Antiviral Compounds

Abstract

Provided herein are compounds of formula (I) or pharma- ceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds described herein (including pharma- ceutically acceptable salts of the compounds described herein), and methods of synthesizing the same.Also provided herein are methods of treating diseases and / or conditions with compounds of formula (I), or pharma- ceutically acceptable salts thereof. [Formula 1] TIFF2024525589000338.tif40128

Description

[Technical Field]

[0001] (Incorporation by reference of any priority application) For example, 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 U.S. Provisional Patent Application Nos. 63 / 203,135, filed July 9, 2021, 63 / 261,480, filed September 22, 2021, 63 / 264,212, filed November 17, 2021, 63 / 265,479, filed December 15, 2021, and 63 / 268,052, filed February 15, 2022, are incorporated by reference herein under 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 for synthesizing them. Also disclosed herein are methods for 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, muscle or joint pain, chills, nausea, vomiting, and diarrhea. In severe cases, symptoms may include difficulty walking, confusion, pale face or lips, cough, 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 the 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 can 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, including fully saturated (no double or triple bonds) hydrocarbon groups. The alkyl group can have 1 to 20 carbon atoms. (Whenever numerical ranges such as "1 to 20" appear herein, they refer to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms; this definition also extends to appearances of the term "alkyl" where no numerical range is specified.) The alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound may 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, C2~6 Alkynyl, 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 rings 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, heterocyclyl groups can 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 heterocycles 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, "cycloalkyl(alkyl)" refers to a cycloalkyl group bonded as a substituent via a lower alkylene group. The lower alkylene and cycloalkyl groups of the cycloalkyl(alkyl) may be substituted or unsubstituted. The cycloalkyl(alkyl) group may be unsubstituted or substituted.

[0032] 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).

[0033] 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.

[0034] "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).

[0035] 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." Furthermore, 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 (e.g.,

[0036] [ka] ).

[0037] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group where each X is a halogen.

[0048] 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).

[0049] As used herein, the term "amino" refers to the group --NH.sub.2.

[0050] As used herein, the term "hydroxy" refers to an --OH group.

[0051] A "cyano" group refers to a "-CN" group.

[0052] As used herein, the term "azido" refers to the group --N.sub.3.

[0053] An "isocyanato" group refers to a "-NCO" group.

[0054] A "thiocyanato" group refers to a "-SCN" group.

[0055] An "isothiocyanato" group refers to a "-NCS" group.

[0056] A "mercapto" group refers to a "-SH" group.

[0057] A "carbonyl" group refers to a -C(=O)- group.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] "Monosubstituted amine" is "-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.

[0067] "Disubstituted amine" is "-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.

[0068] The "ketoamide" group is defined as "-C(=O)-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). Ketoamides may be substituted or unsubstituted.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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).

[0077] 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.

[0078] 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.

[0079] compound Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0080] [ka] In the formula, ring A 1 teeth,

[0081] [ka] and ring A 1 is =O, =CH2, deuterium, halogen, hydroxy, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3~6 and R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 6 )2) and -C(=O)CH2-O-((P=O)(OR 7 ) 2) and each R 6 and each R 7 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 monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), or unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl). 4may be hydrogen, deuterium, or halogen; R 5 teeth

[0082] [ka] substituted monocyclic C 3~6 cycloalkyl or substituted 4- to 6-membered monocyclic heterocyclyl, R 8 and R 10 is unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 Cycloalkyl, unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl and unsubstituted monocyclic C 3~6 cycloalkyl(CH), where C 2~6 If the alkyl is substituted, C 2~6 Alkyl is selected from halogen, cyano, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted C 1~4 Alkoxy and unsubstituted C 1~4 substituted 1, 2, 3 or 4 times with substituents independently selected from haloalkoxy, or C 2~6 Alkyl is substituted 1 to 13 times with deuterium, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl and unsubstituted C1~4 and R 9 is unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~6 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~6 cycloalkyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted monocyclic heterocyclyl; 1~6 Alkyl is C 1~4 substituted monocyclic C 3~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl and Unsubstituted Monocyclic C 3~6 cycloalkyl; and 1~6 Haloalkyl is an unsubstituted C 1~4 substituted once or twice with alkoxy, R 11 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl, -(NH) m - optionally substituted 5-6 membered monocyclic heteroaryl, -O- optionally substituted C 1~6 alkyl, -O- optionally substituted C 3~8 cycloalkyl and -O- optionally substituted C 3~8 Cycloalkyl(C 1~4 alkyl), where m can be 0 or 1.

[0083] 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 1~4 alkyl), -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 can be unsubstituted and can be -C(=O)-N-sulfonamido.

[0084] R y1 , R y2 and R z1 can be a variety of groups. In some embodiments, R y1 , R y2 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 3~8cycloalkenyl), 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 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 1~4alkyl-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 3~6 Cycloalkyl), -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.

[0085] 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 z1 is 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).

[0086] Prodrug-type and phosphate-containing moieties are R 1 In some embodiments, R 1 may be -CH(OH)-(S(=O)-O-). In other embodiments, R 1 is -CH(OH)((P=O)(OR 6 )2), wherein each R 6 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 7 )2), wherein each R 7 are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 2~6Alkenyl, unsubstituted C 1~6 haloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aryl (C 1~4 alkyl). 6 and R 7 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.

[0087] In some embodiments, R 1 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.

[0088] As described herein, ring A 1 teeth

[0089] [ka] and ring A 1 In some embodiments, ring A 1 is a non-permutation

[0090] [ka] In other embodiments, ring A 1 is replaced

[0091] [ka] In yet another embodiment, ring A 1 is a non-permutation

[0092] [ka] In yet another embodiment, ring A 1 is replaced

[0093] [ka] In some embodiments, ring A 1 is a non-permutation

[0094] [ka] In other embodiments, ring A 1 is replaced

[0095] [ka] In yet another embodiment, ring A 1 is a non-permutation

[0096] [ka] In yet another embodiment, ring A 1 is replaced

[0097] [ka] In some embodiments, ring A 1 is a non-permutation

[0098] [ka] In other embodiments, ring A 1 is replaced

[0099] [ka] In yet another embodiment, ring A 1 is a non-permutation

[0100] [ka] In yet another embodiment, ring A 1 is replaced

[0101] [ka] In some embodiments, ring A 1 is a non-permutation

[0102] [ka] In other embodiments, ring A 1 is a substitution

[0103] [ka] In yet another embodiment, ring A 1 is a non-permutation

[0104] [ka] In yet another embodiment, ring A 1 is replaced

[0105] [ka] Those skilled in the art will recognize that ring A 1 the nitrogen shown in each of the ring structures for corresponds to the ring nitrogen shown in formula (I);

[0106] [ka] The carbon adjacent to the ring nitrogen having R 4 Understand that corresponds to the carbon atom to which it is bonded. For example, ring A 1 but

[0107] [ka] It will be appreciated by those skilled in the art that, when

[0108] [ka]

[0109] As provided herein, Ring A 1 is =O, =CH2, deuterium, halogen, hydroxy, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3~6 Ring A may be optionally substituted with one or more moieties independently selected from monocyclic cycloalkyl. 1 Examples of suitable substituents that may be present on are halogen (e.g., F or Cl), unsubstituted C 1~4 Alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl), unsubstituted C 1~4 haloalkyl (including -CF3, -CCl3-CHF2-C(CH3)F2, -CHCl2-CH2F, -CH(CH3)F, -CH2CF3-CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F and -CH2CH2CH2Cl), unsubstituted C 2~4 Alkenyl (such as ethenyl, propenyl, and butenyl) and unsubstituted or substituted C 3~6Includes monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). 1 is unsubstituted or substituted C 3~6 When substituted by monocyclic cycloalkyl, unsubstituted or substituted C 3~6 A monocyclic cycloalkyl can have one hydrogen replaced. In some embodiments, an unsubstituted or substituted C 3~6 Monocyclic cycloalkyl is an unsubstituted or substituted C 3~6 Monocyclic cycloalkyl is spiro-type on ring A 1 Ring A is bonded to 1 Two hydrogen atoms of ring A can be replaced. 1 Unsubstituted or substituted C replacing two hydrogens 3~6 Examples of monocyclic cycloalkyls include:

[0110] [ka] wherein each may be unsubstituted or substituted as described herein. 1 Examples include, but are not limited to:

[0111] [ka]

[0112] 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).

[0113] As provided herein, R 3 is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 In some embodiments, R3 is an unsubstituted monocyclic nitrogen-containing heteroaryl (C 1~4 In other embodiments, R 3 is a substituted monocyclic nitrogen-containing heteroaryl (C 1~4 In still other embodiments, R 3 is an unsubstituted bicyclic nitrogen-containing heterocyclyl (C 1~4 In still other embodiments, R 3 is a substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl). 3 is a bicyclic nitrogen-containing heterocyclyl (C 1~4 When R is an alkyl, the two rings of the bicyclic heterocyclyl can be connected in a fused (including bridged) or spiro fashion. 3 is an unsubstituted monocyclic nitrogen-containing heteroaryl (C 1~4 In other embodiments, R 3 is a substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl).

[0114] Those skilled in the art will understand that when two rings are connected in a spiro fashion, the two rings are connected by a single ring atom. For example, the structure

[0115] [ka] In the formula, rings C1 and C2 are connected in a spiro-type manner. When two rings described herein are connected in a fused manner, the two rings are linked by two or more ring atoms. In some cases, the two rings may be connected by two adjacent ring atoms. For example, rings D1 and D1 are connected in a fused manner by two adjacent ring atoms.

[0116] [ka] In some cases, the two rings described herein may be connected by more than two atoms shared between the two rings.

[0117] [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.

[0118] Monocyclic and bicyclic nitrogen-containing heterocyclyls (C 1~4 The number of ring atoms in an alkyl group can vary. Non-limiting examples include 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 heterocyclyl (C 1~4 alkyl) and 10-membered bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl). 3 Examples of groups include: azepan-2-one (C 1~4 alkyl), imidazolidin-2-one (C 1~4 alkyl), tetrahydropyrimidin-2-one (C 1~4 alkyl), pyrrolidin-2-one (C 1~4 alkyl), piperidin-2-one (C 1~4 alkyl), pyrazolidin-3-one (C 1~4 alkyl), oxazolidin-4-one (C 1~4 alkyl), 1,4-oxazepan-3-one (C 1~4 alkyl), morpholin-3-one (C 1~4 alkyl),

[0119] [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 can be deuterium, 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).

[0120] R 3 Non-limiting examples of moieties include:

[0121] [ka]

[0122] 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).

[0123] As provided herein, R 5 teeth

[0124] [ka] In some embodiments, R 9 is the unsubstituted C 1~6 It may also be haloalkyl. For example, R9 is -CF3-CClF 2. -CCl3-CHF2-C(CH3)F2, -CHCl2-CH2F, -CH(CH3)F, -CH2CF3, -CH(CH3)CF3-CH2CH2CF3-CH2CH(CH3)CF3-CF2CF3-CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F and -CH2CH2CH2Cl. In some embodiments, R 9 In other embodiments, R 9 is a substitution C 1~6 haloalkyl, where C 1~6 Haloalkyl is an unsubstituted C 1~4 It may be substituted once or twice with alkoxy. 1~6 One or two unsubstituted haloalkyl groups 1~4 When substituted with alkoxy, C 1~6 One or more hydrogens of a haloalkyl may be an unsubstituted C 1~4 It may be substituted with alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy). 1~4 Alkoxy-substituted C 1~6 Examples of haloalkyl include -C(OCH3)F2, -C(OCH3)Cl2, -CH(OCH3)F, -C(OCH3)(CH3)F, -CH(OCH3)CF3, -C(OCH3)(CH3)CF3, -CH2CH(OCH3)CF3, -CH2C(OCH3)(CH3)CF3, -CH(OCH3)Cl, -CH2CH(OCH3)F, -CH2CH(OCH3)Cl, -CH2CH2CH(OCH3)F, and -CH2CH2CH(OCH3)Cl. In yet other embodiments, R 9 is the unsubstituted C 1~6 It may be alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight or branched chain), and hexyl (straight or branched chain)). 9 is the unsubstituted C 1~4 C substituted once or twice with alkoxy 1~6 It can be alkyl.1~6 Alkyl is unsubstituted C 1~4 If substituted with alkoxy, C 1~6 The hydrogen of the alkyl is an unsubstituted C 1~4 Unsubstituted C can be substituted with alkoxy. 1~4 C substituted once or twice with alkoxy 1~6 A non-limiting list of alkyl includes -CH2(OCH3), -CH(OCH3)2, -CH(CH3)(OCH3), and -C(CH3)2(OCH3). In some embodiments, R 9 can be an unsubstituted or substituted monocyclic heteroaryl. A variety of unsubstituted or substituted monocyclic heteroaryls are included in R 9 For example, heteroaryl can be a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S). Exemplary heteroaryls of unsubstituted or substituted monocyclic heteroaryls include, but are not limited to, furan, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine, and pyrazine. In yet other embodiments, R 9 R can be unsubstituted or substituted monocyclic heterocyclyl. 9 A non-limiting list of monocyclic heterocyclyls for R include oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, and morpholine. 9 For example, the heteroaryl may be substituted with halogen, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl and unsubstituted C 1~6 and optionally substituted one, two or three times with a moiety selected from the group consisting of halogen, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl and unsubstituted C 1~6 Alkoxy is described herein.

[0125] In some embodiments, R9 is an unsubstituted monocyclic C cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl 3~6 In other embodiments, R 9 is a halogen-substituted monocyclic C 3~6 In yet other embodiments, R 9 is the unsubstituted C 1~4 Alkyl-substituted monocyclic C 3~6 In yet other embodiments, R 9 is the unsubstituted C 1~4 Alkoxy-substituted monocyclic C 3~6 In some embodiments, R 9 is the unsubstituted C 2~4 Alkenyl-substituted monocyclic C 3~6 In other embodiments, R 9 is the unsubstituted C 1~4 Haloalkyl-substituted monocyclic C 3~6 In yet other embodiments, R 9 is an unsubstituted monocyclic C such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl 3~6 Cycloalkyl-substituted monocyclic C 3~6 In some embodiments, R 9 is an unsubstituted bicyclic C 5~6 In other embodiments, R 9 is a substituted bicyclic C 5~6 It can be a cycloalkyl. 5~6 The two rings of a cycloalkyl can be connected in a spiro or fused fashion. 9 is a halogen-substituted bicyclic C 5~6 In yet other embodiments, R 9 is the unsubstituted C 1~4 Alkyl-substituted bicyclic C 5~6 In yet other embodiments, R 9 is the unsubstituted C 1~4 Alkoxy-substituted bicyclic C 5~6In some embodiments, R 9 is the unsubstituted C 2~4 Alkenyl-substituted bicyclic C 5~6 In other embodiments, R 9 is the unsubstituted C 1~4 Haloalkyl-substituted bicyclic C 5~6 In yet other embodiments, R 9 is an unsubstituted monocyclic C 3~6 Bicyclic C substituted with cycloalkyl (including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl) 5~6 It can be a cycloalkyl. 5~6 A non-limiting list of cycloalkyl includes spiro[2.2]pentane, spiro[2.3]hexane, bicyclo[1.1.1]pentane, and bicyclo[2.1.1]hexane.

[0126] Suitable halogen-substituted monocyclic C 3~6 Cycloalkyl includes halogen-substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl, and halogen-substituted cyclohexyl. Additional monocyclic C 3~6 Cycloalkyl includes unsubstituted C 1~4 Alkyl-substituted cyclopropyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 2~4 Alkenyl, unsubstituted C 1~4 Haloalkyl and / or unsubstituted monocyclic C 3~6 Cycloalkyl, unsubstituted C 1~4 Alkyl-substituted cyclobutyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 2~4 Alkenyl, unsubstituted C 1~4 Haloalkyl and / or unsubstituted monocyclic C 3~6 Cycloalkyl, unsubstituted C 1~4 Alkyl-substituted cyclopentyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 2~4 Alkenyl, unsubstituted C 1~4 Haloalkyl and / or unsubstituted monocyclic C 3~6 Cycloalkyl and unsubstituted C1~4 Alkyl-substituted cyclohexyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 2~4 Alkenyl, unsubstituted C 1~4 Haloalkyl and / or unsubstituted monocyclic C 3~6 Cycloalkyl. Halogen-substituted monocyclic C 3~6 Cycloalkyl and / or bicyclic C 5~6 Number of halogens on cycloalkyl, monocyclic C 3~6 Cycloalkyl and / or bicyclic C 5~6 Unsubstituted C on cycloalkyl 1~4 Number of alkyl groups above, monocyclic C 3~6 Cycloalkyl and / or bicyclic C 5~6 Unsubstituted C on cycloalkyl 1~4 Number of alkoxy groups, monocyclic C 3~6 Cycloalkyl and / or bicyclic C 5~6 Unsubstituted C on cycloalkyl 2~4 Number of alkenyls, monocyclic C 3~6 Cycloalkyl and / or bicyclic C 5~6 Unsubstituted C on cycloalkyl 1~4 The number of haloalkyls and monocyclic C 3~6 Cycloalkyl and / or bicyclic C 5~6 Unsubstituted monocyclic C on cycloalkyl 3~6 The number of cycloalkyls can vary. For example, 1, 2, 3, or 4 halogens can be used to form a halogen-substituted monocyclic C 3~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 1~4 Alkyl is an unsubstituted C 1~4 Alkyl-substituted monocyclic C 3~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 1~4 Alkoxy is an unsubstituted C 1~4 Alkoxy-substituted monocyclic C 3~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 2~4 Alkenyl is an unsubstituted C 2~4 Alkenyl-substituted monocyclic C 3~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 1~4 Haloalkyl is an unsubstituted C1~4 Haloalkyl-substituted monocyclic C 3~6 cycloalkyl, and 1 or 2 unsubstituted monocyclic C 3~6 Cycloalkyl is a monocyclic C 3~6 cycloalkyl, and 1, 2, 3 or 4 halogens may be present on the cycloalkyl; 5~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 1~4 Alkyl is an unsubstituted C 1~4 Alkyl-substituted bicyclic C 5~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 1~4 Alkoxy is an unsubstituted C 2~4 Alkoxy-substituted bicyclic C 5~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 2~4 Alkenyl is an unsubstituted C 2~4 Alkenyl-substituted bicyclic C 5~6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C 1~4 Haloalkyl is an unsubstituted C 1~4 Haloalkyl-substituted bicyclic C 5~6 cycloalkyl, and 1 or 2 unsubstituted monocyclic C 3~6 Cycloalkyl is a bicyclic C 5~6 In some embodiments, a monocyclic C 3~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 2~4 Alkenyl and unsubstituted C 1~4 In another embodiment, the bicyclic C 5~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Alkoxy, unsubstituted C 2~4 Alkenyl and unsubstituted C 1~4 and haloalkyl. 3~6Suitable halogens that may be present on the cycloalkyl include, but are not limited to, fluoro (F) and chloro (Cl). 1~4 Haloalkyl includes, but is not limited to, -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F and -CH2CH2CH2Cl.

[0127] In some embodiments, R 5 teeth,

[0128] [ka] R 10 are independently unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 cycloalkyl and unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl; C 2~6 If alkyl is substituted, C 2~6 Alkyl is halogen and unsubstituted C 1~4 and may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy; 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, unsubstituted C1~4 Haloalkyl and unsubstituted C 1~4 and R 11 is -(NH) m -, where m can be 0 or 1. In some embodiments, R 11 R can be an optionally substituted monocyclic 4- to 6-membered heterocyclyl. 11 Examples of heterocyclyl for R include optionally substituted 4- to 6-membered monocyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N (nitrogen), O (oxygen), and S (sulfur). 11 A non-limiting list of heterocyclyls for include azetidine, pyrrolidine, and piperidine. In other embodiments, m can be 0 and R 11 In other embodiments, m can be 0 and R 11 In yet other embodiments, m can be 1 and R 11 In other embodiments, m can be 1 and R 11 R can be a 5-6 membered monocyclic heteroaryl substituted with -(NH)-. 11 Examples of 5- to 6-membered monocyclic heteroaryls that may be present for include 5- to 6-membered monocyclic heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N (nitrogen), O (oxygen), and S (sulfur). Examples of suitable 5- to 6-membered monocyclic heteroaryls include, but are not limited to, imidazole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole. In yet another embodiment, R 11 is an optionally substituted C of -O- 1~6 In yet other embodiments, R 11 is an optionally substituted C of -O- 3~8 In some embodiments, R11 is an optionally substituted C of -O- 3~8 Cycloalkyl(C 1~4 alkyl). 3~8 cycloalkyl and -O- optionally substituted C 3~8 Cycloalkyl(C 1~4 The cycloalkyl of alkyl) is a monocyclic C 3~6 Cycloalkyl or bicyclic C 5~8 The C of an optionally substituted cycloalkyl of -O- can be cycloalkyl. 1~4 Alkyl (C 1~4 alkyl) can be -CH-, -CHCH-, -CHCHCH-, or -CHCHCHCHCH-. As described herein, R 11 R can be substituted. 11 Exemplary groups that may be present on include halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Alkoxy and unsubstituted C 1~4 Haloalkyl is an example.

[0129] R 8 and / or R 10 The part is C 2~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 The cycloalkyl or monocyclic 4-6 membered heterocyclyl may be substituted or unsubstituted. In some embodiments, R 8 and / or R 10 is the unsubstituted C 2~6 In other embodiments, R 8 and / or R 10 is a substitution C 2~6 It can be alkyl. Exemplary C 2~6 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear and branched), and hexyl (linear and branched). In some embodiments, R 8 and / or R10 is the unsubstituted C 2~6 In other embodiments, R 8 and / or R 10 is a substitution C 2~6 In yet other embodiments, R 8 and / or R 10 is the unsubstituted C 2~6 In yet other embodiments, R 8 and / or R 10 is a substitution C 2~6 It may be alkynyl.

[0130] Cyclic moieties, including monocyclic and bicyclic moieties, are also included in R 8 and / or R 10 In some embodiments, R 8 and / or R 10 is an unsubstituted monocyclic C 3~6 In some embodiments, R 8 and / or R 10 is a substituted monocyclic C 3~6 For example, R 8 and / or R 10 can be substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. 8 and / or R 10 is an unsubstituted bicyclic C 5~8 In other embodiments, R 8 and / or R 10 is an unsubstituted bicyclic C 5~8 It can be a cycloalkyl. 5~8 The two rings of a cycloalkyl can be fused or spiro-connected. Examples of fused and spiro-connected rings are provided herein. In some embodiments, R 8 and / or R 10 can be unsubstituted or substituted bicyclo[1.1.1]pentyl. In yet other embodiments, R 8 and / or R 10can be an unsubstituted monocyclic 4-6 membered heterocyclyl. 8 and / or R 10 R can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl. 8 and / or R 10 The number of heteroatoms present in the monocyclic 4-6 membered heterocyclyl for can vary. Suitable heteroatoms include, but are not limited to, O (oxygen), S (sulfur), and N (nitrogen). Examples of monocyclic 4-6 membered heterocyclyls are oxetane, thietane, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, and piperidine (including unsubstituted or substituted forms of each of the foregoing). In some embodiments, R 8 and / or R 10 is an unsubstituted monocyclic C 3~6 It can be cycloalkyl(CH2)-. Various monocyclic C 3~6 Cycloalkyl is described herein. Examples include R 8 and / or R 10 may be selected from cyclopropyl(CH2)-, cyclobutyl(CH2)-, cyclopentyl(CH2)-, and cyclohexyl(CH2)-.

