片剂形式。
可通过混合本文所述的化合物和载体或赋形剂来制备另一种制剂。合适的载体和赋形剂是本领域技术人员熟知的,并且在例如Ansel,Howard C.,等人,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.,等人,Remington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&Wilkins,2000;和Rowe,Raymond C.Handbook of Pharmaceutical Excipients.Chicago,Pharmaceutical Press,2005中有详细描述。制剂还可包括一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、避光剂、助流剂、加工助剂、着色剂、甜味剂、加香剂、调味剂、稀释剂及其它提供药物(即,本文所述的化合物或其药物组合物)的优雅外观或有助于生产药物产品(即,药剂)的已知添加剂。
在一实施方案中,制剂响应于与结肠的酶(例如由肠细菌产生的酶)接触而释放所述化合物。可使用某些基于淀粉的胶囊包衣,它们在胃和小肠中具有抗消化性,但是一旦剂型到达结肠就会被微生物(正常肠道菌群)酶降解。
在一实施方案中,口服施用本发明的化合物。在另一实施方案中,将所述化合物配制成用于经结肠递送。可响应于pH时间、微生物和压力而实施经结肠递送。在一实施方案中,所述制剂响应于结肠pH释放所述化合物。在所述制剂经过GI道时,通过pH增加触发所述化合物的释放。制剂是基于这样的聚合物,其在胃和小肠上段中的较低pH下是不溶的,而在远端小肠所处的较高pH下是可溶的,例如聚合物是可经受低至的环境的丙烯酸和纤维素的衍生物。合适的肠溶聚合物包括邻苯二甲酸聚乙酸乙烯酯(PVAP)例如偏苯三酸乙酸纤维素(CAT),邻苯二甲酸羟丙基甲基纤维素(HPMCP)例如HP-50、HP-55、HP-55S,琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)例如LF级、MF级或HF级,甲基丙烯酸共聚物例如L100-55、L30D-55、L-1000、L12.5、S-100、S12.5、FS30D,邻苯二甲酸乙酸纤维素(CAP)例如和虫胶例如125或125N。
在本发明的一方面提供了抑制皮质醇通过HSD2向皮质酮转化的方法,包括使HSD2与式I的化合物接触。在本发明的另一方面提供了促进在哺乳动物中激活MR的方法,包括对所述哺乳动物施用有效量的式I的化合物。在本发明的另一方面提供了降低哺乳动物的血浆中的钾水平的方法,包括对所述哺乳动物施用有效量的式I的化合物。在本发明的另一方面提供了促进钾离子向哺乳动物的结肠腔中分泌的方法,包括对所述哺乳动物施用有效量的式I的化合物。
在本发明的一方面提供了治疗和/或预防哺乳动物的高钾血症的方法,包括对所述哺乳动物施用有效量的式I的化合物。高钾血症特别频发于患有慢性肾脏疾病(CKD)、高血压、心力衰竭和糖尿病的患者中。因此,在本发明的实施方案中,治疗和/或预防高钾血症的方法在患有CKD高血压、心力衰竭和糖尿病的患者中进行。经常用某些类药物治疗罹患这些疾患的患者,如血管紧张素转化酶(ACE)抑制剂、血管紧张素-受体阻滞剂(ARB)或肾素-血管紧张素-醛固酮***(RAAS)的其它抑制剂,以便对血压进行调控。然而,这类药物会促进钾滞留。因此,提供了一种治疗和/或预防哺乳动物的高钾血症的方法,包括与RAAS***的抑制剂组合施用式I的化合物。在一实施方案中,RAAS抑制剂是ACE抑制剂。
本文所述的化合物及其立体异构体、非对映体、对映体、互变异构体和药学上可接受的盐可单独使用,或者与通过不同作用机制起效的其它抗高钾血症剂组合使用。本发明的化合物可在单一药物组合物中与其它抗高钾血症剂一起施用,或者可单独施用,并且当单独施用时,可同时或按任意顺序依次进行。这种依次施用在时间上可接近或远隔。
在一实施方案中,另一种抗高钾血化合物是钾离子结合剂,如交联聚磺酸苯乙烯(PSS)聚合物树脂。在一实施方案中,PSS树脂与二乙烯基苯(DVB)共聚物交联。DVB交联的PSS是控制住院患者的高钾血症最常用的药物。PSS通常以钠盐或钙盐的形式提供,并且其在肠腔中以钠离子或钙离子交换分泌的钾离子。这大都发生在结肠中,这是肠道中钾分泌最多的部位。在一实施方案中,WO2016111855(以引用的方式并入本文)中描述了抗高钾血PSS树脂。在一实施方案中,PSS树脂是与DVB共聚物交联的PSS聚合物树脂的钙盐。在一实施方案中,PSS树脂与1.0至1.9%的DVB交联。在一实施方案中,PSS树脂与1.6至1.9%的DVB交联。在一实施方案中,PSS树脂与约1.8%的DVB交联。
在一实施方案中,另一种抗高钾血症剂是 或RDX7675。在另一实施方案中,另一种抗高钾血症剂是掺有钾结合羧酸根基团的氟丙烯酸酯聚合物,例如帕替罗默在一实施方案中,另一种抗高钾血症剂是不溶性非吸收的硅酸锆钠,其将钾离子捕获在其晶格结构内,例如ZS-9在一实施方案中,另一种抗高钾血症剂是交联聚丙烯酸,例如CLP-1001。
在本发明的另一方面,意外地发现HSD2抑制与钠-氢交换剂(NHE)的抑制组合协同地增加了钾向粪便中的***。NHE存在于肾脏的肾元近端的细管中以及肠的肠上皮细胞顶端膜中。被称为NHE3的同种型主要负责维持钠的平衡,并且也间接关联血液pH的缓冲。NHE3反向转运体在细胞将一个氢离子从细胞喷射到肠腔和近端细管腔中时将一个钠离子输入到细胞的胞质溶胶中。如图1中所示,已表明当抑制HSD2和NHE时,对粪便钾***有协同作用。因此,提供了一种从哺乳动物的血浆和/或组织中排除钾的方法,包括与增加结肠中的液体量的化合物组合对所述哺乳动物施用有效量的HSD2抑制剂或MR激动剂。还提供了从哺乳动物的血浆和/或组织中排除钾的方法,包括与从血浆和/或组织中排除钠的化合物组合对所述哺乳动物施用有效量的HSD2抑制剂或MR激动剂。还提供了从哺乳动物的血浆和/或组织中排除钾的方法,包括与促进钠向胃肠道中***的化合物组合对所述哺乳动物施用有效量的HSD2抑制剂或MR激动剂。在一实施方案中,所述化合物是增加结肠中的液体的轻泻剂。在一实施方案中,所述轻泻剂是比沙可啶。在一实施方案中,所述轻泻剂是匹可硫酸盐。在一实施方案中,所述轻泻剂是MgOH。在一实施方案中,所述轻泻剂是(PEG3350)。在一实施方案中,所述轻泻剂是乳果糖。在一实施方案中,所述化合物是肠鸟苷酸环化酶的激活剂。在一实施方案中,鸟苷酸环化酶激动剂是利那洛肽。在一实施方案中,鸟苷酸环化酶激动剂是普卡那肽(plecanatide)。在一实施方案中,所述化合物是肠ClC-2氯离子通道的激活剂。在一实施方案中,ClC-2氯离子通道激活剂是鲁比前列酮。
还提供了从哺乳动物的血浆和/或组织中排除钾的方法,包括与NHE抑制剂组合对所述哺乳动物施用有效量的HSD2抑制剂或MR激动剂。在一实施方案中,同时施用所述HSD2抑制剂或MR激动剂和所述NHE抑制剂化合物。在一实施方案中,依次施用所述HSD2或MR激动剂和所述NHE抑制剂化合物。在一实施方案中,在所述NHE抑制剂或MR激动剂之前施用所述HSD2抑制剂或MR激动剂。在一实施方案中,在所述HSD2抑制剂或MR激动剂之前施用所述NHE抑制剂或MR激动剂化合物。在一实施方案中,所述NHE抑制剂是NHE3抑制剂。
在本发明的另一方面提供了包含HSD2抑制剂和NHE抑制剂的药物组合物。在另一方面提供了包含MR激动剂和NHE抑制剂的药物组合物。
在另一方面提供了治疗哺乳动物的高钾血症的方法,包括与NHE抑制剂组合对所述哺乳动物施用有效量的HSD2抑制剂或MR激动剂。在一实施方案中,所述NHE抑制剂是NHE3抑制剂。
在一实施方案中,所述MR激动剂是氟氢可的松。
在另一方面提供了治疗哺乳动物的高钾血症的方法,包括与NHE抑制剂组合对所述哺乳动物施用有效量的HSD2抑制剂。在一实施方案中,所述NHE抑制剂是NHE3抑制剂。在另一方面提供了包含HSD2抑制剂和NHE抑制剂的组合物。在一实施方案中,所述组合物是药物组合物。在一实施方案中,存在有效量的HSD2抑制剂化合物和NHE抑制剂化合物。在一实施方案中,所述组合物进一步包含药学上可接受的载体、赋形剂和/或稀释剂。在一实施方案中,所述HSD2抑制剂是甘草次酸或其类似物。在一实施方案中,所述HSD2抑制剂是甘草次酸。在一实施方案中,所述HSD2抑制剂是甘草甜素。在一实施方案中,所述HSD2抑制剂是根据本文式I的化合物。在一实施方案中,所述NHE抑制剂是NHE3抑制剂。在一实施方案中,所述NHE3抑制剂是以下文献中描述的化合物:第5,866,610、6,399,824、6,911,453、6,703,405、6,005,010、6,736,705、6,887,870、6,737,423、7,326,705、5,824,691(WO94/026709)、6,399,824(WO02/024637)号美国专利;第2004/0039001(WO02/020496)、2005/0020612(WO03/055490)、2004/0113396(WO03/051866)、2005/0020612、2005/0054705、2008/0194621、2007/0225323、2004/0039001、2004/0224965、2005/0113396、2007/0135383、2007/0135385、2005/0244367、2007/0270414号美国专利公布;第WO 01/072742、WO 01/021582(CA2387529)、WO97/024113(CA02241531)WO2010078449、WO2014029983、WO2014029984号国际专利公布;和第EP0744397(CA2177007)号欧洲专利,这些文献中的每一者以全文引用的方式并入本文。
在一实施方案中,所述NHE抑制剂是最低程度全身性的化合物,即其在肠中抑制NHE,并且基本上是不可生物利用的。在一实施方案中,所述NHE抑制剂是化合物式(I)或(IX):
其中:
NHE是NHE结合小分子,其包含(i)含杂原子部分,和(ii)直接或间接地与其结合的环状或杂环支架或支撑部分,含杂原子部分选自取代的胍基部分和取代的杂环部分,其可任选与支架或支撑部分稠合以形成稠合双环结构;且,
Z是其上具有至少一个用于与NHE结合小分子连接的位点的部分,所得NHE-Z分子具有使其基本上不可渗透或基本上全身不可生物利用的整体物理化学特性;且,
E是值为1或更大的整数。
在某些实施方案中,NHE-Z分子中可自由旋转的键的总数为至少约10。在某些实施方案中,NHE-Z分子中氢键给体的总数为至少约5。在一些实施方案中,NHE-Z分子中氢键受体的总数为至少约10。在某些实施方案中,NHE-Z分子中氢键给体和氢键受体的总数为至少约10。在一些实施方案中,NHE-Z结合化合物的Log P为至少约5。在某些实施方案中,NHE-Z结合化合物的log P小于约1或小于约0。在某些实施方案中,支架是5元或6元环状或杂环部分。在某些实施方案中,支架是芳族的。
在一些实施方案中,NHE结合小分子的支架与部分Z结合,所述化合物具有式(II)的结构:
其中:
Z是其上具有一个或多个用于与一个或多个NHE结合小分子连接的位点的核心,所得NHE-Z分子具有使其基本上不可渗透或基本上全身不可生物利用的整体物理化学特性;
B是NHE结合小分子的含杂原子部分,并且选自取代的胍基部分和取代的杂环部分,其可任选与支架部分稠合以形成稠合双环结构;
支架是NHE结合小分子的环状或杂环支架或支撑部分,其直接或间接与含杂原子部分B结合,并且任选被一个或多个另外的烃基或杂烃基部分取代;
X是键或选自以下的间隔部分:取代或未取代的烃基或杂烃基部分,特别是取代或未取代的C1-7烃基或杂烃基,以及取代或未取代的饱和或不饱和环状或杂环部分,其连接B和支架;且
D和E是值各自独立地为1或更大的整数。
在一些实施方案中,所述化合物是低聚物、树枝状聚合物或聚合物,并且进一步地,其中Z是其上具有两个或更多个用于直接或通过连接部分L间接与多个NHE结合小分子连接的位点的核心部分,所述化合物具有式(X)的结构:
其中L是键或连接核心与NHE结合小分子的连接基,且n是2或更大的整数,并且进一步地,其中每个NHE结合小分子可彼此相同或不同。
在一些实施方案中,NHE结合小分子具有式(IV)的结构:
或其立体异构体、前药或药学上可接受的盐,其中:
每个R1、R2、R3、R5和R9独立地选自H、卤素、-NR7(CO)R8、-(CO)NR7R8、-SO2-NR7R8、-NR7SO2R8、-NR7R8、-OR7、-SR7、-O(CO)NR7R8、-NR7(CO)OR8和-NR7SO2NR8,其中R7和R8独立地选自H或连接NHE结合小分子与L的键,条件为至少一个是连接NHE结合小分子与L的键;
R4选自H、C1-C7烷基或连接NHE结合小分子与L的键;
R6缺失或选自H和C1-C7烷基;且
Ar1和Ar2独立地表示芳族环或杂芳族环。
在某些实施方案中,NHE结合小分子具有以下结构:
或其立体异构体、前药或药学上可接受的盐,其中:
每个R1、R2和R3独立地选自H、卤素、-NR7(CO)R8、-(CO)NR7R8、-SO2-NR7R8、-NR7SO2R8、-NR7R8、-OR7、-SR7、-O(CO)NR7R8、-NR7(CO)OR8和-NR7SO2NR8,其中R7和R8独立地选自H或连接NHE结合小分子与L的键,条件为至少一个是连接NHE结合小分子与L的键。
在一些实施方案中,NHE结合小分子具有以下结构之一:
或其立体异构体、前药或药学上可接受的盐。在某些实施方案中,L是聚亚烷基二醇连接基。在某些实施方案中,L是聚乙二醇连接基。在一些实施方案中,n是2。
在某些实施方案中,所述核心具有以下结构:
其中:
X选自由键、-O-、-NH-、-S-、C1-6亚烷基、-NHC(=O)-、-C(=O)NH-、-NHC(=O)NH-、-SO2NH-和-NHSO2-组成的组;
Y选自由键、任选取代的C1-8亚烷基、任选取代的芳基、任选取代的杂芳基、聚乙二醇连接基、-(CH2)1-6O(CH2)1-6-和-(CH2)1-6NY1(CH2)1-6-组成的组;且
Y1选自由氢、任选取代的C1-8烷基、任选取代的芳基或任选取代的杂芳基组成的组。
在一些实施方案中,所述核心选自由以下组成的组:
其中:L是键或连接部分;NHE是NHE结合小分子;且n是非零整数。
在一实施方案中,所述NHE抑制剂是:
N,N',N”-(2,2',2”-次氮基三(乙烷-2,1-二基))三(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(2,2'-(乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(1,4-亚苯基双(亚甲基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(1,4-亚苯基双(亚甲基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(丁烷-1,4-二基)双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(十二烷-1,12-二基)双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N',N”,N”'-(3,3',3”,3”'-(丁烷-1,4-二基双(氮烷三基))四(丙烷-3,1-二基))四(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(丁烷-1,4-二基)双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(十二烷-1,12-二基)双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N',N”-(2,2',2”-次氮基三(乙烷-2,1-二基))三(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N',N”,N”'-(3,3',3”,3”'-(丁烷-1,4-二基双(氮烷三基))四(丙烷-3,1-二基))四(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(1,4-亚苯基双(亚甲基))双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(2,2'-(乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N1,N8-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)辛二酰胺;
2-(N-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基)氨磺酰基氨基)乙基膦酸;
2-(N-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基)氨磺酰基氨基)乙基膦酸;
N,N'-(丁烷-1,4-二基)双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺];
N,N'-(1,4-亚苯基双(亚甲基))双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺];
N,N'-(2,2'-(乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺];
N,N'-(2,2'-(2,2'-氧基双(乙烷-2,1-二基)双(氧基))双(乙烷-2,1-二基))双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺]
(E)-3-(4-(4-(N-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)氨磺酰基)苯氧基)-3,5-二氟苯基)-N-(二氨基亚甲基)-2-甲基丙烯酰胺;
N,N'-(13-氧代-3,6,9,17,20,23-六氧杂-12,14-二氮杂二十五烷-1,25-二基)双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺];
N,N'-(13,20二氧代-3,6,9,24,27,30-六氧杂-12,21-二氮杂三十二烷-1,32-二基)双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺];
N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-氧基双(亚甲基)双(1H-1,2,3-***-4,1-二基))双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双[(E)-N-(二氨基亚甲基)-3-(3,5-二氟-4-(4-氨磺酰基苯氧基)苯基)-2-甲基丙烯酰胺];
N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-氧基双(亚甲基)双(1H-1,2,3-***-4,1-二基))双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺)
1-(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-1H-1,2,3-***-4,5-二羧酸;
N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N31-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-4,7,10,13,16,19,22,25,28-九氧杂三十一烷-1,31-二酰胺;
N1,N31-双(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-4,7,10,13,16,19,22,25,28-九氧杂三十一烷-1,31-二酰胺;
N,N'-(13-氧代-3,6,9,17,20,23-六氧杂-12,14-二氮杂二十五烷-1,25-二基)双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N1,N31-双(2-(2-(2-(2-(4-(4-((E)-3-(二氨基亚甲基氨基)-2-甲基-3-氧代丙-1-烯基)-2,6-二氟苯氧基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-4,7,10,13,16,19,22,25,28-九氧杂三十一烷-1,31-二酰胺;
N,N'-(13-氧代-3,6,9,17,20,23-六氧杂-12,14-二氮杂二十五烷-1,25-二基)双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N1,N4-双(20-(4-(4-((E)-3-(二氨基亚甲基氨基)-2-甲基-3-氧代丙-1-烯基)-2,6-二氟苯氧基)苯基磺酰氨基)-3,6,9,12,15,18-六氧杂二十基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-乙基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
3,3'-(2,2'-(2,2'-(2,2'-氧基双(乙烷-2,1-二基)双(氧基))双(乙烷-2,1-二基))双(6,8-二氯-1,2,3,4-四氢异喹啉-4,2-二基))二苯胺;
N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(1-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基氨基)-1-氧代-5,8,11-三氧杂-2-氮杂十三烷-13-基)-2,3-二羟基琥珀酰胺;
N1,N2-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)草酰胺;
N1,N4-双(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)琥珀酰胺;
2,2'-氧基双(N-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)乙酰胺);
(2R,3R)-N1,N4-双(2-(2-(2-(3-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基氨基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N2-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)草酰胺;
N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)琥珀酰胺;
N1,N3-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,2-二甲基丙二酰胺;
N1,N3-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-2,2-二甲基丙二酰胺;
N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(吡啶-2,6-二基双(氧基))双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
2,2'-(甲基氮烷二基)双(N-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)乙酰胺)三(2,2,2-三氟乙酸酯);
5-氨基-N1,N3-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)间苯二甲酰胺三(2,2,2-三氟乙酸酯);
2,2'-氧基双(N-(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)乙酰胺);
5-溴-N1,N3-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)间苯二甲酰胺双(2,2,2-三氟乙酸酯);
N1,N3-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-2-羟基丙二酰胺双(2,2,2-三氟乙酸酯);
N1,N2-双(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)草酰胺;
N1,N4-双(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)琥珀酰胺;
3,5-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基氨基甲酰基)苯磺酸;
N1,N3-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-5-羟基间苯二甲酰胺;
(2R,3R)-N1,N4-双(3-((3-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)丙基)(甲基)氨基)丙基)-2,3-二羟基琥珀酰胺;
2,2'-氧基双(N-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)乙酰胺);
N1,N3-双(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-2,2-二甲基丙二酰胺;
N1,N2-双(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)草酰胺;
2,2'-氧基双(N-(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)乙酰胺);
N1,N4-双(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)琥珀酰胺;
N1,N4-双(2-(2-(2-(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)琥珀酰胺;
2,2'-氧基双(N-(2-(2-(2-(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)乙酰胺);
(S或R)-N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双(3-((S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
(S或R)-N,N'-(2,2'-(2,2'-(2,2'-(1,4-亚苯基双(氮烷二基))双(氧代亚甲基)双(氮烷二基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(3-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(丁烷-1,4-二基)双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙酰氨基)乙酰氨基)乙酰胺);
N1,N4-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N,N'-(2,2'-(2,2'-(2,2'-(1,4-亚苯基双(亚甲基))双(氮烷二基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
(2R,3R)-N1,N4-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N,N'-(13,20-二氧代-3,6,9,24,27,30-六氧杂-12,14,19,21-四氮杂三十二烷-1,32-二基)双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(1,1'-(1,4-亚苯基双(氮烷二基))双(1-氧代-5,8,11-三氧杂-2-氮杂十三烷-13,1-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
(2R,3R)-N1,N4-双(20-(4-(4-((E)-3-(二氨基亚甲基氨基)-2-甲基-3-氧代丙-1-烯基)-2,6-二氟苯氧基)苯基磺酰氨基)-3,6,9,12,15,18-六氧杂二十基)-2,3-二羟基琥珀酰胺;
(E)-3-(4-(4-(N-(20-氨基-3,6,9,12,15,18-六氧杂二十基)氨磺酰基)苯氧基)-3,5-二氟苯基)-N-(二氨基亚甲基)-2-甲基丙烯酰胺;
(2R,3R)-N1,N4-双(2-(2-(2-(2-(4-(4-((E)-3-(二氨基亚甲基氨基)-2-甲基-3-氧代丙-1-烯基)-2,6-二氟苯氧基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
2,2',2”-次氮基三(N-(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)乙酰胺);
N-(32-氨基-3,6,9,12,15,18,21,24,27,30-十氧杂三十二基)-3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺;
N1,N3,N5-三(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)苯-1,3,5-三羧酰胺;
N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)对苯二甲酰胺;
N1,N31-双(32-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)-3,6,9,12,15,18,21,24,27,30-十氧杂三十二基)-4,7,10,13,16,19,22,25,28-九氧杂三十一烷-1,31-二酰胺;
2R,3R)-N1,N4-双(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N3-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)苯-1,3-二磺酰胺;
N4,N4'-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)联苯-4,4'-二磺酰胺;
(14R,15R)-1-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)-14,15-二羟基-13-氧代-3,6,9-三氧杂-12-氮杂十六烷-16-酸;
(2S,3S)-N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(3-((R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(3-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(4-((R或S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N4-双(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N3-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)间苯二甲酰胺;
(2R,3S)-N1,N4-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
N1,N2-双(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)邻苯二甲酰胺;
N1,N4-双(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)对苯二甲酰胺;
N,N'-(10-氧代-3,6,14,17-四氧杂-9,11-二氮杂十九烷-1,19-二基)双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N1,N4-双(2-(2-(2-(2-(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)对苯二甲酰胺;
N1,N4-双(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙基)对苯二甲酰胺;
N,N'-(10-氧代-3,6,14,17-四氧杂-9,11-二氮杂十九烷-1,19-二基)双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(2,2'-(2,2'-(2,2'-(1,4-亚苯基双(氮烷二基))双(氧代亚甲基)双(氮烷二基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
亚苯基双(氮烷二基))双(氧代亚甲基)双(氮烷二基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(氧基)双(乙烷-2,1-二基))双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺;
(2S,3S)-N1,N4-双(2-(2-(2-(2-(3-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
(2R,3R)-N1,N4-双(2-(2-(2-(2-(3-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
(2S,3S)-N1,N4-双(2-(2-(2-(2-(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
(2R,3R)-N1,N4-双(2-(2-(2-(2-(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-2,3-二羟基琥珀酰胺;
(S或R)-N,N'-(13,20-二氧代-3,6,9,24,27,30-六氧杂-12,14,19,21-四氮杂三十二烷-1,32-二基)双(3-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
(S或R)-N,N'-(1,1'-(1,4-亚苯基双(氮烷二基))双(1-氧代-5,8,11-三氧杂-2-氮杂十三烷-13,1-二基))双(3-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N1,N4-双(2-(2-(2-(2-(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)-对苯二甲酰胺;
N1-(2-(2-(2-(2-(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基磺酰氨基)乙氧基)乙氧基)乙氧基)乙基)琥珀酰胺;
N,N'-(13,20-二氧代-3,6,9,24,27,30-六氧杂-12,14,19,21-四氮杂三十二烷-1,32-二基)双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
