Antiviral compounds for treating coronavirus, picornavirus and norovirus infections

Abstract

Provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharmaceutically acceptable salts of the compounds described herein), and methods for synthesizing the same. Also provided herein are methods for treating coronavirus, picornavirus, and norovirus infections with compounds of formula (I), or pharmaceutically acceptable salts thereof. [Formula 1] TIFF2023530267000408.tif56128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) Any and all applications that identify a claim of foreign or domestic priority in an Application Data Sheet or claim submitted with this application, including, for example, U.S. Provisional Patent Application Nos. 63 / 037,200, filed June 10, 2020, 63 / 055,679, filed July 23, 2020, 63 / 085,871, filed September 30, 2020, 63 / 086,787, filed October 2, 2020, 63 / 125,562, filed December 15, 2020, and 63 / 155,113, filed March 1, 2021, are incorporated herein by reference pursuant to 37 CFR 1.57 and Rules 4.18 and 20.6.

[0002] FIELD OF THE INVENTION This application relates to the fields of chemistry, biochemistry, and medicine. Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharmaceutically acceptable salts of the compounds described herein), and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and / or conditions with compounds of formula (I), or pharmaceutically acceptable salts thereof. [Background technology]

[0003] Single-stranded positive-sense RNA viruses ((+)ssRNA viruses) are viruses that use positive-sense, single-stranded RNA as their genetic material. Single-stranded positive-sense RNA viruses can be enveloped or non-enveloped. Coronaviridae, Picornaviridae, and Noroviruses are each (+)ssRNA viruses. Each of the aforementioned viruses is known to infect mammals, including humans. Summary of the Invention [Means for solving the problem]

[0004] Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0005] Some embodiments disclosed herein relate to pharmaceutical compositions that can include an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to methods of treating a coronavirus infection, which may include administering to a subject identified as suffering from a coronavirus infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating a coronavirus infection.

[0007] Some embodiments disclosed herein relate to methods of inhibiting coronavirus growth, which may include contacting a cell infected with coronavirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in inhibiting coronavirus replication.

[0008] Some embodiments described herein relate to methods of treating a picornavirus infection, which may include administering to a subject identified as suffering from a picornavirus infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating a picornavirus infection.

[0009] Some embodiments disclosed herein relate to methods of inhibiting the growth of picornaviruses, which may include contacting a cell infected with a picornavirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in inhibiting the replication of a picornavirus.

[0010] Some embodiments described herein relate to methods of treating a Norovirus infection, which may include administering to a subject identified as suffering from a Norovirus infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating a Norovirus infection.

[0011] Some embodiments disclosed herein relate to methods of inhibiting the growth of Norovirus, which may include contacting a cell infected with Norovirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for use in inhibiting the replication of Norovirus.

[0012] These and other embodiments are described in more detail below. DETAILED DESCRIPTION OF THE INVENTION

[0013] Coronaviruses are a family of enveloped, single-stranded, positive-sense, spherical RNA viruses. Coronaviruses are named for the crown-like spikes on their surface. The Coronavirus family includes two subfamilies: coronaviruses and toroviruses. Coronaviruses have a helical nucleocapsid, while toroviruses have a tubular nucleocapsid. Coronaviruses include Middle East Respiratory Syndrome Coronavirus (MERS-CoV), SARS, and SARS-CoV-2.

[0014] Coronavirus disease 2019 (COVID-19), also known as novel coronavirus pneumonia or 2019-nCoV acute respiratory disease, is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (also known as novel coronavirus 2019 or 2019-nCoV). The disease was first identified in December 2019 and has spread globally, causing a pandemic. Symptoms of COVID-19 include fever, cough, shortness of breath, fatigue, headache, loss of smell, nasal congestion, sore throat, sputum production, muscle or joint pain, chills, nausea, vomiting, and diarrhea. In severe cases, symptoms may include difficulty waking, confusion, pale face or lips, hemoptysis, low white blood cell count, and kidney failure. Complications may include pneumonia, viral sepsis, acute respiratory distress syndrome, and kidney failure.

[0015] COVID-19 poses a particular threat to public health. The virus is highly contagious, and current research indicates that it can be transmitted by asymptomatic or pre-symptomatic carriers. Similarly, because the early stages of the disease progress slowly, carriers often are unaware that they are infected, exposing many others to the virus. The combination of COVID-19's easily transmitted nature, high patient hospitalization rates, and mortality makes the virus a substantial public health risk, especially for countries without healthcare systems equipped to provide supportive care for pandemic-level patient numbers. There is no vaccine or specific antiviral treatment for COVID-19, and therefore, there is an urgent need for a treatment or cure.

[0016] SARS-CoV-2 is not the only coronavirus that causes disease. It is a β-coronavirus, a genus of coronaviruses that includes other human pathogens, including SARS-CoV (the causative agent of SARS), MERS-CoV (the causative agent of MERS), and HCoV-OC43 (a common cold pathogen). These viruses vary widely in their infectiousness and the severity of the disease they cause. β-coronaviruses can also spread to and from humans and animals, manifesting as zoonotic diseases. Furthermore, nonhuman species, such as camels, bats, tigers, nonhuman primates, and rabbits, may be susceptible to β-coronaviruses. Therefore, there is an urgent need for treatments or cures for multiple coronaviruses.

[0017] The present disclosure provides molecules useful against coronaviruses, particularly SARS-CoV-2, the causative agent of COVID-19 in humans. Thus, the present disclosure fulfills a need in the art for compounds that can safely and effectively treat or prevent coronavirus infection in humans.

[0018] Picornaviruses are a family of positive-strand RNA, non-enveloped viruses. Picornaviruses have 60 identical subunits (vertices) containing five promoters. Each promoter is composed of one copy of four proteins, designated VP1, VP2, VP3, and VP4. Picornaviruses are classified into several genera, including enteroviruses, aphthoviruses, cardioviruses, and hepatoviruses. Enteroviruses known to infect humans include, but are not limited to, rhinovirus A, rhinovirus B, rhinovirus C, coxsackievirus A, coxsackievirus B, and poliovirus. There is no specific treatment for picornavirus infections.

[0019] Norovirus is a positive-sense, single-stranded, non-enveloped virus of the Caliciviridae family. Norovirus is often spread via the fecal-oral route and is a common cause of gastroenteritis. Infected subjects may experience nausea, non-bloody diarrhea, vomiting, and / or abdominal pain. Patients infected with norovirus may become severely dehydrated and require medical treatment. As with picornavirus infections, there is no specific treatment for norovirus infections. Therefore, there is a need for compounds that effectively treat or prevent picornavirus and / or norovirus infections.

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0021] Whenever a group is described as being "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the indicated substituents. If no substituents are specified, it means that the specified "optionally substituted" or "substituted" group may be substituted with one or more groups (e.g., 1, 2, or 3) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido(alkyl), isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amine, and disubstituted amine.

[0022] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified with respect to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described by those definitions is assumed.

[0023] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms. (Whenever a numerical range such as "1 to 20" appears herein, it refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on up to 20 carbon atoms; however, this definition also encompasses the term "alkyl" without a specified numerical range.) The alkyl group can also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0024] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain. The length of the alkenyl can vary. For example, an alkenyl can be C 2~4 Alkenyl, C 2~6 Alkenyl, or C 2~8 It may be alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl, and ethenyl. Alkenyl groups may be unsubstituted or substituted.

[0025] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. The length of an alkynyl group can vary. For example, an alkynyl group can be C 2~4 Alkynyl, C 2~6Alkynyl, or C 2~8 It can be alkynyl. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.

[0026] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of more than one ring, the rings may be joined together in a fused or spiro fashion. A cycloalkyl group can contain 3 to 10 atoms in the ring(s); 3 to 8 atoms in the ring(s); or 3 to 6 atoms in the ring(s). A cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0027] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized π-electron system throughout all rings (otherwise, the group is an "aryl" as defined herein). When composed of more than one ring, the rings may be connected together in a fused or spiro fashion. Cycloalkenyl groups can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. Cycloalkenyl groups can be unsubstituted or substituted.

[0028] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C6. 14 Aryl groups, C6-C 10The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0029] As used herein, "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems (ring systems having a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1 to 5 heteroatoms), i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0030] As used herein, "heterocyclyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with one to five heteroatoms, constitute the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized π-electron system does not occur throughout all rings. The number of atoms in the rings of a heterocyclyl group may vary. For example, a heterocyclyl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to define them as including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be joined by fusion. Additionally, any nitrogen in a heterocyclyl may be quaternized. A heterocyclyl group can be substituted or unsubstituted.Examples of such "heterocyclyl" groups include 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, tetrahydro-1,4-thi ... Examples of suitable amines include, but are not limited to, thiazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrroldione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0031] As used herein, "aryl(alkyl)" refers to an aryl group bonded as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0032] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group bonded as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs.

[0033] "(Heterocyclyl)alkyl" refers to a heterocyclic group bonded as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of the heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0034] A "lower alkylene group" is a straight-chain -CH- linking group that forms a bond to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent listed in the definition of "substituted." Additionally, when a lower alkylene group is substituted, the lower alkylene can be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group.

[0035] [ka]

[0036] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzyloxy. In some cases, alkoxy can be -OR, where R is an unsubstituted C 1~4 Alkyl. Alkoxy can be substituted or unsubstituted.

[0037] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) bonded as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0038] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be substituted or unsubstituted.

[0039] As used herein, "haloalkoxy" refers to O-alkyl groups and O-monocyclic cycloalkyl groups in which one or more of the hydrogen atoms have been replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chloro-substituted cyclobutyl, and fluoro-substituted cyclobutyl. In some cases, haloalkoxy can be -OR, where R is a C substituted with 1, 2, or 3 halogens. 1~4 The haloalkoxy may be substituted or unsubstituted.

[0040] A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The sulfenyl can be substituted or unsubstituted.

[0041] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl. Sulfinyl can be substituted or unsubstituted.

[0042] A "sulfonyl" group refers to a "SO2R" group, where R can be the same as defined for sulfenyl. The sulfonyl can be substituted or unsubstituted.

[0043] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The O-carboxy can be substituted or unsubstituted.

[0044] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. Ester and C-carboxy can be substituted or unsubstituted.

[0045] A "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl can be substituted or unsubstituted.

[0046] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group where each X is a halogen.

[0047] The "trihalomethanesulfonamide" group is "X3CS(O)2N(R A )— group, where each X is a halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0048] As used herein, the term "amino" refers to the group --NH.sub.2.

[0049] As used herein, the term "hydroxy" refers to an --OH group.

[0050] A "cyano" group refers to a "-CN" group.

[0051] As used herein, the term "azido" refers to the group --N.sub.3.

[0052] An "isocyanato" group refers to a "-NCO" group.

[0053] A "thiocyanato" group refers to a "-CNS" group.

[0054] An "isothiocyanato" group refers to a "-NCS" group.

[0055] A "mercapto" group refers to a "-SH" group.

[0056] A "carbonyl" group refers to a -C(=O)- group.

[0057] The "S-sulfonamide" group is defined as "-SO2N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). S-sulfonamides may be substituted or unsubstituted.

[0058] The "N-sulfonamide" group is "RSO2N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-sulfonamides may be substituted or unsubstituted.

[0059] The "O-carbamyl" group is defined as "-OC(=O)N(R A R B ) group, where R A and R Bmay be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0060] The "N-carbamyl" group is "ROC(=O)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-carbamyl may be substituted or unsubstituted.

[0061] The "O-thiocarbamyl" group is defined as "-OC(=S)-N(R A R B ) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0062] The "N-thiocarbamyl" group is "ROC(=S)N(R A )-" group, where R and R A may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-thiocarbamyl may be substituted or unsubstituted.

[0063] A "C-amido" group is defined as "-C(=O)N(R A R B) group, where R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amides may be substituted or unsubstituted.

[0064] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). N-amides may be substituted or unsubstituted.

[0065] The "monosubstituted amine" group is defined as "-NHR A " group, where R A may be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, monosubstituted amines may be substituted with -NHR A wherein R A is the unsubstituted C 1~6 It can be alkyl or unsubstituted or substituted benzyl.

[0066] A "disubstituted amine" group is defined as "-NR A R B " group, where R A and R Bmay be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, monosubstituted amines may be substituted with -NR A R B wherein R A and R B are independently unsubstituted C 1~6 It can be alkyl or unsubstituted or substituted benzyl.

[0067] A "ketoamide" group is a -C(=O)-C(=O)N(R A R B ) group, wherein R A and R B may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Ketoamides may be substituted or unsubstituted.

[0068] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0069] Where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0070] As used herein, the abbreviations for any protecting groups, amino acids, and other compounds are consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)), unless otherwise indicated.

[0071] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium or potassium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0072] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example above, the term "comprising" should be construed to mean "including without limitation," "including but not limited to," etc. As used herein, the term "comprising" is synonymous with "comprising," "containing," or "featuring," and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "examples" is used to provide illustrative examples of items under description, not an exhaustive or limiting list thereof. Additionally, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0073] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate for context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality.

[0074] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0075] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0076] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure can include any isotope of that element. For example, in a compound structure, a hydrogen atom can be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0077] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0078] compound Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0079] [ka] In the formula, Z 1 may be -C(=O)- or -CH(CF3)-, and Z 2 is O (oxygen), S (sulfur) or NR 8 where R 8 is H or unsubstituted C 1~4 may be alkyl, Z 3 may be N (nitrogen) or C (carbon), and Z 3 When N, R 5 No, Ring A 1 may be selected from unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein azetidine, pyrrolidine and piperidine are not deuterium, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 2~4 Alkenyl, unsubstituted or substituted C 1~8 Alkoxy, unsubstituted or substituted C 3~6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C 1~4 one or more R independently selected from haloalkyl x Azetidine, pyrrolidine and piperidine are monocyclic C 3~7 Cycloalkyl, Bicyclic C 5~9 Cycloalkyl, monocyclic C 3~7 Cycloalkenyl, Bicyclic C 5~9 and phenyl, wherein the cyclic moiety is connected in a fused or spiro fashion to azetidine, pyrrolidine, and piperidine; 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, and unsubstituted or substituted C 3~6monocyclic cycloalkyl; R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, unsubstituted or substituted -C(=O)-N-sulfonamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 9 )2), -C(=O)CH2-O-((P=O)(OR 10 )2), -C(=O)CH2-OC(R 11A )2-O-((P=O)(OR 11B )2), -C(=O)CH2-OC(R 12A )2-OC(=O)-OR 12B and -C(=O)CH2-OC(R 13A )2-OC(=O)-R 13B wherein each R 9 , each R 10 , each R 11B and R 12B and R 13B are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl), and each R 11A , each R 12A and each R 13A are independently hydrogen or unsubstituted C 1~4 may be alkyl, and R 2 may be hydrogen, deuterium, or halogen, and R 3 is an unsubstituted or substituted C-amide (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R4 may be hydrogen, deuterium, or halogen, and R 5 is hydrogen, deuterium, halogen, unsubstituted C 1~6 Alkyl and unsubstituted C 1~4 haloalkyl, and R 6 and R 7 is hydrogen, deuterium, halogen, unsubstituted C 1~6 Alkyl or substituted C 1~6 may be independently selected from alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, and unsubstituted or substituted sulfonyl, or R 6 and R 7 is R 6 and R 7 may be taken together with the carbon to which they are attached to form an optionally substituted 4-9 membered saturated or unsaturated ring or ring system which may optionally contain one or two ring heteroatoms selected from O (oxygen), N (nitrogen) and S (sulfur).

[0080] Substituent R 1 can be a variety of moieties. In some embodiments, R 1 may be an unsubstituted ketoamide. In some embodiments, R 1 may be a substituted ketoamide. A ketoamide has the structure -C(=O)-C(=O)NR y1 R z1 In some embodiments, R 1 may be acyl, for example, R 1 -C(=O)H, -C(=O)(unsubstituted C 1~4 In some embodiments, R may be -C(=O) (unsubstituted to substituted alkyl), -C(=O) (unsubstituted to substituted benzyl), -C(=O) (unsubstituted to substituted monocyclic heteroaryl), or -C(=O) (unsubstituted to substituted bicyclic heteroaryl). 1 R may be a substituted acyl. 1 The acyl has the structure -C(=O)R y2 When the acyl is substituted, groups that may be present on the acyl include hydroxy, substituted or unsubstituted alkoxy (e.g., —O—(unsubstituted C 1~4alkyl), -O-(unsubstituted C 3~6 cycloalkyl), substituted or unsubstituted phenoxy, or substituted or unsubstituted benzyloxy), or -O-(C=O)-(unsubstituted C 1~6 In some embodiments, R 1 may be unsubstituted and may be —C(═O)—N-sulfonamido. In other embodiments, R 1 may be substituted and may be —C(═O)—N-sulfonamide. As described herein, N-sulfonamide is a group having the structure “RSO2N(R A )-" and R 1 But -C(=O)-N(R y3 )SO2R y4 It becomes possible.

[0081] R y1 , R y2 , R y3 , R y4 and R z1 can be a variety of groups. In some embodiments, R y1 , R y2 , R y3 , R y4 and R z1 is hydrogen, C 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 3~8 Cycloalkyl (e.g., monocyclic C 3~8 cycloalkyl), C 3~8 Cycloalkenyl (e.g., monocyclic C 3~8 cycloalkenyl), aryl (e.g., phenyl or naphthyl), heteroaryl (including monocyclic or bicyclic heteroaryl), heterocyclyl (e.g., monocyclic or bicyclic heterocyclyl), aryl(alkyl) (e.g., benzyl), heteroaryl(alkyl) (including monocyclic heteroaryl(CH)- and monocyclic (heteroaryl(CHCH)-), or heterocyclyl(alkyl) (e.g., monocyclic heterocyclyl(CH)- and monocyclic heterocyclyl(CHCH)-), wherein R y1 , R y2 , Ry3 , R y4 and R z1 Each of the groups can be unsubstituted or substituted. In some embodiments, R y1 , R y2 and R z1 is H, C 1~8 Alkyl, unsubstituted C 1~4 haloalkyl (including -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F, and -CH2CH2CH2Cl), -C 1~4 Alkyl(OH) (including -CH2OH, -CH2CH2OH, and -CH(CH3)OH), -C 1~4 Alkyl (C 1~4 alkoxy) (e.g., —CH2O(unsubstituted C 1~4 alkyl), and -CHCHO (unsubstituted C 1~4 alkyl), -C 1~4 Alkyl-O-(monocyclic C 3~6 cycloalkyl) (e.g., —CH2O(monocyclic C 3~6 Cycloalkyl), -CH2CH2O (monocyclic C 3~6 Cycloalkyl), -C 1~4 alkyl-O-(phenyl) (e.g., —CHO(phenyl) and —CHCHO(phenyl)), —C 1~4 alkyl-O-(5- to 6-membered monocyclic heteroaryl) (e.g., —CHO(5- to 6-membered monocyclic heteroaryl) and —CHCHO(5- to 6-membered monocyclic heteroaryl)), —C 1~4 alkyl-O-(5- to 6-membered monocyclic heterocyclyl) (e.g., —CHO(5- to 6-membered monocyclic heterocyclyl) and —CHCHO(5- to 6-membered monocyclic heterocyclyl)), —C 1~4 Alkyl-O-(monocyclic C 3~6 Cycloalkyl(C 1~4 alkyl) (e.g., -C 1~4 Alkyl-O-CH2-(monocyclic C 3~6 cycloalkyl), and -C 1~4 Alkyl-O-CH2CH2-(monocyclic C 3~6Cycloalkyl), -C 1~4 alkyl-O-(benzyl) (e.g., —CHO(benzyl) and —CHCHO(benzyl)), —C 1~4 Alkyl-O-(5-6 membered monocyclic heteroaryl(C 1~4 alkyl), -C 1~4 Alkyl-O-(5-6-membered monocyclic heterocyclyl(C 1~4 alkyl), -C 1~4 Alkyl-O(C=O)(unsubstituted C 1~6 alkyl) (e.g., —CH2O(C═O) (unsubstituted C 1~6 alkyl), monocyclic C 3~8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl), monocyclic heteroaryl (e.g., imidazole, 1,3,4-oxadiazole, and pyridinyl), monocyclic heterocyclyl (e.g., tetrahydrofuran and tetrahydropyran), bicyclic heteroaryl (e.g., benzothiazole, benzimidazole, and benzoxazole), bicyclic heterocyclyl, monocyclic C 3~6 and may be independently selected from cycloalkyl(alkyl), aryl(alkyl) (e.g., benzyl), heteroaryl(alkyl) (e.g., monocyclic heteroaryl-(CH)-, e.g., pyridinyl-(CH)-), and heterocyclyl(alkyl) (e.g., monocyclic heterocyclyl-(CH)-), where R y1 , R y2 and R z1 Each of the groups can be unsubstituted or substituted.

[0082] In some embodiments, R 1 is -C(=O)R y2 wherein R y2 -C 1~4 In some embodiments, R 1 is -C(=O)-C(=O)NR y1 R z1 wherein R y1 can be H, and R z1is R in the previous paragraph. z1 In some embodiments, R may be any of the moieties listed for 1 is -C(=O)-C(=O)NR y1 R z1 wherein R y1 can be H, and R z1 is a monocyclic C 3~8 It may be cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl).

[0083] Prodrug-type and phosphate-containing moieties are R 1 In some embodiments, R 1 is -CH(OH)-(S(=O)2-O - In other embodiments, R 1 is -CH(OH)((P=O)(OR 9 )2), wherein each R 9 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 In still other embodiments, R 1 is -C(=O)CH2-O-((P=O)(OR 10 )2), wherein each R 10 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 In still other embodiments, R 1 is -C(=O)CH2-OC(R 11A )2-O-((P=O)(OR 11B )2), wherein each R 11A are independently hydrogen or unsubstituted C 1~4 alkyl, and each R 11Bare independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 In some embodiments, R 1 is -C(=O)CH2-OC(R 12A )2-OC(=O)-OR 12B wherein each R 12A are independently hydrogen or unsubstituted C 1~4 alkyl, and R 12B are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 In some embodiments, each R 9 may be hydrogen. In some embodiments, each R 10 may be hydrogen. In some embodiments, each R 11A may be hydrogen. In some embodiments, each R 11B is the unsubstituted C 1~6 In some embodiments, each R 12A may be hydrogen. In some embodiments, R 12B is the unsubstituted C 1~6 In some embodiments, R 1 is -C(=O)CH2-OC(R 13A )2-OC(=O)-R 13B wherein each R 13A are independently hydrogen or unsubstituted C 1~4 alkyl, and R 13B are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 In some embodiments, each R13A may be hydrogen. 11B , R 12B and / or R 13B Suitable unsubstituted C for 1~6 Examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl (branched and straight chain), and hexyl (branched and straight chain). 1 R may be -C(=O)CH2-O-((P=O)(OH)2). 9 , R 10 , R 11B and R 12B Examples of groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight and branched chain), hexyl (straight and branched chain), ethenyl, propenyl, butenyl, pentenyl, hexenyl, chloromethyl, fluoromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl.

[0084] In some embodiments, R 1 may be cyano. In other embodiments, R 1 is the unsubstituted C 2~5 In yet other embodiments, R 1 is a substitution C 2~5 It may be alkynyl. 2~5 Alkynyl can have a variety of structures, for example, C 2~5 Alkynyl has the structure -(CH2)1-C 2~4 Alkynyl or -(CH2)2-C 2~3 It may have alkynyl.

[0085] As provided herein, Z 1 may be -C(=O)-, such that a compound of formula (I) may have the structure of a compound of formula (Ia). Also, as provided herein, Z may be -C(=O)-, such that a compound of formula (I) may have the structure of a compound of formula (Ib). 1may be —CH(CF3)—.

[0086] [ka]

[0087] Ring A 1 may be azetidine, pyrrolidine, or piperidine. Each of the azetidine, pyrrolidine, or piperidine may be optionally substituted. In some embodiments, ring A 1 In other embodiments, ring A may be an unsubstituted azetidine. 1 In yet other embodiments, ring A may be unsubstituted pyrrolidine. 1 As provided herein, ring R may be an unsubstituted piperidine. 1 can be substituted. For example, in some embodiments, ring A 1 may be a substituted azetidine. 1 In yet another embodiment, ring A may be a substituted pyrrolidine. 1 may be a substituted piperidine.

[0088] Ring A 1 When is substituted, the ring may contain deuterium, halogen (e.g., fluoro and chloro), unsubstituted or substituted C 1~4 Alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl), unsubstituted or substituted C 2~4 alkenyl (e.g., -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CH2CH2CH=CH2, -CH2CH=CHCH3 and -CH=CH2CHCH3), unsubstituted or substituted C 1~8 Alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched and straight chain), hexoxy (branched and straight chain), and C 3~8 Cycloalkyloxy (monocyclic C 3~8 (including cycloalkyloxy), unsubstituted or substituted C3~6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C 1~4 one or more R independently selected from haloalkyl (e.g., CF, CHF, CHF, and CCl); x R x About C 3~6 The cycloalkyl, aryl, heteroaryl, and heterocyclyl may be monocyclic. For example, each R x can independently be unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered monocyclic heteroaryl, or unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl.

[0089] Ring A 1 can be connected in a fused or spiro fashion to an unsubstituted or substituted cyclic moiety as described herein. As described herein, a cyclic moiety is a monocyclic C 3~7 Cycloalkyl, Bicyclic C 5~9 Cycloalkyl, monocyclic C 3~7 Cycloalkenyl, Bicyclic C 5~9 The ring A may be selected from cycloalkenyl, cycloalkenyl, and phenyl. 1 and when the cyclic moieties described herein are connected in a spiro fashion, ring A 1 and cyclic moieties may be joined by a single ring atom. For example, the structure

[0090] [ka] In the formula, rings C1 and C2 are connected in a spiro fashion. 1 and when the cyclic moieties described herein are connected in a fused fashion, ring A 1 and the cyclic moiety is connected by two or more ring atoms. 1The cyclic moieties described herein may be connected by two adjacent ring atoms. In one example, rings D1 and D2 are connected in a fused manner by two adjacent ring atoms.

[0091] [ka] In some cases, ring A 1 And the cyclic moieties described herein can be connected by three or more atoms shared between the two rings.

[0092] [ka] is an example of two rings connected by three or more ring atoms. When two rings are connected by three or more ring atoms, the three or more ring atoms connecting the two rings are referred to as "bridging" atoms by those skilled in the art. Furthermore, based on the disclosure provided herein, those skilled in the art will understand that two rings connected in a "bridged" fashion are examples of two rings connected in a fused fashion.

[0093] In some embodiments, ring A 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a monocyclic C 3~7 In other embodiments, ring A may be connected to the cycloalkyl in a fused manner. 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a monocyclic C 3~7 In some embodiments, ring A may be connected to the cycloalkyl in a spiro fashion. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a monocyclic C 3~7 In other embodiments, ring A may be connected to the cycloalkyl in a fused manner. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a monocyclic C 3~7 In some embodiments, ring A may be connected to the cycloalkyl in a spiro fashion. 1may be an unsubstituted or substituted piperidine, where the piperidine is a monocyclic C 3~7 In other embodiments, ring A may be connected to the cycloalkyl in a fused manner. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a monocyclic C 3~7 It may be connected to the cycloalkyl in a spiro fashion.

