WO2023065606A1 - 新型氘代氰基类化合物、其制备方法、组合物及应用 - Google Patents
新型氘代氰基类化合物、其制备方法、组合物及应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention belongs to the field of medicine, and in particular relates to a novel deuterated cyano compound, its preparation method, composition and application, and the above-mentioned pharmaceutical composition is used to prepare medicine for treating and preventing viral infection.
- the coronavirus in the human body was first isolated in the UK in the 1960s.
- the virus got its name from the crown-shaped protrusions on its surface. It may be associated with respiratory infections in humans, pigs, cats, dogs, rats and chickens.
- the SARS virus belongs to the order Nesting Viridae, Coronaviridae, and the genus Coronaviridae, and is a subgroup B coronavirus of the genus Beta. Most of the virus particles are round, with a capsule, and there are coronal-arranged fibers around the periphery. They are distributed in the cytoplasm and are round. The diameter of the virus is between 80 and 120nm.
- SARS is an infectious disease with rapid onset, rapid spread and high fatality rate.
- MERS virus is a ⁇ genus C subgroup coronavirus, its full name is Middle East Respiratory Syndrome Coronavirus (MERS-CoV for short), and it causes Middle East Respiratory Syndrome (Middle East Respiratory Syndrome, MERS for short) after infection. ).
- MERS-CoV was first discovered in Saudi Arabia in September 2012. It was named "SARS-like virus” because of its similar clinical symptoms to SARS. It also became the sixth known human coronavirus and the first isolated in the past 10 years. 3 types.
- the new coronavirus is a new strain of coronavirus that has never been found in humans before. It was first discovered and reported in 2019, and it is still raging in many countries around the world, and has not been well controlled in many countries and regions.
- coronavirus Common signs after a person is infected with a coronavirus include respiratory symptoms, fever, cough, shortness of breath, and dyspnea. In more severe cases, infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death. There is no specific treatment for the disease caused by the new coronavirus.
- the present invention designs and discloses novel deuterated cyano compounds, on the basis of comparable activity of virus inhibitors , achieving better pharmacokinetic properties and therapeutic effects than PF-07321332, and better druggability.
- the preparation method, pharmaceutical composition and application thereof are disclosed, the production scale-up of the medicine can be realized, and the medicine has good clinical value.
- the present invention relates to novel deuterated cyano compound, its preparation method, composition and application.
- the present invention discloses a deuterated cyano compound represented by formula I, or a pharmaceutically acceptable salt, isomer or prodrug thereof:
- R 1 ⁇ R 17 are combinations of “hydrogen” isotopes (including isotopes “protium” and “deuterium”);
- the above compound is characterized in that at least one of R 1 to R 2 is deuterium, at least one of R 6 to R 7 is deuterium, and R 9 to R 17 are all deuterium.
- the invention discloses a preparation method of deuterated cyano compounds, which comprises the following steps:
- the invention discloses a pharmaceutical composition, which is characterized in that it contains a pharmaceutically acceptable carrier and a compound described in formula I, or a pharmaceutically acceptable salt thereof.
- the invention discloses a pharmaceutical composition, which is characterized in that it is saturated with another therapeutic drug, and the additional therapeutic drug is an antiviral drug.
- the invention discloses the use of the above-mentioned pharmaceutical composition, which is characterized in that it is used for preparing a pharmaceutical composition for inhibiting 3CL protease.
- the invention discloses the application of the above pharmaceutical composition, wherein the virus infects human coronavirus, new coronavirus (SARS-CoV-2), SARS coronavirus and MERS coronavirus.
- SARS-CoV-2 new coronavirus
- SARS coronavirus SARS coronavirus
- MERS coronavirus MERS coronavirus
- the compound has one of the structures shown in Table 1 below.
- the present invention contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein.
- the pharmaceutical compositions are in the form of tablets, capsules, pills, or aqueous buffers, such as saline or phosphate buffers.
- the present invention relates to the use of the compounds described herein in the preparation of a medicament for the treatment or prevention of viral infections, such as human coronavirus, new coronavirus (SARS-CoV-2), SARS Coronavirus and MERS-CoV infection.
- viral infections such as human coronavirus, new coronavirus (SARS-CoV-2), SARS Coronavirus and MERS-CoV infection.
- the present invention is directed to methods of preparing compounds by admixing the starting materials and reagents disclosed herein under conditions that form the compounds disclosed herein.
- the present invention designs and discloses a novel deuterated cyano compound, which realizes better pharmacokinetic properties and therapeutic effects than PF-07321332 on the basis of equivalent virus inhibitor activity, and better druggability.
- the preparation method, pharmaceutical composition and application thereof are disclosed, the production scale-up of the medicine can be realized, and the medicine has good clinical value.
- LiHMDS lithium bis(trimethylsilyl)amide
- Ru/C ruthenium carbon
- TFAA (10.2g, 0.1mol) was added dropwise to compound F (23g, 0.085mol), TEA (38.6g, 0.382mol) in DCM (230ml) solution, after the addition, the reaction adjusted Stir at room temperature for 12 hours. After the basic reaction of the raw materials was detected by TCL, the reaction solution was washed with water and saturated sodium chloride in sequence, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain white solid powder G: 18.2 g, with a yield of 85%.
- Compound H-4D can be synthesized according to the representative routes described in Example 2 and Example 4.
- Embodiment 6 is a diagrammatic representation of Embodiment 6
- Embodiment 7 is a diagrammatic representation of Embodiment 7:
- Embodiment 8 is a diagrammatic representation of Embodiment 8
- Compound K-9D can be synthesized according to the representative route described in Example 6.
- Embodiment 9 is a diagrammatic representation of Embodiment 9:
- Compound K-10D can be synthesized according to the representative route described in Example 7.
- Vero E6 cells were seeded into 12-well plates at 3 ⁇ 105 cells/well, added with 10% FBS in DMEM medium, and cultured overnight in a 37°C, 5% CO2 incubator.
- Drug action remove the culture medium of Vero cells in the 12-well plate, and wash the VeroE6 cells with PBS buffer; add the compound (final concentration 100nM) to 50 ⁇ L/well cell solution, and place it in a 37°C, 5% CO2 incubator for incubation After 1 hour, set 50 ⁇ L/well medium as a control.
- Virus-infected cells Infect cells with SARS-CoV-2 virus for 2 hours, remove infected virus and drug mixture, add DMEM medium with 10% FBS, and culture in 37°C, 5% CO 2 incubator for 2-3 sky.
- PCR measurement Collect the supernatant of the culture medium, put it in a 56°C incubator and keep it for 30 minutes, extract the viral RNA with the viral RNA extraction kit, and perform the PCR reaction with the viral nucleic acid detection kit according to the instructions, and the CT value displayed by the PCR instrument
- the calculation formula for calculating the 2 - ⁇ CT value virus replication inhibition rate is: (1-2 - ⁇ CT ) ⁇ 100%, wherein, 2 - ⁇ CT value is the relative virus replication rate of the drug group and the control group (tannic acid), the results see Table 2.
- This embodiment is the detection of inhibition of protease activity targeting SARS-CoV-2 virus M Pro
- 3-chymotrypsin-like protease 3-chymotrypsin-like protease
- M Pro the main protease
- ORF1 located in nsp5
- ORF5 located in the central region of the replicase gene, It is a key protein in the replication of the new coronavirus RNA. Its mechanism of action is: after the new coronavirus invades cells, it will use the host cells to synthesize two ultra-long replicase polypeptides (ppla and pplab) necessary for its own replication.
