Spirooxindole compounds and their use for the preparation of antiviral protease inhibitor drugs

Abstract

Provided is a compound represented by general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, and use thereof for preparing an antiviral protease inhibitor drug.

Description

Technical Field

[0001] This application belongs to the field of chemical pharmaceuticals, specifically relating to a class of spirocyclic indole compounds and their use in the preparation of antiviral protease inhibitor drugs. Background Technology

[0002] Viruses have consistently played a significant role in the development of infectious diseases throughout human evolution. Lacking cellular form and with relatively simple structures, they cannot function independently and must rely on infected host cells for survival and reproduction. To ensure their survival and propagation, viruses must invade host cells, and through natural selection, they have acquired unique abilities to attack host cells. Influenza, a highly contagious and rapidly spreading disease, has always been a major concern, posing a significant threat to human health and daily life worldwide. Similarly, during peak viral seasons, enteroviruses causing hand-foot-and-mouth disease and acute gastroenteritis are infectious diseases that require vigilance in daily life. Furthermore, the continued global prevalence of HIV and HCV also poses a substantial threat to human health and well-being.

[0003] In recent years, the challenges posed by coronaviruses to human health and safety have received considerable attention. For example, upper respiratory tract infections caused by HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 rank second among the causes of the common cold each year. In particular, the outbreaks of severe acute respiratory syndromes (SARS, 2003), Middle East respiratory syndrome (MERS, 2012), and the ongoing and severe impact of COVID-19 on human health, life, production, and the economy over the past two decades have been significant.

[0004] The clinical symptoms of coronaviruses are diverse. Taking COVID-19 as an example, early-stage infections mainly present with fever, fatigue, and dry cough; severe infections can lead to respiratory distress, an excessive immune response, and a cytokine storm, causing multiple organ failure and threatening human life. Furthermore, coronaviruses can spread through various routes, including direct transmission, aerosols, and contact, posing a risk of human-to-human and community transmission. Human understanding of coronaviruses dates back to the last century. As early as 1965, the first human coronavirus was isolated, and its crown-like structure, observed under an electron microscope, led to its name. The novel coronavirus (SARS-CoV-2) belongs to the Coronaviridae family, and its structure consists of positive-sense single-stranded RNA and a capsid protein surrounding the genetic material. The infection and replication of SARS-CoV-2 mainly involves the recognition and binding of the spike glycoprotein on the envelope to the receptor angiotensin-converting enzyme 2 (ACE2) located on the surface of the host cell. Under the cleavage action of the host cell's TMPRSS2 protein and cathepsins, the viral particle envelope fuses with the host cell membrane, and subsequently, the viral genomic RNA enters the host cell. The positive-sense single-stranded RNA uses itself as a template, with the help of host cell protein synthesis elements, to guide the synthesis of virus-related proteins. Among them, the polyprotein encoded by the Open Reading Frame 1 ab (ORF1ab) gene plays an important role in the replication and assembly of SARS-CoV-2. This polyprotein can be converted into two types of cysteine ​​proteases: papain-like protease (PL). pro ) and 3-chymotrypsin-like protease (3CL) pro Or M pro Under the action of [unclear - possibly a specific protein or process], SARS-CoV-2 RNA undergoes site-specific cleavage, producing several non-structural functional proteins crucial to its life cycle, including RNA-dependent RNA polymerase (RdRp), a protein required for viral replication. Under the action of these cleaved non-structural functional proteins, SARS-CoV-2 RNA begins to replicate in the host cell, simultaneously translating its necessary structural proteins, such as spike proteins, membrane proteins, nucleocapsid proteins, and envelope proteins. Furthermore, all the components required to constitute the virus begin to assemble, releasing progeny viruses from the host cell, completing the viral infection cycle.

[0005] 3CL proThe protease, encoded by the ORF1ab gene and translated, is the fifth non-structural functional protein located on the polysome. It cleaves at 11 different sites on the polysome via glutamine (Gln) at the P1 site. As mentioned above, these non-structural functional proteins play an indispensable role in the viral life cycle; therefore, inhibiting 3CL... pro The activity of proteases can effectively inhibit viral replication. Based on this unique mechanism of action, 3CL pro The inhibitory ability of highly efficient and specific protease inhibitors against viral replication is not affected by the various spike protein mutations that evolve during viral transmission. Furthermore, no cysteine ​​protease recognizing Gln has been found in the human body to date. Therefore, 3CL... pro Using targets as an entry point for antiviral drug development offers greater safety.

[0006] The COVID-19 pandemic continues to spread globally, and countries around the world have implemented a series of policies to control the epidemic, improve hygiene standards, and increase investment in research and development of SARS-CoV-2. Significant breakthroughs have been made in the development of vaccines for the novel coronavirus, with various domestic and international vaccines, including traditional inactivated vaccines, novel mRNA vaccines, adenovirus vaccines, and recombinant antigen protein vaccines, receiving approval or emergency use authorization from regulatory agencies in various countries, becoming powerful weapons to block the spread of the novel coronavirus. However, the development of anti-COVID-19 drugs faces various challenges, with progress lagging far behind urgent clinical needs. For example, Remdesivir, which received widespread attention and high hopes at the beginning of the COVID-19 outbreak and was granted emergency use authorization, was found to have unsatisfactory treatment effects in subsequent large-scale clinical trials. AT-527, jointly developed by Roche and Atea, also failed in Phase II clinical trials. Currently, only a handful of small molecule drugs have been reported to have relatively ideal clinical efficacy against the novel coronavirus, such as Molnupiravir, developed by Merck / Ridgeback targeting RdRp, and Pfizer's 3CL-targeting drug. pro Paxlovid is a representative example of a protease.

[0007] The novel coronavirus has caused severe damage and threat to human production, life, and even lives. Therefore, there is an urgent need to develop a series of anti-novel coronavirus drugs with good safety and high efficacy. Compared with large-molecule neutralizing antibody drugs, oral small-molecule drugs have advantages such as low production cost, easy transportation and storage, high drug accessibility, and strong patient compliance. Developing small-molecule drugs for the novel coronavirus is crucial for controlling viral transmission, reducing infection and pathogenicity, and ultimately alleviating and eliminating this global public health crisis. Especially important are 3CL drugs. proThe development of inhibitors targeting specific targets aims to fill the significant gap in the fight against the novel coronavirus, promote public health, improve quality of life, and foster social harmony and progress. Summary of the Invention

[0008] This application discloses a class of spirocyclic indole compounds and their use in the preparation of antiviral protease inhibitor drugs.

[0009] In a first aspect, this application discloses a compound represented by the following general formula (I):

[0010]

[0011] (I)

[0012] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof; wherein:

[0013] Ring A is a cycloalkyl, heterocyclic, aryl, or heteroaryl group containing 0-3 heteroatoms or 5-6 ring atoms;

[0014] X is selected from O or NH;

[0015] R1 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -C(O) C(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0016] R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b-C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0017] R2 and R2' can form 3-6 membered cycloalkyl or heterocyclic groups together with the carbon atom they are attached to;

[0018] R2 can be connected to R6 and together with the atoms they are connected to, form a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is optionally surrounded by 1-3 R atoms. a replace;

[0019] R3 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a , , Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0020] R4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0021] Two R4 atoms can be linked together with the ring atoms attached to them to form 3-6 membered cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0022] R5 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0023] R1 and R5 can be linked together with the ring atoms they are attached to to form 3-6 membered cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0024] Two R5 atoms can be linked together with the ring atoms attached to them to form 3-6 membered cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0025] R6 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0026] R7 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0027] Two R7s can be linked together with the ring atoms they are attached to to form 3-6 membered cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0028] R8 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0029] Each R a R b Each group is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, carbonyl, hydroxyl, cyano, nitro, benzyl, and -C(O)NR. c R d -C(O)R c -C(O)OR c -OR c -OC(O)R c -OC(O)OR c -OC(O)NR c R d -NR c R d -SR c -S(O)R c -S(O)2R c Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or benzyl group may optionally be surrounded by 1-3 R groups. c replace;

[0030] Each R c R d Each group is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halogenated C1-C6 alkyl, alkoxy, halogenated alkoxy, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl; and

[0031] Each n is independently selected from 0, 1, 2, or 3.

[0032] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (Ia):

[0033]

[0034] (Ia)

[0035] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof; wherein:

[0036] Ring A is a cycloalkyl, heterocyclic, aryl, or heteroaryl group containing 0-3 heteroatoms or 5-6 ring atoms;

[0037] R1 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -C(O) C(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0038] R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NRa R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0039] R3 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a , , Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0040] R4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2Ra Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0041] R5 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0042] Each R a R b Each group is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, carbonyl, hydroxyl, cyano, nitro, benzyl, and -C(O)NR. c R d -C(O)R c -C(O)OR c -OR c -OC(O)R c -OC(O)OR c -OC(O)NR c R d -NR c R d -SR c -S(O)R c -S(O)2R c Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or benzyl group may optionally be surrounded by 1-3 R groups. c replace;

[0043] Each R c R d Each group is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halogenated C1-C6 alkyl, alkoxy, halogenated alkoxy, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl; and

[0044] Each n is independently selected from 0, 1, 2, or 3.

[0045] In some embodiments, the compound represented by general formula (I) is a compound represented by general formula (Ib):

[0046]

[0047] (Ib)

[0048] Or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof; wherein:

[0049] Y is either C or N;

[0050] R1 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -C(O) C(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0051] R2 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)Ra -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0052] R3 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a , , Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0053] R4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NRa R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0054] R5 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b -C(O)R a -C(O)OR a -OR a -OC(O)R a -OC(O)OR a -OC(O)NR a R b -NR a R b -SR a -S(O)R a -S(O)2R a Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be surrounded by 1-3 R groups. a replace;

[0055] Each R a R b Each group is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, carbonyl, hydroxyl, cyano, nitro, benzyl, and -C(O)NR. c R d -C(O)R c -C(O)OR c -OR c -OC(O)R c -OC(O)OR c -OC(O)NR c R d -NR c R d -SR c -S(O)R c -S(O)2Rc Or containing 0-3 heteroatoms of 3-10 membered cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or benzyl group may optionally be surrounded by 1-3 R groups. c replace;

[0056] Each R c R d Each group is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halogenated C1-C6 alkyl, alkoxy, halogenated alkoxy, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl; and

[0057] Each n is independently selected from 0, 1, 2, or 3.

[0058] In some implementations, R1 is selected from -CHO, -CN, , or .

[0059] In some implementations, R2 is selected from... , , , , , , , , , , , , , , , , or .

[0060] In some implementations, R3 is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0061] In some embodiments, the compound represented by general formula (I) is selected from:

[0062] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , or .

[0063] Secondly, this application provides the use of the aforementioned compound, its isomers, or pharmaceutically acceptable salts thereof in the preparation of antiviral drugs.

[0064] In some implementations, the virus is a coronavirus, enterovirus 68, enterovirus 69, enterovirus 70, enterovirus 71, enterovirus 72, coxsackievirus, norovirus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, influenza virus, or Ebola virus.

[0065] Thirdly, this application provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, its isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.

[0066] the term:

[0067] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0068] The term "isomer" includes enantiomers, diastereomers, and geometric (or conformational) isomers of a given structure. For example, this application includes R and S configurations for each asymmetry center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers.

[0069] The term "pharmaceutically acceptable salt" refers to salts such as their acid addition salts and / or base salts. Suitable acid addition salts are formed from acids, which form non-toxic salts, such as hydrochlorides / chlorides. Suitable base salts are formed from bases, which form non-toxic salts, such as calcium and sodium salts. Hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts.

[0070] The term “therapeutic effective amount” means the following amounts of the compound of this application, which (i) treat a specific disease, symptom or disorder; (ii) reduce, alleviate or eliminate one or more symptoms of a specific disease, symptom or disorder; or (iii) prevent or delay the onset of one or more symptoms of a specific disease, symptom or disorder described in this application.

[0071] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, excipient, or medium that does not impair the pharmacological activity of the compound formulated with it.

[0072] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0073] The term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight-chain and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, the term "C 2-6 "Alkenyl" includes straight-chain or branched unsaturated groups with 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.

[0074] The term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight-chain and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms. For example, "C 2-6 "Alkyne" includes straight-chain or branched unsaturated groups with 2 to 6 carbon atoms (having at least one carbon-carbon triple bond).

[0075] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the alkyl group is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0076] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), and most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0077] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom). It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles (e.g., 7, 8, 9, or 10 quintiles). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings. Monospirocycloalkyl and bispirocycloalkyl groups are preferred, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl groups.

[0078] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.

[0079] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0080] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, it comprises 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 to 6 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, or pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0081] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 cyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. Preferably, it is 6 to 14 cyclic, more preferably 7 to 10 cyclic. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred, and 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups being more preferred.

[0082] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0083] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, but each ring does not have a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0084] The heterocyclic group includes heterocyclic groups (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0085] , and .

[0086] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0087] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferred examples include imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrolel, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, and pyridazinyl.

[0088] The heteroaryl group includes, as described above, a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0089] , , , , and .

[0090] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0091] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0092] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0093] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0094] The term “deuterated alkoxy” refers to an alkoxy group that is replaced by one or more deuterium atoms, where the alkoxy group is as defined above.

[0095] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0096] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0097] The term "heterocyclic alkyl" refers to an alkyl group that is substituted with one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0098] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0099] The term "hydroxyl group" refers to the -OH group.

[0100] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0101] The term "amino" refers to -NH2.

[0102] The term "cyano" refers to -CN.

[0103] The term "nitro" refers to -NO2.

[0104] The term "carboxyl group" refers to -C(O)OH. Detailed Implementation

[0105] Example 1

[0106] N-((S)-1-((3R,5'S)-5'-formyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)cinnamamide (T-001)

[0107]

[0108] Step 1: L Preparation of -tryptophan methyl ester hydrochloride (001-2). Add to a 3 L flask... LTryptophan 001-1 (200.0 g, 0.98 mol) was dissolved in methanol (1.3 L) to give a suspension. SOCl2 (142 mL, 1.96 mol, 2.0 eq.) was then added dropwise under an ice-water bath. After the addition was complete, the reaction mixture was heated under reflux in a 70 °C oil bath for 2 hours. The mixture was then cooled to room temperature, concentrated, and the crude product was further slurried with ethyl acetate. The mixture was filtered and dried to give the title compound 001-2 (242.4 g, 97% yield). MS ( m / z 202.1 (Mw-NH2) + .

[0109] Step 2: Preparation of (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (001-3). 001-2 (242.4 g, 0.95 mol) and an aqueous formaldehyde solution (128 mL, 1.42 mol, 37 wt%, 1.5 eq.) were added to a 3 L flask and dissolved in methanol (1.5 L) to obtain a suspension. The suspension was then heated under reflux in a 95 °C oil bath for 1 hour. The mixture was then cooled to room temperature, concentrated, and the crude product was further slurried with methyl tert-butyl ether. The mixture was filtered and dried to give the title compound 001-3 (240.0 g, 95% yield). MS ( m / z 231.1 (Mw+H) + .

[0110] Step 3: 2-(tert-butyl)-3-methyl( S Preparation of 1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2,3-dicarboxylate (001-4). 001-3 (240.0 g, 0.90 mol) was added to a 3 L flask and dissolved in 2-methyltetrahydrofuran (1.2 L) to obtain a suspension. NEt3 (251 mL, 1.80 mol, 2.0 eq.) and water (300 mL) were added under ice-water bath conditions. The mixture was stirred for 20 min, then Boc2O (215.8 g, 0.99 mol, 1.1 eq.) was added dropwise, and the mixture was allowed to warm naturally to room temperature and stirred for 16 h. The organic phase was collected and washed successively with 1.0 M HCl aqueous solution (600 mL × 3), saturated NaHCO3, and saturated NaCl. The solution was dried over MgSO4, filtered, and concentrated to give the title compound 001-4 (280.2 g, 94% yield). MS ( m / z 329.2 (Mw-H) - .

[0111] Step 4: Preparation of 1'-(tert-butyl)5'-methyl(3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (001-5). 001-4 (50.0 g, 0.15 mol) was added to a 2 L flask, followed by 2-methyltetrahydrofuran (300 mL), H2O (370 mL), and AcOH (124 mL). An ice-salt bath was used to maintain the internal temperature of the reaction solution below -5 °C. NBS (26.9 g, 0.15 mol, 1.0 eq.) was added in multiple batches, maintaining the internal temperature below -1 °C. After the reaction was complete, saturated NaHCO3 was added to quench the reaction, and EA (500 mL) was added for extraction. The organic phases were combined, washed successively with water and saturated NaCl, dried over MgSO4, and concentrated. Column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 001-5 (42.3 g, 81% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.68 (s, 1H), 7.24 (t, J = 7.6 Hz,1H), 7.13 – 7.04 (m, 1H), 7.03 – 6.95 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.69– 4.49 (m, 1H), 3.72 (s, 3H), 3.61 – 3.45 (m, 2H), 2.43 – 2.36 (m, 1H), 2.32– 2.20 (m, 1H), 1.47 – 1.28 (m, 9H). MS ( m / z 347.1 (Mw+H) + .

[0112] Step 5: Preparation of (3R, 5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid methyl ester (001-6). 001-5 (34.0 g, 98 mmol) was dissolved in 500 mL of a DCM / TFA solution at a volume ratio of 2:1 and stirred at room temperature for 30 minutes. The volatiles were removed by concentration, and then a small amount of toluene was added for further concentration. The crude product was used directly in the next step.

[0113]

[0114] Step 6: Cinnamyl- LPreparation of leucine tert-butyl ester (001-7). Cinnamic acid (9.00 g, 60.74 mmol, 1.05 eq.) and CDI (9.38 g, 57.85 mmol, 1.0 eq.) were dissolved in DCM (150 mL) and stirred at room temperature for 1 hour. Then, [the following was added] L -Leucine tert-butyl hydrochloride (12.92 g, 57.85 mmol, 1.0 eq.), the reaction mixture was stirred for 16 hours. After the reaction was complete, water was added to quench the reaction and the organic phase was separated. The mixture was washed successively with water, saturated citric acid, and saturated NaCl, and concentrated. Column chromatography (EA / Hep increased from 5% to 20%) yielded a white solid 001-7 (9.60 g, yield 52%). MS ( m / z ) 262.1(Mw- t Bu+2H) + .

[0115] Step 7: Cinnamyl- L Preparation of leucine (001-8). 001-7 (5.00 g, 15.75 mmol) was dissolved in a dioxane solution of HCl (4 N, 50 mL) and heated at 50 °C for 16 hours. The volatiles were removed by concentration, and the solution was dried under vacuum to give the title compound 001-8 (4.08 g, 99% yield). MS (m / z) 262.2 (Mw+H) + .

[0116] Step 8: Preparation of methyl(3R,5'S)-1'-(cinnamoyl-L-leucine)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate (001-9). 001-6 (0.24 g, 0.98 mmol) was dissolved in DCM (10 mL) and placed in an ice-water bath. Then, 001-8 (0.28 g, 1.08 mmol, 1.1 eq.), DIPEA (0.86 mL, 4.91 mmol, 5.0 eq.), and HATU (0.45 g, 1.18 mmol, 1.2 eq.) were added sequentially. The mixture was then brought to room temperature, and the reaction solution was stirred for 2 hours. The reaction solution was diluted with DCM (30 mL), washed sequentially with water, saturated citric acid, and saturated NaCl, and then concentrated. Column chromatography (EA / Hep increased from 5% to 50%) yielded the title compound 001-9 (0.31 g, 63% yield). MS ( m / z 488.2 (Mw-H) - .

[0117] Step 9: Preparation of N-((S)-1-((3R,5'S)-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)cinnamamide (001-10). 001-9 (0.31 g, 0.63 mmol) was dissolved in DCM (10 mL) and MeOH (2 mL) and cooled in an ice-water bath. Then, NaBH4 (0.24 g, 6.30 mmol, 10 eq.) was added in multiple batches to obtain a suspension, which was allowed to rise naturally to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with saturated NH4Cl (10 mL) and then extracted multiple times with DCM. The organic phases were combined, washed successively with water and saturated NaCl, dried over MgSO4, and filtered. After concentration, a yellow oily substance, 001-10 (0.24 g, 84% yield), was obtained. MS ( m / z 462.2 (Mw+H) + .

[0118] Step 10: Preparation of N-((S)-1-((3R,5'S)-5'-formyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)cinnamamide (T-001). 001-10 (0.24 g, 0.52 mmol) was dissolved in DCM (10 mL), and then Dess-Martin oxidizing reagent (0.26 g, 0.61 mmol, 1.2 eq.) was added. The resulting reaction mixture was stirred at room temperature for 2 hours. After washing with water, the mixture was separated using a C-18 reversed-phase column (eluent: MeCN / H2O, aqueous phase containing 0.1% formic acid), and lyophilized to give the title compound T-001 (36 mg, 15% yield). 1 H NMR (400 MHz, CDCl3) δ9.68 (s, 1H), 8.27 (s, 1H), 7.85 – 7.71 (m, 1H), 7.64 – 7.50 (m, 2H), 7.48 –7.35 (m, 4H), 7.18 – 7.07 (m, 1H), 7.04 – 6.83 (m, 2H), 6.62 – 6.35 (m, 1H), 5.86 – 5.67 (m, 1H), 5.29 – 5.05 (m, 1H), 4.79 – 4.53 (m, 1H), 4.00 (t, J =12.0 Hz, 1H), 3.77 (d, J= 12.0 Hz, 1H), 2.76 – 2.63 (m, 1H), 2.33 – 2.26 (m,1H), 2.02 – 1.85 (m, 2H), 1.24 – 1.18 (m, 1H), 1.10 – 0.96 (m, 6H). MS ( m / z 458.2 (Mw-H) - .

[0119] Example 2

[0120] Benzyl((S)-1-((3R,5'S)-5'-formyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (T-002)

[0121]

[0122] Step 1: Preparation of methyl (3R, 5'S)-1'-(((benzyloxy)carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid ester (002-2). Following the synthetic method described for 001-9, 001-6 (7.11 g, 28.87 mmol) and 002-1 (9.19 g, 34.64 mmol, 1.2 eq.) were added to give the title compound 002-2 (13.82 g, 97% yield, yellow oil). MS ( m / z 494.2 (Mw+H) + .

[0123] Step 2: Preparation of benzyl((S)-1-((3R,5'S)-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (002-3). Following the synthesis of 001-10, 002-2 (1.00 g, 2.02 mmol) was added, and column chromatography (EA / Hep increased from 20% to 100%) was used to separate the title compound 002-3 (0.45 g, 48% yield). MS ( m / z 464.2 (Mw-H) - .

[0124] Step 3: Preparation of benzyl((S)-1-((3R,5'S)-5'-formyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (T-002). Following the synthesis of T-001, 002-3 (226 mg, 0.48 mmol) was added to give the title compound T-002 (29 mg, 12% yield, white solid). 1 H NMR (400MHz, CDCl3) δ 9.63 (s, 1H), 8.28 (s, 1H), 8.10 – 7.90 (m, 1H), 7.48 – 7.30 (m, 6H), 7.24 (d, J = 7.6 Hz, 1H), 7.17 – 7.08 (m, 1H), 7.03 – 6.89 (m, 1H), 5.31 – 5.05 (m, 2H), 4.60 – 4.42 (m, 1H), 4.43 – 4.27 (m, 1H), 3.91 – 3.84(m, 1H), 3.56 – 3.30 (m, 1H), 2.77 – 2.60 (m, 1H), 2.50 – 2.32 (m, 1H), 1.88– 1.65 (m, 2H), 1.40 – 1.25 (m, 1H), 1.10– 0.75 (m, 6H). MS ( m / z 462.2 (Mw-H) - .

[0125] Example 3

[0126] N-((S)-1-((3R,5'S)-5'-formyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1H-indole-2-carboxamide (T-003)

[0127]

[0128] Following the synthesis of T-001, 003-1 (200 mg, 0.42 mmol) was added to give the title compound T-003 (29 mg, 13% yield, white solid). 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 7.98 – 7.77 (m,1H), 7.57 – 7.36 (m, 7H), 7.22 – 7.11 (m, 2H), 6.99 – 6.89 (m, 2H), 4.90 –4.88 (m, 1H), 4.63 – 4.32 (m, 1H), 4.24 – 4.00 (m, 1H), 3.66 (d, J = 10.4 Hz,1H), 2.69 – 2.37 (m, 2H), 1.96 – 1.73 (m, 2H), 1.17 – 1.08 (m, 1H), 1.03 –0.84 (m, 6H). MS ( m / z 501.2 (Mw-H) - .

