TW202334123A

TW202334123A - Compounds, conjugates and methods thereof for preventing and treating coronavirus infection

Info

Publication number: TW202334123A
Application number: TW111150216A
Authority: TW
Inventors: 彭程; 宋國偉; 武進; 錢夢飛; 宋治東; 袁帥; 凌煒康; 高凡; 袁海卿; 鄔征
Original assignee: 大陸商蘇州愛科百發生物醫藥技術有限公司
Priority date: 2021-12-31
Filing date: 2022-12-27
Publication date: 2023-09-01
Also published as: WO2023125846A1

Abstract

The present invention relates to a compound represented by formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts:

The above compounds and drug conjugates have a good inhibitory activity of SARS-CoV-2 coronavirus 3CL protease, and can be used to prevent and treat pneumonia caused by SARS-CoV-2 coronavirus infection.

Description

Compounds and conjugates and methods for preventing and treating coronavirus infections

本發明涉及醫藥領域，特別是涉及一種用於預防和治療冠狀病毒感染的化合物及其偶聯物和方法。 The present invention relates to the field of medicine, and in particular to a compound and its conjugate and method for preventing and treating coronavirus infection.

本發明涉及抑制病毒複製活性的化合物和方法，包括將SARS-CoV-2相關3C-like(3CL)蛋白酶與治療有效量的SARS-CoV-2相關3C-like蛋白酶抑制劑接觸。本發明還涉及通過向需要的患者提供治療有效量的SARS-CoV-2相關3C樣蛋白酶抑制劑治療患者冠狀病毒病2019(COVID-19)的方法。本發明還涉及在患者中治療COVID-19的方法，該方法包括向需要該藥物組合物的患者施用該藥物組合物，該藥物組合物包含治療有效量的SARS-CoV-2相關3C樣蛋白酶抑制劑。COVID-19的病原體被確定為一種新型冠狀病毒，被命名為嚴重急性呼吸綜合征冠狀病毒2(SARS-CoV-2)。研究還發現，SARS-CoV-2與2002-2003年SARS疫情的病原體SARS-CoV(嚴重急性呼吸綜合征冠狀病毒)有79%的同源性，與中東呼吸綜合征冠狀病毒(MERS-CoV)有50%的同源性。 The present invention relates to compounds and methods for inhibiting viral replication activity, comprising contacting SARS-CoV-2-related 3C-like (3CL) protease with a therapeutically effective amount of a SARS-CoV-2-related 3C-like protease inhibitor. The present invention also relates to methods of treating coronavirus disease 2019 (COVID-19) in a patient by providing a therapeutically effective amount of a SARS-CoV-2-related 3C-like protease inhibitor to the patient in need thereof. The invention also relates to a method of treating COVID-19 in a patient, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a SARS-CoV-2 related 3C-like protease inhibitor agent. The causative agent of COVID-19 was identified as a new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The study also found that SARS-CoV-2 is 79% homologous to SARS-CoV (severe acute respiratory syndrome coronavirus), the causative agent of the 2002-2003 SARS epidemic, and is 79% homologous to Middle East respiratory syndrome coronavirus (MERS-CoV). There is 50% homology.

最近的證據清楚地表明，新出現的冠狀病毒SARS-CoV-2──COVID-19的病原體獲得了人際傳播能力，導致病毒在社區傳播。COVID-19的症狀包括發熱、咳嗽、氣短、疲勞、頭痛、嗅覺喪失、鼻塞、喉嚨痛、咳痰、肌肉或關節疼痛、發冷、噁心、嘔吐和腹瀉。在嚴重的病例中，症狀包括醒來困難、意識混亂、臉或嘴唇發藍、咳血、白細胞減少和腎衰竭。併發症包括肺炎、病毒性敗血症、急性呼吸窘迫綜合征和腎衰竭。 Recent evidence clearly shows that the emerging coronavirus SARS-CoV-2, the causative agent of COVID-19, has acquired human-to-human transmissibility, resulting in community spread of the virus. COVID-19 Symptoms include fever, cough, shortness of breath, fatigue, headache, loss of smell, nasal congestion, sore throat, phlegm production, muscle or joint pain, chills, nausea, vomiting and diarrhea. In severe cases, symptoms include difficulty waking up, confusion, bluish discoloration of the face or lips, coughing up blood, low white blood cells, and kidney failure. Complications include pneumonia, viral sepsis, acute respiratory distress syndrome, and renal failure.

SARS-CoV-2冠狀病毒屬於冠狀病毒科冠狀病毒屬，為具有包膜的單鏈正義RNA病毒。和其他已知冠狀病毒類似，SARS-CoV-2冠狀病毒也經過吸附、穿入、脫殼、生物合成、子代病毒的組裝與釋放等幾個過程完成子代病毒的增殖。SARS-CoV-2冠狀病毒感染宿主細胞起始于病毒包膜表面的刺突糖蛋白與宿主細胞表面的受體結合，隨後發生膜融合，病毒進入宿主細胞，在細胞溶酶體等細胞器作用下，釋放出病毒的遺傳物質單鏈正義RNA，在宿主細胞的線粒體、核糖體等蛋白質合成元件以及必須的原料等作用下，翻譯產生多聚蛋白，之後，SARS-CoV-2冠狀病毒的兩大必需半胱氨酸蛋白酶：木瓜樣蛋白酶(papain-like protease,PL pro)和3C樣蛋白酶(3C-like protease,3CL pro)在特定位點切割加工多聚蛋白前體，產生多個對病毒生命週期非常重要的非結構蛋白。在這些非結構蛋白的作用下，病毒RNA複製出子代病毒核酸物質，並大量翻譯出所需的結構蛋白，完成子代病毒的組裝和釋放。SARS-CoV-2冠狀病毒感染細胞的生命週期的任何環節或關鍵酶均可以作為抗病毒藥物的研究靶點，如水解切割多聚蛋白前體的半胱氨酸蛋白酶PL pro和3CL pro，負責完成子代病毒遺傳物質複製的RNA聚合酶等。 SARS-CoV-2 coronavirus belongs to the family Coronaviridae and is an enveloped single-stranded positive-sense RNA virus. Similar to other known coronaviruses, SARS-CoV-2 coronavirus also completes the proliferation of progeny viruses through several processes such as adsorption, penetration, uncoating, biosynthesis, assembly and release of progeny viruses. The infection of host cells by SARS-CoV-2 coronavirus begins when the spike glycoprotein on the surface of the virus envelope binds to the receptor on the surface of the host cell. Subsequently, membrane fusion occurs. The virus enters the host cell and acts in cellular organelles such as lysosomes. Under the influence of the virus, the single-stranded positive-sense RNA, the genetic material of the virus, is translated to produce polyprotein under the action of the host cell's mitochondria, ribosomes and other protein synthesis components as well as necessary raw materials. Afterwards, the two parts of the SARS-CoV-2 coronavirus Large essential cysteine protease: papain-like protease (PL pro) and 3C-like protease (3CL pro) cleave and process polyprotein precursors at specific sites to produce multiple pairs of viruses Non-structural proteins of very important life cycle. Under the action of these non-structural proteins, viral RNA copies progeny viral nucleic acid materials and translates the required structural proteins in large quantities to complete the assembly and release of progeny viruses. Any link or key enzyme in the life cycle of SARS-CoV-2 coronavirus-infected cells can be used as a research target for antiviral drugs, such as the cysteine proteases PL pro and 3CL pro that hydrolyze and cleave polyprotein precursors, which are responsible for RNA polymerase that completes the replication of the genetic material of progeny viruses, etc.

3CL蛋白酶(3chymotrypsin-like protease,3CL pro)，又稱主蛋白酶(M pro)，是冠狀病毒RNA翻譯出多聚蛋白pp1a和pp1ab後水解產生多個非結構蛋白過程中的關鍵蛋白酶，對病毒的複製和感染至關重要，抑制3CL蛋白酶的催化功能可有效抑制病毒多聚蛋白前體的切割，阻斷病毒複製，抑制子代病毒生成。3CL pro屬於半胱氨酸蛋白酶，是催化單正鏈RNA病毒前體蛋白水解的關鍵蛋白酶，對SARS-CoV-2等冠狀病毒的複製活性具有重要的作用。因此，3CL pro是目前公認的研發抗冠狀病毒藥物的理想靶點。 3CL protease (3chymotrypsin-like protease, 3CL pro), also known as the main protease (M pro), is a key protease in the process of hydrolyzing the polyprotein pp1a and pp1ab from the coronavirus RNA to produce multiple non-structural proteins. It is very important to the virus. Essential for replication and infection, inhibition of 3CL protease The catalytic function can effectively inhibit the cleavage of viral polyprotein precursors, block viral replication, and inhibit the production of progeny viruses. 3CL pro is a cysteine protease, a key protease that catalyzes the proteolysis of single positive-strand RNA virus precursors, and plays an important role in the replication activity of coronaviruses such as SARS-CoV-2. Therefore, 3CL pro is currently recognized as an ideal target for the development of anti-coronavirus drugs.

疫情對公眾健康的威脅尤為嚴重。冠狀病毒具有高度傳染性，目前的研究表明，它可以通過無症狀攜帶者或症狀前的人傳播。同樣，這種疾病的早期發展非常緩慢，攜帶者往往意識不到自己已被感染，導致他們將許多人暴露在病毒之下。COVID-19的傳播容易程度、患者的高住院率和死亡率結合在一起，使病毒感染成為一個重大的公共衛生風險，特別是對於沒有醫療系統、無法為大流行水準的患者提供支援性護理的國家。輝瑞口服藥Paxlovid獲得FDA緊急使用授權，其主要成分為3CLpro抑制劑nirmatrelvir，但其體內半衰期較短，需要與ritonavir(CYP3A抑制劑)聯合使用來提高體內暴露量進而提升藥效。針對SARS-CoV-2冠狀病毒3CL pro開發出結構新穎、低毒高效、更加穩定且具有自主智慧財產權的口服抗病毒藥物，以滿足國內外SARS-CoV-2冠狀病毒感染患者的臨床需求，具有重大的社會意義。綜上所述，本領域迫切需要開發針對SARS-CoV-2冠狀病毒3CL蛋白酶的抑制劑用於預防和治療SARS-CoV-2冠狀病毒感染引起的肺炎。 The epidemic poses a particularly serious threat to public health. The coronavirus is highly contagious and current research shows it can be spread by asymptomatic carriers or pre-symptomatic people. Likewise, the disease develops very slowly in its early stages, and carriers often don't realize they are infected, causing them to expose many people to the virus. The ease with which COVID-19 spreads and the high rates of hospitalization and death among patients combine to make the viral infection a significant public health risk, especially for those without health systems capable of providing pandemic-level supportive care to patients. nation. Pfizer's oral drug Paxlovid has received emergency use authorization from the FDA. Its main ingredient is the 3CLpro inhibitor nirmatrelvir, but its half-life in the body is short. It needs to be used in combination with ritonavir (CYP3A inhibitor) to increase body exposure and thereby improve drug efficacy. Developed for SARS-CoV-2 coronavirus 3CL pro, an oral antiviral drug with novel structure, low toxicity, high efficiency, more stability and independent intellectual property rights, to meet the clinical needs of patients infected with SARS-CoV-2 coronavirus at home and abroad. great social significance. In summary, there is an urgent need in the field to develop inhibitors targeting the SARS-CoV-2 coronavirus 3CL protease for the prevention and treatment of pneumonia caused by SARS-CoV-2 coronavirus infection.

為了解決上述問題，本發明提供了一類針對SARS-CoV-2冠狀病毒3CL蛋白酶的抑制劑，該抑制劑能夠用於預防和治療SARS-CoV-2冠狀病毒感染引起的肺炎。 In order to solve the above problems, the present invention provides a type of inhibitor against SARS-CoV-2 coronavirus 3CL protease, which inhibitor can be used to prevent and treat pneumonia caused by SARS-CoV-2 coronavirus infection.

為了解決上述技術問題，本發明提供了以下技術方案： In order to solve the above technical problems, the present invention provides the following technical solutions:

本發明提供了一種式I所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： The invention provides a compound represented by formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

本發明所提供的化合物具有很好地抑制SARS-CoV-2冠狀病毒3CL蛋白酶的活性，能夠用於預防和治療SARS-CoV-2冠狀病毒感染引起的肺炎。 The compound provided by the invention has the activity of well inhibiting SARS-CoV-2 coronavirus 3CL protease and can be used to prevent and treat pneumonia caused by SARS-CoV-2 coronavirus infection.

為使本發明的技術方案和有益效果能夠更加明顯易懂，下面通過列舉具體實施例的方式進行詳細說明。除非另有定義，本文所使用的技術和科學技術名詞與本申請所屬的技術領域中的技術和科學技術名詞的含義相同。 In order to make the technical solutions and beneficial effects of the present invention more obvious and understandable, detailed descriptions are given below by enumerating specific embodiments. Unless otherwise defined, technical and scientific terms used herein have the same meaning as those in the technical field to which this application belongs.

一方面，本發明提供一種式I所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the one hand, the present invention provides a compound represented by Formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

其中， in,

m，n各自獨立地為0至4中的任一整數； m, n are each independently any integer from 0 to 4;

每一個R¹各自獨立地選自氫、氘、氰基、鹵素、胺基(NH₂)、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基；或者兩個R¹及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基； Each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine (NH ₂ ), hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy and a C _1-6 alkyl group that is unsubstituted or substituted by a substituent selected from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; or two R ¹ and the carbon atoms connected thereto form C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

每一個R²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基；或者兩個R²及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基； Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C 1-6 alkyl, C _3-7 ring substituted by a substituent selected from the group consisting _of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy Alkyl and 3-7 membered heterocycloalkyl; or two R ² and the carbon atoms connected to form C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

R³係選自氰基、醛基、-(CO)CH₃和-(CO)CF₃所組成的群組； R ³ is selected from the group consisting of cyano group, aldehyde group, -(CO)CH ₃ and -(CO)CF ₃ ;

每一個R⁴各自獨立地選自氫、氘、未取代或被選自氰基、胺基、羥基、鹵素、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基； Each R ⁴ is independently selected from hydrogen, deuterium, unsubstituted or selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl substituted by a group consisting of a 5-10 membered heteroaryl substituent;

R⁵選自氫、氘和C_1-6烷基； R ⁵ is selected from hydrogen, deuterium and C _1-6 alkyl;

或者任一R⁴和R⁵及其相連的C原子和N原子形成取代或未取代的5-7元環，所述取代是被1-4個選自氫、氘、氰基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所取代；或者5-7元環的取代基與所述5-7元環形成並環； Or any R ⁴ and R ⁵ and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, the substitution is by 1-4 selected from hydrogen, deuterium, cyano, halogen, tritium Substituted with fluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl substituents; or 5-7 membered The substituent of the ring forms a combined ring with the 5-7 membered ring;

R⁶係選自氫、氘和C_1-6烷基所組成的群組； R ⁶ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

或者任一R⁴和R⁶及其相連的C原子和N原子形成取代或未取代的5-7元環，所述取代是被1-4個選自氫、氘、氰基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代；或者所述5-7元環的兩個取代基與同一個碳原子或相鄰兩個碳原子形成被氫、氘、C_1-6烷基、C_1-6烷氧基和C_1-6的氘代烷基的取代基所取代的C_3-7環烷基； Or any R ⁴ and R ⁶ and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, the substitution is by 1-4 selected from hydrogen, deuterium, cyano, halogen, tritium Substituted by the group consisting of fluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl substituents; Or the two substituents of the 5-7 membered ring are formed by hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 with the same carbon atom or two adjacent carbon atoms. C _3-7 cycloalkyl substituted by a deuterated alkyl substituent;

R⁷係選自氫、氘、取代或未取代的C_1-6烷基、芳基-C_1-6烷基、C_3-7環烷基、C_3-7環烷基-C_1-6烷基、3-7元雜環烷基、C_3-7元雜環烷基-C_1-6烷基、C_6-10芳基、5-10元雜芳基和苯並C_5-7環烷基所組成的群組，所述取代是被1-4個係選自氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、-C(=O)NH₂、-SO₂NH₂、C_1-6烷基、C_1-6烷氧基、C_3-7環烷基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代，任選的，所述C_6-10芳基、5-10元雜芳基被係選自C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代，所述-C(=O)NH₂和-SO₂NH₂可被1-2個C_1-6烷基取代； R ⁷ is selected from hydrogen, deuterium, substituted or unsubstituted C _1-6 alkyl, aryl-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 6} alkyl, 3-7 membered heterocycloalkyl, C _3-7 membered heterocycloalkyl-C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl and benzo C _5- A group consisting of ₇ cycloalkyl groups, the substitution is 1-4 selected from cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, -C(=O)NH _2. Composed of -SO ₂ NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl substituents optionally, the C _6-10 aryl group and the 5-10 membered heteroaryl group are composed of substituents selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy groups. group, the -C(=O)NH ₂ and -SO ₂ NH ₂ can be substituted by 1-2 C _1-6 alkyl groups;

R⁸係選自氫、氘和C_1-6烷基所組成的群組； R ⁸ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

或者R⁷和R⁸及其相連的C原子和N原子形成未取代或被選自氫、氘、氰基、胺基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代的5-7元環； Or R ⁷ and R ⁸ and their attached C atoms and N atoms form unsubstituted or selected from hydrogen, deuterium, cyano, amine, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkane A 5-7 membered ring substituted by a group consisting of a substituent of a C _1-6 alkoxy group, a C _6-10 aryl group and a 5-10 membered heteroaryl group;

R⁹係選自取代或未取代的C_1-6烷基、C_3-7環烷基、3-7元雜環烷基、C_1-6烷基胺基、C_1-6烷氧基、C_3-7環烷氧基、C_3-7環烷基胺基、3-7元雜環烷氧基、C_3-7元雜環烷基胺基、C_6-10芳基、C_6-10芳基氧基、5-10元雜芳基、6-14元螺雜環基、5-11元橋雜環基、-NH-C(O)-C_1-6烷基、-NH-C(O)-NH-C_1-6烷基和4-11元稠合雜環基所組成的群組，所述取代是被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代的或未取代的C_1-6烷基、被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代的或未取代的C_3-7環烷基、被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代的或未取代的C_6-10芳基和被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代的或未取代的5-10元雜芳基的取代基所組成的群組所取代；或者R⁷和R⁹及其相連的碳原子形成取代或未取代的5-8元環，所述取代是被1-4個選自氰基、氨基、羥基、鹵素、三氟甲基、三氟甲氧基、被1-4個係選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代的或未取代的C_1-6烷基和被1-4個係選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代的或未取代的C_6-10芳基的取代基所組成的群組所取代。 R ⁹ is selected from substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _1-6 alkylamino, C _1-6 alkoxy , C _3-7 cycloalkoxy group, C _3-7 cycloalkylamino group, 3-7 membered heterocycloalkoxy group, C _3-7 membered heterocycloalkylamino group, C _6-10 aryl group, C _6-10 aryloxy group, 5-10 membered heteroaryl group, 6-14 membered spiroheterocyclyl group, 5-11 membered bridged heterocyclyl group, -NH-C(O)-C _1-6 alkyl group, - A group consisting of NH-C(O)-NH-C _1-6 alkyl and 4-11 membered fused heterocyclic groups, the substitution is by 1-4 selected from hydrogen, deuterium, cyano, amine Base, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, 1-4 selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C The substituted or unsubstituted C _1-6 alkyl group consisting of the substituents of 1-6 alkyl and C _6-10 aryl groups is replaced by 1-4 selected from hydrogen, deuterium, cyano group _, and amino group Substituted or unsubstituted C _3-7 cycloalkyl substituted by the group consisting of hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl substituents group, substituted by 1-4 substituents selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl The group consists of a substituted or unsubstituted C _6-10 aryl group and 1-4 selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy _or ^R ₇ Form a substituted or unsubstituted 5-8 membered ring with R ⁹ and the carbon atoms connected to it, and the substitution is by 1-4 selected from cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy group, substituted by 1-4 groups selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl The group consisting of a substituted or unsubstituted C _1-6 alkyl group and 1-4 groups selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethyl substituted by a group consisting of an oxygen group, a C _1-6 alkyl group and a C _6-10 aryl substituent or a group consisting of an unsubstituted C _6-10 aryl substituent.

在某些實施方式中，每一個R¹各自獨立地係選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基和C_1-6烷基所組成的群組。 In certain embodiments, each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1- A group consisting of ₆ alkoxy groups and C _1-6 alkyl groups.

在某些實施方式中，每一個R¹各自獨立地選自氫、氘、鹵素和C_1-6烷基所組成的群組。 In certain embodiments, each R ¹ is independently selected from the group consisting of hydrogen, deuterium, halogen, and C _1-6 alkyl.

在某些實施方式中，每一個R¹各自獨立地選自氫、鹵素和C_1-3烷基所組成的群組。 In certain embodiments, each R ¹ is independently selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl.

在某些實施方式中，每一個R¹各自獨立地選自氫。 In certain embodiments, each ^R1 is independently selected from hydrogen.

在某些實施方式中，每一個R²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基和C_1-6烷基所組成的群組。 In certain embodiments, each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 The group consisting of alkoxy and C _1-6 alkyl.

在某些實施方式中，每一個R²各自獨立地選自氫、氘、鹵素和C_1-6烷基所組成的群組。 In certain embodiments, each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, and C _1-6 alkyl.

在某些實施方式中，每一個R²各自獨立地選自氫、鹵素和C_1-3烷基所組成的群組。 In certain embodiments, each R ² is independently selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl.

在某些實施方式中，每一個R²各自獨立地選自氫。 In certain embodiments, each ^R2 is independently selected from hydrogen.

在某些實施方式中，R³選自氰基、醛基、-(CO)CH₃和-(CO)CF₃所組成的群組。 In certain embodiments, R ³ is selected from the group consisting of cyano, aldehyde, -(CO)CH ₃ and -(CO)CF ₃ .

在某些實施方式中，R³選自氰基和-(CO)CH₃所組成的群組。 In certain embodiments, ^R is selected from the _group consisting of cyano and -(CO)CH.

在某些實施方式中，R³選自氰基。 In certain embodiments, ^R3 is selected from cyano.

在某些實施方式中，任一R⁴和R⁶及其相連的C原子和N原子形成取代或未取代的5-6元環。 In certain embodiments, any R ⁴ and R ⁶ and the C atom and N atom to which they are attached form a substituted or unsubstituted 5-6 membered ring.

在某些實施方式中，任一R⁴和R⁶及其相連的C原子和N原子形成取代或未取代的吡咯烷基和呱啶基。 In certain embodiments, any of R ⁴ and R ⁶ and the C atom and N atom to which they are attached form a substituted or unsubstituted pyrrolidinyl and piridinyl group.

在某些實施方式中，所述取代是被1-4個選自氫、氘、氰基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by 1-4 selected from hydrogen, deuterium, cyano, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkyl Substituted by the group consisting of an oxygen group, a C _6-10 aryl group and a 5-10 membered heteroaryl substituent.

在某些實施方式中，所述取代是被1-4個選自鹵素、三氟甲基和C_1-6烷基的取代基所組成的群組所取代。 In certain embodiments, the substitution is with a group consisting of 1-4 substituents selected from the group consisting of halogen, trifluoromethyl, and C _1-6 alkyl.

在某些實施方式中，所述取代是被1-4個選自氟、氯、溴、三氟甲基、甲基、乙基、正丙基和異丙基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by the group consisting of 1-4 substituents selected from fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, n-propyl, and isopropyl replaced.

在某些實施方式中，所述5-6元環的兩個取代基與同一個碳原子或相鄰兩個碳原子形成被氫、氘、C_1-6烷基、C_1-6烷氧基和C_1-6的氘代烷基的取代基所取代的C_3-7環烷基。 In certain embodiments, the two substituents of the 5-6 membered ring are formed by hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy with the same carbon atom or two adjacent carbon atoms. A C _3-7 cycloalkyl group substituted by a substituent of a C _1-6 deuterated alkyl group.

在某些實施方式中，所述5-6元環的兩個取代基與同一個碳原子或相鄰兩個碳原子形成被氫、氘、C_1-6烷基、C_1-6烷氧基和C_1-6的氘代烷基的取代基所取代的C_3-5環烷基。 In certain embodiments, the two substituents of the 5-6 membered ring are formed by hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy with the same carbon atom or two adjacent carbon atoms. A C _3-5 cycloalkyl group substituted by a substituent of a C _1-6 deuterated alkyl group.

在某些實施方式中，所述5-6元環的兩個取代基與同一個碳原子或相鄰兩個碳原子形成被氫、氘、C_1-6烷基、C_1-6烷氧基和C_1-6的氘代烷基的取代基所取代的環丙基和環丁基。 In certain embodiments, the two substituents of the 5-6 membered ring are formed by hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy with the same carbon atom or two adjacent carbon atoms. cyclopropyl and cyclobutyl groups substituted by substituents of C _1-6 deuterated alkyl groups.

在某些實施方式中，R⁵選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ⁵ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R⁵選自氫。 In certain embodiments, ^R5 is selected from hydrogen.

在某些實施方式中，R⁷選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, R ⁷ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R⁷選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ⁷ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R⁷選自氫。 In certain embodiments, ^R7 is selected from hydrogen.