- the replicase polypeptide needs to be further cut into multiple proteins (such as RdRp, helicase, etc.), and further assembled into the replication transcription machinery required for the virus to initiate the replication of its own genetic material.
- M Pro has at least 11 cleavage sites on the replicase polypeptide, and only when these sites on the replicase polypeptide are cut normally, it is assembled into a replication transcription machine and starts virus replication.
- M Pro protease is very important in the process of virus replication, and there is no similar protein in the human body, the main protease M Pro becomes a potential key drug target against the new coronavirus.
- the inhibitory activity of nucleoside derivatives against SARS-CoV-2-M Pro protease was evaluated by fluorescence resonance energy transfer method.
- the volume of the entire enzymatic reaction system is 120 ⁇ L
- the final concentration of protease is 30 nM
- the final concentration of substrate is 20 ⁇ M
- the buffer solution of the reaction system includes 50 mM Tris, pH 7.3 1 mM EDTA.
- the test time is 10min, and the fluorescence value is read every 30s.
- This example is a pharmacokinetic study of the compound on rats.
- Plasma samples were processed using a protein precipitation method using acetonitrile:methanol containing 500:50, containing propranolol (50ng/ml) as an internal standard, and then according to a standard curve prepared in blank plasma ( 0.1-2500ng/ml) for quantification. Analytes in plasma samples were quantified using LC-MS/MS. Briefly, a Waters ACQUITY Ultra Performance Liquid Chromatography System coupled to a Sciex 6500 Triple Quadrupole Mass Spectrometer was used. Chromatographic separation was accomplished using a Waters Acquity UPLC BEH C18 column (1.7m, 2.150mm). Optimize mobile phases to achieve good separation between analytes.
- solvent A consisted of 0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (95:5 v/v) and solvent B consisted of 0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (5:95 v/v).
- the gradient generally starts at 3-30% B until approximately 1.2 minutes, then increases to 50-65% B to 1.6 minutes, then decreases to 10-30% B until approximately 1.7-1.9 minutes.
- Analyst 1.7 software was used for peak integration and standard curve regression.
- the compound has a better longer half-life and higher plasma exposure in animals, and thus has a better therapeutic effect.
- the pharmaceutical carriers used in oral tablets include regulators, fillers, binders, disintegrants, additives, glidants, lubricants, film coating materials, plasticizers, coloring agents, and the like.
- Compound 2 drug ingredients 200 starch fillers, disintegrants 100 Calcium hydrogen phosphate filler 20 pregelatinized starch filler 40 citric acid Regulator 2
- Compound 2 was ground and sieved according to the above formula, and then mixed evenly with fillers, disintegrants, regulators and additives that had been ground and sieved, and 10% starch slurry was added to make a soft material in a blender.
- the material is made into wet granules on a swinging machine, dried in an oven, mixed evenly with a lubricant, and pressed into tablet cores.
- the tablet core is made into a film-coated tablet with Opadry.
- the pharmaceutical carriers used in capsules include fillers, binders, disintegrants, additives, lubricants and the like.
- compound 2 and various auxiliary materials were ground and sieved, mixed with fillers, binders and disintegrants in a certain proportion, added to a dry granulator and pressed into strips, and then crushed by a crusher to produce into particles.
- the granules are evenly mixed with an appropriate amount of lubricant and disintegrant, and then filled into capsules.
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Abstract
一种如式I所示的新型氘代氰基类化合物，或其药学上可接受的盐、异构体或前药。以及上述氘代化合物的制备方法、组合物及应用。该类化合物作为3CL蛋白酶抑制剂，在病毒抑制活性相当的基础上，实现了更优的药动学性质和治疗效果，成药性更好，式(I)如下所示：
Description
本发明属于医药领域，具体地，涉及涉及新型氘代氰基类化合物、其制备方法、组合物及应用，上述药物组合物用于制备治疗和预防病毒感染的药物。
人体内的冠状病毒最早于1960年代在英国被分离出来，病毒因其表面皇冠状的突起物而得名。它可能与人、猪、猫、狗、鼠和鸡的呼吸系统感染相关。SARS病毒属于套式病毒目、冠状病毒科、冠状病毒属，为β属B亚群冠状病毒。病毒粒子多呈圆形，有囊膜，外周有冠状排列的纤突,分布于细胞浆中，呈圆形，病毒直径在80～120nm之间。SARS是一种起病急、传播快、病死率高的传染病，被传染的病人多数都与患者直接或间接接触，或生活在流行区内。MERS病毒是一种β属C亚群冠状病毒，全名为中东呼吸综合征冠状病毒(Middle East Respiratory Syndrome Coronavirus，简称MERS-CoV)，感染后引发中东呼吸综合征(Middle East Respiratory Syndrome，简称MERS)。MERS-CoV最早于2012年9月在沙特被发现，早期因与SARS临床症状相似得名“类SARS病毒”，也成为第6种已知的人类冠状病毒，也是过去10年内被分离出来的第3种。新型冠状病毒是以前从未在人体中发现的冠状病毒新毒株，2019年首次被发现并报道，至今仍然在全球多个国家流行肆虐，并在很多国家区域并未得到很好的控制。
