Novel spiropyrrolidine-inducing antiviral agents

Abstract

The present invention discloses a compound of formula (Ia) and pharmaceutically acceptable salts thereof that inhibit coronavirus replication activity. The present invention further relates to a pharmaceutical composition comprising the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, and a method for treating or preventing coronavirus infection in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof to the subject. [Formula 1] TIFF2023551174000371.tif34166

Description

[Technical Field] 【0001】 The present invention relates to compounds and methods for inhibiting coronavirus replication activity by targeting a 3C-like protease (sometimes referred to as "3CLpro," "main protease," or "Mpro") with a therapeutically effective dose of a 3C-like protease inhibitor. The present invention further relates to pharmaceutical compositions containing a coronavirus 3C-like protease inhibitor in mammals, by administering an effective dose of such a coronavirus 3C-like protease inhibitor. [Background technology] 【0002】 Coronaviruses are a family of single-stranded, positive-chain RNA viruses with a viral envelope, classified under the order Nidovirales. The coronavirus family includes pathogens from many animal species, including humans, horses, cattle, pigs, birds, cats, and monkeys, and has been known for over 60 years. For example, the isolation of the prototype mouse coronavirus strain JHM was reported in 1949. Coronaviruses are common viruses that generally cause mild to moderate upper respiratory tract illnesses in humans, and are named for the crown-like spikes on the surface of their envelope. There are four major subgroups known as alpha, beta, gamma, and delta coronaviruses, with the first coronaviruses identified in the mid-1960s. Coronaviruses known to infect humans include alpha coronavirus 229E and NL63; as well as beta coronavirus OC43, HKU1, SARS-CoV (the coronavirus that causes severe acute respiratory syndrome or SARS), and MERS-CoV (the coronavirus that causes Middle East respiratory syndrome or MERS). Human coronaviruses 229E, NL63, OC43, and HKU1 are commonly infectious, and symptoms typically include mild to moderate, short-lived upper respiratory tract illness, such as runny nose, cough, sore throat, and fever. Occasionally, human coronaviruses can cause lower respiratory tract illness, such as pneumonia, which is more common in people with cardiopulmonary disease or an immunocompromised immune system, or in the elderly. The transmission of common human coronaviruses is not fully understood. However, human coronaviruses are most likely transmitted from infected individuals to others through airborne means such as coughing and sneezing, and through close personal contact such as touching or shaking hands. These viruses can also be transmitted by touching contaminated objects or surfaces and then touching the mouth, nose, or eyes. 【0003】 Coronaviruses are enveloped, positively oriented single-stranded RNA viruses. The genomic RNA of CoV has a 5' cap structure and a 3' poly-A tail and contains at least six open reading frames (ORFs). The first ORF (ORF 1a / b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed into 16 non-structural proteins by a 3C-like protease (3CLpro), also known as the main protease (Mpro). These non-structural proteins are involved in the production of subgenomic RNA encoding four structural proteins: envelope, membrane, spike, and nucleocapsid proteins, and, in particular, accessory proteins. Consequently, it is understood that the 3C-like protease plays a crucial role in the life cycle of coronaviruses. 【0004】 3CLpro is a cysteine ​​protease involved in most cleavage events within precursor polyproteins. Active 3CLpro is a homodimer containing two protomers, characterized by a Cys-His bimolecule located between domains I and II. 3CLpro is conserved among coronaviruses, and several common features are shared among 3CLpro substrates in various coronaviruses. Since there is no human homolog of 3CLpro, it is an ideal antiviral target. Compounds have been reported to inhibit 3CLpro activity, but they are not approved as coronavirus therapies. (See International Publication No. 2004101742 A2, U.S. Publication No. 2005 / 0143320 A1, U.S. Publication No. 2006 / 0014821 A1, U.S. Publication No. 2009 / 0137818 A1, International Publication No. 2013 / 049382 A2, International Publication No. 2013 / 166319 A1, International Publication No. 2018042343, International Publication No. 2018023054, International Publication No. 2005113580, and International Publication No. 2006061714). 【0005】 More effective therapies for coronavirus infection are needed due to the high level of unmet medical needs. This invention provides compounds that inhibit the life cycle of the coronavirus, as well as methods for preparing and using these compounds. These compounds are useful in treating or preventing coronavirus infection and reducing the incidence of disease complications such as organ failure or death. [Overview of the Initiative] 【0006】 The present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, and methods for treating or preventing viral (particularly coronavirus) infectivity in subjects requiring such treatment with the compounds. The compounds of the present invention inhibit proteins encoded by coronaviruses or interfere with the life cycle of coronaviruses and are also useful as antiviral agents. Furthermore, the present invention provides methods for preparing the compounds. 【0007】 In certain embodiments, the present invention provides compounds represented by formula (Ia), as well as pharmaceutically acceptable salts, esters, and prodrugs thereof. [ka] During the ceremony, A is 1)-R 11 ; 2)-OR 12 and 3)-NR 13 R 14 Selected from, B is an optionally substituted aryl or optionally substituted heteroaryl, X is 1)-CN; 2)-C(O)R 15 ; 3)-CH(OH)SO3R 16 4)-C(O)NR 13 R 14 and 5)-C(O)C(O)NR 13 R 14 selected from R1, R2, and R3 are each independently 1) hydrogen; 2) optionally substituted -C1-C8 alkyl; 3) optionally substituted -C2-C8 alkenyl; 4) optionally substituted -C2-C8 alkynyl; 5) optionally substituted -C3-C8 cycloalkyl; 6) optionally substituted 3- to 8-membered heterocycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted heteroaryl; and 10) optionally substituted heteroarylalkyl selected from, or R1 and R2 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring. R4 is hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C3-C6 cycloalkyl. R 11 and R 12 are each independently 1) optionally substituted -C1-C8 alkyl; 2) optionally substituted -C2-C8 alkenyl; 3) optionally substituted -C2-C8 alkynyl; 4) optionally substituted -C3-C8 cycloalkyl; 5) optionally substituted 3- to 8-membered heterocycloalkyl; 6) optionally substituted aryl; 7) optionally substituted arylalkyl; 8) optionally substituted heteroaryl; and 9) Optionally substituted heteroarylalkyl groups Selected from, R 13 and R 14 Each of them operates independently. 1) Hydrogen; 2) Substitutable C1-C8 alkyl; 3) Substituted -C2-C8 alkenyls; 4) Substitutable -C2-C8 alkynyl; 5) Substituted -C3-C8 cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Aryls that may be substituted; 8) Arylalkyls which may be substituted; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl which may be substituted Selected from, or R 13 and R 14 These, together with the nitrogen atoms to which they are bonded, form a substituted, possibly substituted, 3- to 8-membered heterocyclic ring. R 15 is hydrogen, hydroxyl, or optionally substituted C1-C8 alkyl, R 16 is hydrogen or Na + That is the case. 【0008】 In certain embodiments, the present invention provides compounds represented by formula (I), as well as pharmaceutically acceptable salts, esters, and prodrugs thereof. [ka] , During the ceremony, A is 1)-R 11 ; 2)-OR 12 and 3)-NR 13 R 14 Selected from, where B is an optionally substituted aryl or optionally substituted heteroaryl, X is 1)-CN; 2)-C(O)R 15 ; 3)-CH(OH)SO3R 16 4)-C(O)NR 13 R 14 and 5)-C(O)C(O)NR 13 R 14 Selected from, R1, R2, and R3 are independent of each other. 1) Hydrogen; 2) Substitutable C1-C8 alkyl; 3) Substituted -C2-C8 alkenyls; 4) Substitutable -C2-C8 alkynyl; 5) Substituted -C3-C8 cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Aryls that may be substituted; 8) Arylalkyls which may be substituted; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl which may be substituted Alternatively, R1 and R2, together with the carbon atoms to which they are bonded, may form a substituted or substituted 3- to 8-membered carbocyclic ring or a substituted or substituted 3- to 8-membered heterocyclic ring. R 11 and R 12 Each is independent of the others. 1) Substitutable C1-C8 alkyl; 2) Substituted -C2-C8 alkenyls; 3) Substituted -C2-C8 alkynyl; 4) Substituted -C3-C8 cycloalkyl; 5) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 6) Aryls that may be substituted; 7) Arylalkyls which may be substituted; 8) heteroaryls which may be substituted; and 9) Optionally substituted heteroarylalkyl groups Selected from, R 13 and R 14 Each of them operates independently. 1) Hydrogen; 2) Substitutable C1-C8 alkyl; 3) Substituted -C2-C8 alkenyls; 4) Substitutable -C2-C8 alkynyl; 5) Substituted -C3-C8 cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Aryls that may be substituted; 8) Arylalkyls which may be substituted; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl which may be substituted Selected from, or R 13 and R 14 These, together with the nitrogen atoms to which they are bonded, form a substituted, possibly substituted, 3- to 8-membered heterocyclic ring. R 15 is hydrogen, hydroxyl, or optionally substituted C1-C8 alkyl, R 16 is hydrogen or Na + That is the case. [Modes for carrying out the invention] 【0009】 One embodiment of the present invention is a compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof. 【0010】 In one embodiment of the present invention, the compound of formula (Ia) is represented by formula (Ia-A) or formula (Ia-B), or is a pharmaceutically acceptable salt, ester, or prodrug thereof. [ka] In the formula, A, B, X, R1, R2, R3, and R4 are as defined above. 【0011】 In a preferred embodiment, the compound of formula (Ia) has the stereochemistry shown in formula (Ia-A). 【0012】 In one embodiment of the present invention, the compound of formula (I) is represented by formula (IA) or formula (IB), or is a pharmaceutically acceptable salt, ester, or prodrug thereof. [ka] In the formula, A, B, X, R1, R2, and R3 are as defined above. 【0013】 In a preferred embodiment, the compound of formula (I) has the stereochemistry shown in formula (IA). 【0014】 In certain embodiments of the compounds of formula (I) or formula (Ia), R1 is hydrogen or an optionally substituted -C1-C4 alkyl; optionally substituted -C3-C6 cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted heteroarylalkyl. In certain embodiments of the compounds of formula (I) or formula (Ia), R1 is an optionally substituted -C1-C6 alkyl; optionally substituted -C3-C6 cycloalkyl; optionally substituted C3-C6 cycloalkyl-C1-C2-alkyl-; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted heteroarylalkyl. 【0015】 In certain embodiments of the compounds of formula (I) or formula (Ia), R2 is hydrogen or an optionally substituted -C1-C4 alkyl; optionally substituted -C3-C6 cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted heteroarylalkyl. 【0016】 In certain embodiments of the compounds of formula (I) or formula (Ia), R3 is hydrogen or an optionally substituted -C1-C4 alkyl group, and R4 is hydrogen or an optionally substituted -C1-C4 alkyl group. 【0017】 In certain embodiments of the compounds of formula (I) or formula (Ia), R3 is hydrogen, -Me, -Et, -Pr, -i-Pr, -allyl, -CF3, -CD3, or cyclopropyl. 【0018】 In certain embodiments of the compound of formula (Ia), R4 is hydrogen, -Me, -Et, -Pr, -i-Pr, -allyl, -CF3, or cyclopropyl. 【0019】 In certain embodiments of the compound of formula (I) or formula (Ia), X is -CN. 【0020】 In certain embodiments of the compounds of formula (I) or formula (Ia), X is -C(O)H. 【0021】 In certain embodiments of the compounds of formula (I) or formula (Ia), X is -C(O)CH2OH, -C(O)CH2Cl, or -C(O)CH2F. 【0022】 In certain embodiments of the compound of formula (I) or formula (Ia), X is -C(O)C(O)NR 13 R 14 And in the formula, R 13 and R 14 This has already been defined. 【0023】 In certain embodiments of the compounds of formula (I) or formula (Ia), A may be derived from and substituted from one of the following by the removal of a hydrogen atom: [ka] 【0024】 In certain embodiments of the compound of formula (I) or formula (Ia), A is selected from the following groups, and A may be substituted: [ka] Preferably, the substituents are independently selected from halogens, CN, NH2, optionally substituted C1-C3 alkoxys, optionally substituted C1-C3 alkyls, optionally substituted C3-C6 cycloalkyls, optionally substituted aryls, and optionally substituted heteroaryls. Preferably, the number of substituents is 0 to 3. 【0025】 In certain embodiments of the compounds of formula (I) or formula (Ia), A is selected from the following groups, and A may be substituted. [ka] 【0026】 In certain embodiments of the compounds of formula (I) or formula (Ia), A is selected from the following groups, and A may be substituted. [ka] Preferably, the substituents of A are independently selected from halogens, CN, NH2, optionally substituted C1-C3 alkoxys, optionally substituted C1-C3 alkyls, optionally substituted C3-C6 cycloalkyls, optionally substituted aryls, and optionally substituted heteroaryls. Preferably, the number of substituents is 0 to 3. 【0027】 In certain embodiments of the compound of formula (I) or formula (Ia), A is selected from the following groups, and A may be substituted: [ka] Preferably, the substituents are independently selected from halogens, CN, NH2, optionally substituted C1-C3 alkoxys, optionally substituted C1-C3 alkyls, optionally substituted C3-C6 cycloalkyls, optionally substituted aryls, and optionally substituted heteroaryls. Preferably, the number of substituents is 0 to 3. 【0028】 In certain embodiments of the compound of formula (I) or formula (Ia), B is selected from the following groups and may be substituted. [ka] 【0029】 In a particular embodiment, the compound of formula (Ia) is formula (Ia-1): [ka] This is expressed as follows, where A, B, R1, R2, R4, and X are as defined above. 【0030】 In a particular embodiment, the compound of formula (Ia) is formula (Ia-2): [ka] This is expressed as follows, where A, B, R1, R3, R4, and X are as defined above. 【0031】 In a particular embodiment, the compound of formula (Ia) is formula (Ia-3): [ka] This is expressed as follows, where A, B, R1, R4, and X are as defined above. 【0032】 In a particular embodiment, the compound of formula (I) is formula (I-1): [ka] This is expressed as follows, where A, B, R1, R2, and X are as defined above. 【0033】 In a particular embodiment, the compound of formula (I) is formula (I-2): [ka] This is expressed as follows, where A, B, R1, R3, and X are as defined above. 【0034】 In a particular embodiment, the compound of formula (I) is formula (I-3): [ka] This is expressed as follows, where A, B, R1, and X are as defined above. 【0035】 In a particular embodiment, the compound of formula (Ia) is formula (IIa): [ka] This is expressed as follows, where A, R1, R2, R3, R4 and X are as defined above. Each R9 is 1) Halogen; 2)-CN; 3)-OR 13 ; 4)-SR 13 ; 5)-NR 13 R 14 ; 6)-OC(O)NR 13 R 14 ; 7) Substituted C1-C6 alkyl groups; 8) Substituted -C3-C8 cycloalkyl; 9) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 10) Aryls that may be substituted; and 11) Optionally substituted heteroaryls Selected independently from, n is 0, 1, 2, 3, or 4. 【0036】 In a particular embodiment, the compound of formula (I) is of formula (II): [ka] This is expressed as follows, where A, R1, R2, R3, and X are as defined above. Each R9 is 1) Halogen; 2)-CN; 3)-OR 13 ; 4)-SR 13 ; 5)-NR 13 R 14 ; 6)-OC(O)NR 13 R 14 ; 7) Substituted C1-C6 alkyl groups; 8) Substituted -C3-C8 cycloalkyl; 9) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 10) Aryls that may be substituted; and 11) Optionally substituted heteroaryls Selected independently from, n is 0, 1, 2, 3, or 4. 【0037】 In a particular embodiment, each R9 is independently selected from chloro, fluoro, methoxy, and trifluoromethoxy. 【0038】 In a particular embodiment, the compound of formula (Ia) is formula (IIIa-1): [ka] This is expressed as follows, where A, R1, R3, R4, R9, n, and X are as defined above. 【0039】 In a particular embodiment, the compound of formula (Ia) is formula (IIIa-2): [ka] This is expressed as follows, where A, R1, R2, R4, R9, n, and X are as defined above. 【0040】 In certain embodiments, the compound of formula (I) is formula (III): [ka] This is expressed as follows, where A, R1, R2, R9, n, and X are as defined above. 【0041】 In a particular embodiment, the compound of formula (Ia) is (IVa-1) to (IVa-6): [ka] It is expressed as one of the following, in the formula A, B, R1, R2, R3, R4, R 13 and R 14 This is as defined earlier. 【0042】 In certain embodiments, the compound of formula (I) is (IV-1) to (IV-6): [ka] It is expressed as one of the following, in the formula A, B, R1, R2, R3, R 13 and R 14 This is as defined earlier. 【0043】 In a particular embodiment, the compound of formula (Ia) is a compound of formula (Va-1) to (Va-6): [ka] It is expressed as one of the following, in the formula A, R1, R2, R3, R4, R9, R 13 , R 14 And n are as defined above. 【0044】 In certain embodiments, the compound of formula (I) is a compound of formula (V-1) to (V-6): [ka] It is expressed as one of the following, in the formula A, R1, R2, R3, R9, R 13 , R 14 And n are as defined above. 【0045】 In certain embodiments, the compound of formula (Ia) is defined as formulas (VIa-1) to (VIa-6): [ka] It is expressed as one of the following, in the formula A, R1, R3, R4, R9, R 13 , R 14 And n are as defined above. 【0046】 In certain embodiments, the compound of formula (I) is formula (VI-1) to (VI-6): [ka] It is expressed as one of the following, in the formula A, R1, R3, R9, R 13 , R 14 And n are as defined above. 【0047】 In certain embodiments, the compound of formula (I) is represented by formulas (VII-1) to (VII-5): [Chemical formula] It is represented by one of the following, where A, R1, R3, and X are as defined above. Preferably, A is selected from the following, [Chemical formula] R1 is selected from the following, [Chemical formula] X is selected from the following. [Chemical formula] 【0048】 In certain embodiments, the compound of formula (I) is of formula (VII-6) to (VII-9): [Chemical formula] It is represented by one of the following, where A, R1, R3, R9, and X are as defined above. Preferably, A is selected from the following, [Chemical formula] R1 is selected from the following, [Chemical formula] X is selected from the following. [Chemical formula] 【0049】 In certain embodiments, the compound of formula (I) is of formula (VII-1a) to (VII-5a): [Chemical formula] represented by one of the following, where A, R1, R3, and x are as defined above. Preferably, A is selected from the following: [Chemical Formula] R1 is selected from the following: [Chemical Formula] X is selected from the following. [Chemical Formula] 【0050】 In certain embodiments, the compound of formula (I) is of formula (VII-6a)-(VII-9a): [Chemical Formula] represented by one of the following, where A, R1, R3, R9, and X are as defined above. Preferably, A is selected from the following: [Chemical Formula] R1 is selected from the following: [Chemical Formula] X is selected from the following. [Chemical Formula] 【0051】 In certain embodiments, the compound of formula (I) is represented by one of formula (VII-1)-(VII-9) and formula (VII-1a)-(VII-9a), where A is selected from the following: [Chemical Formula] X is selected from the following: [Chemical formula] R1 is selected from the following. [Chemical formula] 【0052】 In certain embodiments, the compound of formula (Ia) is of formula (VIII-1) to (VIII-5): [Chemical formula] and is represented by one of them, wherein A, X, R1, R3, R4, and R9 are as defined above. 【0053】 In certain embodiments, the compound of formula (Ia) is of formula (VIII-1a) to (VIII-5a): [Chemical formula] and is represented by one of them, wherein A, R1, R3, and R9 are as defined above. 【0054】 In certain embodiments, the compound of formula (Ia) is of formula (IX-1) to (IX-5): [Chemical formula] and is represented by one of them, wherein A, X, R1, R3, R4, and R9 are as defined above. 【0055】 In certain embodiments, the compound of formula (Ia) is of formula (IX-1a) to (IX-5a): [Chemical formula] and is represented by one of them, wherein A, R1, R3, and R9 are as defined above. 【0056】 In certain embodiments, the compound of formula (Ia) is represented by one of the formulas (VIII-1) to (VIII-5) and (IX-1) to (IX-5), where R3 is hydrogen, -Me, -Et, -Pr, -i-Pr, -allyl, -CF3, -CD3, or cyclopropyl; R4 is hydrogen, -Me, -Et, -Pr, -i-Pr, -allyl, -CF3, or cyclopropyl; R9 is a halogen, -OCH3, -NH2, -CH3, or -CF3; and A is selected from the following: [ka] X is selected from the following: [ka] R1 is selected from the following: [ka] . 【0057】 In a particular embodiment, the compound of formula (Ia) is (X-1)~(X-3): [ka] It is expressed as one of the following, where m is 0, 1, 2, 3, 4 or 5, and v is 0, 1 or 2, R 10 may be substituted with -C1-C4 alkyl or It is a -C3-C6 cycloalkyl group which may be substituted, and X, R1, R3, R4, R9, and n are as previously defined. 【0058】 In certain embodiments, the compound of formula (Ia) is a compound of formulas (XI-1) to (XI-3): [ka] It is expressed as one of the following, in the formula R1, R 3、 R4, R9, R 10m, n, and v are as defined above. 【0059】 In certain embodiments, the compound of formula (Ia) is (XI-1a) to (XI-3a): [ka] It is expressed as one of the following, in the formula R1, R 3、 R9, R 10 m, n, and v are as defined above. 【0060】 In certain embodiments, the compound of formula (Ia) is a compound of formula (XI-1b) to (XI-3b): [ka] It is expressed as one of the following, in the formula R1, R 3、 R9, R 10 m, n, and v are as defined above. 【0061】 In certain embodiments, the compound of formula (Ia) is a compound of formulas (XII-1) to (XII-6): [ka] It is expressed as one of the following, in the formula R1, R 4、 R9, R 10 m, n, and v are as defined above. 【0062】 In certain embodiments, the compound of formula (Ia) is represented by formulas (XII-1a) to (XII-6a): [ka] It is expressed as one of the following, in the formula R1, R9, R 10 m, n, and v are as defined above. 【0063】 In certain embodiments, the compound of formula (Ia) is a compound of formula (XII-1b) to (XII-6b): [ka] It is expressed as one of the following, in the formula R1, R9, R 10 m, n, and v are as defined above. 【0064】 In certain embodiments, the compound of formula (Ia) is a compound of formula (XII-1c) to (XII-6c): [ka] It is expressed as one of the following, in the formula R1, R9, R 10 m, n, and v are as defined above. 【0065】 In certain embodiments, the compound of formula (Ia) is a compound of formula (XII-1c) to (XII-6d): [ka] It is expressed as one of the following, in the formula R1, R9, R 10 m, n, and v are as defined above. 【0066】 In certain embodiments, the compound of formula (Ia) is a compound of formulas (XIII-1) to (XIII-6): [ka] It is expressed as one of the following, in the formula R4, R9, R 10 m, n, and v are as defined above. 