[0094] In some embodiments, ring A 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a bicyclic C 5~9 In other embodiments, ring A may be connected to the cycloalkyl in a fused manner. 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a bicyclic C 5~9 In some embodiments, ring A may be connected to the cycloalkyl in a spiro fashion. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a bicyclic C 5~9 In other embodiments, ring A may be connected to the cycloalkyl in a fused manner. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a bicyclic C 5~9 In some embodiments, ring A may be connected to the cycloalkyl in a spiro fashion. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a bicyclic C 5~9 In other embodiments, ring A may be connected to the cycloalkyl in a fused manner. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a bicyclic C 5~9 It may be connected to the cycloalkyl in a spiro fashion.

[0095] In some embodiments, ring A 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a monocyclic C 3~7 In another embodiment, ring A may be connected to the cycloalkenyl in a fused manner. 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a monocyclic C 3~7In some embodiments, ring A may be connected to the cycloalkenyl in a spiro fashion. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a monocyclic C 3~7 In another embodiment, ring A may be connected to the cycloalkenyl in a fused manner. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a monocyclic C 3~7 In some embodiments, ring A may be connected to the cycloalkenyl in a spiro fashion. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a monocyclic C 3~7 In another embodiment, ring A may be connected to the cycloalkenyl in a fused manner. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a monocyclic C 3~7 It may be connected to the cycloalkenyl in a spiro fashion.

[0096] In some embodiments, ring A 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a bicyclic C 5~9 In another embodiment, ring A may be connected to the cycloalkenyl in a fused manner. 1 may be an unsubstituted or substituted azetidine, wherein the azetidine is a bicyclic C 5~9 In some embodiments, ring A may be connected to the cycloalkenyl in a spiro fashion. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a bicyclic C 5~9 In another embodiment, ring A may be connected to the cycloalkenyl in a fused manner. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine is a bicyclic C 5~9 In some embodiments, ring A may be connected to the cycloalkenyl in a spiro fashion. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a bicyclic C 5~9 In another embodiment, ring A may be connected to the cycloalkenyl in a fused manner. 1 may be an unsubstituted or substituted piperidine, where the piperidine is a bicyclic C5~9 The monocyclic C may be spiro-attached to the cycloalkenyl. 3~7 Cycloalkyl, Bicyclic C 5~9 Cycloalkyl, monocyclic C 3~7 Cycloalkenyl and bicyclic C 5~9 Examples of cycloalkenyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[3.1.0]hexane, spiro[2.2]pentane, spiro[2.4]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[2.2.2]octane, and bicyclo[2.2.2]oct-2-ene.

[0097] In some embodiments, ring A 1 may be an unsubstituted or substituted azetidine, where the azetidine may be connected to the phenyl in a fused manner. 1 may be unsubstituted or substituted pyrrolidine, where the pyrrolidine may be connected to the phenyl in a fused manner. 1 may be an unsubstituted or substituted piperidine, where the piperidine may be connected to the phenyl in a fused manner.

[0098] As provided herein, cyclic moieties (e.g., monocyclic C 3~7 Cycloalkyl, Bicyclic C 5~9 Cycloalkyl, monocyclic C 3~7 Cycloalkenyl, Bicyclic C 5~9 Cycloalkenyl, cycloalkenyl, and phenyl) may be unsubstituted or substituted with one or more moieties. Each moiety that may be present on the cyclic moiety is selected from the group consisting of halogen (e.g., fluoro or chloro), unsubstituted C 1~4 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl), unsubstituted C 2~4Alkenyl (e.g., ethenyl, propenyl, and butenyl), and unsubstituted or substituted monocyclic C 3~6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and their monocyclic C 3~6 The rings A and B may be independently selected from halo-substituted cycloalkyls. 1 and monocyclic C 3~7 Cycloalkyl, Bicyclic C 5~9 Cycloalkyl, monocyclic C 3~7 Cycloalkenyl or bicyclic C 5~9 Examples of cycloalkenyls include, but are not limited to:

[0099] [ka] Ring A is connected in a fused manner 1 and an exemplary bicyclic ring having phenyl is

[0100] [ka] is.

[0101] In some embodiments, R 4 may be hydrogen. In other embodiments, R 4 may be deuterium. In yet other embodiments, R 4 may be halogen (such as fluoro or chloro).

[0102] Z 2 and Z 3 The five-membered ring containing Z 2 is O (oxygen) and Z 3 When is C, it can be a furan ring. 2 is S and Z 3 When C, Z 2 and Z 3 The five-membered ring containing Z may be a thiophene ring. 2 and Z 3 Five-membered rings containing Z 3When is C, it can be a pyrrole ring, in which case Z 2 The nitrogen is hydrogen or unsubstituted C 1~4 can be attached to alkyl (Z 2 is NR 8 In this case, R 8 is H or unsubstituted C 1~4 (It can be alkyl). Z 2 NR 8 and Z 3 When N, Z 2 and Z 3 The five-membered ring containing Z may be imidazole. 2 is O, S or NR 8 and Z 3 is N or CR 5 Examples of formula (I) where: are shown below in formulas (Ic), (Id), (Ie), (If), (Ig) and (Ih), respectively.

[0103] [ka]

[0104] In some embodiments, Z 1 may be —C(═O)— in formula (Ic), formula (Id), formula (Ie) and / or formula (If). In other embodiments, Z 1 can be —CH(CF 3 )— in formula (Ic), formula (Id), formula (Ie) and / or (If).

[0105] Z 2 and Z 3 The five-membered ring containing Z may be unsubstituted or substituted. 2 and Z 3 The five-membered ring containing 1~6 In some embodiments, R 5 , R 6 , and R 7 may each be hydrogen. In other embodiments, R 5 , R 6 and R 7 At least one of the following is deuterium, halogen, or unsubstituted C1~6 Alkyl or unsubstituted C 1~4 In some embodiments, R 5 , R 6 and R 7 One of the following is deuterium, halogen, unsubstituted C 1~6 Alkyl or unsubstituted C 1~4 In other embodiments, R 5 , R 6 and R 7 Two of them are deuterium, halogen, and unsubstituted C 1~6 Alkyl or unsubstituted C 1~4 In yet other embodiments, R 5 , R 6 and R 7 All of the above are deuterium, halogen, and unsubstituted C 1~6 Alkyl or unsubstituted C 1~4 R may be haloalkyl. 5 , R 6 and / or R 7 For R, the halogen can be fluoro or chloro. 5 , R 6 and / or R 7 For unsubstituted C 1~6 Alkyl can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched or straight chain) or hexyl (branched or straight chain). R 5 , R 6 and / or R 7 Exemplary unsubstituted C 1~4 Haloalkyl includes CF, CHF, CHF, CCl, CHCl, and CHCl. ​​In some embodiments, Z 3 is CR 5 and R 5 is hydrogen, deuterium, halogen, unsubstituted C 1~6 Alkyl and unsubstituted C 1~4 haloalkyl may be selected, R 6 is halogen, unsubstituted C 1~6alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, and unsubstituted or substituted sulfonyl; R 7 is hydrogen, deuterium, halogen, unsubstituted C 1~6 It may be selected from alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, and unsubstituted or substituted sulfonyl.

[0106] Z 2 and Z 3 The five-membered ring containing R may be fused to a four- to nine-membered saturated or unsaturated ring or ring system, which may optionally contain one or two ring heteroatoms selected from O (oxygen), N (nitrogen), and S (sulfur). When the ring or ring system contains one or more sulfurs, each sulfur may be oxidized to a sulfoxide (S(=O)) or sulfone (S(=O)2). The four- to nine-membered saturated or unsaturated ring may be fused to a four- to nine-membered saturated or unsaturated ring, which may optionally contain one or two ring heteroatoms selected from O (oxygen), N (nitrogen), and S (sulfur). When the ring or ring system contains one or more sulfurs, each sulfur may be oxidized to a sulfoxide (S(=O)) or sulfone (S(=O)2). 6 and R 7 , R 6 and R 7 may be formed together with each carbon to which R is attached. 6 and R 7 is R 6 and R 7 may be taken together with the respective carbons to which they are attached to form an optionally substituted 4- to 9-membered saturated ring which may optionally contain one or two ring heteroatoms selected from O, N, and S. For example, R 6 and R 7 is R 6 and R 7 together with the carbons to which they are attached can form an optionally substituted 4- to 9-membered monocyclic cycloalkyl ring.

[0107] In some embodiments, R 6 and R 7 is R 6 and R 7may be taken together with the respective carbons to which R is attached to form an optionally substituted 4-9 membered unsaturated ring, which may optionally contain one or two ring heteroatoms selected from O, N, and S. In some embodiments, the 4-9 membered saturated or unsaturated ring may be a substituted or unsubstituted 4-9 membered monocyclic cycloalkyl ring, a substituted or unsubstituted 4-9 membered monocyclic cycloalkenyl ring, a substituted or unsubstituted 4-9 membered monocyclic heterocyclyl ring, a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 4-9 membered monocyclic heteroaryl ring. In some embodiments, R 6 and R 7 is R 6 and R 7 may be taken together with the carbons to which they are attached to form a substituted or unsubstituted 4-9 membered monocyclic cycloalkyl ring. 6 and R 7 is R 6 and R 7 may be taken together with the carbons to which they are attached to form a substituted or unsubstituted 4-9 membered monocyclic cycloalkenyl ring. 6 and R 7 is R 6 and R 7 may be taken together with the carbons to which they are attached to form a substituted or unsubstituted 5-6 membered monocyclic heterocyclyl ring. 6 and R 7 is R 6 and R 7 may be taken together with the respective carbons to which they are attached to form a substituted or unsubstituted phenyl. 6 and R 7 is R 6 and R 7 may be taken together with the respective carbons to which they are attached to form a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. In some embodiments, R 6 and R 7 is R 6 and R 7R may be taken together with the carbons to which it is bonded to form a substituted or unsubstituted 4- to 9-membered bicyclic cycloalkyl, a substituted or unsubstituted 4- to 9-membered bicyclic cycloalkenyl, a substituted or unsubstituted 4- to 9-membered bicyclic heteroaryl, or a substituted or unsubstituted 4- to 9-membered bicyclic heterocyclyl. 6 and R 7 , R 6 and R 7 The 4-9 membered saturated or unsaturated ring that may be formed when taken together with each carbon to which it is attached may be unsubstituted or substituted.

[0108] R 6 and R 7 , R 6 and R 7 The ring system that can be formed together with the respective carbons to which R is attached can be an unsubstituted or substituted bicyclic ring system, where the ring system can be a 4-9 membered saturated or unsaturated ring system that can optionally contain one or two ring heteroatoms selected from O, N, and S. In some embodiments, the 4-9 membered saturated or unsaturated ring system can be a saturated bicyclic ring system. In other embodiments, the 4-9 membered saturated or unsaturated ring system can be an unsaturated bicyclic ring system. As described herein, the ring system can be a ring system in which the ring atoms are carbon. The ring system can also be a ring system containing one or two ring heteroatoms selected from O, N, and S. For example, R 6 and R 7 , R 6 and R 7 The ring system formed by taken together with the carbons to which each is attached can be a bicyclic cycloalkyl, bicyclic cycloalkenyl, bicyclic aryl, bicyclic heteroaryl, or bicyclic heterocyclyl.

[0109] R 6 and R 7 , R 6 and R 7Examples of optionally substituted 4- to 9-membered cycloalkyl rings that can be formed by taking together the carbons to which R is attached are optionally substituted 4- to 9-membered monocyclic cycloalkyl rings, such as optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, and optionally substituted cycloheptyl. 6 and R 7 , R 6 and R 7 The ring system formed by taking together the carbons to which is attached can be a bicyclic hydrocarbon ring system, such as bicyclo[2.2.1]heptane. Examples of 4- to 9-membered heterocyclyl, 4- to 7-membered aryl, and 4- to 7-membered heteroaryl rings include, but are not limited to, phenyl, furan, thiophene, pyridine, piperazine, pyridazine, pyrimidine, pyridin-2-one, tetrahydrothiophene 1,1-dioxide, and tetrahydro-2H-thiopyran 1,1-dioxide.

[0110] When substituted, Z 2 and Z 3 and / or R 6 and R 7 , R 6 and R 7 The 4-9 membered saturated or unsaturated ring or ring system formed by taking together the carbons to which is attached can be substituted with deuterium, halogen (e.g., fluoro, chloro, and bromo), cyano, unsubstituted C 1~6 Alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl (branched and straight chain) and hexyl (branched and straight chain)), unsubstituted C 2~6 Alkenyl, unsubstituted C 2~6 Alkynyl, unsubstituted or substituted C 3~6 Cycloalkyl (e.g., unsubstituted or substituted monocyclic C 3~6cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered monocyclic heteroaryl (e.g., 5- or 6-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from O, S, and N, including pyrazole and pyridine), unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl (e.g., 5- or 6-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from O, S, and N), unsubstituted C 1~4 Alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), unsubstituted or substituted C 3~6 Cycloalkoxy (e.g., unsubstituted or substituted monocyclic C 3~6 cycloalkoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy), unsubstituted or substituted phenoxy, unsubstituted or substituted benzyloxy, unsubstituted or substituted -O-CH2-heteroaryl (e.g., unsubstituted or substituted -O-CH2-monocyclic heteroaryl), unsubstituted or substituted -O-CH2-heterocyclyl (e.g., unsubstituted or substituted -O-CH2-monocyclic heterocyclyl), unsubstituted C 1~4 haloalkyl (including -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CF3, and -CH2Cl), unsubstituted C 1~4 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2, and -OCH2Cl), unsubstituted or substituted acyl (e.g., -C(=O)H, and -C(=O)(unsubstituted C 1~4 alkyl), unsubstituted or substituted C-carboxy (e.g., —C(═O)OH, and —C(═O)—O—(unsubstituted C 1~4 alkyl), unsubstituted sulfenyl (e.g., -S(unsubstituted C 1~4 alkyl), -SF5, -SCF3, unsubstituted sulfonyl (e.g., -S(=O)2(unsubstituted C 1~4 alkyl), -NH(unsubstituted C 1~4 alkyl), -OS(=O)2(unsubstituted C 1~4 alkyl), -(unsubstituted C1~4 alkyl)-OP-(OH)2, and -(unsubstituted C 1~4 alkyl)-OP-(O(unsubstituted C 1~4 -(unsubstituted C 1~4 alkyl)-OP-(OH)2 and -(unsubstituted C 1~4 alkyl)-OP-(O(unsubstituted C 1~4 Examples of alkyl))2 include -CH2-OP-(OH)2 and -CH2-OP-(OCH3)2.

[0111] In some embodiments, Z 2 and Z 3 and Z fused to a 4-7 membered saturated or unsaturated ring or ring system which may optionally contain one or two ring heteroatoms selected from O, N and S. 2 and Z 3 The five-membered ring containing Z may be mono-, di-, or tri-substituted. 2 and Z 3 and Z fused to a 4-7 membered saturated or unsaturated ring or ring system which may optionally contain one or two ring heteroatoms selected from O, N and S. 2 and Z 3 The five-membered ring, including the ring, may be unsubstituted. A variety of saturated and unsaturated rings or ring systems are described herein. Possible substituents that may be present on the rings and / or ring systems referred to in this paragraph include deuterium, halogen (e.g., fluoro, chloro, and bromo), cyano, unsubstituted C 1~6 Alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl (branched and straight chain) and hexyl (branched and straight chain)), unsubstituted C 2~6 Alkenyl, unsubstituted C 2~6 Alkynyl, unsubstituted or substituted C 3~6 Cycloalkyl (e.g., unsubstituted or substituted monocyclic C 3~6cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; unsubstituted or substituted phenyl; unsubstituted or substituted 5- or 6-membered monocyclic heteroaryl (including, for example, 5- or 6-membered nitrogen-containing monocyclic heteroaryl, pyrazole, and pyridine); unsubstituted C 1~4 Alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), unsubstituted or substituted C 3~6 Cycloalkoxy (e.g., unsubstituted or substituted monocyclic C 3~6 cycloalkoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy and cyclohexoxy), unsubstituted or substituted phenoxy, unsubstituted or substituted benzyloxy, unsubstituted C 1~4 haloalkyl (including -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CF3 and -CH2Cl), unsubstituted C 1~4 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2 and -OCH2Cl), unsubstituted or substituted acyl (e.g., -C(=O)H and -C(=O)(unsubstituted C 1~4 alkyl), unsubstituted or substituted C-carboxy (e.g., —C(═O)OH and —C(═O)—O—(unsubstituted C 1~4 alkyl), unsubstituted sulfenyl (e.g., -S(unsubstituted C 1~4 alkyl), unsubstituted sulfonyl (e.g., —S(═O)2(unsubstituted C 1~4 alkyl), -NH(unsubstituted C 1~4 alkyl), -OS(=O)2(unsubstituted C 1~4 alkyl), -(unsubstituted C 1~4 alkyl)-OP-(OH)2, and -(unsubstituted C 1~4 alkyl)-OP-(O(unsubstituted C 1~4 alkyl))2. 1~4 alkyl)-OP-(OH)2 and -(unsubstituted C 1~4 alkyl)-OP-(O(unsubstituted C 1~4Examples of alkyl))2 include -CH2-OP-(OH)2 and -CH2-OP-(OCH3)2.

[0112] Z 2 and Z 3 and exemplary fused rings derived from 4-7 membered saturated or unsaturated rings or ring systems which may optionally contain one or two ring heteroatoms selected from O, N, and S include optionally substituted 4,5,6,7-tetrahydro-1H-indole, optionally substituted indolyl, optionally substituted benzofuran, optionally substituted benzo[b]thiophene, optionally substituted benzimidazole, optionally substituted benzo[d]oxazole, optionally substituted benzo[d]thiazole, optionally substituted pyrrolo[2,3-b]pyridine, optionally substituted pyrrolo[2,3-c]pyridine, optionally substituted pyrrolo[ 3,2-b]pyridine, optionally substituted pyrrolo[3,2-c]pyridine, optionally substituted 1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one, optionally substituted 6H-thieno[2,3-b]pyrrole, optionally substituted 3,4-dihydro-2H-thieno[3,2-b]pyrrole 1,1-dioxide, optionally substituted 1,5,6,7-tetrahydrothiopyran o[3,2-b]pyrrole 4,4-dioxide, optionally substituted 4,5,6,7-tetrahydro-1H-4,7-methanoindole, and optionally substituted 3,6-dihydro-2H-furo[2,3-e]indole, for example:

[0113] [ka] wherein each of these moieties can be unsubstituted or substituted as described herein.

[0114] As provided herein, R 3 is an unsubstituted or substituted C-amide (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), and unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4In some embodiments, R 3 is the unsubstituted C-amide (C 1~4 In other embodiments, R 3 is a substituted C-amide (C 1~4 In still other embodiments, R 3 is an unsubstituted monocyclic nitrogen-containing heteroaryl (C 1~4 In still other embodiments, R 3 is a substituted monocyclic nitrogen-containing heteroaryl (C 1~4 The number of ring atoms may be a monocyclic nitrogen-containing heteroaryl (C alkyl). 1~4 For example, unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl) is a 5- or 6-membered heteroaryl (C 1~4 In some embodiments, R 3 is an unsubstituted monocyclic nitrogen-containing heterocyclyl (C 1~4 In other embodiments, R 3 is a substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 In still other embodiments, R 3 is an unsubstituted bicyclic nitrogen-containing heteroaryl (C 1~4 In still other embodiments, R 3 is a substituted bicyclic nitrogen-containing heteroaryl (C 1~4 In some embodiments, R 3 is an unsubstituted bicyclic nitrogen-containing heterocyclyl (C 1~4 In other embodiments, R 3 is a substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl). 3 is a bicyclic nitrogen-containing heteroaryl (C 1~4 When R is a cyclic heteroaryl, the two rings of the bicyclic heteroaryl may be connected in a fused (including bridged) fashion. 3 is a bicyclic nitrogen-containing heterocyclyl (C 1~4When the bicyclic heterocyclyl is a heterocyclic ring (alkyl), the two rings of the bicyclic heterocyclyl may be connected in a fused (including bridged) or spiro fashion.

[0115] Monocyclic and bicyclic nitrogen-containing heteroaryls (C 1~4 alkyl), and monocyclic and bicyclic nitrogen-containing heterocyclyl (C 1~4 For alkyl), the number of ring atoms can vary. Non-limiting examples include unsubstituted or substituted 5-membered monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted 6-membered monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted 5-membered monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), 6-membered monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted 9-membered bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted 10-membered bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted 9-membered bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and 10-membered bicyclic nitrogen-containing heterocyclyl (C 1~4 Suitable R 3 Examples of groups include the following: (C 1~4 alkyl)2NC(=O)-CH2-, (C 1~4 alkyl)2NC(=O)-CH2CH2-, (C 1~4 alkyl)2NC(=O)-CH2CH2CH2-, pyrrolidin-2-one (C 1~4 alkyl), piperidin-2-one (C 1~4 alkyl), azepan-2-one (C 1~4 alkyl), imidazolin-2-one (C 1~4 alkyl), tetrahydropyrimidin-2-one (C 1~4 alkyl), 1,3-dihydro-2H-imidazol-2-one (C 1~4 alkyl), imidazole (C 1~4 alkyl), pyrazole (C 1~4 alkyl),

[0116] [ka] wherein n1 can be 1, 2, 3, or 4;

[0117] [ka] wherein each m1 independently can be 1, 2, 3, or 4 (including substituted or unsubstituted versions of the above). 3 The group may be substituted with one or more moieties independently selected from those listed under "optionally substituted." In some embodiments, the R 3 The group is halogen, hydroxy, unsubstituted C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 1~4 Alkoxy, amino, -(unsubstituted C 1~4 alkyl)-OP-(OH) (e.g., -CH-OP-(OH)), and -(unsubstituted C 1~4 alkyl)-OP-(O(unsubstituted C 1~4 alkyl))2 (e.g., —CH2-OP-(OCH3)2).

[0118] R 3 Non-limiting examples of moieties include:

[0119] [ka]

[0120] In some embodiments, R 2 may be hydrogen. In other embodiments, R 2 may be deuterium. In yet other embodiments, R 2 may be halogen (eg, fluoro or chloro).

[0121] In some embodiments, R 1 may be an unsubstituted or substituted ketoamide, R 2may be hydrogen, and R 3 is a monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and ring A 1 may be unsubstituted or substituted pyrrolidine, where pyrrolidine is an optionally substituted monocyclic C 3~7 may be connected to a cycloalkyl (e.g., an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl);

[0122] [ka] where R 6 and R 7 is R 6 and R 7 together with the carbons to which R is attached may be a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl ring. 1 may be a hydroxy-substituted acyl (e.g., R 1 may be —C(═O)CHOH), R 2 may be hydrogen, and R 3 is a monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and ring A 1 may be unsubstituted or substituted pyrrolidine, where pyrrolidine is an optionally substituted monocyclic C 3~7 may be connected to a cycloalkyl (e.g., an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl);

[0123] [ka] teeth,

[0124] [ka] where R 6 and R 7 is R 6 and R 7together with the carbons to which R is attached may be a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl ring. 1 is -C(=O)CH2-O-((P=O)(OR 10 )2) (e.g., —C(═O)CH—O—((P═O)(OH))), R 2 may be hydrogen, and R 3 is a monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and ring A 1 may be unsubstituted or substituted pyrrolidine, where pyrrolidine is an optionally substituted monocyclic C 3~7 may be connected to a cycloalkyl (e.g., an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl);

[0125] [ka] teeth,

[0126] [ka] where R 6 and R 7 is R 6 and R 7 together with the carbons to which they are attached may be a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl ring.

[0127] In some embodiments, R 1 is -C(=O)R y2 R may be y2 may be a moiety described herein (e.g., -C 1~4 alkyl(OH)-, e.g., -CHOH), R 2 may be hydrogen, and R 3 teeth,

[0128] [ka] wherein R 3 may be unsubstituted or substituted as described herein, and ring A 1 teeth,

[0129] [ka] wherein ring A 1 may be unsubstituted or substituted as described herein (e.g., substituted with 1 or 2 fluoro);

[0130] [ka] teeth,

[0131] [ka] wherein each of these moieties can be unsubstituted or substituted as described herein (e.g., halogen, unsubstituted C 1~4 Alkyl, -O-(unsubstituted C 1~4 alkyl) and unsubstituted C 1~4 In some embodiments, R 1 is -C(=O)-C(=O)NR y1 R z1 R may be y1 may be H, and R z1 is R as described herein z1 In some embodiments, R may be any of the moieties provided for 1 is -C(=O)-C(=O)NR y1 R z1 R may be y1 may be H, and R z1 is a monocyclic C 3~8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl), R 2 may be hydrogen, and R3 teeth,

[0132] [ka] wherein R 3 may be unsubstituted or substituted as described herein, and ring A 1 teeth,

[0133] [ka] wherein ring A 1 may be unsubstituted or substituted as described herein (e.g., substituted with 1 or 2 fluoro);

[0134] [ka] teeth,

[0135] [ka] wherein each of these moieties can be unsubstituted or substituted as described herein (e.g., halogen, unsubstituted C 1~4 Alkyl, -O-(unsubstituted C 1~4 alkyl) and unsubstituted C 1~4 haloalkyl).

[0136] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is Z 1 may be —C(═O)— or —CH(CF3)—, and Z 2 is O, S or NR 8 where R 8 is H or unsubstituted C 1~4 may be alkyl, Z 3 may be C, and ring A 1may be selected from unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein azetidine, pyrrolidine and piperidine are each independently selected from deuterium, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 1~8 Alkoxy, unsubstituted or substituted C 3~6 one or more R independently selected from cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl; x Azetidine, pyrrolidine and piperidine are optionally substituted with a monocyclic C 4~7 cycloalkyl, which may be connected in a fused or spiro fashion to halogen and unsubstituted C 1~4 alkyl; R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, unsubstituted or substituted -C(=O)-N-sulfonamide, -CH(OH)-(S(=O)2-O - ), and -CH(OH)((P=O)(OR 9 ) 2) wherein each R 9 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl), and R 2 may be hydrogen, deuterium, or halogen; R 3 is an unsubstituted or substituted C-amide (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4may be hydrogen, deuterium, or halogen; R 5 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, and R 6 and R 7 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, or R 6 and R 7 is R 6 and R 7 may be taken together with the carbon to which they are attached to form a 4- to 7-membered saturated or unsaturated ring which may optionally contain one or two heteroatoms selected from O, N, and S.

[0137] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is Z 1 may be —C(═O)— or —CH(CF3)—, and Z 2 is O, S or NR 8 where R 8 is H or unsubstituted C 1~4 may be alkyl, Z 3 may be C, and ring A 1 may be selected from unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein azetidine, pyrrolidine and piperidine are each independently selected from deuterium, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 2~4 Alkenyl, unsubstituted or substituted C 1~8 Alkoxy, unsubstituted or substituted C 3~6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C 1~4 one or more R independently selected from haloalkyl x Azetidine, pyrrolidine and piperidine are optionally substituted with a monocyclic C 3~7 cycloalkyl, which may be connected in a fused or spiro fashion to halogen and unsubstituted C 1~4alkyl; R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, unsubstituted or substituted -C(=O)-N-sulfonamide, -CH(OH)-(S(=O)2-O - ), and -CH(OH)((P=O)(OR 9 ) 2) wherein each R 9 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl), and R 2 may be hydrogen, deuterium, or halogen; R 3 is an unsubstituted or substituted C-amide (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, deuterium, or halogen; R 5 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, and R 6 and R 7 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, or R 6 and R 7 is R 6 and R 7 may be taken together with the carbon to which they are attached to form an optionally substituted 4- to 7-membered saturated or unsaturated ring which may optionally contain one or two heteroatoms selected from O, N, and S.