人感染了冠状病毒后常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等。在较严重病例中，感染可导致肺炎、严重急性呼吸综合征、肾衰竭，甚至死亡。对于新型冠状病毒所致疾病没有特异治疗方法。
2021年，Dafydd R.Owen在公开了论文An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19,描述了3CL蛋白酶抑制剂-PF-07321332作为病毒抑制的药效作用，通过抑制主蛋白酶，PF-07321332可防止病毒将长蛋白链切割成其自我复制所需的部分。该化合物正在进行Ⅲ期临床评估治疗COVID-19的临床疗效。通常，该多肽类化合物PF-07321332在体内由于首过效应易代谢分解，常需要与其他药物(蛋白酶保护剂)联用改进其药动学性质，PF-07321332的药动学和代谢性质有待改进。
因此，本领域仍需要开发具有更好抑制活性或药代动力学性质的新型3CL蛋白酶抑制剂类化合物，本发明设计、公开了新型氘代氰基类化合物，在病毒抑制剂活性相当的基础上，实现了比PF-07321332更优的药动学性质和治疗效果，成药性更好。同时公开了其制备方法、药物组合物和应用，可实现该药物的生产放大，且有较好的临床价值。
公开内容
本发明涉及新型氘代氰基类化合物、其制备方法、组合物及应用。
本发明公开了一种式Ⅰ所示的氘代氰基类化合物，或其药学上可接受的盐、异构体或前药：
其中R
1～R
17为“氢”同位素(包括同位素“氕”和“氘”)的组合；
上述化合物，其特征在于，R
1～R
2至少1个为氘，R
6～R
7至少1个为氘，R
9～R
17均为氘。
本发明公开了氘代氰基类化合物的制备方法，其包括下列步骤：
(1)在有机溶剂中，在缩合剂作用下，化合物I-1与化合物I-2进行缩合反应，制得中间体I-3；
(2)在有机溶剂中，在碱的作用下，中间体I-3进行水解反应，制得中间体I-4；
(3)在有机溶剂中，在缩合剂作用下，中间体I-4与化合物I-5进行缩合反应，制得化合物I；
本发明公开了一种药物组合物，其特征在于，它含有药学上可接受载体和式Ⅰ所述化合物，或其药学上可接受的盐。
本发明公开了一种药物组合物，其特征在于，它饱和另外的治疗药物，所述的另外的治疗药物为抗病毒药物。
本发明公开了上述药物组合物的用途，其特征在于，用于制备抑制剂3CL蛋白酶的药物组合物。
本发明公开了上述药物组合物的用途，其中所述病毒感染式人冠状病毒、新冠病毒(SARS-CoV-2)、SARS冠状病毒和MERS冠状病毒。
在各个不同的实施方案中，所述化合物具有以下表1中所示的结构之一。
表1 代表性化合物
在某些实施方案中，本发明考虑了包含药学上可接受的赋形剂和本文公开的化合物的药物组合物。在某些实施方案中，药物组合物为片剂、胶囊剂、丸剂或含水缓冲剂，例如盐水或磷酸盐缓冲剂的形式。
在某些实施方案中，本发明涉及本文所述的化合物在制备用于治疗或预防病毒感染的药物中的用途，所述病毒感染例如为人冠状病毒、新冠病毒(SARS-CoV-2)、SARS冠状病毒和MERS冠状病毒感染。
在某些实施方案中，本发明涉及通过在形成本文公开的化合物的条件下混合本文公开的起始材料和试剂来制备化合物的方法。
本发明设计、公开了新型氘代氰基类化合物，在病毒抑制剂活性相当的基础上，实现了比PF-07321332更优的药动学性质和治疗效果，成药性更好。同时公开了其制备方法、药物组合物和应用，可实现该药物的生产放大，且有较好的临床价值。
以下详细的说明都仅是示例性和解释性的，而非限制性的。
以下实施例，除非另外指出，否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
以下描述的程序可用于合成化合物1～63。
本文采用了以下缩写:
BOP：苯并三氮唑-1-基氧-三(二甲胺基)鏻鎓六氟磷酸盐
(Boc)
2O：二碳酸二叔丁酯
DCM：二氯甲烷
D
2O：重水
EA：乙酸乙酯
EDCI：1-(3-二甲胺基丙基)-3-乙基碳二亚胺
HCl/EA：氯化氢乙酸乙酯溶液
HOBt：1-羟基苯并三氮唑
LiHMDS：双(三甲基硅基)胺基锂
MeOH：甲醇
MTBE：甲基叔丁基醚
NaOH：氢氧化钠
NH
3/MeOH：氨甲醇溶液
Ni：雷尼镍
NMM：N-甲基吗啉
SM1：L-谷氨酸
SOCl
2：二氯亚砜
TEA：三乙胺
THF：四氢呋喃
Ru/C：钌碳
实施例1：
(S)-2-氨基-3-((S)-2-羰基吡咯烷-3-基)丙腈盐酸盐(化合物H)的合成
代表性路线
中间体化合物A的制备
将L-谷氨酸(SM1：100g，0.68mol)的MeOH(500ml)溶液调温至-5-5℃，滴加SOCl
2(202g，1.70mol)。加完后升温至回流搅拌反应。TCL检测原料基本反应完全后，浓缩至干，加入MeOH(1L)，滴加TEA(172g，1.70mol)，-5-5℃滴加(Boc)
2O(148.4g，1eq)，在50-60℃搅拌3-5小时，TCL检测原料基本反应完全后，浓缩至干，加入饱和碳酸氢钠(500ml)，使用MTBE(1L，0.5L，0.5L)萃取3次，合并有机相使用无水硫酸钠干燥，浓缩至干得到淡黄色油状产物A 178g，收率95％。
LC-MS(ESI，m/z，C
12H
21NO
6，276，M+H)
1H NMR(400MHz,CDCl
3)δ:5.40-5.37(m,1H),4.35-4.30(m,1H),3.74(s,3H),3.68(s,3H),2.47-2.40(m,2H),2.17-2.16(m,2H),1.99-1.94(m,1H),1.44(s,9H)。
中间体化合物B的制备
将化合物A(150g，0.545mol)的THF(450ml)溶液调温至-78℃，控温滴加LiHMDS(1M，1.2L，1.2mol)。加完后保温搅拌反应2小时。控温滴加溴乙腈(98g，，0.817mol)。加完后保温搅拌反应4小时。TCL检测原料基本反应完全后，滴加醋酸四氢呋喃溶液淬灭反应，饱和氯化钠水溶液洗涤，有机相使用无水硫酸钠干燥后浓缩至干，得到化合物B粗品，经柱层析(PE:EA＝1:1)纯化，得到淡黄色油状化合物B：142g，收率95％。
LC-MS(ESI，m/z，C
14H
22N
2O
6，315，M+H)
1H NMR(400MHz,CDCl
3)δ:5.19-5.17(m,1H),4.38-4.33(m,1H),3.77(s,6H),2.88-2.79(m,3H),2.19-2.14(m,2H),1.45(s,9H)。
中间体化合物D的制备
将化合物B(50g，0.159mol)、MeOH(150ml)、冰醋酸(150ml)和雷尼镍(10g)加入氢化瓶中，置换氢气，氢气保持50-60psi。保温保压搅拌反应4小时。TCL检测原料基本反应完全后，氮气置换，过滤，滤液浓缩置换为THF(500ml)溶液。加入TEA(100ml)，调温至50-60℃保温搅拌16小时。TCL检测原料基本反应完全后，加入水(150ml)溶清反应液，分层，水相使用DCM萃取两次，合并有机相后干燥浓缩得到油状粗品D。经柱层析纯化得到白色固体粉末D：27.8g，收率61％。
LC-MS(ESI，m/z，C
13H
22N
2O
5，287，M+H)
1H NMR(400MHz,CDCl
3)δ:6.35(s,1H),5.54-5.52(m,1H),4.32-4.30(m,1H),3.74(s,3H),3.37-3.33(m,2H),2.50-2.46(m,2H),2.17-2.13(m,1H),1.87-1.81(m,2H),1.44(s,9H)。
中间体化合物E的制备
将化合物D(27g，0.094mol)、MeOH(270ml)和NaOH(10g,0.25mol)加入反应瓶中。搅拌反应4小时。TCL检测原料基本反应完全后，浓缩置换为EA(270ml)溶液，加入水(100ml)。在0-10℃下，使用1N盐酸溶液调节反应液pH 5-6，分层，水相使用EA萃取两次，合并有机相浓缩至干得到白色固体粉末E：25g，收率97％。
LC-MS(ESI，m/z，C
13H
20N
2O
5，273，M+H)
1H NMR(400MHz,CDCl
3)δ:6.37(s,1H),5.58-5.53(m,1H),4.52-4.50(m,1H),3.38-3.35(m,2H),2.53-2.48(m,2H),2.19-2.16(m,1H),1.88-1.84(m,2H),1.45(s,9H)。
中间体化合物F的制备
将TEA(10.2g，0.1mol)滴加到化合物E(25g，0.092mol)的THF(250ml)溶液中，搅拌30分钟。在-5-5℃下滴加氯甲酸乙酯(13.0g，0.12mol)，加完搅拌1小时，在-5-5℃下滴加NH
3/MeOH(10M，100ml)，加完升至室温搅拌2小时。TCL检测原料基本反应完全后，浓缩置换为EA(250ml)溶液，水洗，饱和氯化钠洗，无水硫酸钠干燥有机相。有机相浓缩至干得到白色固体粉末F：23g，收率92％。
LC-MS(ESI，m/z，C
12H
21N
3O
4，272，M+H)
中间体化合物G的制备
在-5-5℃下，将TFAA(10.2g，0.1mol)滴加到化合物F(23g，0.085mol)、TEA(38.6g，0.382mol)的DCM(230ml)溶液中，加完后反应调至室温搅拌12小时。TCL检测原料基本反应完全后，反应溶液依次使用水、饱和氯化钠洗涤，无水硫酸钠干燥，浓缩至干得到白色固体粉末G：18.2g，收率85％。
LC-MS(ESI，m/z，C