【0067】 In certain embodiments, the compound of formula (Ia) is defined as formula (XIII-1a) to (XIII-6a): [ka] It is expressed as one of the following, in the formula R9, R 10 m, n, and v are as defined above. 【0068】 In a particular embodiment, the compound of formula (Ia) is a compound of formulas (XIV-1) to (XIV-6): [ka] It is expressed as one of the following, in the formula R4, R9, R 10 m, n, and v are as defined above. 【0069】 In certain embodiments, the compound of formula (Ia) is defined as formula (XIV-1a) to (XIV-6a): [ka] It is expressed as one of the following, in the formula R9, R 10 m, n, and v are as defined above. 【0070】 In a particular embodiment, the compound of formula (Ia) is formula (XV): [ka] This is expressed as follows, where A, R1, R4, R9, n, and X are as defined above. 【0071】 In certain embodiments, the compound of formula (Ia) is formula (XVI-1) to (XVI-3): [ka] It is expressed as one of the following, in the formula R1, R4, R9, R 10 m, n, and v are as defined above. 【0072】 In a particular embodiment, the compound of formula (Ia) is a compound of formula (XVII-1) to (XVII-3): [ka] It is expressed as one of the following, in the formula R9, R 10, m, n, and v are as defined above. 【0073】 In certain embodiments, the compound of formula (Ia) is of formula (XVIII-1) or formula (XVIII-2): 【Chemical formula】 where one U is N or NR 13 and another U is N, NR 13 or CR 13 and another U is N, NR 13 or CR 13 and the fourth U is O, S, N, NR 13 or CR 13 and each V is independently CR 13 or N, and R1, R3, R4, R9, n and X are as defined above. 【0074】 In certain embodiments, the compound of formula (Ia) is of formula (XIX-1) to (XIX-9): 【Chemical formula】 and is represented by one of them, where R1, R3, R4, R9, n and X are as defined above. 【0075】 In certain embodiments, the compound of formula (Ia) is of formula (XX-1) to (XX-9): 【Chemical formula】 and is represented by one of them, where R1, R3, and R9 are as defined above. 【0076】 Definition The following lists the definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout this specification and the claims, individually or as part of a larger group, unless specifically limited in a particular instance. 【0077】 As used herein, the term "aryl" refers to monocyclic or polycyclic carbocyclic ring systems containing at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. Polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. Polycyclic aryl can include fused rings, covalently bonded rings, or combinations thereof. 【0078】 As used herein, the term "heteroaryl" refers to monocyclic or polycyclic aromatic radicals having one or more ring atoms selected from S, O, and N, with the remaining ring atoms being carbon, and any N or S contained within the ring optionally being oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. Polycyclic heteroaryl can include fused rings, covalently bonded rings, or combinations thereof. 【0079】 According to the present invention, the aromatic group can be substituted or unsubstituted. 【0080】 The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings in which at least one ring is aromatic, and the two rings may be fused or covalently bonded. 【0081】 As used herein, the term "alkyl" refers to saturated, straight-chain or branched-chain hydrocarbon radicals. "C 1- C4 alkyl", "C 1- C6 alkyl", "C 1- C8 alkyl", "C 1- C 12"Alkyl," "C2-C4 alkyl," or "C3-C6 alkyl" refers to alkyl groups containing 1-4, 1-6, 1-8, 1-12, 2-4, and 3-6 carbon atoms, respectively. 1- Examples of C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl groups. 【0082】 As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C2-C8 alkenyl,” “C2-C 12 "Alkenyl," "C2-C4 alkenyl," "C3-C4 alkenyl," or "C3-C6 alkenyl" refers to an alkenyl group containing 2-8, 2-12, 2-4, 3-4, or 3-6 carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, and octenyl. 【0083】 As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. 12 "Alkynyl," "C2-C4 alkynyl," "C3-C4 alkynyl," or "C3-C6 alkynyl" refers to an alkynyl group containing 2-8, 2-12, 2-4, 3-4, or 3-6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, heptynyl, and octynyl. 【0084】 As used herein, the term "cycloalkyl" refers to monocyclic or polycyclic saturated carbocyclic rings, or bicyclic or tricyclic group condensations, crosslinks, or spiro systems, where the carbon atoms may be oxosubstituted or substituted with extracyclic olefin double bonds. Preferred cycloalkyl groups include C3-C 12 Examples include cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. 12 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, and spiro[4.4]nonanyl. 【0085】 As used herein, the term "cycloalkenyl" refers to a monocyclic or polycyclic carbocyclic ring having at least one carbon-carbon double bond, or a bicyclic or tricyclic group condensation, bridge, or spiro system, wherein the carbon atoms may be oxosubstituted or substituted with extracyclic olefin double bonds. Preferred cycloalkenyl groups include C3-C 12 Examples include cycloalkenyl, C3-C8 cycloalkenyl, or C5-C7 cycloalkenyl groups. 12 Examples of cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hepta-2-enyl, bicyclo[3.1.0]hexa-2-enyl, spiro[2.5]octa-4-enyl, spiro[4.4]nona-2-enyl, and bicyclo[4.2.1]nona-3-en-12-yl. 【0086】 As used herein, the term "arylalkyl" means a functional group in which an alkylene chain is bonded to an aryl group, such as -CH2CH2-phenyl or benzyl. The term "substituted arylalkyl" means an arylalkyl functional group in which an aryl group is substituted. Similarly, the term "heteroarylalkyl" means a functional group in which an alkylene chain is bonded to a heteroaryl group. The term "substituted heteroarylalkyl" means a heteroarylalkyl functional group in which a heteroaryl group is substituted. Preferably, as used herein, arylalkyl is aryl-C1-C6 alkyl, and heteroarylalkyl is heteroaryl-C1-C6 alkyl. 【0087】 As used herein, the term “alkoxy,” when used alone or in combination with other terms, means an alkyl group having a specified number of carbon atoms bonded to the rest of the molecule via an oxygen atom, such as methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy), and their higher homologs and isomers, unless otherwise specified. Preferred alkoxys are (C2-C3)alkoxys. 【0088】 It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moieties described herein may also be aliphatic or alicyclic groups. 【0089】 An "aliphatic" group is a non-aromatic moiety consisting of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, which may contain one or more unsaturated units, such as double and / or triple bonds. Examples of aliphatic groups include functional groups such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH or C(O)NHS(O)2NH2, groups containing one or more functional groups, non-aromatic hydrocarbons (which may be substituted), and groups in which one or more carbon atoms of a non-aromatic hydrocarbon (which may be substituted) are replaced by a functional group. The carbon atoms of the aliphatic group may be oxosubstituted. The aliphatic group may be linear, branched, cyclic, or a combination thereof, and preferably contains about 1 to about 24 carbon atoms, more typically about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, the aliphatic group explicitly includes, for example, alkoxyalkyl groups, polyalkoxyalkyl groups, such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group may optionally be substituted. 【0090】 The terms “heterocyclic” or “heterocycloalkyl” can be used interchangeably and refer to non-aromatic rings or bicyclic or tricyclic group condensations, bridges or spiro systems, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen; (ii) each ring system may be saturated or unsaturated; (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized; (iv) the nitrogen heteroatom may optionally be quaternized; (v) any of the above rings may be condensed to an aromatic ring; and (vi) the remaining ring atoms are carbon atoms which may optionally be oxosubstituted or optionally substituted with an extracyclic olefin double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinozalinyl, pyridadinyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepant-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups may have a C bond or an N bond (if possible). 【0091】 It will be understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moieties, etc., described herein may be divalent or polyvalent when used as a bond to link two or more groups or substituents that may be present on the same or different atoms. Those skilled in the art can readily determine the valency of any such group from the context in which it arises. 【0092】 The term "substituted" refers to one, two, or three or more hydrogen atoms, but is not limited to -F, -Cl, -Br, -I, -OH, C 1- C 12-alkyl;C2-C 12 -Alkenyl, C2-C 12 -Alkinyl, -C3-C 12 -Cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thio, -NH-C 1- C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12 -Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -OC 1- C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C 1- C 12 -alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C 12 -Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C 1- C 12 -alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 -Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 -alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C 12 -Cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C 1- C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C 12-Cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1C 12 -alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C 12 -Cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C 1- C 12 -alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclo-alkyl, -NHCO2-C 1- C 12 -alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-C 12 -Cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C 1- C 12 -alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 -Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C 1- C 12 -alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-alkynyl, -NHC(S)NH-C3-C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C 1- C 12-alkyl, -NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-C 12 -Cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C 1- C 12 -alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-C 12 -Cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C 1- C 12 -alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-C 12 -Cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C 1- C 12 -alkyl, -S(O)-C2-C8-alkenyl, -S(O)-C2-C8-alkynyl, -S(O)-C3-C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C 1- C 12 -alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -SO2NH-C3-C 12 -Cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C 1- C 12 -alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkynyl, -NHSO2-C3-C 12-Cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -SC 1- C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12 This refers to substitution by independently replacing with substituents including -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl substituents. In certain embodiments, the substituents are halos, preferably Cl and F;C 1- C4 alkyl, preferably methyl and ethyl; halo-C 1- C4-alkyl, e.g., fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, e.g., cyclopropyl; C 1- C4-alkoxy, e.g., methoxy and ethoxy; halo-C 1- C4-alkoxy, e.g., fluoromethoxy, difluoromethoxy, and trifluoromethoxy; acetyl; -CN; -OH; NH2; C 1- C4-alkylamino;di(C 1- C4-alkyl)amino; and NO2 are independently selected. It is understood that aryl, heteroaryl, alkyl, etc. may be further substituted. In some cases, each substituent in the substituted moiety may be further substituted with one or more groups, each group being C 1- A substituted alkyl group can be independently selected from C4-alkyl-CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2. Preferably, the substituted alkyl group is substituted with one or more halogen atoms, more preferably with one or more fluorine or chlorine atoms. 【0093】 As used herein, the terms "halo" or "halogen" refer to a fluorine, chlorine, bromine, or iodine atom, either alone or as part of another substituent. 【0094】 As used herein, the term “may be substituted” means that the group referred to may be substituted or unsubstituted. In one embodiment, the group referred to may be substituted with zero substituents, i.e., the group referred to is unsubstituted. In another embodiment, the group referred to may be substituted with one or more further groups individually and independently selected from the groups described herein. 【0095】 The term "hydrogen" includes hydrogen and deuterium. Furthermore, the enumeration of atoms includes other isotopes of that atom, insofar as the resulting compound is pharmaceutically acceptable. 【0096】 As used herein, the term “hydroxyl-activating group” refers to an unstable chemical moiety known in the art to activate a hydroxyl group to be eliminated during synthetic procedures such as substitution or elimination reactions. Examples of hydroxyl-activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, and phosphonates. 【0097】 As used herein, the term "activated hydroxyl" refers to a hydroxyl group activated with one of the hydroxyl activating groups defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, and phosphonate groups. 【0098】 As used herein, the term “hydroxy protecting group” refers to an unstable chemical moiety known in the art to protect a hydroxyl group from undesirable reactions during a synthetic procedure. After the synthetic procedure, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are generally described in T. Greene and P. G. M. W. Tuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, and triisopropylsilyl. 【0099】 As used herein, the term "protected hydroxyl" refers to a hydroxyl group protected by a hydroxyl protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, and methoxymethyl groups. 【0100】 As used herein, the term “hydroxyprodrug group” refers to a promoiety group, which is known in the art to transiently alter the physicochemical, and therefore biological, properties of a parent drug by coating or masking a hydroxyl group. After the synthesis procedure, the hydroxyprodrug groups described herein must be able to revert to a hydroxyl group in vivo. Hydroxyprodrug groups known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992). 【0101】 As used herein, the term “amino protecting group” refers to an unstable chemical moiety known in the art to protect an amino group from undesirable reactions during a synthetic procedure. After the synthetic procedure, the amino protecting groups described herein can be selectively removed. Amino protecting groups known in the art are generally described in T. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, and benzyloxycarbonyl. 【0102】 As used herein, the term "protected amino" refers to an amino group protected by the amino protecting group defined above. 【0103】 The term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom in substitution reactions such as nucleophilic substitution reactions. Examples of typical leaving groups include chloro, bromo, and iodine groups; sulfonic acid ester groups, such as mesylate, tosylate, brosylate, and nosylate; and acyloxy groups, such as acetoxy and trifluoroacetoxy. 【0104】 As used herein, the term “aprotic solvent” refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, and chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether and bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be apparent to those skilled in the art that, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature range, individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example, in *Organic Solvents Physical Properties and Methods of Purification*, 4th ed. (edited by John A. Riddick et al.), Vol. II, in *Techniques of Chemistry Series*, John Wiley & Sons, NY, 1986. 【0105】 As used herein, the term “protic solvent” refers to solvents that tend to provide protons, such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to them that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature range. Further discussion of protic solvents can be found in organic chemistry textbooks or specialized monographs, e.g., in *Organic Solvents: Physical Properties and Methods of Purification*, 4th ed. (edited by John A. Riddick et al.), Vol. II, in *Techniques of Chemistry Series*, John Wiley & Sons, NY, 1986. 【0106】 The combinations of substituents and variables envisioned in the present invention simply result in the formation of stable compounds. As used herein, the term “stable” means a compound that is stable enough to enable production and maintains the integrity of the compound over a sufficient period of time to serve the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). 【0107】 The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high-pressure liquid chromatography, or recrystallization. Further methods for synthesizing the compounds of the formulas herein will be obvious to those skilled in the art, as can be understood. Furthermore, the desired compounds can be obtained by carrying out various synthetic steps in an alternative order or sequence. Useful synthetic chemical transformations and protecting group methodologies (protection and deprotection) for synthesizing the compounds described herein are known in the art, including, for example, those described in R. Larock, Comprehensive Organic Transformations, 2nd ed. Wiley-VCH (1999); TW. Greene and PG. MWuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions. 【0108】 As used herein, the term “subject” refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. The subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, and so on. 【0109】 The compounds of the present invention can be modified by adding appropriate functional groups to enhance their selective biological properties. Such modifications are known in the art and may include those that increase biopenetration into a given biological system (e.g., blood, lymphatic system, central nervous system), enhance oral availability, increase solubility to enable administration by injection, alter metabolism, and alter excretion rate. 【0110】 The compounds described herein contain one or more chiral centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers, which can be defined from the viewpoint of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids as (D)- or (L)-. The present invention means that all such possible isomers are included as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the above procedure or by resolution of racemic mixtures. Resolution can be carried out by chromatography in the presence of a resolving agent, by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Where the compounds described herein contain olefinic double bonds, other unsaturated or other geometrically chiral centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers or cis and trans isomers. Similarly, all tautomers are intended to be included. Tautomers may be cyclic or acyclic. Any carbon-carbon double bond configurations appearing herein are selected for convenience only and are not intended to specify any particular configuration unless otherwise stated herein. Thus, any carbon-carbon double bond or carbon-heteroatom double bond optionally shown as trans herein may be cis, trans, or a mixture of the two in any proportion. 【0111】 Certain compounds of the present invention may also exist in different stable conformations that may be separable. Torsional chirality resulting from restricted rotation around a chiral single bond, for example, due to steric hindrance or ring strain, may allow for the separation of different conformational isomers. The present invention includes each conformational isomer of these compounds and mixtures thereof. 【0112】 As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that provides a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:2-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free basic functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts, but not limited to, include non-toxic acid addition salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobio Examples of alkali metal salts include, but are not limited to, sodium, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, picrate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium compounds, quaternary ammonium compounds, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates. 【0113】 As used herein, the term “pharmaceutically acceptable ester” refers to an ester that hydrolyzes in vivo and includes those that readily decompose in the human body, leaving a parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanes, alkenes, cycloalkanoates, and alkanedioates, where each alkyl or alkenyl moiety has, advantageously, six or fewer carbon atoms. Examples of specific esters include, but are not limited to, formate esters, acetate esters, propionate esters, butyrate esters, acrylic acid esters, and ethyl succinate esters. 【0114】 Pharmaceutical composition The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of the present invention, formulated with one or more pharmaceutically acceptable carriers or excipients. 【0115】 As used herein, the term “pharmaceutically acceptable carrier or excipient” means any kind of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch, potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols, e.g., propylene glycol; esters, e.g., ethyl oleate, ethyl laurate; agar; buffers, e.g., magnesium hydroxide, aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, as well as phosphate buffers, and other non-toxic compatible lubricants, e.g., sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances, preservatives, and antioxidants, which may also be present in the composition at the discretion of the compounder. 【0116】 The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably by oral or injectable administration. The pharmaceutical compositions of the present invention may contain any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques. 【0117】 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. 【0118】 Preparations for injection, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using appropriate dispersants or wetting and suspending agents. Sterile preparations for injection may also be sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Furthermore, sterile fixatives have conventionally been used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in preparations for injection. 【0119】 Injectable formulations can be sterilized, for example, by filtration using a bacterial capture filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. 【0120】 To prolong the effects of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of a drug depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle. Depot formulations for injection are prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues. 【0121】 The compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compounds. 【0122】 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is accompanied by at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate and / or: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents. f) an absorption enhancer, such as paraffin; g) a wetting agent, such as cetyl alcohol and glycerol monostearate; h) an absorbent, such as kaolin and bentonite clay; and i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. 