[0129] Example 4

[0130] N-((S)-4-methyl-1-oxo-1-((3R,5'S)-2-oxo-5'-(thiazolyl-2-carbonyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)pentan-2-yl)cinnamamide (T-004)

[0131]

[0132] Step 1: Preparation of (3R, 5'S)-1'-(tert-Butoxycarbonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid (004-1). 001-5 (9.50 g, 27.4 mmol) was dissolved in THF (160 mL) and placed in an ice-water bath. Then, LiOH·H₂O (2.28 g, 54.8 mmol, 2.0 eq.) was dissolved in water (80 mL) and added dropwise to the THF solution. After the addition was complete, the mixture was brought to room temperature and stirred for 3 hours. The pH was adjusted to 4.0 using an aqueous HCl solution (1 N), concentrated, and extracted three times with EA. The organic phases were combined, washed with saturated NaCl, dried over MgSO₄, filtered, and concentrated to give the title compound 004-1 (7.21 g, 79% yield), which was used directly in the next step. MS ( m / z 331.1 (Mw-H) - .

[0133] Step 2: Preparation of tert-butyl(3R,5'S)-5'-(methoxy(methyl)carbamoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid ester (004-2). 004-1 (2.70 g, 8.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.95 g, 9.7 mmol, 1.2 eq.) were dissolved in DCM (30 mL). The mixture was cooled in an ice-water bath, and then DIPEA (3.5 mL, 2.5 eq.) and HATU (6.14 g, 16.2 mmol, 2.0 eq.) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with water and saturated NaCl, and concentrated. Column chromatography (EA / Hep = 100%) was used to separate the title compound 004-2 (2.84 g, 93% yield). MS ( m / z 376.2 (Mw-H) - .

[0134] Step 3: Preparation of tert-butyl(3R,5'S)-2-oxo-5'-(thiazol-2-carbonyl)spiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid ester (004-3). Under nitrogen protection, 2-bromothiazole (0.44 g, 2.65 mmol) was added to a 100 mL three-necked flask and dissolved with THF (20 mL), cooled in a dry ice ethanol bath. Then, the ester was slowly added dropwise. n -BuLi (1.1 mL, 2.0 eq.) was reacted at low temperature for 30 minutes. 004-2 (500 mg, 1.32 mmol) was dissolved in THF and added dropwise to the above reaction solution. The mixture was stirred in a dry ice-ethanol bath for 2 hours. The reaction was quenched dropwise with methanol and concentrated. Column chromatography (EA / Hep 80%) yielded the title compound 004-3 (0.17 mg, 32% yield). MS ( m / z 400.1 (Mw-H) - .

[0135] Steps 4 and 5: Preparation of N-((S)-4-methyl-1-oxo-1-((3R,5'S)-2-oxo-5'-(thiazolyl-2-carbonyl)spiro[indol-3,3'-pyrrolidine]-1'-yl)pentan-2-yl)cinnamamide (T-004). Following the synthetic method of T-001, 004-4 (80 mg, 0.26 mmol) and 001-8 (83 mg, 0.32 mmol, 1.2 eq.) were added to give the title compound T-004 (27 mg, 19% yield, white solid). MS ( m / z 541.1 (Mw-H) - .

[0136] Example 5

[0137] N-((S)-1-((3R,5'S)-5'-(benzo[d]thiazolyl-2-carbonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)cinnamamide (T-005)

[0138]

[0139] Following the synthetic method for T-004, 005-2 (112 mg, 0.32 mmol) was added to yield the title compound T-005 (8 mg, 4% yield, yellow solid). MS ( m / z 606.1 (Mw+H) + .

[0140] Example 6

[0141] N-((S)-1-((3R,5'S)-5'-(2-(benzylamino)-2-oxoacetyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1H-indole-2-carboxamide (T-006)

[0142]

[0143] Step 1: Preparation of 1-((3R, 5'S)-1'-((1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indole-3,3'-pyrrolidine]-5'-yl)-2-(benzylamino)-2-oxoethyl acetate (006-1). T-003 (127 mg, 0.27 mmol), DCM (10 mL), benzyl isonitrile (35 mg, 0.29 mmol, 1.1 eq.), and AcOH (32 mg, 0.54 eq.) were added sequentially to a 50 mL single-necked flask, and the mixture was stirred at room temperature for 20 hours. The reaction was then quenched with water, and the mixture was extracted three times with DCM. The combined organic phases were washed with saturated NaCl, dried over MgSO4, filtered, and concentrated to give the title compound 006-1 (223 mg, crude product), which was used directly in the next step. MS ( m / z 648.3 (Mw-H) - .

[0144] Step 2: Preparation of N-((S)-1-((3R,5'S)-5'-(2-(benzylamino)-1-hydroxy-2-oxoethyl)-2-oxospiro[indol-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1H-indol-2-carboxamide (006-2). 006-1 (170 mg) was added to a 50 mL single-necked flask and dissolved in methanol (15 mL). Then, 3 mL of an aqueous solution containing LiOH·H₂O (22 mg, 0.52 mmol, 2.0 eq.) was added. The resulting reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated and then redissolved with EA. The organic phase was washed successively with water and saturated NaCl, and dried over MgSO₄. The mixture was filtered and concentrated to give the title compound 006-2 (201 mg, crude product). MS ( m / z 608.2 (Mw+H) + .

[0145] Step 3: Preparation of N-((S)-1-((3R,5'S)-5'-(2-(benzylamino)-2-oxoacetyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1H-indole-2-carboxamide (T-006). 006-2 (159 mg), NaHCO3 (11 mg, 0.13 mmol, 0.5 eq.), and Dess-Martin oxidizing reagent (133 mg, 0.31 mmol, 1.2 eq.) were added to a 50 mL single-necked flask and dissolved in DCM. The mixture was stirred at room temperature for 1 hour. The solution was washed with water and concentrated. The title compound T-006 (45 mg, 28% yield) was isolated by column chromatography (EA / Hep increased from 40% to 70%). MS ( m / z 604.2 (Mw-H) - .

[0146] Example 7

[0147] tert-Butyl(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid ester (T-007)

[0148]

[0149] Step 1: Preparation of tert-butyl(3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid ester (007-1). 007-1 (3.32 g, 9.99 mmol) was dissolved in acetonitrile (50 mL) and placed in an ice-water bath. DIPEA (5.2 mL, 3.0 eq.), EDCI (2.49 g, 12.99 mmol, 1.3 eq.), and HOBt (0.13 g, 0.1 mmol, 0.1 eq.) were added, and the mixture was stirred for 15 minutes. Then, NH4Cl (0.99 g, 20.00 mmol, 2.0 eq.) was added, and the mixture was allowed to rise naturally to room temperature, with stirring continuing for 16 hours. The mixture was concentrated, EA was redissolved, and the solution was washed successively with water, 1 N HCl, saturated NaHCO3, and saturated NaCl, and dried over MgSO4. The mixture was filtered and concentrated to give the title compound 007-1 (3.21 g, 97% yield). The crude product was used directly in the next reaction. MS ( m / z 330.2 (Mw-H) - .

[0150] Step 2: Preparation of tert-butyl(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylic acid ester (T-007). 007-1 (3.21 g) was dissolved in DCM (50 mL), and Burgess reagent (6.90 g, 28.96 mmol, 3.0 eq.) was added in portions, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl, and the mixture was separated. The organic phase was washed successively with water and saturated NaCl, and concentrated. Column chromatography (EA / Hep increased from 5% to 50%) yielded the title compound T-007 (1.48 g, 49% yield). 1 H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.35 – 7.28 (m, 1H), 7.12 – 7.04(m, 1H), 7.03 – 6.97 (m, 2H), 5.05 – 4.73 (m, 1H), 3.91 – 3.76 (m, 2H), 2.89– 2.75 (m, 1H), 2.70 – 2.47 (m, 1H), 1.65 – 1.34 (m, 9H). MS (m / z) 312.1 (Mw-H) - .

[0151] Example 8

[0152] tert-Butyl((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (T-008)

[0153]

[0154] Step 1: Preparation of methyl (3R,5'S)-1'-((tert-butyloxycarbonyl)-L-leucine)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid ester (008-1). 008-1 (8.50 g, 24.54 mmol) was dissolved in 60 mL of DCM / TFA at a volume ratio of 2:1 and stirred at room temperature for 1 hour. The volatiles were removed by concentration, and then toluene was added followed by further concentration. The solution was redissolved in DCM (80 mL), cooled in an ice-salt bath, and then DIPEA (21.4 mL, 0.12 mol, 5.0 eq.), Boc- L -Leucine (8.51 g, 36.81 mmol, 1.5 eq.) and HATU (15.86 g, 41.72 mol, 1.7 eq.). The reaction mixture was stirred at room temperature for 2 hours, washed successively with water and saturated NaCl, and concentrated. Column chromatography (EA / Hep increased from 5% to 50%) yielded the title compound 008-1 (10.61 g, 94% yield). MS ( m / z 458.2 (Mw-H) - .

[0155] Step 2: Preparation of (3R, 5'S)-1'-((tert-butoxycarbonyl)-L-leucine)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid (008-2). Following the synthetic method of 004-1, 008-1 (5.60 g, 12.19 mmol) was added to give the title compound 008-2 (5.37 g, 99% yield). MS ( m / z 444.2 (Mw-H) - .

[0156] Step 3: Preparation of tert-butyl((S)-1-((3R,5'S)-5'-carbamoyl-2-oxospiro[indol-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (008-3). Following the synthetic method of 007-1, 008-2 (5.35 g, 12.00 mmol) was added to give the title compound 008-3 (5.33 g, 99% yield). MS ( m / z 444.3 (Mw-H) - .

[0157] Step 4: Preparation of tert-butyl((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (T-008). Following the synthetic method of T-007, 008-3 (2.65 g, 5.96 mmol) was added to give the title compound T-008 (1.20 g, 47% yield). 1 H NMR (400MHz, CDCl3) δ 8.76 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.24 (d, J = 8.8 Hz, 1H), 5.04 (t, J = 8.8 Hz, 1H), 4.49 – 4.35 (m, 1H), 4.26 (d, J = 10.8 Hz, 1H), 4.00 (t, J = 10.8 Hz, 1H), 2.87 (dd, J = 12.8, 9.2 Hz, 1H), 2.53 (dd, J = 12.8, 9.2 Hz, 1H), 1.77 – 1.69 (m, 2H), 1.52 – 1.43 (m, 1H), 1.37 (s, 9H), 1.03 – 0.94 (m, 6H). MS ( m / z 425.2 (Mw-H) - .

[0158] Example 9

[0159] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)cinnamamide (T-009)

[0160]

[0161] T-008 (0.10 g, 0.23 mmol) was dissolved in 3 mL of TFA / DCM at a volume ratio of 1:2 and stirred at room temperature for 1 hour. The solution was concentrated, and a small amount of toluene was added to further remove residual TFA. The resulting oily liquid was redissolved in DCM (10 mL) and placed in an ice-salt bath. DIPEA (0.16 mL, 0.92 mmol, 4.0 eq.), cinnamic acid (42 mg, 0.28 mmol, 1.2 eq.), and HATU (134 mg, 0.35 mmol, 1.5 eq.) were added sequentially. The resulting reaction mixture was stirred in an ice-salt bath for another 1 hour. The solution was washed with water and saturated NaCl, and concentrated. Column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-009 (49 mg, 45% yield). 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.52 – 7.46 (m,3H), 7.43 – 7.36 (m, 4H), 7.03 (t, J = 7.6 Hz, 1H), 6.99 – 1.68 (m, 2H), 6.57(d, J = 8.4 Hz, 1H), 6.45 (d, J = 15.6 Hz, 1H), 5.05 (t, J = 8.0 Hz, 1H),4.93 – 4.81 (m, 1H), 4.29 (d, J = 10.2 Hz, 1H), 4.05 (t, J = 10.2 Hz, 1H),2.96 – 2.83 (m, 1H), 2.64 – 2.49 (m, 1H), 1.85 – 1.68 (m, 2H), 1.40 – 1.28(m, 1H), 0.98 (d, J = 6.4 Hz, 6H). MS ( m / z 455.2 (Mw-H) - .

[0162] Example 10

[0163] N-((S)-1-((3S,5'R)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)cinnamamide (T-010)

[0164]

[0165] Following the synthetic method of T-009, 010-9 (100 mg, 0.23 mmol) and cinnamic acid (41 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-010 (64 mg, 60% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.79 – 7.59 (m, 1H), 7.58 – 7.48 (m, 2H), 7.48 – 7.34 (m, 3H), 7.25 – 6.90 (m, 5H), 6.63 – 6.30 (m, 2H), 5.10– 4.93 (m, 1H), 4.26 – 4.08 (m, 1H), 3.88 – 3.75 (m, 1H), 2.96 (dd, J = 10.2,8.0 Hz, 1H), 2.73 – 2.46 (m, 1H), 1.97 – 1.78 (m, 2H), 1.40 – 1.22 (m, 1H),1.09 – 0.80 (m, 6H). MS ( m / z 455.2 (Mw-H) - .

[0166] Example 11

[0167] Benzyl((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (T-011)

[0168]

[0169] Following the synthetic method of T-008, 011-1 (84 mg, 0.18 mmol) was added, and the title compound T-011 (36 mg, 40% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.63(s, 1H), 8.43 (s, 1H), 7.69 – 7.63 (m, 1H), 7.57 – 7.50 (m, 1H), 7.43 – 7.31(m, 4H), 7.28 – 7.22 (d, J= 7.7 Hz, 1H), 7.08 – 7.01 (m, 1H), 6.90 (t, J =6.4 Hz, 1H), 5.02 (s, 2H), 4.97 – 4.87 (m, 1H), 4.32 – 4.20 (m, 1H), 4.07 (d, J = 10.2 Hz, 1H), 3.89 (d, J = 10.2 Hz, 1H), 2.69 (dd, J = 13.2, 8.0 Hz, 1H), 2.59 (dd, J = 13.2, 8.0 Hz, 1H), 1.76 – 1.68 (m, 2H), 1.46 – 1.35 (m, 1H), 0.85 – 0.77 (m, 6H). MS ( m / z 461.2 (Mw+H) + .

[0170] Example 12

[0171] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-2-(4-(trifluoromethoxy)phenoxy)acetamide (T-012)

[0172]

[0173] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 2-(4-(trifluoromethoxy)phenoxy)acetic acid (66 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-012 (81 mg, 63% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.27 – 7.13 (m, 3H), 7.01 – 6.91 (m, 6H), 5.05 (t, J = 8.4 Hz, 1H), 4.85 – 4.70 (s, 1H), 4.21 (s, 2H), 4.15 (d, J = 10.0 Hz, 1H), 4.00 (d, J = 10.0 Hz, 1H), 2.87 (dd,J = 12.8, 8.8 Hz, 1H), 2.57 (dd, J = 12.8, 8.8 Hz, 1H), 1.76 – 1.59 (m, 2H), 1.41 – 1.31 (m, 1H), 0.96 (s, 6H). 19 F NMR (376 MHz, CDCl3) δ -58.4 (s). MS( m / z 543.1 (Mw-H) - .

[0174] Example 13

[0175] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indol-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-1H-pyrrole-2-carboxamide (T-013)

[0176]

[0177] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 2-pyrrolecarboxylic acid (32 mg, 0.29 mmol, 1.2 eq.) were added, and the title compound T-013 (73 mg, 74% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 7.82 (s, 1H), 7.27 – 7.22 (m,1H), 6.98 – 6.89 (m, 4H), 6.69 (s, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.28 (dd, J = 6.0, 2.8 Hz, 1H), 5.04 (t, J = 8.4 Hz, 1H), 4.89 (dd, J = 13.2, 8.4 Hz, 1H), 4.26 (d, J = 10.4 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 2.90 (dd, J =13.2, 8.4 Hz, 1H), 2.56 (dd, J= 13.2, 8.4 Hz, 1H), 1.80 – 1.72 (m, 2H), 1.32– 1.29 (m, 1H) 1.00 (dd, J = 6.4, 2.0 Hz, 6H). MS ( m / z 442.2 (Mw+Na) + .

[0178] Example 14

[0179] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1H-indole-2-carboxamide (T-014)

[0180]

[0181] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 2-indolecarboxylic acid (45 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-014 (13 mg, 12% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 9.16 (s, 1H), 7.65 (d, J =7.6 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 – 7.22 (m, 1H), 7.20 – 7.10 (m,2H), 7.04 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.90 – 6.85 (m, 2H), 5.10 (t, J = 8.4 Hz, 1H), 5.01 – 4.91 (m, 1H), 4.31 (d, J = 8.0 Hz, 1H), 4.08 (d, J =8.0 Hz, 1H), 2.89 (dd, J = 13.2, 8.4 Hz, 1H), 2.56 (dd, J = 13.2, 8.4 Hz,1H), 1.87 – 1.79 (m, 2H), 1.33 – 1.26 (m, 1H), 1.01 (d,J = 6.1 Hz, 6H). MS( m / z 468.2 (Mw-H) - .

[0182] Example 15

[0183] N-((S)-1-((3S,5'R)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide (T-015)

[0184]

[0185] Following the synthetic method of T-009, 010-9 (100 mg, 0.23 mmol) and 2-indolecarboxylic acid (45 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-015 (20 mg, 18% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 9.16 (s, 1H), 7.71 – 7.53 (m,1H), 7.51 – 7.25 (m, 4H), 7.15 – 6.83 (m, 5H), 5.06 – 4.89 (m, 2H), 4.34 (d, J = 9.2 Hz, 1H), 3.74 (d, J = 9.2 Hz, 1H), 2.98 – 2.90 (m, 1H), 2.67 – 2.58(m, 1H), 1.99 – 1.79 (m, 2H), 1.42 – 1.34 (m, 1H), 1.15 – 1.03 (m, 6H). MS( m / z 498.2 (Mw-H) - .

[0186] Example 16

[0187] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-016)

[0188]

[0189] Following the synthetic method of T-009, T-008 (93 mg, 0.22 mmol) and 4-methoxy-2-indolecarboxylic acid (50 mg, 0.26 mmol, 1.2 eq.) were added, and the title compound T-016 (10 mg, 9% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 9.03 (s, 1H), 7.72 (s,1H), 7.35 – 7.05 (m, 3H), 7.03 – 6.72 (m, 4H), 6.49 (s, 1H), 5.13 (s, 1H),4.93 (s, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.07 (d, J = 8.8 Hz, 1H), 3.92 (s,3H), 2.96 – 2.76 (m, 1H), 2.60 – 6.43 (m, 1H), 1.99 – 1.79 (s, 2H), 1.33 –1.22 (m, 1H), 1.09 – 0.84 (m, 6H). MS ( m / z 498.2 (Mw-H) - .

[0190] Example 17

[0191] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-5-(trifluoromethyl)-1H-indole-2-carboxamide (T-017)

[0192]

[0193] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 5-trifluoromethylindole-2-carboxylic acid (59 mg, 0.26 mmol, 1.1 eq.) were added, and the title compound T-017 (61 mg, 48% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 8.64 (s, 1H), 7.96 (s, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 7.2 Hz,1H), 6.96 – 6.84 (m, 2H), 5.11 (t, J = 8.2 Hz, 1H), 4.99 – 4.93 (m, 1H), 4.28(d, J = 10.0 Hz, 1H), 4.10 (d, J = 10.0 Hz, 1H), 2.91 (dd, J = 13.2, 8.4 Hz, 1H), 2.60 (dd, J = 13.2, 8.4 Hz, 1H), 1.94 – 1.82 (m, 2H), 1.32 – 1.24 (m,1H), 1.09 – 0.97 (m, 6H). 19 F NMR (376 MHz, CDCl3) δ -60.6 (s). MS ( m / z 536.2 (Mw-H) - .

[0194] Example 18

[0195] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-4,7-difluoro-1H-indole-2-carboxamide (T-018)

[0196]

[0197] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 4,7-difluoroindole-2-carboxylic acid (56 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-018 (31 mg, 26% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 7.64 (s, 1H), 7.11 –7.03 (m, 2H), 6.98 – 6.86 (m, 5H), 6.77 – 6.68 (m, 1H), 5.09 (t, J = 8.8 Hz,1H), 4.99 – 4.89 (m, 1H), 4.26 (d, J = 10.0 Hz, 1H), 4.08 (d, J = 10.2 Hz,1H), 2.99 – 2.87 (m, 1H), 2.61 – 2.53 (m, 1H), 1.84 – 1.72 (m, 2H), 1.33 –1.28 (m,1H), 1.05 – 1.01 (m, 6H). 19 F NMR (376 MHz, CDCl3) δ -125.9 (d, J =23.2 Hz), -139.4 (d, J = 26.2 Hz). MS ( m / z 504.2 (Mw-H) - .

[0198] Example 19

[0199] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6,7-trifluoro-1H-indole-2-carboxamide (T-019)

[0200]

[0201] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 4,6,7-trifluoroindole-2-carboxylic acid (61 mg, 0.28 mmol, 1.2 eq) were added, and the title compound T-019 (15 mg, 12% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 7.74 (s, 1H), 7.39 –7.32 (m, 2H), 7.15 – 7.08 (m, 1H), 7.01 – 6.91 (m, 3H), 6.81 – 6.66 (m, 1H),5.31 – 5.20 (m, 1H), 5.06 (t, J = 8.4 Hz, 1H), 4.24 (d, J = 10.0 Hz, 1H), 4.02 (d, J = 10.0 Hz, 1H), 2.91 (dd, J = 13.2, 8.8 Hz, 1H), 2.60 (dd, J =13.2, 8.8 Hz, 1H), 1.86 – 1.72 (m, 2H), 1.21 – 1.12 (m, 1H), 1.04 – 0.98 (m, 6H). 19 F NMR (376 MHz, CDCl3) δ -122.0 – -122.3 (m), -141.8– -141.9 (m), -164.2 – -164.6 (m). MS ( m / z 522.2 (Mw-H) - .

[0202] Example 20

[0203] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-1H-benzo[d]imidazol-2-carboxamide (T-020)

[0204]

[0205] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and 1H-benzimidazole-2-carboxylic acid (57 mg, 0.35 mmol, 1.5 eq.) were added, and the title compound T-020 (8 mg, 7% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.84 (s, 1H), 8.51 (d, J= 8.4 Hz, 1H), 7.83 – 7.73 (m, 1H), 7.44 (s, 1H), 7.41 – 7.31 (m, 2H), 7.04(t, J = 7.2 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.74 – 6.61(m, 2H), 5.10 (t, J = 8.0 Hz, 1H), 5.00 – 4.85 (m, 1H), 4.10 (d, J = 10.2 Hz, 1H), 4.00 (d, J =10.2 Hz, 1H), 2.79 – 2.73 (dd, J = 13.2, 8.4 Hz, 1H), 2.42 (dd, J = 13.2, 8.4Hz, 1H), 1.75 – 1.63 (m, 2H), 1.43 – 1.32 (m, 1H), 0.98 (d, J = 6.0 Hz, 6H).MS ( m / z 471.1 (Mw-H) - .

[0206] Example 21

[0207] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)benzo[d]thiazolyl-2-carboxamide (T-021)

[0208]

[0209] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and benzothiazolyl-2-carboxylic acid (51 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-021 (32 mg, 28% yield, pale white solid) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.72 (s, 1H), 9.28 (d, J=7.2 Hz, 1H), 8.30 – 8.16 (m, 2H), 7.71 – 7.59 (m, 2H), 7.20 – 7.08 (m, 2H), 6.96 – 6.85 (m, 2H), 5.18 (t, J = 8.0 Hz, 1H), 4.74 – 4.61 (m, 1H), 4.12 (d, J = 10.0 Hz, 1H), 3.86 (d, J = 10.0 Hz, 1H), 2.69 – 2.58 (s, 1H), 2.41 – 2.31(s, 1H), 1.75 – 1.64 (m, 2H), 1.40 – 1.24 (m, 1H), 0.96 – 0.85 (m, 6H). MS( m / z 486.1 (Mw-H) - .

