CN110655520A - 嘧啶并环化合物及其制备方法和应用 - Google Patents
嘧啶并环化合物及其制备方法和应用 Download PDFInfo
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- CN110655520A CN110655520A CN201810692211.4A CN201810692211A CN110655520A CN 110655520 A CN110655520 A CN 110655520A CN 201810692211 A CN201810692211 A CN 201810692211A CN 110655520 A CN110655520 A CN 110655520A
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- pyrimido
- azaspiro
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- BDWZTXXLZMHGAA-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)-4-(1-hydroxy-2-phenylmethoxyethyl)piperidine-1-carboxylate Chemical compound C(C1=CC=CC=C1)OCC(O)C1(CCN(CC1)C(=O)OC(C)(C)C)CO BDWZTXXLZMHGAA-UHFFFAOYSA-N 0.000 description 2
- MZQDMBLLRIEPTM-UHFFFAOYSA-N tert-butyl 4-formyl-4-prop-2-enylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC=C)(C=O)CC1 MZQDMBLLRIEPTM-UHFFFAOYSA-N 0.000 description 2
- IMEKDXXPNDWOAG-UHFFFAOYSA-N tert-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate Chemical compound O=C1COCC12CCN(CC2)C(=O)OC(C)(C)C IMEKDXXPNDWOAG-UHFFFAOYSA-N 0.000 description 2
- KPVGSBWJGVRKFU-UHFFFAOYSA-N tert-butyl N-(5,6-dichloropyridin-2-yl)carbamate Chemical compound ClC=1C=CC(=NC=1Cl)NC(OC(C)(C)C)=O KPVGSBWJGVRKFU-UHFFFAOYSA-N 0.000 description 2
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
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- 238000012384 transportation and delivery Methods 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
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- 239000000080 wetting agent Substances 0.000 description 2
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- 238000010254 subcutaneous injection Methods 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- NINPBWKLSQKRJE-UHFFFAOYSA-N tert-butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11C(O)COC1 NINPBWKLSQKRJE-UHFFFAOYSA-N 0.000 description 1
- IUZIFIOHJXBRGT-UHFFFAOYSA-N tert-butyl N-(5,6-dichloro-4-sulfanylidene-1H-pyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)Nc1cc(=S)c(Cl)c(Cl)[nH]1 IUZIFIOHJXBRGT-UHFFFAOYSA-N 0.000 description 1
- NUMPDPIUZKQJTH-UHFFFAOYSA-N tert-butyl N-[1-(4-methylpiperidin-4-yl)-2-oxo-2-phenylethyl]carbamate Chemical compound C(C1=CC=CC=C1)(=O)C(C1(CCNCC1)C)NC(OC(C)(C)C)=O NUMPDPIUZKQJTH-UHFFFAOYSA-N 0.000 description 1
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- VACLTXTYDFLHJW-UHFFFAOYSA-N tert-butyl n-(2-chloroethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCl VACLTXTYDFLHJW-UHFFFAOYSA-N 0.000 description 1
- MVUNGZMGWJXPIM-UHFFFAOYSA-N tert-butyl n-(4-methylpiperidin-4-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1(C)CCNCC1 MVUNGZMGWJXPIM-UHFFFAOYSA-N 0.000 description 1
- VKIYCSNDWNMPKU-UHFFFAOYSA-N tert-butyl n-[(4-methylpiperidin-4-yl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1(C)CCNCC1 VKIYCSNDWNMPKU-UHFFFAOYSA-N 0.000 description 1
- ZCLBJFOUCSBWAR-UHFFFAOYSA-N tert-butyl n-[(4-phenylpiperidin-4-yl)methyl]carbamate Chemical compound C=1C=CC=CC=1C1(CNC(=O)OC(C)(C)C)CCNCC1 ZCLBJFOUCSBWAR-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本发明公开了嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体、溶剂化物或其同位素标记化合物,本发明也提供了该类化合物的制备方法、含有该类化合物的组合物以及该类化合物用于在制备预防和/或治疗与SHP2活性异常相关疾病或病症的药物方面的用途。
Description
技术领域
本发明公开了嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体、溶剂化物或其同位素标记化合物。本发明也提供了该类化合物及其中间体化合物的制备方法、含有该类化合物的组合物以及该类化合物用于在制备预防和/或治疗与SHP2活性异常相关疾病或病症的药物用途。
背景技术
酪氨酸磷酸酶SHP2由两个N-末端Src同源2结构域(N-SH2和C-SH2)和一个蛋白酪氨酸磷酸酶催化结构域(PTP)构成。在基础状态下,N-SH2能够与PTP结合形成一个环状结构,从而阻碍PTP与底物的结合,使得酶催化活性被抑制;当上游受体蛋白的酪氨酸被磷酸化后,N-SH2与之相结合,PTP催化域得到释放从而发挥出磷酸酶活性。
在细胞水平上,SHP2通过在诸多受体酪氨酸激酶的细胞质下游的功能作用,参与多个肿瘤细胞信号传导通路,如RTK/Ras/MAPK、JAK/STAT和PI3K/Akt等。通过对这些激酶以及信号通路的调控作用,SHP2与许多重要的细胞生命活动密切相关,如细胞增殖、迁移、分化、死亡、细胞因子的调控及肿瘤发生等等。
同时,SHP2也参与程序性死亡受体1(PD1)介导的免疫***抑制。T细胞的PD-1与PD-L1结合后,在细胞内能搞招募大量的SHP2。SHP2能够将T细胞内抗原受体通路蛋白去磷酸化,从而抑制T细胞的激活。因此,抑制SHP2的活性能够在肿瘤微环境中逆转免疫抑制。
SHP2是蛋白酪氨酸磷酸酶家族中的重要一员,与人类多种疾病相关,如努南综合征(Noonan Syndrome)、豹综合征(Leopard Syndrome)、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤等等。
近期内发表的一系列专利,如WO2018/013597A1、WO2017/210134A1、WO2017/211303A1、WO 2017/216706A1、WO 2016/203406A1、WO 2016/203405A1、WO 2016/203404A1、WO2015/107495A1、WO2015/107494A1和WO 2015/107493A1等等,表明了SHP2作为一个新颖的可成药靶点,引起了越来越多的关注。围绕SHP2抑制剂的开发,有针对SHP2的PTP催化区域的抑制剂开发和非催化区域的变构抑制剂开发两大策略;由于PTP催化区域抑制剂有选择性和成药性差的问题,目前更多的研究趋于变构抑制剂的开发。上述专利公开的均为变构抑制,但大多数对肿瘤细胞的抑制活性不高,如WO 2015/107493 A1公开的化合物SHP099(6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-胺)等,有待于进一步开发结构新颖且生物活性好、成药性高的SHP2抑制剂。
发明内容
本发明提供的嘧啶并环化合物是一类全新的SHP2抑制剂,表现出对肿瘤细胞很好的抑制活性且成药性好,具有广阔的药物开发前景。而且该类化合物的制备方法简单,有利于工业化生产。
第一方面,本发明提供式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,
其中
Z1为C、Z2为N或Z1为N、Z2为C;
X独立地为S或不存在;
Y独立地为C或N;
n独立地为0、1或2;
R1独立地为0-4个R1a取代的苯基、0-4个R1a取代的含有1-4个氮杂芳基、0-4个R1a取代的萘基、0-4个R1a取代的含有1-4个氮杂萘芳基、0-4个R1a取代或未取代的苯并杂环、0-4个R1a取代或未取代的含有1-4个氮杂芳并环、0-4个R1a取代的含有1-4个N、NR1b、O或S(O)m杂原子的杂芳环、R1c取代或未取代的C1-8烷基、R1c取代或未取代的C1-8卤代烷基;其中m选自0、1和2;
R1a独立的为卤素、R1a1取代或未取代的C1-4烷氧基、R1a1取代或未取代的C1-4烷基、三氟甲基、C(=O)OR1a2、NR1a2R1a3、NHC(=O)R1a4、R1a1取代或未取代的C3-8环烷基;R1a1独立的为卤素或C1-4烷基;R1a2、R1a3独立的为氢、C1-4烷基;R1a4独立的为C1-4烷基、取代或未取代的烯基、酰胺、C3-12单或多杂环;
R1b独立的为氢、R1a1取代或未取代的C1-4烷基;
R1c独立的为氢、-C(=O)OR1a2、R1a1取代或未取代的C1-4烷基;
R2a、R2b、R3a和R3b独立的为氢、R1a1取代或未取代的C1-4烷基;
当Y=N时,R4独立的为氢、R1a1取代或未取代的C1-4烷基;R5不存在;
当Y=C时,R4、R5独立的为氢、芳基、C1-4烷基、C1-4烷氧基、-O-C1-4烷基、氨基、C1-4烷基取代氨基、-O-C1-4烷基取代氨基,或者R4和R5与Y一起形成0-3个R4a取代的3至7元饱和或部分不饱和的螺环,该环可任选含有1-3个独立的选自N、C(=O)和/或O杂原子或基团;
R4a独立的为氢、卤素、R1a1取代或未取代的C1-4烷氧基、R1a1取代或未取代的C1-4烷基、羟基、氨基、C1-4烷基氨基。
其中优选例中,R1选自以下结构:
其中,o为0、1、2、3或4;环A为含有1-4个N原子的杂芳基;环B为含有1-4个N、S、O杂原子的杂芳基;G独立的为C、C(=O)、N、S或O杂原子或基团;R1aa、R1ab独立的为R1a;R1ac独立的为R1c取代或未取代的C1-8烷基、R1c取代或未取代的C1-8卤代烷;
在另一优选例中,R2a、R2b、R3a和R3b独立地为氢或甲基;
在另一优选例中,当Y=N时,R4独立的为氢、甲基;R5不存在;
在另一优选例中,当Y=C时,R4、R5独立的为氢、甲基、乙基、苯基、氨基、甲基氨基或乙基氨基;
在另一优选例中,当Y=C时,R4和R5与Y一起形成的环选自以下结构:
其中,p为0、1、2或3;R4a如上定义;
在另一优选例中,当Y=C时,R4和R5与Y一起形成的环为以下构型:
其中,p、R4a如上定义;
在另一优选例中,所述的化合物选自下列任一化合物:
第二方面,本发明提供式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体、溶剂化物或其同位素标记化合物。式(I)所示化合物中能够被同位素标记的原子包括但不局限于氢、碳、氮、氧、磷、氟、氯和碘等。它们可分别被同位素2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I等代替。
本发明还提供式(I)所示的嘧啶并环化合物及其中间体化合物的制备方法,主要包括以下方面:
本发明提供式(I)的制备方法,包括如下步骤:
其中,F代表硼酸、硫醇或硫钠;
W1代表卤素,优选Br、I;X、Y、Z1、Z2、n、R1、R2a、R2b、R3a、R3b、R4和R5的的定义如上所述。
本发明还提供化合物I-B的制备方法,其包含如下步骤:
在酸性或碱性条件下脱除中间体I-B1的氨基保护基得到化合物I-B,反应方程式如下:
其中,X、Z1、Z2、n、p、R1、R2a、R2b、R3a、R3b、R4、R5和R4a如上定义;Pg选自为保护基Boc、Ac、S(=O)tBu;R4Pg、R5Pg与连接碳一起,选自以下结构:
R4、R5与连接碳一起,选自以下结构:
本发明还提供化合物I-C的制备方法,其包含如下步骤:
中间体I-C1的氨基酰基化后得到化合物I-C,反应方程式如下:
其中,X、Y、n、R2a、R2b、R3a、R3b、R4、R5、R1a和R1a4的定义如上所述。
本发明还提供一种化合物A,
其中,W1、R2a、R2b、R3a、R3b、R4、R5、Y、n的定义如上所述。
本发明还提供化合物A的制备方法,其包含以下步骤:
卤代中间体E在碱性条件下被中间体胺C取代得到中间体化合物A,反应方程式如下:
其中,W2代表卤素,优选Cl、Br;W1、Y、n、R2a、R2b、R3a、R3b、R4和R5的定义如上所述。
本发明还提供一种化合物C-1,
其中,U独立的为C或O;q选自0、1或2;Pg选自为保护基Boc、Ac、S(=O)tBu;n、R2a、R2b、R3a、R3b和R4a的定义如上所述。
本发明还提供化合物C-1的制备方法,其包含以下步骤:
螺环酮化合物C-1a还原氨化得到中间体C-1b,C-1b选择性脱保护后得到C-1,反应方程式如下:
其中,Pg1选自为保护基Boc、苯甲酰基、苄基;Pg、U、q、n、R2a、R2b、R3a、R3b和R4a的定义如上所述。
本发明还提供一种化合物C-2,
其中,R6独立的为C1-8烷基、取代或为取代的芳基、取代或为取代的烯基;U、q、Pg、n、R2a、R2b、R3a、R3b和R4a的定义如上所述;
本发明还提供化合物C-2的制备方法,其包含以下步骤:
螺环酮化合物C-1a与R6取代的亲核试剂加成得到羟基化合物C-2a;化合物C-2a经Ritter反应转化成氨基化合物C-2b,然后选择性脱除其保护基Pg1得到C-2,反应方程式如下:
其中,R6、U、q、Pg1、Pg、n、R2a、R2b、R3a、R3b和R4a的定义如上所述;
本发明还提供一种化合物C-3,
其中,R6、Pg、n、R2a、R2b、R3a和R3b的定义如上所述。
本发明还提供化合物C-3的制备方法,包含以下步骤:
化合物C-3a的酯基邻位脱氢与R6取代的亲电试剂取代后得到化合物C-3b;化合物C-3b水解酯基得到酸C-3c;酸C-3c经重排后得到胺C-3d,然后选择性脱除保护基Pg1得到C-3,反应方程式如下:
其中,R6、Pg1、Pg、n、R2a、R2b、R3a和R3b的定义如上所述。
本发明还提供一种化合物C-4,
其中,R6、Pg、n、R2a、R2b、R3a和R3b的定义如上所述;
本发明还提供化合物C-4的制备方法,包含以下步骤:
氰基化合物C-4a还原并保护氨基后得到中间体C-4b,然后选择性脱除保护基Pg1得到C-4,反应方程式如下:
其中,Pg1、Pg、R6、n、R2a、R2b、R3a和R3b的定义如上所述。
本发明还提供一种化合物E,
其中,W1代表卤素,优选Br、I;W2代表卤素,优选Cl、Br、I;
本发明还提供化合物E的制备方法,包含以下步骤:
4-氯嘧啶化合物E-1被肼取代得到中间体E-2;中间体E-2缩合环化得到卤代中间体E,反应方程式如下:
其中,W1、W2的定义如上所述。
本发明还提供化合物F,
其中,V独立的为C或N;R1a的定义如上所述。
本发明还提供化合物F-1的制备方法,包含以下步骤:
卤代化合物F-1a与巯基丙酸甲酯在催化偶联条件下得到中间体F-1b-1,然后在碱性条件下得到相应的硫钠化合物F-1c,然后在酸性条件下得到F-1;或卤代化合物F-1a与叔丁硫钠取代得到中间体F-1b-2,然后在酸性条件下得到F-1。
上述制备F-1的反应方程式如下:
其中,W3为卤素,优选Br、I;V、R1a的定义如上所述。
本发明所涉及到的惰性溶剂选自:二氯甲烷、氯仿、1,2-二氯乙烷、二氧六环、DMF、乙腈、DMSO、NMP、THF或其组合。
本发明所涉及到的碱包括有机碱和无机碱。
本发明所涉及到的有机碱优选为:TEA、DIPEA或其组合。
本发明所涉及到的无机碱优选为:氢化钠、碳酸钾、碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠、LiHMDS、LDA、丁基锂或其组合。
本发明所述的式(I)所示嘧啶并环化合物的同位素标记化合物可通过与未标记化合物类似的合成方法来制备,所不同的是把未标记的起始原料和/或试剂换成同位素标记的起始原料和/或试剂。
本发明还提供一种药物组合物,包含式(I)嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或式(I)嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物、以及药学上可接受的辅料。所述药学上可接受的辅料优先选自稀释剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂。
本发明还提供了所述的式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或式(I)嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物用于制备治疗与SHP2活性异常相关疾病或病症的药物方面的用途。作为优选,所述疾病或病症包括但不局限于包括努南综合症、豹综合症、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤或成胶质细胞瘤。
本发明还提供了一种药物制剂,包含所述的式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或式(I)嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物。可以合适的方式服用,比如作为片剂、胶囊(如持续释放或定时释放的胶囊)、药丸、粉末、颗粒(如小颗粒)、酏剂、酊剂、悬浮液(如纳米混悬液、微悬浮液)和喷雾干燥的分散体等形式的悬浮物、糖浆、乳液、溶液等形式,可用于口服、舌下含服、包括皮下注射、静脉注射、肌肉注射、胸骨内注射、注入等形式的注射、鼻部服用(比如鼻膜吸入)、局部表面(如乳霜和药膏)、直肠给药(如栓剂)等等方式。本发明公开的化合物可以单独服用也可以与适当的药物载体一起服用。