[0138] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is Z 1 may be —C(═O)— or —CH(CF3)—, and Z 2 is O, S or NR 8 where R 8 is H or unsubstituted C 1~4 may be alkyl, Z 3 may be N (nitrogen) or C (carbon), and Z 3 When N, R 5 No, Ring A 1 may be selected from unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein azetidine, pyrrolidine and piperidine are each independently selected from deuterium, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 2~4 Alkenyl, unsubstituted or substituted C 1~8 Alkoxy, unsubstituted or substituted C 3~6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C 1~4 one or more R independently selected from haloalkyl x Azetidine, pyrrolidine and piperidine are optionally substituted with a monocyclic C 3~7 cycloalkyl, which may be connected in a fused or spiro fashion to halogen and unsubstituted C 1~4 alkyl; R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, unsubstituted or substituted -C(=O)-N-sulfonamide, -CH(OH)-(S(=O)2-O - ), and -CH(OH)((P=O)(OR 9 ) 2) wherein each R 9 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl), and R 2 may be hydrogen, deuterium, or halogen; R 3 is an unsubstituted or substituted C-amide (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, deuterium, or halogen; R 5 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, and R 6 and R 7 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, or R 6 and R 7 is R 6 and R 7 may be taken together with the carbon to which they are attached to form an optionally substituted 4- to 7-membered saturated or unsaturated ring which may optionally contain one or two heteroatoms selected from O, N, and S.

[0139] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is Z 1 may be —C(═O)— or —CH(CF3)—, and Z 2 is O, S or NR 8 where R 8 is H or unsubstituted C 1~4 may be alkyl, Z 3 may be N or C, and Z 3 When N, R 5 No, Ring A 1may be selected from unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein azetidine, pyrrolidine and piperidine are each independently selected from deuterium, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 2~4 Alkenyl, unsubstituted or substituted C 1~8 Alkoxy, unsubstituted or substituted C 3~6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C 1~4 one or more R independently selected from haloalkyl x Azetidine, pyrrolidine and piperidine are optionally substituted with a monocyclic C 3~7 Cycloalkyl, monocyclic C 3~7 and phenyl, wherein the cyclic moiety is connected in a fused or spiro fashion to azetidine, pyrrolidine, and piperidine; 1~4 Alkyl and unsubstituted C 2~4 alkenyl, optionally substituted with one or more moieties independently selected from the group consisting of R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, unsubstituted or substituted -C(=O)-N-sulfonamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 9 )2), and -C(=O)CH2-O-((P=O)(OR 10 ) 2) wherein each R 9 and R 10 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl), and R 2 may be hydrogen, deuterium, or halogen; R 3 is an unsubstituted or substituted C-amide (C 1~4alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, deuterium, or halogen; R 5 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, and R 6 and R 7 is hydrogen, deuterium, halogen, and unsubstituted C 1~6 alkyl, or R 6 and R 7 is R 6 and R 7 may be taken together with the carbon to which they are attached to form an optionally substituted 4- to 7-membered saturated or unsaturated ring which may optionally contain 1 or 2 ring heteroatoms selected from O, N, and S.

[0140] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is Z 1 may be —C(═O)— or —CH(CF3)—, and Z 2 is O, S or NR 8 where R 8 is H or unsubstituted C 1~4 may be alkyl, Z 3 may be N or C, and Z 3 When N, R 5 No, Ring A 1 may be selected from unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein azetidine, pyrrolidine and piperidine are not deuterium, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 2~4 Alkenyl, unsubstituted or substituted C 1~8 Alkoxy, unsubstituted or substituted C3~6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C 1~4 one or more R independently selected from haloalkyl x Azetidine, pyrrolidine and piperidine are monocyclic C 3~7 Cycloalkyl, Bicyclic C 5~9 Cycloalkyl, monocyclic C 3~7 Cycloalkenyl, Bicyclic C 5~9 and phenyl, wherein the cyclic moiety is connected in a fused or spiro fashion to azetidine, pyrrolidine, and piperidine; 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, and unsubstituted or substituted C 3~6 monocyclic cycloalkyl; R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, unsubstituted or substituted -C(=O)-N-sulfonamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 9 )2), -C(=O)CH2-O-((P=O)(OR 10 )2), -C(=O)CH2-OC(R 11A )2-O-((P=O)(OR 11B )2), and -C(=O)CH2-OC(R 12A )2-OC(=O)-OR 12B wherein each R 9 , each R 10 , each R 11B and each R 12B are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6 Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl), and each R 11A and each R12A are independently hydrogen or unsubstituted C 1~4 may be alkyl, and R 2 may be hydrogen, deuterium, or halogen; R 3 is an unsubstituted or substituted C-amide (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C 1~4 alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, deuterium, or halogen; R 5 But hydrogen, deuterium, halogen, unsubstituted C 1~6 Alkyl and unsubstituted C 1~4 haloalkyl, and R 6 and R 7 is hydrogen, deuterium, halogen, unsubstituted or substituted C 1~6 may be independently selected from alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, and unsubstituted or substituted sulfonyl, or R 6 and R 7 is R 6 and R 7 may be taken together with the carbon to which they are attached to form an optionally substituted 4-9 membered saturated or unsaturated ring or ring system which may optionally contain 1 or 2 ring heteroatoms selected from O, N and S.

[0141] Examples of compounds of formula (I) include:

[0142] [ka]

[0143] [ka]

[0144]

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[0145]

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[0146]

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[0147]

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[0148]

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[0149]

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[0150]

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[0151]

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[0152]

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[0153]

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[0154]

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[0155]

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[0156]

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[0157]

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[0158]

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[0159]

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[0160]

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[0161]

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[0162]

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[0163]

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[0164]

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[0165] [ka]

[0166] [ka]

[0167] [ka]

[0168] [ka]

[0169] [ka]

[0170] [ka] Or a pharmaceutically acceptable salt of any of the above.

[0171] Additional examples of compounds of formula (I) include:

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] [ka]

[0176]

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[0177]

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[0178]

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[0179]

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[0180]

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[0181]

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[0182]

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[0183]

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[0184]

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[0185]

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[0186]

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[0187]

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[0188]

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[0189]

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[0190]

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[0191]

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[0192]

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[0193]

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[0194]

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[0195]

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[0196]

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[0197] [ka]

[0198] [ka]

[0199] [ka]

[0200] [ka]

[0201] [ka] Or a pharmaceutically acceptable salt of any of the above.

[0202] In some embodiments, R 1 cannot be unsubstituted or substituted acyl. For example, in some embodiments, R 1 cannot be unsubstituted acyl, e.g., —C(═O)H. In some embodiments, R 1 When is unsubstituted or substituted acyl (e.g., —C(═O)H), R 3 is unsubstituted or substituted

[0203] [ka] In some embodiments, R 1 When is unsubstituted or substituted acyl (e.g., —C(═O)H),

[0204] [ka] In some embodiments, R 1is unsubstituted or substituted acyl (e.g., —C(═O)H);

[0205] [ka] When R 3 represents unsubstituted or substituted pyrrolidin-2-one (C 1~4 alkyl)

[0206] [ka] In some embodiments, R 1 When is unsubstituted or substituted acyl (e.g., —C(═O)H), ring A 1 teeth,

[0207] [ka] In some embodiments, R 1 When is unsubstituted or substituted acyl (e.g., —C(═O)H), ring A 1 teeth,

[0208] [ka] Unsubstituted C 1~4 Alkyl-substituted

[0209] [ka] It cannot be.

[0210] synthesis The compounds of formula (I), along with the compounds described herein, can be prepared in a variety of ways. General synthetic routes for preparing compounds of formula (I) are shown and described herein, along with some examples of starting materials used to synthesize the compounds described herein. Furthermore, for purposes of the general synthetic routes, the structures shown are appropriately protected as known by those skilled in the art, and the general structures are meant to include these protecting groups. The routes shown and described herein are exemplary only and are not intended to, and should not be construed as, limiting the scope of the claims in any way. Those skilled in the art will recognize modifications to the disclosed syntheses and will be able to devise alternative routes based on the disclosures herein, and all such modifications and alternative routes are within the scope of the claims.

[0211] Scheme A

[0212] [ka]

[0213] Scheme A describes the synthesis of compounds of general formula (A-6). Activation of an amino ester of general formula (A-1) (Alk represents alkyl) with an acid of general formula (A-2) by converting the carboxylic acid to an acid chloride followed by reaction with an amino acid in the presence of a base, or activation of the acid with a coupling reagent (such as HATU) followed by coupling with an amino ester in the presence of a base (such as DIPEA), gives compounds of general formula (A-3). The ester functionality of general formula (A-3) can be hydrolyzed, for example, using LiOH in MeOH under typical conditions where -OAlk is -OMe, to give compounds of general formula (A-4). Further coupling of a carboxylic acid of general formula (A-4) with an amine of general formula (A-5) can provide compounds of general formula (A-6). For general synthetic purposes, R 1 is a potential functional group and R 1 can be converted to functional groups as described herein for

[0214] Scheme B

[0215] [ka]

[0216] An example is shown in Scheme B, where a carboxylic acid of general formula A-4 is coupled with an amino acid of general formula (B-1), for example, under the influence of a coupling reagent (such as T3P) and a base (e.g., DIPEA). The resulting compound of general formula (B-2) can be oxidized to give a compound of general formula (B-3). In Scheme B, R y1 is R 1 are some of the ketoamides described herein with respect to

[0217] Scheme B1

[0218] [ka]

[0219] Alternatively, as shown in Scheme B1, an amino acid of general formula (B1-1) (wherein the nitrogen-protecting group is PG) can be converted into a compound of general formula (B-2) in the same manner as described for the conversion of a compound of general formula (A-4) into a compound of general formula (B-2). B1 , for example, with -Boc) is coupled with a compound of general formula (B-1). The protecting group is then removed, for example, by the addition of PG B1 When is equal to Boc, it can be removed by treatment with acid, followed by coupling with a compound of general formula (A-2) to form a compound of general formula (B-2).

[0220] Scheme B2

[0221] [ka]

[0222] As described herein, R 1may be a substituted acyl, and possible groups that may be present on the acyl include hydroxy, substituted or unsubstituted alkoxy (e.g., -0-(unsubstituted C 1~4 alkyl) and -0-(unsubstituted C 3~6 Cycloalkyl), unsubstituted C 1~4 Alkyl (unsubstituted C 1~4 In Scheme B2, R is R 1 may represent any of the aforementioned moieties that may be present on the substituted acyl. Compounds of general formula (B2-2) and (B2-3) can be prepared as described in Scheme B2. Amino-ketone compounds of general formula (B2-1) can be coupled to carboxylic acids of general formula (A-4) or (B1-1) under typical amide coupling conditions. Compounds of general formula (B2-2) can optionally be further converted to hydroxyketones of general formula (B2-3), for example, by catalytic hydrogenolysis when R represents a benzyl group. PG of compounds of general formula (B2-4) B1 can be deprotected (e.g., PG B1 is a Boc group, by treatment with HCl in EtO). The amine can then be coupled with a carboxylic acid of general formula (A-2) under typical amide bond forming conditions to give compounds of general formula (B2-2).

[0223] Scheme C

[0224] [ka]

[0225] Compounds of general formula (B-1) can be prepared as outlined in Scheme C. Aldehydes of general formula C-1 (PG 1(C-1) can be a nitrogen protecting group, e.g., -Boc, and an isonitrile of general formula (C-2) can be condensed in a Passerini-like reaction to a compound of general formula (C-3) in the presence of a carboxylic acid (e.g., benzoic acid). After hydrolysis, a compound of general formula (C-4) can be obtained. PG 1 For example, PG 1 When is Boc, it can be removed by treatment with HCl.

[0226] Scheme C1

[0227] [ka]

[0228] Aminoketones of general formula (B2-1) can be prepared as outlined in Scheme C1. Protected amino acids of general formula (C1-1) can be converted to their corresponding Weinreb amides under typical amide coupling conditions. Addition of an organometallic reagent to the Weinreb amide, followed by workup, provides ketones of general formula (C1-3). An example where R can be benzyl is the formation of the organometallic reagent by mixing Mg, HgCl2, and benzyl chloromethyl ether, followed by addition to the Weinreb amide of general formula (C1-2), followed by workup with saturated ammonium chloride. The protecting group (PG 1 ) can be removed (e.g., PG 1 (When C1-1 is Boc, the protecting group can be removed using HCl) to form an amino ketone of general formula (B2-1). Using HCl for deprotection, compounds of general formula (B2-1) can be obtained as HCl salts. Examples of C1-1 are (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoic acid and (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid, prepared as provided in the synthesis of intermediates and Example 42.

[0229] Scheme D1

[0230] [ka]

[0231] Scheme D2

[0232] [ka]

[0233] R as described herein 1 Other transformations of PG are shown in Schemes D1 and D2. 2 represents a suitable protecting group, and R z1 and R y1 is R 1 are some of the ketoamides described herein with respect to

[0234] Scheme E

[0235] [ka]

[0236] Methods for preparing a subgroup of amino acids of general formula (E-8) are described in Scheme E. Lactams of general formula (E-1) can be prepared by coupling them with a suitable protecting group PG E Such PG E An example of a protecting group is the Boc group. For the purposes of Scheme E, this protecting group can be removed at any relevant stage, thus leaving PG Ecan be hydrogen for any of the compounds of general formula (E-4), (E-5), (E-6), (E-7), (E-8), and (E-9). A lactam of general formula (E-2) can be reacted with an aldehyde of general formula (E-3) (S- or R-Garner aldehyde). The resulting alcohol of general formula (E-4) can be eliminated to give an alkene compound of general formula (E-5) (e.g., by sequential conversion of the hydroxy to the corresponding mesylate, followed by elimination under basic conditions). The double bond can be reduced (e.g., by hydrogenation, optionally under the influence of a diastereoselective homogeneous or heterogeneous catalyst) to give a compound of general formula (E-6). The acetonide in the compound of general formula (E-6) can be eliminated to give a Boc-protected amino alcohol of general formula (E-7), which can then be oxidized to a carboxylic acid of general formula (E-8). Alternatively, the acetonide in a compound of general formula (E-5) can be deprotected to give a compound of general formula (E-9). Reduction of the double bond of a compound of general formula (E-9) (e.g., by hydrogenation, optionally under the influence of a diastereoselective homogeneous or heterogeneous catalyst) can be used to give a compound of general formula (E-7). A compound of general formula (E-4) can be deoxygenated, for example, by Barton-type deoxygenation, to give a compound of general formula (E-6). A similar synthetic strategy can be used, starting from a cyclic sulfonamide instead of a lactam of general formula (E-1).

[0237] Scheme F

[0238] [ka]

[0239] The compound of formula (I) can include a prodrug moiety. The method of including a prodrug moiety is described in Scheme F. For example, an aldehyde of general formula (F-1) can be converted to the corresponding bisulfite adduct of general formula (F-2) by treatment with NaHSO. A hydroxyketone of general formula (F-3) can be converted to the corresponding phosphate of general formula (F-5) by treatment with, for example, di-tert-butyl N,N-dipropan-2-yl phosphoramidite and tetrazole, followed by oxidation with HO, to give a compound of general formula (F-4). The compound of general formula (F-4) can be deprotected (e.g., by treatment with TFA) to give a compound of general formula (F-5).

[0240] Scheme G

[0241] [ka]

[0242] As a subgroup of carboxylic acids of general formula (A-2), indolecarboxylic acids of general formula (G-4) can be prepared via, among other methods, the Hemmetsberger indole synthesis. In Scheme G, "R" represents possible substituents that may be present on the depicted ring. Aromatic aldehydes of general formula (G-1) can be condensed with alkyl (Alk) 2-azidoacetates, for example, under the influence of sodium methoxide in methanol at -10 °C. Azides of general formula (G-2) can be thermally converted to compounds of general formula (G-3), for example, by heating in xylene at 120 °C. Alkyl (Alk) esters G-3 can be hydrolyzed to carboxylic acids of general formula (G-4), for example, by treatment with NaOH in THF / HO. This method can be extended to 5-, 6-, and 7-azaindoles related to (G-4) (see Roy et al., Synthesis 2005(16):2751-2757) and other heteroaryls.

[0243] Scheme H

[0244] [ka]

[0245] Scheme H shows some examples of amino acids / esters of general formula (A-1) and (B1-1). Examples include, but are not limited to, proline derivatives shown, obtained from intermediates, or obtained according to methods outlined in Calaza et al., European Journal of Organic Chemistry (2015), 2015(8):1633-1658.

[0246] Scheme I

[0247] [ka]

[0248] Scheme I shows the R y1 and R z1 R 1 The synthesis of the amino ester (PG) of general formula (I-11) is described. 1 The α-hydroxy acid can be converted to an α-hydroxy ester of general formula (I-6). PG 1 For example, PG 1When is Boc, it can be removed under acidic conditions. Amines of general formula (I-7) can be coupled with carboxylic acids of general formula (A-4) in the presence of a coupling agent (such as EDC and HOAt) and a base (such as DIPEA) to give compounds of general formula (I-8). After ester hydrolysis, compounds of general formula (I-9) can be coupled with amines under typical amide bond forming conditions. The resulting α-hydroxyamides of general formula (I-10) can be oxidized to give compounds of general formula (I-11).

[0249] Pharmaceutical Composition Some embodiments described herein relate to pharmaceutical compositions, which can include an effective amount of a compound described herein (e.g., a compound described herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, excipient, or combination thereof. The pharmaceutical compositions described herein are suitable for human and / or veterinary use.

[0250] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0251] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that is not pharmacologically active but may be pharmaceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the composition of human blood.

[0252] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient.

[0253] Appropriate formulation design depends on the selected administration route.The techniques for formulation and administration of the compounds described herein are known to those skilled in the art.There are multiple techniques for administering compounds in the art, including but not limited to oral, rectal, topical, aerosol, injection, inhalation, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection.Pharmaceutical compositions are generally tailored to the specific intended administration route.

[0254] Alternatively, the compounds can be administered locally rather than systemically, for example, by injecting the compound directly into the site of infection, often in a depot or sustained-release formulation. Additionally, the compounds can be administered in a targeted drug delivery system, for example, in liposomes coated with tissue-specific antibodies. Liposomes can be targeted to and taken up selectively by organs.

[0255] The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes. As described herein, the compounds used in the pharmaceutical compositions may be provided as salts with pharmaceutically compatible counterions.

[0256] How to use Some embodiments described herein relate to methods of treating a coronavirus infection, which may include administering to a subject identified as suffering from a coronavirus infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a coronavirus infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of a coronavirus infection.

[0257] Some embodiments disclosed herein relate to methods of treating a coronavirus infection, which may include contacting a cell infected with a coronavirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a coronavirus infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of a coronavirus infection.

[0258] Some embodiments disclosed herein relate to methods of inhibiting coronavirus growth, which may include contacting a cell infected with coronavirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting coronavirus replication. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting coronavirus growth.

[0259] In some embodiments, the coronavirus can be an alpha-coronavirus or a beta-coronavirus. In some embodiments, the coronavirus can be selected from CoV 229E, CoV NL63, CoV OC43, CoV HKU1, Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV, and SARS-CoV-2.

[0260] Some embodiments described herein relate to methods of treating a picornavirus infection, which may include administering to a subject identified as suffering from a picornavirus infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a picornavirus infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of a picornavirus infection.

[0261] Some embodiments disclosed herein relate to methods of treating a picornavirus infection, which may include contacting a cell infected with a picornavirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a picornavirus infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of a picornavirus infection.

[0262] Some embodiments disclosed herein relate to methods for inhibiting the proliferation of picornaviruses, which may include contacting a cell infected with a picornavirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the replication of picornaviruses. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting the proliferation of picornaviruses.

[0263] In some embodiments, the picornavirus can be a rhinovirus, including rhinovirus A, B, and / or C. In some embodiments, the compounds described herein, including compounds of Formula (I) or pharmaceutically acceptable salts thereof, can be used to treat one type or serotype of rhinovirus.

[0264] Some embodiments described herein relate to methods of treating a Norovirus infection, which may include administering to a subject identified as suffering from a Norovirus infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a Norovirus infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of a Norovirus infection.

[0265] Some embodiments disclosed herein relate to methods of treating a Norovirus infection, which may include contacting a cell infected with a Norovirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a Norovirus infection. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of a Norovirus infection.

[0266] Some embodiments disclosed herein relate to methods for inhibiting the growth of Norovirus, which may include contacting a cell infected with Norovirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the replication of Norovirus. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for inhibiting the growth of Norovirus.

[0267] Some embodiments disclosed herein relate to methods for treating respiratory symptoms developed for coronavirus and / or picornavirus infection, which may include administering to a subject experiencing respiratory symptoms an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting coronavirus and / or picornavirus infected cells in a subject experiencing respiratory symptoms. Other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating respiratory symptoms due to coronavirus and / or picornavirus infection with an effective amount of the compound or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for the treatment of respiratory symptoms due to coronavirus and / or picornavirus infection.

[0268] A subject infected with coronavirus may be asymptotic. Coronavirus infection may manifest through one or more symptoms. Examples of symptoms include, but are not limited to, cough, sore throat, runny nose, sneezing, headache, fever, shortness of breath, muscle pain, abdominal pain, fatigue, difficulty breathing, persistent chest pain or pressure, difficulty walking, loss of smell and taste, muscle or joint pain, chills, nausea or vomiting, nasal congestion, diarrhea, hemoptysis, conjunctival congestion, sputum production, chest tightness, and / or palpitations. Coronavirus infection may cause complications. A non-limiting list of complications includes, but is not limited to, sinusitis, otitis media, pneumonia, acute respiratory distress syndrome, disseminated intravascular coagulation, pericarditis, and / or renal failure.

[0269] Similar to coronaviruses, subjects infected with picornaviruses may be asymptomatic. Alternatively, subjects may exhibit one or more symptoms. Examples of picornavirus infection symptoms include, but are not limited to, aseptic meningitis, rash, conjunctivitis, runny nose, headache, cough, fever, sore throat, chest pain and / or abdominal pain, and paralysis. As provided herein, subjects infected with noroviruses may exhibit one or more symptoms, including, but not limited to, nausea, non-bloody diarrhea, vomiting, and abdominal pain. An example of a complication that may result from norovirus infection is dehydration, including severe dehydration.

[0270] Various indicators for determining the effectiveness of a method for treating coronavirus, picornavirus, and / or norovirus infection are also known to those skilled in the art. Examples of suitable indicators include a reduction in viral load (i.e., load) indicated by a reduction in coronavirus (e.g., serum 10 5 These include, but are not limited to, reduced plasma viral load, reduced viral replication, reduced time to seroconversion (no virus detectable in patient serum), increased rate of sustained viral response to treatment, reduced morbidity or mortality in clinical outcomes, reduced need for mechanical ventilation and / or reduced total time on mechanical ventilation, reduced hospitalization rate and / or reduced ICU (intensive care unit) and / or hospital stay.

[0271] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily imply a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. Furthermore, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0272] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject can be a human, for example, a human subject aged 60 or over.

[0273] The term "effective amount" is used to refer to the amount of an active compound or drug that elicits the indicated biological or medical response. For example, an effective amount of a compound may be the amount necessary to alleviate or ameliorate the symptoms of a disease or prolong the survival of the treated subject. This response may occur in a tissue, system, animal, or human and includes alleviation of the signs or symptoms of the disease being treated. Determining an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages can be adjusted to achieve the desired effect and will depend on factors such as body weight, diet, concurrent medications, and other factors that one skilled in the medical field would recognize.

[0274] In some embodiments, the subject may be asymptomatic, e.g., the subject may be infected with a coronavirus but not exhibit any symptoms of the viral infection. In some embodiments, the subject may have an underlying disease, such as asthma, hypertension, immunocompetent subjects (e.g., subjects with cancer, HIV and / or a genetic immunodeficiency, bone marrow transplant subjects, solid organ transplant subjects, subjects with stem cells for cancer treatment, and / or subjects using oral or intravenous corticosteroids or other medications referred to as immunosuppressants), liver disease, subjects at risk for serious illness, chronic kidney disease undergoing dialysis treatment, chronic lung disease, diabetes, hemoglobin disorders, serious cardiac conditions (e.g., heart failure, coronary artery disease, congenital heart disease, cardiomyopathies, and pulmonary hypertension), severe obesity (e.g., subjects with a body mass index (BMI) of 40 or greater), and individuals in nursing homes or convalescent homes. Additional examples and / or further information are provided by the CDC (https: / / www.cdc.gov / coronavirus / 2019-ncov / need-extra-precautions / groups-at-higher-risk.html).

[0275] The compounds described herein, including compounds of Formula (I) or pharmaceutically acceptable salts thereof, can be administered after a subject has been infected with a coronavirus. Additionally and / or alternatively, the compounds described herein, including compounds of Formula (I) or pharmaceutically acceptable salts thereof, can be administered prophylactically.

[0276] An example of a drug that has been used to treat coronavirus infection is remdesivir. However, compounds used to treat coronavirus may have drawbacks, including, but not limited to, one or more adverse side effects, the need for subcutaneous administration, and / or high cost. A potential advantage of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be fewer adverse side effects, a delayed onset of adverse side effects, and / or reduced severity of adverse side effects.

[0277] Coronavirus infection can be treated by inhibiting a specific mechanism. In some embodiments, a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) can be selective for a coronavirus protease. For example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be selective for a coronavirus protease compared to one or more host proteases selected from cathepsin L, cathepsin B, cathepsin D, leukocyte elastase, chymotrypsin, trypsin, thrombin, pepsin, caspase 2, elastase, and calpain. In some embodiments, the selectivity of a coronavirus protease over a host protease (e.g., one described herein) can be greater than 2-fold. In some embodiments, the selectivity of a coronavirus protease over a host protease (e.g., one described herein) can be greater than 10-fold. In some embodiments, the selectivity of a coronavirus protease over a host protease (e.g., one described herein) can be greater than 100-fold.

[0278] Studies have shown that SARS-CoV-2 entry into target cells is a process that can be mediated by multiple proteases, including cysteine ​​cathepsin L and / or transmembrane protease serine 2 (TMPRSS2) (Shang et al., PNAS (2020) 117:11727, and Hoffmann et al., Cell (2020) 181:271-280). The cathepsin L inhibitor K117777, which lacks inhibitory effects on 3CL, can potently inhibit SARS-CoV-2 in VeroE6, A549-ACE2, and / or HeLa-ACE2 (Mellott et al., bioRxiv (2020) 2020.2010.2023.347534). It has also been shown that the potent antiviral effect of K117777 is abolished when TMPRSS2 is expressed in A549-ACE2 (Steuten et al., bioRxiv (2020) 2020.2011.2021.392753). For example, off-target activity of 3CL inhibitors against cathepsin L can lead to inaccurate assessment of the 3CL component in the cellular potency of the compound. For example, the compounds described herein (e.g., compounds of Formula (I) or pharmaceutically acceptable salts thereof) may have greater selectivity for coronavirus proteases over host proteases such as cathepsin L. Selectivity can be measured, for example, by IC 50 and / or Ki values ​​can be determined by one of skill in the art. In some embodiments, the compounds described herein do not significantly inhibit cathepsin L (e.g., IC 50 ≥ 10,000 nM or > 3.3 μM) inhibit coronavirus proteases (e.g., SARS-Cov-2 3Clpro).

[0279] A drawback of antiviral treatment can be the development of resistance, including cross-resistance. Resistance can lead to treatment failure. As used herein, the term "resistance" refers to a viral strain that exhibits a delayed, attenuated, and / or ineffective response to an antiviral agent. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof can be provided to a subject infected with a coronavirus strain that is resistant to one or more other antiviral agents. In some embodiments, the development of resistant coronavirus strains is delayed when the subject is treated with a compound described herein or a pharmaceutically acceptable salt thereof compared to the development of resistant coronavirus strains when the subject is treated with one or more other antiviral agents.