[0210] Example 22

[0211] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)quinoxaline-2-carboxamide (T-022)

[0212]

[0213] Following the synthetic method of T-009, T-008 (0.10 g, 0.23 mmol) and quinoline-2-carboxylic acid (49 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-022 (83 mg, 73% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H),8.26 – 8.15 (m, 2H), 7.94 – 7.87 (m, 2H), 7.69 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.74 (t, J= 7.6 Hz, 1H), 5.06 (t, J = 8.4 Hz, 1H), 5.02 – 4.94 (m, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 10.0 Hz, 1H), 2.90 (dd, J = 12.8, 8.8 Hz, 1H), 2.55 (dd, J = 12.8, 8.8 Hz, 1H), 1.90 – 1.76 (m, 2H), 1.46 – 1.38 (m, 1H), 1.02 (d, J =6.0 Hz, 6H). MS ( m / z 481.2 (Mw-H) - .

[0214] Example 23

[0215] tert-Butyl((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (T-023)

[0216]

[0217] Following the synthesis method of T-009, T-008 (0.10 g, 0.23 mmol) and Boc- were added. L -Tertiary leucine (81 mg, 0.35 mmol, 1.5 eq.) was separated by column chromatography (EA / Hep increased from 5% to 50%) to give the title compound T-023 (83 mg, yield 66%). 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.32 – 7.24 (m, 1H), 7.02(t, J = 7.6 Hz, 1H), 6.96 – 6.88 (m, 2H), 6.56 (d, J = 7.6 Hz, 1H), 5.14 (d, J = 9.4 Hz, 1H), 5.03 (t, J = 8.8 Hz, 1H), 4.68 (dd, J= 13.2, 7.6 Hz, 1H), 4.23 (d, J = 10.2 Hz, 1H), 4.02 (d, J = 10.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 2.87 (dd, J = 12.8, 9.2 Hz, 1H), 2.53 (dd, J = 12.8, 9.2 Hz, 1H), 1.77 –1.70 (m, 2H), 1.44 (s, 9H), 1.31 – 1.24 (m, 1H), 0.99 (s, 9H), 0.98 – 0.89(m, 6H). MS ( m / z 538.1 (Mw-H) - .

[0218] Example 24

[0219] (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-024)

[0220]

[0221] T-023 (318 mg, 0.59 mmol) was dissolved in 9 mL of TFA / DCM at a volume ratio of 1:2 and stirred at room temperature for 1 hour. The solution was concentrated, and a small amount of toluene was added to further remove residual TFA. The resulting crude product was dissolved in MeOH (5 mL), and then DIPEA (1.0 mL, 5.90 mmol, 10.0 eq.) and CF3CO2Et (2.53 g, 17.79 mmol, 30.2 eq.) were added. The resulting mixture was heated in an oil bath at 50 °C for 16 hours. The solution was concentrated, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-024 (125 mg, 39% yield). 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H),7.32 (t, J = 7.6 Hz, 1H), 7.09 – 6.98 (m, 3H), 6.94 (d, J = 7.6 Hz, 1H), 6.68(d, J= 7.6 Hz, 1H), 5.07 (t, J = 8.4 Hz, 1H), 4.69 – 4.61 (m, 1H), 4.38 (d, J = 9.2 Hz, 1H), 4.13 (d, J = 7.6 Hz, 1H), 4.03 (d, J = 9.2 Hz, 1H), 2.89(dd, J = 13.2, 9.2 Hz, 1H), 2.58 (dd, J = 13.2, 9.2 Hz, 1H), 1.73 – 1.62 (m,2H), 1.42 – 1.35 (m, 1H), 1.04 (s, 9H) 1.02 (d, J = 6.0 Hz, 6H). 19 F NMR (376MHz, CDCl3) δ -75.6 (s, 3F). MS ( m / z 534.2 (Mw-H) - .

[0222] Example 25

[0223] N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropionamide (T-025)

[0224]

[0225] T-023 (60 mg, 0.11 mmol) was dissolved in 3 mL of TFA / DCM at a volume ratio of 1:2 and stirred at room temperature for 1 hour. The solution was concentrated, and a small amount of toluene was added to further remove residual TFA. The resulting crude product was dissolved in DCM (5 mL) and placed in an ice-water bath. DIPEA (96 μL, 0.55 mmol, 5.0 eq.) and cyclopropylformyl chloride (23 mg, 0.22 mmol, 2 eq.) were added, and the reaction was continued in an ice-water bath for 30 minutes. The solution was concentrated, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-025 (10 mg, 18% yield). 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.31 (d, J= 7.6Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.05 – 6.88 (m, 3H), 6.47 (d, J = 9.2 Hz, 1H), 5.08 (t, J = 8.0 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.47 (d, J = 9.2 Hz, 1H), 4.17 (d, J = 10.0 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 2.86 (dd, J =12.4, 8.0 Hz, 1H), 2.53 (dd, J = 12.4, 8.0 Hz, 1H), 1.92 (s, 1H), 1.68 (s,2H), 1.49 – 1.38 (m, 1H), 1.07 – 0.89 (m, 19H). MS ( m / z 506.3 (Mw-H) - .

[0226] Example 26

[0227] (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-2-(cyclopropanesulfonamide)-3,3-dimethylbutylamine (T-026)

[0228]

[0229] Following the synthetic method of T-025, T-023 (49 mg, 0.09 mmol) and cyclopropylsulfonyl chloride (26 mg, 0.18 mmol, 2.0 eq.) were added, and the title compound T-026 (15 mg, 30% yield, white solid) was isolated by column chromatography (EA / Hep increased from 5% to 100%). 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.32 – 7.26 (m,1H), 7.04 – 6.87 (m, 4H), 5.40 (d, J = 9.6 Hz, 1H), 5.19 (t, J= 8.4 Hz, 1H),4.75 – 4.66 (m, 1H), 4.18 (d, J = 10.0 Hz, 1H), 4.02 (d, J = 10.0 Hz, 1H), 3.61 (d, J = 10.0 Hz, 1H), 2.84 (dd, J = 13.2, 8.4 Hz, 1H), 2.54 (dd, J =13.2, 8.4 Hz, 1H), 2.43 – 2.33 (m, 1H), 1.74 – 1.56 (m, 4H), 1.16 – 1.13 (m,1H), 0.99 – 0.92 (m, 9H), 0.90 – 0.83 (m, 8H). MS ( m / z 542.2 (Mw-H) - .

[0230] Example 27

[0231] (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-2-(2,2-difluoroacetamide)-3,3-dimethylbutylamine (T-027)

[0232]

[0233] T-023 (49 mg, 0.09 mmol) was dissolved in 6 mL of TFA / DCM at a volume ratio of 1:2 and stirred at room temperature for 1 hour. The solution was concentrated, and a small amount of toluene was added to further remove residual TFA. The resulting crude product was dissolved in DCM (10 mL) and placed in an ice-water bath. DIPEA (80 μL, 0.45 mmol, 5.0 eq.) and difluoroacetic anhydride (24 mg, 0.14 mmol, 1.5 eq.) were added sequentially, and the mixture was stirred for another 1 hour. The reaction was quenched with saturated NH4Cl, and the organic phases were combined and washed sequentially with water and saturated NaCl. Column chromatography (EA / Hep increased from 5% to 100%) yielded the title compound T-027 (21 mg, 44% yield, white solid). 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.33 – 7.29 (m, 1H), 7.13 – 6.82 (m, 5H), 5.94 (t, J= 54.2 Hz, 1H), 5.08 (t, J = 8.4 Hz, 1H),4.73 – 4.63 (m, 1H), 4.43 (d, J = 9.2 Hz, 1H), 4.18 (d, J = 10.0 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 2.87 (dd, J = 13.2, 8.0 Hz, 1H), 2.56 (dd, J =13.2, 8.0 Hz, 1H), 1.84 – 1.70 (m, 2H), 1.35 – 1.30 (m, 1H), 1.02 (s, 9H), 0.99 – 0.92 (m, 6H). MS ( m / z 516.2 (Mw-H) - .

[0234] Example 28

[0235] N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-1-fluorocyclopropane-1-carboxamide (T-028)

[0236]

[0237] Following the synthetic method of T-009, T-023 (49 mg, 0.09 mmol) and 1-fluorocyclopropylcarboxylic acid (14 mg, 0.13 mmol, 1.5 eq.) were added, and the title compound T-028 (16 mg, 33% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.33 – 7.26 (m, 1H), 7.07 –6.88 (m, 5H), 5.08 (t, J = 8.8 Hz, 2H), 4.72 – 4.60 (m, 1H), 4.40 (d, J = 8.8Hz, 1H), 4.25 (d, J = 10.0 Hz, 1H), 4.01 (t, J= 10.0 Hz, 1H), 2.94 – 2.87(dd, J = 13.2, 8.0 Hz, 1H), 2.55 (dd, J = 13.2, 8.0 Hz, 1H), 1.77 – 1.65 (m,2H), 1.43 – 1.31 (m, 3H), 1.03 (s, 9H), 1.00 – 0.94 (m, 6H), 0.92 – 0.83 (m,2H). MS ( m / z 524.3 (Mw-H) - .

[0238] Example 29

[0239] (S)-N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-2,2-difluorocyclopropane-1-carboxamide (T-029)

[0240]

[0241] Following the synthetic method of T-009, T-023 (49 mg, 0.09 mmol) and (1S)-2,2-difluorocyclopropyl-1-carboxylic acid (14 mg, 0.11 mmol, 1.3 eq.) were added, and the title compound T-029 (16 mg, 32% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.31 (t, J = 7.6Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 7.00 – 6.90 (m, 2H), 6.54 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 9.2 Hz, 1H), 5.06 (t, J = 8.8 Hz, 1H), 4.70 – 4.58 (m, 1H), 4.39 (d, J = 9.2 Hz, 1H), 4.17 (d, J = 10.0 Hz, 1H), 4.03 (d, J= 10.0 Hz, 1H), 2.89 (dd, J = 13.2, 8.4 Hz, 1H), 2.56 (dd, J = 13.2, 8.4 Hz, 1H), 2.36 –2.26 (m, 1H), 2.18 – 2.08 (m, 1H), 1.75 – 1.58 (m, 3H), 1.24 – 1.16 (m, 1H),1.01 (s, 9H), 0.99 – 0.91 (m, 6H). MS ( m / z 542.3 (Mw-H) - .

[0242] Example 30

[0243] (S)-2-acetamido-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-3-methylbutanamine (T-030)

[0244]

[0245] Following the synthesis method of T-009, T-008 (0.10 g, 0.23 mmol) and... N -acetyl- L -valine (45 mg, 0.28 mmol, 1.2 eq) yielded the title compound T-030 (39 mg, 36% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.58 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.30 – 7.20 (m, 1H), 6.95 – 6.64 (m, 2H), 4.98 (t, J = 8.0 Hz, 1H), 4.67 – 4.39 (m, 1H), 4.30 – 4.16 (d, J = 7.3 Hz, 1H), 4.01(d, J = 10.0 Hz, 1H), 3.86 (d, J= 10.0 Hz, 1H), 3.86 (d, J = 10.0 Hz, 1H) ,2.68 – 2.58 (m, 2H), 1.84 (s, 3H), 1.66 – 1.56 (m, 2H), 1.31 – 1.29 (m, 1H),0.86 – 0.76 (m, 12H). MS ( m / z 466.3 (Mw-H) - .

[0246] Example 31

[0247] N-((S)-2-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-031)

[0248]

[0249] Step 1: Preparation of tert-butyl(S)-2-((S)-1-(3R,5'S)-5'-cyano-2-oxaspiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-ylamino)-1-cyclopropyl-2-oxoethyl)carbamate (031-2). Following the synthetic method of T-009, T-008 (500 mg, 1.17 mmol) and 031-1 (500 mg, 2.32 mmol, 2.0 eq.) were added, and column chromatography (EA / Hep increased from 10% to 50%) was used to separate the title compound 031-2 (33 mg, 4% yield). MS ( m / z 524.2 (Mw+H) + .

[0250] Step 2: Preparation of N-((S)-2-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-031). Following the synthetic method of T-024, 031-2 (33 mg, 0.063 mmol) was added, and column chromatography (EA / Hep increased from 40% to 80%) was used to separate the title compound T-031 (11 mg, 34% yield). 1 H NMR (400 MHz, CDCl3) δ9.07 (s, 1H), 7.40 (d,J = 7.6 Hz, 1H), 7.33 – 7.25 (m, 2H), 7.03 (t, J = 7.6Hz, 1H), 6.99 – 6.94 (m, 2H), 5.05 (t, J = 8.4 Hz, 1H), 4.78 – 4.67 (m, 1H), 4.11 (d, J = 10.4 Hz, 1H), 4.08 – 3.98 (m, 2H), 2.83 (dd, J = 13.2, 8.4Hz, 1H), 2.57 (dd, J = 13.2, 8.4 Hz, 1H), 1.72 – 1.55 (m, 3H), 1.22 – 1.09 (m,1H), 0.94 (dd, J = 10.0, 6.0 Hz, 6H), 0.77 – 0.60 (m, 2H), 0.57 – 0.44 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -75.6 (s, 3F). MS ( m / z 542.1 (Mw+Na) + .

[0251] Example 32

[0252] tert-Butyl((S)-2-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-1-(3,3-difluorocyclobutyl)-2-oxoethyl)carbamate (T-032)

[0253]

[0254] Following the synthesis method of T-009, T-008 (0.50 g, 1.17 mmol) and ( S The title compound T-032 (290 mg, 43% yield) was isolated by column chromatography (EA / Hep increased from 0% to 50%) using 0.26 g ((tert-butoxycarbonyl)amino)-2-(3,3-difluorocyclobutyl)acetic acid (0.40 mmol, 1.2 eq.). 1 H NMR (400 MHz, CDCl3) δ8.46 (s, 1H), 7.30 (t, J= 7.2 Hz, 1H), 7.12 – 7.00 (m, 2H), 6.98 – 6.89 (m,2H), 5.11 – 4.97 (m, 2H), 4.65 (dd, J = 13.2, 7.6 Hz, 1H), 4.17 (t, J = 7.6Hz, 1H), 4.08 (d, J = 10.0 Hz, 1H), 3.98 (d, J = 10.0 Hz, 1H), 2.89 – 2.80(m, 1H), 2.61 – 2.49 (m, 3H), 2.48 – 2.30 (m, 3H), 1.70 – 1.63 (m, 2H), 1.45(s, 9H), 1.33 – 1.19 (m, 1H), 0.92 (dd, J = 12.4, 6.0 Hz, 6H). 19 F NMR (376MHz, CDCl3) δ -83.3 (d, J = 194.5 Hz), -95.5 (d, J = 194.5 Hz). MS ( m / z 596.2 (Mw+Na) + .

[0255] Example 33

[0256] N-((S)-2-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-1-(3,3-difluorocyclobutyl)-2-oxoethyl)cyclopropaneformamide (T-033)

[0257]

[0258] Following the synthetic method of T-025, T-032 (50 mg, 0.09 mmol) was added, and the title compound T-033 (13 mg, 27% yield) was isolated by column chromatography (EA / Hep increased from 30% to 70%). 1 H NMR (400 MHz, MeOH- d 4) δ7.28 (t, J = 7.6 Hz, 1H), 7.12 – 7.00 (m, 2H), 6.96 (d, J= 7.6 Hz, 1H), 5.12(t, J = 8.0 Hz, 1H), 4.62 – 4.48 (m, 1H), 4.46 – 4.33 (m, 1H), 4.16 (d, J =10.2 Hz, 1H), 3.94 (d, J = 10.2 Hz, 1H), 2.71 – 2.61 (m, 6H), 1.76 – 1.51 (m,4H), 1.38 – 1.23 (m, 1H), 1.08 – 0.86 (m, 6H), 0.79 – 0.62 (m, 4H). 19 F NMR (376 MHz, MeOH-) d 4) δ -80.2 (d, J = 194.3 Hz), -94.3 (d, J = 194.3 Hz). MS ( m / z 540.3 (Mw+H) + .

[0259] Example 34

[0260] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1-(2,2,2-trifluoroacetamido)cyclopropane-1-carboxamide (T-034)

[0261]

[0262] Step 1: Preparation of tert-butyl(1-((S)-1-(3R,5'S)-5'-cyano-2-oxaspiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)carbamate (034-2). Following the synthetic method of T-009, T-008 (399 mg, 0.93 mmol) and 034-1 (240 mg, 1.2 mmol, 1.3 eq.) were added, and column chromatography (EA / Hep increased from 30% to 60%) was used to separate the title compound 034-2 (203 mg, 43% yield). MS ( m / z 508.2 (Mw-H) - .

[0263] Step 2: Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)-1-(2,2,2-trifluoroacetamido)cyclopropane-1-carboxamide (T-034). Following the synthetic method for T-024, 034-2 (100 mg, 0.92 mmol) was added, and column chromatography (EA / Hep increased from 40% to 80%) was used to separate the title compound T-034 (66 mg, 66% yield). 1 H NMR (400 MHz, CDCl3) δ 9.26 (s,1H), 8.16 (s, 1H), 7.31 – 7.23 (m, 2H), 7.08 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 5.02 (t, J = 8.0 Hz, 1H), 4.76 –4.66 (m, 1H), 4.21 (d, J = 10.4 Hz, 1H), 3.97 (d, J = 10.4 Hz, 1H), 2.78 (dd, J = 13.2, 8.4 Hz, 1H), 2.57 (dd, J = 13.2, 8.4 Hz, 1H), 1.71 – 1.58 (m, 4H), 1.45 – 1.38 (m, 1H), 1.21 – 1.06 (m, 2H), 0.99 – 0.88 (m, 6H). MS ( m / z 504.2(Mw+H) + .

[0264] Example 35

[0265] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-1H-indole-2-carboxamide (T-035)

[0266]

[0267] Following the synthetic method of T-009, 035-01 (79 mg, 0.18 mmol) and 2-indolecarboxylic acid (36 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-035 (20 mg, 23% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.53 (s, 1H), 10.71 (s, 1H), 8.73 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.28 (s,1H), 7.24 – 7.12 (m, 3H), 7.04 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.17 (t, J = 7.6 Hz, 1H), 4.75 (dd, J = 14.4, 7.2Hz, 1H), 4.20 (d, J = 10.4Hz, 1H), 3.98 (d, J = 10.4 Hz, 1H), 2.67 – 2.59 (m,1H), 2.48 – 2.43 (m, 1H), 1.82 – 1.59 (m, 2H), 0.85 – 0.74 (m, 1H), 0.51 –0.32 (m, 2H), 0.30 – 0.11 (m, 2H). MS ( m / z 490.1 (Mw+Na) + .

[0268] Example 36

[0269] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-036)

[0270]

[0271] Following the synthetic method of T-009, 035-01 (79 mg, 0.18 mmol) and 4-methoxy-2-indolecarboxylic acid (43 mg, 0.22 mmol, 1.2 eq.) were added, and the title compound T-036 (20 mg, 22% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.52 (s, 1H), 10.71 (s, 1H), 8.64(d, J = 6.8 Hz, 1H), 7.37 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.17 – 7.05 (m,2H), 7.02 – 6.92 (m, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.17 (t, J = 7.6 Hz, 1H), 4.71 (d, J = 7.2 Hz, 1H), 4.20 (d, J = 10.4 Hz, 1H), 3.97 (d, J = 10.4 Hz, 1H), 3.90 (s, 3H), 2.78 – 2.59 (m, 1H), 2.40 –2.28 (m, 1H), 1.87 – 1.54 (m, 2H), 0.92 – 0.78(m, 1H), 0.46 – 0.35 (m, 2H),0.26 – 0.09 (m, 2H). MS ( m / z 520.1 (Mw+Na) + .

[0272] Example 37

[0273] tert-Butyl((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (T-037)

[0274]

[0275] Following the synthesis method of T-009, 035-01 (418 mg, 0.99 mmol) and N -Boc- L -Tertiary leucine (274 mg, 1.18 mmol, 1.2 eq.) was separated by column chromatography (EA / Hep increased from 5% to 50%) to give the title compound T-037 (270 mg, 51% yield). 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.30 – 7.24 (m, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.96 – 6.89 (m, 2H), 6.69 (d, J = 7.2 Hz, 1H), 5.17(d, J = 9.2 Hz, 1H), 5.06 (t, J = 8.8 Hz, 1H), 4.76 – 4.65 (m, 1H), 4.23 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 10.0 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H), 2.88(dd, J = 13.2, 9.2 Hz, 1H), 2.55 (dd, J = 13.2, 9.2 Hz, 1H), 1.75 – 1.67 (m,2H), 1.44 (s, 9H), 1.01 (s, 9H), 0.80 – 0.72 (m, 1H), 0.63 – 0.50 (m, 2H),0.24 – 0.10 (m, 2H). MS ( m / z 560.2 (Mw+Na) + .

[0276] Example 38

[0277] N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropionamide (T-038)

[0278]

[0279] Following the synthetic method of T-025, T-037 (614 mg, 1.14 mmol) was added, and the title compound T-038 (145 mg, 25% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.48(s, 1H), 7.31 – 7.24 (m, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.96 – 6.89 (m, 3H), 6.32 (d, J = 9.2 Hz, 1H), 5.09 (t, J = 8.6 Hz, 1H), 4.67 (dd, J = 13.6, 7.6Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 4.24 (d, J = 10.0 Hz, 1H), 4.06 (d, J =10.0 Hz, 1H), 2.92 – 2.82 (m, 1H), 2.55 (dd, J = 13.6, 8.0 Hz, 1H), 1.85 –1.74 (m, 2H), 1.47 – 1.36 (m, 1H), 1.32 – 1.24 (m, 1H), 0.99 (s, 9H), 0.98 –0.92 (m, 2H), 0.79 – 0.71 (m, 2H), 0.63 – 0.54 (s, 2H), 0.25 – 0.12 (m, 2H).MS ( m / z 504.3 (Mw-H) - .

[0280] Example 39

[0281] (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(methanesulfonamido)butyramide (T-039)

[0282]

[0283] T-037 (1.85 g, 3.45 mmol) was dissolved in 30 mL of TFA / DCM at a volume ratio of 1:2 and stirred at room temperature for 1 hour. The solution was concentrated, and a small amount of toluene was added to further remove residual TFA. The resulting crude product was dissolved in DCM (20 mL) and placed in an ice-water bath. DIPEA (2.4 mL, 13.80 mmol, 4.0 eq.) was added. Then, methanesulfonic anhydride (0.90 g, 5.17 mmol, 1.5 eq.) was added, and the mixture was allowed to rise naturally to room temperature for another 16 hours. The reaction was quenched with saturated NH4Cl, extracted, concentrated, and separated by column chromatography (EA / Hep increased from 0% to 100%) to obtain the title compound T-039 (0.85 g, 48% yield). 1 HNMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.37 – 7.30 (m, 1H), 7.09 – 6.89 (m,4H), 6.65 (d, J = 7.2 Hz, 1H), 5.10 (t, J = 8.4 Hz, 1H), 4.71 – 4.63 (m, 1H), 4.35 – 4.31 (m, 1H), 4.12 (d, J = 10.4 Hz, 1H), 4.07 (d, J = 10.4 Hz, 1H),3.12 (s, 3H), 2.95 – 2.85 (m, 1H), 2.66 – 2.54 (m, 1H), 1.81 – 1.67 (m, 2H),1.05 (s, 9H), 0.76 (s, 1H), 0.66 – 0.55 (m, 2H), 0.20 – 0.15 (m, 2H).