N,N'-(1,1'-(1,4-亚苯基双(氮烷二基))双(1-氧代-5,8,11-三氧杂-2-氮杂十三烷-13,1-二基))双(4-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
(S或R)-N,N'-(13-氧代-3,6,9,17,20,23-六氧杂-12,14-二氮杂二十五烷-1,25-二基)双(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);
(S或R)-N,N'-(13,20-二氧代-3,6,9,24,27,30-六氧杂-12,14,19,21-四氮杂三十二烷-1,32-二基)双(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺);或
(S或R)-N,N'-(1,1'-(1,4-亚苯基双(氮烷二基))双(1-氧代-5,8,11-三氧杂-2-氮杂十三烷-13,1-二基))双(4-((S或R)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺)。
在一实施方案中,所述NHE抑制剂是:
在一些实施方案中,所述化合物具有以下式(I-H)的结构:
或其立体异构体、前药或药学上可接受的盐,
其中:
(a)n是2或更大的整数;
(b)核心是其上具有两个或更多个用于与两个或更多个NHE结合小分子部分连接的位点的核心部分;
(c)L是键或连接核心部分与两个或更多个NHE结合小分子部分的连接基;且
(d)NHE是具有以下式(XI-H)的结构的NHE结合小分子部分:
其中:
B选自由芳基和杂环基组成的组;
每个R5独立地选自由以下组成的组:氢、卤素、任选取代的C1-4烷基、任选取代的C1-4烷氧基、任选取代的C1-4硫代烷基、任选取代的杂环基、任选取代的杂环基烷基、任选取代的芳基、任选取代的杂芳基、羟基、氧代基、氰基、硝基、-NR7R8、-NR7C(=O)R8、-NR7C(=O)OR8、-NR7C(=O)NR8R9、-NR7SO2R8、-NR7S(O)2NR8R9、-C(=O)OR7、-C(=O)R7、-C(=O)NR7R8、-S(O)1-2R7和-SO2NR7R8,其中R7、R8和R9独立地选自由氢、C1-4烷基或连接NHE结合小分子部分与L的键组成的组,条件为至少一个是连接NHE结合小分子部分与L的键;
R3和R4独立地选自由以下组成的组:氢、任选取代的C1-4烷基、任选取代的环烷基、任选取代的环烷基烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂环基和任选取代的杂芳基;或者
R3和R4与它们所键合的氮一起形成任选取代的4-8元杂环基;且
每个R1独立地选自由以下组成的组:氢、卤素、任选取代的C1-6烷基和任选取代的C1-6烷氧基。在一些实施方案中,n是2。在某些实施方案中,L是聚亚烷基二醇连接基。在某些实施方案中,L是聚乙二醇连接基。
在某些实施方案中,所述核心具有以下结构:
其中:
X选自由键、-O-、-NH-、-S-、C1-6亚烷基、-NHC(=O)-、-C(=O)NH-、-NHC(=O)NH-、-SO2NH-和-NHSO2-组成的组;
Y选自由键、任选取代的C1-8亚烷基、任选取代的芳基、任选取代的杂芳基、聚乙二醇连接基、-(CH2)1-6O(CH2)1-6-和-(CH2)1-6NY1(CH2)1-6-组成的组;且
Y1选自由氢、任选取代的C1-8烷基、任选取代的芳基或任选取代的杂芳基组成的组。
在一些实施方案中,所述核心选自由以下组成的组:
在某些实施方案中,所述NHE结合小分子部分具有以下式(XII-H)的结构:
其中:
每个R3和R4独立地选自由以下组成的组:氢和任选取代的C1-4烷基,或者R3和R4与它们所键合的氮合起来形成任选取代的4-8元杂环基;
每个R1独立地选自由氢、卤素、C1-6烷基和C1-6卤代烷基组成的组;且
R5选自由-SO2-NR7-和-NHC(=O)NH-组成的组,其中R7是氢或C1-4烷基。
在一些实施方案中,R3和R4与它们所键合的氮合起来形成任选取代的5或6元杂环基。在某些实施方案中,所述任选取代的5或6元杂环基是吡咯烷基或哌啶基。在某些实施方案中,所述任选取代的5或6元杂环基是各自被至少一个氨基或羟基取代的吡咯烷基或哌啶基。在一些实施方案中,R3和R4独立地为C1-4烷基。在某些实施方案中,R3和R4是甲基。在一些实施方案中,每个R1独立地选自由氢或卤素组成的组。在某些实施方案中,每个R1独立地选自由氢、F和Cl组成的组。
在某些实施方案中,所述化合物具有以下式(I-I)的结构:
或其立体异构体、前药或药学上可接受的盐,其中:
(a)NHE是具有以下式(A-I)的结构的NHE结合小分子部分:
其中:
每个R1、R2、R3、R5和R9独立地选自H、卤素、-NR7(CO)R8、-(CO)NR7R8、-SO2-NR7R8、-NR7SO2R8、-NR7R8、-OR7、-SR7、-O(CO)NR7R8、-NR7(CO)OR8和-NR7SO2NR8,其中R7和R8独立地选自H、C1-6烷基、-C1-6烷基-OH或连接NHE结合小分子与L的键,条件为至少一个是连接NHE结合小分子与L的键;
R4选自H、C1-C7烷基或连接NHE结合小分子与L的键;
R6缺失或选自H和C1-C7烷基;且
Ar1和Ar2独立地表示芳族环或杂芳族环;
(b)核心是具有以下式(B-I)的结构的核心部分:
其中:
X选自C(X1)、N和N(C1-6烷基);
X1选自氢、任选取代的烷基、-NXaXb、-NO2、-NXc-C(=O)-NXc-Xa、-C(=O)NXc-Xa、-NXc-C(=O)-Xa、-NXc-SO2-Xa、-C(=O)-Xa和-OXa,
每个Xa和Xb独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的环烷基烷基、任选取代的杂环基、任选取代的杂环基烷基、任选取代的芳基、任选取代的芳烷基、任选取代的杂芳基和任选取代的杂芳基烷基;
Y是C1-6亚烷基;
当X是CX1时,Z选自-NZa-C(=O)-NZa-、-C(=O)NZa-、-NZa-C(=O)-和杂芳基;
当X是N或N(C1-6烷基)时,Z选自-NZa-C(=O)-NZa-、-NZa-C(=O)-和杂芳基;且
每个Xc和Za独立地选自氢和C1-6烷基;且
(c)L是键或连接核心部分与NHE结合小分子部分的连接基。
在一些实施方案中,所述NHE结合小分子部分具有以下结构:
其中:
每个R1、R2和R3独立地选自H、卤素、-NR7(CO)R8、-(CO)NR7R8、-SO2-NR7R8、-NR7SO2R8、-NR7R8、-OR7、-SR7、-O(CO)NR7R8、-NR7(CO)OR8和-NR7SO2NR8,其中R7和R8独立地选自H、C1-6烷基、-C1-6烷基-OH或连接NHE结合小分子与L的键,条件为至少一个是连接NHE结合小分子与L的键。
在一些实施方案中,所述NHE结合小分子部分具有以下结构之一:
在一些实施方案中,L是聚亚烷基二醇连接基。在某些实施方案中,L是聚乙二醇连接基。在一些实施方案中,X是C(X1)。在一些实施方案中,每个Xc是氢。在某些实施方案中,X是N。在某些实施方案中,每个Za是氢。
在一些实施方案中,所述化合物具有式(II)的结构:
或其立体异构体、前药或药学上可接受的盐,
其中:
(a)NHE是具有式(A-I)的结构的NHE结合小分子部分:
其中:
每个R1、R2、R3、R5和R9独立地选自H、卤素、-NR7(CO)R8、-(CO)NR7R8、-SO2-NR7R8、-NR7SO2R8、-NR7R8、-OR7、-SR7、-O(CO)NR7R8、-NR7(CO)OR8和-NR7SO2NR8,其中R7和R8独立地选自H、C1-6烷基、-C1-6烷基-OH或连接NHE结合小分子与L的键,条件为至少一个是连接NHE结合小分子与L的键;
R4选自H、C1-C7烷基或连接NHE结合小分子与L的键;
R6缺失或选自H和C1-C7烷基;且
Ar1和Ar2独立地表示芳族环或杂芳族环;
(b)核心是具有以下式(C-I)的结构的核心部分:
其中:
W选自亚烷基、聚亚烷基二醇、-C(=O)-NH-(亚烷基)-NH-C(=O)-、-C(=O)-NH-(聚亚烷基二醇)-NH-C(=O)-、-C(=O)-(亚烷基)-C(=O)-、-C(=O)-(聚亚烷基二醇)-C(=O)-和环烷基,
X是N;
Y是C1-6亚烷基;
Z选自-NZa-C(=O)-NZa-、-C(=O)NZa-、-NZa-C(=O)-和杂芳基;
每个Za独立地选自氢和C1-6烷基;且
(c)L是键或连接核心部分与NHE结合小分子的连接基。
在某些实施方案中,所述NHE结合小分子部分具有以下结构:
其中:
每个R1、R2和R3独立地选自H、卤素、-NR7(CO)R8、-(CO)NR7R8、-SO2-NR7R8、-NR7SO2R8、-NR7R8、-OR7、-SR7、-O(CO)NR7R8、-NR7(CO)OR8和-NR7SO2NR8,其中R7和R8独立地选自H、C1-6烷基、-C1-6烷基-OH或连接NHE结合小分子与L的键,条件为至少一个是连接NHE结合小分子与L的键。
在某些实施方案中,所述NHE结合小分子部分具有以下结构之一:
在另一实施方案中,所述NHE抑制剂是:
及其药学上可接受的盐、前药、溶剂合物、水合物、异构体和互变异构体,
其中:
连接基是-(CHR13)p-[Y-(CH2)r]s-Z-R13-(CH2)t-Z-;
W在每次出现时独立地为S(O)2、C(O)或-(CH2)m-;
Z在每次出现时独立地为键、C(O)或-C(O)NH-;
Y在每次出现时独立地为O、S、NH、N(C1-C3烷基)或-C(O)NH-;
Q是键、NH、-C(O)NH-、-NHC(O)NH-、-NHC(O)N(CH3)-或-NHC(O)NH-(CHR13);m是1至2的整数;n是1至4的整数;
r和p在每次出现时独立地为0至8的整数;
s是0至4的整数;
t是0至4的整数;
u是0至2的整数;
R1和R2独立地为H、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、芳基、含有1-5个选自由N、S、P和O组成的组的杂原子的杂芳基,其中每个烷基、烯基、环烯基、炔基、环烷基、杂环基、芳基或杂芳基任选被一个或多个卤素、OH、CN、-NO2、氧代基、-SR9、-OR9、-NHR9、-NR9R10、-S(O)2N(R9)2-、-S(O)2R9、-C(O)R9、-C(O)OR9、-C(O)NR9R10、-NR9S(O)2R10、-S(O)R9、-S(O)NR9R10、-NR8S(O)R9、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、杂环、芳基或杂芳基取代;或者
R1和R2与它们所连接的氮一起可形成含有1-5个选自由N、S、P和O组成的组的杂原子的杂环基或杂芳基,其中所述杂环基或杂芳基任选被一个或多个卤素、OH、CN、-NO2、氧代基、-SR9、-OR9、-NHR9、-NR9R10、-S(O)2N(R9)2-、-S(O)2R9、-C(O)R9、-C(O)OR9、-C(O)NR9R10、-NR9S(O)2R10、-S(O)R9、-S(O)NR9R10、-NR9S(O)R10、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、杂环、芳基或杂芳基取代;
R3和R4独立地为卤素、OH、CN、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基或-C(O)NR9R10;
R5、R6、R7和R8独立地为H、卤素、OH.CN、-NO2、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、芳基、含有1-5个选自由N、S、P和O组成的组的杂原子的杂芳基、-SR9、-OR9、-NHR9、-NR9R10、-S(O)2N(R9)2-、-S(O)2R9、-C(O)R9、-C(O)OR9、-NR9S(O)2R10、-S(O)R9、-S(O)NR9R10、-NR8S(O)R9;
R9和R10独立地为H、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、芳基或含有1-5个选自由N、S、P和O组成的组的杂原子的杂芳基
X是键、H、N、O、CR11R12、CR11、C、-NHC(O)NH-或C3-C6环烷基;
R11和R12独立地为H、C1-C6烷基、OH、NH2、CN或NO2;
R13在每次出现时独立地为键、H、C1-C6烷基、C4-C8环烯基、C3-C8环烷基、杂环基、芳基或杂芳基,其中每个环烯基、环烷基、杂环基、芳基或杂芳基任选被一个或多个R19取代;
R14在每次出现时独立地为H、C1-C6烷基或C1-C6卤代烷基;或者
R6和R14与它们所连接的原子一起可在每次出现时独立地结合形成5至6元杂环基,其中每个C3-C8环烷基或杂环基任选被一个或多个R19取代;或者
R13和R14与它们所连接的原子一起可在每次出现时独立地结合形成C3-C8环烷基、杂环基、芳基或含有1-5个选自由N、S、P和O组成的组的杂原子的杂芳基,其中每个杂环基或杂芳基任选被一个或多个R19取代;
R15、R16、R17和R18在每次出现时独立地为H、OH、NH2或C1-C3烷基,其中所述烷基任选被一个或多个R19取代;且
R19在每次出现时独立地为H、OH、NH2、氧代基、C1-C6烷基、C1-C6H卤代烷基、C1-C6烷氧基。
在一实施方案中,所述NHE3抑制剂是根据前式的化合物,条件是:
(1)当X是H时,n是1;
(2)当X是键、O或CR11R12时,n是2;
(3)当n是3时,X是CR11或N;
(4)当n是4时,X是C;
(5)在这时Q或X中仅一者是-NHC(O)NH-,
(6)R1和R2与它们所连接的氮一起不能形成吡咯烷基;
在一实施方案中,所述NHE3化合物具有根据下式的结构:
及其药学上可接受的盐、前药、溶剂合物、水合物、异构体和互变异构体,其中:
连接基是-(CHR8)p-[Y-(CH2)r]s-Z-R8-(CH2)t-Z-;
Q是键或-NHC(O)NH-;
Z在每次出现时独立地为键、C(O)或-C(O)NH-;
Y在每次出现时独立地为O、S、NH、N(C1-C3烷基)或-C(O)NH-;
X是键、N、O、CR11R12、CR11、C或-NHC(O)NH-;
n是2至4的整数;
r和p在每次出现时独立地为0至8的整数;
s是0至4的整数;
t是0至4的整数;
u是0至2的整数;
R1和R2独立地为卤素、OH、CN、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基或-C(O)NR9R10;
R3、R4、R5和R6独立地为H、卤素、OH.CN、-NO2、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、芳基、含有1-5个选自由N、S、P和O组成的组的杂原子的杂芳基、-SR9、-OR9、-NHR9、-NR9R10、-S(O)2N(R9)2-、-S(O)2R9、-C(O)R9、-C(O)OR9、-NR9S(O)2R10、-S(O)R9、-S(O)NR9R10、-NR8S(O)R9;
R7在每次出现时独立地为H、C1-C6烷基或C1-C6卤代烷基;
R8在每次出现时独立地为键、H、C1-C6烷基、C4-C8环烯基、C3-C8环烷基、杂环基、芳基或杂芳基,其中每个环烯基、环烷基、杂环基、芳基或杂芳基任选被一个或多个R17取代;或者
R7和R8与它们所连接的原子一起可在每次出现时独立地结合形成含有1-5个选自由N、S、P和O组成的组的杂原子的杂环基或杂芳基,其中每个杂环基或杂芳基任选被一个或多个R17取代;
R9和R10独立地为H、C1-C6烷基、C2-C6烯基、C4-C8环烯基、C2-C6炔基、C3-C8环烷基、杂环基、芳基或含有1-5个选自由N、S、P和O组成的组的杂原子的杂芳基;
R11和R12独立地为H、C1-C6烷基、OH、NH2、CN或NO2;
R13、R14、R15和R16在每次出现时独立地为H、OH、NH2或C1-C3烷基,其中所述烷基任选被一个或多个R17取代;且
R17在每次出现时独立地为H、OH、NH2、氧代基、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基。
在一实施方案中,所述NHE3抑制剂化合物具有根据前式的结构,条件是:
(1)当X是键、O或CR11R12时,n是2;
(2)当n是3时,X是CR11或N;
(3)当n是4时,X是C;
(4)在这时Q或X中仅一者是-NHC(O)NH-;
在一实施方案中,所述NHE3抑制剂化合物具有根据下式的结构:
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[5-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[5-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双(5-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺);
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺;
N,N'-(10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六烷-1,26-二基)双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[5-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[5-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[5-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(3S,3'S)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-甲基苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[5-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[5-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[5-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-2-甲基苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)-4-氟苯磺酰胺];
N,N'-[(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(哌啶-1,4-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(哌啶-1,4-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
1,1'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[N-([3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)苯基]磺酰基)甲酰胺];
1,1'-[(3R,3'R)-(7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十烷-1,20-二基)双(吡咯烷-1,3-二基)]双[N-([3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基]磺酰基)甲酰胺];
1,1'-(5,12-二氧代-4,6,11,13-四氮杂十六烷-1,16-二基)双[N-([3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基]磺酰基)哌啶-4-羧酰胺];
1,1'-(5,12-二氧代-4,6,11,13-四氮杂十六烷-1,16-二基)双[N-([3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基]磺酰基)哌啶-3-羧酰胺];
N1,N18-双([3-(6,8-二氯-2-二甲基-1,2,3,4-四氢异喹啉-4-基)苯基]磺酰基)-6,13-二氧代-5,7,12,14-四氮杂十八烷二酰胺;
N,N'-[(3S,3'S)-(6,13-二氧代-5,7,12,14-四氮杂十八烷二酰基)双(吡咯烷-1,3-二基)]双[3-(6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3S,3'S)-(6,13-二氧代-5,7,12,14-四氮杂十八烷二酰基)双(吡咯烷-1,3-二基)]双[3-(6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
1-[2-(2-[(1-[(3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]哌啶-4-基)氧基]乙氧基)乙基]-3-[4-(3-[2-(2-[(1-[(3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]哌啶-4-基)氧基]乙氧基)乙基]脲基)丁基]脲;
1-(2-(2-(((R)-1-((3-((S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基)磺酰基)吡咯烷-3-基)氧基)乙氧基)乙基)-3-(4-(3-(2-(2-(((R)-1-((3-((S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯基)磺酰基)吡咯烷-3-基)氧基)乙氧基)乙基)脲基)丁基)脲;
1-(2-[2-([(S)-1-[(3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]吡咯烷-3-基]氧基)乙氧基]乙基)-3-(4-[3-(2-[2-([(S)-1-[(3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]吡咯烷-3-基]氧基)乙氧基]乙基)脲基]丁基)脲;
3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]-N-[(3R,28R)-28-[(3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰氨基]-2,29-二甲基-12,19-二氧代-5,8,23,26-四氧杂-11,13,18,20-四氮杂三十烷-3-基]苯磺酰胺;
N,N'-(10-氧代-3,6,14,17-四氧杂-9,11-二氮杂十九烷-1,19-二基)双[3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N,N'-[(3S,3'S)-(7-氧代-3,11-二氧杂-6,8-二氮杂十三烷-1,13-二基]双[吡咯烷-1,3-二基))双(3-(6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基)苯磺酰胺];
N1,N18-双(1-[(3-[(S)-6,8-二氯-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]哌啶-4-基)-6,13-二氧代-5,7,12,14-四氮杂十八烷二酰胺;
N1,N18-双(1-[(3-[(S)-6-氯-8-氰基-2-甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]哌啶-4-基)-6,13-二氧代-5,7,12,14-四氮杂十八烷二酰胺;或
N1,N18-双(1-[(3-[(S)-6-氯-2,8-二甲基-1,2,3,4-四氢异喹啉-4-基]苯基)磺酰基]哌啶-4-基)-6,13-二氧代-5,7,12,14-四氮杂十八烷二酰胺。
在本发明的一个实施方案中,所述NHE3抑制剂是根据下式的化合物:
在本发明的一个实施方案中,所述NHE3抑制剂是根据下式的化合物:
在一实施方案中,所述NHE3抑制剂是以下化合物之一:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢,-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-氟-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-氟-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)-丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲氧基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲氧基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-氟-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-氟-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]-氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲氧基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-(三氟甲氧基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲氧基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲二盐酸盐;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-(二甲氨基)-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]-氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-2-[(3R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-6-氯-4-甲基-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-[(3R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]氨基甲酰基]-氨基)丁基]脲;
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]乙氧基)乙基]氨基甲酰基]-氨基)丁基]脲;
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]氨基甲酰基]-氨基)丁基]脲;
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]氨基甲酰基]-氨基)丁基]脲;
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]氨基甲酰基]氨基)丁基]脲;
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰基]吡咯烷-3-基]甲氧基]吡啶-2-基)甲基]氨基甲酰基]氨基)丁基]脲;
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)氨基甲酰基]氨基]丁基)脲;
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)氨基甲酰基]氨基]丁基)脲;
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)氨基甲酰基]氨基]丁基)脲;
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]吡咯烷-1-基]乙氧基]乙基)氨基甲酰基]氨基]丁基)脲;
1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1H-1,2,3-***-4-基]甲基)-3-(4-[[([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1H-1,2,3-***-4-基]甲基)氨基甲酰基]氨基]丁基)脲;
(2R,3S,4R,5S)-N1,N6-双([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1H-1,2,3-***-4-基]甲基)-2,3,4,5-四羟基己二酰胺;
3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]丁基]-1H-1,2,3-***-4-基)甲基]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]丁基]-1H-1,2,3-***-4-基)甲基]氨基甲酰基]氨基)-丁基]脲;
3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]己基]-1H-1,2,3-***-4-基)甲基]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]己基]-1H-1,2,3-***-4-基)甲基]氨基甲酰基]氨基)-丁基]脲;
(4R,4aS,8S,8aR)-N4,N8-双([1-(4-[4-((1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基氧基)苯基磺酰胺]丁基)-1H-1,2,3-***-4-基]甲基)-2,2,6,6-四甲基-四氢-[1,3]二噁并[5,4-d][1,3]二噁英-4,8-二羧酰胺;
(4R,4aS,8S,8aR)-N4,N8-双([1-(6-[4-((1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基氧基)苯基磺酰氨基]己基)-1H-1,2,3-***-4-基]甲基)-2,2,6,6-四甲基-四氢-[1,3]二噁并[5,4-d][1,3]二噁英-4,8-二羧酰胺;
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]辛基]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]辛基]-氨基甲酰基)氨基]丁基]脲;
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]辛基]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]辛基]氨基甲酰基)氨基]丁基]脲;
3-[8-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]辛基]-1-[4-[([8-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]辛基]-氨基甲酰基)氨基]丁基]脲;
3-[8-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]辛基]-1-[4-[([8-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]辛基]氨基甲酰基)氨基]丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(2R)-2-甲基哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(2R)-2-甲基哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(2S)-2-甲基哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(2S)-2-甲基哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-氮杂双环[2.2.1]庚烷-2-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-氮杂双环[2.2.1]庚烷-2-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-氮杂双环[2.2.2]辛烷-2-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-氮杂双环[2.2.2]辛烷-2-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-氮杂双环[3.2.1]辛烷-8-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-氮杂双环[3.2.1]辛烷-8-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-氮杂双环[3.3.1]壬烷-9-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-氮杂双环[3.3.1]壬烷-9-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(4-甲基哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(4-甲基哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(4-甲基哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(4-甲基哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-乙酰基哌嗪-1-基)-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-乙酰基哌嗪-1-基)-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-乙酰基哌嗪-1-基)-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-乙酰基哌嗪-1-基)-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
4-[(1S,2S)-4,6-二氯-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[4-(二甲基氨基甲酰基)哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]氨基甲酰基]氨基)乙氧基]乙氧基]乙基)氨磺酰基]苯氧基]-2,3-二氢-1H-茚-2-基]-N,N-二甲基哌嗪-1-羧酰胺;