在某些實施方式中，R⁸選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ⁸ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R⁸選自氫。 In certain embodiments, ^R8 is selected from hydrogen.

在某些實施方式中，m為0至3中的任一整數。 In certain embodiments, m is any integer from 0 to 3.

在某些實施方式中，m為0-2中的任一整數。 In certain embodiments, m is any integer from 0 to 2.

在某些實施方式中，m為0-1中的任一整數。 In certain embodiments, m is any integer from 0 to 1.

在某些實施方式中，m為0。 In certain embodiments, m is 0.

在某些實施方式中，n為0至3中的任一整數。 In certain embodiments, n is any integer from 0 to 3.

在某些實施方式中，n為0-2中的任一整數。 In certain embodiments, n is any integer from 0 to 2.

在某些實施方式中，n為0-1中的任一整數。 In certain embodiments, n is any integer from 0 to 1.

在某些實施方式中，n為1。 In certain embodiments, n is 1.

另一方面，本發明提供一種式I-1所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

其中， in,

每一個R¹各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基；或者兩個R¹及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基； Each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C 1-6 alkyl, C _3-7 ring substituted by a substituent selected from the group consisting _of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy Alkyl and 3-7 membered heterocycloalkyl; or two R ¹ and the carbon atoms connected to form C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

R⁵選自氫、氘和C_1-6烷基所組成的群組； R ⁵ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

R⁸係選自氫、氘、C_1-6烷基所組成的群組； R ⁸ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl;

環A和環B各自獨立地選自取代或未取代的C_3-7環烷基、3-7元雜環烷基、C_6-10芳基、5-10元雜芳基、6-14元螺雜環基、5-11元橋雜環基和4-11元稠雜環基所組成的群組；所述取代是被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代。 Ring A and Ring B are each independently selected from substituted or unsubstituted C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 6-14 A group consisting of 1-membered spiroheterocyclyl, 5-11-membered bridged heterocyclyl and 4-11-membered fused heterocyclyl; the substitution is by 1-4 selected from hydrogen, deuterium, cyano group, amine group, Substituted by the group consisting of hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl substituents.

在某些實施方式中，每一個R¹各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基和C_1-6烷基所組成的群組。 In certain embodiments, each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 The group consisting of alkoxy and C _1-6 alkyl.

在某些實施方式中，每一個R²各自獨立地選自氫、氘、鹵素和C_1-6烷基。 In certain embodiments, each R ² is independently selected from hydrogen, deuterium, halogen, and C _1-6 alkyl.

在某些實施方式中，R⁵係選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ⁵ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R⁷係選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, R ⁷ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R⁷係選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ⁷ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R⁸係選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ⁸ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，m為0。 In certain embodiments, m is 0.

在某些實施方式中，n為1。 In certain embodiments, n is 1.

在某些實施方式中，環A係選自取代或未取代的C_3-7環烷基和3-7元雜環烷基所組成的群組。 In certain embodiments, Ring A is selected from the group consisting of substituted or unsubstituted C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl.

在某些實施方式中，環A係選自取代或未取代的C_3-5環烷基和3-5元雜環烷基所組成的群組。 In certain embodiments, Ring A is selected from the group consisting of substituted or unsubstituted C _3-5 cycloalkyl and 3-5 membered heterocycloalkyl.

在某些實施方式中，環A係選自取代或未取代的環丙基、環丁基、環戊基、吡咯烷基、四氫吡喃基、呱啶基、呱嗪基和嗎啉基所組成的群組。 In certain embodiments, Ring A is selected from the group consisting of substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, pyridinyl, pyridinyl, and morpholinyl the group formed.

在某些實施方式中，所述取代是被1-4個係選自氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by 1-4 groups selected from deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, and C Substituted by a group consisting of _6-10 aryl substituents.

在某些實施方式中，所述取代是被1-4個係選自鹵素、三氟甲基和C_1-6烷基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by a group of 1-4 substituents selected from the group consisting of halogen, trifluoromethyl, and C _1-6 alkyl.

在某些實施方式中，所述取代是被1-4個係選自氟、氯、溴、三氟甲基、甲基、乙基、正丙基和異丙基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by 1-4 substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl. group replaced.

在某些實施方式中，環B係選自取代或未取代的C_6-10芳基和5-10元雜芳基所組成的群組。 In certain embodiments, Ring B is selected from the group consisting of substituted or unsubstituted C _6-10 aryl and 5-10 membered heteroaryl.

在某些實施方式中，環B係選自取代或未取代的C_6-10芳基和5-10元雜芳基所組成的群組，所述雜芳基含有1-3個雜原子，所述雜原子係選自N、O和S所組成的群組。 In certain embodiments, Ring B is selected from the group consisting of substituted or unsubstituted C _6-10 aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms, The heteroatoms are selected from the group consisting of N, O and S.

在某些實施方式中，環B係選自取代或未取代的苯基、呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、三唑基和四唑基所組成的群組。 In certain embodiments, Ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, The group consisting of triazolyl and tetrazolyl groups.

在某些實施方式中，所述取代是被1-4個係選自鹵素、三氟甲基、C_1-6烷基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by a group of 1-4 substituents selected from the group consisting of halogen, trifluoromethyl, and C _1-6 alkyl.

另一方面，本發明提供一種式I-2所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-2 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

其中， in,

R⁵係選自氫、氘和C_1-6烷基所組成的群組； R ⁵ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

或者R⁷和R⁸及其相連的C原子和N原子形成未取代或被係選自氫、氘、氰基、胺基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代的5-7元環； Or R ⁷ and R ⁸ and their attached C atoms and N atoms form unsubstituted or selected from hydrogen, deuterium, cyano, amine, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 A 5-7 membered ring substituted by a group consisting of alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl substituents;

環A和環B各自獨立地係選自取代或未取代的C_3-7環烷基、3-7元雜環烷基、C_6-10芳基、5-10元雜芳基、6-14元螺雜環基、5-11元橋雜環基和4-11元稠雜環基所組成的群組；所述取代是被1-4個係選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代。 Ring A and Ring B are each independently selected from substituted or unsubstituted C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 6- A group consisting of 14-membered spiroheterocyclyl, 5-11-membered bridged heterocyclyl and 4-11-membered fused heterocyclyl; the substitution is 1-4 selected from hydrogen, deuterium, cyano, amine Substituted by the group consisting of substituents such as hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl.

在某些實施方式中，每一個R¹各自獨立地係選自氫、氘、鹵素和C_1-6烷基所組成的群組。 In certain embodiments, each R ¹ is independently selected from the group consisting of hydrogen, deuterium, halogen, and C _1-6 alkyl.

在某些實施方式中，每一個R²各自獨立地係選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基和C_1-6烷基所組成的群組。 In certain embodiments, each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1- A group consisting of ₆ alkoxy groups and C _1-6 alkyl groups.

在某些實施方式中，每一個R²各自獨立地係選自氫、氘、鹵素和C_1-6烷基所組成的群組。 In certain embodiments, each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, and C _1-6 alkyl.

在某些實施方式中，所述取代是被1-4個係選自氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所取代所組成的群組。 In certain embodiments, the substitution is by 1-4 groups selected from deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, and C A group consisting of _6-10 aryl substituents.

另一方面，本發明提供一種式I-2-1所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-2-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt :

其中， in,

每一個R¹各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基；或者兩個R¹及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基； Each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C _1-6 alkyl, C _3-7 substituted by a substituent selected from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy Cycloalkyl and 3-7-membered heterocycloalkyl; or two R ¹ and the carbon atoms they are connected to form C _3-6 cycloalkyl or 3-7-membered heterocycloalkyl;

在某些實施方式中，環A選自取代或未取代的C_3-7環烷基和3-7元雜環烷基所組成的群組。 In certain embodiments, Ring A is selected from the group consisting of substituted or unsubstituted C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl.

在某些實施方式中，環A選自取代或未取代的C_3-5環烷基和3-5元雜環烷基所組成的群組。 In certain embodiments, Ring A is selected from the group consisting of substituted or unsubstituted C _3-5 cycloalkyl and 3-5 membered heterocycloalkyl.

在某些實施方式中，環A選自取代或未取代的環丙基、環丁基、環戊基、吡咯烷基、四氫吡喃基、呱啶基、呱嗪基和嗎啉基所組成的群組。 In certain embodiments, Ring A is selected from the group consisting of substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piridinyl, pyridinyl, and morpholinyl. groups formed.

在某些實施方式中，所述取代是被1-4個選自氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by 1-4 selected from deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C ₆ -Substituted by a group consisting of ₁₀ aryl substituents.

在某些實施方式中，環B選自取代或未取代的C_6-10芳基和5-10元雜芳基所組成的群組。 In certain embodiments, Ring B is selected from the group consisting of substituted or unsubstituted C _6-10 aryl and 5-10 membered heteroaryl.

在某些實施方式中，環B選自取代或未取代的C_6-10芳基和5-10元雜芳基所組成的群組，所述雜芳基含有1-3個雜原子，所述雜原子選自N、O和S所組成的群組。 In certain embodiments, Ring B is selected from the group consisting of substituted or unsubstituted C _6-10 aryl and 5-10 membered heteroaryl, the heteroaryl containing 1-3 heteroatoms, so The heteroatoms are selected from the group consisting of N, O and S.

在某些實施方式中，環B選自取代或未取代的苯基、呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、三唑基和四唑基所組成的群組。 In certain embodiments, Ring B is selected from substituted or unsubstituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tris The group consisting of azolyl and tetrazolyl groups.

在某些實施方式中，所述取代是被1-4個選自鹵素、三氟甲基、C_1-6烷基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by a group of 1-4 substituents selected from the group consisting of halogen, trifluoromethyl, and C _1-6 alkyl.

另一方面，本發明提供一種式I-3所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-3 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

其中， in,

R⁷選自氫、氘、取代或未取代的C_1-6烷基、芳基-C_1-6烷基、C_3-7環烷基、C_3-7環烷基-C_1-6烷基、3-7元雜環烷基、C_3-7元雜環烷基-C_1-6烷基、C_6-10芳基、5-10元雜芳基和苯並C_5-7環烷基所組成的群組，所述取代是被1-4個選自氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、-C(=O)NH₂、-SO₂NH₂、C_1-6烷基、C_1-6烷氧基、C_3-7環烷基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代，任選的，所述C_6-10芳基、5-10元雜芳基被選自C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代，所述-C(=O)NH₂和-SO₂NH₂可被1-2個C_1-6烷基取代； R ⁷ is selected from hydrogen, deuterium, substituted or unsubstituted C _1-6 alkyl, aryl-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 Alkyl, 3-7 membered heterocycloalkyl, C _3-7 membered heterocycloalkyl-C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl and benzo C _5-7 The group consisting of cycloalkyl groups, the substitution is by 1-4 selected from cyano group, amine group, hydroxyl group, halogen, trifluoromethyl group, trifluoromethoxy group, -C(=O)NH ₂ , - A group consisting of substituents of -SO ₂ NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl Substituted by the group, optionally, the C _6-10 aryl group and the 5-10 membered heteroaryl group are selected from the group consisting of substituents of C _1-6 alkyl and C _1-6 alkoxy groups. Substitution, the -C(=O)NH ₂ and -SO ₂ NH ₂ can be substituted by 1-2 C _1-6 alkyl groups;

R⁸選自氫、氘和C_1-6烷基所組成的群組； R ⁸ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

或者R⁷和R⁸及其相連的C原子和N原子形成未取代或被選自氫、氘、氰基、胺基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代5-7元環； Or R ⁷ and R ⁸ and their attached C atoms and N atoms form unsubstituted or selected from hydrogen, deuterium, cyano, amine, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkane The 5-7 membered ring is substituted by a group consisting of a substituent of a C _1-6 alkoxy group, a C _6-10 aryl group and a 5-10 membered heteroaryl group;

R¹⁰，R¹¹，每一個R¹²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基、取代或未取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基所組成的群組；所述取代是被1個或多個選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代； R ¹⁰ , R ¹¹ , each R ¹² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkyl The group consisting of oxygen, substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by 1 or more selected from cyano Substituted by the group consisting of substituents such as amine group, hydroxyl group, halogen, C _1-6 alkyl group and C _1-6 alkoxy group;

環B選自取代或未取代的C_3-7環烷基、3-7元雜環烷基、C_6-10芳基、5-10元雜芳基、6-14元螺雜環基、5-11元橋雜環基和4-11元稠雜環基所組成的群組；所述取代是被1-4個選自氫、氘、氰基、胺基、羥基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基和C_6-10芳基的取代基所組成的群組所取代。 Ring B is selected from substituted or unsubstituted C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 6-14 membered spiroheterocyclyl, A group consisting of 5-11-membered bridged heterocyclyl and 4-11-membered fused heterocyclyl; the substitution is by 1-4 selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoro Substituted from the group consisting of methyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl substituents.

在某些實施方式中，R¹⁰選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, R ¹⁰ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R¹⁰選自氫和C_1-3烷基。 In certain embodiments, R ¹⁰ is selected from hydrogen and C _1-3 alkyl.

在某些實施方式中，R¹⁰選自氫和甲基所組成的群組。 In certain embodiments, R ¹⁰ is selected from the group consisting of hydrogen and methyl.

在某些實施方式中，R¹¹選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, R ¹¹ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R¹¹選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ¹¹ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R¹¹選自氫和甲基所組成的群組。 In certain embodiments, R ¹¹ is selected from the group consisting of hydrogen and methyl.

在某些實施方式中，每一個R¹²各自獨立地選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, each R ¹² is independently selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，每一個R¹²各自獨立地選自氫和C_1-3烷基所組成的群組。 In certain embodiments, each R ¹² is independently selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，每一個R¹²各自獨立地選自氫和甲基所組成的群組。 In certain embodiments, each R ¹² is independently selected from the group consisting of hydrogen and methyl.

另一方面，本發明提供一種式I-3-1所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-3-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt :

其中， in,

每一個R²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基；或者兩個R²及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基所組成的群組； Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C 1-6 alkyl _, C _3-7 cycloalkyl and 3- substituted with substituents selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy 7-membered heterocycloalkyl; or two R ² and its connected carbon atoms form a group consisting of C _3-6 cycloalkyl or 3-7-membered heterocycloalkyl;

R¹⁰，R¹¹，每一個R¹²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基，取代或未取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基所組成的群組；所述取代是被1個或多個選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代； R ¹⁰ , R ¹¹ , each R ¹² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkyl Oxygen group, a group consisting of substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by 1 or more selected from cyano Substituted by the group consisting of substituents such as amine group, hydroxyl group, halogen, C _1-6 alkyl group and C _1-6 alkoxy group;

在某些實施方式中，R⁵選自氫和C_1-3烷基。 In certain embodiments, ^R5 is selected from hydrogen and _C1-3 alkyl.

在某些實施方式中，R⁷選自氫、氘和C_1-6烷基。 In certain embodiments, R ⁷ is selected from hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R⁷選自氫和C_1-3烷基。 In certain embodiments, R ⁷ is selected from hydrogen and C _1-3 alkyl.

在某些實施方式中，R¹⁰選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ¹⁰ is selected from the group consisting of hydrogen and C _1-3 alkyl.

另一方面，本發明提供一種式I-4所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-4 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

其中， in,

每一個R²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基；或者兩個R²及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基； Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C _1-6 alkyl, C _3-7 substituted by a substituent selected from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy Cycloalkyl and 3-7 membered heterocycloalkyl; or two R ² and the carbon atoms connected to form C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

或者R⁷和R⁸及其相連的C原子和N原子形成未取代或被係選自氫、氘、氰基、胺基、鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、C_6-10芳基和5-10元雜芳基的取代基所組成的群組所取代5-7元環； Or R ⁷ and R ⁸ and their attached C atoms and N atoms form unsubstituted or selected from hydrogen, deuterium, cyano, amine, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 The 5-7 membered ring is substituted by a group consisting of alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl substituents;

R¹⁰，R¹¹，每一個R¹²和R^12’各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基，取代或未取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基所組成的群組；所述取代是被1個或多個係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代； R ¹⁰ , R ¹¹ , each R ¹² and R ^12' are independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, a group consisting of substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by 1 or more Each system is substituted by a group consisting of a cyano group, an amino group, a hydroxyl group, a halogen group, a C _1-6 alkyl group and a C _1-6 alkoxy group;

R¹³選自氫、氘、氰基、鹵素、胺基、羥基、-NO₂、C_1-6烷基胺基、C_1-6烷氧基、取代或未取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基所組成的群組；所述取代是被一個或多個係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代； R ¹³ is selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, substituted or unsubstituted C _1-6 alkyl , a group consisting of C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by one or more systems selected from cyano, amino, hydroxyl, halogen, C _1-6 alkyl Substituted by a group consisting of a substituent group and a C _1-6 alkoxy group;

q為0至4中的任一整數。 q is any integer from 0 to 4.

在某些實施方式中，每一個R¹各自獨立地係選自氫、鹵素和C_1-3烷基所組成的群組。 In certain embodiments, each R ¹ is independently selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl.

在某些實施方式中，每一個R²各自獨立地係選自氫、鹵素和C_1-3烷基所組成的群組。 In certain embodiments, each R ² is independently selected from the group consisting of hydrogen, halogen, and C _1-3 alkyl.

在某些實施方式中，R¹⁰係選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, R ¹⁰ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R¹⁰係選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ¹⁰ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R¹⁰係選自氫和甲基所組成的群組。 In certain embodiments, R ¹⁰ is selected from the group consisting of hydrogen and methyl.

在某些實施方式中，R¹¹係選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, R ¹¹ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，R¹¹係選自氫和C_1-3烷基所組成的群組。 In certain embodiments, R ¹¹ is selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，R¹¹係選自氫和甲基所組成的群組。 In certain embodiments, R ¹¹ is selected from the group consisting of hydrogen and methyl.

在某些實施方式中，每一個R¹²和R^12’各自獨立地係選自氫、氘和C_1-6烷基所組成的群組。 In certain embodiments, each R ¹² and R ^12' are each independently selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl.

在某些實施方式中，每一個R¹²和R^12’各自獨立地係選自氫和C_1-3烷基所組成的群組。 In certain embodiments, each R ¹² and R ^12' are each independently selected from the group consisting of hydrogen and C _1-3 alkyl.

在某些實施方式中，每一個R¹²和R^12’各自獨立地係選自氫和甲基所組成的群組。 In certain embodiments, each R ¹² and R ^12' are independently selected from the group consisting of hydrogen and methyl.

在某些實施方式中，R¹³係選自氫、氘、氰基、鹵素、胺基、羥基、-NO₂、C_1-3烷基胺基、C_1-3烷氧基，取代或未取代的C_1-3烷基、C_3-6環烷基和3-6元雜環烷基所組成的群組。 In certain embodiments, R ¹³ is selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, -NO ₂ , C _1-3 alkylamino, C _1-3 alkoxy, substituted or unsubstituted The group consisting of substituted C _1-3 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl.

在某些實施方式中，R¹³係選自氫、鹵素、胺基、羥基、-NO₂和取代或未取代的C_1-3烷基所組成的群組。 In certain embodiments, R ¹³ is selected from the group consisting of hydrogen, halogen, amine, hydroxyl, -NO ₂ and substituted or unsubstituted C _1-3 alkyl.

在某些實施方式中，R¹³係選自氫、氟、氯、溴、取代或未取代的甲基、乙基、正丙基和異丙基所組成的群組。 In certain embodiments, R ¹³ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted methyl, ethyl, n-propyl and isopropyl.

在某些實施方式中，所述取代是被一個或多個係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代。 In certain embodiments, the substitution is by one or more substituents selected from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy. group replaced.

在某些實施方式中，所述取代是被一個或多個係選自鹵素、C_1-3烷基和C_1-3烷氧基的取代基所組成的群組所取代。 In certain embodiments, the substitution is with one or more substituents selected from the group consisting of halogen, C _1-3 alkyl, and C _1-3 alkoxy.

在某些實施方式中，所述取代是被一個或多個係選自氟、氯、溴、甲基、乙基、正丙基和異丙基的取代基所組成的群組所取代。 In certain embodiments, the substitution is with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, and isopropyl.

在某些實施方式中，q為0至3中的任一整數。 In certain embodiments, q is any integer from 0 to 3.

在某些實施方式中，q為0-2中的任一整數。 In certain embodiments, q is any integer from 0 to 2.

在某些實施方式中，q為1或2。 In certain embodiments, q is 1 or 2.

另一方面，本發明提供一種式I-4-1所示的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽： On the other hand, the present invention provides a compound represented by formula I-4-1 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt :

其中， in,

每一個R²各自獨立地選自氫、氘、氰基、鹵素、胺基、羥基、=O、-NO₂、C_1-6烷基胺基、C_1-6烷氧基以及未取代或被選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基、或者兩個R²及其相連的碳原子形成C_3-6環烷基或3-7元雜環烷基； Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C 1-6 alkyl, C _3-7 ring substituted by a substituent selected from the group consisting _of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy Alkyl and 3-7 membered heterocycloalkyl, or two R ² and the carbon atoms to which they are connected form C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

R¹³選自氫、氘、氰基、鹵素、胺基、羥基、-NO₂、C_1-6烷基胺基、C_1-6烷氧基、取代或未取代的C_1-6烷基、C_3-7環烷基和3-7元雜環烷基所組成的群組；所述取代是被一個或多個係選自氰基、胺基、羥基、鹵素、C_1-6烷基和C_1-6烷氧基的取代基所組成的群組所取代； R ¹³ is selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, substituted or unsubstituted C _1-6 alkyl , the group consisting of C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by one or more systems selected from cyano, amino, hydroxyl, halogen, C _1-6 alkyl Substituted by a group consisting of a substituent group and a C _1-6 alkoxy group;

q為0至4中的任一整數。 q is any integer from 0 to 4.

在某些實施方式中，q為1或2。 In certain embodiments, q is 1 or 2.

另一方面，本發明提供一種化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽，所述化合物為如下任一種： On the other hand, the present invention provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt. The compound is any one of the following:

、

和

,

and

。

.

、

和

,

and

。

.

另一方面，本發明還提供了一種式I所示化合物的製備方法，具體如下： On the other hand, the present invention also provides a preparation method of the compound represented by formula I, specifically as follows:

第1步：化合物I-2-1與I-2-2發生縮合反應，得到化合物I-2-3； Step 1: Compound I-2-1 and I-2-2 undergo a condensation reaction to obtain compound I-2-3;

第2步：化合物I-2-3酯基在鹼性條件下發生水解，得到化合物I-2-4； Step 2: The ester group of compound I-2-3 is hydrolyzed under alkaline conditions to obtain compound I-2-4;

第3步：化合物I-2-4與化合物I-2-5發生縮合反應，得到化合物I-2-6； Step 3: Compound I-2-4 and compound I-2-5 undergo a condensation reaction to obtain compound I-2-6;

第4步：化合物I-2-6發生胺基保護基的脫除，得到化合物I-2-7； Step 4: Compound I-2-6 undergoes removal of the amino protecting group to obtain compound I-2-7;

第5步：化合物I-2-7與化合物I-2-8發生縮合反應，得到式I的化合物； Step 5: Compound I-2-7 and compound I-2-8 undergo a condensation reaction to obtain the compound of formula I;

其中PG為胺基的保護基，包括叔丁氧羰基(t-Boc)、苄氧羰基(CBz)、2-聯苯基-2-丙氧羰基(BPoc)、鄰苯二甲醯亞胺基(Pht)、對甲苯磺醯基(Tos)、三苯甲基(Trt)、甲醯基、三氟乙醯基、笏甲氧羰基(Fmoc)、對甲氧基苄基(PMB)、苄基(Bn)、烯丙氧羰基(Alloc)等。其中PG優選為叔丁氧羰基(t-Boc)。 Among them, PG is the protecting group of amine group, including tert-butoxycarbonyl (t-Boc), benzyloxycarbonyl (CBz), 2-biphenyl-2-propoxycarbonyl (BPoc), phthalimide group (Pht), p-toluenesulfonyl (Tos), trityl (Trt), formyl, trifluoroethyl, methoxycarbonyl (Fmoc), p-methoxybenzyl (PMB), benzyl group (Bn), allyloxycarbonyl (Alloc), etc. Among them, PG is preferably tert-butoxycarbonyl (t-Boc).

本發明還提供了一種藥物組合物，包括至少一種前述化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物及藥學上可接受的鹽，以及藥學上可接受的載體、稀釋劑或賦形劑。 The present invention also provides a pharmaceutical composition, including at least one of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and pharmaceutically acceptable salts. carrier, diluent or excipient.

在某些實施方式中，所述的藥物組合物的單位劑量為0.001mg-1000mg。 In certain embodiments, the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.

在某些實施方式中，基於組合物的總重量，所述的藥物組合物含有0.01%-99.99%的前述化合物。在某些實施方式中，所述的藥物組合物含有0.1%-99.9%的前述化合物。在某些實施方式中，所述的藥物組合物含有0.5%-99.5%的前述化合物。在某些實施方式中，所述的藥物組合物含有1%-99%的前述化合物。在某些實施方式中，所述的藥物組合物含有2%-98%的前述化合物。 In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compounds based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compounds. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

在某些實施方式中，基於組合物的總重量，所述的藥物組合物含有0.01%-99.99%的藥學上可接受的載體、稀釋劑或賦形劑。在某些實施方式中，所述的藥物組合物含有0.1%-99.9%的藥學上可接受的載體、稀釋劑或賦形劑。在某些實施方式中，所述的藥物組合物含有0.5%-99.5%的藥學上可接受的載體、稀釋劑或賦形劑。在某些實施方式中，所述的藥物組合物含有1%-99%的藥學上可接受的載體、稀釋劑或賦形劑。在某些實施方式中，所述的藥物組合物含有2%-98%的藥學上可接受的載體、稀釋劑或賦形劑。 In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable carriers, diluents or excipients.