[0284] Example 40

[0285] (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-040)

[0286]

[0287] Following the synthesis method of T-024, T-037 (100 mg, 0.18 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the white solid T-040 (20 mg, yield 20%). 1 H NMR (400 MHz, CDCl3) δ 8.50 (s,1H), 7.32 (t, J = 7.2 Hz, 1H), 7.10 – 7.04 (m, 1H), 7.03 – 6.97 (m, 3H), 6.94(d, J = 7.2 Hz, 1H), 5.12 (t, J = 8.4 Hz, 1H), 4.72 (dd, J = 13.6, 7.6 Hz, 1H), 4.42 (d, J = 9.6 Hz, 1H), 4.18 (t, J = 10.4 Hz, 1H), 4.09 (t, J = 10.4Hz, 1H), 2.88 (dd, J = 13.8, 8.4 Hz, 1H), 2.59 (dd, J = 13.8, 8.4 Hz, 1H),1.85 – 1.71 (m, 2H), 1.04(s, 9H), 0.81 – 0.71 (m, 1H), 0.66 – 0.53 (m, 2H),0.23 – 0.14 (m, 2H). MS ( m / z 532.2 (Mw-H) - .

[0288] Example 41

[0289] tert-Butyl((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)carbamate (T-041)

[0290]

[0291] Following the synthesis method of T-008, 041-1 (124 mg, 0.25 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the white solid T-041 (102 mg, yield 85%). 1 H NMR (400 MHz, DMSO-d 6) δ 10.65(s, 1H), 7.44 – 7.19 (m, 3H), 7.18 – 6.81 (m, 6H), 5.07 (t, J = 8.0 Hz, 1H), 4.44 – 4.24 (m, 1H), 4.14 – 4.04 (m, 1H), 3.61 (d, J = 7.2 Hz, 1H), 3.03 –2.75 (m, 2H), 2.57 (dd, J = 12.8, 8.4 Hz, 1H), 2.39 (dd, J = 12.8, 8.4 Hz,1H), 1.22 (s, 9H). MS ( m / z 477.2 (Mw-H) - .

[0292] Example 42

[0293] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-1H-indole-2-carboxamide (T-042)

[0294]

[0295] Following the synthetic method of T-009, T-041 (80 mg, 0.17 mmol) and 2-indolecarboxylic acid (35 mg, 0.22 mmol, 1.3 eq.) were added, and the title compound T-042 (55 mg, 63% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.42 (s, 1H), 10.67 (s, 1H), 8.87 (s, 1H), 7.78 – 7.55 (m, 2H), 7.50 – 6.80 (m, 10H), 5.76 (s, 1H), 5.25 – 4.80 (m, 2H),4.18– 4.01 (m,1H), 3.76 – 3.61 (m, 1H), 2.85 – 2.38 (s, 4H). MS ( m / z 522.1(Mw+H) + .

[0296] Example 43

[0297] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-043)

[0298]

[0299] Following the synthetic method of T-009, T-041 (100 mg, 0.21 mmol) and 4-methoxy-2-indolecarboxylic acid (50 mg, 0.26 mmol, 1.2 eq.) were added, and the title compound T-043 (67 mg, 58% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.89 (s, 1H), 7.80 (s,1H), 7.28 (dr, 2H), 7.13 – 6.92 (m, 6H), 6.86 – 6.70 (m, 3H), 6.46 (d, J =6.8 Hz, 1H), 5.19 – 4.97 (m, 2H), 4.06 (d, J = 9.6 Hz, 1H), 3.89 (s, 3H), 3.53 (d, J = 9.6 Hz, 1H), 3.22 (d, J = 8.0 Hz, 2H), 2.76 (d, J = 11.2 Hz, 1H), 2.41 (d, J = 11.2 Hz, 1H). 19 F NMR (376 MHz, CDCl3) δ -112.3 (s, 1F). MS( m / z 550.2 (Mw-H) - .

[0300] Example 44

[0301] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-4,7-difluoro-1H-indole-2-carboxamide (T-044)

[0302]

[0303] Following the synthetic method of T-009, T-041 (100 mg, 0.21 mmol) and 4,7-difluoro-2-indolecarboxylic acid (50 mg, 0.25 mmol, 1.2 eq.) were added, and the title compound T-044 (33 mg, 28% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 8.30 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 13.6, 7.6 Hz, 1H), 7.27 – 7.18 (m, 1H), 7.15(d, J = 7.6 Hz, 1H), 7.09 – 7.00 (m, 3H), 6.96 – 6.82 (m, 4H), 6.68 (td, J =9.2, 3.2 Hz, 1H), 5.15 – 5.02 (m, 2H), 4.12 (d, J = 10.4 Hz, 1H), 3.57 (d, J = 10.4 Hz, 1H), 3.38 – 3.21 (m, 2H), 2.88 – 2.78 (m, 1H), 2.65 – 2.52 (m,1H). 19 F NMR (376 MHz, CDCl3) δ -118.9 (s, 1F), -125.9 (s, 1F), 138.9 (s, 1F).MS ( m / z 556.1 (Mw-H) - .

[0304] Example 45

[0305] N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropionamide (T-045)

[0306]

[0307] Step 1: Preparation of tert-butyltert-butyl(S)-1-((S)-1-(3R,5'S)-5'-cyano-2-oxaspiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-ylamino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (045-2). Following the synthetic method of T-009, 041-1 (500 mg, 1.04 mmol) and 045-1 (291 mg, 1.26 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 35% to 70%) was used to separate the title compound 045-2 (450 mg, 72% yield). MS ( m / z 590.2 (Mw-H) - .

[0308] Step 2: Preparation of N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropionamide (T-045). Following the synthetic method for T-025, 045-2 (100 mg, 0.17 mmol) was added, and column chromatography (EA / Hep increased from 35% to 70%) was used to separate the title compound T-045 (47 mg, 50% yield). 1 H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.34 (dd, J = 14.0, 8.0 Hz, 1H), 7.24 (t, J =7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.10 – 6.94 (m, 4H), 6.94 – 6.83 (t, J = 7.6Hz, 2H), 6.34 (d, J = 9.2 Hz, 1H), 5.02 (t, J = 8.4 Hz, 1H), 4.79 (dd, J =14.0, 8.0 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.25(d, J= 10.4 Hz, 1H), 3.20 – 3.01 (m, 2H), 2.68 (dd, J = 13.2, 9.2 Hz, 1H), 2.46 (dd, J = 13.2, 9.2 Hz, 1H), 2.09 – 2.01 (s, 1H), 0.96 (s, 9H), 0.90 –0.88 (m, 2H), 0.82 – 0.74 (m, 2H). MS ( m / z 558.2 (Mw-H) - .

[0309] Example 46

[0310] (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-046)

[0311]

[0312] Following the synthetic method of T-024, 045-2 (100 mg, 0.16 mmol) was added, and column chromatography (EA / Hep increased from 30% to 60%) was used to separate the title compound T-046 (58 mg, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 8.45(s, 1H), 7.39 – 7.28 (m, 2H), 7.12 – 6.95 (m, 7H), 6.87 (d, J = 7.2 Hz, 1H), 5.06 (t, J = 8.8 Hz, 1H), 4.89 – 4.79 (m, 1H), 4.43 (t, J = 9.2 Hz, 1H), 3.89(d, J = 10.4 Hz, 1H), 3.30 (d, J = 10.4 Hz, 1H), 3.19 – 3.02 (m, 2H), 2.73(dd, J = 13.2, 8.8 Hz, 1H), 2.51 (dd, J = 13.2, 8.8 Hz, 1H), 1.02 (s, 9H). 19FNMR (376 MHz, CDCl3) δ -75.6 (s, 3F), -111.8 (s, 1F). MS ( m / z 586.2 (Mw-H) - .

[0313] Example 47

[0314] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclohexyl-1-oxopropane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-047)

[0315]

[0316] Following the synthetic method of T-009, 047-01 (100 mg, 0.21 mmol) and 4-methoxy-2-indolecarboxylic acid (54 mg, 0.28 mmol, 1.3 eq.) were added, and the title compound T-047 (101 mg, 87% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.28 (s, 1H), 7.24 –7.13 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H), 6.94 – 6.82 (m, 3H), 6.53 (d, J = 7.8Hz, 1H), 5.10 (t, J = 8.4 Hz, 1H), 4.99 – 4.89 (m, 1H), 4.29 (d, J = 10.2 Hz, 1H), 4.05 (d, J = 10.2 Hz, 1H), 3.97 (s, 1H), 2.91 (dd, J = 13.2, 8.8 Hz, 2H), 2.56 (dd, J = 13.2, 8.8 Hz, 1H), 1.90 – 1.70 (m, 9H), 1.23 – 0.98 (m,4H). MS ( m / z 538.2 (Mw-H) - .

[0317] Example 48

[0318] N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4,4-difluorocyclohexane-1-carboxamide (T-048)

[0319]

[0320] Following the synthetic method of T-009, 035-01 (100 mg, 0.24 mmol) and 4,4-difluorocyclohexanecarboxylic acid (46 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-048 (12 mg, 11% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.39 – 7.31 (m, 1H), 7.10 – 7.02 (m, 1H), 6.98 – 6.92 (m, 2H), 6.43 (d, J = 7.6 Hz, 1H), 5.05 (t, J =8.4 Hz, 1H), 4.80 – 4.68 (m, 1H), 4.17 (d, J = 10.4 Hz, 1H), 4.05 (d, J =10.4 Hz, 1H), 2.92 – 2.84 (m, 1H), 2.60 – 2.53 (m, 1H), 2.29 – 2.11 (m, 4H), 1.98 – 1.88 (m, 1H), 1.83 – 1.71 (m, 6H), 0.77 – 067 (m, 1H), 0.65 – 0.52 (m,2H), 0.22 – 0.15 (m, 2H). MS ( m / z 469.2 (Mw-H) - .

[0321] Example 49

[0322] N-((S)-1-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropionamide (T-049)

[0323]

[0324] Following the synthetic method of T-025, 049-1 (198 mg, 0.36 mmol) was added, and column chromatography (EA / Hep increased from 25% to 50%) was used to separate the title compound T-049 (20 mg, 11% yield). 1 H NMR (400 MHz, CDCl3) δ 8.67(s, 1H), 7.00 (t, J = 8.4 Hz, 1H), 6.89 (dd, J = 8.4, 4.0 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.31 (d, J = 9.2 Hz, 1H), 5.06 (t, J = 8.6 Hz, 1H), 4.67 – 4.54 (m, 1H), 4.42 – 4.27 (m, 2H), 4.10 – 4.00 (d, J =10.4 Hz, 1H), 2.88 (dd, J = 12.6, 8.4 Hz, 1H ), 2.55 (dd, J = 12.6, 8.4 Hz,1H), 1.84 – 1.72 (m, 3H), 0.99 (s, 9H), 0.92 – 0.85 (m,2H), 0.82 – 0.68 (s,3H), 0.65 – 0.52 (s, 2H), 0.25 – 0.13 (s, 2H). 19 F NMR (376 MHz, CDCl3) δ -118.4 (s, 1F). MS ( m / z 522.2 (Mw-H) - .

[0325] Example 50

[0326] (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanylamine (T-050)

[0327]

[0328] Following the synthetic method of T-024, 049-1 (198 mg, 0.36 mmol) was added, and column chromatography (EA / Hep increased from 25% to 40%) was used to separate the title compound T-050 (65 mg, 33% yield). 1 H NMR (400 MHz, CDCl3) δ 8.18(s, 1H), 7.09 – 6.98 (m, 2H), 6.96 – 6.90 (m, 1H), 6.77 – 6.66 (m, 2H), 5.08(t, J = 8.4 Hz, 1H), 4.68 – 4.58 (m, 1H), 4.36 (d, J = 9.2 Hz, 1H), 4.22 (t, J = 10.4 Hz, 1H), 4.08 (d, J = 10.4 Hz, 1H), 2.98 – 2.86 (m, 1H), 2.64 – 2.52(m, 1H), 1.85 – 1.68 (m, 2H), 1.05 (s, 9H), 0.93 – 0.83 (s, 1H), 0.68 – 0.56(s, 2H), 0.27 – 0.13 (s, 2H). 19 F NMR (376 MHz, CDCl3) δ -75.7 (s, 3F), -118.33 (s, 1F). MS ( m / z 550.2 (Mw-H) - .

[0329] Example 51

[0330] (3R, 5'S)-5'-cyano-1'-((S)-3-cyclopropyl-2-(4-methoxy-1H-indole-2-carbamoyl)propionyl)-N,N-dimethyl-2-oxospiro[indoline-3,3'-pyrrolidine]-5-carboxamide (T-051)

[0331]

[0332] Step 1: Preparation of 1'-(tert-butyl)5'-methyl(3R,5'S)-5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylic acid ester (051-1). 001-5 (10.00 g, 28.87 mmol) was dissolved in DCM (30 mL), and NBS (6.17 g, 34.67 mmol, 1.2 eq.) and AcOH (0.5 mL) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After washing with water, concentration, and separation by column chromatography (EA / Hep increased from 5% to 50%), the title compound 051-1 (10.41 g, 85% yield) was obtained. MS ( m / z 425.0 (Mw+H) + .

[0333] Step-2: Preparation of (3R, 5'S)-1'-(tert-butoxycarbonyl)-5'-(methoxycarbonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5-carboxylic acid ester (051-2). Under a nitrogen atmosphere, 051-1 (2.00 g, 4.70 mmol), formic acid (1.52 g, 33.02 mmol, 7.0 eq.), DCC (0.97 g, 4.71 mmol, 1.0 eq.), Pd(OAc)2 (0.11 g, 0.48 mmol, 0.1 eq.), XantPhos (0.27 g, 0.47 mol, 0.1 eq.), and TEA (1.3 mL, 9.43 mmol, 2.0 eq.) were added sequentially to DMF (10 mL). The resulting mixture was heated in an oil bath at 100 °C for 16 hours. After cooling to room temperature, the reaction was quenched with saturated NH4Cl, the pH was adjusted to 3-4 with 1 N hydrochloric acid aqueous solution, and the mixture was extracted with EA and concentrated. Column chromatography (EA / Hep increased from 80 to 100%) yielded the title compound 051-2 (2.61 g, crude product contained trace impurities). MS ( m / z 389.1 (Mw-H) - .

[0334] Step 3: Preparation of 1'-(tert-butyl)5'-methyl(3R,5'S)-5-(dimethylcarbamoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylic acid ester (051-3). 051-2 (224 mg, 0.57 mmol) was dissolved in DCM (10 mL), and dimethylamine (71 mg, 0.87 mmol, 1.5 eq.), DIPEA (0.5 mL, 2.87 mmol, 5.0 eq.), and HATU (327 mg, 0.86 mmol, 1.5 eq.) were added under ice-water bath. The resulting reaction mixture was stirred for 2 hours, quenched with saturated NH4Cl, extracted with EA, concentrated, and separated by column chromatography (EA / Hep increased from 80% to 100%) to obtain the title compound 051-3 (238 mg, 99% yield). MS ( m / z 416.1 (Mw-H) - .

[0335] Steps 4 and 5: Preparation of methyl (3R,5′)-1′-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropane)-5-(dimethylcarbamoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxylic acid ester (051-4). Following the synthetic method of 008-1, 051-3 (238 mg, 0.57 mmol) and Boc- L Cyclopropylalanine (157 mg, 0.68 mmol, 1.2 eq.) was separated by column chromatography (EA / HeP increased from 80 to 100%) to give the title compound 051-4 (210 mg, 69% yield). MS ( m / z 527.2 (Mw-H) - .

[0336] Steps 6 and 7: Preparation of tert-butyl((S)-1-((3R,5'S)-5'-carbamoyl-5-(dimethylcarbamoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamate (051-5). Following the synthetic method described in 008-3, 051-4 (210 mg, 0.40 mmol) was added to give the title compound 051-5 (96 mg, 32% yield). MS ( m / z 514.1 (Mw+H) +

[0337] Step 8: Preparation of tert-butyl((S)-1-((3R,5'S)-5'-cyano-5-(dimethylcarbamoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamate (051-6). Following the synthetic method described in T-008, 051-5 (96 mg, 0.19 mmol) was added to give the title compound 051-6 (64 mg, 69% yield). MS ( m / z 494.2 (Mw-H) - .

[0338] Step 9: Preparation of (3R, 5'S)-5'-cyano-1'-((S)-3-cyclopropyl-2-(4-methoxy-1H-indole-2-carboxamido)propionyl)-N,N-dimethyl-2-oxospiro[indole-3,3'-pyrrolidine]-5-carboxamide (T-051). Following the synthetic method of T-009, 051-06 (64 mg, 0.13 mmol) and 4-methoxy-2-indolecarboxylic acid (30 mg, 0.16 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 70% to 100%) was used to separate the title compound T-051 (40 mg, 55% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 11.49 (s, 1H), 10.90 (s, 1H), 8.72 (s, 1H), 8.30 – 8.10 (dr, 1H), 7.51 – 7.17 (m, 3H), 7.14 – 6.86 (m, 2H), 6.53 (s, 1H),5.20 (s, 1H), 4.72 (s, 1H), 4.33 (d, J = 10.0 Hz, 1H), 4.03 (d, J = 10.0 Hz,1H), 3.90 (s, 3H), 2.98 – 2.77 (m, 2H), 2.51 (s, 6H), 1.77 – 1.63 (m, 2H), 0.86 – 0.76 (m, 1H), 0.52 – 0.35 (s, 2H), 0.28 – 0.10 (m, 2H). MS ( m / z 569.2(Mw+H) + .

[0339] Example 52

[0340] N-((S)-1-(5-cyano-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-1-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-052)

[0341]

[0342] Step 1: Preparation of 9-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrrole[2,3-b:5,4-c']bipyridine-6-carboxylic acid (052-2). 052-1 (5.00 g, 24.36 mmol) was dissolved in water (50 mL) to obtain a suspension. Formaldehyde aqueous solution (4.48 g, 48.67 mmol, 37 wt%, 2.0 eq.) was added, and the mixture was stirred at room temperature for 1 hour, followed by heating at 40 °C for 15 hours. The reaction solution was used directly in the next step without further treatment. MS ( m / z 248.1 (Mw+H) + .

[0343] Step 2: Preparation of 6,7,8,9-tetrahydro-5H-pyrrole[2,3-b:5,4-c']bipyridine-6-carboxylic acid (052-3). Ammonia (36%, 10 mL) was added to the reaction solution from Step 1, and the reaction mixture was stirred at 18°C ​​for 16 hours. The concentration yielded the title compound 052-3 (5.28 g, crude product). MS ( m / z 218.1 (Mw+H) + .

[0344] Step 3: Preparation of methyl 6,7,8,9-tetrahydro-5H-pyrrole[2,3-b:5,4-c']bipyridine-6-carboxylic acid (052-4). 052-3 (5.28 g) was dissolved in methanol (60 mL), and SOCl2 (5.78 g) was added dropwise under an ice-water bath, followed by heating to 70 °C for 2 hours. The solution was concentrated to give the title compound 052-4 (6.50 g, crude product).

[0345] Step 4: Preparation of 7-(tert-butyl)-6-methyl 5,6,8,9-tetrahydro-7H-pyrrole[2,3-b:5,4-c']bipyridine-6,7-dicarboxylate (052-5). 052-4 (6.50 g) was dissolved in THF (50 mL) and H₂O (50 mL), followed by the addition of Na₂CO₃ (7.72 g) and (Boc)₂O (5.29 g). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added, followed by extraction with EA and concentration. Column chromatography (EA / Hep increased from 10% to 100%) yielded the title compound 052-5 (1.36 g). MS ( m / z 332.0 (Mw+H) + .

[0346] Step 5: Preparation of 1-(tert-butyl)5-methyl(3R,5S)-2'-oxo-1',2'-dihydrospirocyclic [pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-1,5-dicarboxylic acid ester (052-6). 052-5 (1.30 g, 3.92 mmol) was dissolved in 2-methyltetrahydrofuran (9 mL) and placed in an ice-salt bath. Water (9 mL) and AcOH (3 mL) were added. The internal temperature was controlled below -5 °C, and NBS (0.63 g, 3.56 mmol, 0.9 eq.) was added in batches, and the reaction was continued at this temperature for 2 hours. The reaction was quenched with saturated NaHCO3 solution, extracted with EA, dried over anhydrous MgSO4, filtered, and concentrated to give the title compound 052-6 (1.36 g, 99% yield, major components being a pair of corresponding isomers). MS ( m / z 348.1 (Mw+H) + .

[0347] Steps 6 and 7: Preparation of methyl 1-(S)-2-(tert-butoxycarbonyl)amino)-3-cyclopropylpropionyl)-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (052-7). 052-6 (1.36 g, 3.92 mmol) was dissolved in dioxane (10 mL), followed by the addition of HCl / dioxane (4 M, 10 mL). The resulting liquid was stirred at room temperature for 16 hours, and the crude product was concentrated for the next step. The crude product was dispersed in DCM (15 mL), and Boc- was added sequentially under an ice-water bath. LCyclopropylalanine (1.00 g, 4.36 mmol, 1.1 eq.), HATU (1.78 g, 4.68 mmol, 1.2 eq.), and DIPEA (2.0 mL, 11.76 mmol, 3.0 eq.). The mixture was stirred in an ice bath for 2 hours, concentrated, and separated by column chromatography (EA / HeP increased from 10% to 70%) to give the title compound 052-7 (2.00 g, containing trace impurities). MS ( m / z 459.2 (Mw+H) + .

[0348] Step 8: Preparation of tert-butyl((2S)-1-(5-aminocarbamoyl-2'-oxo-1',2'-dihydrospirocyclic [pyrrolidine-3,3'-pyrrolo[2,3-b]pyridin]-1-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamate (052-8). 052-7 (1.00 g) was dissolved in ammonia-methanol (7 N, 15 mL) and placed in a pressure-resistant stainless steel reactor, heated to 80 °C for 48 hours. The concentration yielded the title compound 052-8 (0.97 g, containing trace impurities). MS ( m / z 326.1 (Mw-Boc+2H) + .

[0349] Step-9: Preparation of tert-butyl((2S)-1-(5-cyano-2'-oxo-1',2'-dihydrospirocyclic [pyrrolidine-3,3'-pyrrolo[2,3-b]pyridin]-1-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamate (052-9). Following the synthetic method of T-008, 052-8 (0.97 g) was added to yield the title compound 052-9 (0.92 g, crude product). MS ( m / z )326.1 (Mw-Boc+2H) + .

[0350] Step 10: Preparation of N-((S)-1-(5-cyano-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolidin[2,3-b]pyridine]-1-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-052). Following the synthetic method of T-009, 052-9 (353 mg, 0.83 mmol) and 4-methoxy-2-indolecarboxylic acid (190 mg, 0.99 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 10% to 100%) was used to separate the title compound T-052 (15 mg, 4% yield). 1 H NMR (400 MHz, DMSO-d 6) 11.34 - 11.65 (m, 2H), 8.63 - 8.80 (m,1H), 8.09 - 8.13 (m, 1H), 7.51 - 7.59 (m, 1H), 7.37 (s, 1H), 6.96 - 7.13 (m,3H), 6.51 (d, J = 9.6 Hz, 1H), 5.00 - 5.20 (m, 1H), 4.60 - 4.75 (m, 1H), 3.99- 4.08 (m, 2H), 3.89 (s, 3H), 3.59 - 3.61(m, 1H), 2.67 - 2.6 (m, 2H), 1.75 -1.78 (m, 3H), 0.22 - 043 (m, 3H). MS ( m / z 469.3 (Mw-H) - .

[0351] Example 53

[0352] N -((2 S )-1-((3 R 5' S )-5'-cyano-2'-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)cinnamamide (T-053)

[0353]

[0354] Step 1: Preparation of (3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester (053-1). Following the synthetic method of 001-3, 001-2 (10.00 g, 39.2 mmol) was added to give the title compound 053-1 (9.59 g, 99% yield, crude product). MS ( m / z 245.1 (Mw+ H) + .

[0355] Step 2: Preparation of 2-(tert-butyl)-3-methyl(3S)-1-methyl-1,3,4,9-tetrahydro-2H-pyridine[3,4-b]indole-2,3-dicarboxylate (053-2). Following the synthetic method of 001-4, 053-1 (9.59 g, 39.2 mmol) was added and separated by column chromatography (EA / Hep increased from 5% to 40%) to obtain the title compound 053-2 (8.66 g, 64% yield).