4-[(1S,2S)-4,6-二氯-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[4-(二甲基氨基甲酰基)哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]氨基甲酰基]氨基)乙氧基]乙氧基]乙基)氨磺酰基]-2-甲基苯氧基]-2,3-二氢-1H-茚-2-基]-N,N-二甲基哌嗪-1-羧酰胺;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-[甲基(丙烷-2-基)氨基]哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-[(3R)-3-[甲基(丙烷-2-基)氨基]哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3,5-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3,5-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;盐酸盐;
1-[2-(2-[2-[(3-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-2,4-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3,5-二甲基苯)-磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2,5-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2,5-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-2,5-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-2,5-二甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;盐酸盐;
1-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3,5-二氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-3,5-二氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
4-([(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基)-N-[26-([4-([(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基)-3,5-二氟苯基]磺酰氨基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六基]-3,5-二氟苯磺酰胺;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-5-氟-2-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-5-氟-2-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-5-氟-2-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-5-氟-2-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-2-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-2-氟-5-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]-2-氧代吡咯烷-1-基]乙氧基]乙基)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]-2-氧代吡咯烷-1-基]乙氧基]乙基)氨基甲酰基]氨基]-丁基)脲;
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]-2-氧代吡咯烷-1-基]乙氧基]乙基)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-氯-4-氰基-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基]-3-甲基苯)磺酰氨基]-2-氧代吡咯烷-1-基]乙氧基]乙基)氨基甲酰基]-氨基]丁基)脲;
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰基]吡咯烷-3-基]氧基]乙氧基)乙基]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰基]吡咯烷-3-基]氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰基]吡咯烷-3-基]氧基]乙氧基)乙基]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰基]吡咯烷-3-基]氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰基]哌啶-4-基]氧基)乙氧基]乙基]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)-磺酰基]哌啶-4-基]氧基)乙氧基]乙基]氨基甲酰基)氨基]丁基]脲;
1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]丙氧基]乙氧基]乙基)-3-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]丙氧基]乙氧基]乙基)氨基甲酰基]氨基]丁基)脲;盐酸盐;
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]丙氧基]乙氧基]乙基)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]丙氧基]乙氧基]乙基)氨基甲酰基]氨基]丁基)脲;
3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-3-甲基丁氧基]乙氧基]乙基)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-3-甲基丁氧基]乙氧基]乙基)氨基甲酰基]氨基]丁基)-脲二盐酸盐;
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-3-甲基丁氧基]乙氧基]乙基)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-3-甲基丁氧基]乙氧基]乙基)氨基甲酰基]-氨基]丁基)脲;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-2-甲基丙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]苯)磺酰氨基]-2-甲基丙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;盐酸盐;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-甲氧基苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-甲氧基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-甲基苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基]-2-氟苯)磺酰氨基]乙氧基]乙氧基)乙基]氨基甲酰基]氨基)丁基]脲;
4-([(1S,2S)-2-[(R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基)-N-[26-([4-([(1S,2S)-2-[(R)-3-氨基哌啶-1-基]-4,6-二氯-2,3-二氢-1H-茚-1-基]氧基)-2-氯苯基]磺酰氨基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六基]-2-氯苯磺酰胺;
4-([(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3-氟苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]-3-氟苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-二氯-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3-氟苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]-3-氟苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3-氟苯基)磺酰胺)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]-3-氟苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3-氟苯基)磺酰胺)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]-3-氟苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基)-3-氟苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基)-3-氟苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-二氯-2-(二甲氨基)-2,3-二氢-1H-茚-1-基]氧基)-3-氟苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基)-3-氟苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-2-[(R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-2-[(R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基)-3-甲基苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]-3-甲基苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-2-[(R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-2-[(R)-3-(二甲氨基)哌啶-1-基]-4-甲基-2,3-二氢-1H-茚-1-基]氧基)-3-甲基苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]-3-甲基苯磺酰胺;四(三氟乙酸盐);
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[1-(18-[4-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)哌啶-1-基]-6,13,18-三氧代-5,7,12,14-四氮杂十八烷酰基)哌啶-4-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-4,11,14-三氧代-3,5,10,12-四氮杂十四烷酰基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-2,13-二甲基-4,11,14-三氧代-3,5,10,12-四氮杂十四烷酰基]吡咯烷-3-基]苯磺酰胺;
N1,N14-双(2-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-2-氧代乙基)-4,11-二氧代-3,5,10,12-四氮杂十四烷二酰胺;
N1,N14-双(2-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-2-氧代乙基)-4,11-二氧代-3,5,10,12-四氮杂十四烷二酰胺;
N1,N18-双(1-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰基)哌啶-4-基)-6,13-二氧代-5,7,12,14-四氮杂十八烷二酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[26-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六基]苯磺酰胺;
-([(1S,2S)-6-氯-4-氰基-2-[(S)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[26-([4-([(1S,2S)-6-氯-4-氰基-2-[(S)-3-(二甲氨基)哌啶-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[1-(20-[4-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰胺]哌啶-1-基)-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基]哌啶-4-基)苯磺酰胺;
N1,N18-双([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰基)-6,13-二氧代-5,7,12,14-四氮杂十八烷二酰胺;
N-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰基)-1-[16-(4-[([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰基)氨基甲酰基]哌啶-1-基)-5,12-二氧代-4,6,11,13-四氮杂十六基]哌啶-4-羧酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(4-甲基-1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(4-甲基-1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(4-甲基-1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(4-甲基-1,4-二氮杂环庚烷-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-2-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-二氮杂双环[2.2.1]-庚烷-2-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-2-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-二氮杂双环[2.2.1]-庚烷-2-基]-6-氯-4-氰基-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(S)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(S)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(S)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(S)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(3S,5R)-3,5-二甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(3S,5R)-3,5-二甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(3S,5R)-3,5-二甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(3S,5R)-3,5-二甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-2-氧代哌啶-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)-2-氧代哌啶-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)乙氧基]乙氧基)乙基]脲基)环己基]脲基)-乙氧基]乙氧基)乙基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-6,13,18-三氧代-5,7,12,14-四氮杂十八烷酰基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯磺酰胺;
N-(2-[2-(2-氨基乙氧基)乙氧基]乙基)-4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯磺酰胺;
N-[1-(4-氨基丁酰基)哌啶-4-基]-4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-(3-氧代-7,10-二氧杂-2,4-二氮杂十二烷-12-基)苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-(1-[4-(3-甲基脲基)丁酰基]哌啶-4-基)苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[(2S,3R,4S,5R)-1,3,4,5,6-五羟基己烷-2-基]苯磺酰胺;
4-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-N-[(2S,3R,4S,5R)-1,3,4,5,6-五羟基己烷-2-基]哌啶-1-羧酰胺;
4-(3-[4-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-4-氧代丁基]脲基)-N-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰基)丁酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)哌啶-1-基]-4-氧代丁基)脲基]丁酰基)哌啶-4-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[19-([4-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-10-氧代-3,6,14,17-四氧杂-9,11-二氮杂十九基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-酰氨基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[26-([4-([(1S,2S)-6-氯-4-酰氨基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六基]苯磺酰胺;
4-([(1S,2S)-4-氰基-6-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-N-[26-([4-([(1S,2S)-4-氰基-6-甲基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)-10,17-二氧代-3,6,21,24-四氧杂-9,11,16,18-四氮杂二十六基]苯磺酰胺;
1,1'-(丁烷-1,4-二基)双[3-(4-[6-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3,4-二氢异喹啉-2(1H)-基]-4-氧代丁基)脲];
1,1'-(丁烷-1,4-二基)双[3-(4-[7-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3,4-二氢异喹啉-2(1H)-基]-4-氧代丁基)脲];
N,N'-(6,14-二氧代-10-氧杂-5,7,13,15-四氮杂十九烷-1,19-二基)双[6-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3,4-二氢异喹啉-2(1H)-羧酰胺];
N,N'-(6,14-二氧代-10-氧杂-5,7,13,15-四氮杂十九烷-1,19-二基)双[7-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-3,4-二氢异喹啉-2(1H)-羧酰胺];
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-6,13,18-三氧代-5,7,12,14-四氮杂十八烷酰基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-6,13,18-三氧代-5,7,12,14-四氮杂十八烷酰基)吡咯烷-3-基]苯磺酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[1-(18-[4-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)哌啶-1-基]-6,13,18-三氧代-5,7,12,14-四氮杂十八烷酰基)哌啶-4-基]苯磺酰胺;
N1,N14-双(2-[(S)-3-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-2-氧代乙基)-4,11-二氧代-3,5,10,12-四氮杂十四烷二酰胺;
4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[1-(20-[4-([4-([(1S,2S)-6-氯-4-氰基-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)哌啶-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)哌啶-4-基]苯磺酰胺;
4-([(1S,2S)-4,6-二氯-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-二氯-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-7,14-二氧代-3,18-二氧杂-6,8,13,15-四氮杂二十基)吡咯烷-3-基]苯磺酰胺;
N1,N14-双(2-[(S)-3-([4-([(1S,2S)-4,6-二氯-2-[(R)-3-甲基哌嗪-1-基]-2,3-二氢-1H-茚-1-基]氧基)苯基]磺酰氨基)吡咯烷-1-基]-2-氧代乙基)-4,11-二氧代-3,5,10,12-四氮杂十四烷二酰胺;
1,1'-(丁烷-1,4-二基)双(3-[2-(2-[6-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-1-氧代异吲哚啉-2-基]乙氧基)乙基]脲);和
1,1'-(丁烷-1,4-二基)双(3-[2-(2-[5-([(1S,2S)-6-氯-4-氰基-2-(哌嗪-1-基)-2,3-二氢-1H-茚-1-基]氧基)-1-氧代异吲哚啉-2-基]乙氧基)乙基]脲)。
实施例
通过参考以下实施例将会更全面地理解本发明。然而,它们不应被解释为限制本发明的范围。例如,通过本领域技术人员显而易见的改性可以成功地进行未示例的化合物的合成,例如通过适当地保护干扰基团、通过利用除所述的那些以外的本领域中已知的其它合适的试剂和/或通过常规地改变反应条件。或者,本文公开或本领域中已知的其它反应将被认为适用于制备本文所述的其它化合物。
实施例1(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(甲氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(1-9)
(4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-十八氢苉-3-羧酸(1-2)的合成。向用CO惰性气氛吹扫并保持的1-L压力罐反应器(10atm)里放入(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(((三氟甲基)磺酰基)氧基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-十八氢苉-2-羧酸苄酯(根据美国专利20160151387中所述的方法制备)(11g,15.92mmol,1.00当量)、Pd(PPh3)4(4g,3.46mmol,0.20当量)、THF(250mL)和水(150mL)。将所得溶液在50℃下搅拌2天。将所得溶液用3x150mL DCM萃取并合并有机层。将所得混合物用3x 150mL盐水洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:10)的硅胶柱上。采用以下条件(CombiFlash-1)通过快速制备型HPLC纯化粗产物(20mL):柱,C18硅胶;流动相,ACN:水=100:0;检测器,UV 254nm。获得1L产物。这样得到6.5g(69.6%)的1-2,为浅黄色固体。
(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-十八氢苉-2,10-二羧酸2-苄酯10-((2-(三甲基甲硅烷基)乙氧基)甲基)酯(1-3)的合成。向250-mL圆底烧瓶里放入1-2(3g,5.11mmol,1.00当量)、DMF(30mL)、DMAP(102.4mg,0.84mmol,0.10当量)。接着伴随在0℃下搅拌滴加TEA(3mL,5.80当量)。伴随在0℃下搅拌向此中滴加SEMCl(4.2mL,4.80当量)。将所得溶液在室温下搅拌1.5h。然后通过添加50mL K2CO3水溶液淬灭反应。将所得溶液用250mL DCM稀释。将所得混合物用3x150 mL盐水洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:10)的硅胶柱上。这样得到3.5g(95.5%)的1-3,为浅黄色油状物。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(((2-(三甲基甲硅烷基)乙氧基)甲氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(1-4)的合成。向用H2惰性气氛吹扫并保持的300-mL压力罐反应器(40atm)里放入1-3(6.6g,9.20mmol,1.00当量)、干燥活性碳载钯(1.32g,0.20当量)、丙酮(150mL)。将所得溶液在50℃下搅拌过夜。通过过滤收集固体。将所得混合物在真空下浓缩。这样得到4.2g(73%)的1-4,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-((2-(三甲基甲硅烷基)乙氧基)甲基)酯(1-5)的合成。向250-mL圆底烧瓶里放入1-4(5.25g,8.35mmol,1.00当量)、DMF(70mL)、Cs2CO3(4.1g,12.58mmol,1.50当量)、BnBr(2.86g,16.72mmol,2.00当量)。将所得溶液在60℃下搅拌2h。将所得溶液用250mL DCM稀释。将所得溶液用2x100 mL DCM萃取,合并有机层并在烘箱中减压干燥。将所得残留物施加到具有EtOAc/石油醚(1:10)的硅胶柱上。这样得到6g(99%)的1-5,为灰白色固体。
(3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-羧酸(1-6)的合成。向250-mL圆底烧瓶里放入1-5(5.6g,7.79mmol,1.00当量)、THF(40mL)。接着添加盐酸(4M,30mL)。将所得溶液在60℃下搅拌2h。用碳酸氢钠(饱和)将溶液的pH值调节到3。将所得溶液用3x 100mL DCM萃取并合并有机层。将所得混合物用2x150mL盐水洗涤。将混合物经无水硫酸钠干燥。采用以下条件(CombiFlash-1)通过快速制备型HPLC纯化粗产物(20mL):柱,C18硅胶;流动相,ACN:水=100:0;检测器,UV 254nm。获得1L产物。这样得到3.1g(68%,97%纯度)的1-6,为白色固体。MS(ES,m/z):[M+H]+=589.4;1H-NMR(400MHz,氯仿-d):δ0.76(s,4H),0.91(s,5H),1.01-1.21(m,12H),1.24-1.49(m,9H),1.56-1.75(m,4H),1.83(td,J=13.6,4.6Hz,1H),1.91-2.10(m,5H),2.23(d,J=8.2Hz,1H),2.37(s,1H),2.86(d,J=13.2Hz,1H),5.11(d,J=12.0Hz,1H),5.23(d,J=12.4Hz,1H),5.57(s,1H),7.30-7.45(m,5H)。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(氯羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(1-7)的合成。在室温下将草酰氯(0.144mL,1.70mmol)滴加到在DCM(50mL)中的1-6(0.50g,0.85mmol)和DMF(1滴)中。将混合物在室温下搅拌1小时,然后蒸发至干。该物质不经纯化即用于以下步骤。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-甲酯(1-8)的合成。向250-mL圆底烧瓶里放入1-7(200mg,0.33mmol,1.00当量)、MeOH(20mL)、TEA(0.274mL,6.00当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。这样得到198mg(100%)的1-8,为浅黄色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(甲氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(1-9)的合成。向用H2惰性气氛吹扫并保持的250-mL圆底烧瓶里放入1-8(198mg,0.33mmol,1.00当量)、MeOH(40mL)、Pd/C(20mg)。将所得溶液在室温下搅拌1h。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(200mg):柱,XBridge Prep C18 OBD柱,190*150mm 5um;流动相,水(10mmol/L NH4HCO3+0.1%NH3·H2O)和ACN(50.0%ACN,7分钟内达到62.0%);检测器,UV 254/220nm。获得111.8mg产物。这样得到111.8mg(66%)的1-9,为浅黄色固体。MS(ES,m/z):[M+H]+=513.60;1H NMR(400MHz,氯仿-d)δ0.76(d,J=11.2Hz,1H),0.84(s,3H),0.88-0.96(m,4H),0.99-1.08(m,4H),1.18(s,3H),1.19-1.28(m,7H),1.31-1.39(m,4H),1.40-1.48(m,4H),1.50-1.59(m,1H),1.60-1.72(m,3H),1.79-1.89(m,1H),1.91-2.09(m,4H),2.15-2.25(m,2H),2.37(s,1H),2.82(dt,J=10.4,3.2Hz,1H),3.65(s,3H),5.70(s,1H),9.89(s,1H)。
实施例2(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸(2-1)
向50-mL圆底烧瓶里放入1-6(300mg,0.51mmol,1.00当量)、MeOH(30mL)、Pd/C(30mg,0.10当量)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌2h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:流动相,水(0.05%TFA)和ACN(60.0%ACN,8分钟内达到77.0%);检测器,UV 254nm。这样得到110mg(43%)的2-1,为白色固体。MS(ES,m/z):[M+H]+=499.25;1H-NMR(400MHz,MeOH-d4):δ0.81(s,4H),0.91(s,3H),0.93-1.01(m,2H),1.11(s,3H),1.13-1.20(m,9H),1.21-1.31(m,1H),1.32-1.54(m,9H),1.63-1.81(m,3H),1.81-2.00(m,4H),2.09-2.26(m,3H),2.50(s,1H),2.75(d,J=13.2Hz,1H),3.34(s,2H),5.59(s,1H)。
实施例3(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(异丙氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(3-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-异丙酯(3-1)的合成。向25-mL圆底烧瓶里放入1-7(154mg,0.25mmol,1.00当量)、DCM(10mL)、丙-2-醇(46mg,0.77mmol,3.00当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.05mL,1.50当量)。将所得溶液在室温下搅拌2天。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:5)的硅胶柱上。这样得到114mg(71%)3-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(异丙氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(3-2)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入3-1(114mg,0.18mmol,1.00当量)、THF(10mL)、Pd/C(12mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(100mg):柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%NH3H2O)和ACN(41.0%ACN,8分钟内达到57.0%);检测器,uv 254nm。获得34.9mg产物。这样得到34.9mg(36%)的3-2,为白色固体。MS(ES,m/z):[M+H]+=541.40;1H NMR(400MHz,氯仿-d)δ0.74(d,J=11.2Hz,1H),0.83-0.94(m,7H),1.01-1.05(m,4H),1.13-1.17(m,3H),1.18-1.27(m,13H),1.32-1.52(m,9H),1.60-1.70(m,3H),1.78-1.88(m,1H),1.91-2.07(m,4H),2.11-2.21(m,2H),2.37(s,1H),2.83(d,J=13.2Hz,1H),4.97-5.04(m,1H),5.70(s,1H),9.9(s,1H)。