【0123】 Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. 【0124】 Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain opacifying agents and may be compositions that release the active ingredient alone or preferentially, in a delayed manner, in a specific portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. 【0125】 Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions and, if necessary, with any required preservatives or buffers. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of the present invention. 【0126】 The ointments, pastes, creams, and gels may contain, in addition to the active compound of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. 【0127】 The powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional spraying agents such as chlorofluorohydrocarbons. 【0128】 Transdermal patches offer the additional advantage of controlling the delivery of compounds to the body. Such dosage forms can be prepared by dissolving or aliquoting the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel. 【0129】 For pulmonary delivery, the therapeutic compositions of the present invention are formulated and administered to the patient in solid or liquid particle form by direct administration, for example, by inhalation into the respiratory system. The solid or liquid particle forms of the active compounds prepared for carrying out the present invention include breathable-sized particles, i.e., particles small enough to pass through the mouth and larynx and enter the bronchi and alveoli of the lungs upon inhalation. The delivery of aerosolized therapeutics, in particular aerosolized antibiotics, is known in the art (see, for example, U.S. Patent No. 5,767,068 by Van Devanter et al., Patent No. 5,508,269 by Smith et al., and International Publication No. 98 / 43650 by Montgomery, all of which are incorporated herein by reference). 【0130】 Antiviral activity In certain embodiments, the present invention provides a method for treating or preventing a viral infection in a subject requiring treatment or prevention of a viral infection, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. The viral infection is preferably a coronavirus infection. In certain embodiments, the coronavirus is SARS-CoV-1, SARS-CoV-2, or MERS-CoV. Preferably, the coronavirus is SARS-CoV-2. 【0131】 The viral suppression dose or amount of the compound of the present invention may range from about 0.01 mg / kg to about 500 mg / kg, or from about 1 to about 50 mg / kg. The suppression dose or amount also varies depending on the route of administration and the possibility of concomitant use with other drugs. 【0132】 According to the therapeutic method of the present invention, viral infection is treated or prevented in a patient, such as a human or another animal, by administering a therapeutically effective amount of the compound of the present invention to the patient in the amount and time necessary to achieve the desired result. 【0133】 The “therapeutic effective dose” of the compounds of the present invention means the amount of the compound that imparts a therapeutic effect to the treated subject with a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by several tests or markers) or subjective (i.e., the subject shows an indicator of the effect or feels the effect). The therapeutic effective dose of the above compounds may be in the range of, for example, about 0.1 mg / kg to about 500 mg / kg, preferably about 1 to about 50 mg / kg. The effective dose also varies depending on the route of administration and the possibility of concomitant use with other drugs. However, it will be understood that the total daily dose of the compounds and compositions of the present invention should be determined by the attending physician within the bounds of sound medical judgment. The specific therapeutic effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the activity of the particular compound used; the particular composition used; the patient’s age, weight, overall health, sex, and diet; the timing of administration, route of administration, and excretion rate of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used; and similar factors well known in the medical field. 【0134】 The total daily dose of the compounds of the present invention administered to humans or other animals in single or divided doses may be, for example, 0.01 to 50 mg / kg body weight or more, usually 0.1 to 25 mg / kg body weight. Single-dose compositions may contain such amounts or a fraction thereof that constitutes the daily dose. Generally, therapeutic regimens according to the present invention involve administering to patients requiring such treatment about 10 mg to about 1000 mg of the compounds of the present invention per day in single or multiple doses. 【0135】 The compounds of the present invention described herein may be administered, for example, by intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or subcutaneous injection, or orally, orally, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, in doses ranging from about 0.1 to about 500 mg / kg body weight, or in doses of 1 mg to 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods described herein aim to achieve the desired or described effect by administering an effective amount of the compound or compound composition. Typically, the pharmaceutical compositions of the present invention are administered about 1 to about 6 times per day, or alternatively, as continuous infusions. Such administrations can be used as chronic or acute therapy. The amount of active ingredient that can be combined with pharmaceutically excipients or carriers to make a single dosage form varies depending on the host being treated and the specific mode of administration. Typical preparations contain about 5% to about 95% (w / w) of the active compound. Alternatively, such preparations may contain approximately 20% to 80% of the active compound. 【0136】 Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for any particular patient depends on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, concomitant medications, severity and course of the disease, condition or symptom, the patient's disposition to the disease, condition or symptom, and the judgment of the treating physician. 【0137】 If the patient's condition improves, a maintenance dose of the compound, composition, or combination of the present invention may be administered as needed. Thereafter, depending on the symptoms, the dose, frequency, or both may be reduced to a level where the improved state is maintained and the symptoms are alleviated to the desired level. However, the patient may require long-term, intermittent treatment in response to any relapses of disease symptoms. 【0138】 Combination therapy and alternative therapy The compounds of the present invention may be used in combination with one or more antiviral or anti-inflammatory agents useful for the prevention or treatment of viral diseases or related pathophysiology. Accordingly, the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be used alone or in combination with other antiviral or anti-inflammatory agents.The compounds herein and their pharmaceutically acceptable salts are useful in the prevention or treatment of respiratory diseases, inflammatory diseases, and autoimmune diseases, one or more other agents, e.g., antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors Harmful agents, Syk inhibitors, protease inhibitors, e.g., elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors, e.g., sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors, or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert) (-butylthio)-1-(4-(6-ethoxypyridine-3-yl)benzyl)-5-((5-ethylpyridine-2-yl)methoxy)-1H-indole-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapies, e.g., anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1, and similar agents; cytokine receptor therapies, e.g., etanercept and similar agents; antigen-nonspecific immunotherapy These may be used in combination with anti-infective agents, including antibiotics, antifungals, anthelmintics, antimalarials, antiparasitic agents, antituberculosis agents, and antivirals, including those listed at https: / / www.drugs.com / drug-class / anti-infectives.html, such as interferons or other cytokines / chemokines, chemokine receptor modulators, e.g., CCR3, CCR4, or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists, and similar agents.Generally, combination therapy is preferred over alternating therapy because it induces multiple simultaneous stresses on the virus. 【0139】 If the composition of the present invention comprises a combination of a compound of a formula described herein and one or more further therapeutic or prophylactic agents, both the compound and the additional agents should be present at a dosage level of about 1 to 100%, more preferably about 5 to 95%, of the dosage typically administered in a monotherapy regimen. The additional agents may be administered separately from the compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form combined with the compound of the present invention in a single composition. 【0140】 "Additional therapeutic or prophylactic agents" include, but are not limited to, immunotherapies (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents (e.g., corticosteroids or NSAIDs), bronchodilators (e.g., beta-2 adrenergic agonists and xanthines, e.g., theophylline), mucolytics, antimuscarinic agents, anti-leukotriene agents, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants, and / or antibacterial and antiviral agents (e.g., ribavirin and amantidine). Compositions according to the present invention may also be used in combination with gene replacement therapy. 【0141】 Abbreviation The following abbreviations may be used in the following explanation of schemes and examples: Ac, acetyl; AcOH, acetic acid; Boc2O, di-tert-butyl dicarbonate; Boc, t-butoxycarbonyl; Bz, benzoyl; Bn, benzyl; t-BuOK, potassium tert-butoxide; Brine, aqueous sodium chloride solution; CDI, carbonyldiimidazole; DCM or CH2Cl2, dichloromethane; CH3, methyl; CH3CN, acetonitrile; Cs2CO3, cesium carbonate; CuCl, copper(I) chloride; CuI, copper(I) iodide; dba, dibenzylideneacetone; DBU, 1,8-diazabicyclo[5.4.0]-unde-7-ene; DEAD, diethylazodicarboxylate; DIAD, diisopropylazodicarboxylate; DIPEA or (i-Pr)2EtN, N,N,-diisopropylethylamine; DMP or Dess-Martin periodinane, 1,1,2-tris(acetyloxy)-1,2-dihydro-1,2-benzoiodoxol-3-(1H)-one; DMAP, 4-dimethylaminopyridine; DME, 1,2-dimethoxyethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; siRNA, ethyl acetate; EtOH, ethanol; Et2O, diethyl ether; HATU, O-(7-azabenzotriazol-2-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate; HCl, hydrogen chloride; K2CO3, potassium carbonate; n-BuLi, n-butyllithium; DD Q, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA, lithium diisopropylamide; LiTMP, lithium 2,2,6,6-tetramethyl-piperidinate; MeOH, methanol; Mg, magnesium; MOM, methoxymethyl; Ms, mesyl or -SO2-CH3; NaHMDS, sodium bis(trimethylsilyl)amide; NaCl, sodium chloride; NaH, sodium hydride; NaHCO3, sodium bicarbonate or sodium bicarbonate; Na2CO3, sodium carbonate; NaOH, sodium hydroxide; Na2SO4, sodium sulfate; NaHSO 3、Sodium bisulfite or sodium bisulfite; Na2S2O3, sodium thiosulfate; NH2NH2, hydrazine; NH4Cl, ammonium chloride; Ni, nickel; OH, hydroxyl; OsO4, osmium tetroxide; OTf, triflate; PPA, polyphosphate; PTSA, p-toluenesulfonic acid; PPTS, pyridinium p-toluenesulfonate; TBAF, tetrabutylammonium fluoride; TEA or Et3N, triethylamine; TES, triethylsilyl; TESCl, triethylsilyl chloride; TESOTf, triethylsilyltrifluoromethanesulfonate; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMEDA, N,N,N',N'-tetramethylethylene Diamines; TPP or PPh3, triphenylphosphine; Tos or Ts, tosyl or -SO2-C6H4CH3; Ts2O, tolylsulfonic anhydride or tosyl anhydride; TsOH, p-tolylsulfonic acid; Pd, palladium; Ph, phenyl; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)4, tetrakis(triphenylphosphine)-palladium(0); PdCl2(PPh3)2, trans-dichlorobis-(triphenylphosphine)palladium(II); Pt, platinum; Rh, rhodium; rt, room temperature; Ru, ruthenium; TBS, tert-butyldimethylsilyl; TMS, trimethylsilyl; and TMSCl, trimethylsilyl chloride. 【0142】 Synthesis method The compounds and processes of the present invention will be better understood in connection with the following synthetic scheme (intended for illustrative purposes only and not to limit the scope of the invention) illustrating a method by which the compounds of the present invention can be prepared. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structure, substituents, derivatives and / or methods of the present invention, can be made without departing from the spirit of the invention and the scope of the appended claims. 【0143】 Scheme 1 [ka] Scheme 1 shows a general method for preparing the compound of formula (IV-1) from an aminoester compound (X-1), where B is as previously defined and PG1 is a C1-C4 alkyl or Bn. Treatment of the amine (X-1) with formaldehyde yields a cyclized amine (X-2), which is converted to (X-3) using a suitable protecting group PG2 (e.g., Boc). Treatment of (X-3) at low temperature with NBS in an AcOH-containing solvent yields a rearranged helical proline derivative (X-4). Examples of this conversion sequence are reported in the literature (Pellegrini C. et al. "Synthesis of the Oxindole Alkaloid(-)-Horsfiline," Tetrahedron Asymmetry, 1994, vol.5, No.10, pp 1979-1992; Efremov, IV et al. "Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of β-Secretase (BACE1) through Fragment-Based Drug Design," Journal of Medicinal Chemistry, 2012, 55, 9069-9088). When the ester (X-4) is treated with NH3 (e.g., ammonia in MeOH, NH3OH, etc.), an amide compound (X-5) is obtained, which is then converted to an amine compound (X-6) by removing the protecting group PG2 (e.g., TFA, HCl, etc.). The condensation of an amine (X-6) and an acid (X-7) under amide coupling conditions (e.g., HATU, EDC, DCC, etc.) yields an amide compound (X-8) (where A, R1, R2, and R3 are as previously defined). The amide (X-8) can be converted to a nitrile compound (IV-1) under dehydration conditions such as TFAA / Et3N, Pd(OCOCF3)2 / Cl2CHCN, Burgess reagent, or T3P, but is not limited to these. Alternatively, condensation of the amine (X-6) with the acid (X-9) under amide coupling conditions (e.g., HATU, EDC, DCC, etc.) yields the amide compound (X-10) (R1, R2, and R3 are as previously defined, and PG3 is a suitable protecting group (e.g., Cbz)). Removal of PG3 (e.g., hydrogenation) yields the amine compound (X-11). Condensation of the amine (X-11) with the acid (A-COOH) under amide coupling conditions (e.g., HATU, EDC, DCC, etc.) or acyl halide formation conditions (e.g., Ghosez reagent) yields the amide compound (X-8) (A is as previously defined). 【0144】 Scheme 2 [ka] Scheme 2 shows a general method for synthesizing the aldehyde compound of formula (IV-2), where A, R1, R2, R3, and B are previously defined. The ester compound of formula (X-4), where B, PG1, and PG2 are previously defined, is reduced to the alcohol compound (X1-1) using a reducing agent, for example, but not limited to LiBH4, NaBH4, DIBAL-H, etc. The protecting group PG2 (e.g., Boc) of (XI-1) is removed under acidic conditions using TFA, HCl, formic acid, TMSOTf / lutidine, etc. Compound (XI-3) (A, R1, R2, and R3 are previously defined) is obtained by coupling the amine compound (XI-2) with the acid compound (X-7) using a coupling reagent such as HATU, EDC, or DCC. The alcohol of (XI-3) is oxidized with a mild oxidizing reagent such as DMSO / Ac2O, Dess-Martin periodinane, IBX, SO3-pyridine / DMSO / Et3N to produce the aldehyde compound (IV-2). 【0145】 Scheme 3 [ka] Scheme 3 shows a general method for synthesizing the hydroxymethyl ketone compound of formula (IV-3). Acidic compound (XII-1) is obtained by hydrolysis of the ester compound (X-4), where B, PG1, and PG2 are previously defined. The amide (XII-2) can be obtained from acidic compound (XII-1) by coupling with N,O-dimethylhydroxyamine using reagents such as HATU, EDC, and DCC. Ketone compound (XII-3) is obtained by treating amide (XII-2) at low temperature (e.g., -60°C) with organometallic regeat produced by BOM-Cl, Mg, and HgCl2. Amine compound (XII-4) is obtained by removal of PG2 (e.g., PTSA if PG2 is BOC). Compound (XII-5) is obtained by coupling amine (XII-4) with acid (X-7) using amide coupling reagents such as HATU, EDC, and DCC (A, R1, R2, and R3 are previously defined). When the benzyl group of (XII-5) is removed under hydrogenation conditions (Pd / C, H2), the compound of formula (IV-3) is obtained. 【0146】 Scheme 4 [ka] Scheme 4 shows a general method for synthesizing the chloromethyl ketone compound of formula (IV-4). Chloroketone compound (XIII-1) is obtained by treating the ester compound (X-4) with an organometallic reagent produced by ICH2Cl and a suitable base, such as LDA, MeLi / LiBr, or BuLi. Amine compound (XIII-2) is obtained by removal of PG2 (e.g., PTSA if PG2 is BOC). Compound (IV-4) is obtained by coupling the amine (XIII-2) with an acid (X-7) using a coupling reagent such as HATU, EDC, or DCC (A, R1, R2, and R3 are previously defined). 【0147】 Scheme 5 [ka] Scheme 5 shows a general method for synthesizing the fluoromethyl ketone compound of formula (IV-5). Removal of the Bn group from compound (XII-3) by Pd-catalyzed hydrogenation yields the alcohol compound (XIV-1). The alcohol (XIV-1) is converted to the fluoromethyl ketone compound (XIV-2) under conditions such as SF4, Tf2O / lutidine / TBAF, or C4F9SO2F / HF-Et3N. Removal of PG2 (e.g., PTSA if PG2 is BOC) yields the amine compound (XIV-3). Coupling of the amine (XIV-3) with the acid (X-7) using amide coupling reagents such as HATU, EDC, or DCC yields compound (IV-5) (A, R2, and R3 are previously defined). 【0148】 Scheme 6 [ka] Scheme 6 shows a general method for synthesizing the α-ketone amide compound of formula (IV-6). A, R1, R2, R3, and B are aldehyde compounds of formula (IV-2) as previously defined, R 13 When treated with the previously defined isonitrile compound (XV-1), α-hydroxylamide (XV-2) is obtained. When compound (XV-2) is oxidized with a suitable oxidizing agent, such as Dess-Martin periodinane, (COCl)2 / DMSO / Et3N, PCC, or SO3-pyridine / DMSO / Et3N, α-ketoamide of formula (IV-6') is obtained. 【0149】 Scheme 7 [ka] Alternatively, nitrile compound (IV-1) can be synthesized from aldehyde compound (IV-2) using the method shown in Scheme 7. Condensation of aldehyde (IV-2) with hydroxyamine hydrochloride in a suitable solvent such as DMSO, i-PrOH, or pyridine yields oxime compound (XVI-1). Treatment of oxime compound (XVI-1) under acid-catalyzed dehydration conditions such as (Cu(OAc)2 / MeCN, HCl, etc.) yields nitrile compound (IV-1). 【0150】 Scheme 8 [ka] Scheme 8 shows a general method for synthesizing a functionalized spiro ring of formula XX-2 (where Q1 is defined as a halogen or optionally substituted alkyl). A functionalized spiro ring XX-2 can be obtained by treating a spirocyclic compound of formula XX-1, where B, PG1, and PG2 are defined previously, with an electrophile including but not limited to sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide, SelectFluor, or NFSI. 【0151】 example The compounds and processes of the present invention are intended to be illustrative only and are better understood in relation to the following examples, which are not intended to limit the scope of the invention. The starting materials are available from commercial vendors or are manufactured by methods well known to those skilled in the art. 【0152】 General conditions: Mass spectra were performed using an LC-MS system with electrospray ionization. These were Agilent 6120 Infinity II systems with an Agilent 1290 Quadrupole detector. Spectra were obtained using a ZORBAX Eclipse XDB-C18 column (4.6 × 30 mm, 1.8 micron). Spectra were obtained at 298 K using mobile phases of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra were obtained using the following solvent gradients: 5% (B) at 0–1.5 min, 5–95% (B) at 1.5–4.5 min, and 95% (B) at 4.5–6 min. The solvent flow rate was 1.2 mL / min. The compound was detected at wavelengths of 210 nm and 254 nm. [M+H] + This refers to monoisotopic molecular weight. 【0153】 NMR spectra were performed using a Bruker 400 MHz spectrometer. Spectra were measured at 298 K and indicated using solvent peaks. 1 The chemical shifts in 1H NMR are reported in parts per million (ppm). 【0154】 Compounds were purified by reverse-phase high-performance liquid chromatography (RPHPLC) using a Gilson GX-281 automated liquid processing system. Unless otherwise specified, compounds were purified using a Phenomenex Kinetex EVO C18 column (250 × 21.2 mm, 5 micron). Unless otherwise specified, compounds were purified at 298 K using a gradient elution from 0% to 100% (B) with water (A) and acetonitrile (B) as mobile phases. The solvent flow rate was 20 mL / min, and compounds were detected at a wavelength of 254 nm. 【0155】 Alternatively, the compound was purified by normal-phase liquid chromatography (NPLC) using the Teledyne ISCO Combiflash purification system. The compound was also purified using a REDISEP silica gel cartridge. The compound was purified at 298K and detected at a wavelength of 254nm. 【0156】 Example 1 [ka] 【0157】 Process 1-1 Methyl(S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride (500 mg, 1.875 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (523 μl, 3.75 mmol) and a 2.0 M solution of di-tert-butyl dicarbonate in DCM (1031 μl, 2.062 mmol) were added. The mixture was stirred at room temperature for 3 hours, quenched with saturated NaHCO3, and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified on silica gel with 0-30% siRNA / cyclohexane to obtain compound (1-1) (578 mg, 1.749 mmol, 93% yield). 【0158】 Process 1-2 Compound (1-1) was dissolved in THF (15 ml), AcOH (10 ml), and water (10 ml). The solution was cooled to -15°C. A solution of NBS (328 mg, 1.843 mmol) in THF (5 mL) was added dropwise. The mixture was slowly warmed to 5°C over 1 hour. The reaction product was quenched with Na2SO3 and saturated NaHCO3 and extracted with DCM (2×). The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified on silica gel with 0-50% siRNA / cyclohexane to obtain compound (1-2) (328 mg, 0.947 mmol, yield 53.9%). 【0159】 Process 1-3 Compound (1-2) (328 mg, 0.947 mmol) was dissolved in MeOH (3 ml). A solution of 7 N ammonia in MeOH (5 mL, 35.0 mmol) was added. The mixture was stirred at room temperature for 5 days. The solvent was removed under vacuum. The residue was purified using silica gel with 0-10% MeOH / DCM and a C18 column with 0-50% MeCN / H2O to obtain compound (1-3) (101 mg, 0.305 mmol, yield 32.2%). 【0160】 Process 1-4 Compound (1-3) (100 mg, 0.302 mmol) was dissolved in DCM, and trifluoroacetic acid (232 μl, 3.02 mmol) was added. The mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. DCM (10 mL) and toluene (10 mL) were added. The solvent was removed under vacuum. The residue was dissolved in MeOH, and 1 M HCl (0.6 mL, 2 equivalents) was added. The solvent was removed. The resulting compound (1-4) (91 mg, 0.340 mmol, quantitative yield) was used in the next step. 【0161】 Process 1-5 Compound (1-4) (15 mg, 0.056 mmol) and ((benzyloxy)carbonyl)-L-leucine (14.87 mg, 0.056 mmol) were dissolved in THF (0.5 ml) and DMF (0.1 ml). DIPEA (30.0 μL, 0.168 mmol) and HATU (21.30 mg, 0.056 mmol) were added. The mixture was stirred at room temperature for 20 minutes, quenched with water, and extracted with butyl (2x). The organic layer was loaded onto silica gel and eluted with 0-70% acetone / cyclohexane to obtain compound (1-5) (15 mg, 0.031 mmol, yield 55.9%). 