13H
20N
2O
3，253，M+H)
中间体化合物H的制备
在0-10℃下，将化合物G(18.2g，0.072mol)加到4mol/L的盐酸乙酸乙酯溶液(150ml)中，在0-10℃下搅拌1小时后，升温至室温搅拌2小时。TCL检测原料基本反应完全后，浓缩至干得到白色固体产物H：13.0g，收率95％。
LC-MS(ESI，m/z，C
7H
12ClN
3O，154，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.42(s,2H),8.25(s,1H),7.83(s，1H)3.51-3.40(m,3H),2.15-1.84(m,5H)。
实施例2：
(S)-2-氨基-3-((S)-2-羰基吡咯烷-3-基-5,5-二氘代)丙腈盐酸盐(化合物H-2D1)的合成
代表性路线
化合物B的制备参见实施例1。
在0-10℃下，将硼氘化钠(6.7g，0.16mol)分批加入化合物B(50g，0.159mol)、氯化钴(20.6g)的THF(500ml)溶液中。加完调至室温反应4小时。TCL检测原料基本反应完全后，在-5-5℃下，加入水和稀盐酸淬灭后分层，水相使用EA萃取，合并有机相后浓缩置换为THF(500ml)溶液，加入TEA(100ml)，调温至50-60℃保温搅拌16小时。TCL检测原料基本反应完全后，加入水(150ml)溶清反应液，分层，水相使用DCM萃取两次，合并有机相后干燥浓缩得到油状粗品D-2D1。经柱层析纯化得到白色固体粉末D-2D1：32.1g，收率70％。
LC-MS(ESI，m/z，C
13H
20D
2N
2O
5，289，M+H)
后续中间体的制备参照实施例1。
得到化合物H-2D1：15.3g。
LC-MS(ESI，m/z，C
7H
10D
2ClN
3O，156，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.42(s,2H),8.26(s,1H),7.82(s,1H),3.56(m,1H),2.19-1.92(m,5H)。
实施例3：
(s)-2-氨基-3-((s)-2-羰基吡咯烷-3-基)丙腈-2-氘代盐酸盐(化合物H-1D)的合成
代表性路线
中间体化合物E的制备参见实施例1。
中间体化合物E-1D的制备
将化合物E(10g，36.7mmol)，Ru/C(0.5g，5wt％)，NaOH(4.4g，0.11mol)和重水(100ml)加入氢化瓶中。氢气置换3次，于0.1-0.12MPa和70-75℃保温搅拌反应52小时。HNMR监测反应至转化完全，降温，过滤，滤液调pH＝5-6，EA萃取三次，合并有机相浓缩至干得到化合物E-1D：9.2g，收率92％。
LC-MS(ESI，m/z，C
12H
19DN
2O
5，274，M+H)
后续中间体的制备参照实施例1。
得到化合物H-1D：4.8g。
LC-MS(ESI，m/z，C
7H
11DClN
3O，155.2，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.43(s,2H),8.27(s,1H),7.82(s,1H),3.53-3.44(m,2H),2.20-1.92(m,5H)。
实施例4：
(s)-2-氨基-3-((s)-2-羰基吡咯烷-3-基-3-氘代)丙腈-2-氘代盐酸盐(化合物H-2D2)的合成
代表性路线
中间体化合物F-1D的制备参见实施例1。
中间体化合物F-2D2的制备
将化合物F-1D(13.6g，0.05mol)，碳酸钾(20.7g，0.15mol)和重水(150ml)加入反应瓶中，80℃下搅拌48小时，用EA萃取，无水硫酸钠干燥，经SFC拆分，浓缩至干得到白色固体产物F-2D2：6.3g，收率46％。
LC-MS(ESI，m/z，C
12H
19D
2N
3O
4，274，M+H)
后续中间体的制备参照实施例1。
得到化合物H-2D2：3.6g。
LC-MS(ESI，m/z，C
7H
10D
2ClN
3O，156，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.42(s,2H),8.26(s,1H),7.82(s,1H),3.53-3.40(m,2H),2.20-1.95(m,4H)。
实施例5：
(s)-2-氨基-3-((s)-2-羰基吡咯烷-3-基-3-氘代-5,5-二氘代)丙腈-2-氘代盐酸盐(化合物H-4D)的合成
化学式：C
7H
8D
24FClN
3O
分子量：193.67
化合物H-4D可根据实施例2和实施例4描述的代表性路线合成。
LC-MS(ESI，m/z，C
7H
8D
2ClN
3O，158，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.43(s,2H),8.24(s,1H),7.81(s,1H),2.20-1.94(m,4H)。
实施例6：
(s)-3,3-二甲基-2-(2,2,2-三氟乙酰胺)丁酸(K)的合成
代表性路线
在-5-5℃下，将三氟乙酸甲酯(10.2g，80mmol)和无水四氢呋喃加入反应瓶中。保温搅拌15分钟后，
加入L-叔亮氨酸(10g，76.2mmol)，加完后保温搅拌1小时。TLC检测反应转化基本完全，浓缩后得到粗品化合物K，柱层析纯化得到白色固体粉末K：15.6g，收率90％。
LC-MS(ESI，m/z，C
8H
12F
3NO
3，228，M+H)
1H NMR(400MHz,DMSO)δ:12.22(s,1H),8.30(s,1H),4.09(s,1H),0.92(s,9H)。
实施例7：
(s)-3,3-二甲基-2-(2,2,2-三氟乙酰胺)-2-氘代-丁酸(K-1D)的合成
代表性路线
中间体化合物SM2-1D的制备
将化合物L-叔亮氨酸(10g，76.2mmol)，Ru/C(0.5g，5wt％)，NaOH(4.4g，0.11mol)和重水(100ml)加入氢化瓶中。氢气置换3次，于0.1-0.12MPa和70-75℃保温搅拌反应52小时。HNMR监测反应至转化完全，降温，过滤，滤液调pH＝5-6，EA萃取三次，合并有机相浓缩至干得到白色固体产物SM2-1D：9.5g，收率94％。
LC-MS(ESI，m/z，C
6H
12DNO
2，133，M+H)
中间体化合物K-1D的制备
在-5-5℃下，将三氟乙酸甲酯(9.6g，75.4mmol)和无水四氢呋喃加入反应瓶中。保温搅拌15分钟后，加入SM2-1D(9.5g，71.8mmol)，加完后保温搅拌1小时。TLC检测反应转化基本完全，加入一定量的稀盐酸游离产物，浓缩后得到粗品化合物K-1D，柱层析纯化得到白色固体粉末K-1D：15.1g，收率92％。
LC-MS(ESI，m/z，C
8H
11DF
3NO
3，229，M+H)
1H NMR(400MHz,DMSO)δ:12.18(s,1H),8.14(s,1H),0.91(s,9H)。
实施例8：
(s)-3,3-二氘代甲基-2-(2,2,2-三氟乙酰胺)-4,4,4-氘代-丁酸(K-9D)的合成
代表性路线
化学式：C
8H
3D
9F
3NO
3
分子量：236.24
化合物K-9D可根据实施例6描述的代表性路线合成。
LC-MS(ESI，m/z，C
8H
3D
9F
3NO
3，237，M+H)
1H NMR(400MHz,DMSO)δ:12.23(s,1H),8.30(s,1H),4.19(s,1H)。
实施例9：
(s)-3,3-二氘代甲基-2-(2,2,2-三氟乙酰胺)-2-4,4,4-氘代-丁酸(K-10D)的合成
化学式：C
8H
2D
10F
3NO
3
分子量：237.24
化合物K-10D可根据实施例7描述的代表性路线合成。
LC-MS(ESI，m/z，C
8H
2D
10F
3NO
3，238.1，M+H)
1H NMR(400MHz,DMSO)δ:12.22(s,1H),8.18(s,1H)。
实施例10：
(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-氘-甲酸甲酯(SM3-1D)的合成
代表性路线
将化合物(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-甲酸甲酯(SM3:10g，48.6mmol)，Ru/C(0.5g，5wt％)，NaOH(9.7g，0.24mol)和重水(100ml)加入氢化瓶中。氢气置换3次，于0.1-0.12MPa和70-75℃保温搅拌反应52小时。HNMR监测反应至转化完全，降温，过滤，滤液调pH＝5-6，EA萃取三次，合并有机相浓缩至干得到白色固体产物M：7g，收率92％
将化合物M和MeOH(100ml)加入反应瓶中，在0-10℃下，通入饱和的氯化氢气体，回流反应1小时。降至室温，TLC监测反应转化完全，过滤烘干得到白色固体产物SM3-1D：8.9g，收率96％。
LC-MS(ESI，m/z，C
9H
15DClNO
2，171，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.22(s,1H),3.70(s,3H),2.87-2.63(m,2H),2.07(m,1H),1.68(d,1H),1.06-0.98(m,1H),0.87(s,6H)。
实施例11：
(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4,4-氘-甲酸甲酯(SM3-3D)的合成
代表性路线
将化合物SM3-1D(10g，48.4mmol)，碳酸钾(31.6g，0.23mol)和重水(150ml)加入反应瓶中，60℃下搅拌48小时，用EA萃取，无水硫酸钠干燥，再加入氯化氢乙酸乙酯溶液(4mol/L，150ml)，搅拌4小时后，浓缩至干得到白色固体产物SM3-3D：9.3g，收率92％。
LC-MS(ESI，m/z，C
9H
13D
3ClNO
2，173，M(free base)+H)