实施例4(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-六氟-2-甲基丙烷-2-基)氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(4-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(1,1,1,3,3,3-六氟-2-甲基丙烷-2-基)酯(4-1)的合成。向50-mL圆底烧瓶里放入1-7(154mg,0.25mmol,1.00当量)、DCM(10mL)、1,1,1,3,3,3-六氟-2-甲基丙-2-醇(93mg,0.51mmol,2.00当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.053mL,1.50当量)。将所得溶液在室温下搅拌2h。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:5)的硅胶柱上。这样得到226mg(118%)的4-1,为白色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-六氟-2-甲基丙烷-2-基)氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(4-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入4-1(226mg,0.30mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(23mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(190mg):柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(10mmol/L NH4HCO3+0.1%NH3·H2O)和ACN(5.0%ACN,1分钟内达到55.0%,7分钟内达到68.0%);检测器,UV 254nm。获得80.9mg产物。这样得到80.9mg(41%)的4-2,为白色固体。MS(ES,m/z):[M+H]+=663.30;1H NMR(400MHz,MeOH-d4)δ0.82-0.98(m,7H),1.00-1.13(m,5H),1.17-1.30(m,10H),1.39-1.61(m,9H),1.65-1.83(m,3H),1.84-2.09(m,7H),2.12-2.28(m,2H),2.35(dd,J=12.8,3.2Hz,1H),2.53(s,1H),2.81(dt,J=10.4,3.6Hz,1H),5.62(s,1H)。
实施例5(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-羟基乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(5-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-(苄氧基)乙基)酯(5-1)的合成。向25-mL圆底烧瓶里放入1-7(154mg,0.25mmol,1.00当量)、DCM(10mL)、2-(苄氧基)乙-1-醇(58mg,0.38mmol,1.50当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.05mL,1.50当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:5)的硅胶柱上。这样得到107mg(58%)的5-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-羟基乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(5-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入5-1(107mg,0.15mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(20mg)。将所得溶液在室温下搅拌7天。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(100mg):柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(10mmol/L NH4HCO3+0.1%NH3·H2O)和ACN(40.0%ACN,8分钟内达到70.0%);检测器,uv 254nm。获得23.2mg产物。这样得到23.2mg(29%)的5-2,为白色固体。MS(ES,m/z):[M+H]+=543.35;1HNMR(400MHz,MeOH-d4):δ0.74(s,3H),0.77-0.83(m,4H),0.89-0.95(m,5H),1.05-1.09(m,9H),1.13-1.17(m,1H),1.26-1.44(m,9H),1.55-1.71(m,3H),1.72-1.81(m,2H),1.82-1.94(m,2H),1.96-2.10(m,1H),2.11-2.24(m,2H),2.40(s,1H),2.67(d,J=13.2Hz,1H),3.63(t,J=5.0Hz,2H),4.03(t,J=5.0Hz,2H),5.51(s,1H)。
实施例6(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2,2,2-三氟乙氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(6-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2,2,2-三氟乙基)酯(6-1)的合成。向25-mL圆底烧瓶里放入1-7(154mg,0.25mmol,1.00当量)、DCM(10g,117.74mmol,464.30当量)、2,2,2-三氟乙-1-醇(51mg,0.51mmol,2.00当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.053mL,1.50当量)。将所得溶液在室温下搅拌2h。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:5)的硅胶柱上。这样得到256mg(150%)的6-1,为白色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2,2,2-三氟乙氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(6-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入6-1(256mg,0.38mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(26mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(200mg):柱,XBridge Prep OBD C18柱,19*250mm,5um;流动相,水(0.05%TFA)和ACN(82.0%ACN,8分钟内达到89.0%);检测器,UV 254nm。获得96.9mg产物。这样得到96.9mg(44%)的6-2,为白色固体。MS(ES,m/z):[M+H]+=581.30;1H NMR(400MHz,MeOH-d4):δ0.82-1.00(m,7H),1.01-1.11(m,5H),1.17-1.37(m,10H),1.38-1.60(m,9H),1.67-1.81(m,3H),1.82-1.92(m,2H),1.93-2.09(m,2H),2.11-2.27(m,2H),2.38(dd,J=12.8,3.6Hz,1H),2.54(s,1H),2.81(dt,J=13.5,3.4Hz,1H),4.50-4.76(m,2H),5.61(s,1H)。
实施例7(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-咪唑-1-基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(7-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸10-(2-(1H-咪唑-1-基)乙基)酯2-苄酯(7-1)的合成。向25-mL圆底烧瓶里放入1-7(137mg,0.23mmol,1.00当量)、DCM(10mL)、2-(1H-咪唑-1-基)乙-1-醇(51mg,0.45mmol,2.00当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.047mL,1.50当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(20:1)的硅胶柱上。这样得到140mg(91%)的7-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-咪唑-1-基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(7-2)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入7-1(140mg,0.20mmol,1.00当量)、THF(10mL)、Pd/C(14mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(120mg):柱,XBridge Prep C18 OBD柱,19*150mm 5um;流动相,水(10mmol/LNH4HCO3+0.1%NH3·H2O)和ACN(30.0%ACN,7分钟内达到66.0%);检测器,UV 254/220nm。获得67.4mg产物。这样得到67.4mg(55%)的7-2,为白色固体。MS(ES,m/z):[M+H]+=593.40;1H NMR(400MHz,MeOH-d4):δ0.69(s,3H),0.71-0.75(m,4H),0.80(s,3H),0.84-0.98(m,2H),1.04-1.09(m,9H),1.10-1.21(m,2H),1.27-1.30(m,3H),1.31-1.32(m,4H),1.35-1.38(m,1H),1.49-1.58(m,1H),1.58-1.69(m,2H),1.70-1.90(m,4H),1.99-2.19(m,3H),2.39(s,1H),2.64(d,J=13.6Hz,1H),4.20-4.33(m,4H),5.49(s,1H),6.87(s,1H),7.07(s,1H),7.69(s,1H)。
实施例8(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-吗啉代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(8-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-吗啉代乙基)酯(8-1)的合成。向25-mL圆底烧瓶里放入1-7(137mg,0.23mmol,1.00当量)、DCM(10mL)、2-(吗啉-4-基)乙-1-醇(59mg,0.45mmol,2.00当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.047mL,1.50当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(20:1)的硅胶柱上。这样得到151mg(95%)的8-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-吗啉代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(8-2)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入8-1(151mg,0.22mmol,1.00当量)、THF(10mL)、Pd/C(15mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(150mg):柱,XBridge Prep C18 OBD柱,19*150mm 5um;流动相,水(10mmol/L NH4HCO3)和ACN(30.0%ACN,7分钟内达到66.0%);检测器,UV 254/220nm。获得28.6mg产物。这样得到28.6mg(22%)的8-2,为白色固体。MS(ES,m/z):[M+H]+=612.70;1H NMR(300MHz,氯仿-d):δ0.49-0.98(m,8H),1.02(s,4H),1.09-1.28(m,10H),1.29-1.48(m,8H),1.49-1.75(m,4H),1.77-2.12(m,5H),2.20(d,J=12.9Hz,2H),2.37(s,1H),2.44-2.75(m,6H),2.83(d,J=13.5Hz,1H),3.72(s,4H),4.00-4.70(m,2H),5.70(s,1H)。
实施例9(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((((R)-奎宁环-3-基)氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(10-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-((R)-奎宁环-3-基)酯(10-1)的合成。向25-mL圆底烧瓶里放入1-7(154mg,0.25mmol,1.00当量)、DCM(10mL)、(3R)-1-氮杂双环[2.2.2]辛-3-醇(65mg,0.51mmol,2.02当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.053mL,1.50当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(10:1)的硅胶柱上。这样得到72mg(41%)的10-1,为白色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((((R)-奎宁环-3-基)氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(10-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入10-1(72mg,0.10mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(7mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(50mg):柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(40.0%ACN,8分钟内达到54.0%);检测器,UV 254nm。获得11.3mg产物。这样得到11.3mg(18%)的10-2,为白色固体。MS(ES,m/z):[M+H]+=608.40;1H NMR(400MHz,MeOH-d4):δ0.84-1.93(m,4H),0.95(s,3H),0.99-1.12(m,5H),1.16-1.23(m,9H),1.24-1.38(m,2H),1.39-1.53(m,8H),1.54-1.65(m,1H),1.68-1.80(m,3H),1.81-2.05(m,6H),2.06-2.19(m,2H),2.20-2.29(m,2H),2.31-2.41(m,2H),2.53(s,1H),2.82(dt,J=13.2,3.4Hz,1H),3.21-3.30(m,2H),3.38-3.44(m,2H),3.78(ddd,J=14.0,8.7,2.1Hz,1H),5.12(dt,J=7.8,3.5Hz,1H),5.61(s,1H)。
实施例10(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-(吡啶-2-基)乙氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(11-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-(吡啶-2-基)乙基)酯(11-1)的合成。向25-mL圆底烧瓶里放入1-7(154mg,0.25mmol,1.00当量)、DCM(10mL)、2-(吡啶-2-基)乙-1-醇(63mg,0.51mmol,2.00当量)、DMAP(3mg,0.02mmol,0.10当量)、TEA(0.053mL,1.50当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到217mg(123%)的11-1,为白色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-(吡啶-2-基)乙氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(11-2)的合成。向25-mL圆底烧瓶里放入11-1(176mg,0.25mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(18mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物(150mg):柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(40.0%ACN,8分钟内达到55.0%);检测器,UV 254nm。获得35.8mg产物。这样得到35.8mg(23%)的11-2,为白色固体。MS(ES,m/z):[M]+=604.35;1H NMR(400MHz,MeOH-d4):δ0.77(s,3H),0.79-0.90(m,7H),0.91-1.01(m,1H),1.03-1.10(m,1H),1.17(d,J=14.4Hz,9H),1.25-1.33(m,1H),1.37-1.50(m,9H),1.58-1.82(m,3H),1.82-2.08(m,4H),2.09-2.30(m,3H),2.49(s,1H),2.75(dt,J=13.6,3.5Hz,1H),3.39(t,J=6.2Hz,2H),4.50(t,J=6.2Hz,2H),5.60(s,1H),7.87(t,J=6.8Hz,1H),7.97(d,J=8.0Hz,1H),8.45(td,J=8.0,1.6Hz,1H),8.75(dd,J=6.0,0.8Hz,1H)。
实施例11(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-氨基-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(12-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸10-(2-氨基-2-氧代乙基)酯2-苄酯(12-1)的合成。向50-mL圆底烧瓶里放入1-6(59mg,0.10mmol,1当量)、DMF(5mL,0.07mmol,0.683当量)、TBAI(18mg,0.05mmol,0.486当量)、2-氯乙酰胺(11mg,0.12mmol,1.174当量)、K2CO3(17mg,0.12mmol,1.228当量)。将所得溶液在65℃下搅拌2小时。将所得溶液用30mL DCM稀释。将所得混合物用2x15 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物浓缩。将残留物施加到具有EA的硅胶柱上。这样得到50mg(77.26%)的12-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-氨基-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(12-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入12-1(200mg,0.31mmol,1当量)、MeOH(10mL,0.31mmol,1.008当量)、Pd/C(20mg,0.19mmol,0.607当量)。将所得溶液在室温下搅拌1小时。将固体滤出。采用以下条件(2#-AnalyseHPLC-SHIMADZU(HPLC-10))通过制备型HPLC纯化粗产物:柱,XBridge ShieldRP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到54%,7分钟内达到68%);检测器,uv 254nm。这样得到84.6mg(49.16%)的12-2,为白色固体。MS(ES,m/z):[M+H]+=556.46;1H-NMR(400MHz,MeOH-d4):δ0.82-0.96(m,7H),0.99-1.08(m,5H),1.13-1.19(m,9H),1.23(d,J=3.2Hz,1H),1.40-1.49(m,8H),1.55-1.60(m,1H),1.67-1.76(m,3H),1.83-2.00(m,4H),2.15-2.19(m,2H),2.35(d,J=0.4Hz,1H),2.50(s,1H),2.78(d,J=1.6Hz,1H),4.51(q,J=4.8Hz,2H),5.58(s,1H)。
实施例12(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((羧甲氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(13-3)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-甲氧基-2-氧代乙基)酯(13-1)的合成。向50-mL圆底烧瓶里放入1-6(590mg,1.00mmol,1.00当量)、丙酮(20mL)、TEA(510mg,5.04mmol,5.00当量)、2-氯乙酸甲酯(440mg,4.05mmol,4.00当量)。将所得溶液加热至回流4小时。将所得混合物在真空下浓缩。将所得固体用3x10 mL己烷洗涤。这样得到600mg(91%)的13-1,为白色固体。
2-(((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-羰基)氧基)乙酸(13-2)的合成。向50-mL圆底烧瓶里放入苄基13-1(600mg,0.91mmol,1.00当量)、THF(10mL)、水(10mL)、LiOH.H2O(190mg,4.52mmol,5.00当量)。将所得溶液在室温下搅拌3h。将所得溶液用30mL水稀释。用1.0M盐酸将溶液的pH值调节到2-3。将所得溶液用3x30 mL DCM萃取并合并有机层。将所得混合物用1x40 mL水和1x40mL饱和氯化钠洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。这样得到520mg(89%)的13-2,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((羧甲氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(13-3)的合成。向100-mL圆底烧瓶里放入13-2(150mg,0.23mmol,1当量)、EA(16mL)、Pd/C(4.9mg,0.05mmol,0.199当量)。向上述***中引入H2(g)。将所得溶液在室温下搅拌过1夜。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物(130mg):柱,XBridge Prep C18 OBD柱,19*150mm 5um;流动相,水(0.05%T FA)和ACN(5%B相,1分钟内达到62%,7分钟内达到76%);检测器,uv。获得产物。这样得到89.2mg(69.09%)的13-3,为白色固体。MS(ES,m/z):[M+H]+=557.30;1H NMR(400MHz,MeOH-d4):δ0.84(s,3H),0.85-0.89(m,1H),0.93(s,3H),0.95-1.09(m,2H),1.10(s,3H),1.17(t,J=4.5Hz,9H),1.20-1.30(m,1H),1.38-1.62(m,9H),1.63-1.79(m,3H),1.80-2.09(m,4H),2.10-2.28(m,2H),2.33(q,J=5.5Hz,1H),2.51(s,1H),2.78(d,J=13.2Hz,1H),4.58(q,J=13.2Hz,2H),5.58(s,1H)。
实施例13(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(14-1)
向100-mL圆底烧瓶里放入13-1(125mg,0.19mmol,1当量)、EA(12mL)、Pd/C(25mg,0.23mmol,1.242当量)。向上述***中引入H2(g)。将所得溶液在室温下搅拌过1夜。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物(100mg):柱,XBridgePrep C18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(66%B相,8分钟内达到83%);检测器,uv。获得产物。这样得到127.6mg(118.20%)的14-1,为白色固体。MS(ES,m/z):[M+H]+=571.30;1H NMR(400MHz,MeOH-d4)δ:0.84(s,3H),0.85-0.89(m,1H),0.93(s,3H),0.98-1.31(m,16H),1.32-1.59(m,9H),1.65-1.79(m,3H),1.80-2.04(m,4H),2.08-2.27(m,2H),2.51(s,1H),2.78(d,J=13.2Hz,1H),3.73(s,3H),4.62(q,J=14.5Hz,2H),5.58(s,1H)。
实施例14(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(叔丁氧基)-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(15-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-(叔丁氧基)-2-氧代乙基)酯(15-1)的合成。向100-mL圆底烧瓶里放入1-6(295mg,0.50mmol,1当量)、DMF(5mL,0.07mmol)、TBAI(92mg,0.25mmol,0.497当量)、K2CO3(83mg,0.60mmol,1.199当量)、2-氯乙酸叔丁酯(91mg,0.60mmol,1.206当量)。将所得溶液在65℃下搅拌2小时。将所得溶液用50mL DCM稀释。将所得混合物用2x15 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物浓缩。将残留物施加到具有EtOAc/石油醚(1:3)的硅胶柱上。这样得到200mg(56.79%)的15-1,为黄色油状物。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(叔丁氧基)-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(15-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入苄基15-1(200mg,0.28mmol,1当量)、MeOH(10mL,0.31mmol)、Pd/C(30mg,0.28mmol)。将所得溶液在室温下搅拌过夜。将所得混合物浓缩。采用以下条件(2#-AnalyseHPLC-SHIMADZU(HPLC-10))通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到80%,7分钟内达到90%);检测器,UV 254nm。获得产物。这样得到21mg(12.04%)的15-2,为白色固体。MS(ES,m/z):[M+H]+=613.40;1H-NMR(400MHz,MeOH-d4):δ0.72-0.99(m,8H),1.00-1.29(m,15H),1.32-1.59(m,17H),1.63-1.68(m,4H),1.91-2.17(m,5H),2.20-2.27(m,1H),2.29(d,J=1.6Hz,1H),2.38(s,1H),2.84(d,J=1.6Hz,1H),4.47(q,J=5.6Hz,2H),5.71(s,1H)。
实施例15(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-10-(甲氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-十八氢苉-2-羧酸(27-2)
(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-十八氢苉-2,10-二羧酸2-苄酯10-甲酯(27-1)的合成。将在醚(2M)中的(三甲基甲硅烷基)重氮甲烷滴加到在MeOH(3mL)中的1-2(100mg,0.170mmol)中,直到黄色持久存在(添加~1.2mmol)。在室温下搅拌反应30分钟,然后蒸发,得到27-1(0.1g,定量),为白色固体。
(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-10-(甲氧基羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-十八氢苉-2-羧酸(27-2)的合成。向用氢(1atm)惰性气氛吹扫并保持的100-mL圆底烧瓶里放入27-1(100mg,0.17mmol,1.00当量)、MeOH(25mL)、Pd/C(20mg)。将所得溶液在室温下搅拌过夜。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(70.0%ACN,7分钟内达到82.0%);检测器,UV254nm。这样得到25.7mg(30%)的27-2,为白色固体。MS(ES,m/z):[M+H]+=511.25;1H-NMR(400MHz,MeOH-d4,ppm):δ0.73-0.83(m,3H),0.91-0.97(m,1H),1.03-1.17(m,15H),1.18-1.23(m,2H),1.28-1.35(m,6H),1.41-1.52(m,2H),1.53-1.69(m,3H),1.71-1.93(m,4H),2.03-2.18(m,2H),2.45(s,1H),3.15-3.21(m,1H),3.58(s,3H),5.54(s,1H),6.76(d,J=2.0Hz,1H)。
实施例16(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(29-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(29-1)的合成。向250-mL圆底烧瓶里放入2-氨基乙酸甲酯盐酸盐(540mg,4.30mmol,3.00当量)、DCM(60mL)、TEA(0.59mL,3.00当量)、PH-RDX-013-291-4(860mg,1.42mmol,1.00当量)在DCM(30mL)中的溶液。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。这样得到900mg(96%)的29-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(29-2)的合成。向250-mL圆底烧瓶里放入29-1(500mg,0.76mmol,1.00当量)EtOAc(15mL)、MeOH(15mL)、Pd/C(50mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。将所得混合物在真空下浓缩。将残留物溶解在8mL THF-MeOH(1:1)中。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridgeShield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(52.0%ACN,8分钟内达到70.0%);检测器,UV 254nm。这样得到284.1mg(66%)的29-2,为白色固体。MS-PH(ES,m/z):[M+H]+=570.30;1H NMR(400MHz,MeOH-d4,ppm):δ0.74(s,3H),0.76(s,1H),0.83(s,3H),0.90-0.95(m,2H),0.97(s,3H),1.06(s,6H),1.08(s,3H),1.16(d,J=13.6Hz,1H),1.27-1.29(m,4H),1.31(s,3H),1.34-1.38(m,2H),1.56-1.67(m,3H),1.77(d,J=13.6Hz,2H),1.85-1.92(m,2H),1.98-2.06(m,2H),2.11-2.15(m,1H),2.40(s,1H),2.67-2.71(m,1H),3.61(s,3H),3.75(d,J=17.6Hz,1H),3.85(d,J=17.2Hz,1H),5.49(s,1H)。
实施例17(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((羧甲基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(30-3)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(叔丁氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(30-1)的合成。向250-mL圆底烧瓶里放入2-氨基乙酸叔丁酯盐酸盐(828mg,4.94mmol,3.00当量)、DCM(80mL)、TEA(0.728mL,6.00当量)、1-7(1.0g,1.65mmol,1.00当量)在DCM(20mL)中的溶液。将所得溶液在室温下搅拌2h。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到1.19g(99%)的30-1,为浅黄色固体。
