CN111518077A - 一种新型抗肿瘤ido抑制剂的制备方法 - Google Patents
一种新型抗肿瘤ido抑制剂的制备方法 Download PDFInfo
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- CN111518077A CN111518077A CN202010457584.0A CN202010457584A CN111518077A CN 111518077 A CN111518077 A CN 111518077A CN 202010457584 A CN202010457584 A CN 202010457584A CN 111518077 A CN111518077 A CN 111518077A
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- XHNJFNLTFMAPQB-UHFFFAOYSA-N ethyl 2-(4-oxocyclohexyl)acetate Chemical compound CCOC(=O)CC1CCC(=O)CC1 XHNJFNLTFMAPQB-UHFFFAOYSA-N 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
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- 150000003949 imides Chemical class 0.000 description 1
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- 230000008629 immune suppression Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000008975 immunomodulatory function Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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- 230000006698 induction Effects 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- LBQAJLBSGOBDQF-UHFFFAOYSA-N nitro azanylidynemethanesulfonate Chemical group [O-][N+](=O)OS(=O)(=O)C#N LBQAJLBSGOBDQF-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
本发明涉及一种新型抗肿瘤IDO抑制剂式(I)的制备方法，由该方法所制备得到的化合物具有对色氨酸代谢具有明显的抑制活性。
Description
本申请是分案申请，其母案的中国申请号是：201980004340.2，国际申请号是PCT/CN2019/071704，国际申请日是2019年01月15日。
本发明要求中国专利申请CN201810044798.8的优先权，该优先权文件的说明书、说明书附图和权利要求书所记载的内容全文引入本发明的说明书并被作为本发明说明书原始记载的一部分。申请人进一步声明，申请人拥有基于该优先权文件修改本发明的说明书和权利要求书的权利。
技术领域
本发明涉及药物领域，具体的是涉及一种新型抗肿瘤IDO抑制剂的制备方法。
背景技术
色氨酸(TRP)是一种用于蛋白质生物合成的α-氨基酸。它含有α-氨基、α-羧酸基团和侧链吲哚。它是人类必不可少的，人的身体不能合成它，而必须从饮食中获得。色氨酸也是合成神经递质5-羟色胺(serotonin)和激素N-乙酰-5-甲氧基色胺(melatonin)的前体。血红素依赖酶吲哚胺2,3-双加氧酶(也叫IDO,或IDO1)是肝外负责将色氨酸转换为N-甲酰基-犬尿氨酸的代谢酶，这是色氨酸代谢过程中的第一步，也是整个过程的限速步骤。N-甲酰基-犬尿氨酸是多种生物活性分子犬尿氨酸(kynurenine，或Kyn)的前体，犬尿氨酸具有免疫调节功能(Schwarcz et al,Nat.Rev.Neurosci.2012；13(7):465)。
吲哚胺2,3-双加氧酶(IDO)广泛表达于实体肿瘤(Uyttenhove et al,Nat.Med.2003；10:1269)，在原发癌和转移癌细胞中也均有表达。在肿瘤中IDO由促炎因子诱导产生，包括由浸润淋巴细胞产生的I型和II型干扰素(Tnani and Bayard,BiochimBiophys Acta.1999；1451(l):59；Mellor and Munn,Nat.Rev.Immunol.2004；4(10):762；Munn,Front Biosci.2012；4:734)和转化生长因子-β(TGF-β)(Pallotta et al,Nat.Immunol.2011；12(9):870)。近年来，越来越多的证据表明，IDO作为一种诱导型酶，在免疫细胞调节中起着重要作用。色氨酸水平的降低和犬尿氨酸的增加会抑制免疫效应细胞，并通过诱导和维持调节性T细胞促进适应性免疫抑制；免疫***中色氨酸的浓度和T细胞正性相关。在肿瘤免疫微环境中，活化或过表达的IDO导致色氨酸耗竭，而后导致T细胞死亡、免疫***失活，并最终导致发生肿瘤免疫耐受和免疫逃逸。现有研究表明，由IDO所导致的免疫平衡失调深入的参与了肿瘤的生成和进展。因而IDO成为肿瘤等免疫治疗的重要靶点。IDO除了和肿瘤相关外，也和病毒感染、抑郁、器官移植排斥或自身免疫性疾病相关(Johnson and Munn,Immunol.Invest.2012；41(6-7):765)。因而，靶向IDO的药物对于治疗上述疾病也具有巨大价值。总之，开发具有活性和选择性的IDO抑制剂，通过调节犬尿氨酸通道并维持身体内色氨酸水平来有效地治疗由于犬尿氨酸途径中的有害物质而产生的疾病，无论是作为单剂或联合疗法都很有必要。