本發明所涉及的全部化合物及包含本發明化合物的混合物、組合物等，可以經任一給藥途徑給予到生物體內。給藥途徑可以是口服給藥，靜脈注射，肌肉注射，皮下注射，直腸給藥，陰道給藥，舌下含化，鼻腔吸入，口腔吸入，滴眼，也可局部或全身經皮給藥。 All compounds involved in the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be administered into the living body via any administration route. The route of administration can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or local or systemic transdermal administration.

本發明所涉及的全部化合物及包含本發明化合物的混合物、組合物等，可以配製成單一劑量，其中含有本發明的活性化合物以及載體、賦形劑等，給藥劑型可以是片劑，膠囊劑，注射劑，顆粒劑，粉劑，栓劑，丸劑，乳膏劑，糊劑，凝膠劑，散劑，口服溶液，吸入劑，混懸劑，幹懸劑，貼劑，洗劑等。這些劑型中可以含有藥物製劑常用的成分，例如稀釋劑，吸收劑，潤濕劑，粘合劑，崩解劑，著色劑，pH調節劑，抗氧劑，抑菌劑，等滲調節劑，抗粘劑等。 All compounds involved in the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be formulated into a single dose, which contains the active compound of the present invention, carriers, excipients, etc., and the dosage form can be tablets, capsules Agents, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, bacteriostatic agents, isotonic regulators, Anti-adhesive agents, etc.

上述各類劑型的合適配方可從公開途徑獲得，例如Remington：The Science and Practice of Pharmacy，第21版，Lippincott Williams & Wilkins於2006年出版和Rowe,Raymond C.Handbook of Pharmaceutical Excipients,Chicago,Pharmaceutical Press於2005年出版。因此本領域的技術人員可以容易的製備。 Suitable formulations for each of the above types of dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press. Published in 2005. Therefore, those skilled in the art can easily prepare it.

根據不同個體所患疾病的性質，強度，患者的年齡、性別、體重，給藥途徑等因素，可以選擇不同的給藥劑量。本發明的化合物的給藥劑量可以為每日0.01至500mg/kg，優選每日劑量為1-100mg/kg，可單次或多次給藥。 Different dosages can be selected according to the nature and intensity of the disease suffered by different individuals, the patient's age, gender, weight, route of administration and other factors. The dosage of the compound of the present invention can be 0.01 to 500 mg/kg per day, preferably the daily dosage is 1-100 mg/kg, and can be administered single or multiple times.

本發明所提供的前述任一項所述的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽，前述任一項的藥物偶聯物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物及藥學上可接受的鹽，具有下述任意一種或多種用途中的應用： Any of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts provided by the present invention, any of the aforementioned Drug conjugates or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, with any one or more of the following uses:

(1)抑制3C-like蛋白酶活性； (1) Inhibit 3C-like protease activity;

(2)抑制病毒複製活性，優選是抑制冠狀病毒活性，特別優選是抑制SARS-CoV-2病毒活性； (2) Inhibit virus replication activity, preferably inhibit coronavirus activity, particularly preferably inhibit SARS-CoV-2 virus activity;

(3)治療COVID-19；和/或 (3) Treat COVID-19; and/or

(4)製備具有(1)、(2)和/或(3)用途的藥物。 (4) Preparation of medicines with uses (1), (2) and/or (3).

本發明還提供一種抑制病毒複製活性的方法，包括對受試者施用治療有效量的前述任一項所述的化合物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物、偶聯物及藥學上可接受的鹽，和/或前述任一項的藥物偶聯物或其立體異構體、溶劑化物、水合物、前藥、穩定的同位素衍生物及藥學上可接受的鹽。優選的，所述病毒為冠狀病毒，優選為SARS-CoV-2。 The present invention also provides a method for inhibiting viral replication activity, which includes administering to a subject a therapeutically effective amount of any of the compounds described above or their stereoisomers, solvates, hydrates, prodrugs, and stable isotope derivatives. substances, conjugates and pharmaceutically acceptable salts, and/or drug conjugates of any of the foregoing or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts Take that with a grain of salt. Preferably, the virus is a coronavirus, preferably SARS-CoV-2.

技術名詞解釋： Explanation of technical terms:

除非有相反陳述，在說明書和權利要求書中使用的技術名詞具有下述含義。 Unless stated to the contrary, technical terms used in the specification and claims have the following meanings.

技術名詞“C_1-6烷基”單獨或者以組合方式表示包含1-6個，特別是1-4個碳原子的飽和直鏈或支鏈的烷基，包括甲基、乙基、丙基、異丙基、丁基、仲丁基、異丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3,-二甲基-2-丁基等。優選地，“C_1-6烷基”是甲基、乙基、異丙基、叔丁基中的任一種。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，所述取代基優選為一個或多個以下基團，其獨立地係選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、氧代基、羧基或羧酸酯基所組成的群組。 The technical term "C _1-6 alkyl" alone or in combination means a saturated straight-chain or branched alkyl group containing 1-6, especially 1-4 carbon atoms, including methyl, ethyl, and propyl. , isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2 -Butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl- 2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3, 3,-dimethyl-2-butyl, etc. Preferably, "C _1-6 alkyl" is any one of methyl, ethyl, isopropyl and tert-butyl. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment. The substituents are preferably one or more of the following groups, which are independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, A group consisting of cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups.

技術名詞“C_3-7環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，其表示具有3到7個，特別是3-6個碳原子的飽和環烷基，包括環丙基、環丁基、環戊基、環己基、環庚基等。特別的“C_3-7環烷基”是環丙基、環戊基、環己基等。 The technical term "C _3-7 cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means a saturated cycloalkyl group having 3 to 7, especially 3 to 6 carbon atoms, Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Particular "C _3-7 cycloalkyl" is cyclopropyl, cyclopentyl, cyclohexyl, etc.

技術名詞“C_3-5環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，其表示具有3到5個碳原子的飽和環烷基，包括環丙基、環丁基、環戊基等。 The technical term "C _3-5 cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which represents a saturated cycloalkyl group with 3 to 5 carbon atoms, including cyclopropyl, cyclobutyl base, cyclopentyl, etc.

技術名詞“C_1-6烷氧基”單獨或者以組合方式表示基團C_1-6烷基-O-，其中“C_1-6烷基”表示如以上所定義。 The technical term "C _1-6 alkoxy" means, alone or in combination, the group C _1-6 alkyl-O-, where "C _1-6 alkyl" means as defined above.

技術名詞“C_1-6烷基胺基”單獨或者以組合方式表示基團C_1-6烷基-NH-，其中“C_1-6烷基”表示如以上所定義。 The technical term "C _1-6 alkylamino" means, alone or in combination, the group C _1-6 alkyl-NH-, where "C _1-6 alkyl" means as defined above.

技術名詞“雜環烷基”指由碳原子與氮、氧或硫等雜原子組成的飽和或部分不飽和(包含1或2個雙鍵)的非芳香環狀基團，此環狀基團可以是單環或雙環基團，在本發明中，雜環烷基中雜原子個數優選1、2、3或4，雜環烷基中的氮、碳或硫原子可任選地被氧化。“雜環烷基”上的氫原子獨立任選地被一個或多個本發明所描述的取代基所取代。“雜環烷基”可以通過環上任意的環原子連結到母體分子上。 The technical term "heterocycloalkyl" refers to a saturated or partially unsaturated (including 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms such as nitrogen, oxygen or sulfur. This cyclic group It can be a monocyclic or bicyclic group. In the present invention, the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4. Nitrogen, carbon or sulfur atoms in may optionally be oxidized. The hydrogen atoms on "heterocycloalkyl" are independently optionally substituted with one or more substituents described herein. "Heterocycloalkyl" can be linked to the parent molecule through any ring atom on the ring.

技術名詞“3-7元雜環烷基”是指單環雜環烷基中包含3-7個碳原子和雜原子；例如氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、呱啶基、嗎啉基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基。 The technical term "3-7 membered heterocycloalkyl" refers to a monocyclic heterocycloalkyl group containing 3-7 carbon atoms and heteroatoms; such as aziridinyl, azetidinyl, oxetanyl, Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piridinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.

技術名詞“5-6元雜環烷基”是指單環雜環烷基中包含5-6個碳原子和雜原子；例如吡咯烷基、四氫呋喃基、四氫噻吩基、呱啶基、嗎啉基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基。 The technical term "5-6 membered heterocycloalkyl" refers to a monocyclic heterocycloalkyl group containing 5-6 carbon atoms and heteroatoms; such as pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyridinyl, etc. Phyllinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.

技術名詞“6-14元螺雜環基”指6至14元，單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為係選自氮、氧和硫的雜原子所組成的群組，所述的硫可任選被氧代(即形成亞碸或碸)，其餘環原子為碳。其可以含有一個或多個雙鍵。更優選為7至10元(例如7、8、9或10元)。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，優選為單螺雜環基和雙螺雜環基。更優選為3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元單螺雜環基。螺雜環基的非限制性實例包括： The technical term "6-14-membered spiroheterocyclyl" refers to a polycyclic heterocyclic group with 6 to 14 members, sharing one atom (called a spiro atom) between the single rings, in which one or more ring atoms are selected from nitrogen. , a group consisting of heteroatoms of oxygen and sulfur, the sulfur may be optionally oxo-substituted (ie, forming sulfur or sulfur), and the remaining ring atoms are carbon. It may contain one or more double bonds. More preferably, it is 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclic group. Non-limiting examples of spiroheterocyclyl include:

技術名詞“4-11元稠雜環基”指4至11元，系統中的每個環與體系中的其他環共用毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，其中一個或多個環原子為係選自氮、氧和硫的雜原子所組成的群組，所述的硫可任選被氧代(即形成亞碸或碸)，其餘環原子為碳。更優選為7至10元(例如7、8、9或10元)。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，優選為雙環或三環，更優選為3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元雙環稠雜環基。稠雜環基的非限制性實例包括： The technical term "4-11 membered fused heterocyclyl" refers to a polycyclic heterocyclic group with 4 to 11 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings can Contains one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. group, the sulfur may optionally be oxo-substituted (i.e., to form sulfur or sulfur), and the remaining ring atoms are carbon. More preferably, it is 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 One-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:

技術名詞“5-11元橋雜環基”指5至11元，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，其中一個或多個環原子為係選自氮、氧和硫的雜原子所組成的群組，所述的硫可任選被氧代(即形成亞碸或碸)，其餘環原子為碳。優選為6至11元，更優選為7至10元(例如7、8、9或10元)。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，優選為雙環、三環或四環，更優選為雙環或三環。橋雜環基的非限制性實例包括： The technical term "5-11-membered bridged heterocyclyl" refers to a polycyclic heterocyclic group with 5 to 11 members, and any two rings share two atoms that are not directly connected. It may contain one or more double bonds, one of which Or a plurality of ring atoms are a group consisting of heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxo-substituted (ie, forming sulfur or sulfur), and the remaining ring atoms are carbon. It is preferably 6 to 11 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

技術名詞“C_6-10芳基”指具有共軛的π電子體系的6至10元全碳單環或稠合多環(稠合多環是共用毗鄰碳原子對的環)基團，例如苯基和萘基。所述芳基環包括如上所述的芳基環稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The technical term "C _6-10 aryl" refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include :

芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，所述取代基優選獨立地任選係選自鹵素、烷基、烷氧基、鹵代烷基、鹵代烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所組成的群組。 Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of halogen, alkyl, alkoxy, In haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl A group of one or more substituents.

技術名詞“5-10元雜芳基”指包含1至4個(例如1、2、3和4個)雜原子、5至10個環原子的雜芳族體系，其中雜原子係選自氧、硫和氮所組成的群組，(例如5、6、7、8、9或10元)，更優選為5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述雜芳基環包括如上述的雜芳基稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The technical term "5-10 membered heteroaryl" refers to a heteroaromatic system containing 1 to 4 (such as 1, 2, 3 and 4) heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen , a group consisting of sulfur and nitrogen, (such as 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl group fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include :

雜芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，所述取代基優選獨立地任選自鹵素、烷基、烷氧基、鹵代烷基、鹵代烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所組成的群組。 Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl One of radical, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or a group of multiple substituents.

技術名詞“苯並C_5-7環烷基”是指苯基與C_5-7環烷基形成並環，結構為：

，其中，n為1、2或3，同時，苯並C_5-7環烷基既可以是苯基與連接位置相連接，也可以是C_5-7環烷基與連接位置相連接；並且苯並C_5-7環烷基既可以是苯基被取代，也可以是C_5-7環烷基被取代。 The technical term "benzo C _5-7 cycloalkyl" refers to the formation of a parallel ring between phenyl and C _5-7 cycloalkyl. The structure is:

, where n is 1, 2 or 3, and at the same time, the benzo C _5-7 cycloalkyl group can be either a phenyl group connected to the connection position, or a C _5-7 cycloalkyl group connected to the connection position; and The benzo C _5-7 cycloalkyl group may be a substituted phenyl group or a substituted C _5-7 cycloalkyl group.

技術名詞“胺基”單獨或者以組合方式表示伯胺基(-NH₂)，仲胺基(-NH-)或叔胺基(

) The technical term "amine group" means primary amine group (-NH ₂ ), secondary amine group (-NH-) or tertiary amine group (

)

技術名詞“鹵素”單獨或者以組合方式表示氟，氯，溴或碘。特別的是氟，氯或溴。 The technical term "halogen" means fluorine, chlorine, bromine or iodine alone or in combination. Particularly fluorine, chlorine or bromine.

技術名詞“氰基”單獨或組合的是指基團-CN。 The technical term "cyano" alone or in combination refers to the group -CN.

技術名詞“羥基”單獨或組合的是指基團-OH。 The technical term "hydroxy" alone or in combination refers to the group -OH.

技術名詞“醛基”單獨或組合的是指基團-CHO。 The technical term "aldehyde group" alone or in combination refers to the group -CHO.

技術名詞“取代的”指基團中的一個或多個氫原子，優選為最多5個，更優選為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(通過實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 The technical term "substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which the person skilled in the art can without undue effort The circumstances under which substitutions are possible or impossible are determined (either experimentally or theoretically). For example, an amine or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, olefinic) bond.

本發明所述化合物的化學結構中，鍵“

”並未指定構型，即鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structure of the compound of the present invention, the bond "

"No configuration, i.e. key, was specified"

"can be"

"or"

”, or both “

"and"

"Two configurations.

技術名詞“立體異構體”是指具有相同化學構造，但原子或基團在空間上排列方式不同的化合物。立體異構體包括對映異構體、非對映異構體、構象異構體(旋轉異構體)、幾何(順/反)異構體、阻轉異構體，等等。 The technical term "stereoisomers" refers to compounds that have the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.

技術名詞“同位素衍生物”指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本發明的結構，用“氘”或“氚”代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-，¹³C-，或者¹⁴C-富集的碳(¹¹C-，¹³C-，或者¹⁴C-碳標記；¹¹C-，¹³C-，或者¹⁴C-同位素)代替碳原子的化合物處於本發明的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。本發明的各種氘化形式的化合物是指與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。本領域技術人員能夠參考相關文獻合成氘化形式的化合物。在製備氘代形式的化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢。 The technical term "isotope derivatives" refers to compounds whose structures differ only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present invention, "deuterium" or "tritium" is used instead of hydrogen, or ^18F -fluorine labeling ( ^18F isotope) is used instead of fluorine, or ^11C- , ^13C- , or ^14C -enrichment Compounds in which the carbon atom is replaced by a carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon label; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotope) are within the scope of the invention. Such compounds may be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The various deuterated forms of the compounds of the present invention mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of compounds. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran. , Deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds often retain comparable activity to non-deuterated compounds, and when deuterated at certain sites, better metabolic stability can be achieved, resulting in certain therapeutic advantages.

技術名詞“藥學上可接受的鹽”表示本發明的化合物以它們的藥用鹽的形式存在，包括酸加成鹽和堿加成鹽。藥學上可接受的鹽在S.M.Berge在J.Pharmaceutical Sciences(66卷：1-19頁，1977年)中描述的pharmaceutically salts中有所描述。在本發明中，藥學上可接受的無毒的酸加成鹽表示本發明中的化合物與有機或無機酸形成的鹽，有機或無機酸包括但不限於鹽酸，硫酸，氫溴酸，氫碘酸，磷酸，硝酸，高氯酸，乙酸，草酸，馬來酸，富馬酸，酒石酸，苯磺酸，甲磺酸，水楊酸，琥珀酸，檸檬酸，乳酸，丙酸，苯甲酸，對甲苯磺酸，蘋果酸等。藥學上可接受的無毒的堿加成鹽表示本發明中的化合物與有機或無機堿所形成的鹽，包括但不限於鹼金屬鹽，例如鋰，鈉或鉀鹽；鹼土金屬鹽，例如鈣或鎂鹽；有機堿鹽，例如通過與含N基團的有機堿形成的銨鹽或N⁺(C_1-6烷基)₄鹽。 The technical term "pharmaceutically acceptable salts" means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and aldehyde addition salts. Pharmaceutically acceptable salts are described in Pharmaceutical Salts by SM Berge in J. Pharmaceutical Sciences (Vol. 66: pp. 1-19, 1977). In the present invention, pharmaceutically acceptable nontoxic acid addition salts refer to salts formed by compounds in the present invention and organic or inorganic acids, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, and hydroiodic acid. , Phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, right Toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic alkaloid addition salts represent salts formed by compounds in the present invention and organic or inorganic alkaloids, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or Magnesium salt; organic salt, such as ammonium salt or N ⁺ (C _1-6 alkyl) ₄ salt formed with an organic salt containing N groups.

技術名詞“溶劑化物”是指本發明的化合物與一種或多種，優選地為1-3種，無論是有機的還是無機的溶劑分子的物理結合。該物理結合包括氫鍵。在某些情況下，例如，當在結晶固體的晶格中摻入一種或多種，優選1-3種溶劑分子時，溶劑化物將被分離。示例性的溶劑化物包括但不限於水合物、乙醇化物、甲醇化物和異丙醇化物。溶劑化方法是本領域公知的。 The technical term "solvate" refers to the physical combination of a compound of the present invention and one or more, preferably 1 to 3, solvent molecules, whether organic or inorganic. This physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1 to 3 solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methoxides, and isopropanolates. Solvation methods are well known in the art.

技術名詞“前藥”是指可以在生理條件下，例如通過在血液中水解，在體內轉化以產生活性原藥化合物。 The technical term "prodrug" refers to a compound that can be converted in the body under physiological conditions, such as by hydrolysis in the blood, to produce the active drug substance.

技術名詞“藥物組合物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。藥物組合物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 The technical term "pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other physiologically/pharmaceutically acceptable components such as carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

以上對本發明的涉及的技術名詞進行了定義，本領域技術人員還可以結合現有技術對以上技術名詞進行理解，以下基於本發明的內容以及對技術名詞的定義進一步進行描述。 The technical terms involved in the present invention have been defined above. Those skilled in the art can also understand the above technical terms in conjunction with the existing technology. The following is further described based on the content of the present invention and the definitions of technical terms.

以下結合實施例進一步描述本發明所述的化合物、可藥用鹽的製備，但這些實施例並非限制本發明中的範圍。 The preparation of the compounds and pharmaceutically acceptable salts of the present invention will be further described below with reference to examples, but these examples do not limit the scope of the present invention.

本發明中實施例中未注明具體條件的實驗方法，通常按照常規條件，或按照原料或商品製造廠商所建議的條件。未注明具體來源的試劑，為市場購買的常規試劑。 Experimental methods without specifying specific conditions in the examples of the present invention usually follow conventional conditions, or conditions recommended by raw material or product manufacturers. Reagents whose specific sources are not indicated are conventional reagents purchased in the market.

實施例1：中間體叔丁基((S)-1-((1R,2S,5S)-2-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)氨甲醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-3-基)-3,3-二甲基-1-氧代丁烷-2-基)胺基甲酸酯(中間體A)的製備Example 1: Intermediate tert-butyl ((S)-1-((1R,2S,5S)-2-((S)-1-amino-1-oxo-3-((S)-2) -Oxopyrrolidin-3-yl)propan-2-yl)carbamate)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- Preparation of dimethyl-1-oxobutan-2-yl)carbamate (Intermediate A)

第1步：叔丁基((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)胺基甲酸酯(中間體2-2)的製備 Step 1: tert-Butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate Preparation of (Intermediate 2-2)

將(S)-2-((叔丁氧基羰基)胺基)甲基-3-((S)-2-氧吡咯烷-3-基)丙酸甲酯(5.0g,17.5mmol)加入氨甲醇溶液(80mL,7M)中，80℃攪拌8小時，反應完畢後減壓濃縮得白色固體粗品(5.0g，超量)，直接進行下一步反應。 (S)-2-((tert-butoxycarbonyl)amino)methyl-3-((S)-2-oxopyrrolidin-3-yl)propionic acid methyl ester (5.0g, 17.5mmol) was added Ammonia-methanol solution (80 mL, 7 M) was stirred at 80°C for 8 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a white solid crude product (5.0 g, excess), which was directly used for the next step of the reaction.

第2步：(S)-2-胺基-3-((S)-2-氧吡咯烷-3-基)丙醯胺鹽酸鹽(中間體2-3)的製備 Step 2: Preparation of: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (intermediate 2-3)

將叔丁基((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)胺基甲酸酯(5.0g，按17.5mmol計)加入鹽酸1，4-二氧六環溶液(80mL,4M)中，室溫攪拌12小時，反應完畢後減壓濃縮並用甲基叔丁基醚拌漿，固體乾燥得白色固體(3.4g，收率：93.7%)，直接進行下一步反應。 Tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (5.0 g , calculated as 17.5 mmol) was added to 1,4-dioxane hydrochloric acid solution (80 mL, 4 M), stirred at room temperature for 12 hours, after the reaction was completed, concentrated under reduced pressure and mixed with methyl tert-butyl ether, and the solid was dried to obtain white Solid (3.4g, yield: 93.7%), proceed directly to the next reaction.

第3步：甲基(1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-羧酸甲酯(中間體2-5)的製備 Step 3: Methyl (1R, 2S, 5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6,6-dimethyl Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (intermediate 2-5)

將(1R,2S,5S)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-羧酸甲酯鹽酸鹽(5.0g,20.7mmol)和N-(叔丁氧羰基)-L-叔亮氨酸(4.8g,20.7mmol)溶於二氯甲烷(80mL)中，依次加入DIEA(8.0g,62.1mmol)和HATU(11.8g,31.1mmol)，室溫攪拌3小時，反應完畢後加入二氯甲烷(100mL)，並用飽和氯化銨(200mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(PE：EA=1：1)提純得棕色固體(9.47g，超量)。 Combine (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (5.0g, 20.7mmol) and N-( Tert-butoxycarbonyl)-L-tert-leucine (4.8g, 20.7mmol) was dissolved in dichloromethane (80mL), DIEA (8.0g, 62.1mmol) and HATU (11.8g, 31.1mmol) were added in sequence, and the chamber Stir at warm temperature for 3 hours. After the reaction is completed, add methylene chloride (100mL) and wash with saturated ammonium chloride (200mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (PE: EA=1 : 1) Purify to obtain brown solid (9.47g, excess).

第4步：(1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-羧酸(中間體2-6)的製備 Step 4: (1R, 2S, 5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (intermediate 2-6)

將(1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-羧酸甲酯(9.47g，按20.7mmol計)溶於THF(50mL)和H₂O(50mL)的混合液中，在25℃下加入LiOH-H₂O(2.6g，62.1mmol)。將混合物在25℃下攪拌6h。完成後，用1M鹽酸水溶液調節混合物的pH=2-3，用乙酸乙酯(150mL*3)萃取。用鹽水(200mL)洗滌有機層，在無水Na₂SO₄上乾燥，過濾，濃縮得棕色油狀物(9.34g，超量)，直接進行下一步反應。 (1R, 2S, 5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (9.47g, based on 20.7mmol) was dissolved in a mixture of THF (50mL) and H ₂ O (50mL), and LiOH- was added at 25°C. H ₂ O (2.6 g, 62.1 mmol). The mixture was stirred at 25 °C for 6 h. After completion, adjust the pH of the mixture to 2-3 with 1M hydrochloric acid aqueous solution, and extract with ethyl acetate (150mL*3). The organic layer was washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a brown oil (9.34 g, excess amount), which was directly used for the next reaction.