[0131] As described herein, R 8 and / or R 10 may be substituted. In some embodiments, R 8 and / or R 10 is substituted C 2~6 If it is alkyl, C 2~6 Alkyl is selected from halogen, cyano, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted C 1~4 Alkoxy and unsubstituted C 1~4 In some embodiments, R 8 and / or R 10 is C substituted 1 to 13 times with deuterium. 2~6 In some embodiments, R 8and / or R 10 is C substituted 1-9 times with deuterium, 1-6 times with deuterium, 1-5 times with deuterium, or 1-3 times with deuterium 2~6 Each halogen may independently be F (fluoro) or Cl (chloro). 8 and / or R 10 Substitution for C 2~6 Exemplary unsubstituted and substituted monocyclic C groups that may be present on the alkyl 3~6 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and halogen-substituted monocyclic C 3~6 Cycloalkyl is an example of R 8 and / or R 10 C 2~6 Suitable unsubstituted C that can be substituted on the alkyl 1~4 Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. R 8 and / or R 10 C 2~6 Unsubstituted C which may be substituted on the alkyl 1~4 Examples of haloalkoxy include -OCl, -OCF, -OCHCl, -OCHF, -OCHCl, and -OCHF. In some embodiments, R 8 and / or R 10 But substitution C 2~6 Alkenyl, substituted C 2~6 Alkynyl, substituted monocyclic C 3~6 Cycloalkyl, substituted bicyclic C 5~8 When cycloalkyl or substituted monocyclic 4-6 membered heterocyclyl, each of the above may be selected from halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl and unsubstituted C 1~4 The substituents may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy. 2~6 Alkenyl, substituted C 2~6 Alkynyl, substituted monocyclic C3~6 Cycloalkyl, substituted bicyclic C 5~8 Unsubstituted C, which may be substituted on cycloalkyl or substituted monocyclic 4-6 membered heterocyclyl 1~4 Alkyl, unsubstituted C 2~4 Alkenyl and unsubstituted C 2~4 Examples of alkynyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. 2~6 Alkenyl, substituted C 2~6 Alkynyl, substituted monocyclic C 3~6 Cycloalkyl, substituted bicyclic C 5~8 Suitable halogens and unsubstituted C that may be present on the cycloalkyl or substituted monocyclic 4- to 6-membered heterocyclyl 1~4 Alkoxy is described herein, including in this paragraph. 3~6 A non-limiting list of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and halogen-substituted monocyclic C 3~6 Cycloalkyl is included. 2~6 Alkenyl, substituted C 2~6 Alkynyl, substituted monocyclic C 3~6 Cycloalkyl, substituted bicyclic C 5~8 Unsubstituted C that may be present on cycloalkyl or substituted monocyclic 4- to 6-membered heterocyclyl 1~6 Examples of haloalkyl include, but are not limited to, -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F and -CH2CH2CH2Cl.

[0132] Illustrative R 5 Groups include:

[0133] [ka]

[0134] [ka]

[0135] As described herein, in some embodiments, R 5 is a substituted monocyclic C such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl 3~6 In some embodiments, R 5 can be a substituted 4- to 6-membered monocyclic heterocyclyl. For example, R 5 may be a substituted 4-6 membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms selected from N (nitrogen), O (oxygen) and S (sulfur). 3~6 Cycloalkyl and / or substituted 4-6 membered monocyclic heterocyclyl may be substituted with deuterium, halogen, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl and unsubstituted C 1~6 It may be substituted one, two or three times with a moiety selected from alkoxy.

[0136] Furthermore, R 5 is a monocyclic C 3~6 When it is cycloalkyl or 4- to 6-membered monocyclic heterocyclyl, it is a monocyclic C 3~6 The cycloalkyl or 4- to 6-membered monocyclic heterocyclyl may be substituted in a spiro fashion by an unsubstituted or substituted bicyclic cycloalkenyl or an unsubstituted or substituted bicyclic heterocyclyl. The bicyclic cycloalkenyl may be an unsubstituted or substituted 8- to 10-membered bicyclic cycloalkenyl. The unsubstituted or substituted bicyclic heterocyclyl may be an unsubstituted or substituted 8- to 10-membered bicyclic heterocyclyl, for example, an unsubstituted or substituted 8- to 10-membered bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms selected from N (nitrogen), O (oxygen), and S (sulfur) in the ring. In some embodiments, the bicyclic cycloalkenyl and / or bicyclic heterocyclyl may be substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~6haloalkyl (e.g., -CF3, -CCl3, -CHF2, -C(CH3)F2, -CHCl2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2Cl, -CH2CH2F, -CH2CH2Cl, -CH2CH2CH2F, -CH2CH2CH2Cl) and unsubstituted C 1~4 and a monocyclic C substituted in a spiro fashion by an unsubstituted or substituted bicyclic cycloalkenyl or an unsubstituted or substituted bicyclic heterocyclyl. 3~6 R as cycloalkyl or 4-6 membered monocyclic heterocyclyl 5 Examples of include:

[0137] [ka]

[0138] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a ring A 1 but

[0139] [ka] and ring A 1 But halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3-6 and R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 6 )2) and -C(=O)CH2-O-((P=O)(OR 7 ) 2) and each R 6 and each R 7 are independently hydrogen, unsubstituted C 1~6Alkyl, 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 unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (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

[0140] [ka] and R 8 is unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 cycloalkyl and unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl, wherein C 2~6 If alkyl is substituted, C 2~6 Alkyl is halogen and unsubstituted C 1~4 may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4alkoxy; R 9 is the unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl and unsubstituted or substituted monocyclic C 3~6 cycloalkyl, and substituted monocyclic C 3~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 It is substituted 1, 2, 3 or 4 times with substituents independently selected from haloalkyl.

[0141] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a ring A 1 but

[0142] [ka] and ring A 1 But halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3~6 and R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 6 )2) and -C(=O)CH2-O-((P=O)(OR 7 ) 2) and each R 6 and each R 7 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 3is unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (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,

[0143] [ka] substituted monocyclic C 3~6 cycloalkyl or substituted 4- to 6-membered monocyclic heterocyclyl, R 8 is unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 cycloalkyl and unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl, wherein C 2~6 If alkyl is substituted, C 2~6 Alkyl is halogen and unsubstituted C 1~4 may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl and unsubstituted C 1~4 alkoxy; R 9 is unsubstituted or substituted C 1~6 Alkyl, unsubstituted C 1~6Haloalkyl, unsubstituted or substituted monocyclic C 3~6 cycloalkyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted monocyclic heterocyclyl; 3~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 It is substituted 1, 2, 3 or 4 times with substituents independently selected from haloalkyl.

[0144] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a ring A 1 but

[0145] [ka] and ring A 1 Deuterium, halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3~6 and R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 6 )2) and -C(=O)CH2-O-((P=O)(OR 7 ) 2) and each R 6 and each R 7 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 monocyclic nitrogen-containing heterocyclyl (C 1~4alkyl), unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), and R 4 can be hydrogen, deuterium or halogen, R 5 but

[0146] [ka] and R 10 is unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 cycloalkyl and unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl, wherein C 2~6 If alkyl is substituted, C 2~6 Alkyl is halogen and unsubstituted C 1~4 may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, unsubstituted C 1~4 Haloalkyl and unsubstituted C 1~4 and R 11 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl, -(NH) m- optionally substituted 5-6 membered monocyclic heteroaryl, -O- optionally substituted C 1~6 alkyl, -O- optionally substituted C 3~8 cycloalkyl and -O- optionally substituted C 3~8 Cycloalkyl(C 1~4 alkyl), where m can be 0 or 1.

[0147] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a ring A 1 but

[0148] [ka] and ring A 1 Deuterium, halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3~6 and R 1 is cyano, unsubstituted or substituted C 2~5 Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 6 )2) and -C(=O)CH2-O-((P=O)(OR 7 ) 2) and each R 6 and each R 7 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 monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4alkyl), or unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), and R 4 may be hydrogen, deuterium, or halogen; R 5 but,

[0149] [ka] substituted monocyclic C 3~6 cycloalkyl or substituted 4- to 6-membered monocyclic heterocyclyl, R 8 and R 10 is unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 cycloalkyl and unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl; C 2~6 If the alkyl is substituted, C 2~6 Alkyl is selected from halogen, cyano, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl and unsubstituted C 1~4 may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl and unsubstituted C 1~4and R 9 But unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~6 cycloalkyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted monocyclic heterocyclyl; 3~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl and Unsubstituted Monocyclic C 3~6 cycloalkyl; and R 11 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl, -(NH) m - optionally substituted 5-6 membered monocyclic heteroaryl, -O- optionally substituted C 1~6 alkyl, -O- optionally substituted C 3~8 cycloalkyl and -O- optionally substituted C 3~8 Cycloalkyl(C 1~4 alkyl), where m can be 0 or 1.

[0150] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a ring A 1 but

[0151] [ka] and ring A 1 Deuterium, halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl, unsubstituted C 2~4 Alkenyl and unsubstituted or substituted C 3~6 and R 1 is cyano, unsubstituted or substituted C 2~5Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, -CH(OH)-(S(=O)2-O - ), -CH(OH)((P=O)(OR 6 )2) and -C(=O)CH2-O-((P=O)(OR 7 ) 2) and each R 6 and each R 7 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 monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), or unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C 1~4 alkyl), and R 4 may be hydrogen, deuterium, or halogen; R 5 but,

[0152] [ka] substituted monocyclic C 3~6 cycloalkyl or substituted 4- to 6-membered monocyclic heterocyclyl, R 8 and R 10 is unsubstituted or substituted C 2~6 Alkyl, unsubstituted or substituted C 2~6 Alkenyl, unsubstituted or substituted C 2~6 Alkynyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~8 Cycloalkyl, unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl and unsubstituted monocyclic C 3~6 cycloalkyl(CH)-, C 2~6 If the alkyl is substituted, C 2~6Alkyl is selected from halogen, cyano, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl and unsubstituted C 1~4 may be substituted 1, 2, 3 or 4 times with substituents independently selected from alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 When cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted, C 2~6 Alkenyl, C 2~6 Alkynyl, monocyclic C 3~6 Cycloalkyl, Bicyclic C 5~8 Cycloalkyl and monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 2~4 Alkenyl, unsubstituted C 2~4 Alkynyl, unsubstituted C 1~4 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl and unsubstituted C 1~4 and R 9 is unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~6 Haloalkyl, unsubstituted or substituted monocyclic C 3~6 Cycloalkyl, unsubstituted or substituted bicyclic C 5~6 cycloalkyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted monocyclic heterocyclyl; 1~6 Alkyl is C 1~4 substituted monocyclic C 3~6 Cycloalkyl is substituted with halogen, unsubstituted C 1~4 Alkyl, unsubstituted C 1~4 Haloalkyl and Unsubstituted Monocyclic C 3~6 cycloalkyl; and 1~6 Haloalkyl is an unsubstituted C 1~4 substituted once or twice with alkoxy, R 11 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl, -(NH)m - optionally substituted 5-6 membered monocyclic heteroaryl, -O- optionally substituted C 1~6 alkyl, -O- optionally substituted C 3~8 cycloalkyl and -O- optionally substituted C 3~8 Cycloalkyl(C 1~4 alkyl), where m can be 0 or 1.

[0153] Examples of compounds of formula (I) include:

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] [ka]

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] [ka] or a pharmaceutically acceptable salt of any of the foregoing.

[0165] Additional examples of compounds of formula (I) include:

[0166] [ka]

[0167] [ka]

[0168] [ka]

[0169] [ka]

[0170] [ka]

[0171] [ka]

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] [ka]

[0176] [ka] or a pharmaceutically acceptable salt of any of the foregoing.

[0177] Further examples of compounds of formula (I) include:

[0178] [ka]

[0179] [ka] or a pharmaceutically acceptable salt of any of the foregoing.

[0180] In some embodiments, ring A 1 teeth,

[0181] [ka] R may be 5 teeth,

[0182] [ka] In some embodiments, ring A 1 teeth,

[0183] [ka] R may be 1 may be cyano, and R 2 may be hydrogen, and R 3 is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, R 5 teeth,

[0184] [ka] In some embodiments, ring A 1 teeth,

[0185] [ka] R may be 1 may be cyano, and R 2 may be hydrogen, and R 3 is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, and R 5 teeth,

[0186] [ka] R may be 8 is the unsubstituted C 2~6 may be alkyl, and R 9 is the unsubstituted C 1~6 In some embodiments, ring A may be haloalkyl. 1 teeth,

[0187] [ka] R may be 5 teeth,

[0188] [ka] In some embodiments, ring A 1 teeth,

[0189] [ka] R may be 1 may be cyano, and R 2 may be hydrogen, and R 3 is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, R 5 teeth,

[0190] [ka] In some embodiments, ring A 1 teeth,

[0191] [ka] R may be 1 may be cyano; R 2 may be hydrogen, and R 3 is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C 1~4 alkyl), and R 4 may be hydrogen, and R 5 teeth,

[0192] [ka] R may be 8 is the unsubstituted C 2~6 may be alkyl, and R 9 is the unsubstituted C 1~6 In some embodiments, ring A may be haloalkyl.1 teeth,

[0193] [ka] In some embodiments, ring A 1 teeth,

[0194] [ka] It cannot be.

[0195] 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), along with some examples of starting materials used to synthesize the compounds described herein, are shown and 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.

[0196] Scheme A

[0197] [ka] 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

[0198] Scheme A1

[0199] [ka] Alternatively, as described in Scheme A1, a subgroup of amino acids of general formula (A1-5) can be prepared as described in Scheme A1. A1 ) Amino acids can be coupled with amino esters of general formula (A-1) under known amide-forming conditions, such as HATU and iPr2NEt. The esters of compounds of formula (A1-2) can be deprotected, for example, by using LiOH in THF / HO, to give acids of general formula (A1-3). The protecting group PG A1 For example, PG A1When is Boc, it can be removed by treatment with TFA to give compounds of general formula (A1-4). This compound can be converted to a compound of general formula (A1-5) (e.g., by treatment with ethyl 2,2,2-trifluoroacetate in the presence of triethylamine), or to a compound of general formula (A1-6) (e.g., by treating a compound of general formula (A1-4) with an alkyl trihaloacetate (e.g., ethyl 2,2-dichloro-2-fluoroacetate, methyl 2-chloro-2,2-difluoroacetate, or ethyl 2-chloro-2,2-difluoroacetate) in the presence of a base such as triethylamine (and optionally an additive such as N-methylimidazole), or to an alkyl 2,2,3,3,3-pentafluoropropanoate (e.g., methyl or ethyl 2,2,3,3,3-pentafluoropropanoate) in the presence of a base (e.g., triethylamine and an additive such as N-methylimidazole).

[0200] General methodologies for the synthesis of amino acids of general formula (A1-1), or precursors that can be converted to amino acids of general formula (A1-1) by those skilled in the art, are described in the literature and include the following examples:

[0201] [ka]

[0202] Scheme B

[0203] [ka] In Scheme B, a carboxylic acid of general formula (A-4) can be 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 (such as 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 The ketoamide may be part of a ketoamide as described herein.

[0204] Scheme B1

[0205] [ka] 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, -Boc) can be coupled with a compound of general formula (B-1). B1 In this case, it can be removed by treatment with acid and subsequently coupled with a compound of general formula (A-2) to form a compound of general formula (B-2).

[0206] Scheme B2

[0207] [ka] As described herein, R 1 may be a substituted acyl, and possible groups that may be present on the acyl include hydroxy, substituted or unsubstituted alkoxy (e.g., —O—(unsubstituted C 1~4 alkyl) and -O-(unsubstituted C 3~6 Cycloalkyl), unsubstituted C 1~4 Alkyl (unsubstituted C 1~4 In Scheme B2, R is R 1may 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).

[0208] Scheme B3

[0209] [ka] Using amides of general formula (B3-1) instead of compounds of general formula (B2-1), compounds of general formula (B3-2) can be obtained in a similar manner as described for compounds of formula (B2-2) in Scheme B2. Conversion of compounds of general formula (B3-2) to compounds of general formula B3-3 can occur, for example, under the influence of trifluoroacetic anhydride (TFAA) and pyridine in CHCl or by application of Burgess's reagent.

[0210] Scheme B4

[0211] [ka] For general synthetic purposes, the transformations described in Scheme B3 include those described in Scheme B4, where compounds of general formula (A1-3) can be coupled with amines of general formula (B3-1) to give compounds of general formula (B4-1), where PGA1 can be a protecting group that can be removed (e.g., PG A1 is Boc, by treatment with HCl or TFA. Compounds of general formula (B4-2) can be converted to compounds of general formula (B4-3) by treatment with, for example, an alkyl trihaloacetate, such as ethyl 2,2-dichloro-2-fluoroacetate, methyl 2-chloro-2,2-difluoroacetate, ethyl 2-chloro-2,2-difluoroacetate, or ethyl 2,2,2-trifluoroacetate, in the presence of a base (e.g., triethylamine and optionally an additive, such as N-methylimidazole), or an alkyl 2,2,3,3,3-pentafluoropropanoate (e.g., methyl or ethyl 2,2,3,3,3-pentafluoropropanoate) in the presence of a base (e.g., triethylamine and optionally an additive, such as N-methylimidazole), or a carboxylic acid in the presence of a coupling reagent (such as EDC or HATU) and a base (such as NEt). Compounds of general formula (B4-3) can be converted to compounds of general formula (B4-4) in a similar manner as outlined for the conversion of compounds of general formula (B3-2) to compounds of general formula (B3-3). Alternatively, compounds of general formula (B4-2) can be converted to compounds of general formula (B4-4) (e.g., when -R9 is -CF2CF3, by treatment with T3P and pyridine in the presence of potassium 2,2,3,3,3-pentafluoropropanoate). Compounds of general formula (B4-1) can be converted to compounds of general formula (B3-4) by the PG conversion of compounds of general formula (B3-4). B1 After deprotection, the compound can be obtained by coupling with a compound of general formula (A1-1).

[0212] Scheme C

[0213] [ka] Compounds of general formula (B-1) can be prepared as outlined in Scheme C. An aldehyde 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.

[0214] Scheme C1

[0215] [ka] 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 can provide 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) and workup with saturated ammonium chloride. Protecting groups (PG 1 ) can be removed (e.g., PG 1 (When 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 compounds of general formula (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.

[0216] Scheme D1

[0217] [ka]

[0218] Scheme D2

[0219] [ka] 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

[0220] Scheme E

[0221] [ka] Methods for preparing a subgroup of amino acids of general formula (E-8) are provided in Scheme E. Lactams of general formula (E-1) can be prepared by coupling the lactam 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 Eprovides 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 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).

[0222] Scheme F

[0223] [ka] 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).

[0224] As shown in Scheme G, the synthesis of amino esters of general formula (G2) can be carried out by Arakawa et al., Chemical & Pharmaceutical Bulletin (2003) 51(8), 1015-1020 (-PG G1 can be -Bz, -PG G2 This can be achieved via a Diels-Alder reaction as described in G1 is -Boc and -PG G2 Also described herein are compounds of general formula (G2) in which PG is -t-butyl or Me. G1 and P.G. G2 Depending on the protecting group used, the compound of general formula (G2) can be deprotected. Alternatively, the compound of general formula (G2) can be converted to a compound of general formula (G3) by hydrogenation of the double bond, or to a compound of general formula (G4) by cyclopropanation of the double bond. Cyclopropanation can be carried out, for example, by application of the Simmons-Smith cyclopropanation, by treatment with CHN in the presence of Pd(OAc) or by other methods known and described to those skilled in the art. Alternatively, deuterated intermediates can be used.

[0225] Scheme G

[0226] [ka]

[0227] Scheme H

[0228] [ka] Other intermediates are described in Scheme H. Intermediates of general formula (G2) can be selectively hydroxylated, for example, by hydrosilylation with trichlorosilane in the presence of a chiral Pd catalyst, followed by SiCl / OH exchange (e.g., Breuning et al., Beilstein Journal of Organic Chemistry (2009) 5(81):1-5). Oxidation of alcohols of general formula (H1) can provide ketones of general formula (H2). Ketones of general formula (H2) can be converted to alkenes of general formula (H3), for example, by using Wittig or Tebbe reagents. Conversion of the double bond to a cyclopropyl group can be achieved by treatment with CHN in the presence of Pd(OAc) or other methods described in the literature and known to those skilled in the art, to give compounds of general formula (H4). A similar approach can be performed using isomers of compounds of general formula (H1), and compounds of general formula (H5) can be obtained by using enantiomeric chiral Pd catalysts. Compounds of general formula (H5) can then be converted to compounds of general formula (H6) in a similar manner as outlined for the conversion of compounds of general formula (H1) to compounds of general formula (H4). Alternatively, ketones of compounds of general formula (H2) can be converted to compounds of general formula (H2') by fluorination, for example by application of the DAST reagent. Isomeric compounds of general formula (H7) can be obtained starting from the related isomers. Alcohols of general formula (H1) and (H5) can be converted to the related fluoro derivatives of general formula (H1') and (H5') by treatment with a fluorinating reagent such as DAST (diethylaminosulfur trifluoride).

[0229] Scheme I

[0230] [ka] Other compounds of general formula (I1), (I2) (Johnson et al., Synthetic Communications (2011) 41(18):2769-2793), (I3), (I4), (I5), (I6), (I7), (I8), (I9), (I10), (I11) and (I12) shown in Scheme I can be obtained by methods described in the literature (e.g., de Graaff et al., Org. Biomol. Chem. (2015) 13:10108-10112; and Johnson et al., Synthetic Communications (2011) 41(18):2769-2793) and / or by applying the methodology described herein. Compounds of formula (I), (I2), (I3), (I4), (I5), (I6), (I7), (I8), (I9), (I10), (I11) and (I12) can be used to obtain compounds of formula (I) together with pharmaceutically acceptable salts using methods similar to those described herein.

[0231] Scheme IA

[0232] [ka] As an example, as shown in Scheme IA, a compound of formula (IA1) (Ruliseket et al., J. Org. Chem. (2005) 70(16):6295-6302) can be hydrogenated to give a compound of formula (IA2). After reduction of the compound of formula (IA2), a compound of formula (IA3) can be obtained (e.g., using LiAlH4 (Johnson et al., Synthetic Communications (2011) 41(18):2769-2793)). The compound of formula (IA3) can be oxidized using IBX (de Graaff et al., Org. Biomol. Chem. (2015) 13:10108-10112), followed by the introduction of a nitrile (Liu et al., Org. Process Res. Dev. (2016) 20(2):320-324) to give a compound of formula (IA4). The nitrile can then be converted to a carboxylic acid or ester of a compound of formula (IA5). In the above scheme, racemic material can be obtained by introducing the nitrile from a compound of formula (IA3) to a compound of formula (IA4). Alternatively, achiral methods can be used to provide enantiomerically enriched compounds.

[0233] Scheme J

[0234] [ka] Using the intermediate, compound of formula (J1) (Moody et al., J. Chem. Soc., Perkin Trans. 1 (1997) 23:3519-3530), amino acids of general formula (J2) and (J3) can be prepared using procedures similar to those described for Scheme H.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] Appropriate formulation depends on the selected route of administration.The techniques for formulating and administering 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 route of administration.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] In some embodiments, the coronavirus may be an alpha-coronavirus or a beta-coronavirus. The compounds described herein may be effective against one or more mutants of coronavirus. Examples of mutants include, but are not limited to, the alpha mutant (B.1.1.7), the beta mutant (B.1.351), the gamma mutant (P.1), and the delta mutant (B.1.617.2). In some embodiments, the coronavirus may 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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 can be considered treatment and / or therapy. Moreover, treatment can include actions that may worsen a subject's overall feeling of health or appearance.