大量发表的临床前数据也进一步证实了IDO在抗肿瘤免疫反应中的作用。IDO抑制剂可用于激活T细胞，因而提高T细胞被妊娠、恶性肿瘤或HIV等病毒抑制时T细胞的激活。在癌细胞中强迫IDO诱导被证明具有生存优势(Uyttenhove et al,Nat Med.2003；10:1269)。另有体内研究表明，IDO抑制剂在肿瘤生长中通过降低犬尿氨酸水平而减少对淋巴细胞的依赖(Liu et al,Blood.2010；115(17):3520)。临床前研究还表明IDO抑制剂如果与其他肿瘤药物联用，如放疗、化疗或疫苗等等具有协同效果(Koblish et al,Mol.CancerTher.2010；9(2):489；Hou et al,Cancer Res.2007；67(2):792；Sharma et al,Blood.2009；113(24):6102)。
IDO抑制剂类抗肿瘤药物的研究目前在全球范围内已取得重要进展，如INCB024360，NLG919和BMS-986205均已进入临床。但INCB024360由于存在毒副作用问题，致使现有临床研究剂量(50mg bid,或100mg bid)是最佳剂量(300mgbid,600mg bid)的30％左右，临床活性受到很大限制；同时INCB024360的毒性基团又是药效团，INCB024360及其衍生物存在毒性较大的问题。NLG919的安全性较好，但NLG919的生物活性较差。BMS-986205目前也已经进入临床，但是临床数据有限。还需要用于肿瘤治疗的更好的IDO抑制剂。
发明内容
本发明一方面提供一种如式(I)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
其中
表示：
或者
Cy1选自任选地被取代基取代的5-15元环，所述的取代基选自：卤素、羟基、C1-6烷基、氨基、卤代C1-6烷基、巯基、C1-6烷基巯基、C1-6烷基氨基、二(C1-6烷基)氨基和氰基；
Cy2选自任选地被一个、两个或更多个R2取代的C6-10元环烷基、C6-10元杂环基、C6-10元芳基或C6-10元杂芳基；优选为被一个、两个或更多个R2取代的苯基、吡啶基、环己基、哌啶基、哌嗪基、吡嗪基、嘧啶基、吗啉基；哒嗪基；
R1和R2独立地选自氢原子、卤素、羟基、硝基、氰基、磺酸基、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷基、C1-6烷基硫基、C1-6烷基羰基、C1-6烷氧基羰基、二(C1-6烷基)氨基C2-6烷氧基羰基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、氨基甲酰基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、二(C1-6烷基)氨基C2-6烷基氨基甲酰基、氨磺酰基、C1-6烷基氨磺酰基、二(C1-6烷基)氨磺酰基、二(C1-6烷基)氨基C2-6烷基氨磺酰基、C1-6烷基磺酰基、C1-6烷基亚硫酰基、二(C1-6烷基)膦酰基、羟基C1-6烷基、羟基羰基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基磺酰基C1-6烷基、C1-6烷基亚硫酰基C1-6烷基、二(C1-6烷基)膦酰基C1-6烷基、羟基C2-6烷氧基、C1-6烷氧基C2-6烷氧基、氨基C1-6烷基、C1-6烷基氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基乙酰基、氨基C2-6烷氧基、C1-6烷基氨基C2-6烷氧基、二(C1-6烷基)氨基C2-6烷氧基、羟基C2-6烷基氨基、C1-6烷氧基C2-6烷基氨基、氨基C2-6烷基氨基、C1-6烷基氨基C2-6烷基氨基、二(C1-6烷基)氨基C2-6烷基氨基；或者相邻的两个R1或R2相互环合形成3-8元环，该环中含有0-3个杂原子；
m、n为选自0、1、2、3和4的整数；
Ra、Rb各自独立地选自氢、C1-C6烷基或C3-6环烷基；
X选自CRaRb、NRe或O；
Y选自CRe或N；其中Re表示氢、C1-6烷基或者C3-6环烷基、C1-6卤代烷基。
本发明另一方面提供一种如式(II)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
其中，W1、W2、W3、W4分别独立地选自CRe、C＝O或N；p为选自0、1、2、3和4的整数；R1、R2、Cy1、Ra、Rb、Re、X、Y、m、n如式I所定义；虚线表示单键或者双键。
在本发明的一个实施方案中，Cy1选自以下基团：
其中R3选自氢、C1-C6烷基、C3-C6环烷基；
上述基团可以被一个或两个以上的选自卤素、羟基、C1-6烷基、氨基、卤代C1-6烷基、巯基、C1-6烷基巯基、C1-6烷基氨基、二(C1-6烷基)氨基、氰基的取代基所取代。
本发明一方面提供一种如式(III)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
其中，R1、R2、Ra、Rb、X、Y、W1、W2、W3、W4、m、n、p如式II所定义。
本发明一方面提供一种如式(IV)所示的化合物、其盐、溶剂合物、前药、代谢产物、氮氧化物、立体异构体或同位素衍生物：
其中Q1和Q2分别独立地选自CRaRb、NRe或O；Q3选自CRa或N；其中，R1、R2、Ra、Rb、Re、X、Y、W1、W2、W3、W4、m、p如式II所定义；
在本发明的另一个实施方案中，所述式II化合物具有如式(V)结构：
其中R1、R2、Ra、Rb、X、Y、W1、W2、W3、W4、m、p如上述式II所定义。
在本公开中，
表示
或者
在本公开中，
优选为