第5步：叔丁基((S)-1-((1R，2S，5S)-2-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)氨甲醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-3-基)-3,3-二甲基-1-氧代丁烷-2-基)胺基甲酸酯(中間體2-7)的製備 Step 5: tert-butyl ((S)-1-((1R,2S,5S)-2-((S)-1-amino-1-oxo-3-((S)-2-oxo) Pyrrolidin-3-yl)propan-2-yl)carbamate)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl Preparation of 1-oxobutan-2-yl)carbamate (intermediate 2-7)

將(1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-羧酸(9.34g，按20.7mmol 計)和(S)-2-胺基-3-((S)-2-氧吡咯烷-3-基)丙醯胺鹽酸鹽(4.3g,20.7mmol)溶於二氯甲烷(80mL)中，依次加入DIEA(8.0g,62.1mmol)和HATU(11.8g,31.1mmol)，室溫攪拌6小時，反應完畢後加入二氯甲烷(100mL)，並用飽和氯化銨(100mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色固體(10.5g，收率：97.2%)。 (1R, 2S, 5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxylic acid (9.34g, based on 20.7mmol (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (4.3g, 20.7mmol) was dissolved in dichloromethane (80mL) , add DIEA (8.0g, 62.1mmol) and HATU (11.8g, 31.1mmol) in sequence, stir at room temperature for 6 hours, add dichloromethane (100mL) after the reaction is completed, and wash with saturated ammonium chloride (100mL*2) , the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH=10:1) to obtain a brown solid (10.5g, yield: 97.2%).

第6步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(中間體A)的製備 Step 6: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methane Preparation of amine hydrochloride (intermediate A)

將叔丁基((S)-1-((1R，2S，5S)-2-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)氨甲醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-3-基)-3,3-二甲基-1-氧代丁烷-2-基)胺基甲酸酯(5.0g,9.6mmol)加入鹽酸二氧六環溶液(80mL,7M)中，室溫攪拌8小時，反應完畢後減壓濃縮得白色固體粗品(4.2g，收率：95.5%)，直接進行下一步反應。 Tert-butyl((S)-1-((1R,2S,5S)-2-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-yl)propan-2-yl)carbamate)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1 -Oxobutan-2-yl)carbamate (5.0g, 9.6mmol) was added to dioxane hydrochloride solution (80mL, 7M) and stirred at room temperature for 8 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain a white color. The solid crude product (4.2g, yield: 95.5%) was directly used for the next reaction.

實施例2：(1R,2S,5S)-3-(2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(化合物3)的製備 Example 2: (1R,2S,5S)-3-(2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide)-3,3 -Dimethylbutyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-methamide hydrochloride (compound 3)

第1步：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-((1R，2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物3-1)的製備 Step 1: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide)-3,3-dimethylbutanyl Preparation of acyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 3-1)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(127.28mg,0.28mmol)溶於二氯甲烷(5mL)中，加入(1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-羧酸(60mg,0.23mmol)、2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(132.09mg,0.35mmol)和N,N-二異丙基乙胺(89.80mg,0.69mmol)。將混合物在25℃攪拌2小時。將反應液加到水(50mL)中，加入二氯甲烷(50mL)稀釋，然後用水(50mL)和飽和食鹽水(50mL)洗滌，用無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品，將粗產品通過柱層析(二氯甲烷：甲醇=10：1)純化製備得到白色固體(90mg，收率58.8%)LC-MS(M+1)=662.23。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-Amino-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride The salt (127.28 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL), and (1R, 2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid (60 mg, 0.23 mmol) was added ), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (132.09mg, 0.35mmol) and N,N-diisopropyl Ethylamine (89.80mg, 0.69mmol). The mixture was stirred at 25°C for 2 hours. The reaction solution was added to water (50 mL), diluted with dichloromethane (50 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a white solid (90 mg, yield 58.8%) LC-MS (M+1) = 662.23.

第2步：(1R,2S,5S)-3-(2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(化合物3)的製備 Step 2: (1R,2S,5S)-3-(2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide)-3,3 -Dimethylbutyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-methamide hydrochloride (compound 3)

將(1R,2S,5S)-3-(2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(90mg,0.14mmol)溶於2mL二氯甲烷溶液中，將Burgess試劑(133.28mg,0.56mmol)溶於2mL二氯甲烷中緩慢滴加上述反應體系中，室溫攪拌5h，反應結束後加入飽和食鹽水30mL，二氯甲烷20mL萃取合併有機相無水硫酸鈉乾燥，濃縮蒸幹，製備板製備得白色固體(45mg，收率：51.7%)LC-MS(M+1)=644.22。 (1R,2S,5S)-3-(2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-formamide)-3,3-dimethyl Butyryl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Hexane-2-formamide (90 mg, 0.14 mmol) was dissolved in 2 mL of dichloromethane solution, and Burgess reagent (133.28 mg, 0.56 mmol) was dissolved in 2 mL of dichloromethane and the above reaction was slowly added dropwise In the system, stir at room temperature for 5 hours. After the reaction, add 30 mL of saturated brine, extract with 20 mL of methylene chloride, dry the combined organic phase over anhydrous sodium sulfate, concentrate and evaporate to dryness, and prepare a white solid (45 mg, yield: 51.7%) LC -MS(M+1)=644.22.

¹H NMR(400MHz,DMSO-d ₆)δ ppm 9.00(d,J=8.79Hz,1 H),8.16(d,J=8.79Hz,1 H),7.68(s,1 H),7.57(t,J=8.06Hz,1 H),7.15(dd,J=10.62,1.83Hz,1 H),6.90-6.97(m,1 H),4.96(ddd,J=10.62,8.42,5.13Hz,1 H),4.29-4.36(m,1 H),4.13(s,1 H),3.78-3.89(m,2 H),3.10-3.18(m,1 H),2.99-3.07(m,1 H),2.38-2.46(m,1 H),2.22-2.32(m,2 H),2.03-2.20(m,2 H),1.64-1.76(m,2 H),1.51-1.56(m,1 H),1.28(d,J=7.69Hz,1 H),1.18-1.25(m,2 H),1.02(s,3 H),0.93(s,9 H),0.86(s,3 H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.00 (d, J =8.79Hz, 1 H), 8.16 (d, J = 8.79Hz, 1 H), 7.68 (s, 1 H), 7.57 (t , J =8.06Hz,1 H),7.15(dd, J =10.62,1.83Hz,1 H),6.90-6.97(m,1 H),4.96(ddd, J =10.62,8.42,5.13Hz,1 H ),4.29-4.36(m,1 H),4.13(s,1 H),3.78-3.89(m,2 H),3.10-3.18(m,1 H),2.99-3.07(m,1 H), 2.38-2.46(m,1 H),2.22-2.32(m,2 H),2.03-2.20(m,2 H),1.64-1.76(m,2 H),1.51-1.56(m,1 H), 1.28(d, J =7.69Hz,1H),1.18-1.25(m,2H),1.02(s,3H),0.93(s,9H),0.86(s,3H).

實施例3：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(化合物4)的製備Example 3: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methane Preparation of amine hydrochloride (compound 4)

第1步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(環丙醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物4-1)的製備 Step 1: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-(cyclopropylamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -Preparation of 2-formamide (compound 4-1)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(153.22mg,0.33mmol)溶於二氯甲烷(5mL)中，加入環丙甲酸(24mg,0.28mmol)、2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(159.00mg,0.42mmol)和N,N-二異丙基乙胺(108.09mg,0.84mmol)。將混合物在25℃攪拌2小時。將反應液加到水(50mL)中，加入二氯甲烷(50mL)稀釋，然後用水(50mL)和飽和食鹽水(50mL)洗滌，用無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品，將粗產品通過柱層析(二氯甲烷：甲醇=10：1)純化製備得到白色固體(110mg，收率80.8%)LC-MS(M+1)=490.3。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-Amino-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride The salt (153.22mg, 0.33mmol) was dissolved in dichloromethane (5mL), and cyclopropanecarboxylic acid (24mg, 0.28mmol) and 2-(7-azabenzotriazole)-N,N,N' were added. N'-tetramethylurea hexafluorophosphate (159.00 mg, 0.42 mmol) and N,N-diisopropylethylamine (108.09 mg, 0.84 mmol). The mixture was stirred at 25°C for 2 hours. The reaction solution was added to water (50 mL), diluted with dichloromethane (50 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a white solid (110 mg, yield 80.8%) LC-MS (M+1) = 490.3.

第2步：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-2-(環丙烷甲醯胺)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物4)的製備。 Step 2: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-2-(cyclopropaneformamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide (compound 4) Preparation.

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(環丙醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(110mg,0.22mmol)溶於3mL二氯甲烷溶液中，將Burgess試劑(214.15mg,0.90mmol)溶於2mL二氯甲烷中緩慢滴加上述反應體系中，室溫攪拌5h，反應結束後加入飽和食鹽水30mL，二氯甲烷20mL萃取合併有機相，用無水硫酸鈉乾燥，濃縮蒸幹，高壓製備液相製備得白色固體(90.00mg，收率：85.71%)LC-MS(M+1)=472.28。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-(cyclopropylamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- Formamide (110 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane solution. Burgess reagent (214.15 mg, 0.90 mmol) was dissolved in 2 mL of dichloromethane and slowly added dropwise to the above reaction system. Stir at room temperature for 5 hours. The reaction was completed. Then add 30 mL of saturated brine and 20 mL of methylene chloride to extract and combine the organic phases, dry with anhydrous sodium sulfate, concentrate and evaporate to dryness, and prepare a liquid phase under high pressure to prepare a white solid (90.00 mg, yield: 85.71%) LC-MS (M+ 1)=472.28.

¹H NMR(400MHz,DMSO-d ₆)δ ppm 8.99(d,J=8.79Hz,1 H),8.11(d,J=9.52Hz,1 H),7.67(s,1 H),4.91-5.01(m,1 H),4.35(d,J=8.79Hz,1 H),4.11(s,1 H),3.77-3.88(m,2 H),3.11-3.19(m,1 H),2.98-3.09(m,1 H),2.36-2.46(m,2 H),1.94-2.20(m,3 H),1.78-1.86(m,1 H),1.64-1.76(m,2 H),1.49-1.55(m,1 H),1.20-1.30(m,3 H),0.99-1.06(m,3 H),0.93(s,9 H),0.80-0.85(m,3 H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.99 (d, J =8.79Hz, 1 H), 8.11 (d, J = 9.52Hz, 1 H), 7.67 (s, 1 H), 4.91-5.01 (m,1 H),4.35(d, J =8.79Hz,1 H),4.11(s,1 H),3.77-3.88(m,2 H),3.11-3.19(m,1 H),2.98- 3.09(m,1 H),2.36-2.46(m,2 H),1.94-2.20(m,3 H),1.78-1.86(m,1 H),1.64-1.76(m,2 H),1.49- 1.55(m,1 H),1.20-1.30(m,3 H),0.99-1.06(m,3 H),0.93(s,9 H),0.80-0.85(m,3 H).

實施例4：(1R，2S，5S)-3-(2-((1S，2S)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物5)的製備Example 4: (1R,2S,5S)-3-(2-((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide)-3,3 -Dimethylbutyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-methamide (compound 5)

第1步：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-((1S,2S)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物5-1)的製備 Step 1: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide)-3,3-dimethylbutanyl Preparation of acyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 5-1)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(120.92mg,0.26mmol)溶於二氯甲烷(5mL)中，加入(1S，2S)-2-(4-溴-3-氟苯基)環丙烷-1-羧酸(57mg,0.22mmol)、2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(125.49mg,0.33mmol)和N,N-二異丙基乙胺(DIEA或DIPEA)(85.31mg,0.66mmol)。將混合物在25℃攪拌2小時。將反應液加到水(50mL)中，加入二氯甲烷(50mL)稀釋，然後用水(50mL)和飽和食鹽水(50mL)洗滌，用無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品，將粗產品通過柱層析(二氯甲烷：甲醇=10：1)純化製備得到白色固體(100mg，收率68.6%)LC-MS(M+1)=662.23。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-Amino-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride The salt (120.92 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), and (1S, 2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid (57 mg, 0.22 mmol) was added ), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (125.49mg, 0.33mmol) and N,N-di Isopropylethylamine (DIEA or DIPEA) (85.31 mg, 0.66 mmol). The mixture was stirred at 25°C for 2 hours. The reaction solution was added to water (50 mL), diluted with dichloromethane (50 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a white solid (100 mg, yield 68.6%) LC-MS (M+1) = 662.23.

第2步：(1R，2S，5S)-3-(2-((1S，2S)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物5)的製備 Step 2: (1R,2S,5S)-3-(2-((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide)-3,3 -Dimethylbutyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3- Preparation of azabicyclo[3.1.0]hexane-2-methamide (compound 5)

將(1R,2S,5S)-3-(2-((1S，2S)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(100mg,0.15mmol)溶於2mL二氯甲烷溶液中，將Burgess試劑(143.86mg,0.60mmol)溶於2mL二氯甲烷中緩慢滴加上述反應體系中，室溫攪拌5h，反應結束後加入飽和食鹽水30mL，二氯甲烷20mL萃取合併有機相無水硫酸鈉乾燥，濃縮蒸幹，製備板製備得白色固體(40mg，收率：41.1%)LC-MS(M+1)=644.22。 (1R,2S,5S)-3-(2-((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxamide)-3,3-dimethyl Butyryl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Hexane-2-formamide (100 mg, 0.15 mmol) was dissolved in 2 mL of dichloromethane solution, and Burgess reagent (143.86 mg, 0.60 mmol) was dissolved in 2 mL of dichloromethane and the above reaction was slowly added dropwise In the system, stir at room temperature for 5 hours. After the reaction, add 30 mL of saturated brine, extract with 20 mL of methylene chloride, dry the combined organic phase over anhydrous sodium sulfate, concentrate and evaporate to dryness, and prepare a white solid (40 mg, yield: 41.1%) LC -MS(M+1)=644.22.

¹H NMR(400MHz,DMSO-d ₆)δ ppm 8.97(d,J=8.51Hz,1 H),8.24(d,J=8.97Hz,1 H),7.66(s,1 H),7.59(t,J=7.92Hz,1 H),7.11(dd,J=10.39,1.97Hz,1 H),6.90(dd,J=8.33,1.92Hz,1 H),4.95(ddd,J=10.80,8.56,5.17Hz,1 H),4.36(d,J=8.97Hz,1 H),4.11(s,1 H),3.79-3.89(m,2 H),3.09-3.17(m,1 H),2.98-3.06(m,1 H)2.25-2.42(m,2 H),2.03-2.17(m,3 H),1.63-1.76(m,2 H),1.53(dd,J=7.42,4.94Hz,1 H),1.34-1.43(m,1 H),1.28(d,J=7.69Hz,1 H),1.21(ddd,J=8.35,5.84,3.94Hz,1 H),1.02(s,3 H),0.94(s,9 H),0.84(s,3 H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.97 (d, J =8.51Hz, 1 H), 8.24 (d, J = 8.97Hz, 1 H), 7.66 (s, 1 H), 7.59 (t , J =7.92Hz,1 H),7.11(dd, J =10.39,1.97Hz,1 H),6.90(dd, J =8.33,1.92Hz,1 H),4.95(ddd, J =10.80,8.56, 5.17Hz,1 H),4.36(d, J =8.97Hz,1 H),4.11(s,1 H),3.79-3.89(m,2 H),3.09-3.17(m,1 H),2.98- 3.06(m,1 H)2.25-2.42(m,2 H),2.03-2.17(m,3 H),1.63-1.76(m,2 H),1.53(dd, J =7.42,4.94Hz,1 H ),1.34-1.43(m,1 H),1.28(d, J =7.69Hz,1 H),1.21(ddd, J =8.35,5.84,3.94Hz,1 H),1.02(s,3 H), 0.94(s,9H),0.84(s,3H).

實施例5：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((R)-2-((1R，2R)-2-(2-氟苯基)環丙烷-1-甲醯Example 5: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((R )-2-((1R,2R)-2-(2-fluorophenyl)cyclopropane-1-carboxylic acid 胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物6)的製備Preparation of amino)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide (compound 6)

參照實施例2，在第1步的合成中，採用(1R，2R)-2-(2-氟苯基)環丙烷-1-羧酸為物料，經過2步反應得到化合物6。 Referring to Example 2, in the first step of synthesis, (1R, 2R)-2-(2-fluorophenyl)cyclopropane-1-carboxylic acid was used as the material, and compound 6 was obtained through two steps of reaction.

1H NMR(400MHz,DMSO-d6)：9.01(t,J=9.2Hz,1 H),8.20-8.32(m,1 H),7.68(d,J=8.0Hz,1 H),7.24-7.29(m,1 H),7.14-7.20(m,2 H),7.03-7.11(m,1 H),4.96-5.03(m,1 H),4.43(dd,J=8.8Hz,14.8Hz,1 H),4.16(d,J=2.4Hz,1 H),3.87-3.90(m,2 H),3.12-3.19(m,1 H),3.04-3.10(m,1 H),2.43-2.48(m,1 H),2.34-2.39(m,1 H),2.24-2.28(m,1 H),2.11-2.19(m,2 H),1.67-1.79(m,2 H),1.55-1.59(m,1 H),1.30-1.33(m,1 H),1.24-1.29(m,2 H),1.06(s,3 H),0.97(s,9 H),0.89(s,3 H).MS實測值(ESI+)[(M+H)+]：566。 1H NMR (400MHz, DMSO-d6): 9.01(t, J =9.2Hz,1 H),8.20-8.32(m,1 H),7.68(d, J =8.0Hz,1 H),7.24-7.29( m,1 H),7.14-7.20(m,2 H),7.03-7.11(m,1 H),4.96-5.03(m,1 H),4.43(dd, J =8.8Hz,14.8Hz,1 H ),4.16(d,J=2.4Hz,1 H),3.87-3.90(m,2 H),3.12-3.19(m,1 H),3.04-3.10(m,1 H),2.43-2.48(m ,1 H),2.34-2.39(m,1 H),2.24-2.28(m,1 H),2.11-2.19(m,2 H),1.67-1.79(m,2 H),1.55-1.59(m ,1 H),1.30-1.33(m,1 H),1.24-1.29(m,2 H),1.06(s,3 H),0.97(s,9 H),0.89(s,3 H).MS Actual measured value (ESI+)[(M+H)+]: 566.

實施例6：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物7)的合成Example 6: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- Synthesis of 2-formamide (compound 7)

第1步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物7-2)的製備 Step 1: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-methamide (compound 7-2)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(100mg,218.2umol)、1-氟環丙烷-1-羧酸(25mg,240.02umol)和HATU(165.9mg，436.4umol)溶於THF(4mL)中，開啟攪拌，25℃下向反應液中加入DIPEA(84.4mg,654.6umol)。反應液繼續室溫攪拌1h。反應液直接濃縮，將粗品通過柱層析純化製備得到122mg白色固體(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺。MS實測值(ESI+)[(M+H)+]：508.29。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-Amino-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride Dissolve salt (100mg, 218.2umol), 1-fluorocyclopropane-1-carboxylic acid (25mg, 240.02umol) and HATU (165.9mg, 436.4umol) in THF (4mL), start stirring, and add to the reaction solution at 25°C Add DIPEA (84.4mg, 654.6umol). The reaction solution was continued to stir at room temperature for 1 h. The reaction solution was directly concentrated, and the crude product was purified by column chromatography to obtain 122 mg of white solid (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2) -Oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)- 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide. MS measured value (ESI+)[(M+H)+]: 508.29.

第2步：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物7)的製備 Step 2: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- Preparation of 2-formamide (compound 7)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(122mg,240.6umol)溶於DCM(3mL)中，開啟攪拌，將Burgess試劑(171.36mg，721.8umol)的DCM溶液(3mL)緩慢滴加入上述體系，25℃反應4h，反應液濃縮，將粗產品通過Pre-HPLC製備得到白色固體(4mg)。MS實測值(ESI+)[(M+H)+]：490.28 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1. 0] Hexane-2-formamide (122 mg, 240.6umol) was dissolved in DCM (3mL), stirred, and the DCM solution (3mL) of Burgess reagent (171.36mg, 721.8umol) was slowly added dropwise to the above system, 25 The reaction was carried out at ℃ for 4 hours, the reaction solution was concentrated, and the crude product was prepared by Pre-HPLC to obtain a white solid (4 mg). MS measured value (ESI+)[(M+H)+]: 490.28

¹HNMR(DMSO-d ₆,400MHz)ppm,δ 9.03(d,J=4.2Hz,1H),7.69(s,1H),7.35(d,J=4.0Hz,1H),4.97(s,1H),4.42(d,J=4.4Hz,1H),4.15(s,1H),3.88-3.72(m,2H),3.16-3.03(m,2H),2.13-2.10(m,2H),1.72-1.53(m,3H),1.31-1.18(m,6H),1.017-0.83(m,15H)。 ¹ HNMR(DMSO- d ₆ ,400MHz) ppm, δ 9.03(d, J =4.2Hz,1H),7.69(s,1H),7.35(d, J =4.0Hz,1H),4.97(s,1H) ,4.42(d, J =4.4Hz,1H),4.15(s,1H),3.88-3.72(m,2H),3.16-3.03(m,2H),2.13-2.10(m,2H),1.72-1.53 (m,3H),1.31-1.18(m,6H),1.017-0.83(m,15H).

實施例7：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((2S)-2-(2,2-二氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物8)的合成Example 7: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((2S) )-2-(2,2-difluorocyclopropane-1-methamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0] Synthesis of hexane-2-methamide (compound 8)

第1步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物8-1)的製備 Step 1: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-methamide (compound 8-1)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(100mg,218.2umol)、2,2-二氟環丙烷-1-羧酸(29.3mg，240.02umol)和HATU(165.9mg，436.4umol)溶於THF(4mL)中，開啟攪拌，25℃下向反應液中加入DIPEA(84.4mg,654.6umol)。反應液繼續室溫攪拌1h。反應液直接濃縮，將粗品通過柱層析純化製備得到98mg白色固體(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺。MS實測值(ESI+)[(M+H)+]：526.28 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-Amino-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride Dissolve salt (100mg, 218.2umol), 2,2-difluorocyclopropane-1-carboxylic acid (29.3mg, 240.02umol) and HATU (165.9mg, 436.4umol) in THF (4mL), start stirring, 25℃ DIPEA (84.4mg, 654.6umol) was added to the reaction solution. The reaction solution was continued to stir at room temperature for 1 h. The reaction solution was directly concentrated, and the crude product was purified by column chromatography to obtain 98 mg of white solid (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2) -Oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)- 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide. MS measured value (ESI+)[(M+H)+]: 526.28

第2步：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物8)的製備 Step 2: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- Preparation of 2-formamide (compound 8)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-2-(1-氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(98mg,186.3umol)溶於DCM(3mL)中，開啟攪拌，將Burgess試劑(133.02mg，558.9umol)的DCM溶液(3mL)緩慢滴加入上述體系，25℃反應4h，反應液濃縮，將粗產品通過Pre-HPLC製備得到白色固體(7mg)(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((2S)-2-(2,2-二氟環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺。MS實測值(ESI+)[(M+H)+]：508.27 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-(1-fluorocyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1. 0] Hexane-2-formamide (98 mg, 186.3umol) was dissolved in DCM (3mL), stirred, and the DCM solution (3mL) of Burgess reagent (133.02mg, 558.9umol) was slowly added dropwise to the above system, 25 ℃ for 4 hours, the reaction solution was concentrated, and the crude product was prepared by Pre-HPLC to obtain a white solid (7 mg) (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2) -Oxopyrrolidin-3-yl)ethyl)-3-((2S)-2-(2,2-difluorocyclopropane-1-methamide)-3,3-dimethylbutyl)- 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide. MS measured value (ESI+)[(M+H)+]: 508.27

¹HNMR(DMSO-d ₆,400MHz)δ 9.03(d,J=4.2Hz,1H),8.49-8.41(m,1H),7.70(s,1H),5.01-4.97(m,1H),4.42(q,J=4.4Hz,1H),4.15(s,1H),3.91-3.78(m,2H),3.19-3.05(m,2H),2.82(q,J=7.8Hz,1H),2.28-2.17(m,1 H),1.85-1.74(m,2H),1.65(t,J=7.6Hz,1H),1.37-1.30(m,3H),1.04-0.81(m,17H)。 ¹ HNMR(DMSO- d ₆ ,400MHz) δ 9.03(d, J =4.2Hz,1H),8.49-8.41(m,1H),7.70(s,1H),5.01-4.97(m,1H),4.42( q, J =4.4Hz,1H),4.15(s,1H),3.91-3.78(m,2H),3.19-3.05(m,2H),2.82(q, J =7.8Hz,1H),2.28-2.17 (m,1 H),1.85-1.74(m,2H),1.65(t, J =7.6Hz,1H),1.37-1.30(m,3H),1.04-0.81(m,17H).