本发明还提供了前一方面所述的药物制剂可配方成适当的药物剂量以方便并控制药物的服用量。本发明公开的化合物的剂量方案根据具体的因素有所不同,比如药效学及服用的方式、服用对象、性别、年龄、健康状况以及服药对象的体重、病情特征、其它同时服药状况、服药的频率、肝肾功能以及想达到的效果等等。本发明公开的化合物可以每天单剂量的服用,也可以总剂量分多次服用(比如每天两至四次)。
本发明还提供了式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或式(I)嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物与其他药物联合使用的产品,所述其他药物选自:抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药、细胞保护药物等等,一起联用具有更好的效果。
本发明还提供了式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或式(I)嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物与其他药物联合使用的方法,所述其他药物选自:抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药、细胞保护药物等等,一起联用具有更好的效果。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明具有如下优点:
1、本发明公开的嘧啶并环化合物是一类新颖的变构抑制剂,能够通过与SHP2非催化区域的结合并“锁”住SHP2活性很弱的基础状态,从而达到抑制其活性的目的。本发明公开的嘧啶并环化合物克服了PTP催化区域抑制剂普遍的选择性和成药性差等缺点,表现了很好的生物活性及可成药性,具有很好的药物开发前景。
2、在相同条件的SHP2酶活性抑制实验、磷酸化蛋白激酶(p-ERK)细胞实验和MOLM-13细胞增殖实验等评价体系中,本发明与WO 2015/107493 A1及文献(Nature 2016,535,148-152)所公开的化合物SHP099(6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-胺)相比,表现出了更优越的活性。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
在本文中,取代基中定义的数值范围如0至4、1-4、1至3、1-6等表明该范围内的整数,如0、1、2、3、4、5、6。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。“烷氧基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(=O)-基团。“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1-12个(优选为1-8个,更优选为1-6个)碳原子,且通过单键与分子的其余部分连接,例如包括但不限于甲基、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、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言,术语“烷基”指含有1-6个碳原子的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2-14个(优选为2-10个,更优选为2-6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3-15个碳原子,优选具有3-10个碳原子,更优选具有3-8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烃基中的碳原子可以任选地被氧化。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2-14个碳原子以及1-6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1-3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1-3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6-18个碳原子(优选具有6-10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1-15个碳原子(优选具有1-10个碳原子)和1-6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1-5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1-4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1-3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。在本申请中,“任选地”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基、任选取代的杂环烃基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。
本发明的化合物的所有互变异构形式也将包含在本发明的范围内。本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。在本申请中,“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”包括但不限于脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌、多发性骨髓瘤、间皮瘤、恶性横纹肌样瘤、子宫内膜癌、头颈癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物***的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,The PharmacologicalBasis of Therapeutics,current ed.;Pergamon;and Remington’s,PharmaceuticalSciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述实施例中所用的起始物可由化学品销售商如Aldrich、TCI、Alfa Aesar、毕得、安耐吉等处购得,或者可通过已知的方法来合成。
下述实施例中,冰浴是指-5摄氏度至0摄氏度,室温是指10摄氏度至30摄氏度,回流温度一般是指溶剂常压下溶剂回流温度。反应过夜是指时间为8-15小时。下述实施例中,未限定具体操作温度的,均在室温下进行。
下述实施例中,中间体和最终产物的分离提纯是通过正相或反相色谱柱分离或者其它合适的方法。正相快速色谱柱是用乙酸乙酯和正己烷或甲醇和二氯甲烷等作为流动相。反相制备性高压液相色谱(HPLC)是用C18柱并用UV 214nm和254nm来检测,其流动相为A(水和0.1%甲酸)、B(乙腈)或者流动相A(水和0.1%碳酸氢铵)、B(乙腈)。
各实施例中:LCMS仪器:Pump Agilent 1260 UV检测器:Agilent 1260 DAD MassSpectrometer API 3000
层析柱:Waters sunfire C18,4.6×50mm,5um
流动相:A-H2O(0.1%HCOOH);B-乙腈NMR
仪器:Bruker Ascend 400M(1H NMR:400MHz;13C NMR:100MHz)。
实施例1:中间体5-氯-8-碘-[1,2,4]***并[4,3-c]嘧啶(E-1)的制备
步骤一:2-氯-4-肼基-5-碘嘧啶
向干燥的100mL烧瓶中加入2,4-二氯-5-碘嘧啶(25g,91mmol)和无水乙醇(20mL)。在0℃条件下缓慢加入水合肼(13.66g,272.9mmol)。将混合物在室温下搅拌反应2小时,出现大量固体,过滤,然后用乙醇洗涤,真空下干燥得到棕色固体2-氯-4-肼基-5-碘嘧啶(20g,收率:81%)。
1H NMR(400MHz,CDCl3)δ8.29(s,1H),6.67(s,1H),4.08(s,2H)ppm;LC-MS:m/z271.1[M+H]+。
步骤二:5-氯-8-碘-[1,2,4]***并[4,3-c]嘧啶
向干燥的50mL封管中依次加入2-氯-4-肼基-5-碘嘧啶(10g,37mmol)和原甲酸三甲酯(3.92g,37mmol)。在氮气条件下,将混合物加热至80℃搅拌反应5小时。反应完毕后,反应液冷却至室温,将混合物缓慢倒饱和碳酸氢钠溶液中,并使用乙酸乙酯(3×100mL)萃取,混合有机层并使用饱和食盐水洗涤,经无水硫酸钠干燥,过滤并浓缩得到出产品后,使用硅胶柱色谱分离(乙酸乙酯:石油醚=1:1)得到5-氯-8-碘咪唑并[1,2-c]嘧啶(5.7g,产率55%)。
1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.28(s,1H)ppm;LC-MS:m/z 280.1[M+H]+。
实施例2:中间体(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1A)的制备
步骤一:(R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯
在干燥的100mL单口瓶中依次加入1-氧代-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(2.53g,10mmol),四乙氧基钛(6.84g,30mmol)和50mL的四氢呋喃,在加热回流下搅拌反应4小时。冷却到室温后,加入甲醇(10mL)随后加入硼氢化锂(0.65g,30mmol)。将得到的混合物在室温下搅拌反应3小时。缓慢加入甲醇以淬灭过量的硼氢化物,随后加入盐水。将得到的混合物搅拌15分钟然后通过硅藻土过滤。将含水的混合物用乙酸乙酯(3x 50mL)萃取。合并的机相用MgSO4干燥,过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯:石油醚)得到白色固体(R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(2.86g,收率:80%)。
LC-MS:m/z 359.1[M+H]+.
步骤二:(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1A)
将(R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(2.86g,8mmol)和浓硫酸(2.0mL,32mmol)的二氧六环(50mL)的溶液在室温下搅拌反应2小时。加入Na2CO3饱和水溶液直到pH 11,并将含水的混合物用DCM(3x50mL)萃取。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤,并在减压下除去挥发物,得到白色固体(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺C-1A(1.86g,收率:90%)
1H NMR(400MHz,DMSO-d6)δ4.82(d,J=7.5Hz,1H),3.04(d,J=7.6Hz,1H),2.81(ddd,J=12.1,8.0,4.0Hz,2H),2.60-2.51(m,2H),1.92-1.14(m,10H),1.12(s,9H)ppm;LC-MS:m/z 259.1[M+H]+.
按照实施例2的合成方法,用类似的起始原料反应得到以下中间体C-1B、C-1C、C-1D、C-1E、C-1F、C-1G、C-1H
实施例3:中间体(R)-2-甲基-N-((S)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(C-1I)的制备
步骤一:4-(2-(苄氧基)-1-羟基乙基)哌啶-1,4-二甲酸1-叔丁基-4-甲酯
在氮气保护下,向干燥的500mL三口烧瓶依次加入1-叔丁基-4-甲基哌啶-1,4-二甲酸酯(45g,180mmol)和四氢呋喃(400mL),然后溶液冷却到-78℃,并滴加LiHMDS(261mL,261mmol)。滴加完毕后升至室温,并在室温下搅拌3小时。然后重新冷却到-78℃,缓慢滴加苄氧基乙醛(46g,300mmol)的四氢呋喃(50mL)溶液。反应液慢慢升至室温并搅拌2.5小时。反应完毕后,加入饱和NH4Cl溶液(200mL)淬灭反应。将其用乙酸乙酯(3x 200mL)萃取。合并的有机相用Na2SO4干燥,过滤,滤液减压浓缩,将得到的残留物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/石油醚),得到4-(2-(苄氧基)-1-羟基乙基)哌啶-1,4-二甲酸1-叔丁基-4-甲酯(52g,收率:73.3%)。
1H NMR(400MHz,CDCl3)δ7.36-7.30(m,5H),4.50(s,2H),3.97(s,2H),3.73-3.65(m,2H),3.62(s,3H),3.59-3.48(m,3H),2.88(d,J=6.2Hz,1H),2.23(dd,J=13.7,2.7Hz,1H),2.04-1.88(m,2H),1.74(d,J=14.7Hz,1H),1.56(d,J=4.2Hz,1H),1.44(s,9H)ppm;LC-MS:m/z 294.1[M+H]+.
步骤二:4-(2-(苄氧基)-1-羟基乙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯
向干燥的500mL三口烧瓶中依次4-(2-(苄氧基)-1-羟基乙基)哌啶-1,4-二甲酸-1-叔丁基-4-甲酯(51.4g,130mmol)和四氢呋喃(500mL)溶液,然后向溶液中加入LiBH4(11.44g,520mmol),并室温搅拌6小时。反应完毕后,使用饱和NaHCO3(200mL)淬灭反应。用乙酸乙酯(3x 200mL)萃取。将合并的有机相用Na2SO4干燥,过滤,滤液减压浓缩,并将得到的残留物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/石油醚),得到4-(2-(苄氧基)-1-羟基乙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(27g,收率:57%)。
LC-MS:m/z 266.1[M+H]+.
步骤三:4-(1,2-二羟乙基)-4-(羟甲基)哌啶-1-甲酸叔丁酯
向干燥的500mL单口烧瓶中依次加入4-(2-(苄氧基)-1-羟基乙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(27g,74mmol),甲醇(270mL)和Pd/C(20g),然后用氢气球置换三次,室温搅拌12小时。反应液过滤浓缩得到4-(1,2-二羟乙基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(18.9g,收率:93%)。
LC-MS:m/z 176.1[M+H]+.
步骤四:4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯
向干燥的500mL单口烧瓶中依次加入4-(1,2-二羟乙基)-4-(羟甲基)哌啶-1-甲酸叔丁酯(18.9g,69mmol),三苯基膦(25.2g,86.25mmol)和四氢呋喃(350mL),反应液冷却至0℃并加入DEAD(12.46mL,86mmol).然后升至室温搅拌5小时。反应完毕后,加入水(200mL)淬灭反应。将其用乙酸乙酯(3x 200mL)萃取。合并有机相,并用Na2SO4干燥,过滤,滤液减压浓缩并将得到的残留物通过硅胶色谱法纯化(0至2%梯度的甲醇/二氯甲烷),得到4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(13.2g,收率:74%)。
1H NMR(400MHz,CDCl3)δ4.04(dd,J=10.0,4.6Hz,1H),3.98-3.90(m,1H),3.71-3.63(m,2H),3.64-3.49(m,3H),3.20(dt,J=13.4,6.3Hz,1H),3.07(ddd,J=13.2,9.2,3.5Hz,1H),1.95(d,J=5.2Hz,1H),1.74-1.66(m,1H),1.53-1.46(m,1H),1.39(s,9H),1.27-1.11(m,1H)ppm;LC-MS:m/z 202.1[M-56+H]+.
步骤五:4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯
向干燥的500mL单口烧瓶中依次加入4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(13.2g,51mmol),二氯甲烷(280mL)和Dess-Martin氧化剂(32.2g,76.5mmol),冰浴下搅拌5小时。反应完毕后加入NaHCO3:Na2S2O3(1:1)的饱和溶液(200mL),分离有机相,水相用DCM(3x 100mL)萃取。合并的有机相用Na2SO4干燥,滤液减压浓缩。将得到的残留物通过硅胶色谱法纯化(0至40%梯度的乙酸乙酯/石油醚),得到无色固体4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(12g,收率:92.1%)。
1H NMR(400MHz,CDCl3)δ4.05(d,J=13.6Hz,4H),3.87(d,J=12.9Hz,2H),3.09(ddd,J=13.5,9.8,3.5Hz,2H),1.73(ddd,J=13.9,9.8,4.3Hz,2H),1.53(d,J=15.1Hz,2H),1.46(s,9H)ppm;LC-MS:m/z 200.0[M-56+H]+。
步骤六:(S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯
按照实施例2中间体C-1A步骤一的合成方法,4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯还原胺化得到白色固体(S)-4-((R)-1-甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯。
1H NMR(400MHz,CDCl3)δ4.14(dd,J=9.3,6.2Hz,1H),3.90(d,J=13.8Hz,2H),3.77(s,2H),3.70(dd,J=9.2,5.3Hz,1H),3.63(q,J=6.1Hz,1H),3.27(d,J=6.4Hz,1H),2.90(t,J=12.4Hz,2H),1.71(dt,J=16.6,7.9Hz,2H),1.51(s,2H),1.45(s,9H),1.22(s,9H)ppm;LC-MS:m/z 361.1[M-100]+。
步骤七:(R)-2-甲基-N-((S)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(C-1I)
按照实施例2中间体C-1A步骤二的合成方法,(S)-4-((R)-1-甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯脱除Boc保护基后得到白色固体(R)-2-甲基-N-((S)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺C-1I。
1H NMR(400MHz,DMSO-d6)δ5.30(s,1H),5.23(d,J=8.9Hz,1H),3.93(dd,J=8.6,7.2Hz,1H),3.69(d,J=8.6Hz,1H),3.58(d,J=8.6Hz,1H),3.46(dd,J=8.5,7.0Hz,2H),2.89-2.73(m,2H),2.48-2.42(m,1H),1.69-1.50(m,2H),1.39-1.21(m,3H),1.12(s,9H)ppm;LC-MS:m/z 261.1[M+H]+.