1H NMR(400MHz,DMSO)δ:8.22(s,1H),3.69(s,3H),2.08(s,1H),1.65(d,1H),1.0(d,1H),0.87(s,6H)。
实施例12：
化合物1的合成
代表性路线
中间体化合物M的制备
将化合物K(5g,22mmol)，SM3(4.9g,22mmol)和乙腈(100ml)加入反应瓶中，搅拌，依次加入BOP(9.7g,22mmol)和TEA(4.4g,44mmol)。室温下搅拌2小时，TLC检测反应转化基本完全，加入水(50ml)后用EA萃取三次，合并有机相，依次使用2mol/L HCl，5％NaHCO
3，水洗涤，无水硫酸镁干燥，浓缩至干得到类白色固体产物M：8.0g，收率96.1％。
LC-MS(ESI，m/z，C
17H
25F
3N
2O
4，379，M+H)
化合物1的制备
在室温下，将M(8g，21.1mmol)溶于THF(80ml)和MeOH(80ml)中。加入氢氧化锂(1.5g，62.8mmol)的水溶液(15ml)，室温搅拌2小时。调温至0-10℃，加入乙酸乙酯后使用1N HCl调反应液至酸性，分层，水相使用EA萃取两次，合并有机相后无水硫酸镁干燥，浓缩至干得到粗品，柱层析纯化得到M水解化合物。
将上一步所得的水解化合物和DMF(100ml)投入反应瓶中，调温至0-10℃。在此温度下，依次加入EDCI(4.9g，25.6mmol)，HOBt(3.4g，25.2mmol)，NMM(4.3g，42.5mmol)，并在此温度下搅拌30分钟。在此温度下，分批加入H-2D1(4.0g，21mmol)，加完后在室温下搅拌过夜。TLC检测反应转化基本完全，加入水(80ml)后用EA萃取三次，合并有机相，依次使用0.5mol/L HCl，5％NaHCO
3，水洗涤，无水硫酸镁干燥，浓缩至干得到粗品1，柱层析得到类白色固体产物1：8.4g，收率79.7％。
LC-MS(ESI，m/z，C
23H
30D
2F
3N
5O
4，502，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
通过类似于实施例12描述的制备方法，制备下述实施例13-74。
实施例13：
化合物2的合成
化学式：C
23H
31DF
3N
5O
4
分子量：500.54
LC-MS(ESI，m/z，C
23H
31DF
3N
5O
4，501，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.67(s,1H),4.43-4.41(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例14：
化合物3的合成
化学式：C
23H
30D
2F
3N
5O
4
分子量：501.55
LC-MS(ESI，m/z，C
23H
30D
2F
3N
5O
4，502，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.06-9.02(m,1H),7.69(s,1H),4.44-4.40(m,1H),4.16(s,1H),3.93-3.90(m,1H),3.71-3.68(m,1H),3.14(m,1H),3.05(m,1H),2.18(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.30(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例15：
化合物4的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，503，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.44-4.41(m,1H),4.15(s,1H),3.94-3.91(m,1H),3.71-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例16：
化合物5的合成
化学式：C
23H
28D
4F
3N
5O
4
分子量：503.56
LC-MS(ESI，m/z，C
23H
28D
4F
3N
5O
4，504，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),4.44-4.40(m,1H),4.15(s,1H),3.94-3.90(m,1H),3.72-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例17：
化合物6的合成
化学式：C
23H
31DF
3N
5O
4
分子量：500.54
LC-MS(ESI，m/z，C
23H
31DF
3N
5O
4，501，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.03-4.94(m,1H),4.45-4.41(m,1H),3.94-3.91(m,1H),3.73-3.69(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例18：
化合物7的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，503，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.02-4.94(m,1H),4.44-4.41(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例19：
化合物8的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，503，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.03-4.94(m,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例20：
化合物9的合成
化学式：C
23H
27D
5F
3N
5O
4
分子量：504.57
LC-MS(ESI，m/z，C
23H
27D
5F
3N
5O
4，505，M+H)
1H NMR(400MHz,DMSO)δ:8.32(s,1H),8.18(s,1H),7.79(s,1H),4.50(m,1H),4.24(s,1H),2.20-1.90(m,5H),1.3(d,1H,J＝8Hz),0.97-0.89(m,16H)。
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.02-4.94(m,1H),4.43-4.41(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例21：
化合物10的合成
化学式：C
23H
30D
2F
3N
5O
4
分子量：501.55
LC-MS(ESI，m/z，C
23H
30D
2F
3N
5O
4，502，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.02(m,1H),7.67(s,1H),4.44-4.41(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H), 1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例22：
化合物11的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，502，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.67(s,1H),4.44-4.40(m,1H),3.92-3.90(m,1H),3.71-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例23：
化合物12的合成
化学式：C
23H
27D
5F
3N
5O
4
分子量：504.57
LC-MS(ESI，m/z，C
23H
27D
5F
3N
5O
4，505，M+H)
1H NMR(400MHz,DMSO)δ:8.32(s,1H),8.18(s,1H),7.79(s,1H),4.24(s,1H),3.45-3.35(m,2H),2.2-1.9(m,4H),1.3(d,1H,J＝8Hz),0.97-0.89(m,16H)。
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.04-9.01(m,1H),7.67(s,1H),4.44-4.40(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例24：
化合物13的合成
化学式：C
23H
28D
4F
3N
5O
4
分子量：503.56
LC-MS(ESI，m/z，C
23H
28D
4F
3N
5O
4，504，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.04-9.02(m,1H),7.68(s,1H),4.44-4.40(m,1H),3.93-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例25：
化合物14的合成
化学式：C
23H
27D
5F
3N
5O
4
分子量：504.57
LC-MS(ESI，m/z，C
23H
27D
5F
3N
5O
4，505，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),4.43-4.40(m,1H),3.93-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例26：
化合物15的合成
化学式：C
23H
25D
7F
3N
5O
4
分子量：506.58