實施例8：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-(1-(三氟甲基)環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物9)的合成Example 8: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-3,3-dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-methamide)butyl)-6,6-dimethyl-3-azabicyclo[3.1. 0] Synthesis of hexane-2-methamide (compound 9)

第1步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((R)-3,3-二甲基-2-(1-(三氟甲基)環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物9-1)的製備 Step 1: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((R)-3,3-dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-formamide)butyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 9-1)

將化合物(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((R)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽的粗品(160mg，0.38mmol)溶於二氯甲烷(10mL)中，再加入1-三氟甲基環丙烷-1-甲酸(58mg，0.38mmol)、N,N-二異丙基乙胺(147mg，1.14mmol)、2-(7-偶氮苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(220mg，0.57mmol)室溫攪拌2h。反應結束後，加水淬滅(30mL)，乙酸乙酯萃取(50mL*3)，無水硫酸鈉乾燥，濃縮有機相經TLC板純化(DCM：MeOH=10：1)得無色液體化合物(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((R)-3,3-二甲基-2-(1-(三氟甲基)環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(260mg)。 Compound (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((R)-2-Amino-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide salt The crude acid salt (160 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), and then 1-trifluoromethylcyclopropane-1-carboxylic acid (58 mg, 0.38 mmol) and N,N-diisopropylethyl were added. Amine (147mg, 1.14mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (220mg, 0.57mmol) was stirred at room temperature for 2h . After the reaction was completed, water was added to quench the reaction (30 mL), extracted with ethyl acetate (50 mL*3), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by TLC plate (DCM: MeOH=10:1) to obtain a colorless liquid compound (1R, 2S , 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((R )-3,3-dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-methamide)butyl)-6,6-dimethyl-3-azabicyclo[3.1. 0] Hexane-2-methamide (260 mg).

第2步：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-(1-(三氟甲基)環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物9)的製備 Step 2: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-3,3-dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-methamide)butyl)-6,6-dimethyl-3-azabicyclo[3.1. 0] Preparation of hexane-2-formamide (compound 9)

將化合物(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((R)-3,3-二甲基-2-(1-(三氟甲基)環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(260mg，0.47mmol)溶於二氯甲烷(10mL)中，氮氣環境下加入伯吉斯試劑(333mg，1.4mmol)，反應攪拌3h，反應結束後加水(20mL)淬滅，乙酸乙酯(50mL*3)萃取，無水硫酸鈉乾燥後濃縮，送製備純化，凍幹得白色固體產物(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-(1-(三氟甲基)環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(101mg)。 Compound (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((R)-3,3-dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-formamide)butyl)-6,6-dimethyl-3- Azabicyclo[3.1.0]hexane-2-carboxamide (260 mg, 0.47 mmol) was dissolved in dichloromethane (10 mL), Burgess reagent (333 mg, 1.4 mmol) was added under nitrogen atmosphere, and the reaction was stirred for 3 hours. , after the reaction is completed, add water (20mL) to quench, extract with ethyl acetate (50mL*3), dry with anhydrous sodium sulfate and concentrate, send for preparation and purification, and freeze-dry to obtain the white solid product (1R, 2S, 5S)-N-(( S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(1-( Trifluoromethyl)cyclopropane-1-formamide)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide (101 mg).

LCMS：[M+1]⁺：540.3。¹H NMR(400MHz,DMSO)δ 9.04(d,J=8.5Hz,1H),7.72(s,1H),7.45(d,J=8.9Hz,1H),4.99(t,J=12.3Hz,1H),4.45(d,J=9.0Hz,1H),4.17(s,1H),3.93-3.87(m,1H),3.73(d,J=10.4Hz,1H),3.17(t,J=9.0Hz,1H),3.10-3.01(m,1H),2.41(t,J=9.4Hz,1H),2.21-2.06(m,2H),1.74(dd,J=19.7,9.5Hz,2H),1.57(d,J=12.9Hz,1H),1.33(d,J=7.6Hz,2H),1.24(s,2H),1.15(d,J=11.0Hz,1H),1.05(s,3H),0.95(s,9H),0.84(s,3H). LCMS: [M+1] ⁺ :540.3. ¹ H NMR(400MHz,DMSO)δ 9.04(d,J=8.5Hz,1H),7.72(s,1H),7.45(d,J=8.9Hz,1H),4.99(t,J=12.3Hz,1H ),4.45(d,J=9.0Hz,1H),4.17(s,1H),3.93-3.87(m,1H),3.73(d,J=10.4Hz,1H),3.17(t,J=9.0Hz ,1H),3.10-3.01(m,1H),2.41(t,J=9.4Hz,1H),2.21-2.06(m,2H),1.74(dd,J=19.7,9.5Hz,2H),1.57( d,J=12.9Hz,1H),1.33(d,J=7.6Hz,2H),1.24(s,2H),1.15(d,J=11.0Hz,1H),1.05(s,3H),0.95( s,9H),0.84(s,3H).

實施例9：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-((1R，2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物10)的製備Example 9: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-3,3-dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-formamide)butyl)-6,6-dimethyl-3-azabicyclo[ 3.1.0] Preparation of hexane-2-methamide (compound 10)

第1步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-3,3-二甲基-2-((1R，2R)-2-苯基環丙烷-1-甲醯胺基)丁醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物10-1)的製備 Step 1: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-3,3-dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-formamide)butyryl)-6,6-di Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 10-1)

將中間體A(200mg,0.44mmol)和(1R,2R)-2-苯基環丙烷-1-甲酸(65mg,0.40mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(170mg,1.32mmol)和HATU(250mg,0.66mmol)，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色油狀物(250mg，收率：98.0%)。 Intermediate A (200mg, 0.44mmol) and (1R,2R)-2-phenylcyclopropane-1-carboxylic acid (65mg, 0.40mmol) were dissolved in dichloromethane (10mL), and DIEA (170mg, 1.32 mmol) and HATU (250 mg, 0.66 mmol), stir at room temperature for 3 hours, add methylene chloride (20 mL) after the reaction is completed, and wash with saturated ammonium chloride (30 mL*2), the organic phase is dried over anhydrous sodium sulfate, and the pressure is reduced Concentrate and purify with silica gel column chromatography (DCM: MeOH=10:1) to obtain brown oil (250 mg, yield: 98.0%).

第2步：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-((1R，2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物10)的製備 Step 2: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-3,3-dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-methane Preparation of amino)butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 10)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-3,3-二甲基-2-((1R，2R)-2-苯基環丙烷-1-甲醯胺基)丁醯)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(250mg,0.44mmol)和伯吉斯試劑(310mg,1.32mmol)溶於二氯甲烷(10mL)中，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備得白色固體(40mg，收率：16.7%)。LCMS[M+1]⁺：548.59；¹H NMR(400MHz,DMSO-d ₆)δ 9.02(d,J=8.0Hz,1H),8.16(d,J=8.6Hz,1H),7.70(s,1H),7.29(t,J=7.5Hz,2H),7.19(t,J=；7.3Hz,1H),7.12(d,J=7.1Hz,2H),4.96-5.04(m,1H),4.37(d,J=8.6Hz,1H),4.16(s,1H),3.86-3.90(m,2H),3.01-3.21(m,3H),2.41-2.49(m,2H),2.21-2.31(m,2H),1.68-1.80(m,2H),1.55-1.60(m,1H),1.32(d,J=7.7Hz,1H),1.20-1.24(m,2H),1.06(s,3H),0.97(s,9H),0.90(s,3H)。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-3,3-dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-formamide)butyl)-6,6-dimethyl- 3-Azabicyclo[3.1.0]hexane-2-methamide (250 mg, 0.44 mmol) and Burgess reagent (310 mg, 1.32 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 3 hours. , after the reaction is completed, add dichloromethane (20mL) and wash with saturated ammonium chloride (30mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and prepared with a preparation plate to obtain a white solid (40mg, yield: 16.7% ). LCMS[M+1] ⁺ : 548.59; ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.02 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H),7.29(t,J=7.5Hz,2H),7.19(t,J=;7.3Hz,1H),7.12(d,J=7.1Hz,2H),4.96-5.04(m,1H),4.37 (d,J=8.6Hz,1H),4.16(s,1H),3.86-3.90(m,2H),3.01-3.21(m,3H),2.41-2.49(m,2H),2.21-2.31(m ,2H),1.68-1.80(m,2H),1.55-1.60(m,1H),1.32(d,J=7.7Hz,1H),1.20-1.24(m,2H),1.06(s,3H), 0.97(s,9H),0.90(s,3H).

實施例10：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-((1R，2S)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物11)的製備Example 10: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-formamide)butyl)-6,6-dimethyl-3-azabicyclo[ 3.1.0] Preparation of hexane-2-methamide (compound 11)

第1步：(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-3,3-二甲基-2-((1R，2S)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物11-1)的製備 Step 1: (1R, 2S, 5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane-2- base)-3-((S)-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-formamide)butyl)-6,6-dimethyl Preparation of base-3-azabicyclo[3.1.0]hexane-2-methamide (compound 11-1)

將中間體A(200mg,0.44mmol)和順式-2-苯基環丙烷-1-羧酸(65mg,0.40mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(170mg,1.32mmol)和HATU(250mg,0.66mmol)，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色油狀物(180mg，收率：72%)。 Intermediate A (200 mg, 0.44 mmol) and cis-2-phenylcyclopropane-1-carboxylic acid (65 mg, 0.40 mmol) were dissolved in dichloromethane (10 mL), and DIEA (170 mg, 1.32 mmol) was added successively. and HATU (250 mg, 0.66 mmol), and stirred at room temperature for 3 hours. After the reaction was completed, add methylene chloride (20 mL) and wash with saturated ammonium chloride (30 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and used Purify by silica gel column chromatography (DCM: MeOH=10:1) to obtain brown oil (180 mg, yield: 72%).

第2步：(1R，2S，5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-((S)-3,3-二甲基-2-((1R，2S)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物11)的製備 Step 2: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S) )-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-formamide)butyl)-6,6-dimethyl-3-azabicyclo[ 3.1.0] Preparation of hexane-2-methamide (compound 11)

將(1R，2S，5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-((S)-3,3-二甲基-2-((1R，2S)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(180mg,0.32mmol)和伯吉斯試劑(230mg,0.96mmol)溶於二氯甲烷(10mL)中，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備得白色固體(11mg，收率：6.3%)。LCMS[M+1]⁺：548.59；¹H NMR(400MHz,DMSO-d ₆)δ8.99(d,J=8.5Hz,1H),8.01-8.12(m,1H),7.70(s,1H),7.10-7.20(m,5H),4.92-5.02(m,1H),4.16-4.28(m,1H),4.12(t,J=36.0Hz,1H),3.65-3.83(m,2H),3.12-3.22(m,1H),3.02-3.11(m,1H),2.32-2.47(m,2H),2.06-2.30(m,3H),1.66-1.80(m,2H),1.39-1.54(m,2H),1.25-1.31(m,1H),1.20-1.24(m,1H),1.03(s,2H),0.97(s,2H),0.93(s,3H),0.83(s,2H),0.76(s,6H)。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 3-((S)-3,3-dimethyl-2-((1R,2S)-2-phenylcyclopropane-1-formamide)butyl)-6,6-dimethyl-3 -Azabicyclo[3.1.0]hexane-2-methamide (180 mg, 0.32 mmol) and Burgess reagent (230 mg, 0.96 mmol) were dissolved in dichloromethane (10 mL), and stirred at room temperature for 3 hours. After the reaction was completed, dichloromethane (20 mL) was added, and washed with saturated ammonium chloride (30 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used a preparation plate to prepare a white solid (11 mg, yield: 6.3%). . LCMS[M+1] ⁺ : 548.59; ¹ H NMR (400MHz, DMSO- d ₆ ) δ8.99 (d, J=8.5Hz, 1H), 8.01-8.12 (m, 1H), 7.70 (s, 1H) ,7.10-7.20(m,5H),4.92-5.02(m,1H),4.16-4.28(m,1H),4.12(t,J=36.0Hz,1H),3.65-3.83(m,2H),3.12 -3.22(m,1H),3.02-3.11(m,1H),2.32-2.47(m,2H),2.06-2.30(m,3H),1.66-1.80(m,2H),1.39-1.54(m, 2H),1.25-1.31(m,1H),1.20-1.24(m,1H),1.03(s,2H),0.97(s,2H),0.93(s,3H),0.83(s,2H),0.76 (s,6H).

實施例11：(1R、2S、5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(4-氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物12)的製備Example 11: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(4-fluorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 12)

第1步：(E)-3-(4-氟苯基)丙烯酸乙酯(化合物12-2)的製備 Step 1: Preparation of: (E)-3-(4-fluorophenyl)ethyl acrylate (compound 12-2)

氮氣保護下，向4-氟苯甲醛(5.0g，40.3mmol)和2-(二乙氧基磷醯)乙酸乙酯(10.8g，48.4mmol)的THF(70mL)溶液中添加氫化鈉(1.8g，44.3mmol)。反應混合物在25下攪拌1.5h。完成後，用NH₄Cl(100mL)將混合物淬滅，並用EA(100mL)萃取三次。用鹽水沖洗合併的有機層三次，並用硫酸鈉乾燥、過濾和濃縮。粗品使用矽膠柱層析(PE：EA=20：1)提純得無色油狀(6.0g，收率：76.9%)。 Under nitrogen protection, add sodium hydride (1.8 g, 44.3mmol). The reaction mixture was stirred at 25°C for 1.5h. Upon completion, the mixture was quenched with NH ₄ Cl (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel column chromatography (PE:EA=20:1) to obtain colorless oil (6.0g, yield: 76.9%).

第2步：(1S,2S)或(1R,2R)-2-(4-氟苯基)環丙烷-1-甲酸乙酯(化合物12-3)的製備 Step 2: Preparation of: (1S, 2S) or (1R, 2R)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 12-3)

氮氣保護下，將碘三甲基亞碸(3.2g，14.4mmol，)添加到叔丁醇鉀(1.5g，13.4mmol)的DMSO(70mL)溶液中。將所得懸浮液加熱至50℃並攪拌1.5小時。將溶液冷卻至25℃，並在1小時內逐滴添加(E)-3-(4-氟苯基)丙烯酸乙酯(2.0g，10.3mmol)的DMSO(20mL)溶液到體系中。反應在25℃下攪拌5h，然後用飽和NH4Cl(150mL)中和，並用EA(150mL*2)萃取，減壓濃縮。通過矽膠柱層析(PE：EA=1：1)純化得無色油狀物(0.7g，收率：32.7%)。 Under nitrogen protection, iodotrimethylstyrene (3.2g, 14.4mmol,) was added to a solution of potassium tert-butoxide (1.5g, 13.4mmol) in DMSO (70mL). The resulting suspension was heated to 50°C and stirred for 1.5 hours. The solution was cooled to 25°C, and a solution of (E)-ethyl 3-(4-fluorophenyl)acrylate (2.0 g, 10.3 mmol) in DMSO (20 mL) was added dropwise to the system over 1 hour. The reaction was stirred at 25°C for 5 h, then neutralized with saturated NH4Cl (150 mL), extracted with EA (150 mL*2), and concentrated under reduced pressure. Purified by silica gel column chromatography (PE:EA=1:1) to obtain colorless oil (0.7g, yield: 32.7%).

第3步：(1S,2S)或(1R,2R)-2-(4-氟苯基)環丙烷-1-羧酸(化合物12-4)的製備 Step 3: Preparation of: (1S, 2S) or (1R, 2R)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (compound 12-4)

將(1S,2S)或(1R,2R)-2-(4-氟苯基)環丙烷-1-羧酸乙酯(160mg，0.77mmol)溶於THF(5mL)和H₂O(5mL)的混合液中，在25℃下加入LiOH-H₂O(100mg，2.31mmol)。將混合物在25℃下攪拌12h。完成後，用1M鹽酸水溶液調節混合物的pH=2-3，用乙酸乙酯(15mL*3)萃取。用鹽水(20mL)洗滌有機層，在無水Na₂SO₄上乾燥，過濾，濃縮得棕色油狀物(120mg，收率：86.3%)。 Dissolve (1S,2S) or (1R,2R)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid ethyl ester (160mg, 0.77mmol) in THF (5mL) and H ₂ O (5mL) To the mixture, LiOH-H ₂ O (100 mg, 2.31 mmol) was added at 25°C. The mixture was stirred at 25 °C for 12 h. After completion, adjust the pH of the mixture to 2-3 with 1M hydrochloric acid aqueous solution, and extract with ethyl acetate (15mL*3). The organic layer was washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated to give a brown oil (120 mg, _yield : 86.3%).

第4步：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)或(1S,2S)-2-(4-氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物12-4)的製備 Step 4: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -yl)-3-((S)-2-((1R,2R) or (1S,2S)-2-(4-fluorophenyl)cyclopropane-1-methamide)-3,3- Preparation of dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 12-4)

將中間體A(300mg,0.66mmol)和(1S,2S)或(1R,2R)-2-(4-氟苯基)環丙烷-1-羧酸(120mg,0.66mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(155mg,1.98mmol)和HATU(380mg,0.99mmol)，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色油狀物(400mg，超量)。 Intermediate A (300 mg, 0.66 mmol) and (1S, 2S) or (1R, 2R)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (120 mg, 0.66 mmol) were dissolved in dichloromethane (10mL), add DIEA (155mg, 1.98mmol) and HATU (380mg, 0.99mmol) in sequence, stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20mL), and use saturated ammonium chloride (30mL*2) Wash, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH=10:1) to obtain a brown oil (400 mg, excess).

第5步：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(4-氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物12)的製備 Step 5: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(4-fluorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 12)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)或(1S,2S)-2-(4-氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(400mg，按0.66mmol計)和伯吉斯試劑(480mg,2.00mmol)溶於二氯甲烷(20mL)中，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備，SFC分離得到單一手性的白色固體(120mg，收率：32.1%)。LCMS[M+1]⁺：566.35；¹H NMR(400MHz,DMSO-d ₆)δ8.97-9.05(m,1H),8.14-8.29(m,1H),7.67-7.72(m,1H),7.08- 7.19(m,4H),4.94-5.03(m,1H),4.33-4.43(m,1H),4.13-4.16(m,1H),3.85-3.91(m,2H),3.01-3.20(m,2H),2.39-2.48(m,1H),2.06-2.32(m,4H),1.66-1.79(m,2H),1.54-1.62(m,1H),1.29-1.33(m,1H),1.11-1.23(m,2H),1.05(s,3H),0.96(s,9H),0.88(d,J=4.5Hz,3H)。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((S)-2-((1R,2R) or (1S,2S)-2-(4-fluorophenyl)cyclopropane-1-methamide)-3,3-dimethyl Butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (400 mg, based on 0.66 mmol) and Burgess reagent (480 mg, 2.00 mmol) were dissolved in dichloromethane (20 mL), stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20 mL), and wash with saturated ammonium chloride (30 mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and used to prepare Plate preparation and SFC separation yielded a single chiral white solid (120 mg, yield: 32.1%). LCMS[M+1] ⁺ : 566.35; ¹ H NMR (400MHz, DMSO- d ₆ ) δ8.97-9.05(m,1H),8.14-8.29(m,1H),7.67-7.72(m,1H), 7.08- 7.19(m,4H),4.94-5.03(m,1H),4.33-4.43(m,1H),4.13-4.16(m,1H),3.85-3.91(m,2H),3.01-3.20(m ,2H),2.39-2.48(m,1H),2.06-2.32(m,4H),1.66-1.79(m,2H),1.54-1.62(m,1H),1.29-1.33(m,1H),1.11 -1.23(m,2H),1.05(s,3H),0.96(s,9H),0.88(d,J=4.5Hz,3H).

實施例12：(1R,2S,5S)-3-((S)-2-((1R,2R)-2-(2-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物14)的製備Example 12: (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(2-chlorophenyl)cyclopropane-1-methamide)-3, 3-Dimethylbutyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 14)

第1步：(E)-3-(2-氯苯基)丙烯酸乙酯(化合物14-2)的製備 Step 1: Preparation of: (E)-3-(2-chlorophenyl)ethyl acrylate (compound 14-2)

將2-氯苯甲醛(化合物14-1)(4g，28mmol)，膦醯基乙酸三乙酯(7.6g，34mmol)，四氫呋喃(200mL)加入反應瓶中，在氮氣保護下分批加入鈉氫(1.36g，34mmol，60%)，在25℃下攪拌1.5小時。反應結束後，加入飽和氯化銨水溶液(200mL)，用乙酸乙酯萃取(150mL*2)，合併有機相，用無水硫酸鈉乾燥，濃縮得到粗品，用矽膠柱層析分離提純(乙酸乙酯/石油醚5%)，得到(E)-3-(2-氯苯基)丙烯酸乙酯(化合物14-2)(3g，收率：51%)，LCMS：[M+1]⁺：211。 Add 2-chlorobenzaldehyde (compound 14-1) (4g, 28mmol), triethyl phosphonoacetate (7.6g, 34mmol), and tetrahydrofuran (200mL) into the reaction flask, and add sodium and hydrogen in batches under nitrogen protection. (1.36g, 34mmol, 60%), stirred at 25°C for 1.5 hours. After the reaction is completed, add saturated ammonium chloride aqueous solution (200mL), extract with ethyl acetate (150mL*2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate to obtain crude product, separate and purify with silica gel column chromatography (ethyl acetate) /petroleum ether 5%) to obtain (E)-3-(2-chlorophenyl)ethyl acrylate (compound 14-2) (3g, yield: 51%), LCMS: [M+1] ⁺ : 211 .

第2步：(1R,2R)-2-(2-氯苯基)環丙烷-1-甲酸乙酯(化合物14-3)的製備 Step 2: Preparation of: (1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 14-3)

將三甲基碘化亞碸(2.2g，10mmol)，叔丁醇鉀(1.1g，10mmol)溶於二甲亞碸(20mL)中，在氮氣保護下加熱至50℃攪拌1.5小時，再滴加(E)-3-(2-氯苯基)丙烯酸乙酯(化合物1-2)(1.5g，7.14mmol)的DMSO溶液(10mL)。反應在25℃下攪拌5h，然後用飽和氯化銨(150mL)中和，並用乙酸乙酯(150mL*2)萃取。用水(100mL)、鹽水(100mL)清洗有機層，用無水硫酸鈉乾燥，過濾並在真空中濃縮以得到粗品。粗品通過矽膠柱層析(乙酸乙酯/石油醚5%)純化，得到(1R,2R)-2-(2-氯苯基)環丙烷-1-甲酸乙酯(化合物14-3)(1.5g，收率93%)，LCMS：[M+1]⁺：225。 Dissolve trimethylstyrene iodide (2.2g, 10mmol) and potassium tert-butoxide (1.1g, 10mmol) in dimethylstyrene (20mL), heat to 50°C under nitrogen protection, stir for 1.5 hours, and drop again. A solution of (E)-ethyl 3-(2-chlorophenyl)acrylate (compound 1-2) (1.5 g, 7.14 mmol) in DMSO (10 mL) was added. The reaction was stirred at 25°C for 5 h, then neutralized with saturated ammonium chloride (150 mL), and extracted with ethyl acetate (150 mL*2). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether 5%) to obtain (1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 14-3) (1.5 g, yield 93%), LCMS: [M+1] ⁺ : 225.

第3步：(1R,2R)-2-(2-氯苯基)環丙烷-1-羧酸(化合物14-4)的製備 Step 3: Preparation of: (1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid (compound 14-4)

將(1R,2R)-2-(2-氯苯基)環丙烷-1-甲酸乙酯(化合物14-3)(1.5g，6.7mmol)溶于甲醇/水(1：1，20mL)中，下加入一水合氫氧化鋰(562mg，13.4mmol)，室溫攪拌過夜，反應結束後加鹽酸(1M)調節pH至2~3，乙酸乙酯(30mL*3)萃取，無水硫酸鈉乾燥後濃縮，得到(1R,2R)-2-(2-氯苯基)環丙烷-1-羧酸(化合物14-4)粗品(400mg，收率：30%)，LCMS：[M+1]⁺：197。 Dissolve (1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 14-3) (1.5g, 6.7mmol) in methanol/water (1:1, 20mL) , add lithium hydroxide monohydrate (562mg, 13.4mmol), stir at room temperature overnight, add hydrochloric acid (1M) after the reaction to adjust the pH to 2~3, extract with ethyl acetate (30mL*3), and dry with anhydrous sodium sulfate Concentrate to obtain (1R, 2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid (compound 14-4) crude product (400 mg, yield: 30%), LCMS: [M+1] ⁺ :197.

第4步：(化合物14-5)的製備 Step 4: Preparation of compound 14-5

將(1R,2R)-2-(2-氯苯基)環丙烷-1-羧酸(化合物14-4)(88mg，0.45mmol)，(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(中間體A)(207mg，0.49mmol)，三乙胺(1mL)，溶於DMF(5mL)中，再加入HATU(209mg，0.55mmol)，室溫攪拌2小時，反應結束後，濃縮得粗品，用製備TLC純化(MeOH/DCM 8%)，得到(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)-2-(2-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物14-5)(240mg，收率：88%)，LCMS：[M+1]⁺：197。 (1R,2R)-2-(2-chlorophenyl)cyclopropane-1-carboxylic acid (compound 14-4) (88 mg, 0.45 mmol), (1R,2S,5S)-N-((S) -1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-3, 3-Dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride (Intermediate A) (207 mg, 0.49 mmol), tris Ethylamine (1mL) was dissolved in DMF (5mL), then HATU (209mg, 0.55mmol) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the crude product was concentrated and purified by preparative TLC (MeOH/DCM 8%). Obtain (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((S)-2-((1R,2R)-2-(2-chlorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6 -Dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 14-5) (240 mg, yield: 88%), LCMS: [M+1] ⁺ : 197.