实施例4:(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(C-1J)的制备
步骤一:(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯
向(S)-2-羟基丙酸乙酯(30g,254mmol)的二氯甲烷(300mL)溶液中加入咪唑(2.75g,304.9mmol)并冷却至0℃。向该溶液中分批加入叔丁基二甲基甲硅烷基氯(46.0g,304.9mmol),并在室温下搅拌16小时。通过TLC分析判断反应完成后,将反应混合物用水淬灭并用二氯甲烷(2×100mL)萃取。将合并的有机层用无水硫酸钠干燥。过滤并减压浓缩,得到(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯(50g,产率84%),为无色液体。
1H NMR(400MHz,CDCl3)δ4.32-4.27(m,1H),4.21-4.12(m,2H),1.37(d,J=6.8Hz,3H),1.27(d,J=7.2Hz,3H),0.90(s,9H),0.08(s,6H)ppm.
步骤二:(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛
在-78℃下向(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯(25g,107.6mmol)的二***(500mL)溶液中缓慢滴加氢化二异丁基铝(1M己烷溶液)(129mL,129.1mmol),并在-78℃下搅拌1小时。通过TLC分析确认反应完成后,使反应混合物温度缓慢升至-40℃,反应用罗谢尔盐(1L)的饱和水溶液淬灭,然后加入***(500mL)。将所得混合物在室温下搅拌2小时。然后用***(200mL)萃取。有机层用饱和盐水(250mL)洗涤,用Na2SO4干燥,过滤并减压浓缩,得到(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛(19g,收率:94%)。
1H NMR(400MHz,CDCl3)δ9.61(s,1H),4.12-4.06(m,1H),1.27(d,J=6.8Hz,3H),0.91(s,9H),0.10(s,6H)ppm.
步骤三:4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-(叔丁基)
在0℃下向搅拌的1-(叔丁基)-4-乙基哌啶-1,4-二羧酸酯(30g,116.6mmol)的THF(250mL)溶液中加入二异丙基氨化锂(2M,在THF中)(93.3mL,186.6mmol),并继续在0℃下搅拌30分钟。然后加入(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛(22g,116.6mmol)的THF(50mL)溶液。所得反应混合物在0℃下搅拌1小时,然后在室温下保持1小时。通过TLC分析判断反应完成后,将反应混合物用饱和NH4Cl溶液淬灭并用乙酸乙酯(2×250mL)萃取。将合并的有机层用水(150mL),盐水(150mL)洗涤,无水硫酸钠干燥。过滤并减压浓缩。粗产物通过硅胶(60-120目)柱色谱法纯化,使用25%乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱剂,得到4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-(叔丁基)(17g,收率:32%),为浅红色油状物。
1H NMR(400MHz,CDCl3)δ4.29-4.09(m,2H),3.96-3.94(m,2H),3.86-3.80(m,1H),3.56-3.54(m,1H),2.86-2.76(m,2H),2.46(d,J=5.2Hz,1H),2.16-2.13(m,1H),2.13-2.04(m,1H),1.77-1.60(m,2H),1.46(s,9H),1.29-1.24(m,3H),1.12(d,J=4Hz,3H),0.89(s,9H),0.05(s,6H)ppm;LCMS:m/z 346[M-100]+.
步骤四:((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯
向搅拌的溶液中加入4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-(叔丁基)(5g,11.21mmol)在THF(50mL)中的溶液中分批加入LiBH4(0.73g,33.65mmol)并在室温下搅拌16小时。反应完毕后,将反应混合物在0℃用饱和NaHCO3溶液猝灭,并在室温搅拌15分钟。滤出沉淀的固体,水相用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产物通过硅胶(100-200目)柱色谱纯化,使用25%乙酸乙酯的石油醚溶液梯度混合物作为洗脱液,得到((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(3g,收率:66%)。
1H NMR(400MHz,CDCl3)δ4.55(t,J=4.8Hz,1H),4.43(d,J=6.4Hz,1H),3.52-3.47(m,5H),3.31-3.28(m,1H),3.05-3.01(m,2H),1.58-1.49(m,2H),1.42-1.38(m,11H),1.11(d,J=6.4Hz,3H),0.85(m,9H),0.04(s,6H)ppm;LC-MS:m/z 404.3[M+H]+。
步骤五:4-((2S)-1,2-二羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯
((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(25g,61.93mmol)的THF(500mL)溶液中加入四丁基氟化胺(1M在THF中)(93mL,92.89mmol),并将所得反应混合物在室温下搅拌2小时。通过TLC分析判断反应完成后,将反应混合物用饱和的NaHCO3溶液淬灭并用乙酸乙酯(2×500mL)萃取。合并的有机相用无水硫酸钠干燥。过滤并减压浓缩得到的粗产品用硅胶(60-120目)柱色谱法纯化粗产物,使用70-90%乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱液,得到4-((2S)-1,2-二羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(12g,收率:67%),为无色液体。
1H NMR(400MHz,DMSO-d6)δ4.72(t,J=4.8Hz,1H),4.61(d,J=5.2Hz,1H),4.50(d,J=7.2Hz,1H),3.72-3.68(m,1H),3.53-3.44(m,4H),3.11-2.98(m,3H),1.68-1.53(m,2H),1.42-1.35(m,11H),1.10(d,J=6.4Hz,3H)ppm;LC-MS:m/z 290.1[M+H]+。
步骤六:(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯
在0℃下向搅拌的NaH(60%,在矿物油中)(1.45g,60.5mmol)的THF(30mL)悬浮液中加入4-((2S)-1,2-二羟基丙基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(5g,17.3mmol)和对甲苯磺酰氯(3.29g,17.3mmol)的THF(20mL)溶液中,并将得到的反应混合物在0℃反应3小时。反应完成后,将反应混合物在-20℃下用饱和NH4Cl溶液(250mL)淬灭,并用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产品用硅胶(100-200目)柱色谱法纯化,使用40%乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱剂,得到(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(2.1g,收率:44%)。
1H NMR(400MHz,CDCl3)δ3.83-3.62(m,5H),3.43(d,J=6.0,1H),3.07-2.97(m,2H),1.72-1.55(m,3H),1.51-1.42(m,11H),1.33(d,J=6.4Hz,3H)ppm;LC-MS:m/z172.2[M-100]+。
步骤七:(S)-叔丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯
将(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯(2.1g,7.74mmol)加入到四氢呋喃(50mL)溶液中,然后加入Dess-Martin氧化剂(4.26g,10.06mmol))并保持搅拌1小时。反应完毕后,减压蒸馏除去溶剂。所得残余产物通过硅胶(100-200目)柱色谱纯化,使用30%乙酸乙酯在石油醚中的溶剂梯度混合物作为洗脱剂,接着用0.1%甲酸和乙腈作为洗脱剂的快速色谱法纯化得到(S)-叔丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯(1.2g,收率:57%)。
1H NMR(400MHz,CDCl3)δ4.20(d,J=9.5Hz,1H),3.94-3.90(m,4H),3.16-3.10(m,1H),3.03-2.97(m,1H),1.81-1.75(m,1H),1.67-1.62(m,1H),1.61-1.57(m,1H),1.42-1.45(m,10H),1.32(d,J=6.0Hz,3H)ppm;LC-MS:m/z 214.1[M-55]+。
步骤八:(3S,4S)-4-((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯
(S)-叔丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯(1.2g,4.46mmol)在THF(15mL)中的搅拌溶液分别为加入(R)-2-甲基丙烷-2-亚磺酰胺(1.07g,8.91mmol)和钛酸四乙酯(4.07g,17.84mmol)。所得反应混合物在90℃下搅拌20小时。将反应混合物冷却至-4℃,加入MeOH(2mL),然后分批加入LiBH4(282mg,12.99mmol)并在相同温度下保持搅拌1小时。反应完毕后,将反应混合物在0℃下用饱和盐水溶液淬灭,并在室温下搅拌15分钟。过滤,溶液用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产品用0.1%甲酸和乙腈作为洗脱液的快速色谱法纯化粗产物,得到(3S,4S)-4-((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(1.2g,收率:72%)。
1H NMR(400MHz,CDCl3)δ4.20-4.15(m,1H),3.90-3.84(m,2H),3.63-3.59(m,1H),3.49-3.43(m,1H),3.31-3.29(m,1H),2.95-2.81(m,2H),1.90-1.71(m,2H),1.49-1.40(m,11H),1.25(s,9H),1.19(d,J=6.5Hz,3H)ppm;LC-MS:m/z 375.2[M+H]+。
步骤九:(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(C-1J)
向(3S,4S)-4-((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(1.1g,2.936mmol)的二氯甲烷(10mL)溶液中滴加三氟乙酸(1.12mL,14.68mmol)并在室温下搅拌6小时。反应完毕后,将反应混合物减压浓缩得到的粗产品用0.1%甲酸和乙腈的色谱法纯化粗产物,得到(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺C-1J(850mg,收率:72%)。
1H NMR(400MHz,DMSO-d6)δ8.40(brs,D2O Exchangeable,1H),8.30(brs,D2OExchangeable,1H),5.28(d,J=12.0Hz,1H),4.13-4.09(m,1H),3.77(d,J=9.0Hz,1H),3.50-3.45(m,2H),3.29-3.26(m,1H),3.19-3.15(m,1H),2.94-2.85(m,2H),1.87-1.80(m,2H),1.69-1.59(m,2H),1.17(s,9H),1.08(d,J=6.0Hz,3H)ppm;LC-MS:m/z 275.2[M+H]+.
实施例5:(R)-2-甲基-N-((3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺和(R)-2-甲基-N-((3R,4R)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺的制备(C-1K)
步骤一:(R)-叔-丁基3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯
按照上述实施4的方法,以(R)-2-((叔-丁基二甲基甲硅烷基)氧代)丙醛为原料可以得到(R)-叔-丁基3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯
步骤二:(3R,4S)-叔-丁基4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯与(3R,4R)-叔-丁基4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯
(R)-叔丁基-3-甲基-4-羰基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯(0.97g,3.71mmol)在THF(5mL)中的搅拌溶液分别为加入(R)-2-甲基丙烷-2-亚磺酰胺(0.873g,7.2mmol)和钛酸四乙酯(3.36ml,14.74mmol)。所得反应混合物在90℃下搅拌18小时。将反应混合物冷却至-4℃,加入MeOH(5mL),然后分批加入LiBH4(80mg,3.71mmol)并在相同温度下保持搅拌1小时。反应完毕后,将反应混合物在0℃下用饱和盐水溶液淬灭,并在室温下搅拌15分钟。过滤,溶液用乙酸乙酯(2×50mL)萃取。合并的有机层用无水硫酸钠干燥。过滤并减压浓缩得到的粗产品用0.1%甲酸和乙腈作为洗脱液的快速色谱法纯化粗产物,得到(3R,4S)-叔-丁基4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯与(3R,4R)-叔-丁基4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸酯(0.5g,收率:36%)。
步骤三:(R)-2-甲基-N-((3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺和(R)-2-甲基-N-((3R,4R)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(C-1K)
按照实施例4步骤九的方法可以得到(R)-2-甲基-N-((3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺混合物和与(R)-2-甲基-N-((3R,4R)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺的混合物.然后用0.1%甲酸和乙腈作为洗脱液的快速色谱法纯化粗产物,得到(R)-2-甲基-N-((3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(119mg,24%收率)和(R)-2-甲基-N-((3R,4R)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(154mg,收率:31%)
(R)-2-甲基-N-((3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺:
1H-NMR(400MHz,DMSO-d6):δ5.45(d,D2O Exchangeable,J=11.0Hz,1H),3.78(d,J=9.0Hz,1H),3.64-3.59(m,2H),3.27-3.25(m,1H),3.17-3.14(m,1H),2.88-2.76(m,3H),1.90-1.85(m,1H),1.82-1.76(m,1H),1.59-1.51(m,2H),1.18-1.17(m,12H)ppm;LC-MS:m/z275.2[M+H]+.
(R)-2-甲基-N-((3R,4R)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺:
1H-NMR(400MHz,DMSO-d6):δ5.04(d,D2O Exchangeable,J=10.5Hz,1H),4.45-4.11(m,1H),3.48(d,J=8.5Hz,1H),3.50-3.46(m,1H),3.43(d,J=9.0Hz,1H),3.14-3.12(m,1H),3.04-3.02(m,1H),3.91-3.87(m,2H),1.73-1.68(m,2H),1.62-1.56(m,2H),1.17(s,9H),1.14(d,J=6.5Hz,3H)ppm;LC-MS:m/z 275.2[M+H]+.
实施例6:2-甲基-N-((S)-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺的合成(C-1L)
步骤一:(R,Z)-N-(8-苯甲酰-2-氧杂-8-氮杂螺[4.5]癸烷-4-亚基)-2-甲基丙烷-2-亚磺酰胺
按照实施例3的方法可以得到(R,Z)-N-(8-苯甲酰-2-氧杂-8-氮杂螺[4.5]癸烷-4-亚基)-2-甲基丙烷-2-亚磺酰胺
LC-MS:m/z 363.2[M+H]+.
步骤二:N-((S)-8-苯甲酰-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺酰胺
将(R,Z)-N-(8-苯甲酰-2-氧杂-8-氮杂螺[4.5]癸烷-4-亚基)-2-甲基丙烷-2-亚磺酰胺(200mg,0.552mmol)溶解在甲苯(5ml)中,反应一体系降温至0℃,接着缓慢滴加甲基溴化镁溶液(1.1ml,3.32mmol),此后反应在室温下搅拌2.5小时。反应用饱和氯化铵淬灭,乙酸乙酯萃取,无水硫酸钠干燥后,减压下旋干后,粗品用制备板分离(20%的乙酸乙酯的石油醚溶液)得到N-((S)-8-苯甲酰-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺酰胺(20mg,收率:10%)。
LC-MS:m/z 379.2[M+H]+.
步骤三:2-甲基-N-((S)-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(C-1L)
将N-((S)-8-苯甲酰-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)-2-甲基丙烷-2-亚磺酰胺(100mg,0.26mmol)溶解在四氢呋喃(5ml)中,反应一体系降温至0℃,接着缓慢加4N NaOH(0.65ml,2.6mmol),此后反应在室温下搅拌2.5小时。反应液用乙酸乙酯萃取(5x10mL)将合并的有机相用MgSO4干燥,过滤,滤液减压浓缩得到2-甲基-N-((S)-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)丙烷-2-亚磺酰胺(50mg,收率:70%)直接用到下一步反应。
LC-MS:m/z 275.2[M+H]+.
实施例7:(R)-N,2-二甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1M)
步骤一:(R)-叔-丁基-1-((R)-N,2-二甲基丙烷-2-基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯
将(R)-叔-丁基-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯(500mg,1.39mmol)溶解在四氢呋喃(10ml)中,反应一体系降温至0℃,接着缓慢加NaH(54mg,2.23mmol),此后加入碘甲烷(396mg,2.79mmol)反应在室温下搅拌过夜。反应液用水淬灭,然后用乙酸乙酯萃取(3x 10mL)将合并的有机相用MgSO4干燥,过滤,滤液减压浓缩得到粗产品,粗产品用硅胶柱分离(50%乙酸乙酯的石油醚溶液)得到(R)-叔-丁基-1-((R)-N,2-二甲基丙烷-2-基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯(400mg,收率:80%)。
LC-MS:m/z 373.2[M+H]+.
步骤二:(R)-N,2-二甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1M)
按照实施例4步骤9的方法可以得到(R)-N,2-二甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺。
LC-MS:m/z 273.2[M+H]+.