除非另外说明，本发明的所有化合物结构也包括其可能存在的立体异构体(包括：enantiomeric,diastereomeric,geometric,conformational,and rotational)。例如，每个手性中心的R和S构型，每个烯烃双键的E和Z异构体都包括在此发明中。对于有些可以自由旋转的键，取代基的位置也可以跟着自由转动，例如：
结构式
也同时代表：
也代表其互变异构体：
所以，一个单一的立体化学异构体，以及其对映体混合物，几何异构体混合物，构象异构体混合物，互变异构体都在本专利申请范畴。
本发明的化合物也可制备成可药用盐的形式，所述可药用盐使用例如以下的无机酸或有机酸而形成：盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸和甲苯磺酸。当提到本发明化合物时，也涵盖本发明化合物的这些可药用盐。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
设计和反应实例
本发明的化合物可参照下面说明通过所知步骤合成得到。所有购买的溶剂和试剂都未经过处理而直接使用。所有合成的化合物可以通过，但不限于以下方法分析验证：LCMS(liquid chromatography mass spectrometry，液相质谱)和NMR(nuclear magneticresonance，核磁共振)。核磁共振(NMR)由BrukerAVANCE-500核磁仪测定，测定时所用的氘代溶剂为氘代二甲基亚砜(d6-DMSO)、氘代氯仿(CDCl3)，四甲基硅烷(TMS)作为内标物。以下缩写表示各种类型的***峰：单峰(s)、双重峰(d)、三重峰(t)、多重峰(m)、宽峰(br)。质谱(MS)的测定采用Thermo Fisher-MSQ Plus液质联用仪，手性化合物的拆分用大赛璐的
AD-H手性柱(0.46cm I.D.×15cm L,HEP:ETOH(0.1％DEA)＝60:40(V/V))分离。
本发明的化合物可参照下面来制备。
通用路线一：
中间体F的合成(顺式和反式混合物、外消旋化合物)
第一步：将4-氧代环己烷乙酸乙酯(2.0g,10.86mmol)溶于60mL超干四氢呋喃中，在氮气氛和-78℃下向该溶液中滴加双(三甲基硅基)氨基钠(2mol/L四氢呋喃溶液)(6.5mL,13.03mmol)。反应液在该温度下搅拌1小时。然后加入N-苯基双(三氟甲烷磺酰)亚胺(4.65g,13.03mmol)的四氢呋喃(20mL)溶液。滴加完毕后反应混合物在室温下继续搅拌过夜直至TLC检测反应原料消耗完全。反应液用5mL硫酸氢钾水溶液淬灭，过滤除去固体，浓缩滤液。向残余液中加入50mL甲基叔丁基醚，有机层用1.0mol/L氢氧化钠溶液洗(3x20mL)，20mL饱和食盐水洗。有机层用无水硫酸钠干燥，过滤，浓缩得到中间体A(3.12g)，橘红色油状液体，收率91％。1H NMR(500MHz,CDCl3)δ5.74–5.70(m,1H),4.15(q,J＝7.0Hz,2H),2.48–2.40(m,1H),2.38–2.32(m,2H),2.30(d,J＝7.0Hz,2H),2.18–2.10(m,1H),1.97–1.89(m,2H),1.57–1.48(m,1H),1.27(t,J＝7.0Hz,3H).
第二步：将中间体A(3.12g,9.86mmol)溶于15mL二氧六环中，依次加入联硼酸频那醇酯(3.26g,12.82mmol)，醋酸钾(2.90g,29.59mmol)，溴化钠(406mg,3.95mmol)和Pd(dppf)Cl2(722mg,0.98mmol)。反应混合物在氮气氛下回流反应过夜。然后蒸干反应溶剂二氧六环，加入乙酸乙酯，用硅藻土过滤，滤液浓缩之后用快速过柱机分离得到中间体B(1.66g)，无色液体，收率57％。1H NMR(500MHz,CDCl3)δ6.54–6.48(m,1H),4.12(q,J＝6.5Hz,2H),2.30–2.02(m,7H),1.84–1.72(m,2H),1.27–1.23(m,15H).
第三步：将中间体B(1.66g,5.64mmol)溶于12mL/3mL二氧六环/水中，依次加入4-氯-6-氟喹啉(860mg,4.74mmol)，碳酸钾(1.96g,14.21mmol)和Pd(PPh3)4(274mg,0.24mmol)。反应混合物在氮气氛下回流反应过夜。然后浓缩反应液，加入50mL水稀释，用乙酸乙酯萃取(3x50mL)，有机相浓缩之后用快速过柱机分离得到中间体C(1.48g)，淡黄色液体，收率100％。MS(ESI):m/z 313.9(M+H)+.1H NMR(500MHz,CDCl3)δ8.81(d,J＝4.5Hz,1H),8.16(dd,J＝8.5,5.5Hz,1H),7.62(dd,J＝10.0,2.5Hz,1H),7.52–7.46(m,1H),7.22(d,J＝4.5Hz,1H),5.86–5.81(m,1H),4.19(q,J＝7.0Hz,2H),2.56–2.26(m,6H),2.08–1.98(m,2H),1.64–1.55(m,1H),1.30(t,J＝7.0Hz,3H).
第四步：将中间体C(1.48g,4.72mmol)溶于30mL乙醇中，加入10％钯碳(300mg)。反应混合物在氢气氛下室温搅拌过夜。然后用硅藻土滤除钯碳，浓缩滤液。残留物用快速过柱机分离得到中间体D(1.31g)，淡黄色液体，收率88％。MS(ESI):m/z 316.0(M+H)+.1H NMR(500MHz,CDCl3)δ8.84–8.79(m,1H),8.13(dd,J＝9.0,5.5Hz,1H),7.66(dd,J＝10.5,2.5Hz,1H),7.51–7.44(m,1H),7.34(d,J＝4.5Hz,1H),4.20–4.14(m,2H),3.26–3.18(m,1H),2.53–2.43(m,2H),2.31(d,J＝7.0Hz,1H),2.07–1.97(m,2H),1.90–1.70(m,5H),1.68–1.58(m,1H),1.31–1.25(m,3H).