【0162】 Process 1-6 Compound (1-5) (60 mg, 0.125 mmol) was dissolved in DCM (1.254 ml) (it did not dissolve). Triethylamine (140 μl, 1.003 mmol) and TFAA (70.8 μl, 0.502 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction product was diluted with DCM and quenched with saturated NaHCO3. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane. Example 1 (14 mg, 0.056 mmol) was obtained as a white powder by preparative HPLC using 20-85% MeCN / 0.1% formic acid-containing H2O. 1 H NMR(400 MHz,Acetone-d6)δ 9.70(s,1H),7.42-7.31(m,5H),7.28(td,J=7.7,1.3 Hz,1H),7.12(d,J=7.4 Hz,1H),7.04-6.96(m,2H),6.65(d,J=8.3 Hz,1H),5.17(t,J=8.3 Hz,1H),5.06-4.94(m,2H),4.48(td,J=9.0,5.0 Hz,1H),4.26(d,J=10.4 Hz,1H),3.99(d,J=10.3 Hz,1H),2.78-2.63(m,2H),1.80(dd,J=13.8,6.9 Hz,1H),1.74-1.56(m,2H),0.96(dd,J=8.7,6.6 Hz,6H).[M+Na] m / e 483.18. 【0163】 The following examples were prepared using the same protocol as described above. [Table 1-1] [Table 1-2] [Table 1-3] 【0164】 Examples 11 and 12 [ka] 【0165】 Process 1 4-Methoxy-1H-indole-2-carboxylic acid (1 g, 5.23 mmol) was dissolved in THF (25 mL). Ethyl L-leucinate hydrochloride (1.024 g, 5.23 mmol), Hünig base (2.3 mL, 13.08 mmol), DMAP (0.032 g, 0.262 mmol), and HATU (2.0 g, 5.23 mmol) were added sequentially. The mixture was stirred at room temperature for 1.5 hours, quenched with water, and extracted with MTBE. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified on silica gel with 0-50% toluene / cyclohexane to obtain compound (11-1) (1.47 g, 4.42 mmol, 85% yield). 【0166】 Process 2 Compound (11-1) (1.47 g, 4.42 mmol) was dissolved in THF (29.5 mL) and water (14.74 mL). LiOH-H2O (0.278 g, 6.63 mmol) was added at 0°C. The mixture was vigorously stirred at 0°C for 30 minutes, quenched with 1 M HCl (6.6 mL), and extracted with HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified using silica gel with 0-15% MeOH / DCM to obtain compound (11-2) (1.32 g). 【0167】 Process 3 Compound (1-4) (50 mg, 0.187 mmol) and compound (11-2) (56.8 mg, 0.187 mmol) were dissolved in THF (1.6 mL) and DMF (0.3 mL). Hünig base (98 μl, 0.560 mmol) and HATU (56.8 mg, 0.149 mmol) were added. The mixture was stirred at room temperature for 30 minutes, quenched with water, and extracted with phenylethylamine. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to obtain compound (11-3) (75 mg, 0.145 mmol, yield 78%) as a mixture of the two diastereomers. 【0168】 Process 4 To a suspension of compound (11-3) (67 mg, 0.129 mmol) in DCM (1.3 mL), triethylamine (144 μl, 1.036 mmol) and TFAA (73.1 μl, 0.518 mmol) were added at 0°C. The mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was diluted with DCM and quenched with saturated NaHCO3. The organic layer was loaded onto silica gel and eluted with 0-50% siRNA / cyclohexane to obtain compound (11-4) (48 mg, 0.096 mmol, yield 74.2%) as a mixture of the two diastereomers. 【0169】 Process 5 By purifying compound (11-4) (5 mg) using preparative HPLC with 20-85% MeCN / 0.1% formic acid-containing H2O, Examples 11 (1.8 mg) and 12 (1.9 mg) were obtained. Example 11: 1 H NMR(400 MHz,Acetone-d6)δ 10.47(s,1H),9.56(s,1H),7.74(d,J=8.1 Hz,1H),7.21(d,J=2.2 Hz,1H),7.10-6.89(m,5H),6.85(d,J=7.7 Hz,1H),6.76(td,J=7.5,1.0 Hz,1H),6.41(dd,J=7.3,1.1 Hz,1H),5.03(t,J=8.2 Hz,1H),4.84-4.74(m,1H),4.23(d,J=10.2 Hz,1H),3.91(d,J=10.3 Hz,1H),3.81(s,3H),2.56(td,J=13.5,8.2 Hz,2H),1.71(ddd,J=14.5,9.9,3.9 Hz,2H),1.58(ddd,J=13.8,9.7,4.9 Hz,1H),0.86(dd,J=11.9,6.4 Hz,6H).[M+Na] m / e 522.19. Example 12: 1H NMR(400 MHz, Acetone-d6)δ 10.75(s,0.33H),10.59(s,0.67H),9.58(s,0.67H),9.54(s,0.33H),8.10(d,J=7.8 Hz,0.33H),7.90(d,J=8.7 Hz,0.67H),7.34-6.71(m,8H),6.42(m,1H),5.90(t,J=8.0 Hz,0.33H),5.06(t,J=8.3 Hz,0.67H),4.98(ddd,J=11.3,7.7,4.0 Hz,0.33H),4.83(td,J=9.1,4.7 Hz,0.67H),4.00(dd,J=11.7,1.4 Hz,0.39H),3.97-3.87(m,1.41H),3.81(m,3H),3.51(d,J=11.7 Hz,0.39H),2.65-2.49(m,1H),1.91(s,2H),1.71-1.51(m,2H),0.96-0.90(m,2H),0.75(dd,J=6.3,4.1 Hz,4H).[M+Na] m / e 522.19. 【0170】 The following example is the same as the one mentioned above. Table 2-1 Table 2-2 【0171】 Example 17 【change】 【0172】 Project 1 To a mixture of (2S)-2-amino-3-cyclobutylpropanoate (0.359 g, 2 mmol) and NaOH (240 mg, 6.00 mmol) in toluene / water (4 mL / 4 mL), Cbz-Cl (0.314 ml, 2.200 mmol) was added at 0°C. After stirring at room temperature for 2 hours, the two layers were separated, and the aqueous layer was washed with MBTE. The aqueous layer was then treated with 1 M HCl solution to adjust the pH to approximately 2. The resulting mixture was extracted with ELISA. The recovered organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain compound (17-1) (0.46 g, 1.659 mmol, yield 83%). 【0173】 Process 2 Compound (17-1) (104 mg, 0.374 mmol), compound (1-4) (80 mg, 0.299 mmol), and DIPEA (183 μl, 1.046 mmol) were added to a room temperature mixture in DCM / DMF (1.0 / 0.5 mL) with HATU (136 mg, 0.359 mmol). The mixture was stirred at room temperature for 20 hours, quenched with water, and extracted with ethyl acetate. The recovered organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain compound (17-2) (98 mg, 0.200 mmol, yield 66.9%). [MH] - ,489.16 【0174】 Process 3 A suspension of (17-2) (25 mg, 0.051 mmol) and Pd-C (5.42 mg, 5.10 μmol) in MeOH (1 mL) was treated with 1 atmH2 for 40 minutes. The mixture was diluted with DCM, filtered through Celite, washed with DCM, and concentrated under vacuum. Product (17-3) was used directly in the next step. [MH] - ,355.15 【0175】 Process 4 A suspension of 4-methoxy-1H-indole-2-carboxylic acid (15 mg, 0.077 mmol), compound (17-3) (18 mg, 0.051 mmol), and HATU (0.029 g, 0.077 mmol) in DCM (0.3 mL) was to be mixed with DIPEA (0.031 ml, 0.179 mmol) in DMF (0.3 mL). The mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with SiO2. The organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column conc to obtain compound (17-4) (19 mg, 0.036 mmol, yield 70.3%). [MH] - ,528.18 【0176】 Process 5 A mixture of compound (17-4) (19 mg, 0.036 mmol) and Et3N (60.0 μl, 0.431 mmol) in DCM (0.6 mL) at 0°C was mixed with TFAA (30.4 μl, 0.215 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction product was quenched with cold saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column to obtain Example 17 (12 mg, 0.023 mmol, yield 65.4%). [MH] - 510.17; 1 H NMR(400 MHz,Methanol-d4)δ 7.26(d,J=0.9 Hz,1H),7.22-7.10(m,3H),7.02(d,J=8.3 Hz,1H),6.99-6.89(m,2H),6.53(d,J=7.7 Hz,1H),5.17(t,J=7.9 Hz,1H),4.71(dd,J=8.0,6.4 Hz,1H),4.30(d,J=10.5 Hz,1H),4.08(d,J=10.5 Hz,1H),3.96(s,3H),2.75-2.62(m,2H),2.52(hept,J=7.7 Hz,1H),2.20-2.12(m,3H),2.15-2.02(m,1H),2.05-1.88(m,2H),1.90-1.80(m,1H),1.83-1.70(m,1H). 【0177】 The following examples were prepared using the same protocol as described above. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] 【0178】 Example 23 [ka] 【0179】 Process 1 A solution of compound (1-2) (2.5 g, 7.22 mmol) in THF (24.06 mL) was added dropwise to a solution of 2 M LiBH4 in THF (10.83 mL, 21.65 mmol). The mixture was stirred at room temperature for 2 hours, and most of the THF was removed under vacuum. The reaction mixture was carefully quenched with 1 N HCl to pH = 5-6 (approximately 22 mL) and extracted with HCl (3 × 40 mL). The combined organic layers were washed with saturated NaHCO3 and brine, dried, and concentrated. The residue was purified on silica gel with 0-50% HCl / cyclohexane to obtain the desired alcohol (23-1) (1.54 g, yield 67%). 【0180】 Process 2 Compound (23-1) (0.5 g, 1.570 mmol) was dissolved in a 4 M HCl dioxane solution (3.93 mL, 15.70 mmol). The mixture was stirred at room temperature for 1 hour and concentrated to dryness. Compound (23-2) (492 mg, 80% yield) was obtained as a yellow solid. LC-MS, ES+: 218.85 [M+1]. 【0181】 Process 3 To a solution of compound (23-2) (960 mg, 3.13 mmol) and ((benzyloxy)carbonyl)-L-leucine (913 mg, 3.44 mmol) in dry DMF (15.64 mL) at 0°C, HATU (1546 mg, 4.07 mmol) and Hünig base (1912 μl, 10.95 mmol) were added. The resulting mixture was stirred at 0°C for 1 hour, diluted with SiO2, and washed with 10% citric acid, water, and brine. The organic layer was dried and concentrated. The residue was purified using silica gel with 0-40% SiO2 / cyclohexane to obtain 1.2 g of compound (23-3). LC-MS, ES+: 466.19 [M+1]. 【0182】 Process 4 Compound (23-3) (800 mg, 1.718 mmol) was dissolved in MeOH (17 mL). 10% Pd carbon (40 mg, 0.038 mmol) was added. The mixture was stirred under hydrogen for 2.5 hours and filtered through a Celite pad. The solvent was removed, and the crude product (23-4) (543 mg, 1.638 mmol, 95% yield) was used in the next step. [M+1] 332.20 【0183】 Process 5 Compound (23-4) (195 mg, 0.588 mmol) and 4-methoxy-1H-indole-2-carboxylic acid (118 mg, 0.618 mmol) were dissolved in CH2Cl2 (5.9 mL). At 0°C, Hünig base (308 μl, 1.765 mmol) and HATU (235 mg, 0.618 mmol) were added. The mixture was stirred at 0°C for 30 minutes. The reaction product was quenched with water and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to obtain compound (23-5) (213 mg, 0.422 mmol, yield 71.7%). 【0184】 Process 6 In a flame-dried flask, anhydrous acetic acid (422 μl, 4.46 mmol) was added to anhydrous DMSO (3.10 mL) at room temperature. After stirring for 10 minutes, compound (23-5) (150 mg, 0.297 mmol) was added all at once. The mixture was stirred at room temperature for 6 hours. The reaction was cooled to 0°C and diluted with water (approximately 8 mL). The white precipitate was collected by filtration, rinsed with water, and dried under vacuum. The solid was purified with silica gel using 0-45% acetone / cyclohexane to obtain Example 23 as a colorless solid (112 mg, yield 75%). [M+H] + 503.16 1H NMR(500 MHz,DMSO-d6)δ 11.52(d,J=2.3 Hz,1H),10.66(s,1H),9.52(d,J=2.1 Hz,1H),8.61(d,J=7.7 Hz,1H),7.40-7.32(m,1H),7.26(d,J=7.9 Hz,1H),7.26-7.18(m,1H),7.17-7.02(m,1H),7.04-6.97(m,2H),6.89(d,J=8.9 Hz,1H),6.52(t,J=8.4 Hz,1H),4.75(s,1H),4.62(td,J=8.1,7.1,3.8 Hz,1H),4.11(d,J=10.5 Hz,1H),3.97(d,J=10.5 Hz,1H),3.89(s,3H),3.88(d,J=7.4 Hz,1H),2.41(dd,J=13.0,9.0 Hz,1H),2.21(dd,J=13.2,6.2 Hz,1H),1.77(m,1H),1.60(m,1H),0.96(d,J=7.0 Hz,3H),0.89(d,J=7.0 Hz,3H). 【0185】 The following examples were prepared using the same protocol as described above. [Table 4-1] [Table 4-2] 【0186】 Example 26 [ka] 【0187】 Process 1 Compound 23-4 (45 mg, 0.136 mmol) was dissolved in DCM (1.358 mL). DIPEA (48.5 μl, 0.272 mmol), 6-cyano-4-methoxy-1H-indole-2-carboxylic acid (32.3 mg, 0.149 mmol), and HATU (51.6 mg, 0.136 mmol) were added. The mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to obtain compound 26-1 (22 mg, 0.042 mmol, yield 30.6%). [M-OH] + ,512.20 【0188】 Process 2 Anhydride acetic acid (78 μl, 0.831 mmol) was added to DMSO (0.415 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes and transferred to a vial containing compound 26-1 (22 mg, 0.042 mmol). The reaction mixture was stirred at room temperature for 6 hours, quenched with water at 0°C, and extracted with ethyl acetate. The organic layer was washed with water and brine and concentrated. The residue was purified on silica gel using 0-50% acetone / cyclohexane to obtain compound 26-2 (15 mg, 0.028 mmol, yield 68.4%). [M+H] + ,528.21 【0189】 Process 3 Compound 26-2 (15 mg, 0.028 mmol) was dissolved in 2-propanol. A 1 M solution of hydroxylamine hydrochloride (56.9 μl, 0.057 mmol) in t-BuOH / H2O (1:1) was added. The mixture was stirred at room temperature for 30 minutes, quenched with aqueous NaHCO3 solution, and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product, compound 26-3 (14 mg, 0.026 mmol, 91% yield), was used in the next step. [M+H] + , 543.22 【0190】 Process 4 To a vial containing compound 26-3 (14 mg, 0.026 mmol), MeCN (0.516 mL) and copper(II) acetate (1.406 mg, 7.74 μmol) were added. The resulting mixture was stirred at 70°C for 2 hours and concentrated under vacuum. The residue was purified on silica gel using 0-50% siRNA / cyclohexane, and subsequently, preparative HPLC was performed to obtain Example 26 (2.8 mg, 5.34 μmol, yield 20.69%). [M+H] + ,525.22; 1 H NMR(400 MHz,Acetone-d6)δ 11.06(s,1H),9.57(s,1H),7.96(d,J=8.3 Hz,1H),7.45(s,1H),7.32(d,J=1.9 Hz,1H),7.08-6.92(m,2H),6.84(d,J=7.8 Hz,1H),6.77-6.68(m,2H),5.03(t,J=8.3 Hz,1H),4.84-4.75(m,1H),4.23(d,J=10.4 Hz,1H),3.91(m,5H),2.58(qd,J=13.3,8.4 Hz,2H),1.72(m,2H),1.61(m,1H),0.85(m,6H). 【0191】 The following examples were prepared using the same protocol as described above. [Table 5-1] [Table 5-2] 【0192】 Example 29 [ka] Sodium bisulfite (9.32 mg, 0.090 mmol) was added to a solution of Example 23 (45 mg, 0.090 mmol) in EtOH (2 mL) and water (0.2 mL). The mixture was stirred at room temperature for 4 hours and then concentrated. DCM was added to the residue, and a white solid precipitated. The recovered solid was washed with acetone and dried to obtain Example 29 as a white solid. [M-Na] - 583.0 1 H NMR(500 MHz,DMSO-d6)δ 11.42(s,1H),10.57(d,J=7.9 Hz,1H),9.88(s,1H),8.47(d,J=8.2 Hz,1H),7.35-7.31(m,1H),7.14-7.05(m,2H),7.02-6.96(m,1H),6.86(ddt,J=24.0,15.0,8.1 Hz,3H),6.50(d,J=7.7 Hz,1H),5.65(d,J=5.5 Hz,1H),4.83-4.78(m,1H),4.70(t,J=9.3 Hz,2H),3.96(d,J=9.3 Hz,1H),3.90(s,3H),3.61(d,J=9.8 Hz,1H),2.79(dd,J=13.1,9.8 Hz,1H),1.81-1.67(m,3H),0.99(td,J=15.4,7.0 Hz,1H),0.90(d,J=6.4 Hz,3H),0.85(d,J=6.1 Hz,3H). 【0193】 The following examples were prepared using the same protocol as described above. [Table 6] 【0194】 Example 31 [ka] 【0195】 Process 1 To Example 23 (18 mg, 0.036 mmol), a solution of acetic acid (2.4 μl, 0.041 mmol) and isocyanocyclopropane (2.64 mg, 0.039 mmol) in DCM (0.20 mL) was added at 0°C. The mixture was stirred at 0°C to room temperature for 5 hours. The reaction mixture was concentrated to dryness and redissolved in MeOH (0.35 mL). A 0.5 M aqueous solution of K2CO3 (179 μl, 0.090 mmol) was added. The mixture was stirred at room temperature for 2 hours. MeOH was removed under vacuum, and the aqueous layer was extracted with ELISA (3×). The combined organic layers were washed with water and brine, dried, and concentrated. The crude product (31-1) was used directly in the next step. [M+1], 588.2 【0196】 Process 2 Dess-Martin Periodinane (0.023 g, 0.054 mmol) was added to a solution of compound (31-1) in DCM (0.360 mL) at 0°C. The mixture was stirred at 0°C for 2.5 hours. At 0°C, the reaction mixture was diluted with DCM, quenched with 10% Na2S2O3, and washed with 5% NaHCO3. The recovered organic layer was washed with water and brine, dried, and concentrated. The residue was purified on silica gel using 0-60% acetone / cyclohexane to obtain Example 31 (6.5 mg). [M-1] - 584.07 1H NMR(400 MHz,Acetone-d6)δ 10.62(s,1H),9.67(s,1H),7.90(d,J=4.9 Hz,1H),7.78(d,J=8.2 Hz,1H),7.31(dd,J=2.3,0.8 Hz,1H),7.29-7.10(m,4H),7.14-6.95(m,2H),6.92(td,J=7.6,1.1 Hz,1H),6.53(dd,J=7.2,1.2 Hz,1H),5.69-5.54(m,1H),4.93(td,J=8.4,6.0 Hz,1H),4.34(d,J=9.9 Hz,1H),4.02(d,J=9.9 Hz,1H),3.94(s,3H),4.00-3.86(m,1H),2.92-2.78(m,1H),2.52-2.38(m,2H),1.89(dt,J=12.9,6.5 Hz,1H),1.72(ddd,J=8.1,5.7,2.3 Hz,2H),1.13-0.93(m,6H),0.83-0.65(m,4H). 【0197】 The following examples were prepared using the same protocol as described above. [Table 7-1] [Table 7-2] [Table 7-3] 【0198】 Example 37 [ka] To a mixture of Example 23 (105 mg, 0.209 mmol) in tert-butanol (2.79 mL), 2 M 2-methyl-2-butene in THF (2.09 mL, 4.18 mmol) was added at room temperature to obtain a clear solution. Aqueous solutions (1.39 mL) of sodium chlorite (236 mg, 2.089 mmol) and monobasic sodium phosphate (251 mg, 2.089 mmol) were added dropwise over 10 minutes. After stirring at room temperature for 1 hour, the reaction mixture was concentrated to remove most of the volatile substances. The resulting mixture was diluted with ethyl acetate, washed with water and brine, dried, and concentrated. The residue was purified by silica gel chromatography using 0-10% MeOH / DCM to obtain Example 37 (40 mg, 36% yield). LC-MS, ES - :516.94 [MH] - . 【0199】 Example 38 [ka] A solution of Example 37 (18 mg, 0.035 mmol), cyclopropanesulfonamide (8.41 mg, 0.069 mmol), EDCI (7.2 mg, 0.038 mmol), and DMAP (4.59 mg, 0.038 mmol) in dry DCM was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM, washed with brine, dried, and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone / cyclohexane to obtain Example 38 (3.5 mg, yield 16%) as a white solid. LC-MS, ES-: 619.80 [MH] - . 【0200】 Example 157 [ka] 【0201】 Step 1: Potassium tert-butoxide (1M, 1.26mL, 1.26 mmol) in THF (4.2mL) was added to a suspension of methyltriphenylphosphonium bromide (479 mg, 1.34 mmol) (evaporated twice simultaneously with dry toluene before use) at 0°C. The mixture became a yellow slurry. This was stirred at 0°C for 0.5 hours. A solution of 157-(200 mg, 0.419 mmol) in THF (1.0 mL) was added dropwise at 0°C. The yellow slurry was stirred at 0°C for 1 hour. The reaction was quenched by adding an excess amount of saturated NH4Cl solution. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-50% ethyl acetate in cyclohexane to obtain 157-2 (160 mg, yield 80%). LC-MS, ES + :476.10 [M+1]. 【0202】 Step 2: To a mixture of 157-2 (112 mg, 0.235 mmol) and NMO (83 mg, 0.706 mmol) in acetone (2.10 mL) / water (0.24 mL) at room temperature, 2.5% osmium tetroxide in tBuOH (443 μL, 0.035 mmol) was added. After dtirring at room temperature for approximately 3 hours, the reaction mixture was quenched with aqueous Na2SO3 solution and then extracted with ethyl acetate (2x). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. Crude 157-3 (118 mg, 98% yield) was used directly in the next step without further purification. LC-MS, ES - :508.1 [MH]. 【0203】 Step 3: A solution of 157-3 (118 mg, 0.232 mmol) and 1H-imidazole (23.65 mg, 0.347 mmol) in CH2Cl2 (2.32 mL) at 0°C was mixed with tert-butylchlorodimethylsilane (36.6 mg, 0.243 mmol). After stirring at room temperature for approximately 2 hours, the reaction mixture was quenched with saturated Na2SO3 and extracted with siRNA (2x). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography using 0-40% siRNA in cyclohexane to obtain 157-4 (126 mg, yield 87%). LC-MS, ES + :624.28 [M+1]. 【0204】 Step 4: A mixture of 157-4 (126 mg, 0.202 mmol) and 10% Pd-C (21.49 mg, 0.020 mmol) in MeOH (2.0 mL) was stirred at room temperature under a hydrogen balloon. After about 1 hour, the reaction mixture was filtered through Celite, washed with MeOH, and concentrated to obtain crude 157-5 (99 mg, 100% yield), which was used directly in the next step. LC-MS, ES + :490.5 [M+1]. 【0205】 Step 5: A mixture of 157-5 (99 mg, 0.202 mmol) and 4,6-difluoro-1H-indole-2-carboxylic acid (39.9 mg, 0.202 mmol) in dry DMF (0.81 mL) at 0°C was mixed with 4-methylmorpholine (66.7 μL, 0.606 mmol), followed by HATU (85 mg, 0.222 mmol). The resulting mixture was then stirred at room temperature for 3-4 hours. Workup: The reaction mixture was diluted with ethyl acetate, washed with water (2x) and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-40% ethyl acetate in cyclohexane to obtain 157-6 (105 mg, 0.157 mmol, 78% yield). LC-MS, ES + :669.22 [M+1]. 【0206】 Step 6: Dess-Martin Periodinane (198 mg, 0.46 mmol) was added to a mixture of 157-6 (104 mg, 0.155 mmol) in DCM (1.56 mL) at 0°C. The mixture was stirred at 0°C for 4-5 hours until TLC (acetone / cyclohexane 1 / 3) indicated that all sm had been consumed. Workup: The reaction mixture was diluted with DCM and quenched with 10% Na2S2O3 and 5% NaHCO3. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-40% acetone / cyclohexane to obtain 157-7 (50 mg, 0.075 mmol, yield 48.2%). LC-MS, ES - :665.0 [MH]. 【0207】 Step 7: A suspension of 157-7 (42 mg, 0.063 mmol) in MeOH (0.63 mL) at room temperature was mixed with concentrated HCl (31.5 μL, 0.378 mmol) in water. After stirring at room temperature for approximately 15 minutes, the reaction mixture was concentrated to dryness under vacuum. The residue was diluted with Â, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone in cyclohexane to obtain Example 157- (26 mg, 0.047 mmol, yield 74.7%). LC-MS, ES -:550.90 [MH].1H NMR(400 MHz,Acetone-d6)δ 10.83(s,1H),9.63(s,1H),7.07(dd,J=7.7,4.5 Hz,3H),6.97-6.83(m,3H),6.74(td,J=10.3,2.1 Hz,1H),5.55(t,J=7.6 Hz,1H),5.12(dd,J=9.6,8.1 Hz,1H),4.56(dd,J=18.6,5.7 Hz,1H),4.42(dd,J=18.6,5.8 Hz,1H),4.26(d,J=10.3 Hz,1H),4.09(t,J=5.7 Hz,1H),3.93(d,J=10.2 Hz,1H),3.46(s,3H),2.44(ddd,J=12.7,8.1,1.3 Hz,1H),2.36(dd,J=12.7,9.6 Hz,1H),1.81(tq,J=14.0,7.4,6.7 Hz,2H),1.63(ddd,J=14.3,12.9,6.7 Hz,1H),1.02(d,J=6.6 Hz,3H),0.96(d,J=6.5 Hz,3H). 【0208】 Example 158 [ka] Example 158 was prepared using the same protocol as described above. [M-1] 569.0; 1H NMR(400 MHz,Acetone-d6)δ 11.25(s,1H),9.63(s,1H),7.13-7.02(m,2H),6.96-6.81(m,4H),5.54(t,J=7.6 Hz,1H),5.14(dd,J=9.7,8.1 Hz,1H),4.57(dd,J=18.7,5.7 Hz,1H),4.42(dd,J=18.7,5.8 Hz,1H),4.23(d,J=10.5 Hz,1H),4.11(t,J=5.7 Hz,1H),3.95(d,J=10.3 Hz,1H),3.45(s,3H),2.45(dd,J=12.7,8.1 Hz,1H),2.36(dd,J=12.7,9.7 Hz,1H),1.90-1.74(m,2H),1.67(dp,J=13.6,6.7 Hz,1H),1.03(d,J=6.6 Hz,3H),0.97(d,J=6.5 Hz,3H). 【0209】 Example 159 [ka] To a solution of Example 158 (11.6 mg, 0.020 mmol) in THF (0.25 mL), lithium chloride (11.20 mg, 0.264 mmol) and Hünig base (10.6 μL, 0.061 mmol) were added at 0°C. Then, methanesulfonyl chloride (3.78 μL, 0.048 mmol) was added. The reaction mixture was stirred at 0°C to room temperature for approximately 6 hours. Workup: The reaction mixture was quenched with saturated NH4Cl and extracted with Â. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-30% acetone in cyclohexane to obtain Example 159 (4.5 mg, yield 37.6%). LC-MS, ES -:586.86 [MH];1H NMR(400 MHz,Acetone-d6)δ 11.22(s,1H),9.64(s,1H),7.18-7.06(m,2H),7.00-6.85(m,3H),5.55(t,J=7.7 Hz,1H),5.13(t,J=8.5 Hz,1H),4.81(d,J=16.5 Hz,1H),4.65(d,J=16.5 Hz,1H),4.23(d,J=10.6 Hz,1H),4.00(d,J=10.3 Hz,1H),3.44(s,3H),2.55-2.38(m,2H),1.92-1.74(m,2H),1.65(dt,J=13.9,6.7 Hz,1H),1.00(dd,J=22.0,6.6 Hz,6H). 【0210】 Example 39 [ka] 【0211】 Process 1 Compound (1-4) (300 mg, 1.121 mmol) and N-((benzyloxy)carbonyl)-N-methyl-L-leucine (344 mg, 1.233 mmol) were mixed with CH2Cl 2 The mixture was taken up in (5 ml) and DMF (1 ml). 4-methylmorpholine (246 μl, 2.241 mmol) and HATU (469 mg, 1.233 mmol) were added. The mixture was stirred at room temperature for 1 hour, diluted with DCM (30 mL), and washed with saturated NaHCO3 solution. The recovered organic layer was washed with 1 M HCl and brine, filtered over Na2SO4, and concentrated under vacuum. The residue was purified on silica gel using 0-100% acetone / cyclohexane to obtain compound (39-1) (417 mg, 0.847 mmol, yield 76%). [M-1] - 491.02 【0212】 Process 2 To a suspension of (39-1) (28 mg, 0.057 mmol) in DCM (0.6 mL) at 0°C, Et3N (79 μl, 0.568 mmol) and TFAA (40.1 μl, 0.284 mmol) were added. The mixture was warmed to room temperature and stirred for 1 hour. The reaction product was quenched with cold NaHCO3 solution and extracted with Â. The organic layer was washed with water, 1N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column to obtain Example 39 (24 mg, 0.051 mmol, 89% yield). [MH] - 473.17 1 H NMR(400 MHz,Methanol-d4)δ 7.35-7.15(m,5H),7.07-6.88(m,4H),5.21-4.88(m,2H),4.77(dd,J=12.1,3.8 Hz,1H),4.19-4.07(m,1H),3.92(d,J=10.7 Hz,1H),3.71(p,J=10.8 Hz,1H),2.93(d,J=4.8 Hz,3H),2.75-2.57(m,2H),1.79(ddt,J=14.4,9.2,5.0 Hz,1H),1.67(dq,J=14.8,7.2,6.6 Hz,1H),1.56-1.47(m,1H),1.05-0.88(m,6H). 【0213】 The following examples were prepared using the same protocol as described above. [Table 8] 【0214】 Example 42 [ka] 【0215】 Process 1 Compound (39-1) (1323 mg, 2.69 mmol) was dissolved in MeOH (30 mL). 