实施例8:中间体(R)-2-甲基-N-((1R)-3-甲基-8-氮杂-螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1N)的制备
步骤一:4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁酯
向干燥1L的烧瓶中依次加入4-甲酰基哌啶-1-甲酸叔丁酯(35.0g,164mmol)、叔丁醇锂(15.77g,197mmol)和烯丙基溴(11.54mL,189mmol)和DMF(328mL),该混合物在0℃下搅拌1小时。反应完毕后,将混合物倒入含有饱和NH4Cl水溶液(50%,500mL)的分离漏斗中,将其用Et2O(5x 50mL)萃取。将合并的有机相用MgSO4干燥,过滤,滤液减压浓缩。将得到的残留物通过硅胶色谱法纯化(0至25%梯度的乙酸乙酯/石油醚),得到无色油状物4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁酯(24g,收率:48%)。
1H NMR(400MHz,CDCl3)δ9.52(s,1H),5.53-5.76(m,1H),4.96-5.19(m,2H),3.80(br.s.,2H),2.97(t,J=11.49Hz,2H),2.26(d,J=7.33Hz,2H),1.95(dt,J=13.71,3.13Hz,2H),1.38-1.58(m,11H)ppm.
步骤二:4-烯丙基-4-(1-羟基烯丙基)哌啶-1-羧酸叔丁酯(C-1N-c)
向1L的干燥三口烧瓶中依次加入4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁酯(24g,95mmol)和THF(300mL),把该溶液冷却到-78℃并在氮气下的保护下缓慢滴加乙烯基溴化镁(1M在THF中,118mL,118mmol)。在1小时内,使得到的溶液缓慢升温至室温。反应完毕后,将混合物倒入含有饱和NH4Cl水溶液(250mL)的分离漏斗中,将其用EtOAc(4x 50mL)萃取。将合并的有机相用MgSO4干燥,过滤,滤液减压浓缩,得到4-烯丙基-4-(1-羟基烯丙基)哌啶-1-甲酸叔丁酯(26.7g),没有进一步纯化即将该化合物用于下一步骤中。
1H NMR(400MHz,CDCl3)δ6.05-5.83(m,2H),5.32-5.21(m,2H),5.12(s,1H),5.08(d,J=3.5Hz,1H),4.05-3.97(m,1H),3.71(s,2H),3.12(ddd,J=13.8,10.4,3.6Hz,2H),2.33(dd,J=14.3,7.8Hz,1H),2.20(dd,J=14.3,7.2Hz,1H),1.60(q,J=4.3Hz,2H),1.57-1.50(m,2H),1.45(s,9H)ppm.
步骤三:4-烯丙酰基-4-烯丙基哌啶-1-甲酸叔丁酯
向干燥的三口烧瓶中依次加入4-烯丙基-4-(1-羟基烯丙基)哌啶-1-甲酸叔丁酯(26.7g,95mmol),Dess-Martin氧化剂(44.3g,105mmol)和无水二氯甲烷(380mL),该混合物在室温下搅拌1小时。反应完毕后将混合物倒入含有NaHCO3:Na2SO3饱和水溶液(1:1,300mL)的分离漏斗中,然后用DCM(4x 50mL)萃取。将合并的有机相用MgSO4干燥,过滤,滤液减压浓缩,得到白色固体。将白色固体混悬在石油醚(250mL)并超声20分钟。将白色混悬液通过硅藻土垫层过滤并在减压下除去,滤液减压浓缩得到黄色油状4-烯丙酰基-4-烯丙基哌啶-1-甲酸叔丁酯(25g,两步收率:94%)。
1H NMR(400MHz,CDCl3)δ6.80(dd,J=16.8,10.3Hz,1H),6.39(dd,J=16.8,1.9Hz,1H),5.70(dd,J=10.3,1.9Hz,1H),5.55(ddt,J=17.5,10.2,7.4Hz,1H),5.09-4.98(m,2H),3.77(s,2H),2.94(s,2H),2.31(d,J=7.4Hz,2H),2.08(d,J=13.8Hz,2H),1.47-1.41(m,11H)ppm。
步骤四:1-氧代-8-氮杂螺[4.5]癸烷-2-烯-8-羧酸叔丁酯
向1L的干燥三口烧瓶中依次加入4-烯丙酰基-4-烯丙基哌啶-1-甲酸叔丁酯(25g,89.6mmol)、甲苯(脱气的,850mL)和Grubbs II催化剂(2.02g,2.38mmol)的甲苯(脱气的,100mL)溶液。将得到的混合物在85℃氮气保护下搅拌45分钟。反应完毕后,减压下除去溶剂,并将得到的残留物通过硅胶色谱法纯化(0-40%梯度的乙酸乙酯/石油醚),得到1-氧代-8-氮杂螺[4.5]癸烷-2-烯-8-甲酸叔丁酯(19g,83mmol),为棕色固体。将该化合物和DDQ(565mg,2.49mmol)的甲苯(540mL)溶液在室温下搅拌15分钟。将得到的亮红色溶液通过硅藻土垫层过滤。加入活性炭(100g),并将得到的混悬液在室温下搅拌2小时。将混合物通过硅藻土垫层过滤,滤液减压浓缩得到的残留物通过硅胶色谱法纯化(0-40%梯度的乙酸乙酯/石油醚),得到白色固体1-氧代-8-氮杂螺[4.5]癸烷-2-烯-8-羧酸叔丁酯(12g,收率:53.3%)。
步骤五:3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯
向氮气保护的250mL干燥三口烧瓶中依次加入CuI(3.8g,20mmol)和无水四氢呋喃(100mL),该溶液冷却到-20℃,并向溶液中缓慢滴加MeLi(1.6M的THF溶液,25mL,40mmol),滴加完毕后反应液在-20℃反应直到溶液澄清。然后在该温度下缓慢滴加1-氧代-8-氮杂螺[4.5]癸烷-2-烯-8-羧酸叔丁酯(2.51g,10mmol)的四氢呋喃溶液(20mL)。反应结束后,将混合物倒入含有饱和NH4Cl水溶液的分离漏斗中,将其用乙酸乙酯(3x 15mL)萃取。将合并的有机相用MgSO4干燥,过滤并滤液减压浓缩通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/石油醚),得到3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-2-烯-8-甲酸叔丁酯(1.6g,收率:60%)。
1H NMR(400MHz,CDCl3)δ3.92(s,1H),3.81(s,1H),3.55(d,J=5.0Hz,1H),3.13-3.04(m,1H),2.96(t,J=10.9Hz,1H),2.56-2.46(m,1H),2.31-2.21(m,2H),1.94-1.75(m,2H),1.62-1.49(m,1H),1.45(s,9H),1.41-1.35(m,2H),1.15(d,J=6.0Hz,3H),0.90(t,J=6.9Hz,3H)ppm.
步骤六和七:(R)-2-甲基-N-((1R)-3-甲基-8-氮杂-螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1N)
按照合成中间体C-1J步骤八和九的合成方法,酮中间体3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-2-烯-8-甲酸叔丁酯经还原胺化并脱除Boc保护基后得到(R)-2-甲基-N-((1R)-3-甲基-8-氮杂-螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺C-1N。
1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,DMSO-d6)δ3.04-2.95(m,1H),2.75(s,2H),2.62-2.53(m,2H),1.93-1.57(m,5H),1.52-1.27(m,13H),0.96(d,J=6.5Hz,3H)ppm;LCMS:m/z 273[M+H]+.
实施例9:中间体((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯(C-4A)的制备
步骤一:1-苯甲酰基-4-甲基哌啶-4-甲腈
在氮气条件下,向100mL的干燥单口烧瓶中依次加入4-甲基哌啶-4-甲腈(496mg,4mmol),DCM(10mL)和三乙胺(611mg,6mmol),然后在室温下缓慢滴加苯甲酰氯(670mg,4.8mmol)。将混合物在室温下进一步搅拌1小时,TLC监测反应至原料反应完毕。用1N HCl溶液猝灭反应后,二氯甲烷(3×20mL)萃取,合并的有机相用Na2SO4干燥,滤液减压浓缩并通过柱硅胶色谱法纯化(0至40%梯度的乙酸乙酯/石油醚)得到1-苯甲酰基-4-甲基哌啶-4-甲腈(650mg,收率:70.72%)。
LC-MS:m/z 229[M+H]+.
步骤二:1-苯甲酰基-((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯
在0℃,氮气条件下,向100mL的干燥烧瓶中依次加入1-苯甲酰基-4-甲基哌啶-4-甲腈(650mg,2.85mmol),氯化镍六水合物(135mg,0.67mmol),二碳酸二叔丁酯(1.86g,8.54mmol)和甲醇(12mL),并加入硼氢化钠(754mg,20mmol)。然后将反应液在室温下搅拌12小时,TLC监测反应至原料反应完毕。反应完毕后,反应液浓缩并用二氯甲烷(3×20mL)萃取,合并的有机相用Na2SO4干燥,滤液减压浓缩并通过柱硅胶色谱法纯化(0至40%梯度的乙酸乙酯/石油醚)得到1-苯甲酰基-((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯(620mg,收率:65.50%)
LC-MS:m/z 333[M+H]+.
步骤三:((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯(C-4A)
向100mL的单口烧瓶中依次加入((1-苯甲酰基-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯(620mg,1.87mmol),乙醇(8mL)和7N NaOH(2mL),然后在氮气的保护下将混合物加热至90℃搅拌8小时,带混合物冷却至室温后,将混合物过滤,用水稀释后使用乙酸乙酯(3×20mL)萃取,合并的有机相用Na2SO4干燥,滤液减压浓缩并通过柱硅胶色谱法纯化(0至80%梯度的乙酸乙酯/石油醚)得到((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯C-4A(300mg,收率:70.5%)。
1H NMR(400MHz,DMSO-d6)δ3.97(q,J=7.0Hz,2H),2.80(d,J=6.4Hz,2H),2.65(d,J=30.3Hz,2H),1.38(s,9H),1.27(dd,J=16.2,7.0Hz,2H),1.10(d,J=12.8Hz,2H),0.81(s,3H)ppm;LC-MS:m/z 229[M+H]+.
实施例10:中间体((4-苯基哌啶-4-基)甲基)氨基甲酸叔丁酯(C-4B)的制备
步骤一:4-氰基-4-苯基哌啶-1-甲酸叔丁酯
在0℃下,向(2-氯乙基)氨基甲酸叔丁酯(2g,8.26mmol)和2-苯乙腈(968mg,8.26mmol)的无水DMF(20mL)溶液中分批加入NaH(60%分散在矿物油中,1.6g,41.3mmol)。将反应混合物在60℃加热16小时。反应完毕后,加冰水(30mL)淬灭,然后3×50mL)萃取。将合并的有机层用饱和食盐水(2×50mL)洗涤,然后用硫酸钠干燥,过滤并减压下浓缩。粗产物通过柱硅胶色谱法纯化(0至40%梯度的乙酸乙酯/石油醚)得到4-氰基-4-苯基哌啶-1-甲酸叔丁酯(500mg,收率:21%)。
LCMS:m/z 187.2[M-100]+.
步骤二:4-(氨基甲基)-4-苯基哌啶-1-甲酸叔丁酯
将4-氰基-4-苯基哌啶-1-甲酸叔丁酯(0.5g,1.75mmol)溶解到20mL甲醇中,然后加入钯碳(50mg),反应液在氢气下反应16小时。反应完毕后,过滤,减压下浓缩得到4-(氨基甲基)-4-苯基哌啶-1-甲酸叔丁酯(0.4g,收率:80%)。
1H NMR(400MHz,CDCl3)δ7.38(t,J=7.6Hz,2H),7.30(d,J=7.5Hz,2H),7.24(d,J=7.2Hz,1H),3.75(d,J=7.8Hz,2H),3.04(t,J=11.2Hz,2H),2.58(brs,2H),2.21(d,J=13.9Hz,2H),1.76-1.61(m,2H),1.44(s,9H)ppm;LC-MS:m/z 191.0[M-100]+.
步骤二:(4-苯基哌啶-4-基)甲胺(C-4B)
将4-(氨基甲基)-4-苯基哌啶-1-甲酸叔丁酯(0.4g,1.37mmol)溶解到10mL甲醇中,然后在室温下加入盐酸1,4-二氧六环溶液(4M,13.7mmol),反应液在室温继续反应2小时。反应完毕后,减压下浓缩得到(4-苯基哌啶-4-基)甲胺C-4B(0.25g,收率:95%),粗产品直接用于下一步反应。
LC-MS:m/z 191.2[M+H]+.
实施例11:中间体6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-硫醇钠(F-1A)的制备
步骤一:(6-氯吡啶-2-基)氨基甲酸叔丁酯
氮气保护下向干燥的250mL三口烧瓶中加入6-氯吡啶-2-胺(8g,62.2mmol)和THF(80mL),混合物在0℃下搅拌10分钟,然后加入NaHDMS(124.4mL,1.0M in THF),然后保持体系0℃下缓慢加入二碳酸二叔丁酯(16.3g,74.7mmol)的四氢呋喃溶液(50mL),继续在0℃反应4小时。反应完毕后,加入H2O(40mL),然后用EtOAc(3x 100mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至10%梯度的乙酸乙酯/石油醚),得到(6-氯吡啶-2-基)氨基甲酸叔丁酯(7g,收率:49%)。
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),7.79-7.58(m,2H),7.02(dd,J=5.5,2.9Hz,1H),1.38(s,9H)ppm;LCMS:m/z 288.1[M+H]+.
步骤二:(5,6-二氯吡啶-2-基)氨基甲酸叔丁酯
向干燥的100mL圆底烧瓶中加入(6-氯吡啶-2-基)氨基甲酸叔丁酯(7g,30.6mmol)和N,N-二甲基甲酰胺(50mL),混合物在室温下搅拌10分钟,然后加入N-氯代丁二酰亚胺(4.50g,33.67mmol),混合物在100℃下反应4小时。反应完毕后,反应夜温度降至室温后加入H2O(50mL),然后用乙酸乙酯(3x80mL)萃取,然后用饱和氯化锂水溶液洗涤(2x40mL)。将有机相用MgSO4干燥,过滤并减压浓缩,得到的残留物通过硅胶色谱法纯化(0至5%梯度的乙酸乙酯/石油醚),得到(5,6-二氯吡啶-2-基)氨基甲酸叔丁酯(5.3g,收率:65.8%)。
1H NMR(400MHz,CDCl3)δ7.86(d,J=8.7Hz,1H),7.69(d,J=8.7Hz,1H),7.24(s,1H),1.51(s,9H);LCMS:m/z 207.1[M-55]+.
步骤三:(5,6-二氯-4-碘吡啶-2-基)氨基甲酸叔丁酯
氮气保护下向干燥的100mL圆底烧瓶中加入(5,6-二氯吡啶-2-基)氨基甲酸叔丁酯(5.3g,20.14mmol)和四氢呋喃(50mL),在-78℃下缓慢滴加正丁基锂(44.3mmol,2.5M inTHF),反应液在此温度下继续搅拌1小时。然后缓慢滴加碘(3.07g,24.17mmol)的四氢呋喃(20mL)溶液,此反应也在-78℃继续反应3小时。反应完毕后,加入H2O(50mL),随后用EtOAc(3x 80mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压浓缩,得到的残留物通过硅胶色谱法纯化(0至5%梯度的乙酸乙酯/石油醚),得到(5,6-二氯-4-碘吡啶-2-基)氨基甲酸叔丁酯(4.3g,收率:55%)。
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.36(s,1H),1.46(s,9H)ppm;LCMS:m/z334.1[M-55]+.