[0356] Step 3: Preparation of 1'-(tert-butyl)5'-methyl(3R,5'S)-2'-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylic acid ester (053-3). Following the synthetic method described in 001-5, 053-2 (2.36 g, 6.8 mmol) was added, and column chromatography (EA / Hep increased from 5% to 30%) was used to separate the title compound 053-3 (1.95 g, 78% yield). MS ( m / z 261.1 (Mw-Boc+2H) + .

[0357] Step 4: Preparation of methyl(3R,5'S)-1'-((tert-butyloxycarbonyl)-L-leucine)-2'-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid ester (053-4). Following the synthesis in T-008, 053-3 (1.95 g, 9.4 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 053-4 (0.78 g, 30% yield). MS ( m / z 474.2 (Mw+ H) + .

[0358] Steps 5 and 6: Preparation of tert-butyl((2S)-1-((3R,5'S)-5'-cyano-2'-methyl-2-oxopyrrolo[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)carbamate (053-5). Following the synthetic method of 052-9, 053-4 (0.78 g, 1.64 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 053-5 (0.38 g, 52% yield). MS ( m / z 439.2 (Mw-H) - .

[0359] Step 7: N -((2 S )-1-((3 R 5' S Preparation of 5'-cyano-2'-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)cinnamamide (T-053). Following the synthetic method of T-009, 053-5 (100 mg, 0.22 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-053 (24 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.64 (d, J = 15.6Hz, 1H), 7.45 – 7.39 (m, 2H), 7.36 – 7.32 (m, 3H), 7.28 – 7.17 (m, 2H), 7.05(t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.27 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 9.6 Hz, 1H), 5.22 (t, J = 8.8 Hz, 1H), 5.02 – 4.90 (m, 1H), 4.84 – 4.75 (m, 1H), 2.80 – 2.75 (m, 1H), 2.69 – 2.60 (m, 1H), 1.81 – 1.70 (m, 2H), 1.61 (s, 3H), 1.17 – 1.12 (m, 1H), 1.00 (d, J = 6.0 Hz, 6H). MS (m / z)469.3 (Mw- H) - .

[0360] Example 54

[0361] Preparation of N-((2S)-1-((3R,5'S)-5'-cyano-2'-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)4-methyl-1-oxopentane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-054)

[0362]

[0363] Following the synthetic method of T-009, 053-5 (100 mg, 0.22 mmol) and 4-methoxy-2-indolecarboxylic acid (48 mg, 0.25 mmol, 1.1 eq.) were added, and the title compound T-054 (18 mg, 15% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 11.41 (s, 1H), 10.45 (s, 1H), 7.00 – 6.92 (m, 2H), 6.88 – 6.81 (m, 3H), 6.78 – 6.68 (m, 2H), 6.23 – 6.13 (s, 2H),5.22 – 5.03 (m, 3H), 3.85 (s, 3H), 2.77 – 2.63 (m, 1H), 2.61 – 2.42 (m, 1H),1.90 – 1.78 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H), 1.37 – 1.26 (m, 1H), 1.08 (dd, J = 9.5, 6.1 Hz, 6H). MS ( m / z 512.3 (Mw-H) - .

[0364] Example 55

[0365] Preparation of N-((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-2-fluorocyclopropane-1-carboxamide (T-055)

[0366]

[0367] Following the synthetic method of T-028, T-023 (49 mg, 0.09 mmol) and 2-fluorocyclopropylcarboxylic acid (12 mg, 0.12 mmol, 1.3 eq.) were added, and the title compound T-055 (11 mg, 23% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%).

[0368] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 3.6 Hz, 1H), 7.35 – 7.28 (m,1H), 7.07 – 6.97 (m, 1H), 6.94 (t, J = 6.0 Hz, 2H), 6.85 – 6.75 (m, 1H), 6.55– 6.25 (m, 1H), 5.06 (t, J= 8.4 Hz, 1H), 4.69 – 4.53 (m, 1H), 4.40 –4.28 (m, 1H), 4.21 (t, J = 9.6 Hz, 1H), 4.03 (dd, J = 10.0, 4.4 Hz, 1H), 2.93– 2.84 (m, 1H), 2.55 (dd, J = 13.2, 8.0 Hz, 1H), 1.95 – 1.82 (dt, J = 15.8,7.3 Hz, 1H), 1.78 – 1.70 (m, 1H), 1.65 (d, J = 5.6 Hz, 2H), 1.00 (s, 9H), 0.98 – 0.94 (m, 6H), 0.93 – 0.84 (m, 3H). MS(m / z) 524.3(Mw- H) - .

[0369] Example 56

[0370] Preparation of N-((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (T-056)

[0371]

[0372] Following the synthetic method of T-028, T-023 (49 mg, 0.09 mmol) and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (17 mg, 0.11 mmol, 1.2 eq.) were added, and the title compound T-056 (28 mg, 53% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.31 – 7.23 (m,1H), 7.05 (d, J = 7.6 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.92 (dd, J = 12.4,7.6 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 5.15 – 5.04 (m, 1H), 4.78 – 4.66 (m,1H), 4.43 (d, J = 8.8 Hz, 1H), 4.25 (d, J = 10.0 Hz, 1H), 4.02 (d, J = 10.0Hz, 1H), 2.87 (dd, J = 12.8, 8.4 Hz, 1H), 2.54 (dd, J = 12.8, 8.4 Hz, 1H), 1.88 (s, 1H), 1.78 – 1.65 (m, 1H), 1.54 – 1.49 (m, 1H), 1.39 – 1.30 (m, 2H), 1.25 – 1.21 (m, 2H), 1.00 (s, 9H), 0.99 – 0.92 (m, 6H). MS (m / z) 574.3 (Mw-H) - .

[0373] Example 57

[0374] Preparation of N-((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-1-methylcyclopropane-1-carboxamide (T-057)

[0375]

[0376] Following the synthetic method of T-028, T-023 (59 mg, 0.11 mmol) and 1-methylcyclopropane-1-carboxylic acid (13 mg, 0.12 mmol, 1.2 eq.) were added, and the title compound T-057 (33 mg, 58% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.36 – 7.23 (m, 1H), 7.01 (t, J= 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 9.2 Hz, 1H), 5.06 (t, J = 8.8 Hz, 1H), 4.62 (q, J = 7.2 Hz, 1H), 4.34 (d, J = 9.2 Hz, 1H), 4.23 (d, J = 10.0 Hz, 1H), 4.02 (d, J = 10.0 Hz, 1H), 2.87 (dd, J = 13.6, 9.8 Hz, 1H), 2.54 (dd, J = 13.6, 9.8 Hz, 1H), 1.66(d, J = 4.4 Hz, 2H), 1.34 (s, 3H), 1.22 – 1.15 (m, 2H), 0.99 (s, 9H), 0.95 –0.85 (m,7H), 0.60 (d, J = 2.8 Hz, 2H). MS (m / z) 574.3 (Mw-H) - .

[0377] Example 58

[0378] Preparation of (S)-N-(S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-058)

[0379]

[0380] Following the synthetic method of T-024, 058-1 (85 mg, 0.15 mmol) was added, and column chromatography (EA / Hep increased from 30% to 40%) was used to separate the title compound T-058 (37 mg, 44% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.73 (s, 1H), 9.15 (d, J= 9.2 Hz, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.8Hz, 1H), 7.05–6.99 (m, 1H), 6.94–6.85 (m, 2H), 5.14 (t, J = 8.0 Hz, 1H),4.68–4.62 (m, 1H), 4.37 (d, J = 9.2 Hz, 1H), 4.11– 3.86 (m, 2H), 2.61 (dd, J = 13.2, 8.4 Hz, 1H), 2.47 (dd, J = 13.2, 8.4 Hz, 1H), 2.21 – 2.08 (m, 1H), 2.02 – 1.90 (m, 1H), 1.37 – 1.27 (m, 6H), 1.01 – 0.88 (m, 9H). MS (m / z) 552.2(Mw-H) - .

[0381] Example 59

[0382] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4,4-dimethyl-1-oxopentane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-059)

[0383]

[0384] 059-01 (200 mg, 0.44 mmol) was dissolved in 9 mL of TFA / DCM at a volume ratio of 1:2 and stirred at room temperature for 1 hour. The solution was concentrated, and a small amount of toluene was added to further remove residual TFA. The resulting crude product was dissolved in DCM (10 mL), and then (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (99 mg, 0.44 mmol), DIPEA (0.3 mL, 1.74 mmol, 4.0 eq.), and HATU (215 mg, 0.56 mmol, 1.3 eq.) were added. The resulting reaction solution was stirred at room temperature for 1 hour. The solution was concentrated, and column chromatography (EA / Hep increased from 25% to 50%) was used to separate the title compound T-059 (70 mg, 28% yield). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.09 – 6.99 (m, 1H), 6.97 –6.85 (m, 2H), 6.75 – 6.68 (m, 1H), 6.65 (d, J = 7.2 Hz, 1H), 5.08 – 5.00 (m,1H), 4.65 – 4.58(m, 1H), 4.34 (d, J = 9.2 Hz, 1H), 4.28 (d, J = 10.0 Hz, 1H), 4.04 (d, J = 10.0 Hz, 1H), 2.90 (dd, J = 13.2, 9.6 Hz, 1H), 2.57 (dd, J =13.2 9.6 Hz, 1H), 1.89 – 1.80 (m, 2H), 1.02 (s, 9H), 0.98 (s, 9H). MS (m / z)566.3 (Mw-H) - .

[0385] Example 60

[0386] Preparation of (3R,5'S)-1'-((1R,2S,5S)-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carbamate (T-060)

[0387]

[0388] Following the synthetic method of T-009, 060-1 (0.12 g, 0.27 mmol) and 4-methoxyindole-2-carboxylic acid (62 mg, 0.32 mmol, 1.2 eq.) were added, and the title compound T-060 (20 mg, 14% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.73 (s, 1H), 7.26 – 7.10 (m, 4H), 7.05 – 6.92 (m, 3H), 6.52 (d, J = 7.6 Hz, 1H), 5.09 (t, J=8.4 Hz, 1H), 4.40– 4.32 (m, 2H), 4.17 – 4.07 (m, 3H), 3.99 (s, 3H), 2.92 –2.81 (m, 1H), 2.57 (dd, J = 13.2, 8.4 Hz, 1H), 1.37 – 1.25 (m, 2H), 1.13 (s, 3H), 0.95 (s, 3H). MS (m / z) 522.2 (Mw-H) - .

[0389] Example 61

[0390] Preparation of (3R,5'S)-1'-((1R,2S,5S)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carbamate (T-061)

[0391]

[0392] Following the synthetic method of T-009, 060-1 (0.12 g, 0.27 mmol) and 4,7-difluoroindole-2-carboxylic acid (63 mg, 0.32 mmol, 1.2 eq.) were added, and the title compound T-061 (14 mg, 14% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 8.01 (s, 1H), 7.28 –7.05 (m, 4H), 7.00 – 6.85 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 5.09 (t, J =8.4 Hz, 1H), 4.41– 4.23 (m, 3H), 4.19 – 4.01 (m, 2H), 2.95 – 2.83 (m, 1H), 2.57 (dd, J = 13.2, 8.4 Hz, 1H), 1.62 – 1.48 (m, 2H), 1.16 (s, 3H), 0.98 (s, 3H). MS (m / z) 528.2 (Mw-H) - .

[0393] Example 62

[0394] Preparation of tert-butyl(1R,2S,5S)-2-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (T-062)

[0395]

[0396] Following the synthetic method of T-009, 035-1 (0.24 g, 0.58 mmol) and 062-1 (180 mg, 0.70 mmol, 1.2 eq.) were added, and the title compound T-062 (40 mg, 12% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 13.6 Hz, 1H), 7.27 – 7.15 (m, 1H), 7.11 – 6.84 (m, 4H), 5.10 – 5.00 (m, 1H), 4.83 – 4.72 (m, 1H), 4.33 – 3.99(m, 2H), 3.69 – 3.38 (m, 3H), 3.00 – 2.84 (m, 1H), 2.54 (dd, J = 13.2, 8.4Hz, 1H), 1.86 – 1.67 (m, 2H), 1.48 (s, 9H), 1.39 – 1.30 (m, 2H), 0.96 – 0.85(m, 6H), 0.78 – 0.71 (m, 1H), 0.66 – 0.49 (m, 2H), 0.19 – 0.11 (m, 2H). MS (m / z) 560.3 (Mw-H) - .

[0397] Example 63

[0398] Preparation of (1R,2S,5S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-6,6-dimethyl-3-(2,2,2-trifluoroacetic acid)-3-azabicyclo[3.1.0]hexane-2-carboxamide (T-063)

[0399]

[0400] Following the synthetic method of T-024, T-062 (24 mg, 0.04 mmol) was used for column chromatography (EA / Hep increased from 5% to 50%) to separate the title compound T-063 (4 mg, 17% yield). 1 H NMR (400 MHz, CDCl3) δ 7.95 (s,1H), 7.33 – 7.29 (m, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.08 – 6.93 (m, 2H), 6.80(d, J = 7.6 Hz, 1H), 5.08 (t, J = 8.4 Hz, 1H), 4.70 (dd, J = 13.4, 7.2 Hz,1H), 4.36 (s, 1H), 4.13 (d, J = 10.4 Hz, 1H), 4.05 (d, J = 10.4 Hz, 1H),3.97– 3.91 (m, 1H), 3.83– 3.76 (m, 1H), 2.87 (dd, J = 13.2, 8.4 Hz, 1H), 2.58(dd, J = 13.2, 8.4 Hz, 1H), 1.85 – 1.69 (m, 2H), 1.11 (s, 3H), 0.95 (m, 3H), 0.93 – 0.84 (m, 2H), 0.79– 0.72 (m, 1H), 0.62 – 0.51 (m, 2H), 0.24 – 0.13 (m,2H). MS (m / z) 556.2 (Mw-H) - .

[0401] Example 64

[0402] Preparation of (S)-N-((S)-1-((3R, 5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-5-(2,2,2-trifluoroacetyl)-5-azaspirocyclic[2,4]heptane-6-carboxamide (T-064)

[0403]

[0404] Step-1: Preparation of tert-butyl(S)-6-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamoyl)-5-azaspirocyclic[2,4]heptane-5-carboxylic acid ester (064-2). Following the synthetic method of T-009, 035-1 (248 mg, 0.58 mmol) and 064-1 (170 mg, 0.70 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 064-2 (60 mg, 19% yield). MS ( m / z 546.3 (Mw-H) - .

[0405] Step-2: Preparation of (S)-N-((S)-1-((3R, 5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-5-(2,2,2-trifluoroacetyl)-5-azaspirocyclic[2,4]heptane-6-carboxamide (T-064). Following the synthetic method of T-024, 064-2 (45 mg, 0.08 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-064 (33 mg, 74% yield). 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H),7.02 – 6.94 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 5.06 (t, J = 8.4 Hz, 1H), 4.75– 4.61 (m, 2H), 4.13 (d, J = 10.4 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 3.68(d, J = 10.4 Hz, 1H), 3.61 (d, J = 10.4 Hz, 1H), 2.87 (dd, J = 13.2, 8.0 Hz, 1H), 2.57 (dd, J= 13.2, 8.0 Hz, 1H), 2.16 (dd, J = 12.8, 8.4 Hz, 1H), 2.05(dd, J = 12.8, 8.4 Hz, 1H), 1.84 – 1.67 (m, 2H), 0.83 – 0.73 (m, 1H), 0.72 –0.66 (m, 4H), 0.63 – 0.53 (m, 2H), 0.23 – 0.14 (m, 2H). MS ( m / z 542.2 (Mw-H) - .

[0406] Example 65

[0407] Preparation of (S)-N-((S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4,4-dimethyl-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (T-065)

[0408]

[0409] Step 1: tert-butyl ( S )-2-((( S )-1-((3 R 5' S Preparation of 5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamoyl)-4,4-dimethylpyrrolidine-1-carboxylate (065-2). Following the synthetic method of T-009, 035-1 (248 mg, 0.58 mmol) and 065-1 (171 mg, 0.70 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 065-2 (62 mg, 19% yield). MS ( m / z 548.3 (Mw-H) - .

[0410] Step 2: Preparation of (S)-N-((S)-1-(3R, 5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4,4-dimethyl-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (T-065). Following the synthetic method of T-024, 065-2 (62 mg, 0.11 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-065 (9 mg, 10% yield). 1 H NMR (400 MHz, DMSO) δ10.73 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.98 – 6.84 (m, 2H), 5.12 (t, J = 7.8 Hz, 1H), 4.62 – 4.40 (m,2H), 4.02 – 3.82 (m, 2H), 3.52 – 3.41 (m, 1H), 3.29 – 3.18 (m, 1H), 2.73 –2.56 (m, 2H), 1.39 – 1.10 (m, 4H), 1.10 (s, 3H), 0.97 (s, 3H), 0.85 – 0.74 (m, 1H), 0.48 – 0.32 (m, 2H), 0.20 – 0.07 (m, 2H). MS ( m / z 544.2 (Mw-H) - .

[0411] Example 66

[0412] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-(2,2,2-trifluoroacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (T-066)

[0413]

[0414] Step 1: Preparation of tert-butyl 2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid ester (066-2). Following the synthetic method of T-009, 035-1 (248 mg, 0.58 mmol) and 066-1 (160 mg, 0.70 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 066-2 (100 mg, 32% yield). MS ( m / z 532.3 (Mw-H) - .

[0415] Step 2: Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-(2,2,2-trifluoroacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (T-066). Following the synthetic method of T-024, 066-2 (100 mg, 0.19 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-066 (15 mg, 15% yield). 1 H NMR (400 MHz, CDCl3) δ 8.59 – 8.41 (m, 1H), 7.27 – 6.90 (m, 4H), 6.91 – 6.70 (m, 1H), 5.18 – 4.99 (m, 1H), 4.93 – 4.73 (m, 1H), 4.66 – 4.50 (m, 1H), 4.21 – 3.83 (m,4H), 2.96 – 2.77 (m, 1H), 2.65 – 2.50 (m, 1H), 1.79 – 1.65 (m, 2H), 0.95 –0.84 (m, 3H), 0.82 – 0.70 (m, 2H), 0.63– 0.53 (s, 2H), 0.28– 0.15 (m, 2H). MS( m / z 528.2 (Mw-H) - .

[0416] Example 67

[0417] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(methylsulfonamido)butyramide (T-067)

[0418]

[0419] Following the synthetic method of T-039, 049-1 (158 mg, 0.28 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-066 (18 mg, 12% yield). 1 H NMR (400 MHz, CDCl3) δ 7.84(s, 1H), 7.10 – 6.99 (m, 1H), 6.92 (dd, J = 8.6, 4.0 Hz, 1H), 6.69 (dd, J =7.6, 2.4 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 5.15 (d, J = 10.0 Hz, 1H), 5.05(t, J = 8.8 Hz, 1H), 4.68 (q, J = 7.2 Hz, 1H), 4.26 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 10.0 Hz, 1H), 3.57 (d, J = 10.0 Hz, 1H), 2.92 – 2.80 (m, 4H), 2.58 (dd, J = 12.8, 8.4 Hz, 1H), 1.75 (t, J = 6.8 Hz, 2H), 1.05 (s, 9H), 0.82– 0.72 (m, 1H), 0.61 (d, J = 7.2 Hz, 2H), 0.25 – 0.15 (m, 2H). MS ( m / z 528.2 (Mw-H) - .

[0420] Example 68

[0421] Preparation of N-(1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carbonyl)cyclopropyl)-4-methoxy-1H-indole-2-carboxamide (T-068)

[0422]

[0423] Following the synthetic method of T-009, 068-01 (100 mg, 0.30 mmol) and 4-methoxyindole-2-carboxylic acid (63 mg, 0.33 mmol, 1.1 eq.) were added, and the title compound T-068 (67 mg, 47% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, MeOD) δ 7.52 – 7.46 (m, 1H), 7.41 – 7.09 (m,4H), 7.06 – 6.88 (m, 2H), 6.51 (d, J = 7.6 Hz, 1H), 5.79– 5.69 (m, 1H), 4.53– 4.14 (m, 1H), 3.93 (s, 3H), 3.75 – 3.44 (m, 1H), 2.98 – 2.69 (m, 1H), 2.51– 2.33 (m, 1H), 1.41 – 1.29 (m, 4H). MS ( m / z 468.1 (Mw-H) - .

[0424] Example 69

[0425] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclobutyl-1-oxopropane-2-yl)-4-methoxy-1H-indole-2-carboxamide (T-069)

[0426]

[0427] Following the synthetic method of T-009, 069-01 (100 mg, 0.23 mmol) and 4-methoxyindole-2-carboxylic acid (52 mg, 0.27 mmol, 1.1 eq.) were added, and the title compound T-069 (42 mg, 36% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.56 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.25 – 7.14 (m, 3H), 7.00 (d, J = 8.4 Hz, 1H), 6.94– 6.80(m, 3H), 6.52 (d, J = 8.0 Hz, 1H), 5.09 (t, J = 8.4 Hz, 1H), 4.82 (q, J = 7.2Hz, 1H), 4.19 (d, J = 10.4 Hz, 1H), 4.04 d, J = 10.4 Hz, 1H), 3.96 (s, 3H), 2.90 (dd, J = 13.2, 8.8 Hz, 1H), 2.51 (dd, J = 13.2, 8.8 Hz, 1H), 2.22 – 2.01 (m, 3H), 2.00 – 1.85 (m, 2H), 1.85 – 1.61 (m, 4H). MS ( m / z 510.2 (Mw-H) - .

[0428] Example 70

[0429] Preparation of N-((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-1-fluorocyclopropane-1-carboxamide (T-070)

[0430]

[0431] Following the synthetic method of T-025, T-037 (90 mg, 0.17 mmol) and 1-fluorocyclopropanecarboxylic acid (23 mg, 0.22 mmol, 1.3 eq) were added, and the title compound T-070 (8 mg, 9% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.34 – 7.30 (m, 1H), 7.07 – 6.98 (m, 2H), 6.98 – 6.92 (m, 2H), 6.82 (d, J = 7.4 Hz, 1H), 5.11 (t, J = 8.4 Hz, 1H), 4.71 (d, J = 6.4 Hz, 1H), 4.37 (d, J = 9.2 Hz, 1H), 4.24 (d, J = 10.0Hz, 1H), 4.06 (d, J = 10.0 Hz, 1H), 2.89 (dd, J = 13.2, 8.8 Hz, 1H), 2.57(dd, J = 13.2, 8.8 Hz, 1H), 1.85 – 1.66 (m, 2H), 1.45 – 1.33 (m, 2H), 1.04(s, 9H), 0.94 – 0.84 (m, 2H), 0.81 – 0.67 (m, 1H), 0.66 – 0.50 (m, 2H), 0.24– 0.11 (m, 2H). MS ( m / z 522.3 (Mw-H) - .

[0432] Example 71

[0433] Preparation of N-((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (T-071)

[0434]

[0435] Following the synthetic method of T-025, T-037 (90 mg, 0.17 mmol) and 1-fluorocyclopropanecarboxylic acid were added, and the title compound T-071 (8 mg, 8% yield) was obtained by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.33 – 7.28 (m, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.94(t, J = 7.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 5.09(t, J = 8.8 Hz, 1H), 4.71 (dd, J = 13.6, 7.6 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.05 (d, J = 10.0 Hz, 1H), 2.88 (dd, J =13.2, 9.2 Hz, 1H), 2.63 – 2.52 (m, 1H), 1.83 – 1.66 (m, 2H), 1.39 – 1.30 (m,2H), 1.03 (s, 9H), 0.93 – 0.83 (m, 2H), 0.78 – 0.70 (m, 1H), 0.63 – 0.50 (m, 2H), 0.24 – 0.13 (m, 2H). MS (m / z) 572.3 (Mw-H)-.

[0436] Example 72

[0437] Preparation of N-((S)-2-(((S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-072)

[0438]

[0439] Step 1: Preparation of tert-butyl((S)-2-(((S)-1-((3R,5S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (072-1). Following the synthetic method of T-009, 035-1 (1.50 g, 3.53 mmol) and 031-1 (913 mg, 4.24 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 072-1 (1.20 g, 43% yield). MS ( m / z 520.3 (Mw-H) - .