10% Pd-C (143 mg, 0.134 mmol) was added. The mixture was stirred under H2 (balloon) for 1 hour and filtered through a Celite pad. The filtrate was concentrated under vacuum to obtain compound (42-1). [M+H] + 359.2 【0216】 Process 2 A suspension of 4-methoxy-1H-indole-2-carboxylic acid (0.111 g, 0.583 mmol), compound (42-1) (0.182 g, 0.507 mmol), and HATU (0.212 g, 0.558 mmol) in DCM (0.35 mL) was to be mixed with DIPEA (0.266 ml, 1.521 mmol) in DMF (0.35 mL). The mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with ethyl acetate. The organic layer was washed with 1N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column to obtain compound (42-2) (160 mg, 0.301 mmol, yield 59.4%). [MH] - ,530.18 【0217】 Process 3 Compound (42-2) (150 mg, 0.282 mmol) was dissolved in CH2Cl2 (1.9 mL). At 0°C, Et3N (0.32 mL, 2.26 mmol) and TFAA (0.16 mL, 1.13 mmol) were added. The mixture was stirred at 0°C for 20 minutes, quenched with aqueous NaHCO3 solution, and extracted with DCM (2×). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified on silica gel using 0-40% acetone / cyclohexane to obtain Example 42 (114 mg, 0.222 mmol, yield 79%). [MH] - 512.18; 1H NMR(400 MHz,Methanol-d4)δ 7.15(t,J=8.0 Hz,1H),7.05(t,J=7.8 Hz,1H),7.01-6.94(m,2H),6.90(s,1H),6.85(dd,J=15.4,7.7 Hz,2H),6.52(d,J=7.7 Hz,1H),5.53(brs,1H),5.19(t,J=8.0 Hz,1H),4.21(d,J=11.0 Hz,1H),3.99(d,J=11.0 Hz,1H),3.96(s,3H),3.40(s,3H),2.75-2.60(m,2H),1.96-1.76(m,2H),1.63(ddt,J=14.6,13.0,6.6 Hz,1H),1.47(s,1H),1.26(t,J=7.1 Hz,1H),1.01(m,6H). 【0218】 The following examples were prepared using the same protocol as described above. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 Table 9-14 Table 9-15 Table 9-16 Table 9-17 Table 9-18 Table 9-19 Table 9-20 Table 9-21 Table 9-22 Table 9-23 Table 9-24 Table 9-25 Table 9-26 Table 9-27 Table 9-28 Table 9-29 Table 9-30 Table 9-31 Table 9-32 Table 9-33 Table 9-34 Table 9-35 Table 9-36 Table 9-37 Table 9-38 Table 9-39 Table 9-40 Table 9-41 Table 9-42 Table 9-43 Table 9-44 Table 9-45 Table 9-46 Table 9-47 Table 9-48 Table 9-49 Table 9-50 Table 9-51 Table 9-52 Table 9-53 Table 9-54 Table 9-55 Table 9-56 Table 9-57 Table 9-58 Table 9-59 Table 9-60 Table 9-61 【0219】 Example 367 【change】 To a solution of Example 366 (17 mg, 0.033 mmol) in DCM (2 mL), TFA (0.03 mL) was added, and the mixture was stirred at room temperature for 4 hours. After removing the solvent, the labeled Example 367 (17 mg, 100%) was obtained. [M+1] 412.47 【0220】 Example 368 [ka] To a solution of Example 367 (61 mg, 0.12 mmol) and 2,4-difluorobenzoic acid (19 mg, 0.12 mmol) in DMF (2 mL), HATU (46 mg, 0.12 mmol) and DIPEA (0.04 mL, 0.36 mol) were added. The mixture was stirred at room temperature for 4 hours and then concentrated. The crude product was subjected to silica chromatography to obtain Example 368 (17 mg, 21%). [M-1] 550.36 【0221】 Example 89 [ka] 【0222】 Process 1 A mixture of (S)-2-(((benzyloxy)carbonyl)amino)-3-cyclobutylpropanoic acid (2.68 g, 9.66 mmol) and MeI (4.83 mL, 77 mmol) in THF (30 mL) at 0°C was gradually mixed with NaH (1.16 g, 29 mmol). The resulting mixture was stirred at room temperature for 2 days, quenched with ice water, and washed with MBTE (2x). The aqueous layer was acidified to approximately pH 2 with 1 N HCl and extracted with ethyl acetate. The recovered organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain the desired compound (89-1) (2.54 g, 90% yield). ESI-MS m / z = 290.12 [MH] - . 【0223】 Process 2 To a solution of compound (1-4) (2.33 g, 6.96 mmol), compound (89-1) (2.54 g, 8.70 mmol), and 4-methylmorpholine (3.06 mL, 27.9 mmol) in DCM / DMF (5 / 5 mL), HATU (2.78 g, 7.31 mmol) was added. The mixture was stirred at room temperature for 2 hours, quenched with water, and extracted with SiO2. The recovered organic layer was washed with water, 1N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column to obtain compound (89-2) (3.16 g, 90% yield). ESI-MS m / z = 503.19 [MH] - . 【0224】 Process 3 A mixture of compound (89-2) (45 mg, 0.089 mmol) and Et3N (99 μl, 0.713 mmol) in DCM (1 mL) at 0°C was to which TFAA (50.4 μl, 0.357 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes, quenched with cold saturated NaHCO3 solution, and extracted with RINKAN. The recovered organic layer was washed with water, 1N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column to obtain Example 89 (23 mg, 53% yield). ESI-MS m / z = 485.19 [MH] - . 【0225】 The following examples were prepared using the same protocol as described above. [Table 10] 【0226】 Example 91 [ka] 【0227】 Process 1 A mixture of compound (89-2) (65 mg, 0.13 mmol) and Pd-C (13.7 mg, 0.013 mmol) in MeOH (1 mL) was treated with H2 using a hydrogen balloon. After 1 hour, the mixture was diluted with DCM, filtered through Celite, and concentrated to obtain compound (91-1) (48 mg, 100%). ESI-MS m / z = 369.19 [MH] - . 【0228】 Process 2 Compound (91-1) (0.032 g, 0.086 mmol), 4,6-difluoro-1H-indole-2-carboxylic acid (0.021 g, 0.108 mmol), and DIPEA (0.045 mL, 0.258 mmol) were mixed in DCM / DMF (0.5 / 0.5 mL) at room temperature, to which HATU (39 mg, 0.103 mmol) was added. The resulting mixture was stirred at room temperature for 20 hours, quenched with water, and extracted with ethyl acetate. The recovered organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column to obtain compound (91-2) (34 mg, 72% yield). ESI-MS m / z = 548.21 [MH] - . 【0229】 Process 3 A mixture of compound (91-2) (34 mg, 0.062 mmol) and Et3N (86 μl, 0.619 mmol) in DCM (1 mL) at 0°C was mixed with TFAA (44 μl, 0.31 mmol). The mixture was stirred at room temperature for 30 minutes, quenched with cold saturated NaHCO3, and extracted with ethyl acetate. The recovered organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-40% acetone / cyclohexane to obtain Example 91 (17 mg, 52% yield). ESI-MS m / z = 530.20 [MH] - . 1H NMR(400 MHz,Acetone-d6)δ 10.65(s,1H),9.51(s,1H),6.97-6.83(m,3H),6.81-6.72(m,2H),6.67(t,J=7.6 Hz,1H),6.60(td,J=10.3,2.1 Hz,1H),5.28(t,J=7.4 Hz,1H),5.05(t,J=8.2 Hz,1H),4.08(d,J=10.7 Hz,1H),3.82(d,J=10.6 Hz,1H),3.28(s,3H),2.69(s,1H),2.67-2.48(m,2H),2.22(hept,J=7.7 Hz,1H),1.89(d,J=7.4 Hz,3H),1.74-1.53(m,4H). 【0230】 The following examples were prepared using the same protocol as described above. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] 【0231】 Example 96 [ka] 【0232】 Process 1 To a solution of ((benzyloxy)carbonyl)-L-leucine (1.56 g, 5.88 mmol) and 3-iodopropa-1-ene (0.807 mL, 8.82 mmol) in THF (30 mL) at 0°C, NaH (0.706 g, 17.64 mmol) was gradually added. The mixture was stirred at room temperature for 4 days, quenched with ice water, and washed twice with MBTE. The aqueous layer was acidified to approximately pH 2 with 1 N HCl and extracted with siRNA. The recovered organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain compound (96-1) (1.15 g, yield 64.0%). ESI-MS m / z = 304.12 [MH] - . 【0233】 Process 2 Compounds (1-4) (221 mg, 0.826 mmol), (96-1) (265 mg, 0.868 mmol), and DIPEA (577 μl, 3.31 mmol) in DCM / DMF (0.8 / 0.8 mL) were mixed with HATU (314 mg, 0.826 mmol). The resulting mixture was stirred at room temperature for 16 hours, quenched with water, and extracted with SiO2. The organic layer was washed with water, 1N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-10% MeOH / DCM to obtain compound (96-2) (262 mg, yield 61.1%). ESI-MS m / z = 517.20 [MH] - . 【0234】 Process 3 A mixture of compound (96-2) (22 mg, 0.042 mmol) and Et3N (59.1 μl, 0.424 mmol) in DCM (1 mL) at 0°C was mixed with TFAA (30.0 μl, 0.212 mmol). The mixture was stirred at room temperature for 30 minutes, quenched with cold saturated NaHCO3 solution, and extracted with ethyl acetate. The organic layer was washed with water, 1N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone / cyclohexane to obtain Example 96 (20 mg, 94% yield). ESI-MS m / z = 499.20 [MH] - . 【0235】 Example 97 [ka] 【0236】 Process 1 A mixture of compound (96-2) (105 mg, 0.202 mmol) and Pd-C (21.55 mg, 0.020 mmol) in MeOH (3 mL) was stirred under H2 using a hydrogen balloon. After 1 hour, the mixture was diluted with DCM, filtered through Celite, and concentrated to obtain compound (97-1) (79 mg, 100%). ESI-MS m / z = 385.19 [MH] - . 【0237】 Process 2 A mixture of compound (97-1) (0.039 g, 0.10 mmol) and Et3N (0.098 mL, 0.70 mmol) in DCM / DMF (0.5 / 0.5 mL) was mixed with Cbz-Cl (0.042 mL, 0.30 mmol). The mixture was stirred at room temperature for 16 hours, quenched with aqueous NH3 solution, and extracted with Â. The organic layer was washed with water and brine, dried over N2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-10% MeOH / DCM to obtain (97-2) (10 mg, yield 19%). ESI-MS m / z = 519.22 [MH] - . 【0238】 Process 3 A mixture of compound (97-2) (10 mg, 0.019 mmol) and Et3N (53.5 μl, 0.384 mmol) in DCM (0.5 mL) was to be mixed with TFAA (27.1 μl, 0.192 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes, quenched with cold saturated NaHCO3 aqueous solution, and extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3 solution, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone / cyclohexane to obtain Example 97 (7.0 mg, yield 72.5%). ESI-MS m / z = 501.22 [MH] - . 【0239】 Example 98 [ka] 【0240】 Process 1 A mixture of 4-fluoro-1H-indole-2-carboxylic acid (0.054 g, 0.30 mmol) and 1-chloro-N,N,2-trimethylpropa-1-ene-1-amine (0.044 mL, 0.330 mmol) in DCM (1 mL) was stirred at room temperature for 1 hour. The resulting mixture was added to a solution of compound (97-1) and Et3N (0.108 mL, 0.85 mmol) in DCM / DMF (0.5 / 0.5 mL). The resulting mixture was stirred at room temperature for 20 hours, quenched with aqueous NH3 solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-10% MeOH / DCM to obtain compound (98-1) (40 mg, yield 69%). ESI-MS m / z = 546.23 [MH] - . 【0241】 Process 2 A mixture of compound (98-1) (40 mg, 0.073 mmol) and Et3N (10.18 μl, 0.073 mmol) in DCM (1 mL) at 0°C was mixed with TFAA (10.32 μl, 0.073 mmol). The mixture was stirred at room temperature for 30 minutes, quenched with cold saturated NaHCO3, and extracted with RINKAN. The organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone / cyclohexane to obtain Example 98 (35 mg, 90% yield). ESI-MS m / z = 528.20 [MH] - . 【0242】 The following examples were prepared using the same protocol as described above. [Table 12] 【0243】 Example 100 [ka] Synthesis of (S)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-methylhexanoic acid 【0244】 Step 1: To a mixture of (S)-2-amino-5-methylhexanoic acid (0.9 g, 6.20 mmol) in toluene / water (12.4 mL / 3 mL) at 0°C, 2N NaOH (9.30 mL, 18.59 mmol) was added, followed by Cbz-Cl (0.973 mL, 6.82 mmol). After stirring at room temperature for 2 hours, the two layers were separated. The aqueous layer was washed with MBTE (2×) and then acidified to approximately pH 2 with 1 N HCl solution at 0°C. The mixture was extracted with siRNA (3×). The combined organic matter was washed with brine, dried over Na₂SO₄, and concentrated to obtain (S)-2-(((benzyloxy)carbonyl)amino)-5-methylhexanoic acid (1.42 g, 5.08 mmol, yield 82%), which was used in the next step without further purification. LC-MS,ES-:277.77 [M-1]. 【0245】 Step 2: To a solution of (S)-2-((((benzyloxy)carbonyl)amino)-5-methylhexanoic acid (660 mg, 2.363 mmol) and paraformaldehyde (426 mg, 14.18 mmol)) in dry acetonitrile (11.8 mL), 4-methylbenzenesulfonic acid hydrate (44.9 mg, 0.236 mmol) was added. The resulting mixture was heated under microwave at 130°C for 10 minutes. After cooling to room temperature, the mixture was filtered through Celite, concentrated, and followed with DCM to obtain crude benzyl(S)-4-isopentyl-5-oxoxazolidine-3-carboxylate as a viscous oil, which was used in the next step without further purification. 【0246】 Step 3: Crude benzyl(S)-4-isopentyl-5-oxoxazolidine-3-carboxylate from the previous step was mixed with DCM (24 mL), triethylsilane (1.89 mL, 11.81 mmol), and 2,2,2-trifluoroacetic acid (7.28 mL, 95 mmol). The mixture was stirred at room temperature for 2 hours, concentrated, and tracked with DCM (3×). The residue was basicized to approximately pH 10 with 1N NaOH at 0°C and washed with ethyl(1×) and MBTE(1×). The aqueous layer was acidified to approximately pH 2 with 1N HCl and extracted with ethyl(2×). The combined organic layers were washed with brine, dried, and concentrated to obtain (S)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-methylhexanoic acid (715 mg, 92% yield in two steps). 1H NMR(400 MHz,DMSO-d6)δ 12.56(s,1H),7.41-7.27(m,5H),5.17-5.00(m,2H),4.48(ddd,J=27.4,11.1,4.7 Hz,1H),2.81(s,2H,N-Me rotamer),2.78(s,1H,N-Me rotamer),1.84(tq,J=9.6,4.6,4.1 Hz,1H),1.70(ddd,J=14.4,9.6,4.5 Hz,1H),1.52(dt,J=12.8,6.5 Hz,1H),1.21-0.99(m,2H),0.84(dd,J=9.2,6.6 Hz,6H). [ka] 【0247】 Synthesis of Example 100 Step 1: A mixture of (S)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-methylhexanoic acid (300 mg, 1.023 mmol) and (1-4) (261 mg, 0.974 mmol) in dry CH2Cl2 (2.96 mL) at 0°C was mixed with DIPEA (510 μl, 2.92 mmol) and HATU (481 mg, 1.266 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with water (2x) and brine, dried, and concentrated. The residue was purified by silica gel chromatography using 0-10% MeOH / DCM to obtain benzyl((S)-1-((3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-5-methyl-1-oxohexane-2-yl)(methyl)carbamate (100-1) (189 mg, yield 38%). LC-MS, ES-: 505.0 [M-1]. 【0248】 Process 2 A mixture of compound (100-1) (31 mg, 0.061 mmol) and Et3N (85 μl, 0.612 mmol) in DCM (0.8 mL) at 0°C was mixed with TFAA (43.2 μl, 0.306 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with DCM, washed with saturated NaHCO3, water, and brine, dried, and concentrated. The residue was purified by silica gel chromatography using 0-40% acetone / cyclohexane to obtain Example 100 (25 mg, yield 84%). LC-MS, ES + :488.96 [M+1]. 【0249】 The following examples were prepared using the same protocol as described above. [Table 13] 【0250】 Example 104 [ka] 【0251】 Step 1: A mixture of compound (100-1) (152 mg, 0.300 mmol) and 10% Pd-C (31.9 mg, 0.030 mmol) in MeOH (3.00 mL) was stirred at room temperature under a hydrogen balloon. After 1 hour, the reaction mixture was filtered through Celite, rinsed with MeOH, and concentrated to obtain crude (3R,5'S)-1'-((S)-5-methyl-2-(methylamino)hexanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (104-1) (112 mg, 0.301 mmol, 100% yield), which was used directly in the next step. LC-MS, ES+: 372.99 [M+H] + . 【0252】 Step 2: A mixture of compound (104-1) (85 mg, 0.228 mmol) and 4,6-difluoro-1H-indole-2-carboxylic acid (47.2 mg, 0.240 mmol) in dry DMF (1.14 mL) at 0°C was mixed with Hünig base (122 μL, 0.685 mmol) and HATU (113 mg, 0.297 mmol). The resulting mixture was then stirred at room temperature for 1 hour, diluted with DCM, and washed with water (2×) and brine. The organic layer was dried and concentrated. The crude product (104-2) was used in the next step without further purification. LC-MS, ES-: 550.2 [MH] - . 【0253】 Step 3: A mixture of crude (3R,5'S)-1'-((S)-2-(4,6-difluoro-N-methyl-1H-indole-2-carboxamide)-5-methylhexanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (104-2) (0.121 g, 0.22 mmol) and Et3N (0.307 mL, 2.20 mmol) in 0°C DCM (2.9 mL) was treated with TFAA (0.155 mL, 1.100 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and brine, dried and concentrated. The residue was purified by silica gel chromatography using 0-40% acetone / cyclohexane to obtain Example 104 (62 mg, 3-step yield 53%). LC-MS,ES-:532.01 [MH] - .1H NMR(400 MHz,Acetone-d6)δ 10.84(s,1H),9.69(s,1H),7.12-6.99(m,3H),6.97-6.93(m,1H),6.90(d,J=7.6 Hz,1H),6.86-6.78(m,1H),6.74(td,J=10.3,2.1 Hz,1H),5.45(dd,J=8.8,6.4 Hz,1H),5.22(t,J=8.2 Hz,1H),4.26(d,J=10.7 Hz,1H),3.99(d,J=10.7 Hz,1H),3.46(s,3H),2.74-2.64(m,2H),2.04-1.91. 【0254】 The following examples were prepared using the same protocol as described above. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] 【0255】 Example 413 [ka] 【0256】 Process 1 [ka] To a 20 ml solution of ((benzyloxy)carbonyl)-L-serine (1.25 g, 5.23 mmol) in DMF at -45°C, 10.97 ml of NaHMDS (1 M in THF) (10.97 mmol) was added. The resulting mixture was stirred at -45°C for 20 minutes, and allyl bromide (0.543 ml, 6.27 mmol) was added (shaking over K2CO3). The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The mixture was cooled to -20°C, quenched with AcOH (0.359 ml, 6.27 mmol), diluted with HCl / 1N HCl, the organic layer was separated, washed with water and brine, dried, filtered, and concentrated. Purification of the residue by CombiFlash using silica gel eluted with 0-60% acetone / cyclohexane yielded O-allyl-N-((benzyloxy)carbonyl)-L-serine (1.04 g, 3.72 mmol, yield 71.3%). 1 H NMR(400 MHz,Chloroform-d)δ 7.45-7.25(m,5H),5.96-5.71(m,1H),5.65(d,J=8.5 Hz,1H),5.26-5.12(m,2H),5.10(d,J=3.3 Hz,2H),4.49(dt,J=7.6,3.4 Hz,1H),3.97(d,J=5.8 Hz,2H),3.90(dd,J=9.5,3.2 Hz,1H),3.68(dd,J=9.5,3.6 Hz,1H). 【0257】 Step 2: [ka] pTSA (23.84 mg, 0.125 mmol) was added to a mixture of O-allyl-N-((benzyloxy)carbonyl)-L-serine (500 mg, 1.790 mmol) and paraformaldehyde (323 mg, 10.74 mmol) in acetonitrile (8 ml). The resulting mixture was stirred at 70°C for 14 hours, cooled to room temperature, filtered through Celite, and the filtrate was collected and concentrated. The residue was tracked by DCM. To the residue, DCM (8 ml), TFA (2759 μl, 35.8 mmol), and triethylsilane (858 μl, 5.37 mmol) were added, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was concentrated and tracked with DCM. The mixture was diluted with toluene, NaOH (1N) solution, and then HCl (1N) to adjust the pH to approximately 4. The organic layer was separated, and the aqueous layer was extracted with toluene (2×). The organic layers were combined, washed with brine, dried, filtered, concentrated, and the residue was purified by CombiFlash of silica gel eluted with 0-5% MeOH / DCM to obtain O-allyl-N-((benzyloxy)carbonyl)-N-methyl-L-serine (287 mg, 0.978 mmol, yield 54.7%). 【0258】 Process 3 [ka] A mixture of O-allyl-N-((benzyloxy)carbonyl)-N-methyl-L-serine (70 mg, 0.239 mmol), (3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (80 mg, 0.239 mmol), and HATU (109 mg, 0.286 mmol) in DCM (2 ml) / DMF (0.4 ml) was to which 4-methylmorpholine (121 mg, 1.193 mmol) was added. The resulting mixture was stirred at room temperature for 14 hours, the mixture was concentrated, the residue was diluted with ELISA, washed with water and brine, dried, filtered, and concentrated again. The residue was purified by CombiFlash using silica gel eluted with 0-10% MeOH / DCM to obtain benzyl((S)-3-(allyloxy)-1-((3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropan-2-yl)(methyl)carbamate (163 mg). LC-MS, ES + :507.22 [M+H]. 【0259】 Process 4 [ka] Benzyl((S)-3-(allyloxy)-1-((3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxopropan-2-yl)(methyl)carbamate (30 mg, 0.06 mmol) and Pd-C (6.39 mg, 6.00 μmol) were mixed with MeOH (1.5 ml), and the resulting mixture was stirred under an H2 balloon for 1.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated. To the residue, 4,6-difluoro-1H-indole-2-carboxylic acid (15 mg, 0.078 mmol), HATU (32 mg, 0.084 mmol), DCM (1 ml), DMF (0.25 ml), and 4-methylmorpholine (24 mg, 0.240 mmol) were added, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified with silica gel eluted with 0-10% MeOH / DCM to obtain (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-O-propyl-L-ceryl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (36 mg). LC-MS, ES + :576.2 [M+Na]. 【0260】 Process 5 [ka] (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-O-propyl-L-ceryl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (36 mg, 0.065 mmol) was added to DCM (2 ml) at room temperature, to which TEA (72.5 μl, 0.52 mmol) and TFAA (45.9 μl, 0.325 mmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, diluted with MeOH (1.2 ml), then NH3 (concentrated 0.8 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated again. The residue was purified by CombiFlash using silica gel eluted with 0-60% acetone / cyclohexane to obtain N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-propoxypropan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (12 mg). LC-MS, ES + :558.2 [M+Na]. 【0261】 Example 414 [ka] 【0262】 Step 1: A solution of (3R,5'S)-1'-((S)-3-cyclopropyl-2-(methylamino)propanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (44 mg, 0.123 mmol) and (S)-2-(4-fluorophenyl)-2-hydroxyacetic acid (22.00 mg, 0.129 mmol) in DMF (0.1 ml) and CH2Cl2 (0.4 ml) was treated with N-methylmorpholine (50 μl, 0.455 mmol) and HATU (52 mg, 0.137 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane and quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% acetone / cyclohexane, (3R,5'S)-1'-((S)-3-cyclopropyl-2-((S)-2-(4-fluorophenyl)-2-hydroxy-N-methylacetamide)propanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (16mg, 0.031 mmol, yield 25.5%) was obtained as a white solid. LC-MS, ES - :507.36 [MH]. 【0263】 Step 2: A solution of (3R,5'S)-1'-((S)-3-cyclopropyl-2-((S)-2-(4-fluorophenyl)-2-hydroxy-N-methylacetamide)propanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (14 mg, 0.028 mmol) in CH2Cl2 (0.4 ml) was treated with TEA (40 μl, 0.287 mmol) and TFAA (16 μl, 0.113 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then quenched with ammonium hydroxide and stirred for a further 30 minutes. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, (S)-N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropan-2-yl)-2-(4-fluorophenyl)-2-hydroxy-N-methylacetamide (12mg, 0.024 mmol, yield 89%) was obtained as a white solid. LC-MS, ES - :489.34 [MH]; 1 H NMR(500 MHz,Methanol-d4)δ 7.35-7.18(m,3H),7.03-6.86(m,5H),5.37-5.27(m,2H),5.05(t,J=7.9 Hz,2H),3.98(d,J=10.6 Hz,1H),3.79(d,J=10.5 Hz,1H),2.93(s,3H),2.67-2.52(m,2H),1.88(dt,J=14.5,7.5 Hz,1H),1.64(dt,J=14.0,7.0 Hz,1H),0.73(ddt,J=10.3,7.4,3.7 Hz,1H),0.57-0.44(m,2H),0.22-0.10(m,2H). 【0264】 The following examples were prepared using the same protocol as described above. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] 【0265】 Example 429 [ka] 【0266】 Step 1: To a solution of methyl L-leucine hydrochloride (200 mg, 1.10 mmol) in THF (3.3 mL), 4-methoxybenzaldehyde (300 mg, 2.2 mmol), DIPEA (192 μL, 1.1 mmol), and MgSO4 (225 mg, 1 / 87 mmol) were added. The reaction mixture was stirred overnight at room temperature. The crude material was filtered through Celite and evaporated to dryness. The crude material was taken into methanol (3.3 mL) and sodium borohydride (83 mg, 2.2 mmol) was added. The reaction mixture was quenched with saturated NH4Cl and extracted with RINKAN. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-70% RINKAN in cyclohexane to obtain the desired product (249 mg, 85%). 【0267】 Step 2: LiOH (1 mL, 2 M, 2 mmol) was added to THF (3 mL) and methanol (2 mL) containing the material from Step 1 (249 mg, 0.94 mmol). Once complete, the reaction mixture was acidified to pH 3 with 1 M HCl, extracted with ethyl acetate, washed with brine, and dried over Na2SO4 to obtain the desired product, which was used without purification. 【0268】 Step 3: HATU (53 mg, 0.139 mmol) and DIPEA (73 μL, 0.418 mmol) were added to a solution of the material from Step 3 (35 mg, 0.139 mmol) and the spiroring intermediate (37 mg, 0.139 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with RINKAN. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-80% acetone in cyclohexane to obtain the desired product (41 mg, 63%). 