步骤四:3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫代)丙酸甲酯
氮气保护下向干燥的100mL圆底烧瓶中依次加入(5,6-二氯-4-碘吡啶-2-基)氨基甲酸叔丁酯(3.2g,8.22mmol),醋酸钯(92mg,0.41mmol),Xantphos(285mg,0.49mmol),DIPEA(2.12g,16.46mmol)和1,4-二氧六环(30mL)。此反应混合物在100℃加热搅拌2小时。过滤并减压浓缩,得到的残留物通过硅胶色谱法纯化(0-30%梯度的乙酸乙酯/石油醚),得到3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫代)丙酸甲酯(3g,收率:96%)。
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.73(s,1H),3.64(s,3H),3.26(t,J=6.9Hz,2H),2.82(t,J=6.9Hz,2H),1.46(s,9H)ppm;LCMS:m/z 326.3[M-55]+.
步骤五:6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-硫醇(F-1A)
向干燥的100mL圆底烧瓶中依次加入3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫代)丙酸甲酯和四氢呋喃(30mL),然后再室温下缓慢滴加乙醇钠的乙醇溶液(21%,6mL),该反应液在室温搅拌1小时。减压下浓缩,然后加入二氯甲烷(10mL),析出大量棕色固体,过滤,并用二氯甲烷洗涤,干燥后得到6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-硫醇钠,然后将硫醇钠用1N HCl,酸化至pH=3,混合物直接减压下旋干,得到的粗品F-1A(2.1g,)直接用于下一步反应
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.61(s,1H),1.41(s,9H)ppm;LCMS:m/z262.2[M-55]+.
按照实施例11的合成方法,用类似的中间体原料反应得到以下中间体F-1B、F-1C、F-1D、F-1E、F-1F、F-1G、F-1H、F-1I、F-1J、F-1K。
实施例12:中间体3-氯-2-甲基吡啶-4-硫醇钠(F-1L)的制备
步骤一:3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯
合成中间体F-1G过程中得到的中间体3-((2,3-二氯吡啶-4-基)硫基)丙酸甲酯用于以下反应。
氮气保护下向干燥的100mL圆底烧瓶中依次加入3-((2,3-二氯吡啶-4-基)硫基)丙酸甲酯(500mg,1.88mmol),Pd(PPh3)4(217mg,0.188mmol),三甲基环三硼氧烷(354mg,2.82mmol),碳酸钾(389mg,2.82mmol)和1,4-二氧六环(10mL)。此反应混合物在氮气保护下100℃加热搅拌6小时。过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至40%梯度的乙酸乙酯/石油醚),得到3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯(320mg,收率:69%)。
步骤二:3-氯-2-甲基吡啶-4-硫醇钠(F-1L)
向干燥的100mL圆底烧瓶中依次加入3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲酯(320mg,1.30mmol)和四氢呋喃(10mL),然后再室温下缓慢滴加乙醇钠的乙醇溶液(21%,2mL),该反应液在室温搅拌1小时。减压下浓缩,然后加入二氯甲烷(10mL),析出大量棕色固体,过滤,并用二氯甲烷洗涤,干燥后得到3-氯-2-甲基吡啶-4-硫醇钠,然后将硫醇钠用1NHCl,酸化至pH=3,混合物直接减压下旋干,得到的粗品F-1L(200mg)直接用于下一步反应
1H NMR(400MHz,DMSO-d6)δ7.37(d,J=4.8Hz,1H),6.97(d,J=4.8Hz,1H),2.31(s,3H)ppm;LCMS:m/z 160.0[M+H]+.
实施例13:中间体6-((叔丁氧基羰基)氨基)-3-氯-2-甲基吡啶-4-硫醇钠(F-1M)的制备
步骤一:3-((6-((叔丁氧基羰基)氨基)-3-氯-2-甲基吡啶-4-基)硫代)丙酸甲酯
合成中间体F-1A过程中得到的中间体3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫代)丙酸甲酯用于以下反应。
氮气保护下向干燥的100mL圆底烧瓶中依次加入3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫代)丙酸甲酯(600mg,1.57mmol),[1,1'-双(叔丁基膦)二茂铁二氯化钯(103mg,0.157mmol),三甲基环三硼氧烷(301mg,2.4mmol),碳酸钾(331mg,2.4mmol),1,4-二氧六环(10mL)和水(1mL)。此反应混合物在氮气保护下100℃加热搅拌6小时。过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至40%梯度的乙酸乙酯/石油醚),得到3-((6-((叔丁氧基羰基)氨基)-3-氯-2-甲基吡啶-4-基)硫代)丙酸甲酯(420mg,收率:74%)。
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.64(s,1H),3.64(s,3H),3.21(t,J=6.9Hz,2H),2.80(t,J=6.9Hz,2H),1.46(s,9H)ppm;LCMS:m/z 361.1[M+H]+.
步骤二:6-((叔丁氧基羰基)氨基)-3-氯-2-甲基吡啶-4-硫醇钠(F-1M)
向干燥的100mL圆底烧瓶中依次加入3-((6-((叔丁氧基羰基)氨基)-3-氯-2-甲基吡啶-4-基)硫代)丙酸甲酯(420mg,1.17mmol)和四氢呋喃(10mL),然后再室温下缓慢滴加乙醇钠的乙醇溶液(21%,2mL),该反应液在室温搅拌1小时。减压下浓缩,然后加入二氯甲烷(10mL),析出大量棕色固体,过滤,并用二氯甲烷洗涤,干燥后得到6-((叔丁氧基羰基)氨基)-3-氯-2-甲基吡啶-4-硫醇钠然后将硫醇钠用1N HCl,酸化至pH=3,混合物直接减压下旋干,得到的粗品F-1M(320mg)直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.63(s,1H),3.64(s,3H),1.46(s,9H)ppm;LCMS:m/z 275.0.
实施例14:中间体3-氨基-2-氯苯硫醇盐酸盐(F-1N)的制备
步骤一:2-氯-3-氨基苯硫醇叔丁酯
氮气保护下向干燥的100mL圆底烧瓶中依次加入2-氯-3-氟苯胺(5g,34.3mmol)和N-甲基吡咯烷酮(50mL),然后加入2-甲基丙烷-2-硫醇(8.66g,96.04mmol)和碳酸铯(22.36g,68.6mmol),反应混合物在120℃加热搅拌16小时。冷却到室温后,反应液用60mL乙酸乙酯稀释,并用依次用饱和氯化锂水溶液(30mL),水(30mL)和饱和氯化钠水溶液(30mL)洗涤,然后用无水硫酸钠干燥,过滤,减压浓缩得到2-氯-3-氨基苯硫醇叔丁酯(6.04g,收率:82%)。
LCMS:m/z 216.1[M+H]+.
步骤二:3-氨基-2-氯苯硫醇盐酸盐(F-1N)
向干燥的100mL圆底烧瓶中加入2-氯-3-氨基苯硫醇叔丁酯(6.04g,28mmol)和浓盐酸(50mL),反应混合物在45℃加热搅拌8小时。自然冷却到室温后,将反应液继续冷却到0℃,大量白色固体析出,过滤,然后依次用浓盐酸,石油醚洗涤得到3-氨基-2-氯苯硫醇盐酸盐F-1N(4.9g,收率:90%)。
LCMS:m/z 160.0[M+H]+.
实施例15:化合物1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-胺的制备
步骤一:(1-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯
在氮气保护下,向干燥的50mL单口烧瓶中依次加入5-氯-8-碘-[1,2,4]***并[4,3-c]嘧啶E1(50mg,0.18mmol)、(4-甲基哌啶-4-基)氨基甲酸叔丁酯(77mg,0.36mmol)、DIEA(46mg,0.36mmol)和NMP(5mL),然后在90℃下搅拌反应2小时。反应完毕后,将获得的残留物倒入水(10mL),于室温下搅拌5分钟。然后用乙酸乙酯(3x50mL)萃取,将合并的有机相用MgSO4干燥,过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至80%梯度的乙酸乙酯/石油醚),得到淡黄色固体(1-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(60mg,收率:73%)。
LCMS:m/z 459.1[M+H]+.
步骤二:(1-(8-((2,3-二氯苯基)硫基)咪唑并[1,2-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯
在干燥的50mL三口烧瓶瓶中依次加入(1-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(60mg,0.13mmol)、碘化亚铜(3mg,0.013mmol)、1,10-菲罗啉(5mg,0.026mmol)、2,3-二氯苯硫酚(36mg,0.2mmol)、磷酸钾(60mg,0.26mmol)和5mL的二氧六环。该混合物在氮气的保护下加热反应3小时。反应结束后,加入饱和NH4Cl溶液(10mL)。然后用乙酸乙酯(3x50mL)萃取。合并的有机相用Na2SO4干燥,过滤,滤液减压浓缩,将得到的残留物通过硅胶色谱法纯化(0至60%梯度的乙酸乙酯/石油醚),得到淡黄色固体(1-(8-((2,3-二氯苯基)硫基)咪唑并[1,2-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(25mg,收率:38%)。
LC-MS:m/z 510.1[M+H]+.
步骤三:1‐(8‐((2,3‐二氯苯基)硫代)‐[1,2,4]***并[4,3‐c]嘧啶‐5‐基)‐4‐甲基哌啶‐4‐胺
在干燥的50mL圆底烧瓶中依次加入(1-(8-((2,3-二氯苯基)硫基)咪唑并[1,2-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(25mg,0.049mmol)和盐酸的1,4-二氧六环溶液(7M,5mL),室温反应1小时。反应结束后,加入饱和NaHCO3溶液(10mL)。然后用乙酸乙酯(3x50mL)萃取。合并的有机相用Na2SO4干燥,过滤,滤液减压浓缩,所得粗产品用高效液相色谱纯化得到产物1-(8-((2,3-二氯苯基)硫代)咪唑并[1,2-c]嘧啶-5-基)-4-甲基哌啶-4-胺(10mg,收率:49%)。
1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.00(s,1H),7.42(t,J=8.4Hz,1H),7.14(t,J=8.0Hz,1H),6.80(t,J=15.0Hz,1H),3.78(dd,J=35.6,5.8Hz,4H),1.75(s,4H),1.26(s,3H)ppm;LC-MS:m/z 410.1[M+H]+.
根据实施例15的合成方法,可以合成以下化合物:
实施例16:1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)哌啶-4-胺
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.31(s,1H),8.02(s,1H),7.44(d,J=6.9Hz,1H),7.14(t,J=8.1Hz,1H),6.83(d,J=8.0Hz,1H),4.18(d,J=13.5Hz,2H),3.44(d,J=7.1Hz,1H),3.27(s,2H),1.99(d,J=10.9Hz,2H),1.68(d,J=9.9Hz,2H)ppm;LC-MS:m/z 395.0[M+H]+.
实施例17:(1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-苯基哌啶-4-基)甲胺
1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),7.99(s,1H),7.46(dt,J=22.1,7.5Hz,5H),7.33(t,J=6.8Hz,1H),7.13(t,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),3.97(d,J=14.4Hz,2H),3.45-3.37(m,2H),2.98(s,2H),2.38(d,J=14.8Hz,2H),2.06(t,J=10.4Hz,2H)ppm;LC-MS:m/z 485.1[M+H]+.
实施例18:(1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)吡咯烷-3-基)甲胺
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),7.92(s,1H),7.86(brs,2H),8.42(d,J=8.0Hz,1H),7.14(t,J=8.0Hz,1H),6.74(d,J=8.0Hz,1H),4.16-3.93(m,4H),3.77-3.72(m,1H),3.01-2.97(m,1H),2.66-2.58(m,1H),2.25-2.18(m,2H),1.88-1.76(m,1H)ppm;LC-MS:m/z 395.1[M+H]+.
实施例19:(1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)甲胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.98(s,1H),7.43(dd,J=8.0,1.3Hz,1H),7.14(t,J=8.0Hz,1H),6.82(dd,J=8.1,1.3Hz,1H),3.92-3.78(m,2H),3.64-3.55(m,2H),2.56(s,2H),1.67(ddd,J=13.2,9.4,3.7Hz,2H),1.53-1.41(m,2H),1.01(s,3H)ppm;LC-MS:m/z 423.1[M+H]+.
实施例20:2-(1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)哌啶-4-基)乙-1-胺
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.00(s,1H),7.44(d,J=8.0Hz,1H),7.14(t,J=8.0Hz,1H),6.83(d,J=8.1Hz,1H),4.20(d,J=13.3Hz,4H),3.20(d,J=12.5Hz,2H),2.83(t,J=7.7Hz,1H),1.82(d,J=12.7Hz,2H),1.59-1.49(m,2H),1.39-1.33(m,2H),1.23(s,2H)ppm;LC-MS:m/z 424.1[M+H]+.
实施例21:8-((2,3-二氯苯基)硫代)-5-(3,5-二甲基哌嗪-1-基)-[1,2,4]***并[4,3-c]嘧啶
1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.14(s,1H),8.03(s,1H),7.45(d,J=7.9Hz,1H),7.14(t,J=8.1Hz,1H),6.83(d,J=8.0Hz,1H),4.12(d,J=12.6Hz,2H),3.23(s,2H),2.94(s,2H),1.15(d,J=5.9Hz,6H)ppm;LC-MS:m/z 410.1[M+H]+.
实施例22:8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-1,8-二氮杂螺[4.5]癸烷
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.02(s,1H),7.43(d,J=8.0Hz,1H),7.14(t,J=8.0Hz,1H),6.85(d,J=8.1Hz,1H),3.97(ddd,J=14.1,6.6,3.9Hz,2H),3.62(ddd,J=13.3,8.9,3.3Hz,2H),3.30(t,J=6.7Hz,2H),2.10(ddd,J=13.1,8.8,3.7Hz,2H),2.00(p,J=6.3Hz,6H)ppm;LC-MS:m/z 435.1[M+H]+.
实施例23:4-((5-(4-氨基-4-甲基哌啶-1-基)-[1,2,4]***并[4,3-c]嘧啶-8-基)硫代)-3-氯吡啶-2-胺
1H NMR(400MHz,CD3OD-d4)δ9.24(s,1H),7.94(s,1H),7.42-7.44(d,J=5.2Hz,1H),5.93-5.94(d,J=5.6Hz,1H),3.97-4.02(d,J=14Hz,2H),3.58-3.60(t,J=10.4Hz,2H),1.92-1.98(m,4H),1.44(s,3H)ppm;LC-MS:m/z 391.1[M+H]+.
实施例24:(R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
步骤一:(R)-N-((R)-8-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺
向干燥的50mL单口烧瓶中依次加入5-氯-8-碘-[1,2,4]***并[4,3-c]嘧啶E1(50mg,0.18mmol)、(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(C-1A)(93mg,0.36mmol)、DIEA(46mg,0.36mmol)和NMP(5mL),然后在90℃下搅拌反应2小时。反应完毕后,将获得的残留物倒入水(10mL),于室温下搅拌5分钟。然后用乙酸乙酯(3x 20mL)萃取,将合并的有机相用MgSO4干燥,过滤并在减压浓缩得到的残留物通过硅胶色谱法纯化(0至80%梯度的乙酸乙酯/石油醚),得到淡黄色固体(R)-N-((R)-8-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺(80mg,收率:88%)。
LC-MS:m/z 503.1[M+H]+.
步骤二:(R)-N-((R)-8-(8-((2,3-二氯苯基)硫基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺
在干燥的50mL三口烧瓶瓶中依次加入(R)-N-((R)-8-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺(80mg,0.16mmol)、碘化亚铜(3mg,0.016mmol)、1,10-菲罗啉(6mg,0.032mmol)、2,3-二氯苯硫酚(34mg,0.192mmol)、磷酸钾(68mg,0.32mmol)和10mL的二氧六环溶液。该混合物在氮气的保护下加热反应3小时。反应结束后,加入饱和NH4Cl溶液(50mL)。将其用乙酸乙酯(3x 20mL)萃取。合并的有机相用Na2SO4干燥,过滤,滤液减压浓缩,将得到的残留物通过硅胶色谱法纯化(0至10%梯度的甲醇/乙酸乙酯),得到淡黄色固体(R)-N-((R)-8-(8-((2,3-二氯苯基)硫基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(60mg,收率:68%)。
LC-MS:m/z 553.1[M+H]+.