LC-MS(ESI，m/z，C
23H
25D
7F
3N
5O
4，507，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.45-4.40(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例27：
化合物16的合成
化学式：C
23H
31DF
3N
5O
4
分子量：500.54
LC-MS(ESI，m/z，C
23H
31DF
3N
5O
4，501，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.06-9.02(m,1H),7.68(s,1H),5.02-4.94(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例28：
化合物17的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，503，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.01-4.94(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例29：
化合物18的合成
化学式：C
23H
30D
2F
3N
5O
4
分子量：501.55
LC-MS(ESI，m/z，C
23H
30D
2F
3N
5O
4，502，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例30：
化合物19的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，503，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例31：
化合物20的合成
化学式：C
23H
28D
4F
3N
5O
4
分子量：503.56
LC-MS(ESI，m/z，C
23H
28D
4F
3N
5O
4，504，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例32：
化合物21的合成
化学式：C
23H
27D
5F
3N
5O
4
分子量：504.57
LC-MS(ESI，m/z，C
23H
27D
5F
3N
5O
4，505，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例33：
化合物22的合成
化学式：C
23H
30D
2F
3N
5O
4
分子量：501.55
LC-MS(ESI，m/z，C
23H
30D
2F
3N
5O
4，502，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.01-4.95(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例34：
化合物23的合成
化学式：C
23H
28D
4F
3N
5O
4
分子量：503.56
LC-MS(ESI，m/z，C
23H
28D
4F
3N
5O
4，504，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.01-4.94(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例35：
化合物24的合成
化学式：C
23H
28D
4F
3N
5O
4
分子量：503.56
LC-MS(ESI，m/z，C
23H
28D
4F
3N
5O
4，504，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.01-4.94(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例36：
化合物25的合成
化学式：C
23H
26D
6F
3N
5O
4
分子量：505.57
LC-MS(ESI，m/z，C
23H
26D
6F
3N
5O
4，506，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.0-4.94(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例37：
化合物26的合成
化学式：C
23H
29D
3F
3N
5O
4
分子量：502.55
LC-MS(ESI，m/z，C
23H
29D
3F
3N
5O
4，503，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例38：
化合物27的合成
化学式：C
23H
28D
4F
3N
5O
4
分子量：503.56
LC-MS(ESI，m/z，C
23H
28D
4F
3N
5O
4，504，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例39：
化合物28的合成
化学式：C
23H
26D
6F
3N
5O
4
分子量：505.57
LC-MS(ESI，m/z，C
23H
26D
6F
3N
5O
4，506，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.03(m,1H),7.68(s,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例40：
化合物29的合成
化学式：C
23H
27D
5F
3N
5O
4
分子量：504.57
LC-MS(ESI，m/z，C
23H
27D
5F
3N
5O
4，505，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例41：
化合物30的合成
化学式：C
23H
26D
6F
3N
5O
4
分子量：505.57
LC-MS(ESI，m/z，C
23H
26D
6F
3N
5O
4，506，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.06-9.02(m,1H),7.68(s,1H),3.93-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例42：
化合物31的合成
化学式：C
23H
24D
8F
3N
5O
4
分子量：507.58
LC-MS(ESI，m/z，C
23H
24D
8F
3N
5O
4，508，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.98(s,9H)，0.85(s,3H)。
实施例43：
化合物32的合成
化学式：C
23H
23D
8F
3N
5O
4
分子量：508.59
LC-MS(ESI，m/z，C
23H
23D
8F
3N
5O
4，509，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例44：
化合物33的合成
化学式：C
23H
21D
11F
3N
5O
4
分子量：510.60
LC-MS(ESI，m/z，C
23H
21D
11F
3N
5O
4，511，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.06-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例45：
化合物34的合成
化学式：C
23H
22D
10F
3N
5O
4
分子量：509.60
LC-MS(ESI，m/z，C
23H
22D
10F
3N
5O
4，510，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例46：
化合物35的合成
化学式：C
23H
21D
11F
3N
5O
4
分子量：510.60
LC-MS(ESI，m/z，C
23H
21D
11F
3N
5O
4，511，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.00(m,1H),7.68(s,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例47：
化合物36的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例48：
化合物37的合成
化学式：C
23H
19D
13F
3N
5O
4
分子量：512.61
LC-MS(ESI，m/z，C
23H
19D
13F
3N
5O
4，513，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),4.43-4.40(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例49：
化合物38的合成
化学式：C
23H
22D
10F
3N
5O
4
分子量：509.60
LC-MS(ESI，m/z，C
23H
22D
10F
3N
5O
4，510，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例50：
化合物39的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例51：
化合物40的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例52：
化合物41的合成
化学式：C
23H
18D
14F
3N
5O
4
分子量：513.62
LC-MS(ESI，m/z，C
23H
18D
14F
3N
5O