[0258] 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 older.

[0259] The term "effective amount" is used to refer to the amount of an active compound or drug that elicits the indicated biological or pharmaceutical 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 may include alleviation of signs or symptoms of the disease being treated. Determination of 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 a compound 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.

[0260] 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, immunocompromised subjects (e.g., subjects with cancer, HIV and / or a genetic immunodeficiency, bone marrow transplant subjects, solid organ transplant subjects, subjects who have had stem cells for cancer treatment, and / or subjects using oral or intravenous corticosteroids or other medications called 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).

[0261] 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.

[0262] 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.

[0263] Coronavirus infection can be treated by inhibiting specific mechanisms. 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 relative to one or more host proteases, e.g., cathepsin L, cathepsin B, cathepsin D, cathepsin K, leukocyte elastase, chymotrypsin, trypsin, thrombin, pepsin, caspase 2, elastase, and calpain. In some embodiments, the selectivity of a coronavirus protease relative to a host protease (e.g., one described herein) can be greater than 2-fold. In some embodiments, the selectivity of a coronavirus protease relative to 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 (such as those described herein) can be greater than 100-fold.

[0264] 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).

[0265] 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.

[0266] 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 alpha 2b, IFN-alpha, and / or PEG-IFN-alpha-2a), IVIG, ivermectin, gamma-globulin, and 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, zanamivir, casirivimab, imdevimab, bamlanivimab, etesevimab, and AT-527 (Good et al., Antimicrobial Agents and Chemotherapy (2021)65(4):e02479-20).

[0267] 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]

[0268] Further embodiments, which in no way limit the scope of the claims, are disclosed in more detail in the examples below.

[0269] 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.

[0270] [ka] Synthesis of intermediates

[0271] To a solution of 1,2-di-tert-butyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (15 g, 52.2 mmol, 1.0 equiv.) in DCM (250 mL) was added triethylamine (9.51 g, 93.9 mmol, 1.8 equiv.) and DMAP (1.91 g, 15.7 mmol, 0.3 equiv.). MsCl (8.97 g, 78.3 mmol, 1.5 equiv.) was added dropwise at 0° C. The mixture was stirred for 2 h at room temperature (rt), and the reaction was quenched with water (100 mL). The solution was extracted with DCM (3×150 mL). The organic layers were combined, washed with brine (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 (1:10) to give 1,2-di-tert-butyl (2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (17.8 g, 89%) as a colorless oil. LC-MS (ESI, m / z): 366 [M+H] + .

[0272] To a solution of 1,2-di-tert-butyl (2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (17.8 g, 48.7 mmol, 1.0 equiv) in MeOH (400 mL) was added (phenyldiselanyl)benzene (9.12 g, 29.2 mmol, 0.6 equiv). Sodium borohydride (2.4 g, 63.3 mmol, 1.3 equiv) was added portionwise at 0° C. The mixture was refluxed overnight and then concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with EA (3×150 mL). The organic layers were combined, washed with brine (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 (1:5) to give 1,2-di-tert-butyl (2S,4S)-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (7.5 g, 32%) as a colorless oil. LC-MS (ESI, m / z): 428 [M+H] + .

[0273] To a solution of 1,2-di-tert-butyl (2S,4S)-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (7.5 g, 17.6 mmol, 1.0 equiv.) in DCM (100 mL) was added pyridine (2.4 mL, 30.5 mmol, 1.7 equiv.) and 30% aqueous HO (5.6 mL, 71.6 mmol, 4.0 equiv.). The mixture was stirred at room temperature for 12 hours, and the reaction was quenched with water (20 mL). The solution was extracted with DCM (3 × 150 mL). The combined organic layers were washed with 1 M citric acid (80 mL), saturated aqueous NaSO (100 mL), and brine (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 (1:9) to give 1,2-di-tert-butyl (2S)-2,5-dihydropyrrole-1,2-dicarboxylate (2.8 g, 53%) as a colorless oil. 1 H NMR (300MHz, DMSO-d6) δ6.02-6.09(m,1H), 5.76-5.83(m,1H), 4.72-4.78(m,1H), 4.05-4.09(m,2H), 1.17-1.42(m,18H). LC-MS(ESI, m / z):270[M+H] + .

[0274] A solution of 1,2-di-tert-butyl (2S)-2,5-dihydropyrrole-1,2-dicarboxylate (2.8 g, 10.4 mmol, 1.0 equiv.) in dicyclopentadiene (60 mL) was stirred at 170 °C under nitrogen for 48 h and then partitioned with DCM (200 mL). After removal of the solvent, the residue was chromatographed on a silica gel column using EA:PE (1:9) to give the product (2.5 g, crude) as a yellow oil. The crude oil was chromatographed on a C18 column using HO:MeCN (2:1) to give di-tert-butyl (1S,3aR,4S,7R,7aS)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-1,2-dicarboxylate (690 mg, 19%) as a white solid. 1H NMR (300MHz, DMSO-d6) δ6.14-6.21(m,2H),3.55-3.60(m,1H),3.23-3.27(m,1H),2.95-3.02(m,2H),2.74-2.87(m,3H),1.24-1.48(m,20H). LC-MS(ESI, m / z):270[M+H] + .

[0275] To a solution of i-tert-butyl (1S,3aR,4S,7R,7aS)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-1,2-dicarboxylate (690 mg, 2.1 mmol, 1.0 equiv.) in dioxane (10 mL) was added hydrochloric acid (10 mL, 9 M). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (320 mg, crude) as a black solid. LC-MS (ESI, m / z): 180 [M+H] + .

[0276] To a solution of (1S,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (320 mg, 1.79 mmol, 1.0 equiv.) in DCM (8 mL) was added di-tert-butyl dicarbonate (429 mg, 1.97 mmol, 1.1 equiv.) and triethylamine (542 mg, 5.34 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (430 mg, crude) as a brown solid. LC-MS (ESI, m / z): 280 [M + H] + .

[0277] [ka]

[0278] A mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (10.0 g, 34.9 mmol, 1.00 equiv) in ammonia (150 mL, 7 M in MeOH) was stirred at 80° C. overnight and concentrated under reduced pressure to give tert-butyl N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (10.0 g, crude) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ7.65(s,1H),7.29(s,1H),7.01(s,1H),6.88-6.95(m,1H),3.84-4.15(m,1H),3.0 9-3.21(m,2H),2.08-2.26(m,2H),1.84-1.96(m,1H),1.60-1.74(m,1H),1.44-1.54(m,1H),1.38(s,9H). LC-MS(ESI, m / z):272[M+H] + .

[0279] [ka]

[0280] A solution of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (710 mg, 2.62 mmol, 1.0 equiv) in ether (12 mL, 2 mol / L) hydrochloric acid was stirred at room temperature for 2 hours and concentrated under reduced pressure to give (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propenamide (500 mg, crude) as a white solid. LC-MS (ESI, m / z): 172 [M+H] + .

[0281] To a solution of (1S,3aR,4S,7R,7aS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (979 mg, 3.5 mmol, 1.2 equiv.) in DMF (2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.44 g, 3.8 mmol, 1.3 equiv.) and N,N-diisopropylethylamine (2.64 g, 20.4 mmol, 7.0 equiv.). After the mixture was stirred at 0° C. for 30 min, (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (500 mg, 2.92 mmol, 1.0 equiv) was added. The mixture was stirred for 2 h at room temperature, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3×10 mL). The organic layers were combined, washed with brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a C18 column with water:MeCN (2:1) to give tert-butyl (1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-2-carboxylate (1.05 g, 75%) as a tan solid. LC-MS (ESI, m / z): 433 [M+H] + .

[0282] tert-Butyl (1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-2-carboxylate (300 mg, 0.69 mmol, 1.0 equiv.) in ether (5 mL, 2 The solution in 100 ml of 1,3-dimethyl-2,3-dioxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (200 mg, crude) as a white solid. LC-MS (ESI, m / z): 333 [M+H] + .

[0283] [ka]

[0284] To a stirred mixture of tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (6.00 g, 26.8 mmol, 1.0 equiv.) and ethyl 2,2,2-trifluoroacetate (7.62 g, 53.6 mmol, 2.0 equiv.) in MeOH (100 mL) was added triethylamine (5.43 g, 53.7 mmol, 2.0 equiv.) at 0 °C. The mixture was stirred for 5 h at 30 °C and then concentrated under reduced pressure to give the crude product. The crude product was diluted with DCM (150 mL) and slurried on 100-200 mesh silica gel (15 g). After removing the DCM, the mixture was loaded onto column chromatography. 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 MeOH:DCM (0% to 10% over 30 min). The collected fractions: 0% MeOH:DCM fraction was selected as the pure fraction, and these fractions were combined and concentrated under reduced pressure to give tert-butyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoate (7.20 g, 90%) as a white solid. 1 H NMR (300MHz, CDCl3) δ6.78-6.90 (m, 1H), 4.32-4.38 (m, 1H), 1.50 (s, 9H), 1.01 (s, 9H). LC-MS (ESI, m / z): 282[MH] - .

[0285] To a mixture of tert-butyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoate (1.03 g, 3.64 mmol, 1.0 equiv) in DCM (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (826 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 226 [MH] - .

[0286] [ka]

[0287] 1,2-Di-tert-butyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate To a solution of 1,2-di-tert-butyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (50 g, 175 mmol, 1.0 equiv.) in toluene (500 mL) was added [tert-butoxy(dimethylamino)methyl]dimethylamine (36.7 g, 210 mmol, 1.2 equiv.). The mixture was stirred at 115 °C under nitrogen for 3 hours and concentrated under reduced pressure to give di-tert-butyl(S,Z)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (46 g, crude) as an orange oil. LC-MS (ESI, m / z): 341 [M+H] + .

[0288] To a solution of di-tert-butyl (S,Z)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (46 g, 135 mmol, 1.0 equiv.) in THF (900 mL) was added DIBAl-H (203 mL, 1 M in toluene, 203 mmol, 1.5 equiv.) dropwise at −78° C. under N. The mixture was stirred at −78° C. for 2 hours and then slowly poured into hydrochloric acid (800 mL, 2 mol / L) at 0° C. The solution was extracted with EA (3×600 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 EA:PE (1:5) to give di-tert-butyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate (16 mg, 36%) as a colorless oil. 1 H NMR (300MHz, DMSO-d6) δ5.98-6.00(m,1H),5.58-5.59(m,1H),4.50-4.54(m,1H),3.04-3.34(m,1H),2.57-2.64(m,1H),1.36-1.44(m,18H). LC-MS(ESI, m / z):298[M+H] + .

[0289] To a solution of di-tert-butyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate (12 g, 40.4 mmol, 1.0 equiv) in THF (200 mL) was added methoxylithium (22 mL, 2.2 M in methanol, 48.4 mmol, 1.2 equiv) under N at −40° C. The mixture was stirred at −40° C. for 30 min. The reaction was quenched with saturated aqueous sodium chloride solution (100 mL). The solution was extracted with EA (3×100 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 EA:PE (1:4) to give 1-(tert-butyl) 5-methyl(S)-2-((tert-butoxycarbonyl)amino)-4-methylenepentanedioate (12 g, 81%) as a colorless viscous oil. LC-MS (ESI, m / z): 330 [M+H] + .

[0290] To a solution of 1-(tert-butyl) 5-methyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenepentanedioate (7 g, 21 mmol, 1.0 equiv.) in MeCN (70 mL) and DMSO (70 mL) was added 2H-pyrazol-3-amine (2.1 g, 25.5 mmol, 1.2 equiv.) and KCO (2.94 mg, 21 mmol, 1.0 equiv.). The mixture was stirred at 60 °C overnight and then concentrated under reduced pressure. The residue was chromatographed on a C18 column with MeCN:HO (3:2) to give tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoate (1.7 g, 19%) as a brown-yellow oil. 1 H NMR(300MHz,DMSO-d6)δ10.76(s,1H),7.18-7.27(m,2H),5.56-5.57(m,1H),4.26-4.36(m,1H), 3.89-4.13(m,1H),2.75-2.79(m,1H),2.10-2.25(m,1H),1.61-1.80(m,1H),1.27-1.53(m,18H). LC-MS(ESI, m / z):381[M+H]+ .

[0291] To a solution of tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoate (800 mg, 3.55 mmol, 1.0 equiv.) in dioxane (8 mL) was added hydrochloric acid (8 mL, 9 M). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoic acid (400 mg, crude) as an off-white semisolid. LC-MS (ESI, m / z): 225 [M+H] + .

[0292] To a solution of (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoic acid (400 mg, 1.78 mmol, 1.0 equiv.) in DCM (6 mL) was added di-tert-butyl dicarbonate (430 mg, 1.96 mmol, 1.1 equiv.) and triethylamine (180 mg, 5.36 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoic acid (530 mg, crude) as a brown-yellow semisolid. LC-MS (ESI, m / z): 325 [M+H] + .

[0293] To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoic acid (530 mg, 1.63 mmol, 1.0 equiv) in DMF (8 mL) was added N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (550 mg, 1.96 mmol, 1.2 equiv), NMI (671 mg, 8.17 mmol, 5.0 equiv), and NH in dioxane (40 mL, 10.0 equiv, 0.4 mol / L). The mixture was stirred at room temperature for 2 hours and then chromatographed on a C18 column with MeCN:HO (1:4) to give tert-butyl ((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (280 mg, 48%) as a brown-yellow oil. LC-MS (ESI, m / z): 324 [M+H] + .

[0294] A solution of tert-butyl ((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (280 mg, 0.87 mmol, 1.0 equiv.) in hydrochloric acid (4 mL, 2 mol / L in dioxane) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanamide (180 mg, crude) as an off-white semisolid. LC-MS (ESI, m / z): 224 [M+H] + .

[0295] (S)-3-((R * )-1-(tert-butoxycarbonyl-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0296] [ka] " *The chiral centers marked with "" are tentatively assigned.

[0297] A 100 mL round-bottom flask was charged with 5,5-dimethylpyrrolidin-2-one (3.5 g, 30.9 mmol, 1.0 equiv), DCM (50 mL), di-tert-butyl dicarbonate (10.8 g, 49.5 mmol, 1.6 equiv), triethylamine (6.24 g, 61.8 mmol, 2.0 equiv), and DMAP (0.38 g, 3.09 mmol, 0.1 equiv). The solution was stirred at 40 °C overnight, and the reaction was quenched with water (150 mL). The solution was extracted with EA (5 × 300 mL). The organic layers were combined, 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 (13:87) to give tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (4.0 g, 58%) as a white solid. LC-MS (ESI, m / z): 214 [M+H] + .

[0298] A 100 mL round-bottom flask was charged with tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (3.6 g, 16.9 mmol, 1.00 equiv) and THF (50 mL). The solution was cooled to −78° C., and LiHMDS (20.2 mL, 1 M in THF, 20.2 mmol, 1.2 equiv) was added. The mixture was stirred at −78° C. for 1 h, and a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (5.81 g, 25.3 mmol, 1.5 equiv) in THF (10 mL) was added under Ar. Stirring was continued at −78° C. for 1 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The solution was extracted with dichloromethane (3×150 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 with EA:PE (1:4) to give tert-butyl (4R)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](hydroxy)methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (7.2 g, 89%) as a colorless oil. LC-MS (ESI, m / z): 443 [M+H] + .

[0299] A 100 mL round-bottom flask was charged with tert-butyl (4R)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](hydroxy)methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1 g, 2.26 mmol, 1.00 equiv.), DCM (10 mL), triethylamine (1.14 g, 11.3 mmol, 5.0 equiv.), and MsCl (0.31 g, 4.52 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight, and the reaction was quenched with water (30 mL). The solution was extracted with dichloromethane (4 × 50 mL). The organic layers were combined, washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (4R)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](methanesulfonyloxy)methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (960 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 521 [M+H] + .

[0300] A 100 mL round-bottom flask was charged with tert-butyl (4R)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](methanesulfonyloxy)methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (900 mg, 1.73 mmol, 1.0 equiv.), DCM (20 mL), and DBU (1.32 g, 8.64 mmol, 5.0 equiv.). The mixture was stirred at room temperature overnight, and the reaction was quenched with water (30 mL). The solution was extracted with dichloromethane (3 × 80 mL). The organic layers were combined, washed with brine (2 × 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 (1:4) to give tert-butyl (4S)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-ylidene]methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (635 mg, 82%) as a colorless oil. LC-MS (ESI, m / z): 425 [M+H] + .

[0301] A 250 mL round-bottom flask was charged with tert-butyl (4S)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-ylidene]methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.4 g, 10.4 mmol, 1.0 equiv.), EA (50 mL), and 10% palladium on activated carbon (5.51 g). The contents of the flask were placed under an atmosphere of hydrogen (3 atm). The mixture was stirred at room temperature overnight. The solid was filtered off. The organic layer was concentrated under reduced pressure to give tert-butyl (4S)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.3 g, 78%) as a colorless oil. LC-MS (ESI, m / z): 427 [M+H] + .

[0302] Tert-butyl (4S)-4-((1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3.6 g) was purified by preparative SFC using the following gradient conditions: Column: Lux 5um Cellulose-2,3 * 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA (0.5% 2M NH3-MeOH); Flow rate: 60 mL / min; Gradient: Isocratic 10% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 4.81; RT2 (min): 6.43; Sample solvent: MeOH--preparative; Injection volume: 1.5 mL; Run number: 27. Purification afforded tert-butyl(S)-4-(((S * )-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (990 mg) was obtained as an off-white solid (Lux Cellulose-2 4.6 * 50 mm, 3 μm, 35 °C. Co-solvent: IPA (0.1% DEA), 10% to 50% in 2.0 min, hold at 50% for 1.0 min: Rt: 0.969 min), tert-butyl (S)-4-(((R * )-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (1.6 g) was obtained as an off-white solid (Lux Cellulose-2 4.6 * 50 mm, 3 μm, 35 °C. Co-solvent: IPA (0.1% DEA), 10% to 50% in 2.0 min, hold at 50% for 1.0 min): Rt: 1.411 min.

[0303] In a 40 mL vial, add tert-butyl (S)-4-(((R *)-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (1.6 g, 3.75 mmol, 1.0 equiv.), para-toluenesulfonate (64.6 mg, 0.375 mmol, 0.1 equiv.), and MeOH (20 mL) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL). The solution was extracted with EA (3 × 30 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (S)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (1.47 g, crude) as an off-white semi-solid. LC-MS (ESI, m / z): 387 [M+H] + .

[0304] tert-Butyl (S)-4-((R * To a solution of )-2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (1.7 g, 4.40 mmol, 1.0 equiv.) in acetone (22 mL) was added 5% sodium bicarbonate solution (22 mL, 13.1 mmol, 3.0 equiv.) and 2,2,6,6-tetramethylpiperidinol (0.14 g, 0.88 mmol, 0.2 equiv.). Chlorosyl sodium (1.15 g, 15.4 mmol, 3.5 equiv.) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight, and the reaction was quenched with water (20 mL). The solution was washed with EtO (2 × 20 mL). The pH of the aqueous solution was adjusted to 2 with concentrated hydrochloric acid (1 mol / L). The solution was extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-3-((R * )-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.2 g, 61%) as a white solid.

[0305] tert-Butyl ((S)-1-hydroxy-3-((S * )-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate

[0306] [ka] " * The absolute configurations of the chiral centers marked with "" have been tentatively assigned.

[0307] A solution of methyl 3-cyanopropanoate (10 g, 88.4 mmol, 1.0 equiv) in EtO (100 mL) was treated with Ti(O i Pr)4 (5.03 g, 17.7 mmol, 0.2 equiv) was added. Subsequently, EtMgBr (194 mL, 1 M in THF, 194 mmol, 2.2 equiv) was added dropwise under N2. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (20 mL). The mixture was extracted with EA (3 x 60 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with PE:MeOH (12:1) to give 4-azaspiro[2.4]heptan-5-one (8.5 g, 69%) as a colorless oil. LC-MS (ESI, m / z): 112 [M+H] + .

[0308] A 250 mL round-bottom flask was charged with 4-azaspiro[2.4]heptan-5-one (8.5 g, 76.5 mmol, 1.0 equiv), DCM (100 mL), di-tert-butyl dicarbonate (26.7 g, 122 mmol, 1.6 equiv), triethylamine (0.77 g, 7.65 mmol, 0.1 equiv), and DMAP (0.93 g, 7.65 mmol, 0.1 equiv). The solution was stirred at 40 °C overnight, and the reaction was quenched with water (70 mL). The solution was extracted with DCM (3 × 100 mL). The organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:12) to give tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (11 g, 58%) as a white solid. LC-MS (ESI, m / z): 212 [M+H] + .

[0309] A 500 mL round-bottom flask was charged with tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (11 g, 52.1 mmol, 1.0 equiv) and THF (150 mL). The solution was cooled to −78° C., and LiHMDS (62.5 mL, 1 M in THF, 62.5 mmol, 1.2 equiv) was added. The mixture was stirred at −78° C. for 1 h, and a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (17.9 g, 78.1 mmol, 1.5 equiv) in THF (50 mL) was added under Ar. Stirring was continued at −78° C. for 1 h. The reaction was quenched with saturated ammonium chloride solution (100 mL). The solution was extracted with EA (3 × 200 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:8) to give tert-butyl (4R)-4-((4-(tert-butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan-6-yl)(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (19.7 g, 69%) as a colorless oil. LC-MS (ESI, m / z): 441 [M+H] + .

[0310] A 500 mL round-bottom flask was charged with tert-butyl (4R)-4-((4-(tert-butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan-6-yl)(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (19.7 g, 44.7 mmol, 1.0 equiv), DCM (250 mL), triethylamine (27.2 g, 268 mmol, 6.0 equiv), and MsCl (20.5 g, 179 mmol, 4.0 equiv). The mixture was stirred at room temperature overnight, and the reaction was quenched with water (100 mL). The solution was extracted with DCM (4 x 150 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (4R)-4-((4-(tert-butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan-6-yl)((methylsulfonyl)oxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (22 g, crude) as an orange oil. LC-MS (ESI, m / z): 519 [M+H] + .

[0311] A 500 mL round-bottom flask was charged with tert-butyl (4R)-4-((4-(tert-butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan-6-yl)((methylsulfonyl)oxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (22 g, 42.4 mmol, 1.0 equiv), DCM (200 mL), and DBU (14.2 g, 93.3 mmol, 2.2 equiv). The mixture was stirred at room temperature overnight, and the reaction was quenched with water (80 mL). The solution was extracted with DCM (3×100 mL). The organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:12) to give tert-butyl 6-{[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methylidene}-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (11.3 g, 57%) as a colorless oil. LC-MS (ESI, m / z): 423 [M+H] + .

[0312] A 250 mL vial was charged with tert-butyl 6-{[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methylidene}-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (11.3 g, 26.7 mmol, 1.0 equiv.), 4-methylbenzenesulfonic acid (5.53 g, 32.1 mmol, 1.2 equiv.), and MeOH (120 mL). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give 6-[(2S)-2-amino-3-hydroxypropylidene]-4-azaspiro[2.4]heptan-5-one (5.8 g, crude) as an orange oil. LC-MS (ESI, m / z): 183 [M+H] + .