[0280] Combination therapy In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, can be used in combination with one or more additional agents for treating and / or inhibiting coronavirus replication, including, but not limited to, ACE inhibitors, anticoagulants, anti-inflammatory agents, ARBs, ASOs, Covid-19 convalescent plasma, entry inhibitors, H2 pump antagonists, H-conducting channels, HIV protease inhibitors, HMG-CoA reductase inhibitors, immunoglobulins, immunosuppressants, immunotherapeutics, monoclonal antibodies, neuraminidase inhibitors, nucleoside inhibitors, nucleoside analog inhibitors, polymerase inhibitors, protease inhibitors, siRNAs, statins, tissue plasminogen activators, antibiotics, antibacterial agents, and vaccines. Examples of additional agents include ascorbic acid, anakinra (Anakin), azithromycin, baloxavir, baricitinib, chloroquine phosphate, colchicine, corticosteroids, epoprostenol, famotidine, favipiravir, IGIV, interferon (e.g., recombinant interferon α2b, IFN-α, and / or PEG-IFN-α-2a), IVIG, ivermectin, gamma-globulin, lopinavir, methylprednisolone ... These include prednisolone, molnupiravir (MK-4482 or EIDD-2801), niclosamide, nitazoxanide, nitric oxide, oseltamivir, peramivir, RANTES, ribavirin, remdesivir, ruxolitinib, sarilumab, siltuximab, sirolimus, statins, tacrolimus, tocilizumab, umifenovir, zanamivir, casirivimab, imdevimab, bamlanivimab, etesevimab, and molnupiravir.

[0281] In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be administered with one or more additional agents in a single pharmaceutical composition. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be administered with one or more additional agents in two or more separate pharmaceutical compositions. Furthermore, the order of administration of a compound described herein or a pharmaceutically acceptable salt thereof with one or more additional agents may vary. [Example]

[0282] Further embodiments, which in no way limit the scope of the claims, are disclosed in more detail in the examples below.

[0283] Example 1 compound Provided below are compounds of formula (I) and pharmaceutically acceptable salts thereof that can be prepared in a variety of ways, including those synthetic schemes shown and described herein. Those skilled in the art will recognize variations of the disclosed synthesis and will be able to devise routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims.

[0284] Synthesis of intermediates Intermediate 1

[0285] [ka]

[0286] To a mixture of 1,5-dimethyl(2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate (75.0 g, 272 mmol, 1.0 equiv.) in tetrahydrofuran (1.2 L) was added lithium bis(trimethylsilyl)amide (599 mL, 599 mmol, 2.2 equiv.) dropwise at −78°C under N2. After stirring at −78°C for 1 h, 2-bromoacetonitrile (35.9 g, 300 mmol, 1.1 equiv.) was added. The mixture was stirred at −78°C under N2 for 2 h. The reaction was quenched with methanol (200 mL) and hydrochloric acid (1.00 L, 2 M). The mixture was extracted with ethyl acetate (EA) (3 × 1.20 L). The organic layers were combined, washed with brine (2 × 1.20 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. After removing dichloromethine, the crude product was diluted with dichloromethane (2.00 L) and slurried with 100-200 mesh silica gel (200 g). The sample was purified by column chromatography (6 × 24 cm column, 600 mL column volume, 330 g silica gel (100-200 mesh)) and eluted with ethyl acetate (EA):petroleum ether (PE) (0% to 50% over 30 min). The collected fractions were selected as pure fractions: 35% to 37% EA:PE fraction. These fractions were combined and concentrated under reduced pressure to give 1,5-dimethyl(2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-(cyanomethyl)pentanedioate (65.2 g, 69%) as a yellow oil. LCMS (ESI, m / z): 215 [M-100+H] + .

[0287] To a mixture of 1,5-dimethyl(2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-(cyanomethyl)pentanedioate (65.2 g, 207 mmol, 1.0 equiv.) in methanol (650 mL):chloroform (65 mL) was added platinum dioxide (6.59 g). The mixture was stirred at room temperature (rt) for 36 h under hydrogen. The mixture was filtered through a Celite pad and washed with methanol (200 mL). Sodium carbonate (48.8 g, 460 mmol, 2.2 equiv.) was added to the filtrate, and the mixture was refluxed for 6 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with dichloromethane (1.50 L). After removing the dichloromethane, a slurry was prepared with 100-200 silica gel mesh (150 g). The sample was purified by column chromatography (column size 6 × 24 cm, column volume: 600 mL, silica gel size (100-200 mesh): 330 g) and eluted with methanol:dichloromethane (0% to 20% over 30 min). The collected fractions: 12% to 13% methanol:dichloromethane fraction were selected as pure fractions. These fractions were combined and concentrated under reduced pressure to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (30.8 g, 37%) as a yellow semi-solid. LCMS (ESI, m / z): 187 [M-100+H] + .

[0288] To a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (29.0 g, 101 mmol, 1.0 equiv.) in tetrahydrofuran (1.00 L) was added lithium borohydride (253 mL, 506 mmol, 5.0 equiv., 2 M in tetrahydrofuran) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (500 mL). The mixture was extracted with chloroform:isopropyl alcohol (5:1, 3×500 mL). The organic layers were combined, washed with brine (2×500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (600 mL). After removing the dichloromethane, a slurry containing 100-200 mesh silica gel (60 g) was prepared. The sample was purified by column chromatography (6 × 24 cm, 600 mL column volume, 330 g of 100-200 mesh silica gel) and eluted with methanol:dichloromethane (0%-20% over 30 min). The collected fractions: 13%-14% methanol:dichloromethane fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give the crude product (24.2 g). The crude product was triturated with EA:n-hexane (300 mL / 60 mL) to give tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (12.4 g, 45%) as a white solid. LCMS(ESI,m / z):159[M-100+H] + .

[0289] To a mixture of tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (7.00 g, 27.1 mmol, 1.0 equiv.) in dichloromethane (100 mL), sodium bicarbonate (2.28 g, 27.1 mmol, 1.0 equiv.) and Dess-Martin periodinane (11.5 g, 27.1 mmol, 1.0 equiv.) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The product was used directly in the next step. LCMS (ESI, m / z): 257 [M+H] + .

[0290] (Isocyanomethyl)benzene (3.81 g, 32.5 mmol, 1.2 equiv.) and benzoic acid (21.5 g, 176 mmol, 6.5 equiv.) were added to the above mixture. The mixture was stirred at room temperature overnight. The reaction was quenched with water (200 mL). The mixture was extracted with EA (3 × 200 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (200 mL), brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (200 mL). After removing the dichloromethane, a slurry was prepared with 100-200 mesh silica gel (20 g). The sample was purified by column chromatography (column size 6 × 24 cm, column volume: 600 mL, silica gel size (100-200 mesh): 330 g) and eluted with methanol:dichloromethane (0% to 20% over 30 min). The collected fractions: 12% to 13% methanol:dichloromethane fraction were selected as pure fractions. These fractions were combined and concentrated under reduced pressure to give (S)-1-(benzylamino)-3-(tert-butoxycarbonylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-ylbenzoate (9.70 g, 67%) as an off-white solid. LCMS (ESI, m / z): 496 [M+H] + .

[0291] To a mixture of (S)-1-(benzylamino)-3-(tert-butoxycarbonylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl benzoate (8.20 g, 16.5 mmol, 1.0 equiv) in tetrahydrofuran (70 mL):water (70 mL) was added lithiumol (793 mg, 33.1 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (150 mL), and the mixture was extracted with EA (3 × 200 mL). The organic layers were combined, washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (200 mL). After removing the dichloromethane, a slurry was made with 100-200 silica gel mesh (15 g). The sample was purified by column chromatography (column size: 6 × 24 cm, column volume: 600 mL, silica gel size (100-200 mesh): 330 g) and eluted with methanol:dichloromethane (0% to 20% over 20 min). The collected fractions: 15% to 17% methanol:dichloromethane fraction were selected as pure fractions. These fractions were combined and concentrated under reduced pressure to give tert-butyl (S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-ylcarbamate (5.60 g, 83%) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ8.29-8.39(m,1H),7.51-7.62(m,1H),7.17-7.34(m,5H),6.13-6.67(m,1H),5.68-5.75(m,1H),4.21-4.41(m,2H) ),3.80-4.05(m,2H),3.03-3.22(m,2H),2.04-2.35(m,2H),1.82-1.99(m,1H),1.56-1.73(m,1H),1.36-1.45(m,9H),0.90-1.34(m,1H). LCMS(ESI,m / z):392[M+H] + .

[0292] To a mixture of tert-butyl (S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-ylcarbamate (5.50 g, 14.1 mmol, 1.0 equiv.) in DCM (10 mL):EA (67.5 mL) was added HCl (14.1 mL, 56.2 mmol, 4.0 equiv., 4 M in dioxane) at 0° C. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give crude (S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (5.2 g, crude) as an off-white solid. LCMS (ESI, m / z): 292 [M+H] + .

[0293] Synthesis of methyl (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanoate

[0294] [ka]

[0295] A 1000 mL three-necked round-bottom flask was charged with dimethyl(tert-butoxycarbonyl)-L-glutamate (50.0 g, 182 mmol, 1.0 equiv.) in THF (500 mL) under N2. Lithium bis(trimethylsilyl)amide (363 mL, 363 mmol, 2.0 equiv., 1 M in THF) was added dropwise at -78 °C. The reaction was stirred at -78 °C for 2 hours. 3-Bromopropanenitrile (48.7 g, 363 mmol, 2.0 equiv.) was added dropwise over 1 hour at -78 °C. The reaction was stirred at -78 °C for 2 hours. The reaction was quenched with pre-cooled methanol (75 mL) and pre-cooled acetic acid in THF (12.5 mL / 100 mL). The reaction was stirred at -78 °C for 30 minutes. The reaction was warmed to 0° C. and concentrated under reduced pressure. The residue was dissolved in EA (200 mL), washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (4:6) to give dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2-cyanoethyl)pentanedioate (19 g, 29%) as a yellow oil. LCMS (ESI, m / z): 329 [M+H] + .

[0296] A 1000 mL round-bottom flask was charged with dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2-cyanoethyl)pentanedioate (27.6 g, 84.0 mmol, 1.0 equiv) in methanol (300 mL). Chloroform (30 mL) and platinum dioxide (2.70 g) were added. The contents of the flask were placed under an atmosphere of H2 (3 atm). The reaction was stirred at room temperature for 36 h. The solid was filtered off. The organic layer was concentrated under reduced pressure to give dimethyl (2S,4S)-2-(3-aminopropyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (30 g, 89% (ELSD)) as an off-white solid. LCMS (ESI, m / z): 333 [M+H] + .

[0297] A 500 mL round-bottom flask was charged with dimethyl (2S,4S)-2-(3-aminopropyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (28 g, 84.2 mmol, 1.0 equiv), methanol (250 mL), and sodium carbonate (19.6 g, 185 mmol, 2.2 equiv) was added. The reaction was stirred at 70 °C for 4 h. The solid was filtered off and concentrated under reduced pressure. The residue was diluted with EA (50 mL), washed with water (2 × 20 mL), washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:dichloromethane (2:3) then methanol:dichloromethane (4:96) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoate (7.2 g, 27%) as a yellow oil. LCMS (ESI, m / z): 301 [M+H] + .

[0298] A 100 mL round-bottom flask was charged with methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoate (1.0 g, 3.33 mmol, 1.0 equiv.) and dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at 0° C. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give methyl (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanoate (0.7 g, crude) as a yellow oil. LCMS (ESI, m / z): 201 [M+H] + .

[0299] Synthesis of (S)-3-((S)-2-amino-4-(benzyloxy)-3-oxobutyl)pyrrolidin-2-one hydrochloride

[0300] [ka]

[0301] To a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (4.00 g, 14.0 mmol, 1.0 equiv) in methanol (20 mL) was added sodium hydride (19 mL, 57.0 mmol, 4.0 equiv, 3 M in water). The mixture was stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 6 with HCl (2 M). The mixture was extracted with EA (3×30 mL). The organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoic acid (3.56 g, 88%) as a pale yellow solid.

[0302] To a mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoic acid (3.56 g, 13.1 mmol, 1.0 equiv.) in dichloromethane (50 mL) was added N,O-dimethylhydroxylamine hydrochloride (1.28 g, 13.1 mmol, 1.0 equiv.), N-methylmorphline (3.97 g, 39.0 mmol, 3.0 equiv.), 1-hydroxybenzotriazole (1.77 g, 13.1 mmol, 1.0 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.76 g, 14.4 mmol, 1.1 equiv.) at 0 °C. The mixture was stirred at 0 °C under N for 2 hours. The reaction was quenched with water (40 mL). The organic layer was washed with HCl (2 × 40 mL, 1 M), water (40 mL), saturated aqueous sodium bicarbonate (2 × 40 mL), and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (3.43 g, 81%) as a pale yellow solid.

[0303] To a mixture of magnesium (2.36 g, 97.0 mmol, 9.0 equiv.) and mercuric chloride (1.76 g, 6.47 mmol, 0.6 equiv.) in THF (120 mL) was added benzyl chloromethyl ether (15.2 g, 97.0 mmol, 9.0 equiv.) at −45° C. under N2. The mixture was stirred at −45° C. to 5° C. for 5 h. Subsequently, the mixture was cooled to −45° C., and tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (3.40 g, 10.8 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature under N2 overnight. The reaction was quenched with saturated aqueous ammonium chloride (200 mL). The mixture was extracted with EA (3 × 200 mL). The organic layers were combined, washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (100 mL). A slurry was made using 100-200 mesh silica gel (10 g) and then loaded onto the column after removing the dichloromethane. The sample was purified by column chromatography (column size: 5 × 24 cm, column volume: 600 mL, silica gel size (100-200 mesh): 330 g) and eluted with methanol:dichloromethane (0%-5% over 20 min). Collected fractions: 3%-4% methanol:dichloromethane fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give tert-butyl N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]carbamate (2.15 g, 45%) as a pale yellow oil. 1 H NMR(300MHz,CDCl3-d)δ7.30-7.42(m,5H),6.21(s,1H),5.82(d,J=7.9Hz,1H),4.52-4.69(m, 3H), 4.18-4.37(m,2H),3.23-3.34(m,2H),2.32-2.54(m,2H),1.72-2.06(m,3H),1.44(s,9H). LCMS(ESI,m / z):277[M-100+H] + .

[0304] To a mixture of tert-butyl N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]carbamate (800 mg, 2.125 mmol, 1.00 equiv) in 1,4-dioxane (8 mL) was added HCl (8 mL, 4 M in 1,4-dioxane) at 0° C. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (3S)-3-[(2S)-2-amino-4-(benzyloxy)-3-oxobutyl]pyrrolidin-2-one hydrochloride (664 mg, crude) as a yellow semi-solid. LCMS (ESI, m / z): 277 [M+H] + .

[0305] Synthesis of (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide:

[0306] [ka]

[0307] To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (3.0 g, 10.5 mmol, 1.0 equiv) in tetrahydrofuran (50 mL) was added lithium borohydride (26.2 mL, 52.4 mmol, 5.0 equiv) dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and concentrated under reduced pressure. The mixture was then diluted with water (20 mL) and extracted with isopropanol:trichloromethane (1:5, 4×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol (19:1) to give tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (2.6 g, crude) as a white solid. The crude product was precipitated by the addition of PE:EA (4:1, 40 mL) to give tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (2.4 g, 79%) as a white solid. LC-MS (ESI, m / z): 259 [M+H] + .

[0308] To a stirred mixture of tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (2.4 g, 9.29 mmol, 1.0 equiv) in dimethyl sulfoxide (40 mL) was added 2-iodoxybenzoic acid (7.80 g, 27.8 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred at room temperature for 3 h and then basified to pH = 8 with saturated sodium bicarbonate (aq). The mixture was diluted with water (20 mL) and extracted with EA (4 x 200 mL). The organic layers were combined, washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (1.5 g, 63%) as a yellow solid. LC-MS (ESI, m / z): 257 [M+H]+ .

[0309] To a stirred mixture of tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (900 mg, 3.51 mmol, 1.0 equiv) in dichloromethane (10 mL) was added isocyanocyclopropane (471 mg, 7.02 mmol, 2.0 equiv) and acetic acid (633 mg, 10.5 mmol, 3.0 equiv) dropwise at 0° C. The mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane:methanol (49:1) to give (2S)-2-[(tert-butoxycarbonyl)amino]-1-(cyclopropylcarbamoyl)-3-[(3S)-2-oxopyrrolidin-3-yl]propyl acetate (820 mg, 55%) as a yellow solid. LC-MS (ESI, m / z): 384 [M+H] + .

[0310] To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-1-(cyclopropylcarbamoyl)-3-[(3S)-2-oxopyrrolidin-3-yl]propyl acetate (810 mg, 2.11 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added lithium hydride (253 mg, 10.5 mmol, 5.0 equiv, in 8 mL of water) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was acidified to pH=6 with hydrochloric acid (2 M). The mixture was extracted with EA (4×60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[(2S)-1-(cyclopropylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (680 mg, 94%) as a yellow solid. LCMS (ESI, m / z): 342 [M+H] + .

[0311] To a stirred mixture of tert-butyl N-[(2S)-1-(cyclopropylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (400 mg, 1.17 mmol, 1.0 equiv.) in dichloromethane (6 mL) was added dropwise trifluoroacetic acid (2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (290 mg, crude) as a brown solid. LC-MS (ESI, m / z): 242 [M+H] + .

[0312] Synthesis of (3S)-3-amino-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide:

[0313] [ka]

[0314] To a solution of tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (1.8 g, 7.02 mmol, 1.0 equiv) in MeOH (21 mL) was added CsF (0.53 g, 3.51 mmol, 0.5 equiv), followed by the slow addition of trimethylsilyl cyanide (0.84 g, 8.43 mmol, 1.2 equiv) at 0° C. The mixture was stirred at room temperature overnight, and the reaction was quenched with water (15 mL). The mixture was extracted with EtOAc (6×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a C18 column with water:MeCN (9:1) to give tert-butyl N-[(2S)-1-cyano-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (1.3 g, 49%) as a white solid. LC-MS (ESI, m / z): 284 [M+H] + .

[0315] To a solution of tert-butyl N-[(2S)-1-cyano-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (1.2 g, 4.24 mmol, 1.0 equiv.) in DMSO (13 mL) was added KCO (1.17 g, 8.47 mmol, 2.0 equiv.) and HO (0.72 g, 21.2 mmol, 5.0 equiv.). The mixture was stirred at room temperature for 3 hours, and the reaction was quenched with water (10 mL). The mixture was extracted with EtOAc (5 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a C18 column with water:MeCN (9:1) to give tert-butyl N-[(2S)-1-carbamoyl-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (460 mg, 32%) as a white solid. LC-MS (ESI, m / z): 302 [M+H] + .

[0316] A solution of tert-butyl N-[(2S)-1-carbamoyl-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (460 mg, 1.53 mmol, 1.0 equiv) in hydrochloric acid (6 mL, 4 M in dioxane) was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give (3S)-3-amino-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (300 mg, 68%) as an off-white solid. LC-MS (ESI, m / z): 202 [M+H] + .

[0317] Synthesis of (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopiperidin-3-yl)butanamide:

[0318] [ka]

[0319] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopiperidin-3-yl]propanoate (3 g, 9.99 mmol, 1.0 equiv.) in tetrahydrofuran (30 mL) was added a solution of lithium borohydride (10 mL, 19.9 mmol, 2.0 equiv., 2 M in THF) at 0° C. The mixture was stirred for 1 hour at 0° C., and the reaction was quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with isopropanol:trichloromethane (1:3, 3×40 mL). The organic layers were combined, washed with brine (2×40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting with DCM:MeOH (9:1) to give tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamate (2.0 g, 73%) as a white solid. LC-MS (ESI, m / z): 273 [M+H] + .

[0320] To a solution of tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamate (2.0 g, 7.34 mmol, 1.0 equiv.) in DMSO (20 mL) was added 2-iodoxybenzoic acid (4.10 g, 14.7 mmol, 2.0 equiv.) at room temperature. The mixture was stirred overnight, and the reaction was quenched with saturated sodium bicarbonate solution (5 mL). The mixture was extracted with EtOAc (4 x 40 mL). The organic layers were combined, washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamate (crude, 1.3 g, 67%) as a white solid. LC-MS (ESI, m / z): 271 [M+H] + .

[0321] To a solution of tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamate (1.3 g, 4.80 mmol, 1.0 equiv.) in DCM (4 mL) was added AcOH (866 mg, 14.4 mmol, 3.0 equiv.) and isocyanocyclopropane (645 mg, 9.62 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure to give the crude product. LC-MS (ESI, m / z): 398 [M+H] + .

[0322] To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-1-(cyclopropylcarbamoyl)-3-[(3S)-2-oxopiperidin-3-yl]propyl acetate (1.90 g, 4.78 mmol, 1.0 equiv) in THF (10 mL) was added lithium hydride (286 mg, 12.0 mmol, 2.5 equiv, in 10 mL of water). The mixture was stirred at 0° C. for 1 hour and acidified to pH=6 with hydrochloric acid (2 M). The mixture was extracted with EA (4×50 mL). The organic layers were combined, dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluting with dichloromethane:methanol (33:1) to give tert-butyl N-[(2S)-1-(cyclopropylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamate (953 mg, 56%) as a yellow solid.

[0323] To a solution of tert-butyl N-[(2S)-1-(cyclopropylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamate (270 mg, 0.760 mmol, 1.0 equiv.) in DCM (9 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (260 mg, crude). LC-MS (ESI, m / z): 256 [M+H] + .

[0324] Example 2 compound 1

[0325] [ka]

[0326] To a stirred mixture of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (260 mg, 1.13 mmol, 1.1 equiv) in N,N-dimethylformamide (10 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (509 mg, 1.33 mmol, 1.3 equiv) and N,N-diisopropylethylamine (532 mg, 4.12 mmol, 4.0 equiv) at 0° C. The mixture was stirred for 20 minutes at 0° C. (3S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (300 mg, 1.03 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred for 1 h at room temperature, and the reaction was quenched with water (30 mL) at room temperature. The residue was extracted with EA (3 × 40 mL). The organic layers were combined, washed with brine (6 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane:methanol (19:1) to afford tert-butyl (2S)-2-(((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)piperidine-1-carboxylate (380 mg, 66%) as a yellow solid. LCMS (ESI, m / z): 503 [M+H] + .

[0327] To a stirred solution of tert-butyl (2S)-2-(((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)piperidine-1-carboxylate (370 mg, 0.740 mmol, 1.0 equiv) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL) dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give (2S)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)piperidine-2-carboxamide (300 mg, 67%) as a yellow solid. LCMS (ESI, m / z): 403 [M+H] + .

[0328] To a stirred mixture of indole-2-carboxylic acid (120 mg, 0.740 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (368 mg, 0.970 mmol, 1.3 equiv) and N,N-diisopropylethylamine (289 mg, 2.24 mmol, 3.0 equiv) in portions at 0° C. The mixture was stirred for 20 minutes at 0° C. (2S)—N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)piperidine-2-carboxamide (300 mg, 0.750 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred for 1 h at room temperature, and the reaction was quenched with water (30 mL) at room temperature. The mixture was extracted with EA (3×40 mL). The organic layers were combined, washed with brine (4×40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane (DCM):methanol (MeOH) (16:1) to give (2S)—N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1-(1H-indole-2-carbonyl)piperidine-2-carboxamide (173 mg, crude) as a white solid. LCMS (ESI, m / z): 546 [M+H] + .

[0329] To a stirred mixture of (2S)—N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1-(1H-indole-2-carbonyl)piperidine-2-carboxamide (50.0 mg, 0.092 mmol, 1.0 equiv) in dichloromethane (3 mL) was added Dess-Martin periodinane (58.0 mg, 0.140 mmol, 1.5 equiv) in portions at 0° C. The reaction was quenched with saturated sodium bicarbonate (5 mL) at 0° C. The residue was extracted with EA (3×30 mL). The organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol:10:1) to give (2S)—N-(4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1-(1H-indole-2-carbonyl)piperidine-2-carboxamide (6.3 mg, 12%) as a pale yellow solid. LCMS (ESI, m / z): 544 [M+H] + .

[0330] Example 3 compound 2

[0331] [ka]

[0332] To a mixture of 1H-indole-2-carboxylic acid (600 mg, 3.72 mmol, 1.0 equiv.), (1S,3aR,6aS)-tert-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate (787 mg, 3.72 mmol, 1.0 equiv.), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.12 g, 5.59 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.44 g, 11.2 mmol, 3.0 equiv.). The mixture was stirred at room temperature overnight, and the reaction was quenched with water (20 mL). The mixture was extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with DCM (20 mL). After removing the DCM, a slurry containing 1.2 g of 100-200 mesh silica gel was prepared and purified by column chromatography (5 × 24 cm, 300 mL column volume, 120 g of 100-200 mesh silica gel) eluted with EA:PE (0% to 50% over 30 min). The collected fractions: 21% to 23% EA:PE fraction were selected as pure fractions. These fractions were combined and concentrated under reduced pressure to give (1S,3aR,6aS)-tert-butyl 2-(1H-indole-2-carbonyl)-octahydrocyclopenta[c]pyrrole-1-carboxylate (865 mg, 62%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ11.60(s,1H),7.65(d,J=8.1Hz,1H),7.44(d,J=8.2Hz,1H),7.21(t,J=7.6Hz, 1H),6.72-7.10(m,2H),4.23-4.74(m,1H),3.58-4.18(m,2H),2.54-2.96(m,2H),1.22-2.04(m,15H). LCMS(ESI,m / z):299[M-56+H] + .

[0333] To a solution of (1S,3aR,6aS)-tert-butyl 2-(1H-indole-2-carbonyl)-octahydrocyclopenta[c]pyrrole-1-carboxylate (300 mg, 0.846 mmol, 1.0 equiv) in DCM (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give crude (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ12.57(br,1H),11.57(s,1H),7.61-7.68(m,1H),7.42-7.48(m,1H),7.16-7.25(m,1H),7.00-7.10 (m,2H),4.34-4.41(m,1H),4.06-4.18(m,1H),3.76-3.86(m,1H),2.78-2.88(m,1H),2.59-2.71(m,1H),1.46-1.92(m,6H). LCMS(ESI,m / z):299[M+H] + .

[0334] (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (250 mg, 0.763 mmol, 1.0 equiv.), (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid (250 mg, 0.839 mmol, To a mixture of N-ethyl-N-isopropylpropan-2-amine (394 mg, 3.051 mmol, 4.0 equiv.) and N-ethyl-N-isopropylpropan-2-amine (394 mg, 3.051 mmol, 4.0 equiv.) in DCM (10 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.07 g, 1.679 mmol, 2.2 equiv., 50% in EA) at 0 °C. The mixture was stirred for 2 h at 0 °C, and the reaction was quenched with water (20 mL). The mixture was extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (10 mL). After removing the DCM, a slurry was made with 100-200 mesh silica gel (500 mg). The sample was purified by column chromatography (4 × 24 cm column, 200 mL column volume, 80 g silica gel (100–200 mesh)) and eluted with MeOH:DCM (0%–15% over 20 min). The collected fractions: 11%–12% MeOH:DCM fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give (1S,3aR,6aS)-N-((S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)-octahydrocyclopenta[c]pyrrole-1-carboxamide (180 mg, 35%) as a yellow solid. LCMS (ESI, m / z): 572 [M+H] + .