第五步：将二异丙胺(1.54g,15.22mmol)溶于18mL四氢呋喃中。在氮气氛和-78℃条件下，向该溶液中滴加2.5M正丁基锂(6.1mL,15.22mmol)的正己烷溶液。然后滴加中间体D(2.4g,7.61mmol)的四氢呋喃(6mL)溶液。反应混合液在-78℃继续搅拌1.5小时。接着滴加碘甲烷(2.16g,15.22mmol)，反应混合液升至室温搅拌过夜。用饱和氯化铵淬灭反应，乙酸乙酯萃取(3x50mL)，合并有机相，用50mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到中间体E(1.96g)，淡黄色液体，收率78％。MS(ESI):m/z 330.5(M+H)+.1H NMR(500MHz,CDCl3)δ8.84–8.79(m,1H),8.16–8.10(dd,1H),7.66(d,J＝10.5Hz,1H),7.51–7.44(m,1H),7.35(d,J＝4.5Hz,1H),4.22–4.14(m,2H),3.32–3.23(m,1H),2.82–2.72(m,1H),2.12–1.98(m,2H),1.96–1.55(m,7H),1.32–1.24(m,3H),1.20(d,J＝6.5Hz,3H).
第六步：将中间体E(400mg,1.21mmol)溶于4mL/4mL四氢呋喃/乙醇中，加入2mL水。然后向溶液中加入氢氧化钠(243mg,6.07mmol)。反应混合物在50℃搅拌过夜，浓缩。加入3mL水稀释，用4mol/L盐酸溶液调节pH＝3，过滤得到中间体F(330mg)，白色固体，收率90％。MS(ESI):m/z 302.6(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.22(s,1H),8.81(d,J＝4.5Hz,1H),8.14–8.06(m,1H),8.01–7.94(m,1H),7.66(t,J＝8.5Hz,1H),7.52(s,1H),3.32–3.23(m,1H),2.76–2.66(m,1H),1.97–1.62(m,7H),1.61–1.51(m,1H),1.49–1.31(m,1H),1.09(d,J＝6.5Hz,3H).
通用路线二：非对称合成路线
中间体K’的非对称合成方法采用文献报道的合成方法(WO2016073774A2)
通用路线三：
第一步：将中间体F(或者K’,1.0eq)溶于N,N-二甲基甲酰胺中，加入HATU(1.1eq)和二异丙基乙胺(3.0eq)。再向反应液中加入取代的1,2-二胺或取代的邻氨基苯胺(1.5eq)。反应混合物在30℃下搅拌过夜。然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，得到粗品中间体不需要纯化直接用于下一步。
第二步：将上一步得到的粗品中间体(1.0eq)溶于醋酸中，混合物在100℃下搅拌反应19小时，然后浓缩反应液。残留物用反向高效液相制备色谱纯化得到最终化合物。
通用路线四：
第一步：将膦酰基乙酸三乙酯(968mg,4.32mmol)溶于16mL超干四氢呋喃中，在0℃冰浴下加入叔丁醇钠(415mg,4.32mmol)。10分钟后，将中间体E’(1g,4.12mmol)的四氢呋喃(4mL)溶液加入反应液中。反应2小时后，用水淬灭。水溶液用20mL乙酸乙酯萃取三次，合并有机相，用20mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用快速过柱机分离得到中间体F”(1.18g)，白色固体，收率92％。MS(ESI):m/z 314.0(M+H)+.1H NMR(500MHz,CDCl3)δ8.81(d,J＝4.5Hz,1H),8.17(dd,J＝9.0,5.5Hz,1H),7.72(dd,J＝10.0,2.5Hz,1H),7.53–7.47(m,1H),7.28(d,J＝4.5Hz,1H),5.75(s,1H),4.19(q,J＝7.0Hz,2H),3.52–3.42(m,1H),2.54–2.48(m,2H),2.26–2.11(m,4H),1.80–1.68(m,2H),1.30(t,J＝7.0Hz,3H).
第二步：将NaH(383mg,9.57mmol)加入15mL二甲基亚砜中，向该悬浊液中加入三甲基碘化亚砜(2.11g,9.57mmol)。混合物在室温下搅拌1.5小时。然后将中间体F”(1.0g,3.19mmol)的二甲基亚砜(5mL)溶液加入到反应液中。反应在室温条件下搅拌过夜。然后用水淬灭，用乙酸乙酯萃取，用快速过柱机分离得到中间体G”(820mg)，无色油状液体，收率78％。MS(ESI):m/z 328.1(M+H)+.1H NMR(500MHz,CDCl3)δ8.83(d,J＝4.5Hz,1H),8.24(dd,J＝9.0,5.5Hz,1H),7.71(dd,J＝10.0,2.5Hz,1H),7.55–7.49(m,1H),7.35(d,J＝4.5Hz,1H),4.19(q,J＝7.0Hz,2H),3.32–3.24(m,1H),2.17(td,J＝13.0,3.5Hz,1H),2.07–1.90(m,4H),1.87–1.78(m,1H),1.58(dd,J＝8.0,5.5Hz,1H),1.46–1.37(m,1H),1.30(t,J＝7.0Hz,3H),1.28–1.24(m,2H),1.16–1.11(m,1H),1.00(dd,J＝8.0,4.5Hz,1H).