[0313] To a solution of 6-[(2S)-2-amino-3-hydroxypropylidene]-4-azaspiro[2.4]heptan-5-one (5.8 g, 31.829 mmol, 1.00 equiv.) in DCM (90 mL) was added triethylamine (25.8 g, 255 mmol, 8.0 equiv.) and di-tert-butyl dicarbonate (20.8 g, 95.5 mmol, 3.0 equiv.). The mixture was stirred at room temperature overnight, and the reaction was quenched with water (30 mL). This mixture was extracted with CDCl3:isopropyl alcohol = 3:1 (3 × 50 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 tert-butyl N-[(2S)-1-hydroxy-3-[(6E)-5-oxo-4-azaspiro[2.4]heptan-6-ylidene]propan-2-yl]carbamate (3.9 g, 39%) as a tan solid. LCMS (ESI, m / z): 283 [M+H] + .

[0314] To a solution of tert-butyl N-[(2S)-1-hydroxy-3-[5-oxo-4-azaspiro[2.4]heptan-6-ylidene]propan-2-yl]carbamate (3.9 g, 13.8 mmol, 1.0 equiv.) in THF (30 mL) and MeOH (90 mL) was added NiCl 6H O (23 g, 96.7 mmol, 7.0 equiv.). NaBH (11 g, 290 mmol, 21.0 equiv.) was added in portions at 0 °C. The mixture was stirred overnight at room temperature, and the reaction was quenched with water (30 mL). This mixture was extracted with CDCl:isopropyl alcohol (3:1) (3 × 60 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 MeCN:HO (4:1) to give tert-butyl N-[(2S)-1-hydroxy-3-{5-oxo-4-azaspiro[2.4]heptan-6-yl}propan-2-yl]carbamate (1.7 g, 39%) as a tan solid. LCMS (ESI, m / z): 285 [M+H] + .

[0315] Tert-butyl N-[(2S)-1-hydroxy-3-{5-oxo-4-azaspiro[2.4]heptan-6-yl}propan-2-yl]carbamate (1.7 g) was purified by SFC using the following gradient conditions: Column: NB-Lux 5um i-Cellulose-5, 2.12 * 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 100 mL / min; Gradient: Isocratic 25% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.37; RT2 (min): 4.02; Sample solvent: MeOH--preparative; Injection volume: 1 mL; Run number: 40. Purification yielded 590 mg of the first eluting tert-butyl ((S)-1-hydroxy-3-((R * 640 mg of the last eluting tert-butyl ((S)-1-hydroxy-3-((S))-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate was obtained as a tan solid. * )-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate as a tan solid.

[0316] (3S)-3-Amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide

[0317] [ka]

[0318] 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 at 0° C. for 1 hour and then concentrated under reduced pressure. The mixture was diluted with water (20 mL) and then extracted with isopropanol. Extraction was performed with 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] + .

[0319] 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]+ .

[0320] 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 hours and then 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] + .

[0321] 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] + .

[0322] 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 trifluoroacetic acid (2 mL) dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and then 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] + .

[0323] tert-Butyl (1S,3aR,4S,7R,7aS)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-2-carboxylate

[0324] [ka]

[0325] A solution of tert-butyl ((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (800 mg, 2.34 mmol, 1.0 equiv) in hydrochloric acid (14 mL, 4 M in dioxane) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (550 mg, crude) as an off-white solid. LC-MS (ESI, m / z): 242 [M+H] + .

[0326] To a solution of (1S,3aR,4S,7R,7aS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (700 mg, 2.5 mmol, 1.1 equiv) in DMF (8 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.13 g, 2.96 mmol, 1.3 equiv) and N,N-diisopropylethylamine (2.06 g, 16 mmol, 7.0 equiv). The mixture was stirred at 0° C. for 30 min, and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (550 mg, 2.28 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3×20 mL). The organic layers were combined, washed with brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with MeOH:DCM (1:12) to give tert-butyl (1S,3aR,4S,7R,7aS)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-2-carboxylate (900 mg, 70%) as a tan solid. LC-MS (ESI, m / z): 503 [M+H] + .

[0327] Example 1 compound 1

[0328] [ka] To a solution of tert-butyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoate (118 mg, 0.42 mmol, 1.2 equiv) in DMF (2 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (171 mg, 0.45 mmol, 1.3 equiv) and N,N-diisopropylethylamine (313 mg, 2.42 mmol, 7.0 equiv). After the mixture was stirred at 0° C. for 30 min, (1S,3aR,4S,7R,7aS)—N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (115 mg, 0.35 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with water (3 mL). The mixture was extracted with EA (3×5 mL). The organic layers were combined, washed with brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a C18 column with water:MeCN (2:1) to give (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (150 mg, 72%) as a tan solid. LC-MS (ESI, m / z): 542 [M+H] + .

[0329] To a solution of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (120 mg, 0.22 mmol, 1.0 equiv) in DCM (3 mL) was added TFAA (88.4 mg, 0.42 mmol, 1.9 equiv) and pyridine (61.3 mg, 0.78 mmol, 3.5 equiv). The mixture was stirred at 0 °C for 4 h, and the reaction was quenched with water (4 mL). The mixture was extracted with DCM (3 x 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 Purification by OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 50% B, 50% B in 7 min; wavelength: 254 nm; RT (min): 5.55 gave (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (1) (53.2 mg, 45% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6,80℃)δ8.66-8.95(m,2H),7.28-7.37(m,1H),5.96-6.23( m,2H),4.87-4.93(m,1H),4.41-4.68(m,1H),3.86-4.17(m,1H),3.58-3.71(m, 1H),3.20-3.51(m,2H),2.83-3.06(m,4H),2.59-2.79(m,1H),2.29-2.38(m,1H) ),2.03-2.28(m,2H),1.61-1.84(m,2H),1.31-1.42(m,2H),0.79-0.90(m,9H). LC-MS (ESI, m / z): 524 [M + H] + .

[0330] Example 2 compound 2

[0331] [ka] To a solution of 4-tert-butyl 3-methyl(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3,4-dicarboxylate (300 mg, 1.02 mmol, 1.0 equiv) in EtO (2.5 mL) was added diazomethane (30 mL, 30.0 equiv) and palladium(II) acetate (45.9 mg, 0.205 mmol, 0.2 equiv) at −30° C. The mixture was stirred at room temperature for 1 hour and then filtered. The filter cake was washed with diethyl ether (3 × 50 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with ethyl acetate (EA):petroleum ether (PE) (1:8) to give 4-tert-butyl 3-methyl(1R,2S,3S,6R,7S,8S,10R)-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3,4-dicarboxylate (200 mg, 58%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ4.25-4.50(m,1H),3.53-3.72(m,4H),3.22-3.30(m,1H),2.52-2.64(m,2H),2.22-2 .42(m,2H),1.21-1.47(m,9H),1.03-1.16(m,1H),0.70-0.95(m,3H),0.39-0.54(m,1H),-0.09-0.05(m,1H). LC-MS(ESI, m / z):208[M+H-Boc] + .

[0332] To a stirred mixture of 4-tert-butyl 3-methyl(1R,2S,3S,6R,7S,8S,10R)-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3,4-dicarboxylate (245 mg, 0.797 mmol, 1.0 equiv) in MeOH (3 mL) and HO (3 mL) was added lithium hydroxide (95.4 mg, 3.98 mmol, 5.0 equiv). The mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 4 with hydrochloric acid (1 M) and then extracted with ethyl acetate (3 × 10 mL). The mixture was concentrated under reduced pressure to give (1R,2S,3S,6R,7S,8S,10R)-4-(tert-butoxycarbonyl)-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3-carboxylic acid (200 mg, 85%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ12.57(s,1H),4.17-4.39(m,1H),3.47-3.76(m,1H),3.12-3.31(m,1H),2.51-2.59(m,2H), 2.20-2.44(m,2H),1.27-1.49(m,9H),1.05-1.22(m,1H),0.69-0.93(m,3H),0.40-0.51(m,1H),-0.06-0.00(m,1H). LC-MS(ESI, m / z):238[M+H-56] + .

[0333] To a stirred mixture of (1R,2S,3S,6R,7S,8S,10R)-4-(tert-butoxycarbonyl)-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3-carboxylic acid (200 mg, 0.682 mmol, 1.0 equiv) in DMF (2 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (311 mg, 0.818 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (528 mg, 4.09 mmol, 6.0 equiv) at room temperature. After stirring the mixture at 0 °C for 10 minutes, (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (141 mg, 0.682 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The mixture was purified on a C18 column using CHCN:water (0.05% FA). The compound fractions were concentrated under reduced pressure to give tert-butyl (1R,2S,3S,6R,7S,8S,10R)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-4-carboxylate (200 mg, 55%) as a white solid. LC-MS (ESI, m / z): 447 [M+H] + .

[0334] To a stirred mixture of tert-butyl (1R,2S,3S,6R,7S,8S,10R)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-4-carboxylate (200 mg, 0.448 mmol, 1.0 equiv) in DCM (1 mL) was added hydrochloric acid (3 mL, 2 M in EtO) at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-2-[(1R,2S,3S,6R,7S,8S,10R)-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (200 mg, crude) as a white solid. LC-MS (ESI, m / z): 347 [M+H] + .

[0335] To a stirred mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (101 mg, 0.446 mmol, 1.1 equiv) in DMF (2 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (184 mg, 0.486 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (314 mg, 2.43 mmol, 6.0 equiv). After the mixture was stirred at 0 °C for 10 min, (2S)-2-[(1R,2S,3S,6R,7S,8S,10R)-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (155 mg, 0.405 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 h. The mixture was purified by C18 column chromatography using CH3CN:water (0.05% FA). The compound fractions were concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S,8S,10R)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (170 mg, 67%) as a white solid. LC-MS (ESI, m / z): 556 [M+H] + .

[0336] To a stirred mixture of (2S)-2-{[(1R,2S,3S,6R,7S,8S,10R)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (100 mg, 0.180 mmol, 1.0 equiv) in DCM (2 mL) was added trifluoroacetic anhydride (75.6 mg, 0.360 mmol, 2.0 equiv) and pyridine (49.8 mg, 0.630 mmol, 3.5 equiv) dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 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 using the following conditions (Column: Xselect Peptide CSH C18 19 * Purification by preparative HPLC using a 150 mm 5 μm column (1; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 34% B to 48% B, 48% B in 10 min; wavelength: 254 nm; RT (min): 8.98) gave (1R,2S,3S,6R,7S,8S,10R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3-carboxamide (9.6 mg, 9%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.47-9.13(m,2H),7.33-7.62(m,1H),4.82-4.95(m,1H),4. 56-4.75(m,2H),3.90-4.04(m,1H),3.57-3.70(m,1H),3.08-3.20(m,2H),2.59-2.72(m, 1H),2.24-2.45(m,4H),2.05-2.20(m,2H),1.60-1.84(m,2H),0.91-1.11(m,9H),0.85-0 .91(m,1H),0.75-0.84(m,2H),0.56-0.65(m,1H),0.38-0.51(m,1H),-0.30-0.00(m,1H).

[0337] Example 3 compound 3

[0338] [ka] To a stirred mixture of (2S,3R)-2-amino-3-(tert-butoxy)butanoic acid (1.00 g, 5.71 mmol, 1.0 equiv.) in methanol (15 mL) was added ethyl 2,2,2-trifluoroacetate (0.970 g, 6.84 mmol, 1.2 equiv.) and triethylamine (1.73 g, 17.1 mmol, 3.0 equiv.). The mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL). The mixture was adjusted to pH 5-6 with hydrochloric acid (1 M) and then extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2S,3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butanoic acid (1.58 g, crude) as a light brown solid. LC-MS (ESI, m / z): 270 [MH] - .

[0339] To a stirred mixture of tert-butyl (1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-4-carboxylate (120 mg, 0.277 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 then concentrated under reduced pressure to give (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (92.0 mg, crude) as a brown oil. LC-MS (ESI, m / z): 333 [M+H] + .

[0340] (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (92.0 mg, 0.277 mmol, 1.0 equiv.), (2S,3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butanoic acid (7 To a stirred mixture of o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.1 mg, 0.277 mmol, 1.0 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (126 mg, 0.332 mmol, 1.2 equiv.) in DMF (4 mL) was added N-ethyl-N-isopropylpropan-2-amine (286 mg, 2.21 mmol, 8.0 equiv.) at 0°C. The mixture was stirred at room temperature for 1 hour. 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 chromatographed on a silica gel column using MeOH:DCM (1:12) to give the desired product. The crude product was purified by C18 column chromatography using CH3CN:water (0.05% TFA), and the fractions were concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S,3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (61.0 mg, crude) as a pale yellow solid. LC-MS (ESI, m / z): 586 [M+H] + .

[0341] To a stirred mixture of (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S,3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (60.0 mg, 0.102 mmol, 1.0 equiv) in DCM (2 mL) was added pyridine (32.4 mg, 0.408 mmol, 4.0 equiv) and trifluoroacetic anhydride (43.1 mg, 0.204 mmol, 2.0 equiv). The mixture was stirred at room temperature for 3 hours. 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 preparative HPLC (column: XBridge Prep Phenyl OBD column, 19 * Purification by 250 mm column, 5 μm column; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 56% B in 10 min, 56% B; wavelength: 254 nm; RT (min): 8.22 gave (1R,2S,3S,6R,7S)-4-[(2S,3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butanoyl]-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (1.7 mg, 2%). LC-MS (ESI, m / z): 512 [M-56+H]. + .

[0342] Example 4 compound 4

[0343] [ka] To a stirred mixture of tert-butyl (1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-4-carboxylate (500 mg, 1.15 mmol, 1.0 equiv) in DCM (6 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (380 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 333 [M+H] + .

[0344] (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (76.0 mg, 0.229 mmol, 1.0 equiv.), (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoic acid (52.9 m To a stirred mixture of o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.275 mmol, 1.2 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.275 mmol, 1.2 equiv.) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (236 mg, 1.83 mmol, 8.0 equiv.) at 0°C. The mixture was stirred at room temperature for 1 hour. The crude product was purified by C18 column using CHCN:water (0.05% TFA). The compound fractions were concentrated under reduced pressure to give tert-butyl N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (105 mg, 78%) as a white solid. LC-MS (ESI, m / z): 546 [M+H] + .

[0345] To a stirred mixture of tert-butyl N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (100 mg, 0.183 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 then concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (81.0 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 446 [M+H] + .

[0346] (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (81.5 mg, 0.183 mmol, 1.0 equiv), o-(7-azabenzotriazol-1-yl) To a stirred mixture of N,N,N',N'-tetramethyluronium hexafluorophosphate (83.5 mg, 0.220 mmol, 1.2 equiv.) and 5-methyl-1,2-oxazole-3-carboxylic acid (23.3 mg, 0.183 mmol, 1.0 equiv.) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (189 mg, 1.46 mmol, 8.0 equiv.). The mixture was stirred at room temperature for 1 hour. The crude product was purified by C18 column chromatography using CHCN:water (0.05% TFA). The compound fractions were concentrated under reduced pressure to give N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-5-methyl-1,2-oxazole-3-carboxamide (74 mg, 62%) as a white solid. LC-MS (ESI, m / z): 554 [M+H] + .

[0347] To a stirred mixture of N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-5-methyl-1,2-oxazole-3-carboxamide (70.0 mg, 0.126 mmol, 1.0 equiv.) in DCM (2 mL) was added pyridine (39.9 mg, 0.504 mmol, 4.0 equiv.) and trifluoroacetic anhydride (53.0 mg, 0.252 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 3 h. The reaction was quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 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 Shield RP18 OBD column, 19 * Purification by HPLC (250 mm, 10 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 65% B, 65% B in 7 min; wavelength: 254 nm; RT (min): 5) gave (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-[(5-methyl-1,2-oxazol-3-yl)formamido]butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (7.70 mg, 11%) as a white solid. LC-MS (ESI, m / z): 537 [M+H] + .

[0348] Example 5 compound 5

[0349] [ka] To a solution of picolinic acid (110 mg, 0.894 mmol, 1.0 equiv.) in dimethylformamide (2 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (408 mg, 1.07 mmol, 1.2 equiv.) and N-ethyl-N-isopropylpropan-2-amine (924 mg, 7.15 mmol, 8.0 equiv.). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (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, which was purified by silica gel column chromatography to give tert-butyl (2S)-3,3-dimethyl-2-(pyridin-2-ylformamido)butanoate (88 mg, 33%). 1 H NMR (400MHz, DMSO-d6) δ8.67-8.73(m,1H),8.40-8.50(m,1H),8.00-8.10(m,2H),7.62-7.69(m,1H),4.26-4.33(m,1H),1.44(s,9H),1.00(s,9H). LCMS(ESI, m / z):293[M+H] + .

[0350] To a solution of tert-butyl (2S)-3,3-dimethyl-2-(pyridin-2-ylformamido)butanoate (88.0 mg, 0.291 mmol, 1.0 equiv.) in DCM (2 mL) was added trifluoroacetic acid (0.7 mL). The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure to give the crude product. LCMS (ESI, m / z): 237 [M+H] + .

[0351] To a solution of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (100 mg, 0.301 mmol, 1 equiv.) in DMF (4 mL) was added (2S)-3,3-dimethyl-2-(pyrimidin-3-yl)propan-2-yl. Lysin-2-ylformamido)butanoic acid (70.8 mg, 0.301 mmol, 1.0 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (137.3 mg, 0.361 mmol, 1.2 equiv.), and N-ethyl-N-isopropylpropan-2-amine (233 mg, 2.41 mmol, 8.0 equiv.) were added. The mixture was stirred at room temperature for 1 hour. The mixture was purified on a C18 column using CHCN:water (0.05% FA). The compound fractions were concentrated under reduced pressure to give N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]pyridine-2-carboxamide (50.0 mg, crude).

[0352] To a stirred mixture of N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]pyridine-2-carboxamide (25.0 mg, 0.045 mmol, 1.0 equiv) in DCM (2 mL) was added trifluoroacetic anhydride (8.81 mg, 0.090 mmol, 2.0 equiv) and pyridine (12.5 mg, 0.158 mmol, 3.5 equiv) dropwise at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 x 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 (25 mg) was purified by HPLC using the following conditions (column: Kinetex EVO C18, 21.2 * Purification by preparative HPLC (250 mm, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 62% B, 62% B in 7 min; wavelength: 254 nm; RT (min): 5) gave (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(pyridin-2-ylformamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (3.2 mg, 12%) as a pale yellow solid. LCMS (ESI, m / z): 533 [M+H] + .

[0353] Example 6 compound 6

[0354] [ka] A mixture of pyrazinoic acid (166 mg, 1.34 mmol, 1.0 equiv.), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (612 mg, 1.61 mmol, 1.2 equiv.), and N-ethyl-N-isopropylpropan-2-amine (1.04 g, 8.05 mmol, 6.0 equiv.) in N,N-dimethylformamide (3 mL) was stirred for 20 minutes. Tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (300 mg, 1.34 mmol, 1.0 equiv.) was added at 0°C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water (2 mL). The mixture was extracted with ethyl acetate (3 x 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) and slurried with 100-200 mesh silica gel (1 g). After removing the dichloromethane, the slurry was loaded onto a column. The sample was purified by column chromatography (4 × 24 cm, 200 mL column volume, 100-200 mesh silica gel) and eluted with EA:PE (0%-40% over 30 min). The collected fractions were: 23%-26% EA:PE fraction, selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give tert-butyl (2S)-3,3-dimethyl-2-(pyrazin-2-ylformamido)butanoate (300 mg, 76%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ9.21(br,1H),8.91-8.95(m,1H),8.75-8.82(m,1H),8.29-8.33(m,1H),4.31-4.34(m,1H),1.45(s,9H),1.01(s,9H). LC-MS(ESI, m / z):294[M+H] + .

[0355] To a mixture of tert-butyl (2S)-3,3-dimethyl-2-(pyrazin-2-ylformamido)butanoate (87.9 mg, 0.300 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-3,3-dimethyl-2-(pyrazin-2-ylformamido)butanoic acid (80.0 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 238 [M+H] + .

[0356] To a mixture of (2S)-3,3-dimethyl-2-(pyrazin-2-ylformamido)butanoic acid (71.1 mg, 0.30 mmol, 1.0 equiv.) and (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (99.6 mg, 0.30 mmol, 1.0 equiv.) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (348 mg, 2.70 mmol, 9.0 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. The crude product was purified by C18 column chromatography using CHCN:water (0.05% NHHCO). The compound fractions were concentrated under reduced pressure to give (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(pyrazin-2-ylformamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (70.0 mg, 43%) as a yellow solid. LC-MS (ESI, m / z): 552 [M+H] + .

[0357] To a mixture of N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]pyrazine-2-carboxamide (55.0 mg, 0.100 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added pyridine (31.5 mg, 0.400 mmol, 4.0 equiv.) and trifluoroacetic anhydride (41.9 mg, 0.200 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL). The mixture was extracted with ethyl acetate (3 x 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 * Purification by HPLC (150 mm, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: MeOH; flow rate: 25 mL / min; gradient: 43% B to 53% B, 53% B in 12 min; wavelength: 254 nm; RT1 (min): 11) afforded (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(pyrazin-2-ylformamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (3.0 mg, 5%) as an off-white solid. LC-MS (ESI, m / z): 534 [M+H] + .

[0358] Example 7 compound 7

[0359] [ka] To a mixture of 4-methoxyaniline (5.0 g, 36.4 mmol, 1.0 equiv.) and magnesium sulfate (24.4 g, 202 mmol, 5.0 equiv.) in DCM (100 mL) was added methyl 2-hydroxy-2-methoxyacetate (4.88 g, 40.5 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 3 hours and filtered. The filter cake was washed with dichloromethane (3 × 100 mL). The mixture was concentrated under reduced pressure to give methyl (2Z)-2-[(4-methoxyphenyl)imino]acetate (8 g, crude) as a brown-yellow oil. 1 H NMR (400MHz, CDCl3) δ7.95(s,1H),7.33-7.43(m,2H),6.85-6.99(m,2H),3.94(s,3H),3.83(s,3H). LC-MS (ESI, m / z): 194[M+H] + .

[0360] To a stirred mixture of powdered molecular sieves (5A, 4 g), sulfamide (0.20 g, 2.07 mmol, 0.05 equiv.), and N,N-dimethylpyridin-4-amine (0.25 g, 2.07 mmol, 0.05 equiv.) in DCM (40 mL) was added methyl (2Z)-2-[(4-methoxyphenyl)imino]acetate (8.00 g, 41.4 mmol, 1.0 equiv.) and isobutyraldehyde (3.58 g, 49.6 mmol, 1.2 equiv.) at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water (150 mL). The mixture was extracted with ethyl acetate (3 × 150 mL). The organic layers were combined, washed with brine (2 × 150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with EA:PE (1:4) to give methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethyl-4-oxobutanoate (4.5 g, 36%) as a pale yellow oil. 1H NMR (400MHz, DMSO-d6) δ9.58(s,1H),6.73(m,4H),5.42(d,J=8.0Hz,1H),4.44(d,J=8.0Hz,1H),3.65(s,3H),3.61(s,3H),0.85-1.34(m,6H). LC-MS(ESI, m / z):266[M+H] + .

[0361] To a stirred mixture of methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethyl-4-oxobutanoate (4.5 g, 16.9 mmol, 1.0 equiv.) and potassium carbonate (4.69 g, 33.9 mmol, 2.0 equiv.) in MeOH (50 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (4.24 g, 22.0 mmol, 1.3 equiv.) dropwise at room temperature under N2. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (200 mL). The mixture was extracted with ethyl acetate (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 chromatographed on a silica gel column with EA:PE (1:9) to give methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethylpent-4-ynoate (1.70 g, 36%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ6.65-6.76(m,4H),5.05(d,J=12.0Hz,1H),3.92(d,J=12.0Hz,1H),3.61-3.64(m,6H),3.09(s,1H),1.34(s,3H),1.29(s,3H). LC-MS(ESI, m / z):262[M+H] + .