4，514，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.43-4.40(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H。
实施例53：
化合物42的合成
化学式：C
23H
21D
11F
3N
5O
4
分子量：510.60
LC-MS(ESI，m/z，C
23H
21D
11F
3N
5O
4，511.3，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例54：
化合物43的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.0(m,1H),7.68(s,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例55：
化合物44的合成
化学式：C
23H
18D
14F
3N
5O
4
分子量：513.62
LC-MS(ESI，m/z，C
23H
18D
14F
3N
5O
4，514.3，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.1(m,1H),7.68(s,1H),4.43-4.40(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例56：
化合物45的合成
化学式：C
23H
19D
13F
3N
5O
4
分子量：512.61
LC-MS(ESI，m/z，C
23H
19D
13F
3N
5O
4，513，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.06-9.02(m,1H),7.68(s,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例57：
化合物46的合成
化学式：C
23H
18D
14F
3N
5O
4
分子量：513.62
LC-MS(ESI，m/z，C
23H
18D
14F
3N
5O
4，514，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),4.43-4.40(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例58：
化合物47的合成
化学式：C
23H
16D
16F
3N
5O
4
分子量：515.63
LC-MS(ESI，m/z，C
23H
16D
16F
3N
5O
4，516，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.06-9.02(m,1H),7.68(s,1H),4.43-4.40(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例59：
化合物48的合成
化学式：C
23H
22D
10F
3N
5O
4
分子量：509.60
LC-MS(ESI，m/z，C
23H
22D
10F
3N
5O
4，510，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例60：
化合物49的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.06-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例61：
化合物50的合成
化学式：C
23H
21D
11F
3N
5O
4
分子量：510.60
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，511，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.41(m,1H),9.05-9.01(m,1H),7.68(s,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例62：
化合物51的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.40(m,1H),9.05-9.00(m,1H),7.68(s,1H),4.15(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例63：
化合物52的合成
化学式：C
23H
18D
14F
3N
5O
4
分子量：513.62
LC-MS(ESI，m/z，C
23H
18D
14F
3N
5O
4，514，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例64：
化合物53的合成
化学式：C
23H
17D
15F
3N
5O
4
分子量：514.63
LC-MS(ESI，m/z，C
23H
17D
15F
3N
5O
4，515，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例65：
化合物54的合成
化学式：C
23H
21D
11F
3N
5O
4
分子量：510.60
LC-MS(ESI，m/z，C
23H
21D
11F
3N
5O
4，511，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),5.0-4.94(m,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例66：
化合物55的合成
化学式：C
23H
19D
13F
3N
5O
4
分子量：512.61
LC-MS(ESI，m/z，C
23H
19D
13F
3N
5O
4，513，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),5.0-4.94(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例67：
化合物56的合成
化学式：C
23H
19D
13F
3N
5O
4
分子量：512.61
LC-MS(ESI，m/z，C
23H
19D
13F
3N
5O
4，513，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.40(m,1H),9.06-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例68：
化合物57的合成
化学式：C
23H
17D
15F
3N
5O
4
分子量：514.63
LC-MS(ESI，m/z，C
23H
17D
15F
3N
5O
4，515，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例69：
化合物58的合成
化学式：C
23H
20D
12F
3N
5O
4
分子量：511.61
LC-MS(ESI，m/z，C
23H
20D
12F
3N
5O
4，512，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.06-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例70：
化合物59的合成
化学式：C
23H
19D
13F
3N
5O
4
分子量：512.61
LC-MS(ESI，m/z，C
23H
19D
13F
3N
5O
4，513，M+H)
1H NMR(600MHz,DMSO)δ:9.43-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例71：
化合物60的合成
化学式：C
23H
17D
15F
3N
5O
4
分子量：514.63
LC-MS(ESI，m/z，C
23H
17D
15F
3N
5O
4，515，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.01(m,1H),7.68(s,1H),3.14(m,1H),3.04(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例72：
化合物61的合成
化学式：C
23H
18D
14F
3N
5O
4
分子量：513.62
LC-MS(ESI，m/z，C
23H
18D
14F
3N
5O
4，514，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.42(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例73：
化合物62的合成
化学式：C
23H
17D
15F
3N
5O
4
分子量：514.63
LC-MS(ESI，m/z，C
23H
17D
15F
3N
5O
4，515，M+H)
1H NMR(600MHz,DMSO)δ:9.44-9.40(m,1H),9.05-9.02(m,1H),7.68(s,1H),3.92-3.90(m,1H),3.70-3.68(m,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例74：
化合物63的合成
化学式：C
23H
15D
17F
3N
5O
4
分子量：516.64
LC-MS(ESI，m/z，C
23H
15D
17F
3N
5O
4，517.3，M+H)
1H NMR(600MHz,DMSO)δ:9.45-9.41(m,1H),9.05-9.02(m,1H),7.68(s,1H),2.19(m,1H),2.10(m,1H),1.73(s,2H),1.57(m,1H),1.33-1.31(m,1H),1.03(s,3H),0.85(s,3H)。
实施例75:
体外抗SARS-CoV-2病毒实验