步骤三:(R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
在干燥的50mL圆底烧瓶中依次加入(R)-N-((R)-8-(8-((2,3-二氯苯基)硫基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.11mmol)和盐酸的1,4-二氧六环溶液(7M,5mL),室温反应1小时。反应液减压蒸馏,所得粗产品用反相高效液相色谱纯化得到产物(R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺(20mg,收率:46%)。
1H NMR(400MHz,MeOH-d4)δ9.15(s,1H),7.90(s,1H),7.23(d,J=8.0Hz,J=1.6Hz,1H),6.97(t,J=8.0Hz,1H),6.74(d,J=8.0Hz,J=1.6Hz,1H),4.03-4.11(m,2H),3.32-3.40(m,2H),3.16(t,J=6.8Hz,1H),2.11-2.14(m,1H),1.51-1.84(m,9H)ppm;LC-MS:m/z 451.1[M+H]+.
按照实施例24的合成方法,可以合成以下化合物:
实施例25:(S)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,MeOD-d4)δ9.27(s,1H),8.55(s,2H),8.02(s,1H),7.35(dd,J=8.0,1.3Hz,1H),7.08(t,J=8.1Hz,1H),6.85(d,J=8.1Hz,1H),4.19(s,3H),3.51-3.48(m,2H),3.21(s,1H),3.15(s,1H),2.31-2.14(m,1H),2.03-1.78(m,7H),1.63(s,2H)ppm;LC-MS:m/z 449.1[M+H]+.
实施例26:(S)-7-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-7-氮杂螺[3.5]壬烷-1-胺
1H NMR(400MHz,MeOH-d4)δ9.15(s,1H),8.34(brs,2H),7.90(s,1H),7.23(dd,J=8.0Hz,J=1.6Hz,1H),6.96(t,J=8.0Hz,1H),6.74(dd,J=8.0Hz,J=1.6Hz,1H),4.11(d,J=12.0Hz,1H),4.00(d,J=13.2Hz,1H),3.44-3.40(m,1H),3.35-3.28(m,1H),2.33-2.29(m,1H),2.03-1.95(m,2H),1.91-1.87(m,2H),1.80-1.70(m,3H)ppm;LC-MS:m/z 435.1[M+H]+.
实施例27:7-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-7-氮杂-螺[3.5]壬-2-胺
1H NMR(400MHz,Methanol-d4)δ9.28(s,1H),8.01(s,1H),7.34(dd,J=8.0,1.4Hz,1H),7.08(t,J=8.0Hz,1H),6.84(dd,J=8.1,1.4Hz,1H),3.90-3.83(m,1H),3.76(t,J=5.7Hz,2H),3.72–3.66(m,2H),2.45(s,2H),2.05(t,J=10.6Hz,2H),1.95(t,J=5.7Hz,1H),1.91(t,J=5.7Hz,1H)ppm;LC-MS:m/z 435.1[M+H]+.
实施例28:(4R)-2-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)八氢环戊[c]吡咯-4-胺
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),7.86(s,1H),7.39(d,J=7.9Hz,1H),7.13(d,J=8.1Hz,1H),6.73(d,J=8.1Hz,1H),4.10-4.04(m,2H),3.53(s,1H),3.16(d,J=4.8Hz,1H),2.79(s,1H),1.86-1.78(m,2H),1.55(d,J=8.5Hz,2H)ppm;LC-MS:m/z 421.1[M+H]+.
实施例29:(R)-3-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-氮杂螺[5.5]十一烷-7-胺
1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),7.98(s,1H),7.43(d,J=7.2Hz,1H),7.14(t,J=8.0Hz,1H),6.81(d,J=8.1Hz,1H),3.99(d,J=13.5Hz,2H),3.59-3.51(m,2H),2.82(d,J=4.6Hz,1H),2.14-1.11(m,14H)ppm;LC-MS:m/z464.1[M+H]+.
实施例30:(R)-1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)氮杂环庚烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.93(s,1H),7.43(d,J=7.4Hz,1H),7.14(t,J=8.1Hz,1H),6.77(d,J=8.0Hz,1H),4.15-3.99(m,2H),3.84(ddd,J=52.8,16.3,7.7Hz,2H),3.21(s,3H),2.01(dd,J=56.3,34.4Hz,5H),1.65-1.47(m,1H)ppm;LC-MS:m/z410.1[M+H]+.
实施例31:(S)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.21(s,1H),8.00(s,1H),7.47-7.39(m,1H),7.14(t,J=8.0Hz,1H),6.82(d,J=8.1Hz,1H),4.00(dd,J=8.8,6.5Hz,2H),3.73(d,J=8.5Hz,1H),3.66(d,J=8.5Hz,1H),3.54-3.46(m,2H),3.39(dd,J=8.9,5.0Hz,2H),3.21-3.17(m,1H),1.92-1.75(m,2H),1.64-1.53(m,2H)ppm;LC-MS:m/z 450.7[M+H]+.
实施例32:(R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-N-甲基-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.28(s,1H),8.00(s,1H),7.43(d,J=8.0Hz,1H),7.14(t,J=8.1Hz,1H),6.82(d,J=8.0Hz,1H),4.08(d,J=14.0Hz,2H),2.64(d,J=21.8Hz,1H),2.37(s,3H),2.06-1.14(m,12H)ppm;LC-MS:m/z 463.1[M+H]+.
实施例33:(1R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.38(d,J=3.5Hz,1H),8.37(s,1H),8.00(d,J=1.0Hz,1H),7.44(d,J=7.1Hz,1H),7.14(t,J=8.0Hz,1H),6.81(dd,J=8.1,1.1Hz,1H),4.15-4.04(m,2H),3.06-2.93(m,2H),2.15(dd,J=19.1,11.5Hz,2H),2.01-1.26(m,8H),1.06-0.99(m,3H)ppm;LC-MS:m/z 464.1[M+H]+.
实施例34:8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(CD3OD-d4)δ9.31(s,1H),8.49(s,1H),8.02(s,1H),7.34-7.37(m,1H),7.07-7.11(m,1H),6.86-6.88(m,1H),4.19-4.21(m,2H),4.10-4.12(m,2H),3.85-3.94(m,2H),3.37(m,1H),3.18(m,1H),2.04(m,2H),1.80(m,2H),1.38(s,3H)ppm;LC-MS:m/z 465.1[M+H]+.
实施例35:(3S,4S)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.18(s,1H),8.01(s,1H),7.44(d,J=7.0Hz,1H),7.14(t,J=8.0Hz,1H),6.82(d,J=7.2Hz,1H),4.12(s,1H),3.89(d,J=6.8Hz,2H),3.74(d,J=8.6Hz,1H),3.59-3.49(m,3H),3.08(d,J=4.8Hz,1H),1.96-1.81(m,2H),1.73(s,2H),1.13(d,J=6.4Hz,3H)ppm;LC-MS:m/z466.1[M+H]+.
实施例36:(3R,4R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.95(s,1H),7.40(d,J=7.9Hz,1H),7.11(t,J=8.1Hz,1H),6.78(d,J=8.0Hz,1H),4.68-4.53(m,4H),3.17-3.08(m,1H),1.89(s,2H),1.71-1.61(m,4H),1.13(d,J=6.5Hz,3H);LC-MS:m/z 465.1[M+H]+.
实施例37:1-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-胺
步骤一:(1-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯
在20mL的封管中室温下依次加入(1-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(55mg,0.12mmol),1,4-二氧六环(2mL),纯净水(0.5mL),(2,3-二氯苯基)硼酸(50mg,0.24mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg,0.012mmol)和碳酸钾(50mg,0.36mmol)。氮气鼓泡一分钟,封管加热至80摄氏度,反应6个小时。反应完毕,向反应液中加入20mL水并用乙酸乙酯(50mL×3)萃取。有机相依次用水(20mL×1),饱和食盐水(20mL×1)洗涤。收集有机相,无水硫酸钠干燥,过滤,滤液减压浓缩。用层析柱法(石油醚:乙酸乙酯=1:1)得到粗产物(1-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(33mg,产率:57%),为淡黄色固体。
LC-MS:m/z 477.1[M+H]+.
步骤二:1-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-胺
按照实施例15步骤三的方法,(1-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯脱除叔丁氧羰基后得到1-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-4-甲基哌啶-4-胺。
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.79-7.72(m,2H),7.56-7.46(m,2H),3.68(t,J=5.3Hz,4H),1.76-1.51(m,4H),1.18(s,3H)ppm;LC-MS:m/z 377.1[M+H]+.
实施例38:(R)-8-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺的合成
步骤一:(R)-N-((R)-8-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺
在20mL的封管中室温下依次加入(R)-N-((R)-8-(8-碘-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.12mmol),1,4-二氧六环(2mL),纯净水(0.5mL),(2,3-二氯苯基)硼酸(50mg,0.24mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg,0.012mmol)和碳酸钾(50mg,0.36mmol)。氮气鼓泡一分钟,封管加热至80摄氏度,反应6个小时。反应完毕,向反应液中加入20mL水并用乙酸乙酯(50mL×3)萃取。有机相依次用水(20mL×1),饱和食盐水(20mL×1)洗涤。收集有机相,无水硫酸钠干燥,过滤,滤液减压浓缩。用层析柱法(石油醚:乙酸乙酯=1:1)得到粗产物(R)-N-((R)-8-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺。(30mg,产率:48%),为淡黄色固体。
LC-MS:m/z 521.1[M+H]+.
步骤二:(R)-8-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
按照实施例24步骤三的方法,(R)-N-((R)-8-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺脱除亚磺酰基后得到(R)-8-(8-(2,3-二氯苯基)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺。
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.81-7.71(m,2H),7.58-7.45(m,2H),3.99(t,J=13.6Hz,2H),3.35(dd,J=22.9,10.6Hz,2H),3.06(t,J=6.2Hz,1H),2.09-1.35(m,10H)ppm;LC-MS:m/z 417.1[M+H]+.
按照实施例24的合成方法,可以合成以下化合物:
实施例39:(R)-3-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)-[1,2,4]***并[4,3-c]嘧啶-8-基)硫代)丙酸甲酯
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.34(s,1H),7.71(s,1H),3.88(t,J=13.3Hz,2H),3.57(s,3H),3.24(t,J=7.0Hz,4H),3.08(t,J=6.3Hz,1H),2.68-2.59(m,2H),2.03-1.39(m,10H)ppm;LC-MS:m/z 391.1[M+H]+.
实施例40:(R)-8-(8-(苯基硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.84(d,J=17.0Hz,1H),7.33-7.19(m,5H),3.98(dd,J=27.7,14.8Hz,2H),3.32(d,J=12.8Hz,2H),3.02(t,J=6.4Hz,1H),2.01-1.39(m,10H)ppm;LC-MS:m/z 381.1[M+H]+.
实施例41:(R)-8-(8-((2-氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),7.96(s,1H),7.50(dd,J=7.7,1.4Hz,1H),7.16(dtd,J=21.0,7.5,1.5Hz,2H),6.87(dd,J=7.8,1.6Hz,1H),4.07(dd,J=15.4,11.3Hz,2H),3.39(dtd,J=13.7,7.7,3.1Hz,2H),3.05(s,1H),2.00(q,J=7.9Hz,1H),1.92-1.36(m,9H)ppm;LC-MS:m/z 415.1[M+H]+.
实施例42:(R)-8-(8-((4-氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.92(s,1H),7.34(d,J=8.6Hz,2H),7.27(d,J=8.6Hz,2H),4.12-3.92(m,2H),3.35(tt,J=13.8,3.4Hz,2H),3.04(d,J=7.0Hz,1H),1.99(t,J=5.3Hz,1H),1.92-1.33(m,9H)ppm;LC-MS:m/z415.1[M+H]+.
实施例43:(R)-8-(8-((2,4-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.98(s,1H),7.70(d,J=2.2Hz,1H),7.20(dd,J=8.6,2.3Hz,1H),6.88(d,J=8.6Hz,1H),4.05(dd,J=12.3,6.8Hz,2H),2.76(t,J=7.3Hz,1H),1.94-1.75(m,4H),1.66-1.53(m,2H),1.45-1.27(m,4H)ppm;LC-MS:m/z 449.1[M+H]+.
实施例44:(R)-8-(8-((2,6-二氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.62(d,J=8.1Hz,2H),7.48(dd,J=8.7,7.5Hz,1H),7.34(s,1H),3.82(s,2H),3.21(td,J=11.7,11.3,9.1Hz,2H),2.72(t,J=7.3Hz,1H),1.85(ddt,J=11.8,7.6,3.9Hz,1H),1.77(td,J=12.6,11.4,7.3Hz,3H),1.64-1.49(m,2H),1.42-1.25(m,4H)ppm;LC-MS:m/z 449.1[M+H]+.
实施例45:(R)-8-(8-((2-异丙基苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.71(s,1H),7.36(d,J=7.7Hz,1H),7.22(ddd,J=8.0,5.5,3.1Hz,1H),7.07-7.02(m,2H),3.95(dd,J=11.9,6.8Hz,2H),3.57-3.47(m,1H),3.32-3.21(m,2H),2.75(t,J=7.3Hz,1H),1.89-1.75(m,4H),1.651.50(m,2H),1.44-1.29(m,4H),1.27(d,J=6.8Hz,6H)ppm;LC-MS:m/z423.1[M+H]+.
实施例46:(R)-8-(8-((2-甲氧苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),7.75(s,1H),7.17(ddd,J=8.5,6.1,2.8Hz,1H),7.03(d,J=8.2Hz,1H),6.80-6.74(m,2H),3.96(dd,J=12.5,8.4Hz,4H),3.86(s,3H),3.35-3.27(m,2H),2.75(t,J=7.2Hz,1H),1.90-1.76(m,2H),1.65-1.15(m,8H)ppm;LC-MS:m/z 411.1[M+H]+.
实施例47:(R)-2-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)-[1,2,4]***并[4,3-c]嘧啶-8-基)硫代)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.96(dd,J=8.2,5.3Hz,2H),7.33(t,J=7.7Hz,1H),7.24(t,J=7.4Hz,1H),6.90(d,J=8.0Hz,1H),4.04(dd,J=12.3,7.8Hz,2H),3.92(s,3H),3.39(d,J=10.5Hz,2H),2.78(t,J=7.2Hz,1H),1.89-1.29(m,10H);LC-MS:m/z 439.1[M+H]+.
实施例48:(R)-N-(4-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)-[1,2,4]***并[4,3-c]嘧啶-8-基)硫代)苯基)乙酰胺
1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.32(s,1H),8.33(s,1H),7.72(s,1H),7.53(d,J=8.5Hz,2H),7.31(d,J=8.5Hz,2H),3.93(t,J=11.8Hz,2H),3.29(s,2H),2.94(s,1H),2.02(s,3H),1.96(s,1H),1.77(t,J=11.4Hz,3H),1.67(s,1H),1.57(d,J=17.2Hz,2H),1.50-1.32(m,3H)ppm;LC-MS:m/z 396.2[M+H]+.