[0362] To a stirred mixture of methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethylpent-4-ynoate (1.14 g, 4.36 mmol, 1.0 equiv.) in CHCN (9 mL) and HO (3 mL) was added cerium ammonium nitrate (12.0 g, 21.8 mmol, 5.0 equiv.) at room temperature. The mixture was stirred at room temperature for 2 hours. THF (10 mL) was added, followed by trimethylamine and di-tert-butyl dicarbonate (5.48 g, 25.1 mmol, 6.0 equiv.). The mixture was stirred at room temperature for 4 hours and then diluted with water (50 mL). The mixture was extracted with ethyl acetate (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 chromatographed on a silica gel column with EA:PE (1:9) to give methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylpent-4-ynoate (800 mg, 63%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.01(d,J=12.0Hz,1H),4.11(d,J=12.0Hz,1H),3.65(s,3H),3.06(s,1H),1.39(s,9H),1.21-1.23(m,6H). LC-MS(ESI, m / z):156[M+H-Boc] + .

[0363] To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylpent-4-ynoate (800 mg, 3.13 mmol, 1.0 equiv.) in THF (6 mL) and HO (2 mL) was added lithium hydride (375 mg, 15.6 mmol, 5.0 equiv.) at room temperature. The mixture was stirred at 60 °C for 1 h. The mixture was acidified to pH = 3 with hydrochloric acid (1 M). The aqueous layer was extracted with ethyl acetate (3 × 20 mL). The mixture was concentrated under reduced pressure to give (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylpent-4-ynoic acid (700 mg, 92%) as a light orange solid. 1H NMR (400MHz, DMSO-d6) δ12.76(s,1H),6.69(d,J=8.0Hz,1H),4.00(d,J=8.0Hz,1H),3.03(s,1H),1.40(s,9H),1.17-1.24(m,6H). LC-MS(ESI,m / z):142[M-100+H] + .

[0364] To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylpent-4-ynoic acid (400 mg, 1.65 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 hour and then concentrated under reduced pressure to give (2S)-2-amino-3,3-dimethylpent-4-ynoic acid (300 mg, crude) as a brown oil. LC-MS (ESI, m / z): 142 [M+H] + .

[0365] To a stirred mixture of (2S)-2-amino-3,3-dimethylpent-4-ynoic acid (234 mg, 1.65 mmol, 1.0 equiv.) and triethylamine (670 mg, 6.63 mmol, 4.0 equiv.) in MeOH (3 mL) was added ethyl 2,2,2-trifluoroacetate (471 mg, 3.31 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 2 hours and then acidified to pH = 4 with hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were concentrated under reduced pressure to give (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoic acid (300 mg, 76%) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),9.67(d,J=8.0Hz,1H),4.45(d,J=8.0Hz,1H),3.09(s,1H),1.25-1.41(m,6H). LC-MS (ESI, m / z): 236[MH] - .

[0366] To a stirred mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoic acid (71.3 mg, 0.300 mmol, 1.0 equiv) in DMF (2 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (137 mg, 0.361 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (232 mg, 1.80 mmol, 6.0 equiv) at room temperature. The mixture was stirred at 0 °C for 10 min, and (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (110 mg, 0.300 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for an additional 1 h. The mixture was purified by C18 column chromatography using CHCN:water (0.05% FA). The compound fractions were concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (120 mg, 51%) as a pale yellow solid. LC-MS (ESI, m / z): 552 [M+H] + .

[0367] To a stirred mixture of (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (120 mg, 0.218 mmol, 1.0 equiv.) in DCM (2 mL) was added pyridine (60.2 mg, 0.763 mmol, 3.5 equiv.) and trifluoroacetic anhydride (91.3 mg, 0.436 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 x 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 (350 mg) was purified using the following conditions (column: XBridge Shield RP18 OBD column, 19 * Purification by preparative HPLC using a 250 mm column, 10 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 min; wavelength: 254 nm; RT (min): 5 gave (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (14.9 mg, 12%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.46-9.16(m,2H),7.27-7.52(m,1H),5.93-6.25(m,2H ),4.78-4.93(m,1H),4.62-4.75(m,1H),3.89-4.09(m,1H),3.55-3.76(m,1H),3.33 -3.47(m,1H),3.09-3.21(m,2H),2.79-3.02(m,4H),2.65-2.78(m,1H),2.27-2.41( m,1H),1.98-2.25(m,2H),1.61-1.91(m,2H),1.32-1.45(m,2H),1.07-1.31(m,6H).

[0368] Example 8 compound 8

[0369] [ka] * The chiral center indicated by is tentatively assigned to (a).

[0370] To a mixture of methyltriphenylphosphanium bromide (68.4 g, 191 mmol, 1.4 equiv.) in tetrahydrofuran (100 mL) was added 1-tetralone (20.0 g, 136 mmol, 1.0 equiv.) at 0 °C. After stirring at 0 °C for 0.5 h, methyltriphenylphosphanium bromide (68.4 g, 191 mmol, 1.4 equiv.) was added. The mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with dichloromethane (100 mL) and slurried with 100-200 mesh silica gel (60 g). After removing the dichloromethane, the mixture was loaded onto a column. The sample was purified by column chromatography (column size: 6 × 24 cm, column volume: 600 mL, silica gel size (100-200 mesh)) and eluted with PE (0% to 10% over 30 min). Collected fractions: The 0% PE fraction was selected as the pure fraction. These fractions were combined and concentrated under reduced pressure to give 1-methylidene-3,4-dihydro-2H-naphthalene (12.0 g, 60%) as a pale yellow oil. LC-MS (ESI, m / z): 145 [M+H] + .

[0371] To a stirred mixture of 1-methylidene-3,4-dihydro-2H-naphthalene (1.00 g, 6.930 mmol, 1.0 equiv.), [Ru(p-cymene)Cl] (212 mg, 0.350 mmol, 0.05 equiv.), and (S)-(i-Pr)-Pybox (209 mg, 0.690 mmol, 0.1 equiv.) in tetrahydrofuran (80 mL) was added ethyl 2-diazoacetate (1.18 g, 10.4 mmol, 1.5 equiv.) in portions over 8 h at 60 °C under nitrogen. The reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (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 sample was purified by column chromatography (column size: 6 x 24 cm, column volume: 600 mL, silica gel size (100-200 mesh)) and eluted with EA:PE (0%-10% over 30 min). The collected fractions: 5-8% PE fractions were selected as pure fractions. These fractions were combined and concentrated under reduced pressure to obtain the crude product. The crude product was analyzed by TLC (mobile phase: EA:PE = 1:40; R f =0.4; detection: UV) to obtain ethyl (1R * ,3R * )-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3-carboxylate as a light yellow oil. 1 H NMR(300MHz,DMSO-d6)δ7.01-7.13(m,3H),6.81-6.86(m,1H),4.02-4.19(m,2H),2.80-2 .84(m,2H),1.76-1.93(m,4H),1.52-1.71(m,2H),1.34-1.43(m,1H),1.16-1.24(m,3H). LC-MS(ESI, m / z):231[M+H] + .

[0372] To a stirred solution of ethyl (1R,3R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3-carboxylate (380 mg, 1.65 mmol, 1.0 equiv.) in ethanol (4 mL) was added sodium hydroxide (461 mg, 11.5 mmol, 7.0 equiv. in 4 mL of water). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove ethanol. The mixture was adjusted to pH 5 with hydrochloric acid (2 M) and then extracted with ethyl acetate (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 (1R,3R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3-carboxylic acid (240 mg, 71%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ 12.24 (br, 1H), 6.89-7.21 (m, 4H), 2.72-2.91 (m, 2H), 1.51-1.89 (m, 6H), 1.26-1.45 (m, 1H). LC-MS(ESI, m / z):203[M+H] + .

[0373] To a mixture of (1R,3R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3-carboxylic acid (71.2 mg, 0.352 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.74 mg, 0.065 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (273 mg, 2.11 mmol, 6.0 equiv) at 0°C. After the mixture was stirred at 0 °C for 20 min, (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (130 mg, 0.352 mmol, 1.0 equiv) was added at 0 °C. The mixture was stirred at room temperature for 1 h. The crude product was purified by C18 column using CH3CN:water (TFA 0.05%). The compound fractions were concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S)-4-{[(1R,3R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalen]-3-yl]carbonyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propenamide (70 mg, 43%) as a yellow solid. LC-MS (ESI, m / z): 517 [M+H]+.

[0374] To a mixture of (2S)-2-{[(1R,2S,3S,6R,7S)-4-{[(1S,3S)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalen]-3-yl]carbonyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (70.0 mg, 0.135 mmol, 1.0 equiv.) in dichloromethane (1 mL) was added pyridine (37.5 mg, 0.473 mmol, 3.5 equiv.) and trifluoroacetic anhydride (56.9 mg, 0.270 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight. The reaction was quenched with water (5 mL). The mixture was extracted with ethyl acetate (3 x 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: XSelect CSH Prep C18 OBD column, 19 * Purification using a 150 mm column, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 41% B to 61% B, 61% B in 7 min; wavelength: 254 nm; RT (min): 5.47 gave (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-{[(1R,3R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalen]-3-yl]carbonyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (17 mg, 25%) as a white solid. LC-MS (ESI, m / z): 499 [M + H] + .

[0375] Example 9 compound 9

[0376] [ka] (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanamide To a solution of (2S)-2-amino-3-{5-oxo-4H,6H,7H-pyrazolo[1,5-a]pyrimidin-6-yl}propanamide (70 mg, 0.31 mmol, 1.0 equiv) in DMF (2 mL) was added N,N,N,N-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl Methyl chloroformamidinium hexafluorophosphate (106 mg, 0.38 mmol, 1.2 equiv.), NMI (180 mg, 2.2 mmol, 7.0 equiv.), and (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanamide (134 mg, 0.35 mmol, 1.1 equiv.) were added. The mixture was stirred at 0 °C for 2 h and then chromatographed on a C18 column with MeCN:HO (3:7) to give (1S,3aR,4S,7R,7aS)-N-((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (75 mg, 36%) as a tan semisolid. LC-MS (ESI, m / z): 594 [M+H] + .

[0377] To a solution of (1S,3aR,4S,7R,7aS)-N-((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (75 mg, 0.13 mmol, 1.0 equiv) in DCM (2 mL) was added pyridine (70 mg, 0.88 mmol, 7.0 equiv) and TFAA (106 mg, 0.5 mmol, 4.0 equiv) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water (2 mL). The mixture was extracted with DCM (3 x 3 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 * Purification using a 150 mm column, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 67% B, 67% B in 7 min; wavelength: 254 nm; RT (min): 5.25 gave (1S,3aR,4S,7R,7aS)-N-((1S)-1-cyano-2-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (4.5 mg, 6%) as a white solid. LC-MS (ESI, m / z): 576 [M + H] + .

[0378] Example 10 compound 10

[0379] [ka] To a mixture of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.0 g, 122 mmol, 1.0 equiv.), triethylamine (22.3 g, 220 mmol, 1.8 equiv.), and N,N-dimethylpyridin-4-amine (4.48 g, 36.7 mmol, 0.3 equiv.) in DCM (500 mL) was added methanesulfonyl chloride (21.0 g, 183 mmol, 1.5 equiv.) dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water (500 mL). The mixture was extracted with DCM (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 chromatographed on a silica gel column with EtOAc:PE (1:1) to give 1-tert-butyl 2-methyl(2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (35.0 g, 85%) as a pale yellow solid. LC-MS (ESI, m / z): 224 [M+H-Boc] + .

[0380] To a mixture of 1-tert-butyl 2-methyl(2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (25.0 g, 77.3 mmol, 1.0 equiv.) and diphenyl diselenide (24.1 g, 77.3 mmol, 1.0 equiv.) in MeOH (600 mL) was added sodium borohydride (3.80 g, 100 mmol, 1.3 equiv.) at 0° C. The mixture was stirred at 70° C. overnight and then concentrated under reduced pressure to remove MeOH. Water (600 mL) was added, and the mixture was extracted with EtOAc (3×600 mL). The organic layers were combined, washed with brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with EtOAc:PE (1:8) to give 1-tert-butyl 2-methyl(2S,4S)-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (26.8 g, 84%) as a yellow oil. LC-MS (ESI, m / z): 286 [M-100+H] + .

[0381] To a mixture of 1-tert-butyl 2-methyl(2S,4S)-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (26.8 g, 69.7 mmol, 1.0 equiv.) and pyridine (9.38 g, 118 mmol, 1.7 equiv.) in DCM (300 mL) was added hydrogen peroxide (31.6 mL, 279 mmol, 4.0 equiv., 30% in water). The mixture was stirred at room temperature for 5 hours. The reaction was quenched with water (500 mL). The mixture was extracted with DCM (3 × 400 mL). The organic layers were combined, washed with citric acid (500 mL, 1 M), saturated aqueous sodium sulfite solution (500 mL), washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with EtOAc:PE (1:5) to give 1-tert-butyl 2-methyl(2S)-2,5-dihydropyrrole-1,2-dicarboxylate (10.5 g, 62%) as a yellow oil. 1 H NMR (300MHz, CDCl3) δ5.91-5.04(m,1H),5.67-5.79(m,1H),4.92-5.09(m,1H),4.17-4.35(m,2H),3.71-3.79(m,3H),1.42-1.52(m,9H). LC-MS (ESI, m / z): 128[M+H-Boc] + .

[0382] A mixture of 1-tert-butyl 2-methyl(2S)-2,5-dihydropyrrole-1,2-dicarboxylate (3.68 g, 16.2 mmol, 1.0 equiv) in dicyclopentadiene (40 mL) was stirred at 170 °C overnight. The mixture was diluted with DCM (500 mL) and slurried with 100-200 mesh silica gel (50 g). The mixture was loaded onto a column. After removing the DCM under reduced pressure, the sample was purified by column chromatography (6 × 24 cm column, 600 mL column volume, 330 g silica gel (100-200 mesh)) eluted with EtOAc:PE (0%-50% over 30 min). The collected fractions were selected as pure fractions: 19%-25% EtOAc:PE fraction. These fractions were combined and concentrated under reduced pressure to give the crude product (2.5 g). The crude product was purified by C18 column chromatography using CH3CN:water (0.05% TFA). The compound fractions were concentrated under reduced pressure to give 4-tert-butyl 3-methyl(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3,4-dicarboxylate (1.70 g, 32%) as a yellow oil. 1 H NMR(300MHz,CDCl3)δ6.12-6.30(m,2H),3.78-3.98(m,1H),3.72(s,3H),3.38-3.51( m, 1H), 3.04-3.21 (m, 2H), 2.77-2.96 (m, 3H), 1.50-1.58 (m, 1H), 1.32-1.46 (m, 10H). LC-MS (ESI, m / z): 194[M+H-Boc] + .

[0383] A mixture of 4-tert-butyl 3-methyl(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3,4-dicarboxylate (500 mg, 1.70 mmol, 1.0 equiv) in hydrogen chloride (10 mL, 2 M in EtO) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give methyl(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylate hydrochloride (391 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 194 [M+H] + .

[0384] To a mixture of methyl (1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylate hydrochloride (391 mg, 1.70 mmol, 1.0 equiv.), (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoic acid (394 mg, 1.70 mmol, 1.0 equiv.), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (777 mg, 2.04 mmol, 1.2 equiv.) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.32 g, 10.2 mmol, 6.0 equiv.) at 0° C. The mixture was stirred at room temperature for 1 h. 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 chromatographed on a silica gel column with EtOAc:PE (8:92) to give methyl (1R,2S,3S,6R,7S)-4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylate (490 mg, 69%) as an off-white semisolid. 1H NMR(300MHz,CDCl3)δ6.03-6.27(m,2H),5.11-5.26(m,1H),4.18-4.36(m,2H),3.72-3.78(m,3H),3.54-3.70(m,2H) ,2.97-3.14(m,2H),2.86-2.94(m,2H),1.49-1.54(m,1H),1.41-1.48(m,9H),1.33-1.39(m,1H),0.92-1.00(m,9H). LC-MS(ESI, m / z):407[M+H] + .

[0385] To a mixture of methyl (1R,2S,3S,6R,7S)-4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylate (490 mg, 1.205 mmol, 1.0 equiv) in THF (5 mL) / water (5 mL) was added lithium hydroxide (144 mg, 6.03 mmol, 5.0 equiv). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove THF, and the pH was adjusted to 5 with 2 M hydrochloric acid. 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 (1R,2S,3S,6R,7S)-4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (465 mg, 97%) as a white solid. 1 H NMR(300MHz,CDCl3)δ6.04-6.30(m,2H),5.21-5.29(m,1H),4.22-4.32(m,2H),3.52-3.79(m,2H) ,3.06-3.24(m,2H),2.91-3.04(m,2H),1.51-1.56(m,1H),1.37-1.47(m,10H),0.95-1.00(m,9H). LC-MS (ESI, m / z):393[M+H] + .

[0386] To a mixture of (1R,2S,3S,6R,7S)-4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (465 mg, 1.18 mmol, 1.0 equiv) in DCM (15 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give (1R,2S,3S,6R,7S)-4-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (346 mg, crude) as a dark blue semisolid. LC-MS (ESI, m / z): 293 [M+H] + .

[0387] To a mixture of (1R,2S,3S,6R,7S)-4-[(2S)-2-2-amino-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (346 mg, 1.18 mmol, 1.0 equiv.) in MeOH (10 mL) was added triethylamine (1.44 g, 14.2 mmol, 12.0 equiv.) and ethyl 2,2,2-trifluoroacetate (1.01 g, 7.10 mmol, 6.0 equiv.). The mixture was stirred overnight at room temperature and concentrated under reduced pressure to remove MeOH. The crude product was purified by C18 column chromatography using CH3CN:water (0.05% TFA). The compound fractions were concentrated under reduced pressure to give (1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (310 mg, 65%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ12.22-13.12(m,1H),8.96-9.49(m,1H),5.88-6.24(m,2H),4.24-4.60(m,1 H),3.94-4.05(m,1H),3.43-3.58(m,2H),2.67-3.04(m,4H),1.30-1.44(m,2H),0.76-1.05(m,9H). LC-MS(ESI, m / z):389[M+H]+ .

[0388] To a mixture of (1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (102 mg, 0.263 mmol, 1.0 equiv) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.316 mmol, 1.2 equiv) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (204 mg, 1.58 mmol, 6.0 equiv) at 0 °C. After stirring at 0° C. for 15 minutes, (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide hydrochloride (73.0 mg, 0.263 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 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 chromatographed on a silica gel column with MeOH:DCM (7:93) to give (3S)-N-cyclopropyl-3-{[(1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamido}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (120 mg, 68%) as a pale yellow solid. LC-MS (ESI, m / z): 612 [M+H] + .

[0389] To a mixture of (3S)-N-cyclopropyl-3-{[(1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamido}-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (120 mg, 0.196 mmol, 1.0 equiv.) in DMSO (3 mL) was added 2-iodoxybenzoic acid (165 mg, 0.588 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (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 to give the crude product. The crude product was chromatographed on a silica gel column with MeOH:DCM (4:96) to give N-cyclopropyl-3-{[(1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamido}-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (31.8 mg, 24%) as a white solid. LC-MS (ESI, m / z): 610 [M+H] + .

[0390] Example 11 compound 11

[0391] [ka] A mixture of tert-butyl (1R,2S,3S,6R,7S)-3-{[(2S)-1-(cyclopropylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-4-carboxylate (150 mg, 0.298 mmol, 1.0 equiv) in hydrogen chloride (2 mL, 2 M in EtO) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (130 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 403 [M+H] + .

[0392] To a mixture of (1R,3R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-3-carboxylic acid (76.03 mg, 0.376 mmol, 1.1 equiv) in N,N-dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (155 mg, 0.410 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (265 mg, 2.05 mmol, 6.0 equiv) at 0°C. The mixture was stirred at 0° C. for 20 minutes, and then (1S,3aR,4S,7R,7aS)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (150 mg, 0.342 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The residue was purified by preparative TLC (dichloromethane:methanol, 12:1) to give (1S,3aR,4S,7R,7aS)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-((1R,2R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (80 mg, 40%) as a yellow solid. LC-MS (ESI, m / z): 587 [M+H] + .

[0393] To a stirred mixture of (1S,3aR,4S,7R,7aS)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-((1R,2R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (80.0 mg, 0.136 mmol, 1.0 equiv.) in DMSO (2 mL) was added 2-iodoxybenzoic acid (114 mg, 0.408 mmol, 3.0 equiv.). The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (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 to give the crude product. The crude product was chromatographed on a silica gel column with dichloromethane:methanol (94:6) to give (1S,3aR,4S,7R,7aS)-N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-((1R,2R)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide as a white solid. LC-MS (ESI, m / z): 585 [M+H] + .

[0394] Example 12 compound 12

[0395] [ka] To a mixture of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (95.0 mg, 0.175 mmol, 1.0 equiv) in EtOAc (3 mL) was added 10% palladium on activated carbon (90.0 mg). The mixture was stirred at room temperature under hydrogen for 3 hours. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give (1S,3aR,4R,7S,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (75.0 mg, crude) as an off-white solid. LC-MS (ESI, m / z): 544 [M+H] + .

[0396] To a mixture of (1S,3aR,4R,7S,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (75.0 mg, 0.138 mmol, 1.0 equiv.) in DCM (2 mL) was added pyridine (76 mg, 0.966 mmol, 7.0 equiv.) and trifluoroacetic anhydride (116 mg, 0.552 mmol, 4.0 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL). The mixture was extracted with DCM (3 × 5 mL). The organic layers were combined, washed with brine (2 x 5 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: XSelect CSH Prep C18 OBD Column, 19 × 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 36% B to 56% B, 56% B in 7 min; Wavelength: 254 nm; RT: 6.18 min) to give (1S,3aR,4R,7S,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (19.6 mg, 26%) as a white solid. 1 H NMR(400MHz,80℃,DMSO-d6)δ8.85-9.20(m,1H),8.60-8.84(m,1H),7.35-7.55(m,1H) ),4.80-4.98(m,1H),4.59-4.75(m,1H),4.30-4.58(m,1H),3.76-3.85(m,1H),3.45 -3.75(m,1H),3.10-3.25(m,2H),2.55-2.70(m,1H),2.30-2.54(m,3H),2.05-2.29( m, 3H), 1.62-1.88 (m, 2H), 1.40-1.60 (m, 2H), 1.05-1.39 (m, 4H), 0.95-1.04 (m, 9H). LC-MS(ESI, m / z):526[M+H] +.

[0397] Example 13 compound 13

[0398] [ka] To a stirred mixture of tert-butyl (1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-4-carboxylate (250 mg, 0.578 mmol, 1.0 equiv) in ethyl acetate (3 mL) was added 10% palladium on activated carbon (120 mg) at room temperature. The mixture was stirred under hydrogen for 1.5 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl (1S,2S,3S,6R,7R)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]decane-4-carboxylate (200 mg, 75%) as a white solid. LC-MS (ESI, m / z): 435 [M+H] + .

[0399] To a stirred mixture of tert-butyl (1S,2S,3S,6R,7R)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]decane-4-carboxylate (200 mg, 0.460 mmol, 1.0 equiv) in DCM (2 mL) was added hydrogen chloride (6 mL, 2 M in EtO) at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-2-[(1S,2S,3S,6R,7R)-4-azatricyclo[5.2.1.0^{2,6}]decan-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (180 mg, crude) as a brown oil. LC-MS (ESI, m / z): 335 [M+H] + .