第5步：(1R,2S,5S)-3-((S)-2-((1R,2R)-2-(2-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物14)的製備 Step 5: (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(2-chlorophenyl)cyclopropane-1-methamide)-3, 3-Dimethylbutyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 14)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)-2-(2-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6- 二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物14-5)(240mg，0.4mmol)溶於二氯甲烷(15mL)中，再加入Burgess試劑(286mg，1.2mmol)，室溫攪拌2小時，反應結束後，濃縮得到粗品，用製備TLC純化(MeOH/DCM 8%)得到粗品，再用手性柱拆分得到(1R,2S,5S)-3-((S)-2-((1R,2R)-2-(2-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物14)(15mg，收率：6.4%)。LCMS：[M+1]⁺：582。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((S)-2-((1R,2R)-2-(2-chlorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6 - Dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 14-5) (240 mg, 0.4 mmol) was dissolved in dichloromethane (15 mL), and then Burgess reagent ( 286 mg, 1.2 mmol), stirred at room temperature for 2 hours, after the reaction was completed, concentrated to obtain the crude product, purified by preparative TLC (MeOH/DCM 8%) to obtain the crude product, and then separated with a chiral column to obtain (1R, 2S, 5S)- 3-((S)-2-((1R,2R)-2-(2-chlorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-N-(( S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-Formamide (compound 14) (15 mg, yield: 6.4%). LCMS:[M+1] ⁺ :582.

實施例13：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物15)的製備Example 13: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-di Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 15)

第1步：(E)-3-(3,4-二氟苯基)丙烯酸乙酯(化合物15-2)的製備 Step 1: Preparation of: (E)-ethyl 3-(3,4-difluorophenyl)acrylate (compound 15-2)

將3，4-二氟苯甲醛(化合物15-1)(2g，14mmol)，膦醯基乙酸三乙酯(4.39g，19.6mmol)，四氫呋喃(100mL)加入反應瓶中，在氮氣保護下分批加入鈉氫(784mg，19.6mmol，60%)，在室溫下攪拌1.5小時。反應結束後，加入飽和氯化銨水溶液(150mL)，用乙酸乙酯萃取(150mL*2)，合併有機相，用無水硫酸鈉乾燥，旋蒸濃縮得到粗品，用矽膠柱層析分離提純(乙酸乙酯/石油醚5%)，得到(E)-3-(3,4-二氟苯基)丙烯酸乙酯(化合物15-2)(1.5g，收率：50%)。LCMS：[M+1]⁺：213。 Add 3,4-difluorobenzaldehyde (compound 15-1) (2g, 14mmol), triethyl phosphonoacetate (4.39g, 19.6mmol), and tetrahydrofuran (100mL) into the reaction flask, and separate under nitrogen protection. Sodium hydrogen (784 mg, 19.6 mmol, 60%) was added in batches and stirred at room temperature for 1.5 hours. After the reaction is completed, add saturated aqueous ammonium chloride solution (150mL), extract with ethyl acetate (150mL*2), combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate and concentrate to obtain a crude product, which is separated and purified by silica gel column chromatography (acetic acid Ethyl ester/petroleum ether 5%) to obtain (E)-3-(3,4-difluorophenyl)ethyl acrylate (compound 15-2) (1.5 g, yield: 50%). LCMS:[M+1] ⁺ :213.

第2步：(1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲酸乙酯(化合物15-3)的製備 Step 2: Preparation of: (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 15-3)

將三甲基碘化亞碸(1.55g，7mmol)，叔丁醇鉀(784mg，7mmol)溶於二甲亞碸(20mL)中，在氮氣保護下加熱至50℃攪拌1.5小時，再滴加(E)-3-(3,4-二氟苯基)丙烯酸乙酯(化合物15-2)(1g，4.71mmol)的DMSO溶液(10mL)。反應在25℃下攪拌5h，然後用飽和氯化銨(150mL)中和，並用乙酸乙酯(150mL*2)萃取。用水(100mL)、鹽水(100mL)清洗有機層，用無水硫酸鈉乾燥，過濾並在真空中濃縮以得到粗品。粗品通過矽膠柱層析(乙酸乙酯/石油醚5%)純化，得到(1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲酸乙酯(化合物15-3)(1g，收率：94%)，LCMS：[M+1]⁺：227。 Dissolve trimethylstyrene iodide (1.55g, 7mmol) and potassium tert-butoxide (784mg, 7mmol) in dimethylstyrene (20mL), heat to 50°C under nitrogen protection, stir for 1.5 hours, and then add dropwise (E)-Ethyl 3-(3,4-difluorophenyl)acrylate (compound 15-2) (1 g, 4.71 mmol) in DMSO (10 mL). The reaction was stirred at 25°C for 5 h, then neutralized with saturated ammonium chloride (150 mL), and extracted with ethyl acetate (150 mL*2). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether 5%) to obtain (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 15-3 ) (1g, yield: 94%), LCMS: [M+1] ⁺ : 227.

第3步：(1R,2R)-2-(3,4-二氟苯基)環丙烷-1-羧酸(化合物15-4)的製備 Step 3: Preparation of: (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid (compound 15-4)

將(1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲酸乙酯(化合物15-3)(1g，4.4mmol)溶于甲醇/水(1：1，15ml)中，加入一水合氫氧化鋰(369mg，8.8mmol)，室溫攪拌過夜，反應結束後加鹽酸(1M)調節pH至2~3，乙酸乙酯(20mL*3)萃取，無水硫酸鈉乾燥後濃縮，得到(1R,2R)-2-(3,4-二氟苯基)環丙烷-1-羧酸(化合物15-4)粗品(500mg，收率：57%)，LCMS：[M+1]⁺：199。 Dissolve (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 15-3) (1g, 4.4mmol) in methanol/water (1:1, 15ml ), add lithium hydroxide monohydrate (369mg, 8.8mmol), stir at room temperature overnight, add hydrochloric acid (1M) after the reaction to adjust the pH to 2~3, extract with ethyl acetate (20mL*3), and dry over anhydrous sodium sulfate After concentration, obtain (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid (compound 15-4) crude product (500 mg, yield: 57%), LCMS: [M +1] ⁺ : 199.

第4步：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物15-5)的製備 Step 4: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -yl)-3-((S)-2-((1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-methamide)-3,3-dimethyl Preparation of butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 15-5)

將(1R,2R)-2-(3,4-二氟苯基)環丙烷-1-羧酸(化合物15-4)(90mg，0.45mmol)，(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺鹽酸鹽(中間體A)(202mg，0.48mmol)，三乙胺(1mL)，溶於DMF(5mL)中，再加入HATU(209mg，0.55mmol)，室溫攪拌2小時，反應結束後，濃縮得粗品，用製備TLC純化(MeOH/DCM 8%)，得到(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物15-5)(271mg，收率：99%)。 LCMS：[M+1]⁺：602。 (1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid (compound 15-4) (90 mg, 0.45mmol), (1R,2S,5S)-N-( (S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino -3,3-Dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide hydrochloride (Intermediate A) (202 mg, 0.48 mmol ), triethylamine (1mL), dissolved in DMF (5mL), then added HATU (209mg, 0.55mmol), stirred at room temperature for 2 hours, after the reaction was completed, concentrated to obtain crude product, purified by preparative TLC (MeOH/DCM 8 %), obtaining (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -yl)-3-((S)-2-((1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-methamide)-3,3-dimethyl Butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 15-5) (271 mg, yield: 99%). LCMS:[M+1] ⁺ :602.

第5步：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物15)的製備 Step 5: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-di Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 15)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物15-5)(271mg，0.45mmol)溶於二氯甲烷(15mL)中，再加入Burgess試劑(322mg，1.35mmol)，室溫攪拌2小時，反應結束後，濃縮得到粗品，用製備TLC純化(MeOH/DCM 8%)得到粗品，再用手性柱拆分得到(1R、2S、5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(3,4-二氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物15)(14mg，收率：5.3%)。LCMS：[M+1]⁺：584。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((S)-2-((1R,2R)-2-(3,4-difluorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)- 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 15-5) (271 mg, 0.45 mmol) was dissolved in dichloromethane (15 mL), and then added Burgess reagent (322 mg, 1.35 mmol), stirred at room temperature for 2 hours, after the reaction was completed, concentrated to obtain the crude product, purified by preparative TLC (MeOH/DCM 8%) to obtain the crude product, and then separated with a chiral column to obtain (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-2-((1R, 2R)-2-(3,4-difluorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[ 3.1.0] Hexane-2-methamide (compound 15) (14 mg, yield: 5.3%). LCMS:[M+1] ⁺ :584.

實施例14：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(4-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物16)的製備Example 14: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(4-chlorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 16)

第1步：(E)-3-(4-氯苯基)丙烯酸乙酯(化合物16-2)的製備 Step 1: Preparation of: (E)-3-(4-chlorophenyl)ethyl acrylate (compound 16-2)

氮氣保護下，向4-氯苯甲醛(5.6g，40.3mmol)和2-(二乙氧基磷醯)乙酸乙酯(10.8g，48.4mmol)的THF(70mL)溶液中添加氫化鈉(1.8g，44.3mmol)。反應混合物在25下攪拌1.5h。完成後，用NH₄Cl(100mL)將混合物淬滅，並用EA(100mL)萃取三次。用鹽水沖洗合併的有機層三次，並用硫酸鈉乾燥、過濾和濃縮。粗品使用矽膠柱層析(PE：EA=20：1)提純得無色油狀(6.3g，收率：74.4%)。 Under nitrogen protection, add sodium hydride (1.8 g, 44.3mmol). The reaction mixture was stirred at 25°C for 1.5h. Upon completion, the mixture was quenched with NH ₄ Cl (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel column chromatography (PE:EA=20:1) to obtain colorless oil (6.3g, yield: 74.4%).

第2步：(1S,2S)或(1R,2R)-2-(4-氯苯基)環丙烷-1-甲酸乙酯(化合物16-3)的製備 Step 2: Preparation of: (1S, 2S) or (1R, 2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 16-3)

氮氣保護下，將碘三甲基亞碸(3.2g，14.4mmol，)添加到叔丁醇鉀(1.5g，13.4mmol)的DMSO(70mL)溶液中。將所得懸浮液加熱至50℃並攪拌1.5小時。將溶液冷卻至25℃，並在1小時內逐滴添加(E)-3-(4-氯苯基)丙烯酸乙酯(2.2g，10.3mmol)的DMSO(20mL)溶液到體系中。反應在25℃下攪拌5h，然後用飽和NH4Cl(150mL)中和，並用EA(150mL*2)萃取，減壓濃縮。通過矽膠柱層析(PE：EA=1：1)純化得無色油狀物(0.7g，收率：30.4%)。 Under nitrogen protection, iodotrimethylstyrene (3.2g, 14.4mmol,) was added to a solution of potassium tert-butoxide (1.5g, 13.4mmol) in DMSO (70mL). The resulting suspension was heated to 50°C and stirred for 1.5 hours. The solution was cooled to 25°C, and a solution of (E)-ethyl 3-(4-chlorophenyl)acrylate (2.2 g, 10.3 mmol) in DMSO (20 mL) was added dropwise to the system over 1 hour. The reaction was stirred at 25°C for 5 h, then neutralized with saturated NH4Cl (150 mL), extracted with EA (150 mL*2), and concentrated under reduced pressure. Purified by silica gel column chromatography (PE:EA=1:1) to obtain colorless oil (0.7g, yield: 30.4%).

第3步：(1S,2S)或(1R,2R)-2-(4-氯苯基)環丙烷-1-羧酸(化合物16-4)的製備 Step 3: Preparation of: (1S, 2S) or (1R, 2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid (compound 16-4)

將(1S,2S)或(1R,2R)-2-(4-氯苯基)環丙烷-1-羧酸乙酯(180mg，0.77mmol)溶於THF(5mL)和H₂O(5mL)的混合液中，在25℃下加入LiOH-H₂O(100mg，2.31mmol)。將混合物在25℃下攪拌12h。完成後，用1M鹽酸水溶液調節混合物的pH=2-3，用乙酸乙酯(15mL*3)萃取。用鹽水(20mL)洗滌有機層，在無水Na₂SO₄上乾燥，過濾，濃縮得棕色油狀物(120mg，收率：75.6%)。 Dissolve (1S,2S) or (1R,2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid ethyl ester (180mg, 0.77mmol) in THF (5mL) and H ₂ O (5mL) To the mixture, LiOH-H ₂ O (100 mg, 2.31 mmol) was added at 25°C. The mixture was stirred at 25 °C for 12 h. After completion, adjust the pH of the mixture to 2-3 with 1M hydrochloric acid aqueous solution, and extract with ethyl acetate (15mL*3). The organic layer was washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated to give a brown oil (120 mg, _yield : 75.6%).

第4步：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)或(1S,2S)-2-(4-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物16-4)的製備 Step 4: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -base)-3-((S)-2-((1R,2R) or (1S,2S)-2-(4-chlorophenyl)cyclopropane-1-methamide)-3,3- Preparation of dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 16-4)

將中間體A(300mg,0.66mmol)和(1S,2S)或(1R,2R)-2-(4-氯苯基)環丙烷-1-羧酸(130mg,0.66mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(155mg,1.98mmol)和HATU(380mg,0.99mmol)，室溫攪拌3 小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色油狀物(400mg，超量)。 Dissolve intermediate A (300mg, 0.66mmol) and (1S, 2S) or (1R, 2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid (130mg, 0.66mmol) in dichloromethane (10mL), add DIEA (155mg, 1.98mmol) and HATU (380mg, 0.99mmol) in sequence, and stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20mL) and wash with saturated ammonium chloride (30mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (DCM: MeOH=10:1) Purify to obtain brown oil (400 mg, excessive amount).

第5步：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(4-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物16)的製備 Step 5: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(4-chlorophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 16)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)或(1S,2S)-2-(4-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(400mg，按0.66mmol計)和伯吉斯試劑(480mg,2.00mmol)溶於二氯甲烷(20mL)中，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備，SFC分離得到單一手性的白色固體(100mg，收率：26.2%)。LCMS[M+1]⁺：582.35；¹H NMR(400MHz,DMSO-d ₆)δ ppm 8.98(d,J=8.60Hz,1 H),8.14(d,J=8.50Hz,1 H),7.66(s,1 H),7.30-7.33(m,2 H),7.10-7.13(m,2 H),4.94-4.96(m,1 H),4.32(d,J=8.60Hz,1 H),4.12(s,1 H),3.79-3.88(m,2 H),3.09-3.16(m,1 H),2.99-3.06(m,1 H),2.51-2.52(m,1 H),2.38-2.46(m,1 H),2.23(s,2 H),2.11(s,1 H),1.63-1.76(m,2 H), 1.51-1.58(m,1 H),1.25-1.30(m,1 H),1.17-1.23(m,1 H),1.11-1.16(m,1 H),1.02(s,3 H),0.93(s,9 H),0.85(s,3 H)。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((S)-2-((1R,2R) or (1S,2S)-2-(4-chlorophenyl)cyclopropane-1-methamide)-3,3-dimethyl Butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (400 mg, based on 0.66 mmol) and Burgess reagent (480 mg, 2.00 mmol) were dissolved in dichloromethane (20 mL), stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20 mL), and wash with saturated ammonium chloride (30 mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and used to prepare Plate preparation and SFC separation yielded a single chiral white solid (100 mg, yield: 26.2%). LCMS[M+1] ⁺ : 582.35; ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 8.98 (d, J =8.60Hz, 1 H), 8.14 (d, J =8.50Hz, 1 H), 7.66 (s,1 H),7.30-7.33(m,2 H),7.10-7.13(m,2 H),4.94-4.96(m,1 H),4.32(d, J =8.60Hz,1 H), 4.12(s,1 H),3.79-3.88(m,2 H),3.09-3.16(m,1 H),2.99-3.06(m,1 H),2.51-2.52(m,1 H),2.38- 2.46(m,1 H),2.23(s,2 H),2.11(s,1 H),1.63-1.76(m,2 H), 1.51-1.58(m,1 H),1.25-1.30(m, 1 H),1.17-1.23(m,1 H),1.11-1.16(m,1 H),1.02(s,3 H),0.93(s,9 H),0.85(s,3 H).

實施例15：(1R、2S、5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(2-溴苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物17)的製備Example 15: (1R, 2S, 5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(2-bromophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 17)

第1步：(E)-3-(2-溴苯基)丙烯酸乙酯(化合物17-2)的製備 Step 1: Preparation of: (E)-3-(2-bromophenyl)ethyl acrylate (compound 17-2)

氮氣保護下，向2-溴苯甲醛(7.5g，40.3mmol)和2-(二乙氧基磷醯)乙酸乙酯(10.8g，48.4mmol)的THF(70mL)溶液中添加氫化鈉(1.8g，44.3mmol)。反應混合物在25下攪拌1.5h。完成後，用NH₄Cl(100mL)將混合物淬滅，並用EA(100mL)萃取三次。用鹽水沖洗合併的有機層三次，並用硫酸鈉乾燥、過濾和濃縮。粗品使用矽膠柱層析(PE：EA=20：1)提純得無色油狀(7.5g，收率：73.5%)。 Under nitrogen protection, add sodium hydride (1.8 g, 44.3mmol). The reaction mixture was stirred at 25°C for 1.5h. Upon completion, the mixture was quenched with NH ₄ Cl (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel column chromatography (PE:EA=20:1) to obtain colorless oil (7.5g, yield: 73.5%).

第2步：(1S,2S)或(1R,2R)-2-(2-溴苯基)環丙烷-1-甲酸乙酯(化合物17-3)的製備 Step 2: Preparation of: (1S, 2S) or (1R, 2R)-2-(2-bromophenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 17-3)

氮氣保護下，將碘三甲基亞碸(3.2g，14.4mmol，)添加到叔丁醇鉀(1.5g，13.4mmol)的DMSO(70mL)溶液中。將所得懸浮液加熱至50℃並攪拌1.5小時。將溶液冷卻至25℃，並在1小時內逐滴添加(E)-3-(2-溴苯基)丙烯酸乙酯(2.6g，10.3mmol)的DMSO(20mL)溶液到體系中。反應在25℃下攪拌5h，然後用飽和NH4Cl(150mL)中和，並用EA(150mL*2)萃取，減壓濃縮。通過矽膠柱層析(PE：EA=1：1)純化得無色油狀物(0.8g，收率：29.3%)。 Under nitrogen protection, iodotrimethylstyrene (3.2g, 14.4mmol,) was added to a solution of potassium tert-butoxide (1.5g, 13.4mmol) in DMSO (70mL). The resulting suspension was heated to 50°C and stirred for 1.5 hours. The solution was cooled to 25°C, and a solution of (E)-ethyl 3-(2-bromophenyl)acrylate (2.6 g, 10.3 mmol) in DMSO (20 mL) was added dropwise to the system over 1 hour. The reaction was stirred at 25°C for 5 h, then neutralized with saturated NH4Cl (150 mL), extracted with EA (150 mL*2), and concentrated under reduced pressure. Purified by silica gel column chromatography (PE:EA=1:1) to obtain colorless oil (0.8g, yield: 29.3%).

第3步：(1S,2S)或(1R,2R)-2-(2-溴苯基)環丙烷-1-羧酸(化合物17-4)的製備 Step 3: Preparation of: (1S, 2S) or (1R, 2R)-2-(2-bromophenyl)cyclopropane-1-carboxylic acid (compound 17-4)

將(1S,2S)或(1R,2R)-2-(2-溴苯基)環丙烷-1-羧酸乙酯(210mg，0.77mmol)溶於THF(5mL)和H₂O(5mL)的混合液中，在25℃下加入LiOH-H₂O(100mg，2.31mmol)。將混合物在25℃下攪拌12h。完成後，用1M鹽酸水溶液調節混合物的pH=2-3，用乙酸乙酯(15mL*3)萃取。用鹽水(20mL)洗滌有機層，在無水Na₂SO₄上乾燥，過濾，濃縮得棕色油狀物(125mg，收率：67.6%)。 Dissolve (1S,2S) or (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylic acid ethyl ester (210 mg, 0.77mmol) in THF (5 mL) and H ₂ O (5 mL) To the mixture, LiOH-H ₂ O (100 mg, 2.31 mmol) was added at 25°C. The mixture was stirred at 25 °C for 12 h. After completion, adjust the pH of the mixture to 2-3 with 1M hydrochloric acid aqueous solution, and extract with ethyl acetate (15mL*3). The organic layer was washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated to give a brown oil (125 mg, _yield : 67.6%).

第4步：(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)或(1S,2S)-2-(2-溴苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物17-4)的製備 Step 4: (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -base)-3-((S)-2-((1R,2R) or (1S,2S)-2-(2-bromophenyl)cyclopropane-1-methamide)-3,3- Preparation of dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 17-4)

將中間體A(300mg,0.66mmol)和(1S,2S)或(1R,2R)-2-(4-氯苯基)環丙烷-1-羧酸(160mg,0.66mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(155mg,1.98mmol)和HATU(380mg,0.99mmol)，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色油狀物(400mg，超量)。 Dissolve intermediate A (300mg, 0.66mmol) and (1S, 2S) or (1R, 2R)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid (160mg, 0.66mmol) in dichloromethane (10mL), add DIEA (155mg, 1.98mmol) and HATU (380mg, 0.99mmol) in sequence, stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20mL), and use saturated ammonium chloride (30mL*2) Wash, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH=10:1) to obtain a brown oil (400 mg, excess).

第5步：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,2R)-2-(2-溴苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物17)的製備 Step 5: (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(( S)-2-((1R,2R)-2-(2-bromophenyl)cyclopropane-1-formamide)-3,3-dimethylbutyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-methamide (compound 17)

將(1R,2S,5S)-N-((S)-1-胺基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-((S)-2-((1R,2R)或(1S,2S)-2-(4-氯苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(400mg，按0.66mmol計)和伯吉斯試劑(480mg,2.00mmol)溶於二氯甲烷(20mL)中，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備，SFC分離得到單一手性的白色固體(110mg，收率：26.7%)。LCMS[M+1]⁺：626.25；1H NMR(400MHz,DMSO-d6)δ ppm 9.01(d,J=8.61Hz,1 H),8.21(d,J=8.97Hz,1 H),7.69(s,1 H),7.62(dd,J=7.97,1.10Hz,1 H),7.30-7.40(m,1 H),7.11-7.22(m,2 H),4.97-4.99(m,1 H),4.45(d,J=8.80Hz,1 H),4.16(s,1 H),3.82-3.94(m,2 H),3.13-3.22(m,1 H),3.02-3.11(m,1 H),2.37-2.48(m,2 H),2.06-2.26(m,3 H),1.67-1.81(m,2 H),1.54-1.58(m,1 H),1.22-1.34(m,3 H),1.06(s,3 H),1.0(s,9 H),0.95(s,3 H)。 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-((S)-2-((1R,2R) or (1S,2S)-2-(4-chlorophenyl)cyclopropane-1-methamide)-3,3-dimethyl Butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (400 mg, based on 0.66 mmol) and Burgess reagent (480 mg, 2.00 mmol) were dissolved in dichloromethane (20 mL), stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20 mL), and wash with saturated ammonium chloride (30 mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and used to prepare Plate preparation and SFC separation yielded a single chiral white solid (110 mg, yield: 26.7%). LCMS[M+1] ⁺ : 626.25; 1H NMR (400MHz, DMSO-d6) δ ppm 9.01 (d, J = 8.61 Hz, 1 H), 8.21 ( d, J = 8.97 Hz, 1 H), 7.69 (s ,1 H),7.62(dd,J=7.97,1.10Hz,1 H),7.30-7.40(m,1 H),7.11-7.22(m,2 H),4.97-4.99(m,1 H), 4.45(d,J=8.80Hz,1 H),4.16(s,1 H),3.82-3.94(m,2 H),3.13-3.22(m,1 H),3.02-3.11(m,1 H) ,2.37-2.48(m,2 H),2.06-2.26(m,3 H),1.67-1.81(m,2 H),1.54-1.58(m,1 H),1.22-1.34(m,3 H) ,1.06(s,3 H),1.0(s,9 H),0.95(s,3 H).

實施例16：(1R，2S，5S)-3-((R)-3,3-二甲基-2-((1R、2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-N-((S)-1-氧代-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物18)的製備Example 16: (1R, 2S, 5S)-3-((R)-3,3-dimethyl-2-((1R, 2R)-2-phenylcyclopropane-1-methamide) Butyl)-6,6-dimethyl-N-((S)-1-oxo-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-nitrogen Preparation of heterobicyclo[3.1.0]hexane-2-methamide (compound 18)

第1步：(S)-2-((1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺基)(化合物18-1)的製備 Step 1: (S)-2-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6 , Preparation of 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide) (compound 18-1)

將(1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-羧酸(9.62g,20.7mmol)和((S)-2-((叔丁氧基羰基)胺基)甲基-3-((S)-2-氧吡咯烷-3-基)丙酸甲酯(3.9g,20.7mmol)溶於二氯甲烷(80mL)中，依次加入DIEA(8.0g,62.1mmol)和HATU(11.8g,31.1mmol)，室溫攪拌6小時，反應完畢後加入二氯甲烷(100mL)，並用飽和氯化銨(100mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=20：1)提純得白色固體(10.0g，收率：90.1%)。 (1R, 2S, 5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxylic acid (9.62g, 20.7mmol) and ((S)-2-((tert-butoxycarbonyl)amino)methyl-3-((S)- Methyl 2-oxopyrrolidin-3-yl)propionate (3.9g, 20.7mmol) was dissolved in dichloromethane (80mL), and DIEA (8.0g, 62.1mmol) and HATU (11.8g, 31.1mmol) were added in sequence. , stirred at room temperature for 6 hours. After the reaction was completed, dichloromethane (100mL) was added, and washed with saturated ammonium chloride (100mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (DCM: MeOH). =20:1) and purified to obtain a white solid (10.0g, yield: 90.1%).