[0440] Step 2: Preparation of N-((S)-2-(((S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-072). Following the synthetic method of T-024, 072-1 (1.20 g, 2.31 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-072 (530 mg, 65% yield). 1 H NMR (400 MHz, CDCl3) δ8.52 (s, 1H), 7.36 – 7.29 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.2Hz, 1H), 7.03 – 6.97 (m, 2H), 5.10 (t, J = 8.4 Hz, 1H), 4.77 (dd, J = 13.6,6.8 Hz, 1H), 4.18 – 3.99 (m, 3H), 2.95 – 2.83 (m, 1H), 2.60 (dd, J 0.21 – 0.12 (m, 2H). MS ( m / z 520.3 (Mw-H)- .

[0441] Example 73

[0442] Preparation of (2S,3R)-N-(S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-hydroxy-2-(2,2,2-trifluoroacetamido)butyramide (T-073)

[0443]

[0444] Step 1: Preparation of tert-butyl((2S,3R)-3-(tert-butoxy)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-oxobutane-2-yl)carbamate (073-2). Following the synthetic method of T-009, 035-1 (250 mg, 0.59 mmol) and 073-1 (195 mg, 0.71 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 073-2 (113 mg, 33% yield). MS ( m / z 580.3 (Mw-H) - .

[0445] Step 2: Preparation of (2S,3R)-N-(S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-hydroxy-2-(2,2,2-trifluoroacetamido)butyramide (T-073). Following the synthetic method of T-024, 073-2 (113 mg, 0.19 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-073 (66 mg, 65% yield). 1 H NMR (400 MHz, DMSO) δ 10.70 (s,1H), 9.20 (d, J = 8.0 Hz, 1H), 8.53 (d, J = 6.8 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.99 – 6.85 (m, 2H), 5.13 (t, J= 7.6 Hz, 1H), 4.92 (d, J = 6.0 Hz, 1H), 4.51 (d, J = 6.8 Hz, 1H), 4.31 – 4.22 (m, 1H), 4.08(d, J = 10.6 Hz, 1H), 3.91 – 3.85 (m, 2H), 2.68 – 2.57 (m, 1H), 2.49 – 2.41(m, 1H), 1.57 (t, J = 6.8 Hz, 2H), 1.10 (d, J = 6.4 Hz, 3H), 0.86 – 0.71 (m,1H), 0.43 – 0.32 (m, 2H), 0.21 – 0.05 (m, 2H). MS ( m / z 520.3 (Mw-H) - .

[0446] Example 74

[0447] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-cyclobutyl-2-(2,2,2-trifluoroacetamido)propionamide (T-074)

[0448]

[0449] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3-cyclobutyl-1-oxopropane-2-yl)carbamate (074-2). Following the synthetic method of T-009, 035-1 (300 mg, 0.71 mmol) and 074-1 (205 mg, 0.84 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 074-2 (342 mg, 88% yield). MS ( m / z 548.3 (Mw-H) - .

[0450] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-cyclobutyl-2-(2,2,2-trifluoroacetamido)propionamide (T-074). Following the synthetic method for T-024, 074-2 (342 mg, 0.62 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-074 (255 mg, 75% yield). 1 H NMR (400 MHz, CDCl3) δ 8.35(s, 1H), 7.32 – 7.28 (m, 1H), 7.17 – 6.89 (m, 5H), 5.13 (t, J = 10.4 Hz, 1H), 4.84 – 4.69 (m, 1H), 4.57 – 4.43 (m, 1H), 4.14 – 3.99 (m, 2H), 2.98 – 2.85(m, 1H), 2.60 (dd, J = 13.2, 8.4 Hz, 1H), 2.40 – 2.28 (m, 1H), 2.01 – 1.91(m, 2H), 1.86 – 1.75 (m, 4H), 1.34 – 1.23 (m, 4H), 0.78 – 0.69 (m, 1H), 0.64–0.51 (m, 2H), 0.22–0.10 (m, 2H). MS ( m / z 544.2 (Mw-H) - .

[0451] Example 75

[0452] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-(3-fluorophenyl)-2-(2,2,2-trifluoroacetamido)propionamide (T-075)

[0453]

[0454] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3-(3-fluorophenyl)-1-oxopropane-2-yl)carbamate (075-2). Following the synthetic method of T-009, 035-1 (400 mg, 0.94 mmol) and 075-1 (320 mg, 1.13 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 075-2 (301 mg, 54% yield). MS ( m / z 588.3 (Mw-H) - .

[0455] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-(3-fluorophenyl)-2-(2,2,2-trifluoroacetamido)propionamide (T-075). Following the synthetic method of T-024, 075-2 (301 mg, 0.51 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-075 (101 mg, 33% yield). 1 H NMR (400 MHz, CDCl3) δ8.74 (s, 1H), 7.37 – 7.30 (m, 3H), 7.10 – 6.89 (m, 7H), 5.11 (t, J = 7.6 Hz, 1H), 4.81 (dd, J = 13.6, 6.4 Hz, 1H), 4.73 (dd, J = 13.6, 6.8 Hz, 1H), 4.13 –4.02 (m, 2H), 3.27 – 3.03 (m, 2H), 2.88 (dd, J = 13.2, 8.4 Hz, 1H), 2.62 (dd, J = 13.2, 8.4 Hz, 1H), 1.80 – 1.73 (m, 2H), 0.76 – 0.65 (m, 1H), 0.61 – 0.42(m, 2H), 0.20 – 0.11 (m, 2H). MS ( m / z 584.2 (Mw-H)- .

[0456] Example 76

[0457] Preparation of N-((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclobutyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-076)

[0458]

[0459] Step 1: Preparation of tert-butyl((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclobutyl-2-oxoethyl)carbamate (076-2). Following the synthetic method of T-009, 035-1 (400 mg, 0.94 mmol) and 076-1 (320 mg, 1.13 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 076-2 (301 mg, 54% yield). MS ( m / z 588.3 (Mw-H) - .

[0460] Step 2: Preparation of N-((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclobutyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-076). Following the synthetic method of T-024, 076-2 (301 mg, 0.51 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-076 (101 mg, 33% yield). 1 H NMR (400 MHz, CDCl3)δ 8.74 (s, 1H), 7.37 – 7.30 (m, 3H), 7.10 – 6.89 (m, 7H), 5.11 (t, J = 7.6Hz, 1H), 4.81 (dd, J = 13.6, 6.4 Hz, 1H), 4.73 (dd, J= 13.6, 6.8 Hz, 1H), 4.13 – 4.02 (m, 2H), 3.27 – 3.03 (m, 2H), 2.88 (dd, J = 13.2, 8.4 Hz, 1H), 2.62 (dd, J = 13.2, 8.4 Hz, 1H), 1.80 – 1.73 (m, 2H), 0.76 – 0.65 (m, 1H), 0.61 – 0.42 (m, 2H), 0.20 – 0.11 (m, 2H). MS ( m / z 584.2 (Mw-H) - .

[0461] Example 77

[0462] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-methyl-2-(2,2,2-trifluoroacetamido)butyramide (T-077)

[0463]

[0464] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-3-methyl-1-oxobutane-2-yl)carbamate (077-2). Following the synthetic method of T-009, 035-1 (152 mg, 0.47 mmol) and 077-1 (153 mg, 0.70 mmol, 1.5 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 077-2 (180 mg, 73% yield). MS ( m / z 522.3 (Mw-H) - .

[0465] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-3-methyl-2-(2,2,2-trifluoroacetamido)butyramide (T-077). Following the synthetic method of T-024, 077-2 (180 mg, 0.34 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-077 (51 mg, 29% yield). 1 H NMR (400 MHz, CDCl3) δ 8.20 (s,1H), 7.39 – 7.30 (m, 1H), 7.16 – 6.90 (m, 5H), 5.10 (t, J = 8.4 Hz, 1H), 4.74(dd, J = 13.6, 7.2 Hz, 1H), 4.41 (dd, J = 8.4, 6.4 Hz, 1H), 4.17 – 4.02 (m,2H), 2.89 (dd, J = 13.2, 8.4 Hz, 1H), 2.60 (dd, J = 13.2, 8.4 Hz, 1H), 2.19 –2.10 (m, 1H), 1.85 – 1.66 (m, 2H), 0.99 (d, J = 6.8 Hz, 6H), 0.80 – 0.70 (m,1H), 0.65 – 0.54 (m, 2H), 0.21 – 0.14 (m, 2H). MS ( m / z 512.2 (Mw-H) - .

[0466] Example 78

[0467] Preparation of N-((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(3,3-difluorocyclobutyl)-2-oxoethyl)-2,2,2-trifluoroacetamide (T-078)

[0468]

[0469] Step 1: Preparation of tert-butyl((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(3,3-difluorocyclobutyl)-2-oxoethyl)carbamate (078-2). Following the synthetic method of T-009, 035-1 (300 mg, 0.71 mmol) and 078-1 (265 mg, 0.85 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 078-2 (233 mg, 58% yield). MS ( m / z 570.6 (Mw-H) - .

[0470] Step 2: Preparation of N-((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(3,3-difluorocyclobutyl)-2-oxoethyl)-2,2,2-trifluoroacetamide (T-078). Following the synthetic method of T-024, 078-2 (233 mg, 0.41 mmol) was added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound T-078 (101 mg, 44% yield). 1 H NMR (400MHz, CDCl3) 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.47 – 7.31 (m, 2H), 7.14– 6.93 (m, 4H), 5.13 (t, J = 8.4 Hz, 1H), 4.81 – 4.68 (m, 2H), 4.15 – 3.98 (m, 2H), 2.72 – 2.46 (m, 7H), 1.85 – 1.67 (m, 2H), 0.89 – 0.71 (m, 1H), 0.67– 0.53 (m, 2H), 0.25 – 0.12 (m, 2H). MS ( m / z 566.2 (Mw-H) - .

[0471] Example 79

[0472] Preparation of (2S,3R)-3-(tert-butoxy)-N-(S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-2-(2,2,2-trifluoroacetamido)butyramide (T-079)

[0473]

[0474] Following the synthetic method of T-009, 035-1 (141 mg, 0.33 mmol) and 079-1 (75 mg, 0.85 mmol, 0.8 eq.) were added, and the title compound T-079 (56 mg, 35% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR 1 H NMR (400 MHz, DMSO- d 6) δ 10.63 – 10.48 (m, 1H), 9.40 – 8.91 (m,1H), 8.59 – 8.27 (m, 1H), 7.55 – 7.14 (m, 2H), 7.06 – 6.69 (m, 2H), 5.35 –5.08 (m, 1H), 4.65 – 4.44 (m, 1H), 4.32 – 4.11 (m, 1H), 4.08 – 3.46 (m, 3H), 2.72 – 2.55 (m, 1H), 2.46 – 2.24 (m, 1H), 1.72 – 1.55 (m, 2H), 1.25 (s, 3H),1.16 – 1.02 (m, 9H), 0.75 – 0.64 (m, 1H), 0.56 – 0.37 (m, 2H), 0.18 – 0.05 (m, 2H). MS ( m / z 576.2 (Mw-H) - .

[0475] Examples 80 and 81

[0476] Preparation of N-(S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(1-methylcyclopropyl)-2-oxoethyl)-2,2,2-trifluoroacetamide (T-080) and N-(R)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(1-methylcyclopropyl)-2-oxoethyl)-2,2,2-trifluoroacetamide (T-081)

[0477]

[0478] Step 1: Preparation of tert-butyl(2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(1-methylcyclopropyl)-2-oxoethyl)carbamate (080-2). Following the synthetic method of T-009, 035-1 (100 mg, 0.24 mmol, 0.9 eq.) and 080-1 (60 mg, 0.26 mmol) were added, and column chromatography (EA / Hep increased from 5% to 70%) was used to separate the title compound 080-2 (70 mg, 50% yield). MS ( m / z 570.6 (Mw-H) - .

[0479] Step 2: Preparation of compounds T-080 and T-081. Compound 080-2 (70 mg, 0.41 mmol) was dissolved in 6 mL of DCM / TFA at a volume ratio of 2:1. The mixture was stirred for 2 hours, concentrated, dried, and then redissolved in 5 mL of DCM. TEA (0.18 mL, 1.31 mmol, 10.0 eq.) and trifluoroacetic anhydride (55 mg, 0.26 mmol, 2 eq.) were added under ice-water bath conditions. The resulting reaction mixture was stirred for another 4 hours. The mixture was then concentrated, and the title compounds T-080 (6 mg) and T-081 (5 mg) were obtained through separation and purification. Compound T-080... 1 H NMR (400 MHz, DMSO- d 6) δ 10.74 (s, 1H), 9.47 (s, 1H), 8.41(d, J = 6.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.03 (d,J = 7.6 Hz, 1H), 6.95– 6.84 (m, 2H), 5.15 (t, J = 8.0 Hz, 1H), 4.65– 4.50 (m, 1H), 4.13– 4.05 (m,2H), 3.90 (d, J = 10.4 Hz, 1H), 2.73– 2.50 (m, 2H), 1.58 (t, J = 7.2 Hz, 2H), 0.98 (d, J = 11.3 Hz, 3H), 0.90 – 0.01 (m, 9H). MS ( m / z 530.2 (Mw-H) - Compound T-081 1 H NMR (400 MHz, DMSO- d 6) δ 10.70 (s, 1H), 9.42 (s, 1H), 8.52 (d, J =7.8 Hz, 1H), 7.26 – 7.20 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95– 6.81 (m,2H), 5.20 – 5.10 (m, 1H), 4.56 (d, J = 7.4 Hz, 1H), 4.12 – 3.91 (m, 3H), 2.67 – 2.54 (m, 2H), 1.67 – 1.45 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H), 0.65 – 0.10(m, 9H). MS ( m / z 531.2 (Mw-H) - .

[0480] Examples 82 and 83

[0481] Preparation of N-((R)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(1-fluorocyclopropyl)-2-oxoethyl)-2,2,2-trifluoroacetamide (T-082) and N-((S)-2-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(1-fluorocyclopropyl)-2-oxoethyl)-2,2,2-trifluoroacetamide (T-083)

[0482]

[0483] Step-1: tert-butyl(2-((() S )-1-((3 R 5' S Preparation of 5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-(1-fluorocyclopropyl)-2-oxoethyl)carbamate (082-2). Following the synthetic method of T-009, 035-1 (200 mg, 0.47 mmol, 1.1 eq.) and 082-1 ​​(100 mg, 0.43 mmol) were added, and column chromatography (EA / Hep increased from 5% to 70%) was used to separate the title compound 082-2 (85 mg, 37% yield). MS ( m / z 538.2 (Mw-H) - .

[0484] Step 2: Preparation of compounds T-082 and T-083. Following the synthesis and isolation method of compound T-080, compound T-082-2 (85 mg, 0.16 mmol) was added to prepare, isolate, and purify the title compounds T-082 (4 mg) and T-083 (6 mg). Compound T-082... 1 H NMR (400 MHz, DMSO- d 6) δ 10.72 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 7.27 – 7.21 (m, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.97 – 6.85 (m, 2H), 5.17 – 5.10 (m, 1H), 4.89 (s, 1H), 4.59 – 4.40 (m, 1H), 4.07 (d,J = 10.4 Hz, 1H), 3.88 (d, J = 10.4 Hz, 1H), 2.63 – 2.53 (m, 2H), 1.63 – 1.51 (m, 2H), 1.24 (s, 1H), 1.13 – 0.95 (m, 3H), 0.80– 0.75 (m, 1H), 0.40 – 0.32 (m, 2H), 0.15 – 0.05 (m, 2H). Compound T-083 1 H NMR (400 MHz, DMSO- d 6) δ 10.70 (s, 1H), 8.73 (s, 1H), 8.48 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.4 Hz,1H), 6.97– 6.85 (m, 2H), 5.20 – 5.11 (m, 1H), 4.75– 4.65 (m, 1H), 4.55 – 4.48(m, 1H), 4.11 (d, J = 10.4 Hz, 1H), 3.92 (d, J = 10.4 Hz, 1H), 2.70 – 2.59(m, 2H), 1.62– 1.50 (m, 2H), 1.24 (s, 1H), 1.04 (d, J = 18.6 Hz, 2H), 0.79 –0.70 (m, 2H), 0.42 – 0.32 (m, 2H), 0.16 – 0.08 (m, 2H). MS ( m / z 534.2 (Mw-H) - .

[0485] Examples 84 and 85

[0486] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(1-fluorocyclopropyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-084) and (S)-N-((R)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(1-fluorocyclopropyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-085)

[0487]

[0488] Intermediate 084-1 was synthesized according to the preparation method of T-023. Then, referring to the synthesis and isolation method of compound T-080, compound 084-1 (200 mg, 0.36 mmol) was added to prepare, isolate, and purify the title compounds T-084 (27 mg) and T-085 (23 mg). Compound T-084 1 H NMR (400 MHz, DMSO- d 6) δ 10.76 (s, 1H), 9.21 (s, 1H), 8.77 (d, J = 7.2 Hz, 1H), 7.27 – 7.15 (m, 1H), 7.00 (d, J = 7.2 Hz, 1H),6.95– 6.85 (m, 2H), 5.17 (t, J = 8.4 Hz, 1H), 4.73 – 4.64 (m, 1H), 4.42 –4.35 (m, 1H), 4.28 – 4.18 (m, 1H), 3.86 (d, J = 10.4 Hz, 1H), 2.60 (dd, J =13.2, 8.4 Hz, 1H), 2.47 (dd, J = 13.2, 8.4 Hz), 2.30 – 2.04 (m, 2H), 1.31 –0.79 (m, 11H), 0.74 – 0.62 (m, 1H), 0.67 – 0.57 (m, 1H). Compound T-085 1 H NMR (400 MHz, DMSO-) d 6) δ 10.72 (s, 1H), 9.36 (d,J = 9.2 Hz, 1H), 8.94 – 8.62 (m,1H), 7.30 – 7.20 (m, 1H), 7.15 – 7.04 (m, 1H), 6.99 – 6.89 (m, 2H), 5.18 –5.02 (m, 1H), 4.82 – 4.70 (m, 1H), 4.43 (t, J = 10.0 Hz, 1H), 4.12 – 3.78 (m,2H), 2.73 – 2.63 (m, 1H), 2.46 (dd, J = 13.4, 7.2 Hz, 1H), 2.37 – 2.18 (m,1H), 2.11 – 1.85 (m, 1H), 0.98 – 0.89 (m, 9H), 0.89 – 0.46 (m, 4H). MS ( m / z 550.2 (Mw-H) - .

[0489] Example 86

[0490] Preparation of N-((S)-2-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-cyclopropyl-2-oxoethyl)-4,7-difluoro-1H-indole-2-carboxamide (T-086)

[0491]

[0492] Intermediate 086-1 was synthesized according to the preparation method of T-008. Then, referring to the synthesis of compound T-009, compound 086-1 (259 mg, 0.58 mmol) and 4,7-difluoroindole-2-carboxylic acid (126 mg, 0.64 mmol, 1.1 eq.) were added, and the title compound T-086 (10 mg, 3% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, DMSO- d6) δ 12.39 (s, 1H), 10.72 (s, 1H), 9.01 (d, J = 6.8 Hz, 1H), 7.39 (s,1H), 7.17 – 6.81 (m, 6H), 5.17 (t, J = 8.0 Hz, 1H), 4.26 – 4.14 (m, 2H), 3.90 (d, J = 10.4 Hz, 1H), 2.63 (dd, J = 13.2, 8.8 Hz, 1H), 2.50 – 2.43 (m, 1H), 1.35 – 1.22 (m, 1H), 0.64 – 0.35 (m, 4H). MS ( m / z 488.2 (Mw-H) - .

[0493] Example 87

[0494] Preparation of N-((S)-2-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-cyclopropyl-2-oxoethyl)-4-methoxy-1H-indole-2-carboxamide (T-087)

[0495]

[0496] Referring to the synthesis of compound T-009, 086-1 (0.12 g, 0.29 mmol) and 4-methoxyindole-2-carboxylic acid (62 mg, 0.32 mmol, 1.1 eq.) were added, and the title compound T-087 (8 mg, 5% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.49 (s, 1H), 10.71 (s, 1H), 8.81 (d, J = 6.8 Hz, 1H), 7.39 (s, 1H), 7.19 (t, J = 8.0Hz, 1H), 7.10 (t, J =7.6 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.95 – 6.83 (m, 2H), 6.51 (d, J = 7.6Hz, 1H), 5.16 (t, J= 8.0 Hz, 1H), 4.24 – 4.09 (m, 2H), 3.88 – 3.80 (m, 4H), 2.68 – 2.57 (m, 1H), 2.47 – 2.35 (m, 1H), 1.34 – 1.22 (m, 2H), 0.62 – 0.48(m, 2H), 0.42 – 0.32(m, 1H). MS ( m / z 482.2 (Mw-H) - .

[0497] Example 88

[0498] Preparation of (S)-N-((S)-2-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-cyclopropyl-2-oxoethyl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-088)

[0499]

[0500] Referring to the synthesis of compound T-008, 086-1 (0.26 g, 0.64 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (150 mg, 0.66 mmol, 1.0 eq.) were added, and the title compound T-088 (20 mg, 6% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, CDCl3) δ 7.97 (s,1H), 7.43 – 7.30 (m, 1H), 7.11 – 6.94 (m, 4H), 6.52 (d, J = 6.0 Hz, 1H),5.07– 4.98 (m, 1H), 4.45 – 4.29 (m, 1H), 4.18 – 4.02 (m, 3H), 2.64 – 2.52 (m,1H), 2.45 – 2.34 (m, 1H), 1.08 (t, J = 10.2 Hz, 9H), 0.95 – 0.40 (m, 5H). MS( m / z 518.1 (Mw-H) - .

[0501] Example 89

[0502] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclohexyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-089)

[0503]

[0504] Intermediate 089-1 was synthesized according to the preparation method of T-008. Then, referring to the synthesis of compound T-009, compound 089-1 (148 mg, 0.32 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (87 mg, 0.38 mmol, 1.2 eq.) were added, and the title compound T-089 (29 mg, 16% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.33 (t, J = 7.6 Hz, 1H),7.09 – 6.87 (m, 4H), 6.34 (d, J = 7.4 Hz, 1H), 5.07 (t, J = 8.4 Hz, 1H), 4.65 (dd, J = 14.0, 7.2 Hz, 1H), 4.33 (d, J = 9.2 Hz, 1H), 4.13 (t, J = 10.0 Hz, 1H), 4.00 (d, J = 10.0 Hz, 1H), 2.89 (dd, J = 13.2, 9.2 Hz, 1H), 2.58 (dd, J = 13.0, 8.0 Hz, 1H), 1.75 – 1.61 (m, 6H), 1.40 – 1.14 (m, 6H), 1.09 – 0.99 (m, 9H), 0.93 – 0.80 (m, 1H). MS ( m / z 574.3 (Mw-H) - .

[0505] Example 90

[0506] Preparation of (S)-N-(1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carbonyl)cyclopropyl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-090)

[0507]

[0508] Intermediate 090-1 was synthesized according to the preparation method of T-008. Then, referring to the synthesis of compound T-009, compound 090-1 (267 mg, 0.67 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (154 mg, 0.67 mmol, 1.0 eq.) were added, and the title compound T-090 (10 mg, 3% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, CDCl3) δ 7.85 – 7.68 (m, 1H), 7.57 – 7.52 (m, 1H), 7.29 – 7.26 (m, 1H), 7.26 – 7.09 (m, 3H), 6.95 (d, J = 7.2 Hz, 1H), 5.47 –5.28 (m, 1H), 4.40 – 4.35 (m, 2H), 4.08 – 3.88 (m,1H), 2.82 – 2.48 (m, 2H),0.99 (s, 9H), 0.94 – 0.84 (m, 4H). MS ( m / z 504.2 (Mw-H) - .