[0335] To a mixture of (1S,3aR,6aS)-N-((S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)-octahydrocyclopenta[c]pyrrole-1-carboxamide (180 mg, 0.315 mmol, 1.0 equiv) in DCM (5 mL) was added Dess-Martin periodinane (200 mg, 0.472 mmol, 1.5 equiv) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated aqueous sodium thiosulfate solution (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by TLC (mobile phase: MeOH:DCM = 1:11, Rf = 0.5, detection: UV) to give (1S,3aR,6aS)-N-(4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)-octahydrocyclopenta[c]pyrrole-1-carboxamide (28.2 mg, 15%) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ11.30-13.70(m,1H),8.98-9.35(m,1H),8.45-8.90(m,1H),7.10-7.95(m,9H),6.45-7.09(m,2H),5.12- 4.66(m,1H),4.03-4.52(m,4H),3.57-3.89(m,1H),2.93-3.15(m,2H),2.60-2.86(m,2H),2.10-2.35(m,2H),1.40-2.08(m,9H). LCMS(ESI,m / z):570[M+H] + .

[0336] Example 4 compound 3

[0337] [ka]

[0338] To a mixture of (2S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (341 mg, 1.59 mmol, 1.3 equiv.) in acetonitrile (6 mL) was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (445 mg, 1.59 mmol, 1.3 equiv.) and N-methylimidazole (351 mg, 4.27 mmol, 3.5 equiv.) at 0°C. The mixture was stirred for 15 minutes at 0°C. (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (400 mg, 1.22 mmol, 1.0 equiv.) was added. The mixture was stirred for 2 hours at room temperature, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3 × 15 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with DCM (10 mL). After removing the DCM, a slurry containing 100-200 mesh silica gel (1 g) was prepared. The sample was purified by column chromatography (4 × 24 cm column, 200 mL column volume, 80 g silica gel (100-200 mesh)) and eluted with MeOH:DCM (0%-15% over 20 min). The collected fractions were selected as pure fractions from 6% to 7% MeOH:DCM. These fractions were combined and concentrated under reduced pressure to give tert-butyl (2S)-2-[[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl]pyrrolidine-1-carboxylate (280 mg, 43%) as a white solid. LCMS (ESI, m / z): 489 [M+H] + .

[0339] To a mixture of tert-butyl (2S)-2-[[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl]pyrrolidine-1-carboxylate (230 mg, 0.471 mmol, 1.0 equiv.) in DCM (4 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred for 1 hour and concentrated under reduced pressure to give crude (3S)-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]-3-[(2S)-pyrrolidin-2-ylformamido]butanamide (180 mg, crude) as a yellow semi-solid. LCMS (ESI, m / z): 389 [M+H] + .

[0340] A mixture of indole-2-carboxylic acid (82.1 mg, 0.510 mmol, 1.1 equiv.), N-ethyl-N-isopropylpropan-2-amine (180 mg, 1.39 mmol, 3.0 equiv.), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (229 mg, 0.602 mmol, 1.3 equiv.) in N,N-dimethylformamide (2 mL) was stirred at 0° C. for 15 minutes. (3S)-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]-3-[(2S)-pyrrolidin-2-ylformamido]butanamide (180 mg, 0.463 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with DCM (10 mL). After removing the DCM, a slurry containing 100-200 mesh silica gel (500 mg) was prepared. The sample was purified by column chromatography (4 × 24 cm column, 200 mL column volume, 80 g of 100-200 mesh silica gel) and eluted with MeOH:DCM (0% to 10% over 20 min). The collected fractions were selected as pure fractions from 5% to 7% MeOH:DCM. These fractions were combined and concentrated under reduced pressure to give (3S)-N-benzyl-2-hydroxy-3-[[(2S)-1-(1H-indole-2-carbonyl)pyrrolidin-2-yl]formamide]-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (160 mg, 62%) as a pale yellow solid. LCMS (ESI, m / z): 532 [M+H] + .

[0341] To a mixture of (3S)-N-benzyl-2-hydroxy-3-[[(2S)-1-(1H-indole-2-carbonyl)pyrrolidin-2-yl]formamide]-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (100 mg, 0.188 mmol, 1.0 equiv) in DCM (2 mL) was added Dess-Martin periodinane (120 mg, 0.282 mmol, 1.5 equiv) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate (3 mL) and saturated aqueous sodium thiosulfate (3 mL). The mixture was extracted with EA (3×3 mL). The organic layers were combined, washed with brine (2×3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:11, Rf = 0.3, detection: UV) to give N-benzyl-3-[[(2S)-1-(1H-indole-2-carbonyl)pyrrolidin-2-yl]formamide]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (10.1 mg, 9%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ11.32-13.58(m,1H),8.95-9.30(m,1H),8.52-8.88(m,1H),7.36-7.82(m,3H),7.10-7.35(m,6H),6.60-7.09(m,2) H),4.76-5.12(m,1H),4.45-4.70(m,1H),4.15-4.35(m,2H),3.85-4.05(m,1H),3.58-4.04(m,1H),3.00-3.20(m,2H),1.50-2.35(m,9H). LCMS(ESI,m / z):530[M+H] + .

[0342] Example 5 compound 4

[0343] [ka]

[0344] To a mixture of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 0.644 mmol, 1.0 equiv.) and di-tert-butyl decarbonate (155 mg, 0.709 mmol, 1.1 equiv.) in DCM (2 mL) was added triethylamine (72.0 mg, 0.709 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give crude (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (165 mg, crude) as a yellow oil. LCMS (ESI, m / z): 200 [M-56+H] + .

[0345] A mixture of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (154 mg, 0.604 mmol, 1.1 equiv), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (313 mg, 0.824 mmol, 1.5 equiv), and N-ethyl-N-isopropylpropan-2-amine (284 mg, 2.20 mmol, 4.0 equiv) in N,N-dimethylformamide (3 mL) was stirred at 0° C. for 0.5 h. (3S)-3-Amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (180 mg, 0.549 mmol, 1.00 equiv) was added. The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with DCM (10 mL). After removing the DCM, a slurry was made with 100-200 mesh silica gel (500 mg). The sample was purified by column chromatography (4 × 24 cm column, 200 mL column volume, 80 g silica gel (100-200 mesh) amount) and eluted with MeOH:DCM (0%-15% over 20 min). The collected fractions: 6%-7% MeOH:DCM fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give tert-butyl (1R,2S,5S)-2-[[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (230 mg, 71%) as a yellow solid. LCMS (ESI, m / z): 529 [M+H] + .

[0346] To a mixture of tert-butyl (1R,2S,5S)-2-[[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (150 mg, 0.284 mmol, 1.0 equiv) in DCM (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give crude (3S)-N-benzyl-3-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamido]-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (120 mg, crude) as a yellow semi-solid. LCMS (ESI, m / z): 429 [M+H] + .

[0347] To a mixture of indole-2-carboxylic acid (49.6 mg, 0.308 mmol, 1.1 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg, 0.420 mmol, 1.5 equiv.) in N,N-dimethylformamide (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (145 mg, 1.12 mmol, 4.0 equiv.) at 0°C. The mixture was stirred at 0° C. for 0.5 hours, followed by the addition of (3S)-N-benzyl-3-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide]-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (120 mg, 0.280 mmol, 1.0 equiv). The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3×10 mL). The organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:12; Rf = 0.3, detection: UV) to give (3S)-N-benzyl-2-hydroxy-3-[[(1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide]-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (70.0 mg, 39.8%) as a yellow solid. LCMS (ESI, m / z): 572 [M+H] + .

[0348] To a mixture of (3S)-N-benzyl-2-hydroxy-3-[[(1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide]-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (70.0 mg, 0.122 mmol, 1.0 equiv) in DCM (3 mL) was added Dess-Martin periodinane (104 mg, 0.245 mmol, 2.0 equiv) at 0°C. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (2 mL) and saturated aqueous sodium bicarbonate (2 mL). The mixture was extracted with EA (3 × 3 mL). The organic layers were combined, washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:12; Rf = 0.4, detection: UV) to obtain N-benzyl-3-[[(1R,2S,5S)-3-(1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (15.5 mg, 20.3%) as a white solid. LCMS (ESI, m / z): 570 [M+H] + .

[0349] Example 6 compound 5

[0350] [ka]

[0351] Compound 5 was prepared similarly as described for compound 1, using (2S,4R)-1-(tert-butoxycarbonyl)-4-phenoxypyrrolidine-2-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. LCMS (ESI, m / z): 622 [M+H] + .

[0352] Example 7 compound 6

[0353] [ka]

[0354] Compound 6 was prepared similarly as described for compound 1, using (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. LCMS (ESI, m / z): 636 [M+H] + .

[0355] Example 8 compound 7

[0356] [ka]

[0357] Compound 7 was prepared similarly as described for compound 1, using (2S,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. LCMS (ESI, m / z): 606 [M+H] + .

[0358] Example 9 compound 8

[0359] [ka]

[0360] Compound 8 was prepared similarly as described for compound 1, using (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. LCMS (ESI, m / z): 556 [M+H] + .

[0361] Example 10 compound 9

[0362] [ka]

[0363] Compound 9 was prepared similarly as described for compound 1, using (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. LCMS (ESI, m / z): 556 [M+H] + .

[0364] Example 11 compound 10

[0365] [ka]

[0366] Compound 10 was prepared similarly as described for compound 1, using (2S,4R)-4-(tert-butoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid instead of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. Boc deprotection was carried out using HCl in dioxane. LCMS (ESI, m / z): 602 [M+H] + .

[0367] Example 12 compound 11

[0368] [ka]

[0369] Compound 11 was prepared similarly as described for compound 10, using (S)-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid instead of (2S,4R)-4-(tert-butoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 558 [M+H] + .

[0370] Example 13 compound 12

[0371] [ka]

[0372] Compound 12 was prepared similarly as described for compound 10, using (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid instead of (2S,4R)-4-(tert-butoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 560 [M+H] + .

[0373] Example 14 compound 13

[0374] [ka]

[0375] To a mixture of (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (317 mg, 1.06 mmol, 1.1 equiv), methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (180 mg, 0.967 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (500 mg, 3.87 mmol, 4.0 equiv) in dichloromethane (10 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.35 g, 2.13 mmol, 2.2 equiv, 50% in EA) at 0 °C. The mixture was stirred for 2 hours at 0°C, and the reaction was quenched with water (20 mL). The mixture was extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:11, Rf = 0.4, detection: UV) to give methyl (2S)-2-[[(1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (110 mg, 22%) as an off-white solid.

[0376] To a mixture of methyl (2S)-2-[[(1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (100 mg, 0.214 mmol, 1.0 equiv.) in THF (1 mL) was added LiBH (0.32 mL, 0.642 mmol, 3.0 equiv., 2 M in THF) at 0 °C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was extracted with chloroform:isopropyl alcohol (5:1, 3 × 3 mL). The organic layers were combined, washed with brine (2 × 3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:11, Rf = 0.4, detection: UV) to give (1S,3aR,6aS)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-(1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (50.0 mg, 48%) as an off-white solid.

[0377] To a mixture of (1S,3aR,6aS)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-(1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (50.0 mg, 0.114 mmol, 1.0 equiv) in dichloromethane (1.00 mL) was added Dess-Martin periodinane (96.7 mg, 0.228 mmol, 2.0 equiv) at 0° C. The mixture was stirred at room temperature for 3 hours, and the reaction was then diluted with saturated aqueous sodium bicarbonate (1 mL) and saturated aqueous sodium thiosulfate. (The mixture was quenched with dichloromethane (3×3 mL). The organic layers were combined, washed with brine (2×2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product (45 mg). The crude product was purified by TLC (Column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; Mobile phase A: water (0.05% NH₃·HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20B to 35B in 9 min, 35B to B in 9 min, B to B in 9 min, B to B in 9 min, B to B in 9 min, B to B in 9 min, B to B in 9 min, 210 nm; RT: 7.33) to give (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (8.3 mg, 15%) as a white solid. LCMS(ESI,m / z):437[M+H] + .

[0378] Example 15 Compound 14A

[0379] [ka]

[0380] A 40 mL vial was charged with 4-methoxy-1H-indole-2-carboxylic acid (348 mg, 1.82 mmol, 1.1 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (693 mg, 1.82 mmol, 1.1 equiv.), N,N-dimethylformamide (5 mL), and N-ethyl-N-isopropylpropan-2-amine (643 mg, 4.97 mmol, 3.0 equiv.). The reaction was stirred for 30 min, and then tert-butyl (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate (500 mg, 1.65 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 3 h, and the reaction was quenched with water (20 mL). The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was diluted with dichloromethane (5 mL). A slurry was made using 100-200 mesh silica gel (4 g) and then loaded onto the column after removing the dichloromethane. The sample was purified by column chromatography (column size: 4 × 24 cm, column volume: 200 mL, amount of silica gel (100-200 mesh): 80 g) and eluted with EA:PE (0%-30% over 30 min). Collected fractions: The 13% EA:PE fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give tert-butyl (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylate (530 mg, 78%) as a white solid. LCMS (ESI, m / z): 329 [M+H-56] + .

[0381] A 40 mL vial was charged with tert-butyl (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylate (200 mg, 0.520 mmol, 1.0 equiv.) and dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was then added at 0 °C. The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (230 mg, crude) as a yellow solid. LCMS (ESI, m / z): 329 [M+H] + .

[0382] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (100 mg, 0.537 mmol, 1.0 equiv.), (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (211 mg, 0.644 mmol, 1.2 equiv.), and N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (165 mg, 0.591 mmol, 1.1 equiv.) in acetonitrile (3 mL) was added 1-methylimidazole (136 mg, 1.66 mmol, 3.1 equiv.). The mixture was stirred at 0 °C. The mixture was then stirred overnight at room temperature and quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:10; Rf = 0.4, detection: UV) to give the desired product, methyl (2S)-2-[[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate 60 mg, 20%) as a yellow solid. LCMS (ESI, m / z): 497 [M+H]+ .

[0383] To a solution of methyl (2S)-2-[[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (60.0 mg, 0.121 mmol, 1.0 equiv.) in THF (2 mL) was added lithium borohydride (7.90 mg, 0.363 mmol, 3.0 equiv.). The mixture was stirred at 0°C and then at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with chloroform:isopropanol (5:1, 3 x 20 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by TLC (mobile phase: methanol: dichloromethane = 1:11, Rf = 0.4, detection: UV) to give (1S,3aR,6aS)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (36 mg, 57%) as a pale yellow solid. LCMS (ESI, m / z): 469 [M+H] + .

[0384] To a solution of (1S,3aR,6aS)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (35.0 mg, 0.075 mmol, 1.0 equiv) in dichloromethane (1 mL) was added Dess-Martin periodinane (63.3 mg, 0.149 mmol, 2.0 equiv). The mixture was stirred at room temperature for 24 hours. The reaction was quenched with saturated sodium bicarbonate (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; Mobile phase A: water (0.05% NH3 HO), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 24B to 42B in 9 min; 210 nm; RT1 (min): 5.48; RT2 (min): 7.43) to give (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (14A, 4.5 mg, 12%) as a white solid and stereoisomer 14B (1.6 mg, 4%) as a white solid.

[0385] Example 16 compound 15

[0386] [ka]

[0387] A 100 mL round-bottom flask was charged with (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (840 mg, 2.82 mmol, 1.0 equiv.), methyl (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanoate (676 mg, 3.38 mmol, 1.2 equiv.), acetonitrile (20 mL), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (869 mg, 3.10 mmol, 1.1 equiv.). 1-Methyl-1H-imidazole (717 mg, 8.73 mmol, 3.1 equiv.) was added at 0 °C. The mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL). The resulting solution was extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (2:1) to give methyl (S)-2-((1S,3aR,6aS)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (780 mg, 53%) as a yellow semi-solid. LCMS (ESI, m / z): 481 [M+H] + .

[0388] A 40 mL vial was charged with methyl (S)-2-((1S,3aR,6aS)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (780 mg, 1.62 mmol, 1.0 equiv.) in THF (10 mL). Lithium borohydride (2.43 mL, 4.87 mmol, 3.0 equiv., 2 M in THF) was added dropwise at 0° C. The mixture was stirred for 30 minutes, and ethanol (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The pH of the reaction was adjusted to 3 with potassium hydrogen sulfate (1 mol / L). The resulting solution was extracted with dichloromethane (5×40 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using dichloromethane:methanol (95:5) to give (1S,3aR,6aS)-N-((S)-1-hydroxy-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (600 mg, 76%) as a white solid. LCMS (ESI, m / z): 453 [M+H] + .

[0389] A 40 mL vial was charged with (1S,3aR,6aS)-N-((S)-1-hydroxy-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (100 mg, 0.221 mmol, 1.0 equiv.) and dichloromethane (5 mL). Dess-Martin periodinane (187 mg, 0.442 mmol, 2.0 equiv.) was added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction was diluted with sodium thiosulfate (1 M) and saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane (6 × 10 mL). The organic layers were combined and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep C18 OBD column, 150 mm 5 μm; Mobile phase A: water (0.05% NH3·HO), Mobile phase B: ACN(1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (24 mg, 24%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6, 80 °C) δ 11.25 (s, 1H), 9.44 (s, 1H), 8.47 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.18-7.22 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.93 (br, 1H), 4.60-4.80 (m, 1H), 4.25 (br, 1H), 4.07 (br, 1H), 3.74-3.78 (m, 1H), 2.72-3.80 (m, signal partially below the HO peak), 2.28 (m, 1H), 2.10-2.12 (m, 1H), 1.36-1.99 (m, 13H). LCMS(ESI,m / z):451[M+H] + .

[0390] Example 17 compound 16

[0391] [ka]

[0392] To a solution of (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (250 mg, 0.763 mmol, 1.0 equiv.), (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (275 mg, 0.839 mmol, 1.1 equiv.), and N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (235 mg, 0.839 mmol, 1.1 equiv.) in acetonitrile (8 mL) was added 1-methylimidazole (313 mg, 3.81 mmol, 5.0 equiv.). The mixture was stirred at 0 °C and then at room temperature overnight. The reaction was quenched with water (20 mL). The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:13; Rf = 0.4, detection: UV) to give (3S)-3-[[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (70.0 mg, 13%) as a yellow solid. LCMS (ESI, m / z): 602 [M+H] + .

[0393] To a solution of (3S)-3-[[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (60.0 mg, 0.100 mmol, 1.0 equiv) in dichloromethane (2 mL) was added Dess-Martin periodinane (84.5 mg, 0.200 mmol, 2.0 equiv). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and 10% sodium thiosulfate solution (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep C18 OBD column, 19 × 150 mm, 5 μm; Mobile phase A: water (0.05% NH₃·HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25B to 52B in 7 min; 210 nm; RT (min): 6.32) to give 3-[[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-N-benzyl-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (9.3 mg, 15%) as an off-white solid. LCMS (ESI, m / z): 600 [M+H] + .

[0394] Example 18 compound 17

[0395] [ka]

[0396] A 40 mL vial was charged with (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (150 mg, 0.333 mmol, 1.0 equiv.) in dichloromethane (2 mL). (Isocyanomethyl)benzene (78.0 mg, 0.666 mmol, 2.0 equiv.) in dichloromethane (1 mL) was added dropwise at 0 °C. Pyridine (105 mg, 1.33 mmol, 4.0 equiv.) in dichloromethane (1 mL) was added dropwise at 0 °C. Trifluoroacetic acid (114 mg, 0.999 mmol, 3.0 equiv) in dichloromethane (1 mL) was added dropwise at 0° C. The reaction was stirred at 0° C. for 50 minutes and then at room temperature overnight. The reaction was concentrated under reduced pressure. The residue was purified by C18 column using acetonitrile:water (0.05% TFA) (30 / 70) to give (1S,3aR,6aS)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (30 mg) as a white solid. LCMS (ESI, m / z): 586 [M+H] + .

[0397] An 8 mL vial was charged with (1S,3aR,6aS)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (30.0 mg, 0.051 mmol, 1.0 equiv.) and dichloromethane (2 mL). Dess-Martin periodinane (43.4 mg, 0.102 mmol, 2.0 equiv.) was added at 0° C. The reaction was stirred at room temperature for 2 hours. The reaction was diluted with sodium thiosulfate (1 M) and saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane (6 × 10 mL). The organic layers were combined and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep Phenyl OBD column, 150 mm 5 μm 13 nm; Mobile phase A: water (0.05% NH₃·H₂O), Mobile phase B: ACN; Purification afforded (1S,3aR,6aS)-N-(4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (1.3 mg, 4.1%) as a white solid. LCMS (ESI, m / z): 584 [M+H] + .

[0398] Example 19 compound 18

[0399] [ka]

[0400] A 40 mL vial was charged with (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (70.0 mg, 0.155 mmol, 1.0 equiv.) in dichloromethane (1 mL). 2-Isocyanopropane (21.5 mg, 0.311 mmol, 2.0 equiv.) in dichloromethane (1 mL) was added dropwise at 0 °C. Pyridine (49.2 mg, 0.621 mmol, 4.0 equiv.) in dichloromethane (1 mL) was added dropwise at 0 °C. Trifluoroacetic acid (53.2 mg, 0.466 mmol, 3.0 equiv) in dichloromethane (1 mL) was added dropwise at 0° C. The reaction was stirred at 0° C. for 50 minutes and then at room temperature overnight. The reaction was quenched with water (5 mL). The resulting solution was extracted with dichloromethane (3×10 mL). The organic layers were combined, washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with dichloromethane:methanol (93:7) to give (1S,3aR,6aS)-N-((2S)-3-hydroxy-4-(isopropylamino)-4-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (40 mg, 40%) as an off-white solid. LCMS (ESI, m / z): 538 [M+H] + .

[0401] An 8 mL vial was charged with (1S,3aR,6aS)-N-((2S)-3-hydroxy-4-(isopropylamino)-4-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (30.0 mg, 0.056 mmol, 1.0 equiv.) and dichloromethane (2 mL). Dess-Martin periodinane (47.3 mg, 0.112 mmol, 2.0 equiv.) was added at 0° C. The reaction was stirred at room temperature for 2 hours. The reaction was diluted with sodium thiosulfate (1 M) and saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane (6 × 10 mL). The organic layers were combined and concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep C18 OBD column, 19 × 150 mm, 5 μm; Mobile phase A: water (0.05% NH₃·H₂O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25B to 50B in 7 min, 210 nm; RT1 (min): 6.32. Purification afforded (1S,3aR,6aS)-2-(1H-indole-2-carbonyl)-N-(4-(isopropylamino)-3,4-dioxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (7.8 mg, 25%) as a white solid. LCMS (ESI, m / z): 536 [M+H] + .

[0402] Example 20 compound 19

[0403] [ka]

[0404] A mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (190 mg, 0.671 mmol, 1.1 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (278 mg, 0.732 mmol, 1.2 equiv.), and N-ethyl-N-isopropylpropan-2-amine (315 mg, 2.44 mmol, 4.0 equiv.) in N,N-dimethylformamide (5 mL) was stirred for 20 minutes at 0° C. (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (200 mg, 0.610 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (100 mL). The mixture was then extracted with EA (3 × 100 mL). The organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (20 mL) and slurried with 100-200 mesh silica gel (2 g). After removing the dichloromethane, the slurry was loaded onto a column. The sample was purified by column chromatography (column size: 5 × 24 cm, column volume: 300 mL, amount of silica gel (100-200 mesh): 120 g) and eluted with methanol:dichloromethane (0% to 12% over 30 min). The collected fractions: 6% to 11% methanol:dichloromethane fraction were selected as pure fractions, and these fractions were combined and concentrated under reduced pressure to give tert-butyl (2S,4R)-2-[[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carboxylate (190 mg, 50%) as a pale yellow solid. LCMS (ESI, m / z): 557 [M+H] + .

[0405] To a mixture of tert-butyl (2S,4R)-2-[[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carboxylate (190 mg, 0.341 mmol, 1.0 equiv.) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (3S)-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]-3-[[(2S,4R)-4-(trifluoromethyl)pyrrolidin-2-yl]formamido]butanamide (210 mg, crude) as a brown solid. LCMS (ESI, m / z): 457 [M+H] + .

[0406] A mixture of indole-2-carboxylic acid (81.6 mg, 0.506 mmol, 1.1 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (209 mg, 0.552 mmol, 1.2 equiv.), and N-ethyl-N-isopropylpropan-2-amine (297 mg, 2.30 mmol, 5.0 equiv.) in N,N-dimethylformamide (5 mL) was stirred for 20 minutes at 0° C. Subsequently, (3S)-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]-3-[[(2S,4R)-4-(trifluoromethyl)pyrrolidin-2-yl]formamido]butanamide (210 mg, 0.460 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (100 mL). The mixture was extracted with EA (3 × 100 mL). The organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (20 mL) and slurried with 100-200 mesh silica gel (2 g). After removing the dichloromethane, the slurry was loaded onto a column. The sample was purified by column chromatography (column size: 5 × 24 cm, column volume: 300 mL, amount of silica gel (100-200 mesh): 120 g) and eluted with methanol:dichloromethane (0%-12% over 30 min). The collected fractions: 5% to 9% methanol:dichloromethane fraction were selected as pure fractions, and these fractions were combined and concentrated under reduced pressure to give (3S)-N-benzyl-2-hydroxy-3-[[(2S,4R)-1-(1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidin-2-yl]formamide]-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (180 mg, 60%) as a light brown solid. LCMS (ESI, m / z): 600 [M+H] + .

[0407] To a mixture of (3S)-N-benzyl-2-hydroxy-3-[[(2S,4R)-1-(1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidin-2-yl]formamide]-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (100 mg, 0.167 mmol, 1.0 equiv) in dichloromethane (5 mL) was added Dess-Martin periodinane (141 mg, 0.334 mmol, 2.0 equiv) at 0 °C. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and 10% sodium thiosulfate solution (10 mL). The mixture was extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product (100 mg) was purified by preparative HPLC using the following conditions: column: XBridge Prep C18 OBD column, 19 × 150 mm 5 μm; mobile phase A: water (0.05% NH₃·H₂O), mobile phase B: ACN; to give N-benzyl-3-[[(2S,4R)-1-(1H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidin-2-yl]formamido]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (29.6 mg, 28%) as a pale pink solid. LCMS (ESI, m / z): 598 [M+H] + .

[0408] Example 21 compound 20

[0409] [ka]

[0410] Compound 20 was prepared similarly as described for compound 19, using (2S,4S)-1-(tert-butoxycarbonyl)-4-cyclohexylpyrrolidine-2-carboxylic acid instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 612 [M+H] +.

[0411] Example 22 compound 21

[0412] [ka]

[0413] Compound 21 was prepared similarly as described for compound 19, using (2S,4R)-1-(tert-butoxycarbonyl)-4-(prop-2-en-1-yl)pyrrolidine-2-carboxylic acid instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 570 [M+H] + .

[0414] Example 23 compound 22

[0415] [ka]

[0416] Compound 22 was prepared similarly as described for compound 19, using (3R,6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 592 [M+H] + .

[0417] Example 24 compound 23

[0418] [ka]

[0419] Compound 23 was prepared similarly as described for compound 19, using (3S,6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 592 [M+H] + .

[0420] Example 25 compound 24

[0421] [ka]

[0422] Compound 24 was prepared similarly as described for compound 19, using (5S)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 570 [M+H] + .