第2步：(S)-2-((1R，2S，5S)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺基)-3-氧代吡咯烷-3-基)丙酸甲酯(化合物18-2)的製備 Step 2: (S)-2-((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutyl)-6,6-dimethyl-3 - Preparation of azabicyclo[3.1.0]hexane-2-methamide)-3-oxopyrrolidin-3-yl)propionic acid methyl ester (compound 18-2)

將(S)-2-((1R，2S，5S)-3-((S)-2-((叔丁氧羰基)胺基)-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺基)(5.0g,9.3mmol)加入鹽酸二氧六環溶液(80mL,7M)中，室溫攪拌8小時，反應完畢後減壓濃縮得白色固體粗品(4.2g，收率：95.5%)，直接進行下一步反應。 (S)-2-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-6,6- Dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide) (5.0g, 9.3mmol) was added to dioxane hydrochloride solution (80mL, 7M) and stirred at room temperature for 8 hours. , after the reaction is completed, concentrate under reduced pressure to obtain a white solid crude product (4.2g, yield: 95.5%), which can be directly used for the next step of the reaction.

第3步：(S)-2-((1R，2S，5S)-3-((R)-3,3-二甲基-2-(1R、2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺)(化合物18-3)的製備 Step 3: (S)-2-((1R,2S,5S)-3-((R)-3,3-dimethyl-2-(1R,2R)-2-phenylcyclopropane-1 Preparation of -formamide)butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) (compound 18-3)

將(1R,2R)-2-苯基環丙烷-1-甲酸(0.17g,1.06mmol)和(S)-2-((1R，2S，5S)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺基)-3-氧代吡咯烷-3-基)丙酸甲酯(0.50g,1.06mmol)溶於二氯甲烷(20mL)中，依次加入DIEA(0.41g,3.18mmol)和 HATU(0.60g,1.59mmol)，室溫攪拌6小時，反應完畢後加入二氯甲烷(30mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=20：1)提純得白色固體(0.48g，收率：78.0%)。 Combine (1R,2R)-2-phenylcyclopropane-1-carboxylic acid (0.17g, 1.06mmol) and (S)-2-((1R,2S,5S)-3-((S)-2-amine (3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide)-3-oxopyrrolidine-3- methyl)propionate (0.50g, 1.06mmol) was dissolved in dichloromethane (20mL), and DIEA (0.41g, 3.18mmol) and DIEA (0.41g, 3.18mmol) were added successively. HATU (0.60g, 1.59mmol) was stirred at room temperature for 6 hours. After the reaction was completed, dichloromethane (30mL) was added and washed with saturated ammonium chloride (30mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and used Purify by silica gel column chromatography (DCM: MeOH=20:1) to obtain a white solid (0.48g, yield: 78.0%).

第4步：(1R，2S，5S)-3-((R)-3,3-二甲基-2-((1R、2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-N-((S)-1-羥基-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物18-4)的製備 Step 4: (1R, 2S, 5S)-3-((R)-3,3-dimethyl-2-((1R, 2R)-2-phenylcyclopropane-1-methamide) Butyl)-N-((S)-1-hydroxy-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-aza Preparation of bicyclo[3.1.0]hexane-2-methamide (compound 18-4)

將(S)-2-((1R，2S，5S)-3-((R)-3,3-二甲基-2-(1R、2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺)(0.30g,0.52mmol)溶於四氫呋喃(10mL)中，冰浴下加入硼氫化鋰(35mg,1.55mmol)，隨後升至室溫攪拌1小時，反應完畢後加入水(20mL)，並用乙酸乙酯(30mL*2)萃取，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=20：1)提純得白色固體(0.25g，收率：87.1%)。 (S)-2-((1R,2S,5S)-3-((R)-3,3-dimethyl-2-(1R,2R)-2-phenylcyclopropane-1-carboxylic acid Amino)butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide) (0.30g, 0.52mmol) was dissolved in tetrahydrofuran (10mL), ice bath Lithium borohydride (35 mg, 1.55 mmol) was added at room temperature, then raised to room temperature and stirred for 1 hour. After the reaction was completed, water (20 mL) was added and extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate and reduced to Concentrate under pressure and purify with silica gel column chromatography (DCM: MeOH=20:1) to obtain a white solid (0.25g, yield: 87.1%).

第5步：(1R，2S，5S)-3-((R)-3,3-二甲基-2-((1R、2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-N-((S)-1-氧代-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物18)的製備 Step 5: (1R, 2S, 5S)-3-((R)-3,3-dimethyl-2-((1R, 2R)-2-phenylcyclopropane-1-methamide) Butyl)-6,6-dimethyl-N-((S)-1-oxo-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-nitrogen Preparation of heterobicyclo[3.1.0]hexane-2-methamide (compound 18)

將(1R，2S，5S)-3-((R)-3,3-二甲基-2-((1R、2R)-2-苯基環丙烷-1-甲醯胺基)丁醯基)-N-((S)-1-羥基-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(250mg,0.45mmol)溶於二氯甲烷(20mL)中，加入戴斯馬丁氧化劑(580mg,1.36mmol)，室溫攪拌3小時，反應完畢後加入飽和硫代硫酸鈉(10mL)，並用飽和碳酸氫鈉(20mL*2)洗，二氯甲烷(30mL*2)萃取，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備，SFC分離得到單一手性的白色固體(110mg，收率：44.3%)。LCMS[M+1]⁺：551.28；¹H NMR(400MHz,DMSO-d ₆)δ ppm 9.51(s,1 H),8.58(d,J=8.4Hz,1 H),8.16(d,J=8.80Hz,1 H),7.62(s,1 H),7.29(t,J=7.2Hz,2 H),7.16-7.21(m,1 H),7.10-7.14(m,2 H),4.32-4.39(m,2 H),4.26(s,1 H),3.83-3.91(m,2 H),3.13-3.21(m,1 H),3.02-3.10(m,1 H),2.40-2.50(m,1 H),2.13-2.32(m,3 H),1.82-1.92(m,1 H),1.60-1.71(m,2 H),1.51-1.57(m,1 H),1.37(d,J=7.69Hz,1 H),1.12-1.26(m,2 H),1.05(s,3 H),0.96(s,9 H),0.89(s,3 H)。 (1R,2S,5S)-3-((R)-3,3-dimethyl-2-((1R,2R)-2-phenylcyclopropane-1-formamide)butyl)- N-((S)-1-hydroxy-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1 .0] Hexane-2-formamide (250 mg, 0.45 mmol) was dissolved in dichloromethane (20 mL), Desmartin oxidant (580 mg, 1.36 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, saturated Sodium thiosulfate (10mL), washed with saturated sodium bicarbonate (20mL*2), extracted with dichloromethane (30mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and prepared using a preparation plate, and SFC separated to obtain a single Chiral white solid (110 mg, yield: 44.3%). LCMS[M+1] ⁺ : 551.28; ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.51 (s, 1 H), 8.58 (d, J = 8.4Hz, 1 H), 8.16 (d, J = 8.80Hz,1 H),7.62(s,1 H),7.29(t, J =7.2Hz,2 H),7.16-7.21(m,1 H),7.10-7.14(m,2 H),4.32- 4.39(m,2 H),4.26(s,1 H),3.83-3.91(m,2 H),3.13-3.21(m,1 H),3.02-3.10(m,1 H),2.40-2.50( m,1 H),2.13-2.32(m,3 H),1.82-1.92(m,1 H),1.60-1.71(m,2 H),1.51-1.57(m,1 H),1.37(d, J =7.69Hz,1 H),1.12-1.26(m,2 H),1.05(s,3 H),0.96(s,9 H),0.89(s,3 H).

實施例17：(1R，2S，5S)-3-((S)-3,3-二甲基-2-((1R、2R)-2-甲基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-N-((R)-1-氧代-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物19)的製備Example 17: (1R, 2S, 5S)-3-((S)-3,3-dimethyl-2-((1R, 2R)-2-methylcyclopropane-1-formamide) Butyl)-6,6-dimethyl-N-((R)-1-oxo-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-nitrogen Preparation of heterobicyclo[3.1.0]hexane-2-methamide (compound 19)

第1步：(1R，2R)-2-甲基環丙烷-1-羧酸(化合物19-2)的製備 Step 1: Preparation of: (1R, 2R)-2-methylcyclopropane-1-carboxylic acid (compound 19-2)

冰浴下，向氫化鈉(1.66g，41.38mmol)的甲苯(80ml)溶液中加入磷醯基乙酸三乙酯(10.05g，44.83mmol)並劇烈攪拌10min，隨後加入S-環氧丙烷(2.00g，34.48mmol)並升至室溫攪拌6h。隨後加入30%氫氧化鈉(30ml)並回流攪拌2h。完成後，冷卻至室溫，分液取出水相，並用HCl調節溶液pH至2-3將混合物淬滅，並用EA(100mL)萃取三次。用鹽水沖洗合併的有機層三次，並用硫酸鈉乾燥、過濾和濃縮。粗品使用矽膠柱層析(PE：EA=3：1)提純得無色油狀物(2.2g，收率：63.8%)。 Under ice bath, add triethyl phosphatide (10.05g, 44.83mmol) to a solution of sodium hydride (1.66g, 41.38mmol) in toluene (80ml) and stir vigorously for 10min, then add S-propylene oxide (2.00 g, 34.48mmol) and raised to room temperature and stirred for 6h. Then 30% sodium hydroxide (30 ml) was added and stirred under reflux for 2 h. After completion, cool to room temperature, separate the aqueous phase, adjust the pH of the solution to 2-3 with HCl, quench the mixture, and extract three times with EA (100 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel column chromatography (PE:EA=3:1) to obtain colorless oil (2.2g, yield: 63.8%).

第2步：(2S)-2-((1R，2S，5S)-3-((2S，3,3-二甲基-2-(2R)-2-甲基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物19-3)的製備 Step 2: (2S)-2-((1R,2S,5S)-3-((2S,3,3-dimethyl-2-(2R)-2-methylcyclopropane-1-methane) Preparation of amino)butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (compound 19-3)

將(1R，2R)-2-甲基環丙烷-1-羧酸(80mg,0.8mmol)和(S)-2-((1R，2S，5S)-3-((S)-2-胺基-3,3-二甲基丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺基)-3-氧代吡咯烷-3-基)丙酸甲酯(0.38g,0.8mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(0.31g,2.4mmol)和HATU(0.45g,1.2mmol)，室溫攪拌2小時，反應完畢後加入二氯甲烷(30mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=20：1)提純得白色固體(0.14g，收率：34.1%)。 Combine (1R, 2R)-2-methylcyclopropane-1-carboxylic acid (80 mg, 0.8 mmol) and (S)-2-((1R, 2S, 5S)-3-((S)-2-amine (3,3-dimethylbutyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide)-3-oxopyrrolidine-3- methyl)propionate (0.38g, 0.8mmol) was dissolved in dichloromethane (10mL), DIEA (0.31g, 2.4mmol) and HATU (0.45g, 1.2mmol) were added in sequence, stirred at room temperature for 2 hours, and reacted After completion, add dichloromethane (30mL) and wash with saturated ammonium chloride (30mL*2). The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH=20:1) to obtain white color. Solid (0.14g, yield: 34.1%).

第3步：(1R，2S，5S)-3-((2S)-3,3-二甲基-2-((2R)-2-甲基環丙烷-1-甲醯胺基)丁醯基)-N-((S)-1-羥基-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物19-4)的製備 Step 3: (1R, 2S, 5S)-3-((2S)-3,3-dimethyl-2-((2R)-2-methylcyclopropane-1-formamide)butyl) -N-((S)-1-hydroxy-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[ 3.1.0] Preparation of hexane-2-methamide (compound 19-4)

將(2S)-2-((1R，2S，5S)-3-((2S，3,3-二甲基-2-(2R)-2-甲基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(0.40g,0.77mmol)溶於四氫呋喃(10mL)中，冰浴下加入硼氫化鋰(50mg,2.31mmol)，隨後升至室溫攪拌1小時，反應完畢後加入水(20mL)，並用乙酸乙酯(30mL*2)萃取，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=20：1)提純得白色固體(0.25g，收率：65.8%)。 (2S)-2-((1R,2S,5S)-3-((2S,3,3-dimethyl-2-(2R)-2-methylcyclopropane-1-formamide) Butyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide (0.40g, 0.77mmol) was dissolved in tetrahydrofuran (10mL), and hydroboration was added under ice bath Lithium (50 mg, 2.31 mmol) was then raised to room temperature and stirred for 1 hour. After the reaction was completed, water (20 mL) was added and extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and washed with silica gel. Purify by column chromatography (DCM: MeOH=20:1) to obtain a white solid (0.25g, yield: 65.8%).

第4步：(1R，2S，5S)-3-((S)-3,3-二甲基-2-((1R、2R)-2-甲基環丙烷-1-甲醯胺基)丁醯基)-6,6-二甲基-N-((R)-1-氧代-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(化合物19)的製備 Step 4: (1R, 2S, 5S)-3-((S)-3,3-dimethyl-2-((1R, 2R)-2-methylcyclopropane-1-methamide) Butyl)-6,6-dimethyl-N-((R)-1-oxo-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-nitrogen Preparation of heterobicyclo[3.1.0]hexane-2-methamide (compound 19)

將(1R，2S，5S)-3-((2S)-3,3-二甲基-2-((2R)-2-甲基環丙烷-1-甲醯胺基)丁醯基)-N-((S)-1-羥基-3-(S)-2-氧代吡咯烷-3-基)丙-2-基)-6,6-二甲基-3-氮雜雙環[3.1.0]己烷-2-甲醯胺(250mg,0.51mmol)溶於二氯甲烷(20mL)中，加入戴斯馬丁氧化劑(DMP)(650mg,1.53mmol)，室溫攪拌3小時，反應完畢後加入飽和硫代硫酸鈉(10mL)，並用飽和碳酸氫鈉(20mL*2)洗，二氯甲烷(30mL*2)萃取，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備，SFC分離得到單一手性的白色固體(40mg，收率：16.0%)。LCMS[M+1]+：489.24；¹H NMR(400MHz,DMSO-d6) δ9.50(s,1H),8.55(d,J=8.0Hz,1H),8.00(d,J=8.0Hz,1H),7.61(s,1H),4.33-4.38(m,2H),4.23(s,1H),3.80-3.86(m,2H),3.05-3.16(m,2H),2.31-2.45(m,1H),2.13-2.20(m,1H),1.72-1.76(m,1H),1.50-1.70(m,4H),1.34(d,J=2.0Hz,1H),1.10-1.18(m,1H),0.98-1.04(m,15H),0.82(s,3H),0.82-0.85(m,1H),0.46-0.48(m,1H)。 (1R,2S,5S)-3-((2S)-3,3-dimethyl-2-((2R)-2-methylcyclopropane-1-formamide)butyl)-N- ((S)-1-Hydroxy-3-(S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] Hexane-2-formamide (250 mg, 0.51 mmol) was dissolved in dichloromethane (20 mL), Desmartin oxidant (DMP) (650 mg, 1.53 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, add Saturated sodium thiosulfate (10mL), washed with saturated sodium bicarbonate (20mL*2), extracted with dichloromethane (30mL*2), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure and prepared using a preparation plate, separated by SFC to obtain Single chiral white solid (40 mg, yield: 16.0%). LCMS[M+1]+: 489.24; ¹ H NMR(400MHz, DMSO-d6) δ9.50(s,1H),8.55(d,J=8.0Hz,1H),8.00(d,J=8.0Hz, 1H),7.61(s,1H),4.33-4.38(m,2H),4.23(s,1H),3.80-3.86(m,2H),3.05-3.16(m,2H),2.31-2.45(m, 1H),2.13-2.20(m,1H),1.72-1.76(m,1H),1.50-1.70(m,4H),1.34(d,J=2.0Hz,1H),1.10-1.18(m,1H) ,0.98-1.04(m,15H),0.82(s,3H),0.82-0.85(m,1H),0.46-0.48(m,1H).

實施例18：(1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-6,6-二甲基-n-(S)-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-氮雜二環[3.1.0]己烷-2-甲醯胺(化合物20)的製備Example 18: (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide) -3,3-dimethylbutyl)-6,6-dimethyl-n-(S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- Preparation of 2-yl)-3-azabicyclo[3.1.0]hexane-2-methamide (compound 20)

第1步：甲基(S)-2-((1R,2S,5S)-3-(S)-2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺基)-3,3-二甲基丁醇基)-6,6-二甲基-3-氮雜二環[3.1.0]己烷-2-甲醯胺基)-3-((S)-2-氧吡咯烷-3-基)丙酸酯的製備 Step 1: Methyl (S)-2-((1R,2S,5S)-3-(S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl) ring Propane-1-formamide)-3,3-dimethylbutanol)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide Preparation of )-3-((S)-2-oxopyrrolidin-3-yl)propionate

將化合物18-2(300mg,0.68mmol)和(1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-羧酸(178mg,0.68mmol)溶於二氯甲烷(10mL)中，依次加入DIEA(219mg,1.7mmol)和HATU(387mg,1.02mmol)，室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用矽膠柱層析(DCM：MeOH=10：1)提純得棕色油狀物(350mg，收率：75.1%)。 Compound 18-2 (300 mg, 0.68 mmol) and (1R, 2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid (178 mg, 0.68 mmol) were dissolved in dichloromethane ( 10mL), add DIEA (219mg, 1.7mmol) and HATU (387mg, 1.02mmol) in sequence, stir at room temperature for 3 hours, after the reaction is completed, add dichloromethane (20mL), and wash with saturated ammonium chloride (30mL*2) , organic phase Dry over anhydrous sodium sulfate, concentrate under reduced pressure and purify with silica gel column chromatography (DCM: MeOH=10:1) to obtain brown oil (350 mg, yield: 75.1%).

第2步：(1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-n-(S)-1-羥基-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-6,6-二甲基-3-氮雜二環[3.1.0]己烷-2-甲醯胺的製備 Step 2: (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide) -3,3-Dimethylbutyl)-n-(S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-methamide

將化合物20-1(350mg,0.51mmol)溶於四氫呋喃(20mL)中，然後加入硼氫化鋰(26mg,1.275mmol)，氮氣保護條件下室溫攪拌3小時，反應完畢後加入二氯甲烷(20mL)，並用飽和氯化銨(30mL*2)洗，有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備得到白色固體(146mg，收率：43%)。 Compound 20-1 (350 mg, 0.51 mmol) was dissolved in tetrahydrofuran (20 mL), then lithium borohydride (26 mg, 1.275 mmol) was added, and stirred at room temperature under nitrogen protection for 3 hours. After the reaction was completed, dichloromethane (20 mL ), and washed with saturated ammonium chloride (30mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and prepared with a preparation plate to obtain a white solid (146mg, yield: 43%).

第3步：(1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-溴-3-氟苯基)環丙烷-1-甲醯胺)-3,3-二甲基丁醯基)-6,6-二甲基-n-(S)-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙-2-基)-3-氮雜二環[3.1.0]己烷-2-甲醯胺的製備 Step 3: (1R,2S,5S)-3-((S)-2-((1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-methamide) -3,3-dimethylbutyl)-6,6-dimethyl-n-(S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- Preparation of 2-yl)-3-azabicyclo[3.1.0]hexane-2-methamide

將化合物20-2(146mg，0.22mmol)溶於DCM(15mL)中，加入戴斯馬丁試劑(186mg，0.44mmol)。反應混合物在25℃下攪拌2h。完成後，用NH₄Cl(30mL)將混合物淬滅，並用EA(20mL)萃取三次有機相經無水硫酸鈉乾燥，減壓濃縮並用製備板製備得到106mg粗品再次製備得到白色固體(34mg，收率：23%)。LCMS[M+1]⁺：582.35；¹H NMR(400MHz,DMSO-d ₆)δ ppm 9.51(s,1 H),8.56(d,J=8.0Hz,1 H),8.16(d,J=8.4Hz,1 H),7.57-7.63(m,2 H),7.17(d,J=10.4Hz,1 H),6.96(d,J=8.4Hz,1 H),4.28-4.41(m,2 H),4.26(s,1 H),3.75-3.98(m,2 H),3.00-3.24(m,2 H),2.38-2.49(m,1 H),2.26-2.33(m,2 H),2.11-2.25(m,1 H),1.78-1.96(m,1 H),1.47-1.72(m,3 H),1.37(d,J=7.51Hz,1 H),1.19-1.32(m,2 H),1.05(s,3 H),0.96(s,9 H),0.89(s,3 H) Compound 20-2 (146 mg, 0.22 mmol) was dissolved in DCM (15 mL), and Desmartin's reagent (186 mg, 0.44 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. After completion, the mixture was quenched with NH ₄ Cl (30 mL) and extracted three times with EA (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and prepared with a preparation plate to obtain 106 mg of crude product. A white solid (34 mg, yield :twenty three%). LCMS[M+1] ⁺ : 582.35; ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.51 (s, 1 H), 8.56 (d, J =8.0Hz, 1 H), 8.16 (d, J = 8.4Hz,1 H),7.57-7.63(m,2 H),7.17(d, J =10.4Hz,1 H),6.96(d, J =8.4Hz,1 H),4.28-4.41(m,2 H),4.26(s,1 H),3.75-3.98(m,2 H),3.00-3.24(m,2 H),2.38-2.49(m,1 H),2.26-2.33(m,2 H) ,2.11-2.25(m,1 H),1.78-1.96(m,1 H),1.47-1.72(m,3 H),1.37(d, J =7.51Hz,1 H),1.19-1.32(m, 2 H),1.05(s,3 H),0.96(s,9 H),0.89(s,3 H)

實施例19：SARS-CoV-2 3CL酶抑制實驗Example 19: SARS-CoV-2 3CL enzyme inhibition experiment

1.試劑和耗材 1. Reagents and consumables

2.實驗步驟 2. Experimental steps

1)配置2×buffer：40mM Tris-HCl(PH：7.4),200mM NaCl,2mM EDTA,10mM TCEP。 1) Configure 2×buffer: 40mM Tris-HCl (PH: 7.4), 200mM NaCl, 2mM EDTA, 10mM TCEP.

2)化合物稀釋，將化合物稀釋至20μM，2倍稀釋，8個梯度。 2) Compound dilution, dilute the compound to 20 μM, 2-fold dilution, 8 gradients.

3)在96孔黑板配置反應體系： 3) Configure the reaction system on the 96-well black plate:

2×buffer：50μL 2×buffer: 50μL

5% BSA：2μL 5% BSA: 2μL

3CL Protease：0.2μL(終濃度15nM) 3CL Protease: 0.2μL (final concentration 15nM)

H₂O：32.8μL H ₂ O: 32.8 μL

待測化合物：5μL Compound to be tested: 5μL

同時設置不加3CL protease的空白對照與不加化合物的100%酶活對照，37℃孵育1h。 At the same time, set up a blank control without adding 3CL protease and a 100% enzyme activity control without adding compounds, and incubate at 37°C for 1 hour.

4)加入10μL底物(終濃度為25μM)，置於37℃孵育30min， 4) Add 10 μL of substrate (final concentration is 25 μM), and incubate at 37°C for 30 minutes.

5)酶標儀檢測螢光強度：激發光波長340nm，發射光波長為490nm。 5) Microplate reader detects fluorescence intensity: the excitation light wavelength is 340nm and the emission light wavelength is 490nm.

3.計算 3. Calculation

抑制率：(RFU_{100%酶活性對照}-RFU_樣品)/(RFU_{100%酶活性對照}-RFU_空白對照)×100% Inhibition rate: (RFU _{100% enzyme activity control} -RFU _sample )/(RFU _{100% enzyme activity control} -RFU _{blank control} )×100%

將所計算的抑制率，用GraphPad Prism 8軟體Nonlinear regression(curve fit)函數中的log(inhibitor)vs.response-Variable slope(four parameters)擬合抑制曲線，計算IC₅₀值。 Use the calculated inhibition rate to fit the inhibition curve using log (inhibitor) vs. response-Variable slope (four parameters) in the Nonlinear regression (curve fit) function of GraphPad Prism 8 software to calculate the IC ₅₀ value.

4.實驗資料： 4.Experimental data:

5.結論： 5. Conclusion:

列表中的化合物均體現了很好的SARS-CoV-2 3CL酶抑制活性，均在nM級別。其中，化合物3、4、14、16、18活性較PF-07321332更優；化合物7、8、9、17和19與PF-07321332的酶抑制活性相當。 The compounds in the list all demonstrate good SARS-CoV-2 3CL enzyme inhibitory activity, all at the nM level. Among them, compounds 3, 4, 14, 16, and 18 have better activity than PF-07321332; compounds 7, 8, 9, 17, and 19 have equivalent enzyme inhibitory activities to PF-07321332.