第三步：将中间体G”(200mg,0.61mmol)溶于10mL乙醇中，加入4mL 2mol/L氢氧化钠溶液。反应液加热至50℃，反应2小时。待反应液冷却至室温，用4mol/L盐酸溶液中和至pH＝1。用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到中间体H”(150mg)，白色固体，产率83％。MS(ESI):m/z 300.0(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.02(br,1H),8.83(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,5.5Hz,1H),8.03(dd,J＝10.0,2.5Hz,1H),7.71–7.64(m,1H),7.38(d,J＝4.5Hz,1H),3.48–3.41(m,1H),2.21–2.13(m,1H),2.01–1.80(m,4H),1.75–1.65(m,1H),1.51(dd,J＝8.0,5.5Hz,1H),1.38–1.32(m,1H),1.11–1.05(m,1H),1.04–0.99(m,1H),0.95(dd,J＝7.5,4.0Hz,1H).
第四步：将中间体H”(1.0eq)溶于N,N-二甲基甲酰胺中，加入HATU(1.1eq)和二异丙基乙胺(3.0eq)。再向反应液中加入取代的1,2-二胺或取代的邻氨基苯胺(1.5eq)。反应混合物在30℃下搅拌过夜。然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。将得到的粗品中间体溶于醋酸中，混合物在100℃下搅拌反应19小时，然后浓缩反应液。残留物用反向高效液相制备色谱纯化得到最终化合物。
通用路线五：
第一步：在-78℃条件下，将正丁基锂(0.49mL,1.22mmol)滴加到二异丙胺(123mg,1.22mmol)的四氢呋喃(15mL)溶液中。再向其中滴加中间体G”(200mg,0.61mmol)的四氢呋喃(5mL)溶液。反应在-78℃下搅拌1小时。然后向反应液中滴加碘甲烷(173mg,1.22mmol)的四氢呋喃(2mL)溶液，反应维持在-78℃半小时后升至室温，搅拌过夜。用饱和氯化铵溶液淬灭，用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到化合物中间体H”’(121mg)，无色油状液体，产率58％。MS(ESI):m/z 342.4(M+H)+.
第二步：将中间体H”’(100mg,0.29mmol)溶于10mL乙醇中，加入2mL 2mol/L氢氧化钠溶液。反应液加热至50℃，反应2小时。待反应液冷却至室温，用4mol/L盐酸溶液中和至pH＝1。用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到中间体I”’(76mg)，白色固体，产率83％。MS(ESI):m/z 314.3(M+H)+.
第三步：将中间体I”’(1.0eq)溶于N,N-二甲基甲酰胺中，加入HATU(1.1eq)和二异丙基乙胺(3.0eq)。再向反应液中加入取代的1,2-二胺或取代的邻氨基苯胺(1.5eq)。反应混合物在30℃下搅拌过夜。然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。将得到的粗品中间体溶于醋酸中，混合物在100℃下搅拌反应19小时，然后浓缩反应液。残留物用反向高效液相制备色谱纯化得到最终化合物。
实施例1：化合物1
化合物1从中间体F(20mg)和4-氯-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。得到化合物1(10.05mg)，白色固体，收率37％。MS(ESI):m/z 408.3(M+H)+.1HNMR(500MHz,d6-DMSO)δ12.40(s,1H),8.79(d,J＝4.5Hz,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.60–7.45(m,2H),7.42(d,J＝4.0Hz,1H),7.15(d,J＝8.5Hz,1H),3.30–3.24(m,1H),2.95–2.88(m,1H),1.95(t,J＝10.5Hz,2H),1.90–1.79(m,2H),1.61–1.47(m,3H),1.45–1.32(m,5H).
实施例2：化合物17和化合物18
化合物17(反式，外消旋)和化合物18(顺式，外消旋)从中间体F(40mg)和4-氟-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物17(8.49mg)，第一个洗脱的异构体，白色固体，收率16％。MS(ESI):m/z392.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.28(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.45–7.39(m,2H),7.34(d,J＝10.0Hz,1H),7.02–6.92(m,1H),3.29–3.23(m,1H),2.93–2.87(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.33(m,5H).
得到化合物18(9.24mg)，第二个洗脱的异构体，白色固体，收率18％。MS(ESI):m/z392.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.31(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.23(d,J＝9.0Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例3：化合物21和化合物22
化合物21(反式，外消旋)和化合物22(顺式，外消旋)从中间体F(40mg)和4-甲基-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物21(11.40mg)，第一个洗脱的异构体，白色固体，收率22％。MS(ESI):m/z 388.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ11.98(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J＝10.5Hz,1H),7.65(t,J＝8.5Hz,1H),7.44–7.38(m,2H),7.20(s,1H),6.93(t,J＝9.5Hz,1H),3.30–3.23(m,1H),2.91–2.83(m,1H),2.39(s,3H),2.00–1.91(m,2H),1.89–1.78(m,2H),1.61–1.46(m,3H),1.44–1.33(m,5H).