[0423] Example 26 compound 25

[0424] [ka]

[0425] Compound 25 was prepared similarly as described for compound 19, using (2S,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid. LCMS (ESI, m / z): 544 [M+H] + .

[0426] Example 27 compound 26

[0427] [ka]

[0428] To a solution of (5S)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (250 mg, 0.98 mmol, 1.0 equiv.) in EA (3 mL) and acetic acid (3 mL) was added PtO2 (178 mg, 0.78 mmol, 0.8 equiv.). Hydrogen (3 atm) was introduced. The mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was chromatographed on a C18 column using MeCN:water (2:3) to give (2S)-1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid (180 mg, 61%) as a white solid. LCMS (ESI, m / z): 258 [M+H] + .

[0429] To a solution of (2S)-1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid (155 mg, 0.60 mmol, 1.0 equiv.) in N,N-dimethylformamide (4 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (344 mg, 0.91 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (390 mg, 3.02 mmol, 5.0 equiv.) were added. The mixture was stirred at 0° C. for 30 minutes. (3S)-3-amino-N-benzyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (107 mg, 0.66 mmol, 1.1 equiv.) was added. The mixture was stirred at 0° C. for 1 h, and the reaction was quenched with water (4 mL). The mixture was extracted with EA (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol:dichloromethane (1:18) to give tert-butyl (2S)-2-(((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-4,4-dimethylpiperidine-1-carboxylate (180 mg, 57%) as a yellow solid. LCMS (ESI, m / z): 531 [M+H] + .

[0430] To a solution of tert-butyl (2S)-2-(((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-4,4-dimethylpiperidine-1-carboxylate (270 mg, 0.51 mmol, 1.0 equiv) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (2S)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-4,4-dimethylpiperidine-2-carboxamide (260 mg, crude) as a colorless oil. LCMS(ESI,m / z):431[M+H]+ .

[0431] To a solution of 1H-indole-2-carboxylic acid (107 mg, 0.66 mmol, 1.1 equiv.) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (390 mg, 3.02 mmol, 5.0 equiv.) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (344 mg, 0.91 mmol, 1.5 equiv.). The mixture was stirred at 0° C. for 30 minutes. (2S)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-4,4-dimethylpiperidine-2-carboxamide (260 mg, 0.6 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was quenched with water (4 mL). The mixture was extracted with EA (3 x 6 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol:dichloromethane (1:18) to give (2S)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1-(1H-indole-2-carbonyl)-4,4-dimethylpiperidine-2-carboxamide (150 mg, 49%) as a yellow solid. LCMS (ESI, m / z): 574 [M+H] + .

[0432] To a solution of (2S)-N-((2S)-4-(benzylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1-(1H-indole-2-carbonyl)-4,4-dimethylpiperidine-2-carboxamide (100 mg, 0.17 mmol, 1.0 equiv) in DMSO (10 mL) was added IBX (97.6 mg, 0.35 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight, and the reaction was quenched with sodium bicarbonate solution (2 mL). The resulting solution was extracted with EA (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using methanol:dichloromethane (1:18) to give (2S)—N-(4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-1-(1H-indole-2-carbonyl)-4,4-dimethylpiperidine-2-carboxamide (18 mg, 24%) as a white solid. LCMS (ESI, m / z): 572 [M+H] + .

[0433] Example 28 Compounds 27A and 27

[0434] [ka]

[0435] (3S)-3-[(2S)-2-amino-4-(benzyloxy)-3-oxobutyl]pyrrolidin-2-one hydrochloride (342 mg, 1.09 mmol, 1.0 equiv.) and (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (359 mg, 1.09 mmol, 1 To a mixture of o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (499 mg, 1.312 mmol, 1.2 equiv.) and N-ethyl-N-isopropylpropan-2-amine (424 mg, 3.28 mmol, 3.0 equiv.) in N,N-dimethylformamide (5 mL) was added at 0° C. The mixture was stirred at room temperature under nitrogen for 1 h. The reaction was quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:13; Rf = 0.4, detection: UV) to give (1S,3aR,6aS)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (27A, 145 mg, 21%) as a yellow solid. 1 H NMR(400MHz,353K,DMSO-d6)δ11.37(s,1H),8.30-8.80(m,1H),7.35-7.6 0(m,1H),7.20-7.38(m,5H),7.00-7.15(m,2H),6.75-6.99(m,1H),6.51( d,J=6.8Hz,1H),4.00-5.02(m,7H),3.87(s,3H),3.55-3.80(m,1H),2.86 -3.16(m,2H),2.55-2.85(m,2H),2.30-2.40(m,1H),1.35-2.20(m,10H). LC-MS(ESI,m / z):587[M+H] + LCMS (ESI, m / z): 587 [M+H] + .

[0436] To a mixture of (1S,3aR,6aS)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (140 mg, 0.239 mmol, 1.0 equiv) in ethanol (5 mL) was added 10% Pd / C (140 mg). The mixture was stirred at room temperature under an H atmosphere overnight. The mixture was filtered through a Celite pad and washed with ethanol (2 × 5 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:14; Rf = 0.4, detection: UV) to give (1S,3aR,6aS)-N-[(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (43.9 mg, 34%) as a white solid. 1 H NMR(400MHz,DMSO-d6,353K)δ11.22(s,1H),8.38(br,1H),7.29(s,1H),7.00-7.15 (m,2H),6.87(s,1H),6.49(d,J=7.6Hz,1H),4.50-4.70(m,1H),4.35-4.49(m,1H), 4.10-4.30 (m, 2H), 3.90-4.08 (m, 1H), 3.75-3.89 (m, 3H), 3.60-3.74 (m, 1H), 2.82-3.00 (m, signal under the HO peak), 2.60-2.80 (m, 2H), 2.30-2.43 (m, 1H), 1.45-2.00 (m, 10H). LCMS (ESI, m / z): 497 [M+H] + .

[0437] Example 29 compound 28

[0438] [ka]

[0439] Compound 28 was prepared similarly as described for compound 26, using (2S,4R)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid instead of (2S)-1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid. LCMS (ESI, m / z): 558 [M+H] + .

[0440] (2S,4R)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid: To a mixture of 1-tert-butyl 2-methyl(2S,4S)-4-ethenylpyrrolidine-1,2-dicarboxylate (Mulamreddy et al., J. Org. Chem. (2018) 83(21):13580-13586) (500 mg, 1.96 mmol, 1.0 equiv) in methanol (10 mL) was added Pd / C (200 mg). The mixture was stirred at room temperature under H2 for 4 hours. The mixture was filtered through a Celite pad and washed with methanol (2 x 5 mL). The filtrate was concentrated under reduced pressure to give crude 1-tert-butyl 2-methyl(2S,4R)-4-ethylpyrrolidine-1,2-dicarboxylate (500 mg, crude) as a pale yellow oil. LCMS(ESI,m / z):158[M-100+H] + .

[0441] To a mixture of 1-tert-butyl 2-methyl(2S,4R)-4-ethylpyrrolidine-1,2-dicarboxylate (500 mg, 1.94 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was added hydrogen chloride (5 mL, 6 M in water). The mixture was stirred at 80° C. for 2 hours and concentrated under reduced pressure to give (2S,4R)-4-ethylpyrrolidine-2-carboxylic acid (278 mg, crude) as a pale yellow oil. LCMS (ESI, m / z): 144 [M+H] + .

[0442] To a mixture of (2S,4R)-4-ethylpyrrolidine-2-carboxylic acid (278 mg, 1.942 mmol, 1.00 equiv.) in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (847 mg, 3.88 mmol, 2.0 equiv.) and triethylamine (589 mg, 5.83 mmol, 3.0 equiv.). The mixture was stirred overnight at room temperature and concentrated under reduced pressure to give (2S,4R)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid (470 mg, crude) as a pale yellow oil. LCMS (ESI, m / z): 188 [M-56+H] + .

[0443] Example 30 compound 29

[0444] [ka]

[0445] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopiperidin-3-yl]propanoate (960 mg, 3.2 mmol, 1.0 equivalent) in dichloromethane (12 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give methyl (2S)-2-amino-3-[(3S)-2-oxopiperidin-3-yl]propanoate (780 mg, 85%) as an orange oil. LCMS (ESI, m / z): 201 [M+H] + .

[0446] To a solution of (3S,6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (780 mg, 2.81 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.6 g, 4.22 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (2.18 g, 16.9 mmol, 6.0 equiv.). The mixture was stirred at 0° C. for 30 minutes. Methyl (2S)-2-amino-3-[(3S)-2-oxopiperidin-3-yl]propanoate (619.63 mg, 3.094 mmol, 1.1 equiv.) was added. The mixture was stirred at 0° C. for 1 hour, and the reaction was quenched with water (15 mL). The mixture was extracted with EA (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol:dichloromethane (1:22) to give tert-butyl (3S,6S)-1,1-difluoro-6-{[(2S)-1-methoxy-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamoyl}-5-azaspiro[2.4]heptane-5-carboxylate (1.07 g, 66%) as a yellow solid. LCMS (ESI, m / z): 460 [M+H] + .

[0447] To a solution of tert-butyl (3S,6S)-1,1-difluoro-6-{[(2S)-1-methoxy-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]carbamoyl}-5-azaspiro[2.4]heptane-5-carboxylate (1.07 g, 2.33 mmol, 1.0 equivalent) in dichloromethane (12 mL), trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give methyl (2S)-2-{[(3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-6-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propanoate (1.0 g, 83%) as an orange oil. LCMS(ESI,m / z):360[M+H] + .

[0448] To a solution of 4-methoxy-1H-indole-2-carboxylic acid (486 mg, 2.54 mmol, 1.1 equiv.) in N,N-dimethylformamide (12 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.32 mg, 3.47 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (1.79 mg, 13.9 mmol, 6.0 equiv.), and the mixture was stirred at 0° C. for 30 min. Methyl (2S)-2-{[(3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptan-6-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propanoate (830 mg, 2.31 mmol, 1.0 equiv.) was added. The mixture was stirred at 0° C. for 1 hour, and the reaction was quenched with water (15 mL). The mixture was extracted with EA (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol:dichloromethane (1:18) to give methyl (2S)-2-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propanoate (950 mg, 62%) as a yellow solid. LCMS (ESI, m / z): 533 [M+H] + .

[0449] To a solution of methyl (2S)-2-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propanoate (950 mg, 1.78 mmol, 1.0 equiv) in THF (10 mL) was added lithium borohydride (1.79 mL, 2 M in tetrahydrofuran, 3.57 mmol, 2.0 equiv) slowly at 0° C. The mixture was stirred at 0° C. for 1.5 hours. The reaction was quenched with water (8 mL), and the mixture was extracted with EA (3×15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol:dichloromethane (1:16) to give (3S,6S)-1,1-difluoro-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (700 mg, 70%) as a white solid. LCMS (ESI, m / z): 505 [M+H] + .

[0450] To a solution of (3S,6S)-1,1-difluoro-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (60 mg, 0.12 mmol, 1.0 equiv.) in dimethyl sulfoxide (2 mL) was added IBX (66.6 mg, 0.24 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight, and the reaction was quenched with sodium bicarbonate solution (2 mL). The resulting solution was extracted with EA (3 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by TLC using methanol:dichloromethane (1:18) to give (3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-N-(1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (14.6 mg, 24%) as a white solid. LCMS (ESI, m / z): 503 [M+H] + .

[0451] Example 31 compound 30

[0452] [ka]

[0453] Compound 30 was prepared similarly as described for compound 26, using (2S,4S)-1-(tert-butoxycarbonyl)-4-vinylpyrrolidine-2-carboxylic acid instead of (2S)-1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid. LCMS (ESI, m / z): 556 [M+H] + .

[0454] (2S,4S)-1-(tert-butoxycarbonyl)-4-vinylpyrrolidine-2-carboxylic acid: To a mixture of 1-tert-butyl 2-methyl(2S,4S)-4-ethenylpyrrolidine-1,2-dicarboxylate (Mulamreddy et al., J. Org. Chem. (2018) 83(21):13580-13586) (1.00 g, 3.92 mmol, 1.0 equiv) in 1,4-dioxane (5 mL), hydrogen chloride (5 mL, 6 M) was added at room temperature. The mixture was stirred at 80 °C for 3 h and concentrated under reduced pressure to remove 1,4-dioxane. The mixture was diluted with water (20 mL) and extracted with EA (3 × 20 mL). The aqueous layers were combined and concentrated under reduced pressure to give (2S,4S)-4-ethenylpyrrolidine-2-carboxylic acid (crude) as an off-white semi-solid. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 142 [M+H] + .

[0455] To a mixture of (2S,4S)-4-ethenylpyrrolidine-2-carboxylic acid (1.00 g, 7.08 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added triethylamine (2.15 g, 21.3 mmol, 3.0 equiv.) and di-tert-butyl dicarbonate (2.32 g, 10.6 mmol, 1.5 equiv.) at room temperature. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (50 mL). The mixture was extracted with EA (3 × 70 mL). The aqueous layers were combined and concentrated under reduced pressure to give (2S,4S)-1-(tert-butoxycarbonyl)-4-ethenylpyrrolidine-2-carboxylic acid (1.1 g, crude) as an off-white solid. LCMS (ESI, m / z): 186 [M+H-56] + .

[0456] Example 32 Compound 31A and Compound 31

[0457] [ka]

[0458] To a mixture of (3S)-3-[(2S)-2-amino-4-(benzyloxy)-3-oxobutyl]pyrrolidin-2-one hydrochloride (250 mg, 0.799 mmol, 1.0 equiv.) and (6S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (193 mg, 0.799 mmol, 1.0 equiv.) in N,N-dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (456 mg, 1.20 mmol, 1.5 equiv.) and N-ethyl-N-isopropylpropan-2-amine (310 mg, 2.40 mmol, 3.0 equiv.) at 0°C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:15; Rf = 0.4, detection: UV) to give the desired product, tert-butyl (6S)-6-{[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]carbamoyl}-5-azaspiro[2.4]heptane-5-carboxylate (200 mg, 46%), as a colorless semi-solid. LCMS (ESI, m / z): 500 [M+H] + .

[0459] A mixture of tert-butyl (6S)-6-{[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]carbamoyl}-5-azaspiro[2.4]heptane-5-carboxylate (140 mg, 0.280 mmol, 1.0 equiv) in hydrogen chloride (5 mL, 2 M in diethyl ether) at 0° C. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (6S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (122 mg, crude) as a white solid. LCMS(ESI,m / z):400[M+H] + .

[0460] (6S)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (122 mg, 0.280 mmol, 1.0 equiv.) and 4-methoxy-1H-indole-2-carboxylic acid (54.0 mg, 0.280 mmol, 1.0 equiv.) To a mixture of o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg, 0.420 mmol, 1.5 equiv.) and N-ethyl-N-isopropylpropan-2-amine (109 mg, 0.840 mmol, 3.0 equiv.) in N,N-dimethylformamide (3 mL) was added at 0°C. The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:14; Rf = 0.4, detection: UV) to give (6S)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (70 mg, 40%) as a pale yellow solid. LCMS (ESI, m / z): 573 [M+H] + .

[0461] To a mixture of (6S)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (65.0 mg, 0.114 mmol, 1.0 equiv) in ethanol (3 mL) was added Pd / C (65.0 mg). The mixture was stirred at room temperature under H2 overnight. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: X Bridge Prep Phenyl OBD column, 5 um, 19* Purification by HPLC (250 nm; water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20B to 40B in 7 min; 210 nm; RT: 6.35) afforded (6S)-N-[(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (10.5 mg, 19%) as a white solid. 1 H NMR(400MHz,353K,DMSO-d6)δ11.24(s,1H),8.30(br,1H),7.30(s,1H),7.00 -7.20(m,2H),6.86(s,1H),6.49(d,J=7.2Hz,1H),4.83(br,1H),4.35-4.55( m,1H),4.10-4.30(m,2H),3.72-3.92(m,5H),3.00-3.12(m,signal below H2O peak), 2.20-2.40(m,2H),1.80-2.15(m,3H),1.50-1.70(m,2H),0.50-0.70(m,4H). LCMS(ESI,m / z):483[M+H] + .

[0462] Example 33 compound 32

[0463] [ka]

[0464] Compound 32 was prepared similarly as described for compound 31, using (2S,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid instead of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. LCMS (ESI, m / z): 533 [M+H] + .

[0465] Example 34 compound 33

[0466] [ka]

[0467] Compound 33 was prepared according to the above synthetic scheme starting from compound 29.

[0468] An 8 mL vial was charged with (3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-N-(1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (150 mg, 0.30 mmol, 1.0 equiv.) in DCM (1 mL). (Isocyanomethyl)benzene (69.8 mg, 0.60 mmol, 2.0 equiv.) in dichloromethane (0.5 mL) was added dropwise at 0° C. Pyridine (94.3 mg, 1.19 mmol, 4.0 equiv.) in DCM (0.5 mL) was added dropwise at 0° C. Trifluoroacetic acid (102 mg, 0.89 mmol, 3.0 equiv) in DCM (1 mL) was added dropwise at 0° C. The reaction was stirred at 0° C. for 50 minutes and at room temperature for 5 hours. The reaction was concentrated under reduced pressure. The residue was purified by C18 column using MeCN:HO (0.05% TFA) (3:7) to give (3S)-N-benzyl-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (53 mg, 22%) as a white solid. LC-MS (ESI, m / z): 638 [M+H] + .

[0469] To a solution of (3S)-N-benzyl-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (50 mg, 0.08 mmol, 1.0 equiv.) in DMSO (2 mL) was added IBX (43.9 mg, 0.16 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 4 hours, and the reaction was quenched with sodium bicarbonate solution (2 mL). The solution was extracted with EA (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using MeOH / DCM (1 / 18) to give N-benzyl-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-oxo-4-[(3S)-2-oxopiperidin-3-yl]butanamide (11.9 mg, 23%) as a white solid. LCMS (ESI, m / z): 636 [M+H] + .

[0470] Example 35 compound 34

[0471] [ka]

[0472] Compound 34 was prepared similarly as described for compound 33, using 2-isocyanopropane instead of (isocyanomethyl)benzene. LCMS (ESI, m / z): 588 [M+H] + .

[0473] Example 36 compound 35

[0474] [ka]

[0475] Compound 35 was prepared similarly as described for compound 16, using (1S,3aR,6aS)-2-(1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid instead of (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid. LCMS (ESI, m / z): 571 [M+H] + .

[0476] Synthesis of (1S,3aR,6aS)-2-(1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid: To a solution of 1H-1,3-benzodiazole-2-carboxylic acid (295 mg, 1.82 mmol, 1.1 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (693 mg, 1.82 mmol, 1.1 equiv.) in N,N-dimethylformamide (6 mL) was added N-ethyl-N-isopropylpropan-2-amine (643 mg, 4.97 mmol, 3.0 equiv.) and stirred at room temperature for 30 minutes. Subsequently, tert-butyl (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate (500 mg, 1.65 mmol, 1.00 equiv.) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched with water (20 mL). The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (5 mL) and slurried with 100-200 mesh silica gel (2 g). After removing the dichloromethane, the slurry was loaded onto a column. The sample was purified by column chromatography (column size: 4 × 24 cm, column volume: 200 mL, amount of silica gel (100-200 mesh): 80 g) and eluted with EA:PE (0% to 40% over 30 min). The collected fractions: 18% EA:PE fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give tert-butyl (1S,3aR,6aS)-2-(1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylate (230 mg, 37%) as a colorless oil. LCMS (ESI, m / z): 356 [M+H] + .

[0477] To a solution of tert-butyl (1S,3aR,6aS)-2-(1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylate (190 mg, 0.535 mmol, 1.0 equiv.) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the crude product, (1S,3aR,6aS)-2-(1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (280 mg, crude), as a yellow oil. LCMS (ESI, m / z): 300 [M+H] + .

[0478] Example 37 compound 36

[0479] [ka]

[0480] To a mixture of 3-methoxybenzene-1,2-diamine (500 mg, 3.62 mmol, 1.0 equiv.) and methyl 2,2,2-trichloroethanimidate (830 mg, 4.70 mmol, 1.3 equiv.) in dichloromethane (10 mL) was added trifluoroacetic acid (1.03 g, 9.05 mmol, 2.5 equiv.). The mixture was stirred at room temperature under a N2 atmosphere for 2 hours. LCMS confirmed the product. LCMS (ESI, m / z): 265 [M+H] + .

[0481] To a mixture of 4-methoxy-2-(trichloromethyl)-1H-1,3-benzodiazole (956 mg, 3.60 mmol, 1.0 equiv) in dichloromethane (10 mL) was added aqueous sodium hydroxide (5 mL, 2 M in water). The mixture was concentrated under reduced pressure to remove dichloromethane, and methanol (5 mL) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 6 with HCl (2 M). Filtration afforded 4-methoxy-1H-1,3-benzodiazole-2-carboxylic acid (530 mg, 72%) as a pale yellow solid. LCMS (ESI, m / z): 193 [M+H] + .

[0482] To a mixture of 4-methoxy-1H-1,3-benzodiazole-2-carboxylic acid (500 mg, 2.60 mmol, 1.0 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.48 g, 3.90 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.35 g, 10.4 mmol, 4.0 equiv.) at 0 °C. After stirring for 15 min, (1S,3aR,6aS)-tert-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate (784 mg, 2.60 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL). The mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was diluted with dichloromethane (20 mL) and slurried with 100-200 mesh silica gel (1 g). After removing the dichloromethane, the mixture was loaded onto a column. The sample was purified by column chromatography (column size: 4 × 24 cm, column volume: 200 mL, amount of silica gel (100-200 mesh): 80 g) and eluted with EA:PE (0% to 50% over 30 min). The collected fractions were selected as pure fractions: 20% to 22% EA:PE fraction. These fractions were combined and concentrated under reduced pressure to give tert-butyl (1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylate (340 mg, 31%) as a yellow semi-solid. LCMS (ESI, m / z): 386 [M+H] + .

[0483] To a mixture of tert-butyl (1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylate (150 mg, 0.389 mmol, 1.0 equiv.) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give crude (1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (128 mg, crude) as a yellow semisolid. LCMS (ESI, m / z): 330 [M+H] + .

[0484] (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (128 mg, 0.390 mmol, 1.0 equiv.), (1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (129 mg, 0.3 To a mixture of o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (223 mg, 0.586 mmol, 1.5 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (223 mg, 0.586 mmol, 1.5 equiv.) in N,N-dimethylformamide (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (202 mg, 1.56 mmol, 4.0 equiv.). The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol: dichloromethane = 1:15; Rf = 0.3, detection: UV) to give (3S)-3-[[(1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (45 mg, 18%) as a pale yellow solid. LCMS (ESI, m / z): 603 [M+H] + .

[0485] To a mixture of (3S)-3-[[(1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (45.0 mg, 0.075 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added Dess-Martin periodinane (64.0 mg, 0.149 mmol, 2.0 equiv.) at 0° C. The mixture was stirred at room temperature for 4 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (1 mL) and saturated aqueous sodium thiosulfate (1 mL). ( The mixture was quenched with EA (3×2 mL). The mixture was stirred for 15 min. The mixture was then extracted with EA (3×2 mL). The organic layers were combined, washed with brine (2×2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (column: XBridge Prep Phenyl OBD column, 5 μm, 19 * Purification by HPLC (250 mm; mobile phase A: water (0.05% NH₃·HO), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35B to 45B in 7 min, 210 nm; RT: 6.35) afforded 3-[[(1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido]-N-benzyl-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (8.2 mg, 17%) as a white solid. LCMS (ESI, m / z): 601 [M+H] + .

[0486] Example 38 compound 37

[0487] [ka]

[0488] Compound 37 was prepared similarly as described for compound 27, using (1S,3aR,6aS)-2-(4-methoxy-1H-1,3-benzodiazole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid instead of (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid. LCMS (ESI, m / z): 498 [M+H] + .

[0489] Example 39 compound 38

[0490] [ka]

[0491] To (3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-N-[(2S)-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-5-azaspiro[2.4]heptane-6-carboxamide (60 mg, 0.12 mmol, 1.0 equiv) in DCM (1 mL) was added isocyanocyclopropane (16 mg, 0.24 mmol, 2.0 equiv) in DCM (0.5 mL) dropwise at 0° C. Acetic acid (21.5 mg, 0.36 mmol, 3.0 equiv) in DCM (0.5 mL) was added dropwise at 0° C. The reaction was stirred at 0° C. for 50 minutes and at room temperature for 5 hours. The mixture was concentrated under reduced pressure to give (2S)-1-(cyclopropylcarbamoyl)-2-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propyl acetate (60 mg, crude, 48%) as a yellow oil. LC-MS (ESI, m / z): 630 [M+H] + .

[0492] To a solution of (2S)-1-(cyclopropylcarbamoyl)-2-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propyl acetate (60 mg, 0.10 mmol, 1.0 equiv) in THF (2 mL) was added lithium hydride (4.56 mg, 0.19 mmol, 2.0 equiv) in water (2 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour, and the reaction was quenched with hydrochloric acid (2 mL, 2 mol / L). The resulting solution was extracted with EA (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol:dichloromethane (1:22) to give (3S)-N-cyclopropyl-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (40 mg, 66%) as a white solid. LC-MS (ESI, m / z): 588 [M+H] + .

[0493] To a solution of (3S)-N-cyclopropyl-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (40 mg, 0.07 mmol, 1.0 equiv.) in DMSO (2 mL) was added IBX (38.1 mg, 0.14 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 2 hours, and the reaction was quenched with sodium bicarbonate solution (2 mL). The resulting solution was extracted with EA (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using MeOH:DCM (1:18) to give N-cyclopropyl-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-oxo-4-[(3S)-2-oxopiperidin-3-yl]butanamide (14.6 mg, 35%) as a white solid. LC-MS (ESI, m / z): 586 [M+H] + .

[0494] Example 40 compound 39

[0495] [ka]

[0496] Compound 39 was prepared similarly as described for compound 31, using (3S,6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid instead of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. 1H NMR(400MHz,353K,DMSO-d6)δ11.32(s,1H),8.40-8.44(m,1H),7.30(s,1H),7.00-7 .18(m,2H),6.88(s,1H),6.50(d,J=6.8Hz,1H),4.95(br,1H),4.70-4.85(m,1H),4.4 0-4.55(m,1H),4.10-4.30(m,2H),4.02-4.09(m,1H),3.80-4.00(m,4H),3.05-3.15 (m,2H),2.50-2.70(m,1H),2.30-2.40(m,1H),1.85-2.10(m,3H),1.50-1.75(m,4H). LCMS(ESI,m / z):519[M+H] + .

[0497] (Example 41) Compound 40

[0498]

change

[0499] To a mixture of 1-tert-butyl 2-methyl(2S,4S)-4-ethenylpyrrolidine-1,2-dicarboxylate (Mulamreddy et al., J. Org. Chem. (2018) 83(21):13580-13586) in 1,4-dioxane (50 mL), hydrochloric acid (30 mL, 4 M in 1,4-dioxane) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and redissolved in dichloromethane (65 mL). Calcium carbonate (15.4 g, 111 mmol, 5.0 equiv) and silver nitrate (3.03 g, 17.8 mmol, 0.8 equiv) were added. The mixture was stirred at room temperature for 2 hours. Benzyl chloroformate (4.56 g, 26.7 mmol, 1.2 equiv) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered. The filtrate was washed with saturated aqueous sodium bicarbonate (60 mL) and brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by C18 column using CHCN:water (0.05% TFA), and the fractions were concentrated under reduced pressure to give 1-benzyl 2-methyl(2S,4S)-4-ethenylpyrrolidine-1,2-dicarboxylate (4.66 g, 54%) as a pale yellow oil. LCMS (ESI, m / z): 290 [M+H] + .