((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-羰基)甘氨酸(30-2)的合成。向100-mL圆底烧瓶里放入30-1(1.19g,1.70mmol,1.00当量)、DCM(10mL)、三氟乙酸(10mL)。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。将所得混合物用2x100 mL正己烷洗涤。这样得到1.0g(91%)的30-2,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((羧甲基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(30-3)的合成。向100-mL圆底烧瓶里放入30-2(560g,848.62mmol,1.00当量)、Pd/C(50mg)、THF(30mL)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridgePrep OBD C18柱,19*250mm,5um;流动相,水(0.05%TFA)和ACN(45.0%ACN,8分钟内达到65.0%);检测器,UV 254nm。这样得到289mg的30-3,为白色固体。MS(ES,m/z):[M+H]+=556.30;1H NMR(300MHz,MeOH-d4,ppm):δ0.87(s,3H),0.90(s,1H),0.96(s,3H),1.02(d,J=14.0Hz,2H),1.10(s,3H),1.19(s,3H),1.20(s,3H),1.22(s,3H),1.28(d,J=14.4Hz,1H),1.40-1.56(m,9H),1.67-2.22(m,10H),2.50(s,1H),2.78(dt,J=13.4Hz,3.3Hz,1H),3.82(d,J=17.4Hz,1H),3.92(d,J=17.4Hz,1H),5.58(s,1H)。
实施例18(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)(甲基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(31-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)(甲基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(31-1)的合成。向100-mL圆底烧瓶里放入2-(甲氨基)乙酸甲酯盐酸盐(172mg,1.23mmol,3.00当量)、DCM(15mL)、TEA(0.171mL,3.00当量)、1-7(250mg,0.41mmol,1.00当量)在DCM(5mL)中的溶液。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。这样得到0.25g(90%)的31-1,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)(甲基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(31-2)的合成。向100-mL圆底烧瓶里放入31-1(250mg,0.37mmol,1.00当量)、MeOH(15mL)、Pd/C(25mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(58.0%ACN,8分钟内达到74.0%);检测器,UV 254nm。这样得到28.6mg(13%)的31-2,为白色固体。MS(ES,m/z):[M+H]+=584.35;1H NMR(400MHz,MeOH-d4,ppm):δ0.84(s,3H),0.92(s,3H),0.93-0.98(m,2H),1.05(s,3H),1.06-1.08(m,1H),1.15(d,J=4.0Hz,3H),1.17(s,3H),1.19(d,J=2.4Hz,3H),1.26(d,J=12.0Hz,1H),1.33-1.43(m,5H),1.45(s,3H),1.48-1.49(m,1H),1.69-1.79(m,3H),1.84-1.90(m,2H),1.92-2.03(m,2H),2.18-2.21(m,2H),2.54(s,1H),2.74-2.80(m,2H),2.93(s,1H),3.19(s,2H),3.70(s,3H),3.98(d,J=17.2Hz,1H),4.23(d,J=17.2Hz,1H),5.55(s,1H)。
实施例19(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(甲氧基羰基)吡咯烷-1-羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(33-2)
((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-羰基)-D-脯氨酸甲酯(33-1)的合成。向100-mL圆底烧瓶里放入(2R)-吡咯烷-2-羧酸盐酸盐(245mg,1.62mmol,3.00当量)、DCM(15mL)、TEA(0.206mL,3.00当量)、1-7(300mg,0.49mmol,1.00当量)在DCM(5mL)中的溶液。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。这样得到320mg(93%)的33-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(甲氧基羰基)吡咯烷-1-羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(33-2)的合成。向100-mL圆底烧瓶里放入33-1(320mg,0.46mmol,1.00当量)、EtOAc(20mL)、Pd/C(32mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。将残留物溶解在8mL MeOH中。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(10mmol/L NH4HCO3+0.1%NH3·H2O)和ACN(35.0%ACN,8分钟内达到65.0%);检测器,UV 254nm。这样得到26mg(9%)的33-2,为白色固体。MS(ES,m/z):[M+H]+=610.4;1H NMR(400MHz,MeOH-d4,ppm):δ0.86(s,3H),0.93(s,1H),0.97(s,3H),1.00(s,3H),1.05-1.09(m,2H),1.17(s,3H),1.18(s,3H),1.21(s,3H),1.27(d,J=14.3Hz,1H),1.35-1.45(m,4H),1.47(s,3H),1.48-1.51(m,2H),1.65-1.87(m,3H),1.90-2.03(m,7H),2.05-2.26(m,3H),2.51-2.55(m,2H),2.81(dt,J=13.4,3.3Hz,1H),3.71-3.76(m,5H),4.44(dd,J=8.6,3.8Hz,1H),5.62(s,1H)。
实施例20(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-二甲氧基-1,5-二氧代戊烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(35-2)
((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-羰基)-L-谷氨酸二甲酯(35-1)的合成。向250-mL圆底烧瓶里放入(2S)-2-氨基戊二酸1,5-二甲酯盐酸盐(261mg,1.23mmol,3.00当量)、DCM(15mL)、TEA(0.171mL,3.00当量)、1-7(250mg,0.41mmol,1.00当量)在DCM(5mL)中的溶液。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。这样得到250mg(81%)的35-1,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-二甲氧基-1,5-二氧代戊烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(35-2)的合成。向100-mL圆底烧瓶里放入35-1(250mg,0.34mmol,1.00当量)、EtOAc(20g,226.99mmol,677.32当量)、Pd/C(30mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(53.0%ACN,8分钟内达到71.0%);检测器,UV 254nm。这样得到33.3mg(15%)的35-2,为白色固体。MS(ES,m/z):[M+H]+=656.35;1H NMR(300MHz,氯仿-d,ppm):δ0.75(d,J=11.1Hz,1H),0.84(s,3H),0.91(s,3H),0.97(s,1H),1.02(s,1H),1.05(s,3H),1.14(s,3H),1.19(s,3H),1.23(s,3H),1.24-1.30(m,1H),1.33-1.49(m,9H),1.59-1.68(m,3H),1.83-2.07(m,7H),2.17-2.22(m,2H),2.24-2.49(m,3H),2.86(d,J=13.5,1H),3.68(s,3H),3.75(s,3H),4.60-4.64(m,1H),5.71(s,1H),6.28(d,J=7.5Hz,1H)。
实施例21(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-二甲氧基-1,4-二氧代丁烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(37-2)
((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-羰基)-D-天冬氨酸二甲酯(37-1)的合成。向100-mL圆底烧瓶里放入(2R)-2-氨基丁二酸1,4-二甲酯盐酸盐(201mg,1.02mmol,1.00当量)、DCM(20mL)、TEA(0.353mL,5.00当量)。将所得溶液在室温下搅拌0.5h。然后接着在室温下伴随搅拌滴加1-7(309mg,0.51mmol,1.00当量)在DCM(10mL)中的溶液。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。这样得到372mg(100%)的37-1,为浅黄色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-二甲氧基-1,4-二氧代丁烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(37-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入37-1(372mg,0.51mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(37mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5.0%ACN,1分钟内达到56.0%,7分钟内达到72.0%);检测器,UV 254nm。这样得到206mg(63%)的37-2,为白色固体。MS(ES,m/z):[M+H]+=642;1H NMR(400MHz,MeOH-d4,ppm):δ0.84(s,4H),0.91(s,3H),0.95-1.00(m,5H),1.13-1.21(m,9H),1.25(d,J=13.2Hz,1H),1.38-1.52(m,9H),1.62-1.81(m,3H),1.82-2.04(m,4H),2.05-2.26(m,3H),2.49(s,1H),2.72-2.86(m,2H),2.95(dd,J=16.4,5.2Hz,1H),3.65(s,3H),3.72(s,3H),4.76(dd,J=8.0,5.6Hz,1H),5.58(s,1H)。
实施例22(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(39-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(39-1)的合成。向100-mL圆底烧瓶里放入(2S)-2-氨基丙酸甲酯盐酸盐(172mg,1.23mmol,2.993当量)、DCM(15mL)、TEA(0.171mL,1.23mmol,2.988当量)、1-7(250mg,0.41mmol,1当量)在DCM(5mL)中的溶液。将所得溶液在室温下搅拌1小时。将所得混合物浓缩。这样得到250mg(90.11%)的PH-RDX-013-455-1,为浅黄色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(39-2)的合成。向100-mL圆底烧瓶里放入39-1(250mg,0.37mmol,1.00当量)、MeOH(25mL)、Pd/C(25mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(53.0%ACN,8分钟内达到71.0%);检测器,UV 254nm。这样得到31.7mg(15%)的39-2,为白色固体。(ES,m/z):[M+H]+=584.35;1H NMR(300MHz,氯仿-d,ppm):δ0.77(d,J=11.7Hz,1H),0.87(s,3H),0.95(s,3H),1.09(s,3H),1.17(s,3H),1.22(s,3H),1.26(s,3H),1.29-1.32(m,1H),1.32-1.51(m,11H),1.59-1.79(m,3H),1.83-2.07(m,9H),2.19(d,J=10.5,1H),2.37(s,1H),2.86(d,J=13.5Hz,1H),3.75(s,3H),4.56-4.66(m,1H),5.71(s,1H),5.95(d,J=7.2Hz,1H)。
实施例23(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-羟基-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(41-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-羟基-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(41-1)的合成。向100-mL圆底烧瓶里放入(2S)-2-氨基-3-羟基丙酸甲酯盐酸盐(211mg,1.36mmol,2.00当量)、DCM(20mL)、TEA(0.283mL,3.00当量)。将所得溶液在室温下搅拌0.5h。然后接着在室温下伴随搅拌滴加1-7(412mg,0.68mmol,1.00当量)在DCM(10mL)中的溶液。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。这样得到468mg(100%)的41-1,为浅黄色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-羟基-1-甲氧基-1-氧代丙烷-2-基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(41-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入41-1(468mg,0.68mmol,1.00当量)、MeOH(20mL)、THF(10mL)、Pd/C(50mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(45.0%ACN,8分钟内达到63.0%);检测器,UV254nm。这样得到283mg(70%)的41-2,为白色固体。MS(ES,m/z):[M+H]+=600.40;1H NMR(400MHz,MeOH-d4,ppm):δ0.81-0.89(m,4H),0.91(s,3H),0.95-1.07(m,2H),1.10(s,3H),1.13-1.20(m,9H),1.20-1.30(m,1H),1.40(s,3H),1.43-1.52(m,5H),1.61-1.79(m,3H),1.80-2.08(m,4H),2.09-2.29(m,3H),2.50(s,1H),2.78(dt,J=13.2,3.2Hz,1H),3.34(s,1H),3.72(s,3H),3.78(dd,J=11.2,4.8Hz,1H),3.88(dd,J=11.2,4.8Hz,1H),4.40-4.57(m,1H),5.58(s,1H),7.87(d,J=7.7Hz,1H)。
实施例24(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-咪唑-1-基)乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(44-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-咪唑-1-基)乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(44-1)的合成。向100-mL圆底烧瓶里放入EDCI(53.4mg,0.28mmol,1.50当量)、DCM(15mL)、DMAP(113mg,0.92mmol,5.00当量)。将所得溶液在室温下搅拌1h。添加30-2(120mg,0.19mmol,1.00当量)。伴随搅拌使所得溶液在55℃下再反应1h。添加2-(1H-咪唑-1-基)乙-1-醇(83mg,0.74mmol,4.00当量)。伴随搅拌使所得溶液在55℃下再反应过夜。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(9:1)的硅胶柱上。这样得到85mg(62%)的44-1,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-咪唑-1-基)乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(44-2)的合成。向100-mL圆底烧瓶里放入44-1(125mg,0.17mmol,1.00当量)、MeOH(20mL)、Pd/C(30mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(32.0%ACN,8分钟内达到50.0%);检测器,UV 254nm。这样得到108.9mg(99%)的44-2,为白色固体。MS(ES,m/z):[M+H]+=650.45;1H NMR(400MHz,MeOH-d4,ppm):δ0.84(s,3H),0.85(s,1H),0.91(s,3H),0.94-0.99(m,1H),1.04(s,3H),1.05-1.07(m,1H),1.15(s,3H),1.17(s,3H),1.19(s,3H),1.26(d,J=13.8Hz,1H),1.37-1.48(m,9H),1.66-1.75(m,3H),1.83-2.19(m,7H),2.49(s,1H),2.78(dt,J=13.4Hz,3.3Hz,1H),3.87-3.91(m,2H),4.51-4.55(m,4H),5.58(s,1H),7.56(s,1H),7.69(s,1H),8.20(t,J=5.8Hz,1H),8.98(s,1H)。
实施例25(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-羟基乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(45-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(苄氧基)乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(45-1)的合成。向100-mL圆底烧瓶里放入EDCI(44mg,0.23mmol,1.50当量)、DCM(15mL)、DMAP(95mg,0.78mmol,5.00当量)。将所得溶液在室温下搅拌1h。添加30-2(100mg,0.15mmol,1.00当量)。伴随搅拌使所得溶液在55℃下再反应1h。添加2-(苄氧基)乙-1-醇(0.088mL,4.00当量)。伴随搅拌使所得溶液在55℃下再反应过夜。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(9:1)的硅胶柱上。这样得到95mg(79%)的45-1,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-羟基乙氧基)-2-氧代乙基)氨基甲酰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(45-2)的合成。向100-mL圆底烧瓶里放入45-1(120mg,0.15mmol,1.00当量)、THF(10mL)、MeOH(10mL)、Pd/C(30mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌2天。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(42.0%ACN,8分钟内达到61.0%);检测器,UV 254nm。这样得到58.8mg(64%)的45-2,为白色固体。MS(ES,m/z):[M+H]+=600.35;1H NMR(300MHz,MeOH-d4 ppm):δ0.83(s,3H),0.86(s,1H),0.92(s,3H),0.96-1.01(m,2H),1.07(s,3H),1.15(s,3H),1.17(s,3H),1.19(s,3H),1.25(d,J=13.9Hz,1H),1.40-1.52(m,9H),1.71(t,J=13.4Hz,3H),1.81-2.03(m,4H),2.07-2.24(m,3H),2.50(s,1H),2.79(dt,J=13.2Hz,3.3Hz,1H),3.71-3.74(m,2H),3.88(d,J=17.4Hz,1H),3.99(d,J=17.4Hz,1H),4.17-4.20(m,2H),5.58(s,1H)。
实施例26(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(2-吗啉代乙氧基)-2-氧代乙基)氨基甲酰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(46-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(2-吗啉代乙氧基)-2-氧代乙基)氨基甲酰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(46-1)的合成。向100-mL圆底烧瓶里放入EDCI(53.4mg,0.28mmol,1.50当量)、DCM(15mL)、DMAP(226mg,1.85mmol,10.00当量)。将所得溶液在室温下搅拌1h。添加30-2(120mg,0.19mmol,1.00当量)。伴随搅拌使所得溶液在55℃下再反应1h。添加2-(吗啉-4-基)乙-1-醇(0.09mL,4.00当量)。伴随搅拌使所得溶液在55℃下再反应2天。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(9:1)的硅胶柱上。这样得到125mg(89%)的46-1,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(2-吗啉代乙氧基)-2-氧代乙基)氨基甲酰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(46-2)的合成。向100-mL圆底烧瓶里放入46-1(160mg,0.21mmol,1.00当量)、MeOH(15mL)、Pd/C(30mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(32.0%ACN,8分钟内达到50.0%);检测器,UV 254nm。这样得到77.2mg(55%)的46-2,为白色固体。MS(ES,m/z):[M+H]+=669.45;1H NMR(300MHz,MeOH-d4,ppm)δ0.87(s,3H),0.92(s,1H),0.96(s,3H),1.02-1.07(m,2H),1.09(s,3H),1.16(s,3H),1.17(s,3H),1.19(s,3H),1.29(d,J=14.3Hz,1H),1.40-1.56(m,10H),1.73(t,J=13.5Hz,3H),1.82-2.10(m,4H),2.14-2.29(m,3H),2.50(s,1H),2.80(dt,J=13.3Hz,3.3Hz,1H),3.53(t,J=5.0Hz,4H),3.72-4.20(m,6H),4.53(q,J=4.6Hz,2H),5.58(s,1H)。
实施例27(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(((新戊酰氧基)甲氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(47-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-((新戊酰氧基)甲基)酯(47-1)的合成。向100-mL圆底烧瓶里放入1-6(100mg,0.17mmol,1当量)、DMF(5mL,0.07mmol)、2,2-二甲基丙酸氯甲酯(30mg,0.20mmol,1.173当量)、TBAI(30mg,0.08mmol,0.478当量)、K2CO3(28mg,0.20mmol,1.193当量)。将所得溶液在65℃下搅拌2小时。将所得溶液用30mL DCM稀释。将所得混合物用2x15 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物浓缩。将残留物施加到具有EtOAc/石油醚(1:3)的硅胶柱上。这样得到65mg(54.45%)的47-1,为黄色油状物。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(((新戊酰氧基)甲氧基)羰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(47-2)的合成。向用H2(1atm)惰性气氛吹扫并保持的100-mL圆底烧瓶里放入47-1(300mg,0.43mmol,1当量)、MeOH(10mL,0.31mmol,0.733当量)、Pd/C(30mg,0.662当量)。将所得溶液在室温下搅拌1小时。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到80%,7分钟内达到95%);检测器,UV 254nm。这样得到47.6mg(18.25%)的47-2,为白色固体。MS(ES,m/z):[M+H]+=613.46;1H NMR(400MHz,MeOH-d4,ppm):δ0.83-0.89(m,7H),1.00-1.06(m,5H),1.15-1.19(m,18H),1.22-1.29(m,3H),1.40-1.51(m,8H),1.65-1.68(m,3H),1.82-1.98(m,3H),2.14-2.29(m,3H),2.50(s,1H),2.77(d,J=13.6Hz,1H),5.58(s,1H),5.69(d,J=5.6Hz,1H),5.78(d,J=5.6Hz,1H)。
实施例28(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((异丙氧基羰基)氧基)甲氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(48-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(((异丙氧基羰基)氧基)甲基)酯(48-1)的合成。向100-mL圆底烧瓶里放入1-6(300mg,0.51mmol,1当量)、DMF(5mg,0.07mmol,0.134当量)、碳酸氯甲酯丙烷-2-基酯(93mg,0.61mmol,1.196当量)、K2CO3(84mg,0.61mmol,1.193当量)、TBAI(90mg,0.24mmol,0.478当量)。将所得溶液在65℃下搅拌2小时。将所得溶液用50mL DCM稀释。将所得混合物用2x25 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物浓缩。将残留物施加到具有EtOAc/石油醚(1:3)的硅胶柱上。这样得到200mg(55.69%)的48-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((异丙氧基羰基)氧基)甲氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(48-2)的合成。向用H2(1atm)惰性气氛吹扫并保持的100-mL圆底烧瓶里放入48-1(300mg,0.43mmol,1当量)、MeOH(10mL,0.31mmol,0.733当量)、Pd/C(30mg,0.662当量)。将所得溶液在室温下搅拌1小时。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到74%,7分钟内达到88%);检测器,UV 254nm。这样得到148.2mg(56.64%)的48-2,为白色固体。MS(ES,m/z):[M+H]+=615.40;1H NMR(400MHz,MeOH-d4,ppm):δ0.83-0.89(m,7H),0.97-1.06(m,5H),1.13-1.23(m,16H),1.40-1.53(m,9H),1.66-2.03(m,7H),2.11-2.30(m,3H),2.50(s,1H),2.77(d,J=13.2Hz,1H),4.84-4.90(m,1H),5.58(s,1H),5.68(d,J=5.6Hz,1H),5.75(d,J=5.6Hz,1H)。
实施例29(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((异丙氧基羰基)氧基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(49-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(1-((异丙氧基羰基)氧基)乙基)酯(49-1)的合成。向100-mL圆底烧瓶里放入1-6(400mg,0.68mmol,1.00当量)、碳酸1-氯乙酯丙烷-2-基酯(135.8mg,0.82mmol,1.20当量)、TBAI(125mg,0.89mmol,0.50当量)、甲烷过氧酸钾(112mg,0.80mmol,1.20当量)、DMF(15mL)。将所得溶液在室温下搅拌2h。将所得溶液用3x150 mL DCM萃取并合并有机层。将所得混合物用2x250 mL盐水洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:3)的硅胶柱上。这样得到450mg混合立体异构体。通过制备型SFC进一步纯化并收集较快的洗脱峰,得到180mg的49-1。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((异丙氧基羰基)氧基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(49-2)的合成。向100-mL圆底烧瓶里放入49-1、Pd/C(40mg)、MeOH(20mL),引入氢(1atm)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:流动相,水(0.05%TFA)和ACN(5.0%ACN,1分钟内达到80.0%,7分钟内达到90.0%);检测器,UV254nm。这样得到87.6mg(56%)的49-2。MS(ES,m/z):[M+H]+=629.4;1H NMR(400MHz,MeOH-d4,ppm):δ0.82(s,4H),0.91(s,3H),0.96-1.11(m,5H),1.15-1.28(m,9H),1.28-1.36(m,7H),1.33-1.58(m,12H),1.71-1.82(m,3H),1.82-2.02(m,2H),2.10-2.25(m,3H),2.53(s,1H),2.80(dt,J=13.6,3.6Hz,1H),4.89(d,J=6.4Hz,1H),5.60(s,1H),6.73(q,J=5.4Hz,1H)。
实施例30(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((异丙氧基羰基)氧基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(50-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-((R)-1-((异丙氧基羰基)氧基)乙基)酯(50-1)的合成。在49-1的纯化中收集较慢的洗脱峰,得到150mg的50-1。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((异丙氧基羰基)氧基)乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(50-2)的合成。向100-mL圆底烧瓶里放入50-1(150mg,0.21mmol,1.00当量)、Pd/C(40mg)、MeOH(20mL),引入H2(1atm)。将所得溶液在室温下搅拌过夜。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:流动相,水(0.05%TFA)和ACN(5.0%ACN,1分钟内达到80.0%,7分钟内达到90.0%);检测器,UV254nm。这样得到79mg(60%)的50-2,为白色固体。MS(ES,m/z):[M+H]+=629.93;1H NMR(400MHz,MeOH-d4,ppm):δ0.78-0.93(m,7H),0.95-1.15(m,5H),1.15-1.21(m,9H),1.21-1.33(m,7H),1.33-1.56(m,12H),1.60-1.80(m,3H),1.83-2.02(m,4H),2.06-2.25(m,3H),2.52(s,1H),2.79(dt,J=13.4,3.6Hz,1H),4.86(d,J=1.8Hz,1H),5.60(s,1H),6.75(q,J=5.4Hz,1H)。