得到化合物22(13.51mg)，第二个洗脱的异构体，白色固体，收率26％。MS(ESI):m/z 388.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.02(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝11.0Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.39(d,J＝8.5Hz,1H),7.20(s,1H),6.93(t,J＝10.0Hz,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.67–1.51(m,2H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例4：化合物13和化合物14
化合物13(反式，外消旋)和化合物14(顺式，外消旋)从中间体F(50mg)和4-氯-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物13(7.93mg)，第一个洗脱的异构体，白色固体，收率12％。MS(ESI):m/z408.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.36(s,1H),8.80(s,1H),8.11–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.65(t,J＝8.5Hz,1H),7.60(s,1H),7.46–7.40(m,2H),7.15(t,J＝10.5Hz,1H),3.30–3.23(m,1H),2.95–2.88(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.32(m,5H).
得到化合物14(10.25mg)，第二个洗脱的异构体，白色固体，收率15％。MS(ESI):m/z 408.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.42(s,1H),8.86(d,J＝4.0Hz,1H),8.13–8.07(m,1H),7.98(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.61–7.56(m,2H),7.45(d,J＝8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
实施例5：化合物33和化合物34
化合物33(反式，外消旋)和化合物34(顺式，外消旋)从中间体F(40mg)和4-三氟甲基-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物33(5.95mg)，第一个洗脱的异构体，白色固体，收率10％。MS(ESI):m/z442.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.63(s,1H),8.79(s,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.91(s,1H),7.67–7.61(m,2H),7.49–7.40(m,2H),3.30–3.23(m,1H),3.02–2.94(m,1H),2.00–1.91(m,2H),1.91–1.82(m,2H),1.61–1.47(m,3H),1.46–1.35(m,5H).
得到化合物34(4.55mg)，第二个洗脱的异构体，白色固体，收率8％。MS(ESI):m/z442.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.66(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.90(s,1H),7.69–7.62(m,2H),7.59(s,1H),7.48–7.41(m,1H),3.52–3.38(m,2H),2.21–2.11(m,1H),2.09–2.01(m,1H),1.94–1.73(m,4H),1.69–1.61(m,1H),1.60–1.54(m,1H),1.37(d,J＝6.0Hz,3H),1.19–1.13(m,1H).
实施例6：化合物27和化合物28
化合物27(反式，外消旋)和化合物28(顺式，外消旋)从中间体F(50mg)和4-甲氧基-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物27(3.67mg)，第一个洗脱的异构体，白色固体，收率5％。(ESI):m/z404.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ11.99(s,1H),8.80(s,1H),8.10–8.07(m,1H),7.98(d,J＝10.0Hz,1H),7.69–7.62(m,1H),7.46–7.39(m,2H),6.92(s,1H),6.78–6.70(m,1H),3.77(s,3H),3.30–3.22(m,1H),2.89–2.82(m,1H),2.00–1.91(m,2H),1.90–1.76(m,2H),1.60–1.46(m,3H),1.44–1.31(m,5H).
得到化合物28(6.69mg)，第二个洗脱的异构体，白色固体，收率9％。(ESI):m/z404.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.02(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.39(d,J＝8.5Hz,1H),7.08(s,1H),6.74(t,J＝10.0Hz,1H),3.76(s,3H),3.46–3.36(m,2H),2.15–2.07(m,1H),2.06–1.98(m,1H),1.92–1.83(m,2H),1.82–1.69(m,2H),1.67–1.59(m,1H),1.58–1.51(m,1H),1.33(d,J＝6.5Hz,3H),1.22–1.14(m,1H).
实施例7：化合物35和化合物36
化合物35(反式，外消旋)和化合物36(顺式，外消旋)从中间体F(50mg)和4-溴-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物35(12.85mg)，第一个洗脱的异构体，白色固体，收率17％。(ESI):m/z452.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.39(d,J＝22.9Hz,1H),8.80(s,1H),8.10–8.04(m,1H),7.98(d,J＝11.0Hz,1H),7.74(s,1H),7.65(t,J＝8.5Hz,1H),7.46–7.38(m,2H),7.26(t,J＝9.0Hz,1H),3.31–3.24(m,1H),2.95–2.87(m,1H),1.99–1.90(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.46–1.30(m,5H).
得到化合物36(15.29mg)，第二个洗脱的异构体，白色固体，收率20％。(ESI):m/z452.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.42(s,1H),8.86(s,1H),8.12–8.07(m,1H),7.98(d,J＝11.0Hz,1H),7.73(s,1H),7.69–7.63(m,1H),7.60–7.56(m,1H),7.49(d,J＝9.0Hz,1H),7.28–7.22(m,1H),3.45–3.38(m,2H),2.15–2.08(m,1H),2.07–1.99(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.59(m,1H),1.58–1.52(m,1H),1.34(d,J＝6.0Hz,3H),1.18–1.11(m,1H).
实施例8：化合物37和化合物38
化合物37(反式，外消旋)和化合物38(顺式，外消旋)从中间体F(40mg)和6-氯-2,3-二氨基吡啶出发，经由通用路线一和通用路线三制备而来。
得到化合物37(4.03mg)，第一个洗脱的异构体，白色固体，收率7％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.79(s,1H),8.80(s,1H),8.11–8.04(m,1H),8.02–7.87(m,2H),7.66(t,J＝8.0Hz,1H),7.44(s,1H),7.24(d,J＝8.0Hz,1H),3.30–3.23(m,1H),2.98–2.89(m,1H),2.00–1.91(m,2H),1.90–1.80(m,2H),1.61–1.47(m,3H),1.45–1.35(m,5H).