實施例20：抗COV-OC43病毒的細胞活性檢測Example 20: Cell activity detection against COV-OC43 virus

冠狀病毒OC43(coronavirus OC43，CoV-OC43)與SARS-CoV-2(severe acute respiratory syndrome coronavirus 2)同屬於β冠狀病毒屬。本實驗通過測試化合物在細胞水準下抗OC43病毒的能力，評估化合物的抗病毒活性。 Coronavirus OC43 (CoV-OC43) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) belong to the genus βcoronavirus. This experiment evaluates the antiviral activity of compounds by testing their ability to resist OC43 virus at the cellular level.

1.實驗材料 1. Experimental materials

2.實驗步驟 2. Experimental steps

1)將MRC-5細胞消化，用含2% FBS，1% P/S的DME培養基稀釋為2×10⁵/mL，每孔50μL接種于96孔板中，置於培養箱過夜培養。 1) Digest MRC-5 cells, dilute them to 2×10 ⁵ /mL with DME medium containing 2% FBS and 1% P/S, inoculate 50 μL per well into a 96-well plate, and place them in an incubator for overnight culture.

2)首先將化合物稀釋至20μM，然後從20μM進行三倍稀釋，共8個稀釋度。每孔加入5μL稀釋好的化合物，置於培養箱1h。 2) First dilute the compound to 20 μM, then make three-fold dilutions from 20 μM, for a total of 8 dilutions. Add 5 μL of diluted compound to each well and place in the incubator for 1 h.

3)用含2% FBS，1% P/S的DMEM培養基稀釋OC43病毒至22222pfu/mL，每孔加入病毒45μL。同時設置不加化合物的病毒對照和不加化合物、病毒的細胞對照。置於培養箱培養4d。 3) Dilute the OC43 virus to 22222pfu/mL with DMEM medium containing 2% FBS and 1% P/S, and add 45 μL of virus to each well. At the same time, set up a virus control without compound and a cell control without compound or virus. Place in the incubator for 4 days.

4)每孔加入50μL的Cell-titer Glo，用酶標儀檢測化學發光。 4) Add 50 μL of Cell-titer Glo to each well, and detect chemiluminescence with a microplate reader.

3.資料處理 3.Data processing

首先計算化合物的病毒抑制率。抑制率=(所測樣品數值-病毒對照組平均值)/(細胞對照組平均值-病毒對照組平均值)。 First calculate the virus inhibition rate of the compound. Inhibition rate = (measured sample value - average value of virus control group) / (average value of cell control group - average value of virus control group).

將所計算的抑制率，用GraphPad Prism 8軟體Nonlinear regression(curve fit)函數中的log(inhibitor)vs.response--Variable slope(four parameters)擬合抑制曲線，計算EC₅₀值。 Use the calculated inhibition rate to fit the inhibition curve using log(inhibitor) vs. response--Variable slope (four parameters) in the Nonlinear regression (curve fit) function of GraphPad Prism 8 software to calculate the EC ₅₀ value.

4.結果匯總 4. Summary of results

5.結論 5.Conclusion

列表中的化合物均在MRC-5細胞中體現了優異的抗OC43冠狀病毒的活性，化合物活性均在nM級別。其中化合物3、10、14、16、和17均比參照陽性分子PF-07321332具有更優異的抗病毒活性。 The compounds in the list all show excellent anti-OC43 coronavirus activity in MRC-5 cells, and the compound activities are all at the nM level. Among them, compounds 3, 10, 14, 16, and 17 all have better antiviral activity than the reference positive molecule PF-07321332.

實施例21：化合物在小鼠中藥代動力學評估Example 21: Evaluation of compound pharmacokinetics in mice

1.小鼠信息：從浙江VT-River公司採購ICR(CD-1)雌性小鼠，體重在20-30g之間。 1. Mouse information: Purchase ICR (CD-1) female mice from Zhejiang VT-River Company, weighing between 20-30g.

2.待測化合物配置：2. Configuration of compounds to be tested:

(1)將已知量的測試品稱重到一個4毫升的玻璃瓶中。 (1) Weigh a known amount of test product into a 4 ml glass bottle.

(2)加入0.126mL cremoror RH40，漩渦聲清溶液。 (2) Add 0.126mL cremoror RH40 and vortex to clear the solution.

(3)加入0.503mL PEG400，渦旋聲清溶液。 (3) Add 0.503mL PEG400 and vortex to clear the solution.

(4)加入0.629mL H2O，漩渦聲清溶液。 (4) Add 0.629mL H2O and vortex to clear the solution.

(5)將劑量製劑50μL移至20mL玻璃瓶中，加入10mL甲醇驗證濃度。 (5) Transfer 50 μL of dosage preparation into a 20 mL glass bottle, and add 10 mL of methanol to verify the concentration.

(6)配置1.00mg/mL濃度的待測化合物溶液，溶媒為10% Cremorphor RH40+40% PEG400+50% H₂O。 (6) Prepare a solution of the compound to be tested with a concentration of 1.00 mg/mL. The solvent is 10% Cremorphor RH40+40% PEG400+50% H ₂ O.

3.給藥和測試3. Administration and Testing

1)每個測試化合物PO給藥3只小鼠，按照0.083、0.25、0.5、1、2、4和8h取血測試。 1) Each test compound was PO administered to 3 mice, and blood was collected for testing at 0.083, 0.25, 0.5, 1, 2, 4 and 8 hours.

2)測試化合物按照10mg/kg給藥。 2) The test compound is administered at 10 mg/kg.

3)測試儀器資訊 3)Testing instrument information

LC/MS/MS Instrumentation Type：AB Sciex API 5000+； LC/MS/MS Instrumentation Type: AB Sciex API 5000+;

HPLC Pump：Shimadzu LC-30AD；Kinetex 2.6μm C18 100A column(50mm * 2.1mm)； HPLC Pump: Shimadzu LC-30AD; Kinetex 2.6μm C18 100A column (50mm * 2.1mm);

流動相：流動相A：W水(0.1% FA)，流動相B：乙腈(0.1% FA)； Mobile phase: mobile phase A: water (0.1% FA), mobile phase B: acetonitrile (0.1% FA);

進樣體積：3μL； Injection volume: 3μL;

HPLC梯度設定： HPLC gradient settings:

4)待測樣品處理： 4) Processing of samples to be tested:

每只小鼠每次取10μL血液，K2EDTA作為抗凝劑；所有樣品中加入2μL的甲醇，加入200μL乙腈含有100ng/mL IS(Tolbutamide)，渦旋1分鐘，4000轉/分離心15分鐘。取上清液。按照上述的測試資訊進行樣品測試。 10 μL of blood was taken from each mouse, and K2EDTA was used as the anticoagulant; 2 μL of methanol was added to all samples, and 200 μL of acetonitrile containing 100ng/mL IS (Tolbutamide) was added, vortexed for 1 minute, and centrifuged at 4000 rpm for 15 minutes. Take the supernatant. Carry out sample testing according to the above test information.

陽性分子PF-07321332(CAS：2628280-40-8)購自上海興默(批號：XM211031-1)。 The positive molecule PF-07321332 (CAS: 2628280-40-8) was purchased from Shanghai Xingmo (batch number: XM211031-1).

4.結果匯總4. Summary of results

測試化合物在血漿中的藥物濃度如下： The drug concentrations of test compounds in plasma are as follows:

從上述的小鼠PK測試中可以看出，與陽性化合物PF-07321332相比，化合物3具有更高的血漿暴露量，血漿中的藥物濃度在0.25h後優勢突出。化合物3更好的藥代動力學表現，預示著更好的體內藥效表現。 It can be seen from the above mouse PK test that compared with the positive compound PF-07321332, compound 3 has a higher plasma exposure, and the drug concentration in the plasma has a prominent advantage after 0.25h. The better pharmacokinetic performance of compound 3 indicates better in vivo pharmacodynamic performance.

應當理解，以上實施例均為示例性的，不用於包含權利要求所包含的所有可能的實施方式。在不脫離本公開的範圍的情況下，還可以在以上實施例的基礎上做出各種變形和改變。同樣的，也可以對以上實施例的各個技術特徵進行任意組合，以形成可能沒有被明確描述的本發明的另外的實施例。因此，上述實施例僅表達了本發明的幾種實施方式，不對本發明專利的保護範圍進行限制。 It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes can also be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, various technical features of the above embodiments may also be combined arbitrarily to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementation modes of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims

A compound represented by formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt:

in,

m, n are each independently any integer from 0 to 4;

Each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted or C _1-6 alkyl, C _3-7 substituted by a substituent selected from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy Cycloalkyl and 3-7-membered heterocycloalkyl; or two R ¹ and the carbon atoms they are connected to form C _3-6 cycloalkyl or 3-7-membered heterocycloalkyl;

Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted Or C _1-6 alkyl, C _3- substituted by a group consisting of a substituent selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy _7- membered cycloalkyl and 3-7-membered heterocycloalkyl; or two R ² and the carbon atoms connected thereto form a C _3-6- membered cycloalkyl or 3-7-membered heterocycloalkyl;

R ³ is selected from the group consisting of cyano group, aldehyde group, -(CO)CH ₃ and -(CO)CF ₃ ;

Each R ⁴ is independently selected from hydrogen, deuterium, unsubstituted or selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl substituted by the group consisting of aryl and 5-10 membered heteroaryl substituents;

R ⁵ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

Or any R ⁴ and R ⁵ and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, and the substitution is by 1-4 systems selected from hydrogen, deuterium, cyano, halogen, A group substitution consisting of substituents of trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl; Or the substituent of the 5-7 membered ring forms a combined ring with the 5-7 membered ring;

R ⁶ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

Or any R ⁴ and R ⁶ and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, and the substitution is made by 1-4 systems selected from hydrogen, deuterium, cyano, halogen, A group substitution consisting of substituents of trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl; Or the two substituents of the 5-7 membered ring are formed by hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 with the same carbon atom or two adjacent carbon atoms. C _3-7 cycloalkyl substituted by a deuterated alkyl substituent;

R ⁷ is selected from hydrogen, deuterium, substituted or unsubstituted C _1-6 alkyl, aryl-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 6} alkyl, 3-7 membered heterocycloalkyl, C _3-7 membered heterocycloalkyl-C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl and benzo C _5- A group consisting of ₇ cycloalkyl groups, the substitution is 1-4 selected from cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, -C(=O)NH _2. Composed of -SO ₂ NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl substituents optionally, the C _6-10 aryl group and the 5-10 membered heteroaryl group are composed of substituents selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy groups. group, the -C(=O)NH ₂ and -SO ₂ NH ₂ can be substituted by 1-2 C _1-6 alkyl groups;

R ⁸ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl;

Or R ⁷ and R ⁸ and their attached C atoms and N atoms form unsubstituted or selected from hydrogen, deuterium, cyano, amine, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 A 5-7 membered ring substituted by a group consisting of alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl substituents;

R ⁹ is selected from substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _1-6 alkylamino, C _1-6 alkoxy , C _3-7 cycloalkoxy group, C _3-7 cycloalkylamino group, 3-7 membered heterocycloalkoxy group, C _3-7 membered heterocycloalkylamino group, C _6-10 aryl group, C _6-10 aryloxy group, 5-10 membered heteroaryl group, 6-14 membered spiroheterocyclyl group, 5-11 membered bridged heterocyclyl group, -NH-C(O)-C _1-6 alkyl group, - A group consisting of NH-C(O)-NH-C _1-6 alkyl and 4-11 membered fused heterocyclic groups, the substitution is 1-4 selected from deuterium, cyano group, and amino group , hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, 1-4 selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C The substituted or unsubstituted C _1-6 alkyl group consisting of the substituents of 1-6 alkyl and C _6-10 aryl groups _is selected from hydrogen, deuterium, cyano, and amine by 1-4 A substituted or unsubstituted C _3-7 ring consisting of a group of substituents such as hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl. Alkyl, 1-4 selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl The group of substituents is a substituted or unsubstituted C _6-10 aryl group and 1-4 groups selected from the group consisting of hydrogen, deuterium, cyano, amine, hydroxy, halogen, trifluoromethyl, trifluoro Substituted by the group consisting of methoxy, C _1-6 alkyl and C _6-10 aryl substituents or unsubstituted 5-10 membered heteroaryl substituents; or R ⁷ and R ⁹ and its connected carbon atoms form a substituted or unsubstituted 5-8 membered ring, the substitution is made by 1-4 selected from cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy group, substituted by 1-4 groups selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl The group consisting of a substituted or unsubstituted C _1-6 alkyl group and 1-4 groups selected from hydrogen, deuterium, cyano, amino, hydroxyl, halogen, trifluoromethyl, trifluoromethyl substituted by a group consisting of an oxygen group, a C _1-6 alkyl group and a C _6-10 aryl substituent or a group consisting of an unsubstituted C _6-10 aryl substituent.

A compound represented by Formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts according to claim 1, characterized by: It has the structure of formula I-1,

in,

m, n are each independently any integer from 0 to 4;

Each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted Or C _1-6 alkyl, C _3- substituted by a group consisting of a substituent selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy _7- membered cycloalkyl and 3-7-membered heterocycloalkyl; or two R ¹ and the carbon atoms connected thereto form a C _3-6- membered cycloalkyl or 3-7-membered heterocycloalkyl;

Or any R ⁴ and R ⁵ and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, and the substitution is made by 1-4 systems selected from hydrogen, deuterium, cyano, halogen, Group substitution consisting of trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 yuan heteroaryl substituents, Or the substituent of the 5-7 membered ring forms a combined ring with the 5-7 membered ring;

Or any R ⁴ and R ⁶ and their connected C atoms and N atoms form a substituted or unsubstituted 5-7 membered ring, and the substitution is made by 1-4 systems selected from hydrogen, deuterium, cyano, halogen, Substituted by the group consisting of trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl and 5-10 membered heteroaryl substituents ; Or the two substituents of the 5-7 membered ring are formed with the same carbon atom or two adjacent carbon atoms by hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy and C _1- C _3-7 cycloalkyl substituted by the deuterated alkyl substituent of ₆ ;

R ⁷ is selected from hydrogen, deuterium, substituted or unsubstituted C _1-6 alkyl, aryl-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _{1- 6} alkyl, 3-7 membered heterocycloalkyl, C _3-7 membered heterocycloalkyl-C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl and benzo C _5- A group consisting of ₇ cycloalkyl groups, the substitution is 1-4 selected from cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, -C(=O)NH _2. Composed of -SO ₂ NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _6-10 aryl and 5-10 membered heteroaryl substituents substituted by the group, optionally, the C _6-10 aryl group and the 5-10 membered heteroaryl group are substituted by a substituent selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy groups, The -C(=O)NH ₂ and -SO ₂ NH ₂ can be substituted by 1-2 C _1-6 alkyl groups;

R ⁸ is selected from the group consisting of hydrogen, deuterium, and C _1-6 alkyl;

Ring A and Ring B are each independently selected from substituted or unsubstituted C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 6- A group consisting of 14-membered spiroheterocyclyl, 5-11-membered bridged heterocyclyl and 4-11-membered fused heterocyclyl; the substitution is selected from deuterium, cyano group, amine group, Substituted by the group consisting of hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl substituents.

A compound represented by formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt according to claim 1 or 2, which The characteristic is that R ³ is selected from the group consisting of cyano group, aldehyde group, -(CO)CH ₃ and -(CO)CF ₃ ; preferably cyano group and -(CO)CH ₃ ; more preferably cyano group base.

A compound represented by formula I according to any one of claims 1-3 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that any R ⁴ and R ⁶ and the connected C atoms and N atoms form a substituted or unsubstituted 5-6 membered ring; preferably a substituted or unsubstituted pyrrolidinyl and pyridyl group ; The substitution is by 1-4 systems selected from hydrogen, deuterium, cyano, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, C ₆ -The group consisting of ₁₀ aryl and 5-10 membered heteroaryl; preferably halogen, trifluoromethyl and C _1-6 alkyl, more preferably fluorine, chlorine, bromine, trifluoromethyl, methyl , ethyl, n-propyl and isopropyl substituents; or the two substituents of the 5-6 membered ring are formed with the same carbon atom or two adjacent carbon atoms and are formed by hydrogen, deuterium, C ₁ -C _3-7 cycloalkyl substituted by substituents of _-6 alkyl, C _1-6 alkoxy and C _1-6 deuterated alkyl; preferably C _3-5 cycloalkyl; more preferably cycloalkyl Propyl and cyclobutyl.

A compound represented by formula I according to any one of claims 1-4 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that m is any integer from 0 to 3; preferably, it is any integer from 0-2; more preferably, it is any integer from 0-1; most preferably, it is 0;

n is any integer from 0 to 3; preferably, it is any integer from 0-2; more preferably, it is any integer from 0-1; most preferably, it is 1.

A compound represented by formula I according to any one of claims 1-5 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable A salt characterized by having a structure of formula I-2,

in,

Ring A and Ring B are each independently selected from substituted or unsubstituted C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 6- A group consisting of 14-membered spiroheterocyclyl, 5-11-membered bridged heterocyclyl and 4-11-membered fused heterocyclyl; the substitution is 1-4 selected from hydrogen, deuterium, cyano, amine Substituted by the group consisting of substituents such as hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl.

A compound represented by formula I according to any one of claims 1-6 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable A salt characterized by having a structure of formula I-2-1,

in,

Each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted Or C _1-6 alkyl, C _3- substituted by a group consisting of a substituent selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy _7- cycloalkyl and 3-7-membered heterocycloalkyl, or two R ¹ and the carbon atoms connected thereto form C _3-6 cycloalkyl or 3-7-membered heterocycloalkyl;

A compound represented by formula I according to any one of claims 2-7 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that the ring A is selected from the group consisting of substituted or unsubstituted C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; preferably substituted or unsubstituted C _{3- 5-} cycloalkyl and 3-5-membered heterocycloalkyl; more preferably substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydropyranyl, piridinyl, pyridinyl and morpholinyl; the substitution is by 1-4 systems selected from deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C ₆ The group consisting of _-10 aryl groups is preferably halogen, trifluoromethyl and C _1-6 alkyl, more preferably fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, n-propyl and Substituted with isopropyl substituent.

A compound represented by formula I according to any one of claims 1-8 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable A salt characterized by having a structure of formula I-3,

in,

Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted Or C _1-6 alkyl, C _3- substituted by a group consisting of a substituent selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy _7- cycloalkyl and 3-7-membered heterocycloalkyl or two R ² and the carbon atoms connected thereto form C _3-6 -cycloalkyl or 3-7-membered heterocycloalkyl;

R ¹⁰ , R ¹¹ , each R ¹² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 The group consisting of alkoxy, substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is selected from one or more systems Substituted from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy substituents;

Ring B is selected from substituted or unsubstituted C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 6-14 membered spiroheterocyclyl , a group consisting of 5-11-membered bridged heterocyclyl and 4-11-membered fused heterocyclyl; the substitution is by 1-4 selected from hydrogen, deuterium, cyano, amine, hydroxyl, halogen, Substituted from the group consisting of trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl substituents.

A compound represented by formula I according to any one of claims 1-9 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable A salt characterized by having a structure of formula I-3-1,

in,

Each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, and unsubstituted Or C 1-6 alkyl, C _3-7 cycloalkyl and C _{1-6 alkyl substituted by a substituent selected from cyano, amine, hydroxyl, halogen, C 1-6} _alkyl and C _1-6 alkoxy. 3-7 membered heterocycloalkyl; or two R ² and the carbon atoms connected thereto form a C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

R ¹⁰ , R ¹¹ , each R ¹² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 Alkoxy, a group consisting of substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is selected from one or more systems Substituted from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy substituents;

A compound represented by formula I according to any one of claims 2-10 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that the ring B is selected from the group consisting of substituted or unsubstituted C _6-10 aryl and 5-10 membered heteroaryl; preferably a substituted or unsubstituted C _6-10 aryl base and a 5-10 membered heteroaryl group, the heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from the group consisting of N, O and S; more preferably substituted or unsubstituted benzene base, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl; the substitution is by 1-4 systems Selected from the group consisting of deuterium, cyano, amine, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl and C _6-10 aryl, preferably halogen, trifluoro Methyl and C _1-6 alkyl are more preferably substituted by fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl substituents.

A compound represented by formula I according to any one of claims 1-11 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable A salt characterized by having a structure of formula I-4,

in,

R ¹⁰ , R ¹¹ , each R ¹² and R ^12' are independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, a group consisting of substituted or unsubstituted C _1-6 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by 1 or A plurality of systems are substituted by a group consisting of substituents selected from cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy;

R ¹³ is selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, substituted or unsubstituted C _1-6 alkyl group, C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by one or more systems selected from cyano, amino, hydroxyl, halogen, C _1-6 alkyl and C ₁ Substituted by a group consisting of _-6 alkoxy substituents;

q is any integer from 0 to 4, preferably any integer from 0 to 3, more preferably any integer from 0 to 2, and most preferably 1 or 2.

A compound represented by formula I according to any one of claims 1-12 or a compound thereof Isomers, solvates, hydrates, prodrugs, stable isotope derivatives, conjugates and pharmaceutically acceptable salts, characterized by having a structure of formula I-4-1,

in,

R ¹³ is selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, -NO ₂ , C _1-6 alkylamino, C _1-6 alkoxy, substituted or unsubstituted C _1-6 alkyl The group consisting of C _3-7 cycloalkyl and 3-7 membered heterocycloalkyl; the substitution is by one or more systems selected from cyano, amino, hydroxyl, halogen, C _1-6 Substituted by a group consisting of alkyl and C _1-6 alkoxy substituents;

A compound represented by formula I according to any one of claims 1-13 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that each R ¹ is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C ₁ The group consisting of _-6 alkoxy and C _1-6 alkyl; preferably hydrogen, deuterium, halogen and C _1-6 alkyl; more preferably hydrogen, halogen and C _1-3 alkyl; most preferably Hydrogen.

A compound represented by formula I according to any one of claims 1-14 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that each R ² is independently selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, =O, -NO ₂ , C _1-6 alkylamino, C ₁ The group consisting of _-6 alkoxy and C _1-6 alkyl; preferably hydrogen, deuterium, halogen and C _1-6 alkyl; more preferably hydrogen, halogen and C _1-3 alkyl; most preferably Hydrogen.

A compound represented by formula I according to any one of claims 1-15 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that R ⁵ is selected from the group consisting of hydrogen and C _1-3 alkyl; preferably hydrogen.

A compound represented by formula I according to any one of claims 1-16 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that R ⁷ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl; preferably hydrogen and C _1-3 alkyl; more preferably hydrogen.

A compound represented by formula I according to any one of claims 1-17 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that R ⁸ is selected from the group consisting of hydrogen and C _1-3 alkyl; preferably hydrogen.

A compound represented by formula I according to any one of claims 9-18 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that R ¹⁰ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl; preferably hydrogen and C _1-3 alkyl; more preferably hydrogen and methyl.

A compound represented by formula I according to any one of claims 9-19 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that R ¹¹ is selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl; preferably hydrogen and C _1-3 alkyl; more preferably hydrogen and methyl.

A compound represented by formula I according to any one of claims 9-20 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that each R ¹² and/or R ^12' is independently selected from the group consisting of hydrogen, deuterium and C _1-6 alkyl; preferably hydrogen and C _1-3 alkyl ; More preferably hydrogen and methyl.

A compound represented by formula I according to any one of claims 12-20 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable The salt is characterized in that R ¹³ is selected from hydrogen, deuterium, cyano, halogen, amine, hydroxyl, -NO ₂ , C _1-3 alkylamino, C _1-3 alkoxy, substituted or Unsubstituted C _1-3 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl; preferably selected from hydrogen, halogen, amino, hydroxyl, -NO ₂ and substituted or unsubstituted C The group consisting of _1-3 alkyl; more preferably selected from hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted methyl, ethyl, n-propyl and isopropyl; the substitution is by one or Multiple systems are selected from the group consisting of cyano, amine, hydroxyl, halogen, C _1-6 alkyl and C _1-6 alkoxy, preferably selected from the group consisting of halogen, C _1-3 alkyl and C ₁ The group consisting of _-3 alkoxy groups is more preferably substituted by a group consisting of substituents selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl and isopropyl.

A compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt, characterized in that the compound is any one of the following:

A pharmaceutical composition comprising the compound described in any one of claims 1-24 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable of salt.

The compound described in any one of claims 1-24 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, conjugate and pharmaceutically acceptable salt, or claim 25 The pharmaceutical composition is used in any one or more of the following uses:

(1) Inhibit 3C-like protease activity;

(2) Inhibit virus replication activity, preferably inhibit coronavirus activity, particularly preferably inhibit SARS-CoV-2 virus activity;

(3) Treat COVID-19; and/or

(4) Preparation of medicines with uses (1), (2) and/or (3).

A method for inhibiting viral replication activity, comprising administering to a subject a therapeutically effective amount of the compound described in any one of claims 1-24 or its stereoisomer, solvate, hydrate, prodrug, or stable isotope Derivatives, conjugates and pharmaceutically acceptable salts, and/or the pharmaceutical composition described in claim 25.

The method for inhibiting viral replication activity as described in claim 27, wherein the virus is a coronavirus, preferably SARS-CoV-2.