【0269】 Step 4: To a 1 mL solution of the material from Step 3 (41 mg, 0.088 mmol) in DCM, TFAA (37 μL, 0.265 mmol) and Et3N (74 μL, 0.530 mmol) were added at 0°C. The crude product was directly loaded onto a silica gel column and subjected to chromatography using 0-80% acetone in cyclohexane to obtain EP-037611 (30 mg, 63%). LC-MS,ES+543.056 [M+H].1H NMR(400 MHz,Acetone-d6 1H NMR(400 MHz,Acetone-d6)δ 9.65(s,1H),7.38-7.26(m,3H),7.19(d,J=7.4 Hz,1H),7.11-7.05(m,1H),7.07-6.95(m,3H),6.97(s,1H),5.04(s,1H),4.81(s,2H),4.06(s,1H),4.00(d,J=10.7 Hz,1H),3.88(d,J=10.2 Hz,1H),3.82(s,3H),2.63(t,J=5.9 Hz,2H),2.56(s,1H),1.94(s,1H),1.37(s,1H),0.85(d,J=7.1 Hz,4H),0.75(d,J=5.9 Hz,2H),0.62(s,1H).19F NMR(400 MHz,Acetone-d6)δ 69.4. 【0270】 The following examples were prepared using the same protocol as described above. [Table 16-1] [Table 16-2] 【0271】 Example 119 [ka] 【0272】 Process 1 To a solution of compound (23-5) (64 mg, 0.127 mmol) in dry acetone (0.634 mL), K2CO3 (26.3 mg, 0.190 mmol) and dimethyl sulfate (18.04 μL, 0.190 mmol) were added at room temperature. The reaction mixture was then heated and refluxed for 2 hours. After 2 hours, another portion of dimethyl sulfate (6.0 μL, 0.06 mmol) was added, and the mixture was heated for a further 3 hours. The reaction mixture was concentrated to dryness. The residue was diluted with Â, washed with water and brine, dried, and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone / cyclohexane to obtain compound (119-1) (53 mg, yield 81%). LC-MS, ES+: 519.14 [M+H] + . 【0273】 Process 2 Dess-Martin periodinane (62.6 mg, 0.148 mmol) was added to a solution of compound (119-1) (51 mg, 0.098 mmol) in dry DCM (0.98 mL) at 0°C. The mixture was stirred at 0°C for 3 hours. The crude reaction mixture was purified by silica gel chromatography using 0-55%  / cyclohexane to obtain Example 119 (28 mg, yield 55%). LC-MS, ES+: 517.06 [M+H] + . 1H NMR(400 MHz,Acetone-d6)δ 10.52(s,1H),9.52(d,J=1.9 Hz,1H),7.75-7.69(m,1H),7.23-7.16(m,3H),7.03-6.95(m,2H),6.92-6.85(m,2H),6.40(dd,J=7.2,1.2 Hz,1H),4.84(ddd,J=9.7,8.3,4.8 Hz,1H),4.54(ddd,J=9.2,6.1,2.0 Hz,1H),4.12(d,J=10.4 Hz,1H),3.96(d,J=10.4 Hz,1H),3.79(s,3H),3.07(s,3H),2.37-2.29(m,1H),2.20(dd,J=13.1,6.1 Hz,1H),1.71(ddd,J=14.5,9.8,4.2 Hz,2H),1.66-1.58(m,1H),0.84(dd,J=10.7,6.4 Hz,6H). 【0274】 Example 120 [ka] 【0275】 Process 1 To a solution of Example 119 (24 mg, 0.046 mmol) in dry DMSO (0.186 mL), hydroxylamine hydrochloride (4.36 mg, 0.063 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with SiO2, washed with water (2×) and brine, dried, and concentrated to obtain crude oxime intermediate (118-1) (21 mg), which was used directly in the next step. LC-MS, ES+: 532.13 [M+H] + . 【0276】 Process 2 To a solution of crude oxime intermediate (120-1) (21 mg, 0.046 mmol) in dry acetonitrile (0.79 mL), Cu(OAc)2 (1.4 mg, 7.9 μmol) was added. The reaction mixture was heated at 70°C for 1 hour and concentrated. The residue was purified by silica gel chromatography using 0-50% acetone / cyclohexane to obtain Example 120 (8 mg, 40% yield). LC-MS, ES+: 514.09 [M+H] + . 1 H NMR(400 MHz,Acetone-d6)δ 10.60(s,1H),7.88(d,J=8.2 Hz,1H),7.35(dd,J=2.3,0.8 Hz,1H),7.29(td,J=7.7,1.2 Hz,1H),7.20-7.08(m,3H),7.02(d,J=7.8 Hz,1H),6.95(td,J=7.6,1.0 Hz,1H),6.55(dd,J=7.4,1.0 Hz,1H),5.17(t,J=8.3 Hz,1H),4.91(ddd,J=9.8,8.2,4.6 Hz,1H),4.34(d,J=10.3 Hz,1H),4.05(d,J=10.4 Hz,1H),3.95(s,3H),3.24(s,3H),2.70(dd,J=8.3,3.9 Hz,2H),1.85(ddd,J=12.7,9.4,4.7 Hz,2H),1.73(dt,J=9.4,5.3 Hz,1H),0.99(dd,J=15.9,6.4 Hz,6H). 【0277】 Example 121 [ka] Process 1 To a solution of Example 42 (30 mg, 0.058 mmol) in dry acetone (0.29 mL), K2CO3 (12.11 mg, 0.088 mmol) and dimethyl sulfate (8.31 μL, 0.088 mmol) were added at room temperature. The reaction mixture was then heated under reflux for 3 hours. The mixture was then concentrated to remove the acetone, diluted with dimethyl ammonium compound, washed with water and brine, dried, and concentrated again. The residue was purified using silica gel with 0-50% acetone / cyclohexane to obtain Example 121 (16 mg, 81%). LC-MS, ES-: 526.03 [M-1]. 1 H NMR(400 MHz,Acetone-d6)δ 10.36(s,1H),7.20-7.10(m,2H),7.10-7.03(m,2H),7.00-6.91(m,2H),6.87(t,J=7.5 Hz,1H),6.55(d,J=7.7 Hz,1H),5.57(dd,J=9.6,5.6 Hz,1H),5.20(t,J=8.1 Hz,1H),4.25(d,J=10.7 Hz,1H),4.00(d,J=10.6 Hz,1H),3.97(s,3H),3.45(s,3H),3.22(s,3H),2.77-2.63(m,2H),1.93(ddd,J=14.4,9.6,5.1 Hz,1H),1.77(ddd,J=14.2,8.7,5.6 Hz,1H),1.62(dtd,J=8.6,6.6,5.0 Hz,1H),0.98(dd,J=23.1,6.6 Hz,6H). 【0278】 Example 122 [ka] 【0279】 Process 1 Compound (1-3) (425 mg, 1.38 mmol) was suspended in DCM (5 mL). Et3N (0.54 mL, 3.9 mmol) and TFAA (0.36 mL, 2.57 mmol) were added dropwise. The mixture was stirred at room temperature for 30 minutes. The second portion of Et3N (0.2 mL), followed by TFAA (0.12 mL), was added. The mixture was stirred at room temperature for 20 minutes and concentrated. The residue was purified with silica gel to obtain compound (122-1) (320 mg, yield 80%). ESI-MS m / z = 314.05 [M+H] + 【0280】 Step 2: Lutidine (0.18 mL, 1.05 mmol) in DCM (1 mL) was cooled to 0°C. TMSOTf (0.2 mL, 0.95 mmol) was added, and the mixture was stirred at 0°C for 5 minutes. In a separate tube, compound (122-1) (100 mg, 0.32 mmol) in DCM (1 mL) was cooled to 0°C. TMSOTf / lutidine solution (1.9 mL) was added dropwise, and the resulting mixture was stirred at 0°C for 20 minutes. NaHCO3 aqueous solution (4 mL) was added, and the mixture was stirred for 10 minutes and extracted with DCM (2x). The combined organic layers were washed with CsF (0.5 M) aqueous solution and brine, dried over Na2SO4, and concentrated to obtain compound (122-2) (68 mg, 100%) as a yellow solid. ESI-MS m / z = 213.88 [M + H] + . [ka] 【0281】 Process 3 Leucine t-butyl hydrochloride (1.0 g, 4.47 mmol) and benzyl isocyanate (595 mg, 4.47 mmol) were mixed in DCM (6 mL). TEA (1.25 mL, 8.95 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified with silica to obtain compound (122-3) (1.5 g) as a colorless syrup. ESI-MS m / z = 321.07 [M+H] +. 【0282】 Process 4 To a solution of compound (122-3) (1.5 g) in DCM (12 mL), TFA (1.27 mL, 23 mmol) was added. The mixture was stirred overnight at room temperature and concentrated. The residue was purified with silica to obtain compound (122-4) (301 mg, 25% in two steps) as a pale yellow oil. ESI-MS m / z = 265.02 [M+H] +. 【0283】 Process 5 To a solution of compound (122-2) (20 mg, 0.094 mmol) and compound (122-4) (32 mg, 1.122 mol) in DMF (1 mL), TCFH (39 mg, 0.14 mmol) and methylimidazole (23 mg, 0.38 mmol) were added. The reaction mixture was stirred at room temperature for 15 minutes, diluted with SiO2, and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified with silica gel to obtain Example 122 (30 mg, 70%) as a yellow solid. ESI-MS m / z = 460.31 [M+H] + ; 1 H NMR(400 MHz,Chloroform-d)δ 9.06(br,1H),7.21(d,J=4.3 Hz,4H),7.18-7.11(m,1H),7.06(t,J=7.8 Hz,1H),6.85(d,J=7.6 Hz,1H),6.83-6.73(m,1H),6.65(d,J=7.9 Hz,1H),6.03(br,1H),5.61(br,1H),4.63(d,J=7.8 Hz,1H),4.45(t,J=8.3 Hz,1H),4.33(d,J=14.6 Hz,1H),4.20(dd,J=20.2,12.6 Hz,2H),3.85(d,J=10.3 Hz,1H),2.72-2.58(m,1H),2.24(dd,J=13.0,8.0 Hz,1H),1.80-1.46(m,3H),0.98-0.81(m,6H). 【0284】 Example 433 [ka] 【0285】 Step 1: Pd / C (w / w 10%, 23 mg, 0.02 equivalents) was added to a solution of N-((benzyloxy)carbonyl)-N-methyl-L-leucine (300 mg, 1.07 mmol) in MeOH (10 mL). After degassing, a hydrogen balloon was introduced. The mixture was stirred at room temperature for 1 hour, and LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated. The crude product was used directly in the next step. 【0286】 Step 2: The crude product (N-Me-leucine) from Step 1 and (isocyanatomethyl)benzene (0.15 g, 1.12 mmol, 1.05 equivalents) were mixed in pyridine (5 mL) and stirred at room temperature for 3 hours. This was filtered and concentrated. The crude product was used directly in the next step. ESI-MS m / z = 279.07 [M+H] + . 【0287】 To a solution of the crude product (125 mg, calculated 0.45 mmol) from Step 3 and Step 2 (037625-1) and intermediate 122-2 (48 mg, 0.225 mmol) in DMF (2 mL), N-(chloro(dimethylamino)methylene)-N-methylmethaneaminium hexafluorophosphate (126 mg, 0.45 mmol) and 1-methyl-1H-imidazole (92 mg, 1.13 mmol) were added. The mixture was stirred overnight at room temperature and concentrated. The crude product was subjected to silica chromatography to obtain the marked compound (40 mg, 38%). ESI-MS m / z = 472.19, [M-1]. 1H NMR(500 MHz,Acetone-d6)δ 9.71(s,1H),7.27(td,J=7.5,1.7 Hz,1H),7.25-7.18(m,2H),7.20-7.14(m,1H),7.12-7.06(m,2H),7.05-6.96(m,3H),6.19(t,J=5.9 Hz,1H),5.31(dd,J=9.3,5.8 Hz,1H),5.15(t,J=8.4 Hz,1H),4.37(dd,J=10.7,1.3 Hz,1H),4.22-4.10(m,2H),3.91(d,J=10.7 Hz,1H),2.92(s,3H),2.82-2.78(m,1H),2.72(ddd,J=13.1,8.5,1.2 Hz,1H),2.66(dd,J=13.2,8.2 Hz,1H),1.73(ddd,J=14.3,9.4,5.2 Hz,1H),1.62(ddd,J=14.0,8.5,5.9 Hz,1H),1.52(dddd,J=15.1,11.8,7.6,5.9 Hz,1H),1.31(s,1H),0.95(dd,J=12.2,6.6 Hz,6H). 【0288】 Example 434 [ka] TIFF0007875859000228.tif2043 【0289】 Step 1: To a solution of N-((benzyloxy)carbonyl)-N-methyl-L-leucine (3.0 g, 10.74 mmol) in DCM (30 mL), t-butyl alcohol (2.05 mL, 21.48 mmol) and DCC (2.66 g, 12.89 mmol) were added. The resulting mixture was stirred overnight at room temperature and filtered. The filtrate was concentrated. The crude product was subjected to silica chromatography to obtain Cbz-N-Me-L-Leu-OtBu (3.2 g, 89%). ESI-MS m / z = 336.03 [M+H] + . 【0290】 Step 2: To a solution of Cbz-N-Me-L-Leu-OtBu (3.2 g, 9.54 mmol) in MeOH (30 mL), Pd / C (w / w 10%, 355 mg, 0.035 equivalents) was added. After degassing, the mixture was stirred under hydrogen (balloon) at room temperature for 1 hour. LC-MS indicated that the reaction was complete. After removing the solvent, the desired product N-Me-L-Leu-OtBu (1.68, 87%) was obtained. ESI-MS m / z = 202.02 [M+H] + . 【0291】 Step 3: Bis(trichloromethyl) carbonate (103 mg, 0.35 mmol) was dissolved in DCM (3 mL). A solution of N-Me-L-Leu-OtBu (200 mg, 0.99 mmol) and TEA (0.54 mL, 3.97 mmol) in DCM (2 mL) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole dihydrochloride (181 mg, 0.99 mmol) and TEA (0.45 mL) in THF (3 mL) were added. The mixture was stirred overnight at room temperature. After concentration, the crude product was subjected to silica chromatography to obtain (037826-1) (225 mg, 67%). ESI-MS m / z = 337.12 [M+H] + . 【0292】 Example 434 was synthesized from (434-1) following the procedure described in Example 122. [M-1], 473.97 【0293】 Example 435 [ka] 【0294】 Process 1 Compounds 1-4 (4.65 g, 17.37 mmol, 1.0 equivalent) and (S)-2-(((benzyloxy)carbonyl)amino)-4,4-dimethylpentanoic acid (1.1 equivalents) in CH2Cl2 (80 mL) and DMF (8 mL) were stirred, to which DIEA (3 equivalents) and HATU (1.1 equivalents) were added. The resulting mixture was stirred at room temperature for 1 hour. The reaction product was quenched with 10% citric acid at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with cyclohexane / acetone (0-50%) to obtain the desired product as an off-white solid. (ES, m / z): [M+H]+=493.35 【0295】 Process 2 To a solution of 435-1 (500.00 mg, 1.015 mmol, 1.00 equivalent) in 10 mL of MeOH, Pd / C (10%, 50 mg) was added in a 50 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated at room temperature under a hydrogen atmosphere using a hydrogen balloon for 1 hour. The mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the desired product. (ES, m / z): [M+H] + =359.25. 【0296】 Process 3 To a stirred solution of 435-2 (79.74 mg, 0.222 mmol, 1 equivalent) and DIEA (57.50 mg, 0.444 mmol, 2 equivalents) in CH2Cl2 (2 mL), isocyanatobenzene (26.5 mg, 0.222 mmol, 1 equivalent) in CH2Cl2 (3 mL) was added dropwise at 0°C. The reaction was monitored by LC-MS until complete conversion was achieved. The mixture was quenched with saturated NaHCO3 solution, extracted with CH2Cl2, and concentrated under vacuum to obtain the desired product (95.5 mg, 89.89%) as a yellow solid, which was used directly in the next step without further purification. 【0297】 Process 4 A mixture of 435-3 (95.5 mg, 0.200 mmol, 1 equivalent), DIEA (206.77 mg, 1.600 mmol, 8 equivalents), and T3P (763.53 mg, 1.200 mmol, 6 equivalents, 50%) in ethyl acetate (1 mL) was stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate (30 mL), and the organic layer was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography to obtain the marked compound (21.5 mg, 23.40%) as a white solid. [M+H] + =460.30,1H NMR(400 MHz,Methanol-d4)δ 1.03(s,9H),1.56-1.71(m,1H),1.82(dd,J=14.5,4.3 Hz,1H),2.69(d,J=8.0 Hz,2H),3.98(d,J=10.3 Hz,1H),4.35(d,J=10.3 Hz,1H),4.61(dd,J=8.5,4.2 Hz,1H),5.17(t,J=8.0 Hz,1H),6.77-7.09(m,3H),7.13-7.76(m,6H). 【0298】 The following examples were prepared using the same protocol as described above. [Table 17-1] [Table 17-2] 【0299】 Example 442 [ka] 【0300】 Step 1: In a purged, nitrogen-filled round-bottom flask, Boc-Asp-Ome 1 (20 g, 81 mmol), DMF (300 ml), cesium carbonate (52.7 g, 162 mmol), and benzyl bromide (11.55 ml, 97 mmol) were added. The resulting solution was stirred at room temperature for 2 hours and then diluted with SiO2. The mixture was washed three times with water and three times with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 2. The crude preparation was then carried out. [ka] 【0301】 Step 2: Crude material 2 (27.3 g, 81 mmol) was added to a purged, nitrogen-filled round-bottom flask containing DMF (162 ml), silver oxide (56.3 g, 243 mmol), and iodomethane (101 ml, 1618 mmol). The resulting solution was heated at 60°C for 1 hour and then diluted with ethyl acetate. The mixture was washed three times with water and three times with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (0-20% ethyl acetate / cyclohexane) to obtain material 3 (17 g, 60% over two steps). 1 H NMR(400 MHz,Chloroform-d)δ 7.44-7.27(m,5H),5.27-5.10(m,2H),4.86-4.56(m,1H),3.73-3.65(m,3H),3.13(dd,J=16.5,6.4 Hz,1H),3.01-2.85(m,3H),2.78(dq,J=15.7,8.0 Hz,1H),1.41(d,J=12.7 Hz,9H). [ka] 【0302】 Step 3: Palladium-carbon (2.120 g, 10 wt%, 1.992 mmol) was added to a round-bottom flask under nitrogen. 3 (7.0 g, 19.92 mmol) was added as a solution in methanol (100 ml). The reaction vessel was evacuated, the hydrogen balloon was filled three times, and then the mixture was stirred at room temperature for 2 hours. The vessel was evacuated, nitrogen was added, and then the mixture was filtered through Celite and concentrated to obtain crude 4 (5.2 g, 100% yield). The crude preparation was then carried out. 1 H NMR(400 MHz,Chloroform-d)δ 10.24(br s,1H),4.64(dt,J=26.4,6.9 Hz,1H),3.67(dd,J=13.9,6.9 Hz,3H),3.07(dd,J=15.6,6.7 Hz,1H),2.97-2.80(m,3H),2.80-2.52(m,1H),1.43(s,9H). [ka] 【0303】 Process 4 To a 35 mL THF solution of 4 (967 mg, 3.70 mmol) in a round-bottom flask, methylmagnesium bromide solution (7.4 mL, 22.2 mmol, 3.0 M in Et2O) was added dropwise under nitrogen at -78°C. The mixture was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for another 1 hour. The reaction product was quenched with saturated ammonium chloride solution and extracted three times by DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (MeOH:DCM 0-10%) to obtain 6 (85 mg, 9%). 1 H NMR(400 MHz,Chloroform-d)δ 11.10(s,1H),4.65(q,J=6.3 Hz,1H),3.31(ddd,J=17.6,10.9,6.5 Hz,1H),2.95(d,J=6.3 Hz,3H),2.80(dd,J=17.6,6.1 Hz,1H),2.22(d,J=2.3 Hz,3H),1.45(d,J=7.7 Hz,9H). [ka] 【0304】 Process 5 5 (85 mg, 0.347 mmol) and (3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (93 mg, 0.347 mmol) were taken into DCM (1.16 mL) and DMF (0.23 mL). At 0°C, 4-methylmorpholine (114 μl, 1.04 mmol) was added and the mixture was stirred for 5 minutes. HATU (132 mg, 0.347 mmol) was added at the same temperature. The mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 2 hours. The mixture was diluted with DCM and washed with saturated sodium bicarbonate solution, 1 M HCl, and brine. The HCl aqueous layer was extracted three more times with DCM. The recovered organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was used in the next step. Observed M+H=458.92 [ka] 【0305】 Process 6 Compound 6 (159 mg, 0.347 mmol) was treated with HCl (1.73 mL, 6.94 mmol, 4.0 M solution in dioxane). The mixture was stirred at room temperature for 30 minutes, and then volatile substances were removed under a nitrogen stream. The crude salt was used in the next step. Observed M+H=340.87 [ka] 【0306】 Process 7 7 (137 mg, 0.347 mmol) and 4,6,-difluoro-1H-indole-2-carboxylic acid (68 mg, 0.347 mmol) were taken into DCM (1.5 mL) and DMF (0.3 mL). 4-Methylmorpholine (114 μl, 1.04 mmol) was added and the mixture was stirred at room temperature for 5 minutes. HATU (132 mg, 0.347 mmol) was added. The mixture was stirred for 2 hours, diluted with DCM, and washed with saturated sodium bicarbonate solution, 1 M HCl, and brine. The aqueous layer was extracted three more times with DCM. The recovered organic layer was passed through a phase separator and concentrated. The crude material was used in the next step. Observed M+H = 537.84 [ka] 【0307】 Process 8 Crude 8 (187 mg, 0.347 mmol) was dissolved in water (1.74 mL) / acetonitrile (1.74 mL) under nitrogen, and 2,2-dichloroacetonitrile (0.56 mL, 6.94 mmol), followed by palladium(II) trifluoroacetate (115 mg, 0.347 mmol), was added. The mixture was heated to 65°C and stirred for 15 minutes. The reaction product was diluted with DCM and brine and extracted three times with DCM. The recovered organic layer was passed through a phase separator and concentrated. Purification of the residue by RPHPLC (0.1% TFA / MeCN / 0.1% TFA / water 20-95%) yielded 30 mg of 9, e.g., 442 (17%). Observed M+Na = 541.7. 1 H NMR(400 MHz,Acetone-d6)δ 10.79(s,1H),9.66(s,1H),7.12-6.96(m,3H),6.96-6.65(m,4H),5.80(dd,J=8.9,5.2 Hz,1H),5.21(t,J=8.2 Hz,1H),4.20(s,1H),3.97(d,J=10.6 Hz,1H),3.52(dd,J=17.2,9.0 Hz,1H),3.40(s,3H),2.96-2.68(m,3H),2.23(s,3H). 【0308】 Example 443 [ka] Example 442 (30 mg, 0.058 mmol) was dissolved in THF (0.58 mL) in a vial under nitrogen. The solution was cooled to -78°C, and methylmagnesium bromide solution (58 μl, 0.173 mmol, 3.0 M in Et2O) was added dropwise. The mixture was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for another 1 hour. The reaction product was quenched with saturated ammonium chloride solution, extracted three times with DCM, and dried over sodium sulfate. The organic layer was filtered, concentrated, and purified by Shimadzu preparative HPLC (0-95% 0.1% FA / H2O and 0.1% FA / acetonitrile) to obtain Example 443 (2 mg, 6%). Observed M+H=535.9 1 H NMR(400 MHz,Acetone-d6)δ 11.16(s,1H),9.69(s,1H),7.36-7.22(m,1H),7.18-7.06(m,3H),7.06-6.84(m,2H),6.84-6.49(m,1H),5.23(t,J=8.2 Hz,1H),4.10-3.81(m,2H),3.45(s,3H),2.72(dd,J=18.5,8.4 Hz,2H),2.56-2.38(m,1H),2.25(s,1H),1.95-1.81(m,1H),1.21(s,6H). 【0309】 Example 444 [ka] Example 444 was synthesized using the same protocol as described in Example 443. [M+H]553.9 【0310】 Example 123 [ka] 【0311】 Process 1 Compound (1-2) (5.00 g) was dissolved in acetic acid (115 mL). Sulfuryl chloride (2.09 g) was slowly added to the resulting solution at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was then concentrated. The crude residue was dissolved in methylene chloride (100 mL), and triethylamine (5.84 g, 8.05 mL, 4.0 equivalents) was added, followed by tert-butyl dicarbonate (4.73 g, 1.5 equivalents). The organic layer was then washed with 1 M HCl (2 × 50 mL), then brine (100 mL), and then dried over magnesium sulfate. After concentration, the crude residue was purified by RPHPLC to obtain compound (123-1) (2.81 g, yield 51%). [M+H] + , 381.1 【0312】 Process 2 Compound (123-1) (2.81 g) was dissolved in 7 M methanolic ammonia (36.1 mL) in a 100 mL pressure vessel. The mixture was heated at 60 °C for 36 hours. After concentration, the crude residue was ground with acetonitrile to obtain compound (123-2) as a colorless solid (1.92 g, yield 71%). [M+H] + , 366.1 【0313】 Process 3 Compound (123-2) (1.61 g) was dissolved in 4 M HCl / 1,4-dioxane (22.0 mL). The resulting mixture was stirred at room temperature for 2 hours. Upon concentration, compound (123-4) (1.33 g) was obtained as a white solid, which was used without further purification. [M+H] + , 266.1 【0314】 Process 4 Compound (123-3) (103.0 mg), compound (123-3b) (98.0 mg), and HATU (149.0 mg) were combined in a 40 mL vial equipped with a stirring bar. DMF (2.27 mL), followed by DIPEA (179 μL), was added. The resulting mixture was stirred overnight at room temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (50 mL), washed with 1 M HCl (2 × 20 mL) and brine (20 mL), and then dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (0-10% MeOH / DCM) to obtain compound (123-4) (58.1 mg, yield 34%). [M+H] + , 497.2 【0315】 Process 5 Compound (123-4) (58.1 mg) was dissolved in 4 M HCl / 1,4-dioxane (585 μL). The resulting mixture was stirred for 1.5 hours. The reaction mixture was concentrated to obtain compound (123-5) (51.0 mg), which was used in the next step without purification. [M+H] + , 397.2 【0316】 Process 6 Compound (123-5) (51.0 mg), compound (123-5b) (26.7 mg), and HATU (51.5 mg) were combined in a 40 mL vial equipped with a stirring bar. DMF (785 μL), followed by DIPEA (62 μL), was added. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 1 M HCl (3 x 20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and then concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH / DCM) to obtain compound (123-6) (26.9 mg, yield 40%). [M+H] + , 576.1 【0317】 Process 7 Compound (123-6) (26.9 mg) was dissolved in a 20 mL vial in a mixture of MeCN (500 μL) and water (500 μL). Next, 2,2-dichloroacetonitrile (56 μL) was added, followed by palladium(II) trifluoroacetate (1.5 mg). The vial was sealed and the mixture was heated at 65 °C for 2 hours. Further addition of 2,2-dichloroacetonitrile (56 μL) and palladium(II) trifluoroacetate (1.5 mg) was added, and the mixture was heated at 70 °C for 20 minutes. After cooling to room temperature, the mixture was purified by RPHPLC to obtain Example 123 as a white solid (10.0 mg, yield 38%). ESI MS m / z = 558.1 [M + H] + . 1 H NMR(400 MHz,acetone-d6,δ ppm):δ 10.96(s,1H),9.80(s,1H),8.18-8.16(m,1H),7.35-7.34(m,1H),7.15-7.09(m,3H),6.97-6.95(m,1H).6.77-6.72(m,1H),5.23(app t,J=8.2,8.2 Hz,1H),5.15-5.09(m,1H),4.46(d,J=10.5 Hz,1H),4.06(10.5 Hz),2.85-2.67(m,2H),2.42-2.18(m,2H),1.47(d,J 19F-1H =3.2 Hz, 3H), 1.41(d, J) 19F-1H =3.2 Hz, 3H). 【0318】 The following examples were prepared using the same protocol as described above. [Table 18-1] [Table 18-2] 【0319】 Example 447 [ka] 【0320】 Process 1 In a 40 mL screw-cap vial equipped with a stirring bar and a pressure-relieving septum, (S)-1-((3R,5'S)-5'-carbamoyl-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentane-2-aminium chloride (1.0 equivalent) was combined with 3-(trifluoromethoxy)benzoic acid (26.9 mg, 1.15 equivalents) and HATU (49.5 mg, 1.15 equivalents). Next, DMF (0.76 mL, 0.15 M) was added, followed immediately by DIPEA (60 μL, 3.0 equivalents). The resulting mixture was stirred at room temperature until the starting materials were completely consumed, as determined by LC-MS. The mixture was diluted with DCM (20 mL) and washed with 1.2 M HCl and brine. The organic layer was passed through a phase separator and concentrated to obtain crude (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-(3-(trifluoromethoxy)benzamide)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide. [M+H] + , 585.3 【0321】 Process 2 In a 40 mL screw-cap vial equipped with a stirring bar and a pressure-relieving septum, the crude (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-(3-(trifluoromethoxy)benzamide)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide produced in step 1 was dissolved in DCM (1.5 mL, 0.075 M). The resulting solution was cooled in an ice bath, and triethylamine (126 μL, 8.0 equivalents) was added, followed by trifluoroacetic anhydride (64 μL, 4.0 equivalents). The resulting mixture was stirred at room temperature for 1 hour. At this point, the mixture was diluted with DCM (10 mL), and 2.0 mL of 30% ammonium hydroxide was added. The mixture was shaken briefly and diluted with saturated sodium bicarbonate aqueous solution (7.5 mL). The organic phase was passed through a phase separator and concentrated. The crude residue was purified by RPHPLC (MeCN / water, 0.1% TFA) to obtain the indicated compound. 