[0500] To a mixture of diethylzinc (69 mL, 69.1 mmol, 20.0 equiv., 1 M in hexanes) in dichloromethane (24 mL) was added dropwise a solution of trifluoroacetic acid (7.88 g, 69.1 mmol, 20.0 equiv.) in dichloromethane (16 mL) at 0 °C under N2. The mixture was stirred for 30 minutes at 0 °C. Diiodomethane (18.5 g, 69.1 mmol, 20.0 equiv.) in dichloromethane (16 mL) was added dropwise. After stirring for 30 minutes at 0 °C, a solution of 1-benzyl 2-methyl(2S,4S)-4-ethenylpyrrolidine-1,2-dicarboxylate (1 g, 3.46 mmol, 1.0 equiv.) in dichloromethane (40 mL) was added. The mixture was stirred at room temperature for 3 days. The reaction was quenched with saturated aqueous sodium bicarbonate (60 mL), and the mixture was extracted with dichloromethane (3 × 60 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified on a C18 column using CHCN:water (0.05% TFA), and the fractions were concentrated under reduced pressure to give 1-benzyl 2-methyl(2S,4S)-4-cyclopropylpyrrolidine-1,2-dicarboxylate (500 mg, 42%) as a pale yellow oil. 1 H NMR(300MHz,CDCl3-d)δ7.29-7.45(m,5H),5.03-5.28(m,2H),4.38-4.54(m,1H),3.56-3.87(m,4H),3.18-3 .34(m,1H),1.96-2.21(m,2H),1.62-1.84(m,1H),0.57-0.73(m,1H),0.42-0.54(m,2H),0.08-0.25(m,2H). LCMS(ESI,m / z):304[M+H] + .

[0501] To a mixture of 1-benzyl 2-methyl(2S,4S)-4-cyclopropylpyrrolidine-1,2-dicarboxylate (200 mg, 0.659 mmol, 1.0 equiv.) in 1,4-dioxane (3 mL) was added hydrogen chloride (3 mL, 6 M in water) at room temperature. The mixture was stirred at 80° C. for 1 hour and concentrated under reduced pressure to give (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclopropylpyrrolidine-2-carboxylic acid (190 mg, crude) as a yellow oil. LCMS (ESI, m / z): 290 [M+H] + .

[0502] To a mixture of (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (216 mg, 0.659 mmol, 1.0 equiv.) and (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclopropylpyrrolidine-2-carboxylic acid (190 mg, 0.659 mmol, 1.0 equiv.) in dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (376 mg, 0.989 mmol, 1.5 equiv.) and N-ethyl-N-isopropylpropan-2-amine (255 mg, 1.98 mmol, 3.0 equiv.) at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL), and the mixture was extracted with EA (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:15; Rf = 0.5, detection: UV) to give benzyl (2S,4S)-2-{[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-4-cyclopropylpyrrolidine-1-carboxylate (160 mg, 38%) as a pale yellow solid. LCMS (ESI, m / z): 563 [M+H] + .

[0503] To a mixture of benzyl (2S,4S)-2-{[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-4-cyclopropylpyrrolidine-1-carboxylate (115 mg, 0.204 mmol, 1.0 equiv) in EA (5 mL) was added Pd / C (120 mg). The mixture was stirred at room temperature under H2 overnight. The mixture was filtered through a Celite pad and washed with EA (3 x 5 mL). The filtrate was concentrated under reduced pressure to give (3S)-N-benzyl-3-{[(2S,4S)-4-cyclopropylpyrrolidin-2-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (80 mg, crude) as a yellow solid. LCMS(ESI,m / z):429[M+H] + .

[0504] To a mixture of (3S)-N-benzyl-3-{[(2S,4S)-4-cyclopropylpyrrolidin-2-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (80.0 mg, 0.187 mmol, 1.0 equiv.) and indole-2-carboxylic acid (30.0 mg, 0.187 mmol, 1.0 equiv.) in dimethylformamide (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (54.0 mg, 0.224 mmol, 1.2 equiv.) and N-ethyl-N-isopropylpropan-2-amine (60.0 mg, 0.468 mmol, 2.5 equiv.). The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:15; Rf = 0.4, detection: UV) to give (3S)-N-benzyl-3-{[(2S,4S)-4-cyclopropyl-1-(1H-indole-2-carbonyl)pyrrolidin-2-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (30 mg, 25%) as a pale yellow solid. LCMS (ESI, m / z): 572 [M+H] + .

[0505] To a mixture of (3S)-N-benzyl-3-{[(2S,4S)-4-cyclopropyl-1-(1H-indole-2-carbonyl)pyrrolidin-2-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (30.0 mg, 0.052 mmol, 1.0 equiv.) in dimethyl sulfoxide (1 mL) was added 2-iodoxybenzoic acid (29.0 mg, 0.104 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 6 hours, and the reaction was quenched with saturated aqueous sodium bicarbonate (3 mL). The mixture was extracted with EA (3 × 3 mL). The organic layers were combined, washed with brine (2 × 3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:14; Rf = 0.4, detection: UV) to give N-benzyl-3-{[(2S,4S)-4-cyclopropyl-1-(1H-indole-2-carbonyl)pyrrolidin-2-yl]formamide}-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (8.0 mg, 26%) as a white solid. LCMS (ESI, m / z): 570 [M+H] + .

[0506] Example 42 Compounds 41A and 41

[0507] [ka]

[0508] To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoate (3.00 g, 10.0 mmol, 1.0 equiv) in methanol (15 mL) was added aqueous sodium hydride (15 mL, 45.0 mmol, 4.0 equiv, 3 M in water). The mixture was stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure to remove methanol, and the pH was adjusted to 6 with HCl (2 M). The mixture was extracted with EA (3×30 mL). The organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoic acid (1.70 g, 60%) as a white solid. LC-MS(ESI,m / z):287[M+H] + .

[0509] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoic acid (1.70 g, 5.93 mmol, 1.0 equiv) in dichloromethane (25 mL) was added N,O-dimethylhydroxylamine hydrochloride (0.575 g, 5.93 mmol, 1.0 equiv), NMM (1.80 g, 17.8 mmol, 3.0 equiv), HOBt (0.800 g, 5.93 mmol, 1.0 equiv), and EDCI (1.25 g, 6.53 mmol, 1.1 equiv) at 0° C. The mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour. The reaction was quenched with water (20 mL). The organic layer was washed with HCl (2×20 mL, 1 M), water (20 mL), saturated aqueous sodium bicarbonate (2×20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate (1.29 g, 66%) as a pale yellow solid. LC-MS (ESI, m / z): 330 [M+H] + .

[0510] To a mixture of Mg (1.39 g, 57.3 mmol, 9.0 equiv.) and HgCl (1.04 g, 3.83 mmol, 0.6 equiv.) in tetrahydrofuran (50 mL) was added benzyl chloromethyl ether (8.99 g, 57.4 mmol, 9.0 equiv.) at −45° C. under a N atmosphere. The mixture was stirred at −45° C. to 5° C. for 5 hours. The mixture was recooled to −45° C., and tert-butyl ((S)-1-(methoxy(methyl)amino)-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate (2.10 g, 6.37 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature under a N atmosphere overnight. The reaction was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with EA (3 × 50 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (20 mL) and slurried with 100-200 mesh silica gel (5 g). After removing the dichloromethane, the slurry was loaded onto a column. The sample was purified by column chromatography (column size: 4 × 24 cm, column volume: 200 mL, amount of silica gel (100-200 mesh): 80 g) and eluted with methanol:dichloromethane (0%-5% over 20 min). The collected fractions: 3% to 4% methanol:dichloromethane fraction were selected as pure fractions, and these fractions were combined and concentrated under reduced pressure to give tert-butyl ((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)carbamate (700 mg, 28%) as a pale yellow oil. LC-MS (ESI, m / z): 391 [M+H] + .

[0511] To a mixture of tert-butyl ((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)carbamate (300 mg, 0.768 mmol, 1.0 equiv) in dioxane (3 mL) was added hydrogen chloride (3 mL, 4 M in 1,4-dioxane) at 0° C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (S)-3-((S)-2-amino-4-(benzyloxy)-3-oxobutyl)piperidin-2-one (250 mg, crude) as a yellow semi-solid. LC-MS (ESI, m / z): 291 [M+H] + .

[0512] To a mixture of (S)-3-((S)-2-amino-4-(benzyloxy)-3-oxobutyl)piperidin-2-one (250 mg, 0.861 mmol, 1.0 equiv), (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (310 mg, 0.947 mmol, 1.1 equiv), and TCFH (265 mg, 0.947 mmol, 1.1 equiv) in acetonitrile (6 mL) was added NMI (353 mg, 4.31 mmol, 5.0 equiv) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (3 mL) and extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (mobile phase: methanol: dichloromethane = 1:20; Rf = 0.4, detection: UV) to obtain (1S,3aR,6aS)-N-((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (95 mg, 18%) as a pale yellow oil. LC-MS (ESI, m / z): 601 [M+H] + .

[0513] To a mixture of (1S,3aR,6aS)-N-((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (90.0 mg, 0.150 mmol, 1.0 equiv) in ethanol (5 mL) was added palladium on carbon (90.0 mg). The mixture was stirred at room temperature under H2 overnight. The mixture was filtered through a pad of Celite and washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was washed with DMF (2 mL) and purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 19 * Purification by HPLC (250 mm, 5 μm; water (0.1% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30B to 52B in 7 min; 254 nm; RT1 (min): 5.70, 6.40) gave (1S,3aR,6aS)-N-[(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (11.0 mg, 14%) as a white solid.

[0514] Example 43 Compound 42A and Compound 42

[0515] [ka]

[0516] A 40 mL vial was charged with (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (164 mg, 0.682 mmol, 1.1 equiv.), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (259 mg, 0.682 mmol, 1.1 equiv.), N,N-diisopropylethylamine (240 mg, 1.86 mmol, 3.0 equiv.), and DMF (5 mL). The mixture was stirred at room temperature for 30 minutes. (S)-3-((S)-2-amino-4-(benzyloxy)-3-oxobutyl)piperidin-2-one (180 mg, 0.620 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The resulting solution was extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with DCM:MeOH (95:5) to give tert-butyl (S)-6-(((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (120 mg, 28%) as a yellow oil. LC-MS (ESI, m / z): 514 [M+H] + .

[0517] A 50 mL round-bottom flask was charged with tert-butyl (S)-6-(((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (100 mg, 0.195 mmol, 1.0 equiv.) and DCM (5 mL). HCl (5 mL, 2 M in ether) was added dropwise at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure at room temperature to give (S)-N-((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (100 mg, crude) as a yellow solid. LC-MS (ESI, m / z): 414 [M+H] + .

[0518] An 8 mL vial was charged with 4-methoxy-1H-indole-2-carboxylic acid (44.4 mg, 0.232 mmol, 1.2 equiv.), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (88.3 mg, 0.232 mmol, 1.2 equiv.), DMF (2.5 mL), and N,N-diisopropylethylamine (75.0 mg, 0.579 mmol, 3.0 equiv.) and stirred at room temperature for 30 min. (S)-N-((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (80 mg, 0.193 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The resulting solution was extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with DCM:MeOH (92:8) to give (S)-N-((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (110 mg, 87%) as a yellow solid. LC-MS (ESI, m / z): 587 [M+H] + .

[0519] An 8 mL vial was charged with (S)—N-((S)-4-(benzyloxy)-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (100 mg, 0.017 mmol, 1.0 equiv.), palladium on carbon (120 mg), and EtOH (5 mL). The contents of the flask were placed under an atmosphere of H2 (3 atm). The mixture was stirred at room temperature overnight. The solids were filtered off. The organic layer was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC using the following gradient conditions: Column: XBridge Prep OBD C18 column, 19 * 250 mm, 5 μm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 27B to 49B in 7 min; 254 nm; RT1 (min): 4.82. Purification afforded (S)-N-((S)-4-hydroxy-3-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (16.0 mg, 18%) as a white solid. 1 H NMR(400MHz,DMSO-d6,80℃)δ11.24(s,1H),8.31-8.47(m,1H),7.05-7.15(m,3H),6.87(s,1H), 6.50(d,J=7.6Hz,1H),4.82(br.s,1H),4.55-4.70(m,1H),4.46-4.52(m,1H),4.12-4.25(m,2H) ,3.88(s,3H),3.81-3.82(m,2H),3.05-3.15(m,partially signal under H2O peak),2.21-2.31(m,2H),2.07-2 .14(m,1H),1.84-1.88(m,2H),1.66-1.73(m,2H),1.35-1.60(m,2H),0.67(s,2H),0.57(s,2H). LC-MS(ESI,m / z):497[M+H] + .

[0520] Example 44 Compound 43A and Compound 43

[0521] [ka]

[0522] Compound 43A(LC-MS(ESI,m / z):587[M+H] + ) and compound 43 (LC-MS(ESI,m / z):497[M+H] + ) was prepared similarly as described for compounds 31A and 31, using (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid instead of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid.

[0523] Example 45 Compound 44A and Compound 44

[0524] [ka]

[0525] Compound 44A(LC-MS(ESI,m / z):601[M+H] + ) and compound 44 were prepared similarly as described for compounds 42A and 42, using (S)-6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid instead of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. Compound 44: 1H NMR(400MHz,DMSO-d6,80℃)δ11.31(s,1H),8.30(d,J=8.0Hz,1H),7.22(s,1H),7.06-7.13(m,2H),6.75-6.76(m,1 H),6.53(d,J=5.6Hz,1H),5.16-5.17(m,1H),4.62(br,1H),4.64-4.69(m,1H),4.45-4.48(m,1H),4.19-4.30(m,2) H),3.89(s,3H),3.44-3.51(m,1H),3.12-3.16(m,2H),2.22-2.33(m,1H),2.06-2.20(m,2H),1.55-1.99(m,2H),1 .69-1.82(m,3H),1.54-1.62(m,1H),1.42-1.51(m,1H),1.00-1.04(m,1H),0.47-0.50(m,1H),0.28-0.34(m,3H). LC-MS(ESI,m / z):511[M+H] + .

[0526] Example 46 Compound 45A and Compound 45

[0527] [ka]

[0528] Compounds 45A and 45 were prepared similarly as described for compounds 42A and 42, using (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid instead of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid.

[0529] Compound 45A: 1H NMR (400MHz, DMSO-d6, 80℃) δ11.34(s,1H),8.57(br,1H),7.26-7.36(m,5H),7.07-7.17(m,3H),6. 92(s,1H),6.53(d,J=7.2Hz,1H),4.90-5.10(m,1H),4.48-4.56(m,3H),4.24-4.36(m,2H),4.03-4 .19(m,1H),3.95-4.05(m,1H),3.90(s,3H),3.20-3.40(m,1H),3.05-3.15(m,2H),2.35-2.50(m,1 H),2.19-2.33(m,2H),2.08-2.18(m,1H),1.69-1.87(m,2H),1.55-1.68(m,1H),1.25-1.50(m,2H). LC-MS(ESI,m / z):629[M+H] + .

[0530] Compound 45: 1 H NMR (400MHz, DMSO-d6, 80℃) δ11.34(s,1H),8.53(br,1H),7.06-7.24(m,3H),6.92(s,1H),6.5 3(d,J=7.6Hz,1H),5.00(br,1H),4.75-4.85(m,1H),4.51-4.57(m,1H),4.15-4.22(m,3H),3.9 2-4.01 (m, 1H), 3.90 (s, 3H), 3.35 (br, 1H), 3.05-3.15 (m, partially under H2O scintillation), 2.45-2.47 (m, 1H), 2.22-2.23 (m, 2H), 2.08-2.16 (m, 1H), 1.71-1.90 (m, 2H), 1.62-1.63 (m, 1H), 1.34-1.51 (m, 2H). LC-MS (ESI, m / z): 539 [M+H] + .

[0531] (Example 47) Compound 46

[0532]

change

[0533] To a solution of (3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-N-[(2S)-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-5-azaspiro[2.4]heptane-6-carboxamide (80 mg, 0.16 mmol, 1.0 equiv) in MeOH (2 mL) was added CsF (12 mg, 0.08 mmol, 0.5 equiv) and trimethylsilyl cyanide (19 mg, 0.19 mmol, 1.2 equiv) at 0° C. The mixture was stirred at room temperature overnight, and the reaction was quenched with water (2 mL). The resulting solution was extracted with EA (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a C18 column with HO:MeCN (2:3) to give (3S,6S)-N-[(2S)-1-cyano-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (70 mg, 75%) as a white solid. LC-MS (ESI, m / z): 530 [M+H] + .

[0534] To a solution of (3S,6S)—N-[(2S)-1-cyano-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (60 mg, 0.11 mmol, 1.0 equiv) in MeOH (2 mL) was added lithium hydride (3.26 mg, 0.136 mmol, 1.2 equiv) and HO (38.5 mg, 1.13 mmol, 10 equiv). The mixture was stirred at room temperature for 2 hours, and the reaction was quenched with water (2 mL). The resulting solution was extracted with EA (3 × 4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with MeOH:DCM (1:25) to give (3S)-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (25 mg, 32%) as a white solid. LC-MS (ESI, m / z): 548 [M+H] + .

[0535] To a solution of (3S)-3-{[(3S,6S)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptan-6-yl]formamide}-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (10 mg, 0.02 mmol, 1.0 equiv.) in DMSO (1 mL) was added IBX (10.2 mg, 0.04 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 3 hours, and the reaction was quenched with sodium bicarbonate solution (2 mL). The resulting solution was extracted with EA (3 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using MeOH:DCM (1:18) to give (3S,6S)-N-(4-amino-3,4-dioxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (3.3 mg, 32%) as a white solid. LC-MS (ESI, m / z): 546 [M+H] + .

[0536] Example 48 Compounds 47A and 47

[0537] [ka]

[0538] To a mixture of (3S)-3-[(2S)-2-amino-4-(benzyloxy)-3-oxobutyl]piperidin-2-one hydrochloride (250 mg, 0.765 mmol, 1.0 equivalent) and (3S,6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (234 mg, 0.842 mmol, 1.1 equivalent) in DMF (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (436 mg, 1.15 mmol, 1.5 equivalent) and N-ethyl-N-isopropylpropan-2-amine (296 mg, 2.29 mmol, 3.0 equivalent). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:15; Rf = 0.6; detection: UV) to obtain tert-butyl (3S,6S)-6-{[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]carbamoyl}-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate (280 mg, 51%) as a yellow solid. LC-MS (ESI, m / z): 550 [M+H] + .

[0539] A mixture of tert-butyl (3S,6S)-6-{[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]carbamoyl}-1,1-difluoro-5-azaspiro[2.4]heptane-5-carboxylate (250 mg, 0.455 mmol, 1.0 equiv) in hydrogen chloride (3 mL, 2 M in EtO) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (3S,6S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (220 mg, crude) as a yellow solid. LC-MS (ESI, m / z): 450 [M+H] + .

[0540] 4-Methoxy-1H-indole-2-carboxylic acid (95.0 mg, 0.498 mmol, 1.1 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (258 mg, 0.679 mmol, 1.5 equiv.), and N-ethyl-N-isopropylpropan-2-amine (176 mg, 1.3 equiv.). To a mixture of (3S,6S)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (220 mg, 0.453 mmol, 1.0 equiv) in DMF (3 mL) was added at 0° C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3×5 mL). The organic layers were combined, washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM=1:15; Rf=0.4, detection: UV) to give (3S,6S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (140 mg, 44%) as a yellow solid.

[0541] Further purification of 40 mg of the above product by preparative HPLC (column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; water (0.1% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 51B to 71B in 7 min; 254 nm; Rt: 4.72) gave (3S,6S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (19.4 mg, 52%) as a white solid. 1H NMR(400MHz,DMSO-d6,80℃)δ11.34(s,1H),8.50-8.53(m,1H),7.25-7.40(m,5H), 7.00-7.24(m,3H),6.91(s,1H),6.53(d,J=7.6Hz,1H),4.90-5.05(m,1H),4.44-4. 60(m,3H),4.20-4.43(m,2H),4.05-4.19(m,1H),3.75-4.03(m,4H),3.05-3.15(m ,2H),2.55-2.65(m,1H),2.15-2.30(m,1H),1.95-2.14(m,2H),1.25-1.85(m,7H). LC-MS(ESI,m / z):623[M+H] + .

[0542] To a mixture of (3S,6S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-1,1-difluoro-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (100 mg, 0.161 mmol, 1.0 equiv.) in EtOH (3 mL) was added Pd / C (120 mg). The mixture was stirred at room temperature under a H atmosphere overnight. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 19 × 250 mm, 5 μm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25B to 50B in 7 min; 254 nm; RT: 6.65) to give (3S,6S)-1,1-difluoro-N-[(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspiro[2.4]heptane-6-carboxamide (49.7 mg, 56%) as a white solid. 1H NMR(400MHz,DMSO-d6,80℃)δ11.33(s,1H),8.35-8.50(m,1H),7.05-7.20(m,3H),6.90(s,1H),6.53(d,J= 7.6Hz,1H),4.85-5.05(m,1H),4.65-4.80(m,1H),4.45-4.60(m,1H),4.12-4.28(m,2H),4.02-4.10(m,1H) ,3.80-4.00(m,4H),3.05-3.15(m,2H),2.55-2.65(m,1H),2.20-2.30(m,1H),2.00-2.19(m,2H),1.80-1. 95(m,1H),1.65-1.75(m,2H),1.60-1.64(m,1H),1.50-1.59(m,1H),1.42-1.49(m,1H),1.25-1.40(m,1H). LC-MS(ESI,m / z):533[M+H] + .

[0543] Example 49 compound 48

[0544] [ka]

[0545] To a mixture of 1-benzyl 2-methyl(2S,4S)-4-cyclopropylpyrrolidine-1,2-dicarboxylate (500 mg, 1.65 mmol, 1.0 equiv) in EA (5 mL) was added Pd / C (300 mg). The mixture was stirred at room temperature under H2 overnight. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give methyl (2S,4S)-4-cyclopropylpyrrolidine-2-carboxylate (240 mg, crude) as a pale yellow oil. LC-MS (ESI, m / z): 170 [M+H] + .

[0546] To a mixture of methyl (2S,4S)-4-cyclopropylpyrrolidine-2-carboxylate (240 mg, 1.42 mmol, 1.0 equiv.) in DCM (5 mL) was added di-tert-butyl dicarbonate (619 mg, 2.84 mmol, 2.0 equiv.) and triethylamine (430 mg, 4.25 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give 1-tert-butyl 2-methyl(2S,4S)-4-cyclopropylpyrrolidine-1,2-dicarboxylate (380 mg, crude) as a colorless oil. LC-MS (ESI, m / z): 214 [M-56+H] + .

[0547] To a mixture of 1-tert-butyl 2-methyl(2S,4S)-4-cyclopropylpyrrolidine-1,2-dicarboxylate (380 mg, 1.41 mmol, 1.0 equiv) in EA (3 mL) / acetic acid (3 mL) was added PtO (256 mg, 1.13 mmol, 0.8 equiv). The mixture was stirred at room temperature under H overnight. The mixture was filtered through a Celite pad and washed with EA (2 × 5 mL). The filtrate was concentrated under reduced pressure to give 1-tert-butyl 2-methyl(2S,4S)-4-isopropylpyrrolidine-1,2-dicarboxylate (380 mg, crude) as a colorless oil. LC-MS (ESI, m / z): 272 [M+H] + .

[0548] To a mixture of 1-tert-butyl 2-methyl(2S,4S)-4-isopropylpyrrolidine-1,2-dicarboxylate (380 mg, 1.40 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) was added hydrochloric acid (2 mL, 6 M in water). The mixture was stirred at 80° C. for 2 hours and concentrated under reduced pressure to give (2S,4S)-4-isopropylpyrrolidine-2-carboxylic acid (220 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 158 [M+H] + .

[0549] To a mixture of (2S,4S)-4-isopropylpyrrolidine-2-carboxylic acid (220 mg, 1.40 mmol, 1.0 equiv.) in DCM (5 mL) was added di-tert-butyl dicarbonate (611 mg, 2.80 mmol, 2.0 equiv.) and triethylamine (425 mg, 4.20 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give (2S,4S)-1-(tert-butoxycarbonyl)-4-isopropylpyrrolidine-2-carboxylic acid (360 mg, crude) as an off-white semisolid. LC-MS (ESI, m / z): 202 [M-56+H] + .

[0550] To a mixture of (2S,4S)-1-(tert-butoxycarbonyl)-4-isopropylpyrrolidine-2-carboxylic acid (314 mg, 1.22 mmol, 1.0 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (696 mg, 1.83 mmol, 1.5 equiv.) and N-ethyl-N-isopropylpropan-2-amine (473 mg, 3.66 mmol, 3.0 equiv.) in DMF (6 mL) was added (3S)-3-amino-N-benzyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (400 mg, 1.22 mmol, 1.0 equiv.) at 0° C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with dichloromethane (10 mL). A slurry was made using 100-200 mesh silica gel (1 g) and loaded onto the column after removing the dichloromethane. The sample was purified by column chromatography (column size: 4 × 24 cm, column volume: 200 mL, amount of silica gel size (100-200 mesh): 80 g) and eluted with MeOH:DCM (0%-10% over 20 min). The collected fractions: 3%-4% MeOH:DCM fraction were selected as pure fractions, and these fractions were combined and concentrated under reduced pressure to give tert-butyl (2S,4S)-2-{[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-4-isopropylpyrrolidine-1-carboxylate (330 mg, 40%) as a yellow solid. LC-MS (ESI, m / z): 531 [M+H] + .

[0551] A mixture of tert-butyl (2S,4S)-2-{[(2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-4-isopropylpyrrolidine-1-carboxylate (320 mg, 0.603 mmol, 1.0 equiv.) in trifluoroacetic acid (2 mL):DCM (6 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (3S)-N-benzyl-2-hydroxy-3-{[(2S,4S)-4-isopropylpyrrolidin-2-yl]formamide}-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (260 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 431 [M+H] + .

[0552] To a mixture of indole-2-carboxylic acid (97.0 mg, 0.604 mmol, 1.0 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (344 mg, 0.906 mmol, 1.5 equiv.), and N-ethyl-N-isopropylpropan-2-amine (234 mg, 1.81 mmol, 3.0 equiv.) in DMF (5 mL) was added (3S)-N-benzyl-2-hydroxy-3-{[(2S,4S)-4-isopropylpyrrolidin-2-yl]formamide}-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (260 mg, 0.604 mmol, 1.0 equiv.) at 0°C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:15; Rf = 0.3, detection: UV) to give (3S)-N-benzyl-2-hydroxy-3-{[(2S,4S)-1-(1H-indole-2-carbonyl)-4-isopropylpyrrolidin-2-yl]formamide}-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (180 mg, 42%) as a yellow solid. LC-MS (ESI, m / z): 574 [M+H]+ .

[0553] To a mixture of (3S)-N-benzyl-2-hydroxy-3-{[(2S,4S)-1-(1H-indole-2-carbonyl)-4-isopropylpyrrolidin-2-yl]formamide}-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (160 mg, 0.279 mmol, 1.0 equiv.) in DMSO (5 mL) was added 2-iodoxybenzoic acid (156 mg, 0.558 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight, and the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:15; Rf = 0.3, detection: UV) to give N-benzyl-3-{[(2S,4S)-1-(1H-indole-2-carbonyl)-4-isopropylpyrrolidin-2-yl]formamide}-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (25.2 mg, 14%) as a white solid. LC-MS (ESI, m / z): 572 [M+H] + .