细胞铺板:将Vero E6细胞以3×10
5个细胞/孔接种到12孔板中，加入10％FBS的DMEM培养基，并置 于37℃、5％CO
2培养箱培养过夜。药物作用：去除12孔板中Vero细胞的培养基，用PBS缓冲液清洗VeroE6细胞；化合物(终浓度100nM)加到50μL/孔细胞液中，置于37℃、5％CO
2培养箱中孵育1小时，设置50μL/孔培养基作为对照。病毒感染细胞：用SARS-CoV-2病毒感染细胞2小时，去除感染的病毒、药物混合液,加入10％FBS的DMEM培养基，置于37℃、5％CO
2培养箱中培养2～3天。PCR测定：收集培养基的上清液，置于56℃培养箱保留30min，用病毒RNA提取试剂盒抽提病毒RNA，用病毒核酸检测试剂盒按照说明书进行PCR反应，通过PCR仪器显示的CT值计算2
-ΔCT值病毒复制抑制率的计算公式为:(1-2
-ΔCT)×100％，其中，2
-ΔCT值为药物组与对照组(单宁酸)的相对病毒复制率，结果见表2。
表2 药物组与对照组病毒复制率结果
实施例76:
本实施例为靶向SARS-CoV-2病毒M
Pro蛋白酶活性抑制检测
检测原理:3-胰凝乳蛋白酶样蛋白酶(3-chymotrypsin-like protease)，即主要蛋白酶(M
Pro,也称为3CL
Pro)，由ORF1编码(定位于nsp5)，位于复制酶基因中心区域,是新型冠状病毒RNA复制时的一个关键蛋白质。其作用机制为:新冠病毒入侵细胞后，会利用宿主细胞合成自身复制必需的两条超长复制酶多肽(ppla和pplab)。复制酶多肽需进一步被剪切成多个蛋白(如RdRp、helicase等)，进一步组装成用于病毒启动自身遗传物质复制所需的复制转录机器。M
Pro在复制酶多肽上存在至少11个切割位点，只有当复制酶多肽上这些位点被正常切割后，组装成复制转录机器,启动病毒复制。鉴于M
Pro蛋白酶在病毒复制过程中至关重要,且人体中并无类似的蛋白质，因此主蛋白酶M
Pro成为一个抗新冠病毒的潜在关键药靶。利用荧光共振能量转移方法评价核苷衍生物对SARS-CoV-2-M
Pro蛋白酶的抑制活性。
具体检测方法:整个酶促反应体系的体积为120μL，蛋白酶的终浓度为30nM，底物终浓度为20μM，反应体系的缓冲液包括50mM Tris、pH 7.3 1mM EDTA。在96孔板中加入SARS-CoV-2-M
Pro蛋白酶和不同浓度的目标化合物，30℃孵育10min，加入底物并迅速放入酶标仪中读数。激发光和发射光分别为340nm和405nm。测试时间为10min，每隔30s读一次荧光值。最终结果取前2min的读值拟合反应速率，并与对照组(DMSO)比较，计算抑制率。以Graghpad prism 7作图,计算SARS-CoV-2病毒核苷衍生物对应时间点IC50值，具体数值见表3。
表3：SARS-CoV-2-M
Pro蛋白酶的IC
50值
| 编号 | IC50(μM) |
| 化合物1 | 2.948±0.265μM |
| 化合物2 | 2.786±0.375μM |
| 化合物16 | 2.723±0.476μM |
| 化合物32 | 2.835±0.503μM |
| PF-07321332 | 2.761±0.382μM |
实施例77:
本实施例为化合物在大鼠上的药代动力学研究。
在7-10周龄，雄性Wistar-Hannover大鼠进行药代动力学研究。在药代动力学研究期间，所有动物都 单独饲养。自由摄取食物和水(动物在进食状态下给药)。动物禁食过夜并在给药后4小时进食。在灌胃给化合物(10mg/kg)后，在预定时间点通过颈静脉插管收集血样。在研究完成时，通过过量吸入麻醉随后放血对动物实施安乐死。将血样收集到含有K
2EDTA的试管中并储存在冰上，直至离心获得血浆，将其储存在-20℃冰箱。
血浆样品的LC-MS/MS分析：血浆样品使用蛋白质沉淀法进行处理，使用含有500:50的乙腈:甲醇，含有propranolol(50ng/ml)作为内标，然后根据空白血浆中制备的标准曲线(0.1-2500ng/ml)进行定量。使用LC-MS/MS对血浆样品中的分析物进行定量。简而言之，使用与配备Sciex 6500三重四极杆质谱仪联用的Waters ACQUITY超高效液相色谱系统。使用Waters Acquity UPLC BEH C18柱(1.7m，2.1 50mm)完成色谱分离。优化流动相以实现分析物之间的良好分离。通常，溶剂A由0.025％甲酸和1mM乙酸铵的水/乙腈溶液(95:5v/v)组成，溶剂B包括0.025％甲酸和1mM乙酸铵的水/乙腈溶液(5:95v/v)。梯度一般从3-30％B开始，直到大约1.2分钟，然后增加到50-65％B到1.6分钟，然后降低到10-30％B，直到约1.7-1.9分钟。Analyst 1.7软件用于峰积分和标准曲线回归。
药代动力学分析：使用非房室分析(Watson v.7.5，Thermo Scientific)计算药代动力学参数。使用线性梯形法则估计从t＝0到无穷大(AUC0-∞)的血浆浓度-时间曲线下面积。结果如下表4所示，本发明
化合物在动物体内具有更好的更长的半衰期和更高的血浆暴露量，因而具有更好的治疗效果。
表4：化合物在大鼠中的药代动力学参数
| 编号 | 剂量(mg/kg) | C max(ng/mL) | T max(h) | AUC 0-∞(ng·h/mL) | T 1/2(h) |
| 化合物1 | 10 | 1393 | 2 | 1974 | 3.5 |
| 化合物2 | 10 | 1480 | 2 | 2325 | 4.2 |
| 化合物16 | 10 | 1452 | 2 | 2294 | 4 |
| 化合物32 | 10 | 1429 | 2 | 2011 | 3.5 |
| PF-07321332 | 10 | 1445 | 2 | 1982 | 2.9 |
实施例78:
对于含氘代氰基化合物的口服片剂制备方法(以化合物2为例)
口服片剂所用的药用载体有调节剂、填充剂、粘合剂、崩解剂、添加剂、助流剂、润滑剂、膜衣材料、增塑剂、着色剂等。
| 组分 | 作用 | 含量(mg/片) |
| 化合物2 | 药物成分 | 200 |
| 淀粉 | 填充剂、崩解剂 | 100 |
| 磷酸氢钙 | 填充剂 | 20 |
| 预胶化淀粉 | 填充剂 | 40 |
| 枸橼酸 | 调节剂 | 2 |
| 亚硫酸氢钠 | 添加剂 | 0.5 |
| 10％淀粉浆 | 粘合剂 | 适量 |
| 硬脂酸镁 | 润滑剂 | 1.5 |
| 白色欧巴代 | 包衣预混料 | 约4 |
| 水、乙醇 | 溶剂 | 适量 |
操作方法：
按上述配方将化合物2分别磨粉过筛,然后与填充剂、崩解剂以及经磨粉过筛处理的调节剂、添加剂混合均匀,加入10％的淀粉浆在搅拌机中制成软材,软材在摇摆机上制成湿粒,置烘箱中干燥,再与润滑剂混合均匀,压制成片芯。片芯用欧巴代包制薄膜衣片。
对于氘代氰基化合物的胶囊剂制备方法(以化合物2为例)
胶囊剂所用的药用载体有填充剂、粘合剂、崩解剂、添加剂、润滑剂等。
| 组分 | 作用 | 含量(mg/粒) |
| 化合物2 | 药物成分 | 200 |
| 乳糖一水合物 | 填充剂 | 82 |
| 预胶化淀粉 | 填充剂、粘合剂 | 38 |
| 羧甲基淀粉钠 | 崩解剂 | 12.5 |
| 硬脂酸镁 | 润滑剂 | 1.5 |
操作方法：
按上述配方将化合物2和各辅料分别磨粉过筛，与填充剂、粘合剂和崩解剂等以一定比例混合均匀，加入干法制粒机中压制成条带，后经破碎机破碎制成颗粒。颗粒与适量润滑剂和崩解剂混合均匀后填充胶囊。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对公开专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (13)
- 一种式Ⅰ所示的氘代氰基类化合物，或其药学上可接受的盐、异构体或前药：
其中：R 1～R 17各自独立地为氢或氘；附加条件是R 1～R 17中至少一个是氘。 - 如权利要求1所述的化合物，其特征在于，R 1～R 2至少1个为氘。
- 如权利要求1所述的化合物，其特征在于，R 4～R 5至少1个为氘。
- 如权利要求1所述的化合物，其特征在于，R 6～R 7至少1个为氘。
- 如权利要求1所述的化合物，其特征在于，R 8为氘。
- 如权利要求1所述的化合物，其特征在于，R 9～R 17均为氘。
- 如权利要求1所述的化合物，其特征在于，所述化合物是选自下组的化合物或其药学上可接受的盐：
- 一种权利要求1-7任一项所述的化合物Ⅰ的制备方法，其包括下列步骤：(1)在有机溶剂中，在缩合剂作用下，化合物I-1与化合物I-2进行缩合反应，制得中间体I-3；(2)在有机溶剂中，在碱的作用下，中间体I-3进行水解反应，制得中间体I-4；(3)在有机溶剂中，在缩合剂作用下，中间体I-4与化合物I-5进行缩合反应，制得化合物I；
- 一种药物组合物，其特征在于，它含有药学上可接受载体和权利要求1-6任一所述化合物，或其药学上可接受的盐。
- 如权利要求8所述的药物组合物，其特征在于，它包含另外的治疗药物，所述的另外的治疗药物为抗病毒药物。
- 一种如权利要求1-6任一项所述的化合物或其药学上可接受的盐，或如权利要求8所述的药物组合物的用途，其特征在于，用于制备抑制3CL蛋白酶的药物组合物。
- 如权利要求11所述的用途，其特征在于，所述的药物组合物用于制备治疗和预防病毒感染的药物。
- 根据权利要求12所述的方法，其中所述病毒感染是人冠状病毒、新冠病毒(SARS-CoV-2)、SARS冠状病毒和MERS冠状病毒。
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| CN116763898A (zh) * | 2023-08-21 | 2023-09-19 | 北京科翔中升医药科技有限公司 | 一种蛋白酶抑制剂化合物在制备猫冠状病毒感染药物中的用途 |
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