得到化合物38(7.12mg)，第二个洗脱的异构体，白色固体，收率12％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.81(s,1H),8.87(d,J＝4.5Hz,1H),8.10(dd,J＝9.5,6.0Hz,1H),8.03–7.90(m,2H),7.67(td,J＝9.0,3.0Hz,1H),7.59(d,J＝4.5Hz,1H),7.23(d,J＝8.5Hz,1H),3.47–3.39(m,2H),2.18–2.12(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.71(m,2H),1.69–1.61(m,1H),1.59–1.53(m,1H),1.35(d,J＝7.0Hz,3H),1.17–1.11(m,1H).
实施例9：化合物39和化合物40
化合物39(反式，外消旋)和化合物40(顺式，外消旋)从中间体F(40mg)和5-氯-2,3-二氨基吡啶出发，经由通用路线一和通用路线三制备而来。
得到化合物39(5.08mg)，第一个洗脱的异构体，白色固体，收率9％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.80(s,1H),8.81(s,1H),8.12–8.05(m,1H),8.04–7.88(m,2H),7.65(t,J＝8.0Hz,1H),7.43(s,1H),7.26(d,J＝8.0Hz,1H),3.31–3.23(m,1H),2.99–2.88(m,1H),2.02–1.90(m,2H),1.93–1.81(m,2H),1.60–1.46(m,3H),1.46–1.34(m,5H).
得到化合物40(8.37mg)，第二个洗脱的异构体，白色固体，收率15％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.81(s,1H),8.81(s,1H),8.12–8.04(m,1H),8.03–7.87(m,2H),7.64(t,J＝8.0Hz,1H),7.45(s,1H),7.26(d,J＝8.0Hz,1H),3.46–3.37(m,2H),2.15–2.07(m,1H),2.05–1.98(m,1H),1.93–1.85(m,2H),1.84–1.68(m,2H),1.67–1.60(m,1H),1.57–1.50(m,1H),1.36(d,J＝6.5Hz,3H),1.25–1.14(m,1H).
实施例10：化合物41和化合物42
化合物41(反式，外消旋)和化合物42(顺式，外消旋)从中间体F(40mg)和6-氯-3,4-二氨基吡啶出发，经由通用路线一和通用路线三制备而来。
得到化合物41(2.98mg)，第一个洗脱的异构体，白色固体，收率5％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.89(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.08(m,1H),7.98(d,J＝11.0Hz,1H),7.70–7.55(m,3H),3.48–3.40(m,1H),3.01–2.92(m,1H),2.05–1.94(m,2H),1.96–1.85(m,2H),1.65–1.49(m,3H),1.48–1.38(m,5H).
得到化合物42(3.17mg)，第二个洗脱的异构体，白色固体，收率6％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.90(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.07(m,1H),7.99(d,J＝11.0Hz,1H),7.71–7.56(m,3H),3.49–3.40(m,2H),2.18–2.11(m,1H),2.07–2.01(m,1H),1.93–1.83(m,2H),1.82–1.72(m,2H),1.69–1.61(m,1H),1.60–1.53(m,1H),1.36(d,J＝6.0Hz,3H),1.17–1.10(m,1H).
实施例11：化合物29和化合物30
化合物29(反式，外消旋)和化合物30(顺式，外消旋)从中间体F(40mg)和4-氯-5-氟-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物29(3.45mg)，第一个洗脱的异构体，白色固体，收率5％。MS(ESI):m/z426.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.49(s,1H),8.79(d,J＝4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J＝9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
得到化合物30(4.15mg)，第二个洗脱的异构体，白色固体，收率6％。MS(ESI):m/z426.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
实施例12：化合物45和化合物46
化合物45(反式，外消旋)和化合物46(顺式，外消旋)从中间体F(40mg)和2-氨基-4-氯苯酚出发，经由通用路线一和通用路线三制备而来。
得到化合物45(6.36mg)，第一个洗脱的异构体，白色固体，收率12％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.87(d,J＝4.5Hz,1H),8.11(dd,J＝9.0,6.0Hz,1H),8.00(dd,J＝11.0,3.0Hz,1H),7.93(d,J＝2.0Hz,1H),7.74(d,J＝8.5Hz,1H),7.69(td,J＝8.5,3.0Hz,1H),7.65(d,J＝4.5Hz,1H),7.42(dd,J＝8.5,2.0Hz,1H),3.65–3.56(m,1H),3.48–3.44(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
得到化合物46(9.27mg)，第二个洗脱的异构体，白色固体，收率17％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
实施例13：化合物43和化合物44
化合物43(反式，外消旋)和化合物44(顺式，外消旋)从中间体F(40mg)和2-氨基-5-氯苯酚出发，经由通用路线一和通用路线三制备而来。
得到化合物43(8.42mg)，第一个洗脱的异构体，白色固体，收率16％。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.56(m,1H),3.48–3.43(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
得到化合物44(10.05mg)，第二个洗脱的异构体，白色固体，收率19％。MS(ESI):m/z 409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.86(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,6.0Hz,1H),8.01(dd,J＝11.0,3.0Hz,1H),7.92(d,J＝2.0Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(td,J＝8.5,3.0Hz,1H),7.63(d,J＝4.5Hz,1H),7.41(dd,J＝8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J＝7.0Hz,3H),1.30–1.25(m,1H).