实施例31(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(二乙氨基)-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(51-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-(二乙氨基)-2-氧代乙基)酯(51-1)的合成。向100-mL圆底烧瓶里放入1-6(589mg,1.00mmol,1当量)、DMF(10mg,0.14mmol)、TBAI(185mg,0.501当量)、K2CO3(165mg,1.19mmol,1.194当量)、2-氯-N,N-二乙基乙酰胺(180mg,1.20mmol,1.203当量)。将所得溶液在65℃下搅拌2小时。将所得混合物浓缩。将残留物施加到具有EtOAc/石油醚(1:3)的硅胶柱上。这样得到600mg(85.45%)的51-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(二乙氨基)-2-氧代乙氧基)羰基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(51-2)的合成。向用H2(1atm)惰性气氛吹扫并保持的100-mL圆底烧瓶里放入51-1(200mg,0.28mmol,1当量)、MeOH(10mL,0.31mmol)、Pd/C(30mg,0.1当量)。将所得溶液在室温下搅拌过1夜。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到66%,7分钟内达到80%);检测器,UV 254nm。这样得到91.4mg(52.43%)的51-2,为白色固体。MS(ES,m/z):[M+H]+=612.55;1H NMR(400MHz,MeOH-d4,ppm):δ0.84-0.98(m,4H),0.93-1.01(m,3H),1.04-1.10(m,2H),1.10-1.18(m,15H),1.21-1.27(m,4H),1.38-1.48(m,8H),1.57-1.60(m,1H),1.61-1.75(m,3H),1.76-2.03(m,4H),2.15-2.19(m,2H),2.34(d,J=13.2Hz,1H),2.51(s,1H),2.77(d,J=13.2Hz,1H),3.30-3.40(m,4H),4.76(s,2H),5.58(s,1H)。
实施例32(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-吗啉代-2-氧代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(52-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-吗啉代-2-氧代乙基)酯(52-1)的合成。向100-mL圆底烧瓶里放入13-2(150mg,0.23mmol,1当量)、DMF(15mL)、HATU(0.2g,0.47mmol,2.041当量)、吗啉(0.06mL,3当量)、DIPEA(0.08mL,0.48mmol,2.087当量)。将所得溶液在室温下搅拌2小时。将所得溶液用500mL DCM萃取。将所得混合物用1x 500mL水洗涤。将所得混合物用1x 500mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。这样得到200mg(120.46%,粗品)的52-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-吗啉代-2-氧代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(52-2)的合成。向100-mL圆底烧瓶里放入52-1(200mg,0.28mmol,1当量)、EA(16mL)、Pd/C(5.9mg,0.06mmol,0.198当量)。向上述***中引入H2(g)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Prep OBD C18柱,19*250mm,5um;流动相,水(0.05%TFA)和ACN(5%B相,2分钟内达到60%,8分钟内达到75%);检测器,UV。这样得到56.7mg(32.43%)的52-2,为白色固体。MS(ES,m/z):[M+H]+=626.45;1H NMR(300MHz,MeOH-d4,ppm):0.85(s,3H),0.89-1.00(m,4H),1.02-1.31(m,15H),1.33-1.52(m,8H),1.52-1.64(m,1H),1.63-1.80(m,3H),1.81-2.08(m,4H),2.09-2.27(m,2H),2.28-2.42(m,1H),2.52(s,1H),2.72-2.88(m,1H),3.42-3.61(m,4H),3.62-3.78(m,4H),4.80-4.86(m,2H),5.58(s,1H)。
实施例33(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(4-甲基哌嗪-1-基)-2-氧代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(53-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(2-(4-甲基哌嗪-1-基)-2-氧代乙基)酯(53-1)的合成。向100-mL圆底烧瓶里放入13-2(150mg,0.23mmol,1当量)、DMF(15mL)、HATU(180mg,0.47mmol,2.041当量)、1-甲基哌嗪(0.077mL,3当量)、DIPEA(0.08mL,0.48mmol,2.087当量)。将所得溶液在室温下搅拌2小时。将所得溶液用200mL DCM萃取。将所得混合物用1x200 mL水洗涤。将所得混合物用1x200 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。这样得到150mg(88.73%)的53-1,为白色半固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-((2-(4-甲基哌嗪-1-基)-2-氧代乙氧基)羰基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(53-2)的合成。向100-mL圆底烧瓶里放入53-1(150mg,0.21mmol,1当量)、EA(16mL)、Pd/C(4.4mg,0.201当量)。向上述***中引入H2(g)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Prep OBD C18柱,19*250mm,5um;流动相,水(0.05%TFA)和ACN(41%B相,8分钟内达到59%);检测器,UV 254nm。这样得到85.8mg(65.27%)的53-2,为白色固体。MS(ES,m/z):[M+H]+=639.45;1H NMR(300MHz,MeOH-d4,ppm):0.79-1.00(m,8H),1.02-1.15(m,5H),1.15-1.22(m,9H),1.23-1.35(m,2H),1.36-1.51(m,8H),1.52-1.64(m,2H),1.73(t,J=13.5Hz,3H),1.80-2.27(m,7H),2.32-2.46(m,1H),2.52(s,1H),2.70-2.88(m,1H),2.95(s,3H),3.20-3.28(m,1H),3.34-3.47(m,2H),3.52-4.09(m,3H),5.58(s,1H)。
实施例34(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(54-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(54-2)的合成。向50-mL圆底烧瓶里放入54-1(按Bioorg.Med.Chem.2010,18,433-454中所述的方法制备)(100mg,0.18mmol,1.00当量)、CH3CN(5mL)、2-溴乙酸甲酯(55mg,0.36mmol,2.00当量)、碳酸钾(74mg,0.54mmol,3.00当量)。将所得溶液在60℃下搅拌过夜。将所得溶液用3x20 mL EtOAc萃取,将有机层合并,经无水硫酸钠干燥,并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1/2)的硅胶柱上。合并收集的级分并在真空下浓缩。这样得到100mg(89%)54-2,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(54-3)的合成。在氢气氛下向50-mL圆底烧瓶里放入54-2(160mg,0.25mmol,1.00当量)、Pd/C(80mg)、MeOH(5mL)。将所得溶液在室温下搅拌2h。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(30.0%ACN,8分钟内达到48.0%);检测器,UV 254nm。这样得到30.7mg(22%)的54-3,为灰白色固体。MS(ES,m/z):[M+H]+=542.45;1H NMR(300MHz,DMSO-d6)δ9.05(s,1H),8.15(s,1H),5.42(s,1H),4.22-3.94(m,3H),3.77(s,3H),2.85(s,1H),2.67(d,J=13.3Hz,1H),2.36(s,1H),2.07(dd,J=11.7,5.5Hz,2H),1.93-1.49(m,7H),1.35(s,8H),1.11(d,J=9.4Hz,7H),1.04(d,J=2.6Hz,6H),0.97(d,J=13.7Hz,2H),0.85(s,4H),0.76(s,3H)。
实施例35(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(双(2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(56-2)
2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氮烷二基)二乙酸二甲酯(56-1)的合成。向50-mL圆底烧瓶里放入54-1(100mg,0.18mmol,1.00当量)、2-溴乙酸甲酯(273mg,1.78mmol,10.00当量)、ACN(10mL)、碳酸钾(370mg,2.68mmol,15.00当量)。将所得溶液在60℃下搅拌过夜。将所得溶液用3x20 mL EtOAc萃取,将有机层合并,经无水硫酸钠干燥,并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1/2)的硅胶柱上。合并收集的级分并在真空下浓缩。这样得到105mg(84%)的56-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(双(2-甲氧基-2-氧代乙基)氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(56-2)的合成。向用H2惰性气氛吹扫并保持的25-mL圆底烧瓶里放入56-1(80mg,0.11mmol,1.00当量)、MeOH(5mL)、Pd/C(80mg)。将所得溶液在室温下搅拌2h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge ShieldRP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(67.0%ACN,8分钟内达到80.0%);检测器,UV 254nm。这样得到36.8mg(53%)的56-2,为白色固体。MS(ES,m/z):[M+H]+=614;1H NMR(300MHz,MeOH-d4)δ5.55(s,1H),3.71(d,J=12.1Hz,10H),2.78(d,J=13.3Hz,1H),2.43(s,2H),2.22-2.05(m,2H),1.91(s,1H),1.82(d,J=13.7Hz,4H),1.70(d,J=13.3Hz,1H),1.58(s,1H),1.38(d,J=4.9Hz,7H),1.25(d,J=6.8Hz,1H),1.23-1.07(m,10H),1.02(d,J=14.5Hz,6H),0.80(d,J=2.6Hz,7H)。
实施例36 2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氮烷二基)二乙酸(57-2)
2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氮烷二基)二乙酸二苄酯(57-1)的合成。向250-mL圆底烧瓶里放入54-1(500mg,0.89mmol,1.00当量)、CH3CN(50mL)、碳酸钾(1.85g,13.39mmol,15.00当量)、2-溴乙酸苄酯(1.42g,6.20mmol,10.00当量)。将所得溶液在60℃下搅拌过夜。添加碳酸钾(0.92g,7.50当量)、2-溴乙酸苄酯(0.71mg,5.00当量)。伴随搅拌使所得溶液在60℃下再反应6h。将所得混合物在真空下浓缩。将残留物溶解在100mL DCM中。将所得混合物用1x100 mL水洗涤。将固体在烘箱中减压干燥。将残留物施加到具有EtOAc/石油醚(1:5)的硅胶柱上。这样得到380mg(50%)的57-1,为浅黄色油状物。
2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氮烷二基)二乙酸(57-2)的合成。向100-mL圆底烧瓶里放入57-1(466mg,0.54mmol,1.00当量)、THF(30mL)、Pd/C(50mg)。向上述***中引入氢。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。将残留物溶解在10mL MeOH中。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Prep OBD C18柱,19*250mm,5um;流动相,水(0.05%TFA)和ACN(32.0%ACN,8分钟内达到55.0%);检测器,UV 254nm。这样得到263.9mg(83%)的PH-RDX-013-431-0,为白色固体。MS(ES,m/z):[M+H]+=586.35;1H NMR(300MHz,MeOH-d4,ppm):δ0.87(s,3H),0.95(s,1H),1.00(s,3H),1.08(d,J=13.6Hz,1H),1.15(s,3H),1.17(s,3H),1.20(s,3H),1.26(s,3H),1.31-1.39(m,2H),1.38-1.59(m,8H),1.65-2.26(m,10H),2.51(s,1H),2.89-2.97(m,2H),3.97(d,J=3.3Hz,4H),5.59(s,1H)。
实施例37(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-2,2-二甲基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(58-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-2,2-二甲基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(58-1)的合成。向用氮惰性气氛吹扫并保持的25-mL圆底烧瓶里放入3-甲氧基-2,2-二甲基-3-氧代丙酸(26mg,0.18mmol,1.00当量)、DMF(5mL)、54-1(100mg,0.18mmol,1.00当量)、DIEA(65mg,0.50mmol,3.00当量)、HATU(102mg,0.27mmol,1.50当量)。将所得溶液在室温下搅拌1h。将所得溶液用3x10 mL EtOAc萃取,将有机层合并,经无水硫酸钠干燥,并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1/2)的硅胶柱上。合并收集的级分并在真空下浓缩。这样得到110mg(90%)的58-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-2,2-二甲基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(58-2)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入58-1(50mg,0.07mmol,1.00当量)、MeOH(10mL)、Pd/C(25mg)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(60.0%ACN,8分钟内达到78.0%);检测器,UV 254nm。这样得到12.3mg(28%)的58-2,为白色固体。MS(ES,m/z):[M+H]+=598;1H NMR(300MHz,MeOH-d4)δ0.81-0.98(m,12H),1.06(d,J=14.2Hz,2H),1.13-1.33(m,12H),1.43(q,J=4.6,4.1Hz,14H),1.71(dd,J=27.4,13.7Hz,4H),1.81-1.98(m,3H),2.20(s,2H),2.52(s,1H),2.77(d,J=13.7Hz,1H),3.72(s,6H),5.59(s,1H),7.11(d,J=9.6Hz,1H)。
实施例38(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(60-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(60-1)的合成。向50-mL圆底烧瓶里放入54-1(90mg,0.16mmol,1当量)、DCM(4mL,0.05mmol,0.293当量)、DIEA(45.7mg,0.35mmol,2.2当量)。接着伴随搅拌滴加2-氯-2-氧代乙酸甲酯(21.7mg,0.18mmol,1.1当量)。将所得溶液在室温下搅拌2小时。将所得混合物在真空下浓缩。这样得到110mg(105.94%)的60-1,为黄色粗固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(60-2)的合成。向用H2惰性气氛吹扫并保持的25-mL圆底烧瓶里放入60-1(104mg,0.16mmol,1当量)、MeOH(5mg,0.16mmol,0.969当量)、Pd/C(50mg,0.47mmol,2.918当量)。将所得溶液在室温下搅拌2.5小时。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(58%B相,8分钟内达到72%);检测器,UV。这样得到45.5mg(50.84%)的60-2,为白色固体。MS(ES,m/z):[M+H]+=555.76;1H NMR(300MHz,DMSO-d6)δ12.18(s,1H),8.30(d,J=9.7Hz,1H),5.41(s,1H),3.77(s,3H),3.57(ddd,J=13.2,9.6,4.1Hz,1H),2.63(d,J=13.4Hz,1H),2.41(s,1H),2.08(q,J=9.8,6.6Hz,2H),1.79(d,J=13.5Hz,3H),1.69(d,J=7.0Hz,3H),1.53(d,J=13.2Hz,1H),1.46-1.16(m,9H),1.17-0.95(m,13H),0.81-0.73(m,9H)。
实施例39(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(62-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(62-1)的合成。向100-mL圆底烧瓶里放入54-1(500mg,0.89mmol,1当量)、3-氯-3-氧代丙酸甲酯(243.9mg,1.79mmol,2当量)、TEA(271.1mg,2.68mmol,3当量)、CH2Cl2(10mL,0.12mmol,0.132当量)。将所得溶液在室温下搅拌1小时。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到439mg(74.49%)的62-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-甲氧基-3-氧代丙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(62-2)的合成。向用H2惰性气氛吹扫并保持的100-mL圆底烧瓶里放入62-1(439mg,0.67mmol,1当量)、THF(200mg,2.77mmol,4.169当量)、MeOH(10mL,0.31mmol,0.469当量)、Pd/C(10mL)。将所得溶液在室温下搅拌1小时。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到56%,7分钟内达到70%);检测器,UV。这样得到61.4mg(16.20%)的62-2,为白色固体。MS(ES,m/z):[M+H]+=570;1H NMR(300MHz,MeOH-d4)δ5.59(s,1H),3.72(s,4H),3.35(s,2H),2.77(dt,J=13.4,3.7Hz,1H),2.53(s,1H),2.18(ddd,J=19.3,13.0,4.5Hz,2H),2.01-1.61(m,7H),1.59-1.34(m,9H),1.33-1.13(m,11H),1.07(d,J=14.9Hz,2H),0.98-0.81(m,10H)。
实施例40(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(64-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(64-1)的合成。向25-mL圆底烧瓶里放入4-甲氧基-4-氧代丁酸(28mg,0.21mmol,1.00当量)、54-1(120mg,0.21mmol,1.00当量)、DMF(5mL)、DIEA(78mg,0.60mmol,3.00当量)、HATU(122mg,0.32mmol,1.50当量)。将所得溶液在室温下搅拌1h。将所得溶液用3x20mL EtOAc萃取,将有机层合并,经无水硫酸钠干燥,并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1/2)的硅胶柱上。合并收集的级分并在真空下浓缩。这样得到140mg(98%)的64-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(64-2)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入64-1(50mg,0.07mmol,1.00当量)、MeOH(5mL)、Pd/C(25mg)。将所得溶液在室温下搅拌1h。将固体滤出。通过从ACN中重结晶来纯化粗产物。这样得到39.9mg(92%)的64-2,为白色固体。MS(ES,m/z):[M+H]+=584;1H NMR(300MHz,MeOH-d4)δ0.81-0.96(m,10H),0.99-1.20(m,11H),1.20-1.58(m,11H),1.59-1.82(m,4H),1.82-2.08(m,3H),2.08-2.33(m,2H),2.42-2.72(m,5H),2.75(dq,J=12.1,5.0,4.2Hz,1H),3.67(s,4H),5.65(s,1H)。
实施例41(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-甲氧基-4-氧代丁-2-烯酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(66-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-甲氧基-4-氧代丁-2-烯酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(66-1)的合成。向8-mL圆底烧瓶里放入(2E)-4-甲氧基-4-氧代丁-2-烯酸(66.48mg,0.51mmol,1.20当量)、54-1(200mg,0.36mmol,1.00当量)、DIEA(220.13mg,1.70mmol,4.00当量)、DMF(2mL)、HATU(343mg,0.90mmol,1.50当量)。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(100:1)的硅胶柱上。这样得到200mg(83%)的66-1,为黄色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-甲氧基-4-氧代丁-2-烯酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(66-2)的合成。向100-mL圆底烧瓶里放入66-1(250mg,0.37mmol,1.00当量)、THF(10mL)、水(5mL)、氢氧化钠(90mg,2.25mmol,6.00当量)、MeOH(10mL)。将所得溶液在60℃下搅拌4天。将残留物施加到具有EtOAc/石油醚(0-35%)的硅胶柱上。这样得到31.8mg(15%)的66-2,为白色固体。MS(ES,m/z):[M+H]+=582;1H NMR(300MHz,MeOH-d4)δ8.26(d,J=9.7Hz,1H),7.08(d,J=15.4Hz,1H),6.69(d,J=15.4Hz,1H),5.59(s,1H),3.71(s,4H),3.35(s,2H),2.79(d,J=13.5Hz,1H),2.57-2.50(m,1H),2.16(t,J=12.3Hz,2H),2.04-1.61(m,6H),1.56-1.38(m,8H),1.38-1.21(m,2H),1.21-0.80(m,20H)。
实施例42(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-羧基-3-甲基丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(68-3)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-3,3-二甲基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(68-1)的合成。向25-mL圆底烧瓶里放入54-1(150mg,0.27mmol,1当量)、DMF(2mL,0.03mmol,0.102当量)、4-甲氧基-3,3-二甲基-4-氧代丁酸(51.5mg,0.32mmol,1.2当量)、DIEA(138.5mg,1.07mmol,4.0当量)、HATU(152.8mg,0.40mmol,1.5当量)。将所得溶液在室温下搅拌过1夜。将所得溶液用EA稀释。将所得混合物用x盐水洗涤。将残留物施加到具有EtOAc/石油醚的硅胶柱上。这样得到170mg(90.38%)的68-1,为灰白色固体。
4-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氨基)-2,2-二甲基-4-氧代丁酸(68-2)的合成。向25-mL圆底烧瓶里放入68-1(100mg,0.14mmol,1当量)、MeOH(5mL,49.40mmol,346.760当量)、THF(5mL,24.69mmol,173.289当量)、H2O(2mL,111.02mmol,779.31当量)、LiOH.H2O(54mg,1.29mmol,9.033当量)。将所得溶液在室温下搅拌过1夜。将所得混合物浓缩。用HCl将溶液的pH值调节到5-6。将所得溶液用3x100 mL EtOAc萃取。将残留物施加到具有DCM/MeOH的硅胶柱上。这样得到80mg(81.63%)的68-2,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-羧基-3-甲基丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(68-3)的合成。向用H2惰性气氛吹扫并保持的25-mL圆底烧瓶里放入68-2(80mg,0.12mmol,1当量)、MeOH(5mL,0.16mmol,1.342当量)、Pd/C(40mg,0.38mmol,3.232当量)。将所得溶液在室温下搅拌2小时。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(10mmol/L NH4HCO3+0.1%NH3·H2O)和ACN(48%B相,8分钟内达到73%);检测器,UV。这样得到14.1mg(20.28%)的68-3,为白色固体。MS(ES,m/z):[M+H]+=598;1H NMR(300MHz,MeOH-d4)δ5.61(s,1H),3.64-3.53(m,1H),2.74(d,J=13.6Hz,1H),2.51(s,3H),2.28-2.09(m,2H),1.91(dd,J=24.4,10.9Hz,3H),1.81-1.60(m,2H),1.43(d,J=10.2Hz,8H),1.24(d,J=1.8Hz,8H),1.16(d,J=4.3Hz,11H),1.05(d,J=14.1Hz,2H),0.96-0.81(m,11H)。
实施例43(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-甲氧基-3,3-二甲基-4-氧代丁酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(69-1)
向用H2惰性气氛吹扫并保持的25-mL圆底烧瓶里放入68-1(116mg,1当量)、MeOH(10mL)、Pd/C(100mg)。将所得溶液在室温下搅拌2小时。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Prep C18 OBD柱19*150nm 5umC-0013;流动相,水(0.05%TFA)和ACN(61%B相,8分钟内达到81%);检测器,UV。这样得到16.5mg的69-1,为白色固体。MS(ES,m/z):[M+H]+=612;1H NMR(300MHz,MeOH-d4)δ5.59(s,1H),3.68(s,3H),3.53(s,1H),2.75(d,J=12.8Hz,1H),2.52(d,J=5.4Hz,3H),2.18(s,2H),1.98-1.81(m,3H),1.70(dd,J=27.6,13.7Hz,4H),1.43(d,J=10.0Hz,10H),1.33-1.12(m,16H),1.05(d,J=13.5Hz,2H),0.90-0.80(m,9H)。
实施例44(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(70-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(70-1)的合成。向100-mL圆底烧瓶里放入54-1(500mg,0.89mmol,1当量)、2-(氯磺酰基)乙酸甲酯(308.3mg,1.79mmol,2当量)、TEA(271.1mg,2.68mmol,3当量)、CH2Cl2(15mL,235.95mmol,264.181当量)、DMAP(11mg,0.09mmol,0.101当量)。将所得溶液在室温下搅拌过1夜。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到250mg(40.22%)的70-1,为黄色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-甲氧基-2-氧代乙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(70-2)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入MeOH(5mL)、THF(5mL)、Pd/c(100mg,0.94mmol,1.308当量)、70-1(500mg,0.72mmol,1当量)。将所得溶液在室温下搅拌1小时。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到59%,7分钟内达到73%);检测器,UV。这样得到44.5mg(10.22%)的70-2,为白色固体。MS(ES,m/z):[M+H]+=606;1H NMR(300MHz,MeOH-d4)δ5.59(s,1H),4.12(s,2H),3.78(s,3H),3.03(dd,J=11.6,5.1Hz,1H),2.76(dt,J=13.5,3.5Hz,1H),2.51(s,1H),2.28-2.08(m,2H),2.01-1.63(m,8H),1.60-1.36(m,8H),1.33-0.99(m,15H),0.83(d,J=8.6Hz,7H)。
实施例45(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-甲氧基-3-氧代丙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(72-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-甲氧基-3-氧代丙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(72-2)的合成。向50-mL圆底烧瓶里放入54-1(300mg,1当量)、DCM(10mL)、3-(氯磺酰基)丙酸甲酯(200mg,2.0当量)、TEA(0.223mL)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:2)的硅胶柱上。这样得到326mg(86%)的72-2,为浅黄色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-甲氧基-3-氧代丙基)磺酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(72-3)的合成。向用H2惰性气氛吹扫并保持的50-mL圆底烧瓶里放入72-2(326mg,0.46mmol,1.00当量)、MeOH(10mL)、THF(10mL)、Pd/C(33mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Prep OBD C18柱,19*250mm,5um;流动相,水(0.05%NH3·H2O)和ACN(34.0%ACN,9分钟内达到50.0%);检测器,UV 254nm。这样得到200mg(70%)的72-3,为白色固体。MS(ES,m/z):[M+H]+=620.70;1H NMR(400MHz,MeOH-d4,ppm):δ0.78-0.96(m,7H),1.01-1.14(m,5H),1.15-1.24(m,9H),1.25-1.33(m,1H),1.38-1.58(m,8H),1.59-2.08(m,8H),2.12-2.29(m,2H),2.52(s,1H),2.73-2.90(m,3H),2.98(dd,J=12.4,4.0Hz,1H),3.35-3.43(m,2H),3.73(s,3H),5.62(s,1H)。
实施例46(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-甲氧基-2-氧代乙氧基)乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(75-2)