1H NMR(400 MHz,Acetone-d6)δ 9.83(s,1H),8.27(d,J=7.7 Hz,1H),7.91(dt,J=7.8,1.3 Hz,1H),7.82-7.80(m,1H),7.64-7.60(m,1H),7.54-7.51(m,1H),7.25(dd,J=8.3,2.1 Hz,1H),7.20(d,J=2.1 Hz,1H),7.01(d,J=8.3 Hz,1H),5.24(t,J=8.3 Hz,1H),5.08-5.03(m,1H),4.54(d,J=10.5,1H),4.06(d,J=10.5 Hz,1H),2.86-2.81(m,1H),2.72(dd,J=13.3,8.2 Hz,1H),2.41-2.22(m,2H),1.50(d,J=6.7 Hz,3H),1.44(d,J=6.7 Hz,3H).[M-1],564.7. 【0322】 The following examples were prepared using the same protocol as described above. [Table 19-1] [Table 19-2] [Table 19-3] 【0323】 Example 454 [ka] 【0324】 Process 1 In a flame-dried 250 mL round-bottom flask, (S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4-methylpentanoic acid (3.00 g, 1.0 equivalent) was combined with iodomethane-d3 (6.00 mL, 8.0 equivalents) in THF (35 mL, 0.34 M). The resulting solution was cooled in an ice bath, and sodium hydroxide (963.0 mg, 90 wt%, 3.0 equivalents) was added. The mixture was warmed to room temperature and stirred for 72 hours. After completion, the mixture was quenched with HCl (12 mL, 6 M aqueous solution, 6.0 equivalents) and further diluted with water (35 mL). The aqueous phase was extracted with ethyl acetate, and the combined organic layer was dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-50% ethyl acetate / cyclohexane) to obtain (S)-2-((tert-butoxycarbonyl)(methyl-d3)amino)-4-fluoro-4-methylpentanoic acid as a white solid (2.74 g, 86%). [M-1], 265.2. 【0325】 Process 2 In a 250 mL round-bottom flask equipped with a stirring bar, (3R,5'S)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (2.73 g, 1.0 equivalent) was combined with (S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4-methylpentanoic acid (2.40 g, 1.0 equivalent) in DCM / DMF (4:1, 0.25 M, DCM 28.9 mL, DMF 7.2 mL). The resulting mixture was cooled in an ice bath, and N-methylmorpholine (3.2 mL, 3.2 equivalents) was added. Next, HATU (3.43 g, 1.0 equivalent) was added. Complete consumption of the starting materials was observed by LC-MS after 25 minutes. The reaction mixture was diluted with DCM (150 mL) and washed with saturated sodium bicarbonate aqueous solution (35 mL), 1.2 M HCl (45 mL), and brine. The combined organic layer was dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-10% MeOH / DCM) to obtain tert-butyl((S)-1-((3R,5'S)-5'-carbamoyl-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl-d3)carbamate as a white solid (4.02 g, 87%). [M+1], 514.2 【0326】 Process 3 In a 250 mL round-bottom flask equipped with a stirring bar, ((S)-1-((3R,5'S)-5'-carbamoyl-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl-d3)carbamate (4.02 g, 1.0 equivalent) was treated with 4 M HCl (39.1 mL, 20 equivalents HCl) in dioxane. The resulting mixture was stirred for 1 hour, at which point LC-MS showed complete conversion. When the reaction product was concentrated, (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-((methyl-d3)amino)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride was obtained as a white solid, which was used directly without purification. [M+H], 414.2 【0327】 Process 4 In a 250 mL round-bottom flask equipped with a stirring bar, the crude (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-((methyl-d3)amino)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (1.0 equivalent) produced in step 3 was combined with 4,6-difluoro-1H-indole-2-carboxylic acid (1.54 g, 1.0 equivalent) in DCM / DMF (5:1, 0.2 M, DCM 32.6 mL, DMF 6.5 mL). The resulting mixture was cooled in an ice bath, and N-methylmorpholine (2.58 mL, 3.0 equivalents), followed by HATU (2.97 g, 1.0 equivalent), was added. The reaction mixture was stirred for 14 hours, at which point complete consumption of the starting materials was observed by LC-MS. The mixture was quenched with 45 mL of saturated sodium bicarbonate aqueous solution, and the layers were separated. The aqueous phase was extracted by DCM, and the combined organic layers were dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (0-80% acetone / cyclohexane) to obtain (3R,5'S)-5-chloro-1'-((S)-2-(4,6-difluoro-N-(methyl-d3)-1H-indole-2-carboxamide)-4-fluoro-4-methylpentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide as a white solid (3.59 g, 77%). [MH], 591.0 【0328】 Process 5 In a 250 mL round-bottom flask equipped with a stirring bar, (3R,5'S)-5-chloro-1'-((S)-2-(4,6-difluoro-N-(methyl-d3)-1H-indole-2-carboxamide)-4-fluoro-4-methylpentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (3.59 g, 1.0 equivalent) was dissolved in DCM (40.4 mL, 0.15 M). The resulting solution was cooled in an ice bath, and triethylamine (5.06 mL, 6.0 equivalents) was added, followed by trifluoroacetic anhydride (2.57 mL, 3.0 equivalents). The mixture was warmed to room temperature and stirred for 45 minutes, at which point LCMS showed complete consumption of the starting material. The mixture was diluted with 150 mL of DCM and washed with saturated sodium bicarbonate aqueous solution (60 mL). The aqueous phase was extracted with methylene chloride. The combined organic layers were washed with brine and dried over magnesium sulfate. After concentration, the crude residue was purified by C18 column chromatography (gradient elution, water / MeCN) to obtain N-((S)-1-((3R,5'S)-5-chloro-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-(methyl-d3)-1H-indole-2-carboxamide as a white solid (3.08 g, yield 88%). 1 H NMR(400 MHz,Acetone-d6)δ 10.68(s,1H),9.80(s,1H),7.09-7.06(m,1H),6.97-6.88(m,4H),6.75(td,J=10.3,2.1 Hz,1H),5.84(dd,J=7.6,5.6 Hz,1H),5.33(dd,J=8.8,7.7 Hz,1H),4.50(d,J=10.9 Hz,1H),3.95(d,J=11.0 Hz,1H),2.84-2.65(m,2H),2.52-2.25(m,2H),1.45(d,J=6.8 Hz,3H),1.40(d,J=7.0 Hz, 3H).[M-1], 573.2. 【0329】 The following examples were prepared using the same protocol as described above. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] 【0330】 Example 472 [ka] 【0331】 Process 1 A solution of methyl(S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (1.10 g, 1.0 equivalent), DABCO (1.07 g, 3.0 equivalents), and 2-iodo-5-(trifluoromethyl)aniline (1.01 g, 1.1 equivalents) in DMF (16 ml, 0.2 M) was sprayed with nitrogen in a 100 mL Schlenk tube for 20 minutes. Palladium(II) acetate (72.0 mg, 0.10 equivalents) was then added, and the mixture was heated under a nitrogen atmosphere at 90°C for 30 hours. After completion, the mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-40% ethyl acetate / cyclohexane) to obtain methyl(S)-2-(bis(tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)-1H-indole-3-yl)propanoate (1.09 g, 70%). [M+1], 487.2. 【0332】 Process 2 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, methyl(S)-2-(bis(tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)-1H-indole-3-yl)propanoate (1.09 g, 1.0 equivalent) was treated with 4 M HCl (11.2 mL, 20 equivalents HCl) in dioxane. The resulting mixture was stirred at room temperature for 12 hours. After completion, the mixture was concentrated to obtain methyl(S)-2-amino-3-(6-(trifluoromethyl)-1H-indole-3-yl)propanoate hydrochloride, which was used in the next step without purification. [M+1], 287.1 【0333】 Process 3 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, methyl(S)-2-amino-3-(6-(trifluoromethyl)-1H-indole-3-yl)propanoate hydrochloride (722 mg, 1.0 equivalent) was combined with aqueous formaldehyde (183 μL, 37 wt%, 1.1 equivalent) in MeOH (4.5 mL, 0.5 M). The resulting mixture was heated at 65 °C for 3 hours. Once determined to be complete by LC-MS, the mixture was concentrated to obtain crude methyl(S)-7-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride, which was used directly in the next step without purification. [M+1], 299.1 【0334】 Process 4 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, (S)-7-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride (1.0 equivalent) was suspended in DCM (5.6 mL, 0.4 M). Then, triethylamine (2.0 equivalents, 623 μL) was added, followed by Boc anhydrous (1.23 mL, 1.1 equivalents, 2 M DCM). The resulting mixture was stirred at room temperature for 20 hours. The reaction product was then concentrated and purified by silica gel column chromatography to obtain 2-(tert-butyl)3-methyl(S)-7-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2,3-dicarboxylate (681 mg, 76%). [M-1], 397.0 【0335】 Process 5 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, 681.0 mg (1.0 equivalent) of 2-(tert-butyl)3-methyl(S)-7-(trifluoromethyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2,3-dicarboxylate was suspended at -40°C in a mixture of THF, water, and acetic acid (10 mL of THF, 1 mL of DI water, and 685 μL of acetic acid). N-bromosuccinimide (304 mg, 1.0 equivalent) was gradually added to the solution. After 2.5 hours, the mixture was warmed to 0°C using an ice bath, and a further 685 μL of acetic acid was added. After 20 minutes, complete consumption of the starting material was observed by LC-MS, and the mixture was slowly added to 75 mL of saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-100% MTBE / cyclohexane) to obtain 1'-(tert-butyl)5'-methyl(3R,5'S)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (591.7 mg, 84%, 6:1 diastereomer mixture) as a colorless oil. [M-1], 413.0 【0336】 Process 6 In a 25 mL pressure tube equipped with a stirring bar, 1'-(tert-butyl)5'-methyl(3R,5'S)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (591.7 mg, 1.0 equivalent) produced in step 5 was dissolved in 7 M NH3 (6.1 mL, 30 equivalents NH3) in MeOH. The resulting mixture was heated at 60°C for 48 hours. At this point, the reaction mixture was concentrated, and the crude residue was purified by RPHPLC (MeCN / water, 0.1% TFA) to obtain tert-butyl(3R,5'S)-5'-carbamoyl-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (311.0 mg, 55%) as a single diastereomer. [M+Na], 422.1 【0337】 Process 7 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, tert-butyl(3R,5'S)-5'-carbamoyl-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (311.0 mg, 1.0 equivalent) was treated with 4 M HCl in dioxane (3.9 mL, 20 equivalents HCl). The resulting mixture was stirred at room temperature for 1 hour and then concentrated to obtain (3R,5'S)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride as a white solid (261.0 mg). [M+1], 300.1 【0338】 Process 8 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, (3R,5'S)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (261.0 mg, 1.0 equivalent) was combined with (S)-2-((tert-butoxycarbonyl)(methyl-d3)amino)-4-fluoro-4-methylpentanoic acid (91.0 mg, 1.15 equivalent) and HATU (130.0 mg, 1.15 equivalent) in DMF (2.0 mL, 0.15 M). Next, DIPEA (156 μL, 3.0 equivalent) was added, and the resulting mixture was stirred for 14 hours. Next, the crude reaction mixture was filtered and purified by RPHPLC (MeCN / water, 1% TFA) to obtain tert-butyl((S)-1-((3R,5'S)-5'-carbamoyl-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl-d3)carbamate (106.6 mg, 65%) as a white solid. [M-1], 546.3 【0339】 Process 9 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, tert-butyl((S)-1-((3R,5'S)-5'-carbamoyl-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl-d3)carbamate (107 mg, 1.0 equivalent) was treated with 4 M HCl (973 μL, 20 equivalents HCl) in dioxane at room temperature. After 1 hour, the mixture was concentrated to obtain (3R,5'S)-1'-((S)-4-fluoro-4-methyl-2-((methyl-d3)amino)pentanoyl)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride, which was used in the next step without purification. [M+1], 448.2 【0340】 Step 10 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, (3R,5'S)-1'-((S)-4-fluoro-4-methyl-2-((methyl-d3)amino)pentanoyl)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (1.0 equivalent) produced in step 9 was combined with 4,6-difluoro-1H-indole-2-carboxylic acid (44.1 mg, 1.15 equivalents) and HATU (85.0 mg, 1.15 equivalents) in DMF (1.3 mL, 0.15 M). Next, DIPEA (102 μL, 3.0 equivalents) was added, and the resulting mixture was stirred at room temperature for 14 hours. The crude reaction mixture was filtered and purified by RPHPLC (MeCN, water, 0.1% TFA) to obtain (3R,5'S)-1'-((S)-2-(4,6-difluoro-N-(methyl-d3)-1H-indole-2-carboxamide)-4-fluoro-4-methylpentanoyl)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (88.3 mg, 72%) as a white solid. [M-1], 625.1 【0341】 Step 11 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, (3R,5'S)-1'-((S)-2-(4,6-difluoro-N-(methyl-d3)-1H-indole-2-carboxamide)-4-fluoro-4-methylpentanoyl)-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (88.3 mg, 1.0 equivalent) was dissolved in DCM (2.8 mL, 0.05 M) at 0°C. Triethylamine (1.27 mL, 9.0 equivalents) was added to the solution, followed by trifluoroacetic anhydride (634 μL, 4.5 equivalents). The resulting mixture was stirred at room temperature for 1.5 hours. After completion, ammonium hydroxide (250 μL, 30 wt%) was added, and the mixture was shaken briefly. Next, the mixture was diluted with saturated sodium bicarbonate aqueous solution (5 mL) and DCM (5.0 mL) and passed through a phase separator. After concentration, the crude residue was purified by RPHPLC (MeCN, water, 0.1% TFA) to obtain N-((S)-1-((3R,5'S)-5'-cyano-2-oxo-6-(trifluoromethyl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-(methyl-d3)-1H-indole-2-carboxamide (1.7 mg, 2%). 1 H NMR(400 MHz,Acetone-d6)δ 10.76(s,1H),9.96(s,1H),7.19-6.99(m,5H),6.74(td,J=10.3,2.1 Hz,1H),5.83(dd,J=7.6,5.5 Hz,1H),5.28(t,J=8.2 Hz,1H),4.52(d,J=11.0 Hz,1H),4.01(d,J=10.9 Hz,1H),2.88-2.71(m,2H),2.48-2.29(m,2H),1.45(d,J=6.3 Hz,3H),1.40(d,J=6.5 Hz,3H).[M-1],607.4. 【0342】 Example 473 [ka] 【0343】 Process 1 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, tert-butyl((S)-1-((3R,5'S)-5'-carbamoyl-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (318.0 mg, 1.0 equivalent) was treated with 4 M HCl (3.1 mL, 20 equivalents HCl) in dioxane. The resulting mixture was stirred at room temperature for 1.5 hours. Based on LC-MS determination that the starting material was completely consumed, the reaction mixture was concentrated to obtain (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (278 mg) as a white solid, which was used in step 2 without purification. [M+1], 411.2 【0344】 Process 2 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (50.0 mg, 1.0 equivalent) was combined with 1-(pyridine-4-yl)cyclopropane-1-carboxylic acid (18.2 mg, 1.0 equivalent) and N-methylmorpholine (40 μL, 3.2 equivalents) in a mixture of DCM / DMF (DCM / DMF 5:1, 0.15 M, DCM 620 μL / DMF 120 μL) at 0°C. Next, HATU (42.5 mg, 1.0 equivalent) was added, and the reaction mixture was stirred for 14 hours. Upon completion, 100 μL of formic acid was added and the mixture was concentrated. The crude residue was purified by RPHPLC (MeCN / water / 0.1% TFA) to obtain (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-(N-methyl-1-(pyridine-4-yl)cyclopropane-1-carboxamide)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (36.2 mg, 58%). [M+1], 556.4. 【0345】 Process 3 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, (3R,5'S)-5-chloro-1'-((S)-4-fluoro-4-methyl-2-(N-methyl-1-(pyridine-4-yl)cyclopropane-1-carboxamide)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (36.2 mg, 1.0 equivalent) was dissolved in DCM (870 μL, 0.075 M), and Burgess reagent (46.5 mg, 3.0 equivalent) was added. The mixture was stirred at room temperature for 14 hours. The mixture was then diluted with saturated aqueous dicarbonate (3 mL) and DCM (5 mL) and passed through a phase separator. After concentration, the residue was purified by RHPLC to obtain N-((S)-1-((3R,5'S)-5-chloro-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)-N-methyl-1-(pyridine-4-yl)cyclopropane-1-carboxamide (11.1 mg, 32%) as a white solid. 1 H NMR(400 MHz,Acetone-d6)δ 8.70(d,J=6.7 Hz,2H),7.54(d,J=6.7 Hz,2H),7.35(dd,J=8.3,2.1 Hz,1H),7.12(d,J=2.1 Hz,1H),7.07(d,J=8.3 Hz,1H),5.61(dd,J=7.4,5.6 Hz,1H),5.26(t,J=8.4 Hz,1H),4.24(d,J=10.6 Hz,1H),4.08(d,J=10.6 Hz,1H),3.00(s,2H),2.85-2.67(m,1H),2.44-2.19(m,2H),1.68-1.58(m,2H),1.46(d,J=7.8 Hz,3H),1.41(d,J=7.7 Hz,3H),1.39-1.24(m,2H).[M+1],538.2. 【0346】 The following examples were prepared using the same protocol as described above. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5] [Table 21-6] [Table 21-7] 【0347】 Example 492 [ka] 【0348】 Step 1: In a 40 mL vial equipped with a pressure-relieving cap and a stirring bar, (2,6-difluorophenyl)methanol (802.0 mg, 1.0 equivalent) was dissolved in DMF (7.4 mL, 0.75 M). The solution was then cooled in an ice bath, and CDI (903.0 mg, 1.0 equivalent) was added. The resulting mixture was then warmed to room temperature. After stirring for 20 minutes, methyl(S)-2-amino-3-cyclopropylpropanoate hydrochloride (1.00 g, 1.0 equivalent) was added, and the reaction mixture was heated at 55 °C for 14 hours. After cooling to room temperature, the reaction mixture was diluted with brine, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-40% ethyl acetate / cyclohexane) to obtain methyl(S)-3-cyclopropyl-2-((((2,6-difluorobenzyl)oxy)carbonyl)amino)propanoate (1.23 g, 71%). [M+1], 314.2 【0349】 Process 2 In a 50 mL round-bottom flask equipped with a stirring bar, (S)-3-cyclopropyl-2-((((2,6-difluorobenzyl)oxy)carbonyl)amino)propanoate (1.23 g, 1.0 equivalent) was dissolved at 0°C in a mixture of MeOH and water (1:1, 0.26 M, 7.6 mL MeOH, 7.6 mL water). Next, LiOH (235.0 mg, 2.5 equivalents) was added. The reaction mixture was then slowly allowed to reach room temperature and stirred for 14 hours. The mixture was concentrated to remove the MeOH and acidified with 6 M HCl. The aqueous phase was extracted by DCM, and the combined organic layers were dried over magnesium sulfate. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-70% ethyl acetate / cyclohexane) to obtain (S)-3-cyclopropyl-2-((((2,6-difluorobenzyl)oxy)carbonyl)amino)propanoic acid (431.0 mg, 37%). [M+1], 300.2 【0350】 Process 3 In a 40 mL vial equipped with a pressure-relieving cap and a stirring bar, (3R,5'S)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (100.0 mg, 1.0 equivalent) and (S)-3-cyclopropyl-2-((((2,6-difluorobenzyl)oxy)carbonyl)amino)propanoic acid (114.0 mg, 1.15 equivalent) were combined in DMF (2.2 mL, 0.15 M). Next, HATU (145.0 mg, 1.15 equivalent) was added, followed immediately by DIPEA (173 μL, 3.0 equivalent). The reaction mixture was stirred at room temperature for 14 hours. After completion, the reaction mixture was diluted with DCM, washed with 1.2 M HCl and brine, and passed through a phase separator. Upon concentration, crude 2,6-difluorobenzyl((S)-1-((3R,5'S)-5'-carbamoyl-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropan-2-yl)carbamate was obtained and used in the next step without purification. [M+1], 547.2. 【0351】 Process 4 In a 40 mL vial equipped with a pressure-relieving cap and a stirring bar, the crude 2,6-difluorobenzyl((S)-1-((3R,5'S)-5'-carbamoyl-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropan-2-yl) carbamate produced in step 3 was dissolved in DCM (4.7 mL, 0.075 M) at 0°C. Triethylamine (346 μL, 7.0 equivalents) was added to the resulting solution, followed by trifluoroacetic anhydride (200 μL, 4.0 equivalents). The reaction mixture was stirred at room temperature for 1 hour, and then quenched with saturated aqueous solution of sodium bicarbonate (5 mL) and 2.0 mL of ammonium hydroxide (30 wt%). The mixture was further diluted with DCM (5 mL) and passed through a phase separator. After concentration, the crude residue was purified by RPHPLC (MeCN / water / 0.1% TFA) to obtain 2,6-difluorobenzyl((S)-1-((3R,5'S)-5-chloro-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropan-2-yl)carbamate (7.9 mg, 4.2%). 1 H NMR(400 MHz,Acetone-d6)δ 9.83(s,1H),7.54-7.46(m,1H),7.33-7.27(m,2H),7.10-7.01(m,3H),6.73(d,J=7.6 Hz,1H),7.10-7.02(m,3H),6.73(d,J=7.6 Hz,1H),5.26(t,J=8.1 Hz,1H),5.20(d,J=11.8 Hz,1H),5.11(d,J=11.8 Hz,1H),4.51(q,J=7.3 Hz,1H),4.38(d,J=10.5 Hz,1H),4.07(d,J=10.5 Hz,1H),2.88-2.81(m,1H),2.71(dd,J=13.3,7.8 Hz,1H),1.76-1.65(m,2H),0.92-0.82(m,1H),0.54-0.46(m,2H),0.27-0.14(m,2H).[M-1],527.0. 【0352】 The following examples were prepared using the same protocol as described above. [Table 22-1] [Table 22-2] 【0353】 Example 497 [ka] 【0354】 Process 1 In a 40 mL screw-cap vial equipped with a pressure-relieving septum and a stirring bar, 1'-(tert-butyl)5'-methyl(3R,5'S)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (209.0 mg, 1.0 equivalent) was treated with 4 M HCl (2.7 mL, 20 equivalents HCl) in dioxane. The mixture was stirred for 2 hours and concentrated to obtain methyl(3R,5'S)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate hydrochloride (174.0 mg), which was used in the next step without purification. [M+1], 281.1 【0355】 Process 2 In a 40 mL screw-cap vial equipped with a pressure-relieving vial and a stirring bar, methyl(3R,5'S)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate hydrochloride (174.0 mg, 1.0 equivalent) was combined with N-(tert-butoxycarbonyl)-N-methyl-L-leucine (135.0 mg, 1.0 equivalent) in a mixture of DCM and DMF (DCM / DMF 5:1, 0.25 M, DCM 1.8 mL, DMF 370 μL). The mixture was cooled in an ice bath, and N-methylmorpholine (181 μL, 3.0 equivalent), followed by HATU (209.0 mg, 1.0 equivalent), was added. The resulting mixture was slowly heated to room temperature and stirred for 14 hours. The reaction mixture was diluted with brine (5 mL) and DCM (5 mL), and the organic phase was passed through a phase separator. After concentration, the crude residue was purified by silica gel column chromatography (gradient elution, 0-55% ethyl acetate / cyclohexane) to obtain methyl(3R,5'S)-1'-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate (246.6 mg, 88%). [M+1], 508.4 【0356】 Process 3 In a 40 mL screw-cap vial equipped with a pressure-relieving vial and a stirring bar, (3R,5'S)-1'-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate (246.6 mg, 1.0 equivalent) was treated with 4 M HCl (2.43 mL, 20 equivalents HCl) in dioxane. The mixture was stirred at room temperature for 2 hours and concentrated to obtain methyl(3R,5'S)-5-chloro-1'-(methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate hydrochloride as a white solid, which was used in the next step without purification. [M+1], 408.2 【0357】 Process 4 In a 40 mL screw-cap vial equipped with a pressure-relieving vial and a stirring bar, methyl(3R,5'S)-5-chloro-1'-(methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate hydrochloride (1.0 equivalent) produced in step 3 was combined with 4,6-difluoro-1H-indole-2-carboxylic acid (96.0 mg, 1.0 equivalent) in a mixture of DCM and DMF (DCM / DMF 5:1, 0.2 M, DCM 2.02 mL, DMF 410 μL). The mixture was cooled in an ice bath, and N-methylmorpholine (160 μL, 3.0 equivalents), followed by HATU (185.0 mg, 1.0 equivalent), was added. The reaction mixture was slowly warmed to room temperature and stirred for 14 hours. Upon completion, the mixture was diluted with DCM (5 mL) and brine (5 mL) and passed through a phase separator. After concentration, the crude residue was purified by silica gel column chromatography to obtain methyl(3R,5'S)-5-chloro-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate (224.4 mg, 79%). [M-1], 585.1 【0358】 Process 5 In a 40 mL screw-cap vial equipped with a pressure-relieving vial and a stirring bar, methyl(3R,5'S)-5-chloro-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylate (224.4 mg, 1.0 equivalent) was dissolved in 1,2-DCE (3.82 mL, 0.1 M). Next, trimethyltin hydroxide (207.0 mg, 3.0 equivalent) was added, and the mixture was heated at 75°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and washed twice with 1.2 M HCl (5 mL) and once with brine. The organic layer was passed through a phase separator. After concentration and purification of the crude residue by RPHPLC, (3R,5'S)-5-chloro-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxylic acid (1.44 mg, 0.7%) was obtained as a white solid. 