[0509] Example 91

[0510] Preparation of (S)-N-((2S,3S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-methyl-1-oxopentane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-091)

[0511]

[0512] Intermediate 091-1 was synthesized according to the preparation method of T-008; then, referring to the synthesis of compound T-009, compound 091-1 (430 mg, 1.01 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (252 mg, 1.11 mmol, 1.1 eq.) were added, and the title compound T-091 (256 mg, 47% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.4 Hz, 1H), 7.41 – 7.30(m, 2H), 7.10 – 6.91 (m, 4H), 5.22 – 5.05 (m, 1H), 4.58 – 4.32 (m, 2H), 4.23– 3.92 (m, 2H), 2.96 – 2.87 (m, 1H), 2.69 – 2.53 (m, 1H), 1.36 – 1.13 (m,4H), 1.15 – 0.99 (m, 13H), 0.96 – 0.90 (m, 3H). MS ( m / z 534.2 (Mw-H) - .

[0513] Example 92

[0514] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4,7-difluoro-1H-indole-2-carboxamide (T-092)

[0515]

[0516] Following the synthetic method of T-009, 092-1 (600 mg, 1.36 mmol) and 4,7-difluoroindole-2-carboxylic acid (320 mg, 1.62 mmol, 1.2 eq.) were added, and the title compound T-092 (70 mg, 10% yield) was isolated by column chromatography (EA / Hep increased from 0% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.06 (s, 1H), 7.39(d, J= 7.6 Hz, 1H), 7.07 (s, 1H), 6.97 – 6.82 (m, 2H), 6.79 – 6.63 (m, 3H), 5.10 (t, J = 8.8 Hz, 1H), 4.98 (q, J = 7.2 Hz, 1H), 4.41 (d, J = 10.4 Hz, 1H), 4.13 (d, J = 10.4 Hz, 1H), 2.94 (dd, J = 13.2, 8.8 Hz, 1H), 2.59 (dd, J = 13.2, 8.8 Hz, 1H), 0.93 – 0.82 (m, 1H), 0.72 – 0.52 (m, 2H), 0.35 – 0.22(m, 2H). MS ( m / z 520.2 (Mw-H) - .

[0517] Example 93

[0518] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-4,7-difluoro-1H-indole-2-carboxamide (T-093)

[0519]

[0520] Following the synthetic method of T-009, 035-1 (600 mg, 1.41 mmol) and 4,7-difluoroindole-2-carboxylic acid (333 mg, 1.62 mmol, 1.2 eq.) were added, and the title compound T-093 (570 mg, 80% yield) was isolated by column chromatography (EA / Hep increased from 0% to 50%). 1 H NMR (400 MHz, CDCl3) δ 9.91 – 9.61 (m, 1H), 8.85 – 8.67(m, 1H), 8.56 – 8.37 (m, 1H), 7.73 – 7.62 (m, 1H), 7.58 – 7.39 (m, 1H), 7.19– 6.65 (m, 5H), 5.14 (t, J = 8.4 Hz, 1H), 5.07 – 4.88 (m, 1H), 4.30 (d, J=10.4 Hz, 1H), 4.23 – 4.10 (m, 1H), 3.04 – 2.88 (m, 1H), 2.72 – 2.54 (m, 1H), 1.98 – 1.81 (m, 1H), 1.01 – 0.79 (m, 1H), 0.74 – 0.56 (m, 2H), 0.38 – 0.18 (m, 2H). MS ( m / z 502.2 (Mw-H) - .

[0521] Example 94

[0522] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (T-094)

[0523]

[0524] Following the synthetic method of T-009, EDCI was used as the condensing agent. 035-1 (120 mg, 0.28 mmol) and 5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (50 mg, 0.28 mmol, 1.0 eq.) were added, and column chromatography (EA / Hep increased from 0% to 60%) was used to separate the title compound T-094 (12 mg, 9% yield). 1 H NMR (400 MHz, CDCl3) δ 11.11 –10.60 (m, 1H), 9.29 – 8.96 (m, 1H), 7.87 – 7.43 (m, 2H), 7.22 – 6.38 (m, 5H),5.17 – 4.79 (m, 2H), 4.40 – 4.02 (m, 2H), 2.89 – 2.41 (m, 2H), 2.00 – 1.77 (m, 2H), 1.18 – 0.19 (m, 5H). MS ( m / z 484.2 (Mw-H) - .

[0525] Example 95

[0526] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclobutyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-095)

[0527]

[0528] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclobutyl-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (095-1). Following the synthetic method of T-009, 069-1 (100 mg, 0.23 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyric acid (62 mg, 0.27 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 095-1 (102 mg, 81% yield). m / z 550.3 (Mw-H) - .

[0529] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclobutyl-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-095). Following the synthetic method of T-024, 095-1 (102 mg, 0.18 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-095 (52 mg, 51% yield). 1 H NMR (400 MHz, DMSO) δ10.72 (s, 1H), 9.09 (d, J = 9.2 Hz, 1H), 8.50 (d, J = 6.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 10.4 Hz, 1H), 6.91 (t, J = 8.0 Hz, 2H), 5.13 (t, J= 8.0 Hz, 1H), 4.46 – 4.28 (m, 2H), 4.13 (d, J = 10.4 Hz, 1H), 3.85 (d, J =10.4 Hz, 1H), 2.58 (dd, J = 13.2, 8.4 Hz, 1H), 2.34 (dd, J = 13.2, 8.4 Hz,1H), 2.02 – 1.90 (m, 2H), 1.83 – 1.52 (m, 7H), 0.93 (s, 9H). MS ( m / z 546.2 (Mw-H) - .

[0530] Example 96

[0531] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3,3-difluorocyclobutyl)-1-oxopropane-2-yl)-4,7-difluoro-1H-indole-2-carboxamide (T-096)

[0532]

[0533] Following the synthetic method of T-009, EDCI was used as the condensing agent. 096-1 (110 mg, 0.22 mmol) and 4,7-difluoroindole-2-carboxylic acid (53 mg, 0.27 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 0% to 60%) was used to separate the title compound T-096 (90 mg, 70% yield). 1 H NMR (400 MHz, DMSO) δ 12.60 – 12.19(m, 1H), 10.72 (s, 1H), 9.05 – 8.82 (m, 1H), 7.38 – 7.30 (m, 1H), 7.18 – 6.97(m, 3H), 6.94 – 6.71 (m, 2H), 5.31 – 5.18 (m, 1H), 4.80 – 4.67 (m, 1H), 4.00 – 3.87 (m, 2H), 2.74 – 2.54 (m, 3H), 2.43 – 2.13 (m, 3H), 1.33 – 1.21 (m,2H), 0.91 – 0.82 (m, 1H). MS ( m / z570.2 (Mw-H) - .

[0534] Example 97

[0535] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(4-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-097)

[0536]

[0537] Step-1: tert-butyl(( S )-1-((( S )-1-((3 R 5' S Preparation of 5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(4-fluorophenyl)-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (097-2). Following the synthetic method of T-009, 097-1 (300 mg, 0.63 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (174 mg, 0.75 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 097-2 (170 mg, 46% yield). MS ( m / z 590.3 (Mw-H) - .

[0538] Step-2: ( S )-N-( (S )-1-((3 R 5' S Preparation of 5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(4-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-097). Following the synthetic method of T-024, 097-2 (70 mg, 0.12 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-097 (30 mg, 43% yield). 1 H NMR (400 MHz, CDCl3) δ8.66 (s, 1H), 7.42 – 6.80 (m, 10H), 5.05 (t, J= 8.4 Hz, 1H), 4.83 (s, 1H), 4.47 (d, J = 8.8 Hz, 1H), 3.96 – 3.77 (m, 2H), 3.17 – 3.98 (m, 2H), 2.81 –2.67 (m, 1H), 2.66 – 2.43 (m, 1H), 1.02 (s, 9H). MS ( m / z 586.2 (Mw-H) - .

[0539] Example 98

[0540] Preparation of N-((S)-2-(((S)-1-(3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-098)

[0541]

[0542] Step 1: Preparation of tert-butyl((S)-2-(((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (098-2). Following the synthetic method of T-009, 098-1 (426 mg, 0.70 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-2-cyclopropylacetic acid (197 mg, 0.91 mmol, 1.3 eq.) were added, and column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 098-2 (220 mg, 58% yield). MS ( m / z 538.3 (Mw-H) - .

[0543] Step 2: Preparation of N-((S)-2-(((S)-1-(3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-098). Following the synthetic method of T-024, 098-2 (220 mg, 0.41 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-098 (21 mg, 10% yield). 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.13 – 7.01 (m, 2H), 6.93 (dd, J = 8.4, 4.4 Hz, 1H), 6.81 – 6.70 (m, 2H), 5.07 (t, J = 8.4 Hz, 1H), 4.68 (dd, J = 13.6, 7.6 Hz, 1H), 4.19 (d, J = 10.4 Hz, 1H), 4.06 (d, J = 10.4 Hz, 1H), 3.93 (t, J = 8.4Hz, 1H), 2.91 (dd, J = 13.2, 8.8 Hz, 1H), 2.60 (dd, J = 13.2, MS ( m / z 534.2 (Mw-H) - .

[0544] Example 99

[0545] Preparation of N-((S)-2-(((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide (T-099)

[0546]

[0547] Step-1: Preparation of tert-butyl((S)-2-(((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (099-2). Following the synthetic method of T-009, 099-1 (2.50 g, 5.03 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-2-cyclopropylacetic acid (1.31 g, 6.01 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 098-2 (610 mg, 20% yield). MS ( m / z 592.2 (Mw-H) - .

[0548] Step-2: N-(( S )-2-((( S )-1-((3 R 5' S Preparation of 2,2,2-trifluoroacetamide (T-099): 5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-2,2,2-trifluoroacetamide. Following the synthetic method of T-024, 098-2 (610 mg, 1.03 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-098 (83 mg, 14% yield). 1H NMR (400MHz, CDCl3) δ 7.85 (s, 1H), 7.13 – 7.01 (m, 2H), 6.93 (dd, J = 8.4, 4.4 Hz, 1H), 6.81 – 6.70 (m, 2H), 5.07 (t, J = 8.4 Hz, 1H), 4.68 (dd, J = 13.6, 7.6Hz, 1H), 4.19 (d, J = 10.4 Hz, 1H), 4.06 (d, J = 10.4 Hz, 1H), 3.93 (t, J =8.4 Hz, 1H), 2.91 (dd, J = 13.2, 8.8 Hz, 1H), 2.60 (dd, J = 13.2, 8.8 MS ( m / z 588.2 (Mw-H) - .

[0549] Example 100

[0550] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-100)

[0551]

[0552] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (100-2). Following the synthetic method of T-009, 100-1 (2.50 g, 5.03 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyric acid (1.16 g, 5.03 mmol, 1.0 eq.) were added, and the mixture was separated by column chromatography (EA / Hep increased from 5% to 50%) to obtain the title compound 100-2 (1.84 g, 60% yield). MS ( m / z 608.2 (Mw-H) - .

[0553] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-100). Following the synthetic method of T-024, 100-2 (1.84 g, 3.02 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-100 (90 mg, 5% yield). 1 H NMR (400 MHz, CDCl3)δ 8.77 (s, 1H), 7.45 – 7.22 (m, 2H), 7.16 – 6.84 (m, 6H), 6.66 (d, J = 6.4Hz, 1H), 5.03 (t, J = 8.0 Hz, 1H), 4.82 (d, J = 6.0 Hz, 1H), 4.47 (d, J = 8.8Hz, 1H), 3.93 (d, J = 8.8 Hz, 1H), 3.27 (d, J = 10.2 Hz, 1H), 3.20 – 3.03 (m,2H), 2.81 – 2.65 (m, 1H), 2.63 – 2.44 (m, 1H), 1.03 (s, 9H). MS ( m / z 604.2 (Mw-H) - .

[0554] Example 101

[0555] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-phenylpropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-101)

[0556]

[0557] Intermediate 101-1 was synthesized according to the preparation method of T-008; then, referring to the synthesis of compound T-009, compound 101-1 (480 mg, 1.00 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (273 mg, 1.21 mmol, 1.2 eq.) were added, and the title compound T-101 (15 mg, yield 2.5%) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.57 – 7.25 (m, 6H), 7.05 – 6.95 (m, 2H), 6.95 – 6.83 (m, 1H), 6.74 – 6.64 (m, 1H), 5.17 – 4.98 (m, 1H),4.85 – 4.71 (m, 1H), 4.43 (t, J = 9.6 Hz, 1H), 4.04 – 3.79 (m, 2H), 3.30 –3.07 (m, 2H), 2.78 – 2.62 (m, 1H), 2.61 – 2.42 (m, 1H), 1.02 – 1.00 (m, 9H).MS ( m / z 586.3 (Mw-H) - .

[0558] Example 102

[0559] Preparation of (S)-N-((S)-3-(3-chlorophenyl)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-102)

[0560]

[0561] Intermediate 102-1 was synthesized according to the preparation method of T-008; then, referring to the synthesis of compound T-009, compound 102-1 (110 mg, 0.22 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyric acid (61 mg, 0.27 mmol, 1.2 eq.) were added, and the title compound T-102 (33 mg, yield 24%) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.33 – 7.25 (m, 4H), 7.15 –7.10 (m, 1H), 7.05 – 6.92 (m, 3H), 6.85 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.6Hz, 1H), 5.02 (t, J = 8.4 Hz, 1H), 4.85 – 4.70 (m, 1H), 4.34 (d, J = 8.4 Hz, 1H), 3.87 (d, J = 8.4 Hz, 1H), 3.22 (d, J = 8.4 Hz, 1H), 3.28 – 3.09 (m, 2H), 2.74 (dd, J = 13.2, 8.8 Hz, 1H), 2.51 (dd, J = 13.2, 8.8 Hz, 1H), 1.02 (s,9H). MS ( m / z 602.2 (Mw-H) - .

[0562] Example 103

[0563] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(2-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-103)

[0564]

[0565] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(2-fluorophenyl)-1-oxopropane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (103-2). Following the synthetic method of T-009, 103-1 (200 mg, 0.40 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyric acid (111 mg, 0.48 mmol, 1.2 eq.) were added and separated by column chromatography (EA / Hep increased from 5% to 50%) to obtain the title compound 103-2 (150 mg, 61% yield). m / z 608.3 (Mw-H) - .

[0566] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(2-fluorophenyl)-1-oxopropane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-100). Following the synthetic method of T-024, 150 mg of 103-2 (0.25 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-103 (110 mg, 73% yield). 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.40 – 7.29 (m, 1H), 7.26 – 7.00 (m, 5H), 6.97 – 6.91 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.04 (t, J = 8.8 Hz, 1H), 4.87 (q, J = 7.2Hz, 1H), 4.39 (d, J = 8.8 Hz, 1H), 4.00 (d, J = 10.4 Hz, 1H), 3.47 (d, J =10.4 Hz, 1H), 3.23 – 3.06 (m, 2H), 2.76 (dd, J = 13.2, 9.2 Hz, 1H), 2.57 –2.47 (m, 1H), 1.02 (, 9H). MS ( m / z 604.2 (Mw-H) - .

[0567] Example 104

[0568] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)cinnamamide (T-104)

[0569]

[0570] Referring to the synthesis of compound T-009, T-041 (100 mg, 0.24 mmol) and cinnamic acid (42 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-104 (70 mg, 57% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.68 (d, J = 6.4 Hz, 1H), 8.62 (d, J = 8.0Hz, 1H), 7.59 – 7.34 (m, 5H), 7.33 – 7.10 (m, 5H), 7.08 – 6.98 (m, 2H), 6.94(t, J = 7.2 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 5.15 (t, J = 8.0 Hz, 1H), 4.85 – 4.78 (m, 1H), 4.12 (d, J = 10.8 Hz, 1H), 3.69 (d, J = 10.8 Hz, 1H), 3.16 – 2.86 (m, 2H), 2.59 (dd, J = 13.2, 8.4 Hz, 1H), 2.42 (dd, J = 13.2, 8.4 Hz, 1H).MS ( m / z 507.2 (Mw-H) - .

[0571] Example 105

[0572] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (T-105)

[0573]

[0574] Referring to the synthesis of compound T-009, T-041 (100 mg, 0.24 mmol) and 5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (51 mg, 0.28 mmol, 1.2 eq.) were added, and the title compound T-105 (20 mg, 15% yield) was isolated by column chromatography (EA / Hep increased from 5% to 50%). 1 H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.44 (s,1H), 7.41 – 7.33 (m, 1H), 7.24 – 7.16 (m, 1H), 7.12 – 6.98 (m, 3H), 6.96 –6.81 (m, 3H), 6.66 (s, 1H), 6.56 (s, 1H), 5.16 – 4.92 (m, 2H), 4.02 (d, J =10.4 Hz, 1H), 3.65 – 3.44 (m, 1H), 3.33 – 3.10 (m, 2H), 2.79 (dd, J = 13.2, 8.8 Hz, 1H), 2.54 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 507.2 (Mw-H) - .

[0575] Example 106

[0576] Preparation of N-((S)-1-(3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-3-fluoro-1H-pyrrole-2-carboxamide (T-106)

[0577]

[0578] Referring to the synthesis of compound T-009, T-041 (311 mg, 0.65 mmol) and 3-fluoro-1H-pyrrole-2-carboxylic acid (101 mg, 0.78 mmol, 1.2 eq.) were added, and the title compound T-106 (190 mg, 60% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.71 (s, 1H), 7.28– 7.18 (m, 2H), 7.12 – 6.99 (m, 3H), 6.96 – 6.83 (m, 3H), 6.83 – 6.65 (m, 2H), 6.03 (t, J = 3.2 Hz, 1H), 5.08 – 4.90 (m, 2H), 4.00 (d, J = 10.0 Hz, 1H), 3.40 (d, J = 10.0 Hz, 1H), 3.28 – 3.18(m, 2H), 2.76 (dd, J = 13.2, 9.1Hz, 1H), 2.52 – 2.42 (m, 1H). MS ( m / z 488.1 (Mw-H) - .

[0579] Example 107

[0580] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-4-(trifluoromethyl)-1H-pyrrole-2-carboxamide (T-107)

[0581]

[0582] Referring to the synthesis of compound T-009, T-041 (225 mg, 0.47 mmol) and 4-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (101 mg, 0.56 mmol, 1.2 eq.) were added, and the title compound T-107 (38 mg, 15% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, DMSO- d 6) δ 12.03 (s, 1H), 10.69 (s, 1H), 8.65 (d, J= 8.4 Hz, 1H), 7.35 – 7.21 (m, 4H), 7.18 – 7.12 (m, 2H), 7.05 – 6.95 (m, 2H), 6.90 – 6.80 (m, 2H), 5.14 (t, J = 8.0 Hz, 1H), 4.94 – 4.80(m, 1H), 4.12 (d, J = 10.4 Hz, 1H), 3.72 (d, J = 10.4 Hz, 1H), 3.17 – 2.95(m, 2H), 2.64 – 2.54 (m, 1H), 2.46 – 2.33 (m, 1H). MS ( m / z 538.2 (Mw-H) - .

[0583] Example 108

[0584] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-5-(trifluoromethyl)thiophene-2-carboxamide (T-108)

[0585]

[0586] Referring to the synthesis of compound T-009, 099-1 (150 mg, 0.30 mmol) and 5-(trifluoromethyl)thiophene-2-carboxylic acid (72 mg, 0.37 mmol, 1.2 eq.) were added, and the title compound T-108 (38 mg, 15% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.49 – 7.34 (m,4H), 7.19 – 7.11 (m, 1H), 7.10 – 6.96 (m, 4H), 6.94 – 6.87 (m, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.10 – 4.97 (m, 2H), 4.05 (d, J = 10.8 Hz, 1H), 3.40 (d, J =10.5 Hz, 1H), 2.84 – 2.69 (m, 2H), 2.53 (dd,J = 13.3, 8.5 Hz, 1H), 2.40 (dd, J = 20.6, 7.0 Hz, 1H). MS ( m / z 538.2 (Mw-H) - .

[0587] Example 109

[0588] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-1H-pyrrole-2-carboxamide (T-109)

[0589]

[0590] Referring to the synthesis of compound T-009, 099-1 (100 mg, 0.27 mmol) pyrrole-2-carboxylic acid (27 mg, 0.24 mmol, 1.2 eq.) was added, and the title compound T-109 (23 mg, 23% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.27 (s, 1H), 10.71 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.33 – 7.16 (m, 3H), 7.06 – 6.93 (m, 3H), 6.88 – 6.77 (m, 3H), 6.12 – 6.02 (m, 1H), 5.19 (t, J = 8.0 Hz, 1H), 4.90 – 4.78 (m, 1H), 4.18 (d, J = 10.4 Hz, 1H), 3.75 (d, J = 10.4 Hz, 1H), 3.13 – 2.97 (m, 2H), 2.62 (dd, J = 13.2, 8.8 Hz, 1H), 2.43 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 488.2 (Mw-H) - .

[0591] Example 110

[0592] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-3-methylisoxazole-5-carboxamide (T-110)

[0593]

[0594] Referring to the synthesis of compound T-009, T-041 (124 mg, 0.26 mmol) and 3-methylisoxazole-5-carboxylic acid (38 mg, 0.30 mmol, 1.2 eq.) were added, and the title compound T-110 (35 mg, 28% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.44 – 7.34 (m,2H), 7.27 – 7.23 (m, 1H), 7.11 – 6.85 (m, 5H), 6.68 (s, 1H), 5.09 – 4.94 (m,2H), 3.93 (d, J = 10.4 Hz, 1H), 3.39 (d, J = 10.4 Hz, 1H), 3.32 – 3.14 (m,2H), 2.83 (s, 1H), 2.77 (dd, J = 13.2, 8.8 Hz, 1H), 2.52 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 486.2 (Mw-H) - .

[0595] Example 111

[0596] Preparation of (3R, 5'S)-1'-((S)-2-(3-aminopyrazin-2-yl)amino)-3-(3-fluorophenyl)propionyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carbamate (T-111)

[0597]

[0598] Step-1: (3) R 5' S )-1'-(( SPreparation of 111-2 (111-1)-3-(3-fluorophenyl)-2-(3-nitropyrazin-2-yl)amino)propionyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carbamate. 111-1 (100 mg, 0.24 mmol) and 2-chloro-3-nitropyrazine (57 mg, 0.36 mmol, 1.5 eq.) were added to a 5 mL microwave-assisted reaction tube. Column chromatography (EA / Hep increased from 5% to 60%) was used to separate the title compound 111-2 (105 mg, 88% yield). MS ( m / z 500.2 (Mw-H) - .

[0599] Step-2: (3) R 5' S )-1'-(( S Preparation of 2-(3-aminopyrazin-2-yl)amino)-3-(3-fluorophenyl)propionyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carbamate (T-111). 111-2 (80 mg, 0.16 mmol) and Pd / C (16 mg) were dissolved in methanol (20 mL), and the atmosphere was purged. The reaction was carried out at room temperature for 22 hours under a hydrogen atmosphere. The mixture was purified by reverse-phase reaction to give compound T-111 (10 mg, 13% yield). MS ( m / z 470.2 (Mw-H) - .

[0600] Example 112

[0601] Preparation of (3R, 5'S)-1'-((S)-2-((4-(3,3-difluoroazacyclobutane-1-yl)-1,3,5-triazin-2-yl)amino)-3-(3-fluorophenyl)propionyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carbamate (T-112)

[0602]

[0603] 111-1 (80 mg, 0.21 mmol) and 2,4-dichloro-1,3,5-triazine (33 mg, 0.22, 1.05 eq) were added to a 5 mL microwave-safe reaction tube and dissolved in acetonitrile (3 mL). DIPEA (74 μL, 2 eq.) was then added, and the mixture was stirred at room temperature for 2 hours. Subsequently, 3,3-difluorozacriane hydrochloride (57 mg, 2.0 eq.) was added directly, and the mixture was heated in a microwave reactor at 80 °C for 1 hour. The mixture was purified by reverse-phase reaction to give compound T-112 (16 mg, 14% yield). 1H NMR (400MHz, DMSO- d 6) δ 10.76 (d, J = 10.8 Hz, 1H), 8.23 ​​– 8.13 (m, 1H), 7.36 – 7.10(m, 4H), 7.13 – 7.01 (m, 1H), 6.97 – 6.69 (m, 3H), 5.30 – 5.07(m, 1H), 4.91 –4.64 (m, 1H), 4.45 – 4.35 (m, 2H), 4.26 (d, J = 10.4 Hz, 1H), 4.21 – 4.08 (m,2H), 3.68 – 3.48 (m, 1H), 3.15 – 2.97 (m, 2H), 2.62 – 2.53 (m, 1H), 2.38(dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 547.2 (Mw-H) - .