2-(2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氨基)-2-氧代乙氧基)乙酸(74-1)的合成。向用氮惰性气氛吹扫并保持的100-mL圆底烧瓶里放入54-1(1.0g,1.79mmol,1当量)、DMAP(0.1g,0.893mmol,0.5当量)、吡啶(10mL,0.13mmol,0.071当量)。接着在冰浴中伴随搅拌在0度下滴加1,4-二噁烷-2,6-二酮(228mg,1.96mmol,1.100当量)。将所得溶液在110摄氏度油浴中搅拌12小时。将所得混合物在真空下浓缩。将所得残留物用100mL水稀释。用HCl(2mol/L)将溶液的pH值调节到7。将所得溶液用3x30 mL EtOAc萃取,经无水硫酸钠干燥并在真空下浓缩。通过TLC(PE:EA=1:2)纯化粗产物。这样得到410mg(33.96%)的74-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-甲氧基-2-氧代乙氧基)乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(75-1)的合成。向25-mL圆底烧瓶里放入74-1(110mg,0.16mmol,1当量)、DCM(6mL,94.38mmol,579.919当量)、MeOH(2mL,49.40mmol,303.524当量)。接着伴随搅拌滴加(三甲基甲硅烷基)重氮甲烷(0.12mL,0.11mmol,1.5当量,在THF中2M)。将所得溶液在室温下搅拌12小时。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到110mg(97.97%)的75-1,为固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-甲氧基-2-氧代乙氧基)乙酰氨基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(75-2)的合成。向用H2惰性气氛吹扫并保持的25-mL圆底烧瓶里放入75-1(110mg,0.16mmol,1当量)、MeOH(2mL,0.06mmol,0.391当量)、Pd/C(50mg,0.47mmol,2.947当量)。将所得溶液在室温下搅拌2小时。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(5%B相,1分钟内达到56%,7分钟内达到70%);检测器,UV。这样得到36.6mg(38.27%)的75-2,为白色固体。MS(ES,m/z):[M+H]+=600.40;1H NMR(300MHz,DMSO-d6)δ12.18(s,1H),7.22(d,J=9.7Hz,1H),5.41(s,1H),4.23(s,2H),3.98(s,2H),3.67(s,3H),3.56(t,J=11.2Hz,1H),2.63(d,J=13.4Hz,1H),2.42(s,1H),2.13-2.01(m,2H),1.86-1.60(m,6H),1.54(d,J=14.9Hz,1H),1.36(d,J=14.0Hz,9H),1.21-0.85(m,13H),0.83-0.72(m,9H)。
实施例47(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-甲氧基-2-氧代乙基)-1H-1,2,3-***-4-基)甲氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(76-4)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(丙-2-炔-1-基氧基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸二苯甲基酯(76-2)的合成。向25-mL圆底烧瓶里放入76-1(如Bioorg.Med.Chem.2010,18,433-454中所述制备)(1.674g,2.63mmol,1.00当量)、THF(2.15mL)、NaHMDS(2.63mL,2.00当量)、3-溴丙-1-炔(0.45mL,2.00当量)、TBAI(486mg,1.32mmol,0.50当量)。将所得溶液在室温下搅拌过夜。将所得溶液用30mL水稀释。将所得溶液用2x50 mL DCM萃取,将有机层合并,经无水硫酸钠干燥,并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:10)的硅胶柱上。这样得到1.395g(79%)的76-2,为浅黄色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-甲氧基-2-氧代乙基)-1H-1,2,3-***-4-基)甲氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸二苯甲基酯(76-3)的合成。向50-mL圆底烧瓶里放入76-2(100mg,0.15mmol,1.00当量)、t-BuOH-H2O(3:1)8mL、2-叠氮基乙酸甲酯(0.043mL,3.00当量)、抗坏血酸钠(17.6mg,0.09mmol,0.60当量)、CuSO4.5H2O(11.1mg,0.04mmol,0.30当量)。向上述***中引入N2(g)。将所得溶液在40℃下搅拌3h。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(10:1)的硅胶柱上。这样得到110mg(94%)的76-3,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-甲氧基-2-氧代乙基)-1H-1,2,3-***-4-基)甲氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(76-4)的合成。向50-mL圆底烧瓶里放入76-3(106mg,0.13mmol,1.00当量)、EtOAc(15mL)、碳载钯(50mg)。向上述***中引入氢。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物溶解在中。采用以下条件通过制备型HPLC纯化粗产物(8mL):柱,XBridge Prep OBD C18柱,19*250mm,5um;流动相,水(0.05%TFA)和ACN(64.0%ACN,9分钟内达到80.0%);检测器,UV254nm。这样得到35.4mg(42%)的76-4,为白色固体。MS(ES,m/z):[M+H]+=624.55;1H NMR(400MHz,DMSO-d6,ppm):δ0.70-0.85(d,7H),0.86(s,3H),0.89-1.01(m,2H),1.02-1.10(m,6H),1.10-1.19(m,4H),1.21-1.56(m,10H),1.62-1.81(m,6H),2.05-2.09(m,2H),2.33(s,1H),2.66(d,J=13.6Hz,1H),2.96(dd,J=11.6,4.4Hz,1H),3.71(s,3H),4.45(d,J=12.4Hz,1H),4.67(d,J=12.4Hz,1H),5.40(d,J=7.2Hz,3H),8.07(s,1H),12.21(br s,1H)。
实施例48(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(79-2)
10-(2-甲氧基-2-氧代乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-二苯甲基酯(79-1)的合成。搅拌78-1(50mg 0.072mmol)、碘甲烷(170mg,1.2mmol)和K2CO3(30mg,0.22mmol)在DMF(0.30mL)中的混合物并在60℃下加热。3小时后,添加EtOAc(20mL),并将混合物用水(5mL)、10%Na2S2O3(3mL)和水(5mL)洗涤。将有机层干燥(Na2SO4),浓缩并通过快速色谱法(4g SiO2,0-20%EtOAc/己烷)纯化,得到标题化合物(32.7mg)。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-甲氧基-2-氧代乙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(79-2)的合成。在1atm的H2下搅拌79-1(32.7mg,0.046mmol)和10%Pd/C(~50%水,18mg湿重)在MeOH(2.0mL)和THF(1.0mL)中的混合物。2小时后,过滤混合物,浓缩并通过快速色谱法(4g SiO2,20-60%EtOAc/己烷)纯化,得到标题化合物(24mg)。MS(ES,m/z):543.3[M+H]+;1H-NMR(CDCl3)δ5.71(s,1H),4.17(d,J=16.2Hz,1H),4.08(d,J=16.2Hz,1H),3.74(s,3H),2.94(dd,J=11.8Hz,J=4.5Hz,1H),2.82(dt,J=13.5Hz,J=3.5Hz,1H),2.34(s,1H),2.18(dd,J=13.3Hz,J=3.5Hz,1H),1.34(s,3H),1.23(s,3h),1.15(s,3H),1.13(s,3H),1.07(s,3H),0.85(s,3H),0.84(s,3H),0.69(d,J=10.2Hz,1H)。
实施例49(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-二甲氧基-1,3-二氧代丙烷-2-基)氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(80-3)
2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氧基)丙二酸二甲酯(80-2)的合成。向100-mL的3颈圆底烧瓶里放入80-1((如Bioorg.Med.Chem.2012,22,3473-3479中所述制备)(680mg,1.21mmol,1.00当量)、甲苯(20mL)、Rh2(OAc)4(8mg)。接着伴随搅拌在1小时内在90℃下滴加1,1-双(甲氧基羰基)二氮杂环丙烷-1-鎓(383mg,2.38mmol,1.96当量)在甲苯(4mL)中的溶液。将所得溶液在90℃下搅拌2h。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:3)的硅胶柱上。这样得到700mg(84%)的80-2,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-二甲氧基-1,3-二氧代丙烷-2-基)氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(80-3)的合成。向用H2(1atm)惰性气氛吹扫并保持的100-mL圆底烧瓶里放入80-2(700mg,1.01mmol,1.00当量)、MeOH(10mL)、碳载钯(70mg)。将所得溶液在室温下搅拌3h。将固体滤出。采用以下条件(2#-AnalyseHPLC-SHIMADZU(HPLC-10))通过制备型HPLC纯化粗产物:柱,XBridge Prep C18 OBD柱,19*150mm,5um;流动相,水(0.05%TFA)和ACN(76.0%ACN,10分钟内达到81.0%);检测器,UV254nm。这样得到59.7mg(10%)的80-3,为白色固体。MS(ES,m/z):[M+H]+=601.40;1H-NMR(400MHz,MeOH-d4,ppm):δ0.78-0.86(m,1H),0.88-0.98(m,6H),0.99-1.07(m,4H),1.16-1.19(m,9H),1.19-1.26(m,1H),1.40-1.52(m,9H),1.63-1.87(m,7H),1.91-1.96(m,1H),2.16-2.24(m,2H),2.46(s,1H),2.77(d,J=13.2Hz,1H),3.08-3.12(m,1H),3.78(s,6H),4.86(s,1H),5.61(s,1H)。
实施例50(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(乙氧基羰基)哌啶-1-基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(88-2)
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(烯丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸二苯甲基酯(82-1)的合成。向250-mL圆底烧瓶里放入76-1(2.3g,3.61mmol,1.00当量)、THF(5mL)、NaHMDS(在THF中2M)(3.61mL,2.00当量)、3-溴丙-1-烯(870mg,7.19mmol,2.00当量)、TBAI(667mg,0.50当量)。将所得溶液在50℃下搅拌5h。将所得溶液用100mL EA稀释。将所得混合物用2x50 mL H2O洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:50)的硅胶柱上。这样得到1.37g(56%)的82-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-10-(环氧乙烷-2-基甲氧基)-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸二苯甲基酯(82-2)的合成。向250-mL圆底烧瓶里放入82-1(1.37g,2.02mmol,1.00当量)在DCM(10mL)中的溶液。接着伴随搅拌滴加m-CPBA(1.75g,10.14mmol,5.00当量)在DCM(10mL)中的溶液。将所得溶液在30℃下搅拌过夜。然后通过添加15mL的3M氢氧化钠淬灭反应。将所得混合物在真空下浓缩。将所得溶液用3x150 mLEtOAc萃取并合并有机层。将所得混合物用1x100 mL水和1x100 mL盐水洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。将残留物施加到具有DCM/EtOAc(50:1)的硅胶柱上。合并收集的级分并在真空下浓缩。这样得到1.1g(78%)的82-2,为白色固体。
1-(3-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((二苯甲基氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氧基)-2-羟丙基)哌啶-4-羧酸乙酯(88-1)的合成。在70℃下加热82-2(430mg,0.62mmol)和异哌啶酸酯(340mg)在THF(6.0mL)和水(1.0mL)中的溶液。2.5小时后,将反应混合物真空浓缩,并直接用于下一步。在一大气压的H2下搅拌88-1(0.62mmol)和湿10%Pd/C(~50%水,100mg湿重)在THF(4.0mL)和MeOH(4.0mL)中的混合物。2小时后,通过快速色谱法(4g SiO2,0-15%MeOH/DCM)纯化最终产物,得到标题化合物。MS(ES,m/z):684.2[M+H]+;1H-NMR(CDCl3)δ5.68(s,1H),4.14(quar,J=7.0Hz,2H),3.95(m,1H),3.67-3.55(m,1H),3.36-3.25(m,1H),3.08-2.92(m,2H),2.33(s,1H),1.36(s,3H),1.25(t,J=7.0Hz,3H),1.20(s,3H),1.13(s,3H),1.12(s,3H),0.98(s,3H),0.82(s,3H),0.79(s,3H)。
实施例51(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((羧甲基)氨基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(94-2)
10-(3-(2-(苄氧基)-2-氧代乙基氨基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-二苯甲基酯(94-1)的合成。将82-2(30mg 0.043mmol)、甘氨酸苄酯(14mg,0.086mmol)和三氟甲基磺酸钙(5mg,0.014mmol)在乙腈(0.5mL)中的混合物在80℃下加热2小时,然后冷却到RT过夜。然后将反应混合物在80℃下加热2小时,添加到5%Na2CO3(5mL)中,并用DCM(4x 10mL)萃取。将合并的萃取物干燥(Na2SO4)并浓缩,得到粗中间体(57mg)。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((羧甲基)氨基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(94-2)的合成。将来自步骤1的粗94-1(57mg)和湿10%Pd/C(50%水,10mg湿重)在MeOH(1mL)和THF(1mL)中的混合物在1atm的H2下搅拌2天。将混合物过滤,浓缩并通过制备型HPLC纯化,得到标题化合物的TFA盐(2.5mg),为白色粉末。MS(ES,m/z):602.2[M+H]+
实施例52(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((羧甲基)(甲基)氨基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(95-2)
10-(3-((2-叔丁氧基-2-氧代乙基)(甲基)氨基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-二苯甲基酯(95-1)的合成。将82-2(40mg,0.058mmol)和叔丁基肌氨酸(46mg,0.32mmol)在THF(0.50mL)和水(0.10mL)中的溶液在65℃下加热5小时。将反应物浓缩至干并通过快速色谱法(4g SiO2,0-5%MeOH/DCM)纯化,得到标题化合物(47mg)。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((羧甲基)(甲基)氨基)-2-羟基丙氧基)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(95-2)的合成。将三氟乙酸(0.30mL)缓慢添加到95-1(47mg,0.056mmol)在DCM(0.30mL)中的溶液中。4.5小时后,添加庚烷(10mL)并将混合物浓缩至干。对粗产物4进行LCMS显示产物含有~10%的内酯。MS(ES,m/z):616.3[M+H]+;1H-NMR(DMSO,d6)δ5.41(s,1H),4.01(br s,2H),3.57(dd,J=10.0Hz,J=4.7Hz,0.5H),3.45(dd,J=9.6Hz,J=6.1Hz,0.5H),3.30-3.05(m,2H),2.84(s,3H),2.80(m,1H),2.66(d,J=13.3Hz,1H),2.34(s,1H),2.13-2.04(m,2H),1.35(s,3H),1.10(s,3H),1.04(s,6H),0.95(s,3H),0.76(s,1H),0.73(s,3H)。
实施例53 1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)-1-氧代-5,8,11-三氧杂-2-氮杂十四烷-14-酸(110-3)
1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)-1-氧代-5,8,11-三氧杂-2-氮杂十四烷-14-酸叔丁酯(110-1)的合成。向250-mL圆底烧瓶里放入1-7(515mg,0.85mmol,1.00当量)、DCM(50mL)、3-2-[2-(2-氨基乙氧基)乙氧基]乙氧基丙酸叔丁酯(589mg,2.12mmol,2.50当量)、TEA(0.885mL,7.50当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到533mg(74%)的110-1,为浅黄色固体。
1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)-1-氧代-5,8,11-三氧杂-2-氮杂十四烷-14-酸(110-2)的合成。向250-mL圆底烧瓶里放入110-1(533mg,0.63mmol,1.00当量)、DCM(15mL)、三氟乙酸(15mL)。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。将所得混合物用2x10mL二***洗涤。这样得到497mg(100%)的110-2,为浅黄色粗油状物。
1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)-1-氧代-5,8,11-三氧杂-2-氮杂十四烷-14-酸(110-3)的合成。向用H2(1atm)惰性气氛吹扫并保持的50-mL圆底烧瓶里放入110-2(150mg,1当量)、THF(10mL)、Pd/C(15mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(42%ACN,8分钟内达到60%);检测器,UV 254nm。这样得到65.8mg(49.5%)的110-3,为白色固体。MS(ES,m/z):[M+H]+=702.40;1H NMR(400MHz,MeOH-d4,ppm):δ0.86(s,3H),0.88(s,1H),0.94(s,3H),0.99-1.11(m,5H),1.17(s,3H),1.19(s,3H),1.21(s,3H),1.21(d,J=7.3Hz,1H),1.35-1.55(m,9H),1.61-2.08(m,8H),2.10-2.29(m,2H),2.52(s,1H),2.57(t,J=6.4Hz,2H),2.80(d,J=13.6Hz,1H),3.34-3.47(m,2H),3.55(t,J=5.4Hz,2H),3.60-3.69(m,8H),3.76(t,J=6.4Hz,2H),5.60(s,1H)。
实施例54(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((3-氧代-2,6,9,12-四氧杂十四烷-14-基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(113-2)
1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)-1-氧代-5,8,11-三氧杂-2-氮杂十四烷-14-酸甲酯(113-1)的合成
向250-mL圆底烧瓶里放入110-2(508mg,0.64mmol,1.00当量)、DCM(15mL)、MeOH(15mL)。接着伴随搅拌在0℃下滴加在正己烷(2M)中的TMSCHN2(0.96mL,3.00当量)。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。这样得到517mg(100%)的113-1,为黄色粗固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((3-氧代-2,6,9,12-四氧杂十四烷-14-基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(113-2)的合成。向用H2(1atm)惰性气氛吹扫并保持的250-mL圆底烧瓶里放入113-1(517mg,1当量)、MeOH(10mg)、THF(10mg)、Pd/C(52mg)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(48%B相,8分钟内达到68%);检测器,UV 254nm。这样得到29.6mg(6.45%)的113-2,为白色固体。MS(ES,m/z):[M+H]+=716.45;1H NMR(400MHz,MeOH-d4,ppm):δ0.86(s,3H),0.88(s,1H),0.94(s,3H),0.97-1.11(m,5H),1.17(s,3H),1.19(s,3H),1.21(s,3H),1.28(d,J=13.8Hz,1H),1.34-1.55(m,9H),1.63-1.81(m,3H),1.82-2.09(m,5H),2.10-2.25(m,2H),2.49(s,1H),2.58(t,J=6.2Hz,2H),2.78(d,J=13.6Hz,1H),3.32-3.35(m,1H),3.36-3.44(m,1H),3.53(t,J=5.2Hz,2H),3.60(s,8H),3.67(s,3H),3.74(t,J=6.2Hz,2H),5.58(s,1H)。
实施例55(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((12-氧代-2,5,8,11-四氧杂十四烷)磺酰氨基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(114-2)
3-(N-((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-3-基)氨磺酰基)丙酸(112-1)的合成。将在THF和水中的72-1(200mg,0.282mmol)和一水合氢氧化锂(13.0mg,0.309mmol)在室温下搅拌4小时。将反应物用6NHCl酸化,在真空下部分蒸发,用水稀释并用DCM萃取。将萃取物干燥(Na2SO4)并蒸发,得到0.195g(99%)112-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((12-氧代-2,5,8,11-四氧杂十四烷)磺酰氨基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(114-1)的合成。向100-mL圆底烧瓶里放入112-1(200mg,0.29mmol,1当量)、DMF(20mL)、2-[2-(2-甲氧基乙氧基)乙氧基]乙-1-醇(190mg,1.16mmol,4.03当量)、EDCI(140mg,0.73mmol,2.54当量)、DMAP(210mg,1.72mmol,5.98当量)。将所得溶液在65℃下搅拌过夜。将所得溶液用200mL EtOAc萃取。将所得混合物用1x200 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。这样得到100mg(41.3%)的114-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((12-氧代-2,5,8,11-四氧杂十四烷)磺酰氨基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(114-2)的合成。向100-mL圆底烧瓶里放入114-1(100mg,0.12mmol,1当量)、THF(5mL)、EA(10mL)、Pd/C(20mg,0.19mmol,1.583当量)。向上述***中引入H2(g,1atm)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(54%B相,8分钟内达到67%);检测器,UV254nm。这样得到7.9mg(8.9%)的114-2,为白色固体。MS(ES,m/z):[M+H]+=752.35;1H NMR(400MHz,MeOH-d4,ppm):δ0.78-0.94(m,7H),0.95-1.24(m,15H),1.53-2.07(m,9H),2.08-2.28(m,2H),2.52(s,1H),2.70-2.90(m,3H),2.97-3.11(m,2H),3.35-3.45(m,5H),3.52-3.62(m,3H),3.63-3.72(m,9H),3.73-3.86(m,2H),4.20-4.32(m,2H),5.60(s,1H),7.25(d,J=12.8Hz,1H)。
实施例56(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(4-氧代-2,8,11,14-四氧杂-5-氮杂十五烷酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,2,12a,12b,13,14b-二十氢苉-2-羧酸(115-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,10-二羧酸2-苄酯10-(12-氧代-2,5,8-三氧杂-11-氮杂十三烷-13-基)酯(115-1)的合成。向200-mL圆底烧瓶里放入13-2(200mg,0.31mmol,1当量)、DCM(10mL,0.12mmol)、DMAP(18mg,0.15mmol,0.477当量)、EDCI(116mg,0.61mmol,1.957当量)、1-[2-(2-氨基乙氧基)乙氧基]-2-甲氧基乙烷(59mg,0.36mmol,1.169当量)。将所得溶液在室温下搅拌过夜。将所得混合物浓缩。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到200mg(81.67%)115-1,为白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-(4-氧代-2,8,11,14-四氧杂-5-氮杂十五烷酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(115-2)的合成。向用H2(1atm)惰性气氛吹扫并保持的100-mL圆底烧瓶里放入115-1(200mg,0.25mmol,1当量)、MeOH(10mL,0.31mmol,1.236当量)、Pd/C(20mg,0.19mmol,0.744当量)。将所得溶液在室温下搅拌过夜。将所得混合物浓缩。采用以下条件(2#-AnalyseHPLC-SHIMADZU(HPLC-10))通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(53%B相,8分钟内达到68%);检测器,UV254nm。这样得到39.3mg(22.17%)的115-2,为白色固体。MS(ES,m/z):[M+H]+=702.50;1NMR-PH-RDX-013-585-0:(400MHz,MeOH-d4,ppm):δ0.81-0.94(m,7H),1.09-1.18(m,5H),1.19-1.21(m,9H),1.22-1.26(m,1H),1.43-1.74(m,12H),1.76-2.01(m,4H),2.15-2.24(m,2H),2.38(d,J=12.8Hz,1H),2.53(s,1H),2.81(d,J=13.2Hz,1H),3.33-3.34(m,3H),3.35-3.43(m,2H),3.56-3.67(m,10H),4.70(AB q,J=11.6Hz,2H),5.60(s,1H)。
实施例57(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-羟基-9-(甲氧基羰基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(123-2)
(2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(乙酰氧基亚氨基)-9-(乙酰氧基甲基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(120-2)的合成。向250-mL圆底烧瓶里放入120-1(如Bioorg.Med.Chem.2010,18,433-454中所述由109-1制备)(1.0g,1.7mmol,1.00当量)、AcOH(100mL)、Na2PdCl4(0.76g,2.04mmol,1.20当量)、NaOAc(0.21g,1.36mmol,0.80当量)。将混合物在室温(~15-20℃)下搅拌72h。然后将其倒在冰上。几小时后,通过过滤收集沉淀,将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物在真空下浓缩。然后添加DCM(120mL)、乙酸酐(0.435g,3.24mmol,1.80当量)、TEA(0.364g,2.72mmol,1.60当量)和DMAP(6mg,0.02当量)。将所得溶液在室温下搅拌1h。将所得混合物用1x300 mL水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物在真空下浓缩。添加吡啶(0.6mL)、THF(100mL),并将溶液在室温下搅拌15分钟。冷却到-78℃后,缓慢添加溶解在AcOH(100mL)中的Pb(OAc)4(4.9g,8.5mmol,5当量)。添加完成后,使混合物升至室温,然后在室温下搅拌16h。添加NaBH4(60mg)在1N NaOH水溶液(50mL)中的溶液,并继续搅拌10分钟。将混合物通过硅藻土过滤。将所得溶液用300mL DCM萃取并合并有机层。将所得混合物用3x300 mL饱和NaHCO3和2x300 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物在真空下浓缩。这样得到1.03g(88%,粗品)的120-2,为浅黄色固体。
(2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(羟基亚氨基)-9-(羟甲基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(120-3)的合成。向250-mL圆底烧瓶里放入120-2(1.03g,1.53mmol,1.00当量)、MeOH(120mL)、碳酸钠(820mg,7.74mmol,5.00当量)。将所得溶液在室温下搅拌16h。将所得混合物在真空下浓缩。将所得溶液用200mL DCM萃取并合并有机层。将所得混合物用2x200 mL碳酸氢钠和1x200 mL盐水洗涤。将固体在烘箱中减压干燥。将固体滤出。将所得混合物在真空下浓缩。这样得到1.1g(粗品)的120-3,为黄色固体。
(2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(羟甲基)-2,4a,6a,6b,9,12a-六甲基-10,13-二氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(120-4)的合成。向250-mL圆底烧瓶里放入NH4OAc(3.88g,27.00当量)、水(80mL)、TiCl3(4mL)。接着伴随搅拌在15分钟内滴加120-3(1.1g,1.87mmol,1.00当量)在THF(70mL)中的溶液。向此中添加THF(70mL)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。将所得溶液用200mL DCM萃取并合并有机层。将所得混合物用1x200 mL碳酸氢钠和1x 200mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物在真空下浓缩。将残留物施加到具有EtOAc/石油醚(1:1)的硅胶柱上。这样得到190mg(18%)的120-4,为白色固体。
(2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-羟基-9-(羟甲基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(121-1)的合成。向100-mL圆底烧瓶里放入120-4(150mg,0.26mmol,1.00当量)、MeOH(20mL)、NaBH4(40mg,1.06mmol,4.00当量)。将所得溶液在室温下搅拌1h。然后通过添加5mL水淬灭反应。将所得混合物在真空下浓缩。将所得溶液用100mLDCM萃取并合并有机层。将所得混合物用x mL和1x100 mL盐水洗涤。将混合物经无水硫酸钠干燥。这样得到140mg(93%)的121-1,为白色固体。