[0400] To a stirred mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (124 mg, 0.550 mmol, 1.2 equiv.) in DMF (2 mL), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (209 mg, 0.550 mmol, 1.2 equiv.) and N-ethyl-N-isopropylpropan-2-amine (355 mg, 2.74 mmol, 6.0 equiv.) were added at room temperature. The mixture was stirred at room temperature for 10 minutes, and (2S)-2-[(1S,2S,3S,6R,7R)-4-azatricyclo[5.2.1.0^{2,6}]decan-3-ylformamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (170 mg, 0.458 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (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 chromatographed on a silica gel column with MeOH:DCM (1:15) to give (2S)-2-{[(1S,2S,3S,6R,7R)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]decan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (135 mg, 54%) as a light yellow solid. LC-MS (ESI, m / z): 553 [M+H] + .

[0401] To a stirred mixture of (2S)-2-{[(1S,2S,3S,6R,7R)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoyl]-4-azatricyclo[5.2.1.0^{2,6}]decan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (135 mg, 0.244 mmol, 1.0 equiv) in DCM (2 mL) was added trifluoroacetic anhydride (102 mg, 0.488 mmol, 2.0 equiv) and pyridine (67.5 mg, 0.854 mmol, 3.5 equiv). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with dichloromethane (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 (100 mg) was purified using the following conditions (column: XBridge Prep C18 OBD column, 19 * Purification by preparative HPLC using a 150 mm column, 5 μm nozzle; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 min; wavelength: 254 nm; RT (min): 5) gave (1S,2S,3S,6R,7R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)pent-4-ynoyl]-4-azatricyclo[5.2.1.0-{2,6}]decane-3-carboxamide (18.8 mg, 14%) as a white solid. LC-MS (ESI, m / z): 536 [M+H] + .

[0402] Example 14 compound 14

[0403] [ka] To a solution of tert-butyl ((S)-1-hydroxy-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate (400 mg, 1.41 mmol, 1.0 equiv) in CCl4 (6 mL) and acetonitrile (6 mL) was added sodium periodate (1.52 g, 7.13 mmol, 5.07 equiv, in 9 mL of water) and ruthenium trichloride (35.0 mg, 0.169 mmol, 0.12 equiv) at 0 °C. The mixture was stirred at room temperature for 2 h and then filtered through Celite. The filtrate was extracted with DCM (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 give the crude product. The crude product was purified by C18 column chromatography using CHCN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoic acid (240 mg, 57%) as a white solid. LC-MS (ESI, m / z): 299 [M+H] + .

[0404] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoic acid (130 mg, 0.436 mmol, 1.0 equiv.) in THF (3 mL), 1-hydroxybenzotriazole (177 mg, 1.31 mmol, 3.0 equiv.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (184 mg, 0.959 mmol, 2.2 equiv.) were added and stirred at 0° C. After stirring for 1 hour, ammonium hydroxide (2.6 mL) was added. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the crude product. The crude product was purified by C18 column using CHCN:water (0.05% FA). The desired fractions were concentrated under reduced pressure to afford tert-butyl ((S)-1-amino-1-oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate (80 mg, 61%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.11-7.6(m,1H),6.47-6.51(m,1H),6.03(br,1H),5.85(m,1H),4.36-4.42(m,1H),2.78-2.85(m, 1H),2.26-2.34(m,1H),2.13-2.21(m,1H),1.89-2.04(m,2H),1.43-1.51(m,9H),0.77-0.98(m,2H),0.67-0.75(m,2H). LC-MS(ESI, m / z):298[M+H] + .

[0405] A mixture of tert-butyl ((S)-1-amino-1-oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate (80.0 mg, 0.269 mmol, 1.0 equiv.) in hydrogen chloride (3 mL, 2 M in diethyl ether) was stirred at room temperature for 5 hours and then concentrated under reduced pressure to give (S)-2-amino-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propanamide hydrochloride (60 mg, crude) as a yellow solid. LC-MS (ESI, m / z): 198 [M+H] + .

[0406] To a mixture of (1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxylic acid (110 mg, 0.283 mmol, 1.1 equiv) in dimethylformamide (2 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117 mg, 0.308 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (199 mg, 1.54 mmol, 6.0 equiv) at 0 °C. After stirring for 20 minutes, (S)-2-amino-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propanamide hydrochloride (60.0 mg, 0.257 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL). The mixture was purified by C18 column using CH3CN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (65 mg, 44%) as a white solid. LC-MS (ESI, m / z): 568 [M+H] + .

[0407] To a mixture of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (60.0 mg, 0.106 mmol, 1.0 equiv.) in DCM (2 mL) was added pyridine (41.8 mg, 0.530 mmol, 5.0 equiv.) and trifluoroacetic anhydride (51.1 mg, 0.244 mmol, 2.3 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with DCM (3 x 30 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 preparative HPLC (column: XBridge Shield RP18 OBD column, 19 * Purification by chromatography (HPLC) on a 250 mm column, 10 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 70% B, 70% B in 7 min; wavelength: 220 nm; RT (min): 5.63 gave (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (27.5 mg, 47%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.75-8.81(m,1H),8.67-8.69(m,1H),7.50-7.57(m,1H),5.93-6.16( m,2H),4.84-4.89(m,1H),4.44-4.64(m,1H),3.98-4.12(m,1H),3.58-3.66(m,1H),3.37-3.47(m, 1H),3.07-3.17(m,1H),2.79-2.93(m,2H),2.63-2.73(m,1H),2.54-2.63(m,1H),2.12-2.29(m,1H) ),1.74-1.99(m,3H),1.32-1.42(m,2H),0.88-0.94(m,9H),0.71-0.77(m,1H),0.48-0.62(m,3H). LC-MS(ESI, m / z):550[M+H] + .

[0408] Example 15 compound 15

[0409] [ka] To a mixture of (1S,3aR,4S,7R,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (500 mg, 1.29 mmol, 1.0 equiv.) in ethyl acetate (10 mL) was added 10% palladium on activated carbon (120 mg). The mixture was stirred at room temperature under hydrogen overnight. The mixture was filtered through a pad of Celite and washed with ethyl acetate (150 mL). The filtrate was concentrated under reduced pressure to give (1S,3aR,4R,7S,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxylic acid (460 mg, crude) as an off-white solid. LC-MS (ESI, m / z): 391 [M+H] + .

[0410] To a mixture of (1S,3aR,4R,7S,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxylic acid (184 mg, 0.471 mmol, 1.1 equiv) in dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (195 mg, 0.514 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (332 mg, 2.57 mmol, 6.0 equiv) at 0 °C. After stirring for 20 minutes, (S)-2-amino-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propanamide hydrochloride (100 mg, 0.428 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL). The mixture was purified by C18 column using CH3CN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give (1S,3aR,4R,7S,7aS)-N-((S)-1-amino-1-oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (140 mg, 57%) as a white solid. LC-MS (ESI, m / z): 570 [M+H] + .

[0411] To a mixture of (1S,3aR,4R,7S,7aS)-N-((S)-1-amino-1-oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (140 mg, 0.246 mmol, 1.0 equiv.) in DCM (3 mL) was added pyridine (77.8 mg, 0.984 mmol, 4.0 equiv.) and trifluoroacetic anhydride (92.9 mg, 0.443 mmol, 1.8 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with DCM (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 chromatographed on a silica gel column with EA:PE (65%-72%) to give (1S,3aR,4R,7S,7aS)-N-((S)-1-cyano-2-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (47.6 mg, 33%) as a white solid. 1 H NMR(400MHz,80℃,DMSO-d6)δ8.94-8.98(m,1H),8.57-8.75(m,1H),7.51-7.59(m,1H),4.83-4.90( m,1H),4.56-4.68(m,1H),4.46-4.48(m,1H),3.70-3.79(m,1H),3.57-3.65(m,1H),2.49-2.68(m, 2H),2.31-2.42(m,2H),2.12-2.22(m,2H),1.89-2.01(m,2H),1.79-1.86(m,1H),1.35-1.49(m,2H ),1.19-1.32(m,3H),1.06-1.14(m,1H),0.93-0.97(m,9H),0.72-0.75(m,1H),0.49-0.62(m,3H). LC-MS (ESI, m / z): 552[M+H] + .

[0412] Example 16 compound 16

[0413] [ka] To a mixture of (1S,3aR,4S,7R,7aS)-2-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (2.00 g, 5.09 mmol, 1.0 equiv.) in DCM (30 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the product (1S,3aR,4S,7R,7aS)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (1.40 g, crude) as a solid. LC-MS (ESI, m / z): 293 [M + H] + .

[0414] To a stirred mixture of (1S,3aR,4S,7R,7aS)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (1.49 g, 5.09 mmol, 1.0 equiv.) in MeOH (10 mL) was added triethylamine (6.19 g, 61.1 mmol, 12.0 equiv.) and ethyl 2,2,2-trifluoroacetate (4.34 g, 30.5 mmol, 6.0 equiv.). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to remove MeOH. The crude product was purified by C18 column chromatography using CH3CN / water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (1.17 g, 59%) as a yellow solid. LC-MS (ESI, m / z): 389 [M+H] + .

[0415] A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoate (1.0 g, 3.32 mmol, 1.0 equiv) in ammonia (20 mL, 7 M in MeOH) was stirred overnight at 80° C. The mixture was concentrated under reduced pressure to give tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate (1.01 g, crude) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ7.36-7.65(m,1H),7.14-7.35(m,1H),6.44-7.12(m,2H),3.74-4 .22(m,1H),2.91-3.30(m,2H),1.99-2.40(m,2H),1.45-1.94(m,4H),0.94-1.44(m,10H). LC-MS(ESI, m / z):286[M+H] + .

[0416] A mixture of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate (120 mg, 0.421 mmol, 1.0 equiv.) in hydrogen chloride (3 mL, 2 M in EtO) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (2S)-2-amino-3-[(3S)-2-oxopiperidin-3-yl]propanamide hydrochloride (80.0 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 186 [M+H] + .

[0417] To a mixture of (1S,3aR,4S,7R,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (162 mg, 0.420 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (191 mg, 0.504 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (325 mg, 2.52 mmol, 6.0 equiv) at 0 °C. After the mixture was stirred at 0° C. for 20 minutes, (2S)-2-amino-3-[(3S)-2-oxopiperidin-3-yl]propanamide hydrochloride (93.0 mg, 0.420 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL). The mixture was extracted with EtOAc (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 was chromatographed on a silica gel column with MeOH:DCM (6:94) to give (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (160 mg, 68%) as a pale yellow solid. LC-MS (ESI, m / z): 556 [M+H] + .

[0418] To a mixture of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (160 mg, 0.288 mmol, 1.0 equiv.) in DCM (3 mL) was added pyridine (91.1 mg, 1.15 mmol, 4.0 equiv.) and trifluoroacetic anhydride (120 mg, 0.576 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (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 to give the crude product. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19 * Purification by chromatography (HPLC) on a 250 mm column, 10 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 55% B, 55% B in 10 min; wavelength: 254 nm; RT1 (min): 8.15) gave (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (38.5 mg, 25%) as an off-white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.75-8.95(m,1H),8.60-8.73(m,1H),7.15-7.40(m,1H),5.90-6 .30(m,2H),4.65-5.10(m,1H),4.40-4.60(m,1H),3.90-4.25(m,1H),3.55-3.75(m,1H),3.35 -3.50(m,1H),3.10-3.20(m,2H),3.00-3.05(m,1H),2.85-3.00(m,2H),2.65-2.80(m,1H),2. 20-2.50(m,2H),1.70-1.95(m,3H),1.50-1.70(m,1H),1.30-1.50(m,3H),0.80-1.05(m,9H). LC-MS(ESI, m / z):538[M+H] + .

[0419] Example 17 Compounds 17a and 17b

[0420] [ka] " * The chiral centers marked with "" are tentatively assigned.

[0421] Tert-butyl ((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (290 mg) was purified by SFC using the following gradient conditions: Column: OptiChiral-C9-5, 3 *25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA (0.5% 2M NH3-MeOH); Flow rate: 100 mL / min; Gradient: Isocratic 35% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.3; RT2 (min): 5.85; Sample solvent: MeOH-----preparative; Injection volume: 4.8 mL; Purification afforded tert-butyl ((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (210 mg) as an off-white solid, which was purified by SFC using the following gradient conditions: Column: Lux 5um Cellulose-4, 3 * 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA (0.5% 2M NH3-MeOH); Flow rate: 100 mL / min; Gradient: Isocratic 40% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 2.87; RT2 (min): 4.33; Sample solvent: MeOH--preparative; Injection volume: 4.8 mL; Run number: 4. Purification afforded tert-butyl ((S)-1-amino-1-oxo-3-((R * )-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (80 mg) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ10.78(s,1H),7.29-7.32(m,2H),6.96-7.06(m,2H),5.59-5.60(m,1H),4.31-4.3 7(m,1H),3.95-4.03(m,2H),2.69-2.80(m,1H),2.09-2.19(m,1H),1.69-1.77(m,1H),1.24-1.37(m,9H). LC-MS(ESI, m / z):324[M+H] + .

[0422] Furthermore, tert-butyl ((S)-1-amino-1-oxo-3-((S)-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (90 mg) was obtained as a gray-white solid. 1 H NMR(300MHz,DMSO-d6)δ10.76(s,1H),7.29-7.33(m,2H),6.95-7.06(m,2H),5.58-5.59(m,1H),4.40-4.4 4(m,1H),3.93-4.07(m,2H),2.75-2.81(m,1H),2.21-2.25(m,1H),1.51-1.61(m,1H),1.20-1.24(m,9H). LC-MS(ESI, m / z):324[M+H] + .

[0423] tert-Butyl ((S)-1-amino-1-oxo-3-((R * A solution of (S)-2-amino-3-((R)-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (70 mg, 0.216 mmol, 1.0 equiv) in hydrochloric acid (2 mL, 4 M in dioxane) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give (S)-2-amino-3-((R)-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanamide (40 mg, crude) as a white solid. LC-MS (ESI, m / z): 224 [M+H] + .

[0424] (S)-2-amino-3-((R *To a solution of (1S,3aR,4R,7S,7aS)-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanamide (40 mg, 0.18 mmol, 1.0 equiv.) in DMF (1 mL) was added (1S,3aR,4R,7S,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxylic acid (77 mg, 0.2 mmol, 1.1 equiv.), N,N,N,N-tetramethylchloroformamidium hexafluorophosphate (66 mg, 0.24 mmol, 1.3 equiv.), and NMI (74 mg, 0.9 mmol, 5.0 equiv.). The mixture was stirred at room temperature for 2 hours. The residue was chromatographed on a C18 column with water:MeCN (3:1) to give (1S,3aR,4R,7S,7aS)-N-((S)-1-amino-1-oxo-3-((R)-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (50 mg, 42%) as an off-white solid. LC-MS (ESI, m / z): 596 [M+H] + .

[0425] (1S,3aR,4R,7S,7aS)-N-((S)-1-amino-1-oxo-3-((R *To a solution of (S)-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (50 mg, 0.08 mmol, 1.0 equiv.) in DCM (3 mL) was added TFAA (35 mg, 0.17 mmol, 2.0 equiv.) and pyridine (23 mg, 0.29 mmol, 3.5 equiv.). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with water (3 mL). The mixture was extracted with DCM (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 HPLC (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 52% B, 52% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.23) to give (1S,3aR,4R,7S,7aS)-N-((S)-1-cyano-2-((R * )-5-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-1H-4,7-methanoisoindole-1-carboxamide (5.1 mg, 10%) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6,80℃)δ10.66(br,1H),8.39-9.09(m,2H),7.24-7.26(m,1H),5.56-5.57(m,1H), 4.93-5.10(m,1H),4.61-4.71(m,1H),4.32-4.59(m,2H),3.98-4.06(m,1H),3.78-3.82(m,1H),3.58- 3.64(m,1H),2.81-2.92(m,1H),2.58-2.69(m,1H),2.41-2.48(m,2H),2.32-2.36(m,1H),2.21-2.23( m,1H),1.92-2.02(m,1H),1.41-1.55(m,2H),1.18-1.32(m,3H),1.08-1.14(m,1H),0.82-0.95(m,9H). LC-MS (ESI, m / z): 578[M+H] + .

[0426] [ka]

[0427] Compound 17b was prepared by the reaction of tert-butyl ((S)-1-amino-1-oxo-3-((S * )-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate instead of tert-butyl ((S)-1-amino-1-oxo-3-((R * )-5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate. 1H NMR (400MHz, DMSO-d6, 80℃) δ10.61(br,1H),8.81-8.95(m,1H),8.67-8.69(m,1H),7.24-7.26(m,1H),5.56 -5.58(m,1H),5.09-5.11(m,1H),4.62-4.73(m,1H),4.31-4.52(m,2H),3.91-4.05(m,1H),3.71-3.83(m,1 H),3.53-3.66(m,1H),2.81-2.96(m,1H),2.62-2.69(m,1H),2.44-2.51(m,2H),2.32-2.37(m,1H),2.18-2 .26(m,1H),1.84-2.05(m,1H),1.38-1.56(m,2H),1.19-1.36(m,3H),1.04-1.17(m,1H),0.82-1.11(m,9H). LC-MS(ESI, m / z):578[M+H] + .

[0428] Example 18 Compound 18

[0429]

change

[0430] To a stirred mixture of (2S)-2-[(1'R,2'S,3'S,6'R,7'S)-4'-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-3'-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (230 mg, 0.404 mmol, 1.0 equiv) in DCM (5 mL) was added pyridine (111 mg, 1.41 mmol, 3.5 equiv) and trifluoroacetic anhydride (152 mg, 0.727 mmol, 1.8 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (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 preparative HPLC (column: Kinetex EVO C18, 21.2* Purification using a 250 mm column, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 40% B to 63% B, 63% B in 10 min; wavelength: 254 nm; RT1 (min): 7.45) afforded (1'R,2'S,3'S,6'R,7'S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4'-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0'-{2,6}]decane]-3'-carboxamide (44.3 mg, 19%) as a white solid. 1 H NMR(400MHz,80℃,DMSO-d6)δ8.91-9.01(m,1H),8.65-8.83(m,1H),7.38-7.53(m,1H),4.81-4.98(m,1H) ),4.60-4.75(m,1H),4.50-4.58(m,1H),3.79-3.88(m,1H),3.63-3.78(m,1H),3.09-3.23(m,2H),2.72 -2.95(m,1H),2.60-2.68(m,1H),2.30-2.41(m,1H),2.09-2.29(m,2H),1.62-1.86(m,2H),1.57-1.61( m,1H),1.31-1.56(m,4H),1.12-1.30(m,1H),0.89-1.09(m,9H),0.50-0.60(m,2H),0.36-0.49(m,2H). LC-MS (ESI, m / z): 552[M+H] + .

[0431] Example 19 compound 19

[0432] [ka] To a mixture of furan-2-carboxylic acid (30.9 mg, 0.276 mmol, 1.0 equiv.) in N,N-dimethylformamide (3 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125 mg, 0.331 mmol, 1.2 equiv.) and N-ethyl-N-isopropylpropan-2-amine (213 mg, 1.65 mmol, 6.0 equiv.) at 0°C. After the mixture was stirred at 0° C. for 20 minutes, (1S,3aR,4S,7R,7aS)—N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (133 mg, 0.276 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL). The mixture was extracted with EtOAc (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 was chromatographed on a silica gel column with MeOH:DCM (7:93) to give (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-(furan-2-carboxamido)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (120 mg, 81%) as a pale yellow solid. LC-MS (ESI, m / z): 540 [M+H] + .

[0433] To a mixture of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-(furan-2-carboxamido)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (120 mg, 0.222 mmol, 1.0 equiv.) in dichloromethane (3 mL) was added pyridine (123 mg, 1.55 mmol, 7.0 equiv.) and trifluoroacetic anhydride (140 mg, 0.666 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (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 to give the crude product. The crude product was purified by preparative HPLC (column: XBridge Prep Phenyl OBD column, 19 * Purification using a 250 mm column, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 65% B in 7 min, 65% B; wavelength: 254 nm; RT1 (min): 6) afforded (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-((S)-2-(furan-2-carboxamido)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (17.4 mg, 15%) as an off-white solid. LC-MS (ESI, m / z): 522 [M+H] + .

[0434] Example 20 compound 20

[0435] [ka] To a mixture of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (43.0 mg, 0.274 mmol, 1.0 equiv) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125 mg, 0.329 mmol, 1.2 equiv) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (212 mg, 1.64 mmol, 6.0 equiv) at 0°C. After stirring at 0°C for 15 minutes, (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (132 mg, 0.274 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The mixture was purified by C18 column chromatography using CHCN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-1-(trifluoromethyl)cyclopropane-1-carboxamide (130 mg, 78%) as a pale yellow solid. LC-MS (ESI, m / z): 582 [M+H] + .

[0436] To a mixture of N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-1-(trifluoromethyl)cyclopropane-1-carboxamide (130 mg, 0.224 mmol, 1.0 equiv) in DCM (2 mL) was added pyridine (71.0 mg, 0.896 mmol, 4.0 equiv) and trifluoroacetic anhydride (85.0 mg, 0.403 mmol, 1.8 equiv). The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL). The mixture was extracted with DCM (3 x 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 (XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 53% B, 53% B in 10 min; wavelength: 254 nm; RT: 7.47 min) to afford (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-{[1-(trifluoromethyl)cyclopropyl]formamido}butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (55.9 mg, 44%) as a white solid. 1H NMR (400MHz, 80℃, DMSO-d6) δ8.60-8.80(m,1H),7.35-7.55(m,1H),6.58-7.00(m,1H),5.98-6.20( m,2H),4.70-4.98(m,1H),4.46-4.55(m,1H),4.00-4.15(m,1H),3.55-3.65(m,1H),3.35-3.54(m, 1H),3.10-3.25(m,2H),3.00-3.09(m,1H),2.80-2.98(m,2H),2.68-2.79(m,1H),2.30-2.42(m,1H ),2.08-2.28(m,2H),1.62-1.89(m,2H),1.30-1.48(m,3H),1.10-1.29(m,3H),0.83-0.98(m,9H). LC-MS(ESI, m / z):564[M+H] + .

[0437] Example 21 Compound 21

[0438]

change

[0439] To a stirred mixture of N-[(2S)-1-[(1R,2S,3S,6R,7S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]cyclopropanecarboxamide (100 mg, 0.195 mmol, 1.0 equiv.) in DCM (2 mL) was added trifluoroacetic anhydride (81.7 mg, 0.390 mmol, 2.0 equiv.) and pyridine (53.9 mg, 0.682 mmol, 3.5 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 x 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 using the following conditions (column: XBridgePrep Phenyl OBD column, 19 * Purification by preparative HPLC using a 250 mm column, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 32% B to 62% B in 7 min, 62% B; wavelength: 254 nm; RT (min): 6) gave (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-2-(cyclopropylformamido)-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (16.5 mg, 16%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.55-8.80(m,1H),7.70-7.85(m,1H),7.30-7.55(m,1H),5.91-6.20( m,2H),4.81-4.98(m,1H),4.40-4.52(m,1H),3.91-4.10(m,1H),3.42-3.62(m,2H),3.08-3.20(m, 2H),2.97-3.02(m,1H),2.81-2.95(m,2H),2.63-2.73(m,1H),2.26-2.41(m,1H),2.05-2.22(m,2H) ),1.60-1.86(m,3H),1.29-1.41(m,2H),0.78-0.96(m,9H),0.66-0.74(m,1H),0.53-0.66(m,3H). LC-MS(ESI, m / z):496[M+H] + .

[0440] Example 22 compound 22

[0441] [ka] A mixture of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (1.04 g, 3.83 mmol, 1.0 equiv) in hydrogen chloride (10 mL, 2 M in EtO) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (0.650 g, crude) as a yellow oil. LC-MS (ESI, m / z): 172 [M+H] + .