[0604] Example 113

[0605] Preparation of (3aS,4S,6aS)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-(3-fluorophenyl)-1-oxopropane-2-yl)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxo[4,5-c]pyrrole-4-carboxamide (T-113)

[0606]

[0607] Referring to the synthesis of compound T-009, T-041 (126 mg, 0.26 mmol) and 113-1 (63 mg, 0.31 mmol, 1.2 eq.) were added, and the reverse synthesis was used to purify the title compound T-113 (35 mg, 28% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.73 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.20 – 8.07 (m, 1H), 7.39 – 7.19 (m, 2H), 7.16 – 6.99 (m, 4H), 6.97 – 6.80 (m, 2H), 5.09 (t,J = 8.0Hz, 1H), 4.80 – 4.64 (m, 2H), 4.51 (d, J = 6.0 Hz, 1H), 4.12 (d, J = 6.0 Hz, 1H), 4.02 (d, J = 10.4 Hz, 1H), 3.13 – 2.87 (m, 2H), 2.65 – 2.53 (m, 1H), 2.44 – 2.34 (m, 1H), 1.15 (s, 6H). MS ( m / z 560.2 (Mw-H) - .

[0608] Example 114

[0609] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-3-yl)propane-2-yl)-4,7-difluoro-1H-indole-2-carboxamide (T-114)

[0610]

[0611] Referring to the synthesis of compound T-009, 114-1 (100 mg, 0.22 mmol) and 4,7-difluoroindole-2-carboxylic acid (51 mg, 0.26 mmol, 1.2 eq.) were added, and the title compound T-114 (70 mg, 60% yield) was isolated by column chromatography (EA / Hep increased from 5% to 100%). 1 H NMR (400 MHz, DMSO- d 6) δ 12.27 (s, 1H), 10.69 (s, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 4.4 Hz, 1H), 8.38 (d, J = 4.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.37 – 7.22 (m, 3H), 7.16 – 6.97 (m, 3H), 6.90 –6.77 (m, 2H), 5.18 (t, J = 8.0 Hz, 1H), 5.02 – 4.92 (m, 1H), 4.14 (d, J=10.4 Hz, 1H), 3.84 (d, J = 10.4 Hz, 1H), 3.21 – 3.10 (m, 2H), 2.62 (dd, J =13.2, 8.8 Hz, 1H), 2.40 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 539.2 (Mw-H) - .

[0612] Example 115

[0613] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-3-yl)propane-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (T-115)

[0614]

[0615] Following the synthesis of compound T-009, EDCI was used as the condensing agent. 114-1 (775 mg, 1.68 mmol) and 5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (300 mg, 1.68 mmol, 1.0 eq.) were added, and column chromatography (EA / Hep increased from 5% to 70%) was used to separate the title compound T-115 (60 mg, 7% yield). 1 H NMR (400 MHz, CDCl3) δ 8.62 –8.57 (m, 1H), 8.51 (d, J = 4.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.38 – 7.31(m, 2H), 7.27 – 7.22 (m, 3H), 6.98 – 6.83 (m, 2H), 6.88 – 6.83 (m, 1H), 6.65– 6.58 (m, 2H), 5.12 – 5.01 (m, 2H), 4.06 (d, J = 10.4 Hz, 1H), 3.64 (d, J =10.4 Hz, 1H), 3.36 – 3.09 (m, 2H), 2.83 (dd, J = 13.2, 8.6 Hz, 1H), 2.56 (dd, J= 13.2, 8.8 Hz, 1H). MS ( m / z 521.2 (Mw-H) - .

[0616] Example 116

[0617] Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-3-yl)propane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-116)

[0618]

[0619] Step 1: Preparation of tert-butyl((S)-1-(((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-3-yl)propane-2-yl)amino)-3,3-dimethyl-1-oxobutane-2-yl)carbamate (116-1). Following the synthetic method of T-009, 114-1 (200 mg, 0.48 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutyric acid (133 mg, 0.58 mmol, 1.2 eq.) were added and separated by column chromatography (EA / Hep increased from 5% to 100%) to obtain the title compound 116-1 (160 mg, 58% yield). MS ( m / z 573.3 (Mw-H) - .

[0620] Step 2: Preparation of (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-3-yl)propane-2-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butyramide (T-116). Following the synthetic method of T-024, 116-1 (160 mg, 0.28 mmol) was added, and column chromatography (EA / Hep increased from 5% to 100%) was used to separate the title compound T-116 (40 mg, 25% yield). 1 H NMR (400 MHz, CDCl3) δ9.30 (s, 1H), 8.57 (dr, 2H), 7.79 – 7.34 (m, 4H), 7.21 – 6.81 (m, 4H), 4.96(t, J= 5.2 Hz, 1H), 4.80 – 4.70 (m, 1H), 4.38 (d, J = 8.8 Hz, 1H), 3.95 (d, J =10.4 Hz, 1H), 3.41 (d, J = 10.4 Hz, 1H), 3.25 – 3.05 (m, 2H), 2.68 (dd, J = 13.2, 8.8 Hz, 1H), 2.46 (dd, J = 13.2, 8.8 Hz, 1H), 0.96 (s, 9H). MS ( m / z 570.5 (Mw-H) - .

[0621] Example 117

[0622] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-3-yl)propane-2-yl)-4,7-difluoro-N-methyl-1H-indole-2-carboxamide (T-117)

[0623]

[0624] Following the synthesis of compound T-009, 117-1 (100 mg, 0.21 mmol) and 4,7-difluoroindole-2-carboxylic acid (49 mg, 0.25 mmol, 1.2 eq.) were added, and the mixture was prepared by reverse phase reaction to give the title compound T-117 (7 mg, 6% yield). MS ( m / z 553.2 (Mw-H) - .

[0625] Example 118

[0626] Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(pyridin-2-yl)propane-2-yl)-3-fluoro-1H-pyrrole-2-carboxamide (T-118)

[0627]

[0628] Referring to the synthesis of compound T-009, EDCI was used as the condensing agent. 118-1 (100 mg, 0.22 mmol) and 3-fluoro-1H-pyrrole-2-carboxylic acid (33 mg, 0.26 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 10%, then MeOH / EA increased from 0 to 10%) was used to separate the title compound T-118 (13 mg, 13% yield). 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.61 (d, J = 4.0 Hz, 1H), 8.32 (s, 1H), 7.78 – 7.66(m, 2H), 7.58 – 7.52 (m, 1H), 7.26 – 7.14 (m, 3H), 6.93 – 6.87 (m, 2H), 6.70– 6.63 (m, 1H), 5.99 (t, J = 4.0 Hz, 1H), 5.26 (q, J = 7.2 Hz, 1H), 5.00 (t, J = 8.4 Hz, 1H), 4.23 (d, J = 10.4 Hz, 1H), 3.81 (d, J = 10.4 Hz, 1H), 3.47 –3.24 (m, 2H), 2.77 (dd, J = 13.2, 8.8 Hz, 1H), 2.50 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 471.1 (Mw-H) - .

[0629] Example 119

[0630] Preparation of N-((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-1-oxo-3-(pyridin-2-yl))propane-2-yl))-4,7-difluoro-1H-indole-2-carboxamide (T-119)

[0631]

[0632] Referring to the synthesis of compound T-009, EDCI was used as the condensing agent. 118-1 (100 mg, 0.22 mmol) and 4,7-difluoroindole-2-carboxylic acid (51 mg, 0.26 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 100%) was used to isolate the title compound T-119 (15 mg, 13% yield). 1 H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H),8.82 (s, 1H), 8.73 – 8.48 (m, 2H), 7.84 – 7.70 (m, 1H), 7.61 – 7.41 (m, 1H),7.21 – 6.98 (m, 3H), 6.96 – 6.81 (m, 4H), 6.75 – 6.56 (m, 1H), 5.42 – 5.35(m, 1H), 5.18 – 5.08 (m, 1H), 4.49 – 4.32 (m, 1H), 4.19 – 3.98 (m, 1H), 3.60– 3.38 (m, 2H), 2.84 (dd, J = 13.2, 8.8 Hz, 1H), 2.59 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 539.2 (Mw-H) - .

[0633] Example 120

[0634] Preparation of N-((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-1-oxo-3-(pyridin-4-yl))propane-2-yl))-4,7-difluoro-1H-indole-2-carboxamide (T-120)

[0635]

[0636] Referring to the synthesis of compound T-009, 120-1 (65 mg, 0.14 mmol) and 4,7-difluoroindole-2-carboxylic acid (30 mg, 0.15 mmol, 1.1 eq.) were added, and the title compound T-120 (20 mg, 27% yield) was isolated by reverse-phase preparation. 1 HNMR (400 MHz, DMSO- d 6) δ 12.27 (s, 1H), 10.69 (s, 1H), 9.01 (d,J = 8.0 Hz, 1H), 8.42 (d, J = 5.6 Hz, 2H), 7.39 (d, J = 5.6 Hz, 2H), 7.32 (d, J = 2.6 Hz,1H), 7.15 – 6.96 (m, 3H), 6.90 – 6.76 (m, 3H), 5.18 (t, J = 8.0 Hz, 1H), 5.06– 4.93 (m, 1H), 4.14 (d, J = 10.8 Hz, 1H), 3.86 (d, J = 10.8 Hz, 1H), 3.22 –3.05 (m, 2H), 2.62 (dd, J = 13.2, 8.8 Hz, 1H), 2.43 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 539.2 (Mw-H) - .

[0637] Example 121

[0638] Preparation of (S))-N-((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))-3-hydroxy-3-methyl-2-(2,2,2-trifluoroacetamido))butyramide (T-121)

[0639]

[0640] Step-1: tert-butyl((S))-1-(((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-

[0641] Preparation of [pyrrolidine]-1'-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))amino))-3-hydroxy-3-methyl-1-oxobutane-2-yl))carbamate (121-2). Following the synthetic method of T-009, T-041 (150 mg, 0.31 mmol) and 121-1 (87 mg, 0.37 mmol, 1.2 eq.) were added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound 121-2 (160 mg, 85% yield). MS ( m / z 592.3 (Mw-H) - .

[0642] Step 2: Preparation of (S)-N-((S))-1-((3R, 5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))-3-hydroxy-3-methyl-2-(2,2,2-trifluoroacetamido))butyramide (T-121). Following the synthetic method of T-024, 121-2 (120 mg, 0.20 mmol) was added, and column chromatography (EA / Hep increased from 5% to 50%) was used to separate the title compound T-121 (50 mg, 42% yield). 1 H NMR (400MHz, DMSO- d 6) δ 10.70 (s, 1H), 9.06 (d, J = 9.2 Hz, 1H), 8.54 (d, J = 7.2 Hz,1H), 7.31 – 7.20 (m, 2H), 7.18 – 7.10 (m, 2H), 7.08 – 6.99 (m, 2H), 6.96 –6.86 (m, 2H), 5.09 (t, J = 8.0 Hz, 1H), 4.95 (s, 1H), 4.73 (q, J = 7.2 Hz, 1H), 4.41 (d, J = 8.8 Hz, 1H), 4.03 (d, J = 10.8 Hz, 1H), 3.56 (d, J = 10.8Hz, 1H), 3.08 – 2.91 (m, 2H), 2.58 – 2.52 (m, 1H), 2.43 – 2.32 (m, 1H), 1.11(d, J = 8.0 Hz, 6H). MS ( m / z 588.2 (Mw-H) - .

[0643] Example 122

[0644] Preparation of N-((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))-1H-pyrazole-5-carboxamide (T-122)

[0645]

[0646] Referring to the synthesis of compound T-009, T-041 (150 mg, 0.31 mmol) and 1H-pyrazole-5-carboxylic acid (42 mg, 0.37 mmol, 1.2 eq.) were added, and the title compound T-122 (80 mg, 54% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, DMSO- d 6) δ 13.27 (s, 1H), 10.69 (s, 1H), 8.21 –8.08 (m, 1H), 7.34 – 7.13 (m, 5H), 7.09 – 6.98 (m, 2H), 6.96 – 6.86 (m, 2H), 6.58 (s, 1H), 5.14 (t, J = 8.0 Hz, 1H), 4.88 (q, 7.2 Hz, 1H), 4.12 (d, J =10.4 Hz, 1H), 3.77 (d, J = 10.4 Hz, 1H), 3.15 – 3.03 (m, 2H), 2.60 (dd, J =13.2, 8.8 Hz, 1H), 2.41 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 472.2 (Mw-H) - .

[0647] Example 123

[0648] Preparation of N-((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))-3-(trifluoromethyl))-1H-pyrazole-5-carboxamide (T-123)

[0649]

[0650] Referring to the synthesis of compound T-009, T-041 (150 mg, 0.31 mmol) and 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (67 mg, 0.37 mmol, 1.2 eq.) were added, and the title compound T-123 (55 mg, 32% yield) was isolated by column chromatography (EA / Hep increased from 5% to 60%). 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.43 – 7.32 (m, 2H), 7.26 – 7.22 (m, 1H), 7.15 – 6.89 (m, 8H), 5.10 – 4.97 (m, 2H), 4.30– 4.11 (m, 1H), 3.90 – 3.79 (m, 1H), 3.28 – 3.16 (m, 2H), 2.79 (dd, J = 13.2, 8.8 Hz, 1H), 2.55 (dd, J = 13.2, 8.8 Hz, 1H). MS ( m / z 539.2 (Mw-H) - .

[0651] Example 124

[0652] (S))-N-((S))-1-((3R,5S))-5-cyano-2'-oxo-1',2'-dihydrospiro[pyrrolidine-3,3'-pyrrolidin[2,3-b]pyridine]-1-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))-2,3-dimethyl-2-(2,2,2-trifluoroacetamido))butyramide

[0653] Preparation of (T-124)

[0654]

[0655] Intermediate 124-1 was synthesized according to the preparation method of T-008; then, referring to the synthesis of compound T-009, compound 102-1 (328 mg, 0.68 mmol) and (S))-3,3-dimethyl-2-(2,2,2-trifluoroacetamido))butyric acid (195 mg, 0.86 mmol, 1.2 eq.) were added, and the title compound T-124 (56 mg, 14% yield) was isolated by column chromatography (EA / Hep increased from 5% to 70%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.34 (s, 1H), 9.07 (d,J = 9.6 Hz, 1H), 8.75 (d, J = 7.2 Hz, 1H), 8.11 (dd, J = 5.2, 1.6 Hz, 1H), 7.33 – 7.22(m, 2H), 7.17 – 7.01 (m, 3H), 6.90 (dd, J = 7.2, 5.2 Hz, 1H), 5.15 (t, J =8.4 Hz, 1H), 4.66 (q, J = 7.2 Hz, 1H), 4.40 (d, J = 9.6 Hz, 1H), 4.12 (d, J =10.4 Hz, 1H), 3.44 (d, J = 10.4 Hz, 1H), 3.13 – 2.89 (m, 2H), 2.58 (dd, J =13.2, 8.8 Hz, 1H), 2.33 (dd, J = 13.2, 8.8 Hz, 1H), 0.89 (s, 9H). MS ( m / z 587.2 (Mw-H) - .

[0656] Example 125

[0657] Preparation of (S))-N-((S))-1-((3R,5'S))-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl))-3-(3-fluorophenyl))-1-oxopropane-2-yl))-N,3,3-trimethyl-2-(2,2,2-trifluoroacetamido))butyramide (T-125)

[0658]

[0659] Intermediate 125-1 was synthesized according to the preparation method of T-008; then, referring to the synthesis of compound T-009, compound 102-1 (42 mg, 0.08 mmol) and (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido))butyric acid (22 mg, 0.15 mmol, 2.0 eq.) were added, and the mixture was purified by reverse-phase separation to obtain the title compound T-124 (6 mg, 13% yield). ( m / z 601.2 (Mw-H)- .

[0660] Experimental Example 1: Novel Coronavirus (SARS-CoV-2) 3CL pro Evaluation of protease inhibitory activity

[0661] The compounds contained in this application are effective against the 3CL of SARS-CoV-2. pro The principle behind the detection of inhibitory activity against protease hydrolysis is as follows: 3CL protease hydrolyzes its substrate. After hydrolysis, the substrate, under excitation light of 320 nm, produces a strong fluorescence at emission light of 390 nm. Compounds that can inhibit this reaction are screened based on this principle. The 3CL protease used in the experimental method... pro The protease and the specific polypeptide substrate for hydrolysis reaction labeled with fluorescent donor and quencher groups at the C-terminus and N-terminus, respectively, MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2, were purchased from Beyotime. Specifically: (1) Prepare a test buffer containing 20 mM Tris-HCl, 7 mM DTT, and pH = 7.5. (2) Dissolve the test compound in DMSO and dilute it in a 3-fold gradient to obtain 12 concentration gradient dilutions of DMSO solution; at the same time, dilute the prepared gradient dilution solution 25 times with the test buffer to obtain a concentration gradient dilution working solution of the test compound. The highest concentration is 4x, which is the highest concentration set for the test. (3) Prepare a 4x final reaction protein concentration working solution using the prepared test buffer. (4) Add 5 mmol / L to each well of the 384-well plate. L of the graded dilution working solution of the analyte and 5 L SARS-CoV-2 3CL pro Centrifuge the protease working solution and incubate at room temperature for 30 minutes. (5) Prepare a 2x final reaction peptide substrate working solution using test buffer, and then add 10 μL of the solution to all wells in step-4. L of the working solution, 3CL in the final reaction system pro The concentrations of the protease and the fluorescently labeled peptide substrate were 200 nM and 10, respectively. M, DMSO concentration is 1%. The same experimental microplate was prepared with wells containing no analyte, wells containing no analyte, and wells with 3CL. pro Protease, positive and negative control wells containing only fluorescently labeled substrate. Incubate at room temperature for 90 minutes. (6) Use a Tecan Spark multi-functional microplate reader for fluorescence detection, with excitation wavelength of 320 nm and emission wavelength of 390 nm. Collect fluorescence intensity data, plot the concentration of the test compound using GraphPad Prism 9.0 software, and fit and analyze the obtained sigmoidal curve to obtain IC50. 50The values ​​are shown in Table 1.

[0662] The results of the activity test are explained below:

[0663] **** ≤ 0.5 μΜ, 0.5 μΜ < *** ≤ 5.0 μΜ, 5.0 μΜ < ** ≤ 50.0 μΜ, * >50 M.

[0664] Experimental Example 2: Novel Coronavirus (SARS-CoV-2) 3CL pro Evaluation of protease inhibitory activity

[0665] Optimize Experiment 1: (1) Prepare a test buffer containing 20 mM Tris-HCl, 7 mM DTT, 0.01% BSA, and pH = 7.5. (2) Dissolve the test compound in DMSO and dilute it in a 3-fold gradient to obtain 12 concentration gradient dilutions of DMSO solution; at the same time, dilute the prepared gradient dilution solution 25 times with the test buffer to obtain a concentration gradient dilution working solution of the test compound. The highest concentration is 4x, which is the highest concentration set for the test. (3) Prepare a 4x final reaction protein concentration working solution (40 nM) using the prepared test buffer. (4) Add 5 ppm of the test buffer to each well of the 384-well plate. L of the graded dilution working solution of the analyte and 5 L SARS-CoV-2 3CL pro Centrifuge the protease working solution and incubate at room temperature for 30 minutes. (5) Dissolve the fluorescent peptide substrate in the test buffer to prepare a 2x final reaction peptide substrate working solution (40 g / L). M), then add 10 to all the reaction wells in step-4. L of the working solution, 3CL in the final reaction system pro The concentrations of the protease and the fluorescently labeled peptide substrate were 10 nM and 20 nM, respectively. M, DMSO concentration is 1%. The same experimental microplate was prepared with wells containing no analyte, wells containing no analyte, and wells with 3CL. pro Protease, positive and negative control wells containing only fluorescently labeled substrate. Incubate at room temperature for 90 minutes. (6) Use a Tecan Spark multi-functional microplate reader for fluorescence detection. The excitation wavelength is 320 nm and the emission wavelength is 390 nm. Collect fluorescence intensity data, plot the concentration of the test compound using GraphPad Prism 9.0 software, and fit the obtained sigmoidal curve to obtain IC50. 50 The values ​​are shown in Table 1.

[0666] Table 1

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686] Note: N / A indicates not tested, IC 50 (μM) a This represents the result of Experiment Example 1, IC. 50 (μM) b This represents the result of Experiment Example 2.

[0687] Example 3: Evaluation of the antiviral activity of compounds against the novel coronavirus (SARS-CoV-2 Delta)

[0688] To determine the inhibitory activity of the compounds against SARS-CoV-2 Delta: Vero E6 cell lines were used as host cells. Gradual concentrations of the compounds were added to well plates and incubated with 2 μM CP-100356 (a P-gp efflux inhibitor). Virus quantification and IC50 of the compounds were then performed using cytopathic effect (CPE). 50 Similarly, the cytotoxicity of a series of compounds against Vero E6 cells was determined in the absence of virus. Viable cell counts were measured using Promega CellTiter-Glo to obtain CC values. 50 The values ​​are shown in Table 2.

[0689] Table 2

[0690]

[0691]

[0692]

[0693] Experimental Example 4: Compounds targeting the novel coronavirus 3CL Pro Protease Jump Dilution Experiment Protocol

[0694] a. Reagent preparation

[0695] Reaction buffer: Prepare reaction buffer-1 with the following components: 20 mM Tris-HCl pH 7.5, 7 mM DTT, 0.01% BSA. Prepare reaction buffer-2 with the following components: 20 mM Tris-HCl pH 7.5, 7 mM DTT, 0.01% BSA, 1% DMSO. 3CL Pro Protease solution: Dilute reaction buffer to 3 Cl. Pro Kinase to a final concentration of 1 μM (200x). 2x substrate solution: Dilute MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2 (coronavirus main protease fluorescent substrate) to 60 μM (final concentration: 30 μM) with reaction buffer-1. Test compound solution: Dilute the compound to an intermediate concentration of 5 μM (1000x) containing 10% DMSO with reaction buffer-1.

[0696] b. Experimental Procedure

[0697] Add 10 μL of 3CL sequentially to the 96-well plate ProThe enzyme solution and 2 μL of diluted test compound solutions at different concentrations were prepared, along with 8 μL of experimental buffer-1. A blank control group and a positive control group (DMSO group) were also included. The enzyme and compound were mixed by shaking the 96-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 30 minutes. After incubation, the mixture was diluted 50-fold with reaction buffer-2, and 10 μL of the diluted solution was added to three replicates in a 384-well plate. 10 μL of 2x substrate solution was added to each well of the 384-well plate, and the plate was centrifuged at 1000 rpm for 1 minute. The final concentrations of each component were 3CL. Pro The final concentration of the test compound was 5 nM, with a substrate concentration of 30 μM. Fluorescence values ​​at excitation light of 320 nm and emission light of 390 nm were detected using a Tecan Spark assay. Enzyme kinetics were read for the first 1 h, then every 30 min for up to 3.5 h, and the data were analyzed.

[0698] Data Analysis

[0699] 4-1. Based on the percentage of the initial rate of different compound groups relative to the DMSO group after the jump experiment (the lower the recovery percentage, the higher the rate of the compound in 3CL). Pro The longer the residence time on the protease, the more likely it is to be plotted in a table, as shown in Table 3.

[0700] Table 3

[0701]

[0702] 4-2. Calculate the concentration of compound T-046 in 3CL. Pro Residence time of proteases

[0703] Substitute the product and corresponding time into the following formula, use GraphPad Prism to fit the curve, and obtain residencetime (τ). The results are shown in Table 4.

[0704]

[0705] in, v i and v s The following formula can be used to obtain it:

[0706]

[0707]

[0708] Table 4

[0709]

[0710] Conclusion: Compound T-046 in 3CL Pro The protease residence time is much longer than that of PF-07321332.

Claims

1. A compound selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of an antiviral drug; wherein the virus is a coronavirus.

3. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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