[0554] Example 50 Compound 49A and Compound 49

[0555] [ka]

[0556] To a mixture of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (215 mg, 0.842 mmol, 1.1 equiv), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (436 mg, 1.15 mmol, 1.5 equiv), and N-ethyl-N-isopropylpropan-2-amine (297 mg, 2.30 mmol, 3.0 equiv) in DMF (3 mL) was added (3S)-3-[(2S)-2-amino-4-(benzyloxy)-3-oxobutyl]piperidin-2-one hydrochloride (250 mg, 0.765 mmol, 1.0 equiv) at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL), and the mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: methanol:dichloromethane = 1:15; Rf = 0.6; detection: UV) to give tert-butyl (1R,2S,5S)-2-{[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (320 mg, 55%) as a yellow semi-solid. LC-MS (ESI, m / z): 528 [M+H] +tert-Butyl (1R,2S,5S)-2-{[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (220 mg, 0.417 mmol, 1.0 equiv.) in hydrogen chloride (3 mL, Et The resulting mixture (2M in 20) was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (1R,2S,5S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (200 mg, crude) as a yellow solid. LC-MS (ESI, m / z): 428 [M+H] + .

[0557] 4-Methoxy-1H-indole-2-carboxylic acid (91.0 mg, 0.474 mmol, 1.1 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (246 mg, 0.646 mmol, 1.5 equiv.), and N-ethyl-N-isopropylpropan-2-amine (167 mg, 1.29 mmol). To a mixture of (1R,2S,5S)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (200 mg, 0.431 mmol, 1.0 equiv) in DMF (3 mL) was added at 0° C. The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3 × 5 mL). The organic layers were combined, washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM=1:15; Rf=0.4, detection: UV) to give (1R,2S,5S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (180 mg, 64%) as a yellow solid.

[0558] 50 mg of the above product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 45B to 75B in 7 min at 254 nm; RT: 5.6) to give (1R,2S,5S)—N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (27.5 mg, 58%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.30-8.80(m,1H),7.22-7.42(m,5H),7.00-7.20(m,3H),6.75-6.99(m,1H),6.40-6.60(m,1H),4.1 0-4.95(m,7H),3.75-3.95(m,4H),3.05-3.20(m,2H),2.18-2.30(m,1H),2.05-2.17(m,1H),1.16-1.95(m,7H),1.08(s,3H),0.92(s,3H). LC-MS(ESI,m / z):601[M+H] + .

[0559] To a mixture of (1R,2S,5S)-N-[(2S)-4-(benzyloxy)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (130 mg, 0.216 mmol, 1.0 equiv.) in ethanol (3 mL) was added Pd / C (160 mg). The mixture was stirred at room temperature under hydrogen overnight. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; water (0.1% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25B to 50B in 7 min, 254 nm; RT: 6.87) to give (1R,2S,5S)-N-[(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl]-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (57.6 mg, 51%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.25-8.80(m,1H),6.75-7.30(m,4H),6.52(s,1H),4.70-5.00(m,1H),4.45-4.69(m,2H),4.05- 4.35(m,3H),3.75-3.95(m,4H),3.10-3.25(m,2H),2.18-2.30(m,1H),2.00-2.17(m,1H),1.15-1.99(m,7H),1.09(s,3H),0.92(s,3H). LC-MS(ESI,m / z):511[M+H] + .

[0560] (Example 51) Compound 50

[0561]

change

[0562] To a solution of benzothiazole (1.07 g, 7.93 mmol, 5.0 equiv.) in THF (10 mL) was added n-butyllithium (3.2 mL, 7.93 mmol, 5.0 equiv.) at −78° C. and stirred at −78° C. under nitrogen for 1 hour. To a solution of tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (500 mg, 1.59 mmol, 1.0 equiv.) in THF (5 mL) was added isopropylmagnesium chloride (1.6 mL, 3.17 mmol, 2.0 equiv., 2 M in THF) at −15° C. under nitrogen, and the mixture was stirred at −15° C. for 20 minutes. This mixture was added to the above solution, and the resulting mixture was stirred at −78° C. under nitrogen for 3 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL). The mixture was extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was diluted with DCM (30 mL) and slurried with 100-200 mesh silica gel (3 g), then loaded onto a column after removing the DCM. The sample was purified by column chromatography (column size 5 × 24 cm, column volume: 300 mL, amount of silica gel (100-200 mesh): 120 g) and eluted with MeOH:DCM (0%-10% over 15 min). The collected fractions: 9% MeOH / DCM fraction was selected as the pure fraction, and these fractions were combined and concentrated under reduced pressure to give tert-butyl N-[(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (457 mg 87% purity) as a yellow solid. LC-MS (ESI, m / z): 290 [M-100+H] + .

[0563] To a solution of tert-butyl N-[(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (427 mg, 1.10 mmol, 1.0 equiv.) in DCM (3 mL) was added hydrochloric acid (4.3 mL, 2 M in EtO). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (S)-3-((S)-2-amino-3-(benzo[d]thiazol-2-yl)-3-oxopropyl)pyrrolidin-2-one hydrochloride (400 mg crude). LC-MS (ESI, m / z): 290 [M+H] + .

[0564] To a mixture of (S)-3-((S)-2-amino-3-(benzo[d]thiazol-2-yl)-3-oxopropyl)pyrrolidin-2-one hydrochloride (400 mg crude) (317 mg, 1.10 mmol, 1.0 equiv) in DMF (4 mL) was added (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclohexyl methyl ester in DMF (4 mL). Penta[c]pyrrole-1-carboxylic acid (360 mg, 1.10 mmol, 1.0 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (584 mg, 1.53 mmol, 1.4 equiv.), and N-ethyl-N-isopropylpropan-2-amine (708 mg, 5.48 mmol, 5.0 equiv.) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The mixture was extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC (Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 60% B, 60% B in 10 min; Wavelength: 254 nm; RT (min): 8.87) to give (1S,3aR,6aS)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (57 mg, 8%) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ10.87-11.53(s,1H),8.45-9.11(br,1H),8.09-8.30(m,2H),7 .53-7.72(m,2H),7.20-7.50(s,1H),7.01-7.15(m,2H),6.80-7.00(m,1H),6.40-6.61( m,1H),5.29-5.62(m,1H),4.52-4.92(m,1H),3.80-4.10(m,1H),3.89(s,3H),3.58-3.7 2(m,1H),3.08-3.22(m,1H),2.85-3.01(m,1H),2.51-2.79(m,3H),1.40-2.25(m,10H). LC-MS(ESI,m / z):600[M+H] + .

[0565] (Example 52) Compound 51

[0566]

change

[0567] To a solution of (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (209 mg, 0.82 mmol, 1.1 equiv.) in DMF (5 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (425 mg, 1.12 mmol, 1.5 equiv.) and N-ethyl-N-isopropylpropan-2-amine (674 mg, 5.22 mmol, 7.0 equiv.). The mixture was stirred at 0°C for 30 minutes, and (3S)-3-amino-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (150 mg, 0.75 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL), and the resulting solution was extracted with EtOAc (3×35 mL). The organic layers were combined, washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using methanol:dichloromethane (9:91) to give tert-butyl (1R,2S,5S)-2-{[(2S)-1-carbamoyl-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 39%) as a pale yellow oil. LC-MS (ESI, m / z): 439 [M+H] + .

[0568] To a solution of tert-butyl (1R,2S,5S)-2-{[(2S)-1-carbamoyl-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 0.30 mmol, 1.0 equiv.) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (3S)-3-{[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-yl]formamido}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (130 mg, 91%) as a yellow oil. LC-MS(ESI,m / z):339[M+H] + .

[0569] To a solution of 4-methoxy-1H-indole-2-carboxylic acid (62 mg, 0.33 mmol, 1.1 equiv.) in DMF (5 mL), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (168 mg, 0.44 mmol, 1.5 equiv.) and N-ethyl-N-isopropylpropan-2-amine (267 mg, 2.07 mmol, 7.0 equiv.) were added. The mixture was stirred at 0° C. for 30 minutes. (3S)-3-{[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamido}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (100 mg, 0.30 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using MeOH:DCM (3:25) to give (3S)-2-hydroxy-3-{[(1R,2S,5S)-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide}-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (30 mg, 17%) as a pale yellow oil. LC-MS (ESI, m / z): 512 [M+H] + .

[0570] To a solution of (3S)-2-hydroxy-3-{[(1R,2S,5S)-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide}-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (30 mg, 0.06 mmol, 1.0 equiv.) in DMSO (2 mL) was added IBX (32.8 mg, 0.12 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 2 hours, and the reaction was quenched with sodium bicarbonate solution (2 mL). The solution was extracted with EtOAc (3 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using MeOH:DCM (1:9) to give (3S)-3-{[(1R,2S,5S)-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl]formamide}-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (0.8 mg, 3%) as a white solid. LC-MS (ESI, m / z): 510 [M+H] +

[0571] Example 53 compound 52

[0572] [ka]

[0573] (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (400 mg, 1.22 mmol, 1.0 equiv.) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (295 mg, 1.22 mmol, 1 equiv.) To a stirred solution of O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (594 mg, 1.56 mmol, 1.3 equiv.) in N,N-dimethylformamide (15 mL) was added O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (594 mg, 1.56 mmol, 1.3 equiv.) and N,N-diisopropylethylamine (621 mg, 4.81 mmol, 4.0 equiv.) in portions at room temperature. The mixture was stirred for 1 h at room temperature, and the reaction was quenched with water (30 mL) at room temperature. The mixture was extracted with EA (3 × 60 mL). The organic layers were combined, washed with brine (3 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol, 8:1) to give (3S)-3-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (320 mg, 46%) as a yellow solid. LC-MS (ESI, m / z): 552 [M+H] + .

[0574] To a stirred mixture of (3S)-3-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (300 mg, 0.540 mmol, 1.0 equiv) in dimethyl sulfoxide (10 mL) was added 2-iodoxybenzoic acid (457 mg, 1.63 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred at room temperature for 6 h, and the reaction was quenched with saturated sodium bicarbonate (5 mL). The mixture was diluted with water (15 mL) and extracted with EA (3 × 60 mL). The organic layers were combined, washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol, 8:1) to give 3-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-N-cyclopropyl-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (100.3 mg, 32%) as a white solid. LC-MS (ESI, m / z): 550 [M+H] + .

[0575] Example 54 Compound 53A and Compound 53

[0576] [ka]

[0577] To a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopiperidin-3-yl]propanoate (800 mg, 2.66 mmol, 1.0 equivalent) in DCM (10 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-3-[(3S)-2-oxopiperidin-3-yl]propanoate (533 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 201 [M+H] + .

[0578] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopiperidin-3-yl]propanoate (533 mg, 2.66 mmol, 1.0 equiv.), (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (874 mg, 2.66 mmol, 1.0 equiv.), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (971 mg, 3.46 mmol, 1.3 equiv.) in DMF (10 mL) was added N-methylimidazole (1.75 g, 21.3 mmol, 8.0 equiv.) at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was diluted with DCM (20 mL). A slurry was made using 100-200 mesh silica gel (2 g) and loaded onto the column after removing the dichloromethane. The sample was purified by column chromatography (column size 5 × 24 cm, column volume: 300 mL, amount of silica gel (100-200 mesh): 120 g) and eluted with MeOH:DCM (0%-8% over 20 min). The collected fractions: 3%-4% MeOH:DCM fraction were selected as pure fractions, and these fractions were combined and concentrated under reduced pressure to give methyl (2S)-2-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propanoate (870 mg, 60%) as a yellow solid. LC-MS (ESI, m / z): 511 [M+H] + .

[0579] To a mixture of methyl (2S)-2-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-3-[(3S)-2-oxopiperidin-3-yl]propanoate (800 mg, 1.57 mmol, 1.0 equiv) in THF (10 mL) was added lithium borohydride (2.35 mL, 4.70 mmol, 3.0 equiv, 2 M in THF) dropwise at 0° C. After stirring at 0° C. for 30 minutes, ethanol (5 mL) was added. The mixture was stirred at 0° C. for 2 hours. The reaction was quenched with potassium hydrogen sulfate (20 mL, 1 M in water). The mixture was extracted with DCM (3×20 mL). The organic layers were combined, dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM=1:15; Rf=0.3, detection: UV) to obtain (1S,3aR,6aS)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (420 mg, 51%) as an off-white solid. LC-MS (ESI, m / z): 483 [M+H] + .

[0580] To a mixture of (1S,3aR,6aS)-N-[(2S)-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (320 mg, 0.663 mmol, 1.0 equiv.) in DMSO (5 mL) was added 2-iodoxybenzoic acid (557 mg, 1.99 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (15 mL). The mixture was extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:15; Rf = 0.4, detection: UV) to give (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-N-[(2S)-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (53A, 130 mg, 39%) as a white solid. LC-MS (ESI, m / z): 481 [M+H] + .

[0581] To a mixture of (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-N-[(2S)-1-oxo-3-[(3S)-2-oxopiperidin-3-yl]propan-2-yl]-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (90 mg, 0.187 mmol, 1.0 equiv.) in ethanol (0.8 mL) / EtOAc (1.6 mL) was added a solution of NaHSO (26.0 mg, 0.244 mmol, 1.3 equiv.) in water (0.4 mL). The mixture was stirred at 50° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was triturated with EtOAc (2 mL) to give sodium (2S)-2-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamido}-1-hydroxy-3-[(3S)-2-oxopiperidin-3-yl]propane-1-sulfonate (37.8 mg, 33%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6, 353K)δ11.10-11.70(m,1H),7.25-8.05(m,1H),7.00-7.20(m,3H),6.70-6.99( m,1H),6.42-6.60(m,1H),4.80-5.50(m,1H),4.35-4.79(m,1H),4.25-4.34(m, 1H),4.08-4.24(m,1H),3.90-4.07(m,1H),3.79-3.89(m,3H),3.60-3.75(m,1H) ),2.88-3.10(m,2H),2.60-2.87(m,2H),2.05-2.30(m,2H),1.10-1.95(m,11H).

[0582] Example 55 compound 54

[0583] [ka]

[0584] To a solution of NaH (1.76 g, 60% in mineral oil, 44.1 mmol, 1.5 equiv) in THF (160 mL) was added imidazole (2 g, 29.4 mmol, 1.0 equiv) slowly at 0 °C under N2. The mixture was stirred at room temperature for 1 h, followed by the slow addition of [2-(chloromethoxy)ethyl]trimethylsilane (7.4 g, 44.1 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at room temperature overnight, and the reaction was quenched with water (100 mL). The solution was extracted with EtOAc (3 × 60 mL). The organic layers were combined, washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (3:7) to give 1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (4 g, 25%) as a pale yellow oil. LC-MS (ESI, m / z): 199 [M+H] + .

[0585] To a solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole (1.57 g, 7.93 mmol, 5.0 equiv.) in THF (10 mL) was added n-butyllithium (3.2 mL, 2.5 M in hexanes, 7.93 mmol, 5.0 equiv.) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. To a solution of tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (500 mg, 1.59 mmol, 1.0 equiv.) in THF (10 mL) was added i-PrMgCl (1.6 mL, 2 M in THF, 3.18 mmol, 2.0 equiv.) slowly at −15° C. under N2. The mixture was stirred at −15° C. for 20 minutes and added to the above solution at −78° C. The mixture was stirred at −78° C. for 3 hours, and the reaction was quenched with ammonium chloride (2 mL). The solution was extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using methanol:dichloromethane (3:97) to give tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)propan-2-yl]carbamate (294 mg, 37%) as a pale yellow oil. LC-MS (ESI, m / z): 453 [M+H] + .

[0586] To a solution of tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)propan-2-yl]carbamate (250 mg, 0.55 mmol, 1.0 equiv.) in dioxane was added hydrogen chloride (10 mL, 4 M in dioxane). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (3S)-3-[(2S)-2-amino-3-(1H-imidazol-2-yl)-3-oxopropyl]pyrrolidin-2-one (125 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 223 [M+H]+

[0587] To a solution of (3S)-3-[(2S)-2-amino-3-(1H-imidazol-2-yl)-3-oxopropyl]pyrrolidin-2-one (100 mg, 0.45 mmol, 1.0 equiv) in DMF (8 mL) was added (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (163 mg, 0.50 mmol, 1.1 equiv), N-ethyl-N-isopropylpropan-2-amine (407 mg, 3.15 mmol, 7.0 equiv), and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (222 mg, 0.59 mmol, 1.3 equiv). The mixture was stirred at room temperature for 2 hours, and the reaction was quenched with water (10 mL). The solution was extracted with EtOAc (3 × 15 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using methanol:dichloromethane (3:47) to give (1S,3aR,6aS)-N-[(2S)-1-(1H-imidazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide (8.4 mg, 3%) as a white solid. LC-MS (ESI, m / z): 533 [M+H] + .

[0588] Example 56 compound 55

[0589] [ka]

[0590] To a solution of (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (194 mg, 0.760 mmol, 1.0 equiv) and (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (250 mg, 0.760 mmol, 1.0 equiv) in DMF (15 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (405 mg, 1.06 mmol, 1.4 equiv) and N-ethyl-N-isopropylpropan-2-amine (491 mg, 3.80 mmol, 5.0 equiv) at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (30 mL) at room temperature. The mixture was extracted with EA (3 × 60 mL). The organic layers were combined, washed with brine (3 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by TLC (mobile phase: MeOH:DCM = 1:11; Rf = 0.5, detection: UV) to give (3S)-3-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (190 mg, 44%). LC-MS (ESI, m / z): 566 [M+H] + .

[0591] To a solution of (3S)-3-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopiperidin-3-yl]butanamide (170 mg, 0.301 mmol, 1.0 equiv) in DMSO (5 mL) was added 2-iodoxybenzoic acid (253 mg, 0.903 mmol, 3.0 equiv) with stirring at room temperature. The mixture was stirred at room temperature for 20 hours. The reaction was quenched with sodium bicarbonate solution (5 mL). The mixture was extracted with EA (4 × 40 mL). The organic layers were combined, washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by TLC (mobile phase: MeOH:DCM = 1:11; Rf = 0.6; detection: UV) to give 3-{[(1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-hexahydro-1H-cyclopenta[c]pyrrol-1-yl]formamide}-N-cyclopropyl-2-oxo-4-[(3S)-2-oxopiperidin-3-yl]butanamide (96.9 mg, 56%) as a white solid. LC-MS (ESI, m / z): 564 [M+H] + .

[0592] Example 57 compound 56

[0593] [ka]

[0594] To a solution of (1S,3aR,6aS)-2-{1-[(benzyloxy)carbonyl]-4-methoxyindole-2-carbonyl}-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxylic acid (253 mg, 0.55 mmol, 1.1 equiv.) in DMF (3 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (283 mg, 0.75 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (450 mg, 3.48 mmol, 7.0 equiv.). The mixture was stirred at 0 °C for 30 min. (3S)-3-Amino-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (100 mg, 0.50 mmol, 1.0 equiv) was added. The mixture was stirred at 0° C. for 1 hour, and the reaction was quenched with water (2 mL). The mixture was extracted with EtOAc (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with MeOH:DCM (1:25) to give benzyl 2-[(1S,3aR,6aS)-1-{[(2S)-1-carbamoyl-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-4-methoxyindole-1-carboxylate (105 mg, 33%) as a yellow solid. LC-MS (ESI, m / z): 646 [M+H] + .

[0595] To 2-[(1S,3aR,6aS)-1-{[(2S)-1-carbamoyl-1...

Claims

1. A compound of formula (I) having the structure: 【Chemistry 1】 During the ceremony, Z １ is -C(=O)- or -CH(CF ３ ) - and Z ２ is O, S or NR ８ In this case, R ８ is H or unsubstituted C １～４ is alkyl, Z ３ is N or C, Z ３ When is N, R ５ Instead, Ring A １ is selected from the group consisting of unsubstituted or substituted azetidine, unsubstituted or substituted pyrrolidine and unsubstituted or substituted piperidine, wherein the azetidine, pyrrolidine and piperidine are each independently selected from the group consisting of deuterium, halogen, unsubstituted or substituted C １～４ Alkyl, unsubstituted or substituted C ２～４ Alkenyl, unsubstituted or substituted C １～８ Alkoxy, unsubstituted or substituted C ３～６ Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted C １～４ one or more R independently selected from the group consisting of haloalkyl ｘ The azetidine, pyrrolidine and piperidine are optionally substituted with a monocyclic C ３～７ Cycloalkyl, Bicyclic C ５～９ Cycloalkyl, monocyclic C ３～７ Cycloalkenyl, bicyclic C ５～９ and phenyl, wherein the cyclic moiety is connected to the azetidine, pyrrolidine, and piperidine in a fused or spiro fashion, and is selected from the group consisting of halogen, unsubstituted C １～４ Alkyl, unsubstituted C ２～４ Alkenyl, and unsubstituted or substituted C ３～６ and optionally substituted with one or more moieties independently selected from the group consisting of monocyclic cycloalkyl; R １ is unsubstituted or substituted C ２～５ Alkynyl, unsubstituted or substituted ketoamide, -C(=O)CH ２ -O-((P=O)(OR １０ ) ２ ), -C(=O)CH ２ -O-C(R １１Ａ ) ２ -O-((P=O)(OR １１Ｂ ) ２ ), -C(=O)CH ２ -O-C(R １２Ａ ) ２ -OC(=O)-OR １２Ｂ and -C(=O)CH ２ -O-C(R １３Ａ ) ２ -OC(=O)-R １３Ｂ wherein each R １０ , each R １１Ｂ and R １２Ｂ and R １３Ｂ are independently hydrogen, unsubstituted C １～６ Alkyl, unsubstituted C ２～６ Alkenyl, unsubstituted C １～６ haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C １～４ alkyl), Each R １１Ａ , each R １２Ａ And each R １３Ａ are independently hydrogen or unsubstituted C １～４ is alkyl, R ２ is hydrogen, deuterium, or a halogen; R ３ is an unsubstituted or substituted C-amide (C １～４ alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C １～４ alkyl), unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C １～４ alkyl), unsubstituted or substituted bicyclic nitrogen-containing heteroaryl (C １～４ alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C １～４ alkyl), R ４ is hydrogen, deuterium, or a halogen; R ５ is hydrogen, deuterium, halogen, unsubstituted C １～６ Alkyl, and unsubstituted C １～４ haloalkyl; R ６ and R ７ is hydrogen, deuterium, halogen, unsubstituted or substituted C １～６ independently selected from the group consisting of alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, and unsubstituted or substituted sulfonyl; or R ６ and R ７ is R ６ and R ７ taken together with the carbon to which they are each attached to form an optionally substituted 4-9 membered saturated or unsaturated ring or ring system which may optionally contain 1 or 2 ring heteroatoms selected from the group consisting of O, N and S, or a pharma- ceutically acceptable salt thereof.

2. R １ The compound of claim 1 , wherein is an unsubstituted or substituted ketoamide.

3. R １ is -C(=O)CH ２ -O-((P=O)(OR １０ ) ２ ) wherein each R １０ are independently hydrogen, unsubstituted C １～６ Alkyl, unsubstituted C ２～６ Alkenyl, unsubstituted C １～６ haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C １～４ 2. The compound of claim 1, wherein

4. Z １ The compound according to any one of claims 1 to 3, wherein is -C(=O).

5. Ring A １ The compound according to any one of claims 1 to 4, wherein is unsubstituted or substituted pyrrolidine.

6. Ring A １ is an unsubstituted or substituted azetidine, said azetidine being a monocyclic C ３～７ Cycloalkyl, Bicyclic C ５～９ Cycloalkyl, monocyclic C ３～７ Cycloalkenyl, bicyclic C ５～９ a cyclic moiety connected to said azetidine in a fused or spiro fashion, selected from the group consisting of halogen, unsubstituted C １～４ Alkyl, and unsubstituted C ２～４ alkenyl, Ring A １ is unsubstituted or substituted pyrrolidine, said pyrrolidine being a monocyclic C ３～７ Cycloalkyl, Bicyclic C ５～９ Cycloalkyl, monocyclic C ３～７ Cycloalkenyl, bicyclic C ５～９ a cyclic moiety connected to said pyrrolidine in a fused or spiro fashion, selected from the group consisting of halogen, unsubstituted C １～４ Alkyl, and unsubstituted C ２～４ alkenyl, Ring A １ is an unsubstituted or substituted piperidine, said piperidine being a monocyclic C ３～７ Cycloalkyl, Bicyclic C ５～９ Cycloalkyl, monocyclic C ３～７ Cycloalkenyl, bicyclic C ５～９ a cyclic moiety connected to said piperidine in a fused or spiro fashion, selected from the group consisting of halogen, unsubstituted C １～４ Alkyl, and unsubstituted C ２～４ The compound of any one of claims 1 to 4, optionally substituted with one or more moieties independently selected from the group consisting of alkenyl.

7. Z ２ is NR ８ And Z ３ is CR ５ The compound according to any one of claims 1 to 6,

8. R ６ and R ７ is R ６ and R ７ are taken together with the carbons to which they are each attached to form an optionally substituted 4-7 membered unsaturated ring which may optionally contain 1 or 2 ring heteroatoms selected from the group consisting of O, N and S.

9. R ６ and R ７ is R ６ and R ７ 9. The compound of claim 8, wherein each of the carbons to which is attached forms an optionally substituted phenyl ring.

10. R ３ is unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C １～４ alkyl), or unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C １～４ The compound according to any one of claims 1 to 9, wherein

11. R ２ is hydrogen, R ４ The compound according to any one of claims 1 to 10, wherein is hydrogen.

12. The compound is 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 2. The compound of claim 1 selected from the group consisting of:

13. The compound is 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical Formula 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 2. The compound of claim 1 selected from the group consisting of:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof for treating a coronavirus infection.

15. The compound is an ACE inhibitor, an anticoagulant, an anti-inflammatory, an ARB, an ASO, a Covid-19 convalescent plasma, an entry inhibitor, a ２ 15. The pharmaceutical composition of claim 14, used in combination with an additional agent selected from the group consisting of pump antagonists, H-conducting channels, HIV protease inhibitors, HMG-CoA reductase inhibitors, immunoglobulins, immunosuppressants, immunotherapeutic agents, neuraminidase inhibitors, nucleoside inhibitors, nucleoside analog inhibitors, polymerase inhibitors, protease inhibitors, siRNA, statins, tissue plasminogen activator, antibiotics, antibacterial agents and vaccines.

16. 16. The pharmaceutical composition of claim 15, wherein the additional agent is selected from the group consisting of ascorbic acid, anakinra, azithromycin, baloxavir, baricitinib, chloroquine phosphate, colchicine, corticosteroids, epoprostenol, famotidine, favipiravir, IGIV, interferon, IVIG, ivermectin, gamma globulin, lopinavir, methylprednisolone, molnupiravir (MK-4482 or EIDD-2801), niclosamide, nitazoxanide, nitric oxide, oseltamivir, peramivir, RANTES, ribavirin, remdesivir, ruxolitinib, sarilumab, siltuximab, sirolimus, statins, tacrolimus, tocilizumab, umifenovir, and zanamivir.

17. A pharmaceutical composition for treating an infection comprising a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof, The pharmaceutical composition, wherein the infection is selected from the group consisting of a picornavirus infection and a norovirus infection.

18. 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, which selectively inhibits a coronavirus protease relative to a host protease.

19. 19. The pharmaceutical composition of claim 18, wherein the compound of formula (I) selectively inhibits the coronavirus protease over the host protease, which is cathepsin L.

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