[0442] To a mixture of (1S,3aR,4S,7R,7aS)-2-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (1.50 g, 3.82 mmol, 1.0 equiv.) in N,N-dimethylformamide (15 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.74 g, 4.58 mmol, 1.2 equiv.) and N-ethyl-N-isopropylpropan-2-amine (3.95 g, 30.5 mmol, 8.0 equiv.) at 0° C. The mixture was stirred for 20 minutes at 0° C. (S)2-Amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (650 mg, 3.82 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL). The mixture was extracted with EtOAc (3×80 mL). The organic layers were combined, washed with brine (2×80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with MeOH:DCM (7:93) to give tert-butyl ((S)-1-((1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1.46 g, 70%) as a pale yellow solid. LC-MS (ESI, m / z): 546 [M+H] + .

[0443] A mixture of tert-butyl ((S)-1-((1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (150 mg, 0.275 mmol, 1.0 equiv) in hydrogen chloride (2 mL, 2 M in EtO) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (133 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 446 [M+H] + .

[0444] To a mixture of (R)-tetrahydrofuran-2-carboxylic acid (32.0 mg, 0.276 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mg, 0.331 mmol, 1.2 equiv) and N-ethyl-N-isopropylpropan-2-amine (213 mg, 1.65 mmol, 6.0 equiv) at 0° C. The mixture was stirred for 20 minutes at 0° C. (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (133 mg, 0.276 mmol, 1.0 equiv) was added at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water (30 mL). The mixture was purified by C18 column using CH3CN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-((R)-tetrahydrofuran-2-carboxamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (80 mg, 54%) as a pale yellow solid. LC-MS (ESI, m / z): 544 [M+H] + .

[0445] To a mixture of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-((R)-tetrahydrofuran-2-carboxamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (50.0 mg, 0.092 mmol, 1.0 equiv.) in DCM (2 mL) was added pyridine (50.9 mg, 0.644 mmol, 7.0 equiv.) and trifluoroacetic anhydride (57.9 mg, 0.276 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL). The mixture was extracted with EtOAc (3 x 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 Shield RP18 OBD column, 19 * Purification using a 250 mm column, 10 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 47% B, 47% B in 10 min; wavelength: 254 nm; RT (min): 5.97 gave (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-((S)-3,3-dimethyl-2-((R)-tetrahydrofuran-2-carboxamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (13.9 mg, 28%) as an off-white solid. 1H NMR (400MHz, 80℃, DMSO-d6) δ8.60-8.90(m,1H),7.35-7.60(m,1H),6.80-7.20(m,1H),5.80-6.20( m,2H),4.65-5.00(m,1H),4.30-4.50(m,1H),4.15-4.30(m,1H),3.95-4.05(m,1H),3.70-3.90(m, 2H),3.50-3.65(m,1H),3.30-3.55(m,1H),3.10-3.25(m,2H),2.90-3.05(m,1H),2.65-2.80(m,3H ),2.25-2.45(m,1H),2.05-2.25(m,3H),1.65-1.95(m,5H),1.30-1.50(m,2H),0.65-1.10(m,9H). LC-MS(ESI, m / z):526[M+H] + .

[0446] Example 23 Compound 23

[0447]

change

[0448] To a stirred mixture of 4-tert-butyl 3-methyl(1S,2S,3S,6R,7R,8R,10S)-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3,4-dicarboxylate (180 mg, 0.524 mmol, 1.0 equiv.) in THF (3 mL) and HO (1 mL) was added lithium hydroxide (37.6 mg, 1.57 mmol, 3.0 equiv.) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH = 4 with hydrochloric acid (2 M) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (1S,2S,3S,6R,7R,8R,10S)-4-(tert-butoxycarbonyl)-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3-carboxylic acid (150 mg, crude) as a pale yellow oil. LC-MS (ESI, m / z): 328 [MH] - .

[0449] To a stirred mixture of (1S,2S,3S,6R,7R,8R,10S)-4-(tert-butoxycarbonyl)-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3-carboxylic acid (150 mg, 0.455 mmol, 1.0 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (207 mg, 0.546 mmol, 1.2 equiv.) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (353 mg, 2.73 mmol, 6.0 equiv.). The mixture was stirred for 10 min at 0 °C. (2S)2-Amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (104 mg, 0.501 mmol, 1.1 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The mixture was purified by C18 column chromatography using CHCN:water (0.05% FA). The desired fractions were concentrated under reduced pressure to give tert-butyl (1S,2S,3S,6R,7R,8R,10S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-4-carboxylate (160 mg, 65%) as a white solid. LC-MS (ESI, m / z): 483 [M+H] + .

[0450] To a stirred mixture of tert-butyl (1S,2S,3S,6R,7R,8R,10S)-3-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-4-carboxylate (160 mg, 0.332 mmol, 1.0 equiv) in DCM (1 mL) was added hydrogen chloride (5 mL, 2 M in EtO). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-2-{[(1S,2S,3S,6R,7R,8R,10S)-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (140 mg, crude) as a white solid. LC-MS (ESI, m / z): 383 [M+H] + .

[0451] To a stirred mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (83.5 mg, 0.367 mmol, 1.1 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (152 mg, 0.401 mmol, 1.2 equiv.) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (259 mg, 2.00 mmol, 6.0 equiv.). The mixture was stirred for 10 minutes at 0°C. (2S)-2-{[(1S,2S,3S,6R,7R,8R,10S)-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (140 mg, 0.334 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The crude product was purified by C18 column chromatography using CH3CN:water (0.05% FA). The desired fractions were concentrated under reduced pressure to give (2S)-2-{[(1S,2S,3S,6R,7R,8R,10S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (140 mg, 63%) as a pale yellow solid. LC-MS (ESI, m / z): 592 [M+H] + .

[0452] To a stirred mixture of (2S)-2-{[(1S,2S,3S,6R,7R,8R,10S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecan-3-yl]formamido}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (140 mg, 0.237 mmol, 1.0 equiv) in DCM (2 mL) was added pyridine (65.5 mg, 0.829 mmol, 3.5 equiv) and trifluoroacetic anhydride (99.4 mg, 0.474 mmol, 2.0 equiv). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL). The mixture was extracted with DCM (3 x 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 using the following conditions (column: XBridgePrep Phenyl OBD column, 19 * Purification by preparative HPLC (250 mm, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 43% B to 73% B, 73% B in 7 min; wavelength: 254 nm; RT (min): 5) gave (1S,2S,3S,6R,7R,8R,10S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-9,9-difluoro-4-azatetracyclo[5.3.1.0^{2,6}.0^{8,10}]undecane-3-carboxamide (30.5 mg, 21%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.91-9.20(m,1H),8.55-8.87(m,1H),7.35-7.55(m,1H),4.81-4 .96(m,1H),4.55-4.73(m,2H),3.91-4.10(m,1H),3.58-3.74(m,1H),3.08-3.20(m,2H),2.73 -2.82(m,2H),2.62-2.72(m,1H),2.50-2.60(m,1H),2.26-2.38(m,1H),2.07-2.20(m,2H),1. 62-1.87(m,3H),1.45-1.57(m,1H),1.26-1.37(m,1H),1.09-1.23(m,1H),0.84-1.03(m,9H). LC-MS (ESI, m / z): 574[M+H] + .

[0453] Example 24 compound 24

[0454] [ka] To a mixture of amino(1-methylcyclopropyl)acetic acid hydrochloride (300 mg, 1.81 mmol, 1.0 equiv) in MeOH (5 mL) was added triethylamine (733 mg, 7.24 mmol, 4.0 equiv) and ethyl 2,2,2-trifluoroacetate (309 mg, 2.17 mmol, 1.2 equiv). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL). The pH was adjusted to 6 with hydrochloric acid (1 M). 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 (1-methylcyclopropyl)(2,2,2-trifluoroacetamido)acetic acid (380 mg, 88%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ12.95(br,1H),9.76(d,J=7.3Hz,1H),3.78(d,J=7.3Hz,1H),1. 07(s,3H),0.69-0.77(m,1H),0.49-0.57(m,1H),0.41-0.48(m,1H),0.31-0.38(m,1H). LC-MS(ESI, m / z):226[M+H] + .

[0455] To a mixture of (1-methylcyclopropyl)(2,2,2-trifluoroacetamido)acetic acid (78.0 mg, 0.347 mmol, 1.0 equiv) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (158 mg, 0.416 mmol, 1.2 equiv) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (269 mg, 2.08 mmol, 6.0 equiv) at 0°C. After stirring at 0°C for 15 minutes, (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (128 mg, 0.347 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The mixture was purified by C18 column chromatography using CHCN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S)-4-[2-(1-methylcyclopropyl)-2-(2,2,2-trifluoroacetamido)acetyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (110 mg, 50%) as an off-white solid. LC-MS (ESI, m / z): 540 [M+H] + .

[0456] To a mixture of (2S)-2-{[(1R,2S,3S,6R,7S)-4-[2-(1-methylcyclopropyl)-2-(2,2,2-trifluoroacetamido)acetyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamide}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (110 mg, 0.204 mmol, 1.0 equiv) in DCM (2 mL) was added pyridine (65.0 mg, 0.816 mmol, 4.0 equiv) and trifluoroacetic anhydride (77.0 mg, 0.367 mmol, 1.8 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The mixture was extracted with DCM (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: YMC-Actus Triart C18 ExRS, 20 × 250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 38% B to 59% B, 59% B in 10 min; wavelength: 254 nm; RT: 7.47 min) to give (1R,2S,3S,6R,7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-[2-(1-methylcyclopropyl)-2-(2,2,2-trifluoroacetamido)acetyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-ene-3-carboxamide (22.1 mg, 20%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.85-9.10(m,1H),8.65-8.80(m,1H),7.34-7.55(m,1H),6.12-6.30(m,1H) ),5.95-6.10(m,1H),4.76-4.95(m,1H),4.35-4.45(m,1H),3.95-4.12(m,1H),3.56-3.70(m,1H),3.30 -3.45(m,1H),3.10-3.25(m,2H),2.80-3.05(m,3H),2.63-2.75(m,1H),2.30-2.40(m,1H),1.98-2.28( m,2H),1.60-1.90(m,2H),1.35-1.46(m,2H),0.95-1.10(m,3H),0.63-0.80(m,2H),0.20-0.55(m,2H). LC-MS(ESI, m / z):522[M+H] + .

[0457] Example 25 compound 25

[0458] [ka] Tricyclo[5.2.1.0^{2,6}]deca-3,8-diene (110 g, 832 mmol, 1.0 equiv.) was stirred at 210 °C. Cyclopentadiene was distilled at 37 °C to 43 °C. Fractions were collected to give the product (46 g, 83%) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6) δ6.60-6.69(m,2H), 4.43-6.56(m,2H), 3.04-3.05(m,2H).

[0459] A mixture of cyclopentadiene (42.0 g, 635 mmol, 1.0 equiv.) and ynal (0.130 g, 0.572 mmol, 0.0009 equiv.) in ethylene dichloride (62.8 g, 635 mmol, 1.0 equiv.) was stirred. After stirring for 20 minutes, sodium hydroxide (139 g, 3462 mmol, 5.45 equiv.) and benzyltriethylazanium chloride (1.30 g, 5.72 mmol, 0.009 equiv.) were added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (50 mL). The mixture was extracted with EtOAc (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 stirred at 130 °C. Spiro[2.4]hepta-4,6-diene was distilled under 0.7 MPa at 60-65° C. The desired fractions were collected to give spiro[2.4]hepta-4,6-diene (10 g, 14%) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6) δ6.47-6.69(m,2H), 6.14-6.24(m,2H), 1.71-1.72(m,4H).

[0460] To a stirred mixture of 1-tert-butyl 2-methyl(2R)-2,5-dihydropyrrole-1,2-dicarboxylate (6.00 g, 26.4 mmol, 1.0 equiv.) in xylene (6 mL) was added spiro[2.4]hepta-4,6-diene (4.87 g, 52.8 mmol, 1.0 equiv.). The mixture was stirred at 140° C. for 2 days and then concentrated under reduced pressure. The crude product was chromatographed on a silica gel column using EA:PE (30:70) to obtain the crude product. The crude product was purified on a C18 column using CH3CN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give 4'-tert-butyl 3'-methyl(1'R,2'S,3'S,6'R,7'S)-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-ene-3',4'-dicarboxylate (1.98 g, 23%) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ6.03-6.36(m,2H),3.70-3.89(m,1H),3.55-3.69(m,3H),3.22-3.37(m,1H ),2.70-3.10(m,3H),2.33-2.42(m,1H),2.22-2.29(m,1H),1.08-1.53(m,9H),0.22-0.48(m,4H). LC-MS(ESI, m / z):220[M+H-Boc] + .

[0461] To a stirred mixture of 4'-tert-butyl 3'-methyl(1'R,2'S,3'S,6'R,7'S)-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-ene-3',4'-dicarboxylate (1.00 g, 3.13 mmol, 1.0 equiv.) in THF (10 mL) was added lithium hydroxide (300 mg, 12.5 mmol, 4.0 equiv.) in water (10 mL). The mixture was stirred at room temperature for 2 h. The pH was adjusted to 6 with hydrochloric acid (2 M). The mixture was extracted with EtOAc (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 (1'R,2'S,3'S,6'R,7'S)-4'-(tert-butoxycarbonyl)-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-ene-3'-carboxylic acid (917 mg, 89%) as a pale yellow oil. LC-MS (ESI, m / z): 250 [M+H-56] + .

[0462] To a stirred mixture of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (500 mg, 2.92 mmol, 1.0 equiv.) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.33 g, 3.51 mmol, 1.2 equiv.) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.02 g, 23.4 mmol, 8.0 equiv.) at 0° C. After stirring at 0° C. for 20 minutes, (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (500 mg, 2.92 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL). The mixture was extracted with EtOAc (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 was chromatographed on a silica gel column using MeOH:DCM (1:11) to give tert-butyl (1'R,2'S,3'S,6'R,7'S)-3'-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0'-{2,6}]decane]-8'-ene-4'-carboxylate (758 mg, 55%) as a yellow solid. LC-MS (ESI, m / z): 359 [MH-Boc] + .

[0463] To a stirred mixture of tert-butyl (1'R,2'S,3'S,6'R,7'S)-3'-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-ene-4'-carboxylate (750 mg, 1.63 mmol, 1.0 equiv) in DCM (10 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give (2S)-2-[(1'R,2'S,3'S,6'R,7'S)-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-en-3'-ylformamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (586 mg, crude) as a brown oil. LC-MS (ESI, m / z): 359 [M+H] + .

[0464] To a stirred mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (371 mg, 1.63 mmol, 1.0 equiv) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (746 mg, 1.96 mmol, 1.2 equiv) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.69 g, 13.1 mmol, 8.0 equiv) at 0°C. After stirring at 0° C. for 20 minutes, (2S)-2-[(1′R,2′S,3′S,6′R,7′S)-4′-azaspiro[cyclopropane-1,10′-tricyclo[5.2.1.0′-{2,6}]decane]-8′-en-3′-ylformamide]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (586 mg, 1.63 mmol, 1.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (15 mL). The mixture was extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (2×15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with MeOH:DCM (1:13) to give (2S)-2-[(1'R,2'S,3'S,6'R,7'S)-4'-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-en-3'-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (667 mg, 70%) as a yellow solid. LC-MS (ESI, m / z): 568 [M+H] + .

[0465] To a stirred mixture of (2S)-2-[(1'R,2'S,3'S,6'R,7'S)-4'-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^{2,6}]decane]-8'-en-3'-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (150 mg, 0.264 mmol, 1.0 equiv) in DCM (4 mL) was added pyridine (73.2 mg, 0.924 mmol, 3.5 equiv) and trifluoroacetic anhydride (99.9 mg, 0.475 mmol, 1.8 equiv). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (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 preparative HPLC (column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 46% B in 10 min, 46% B to 46% B in 11 min, 46% B; Wavelength: 254 nm; RT1 (min): 10.45) and purified to give (1'R,2'S,3'S,6'R,7'S)-N-[(1S)-1-cyano-2-[(3S)-2 -oxopyrrolidin-3-yl]ethyl]-4'-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4'-azaspiro[cyclopropane-1,10'-tricyclo[5.2.1.0^-{2,6}]decane]-8'-ene-3'-carboxamide (43.4 mg, 29%) as a white solid. 1H NMR(400MHz,80℃,DMSO-d6)δ8.75-9.00(m,1H),8.60-8.74(m,1H),7.32-7.59(m,1H),6. 00-6.30(m,2H),4.80-5.00(m,1H),4.45-4.70(m,1H),4.00-4.29(m,1H),3.60-3.98(m, 1H),3.36-3.53(m,1H),3.10-3.30(m,2H),2.75-3.02(m,2H),2.40-2.48(m,1H),2.25-2 .39(m,2H),2.00-2.24(m,2H),1.60-1.90(m,2H),0.83-1.05(m,9H),0.30-0.45(m,4H). LC-MS(ESI, m / z):550[M+H] + .

[0466] Example 26 compound 26

[0467] [ka] To a mixture of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (35.0 g, 109 mmol, 1.0 equiv) and potassium carbonate (31.7 g, 229 mmol, 1.5 equiv) in DMF (250 mL) was added benzyl bromide (31.3 g, 183 mmol, 1.2 equiv) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was filtered through a Celite pad and washed with ethyl acetate (3 × 100 mL). The filtrate was quenched with water (200 mL). The mixture was extracted with ethyl acetate (3 × 500 mL). The organic layers were combined, washed with brine (2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column with EA:PE (25%-30%) to give benzyl (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate (40.0 g, 85%) as a white solid. LC-MS (ESI, m / z): 320 [M+H] + .

[0468] To a mixture of benzyl (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate (40.0 g, 125 mmol, 1.0 equiv) in 1,4-dioxane (200 mL) was added hydrogen chloride (400 mL, 4 M in 1,4-dioxane) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give benzyl (1S,3R)-3-aminocyclopentane-1-carboxylate hydrochloride (25.1 g, crude) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.26(br,3H),7.31-7.42(m,5H),5.12(s,2H),3.42-3.53(m,1H),2.80-2.95(m,1H),2.23-2.33(m,1H),1.60-1.99(m,5H). LC-MS(ESI, m / z):220[M+H] + .

[0469] To a mixture of benzyl (1S,3R)-3-aminocyclopentane-1-carboxylate hydrochloride (25.1 g, 97.8 mmol, 1.0 equiv.) in DCM (400 mL) was added diphenylmethanimine (19.5 g, 108 mmol, 1.1 equiv.). The mixture was stirred at room temperature overnight. The mixture was filtered through a Celite pad and washed with DCM (3 × 100 mL). The mixture was concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column using EA:PE (11%-13%) to give benzyl (1S,3R)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (33.0 g, crude) as a yellow oil. LC-MS (ESI, m / z): 384 [M+H] + .

[0470] To a mixture of benzyl (1S,3R)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (33.0 g, 86.2 mmol, 1.0 equiv.) in THF (400 mL) under nitrogen at −78° C. was added lithium diisopropylamide (56.1 mL, 112 mmol, 1.3 equiv., 2 M in THF) dropwise. After stirring at −78° C. for 1 hour, methyl 2-bromoacetate (26.4 g, 172 mmol, 2.5 equiv.) was added. The mixture was stirred at −78° C. for 1 hour. The mixture was warmed to 0° C. and stirred at 0° C. under nitrogen for 2 hours. The reaction was quenched with water (200 mL). The mixture was extracted with ethyl acetate (3×300 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 chromatographed on a silica gel column with EA:PE (12%-15%) to give benzyl (1S,3R)-3-((diphenylmethylene)amino)-1-(2-methoxy-2-oxoethyl)cyclopentane-1-carboxylate (10.7 g, crude) as a yellow oil. LC-MS (ESI, m / z): 456 [M+H] + .

[0471] To a mixture of benzyl (1S,3R)-3-((diphenylmethylene)amino)-1-(2-methoxy-2-oxoethyl)cyclopentane-1-carboxylate (10.7 g, 23.5 mmol, 1.0 equiv.) in MeOH (150 mL) was added 10% palladium on activated carbon (3.5 g). The mixture was stirred under hydrogen at room temperature overnight and then filtered. The filter cake was washed with MeOH (3×150 mL). The filtrate was concentrated under reduced pressure to give (1S,3R)-3-amino-1-(2-methoxy-2-oxoethyl)cyclopentane-1-carboxylic acid (4.5 g, crude) as a yellow solid. LC-MS (ESI, m / z): 202 [M+H] + .

[0472] To a mixture of (1S,3R)-3-amino-1-(2-methoxy-2-oxoethyl)cyclopentane-1-carboxylic acid (4.5 g, 22.4 mmol, 1.0 equiv) in DCM (50 mL) was added thionyl chloride (4.26 g, 35.8 mmol, 1.6 equiv). The mixture was stirred at 40° C. for 3 hours. The reaction was quenched with water (20 mL). The mixture was extracted with DCM (3×100 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 chromatographed on a silica gel column with EA:PE (70%-85%) to give methyl 2-((1R,4S)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)acetate (400 mg, 9%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ5.99(br,1H),3.89-3.90(m,1H),3.71(s,3H),2.86-2.91(m,1H),2.68-2.72(m,1H),2.0 5-2.09(m,1H),1.92-1.99(m,1H),1.82-1.88(m,1H),1.65-1.73(m,1H),1.60-1.63(m,1H),1.51-1.59(m,1H). LC-MS (ESI, m / z): 184[M+H] + .

[0473] To a mixture of methyl 2-((1R,4S)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)acetate (400 mg, 2.18 mmol, 1.0 equiv) in THF (5 mL) was added lithium borohydride (4.4 mL, 8.73 mmol, 4.0 equiv, 2 M in THF) at 0° C. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (6×50 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 chromatographed on a silica gel column with MeOH:DCM (2%-4%) to give (1R,4S)-4-(2-hydroxyethyl)-2-azabicyclo[2.2.1]heptan-3-one (240 mg, 70%) as a light yellow oil. 1 H NMR(400MHz,CDCl3)δ6.13(br,1H),3.92(s,1H),3.75-3.86(m,2H),3.11(br,1 H),2.06-2.14(m,1H),1.92-2.03(m,3H),1.65-1.77(m,3H),1.41-1.44(m,1H). LC-MS (ESI, m / z): 156[M+H] + .

[0474] To a mixture of (1R,4S)-4-(2-hydroxyethyl)-2-azabicyclo[2.2.1]heptan-3-one (120 mg, 0.773 mmol, 1.0 equiv) in DMSO (2 mL) was added 2-iodoxybenzoic acid (650 mg, 2.31 mmol, 3.0 equiv). The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (5 × 30 mL). The organic layers were combined, washed with brine (2 × 20 mL), saturated aqueous sodium bicarbonate (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((1R,4S)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)acetaldehyde (80.0 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 154 [M + H] + .

[0475] To a solution of 2-((1R,4S)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)acetaldehyde (80.0 mg, 0.522 mmol, 1.0 equiv) in CHOH (2 mL) was added ammonium chloride (83.8 mg, 1.57 mmol, 3.0 equiv). After stirring at room temperature for 2 h, potassium cyanide (44.1 mg, 0.679 mmol, 1.3 equiv) was added. The mixture was stirred at room temperature for 2 days. The mixture was filtered through a Celite pad and washed with CHOH (3 × 20 mL) and DCM (3 × 20 mL). The filtrate was concentrated under reduced pressure to give 2-amino-3-((1R,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)propanenitrile (80.0 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 180 [M+H] + .