实施例49:(R)-8-(8-((4-氨基苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.26(d,J=15.3Hz,1H),8.37(s,1H),7.23(dd,J=33.3,27.4Hz,3H),6.55(t,J=20.4Hz,2H),3.78(dd,J=35.2,22.6Hz,4H),3.26-3.16(m,2H),3.01(t,J=6.5Hz,1H),1.98(d,J=10.5Hz,1H),1.89-1.19(m,9H)ppm;LC-MS:m/z396.1[M+H]+.
实施例50:(R)-8-(8-((3-氨基-2-氯苯基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.32(s,1H),7.87(s,1H),6.80(t,J=7.9Hz,1H),6.59(d,J=7.1Hz,1H),6.01(d,J=6.9Hz,1H),5.51(s,2H),4.03(t,J=12.0Hz,2H),3.39(s,2H),2.96(t,J=6.7Hz,1H),1.96-1.44(m,10H)ppm;LC-MS:m/z 430.1[M+H]+.
实施例51:(R)-N-(3-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)-[1,2,4]***并[4,3-c]嘧啶-8-基)硫代)-2-氯苯基)丙烯酰基酰胺
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.38(s,1H),8.34(s,1H),7.97(s,1H),7.53(d,J=7.7Hz,1H),7.12(t,J=8.0Hz,1H),6.71-6.59(m,2H),6.29(dd,J=17.1,1.8Hz,1H),5.83-5.77(m,1H),4.13-4.03(m,2H),3.53(s,2H),2.94(s,1H),1.92-1.40(m,10H)ppm;LC-MS:m/z 484.1[M+H]+.
实施例52:(R)-8-(8-(吡啶-2-基硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.36(d,J=4.7Hz,1H),7.96(s,1H),7.59(t,J=7.7Hz,1H),7.13(d,J=2.3Hz,1H),7.03(d,J=8.0Hz,1H),4.10-3.90(m,2H),3.40(d,J=11.0Hz,2H),2.82(s,1H),1.59(ddd,J=23.4,10.6,4.0Hz,10H)ppm;LC-MS:m/z382.1[M+H]+.
实施例53:(R)-8-(8-((3-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.56(s,1H),8.28(s,1H),8.19(d,J=5.3Hz,1H),8.04(s,1H),6.84(d,J=5.3Hz,1H),4.11(t,J=12.3Hz,2H),3.43(s,2H),3.00(t,J=6.7Hz,1H),1.99-1.43(m,10H)ppm;LC-MS:m/z 416.1[M+H]+.
实施例54:(R)-8-(8-((2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1HNMR(CD3OD-d4)δ9.42(s,1H),8.34(s,1H),8.03-8.05(m,2H),6.88-6.89(m,1H),4.11-4.12(m,2H),3.44-3.47(m,2H),2.89(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm;LC-MS:m/z 449.8[M+H]+.
实施例55:(R)-8-(8-((3-氯-2-甲基吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.31(s,1H),8.05(d,J=5.4Hz,1H),8.02(s,1H),6.67(d,J=5.3Hz,1H),4.10(t,J=12.9Hz,2H),3.46-3.40(m,2H),3.01(s,1H),1.99(s,1H),1.88-1.66(m,4H),1.65-1.39(m,5H)ppm;LC-MS:m/z 430.1[M+H]+.
实施例56:(R)-8-(8-((3-氯-2-(二甲氨基)吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.98(d,J=4.2Hz,1H),7.82(d,J=5.3Hz,1H),6.31(d,J=5.3Hz,1H),4.16-3.94(m,2H),3.41(dd,J=15.8,12.6Hz,2H),2.91(s,6H),2.84(dd,J=13.1,5.9Hz,1H),1.90-1.36(m,10H)ppm;LC-MS:m/z 459.1[M+H]+.
实施例57:(R)-8-(8-((2-氨基-5-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.37(s,1H),7.99(s,1H),6.56(s,1H),5.78(s,2H),5.59(s,1H),3.98(s,2H),3.72(s,1H),3.63(d,J=8.3Hz,1H),3.12(s,1H),1.67(d,J=79.0Hz,10H)ppm;LC-MS:m/z 432.1[M+H]+.
实施例58:(R)-8-(8-((6-氨基-2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.30(s,1H),8.03(s,1H),6.31(s,2H),5.71(s,1H),4.11(t,J=12.1Hz,2H),3.44(d,J=12.4Hz,2H),2.92(d,J=7.5Hz,1H),1.96-1.77(m,4H),1.70-1.64(m,2H),1.56-1.40(m,4H).
LC-MS:m/z 465.1[M+H]+.
实施例59:(R)-8-(8-((2-甲基吡啶-3-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.26(dd,J=4.7,1.5Hz,1H),7.91(d,J=3.0Hz,1H),7.31(dd,J=8.0,1.4Hz,1H),7.07(dd,J=7.9,4.7Hz,1H),4.05-3.94(m,2H),3.30(s,3H),2.80(t,J=7.3Hz,1H),2.61(s,3H),1.89-1.25(m,10H)ppm;LC-MS:m/z 449.8[M+H]+.
实施例60:(R)-8-(8-((2-(三氟甲基)吡啶-3-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.49(d,J=4.5Hz,1H),8.36(s,1H),8.02(s,1H),7.57(d,J=8.3Hz,1H),7.46(dd,J=8.3,4.5Hz,1H),4.08(s,2H),2.94(s,2H),1.98(dd,J=14.4,7.7Hz,2H),1.88-1.64(m,4H),1.52(d,J=42.8Hz,6H)ppm;LC-MS:m/z450.1[M+H]+.
实施例61:(R)-8-(8-(萘-1-基硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.39(d,J=8.2Hz,1H),8.27(d,J=11.7Hz,1H),8.00(d,J=7.7Hz,1H),7.88(d,J=7.9Hz,1H),7.73(s,1H),7.69-7.59(m,2H),7.47(d,J=7.1Hz,1H),7.44-7.38(m,1H),4.03-3.92(m,2H),3.28(s,2H),2.97(s,1H),1.68(dt,J=107.3,31.9Hz,10H)ppm;LC-MS:m/z 431.2[M+H]+.
实施例62:(R)-8-(8-(喹啉-4-基硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.54(d,J=4.7Hz,1H),8.26(d,J=8.4Hz,1H),8.11-7.99(m,2H),7.85(t,J=7.6Hz,1H),7.74(t,J=7.6Hz,1H),6.95(d,J=4.7Hz,1H),4.19-3.99(m,2H),3.43(dd,J=17.3,8.7Hz,2H),2.88(t,J=7.0Hz,1H),1.94-1.37(m,10H)ppm;LC-MS:m/z 432.2[M+H]+.
实施例63:(R)-8-(8-((1-甲基-1H-咪唑-2-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),7.54(s,1H),7.37(d,J=1.2Hz,1H),6.97(d,J=1.2Hz,1H),3.85(d,J=2.4Hz,5H),3.29-3.20(m,2H),2.73(t,J=7.3Hz,1H),1.87-1.71(m,4H),1.63-1.49(m,2H),1.42-1.25(m,4H)ppm;LC-MS:m/z 385.2[M+H]+.
实施例64:(1R)-8-(8-((2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.25(s,1H),8.04(d,J=5.3Hz,1H),8.02(s,1H),6.67(d,J=5.3Hz,1H),4.02-3.96(m,2H),3.73(d,J=8.4Hz,1H),3.64(d,J=8.5Hz,1H),3.52(d,J=10.0Hz,2H),3.18-3.09(m,3H),2.56(s,3H),1.84(dd,J=40.8,9.5Hz,2H),1.57(d,J=12.5Hz,2H)ppm;LC-MS:m/z434.1[M+H]+.
实施例65:(1R)-8-(8-((2-氨基-3-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(CD3OD-d4)δ9.37(s,1H),7.98(s,1H),7.57(s,1H),6.36(m,2H),5.93(m,1H),4.16(m,2H),3.44(m,2H),3.10(m,1H),2.42(m,1H),1.31-2.13(m,8H),1.01-1.05(m,3H)ppm;LC-MS:m/z 445.1M+H]+.
实施例66:(1R)-8-(8-((6-氨基-2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(CD3OD-d4)δ9.45-9.46(m,1H),8.04(s,1H),6.32(m,2H),5.74(m,1H),4.14-4.17(m,2H),3.45(m,2H),3.14(m,2H),1.45-2.41(m,8H),1.02-1.05(m,3H)ppm;LC-MS:m/z 479.1M+H]+.
实施例67:(S)-8-(8-((2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.08-7.99(m,2H),6.88(d,J=5.3Hz,1H),4.08-3.95(m,3H),3.75-3.66(m,2H),3.51(d,J=13.6Hz,2H),3.24-3.15(m,2H),1.93-1.75(m,2H),1.60(d,J=13.1Hz,2H),1.32(s,2H)ppm;LC-MS:m/z 452.1[M+H]+.
实施例68:(S)-8-(8-((2-氨基-3-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.28(s,1H),7.97(s,1H),7.57(d,J=5.4Hz,1H),6.34(s,2H),5.95(d,J=5.4Hz,1H),3.97(tt,J=13.8,5.4Hz,3H),3.72(d,J=8.5Hz,1H),3.64(d,J=8.4Hz,1H),3.49(dq,J=10.7,4.4,2.9Hz,2H),3.14(t,J=5.9Hz,2H),1.93-1.74(m,2H),1.57(dt,J=14.0,4.3Hz,2H)ppm;LC-MS:m/z 433.1[M+H]+.
实施例69:(S)-8-(8-((3-氯-2-甲基吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.25(s,1H),8.04(d,J=5.3Hz,1H),8.02(s,1H),6.67(d,J=5.3Hz,1H),4.02-3.96(m,2H),3.73(d,J=8.4Hz,1H),3.64(d,J=8.5Hz,1H),3.52(d,J=10.0Hz,2H),3.18-3.09(m,3H),2.56(s,3H),1.84(dd,J=40.8,9.5Hz,2H),1.57(d,J=12.5Hz,2H)ppm;LC-MS:m/z434.1M+H]+.
实施例70:(S)-8-(8-((6-氨基-2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.25(s,1H),8.04(s,1H),6.30(s,2H),5.71(s,1H),4.09-3.92(m,4H),3.73(d,J=8.4Hz,1H),3.65(d,J=8.4Hz,1H),3.49(s,2H),3.16(d,J=6.6Hz,1H),1.88(d,J=10.0Hz,2H),1.59(s,2H)ppm;LC-MS:m/z 468[M+H]+.
实施例71:(3S,4S)-8-(8-((2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.09-7.93(m,2H),6.84(d,J=5.3Hz,1H),4.10(q,J=6.1Hz,2H),3.91(dd,J=13.8,5.5Hz,4H),3.56(m,1H),2.98(d,J=5.0Hz,1H),1.98-1.55(m,4H),1.10(d,J=6.3Hz,3H)ppm;LC-MS:m/z 466.1[M+H]+.
实施例72:(3S,4S)-8-(8-((3-氯-2-甲基吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.04(d,J=5.4Hz,1H),8.01(s,1H),6.67(d,J=5.3Hz,1H),4.12-4.06(m,1H),3.86(s,2H),3.69(d,J=8.4Hz,1H),3.60(dd,J=21.1,9.5Hz,2H),3.52(d,J=8.5Hz,1H),2.96(d,J=4.9Hz,1H),2.56(s,3H),1.88(d,J=48.6Hz,2H),1.64(s,2H),1.08(dd,J=15.3,6.5Hz,3H)ppm;LC-MS:m/z 446.1[M+H]+.
实施例73:(3S,4S)-8-(8-((2-氨基-5-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.99(s,1H),7.82(s,1H),5.83(s,2H),5.76(s,1H),4.14(p,J=6.3Hz,2H),3.96(ddd,J=15.1,10.0,5.1Hz,4H),3.60(s,1H),3.14(d,J=5.0Hz,1H),1.97-1.62(m,4H),1.13(t,J=5.9Hz,3H)ppm;LC-MS:m/z 447.1[M+H]+.
实施例74:(3S,4S)-8-(8-((2-氨基-3-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(CD3OD-d4)δ9.39(s,1H),7.97(s,1H),7.57(s,1H),6.35(m,2H),5.95(m,1H),4.09-4.11(m,1H),3.86-3.90(m,2H),3.70-3.72(m,1H),3.54-3.62(m,3H),3.00-3.02(m,1H),1.93-1.95(m,1H),1.80-1.83(m,1H),1.60-1.70(m,2H),1.10-1.12(m,3H)ppm;LC-MS:m/z 447.1[M+H]+.
实施例75:(3S,4S)-8-(8-((6-氨基-2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.06(s,1H),6.31(s,2H),5.71(s,1H),4.26-4.19(m,1H),4.06(s,2H),3.88(d,J=9.1Hz,1H),3.71(d,J=8.8Hz,1H),3.57-3.37(m,4H),1.91(s,2H),1.69(s,2H),1.21(d,J=6.4Hz,3H)ppm;LC-MS:m/z 481.1[M+H]+.
实施例76:(3R,4S)-8-(8-((3-氯-2-甲基吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.41(d,J=5.4Hz,1H),8.04(d,J=5.3Hz,1H),8.01(s,1H),6.67(d,J=5.2Hz,1H),4.12(dd,J=33.3,13.6Hz,2H),3.73(dd,J=23.6,8.8Hz,2H),3.39(dd,J=16.2,10.4Hz,2H),3.30(s,1H),2.54(d,J=16.4Hz,3H),2.42(d,J=8.2Hz,1H),1.93-1.81(m,2H),1.50(d,J=13.5Hz,2H),1.21(d,J=6.0Hz,3H)ppm;LC-MS:m/z446.1[M+H]+.
实施例77:(3R,4R)-8-(8-((2-氨基-3-氯吡啶-4-基)硫代)-[1,2,4]***并[4,3-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.95(s,1H),7.55(d,J=5.4Hz,1H),6.27(s,2H),5.95(d,J=5.4Hz,1H),4.08(p,J=6.3Hz,2H),3.85-3.81(m,2H),3.55(s,2H),2.95(d,J=5.0Hz,1H),1.99-1.56(m,5H),1.09(d,J=6.4Hz,3H)ppm;LC-MS:m/z 447.1[M+H]+.
实施例78:1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-4-甲基哌啶-4-胺
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.23(s,1H),7.40(dd,J=8.0,1.2Hz,1H),7.12(t,J=8.0Hz,1H),6.74(dd,J=8.1,1.2Hz,1H),4.54-4.30(m,2H),4.15-3.94(m,2H),1.76-1.48(m,4H),1.18(s,3H)ppm;LC-MS:m/z 409.1[M+H]+.
实施例79:(R)-1-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)吖庚环-4-胺
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.21(s,1H),7.41(d,J=7.5Hz,1H),7.13(t,J=8.1Hz,1H),6.74(d,J=7.9Hz,1H),4.15(dd,J=90.0,47.9Hz,4H),3.21(s,2H),2.22(s,1H),1.94(d,J=56.0Hz,5H),1.61(d,J=12.2Hz,1H)ppm;LC-MS:m/z 408.7[M+H]+.
实施例80:(R)-3-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-3-氮杂螺[5.5]十一烷-7-胺
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.24(s,1H),7.42(d,J=7.1Hz,1H),7.12(t,J=8.0Hz,1H),6.73(d,J=8.0Hz,1H),4.84(s,2H),3.67-3.53(m,2H),2.89(d,J=4.3Hz,1H),1.98(dd,J=24.0,13.1Hz,2H),1.48(ddd,J=74.9,37.6,6.9Hz,12H)ppm;LC-MS:m/z 462.7[M+H]+.