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-甲酰基-10-羟基-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(122-1)的合成。向100-mL圆底烧瓶里放入121-1(300mg,0.52mmol,1.00当量)、DCM(25mL)、PH 8.6缓冲液(5mL)、TEMPO(240mg,1.54mmol,3.00当量)、TBACl(0.36g,2.50当量)、NCS(280mg,2.10mmol,4.00当量)。将所得溶液在40℃下搅拌过夜。将所得溶液用200mL DCM萃取并合并有机层。将所得混合物用1x200 mL水和1x200 mL盐水洗涤。将混合物经无水硫酸钠干燥。这样得到0.4g(134%,粗品)的122-1,为黄色半固体。
(3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((苄氧基)羰基)-3-羟基-4,6a,6b,8a,11,14b-六甲基-14-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-二十氢苉-4-羧酸(122-2)的合成。向250-mL圆底烧瓶里放入122-1(400mg,0.70mmol,1.00当量)、叔丁醇(12mL)、水(6mL)、2-甲基丁-2-烯(2mL)、NaH2PO4(0.5g,6.00当量)、NaClO2(0.38g,6.00当量)。将所得溶液在-2℃下搅拌30分钟。将所得混合物在真空下浓缩。将所得溶液用200mL DCM萃取并合并有机层。将所得混合物用1x200 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物在真空下浓缩。这样得到0.758g(184%,粗品)的122-2,为黄色半固体。
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-羟基-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2,9-二羧酸2-苄酯9-甲酯(123-1)的合成。向100-mL圆底烧瓶里放入122-2(500mg,0.85mmol,1.00当量)、DCM(10mL)、MeOH(10mL)、TMSCH2N2(5mL,10.00当量)。将所得溶液在室温下搅拌1h。将所得混合物在真空下浓缩。将所得溶液用200mL DCM萃取并合并有机层。将所得混合物用1x200 mL水和1x200 mL盐水洗涤。将混合物经无水硫酸钠干燥。将固体滤出。将所得混合物在真空下浓缩。这样得到0.6g(117%,粗品)的123-1,为黄色半固体。
(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-羟基-9-(甲氧基羰基)-2,4a,6a,6b,9,12a-六甲基-13-氧代-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(123-2)的合成。向100-mL圆底烧瓶里放入123-1(600mg,0.99mmol,1.00当量)、EtOAc(20mL)、碳载钯(0.12g,0.20当量)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌过夜。将固体滤出。将所得混合物在真空下浓缩。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(48.0%ACN,8分钟内达到62.0%);检测器,UV 254nm。这样得到29.7mg(6%)的123-2,为白色固体。MS(ES,m/z):[M+H]+=515.30;1H NMR(400MHz,MeOH-d4,ppm):δ0.75(s,3H),0.88-1.01(m,2H),1.02-1.18(m,14H),1.28-1.39(m,7H),1.43(d,J=11.6Hz,1H),1.48-1.59(m,2H),1.60-1.70(m,3H),1.71-1.92(m,3H),2.01-2.22(m,2H),2.53(s,1H),2.79(dt,J=13.6,3.5Hz,1H),3.64(s,3H),3.87(dd,J=11.8,4.7Hz,1H),5.54(s,1H)。
实施例58(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-氧代-2-(((R)-奎宁环-3-基)氧基)乙基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(124-2)
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-氧代-2-(((R)-奎宁环-3-基)氧基)乙基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸苄酯(124-1)的合成。向50-mL圆底烧瓶里放入29-1(100mg,0.15mmol,1.00当量)、甲苯(10mL)、(3R)-1-氮杂双环[2.2.2]辛-3-醇(60mg,0.47mmol,3.00当量)、异丙醇钛(IV)(0.14mL,3.00当量)。将所得溶液在110℃下搅拌过夜。将所得混合物在真空下浓缩。将残留物施加到具有DCM/MeOH(5:1)的硅胶柱上。这样得到20mg(17%)的124-1,为灰白色固体。
(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-七甲基-13-氧代-10-((2-氧代-2-(((R)-奎宁环-3-基)氧基)乙基)氨基甲酰基)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-二十氢苉-2-羧酸(124-2)的合成。向100-mL圆底烧瓶里放入124-1(45mg,0.06mmol,1.00当量)、MeOH(20mL)、碳载钯(10mg)。向上述***中引入氢(1atm)。将所得溶液在室温下搅拌1h。将固体滤出。采用以下条件通过制备型HPLC纯化粗产物:柱,XBridge Shield RP18 OBD柱,5um,19*150mm;流动相,水(0.05%TFA)和ACN(30.0%ACN,8分钟内达到56.0%);检测器,UV 254/220nm。这样得到11.6mg(29%)的124-2,为白色固体。MS(ES,m/z):[M+H]+=665.45;1H NMR(300MHz,MeOH-d4,ppm):δ0.84(s,3H),0.87(s,1H),0.92(s,3H),0.96-1.01(m,2H),1.07(s,3H),1.16(s,3H),1.17(s,3H),1.19(s,3H)1.23-1.29(m,1H),1.40-1.53(m,8H),1.63-1.76(m,3H),1.79-2.32(m,11H),2.38(s,1H),2.50(s,1H),2.80(dt,J=13.5Hz,3.3Hz,1H),3.33-3.40(m,6H),3.70-3.79(m,1H),3.88(d,J=17.3Hz,1H),3.99(d,J=17.3Hz,1H),5.10-5.17(m,1H),5.58(s,1H)。
实施例59 HSD2活性
根据Sato等人Gastroenterology.2011年11月;141(5):1762-72的方法将人降结肠上皮干细胞作为3D器官样物质培养。使用TrypLE Express(life technologies)分离器官样物质,并涂铺在含有100ng/mL Wnt3A(W)、50ng/mL EGF(E)、100ng/mL头蛋白(N)、500ng/mL RSpondin1(R)、500nM A83-01(A)和2.5uM thiazovivin(T)的补充基础培养基(SBM-含有10mM HEPES、1:100Glutamax、1:100青霉素/链霉素、1:100N2、1:50B27、1mM N-乙酰半胱氨酸、10nM[Leu15]-胃泌素I的高级DMEM/F12)中的96孔transwell(corning)上。在第3天使用含有ENRA和30nM醛固酮的SBM使培养物分化,并在第6或第7天使用培养物进行测定。将化合物在DMSO中稀释,并通过在DMSO中滴定来制备系列稀释液。然后将化合物稀释到DMEM/F12中。将含有降结肠培养物的Transwell板用DMEM/F12洗涤两次,并将化合物添加到顶端隔室中。将细胞与测试化合物一起在37℃、5%CO2下温育30分钟以在整个细胞膜中达到平衡。准备第二化合物板,其中将在DMSO中连续稀释的化合物稀释到含有40nM皮质醇的DMEM/F12中。在30分钟的预温育步骤后,抽吸顶端培养基,并将在具有40nM皮质醇的DMEM/F12中稀释的化合物添加到transwell的顶面。然后将板在37℃、5%CO2下温育四小时。如制造商(Cisbio)所述使用皮质醇HTRF测定试剂盒测量皮质醇水平。然后绘制浓度-响应曲线,并采用最小二乘法非线性回归确定IC50值。
实施例60稳定性测定
在Agilent 6410三重四极LC-MS***上分析样品,该***由配备PhenomenexGemini 5μm柱(NX-C18,110A,30x2 mm)的Agilent1260LC和带有在正电离模式下运行的电喷雾接口的质谱仪组成。流动相为在水中的0.1%甲酸和在乙腈中的0.1%甲酸。
血浆稳定性-将从雄性大鼠或人汇集的血浆(购自BioreclamationIVT,LLC)预温热至37℃。然后将化合物添加到血浆样品中,使最终浓度达到1μM并涡旋。在时间0、10、20、30和60分钟各自取出100μL重复样品用于提取和分析。通过添加含有500ng/mL内标(拉贝洛尔)的300μL乙腈、涡旋并离心进行母体药物的提取和分析。将150μL上清液添加到100μL去离子水中,并将10μL注射到LC/MS上。
肝S9匀浆稳定性-将从雄性大鼠或人汇集的肝S9匀浆(购自Xenotech,LLC,20mg蛋白质/mL)用0.05M KH2PO4(pH 7.4)缓冲液稀释至0.8mg蛋白质/mL并预温热至37℃。然后将化合物添加到匀浆样品中,使最终浓度达到1μM并涡旋。在时间0、5、15、30和120分钟各自取出100μL重复样品用于提取和分析。通过添加含有100ng/mL内标(拉贝洛尔)的300μL乙腈、涡旋并离心进行母体药物的提取和分析。将150μL上清液添加到100μL去离子水中,并将10μL注射到LC/MS上。
肝微粒体稳定性-将从雄性大鼠或人汇集的肝微粒体(购自Xenotech,LLC,20mg蛋白质/mL)用含有5mM MgCl2的0.05M KH2PO4(pH 7.4)缓冲液稀释至0.5mg蛋白质/mL并预温热至37℃。然后将化合物添加到匀浆样品中,使最终浓度达到1μM并涡旋。然后添加在0.05MKH2PO4(pH 7.4)缓冲液中的NADPH,使最终浓度达到2mM以使反应开始。在时间0、3、6、10、15、20和30分钟各自取出100μL重复样品用于提取和分析。通过添加含有100ng/mL内标(拉贝洛尔)的100μL乙腈、涡旋并离心进行母体药物的提取和分析。将10μL上清液注射到LC/MS上。采用不添加NADPH进行温育作为实验对照。
盲肠-结肠提取物稳定性-使雌性大鼠(未禁食)安乐死,取出盲肠和结肠并称重。用20mL去离子水冲出盲肠和结肠中的肠内含物,并对组织重新称重。将去离子水添加到盲肠-结肠内含物混合物中进行10X w/v稀释。然后通过Polytron均化器将混合物均化2分钟,并在Beckman Allegra 25r离心机中以5000rpm离心10分钟。将上清液取出,并在摇动的水中温热至37℃。然后将1.5mL等分试样添加到化合物中,使最终浓度达到1μM并涡旋。在时间0、10、20、40、60和180分钟各自取出100μL重复样品用于提取和分析。通过添加含有500ng/mL内标(拉贝洛尔)的300μL乙腈、涡旋并离心进行母体药物的提取和分析。将150μL上清液添加到100μL去离子水中,并将10μL注射到LC/MS上。
Claims (24)
1.一种式I的化合物或其盐:
其中,
X是键、-O-、-C(O)-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;
V是-C(O)O-、-C(O)N(R5)-、-C(O)N(R5)O-、-NH-C(O)-N(R5)-或NH-S(O)n-;
L是键、亚烷基,其中所述亚烷基的一个或多个非相邻的亚甲基被-O-置换;二价芳基或二价杂芳基;或者L是亚烷基-Y-亚烷基,其中Y是O、NRx、S、SO、SO2或二价杂环;其中所述亚烷基任选被OH、-C(O)O-R1、烷基或被OH或-C(O)O-R1取代的烷基取代;且其中所述亚烷基的碳和Rx任选一起形成杂环;条件是当X不是键时,则L不是键;
R1是任选被卤素、OH、氨基、氧代基、羧基、酰氧基、烷氧基羰基、烷氧基酰氧基、烷氧基羰氧基、氨基羰基取代的烷基,任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环,和任选被烷基、氧代基、氨基和卤素取代的杂环;以及任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环或杂环;其中任何前述烷基中的一个或多个非相邻的亚甲基被O置换;
R2是H或R1;
R3缺失、是Me;条件是当-X-L-C(O)O-R1取决于R3所依赖的碳时,则R3缺失;或者R3是-Z-L-C(O)O-R1,其中Z是键、-O-、-N(Rx)-、-C(O)N(Rx)-、-N(Rx)-C(O)-、-S(O)n-N(Rx)-或-N(Rx)-S(O)n-;且
R4缺失、是H或OH;条件是当-X-L-C(O)O-R1取决于R4所依赖的碳时,则R4是H或缺失;
R5是H或烷基;
Rx是H、-C(O)O-R1或任选被-C(O)O-R1取代的烷基;且
n是1或2。
3.如权利要求1或权利要求2所述的化合物或盐,其中X是键。
4.如权利要求1或权利要求2所述的化合物或盐,其中L是键。
5.如权利要求1或权利要求2所述的化合物或盐,其中X和L都是键。
6.如权利要求1至5中任一项所述的化合物或盐,其中R2是H。
7.如权利要求1至6中任一项所述的化合物或盐,其中R3是H。
8.如权利要求1至7中任一项所述的化合物或盐,其中R4是H。
9.如权利要求1至2和6至8中任一项所述的化合物盐,其中X缺失,且L是芳基或杂芳基。
10.如权利要求9所述的化合物或盐,其中L是苯基、***或异噁唑。
11.如权利要求10所述的化合物或盐,其中R3是氢。
12.如权利要求11所述的化合物或盐,其中R2和R4各自是H。
13.如权利要求1至2和6至8中任一项所述的化合物或盐,其中X是O。
14.如权利要求1至2和6至8中任一项所述的化合物或盐,其中X是-C(O)-。
15.如权利要求1至14中任一项所述的化合物或盐,其中R1是任选被卤素、OH、氨基、氧代基、羧基、酰氧基、烷氧基羰基、烷氧基酰氧基、烷氧基羰氧基、氨基羰基取代的烷基,任选被烷基、卤代烷基、氧代基、氨基和卤素取代的碳环,和任选被烷基、氧代基、氨基和卤素取代的杂环;以及任选被烷基、卤代烷基、氧代基、氨基和卤素取代的杂环;其中所述烷基中的一个或多个非相邻的亚甲基被O置换。
16.如权利要求15所述的化合物或盐,其中R1是甲基、丙基、羟乙基、2,2,2-三氟乙基、1,1-三氟甲基乙基、2-吗啉代乙基、2-(1H-咪唑-1-基)乙基、2-(吡啶-2-基)乙基、-CH2-C(O)OH、-CH2-C(O)O-Me、-CH2-C(O)NH2、-CH2-C(O)NMe2、-CH2-C(O)O-叔丁基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基、(新戊酰氧基)甲基、((异丙氧基羰基)氧基)甲基、(S)-1-((异丙氧基羰基)氧基)乙基、(R)-1-((异丙氧基羰基)氧基)乙基、2-吗啉代-2-氧代乙基、2-(4-甲基哌嗪-1-基)-2-氧代乙基或(R)-奎宁环-3-基。
17.如权利要求15所述的化合物或盐,其中R1是甲基。
18.一种抑制皮质醇通过HSD2向皮质酮转化的方法,所述方法包括使HSD2与如权利要求1至17中任一项所述的化合物或其药学上可接受的盐接触。
19.一种治疗由皮质醇通过HSD2向皮质酮转化介导的疾病或疾患的方法,所述方法包括对所述哺乳动物施用有效量的如权利要求1至17中任一项所述的化合物或其药学上可接受的盐。
20.一种促进钾离子向哺乳动物的结肠腔中分泌的方法,所述方法包括对所述哺乳动物施用有效量的如权利要求1至17中任一项所述的化合物或其药学上可接受的盐。
21.一种治疗哺乳动物的高钾血症的方法,所述方法包括对所述哺乳动物施用有效量的如权利要求1至17中任一项所述的化合物或其药学上可接受的盐。
22.一种药物组合物,所述药物组合物包含如权利要求1至17中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
23.如权利要求1至17所述的化合物或其药学上可接受的盐在制造用于治疗由HSD2介导的疾患、疾病或病症的药物中的用途。
24.如权利要求1至17所述的化合物或其药学上可接受的盐在制造用于治疗高钾血症的药物中的用途。
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US201762541095P | 2017-08-04 | 2017-08-04 | |
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PCT/US2018/045421 WO2019060051A1 (en) | 2017-08-04 | 2018-08-06 | GLYCYRRHETINIC ACID DERIVATIVES FOR THE TREATMENT OF HYPERKALIEMIA |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1723022A (zh) * | 2002-10-24 | 2006-01-18 | 斯特里克斯有限公司 | 11-β-羟基类固醇脱氢酶1型和2型抑制剂 |
US20100087413A1 (en) * | 2003-09-22 | 2010-04-08 | Thomas Wilckens | Prevention and treatment of inflammation-induced and/or immune-mediated bone loss |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2714880A1 (de) | 1977-04-02 | 1978-10-26 | Hoechst Ag | Cephemderivate und verfahren zu ihrer herstellung |
US5519008A (en) * | 1992-09-10 | 1996-05-21 | Glycomed Incorporated | Derivatives of triterpenoid acids as inhibitors of cell-adhesion molecules ELAM-1 (E-selectin) and LECAM-1 (L-selectin) |
EP0612723B1 (de) | 1993-02-20 | 1997-08-27 | Hoechst Aktiengesellschaft | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, als Inhibitoren des zellulären Na+/H+-Austauschs oder als Diagnostikum sowie sie enthaltendes Medikament |
IL109570A0 (en) | 1993-05-17 | 1994-08-26 | Fujisawa Pharmaceutical Co | Guanidine derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof |
DE19518796A1 (de) | 1995-05-22 | 1996-11-28 | Hoechst Ag | Fluorphenylsubstituierte Alkenylcarbonsäure-guanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE19548812A1 (de) | 1995-12-27 | 1997-07-03 | Hoechst Ag | Verwendung von Inhibitoren des zellulären Na·+·/H·+·-Exchangers (NHE) zur Herstellung eines Medikaments zur Atemstimulation |
DE19633966A1 (de) | 1996-08-22 | 1998-02-26 | Hoechst Ag | Phenylsubstituierte Alkenylcarbonsäure-guanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
AU9001698A (en) * | 1997-09-11 | 1999-03-29 | Snow Brand Milk Products Co., Ltd. | Remedies for hormone-dependent diseases |
DE19945302A1 (de) | 1999-09-22 | 2001-03-29 | Merck Patent Gmbh | Biphenylderivate als NHE-3-Inhibitoren |
US6887870B1 (en) | 1999-10-12 | 2005-05-03 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
DE10015248A1 (de) | 2000-03-28 | 2001-10-04 | Merck Patent Gmbh | Bisamidino-Verbindungen als NHE-3 Inhibitoren |
DE10019062A1 (de) | 2000-04-18 | 2001-10-25 | Merck Patent Gmbh | 2-Guanidino-4-aryl-chinazoline als NHE-3 Inhibitoren |
DE10043667A1 (de) | 2000-09-05 | 2002-03-14 | Merck Patent Gmbh | 2-Guanidino-4-aryl-chinazoline |
DE10046993A1 (de) | 2000-09-22 | 2002-04-11 | Aventis Pharma Gmbh | Substituierte Zimtsäureguanidide, Verfahren zur ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltendes Medikament |
DE10063294A1 (de) | 2000-12-19 | 2002-07-04 | Aventis Pharma Gmbh | Substituierte Heterocyclo-Norbornylamino-Derivate, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US6736705B2 (en) | 2001-04-27 | 2004-05-18 | Hitachi Global Storage Technologies | Polishing process for glass or ceramic disks used in disk drive data storage devices |
US6911453B2 (en) | 2001-12-05 | 2005-06-28 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them |
DE10161767A1 (de) | 2001-12-15 | 2003-06-26 | Merck Patent Gmbh | 2-Guanidino-4-heterocyclyl-chinazoline |
US6703405B2 (en) | 2001-12-22 | 2004-03-09 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolinium salts, process for their preparation, their use as a medicament, and medicament containing them |
DE10163992A1 (de) | 2001-12-24 | 2003-07-03 | Merck Patent Gmbh | 4-Aryl-chinazoline |
US6923466B2 (en) | 2002-12-17 | 2005-08-02 | James Tsai | Collapsible handcart capable of extending the area of carrier by operating handle |
US20050054705A1 (en) | 2003-02-04 | 2005-03-10 | Aventis Pharma Deutschland Gmbh | N-substituted (benzoimidazol-2-yl) phenylamines, process for their preparation, their use as medicament or diagnostic aid, and medicament comprising them |
US20050244367A1 (en) | 2004-05-03 | 2005-11-03 | Ilypsa, Inc. | Phospholipase inhibitors localized in the gastrointestinal lumen |
DE102004046492A1 (de) | 2004-09-23 | 2006-03-30 | Sanofi-Aventis Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
DE102004054847A1 (de) | 2004-11-13 | 2006-05-24 | Sanofi-Aventis Deutschland Gmbh | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE102005044817A1 (de) | 2005-09-20 | 2007-03-22 | Sanofi-Aventis Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
MX2008005666A (es) | 2005-11-03 | 2009-03-02 | Ilypsa Inc | Compuestos multivalentes de indol y uso de los mismos como inhibidores de fosfolipasa-a2. |
EP1951315A2 (en) | 2005-11-03 | 2008-08-06 | Ilypsa, Inc. | Phospholipase inhibitors, including multi-valent phospholipase inhibitors, and use thereof, including as lumen-localized phospholipase inhibitors |
GB0604899D0 (en) | 2006-03-10 | 2006-04-19 | York Pharma Plc | Derivatives of 18-glycyrrhetinic acid |
MX345283B (es) | 2008-12-31 | 2017-01-24 | Ardelyx Inc | Compuestos y metodos para inhibir el antiporte mediado por intercambiador de iones de sodio/iones de hidrogeno (nhe) en el tratamiento de trastornos asociados con retencion de fluido o sobrecarga de sal y trastornos del tracto gastrointestinal. |
EP2228380A1 (en) | 2009-03-13 | 2010-09-15 | onepharm Research & Development GmbH | Novel triterpene derivatives |
KR101886467B1 (ko) | 2011-01-31 | 2018-08-07 | 비브 헬스케어 유케이 (넘버4) 리미티드 | Hiv 성숙 억제 활성을 갖는 c-17 및 c-3 변형 트리테르페노이드 |
KR101889528B1 (ko) | 2012-08-14 | 2018-08-17 | 넥스올리고(주) | 신규한 우르솔릭산 유도체 및 이의 제조 방법 |
CA2880338A1 (en) | 2012-08-21 | 2014-02-27 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
JP6726964B2 (ja) | 2012-08-21 | 2020-07-22 | アーデリクス,インコーポレーテッド | 体液貯留又は塩過負荷に関係する疾患及び消化管疾患の治療におけるnhe仲介の逆輸送を阻害するための化合物並びに方法 |
BR112017013264A2 (pt) | 2014-12-23 | 2018-02-27 | Ardelyx, Inc. | ?sal de cálcio de um polímero de aglutinação de potássio reticulado, polímero de aglutinação de potássio reticulado, composição farmacêutica, e, método para remover potássio do trato gastrointestinal de um paciente?. |
-
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- 2018-08-06 EP EP18759491.6A patent/EP3661945B1/en active Active
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- 2018-08-06 KR KR1020207006241A patent/KR20200074085A/ko not_active Application Discontinuation
- 2018-08-06 US US16/636,596 patent/US11768319B2/en active Active
-
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- 2020-03-03 PH PH12020500432A patent/PH12020500432A1/en unknown
-
2021
- 2021-04-29 ZA ZA2021/02866A patent/ZA202102866B/en unknown
-
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- 2023-01-24 US US18/101,009 patent/US20230273354A1/en active Pending
- 2023-02-27 JP JP2023028553A patent/JP2023054360A/ja active Pending
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1723022A (zh) * | 2002-10-24 | 2006-01-18 | 斯特里克斯有限公司 | 11-β-羟基类固醇脱氢酶1型和2型抑制剂 |
US20100087413A1 (en) * | 2003-09-22 | 2010-04-08 | Thomas Wilckens | Prevention and treatment of inflammation-induced and/or immune-mediated bone loss |
Non-Patent Citations (2)
Title |
---|
CHRISTIAN STANETTY等: "Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11b-hydroxysteroid dehydrogenase 2 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
REGISTRY: "RN 32285-33-9", 《STN COLUMBUS》 * |
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AU2018335130A1 (en) | 2020-03-19 |
PH12020500432A1 (en) | 2021-01-25 |
CA3071992A1 (en) | 2019-03-28 |
SG11202000950TA (en) | 2020-02-27 |
IL272443A (en) | 2020-03-31 |
WO2019060051A1 (en) | 2019-03-28 |
KR20200074085A (ko) | 2020-06-24 |
IL272443B2 (en) | 2024-02-01 |
BR112020002322A2 (pt) | 2020-09-01 |
US11768319B2 (en) | 2023-09-26 |
US20210163524A1 (en) | 2021-06-03 |
EP3661945B1 (en) | 2024-04-03 |
US20230273354A1 (en) | 2023-08-31 |
MX2020001412A (es) | 2020-08-03 |
AU2018335130B2 (en) | 2023-02-16 |
IL272443B1 (en) | 2023-10-01 |
MA49761A (fr) | 2020-06-10 |
EP3661945A1 (en) | 2020-06-10 |
IL306058A (en) | 2023-11-01 |
EA202090438A1 (ru) | 2020-06-15 |
JP2023054360A (ja) | 2023-04-13 |
JP2020529449A (ja) | 2020-10-08 |
ZA202102866B (en) | 2022-10-26 |
UA126584C2 (uk) | 2022-11-02 |
JP7281446B2 (ja) | 2023-05-25 |
AU2023203009A1 (en) | 2023-06-01 |
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