[0476] 2-Amino-3-((1R,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)propanenitrile (80.0 mg, 0.446 mmol, 1.0 equiv.), (1R,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0^{2,6}] To a mixture of dec-8-ene-3-carboxylic acid (191 mg, 0.491 mmol, 1.1 equiv.) and N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (150 mg, 0.535 mmol, 1.2 equiv.) in acetonitrile (3 mL) was added 1-methyl-1H-imidazole (367 mg, 4.46 mmol, 10.0 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 × 30 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 chromatographed on a silica gel column using EA:PE (78%-85%) to give the crude product. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19 *Purification by column chromatography (250 mm, 10 μm column; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 35% B to 55% B, 55% B in 10 min; wavelength: 220 nm; RT1 (min): 8.48) gave (1S,3aR,4S,7R,7aS)-N-(1-cyano-2-((1R,4S)-3-oxo-2-azabicyclo[2.2.1]heptan-4-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (17.4 mg, 7%) as a white solid. 1 H NMR(400MHz,80℃,DMSO-d6)δ8.53-8.94(m,2H),7.47(s,1H),5.93-6.16(m,2H), 4.71-4.88(m,1H),4.46(s,1H),3.99-4.15(m,1H),3.66-3.77(m,1H),3.56-3.67 (m,1H),3.40-3.44(m,1H),2.97-3.02(m,1H),2.78-2.95(m,2H),2.63-2.75(m, 1H), 2.05-2.29(m, 2H), 1.60-1.85(m, 3H), 1.21-1.51(m, 5H), 0.85-0.96(m, 9H). LC-MS(ESI, m / z):550[M+H] + .

[0477] Example 27 compound 27

[0478] [ka] To a mixture of (S)-2,4,6-trimethylbenzenesulfinamide (400 mg, 2.18 mmol, 1.0 equiv.) and magnesium sulfate (1.31 g, 10.9 mmol, 5.0 equiv.) in DCM (12 mL) was added pyrrolidine (16.0 mg, 0.218 mmol, 0.1 equiv.) and ethyl glyoxylate (1.34 g, 6.55 mmol, 3.0 equiv., 50% in toluene). The mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure to give ethyl 2-{[(S)-2,4,6-trimethylbenzenesulfinyl]imino}acetate (584 mg, crude) as a pale yellow oil. LC-MS (ESI, m / z): 268 [M+H] + .

[0479] To a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (300 mg, 2.68 mmol, 1.0 equiv.), 4,5,6,7-tetrachloro-2-hydroxyisoindole-1,3-dione (805 mg, 2.68 mmol, 1.0 equiv.), and N,N-dimethylpyridin-4-amine (33.0 mg, 0.268 mmol, 0.1 equiv.) in DCM (20 mL) was added N,N'-diisopropylcarbodiimide (371 mg, 2.94 mmol, 1.1 equiv.), and the mixture was stirred at room temperature for 1 hour. The mixture was chromatographed on a silica gel column with EtOAc:PE (15:85) to give 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-ylbicyclo[1.1.1]pentane-1-carboxylate (540 mg, 47%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ2.60(s, 1H), 2.30(m, 6H).

[0480] To a mixture of 4,5,6,7-tetrachloro-1,3-dioxoisoindol-2-ylbicyclo[1.1.1]pentane-1-carboxylate (540 mg, 1.38 mmol, 1.0 equiv.), ethyl 2-{[(S)-2,4,6-trimethylbenzenesulfinyl]imino}acetate (585 mg, 2.19 mmol, 1.6 equiv.), and nickel(II) acetate tetrahydrate (85.0 mg, 0.342 mmol, 0.25 equiv.) in 1-methyl-2-pyrrolidinone (10 mL) was added zinc (268 mg, 4.10 mmol, 3.0 equiv.). The mixture was stirred under nitrogen at room temperature overnight. The reaction was quenched with water (30 mL). The mixture was extracted with EtOAc (3 × 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 to give the crude product. The crude product was purified by TLC (mobile phase: EtOAc:PE = 1:5; Rf = 0.5; detection: UV) to give ethyl (2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-{[(S)-2,4,6-trimethylbenzenesulfinyl]amino}acetate (200 mg, 35%) as a pale yellow oil. LC-MS (ESI, m / z): 336 [M+H] + .

[0481] To a mixture of ethyl (2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-{[(S)-2,4,6-trimethylbenzenesulfinyl]amino}acetate (200 mg, 0.596 mmol, 1 equiv.) in MeOH (2 mL) was added hydrogen chloride (0.60 mL, 2.38 mmol, 4.0 equiv., 4 M in EtOH). The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give ethyl (2S)-2-amino-2-{bicyclo[1.1.1]pentan-1-yl}acetate hydrochloride (120 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 170 [M+H] + .

[0482] To a mixture of ethyl (2S)-2-amino-2-{bicyclo[1.1.1]pentan-1-yl}acetate hydrochloride (120 mg, 0.583 mmol, 1.0 equiv.) in DCM (3 mL) was added triethylamine (295 mg, 2.91 mmol, 5.0 equiv.) and di-tert-butyl dicarbonate (153 mg, 0.700 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove DCM. The residue was purified on a C18 column using CHCN:water (0.05% TFA). The desired fractions were concentrated under reduced pressure to give ethyl (2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-[(tert-butoxycarbonyl)amino]acetate (120 mg, crude) as a yellow oil. LC-MS(ESI,m / z):214[M-56+H] + .

[0483] To a mixture of ethyl (2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-[(tert-butoxycarbonyl)amino]acetate (120 mg, 0.446 mmol, 1.0 equiv) in THF (1.5 mL):water (1.5 mL) was added lithium hydride (54.0 mg, 2.23 mmol, 5.0 equiv). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove the THF. The pH was adjusted to 6 with hydrochloric acid (1 M). The mixture was extracted with EtOAc (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 (S)-bicyclo[1.1.1]pentan-1-yl[(tert-butoxycarbonyl)amino]acetic acid (100 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 186 [M-56 + H] + .

[0484] A mixture of (S)-bicyclo[1.1.1]pentan-1-yl[(tert-butoxycarbonyl)amino]acetic acid (100 mg, 0.414 mmol, 1.0 equiv.) in hydrogen chloride (2 mL, 2 M in EtO) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (S)-amino(bicyclo[1.1.1]pentan-1-yl)acetic acid hydrochloride (73 mg, crude) as an off-white solid. LC-MS (ESI, m / z): 142 [M+H] + .

[0485] To a mixture of (S)-amino(bicyclo[1.1.1]pentan-1-yl)acetic acid hydrochloride (73 mg, 0.411 mmol, 1.0 equiv.) in MeOH (2 mL) was added triethylamine (166 mg, 1.64 mmol, 4.0 equiv.) and ethyl 2,2,2-trifluoroacetate (117 mg, 0.822 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to remove MeOH. The mixture was diluted with water (5 mL) and the pH was adjusted to 6 with hydrochloric acid (1 M). The mixture was extracted with EtOAc (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 C18 column using CH3CN:water (0.05% FA). The desired fractions were concentrated under reduced pressure to afford (S)-bicyclo[1.1.1]pentan-1-yl(2,2,2-trifluoroacetamido)acetic acid (40 mg, 37%) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ6.65-6.87(m,1H), 4.70-4.77(m,1H), 2.61(s,1H), 1.79-1.94(m,6H). LC-MS (ESI, m / z): 236[MH] - .

[0486] (2S)-2-[(1R,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (62.0 mg, 0.168 mmol, 1.0 equiv.), (S)-bicyclo[1.1.1]pentan-1-yl(2,2,2-trimethylsilyl)propanamide hydrochloride To a mixture of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (40.0 mg, 0.168 mmol, 1.0 equiv.) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (61.0 mg, 0.218 mmol, 1.3 equiv.) in MeCN (2 mL) was added N-methylimidazole (138 mg, 1.68 mmol, 10.0 equiv.). The mixture was stirred at room temperature for 1 hour and then purified on a C18 column using CHCN:water (0.05% FA). The desired fractions were concentrated under reduced pressure to give (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-(2,2,2-trifluoroacetamido)acetyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamido}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (60.0 mg, 54%) as a yellow solid. LC-MS (ESI, m / z): 552 [M+H] + .

[0487] To a mixture of (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-(2,2,2-trifluoroacetamido)acetyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamido}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (60.0 mg, 0.109 mmol, 1.0 equiv) in DCM (1 mL) was added pyridine (35.0 mg, 0.436 mmol, 4.0 equiv) and trifluoroacetic anhydride (41.0 mg, 0.196 mmol, 1.8 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL). The mixture was extracted with DCM (3 x 5 mL). The organic layers were combined, washed with brine (2 x 5 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 Shield RP18 Purification on an OBD column, 19 × 250 mm, 10 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 38% B to 68% B, 68% B in 7 min; wavelength: 220 nm; RT: 5.28 min) gave (1R,2S,3S,6R,7S)-4-[(2S)-2-{bicyclo[1.1.1]pentan-1-yl}-2-(2,2,2-trifluoroacetamido)acetyl]-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-azatricyclo[5.2.1.0-{2,6}]dec-8-ene-3-carboxamide (6.2 mg, 10%) as a white solid. LC-MS (ESI, m / z): 534 [M+H] + .

[0488] Example 28 compound 28

[0489] [ka] To a solution of methyl (S)-2-((4-methoxyphenyl)amino)-3,3-dimethyl-4-oxobutanoate (5.17 g, 18.6 mmol, 1.1 equiv.) in toluene was added sodium bis(trimethylsilyl)amide (3.42 g, 18.6 mmol, 1.1 equiv.) at 0° C. The mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., a solution of methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethyl-4-oxobutanoate (4.50 g, 16.9 mmol, 1.0 equiv.) in toluene (50 mL) was added. The mixture was stirred at 0° C. for 30 minutes and then poured into ice-cold water (50 mL). The mixture was extracted with ethyl acetate (3×80 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was chromatographed on a silica gel column using EA:PE (6:94) to give the crude product. The crude product was purified by a C18 column using CHCN:water (0.05% FA). The desired fractions were concentrated under reduced pressure to give methyl (S)-2-((4-methoxyphenyl)amino)-3,3-dimethylpent-4-enoate (600 mg, crude) as a brown oil. 1 H NMR (400MHz, DMSO-d6) δ6.26-7.33(m,4H),5.64-6.16(m,1H),4.76-5.27(m,2H),3.72-3.87(m,1H),3.37-3.71(m,6H),0.47-1.43(m,6H). LC-MS(ESI, m / z):264[M+H] + .

[0490] To a stirred mixture of methyl (S)-2-((4-methoxyphenyl)amino)-3,3-dimethylpent-4-enoate (0.460 g, 1.75 mmol, 1.0 equiv) in CHCN (2.4 mL) and HO (0.8 mL) was added cerium ammonium nitrate (4.80 g, 8.73 mmol, 5.0 equiv) at room temperature. The mixture was stirred at room temperature for 2 hours, and THF (2.5 mL), trimethylamine (basified to pH = 8), and di-tert-butyl dicarbonate (2.28 g, 10.4 mmol, 6.0 equiv) were added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched...

Claims

1. A compound of formula (I) having the structure: 【Chemical 1】 During the ceremony, Ring A １ teeth, 【Chemistry 2】 is selected from the group consisting of Ring A １ is =O, =CH ２ , deuterium, halogen, hydroxy, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Haloalkyl, unsubstituted C ２～４ Alkenyl and unsubstituted or substituted C ３～６ monocyclic cycloalkyl; and C ３～６ monocyclic cycloalkyl is attached in a spiro fashion; R １ is cyano, unsubstituted or substituted C ２～５ Alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted ketoamide, —CH(OH)—(S(═O) ２ -O － ), -CH(OH)((P=O)(OR ６ ) ２ ) and —C(═O)CH ２ -O-((P=O)(OR ７ ) ２ ) selected from the group consisting of Each R ６ and each R ７ 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), R ２ is hydrogen, deuterium, or a halogen; R ３ is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C １～４ alkyl), unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C １～４ alkyl), unsubstituted or substituted monocyclic nitrogen-containing heteroaryl (C １～４ alkyl), R ４ is hydrogen, deuterium, or a halogen; R ５ teeth, 【Chemistry 3】 substituted monocyclic C ３～６ cycloalkyl or substituted 4-6 membered monocyclic heterocyclyl; monocyclic C ３～６ Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are Independently, deuterium, halogen, unsubstituted C １～６ Alkyl, unsubstituted C １～６ Haloalkyl and unsubstituted C １～６ substituted one, two or three times with a moiety selected from alkoxy; optionally substituted in a spiro fashion by independently unsubstituted or substituted bicyclic cycloalkenyl or unsubstituted or substituted bicyclic heterocyclyl; R ８ and R １０ is unsubstituted or substituted C ２～６ Alkyl, unsubstituted or substituted C ２～６ Alkenyl, unsubstituted or substituted C ２～６ Alkynyl, unsubstituted or substituted monocyclic C ３～６ Cycloalkyl, unsubstituted or substituted bicyclic C ５～８ Cycloalkyl, unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl and unsubstituted monocyclic C ３～６ Cycloalkyl (CH ２ )—independently selected from the group consisting of Said C ２～６ When alkyl is substituted, the C ２～６ Alkyl is selected from halogen, cyano, unsubstituted or substituted monocyclic C ３～６ Cycloalkyl, unsubstituted C １～４ Alkoxy and unsubstituted C １～４ haloalkoxy, or ２～６ The alkyl is substituted 1 to 13 times with deuterium; Said C ２～６ Alkenyl, the C ２～６ Alkynyl, the monocyclic C ３～６ cycloalkyl, the bicyclic C ５～８ When the cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted, the C ２～６ Alkenyl, the C ２～６ Alkynyl, the monocyclic C ３～６ cycloalkyl, the bicyclic C ５～８ Cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted with halogen, unsubstituted C １～４ Alkyl, unsubstituted C ２～４ Alkenyl, unsubstituted C ２～４ Alkynyl, unsubstituted C １～４ Haloalkyl, unsubstituted or substituted monocyclic C ３～６ Cycloalkyl and unsubstituted C １～４ substituted 1, 2, 3 or 4 times with substituents independently selected from the group consisting of alkoxy; R ９ is unsubstituted or substituted C １～６ Alkyl, unsubstituted or substituted C １～６ Haloalkyl, unsubstituted or substituted monocyclic C ３～６ Cycloalkyl, unsubstituted or substituted bicyclic C ５～６ cycloalkyl, unsubstituted or substituted monocyclic heteroaryl, and unsubstituted or substituted monocyclic heterocyclyl, wherein said substituted C １～６ Alkyl is an unsubstituted C １～４ substituted once or twice with alkoxy, ３～６ Cycloalkyl is substituted with halogen, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Alkoxy, unsubstituted C １～４ Haloalkyl and unsubstituted monocyclic C ３～６ cycloalkyl, wherein the substituted C １～６ Haloalkyl is an unsubstituted C １～４ substituted once or twice with alkoxy; R １１ is an optionally substituted monocyclic 4- to 6-membered heterocyclyl, —(NH) ｍ - optionally substituted 5- to 6-membered monocyclic heteroaryl, -O- optionally substituted C １～６ alkyl, —O— optionally substituted C ３～８ cycloalkyl and -O- optionally substituted C ３～８ Cycloalkyl (C １～４ wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.

2. R １ The compound of claim 1 , wherein is cyano.

3. Ring A １ but non-substitution 【Chemistry 4】 3. The compound of claim 2, wherein:

4. Ring A １ However, =O, =CH ２ , deuterium, halogen, hydroxy, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Haloalkyl, unsubstituted C ２～４ Alkenyl and unsubstituted or substituted C ３～６ substituted with one or more moieties independently selected from the group consisting of monocyclic cycloalkyl 【Chemistry 5】 3. The compound of claim 2, wherein:

5. Ring A １ but non-substitution 【Chemistry 6】 3. The compound of claim 2, wherein:

6. Ring A １ However, =O, =CH ２ , deuterium, halogen, hydroxy, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Haloalkyl, unsubstituted C ２～４ Alkenyl and unsubstituted or substituted C ３～６ substituted with one or more moieties independently selected from the group consisting of monocyclic cycloalkyl 【Chemistry 7】 3. The compound of claim 2, wherein:

7. Ring A １ but non-substitution 【Chemistry 8】 non-replacement 【Chemistry 9】 =O, =CH ２ , deuterium, halogen, hydroxy, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Haloalkyl, unsubstituted C ２～４ Alkenyl and unsubstituted or substituted C ３～６ substituted with one or more moieties independently selected from the group consisting of monocyclic cycloalkyl 【Chemistry 10】 Or, =O, =CH ２ , deuterium, halogen, hydroxy, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Haloalkyl, unsubstituted C ２～４ Alkenyl and unsubstituted or substituted C ３～６ substituted with one or more moieties independently selected from the group consisting of monocyclic cycloalkyl 【Chemistry 11】 3. The compound of claim 2, wherein:

8. Ring A １ but, 【Chemistry 12】 3. The compound of claim 2 selected from the group consisting of:

9. Ring A １ but, 【Chemistry 13】 9. The compound of claim 8 selected from the group consisting of:

10. R ５ but, 【Chemistry 14】 The compound according to any one of claims 3 to 9, wherein

11. R ８ is unsubstituted C ２～６ The compound of claim 10, wherein the compound is alkyl.

12. C ２～６ 12. The compound of claim 11, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

13. R ８ But substitution C ２～６ The compound of claim 10, wherein the compound is alkyl.

14. C ２～６ 14. The compound of claim 13, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

15. R ８ is unsubstituted or substituted C ２～６ Alkenyl, unsubstituted or substituted C ２～６ Alkynyl, unsubstituted or substituted monocyclic C ３～６ Cycloalkyl, unsubstituted or substituted bicyclic C ５～８ Cycloalkyl, unsubstituted or substituted monocyclic 4- to 6-membered heterocyclyl, or unsubstituted monocyclic C ３～６ Cycloalkyl (CH ２ 11. The compound according to claim 10, wherein:

16. R ９ is unsubstituted C １～６ The compound of claim 10, wherein the compound is alkyl.

17. R ９ is unsubstituted C １～６ The compound of claim 10 which is a haloalkyl.

18. unsubstituted C １～６ Haloalkyl is —CF ３ , -CClF ２ , -CCl ３ , -CHF ２ , -C(CH ３ ) F ２ , -CHCl ２ , -CH ２ F, -CH(CH ３ ) F, -CH ２ CF ３ , -CH(CH ３ )CF ３ , -CH ２ CH ２ CF ３ , -CH ２ CH (CH ３ )CF ３ , -CF ２ CF ３ , -CH ２ Cl, -CH ２ CH ２ F, -CH ２ CH ２ Cl, —CH ２ CH ２ CH ２ F and -CH ２ CH ２ CH ２ 18. The compound of claim 17, wherein the compound is selected from the group consisting of: Cl.

19. R ９ is an unsubstituted or substituted monocyclic C ３～６ Cycloalkyl, unsubstituted or substituted bicyclic C ５～６ 11. The compound of claim 10, which is a cycloalkyl, an unsubstituted or substituted monocyclic heteroaryl, or an unsubstituted or substituted monocyclic heterocyclyl.

20. R ５ but, 【Chemistry 15】 【Chemistry 16】 11. The compound of claim 10 selected from the group consisting of:

21. R ５ but, 【Chemistry 17】 11. The compound of claim 10 selected from the group consisting of:

22. R ３ is an unsubstituted monocyclic nitrogen-containing heterocyclyl (C １～４ The compound according to any one of claims 3 to 9, wherein the aryl group is aryl, ...

23. R ３ is a substituted monocyclic nitrogen-containing heterocyclyl (C １～４ The compound according to any one of claims 3 to 9, wherein the aryl group is aryl, ...

24. The monocyclic nitrogen-containing heterocyclyl (C １～４ alkyl) is a 5-membered monocyclic nitrogen-containing heterocyclyl (C １～４ The compound according to any one of claims 3 to 9, wherein the aryl group is aryl, ...

25. The monocyclic nitrogen-containing heterocyclyl (C １～４ alkyl) is a 6-membered monocyclic nitrogen-containing heterocyclyl (C １～４ The compound according to any one of claims 3 to 9, wherein the aryl group is aryl, ...

26. R ３ is an unsubstituted or substituted bicyclic nitrogen-containing heterocyclyl (C １～４ The compound according to any one of claims 3 to 9, wherein the aryl group is aryl, ...

27. R ３ but, 【Chemistry 18】 10. The compound of any one of claims 3 to 9, wherein each m1 is independently 1, 2, 3, or 4.

28. R ３ but, 【Chemistry 19】 The compound according to any one of claims 3 to 9, selected from the group consisting of:

29. R ３ but, 【Chemistry 20】 The compound according to any one of claims 3 to 9, wherein

30. R ３ but, 【Chemical 21】 The compound according to any one of claims 3 to 9, wherein

31. R ２ is hydrogen, and R ４ The compound according to any one of claims 2 to 9, wherein is hydrogen.

32. R １ is cyano and R ２ is hydrogen, Ring A １ but, non-replacement 【Chemical 22】 or =O, =CH ２ , deuterium, halogen, hydroxy, unsubstituted C １～４ Alkyl, unsubstituted C １～４ Haloalkyl, unsubstituted C ２～４ Alkenyl and unsubstituted or substituted C ３～６ substituted with one or more moieties independently selected from the group consisting of monocyclic cycloalkyl 【Chemical 23】 and R ３ is an unsubstituted or substituted monocyclic nitrogen-containing heterocyclyl (C １～４ alkyl), R ４ is hydrogen, R ５ teeth, 【Chemistry 24】 and R ８ is unsubstituted C ２～６ is alkyl, R ９ is unsubstituted C １～６ The compound of claim 1 which is a haloalkyl.

33. Ring A １ but, non-replacement 【Chemistry 25】 and R ３ is an unsubstituted monocyclic nitrogen-containing heterocyclyl (C １～４ 33. The compound of claim 32, wherein:

34. R ５ teeth, 【Chemical 26】 34. The compound of claim 33, selected from the group consisting of:

35. Ring R ３ but, 【Chemical 27】 35. The compound of claim 34, wherein:

36. The compound is 【Chemical Formula 28】 【Chemical 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 10. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

37. The compound is 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 10. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

38. having the following structure 【Chemistry 52】 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

39. having the following structure 【Chemistry 53】 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof for the treatment of coronavirus infection.

41. ACE inhibitors, anticoagulants, anti-inflammatory agents, ARBs, ASOs, Covid-19 convalescent plasma, entry inhibitors, H ２ 41. The pharmaceutical composition of claim 40, 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 activators, antibiotics, antibacterial agents, and vaccines.

42. The additional drug may be 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), or nivolumab.

42. The pharmaceutical composition of claim 41, wherein the compound is selected from the group consisting of closamide, nitazoxanide, nitric oxide, oseltamivir, peramivir, RANTES, ribavirin, remdesivir, ruxolitinib, sarilumab, siltuximab, sirolimus, statins, tacrolimus, tocilizumab, umifenovir, zanamivir, casirivimab, imdevimab, bamlanivimab, etesevimab, and AT-527.

43. 40. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof for selectively inhibiting a coronavirus protease relative to a host protease.

44. 44. The pharmaceutical composition of claim 43, wherein the compound selectively inhibits the coronavirus protease over a host protease selected from the group consisting of cathepsin L, cathepsin B, cathepsin D, cathepsin K, leukocyte elastase, chymotrypsin, trypsin, thrombin, pepsin, caspase 2, elastase, and calpain.

45. 45. The pharmaceutical composition of claim 43 or 44, wherein the host protease is cathepsin L.

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