实施例14：化合物48
化合物48从中间体H”(40mg)和4-甲基-1,2-苯二胺出发，经由通用路线四制备而来。得到化合物48(28.67mg)，白色固体，收率56％。(ESI):m/z 386.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J＝8.0Hz,1H),3.42–3.37(m,1H),2.37(s,3H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.23(d,J＝13.5Hz,1H),1.15–1.03(m,2H).
实施例15：化合物49
化合物49从中间体I”’(40mg)和4-氯-1,2-苯二胺出发，经由通用路线五制备而来。得到化合物49(15.23mg)，白色固体，收率28％。(ESI):m/z 420.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J＝11.0Hz,1H),7.66(t,J＝8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J＝8.0Hz,1H),2.45(s,3H),3.42–3.37(m,1H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.15–1.03(m,2H).
实施例16：化合物19和化合物20
化合物19和化合物20由实施例2中化合物18经过手性柱拆分得到。其中，化合物19对应手性拆分中的前者，化合物20对应手性拆分中的后者。
化合物19：MS(ESI):m/z 392.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.33(s,1H),8.86(s,1H),8.13–8.07(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J＝8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.33(d,J＝6.0Hz,3H),1.21–1.14(m,1H).
化合物20：MS(ESI):m/z 392.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.34(s,1H),8.87(s,1H),8.13–8.07(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J＝8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例17：化合物23和化合物24
化合物23和化合物24由实施例3中化合物22经过手性柱拆分得到。其中，化合物23对应手性拆分中的前者，化合物24对应手性拆分中的后者。
化合物23：MS(ESI):m/z 388.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.03(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J＝10.5Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
化合物24：MS(ESI):m/z 388.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.07(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.97(d,J＝10.5Hz,1H),7.66(t,J＝9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J＝6.5Hz,3H),1.21–1.14(m,1H).
实施例18：化合物15和化合物16
化合物15和化合物16由实施例4中化合物14经过手性柱拆分得到。其中，化合物15对应手性拆分中的前者，化合物16对应手性拆分中的后者。
化合物15：MS(ESI):m/z 408.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.41(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.61–7.56(m,2H),7.46(d,J＝8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
化合物16：MS(ESI):m/z 408.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.46(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J＝10.5Hz,1H),7.67(t,J＝8.5Hz,1H),7.62–7.40(m,3H),7.14(d,J＝8.5Hz,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J＝6.5Hz,3H),1.19–1.12(m,1H).
实施例19：化合物31和化合物32
化合物31和化合物32由实施例11中化合物30经过手性柱拆分得到。其中，化合物31对应手性拆分中的前者，化合物32对应手性拆分中的后者。
化合物31：MS(ESI):m/z 426.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.55(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
化合物32：MS(ESI):m/z 426.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
实施例20：化合物51和化合物52
化合物51(反式，外消旋)和化合物52(顺式，外消旋)从中间体F(40mg)和4,5-二氟-1,2-苯二胺出发，经由通用路线一和通用路线三制备而来。
得到化合物51(3.45mg)，第一个洗脱的异构体，白色固体，收率5％。MS(ESI):m/z410.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.49(s,1H),8.79(d,J＝4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J＝11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J＝9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
得到化合物52(4.15mg)，第二个洗脱的异构体，白色固体，收率6％。MS(ESI):m/z410.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
实施例21：化合物53和化合物54
化合物53和化合物54由实施例21中化合物52经过手性柱拆分得到。其中，化合物53对应手性拆分中的前者，化合物54对应手性拆分中的后者。
化合物53：MS(ESI):m/z 410.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
化合物54：MS(ESI):m/z 410.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J＝11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J＝6.5Hz,3H),1.18–1.11(m,1H).
Claims (2)
1.一种制备化合物A的方法，其中所述方法包括如下步骤：
第一步：在-78℃条件下，将正丁基锂滴加到二异丙胺的四氢呋喃溶液中。再向其中滴加中间体G”的四氢呋喃溶液，反应在-78℃下搅拌1小时。然后向反应液中滴加碘甲烷的四氢呋喃溶液，反应维持在-78℃半小时后升至室温，搅拌过夜。用饱和氯化铵溶液淬灭，用乙酸乙酯萃取水相；合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到化合物中间体H”’；
第二步：将中间体H”’溶于10mL乙醇中，加入2mL 2mol/L氢氧化钠溶液，反应液加热至50℃，反应2小时，待反应液冷却至室温，用4mol/L盐酸溶液中和至pH＝1，用乙酸乙酯萃取水相。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离得到中间体I”’，
第三步：将中间体I”’溶于N,N-二甲基甲酰胺中，加入HATU和二异丙基乙胺，再向反应液中加入取代的1,2-二胺，反应混合物在30℃下搅拌过夜，然后向反应液中加入水和乙酸乙酯，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。将得到的粗品中间体溶于醋酸中，混合物在100℃下搅拌反应19小时，然后浓缩反应液，残留物用反向高效液相制备色谱纯化得到最终化合物A。
2.如权利要求1所述的方法，其中，所述的取代的1,2-二胺选自4-氯-1,2-苯二胺。
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