实施例81:(3R,4S)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ8.48(d,J=6.0Hz,1H),8.23(d,J=6.3Hz,1H),7.41(d,J=8.0Hz,1H),7.12(t,J=8.1Hz,1H),6.74(d,J=8.1Hz,1H),4.95(dd,J=37.1,13.4Hz,2H),3.76(dd,J=26.2,8.9Hz,2H),3.44(d,J=7.8Hz,1H),2.42(d,J=8.1Hz,1H),1.82(t,J=11.6Hz,2H),1.50(d,J=13.6Hz,2H),1.28-1.17(m,5H)ppm;LC-MS:m/z 465.1[M+H]+.
实施例82:(S)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.32(s,1H),8.24(s,1H),7.41(dd,J=8.0Hz,1.2Hz,1H),7.13(t,J=8.0Hz,1H),6.72(dd,J=8.0Hz,J=1.6Hz,1H),4.76(t,J=16.0Hz,2H),4.06(dd,J=9.6Hz,2.4Hz,1H),3.81(s,2H),3.67-3.54(m,3H),3.35(t,J=4.8Hz,1H),1.87-1.81(m,2H),1.68-1.65(m,2H)ppm;LC-MS:m/z 451.1[M+H]+.
实施例83:(3R,4R)-8-(8-((2,3-二氯苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.23(s,1H),7.41(d,J=8.0Hz,1H),7.12(t,J=8.1Hz,1H),6.74(d,J=8.1Hz,1H),4.45(d,J=13.1Hz,2H),4.11-4.05(m,2H),3.96-3.80(m,2H),2.96(d,J=5.1Hz,1H),2.01-1.93(m,2H),1.78-1.56(m,4H),1.09(d,J=6.4Hz,3H);LC-MS:m/z 465.1[M+H]+.
实施例84:(R)-8-(8-(苯基硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.17(s,1H),7.29-7.24(m,2H),7.18(dd,J=12.1,7.2Hz,3H),4.86(t,J=11.7Hz,2H),3.44(t,J=12.5Hz,2H),3.01(t,J=6.7Hz,1H),1.97(dd,J=12.7,7.3Hz,1H),1.85-1.41(m,9H)ppm;LC-MS:m/z 381.2[M+H]+.
实施例85:(R)-8-(8-((2-甲氧苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.34(s,1H),8.10(s,1H),7.14(t,J=7.8Hz,1H),7.02(d,J=8.2Hz,1H),6.75(t,J=7.6Hz,1H),6.64(d,J=7.7Hz,2H),4.87(d,J=12.5Hz,3H),3.88(s,2H),2.93(d,J=7.2Hz,1H),2.02-1.92(m,2H),1.82-1.37(m,8H)ppm;LC-MS:m/z 411.1[M+H]+.
实施例86:(R)-8-(8-((4-氨基苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.35(s,1H),7.75(s,1H),7.21(d,J=8.2Hz,2H),6.52(d,J=8.4Hz,2H),5.39(s,2H),4.69(s,2H),2.87(s,1H),1.93-1.30(m,10H)ppm;LC-MS:m/z 396.2[M+H]+.
实施例87:(R)-8-(8-((2-(三氟甲基)苯基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.47(d,J=10.2Hz,1H),8.22(d,J=11.4Hz,1H),7.57(s,1H),7.54-7.36(m,3H),4.97-4.72(m,2H),3.47(t,J=9.7Hz,2H),2.72(t,J=7.5Hz,1H),1.83-1.26(m,10H);LC-MS:m/z 449.1[M+H]+.
实施例88:(R)-8-(8-(吡啶-3-基硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.36(s,1H),8.17(s,1H),7.27(d,J=7.6Hz,2H),7.23-7.13(m,3H),4.86(t,J=12.3Hz,2H),3.47(d,J=2.6Hz,2H),2.96(t,J=7.0Hz,1H),1.98(q,J=5.7,4.2Hz,1H),1.92-1.34(m,9H)ppm;LC-MS:m/z 382.2[M+H]+.
实施例89:(R)-8-(8-((3-氯吡啶-4-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(CD3OD-d4)δ8.50-8.54(m,2H),8.37(s,1H),8.26(m,1H),8.16-8.17(s,1H),6.79-6.80(m,1H),4.94(m,2H),3.48-3.53(m,2H),2.91(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm;LC-MS:m/z 416.1[M+H]+.
实施例90:(R)-8-(8-((3-(三氟甲基)吡啶-4-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.49(s,1H),8.42(d,J=5.5Hz,1H),8.35(s,1H),8.28(s,1H),7.01(d,J=5.5Hz,1H),4.96(s,2H),3.51(t,J=11.8Hz,3H),2.96(t,J=7.0Hz,1H),2.02-1.35(m,10H)ppm;LC-MS:m/z 450.1[M+H]+.
实施例91:(R)-8-(8-((2-氯吡啶-3-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(CD3OD-d4)δ8.49(m,1H),8.36(s,1H),8.26(m,1H),8.16-8.18(s,1H),7.20-7.23(m,2H),4.96-4.94(m,2H),3.50-3.46(m,2H),2.96-2.90(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm.LC-MS:m/z 416.1[M+H]+.
实施例92:(R)-8-(8-((2-甲基吡啶-3-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.24-8.22(m,1H),8.21(s,1H),7.22(d,J=8.1Hz,1H),7.04(dd,J=7.9,4.5Hz,1H),3.52-3.44(m,2H),3.18-3.10(m,3H),2.59(s,3H),2.04(s,1H),1.86-1.35(m,9H)ppm.LC-MS:m/z 396.1[M+H]+.
实施例93:(R)-8-(8-((6-氨基-2-氯吡啶-3-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.98(s,1H),7.40(d,J=8.5Hz,1H),6.61(s,2H),6.33(d,J=8.5Hz,1H),4.78(s,2H),3.16(d,J=5.0Hz,1H),3.04(s,1H),2.67(s,2H),1.82-1.40(m,10H)ppm;LC-MS:m/z 431.2[M+H]+.
实施例94:(R)-8-(8-((2-氨基-3-氯吡啶-4-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(CD3OD-d4)δ8.48(s,1H),8.20(s,1H),7.55(s,1H),6.36(s,2H),5.87(m,1H),4.90(m,2H),3.45-3.48(m,2H),2.74-2.76(m,1H),1.76-1.83(m,4H),1.51-1.63(m,2H),1.35-1.46(m,4H)ppm;LC-MS:m/z 431.1M+H]+.
实施例95:(R)-8-(8-((6-氨基-2,3-二氯吡啶-4-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-8-氮杂螺[4.5]癸烷-1-胺
1H NMR(400MHz,CD3OD-d4)δ8.25(s,1H),8.09(s,1H),5.64(s,1H),5.06(s,2H),3.45-3.37(m,2H),2.73(t,J=7.5Hz,1H),1.97-1.67(m,5H),1.54(dd,J=11.6,5.0Hz,2H),1.46-1.31(m,3H)ppm;LC-MS:m/z 467.1M+H]+.
实施例96:(S)-8-(8-((3-氯-2-甲基吡啶-4-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.24(d,J=3.4Hz,2H),8.03(d,J=5.3Hz,1H),6.61(d,J=5.4Hz,1H),4.02-3.97(m,2H),3.78(s,2H),3.69(s,2H),3.17(s,3H),2.55(s,3H),1.80(d,J=27.7Hz,2H),1.59(s,2H)ppm;LC-MS:m/z434.1[M+H]+.
实施例97:(3S,4S)-8-(8-((3-氯-2-甲基吡啶-4-基)硫代)-[1,2,4]***并[1,5-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.23(s,1H),8.01(d,J=5.3Hz,1H),6.59(d,J=5.4Hz,1H),4.60(d,J=13.5Hz,2H),4.13(d,J=5.9Hz,1H),3.75(dd,J=21.8,9.9Hz,4H),3.14(d,J=19.8Hz,1H),2.54(s,3H),1.97-1.60(m,4H),1.13(d,J=6.4Hz,3H)ppm;LC-MS:m/z 446.1[M+H]+.
实施例98-100药理相关实施例
实施例98:SHP2酶活性抑制实验
化合物粉末溶于DMSO中制成母液。实验时,化合物存贮液用DMSO进行3-倍梯度稀释,同一化合物设置10个不同的测试浓度。取1μL各浓度点的化合物至检测板(Corning,Costar 3915)孔内,每个浓度点设置2个平行重复。所用蛋白为第76位氨基酸突变的活性蛋白SHP2E76A,所用底物为DiFMUP(Invitrogen,E12020)。SHP2E76A蛋白和底物分别用缓冲液(0.1M NaAc(pH7.2),0.02%Tween 20,0.1%BSA,1mM EDTA,5mM DTT)稀释至1.2nM和20μM。向检测孔中加入50μL酶溶液,随之再加入50μL底物。在Spectra max i3(MolecularDevices)仪器上,每隔1分钟记录(Ex 358nm/Em 455nm)一次荧光信号,以此算出产物的积累速率以表征酶活性。用GraphPad Prism 5进行非线性回归分析,通过Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))方程拟合出酶活性随化合物浓度变化的曲线。求得各化合物的IC50值。结果
下表显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nM;
字母B代表IC50为100nM至1000nM;
字母C代表IC50为1000nM至10000nM;
实施例99磷酸化蛋白激酶(p-ERK)细胞实验
通过AlphaLISA方法检测化合物抑制细胞内蛋白激酶(ERK)的磷酸化水平。
第一步化合物处理细胞。待测化合物先用100%DMSO进行3-倍稀释,共设置9个不同的浓度梯度;接着以每孔30000个细胞密度接种MOLM13细胞到96孔板,每孔体积100μL;随后每孔分别加入0.5μL的DMSO或者不同浓度的待测化合物,每个浓度设置2个重复,DMSO的终浓度控制在0.5%。
第二步裂解细胞。细胞处理2小时之后,除去培养基,磷酸缓冲盐溶液洗涤细胞3次,每孔加入50μl新鲜配置的裂解缓冲液,震荡并室温放置10分钟。第三步 UltraTMp-ERK 1/2(Thr202/Tyr204)试剂盒(Perkin Elmer,ALSU-PERK-A10K))检测磷酸化的细胞外信号调节激酶(p-ERK)。取10μl的上述裂解液至384孔板(Perkin Elmer,6005350),根据产品说明书检测样品的细胞外信号调节激酶的磷酸化水平。使用Spectra max i3(Molecular Devices)上的AlphaScreen检测器读取信号。抑制百分率(%)通过以下公式计算获得:
抑制百分率(%)=(1-化合物处理细胞的p-ERK信号/DMSO处理细胞的p-ERK信号)*100
结果
下表显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nM;
字母B代表IC50为100nM至1000nM;
字母C代表IC50为1000nM至10000nM;
实施例100细胞增殖实验
悬浮于培养基(RPMI-1640,含10%FBS和1%Penicillin-Streptomycin,Gibco)中的MOLM-13细胞以800个细胞(40μL/孔)接种到384孔板上。细胞立即用待测化合物进行处理,化合物浓度分别为50,16.67,5.56,1.85,0.617,0.206,0.069,0.023,0.0076μΜ。3天后,每孔加入5μL的CellTiter-Glo试剂(Promega,ZG7572),室温避光放置10分钟。通过Spectra max i3(Molecular Devices)检测荧光信号。处理细胞的相对生长率与DMSO对照进行比较。
结果
下表显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nM;
字母B代表IC50为100nM至1000nM;
字母C代表IC50为1000nM至10000nM;
按照实施例98所述的SHP2酶活性抑制实验、实施例99所述的磷酸化蛋白激酶(p-ERK)细胞实验和实施例100所述的MOLM-13细胞增殖实验相同的测试方法,申请人针对WO2015/107493 A1或文献(Nature 2016,535,148-152)所公开化合物SHP099(6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-胺)进行了相应的实验,下表中列举了本发明部分实施例所得化合物与SHP099的对比实验数据,通过对比后发现,本发明所述的嘧啶并环化合物具有更优越的活性。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (21)
1.式(I)所示的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,
其中
Z1为C、Z2为N或Z1为N、Z2为C;
X独立地为S或不存在;
Y独立地为C或N;
n独立地为0、1或2;
R1独立地为0-4个R1a取代的苯基、0-4个R1a取代的含有1-4个氮杂芳基、0-4个R1a取代的萘基、0-4个R1a取代的含有1-4个氮杂萘芳基、0-4个R1a取代或未取代的苯并杂环、0-4个R1a取代或未取代的含有1-4个氮杂芳并环、0-4个R1a取代的含有1-4个N、NR1b、O或S(O)m杂原子的杂芳环、R1c取代或未取代的C1-8烷基、R1c取代或未取代的C1-8卤代烷基;其中m选自0、1和2;
R1a独立的为卤素、R1a1取代或未取代的C1-4烷氧基、R1a1取代或未取代的C1-4烷基、三氟甲基、C(=O)OR1a2、NR1a2R1a3、NHC(=O)R1a4、R1a1取代或未取代的C3-8环烷基;R1a1独立的为卤素或C1-4烷基;R1a2、R1a3独立的为氢、C1-4烷基;R1a4独立的为C1-4烷基、取代或未取代的烯基、酰胺、C3-12单或多杂环;
R1b独立的为氢、R1a1取代或未取代的C1-4烷基;
R1c独立的为氢、-C(=O)OR1a2、R1a1取代或未取代的C1-4烷基;
R2a、R2b、R3a和R3b独立的为氢、R1a1取代或未取代的C1-4烷基;
当Y=N时,R4独立的为氢、R1a1取代或未取代的C1-4烷基;R5不存在;
当Y=C时,R4、R5独立的为氢、芳基、C1-4烷基、C1-4烷氧基、-O-C1-4烷基、氨基、C1-4烷基取代氨基、-O-C1-4烷基取代氨基,或者R4和R5与Y一起形成0-3个R4a取代的3至7元饱和或部分不饱和的螺环,该环可任选含有1-3个独立的选自N、C(=O)和/或O杂原子或基团;
R4a独立的为氢、卤素、R1a1取代或未取代的C1-4烷氧基、R1a1取代或未取代的C1-4烷基、羟基、氨基、C1-4烷基氨基。
3.如权利要求1所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,其中R2a、R2b、R3a和R3b独立地为氢或甲基。
4.如权利要求1所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,其中当Y=N时,R4独立的为氢、甲基;R5不存在。
5.如权利要求1所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,其中当Y=C时,R4、R5独立的为氢、甲基、乙基、苯基、氨基、甲基氨基或乙基氨基。
7.如权利要求1所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,其中当Y=C时,R4和R5与Y一起形成的环为以下构型:
其中,p为0、1、2或3;R4a如权利要求1定义。
9.一种如权利要求1-8任一项所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体、溶剂化物或其同位素标记化合物,所述同位素选自2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。
15.一种如权利要求1-8任一项所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求9所述的同位素标记化合物在制备预防和/或治疗与SHP2活性异常相关疾病或病症的药物方面的用途。
16.一种如权利要求15所述的用途,所述疾病或病症选自努南综合症、豹综合症、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤或成胶质细胞瘤。
17.一种药物组合物,包含根据权利要求1-8任一项所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求9所述的同位素标记化合物、以及药学上可接受的辅料。
18.一种药物制剂,包含权利要求1-8任一项所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求9所述的同位素标记化合物。
19.一种如权利要求18所述的药物制剂,所述药物制剂的给予方式选自:口服、舌下含服、皮下注射、静脉注射、肌肉注射、胸骨内注射、鼻部服用、局部表面给药或直肠给药。
20.一种如权利要求18所述的药物制剂,所述药物制剂每天单次服用或多次服用。
21.一种如权利要求1-8任一项所述的嘧啶并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求9所述的同位素标记化合物与其他药物联合使用的产品,所述其他药物选自:抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药、细胞保护药物。
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