1 H NMR(400 MHz,Acetone-d6)δ 10.71(s,1H),9.78(s,1H),7.12-7.05(m,1H),7.02-6.95(m,3H),6.89(d,J=8.3 Hz,1H),6.74(td,J=10.3,2.1 Hz,1H),5.59(t,J=7.5 Hz,1H),4.94(t,J=8.8 Hz,1H),4.38(d,J=10.4 Hz,1H),3.97(d,J=10.5 Hz,1H),3.47(s,3H),2.63-2.46(m,2H),1.81(t,J=7.2 Hz,2H),1.70-1.58(m,1H),1.00(d,J=6.6 Hz,3H),0.95(d,J=6.6 Hz,3H).[M-1],570.9. 【0359】 Example 498 [ka] 【0360】 Step 1: A colorless, clear solution of 1'-(tert-butyl)5'-methyl(3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (3.94 g, 11.4 mmol, dr 10 / 1) in acetonitrile (40 mL) was treated with NBS (2.23 g, 12.5 mmol) in three portions at room temperature. The reaction mixture was stirred at room temperature for 3 hours. It became a pale yellow solution. LC-MS showed no SM. The reaction mixture was quenched with an aqueous solution of Na2S2O3. The mixture was stirred for a further 30 minutes at room temperature. The turbid mixture was further diluted with ELISA (80 mL). The aqueous layer was extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude product as an off-white solid. The crude product was dissolved in DCM (10 mL) and filtered through an 80 g silica gel pad (MTBE) to obtain the desired product (dr 10 / 1) as a white solid. The product was treated with MTBE / hexane (2:1) (30 mL). The mixture was sonicated for 10 minutes to form a milky suspension, which was filtered and washed with MTBE / hexane (2:1) to obtain 1'-(tert-butyl)5'-methyl(3R,5'S)-5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate as a white solid (4.23 g, 10.0 mmol, dr>100 / 1, yield 87%). LC-MS, ES - :422.74,424.64 [MH] - . 【0361】 Step 2: 1'-(tert-butyl)5'-methyl(3R,5'S)-5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (5.3 g, 12.46 mmol) was treated with 7N ammonia in MeOH (40 ml, 280 mmol). The reaction mixture was heated to 50°C and stirred over the weekend. The mixture was concentrated under vacuum to obtain tert-butyl(3R,5'S)-5-bromo-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (5.11 g, 12.5 mmol, yield 100%) as an off-white solid. LC-MS, ES - :408.10,410.07 [MH] - . 【0362】 Step 3: A solution of tert-butyl(3R,5'S)-5-bromo-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (2.39 g, 5.83 mmol) in DMF (4.8 ml) was treated by adding 4 M HCl in dioxane (20 ml, 80 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The resulting solution was added to DCM (100 mL) to precipitate the product. The suspension was filtered, and the solid was dried under high vacuum to obtain (3R,5'S)-5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (1.895 g, 5.47 mmol, yield 94%) as an off-white solid. LC-MS, ES + :265.14,267.16 [M+H] + . 【0363】 Step 4: A suspension of (3R,5'S)-5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (2.06 g, 5.94 mmol) and N-(tert-butoxycarbonyl)-N-methyl-L-leucine (1.531 g, 6.24 mmol) in THF (20.00 ml) and DMF (2.0 ml) was treated at 0°C with N-methylmorpholine (1.960 ml, 17.83 mmol) and 50% T3P in DMF (3.82 ml, 6.54 mmol). The reaction mixture was warmed to room temperature, stirred for 1 hour, and then quenched with a saturated solution of sodium bicarbonate. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M HCl, water, and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain tert-butyl((S)-1-((3R,5'S)-5-bromo-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (2.867 g, 5.33 mmol, yield 90%) as an off-white solid. LC-MS, ES - :535.23,537.27 [MH] - . 【0364】 Step 5: tert-butyl((S)-1-((3R,5'S)-5-bromo-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (2.867 g, 5.33 mmol) was treated with 4 M HCl in dioxane (13.34 ml, 53.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was evaporated and dried under high vacuum to obtain (3R,5'S)-5-bromo-1'-(methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (2.44 g, 5.15 mmol, yield 97%) as a white solid. LC-MS, ES + :437.31,439.27 [M+H] + . 【0365】 Step 6: A solution of (3R,5'S)-5-bromo-1'-(methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (2.44 g, 5.15 mmol) and 4,6-difluoro-1H-indole-2-carboxylic acid (1.117 g, 5.66 mmol) in DMF (25.7 ml) was treated with HATU (2.350 g, 6.18 mmol) and DIPEA (2.70 ml, 15.45 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and then washed with a saturated solution of water and sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was added to a silica gel column (40 g) and eluted with 0% to 75% acetone / hexane to obtain (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (2.7 g, 4.38 mmol, yield 85%) as an off-white solid. LC-MS, ES - :614.39,616.31 [MH] - . 【0366】 Step 7: A solution of (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (41 mg, 0.067 mmol) in n-PrOH (0.5 ml) was treated under N2 with trifluoro(propa-1-en-2-yl)-14-borane, potassium salt (16 mg, 0.108 mmol), TEA (30 μl, 0.215 mmol), and PdCl2 (dppf) (6 mg, 8.20 μmol). The mixture was bubbling with N2 for 5 minutes. The reaction mixture was heated to 90°C and stirred overnight. The mixture was filtered through Celite and concentrated under vacuum. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% acetone / cyclohexane, (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxo-5-(propa-1-en-2-yl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (19mg, 0.033 mmol, yield 49.5%) was obtained as an orange solid. LC-MS, ES - :576.57 [MH] - . 【0367】 Step 8: A solution of (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxo-5-(propa-1-en-2-yl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (19 mg, 0.033 mmol) in DCM (0.4 ml) was added dropwise with TEA (30 μl, 0.215 mmol) and TFAA (15 μl, 0.106 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, N-((S)-1-((3R,5'S)-5'-cyano-2-oxo-5-(propa-1-en-2-yl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (13mg, 0.023 mmol, yield 70.6%) was obtained as a white solid. LC-MS, ES - :558.36 [MH] - ; 1 H NMR(400 MHz,Chloroform-d)δ 9.07(s,1H),8.25(s,1H),7.19(dd,J=8.2,1.8 Hz,1H),6.96(d,J=1.8 Hz,1H),6.91-6.73(m,3H),6.63(td,J=10.0,1.9 Hz,1H),5.38(dd,J=9.0,6.2 Hz,1H),5.09(dd,J=17.1,8.6 Hz,2H),4.91(t,J=1.5 Hz,1H),4.51(d,J=10.5 Hz,1H),3.98(d,J=10.5 Hz,1H),3.46(s,3H),2.89(dd,J=13.2,8.9 Hz,1H),2.66-2.50(m,1H),1.98-1.75(m,5H),1.01(d,J=6.6 Hz,3H),0.96(d,J=6.5 Hz,3H). 【0368】 Example 499 [ka] Step 1: A solution of N-((S)-1-((3R,5'S)-5'-cyano-2-oxo-5-(propa-1-en-2-yl)spiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (8 mg, 0.014 mmol) in THF (0.2 ml) and water (0.1 ml) was treated with potassium osmate dihydrate (3.4 mg, 9.23 μmol) and potassium osmate dihydrate (3.4 mg, 9.23 μmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with a saturated solution of sodium thiosulfate. The mixture was stirred for a further 30 minutes. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane to obtain N-((S)-1-((3R,5'S)-5-acetyl-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (6mg, 10.68μmol, yield 74.7%) as a white solid. LC-MS, ES - :560.37 [MH] - ; 11H NMR (400 MHz, Chloroform-d) δ 9.73 (s, 1H), 8.23 (s, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 8.2, 1.7 Hz, 1H), 6.92 (dd, J = 8.4, 2.2 Hz, 2H), 6.84 - 6.76 (m, 1H), 6.62 (td, J = 10.0, 2.0 Hz, 1H), 5.24 (dd, J = 8.4, 6.8 Hz, 1H), 5.12 (t, J = 8.3 Hz, 1H), 4.75 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.5 Hz, 1H), 3.51 (s, 3H), 2.89 (dd, J = 13.4, 8.3 Hz, 1H), 2.54 (dd, J = 13.5, 8.3 Hz, 1H), 2.38 (s, 3H), 1.98 - 1.79 (m, 2H), 1.70 - 1.62 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 14.2 Hz, 1H). 【0369】 Example 500 [Chemical formula] 【0370】 Step 1: A solution of (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (43 mg, 0.070 mmol) in DMSO (0.5 ml) was treated with copper(I) iodide (3 mg, 0.016 mmol), sodium L-prophosphate (6 mg, 0.044 mmol), and sodium methanesulfinate (13 mg, 0.127 mmol) under N2. The mixture was bubbling with N2 for 5 minutes. The reaction mixture was heated to 90°C and stirred overnight. The mixture was concentrated using a V10 evaporator. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% acetone / cyclohexane, (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-5-(methylsulfonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (16mg, 0.026 mmol, yield 37.3%) was obtained as a white solid. LC-MS, ES - :614.24 [MH] - . 【0371】 Step 2: A solution of (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-5-(methylsulfonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (15 mg, 0.024 mmol) in DCM (0.04 ml) was added dropwise with TEA (30 μl, 0.215 mmol) and TFAA (11 μl, 0.078 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, N-((S)-1-((3R,5'S)-5'-cyano-5-(methylsulfonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (12mg, 0.020 mmol, yield 82%) was obtained as a white solid. LC-MS, ES - :596.31 [MH] - ; 1 H NMR(500 MHz,Methanol-d4)δ 7.80(dd,J=8.3,1.8 Hz,1H),7.64(d,J=1.9 Hz,1H),7.10(d,J=8.2 Hz,1H),6.98-6.89(m,2H),6.65(td,J=10.2,2.0 Hz,1H),5.38(dd,J=8.9,6.3 Hz,1H),5.26(t,J=8.0 Hz,1H),4.36(d,J=10.9 Hz,1H),4.02(d,J=10.8 Hz,1H),3.44(s,3H),2.95(s,3H),2.74(d,J=8.1 Hz,1H),1.92(ddd,J=14.4,8.9,5.6 Hz,1H),1.82(ddd,J=14.2,8.1,6.2 Hz,1H),1.65(ddd,J=12.2,7.9,6.1 Hz,1H),1.34-1.22(m,2H),1.04(d,J=6.7 Hz,3H),0.99(d,J=6.6 Hz,3H),0.93-0.85(m,1H). 【0372】 Example 501 [ka] 【0373】 Step 1: A solution of (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (137 mg, 0.222 mmol) in DMF (0.5 ml) and MeOH (0.5 ml) was treated with TEA (100 μl, 0.717 mmol), xanthophos (20 mg, 0.035 mmol), and palladium(II) acetate (6.8 mg, 0.030 mmol) under carbon monoxide (6.22 mg, 0.222 mmol) (1 atm). The mixture was then bubbled with carbon monoxide (6.22 mg, 0.222 mmol) for 5 minutes. The reaction mixture was heated to 70°C and stirred overnight. The mixture was concentrated under vacuum. 4 g of the crude was added to a silica gel column and eluted with 0% to 100% acetone / cyclohexane to obtain methyl(3R,5'S)-5'-carbamoyl-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5-carboxylate (85 mg, 0.143 mmol, yield 64.2%) as an off-white solid. LC-MS, ES - :594.26 [MH] - . 【0374】 Step 2: A solution of methyl(3R,5'S)-5'-carbamoyl-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5-carboxylate (8 mg, 0.013 mmol) in DCM (0.3 ml) was added dropwise with TEA (20 μl, 0.143 mmol) and TFAA (7 μl, 0.050 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, methyl(3R,5'S)-5'-cyano-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5-carboxylate (7mg, 0.012 mmol, yield 90%) was obtained as a white solid. LC-MS, ES - :576.34 [MH] - ; 11H NMR (500 MHz, Chloroform-d) δ 9.61 (s, 1H), 8.03 (s, 1H), 7.80 (dd, J = 8.1, 1.7 Hz, 1H), 7.76 (d, J = 1.7 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.89 - 6.82 (m, 2H), 6.63 (td, J = 10.0, 2.0 Hz, 1H), 5.25 (dd, J = 8.4, 6.9 Hz, 1H), 5.10 (t, J = 8.4 Hz, 1H), 4.78 (d, J = 10.5 Hz, 1H), 3.99 (d, J = 10.5 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 3H), 2.90 (dd, J = 13.4, 8.5 Hz, 1H), 2.55 (ddd, J = 13.5, 8.4, 1.2 Hz, 1H), 1.93 (ddd, J = 14.3, 8.4, 6.1 Hz, 1H), 1.84 (dt, J = 14.2, 7.3 Hz, 1H), 1.64 (dt, J = 13.7, 6.8 Hz, 2H), 1.03 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.90 - 0.79 (m, 1H). 【0375】 Example 502 【Chem.】 【0376】 Step 1: A solution of (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (21 mg, 0.034 mmol) in 1,4-dioxane (0.4 ml) was treated with Pd(OAc)2 (3 mg, 0.013 mmol), xanthophos (8 mg, 0.014 mmol), Co2(CO)8 (8 mg, 0.023 mmol), DMAP (9 mg, 0.074 mmol), and morpholine (10 μl, 0.115 mmol) under N2. The mixture was bubbling under N2 for 3 minutes. The reaction mixture was heated to 90°C and stirred under microwave irradiation for 30 minutes. After the reaction, the mixture turned into a black suspension. The mixture was filtered through Celite and rinsed three times with acetone. The filtrate was concentrated under vacuum. The crude was added to a 4 g silica gel column and eluted with 0% to 100% acetone / cyclohexane to obtain (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-5-(morpholine-4-carbonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (15 mg, 0.023 mmol, yield 67.7%) as a pale yellow solid. LC-MS, ES - :649.43 [MH] - . 【0377】 Step 2: A solution of (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-5-(morpholine-4-carbonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (5 mg, 7.68 μmol) in THF (0.3 ml) was treated with Burgess's reagent (11 mg, 0.046 mmol). The reaction mixture was stirred at room temperature for 3 hours. When the mixture was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, N-((S)-1-((3R,5'S)-5'-cyano-5-(morpholine-4-carbonyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (4mg, 6.32μmol, yield 82%) was obtained as a white solid. LC-MS, ES - :631.26 [MH] - ; 1 H NMR(400 MHz,Chloroform-d)δ 11.35(s,1H),8.26(s,1H),7.25(d,J=1.7 Hz,1H),7.13(dd,J=8.0,1.6 Hz,1H),6.98(dd,J=9.8,2.3 Hz,1H),6.89-6.83(m,1H),6.71(d,J=8.0 Hz,1H),6.60(td,J=10.0,2.0 Hz,1H),5.05-4.88(m,2H),4.82(d,J=10.2 Hz,1H),3.98(d,J=10.1 Hz,2H),3.89-3.64(m,5H),3.58(s,3H),3.54-3.32(m,3H),2.89(dd,J=13.1,10.4 Hz,1H),2.55-2.41(m,1H),2.18(d,J=2.3 Hz,1H),1.92(dq,J=17.2,6.7 Hz,2H),1.71(p,J=6.7 Hz,2H),1.09(d,J=6.6 Hz,3H),1.03(d,J=6.5 Hz,3H),0.84(s,1H). 【0378】 Example 503 [ka] 【0379】 Step 1: A solution of (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (65 mg, 0.105 mmol) in ethanol (0.3 ml) and water (0.15 ml) was treated with sodium azide (18 mg, 0.277 mmol), copper(I) iodide (4.6 mg, 0.024 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (7 μl, 0.044 mmol) and sodium ascorbate (5.4 mg, 0.027 mmol) under N2. The mixture was bubbling under N2 for 5 minutes. The reaction mixture was heated to 100°C and stirred for 30 minutes under microwave irradiation. The mixture was concentrated in vacuum. 4 g of the crude product was added to a silica gel column and eluted with 0% to 100% acetone / cyclohexane to obtain (3R,5'S)-5-azide-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (33 mg, 0.057 mmol, yield 54.1%) as a yellow solid. LC-MS, ES - :577.36 [MH] - . 【0380】 Step 2: A solution of (3R,5'S)-5-azide-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (33 mg, 0.057 mmol) in DCM (0.5 ml) was added dropwise with TEA (50 μl, 0.359 mmol) and TFAA (25 μl, 0.177 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, N-((S)-1-((3R,5'S)-5-azido-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (14mg, 0.025 mmol, yield 43.8%) was obtained as a white solid. LC-MS, ES - :559.34 [MH] - ; 1 H NMR(400 MHz,Chloroform-d)δ 9.17(s,1H),8.27(s,1H),6.93(s,1H),6.83(dd,J=8.9,3.0 Hz,2H),6.71-6.55(m,2H),6.42(d,J=2.2 Hz,1H),5.39(dd,J=9.2,6.0 Hz,1H),5.03(t,J=8.4 Hz,1H),4.55(d,J=10.6 Hz,1H),3.95(d,J=10.6 Hz,1H),3.50(s,3H),2.88(dd,J=13.4,8.5 Hz,1H),2.53(dd,J=13.4,8.5 Hz,1H),2.18(d,J=2.5 Hz,1H),1.95(ddd,J=14.4,9.1,5.4 Hz,1H),1.79(ddd,J=14.2,8.4,6.0 Hz,1H),1.02(d,J=6.6 Hz,3H),0.96(d,J=6.5 Hz,3H),0.87(d,J=11.0 Hz,1H). 【0381】 Example 504 [ka] 【0382】 Step 1: A solution of (3R,5'S)-5-bromo-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (65 mg, 0.105 mmol) in ethanol (0.3 ml) and water (0.15 ml) was treated with sodium azide (18 mg, 0.277 mmol), copper(I) iodide (4.6 mg, 0.024 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (7 μl, 0.044 mmol) and sodium ascorbate (5.4 mg, 0.027 mmol) under N2. The mixture was bubbling under N2 for 5 minutes. The reaction mixture was heated to 100°C and stirred for 30 minutes under microwave irradiation. The mixture was concentrated in vacuum. 4 g of the crude mixture was added to a silica gel column and eluted with 0% to 100% acetone / cyclohexane to obtain (3R,5'S)-5-amino-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (19 mg, 0.034 mmol, yield 32.6%) as a yellow solid. LC-MS, ES - :551.27 [MH] - . 【0383】 Step 2: A solution of (3R,5'S)-5-amino-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (15 mg, 0.027 mmol) and 1-fluorocyclopropane-1-carboxylic acid (4.7 mg, 0.045 mmol) in DMF (0.1 ml) and DCM (0.3 ml) was treated with HATU (15 mg, 0.039 mmol) and N-methylmorpholine (20 μl, 0.182 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the crude product was added to a 4g silica gel column and eluted with 0% to 100% acetone / cyclohexane, (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-5-(1-fluorocyclopropane-1-carboxamide)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (15mg, 0.023 mmol, yield 87%) was obtained as a pale yellow solid. LC-MS, ES - :637.69 [MH] - . 【0384】 Step 3: A solution of (3R,5'S)-1'-(N-(4,6-difluoro-1H-indole-2-carbonyl)-N-methyl-L-leucyl)-5-(1-fluorocyclopropane-1-carboxamide)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (15 mg, 0.023 mmol) in DCM (0.3 ml) was treated with Burgess's reagent (17 mg, 0.071 mmol). The reaction mixture was stirred at room temperature for 3 hours. When the mixture was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane, N-((S)-1-((3R,5'S)-5'-cyano-5-(1-fluorocyclopropane-1-carboxamide)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (12mg, 0.019 mmol, yield 82%) was obtained as a white solid. LC-MS, ES - :619.25 [MH] - ; 1 H NMR(500 MHz,Chloroform-d)δ 9.43(s,1H),8.28(s,1H),8.20(d,J=5.1 Hz,1H),7.35(dd,J=8.4,2.1 Hz,1H),7.25(d,J=2.2 Hz,1H),6.92(d,J=2.3 Hz,1H),6.79(dd,J=24.3,8.5 Hz,2H),6.63(td,J=10.0,2.0 Hz,1H),5.20(dd,J=10.0,5.2 Hz,1H),5.04(t,J=8.6 Hz,1H),4.42(d,J=10.6 Hz,1H),3.98(d,J=10.5 Hz,1H),3.52(s,3H),2.88(dd,J=13.2,9.0 Hz,1H),2.61-2.49(m,1H),1.99(ddd,J=14.4,10.1,4.8 Hz,1H),1.81-1.56(m,4H),1.52-1.34(m,4H),1.03(d,J=6.4 Hz,3H),0.94(d,J=6.3 Hz,3H),0.78-0.90(m,1H). 【0385】 Example 505 [ka] Step 1: A solution of N-((S)-1-((3R,5'S)-5-azido-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (8 mg, 0.014 mmol) and ethinylcyclopropane (3 μl, 0.035 mmol) in tBuOH (0.2 ml) and water (0.2 ml) was treated with copper(II) sulfate pentahydrate (1.7 mg, 6.81 μmol) and sodium ascorbate (3.3 mg, 0.017 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was added to a 4g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane to obtain N-((S)-1-((3R,5'S)-5'-cyano-5-(4-cyclopropyl-1H-1,2,3-triazole-1-yl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6-difluoro-N-methyl-1H-indole-2-carboxamide (2.4 mg, 3.83 μmol, yield 26.8%) as a white solid. LC-MS, ES + :627.53 [M+H] + ; 1H NMR(500 MHz,Chloroform-d)δ 10.34(s,1H),7.86(s,1H),7.69(d,J=2.0 Hz,1H),7.54(s,1H),7.32(dt,J=9.2,2.6 Hz,2H),7.00(d,J=8.3 Hz,1H),6.83(d,J=2.2 Hz,1H),6.62(td,J=10.0,2.1 Hz,1H),5.00(ddd,J=20.4,8.9,7.3 Hz,2H),4.85(d,J=10.3 Hz,1H),4.04(d,J=10.3 Hz,1H),3.56(s,3H),2.94(dd,J=13.3,9.4 Hz,1H),2.57(dd,J=13.2,8.0 Hz,1H),2.18(d,J=2.9 Hz,2H),2.08-1.94(m,2H),1.80(dt,J=14.1,7.1 Hz,1H),1.70(dt,J=13.5,6.7 Hz,1H),1.26(s,2H),1.05(dd,J=7.6,4.5 Hz,4H),1.02-0.95(m,3H),0.95-0.87(m,3H),0.85(d,J=12.7 Hz,1H). 【0386】 Example 506 [ka] 【0387】 Step 1: To a solution of bromide (85 mg, 0.138 mmol) and pyridine-3-ylboronic acid (25 mg, 0.207 mmol) in THF (0.7 mL), XPhosPd G3 (12 mg, 0.014 mmol) and K3PO4 (0.55 mL, 0.5 M aqueous solution) were added. The reaction mixture was heated at 85°C for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-80% acetone in cyclohexane to obtain the desired product (25 mg, 30%). 【0388】 Step 2: To a 1 mL solution of the material from Step 1 (25 mg, 0.041 mmol) in DCM, TFAA (17 μL, 0.122 mmol) and Et3N (34 μL, 0.244 mmol) were added at 0°C. The crude product was directly loaded onto a silica gel column and subjected to chromatography using 0-80% acetone in cyclohexane to obtain EP-040278 (15 mg, 62%). 595.343 [MH].1H NMR(400 MHz,Acetone-d6)δ 11.07(s,1H),9.89(s,1H),9.02(d,J=2.5 Hz,1H),8.57(dd,J=4.8,1.6 Hz,1H),7.72(dt,J=8.1,1.9 Hz,1H),7.48(dd,J=8.1,1.9 Hz,1H),7.37(d,J=1.9 Hz,1H),7.26(dd,J=8.0,4.8 Hz,1H),7.21-7.15(m,1H),7.15-7.07(m,1H),6.86(dd,J=2.5,0.9 Hz,1H),6.77(td,J=10.3,2.1 Hz,1H),5.56(dd,J=10.7,4.6 Hz,1H),5.37(t,J=8.5 Hz,1H),4.53(d,J=10.8 Hz,1H),4.06(d,J=10.7 Hz,1H),3.39(s,3H),2.83(td,J=6.4,3.0 Hz,5H),2.75(dd,J=13.2,8.6 Hz,1H),2.12-1.92(m,5H),1.83-1.57(m,2H),1.00(dd,J=26.6,6.3 Hz,6H). 【0389】 Example 507 [ka] 【0390】 Step 1: To a solution of bromide (252 mg, 0.409 mmol) in dioxane (2 mL), ethynyltrimethylsilane (87 μL, 0.613 mmol), Pd(PPh3)Cl2 (28.7 mg, 0.041 mmol), CuI (15.6 mg, 0.082 mmol), and Et3N (171 μL, 1.23 mmol) were added. The reaction mixture was heated at 85°C for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-80% acetone in cyclohexane to obtain the desired product (165 mg, 64%). 【0391】 Step 2: K2CO3 (61 mg, 0.439 mmol) was added to a methanol (2 mL) solution of the material from Step 1 (139 mg, 0.219 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-80% acetone in cyclohexane to obtain the desired product (77 mg, 63%). 【0392】 Step 3: To a solution of DMF (2 mL) containing the material from Step 2 (77 mg, 0.137 mmol) and tetrazolo[1,5-a]pyridine (25 mg, 0.206 mmol), CuSO4 pentahydrate (9 mg, 0.036 mmol), sodium ascorbate (7 mg, 0.035 mmol), and water (1 mL) were added. The reaction mixture was heated at 80°C for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography using 0-80% acetone in cyclohexane to obtain the desired product (50 mg, 54%). 【0393】 Step 4: To a 1 mL solution of the material from Step 3 (50 mg, 0.041 mmol) in DCM, TFAA (31 μL, 0.220 mmol) and Et3N (62 μL, 0.440 mmol) were added at 0°C. The crude product was directly loaded onto a silica gel column and subjected to chromatography using 0-80% acetone in cyclohexane to obtain EP-040469. 662.405 [MH]1H NMR(400 MHz,Acetone-d6)δ 10.49(s,1H),9.87(s,1H),8.58-8.49(m,2H),8.18-8.08(m,2H),7.71(d,J=8.2 Hz,1H),7.67(d,J=1.7 Hz,1H),7.52(ddd,J=6.3,4.8,2.2 Hz,1H),7.05(d,J=8.0 Hz,1H),7.03-6.94(m,1H),6.70(dd,J=2.3,1.0 Hz,1H),6.44(td,J=10.3,2.1 Hz,1H),5.67-5.59(m,1H),5.40(t,J=8.4 Hz,1H),4.71(d,J=10.7 Hz,1H),4.00(d,J=10.8 Hz,1H),3.53(s,3H),3.25(s,1H),2.77(dd,J=13.3,8.1 Hz,1H),2.09-2.04(m,2H),1.98(ddd,J=14.3,9.4,5.2 Hz,1H),1.79(ddd,J=14.1,8.6,5.7 Hz,1H),1.62(dt,J=14.4,6.9 Hz,1H),1.44(d,J=0.9 Hz,2H),1.31(s,2H),0.98(dd,J=22.7,6.5 Hz,7H). 【0394】 The following examples were prepared using the same protocol as described above. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] 【0395】 Example 517 [ka] 【0396】 Process 1 1'-(tert-butyl)5'-methyl(3R,5'S)-5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-1',5'-dicarboxylate (897 mg, 2.11 mmol) was dissolved in MTBE (14 mL) and cooled to 0°C. Lithium borohydride (2.0 M in THF, 5.3 mL, 5 equivalents) was slowly added, and the resulting mixture was stirred at 0°C. 2.5 mL of further lithium borohydride solution was added again after 40 and 60 minutes. The reaction was then quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and diethyl ether, and the pooled organic fraction was washed with brine, dried over magnesium sulfate, filtered, and concentrated. When the crude residue was subjected to preparative HPLC, tert-butyl(3R,5'S)-5-bromo-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (202 mg, 0.508 mmol, yield 24%) was obtained. 【0397】 Process 2 60 mg, 0.151 mmol of tert-butyl(3R,5'S)-5-bromo-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate was dissolved in DCM / TFA (1 mL, 1:1 ratio) and stirred at room temperature. After 45 minutes, the mixture was concentrated directly. The residue was redissolved in MeOH and concentrated again. Then the residue was redissolved in ELISA and concentrated again. The resulting residue was used without further purification. 【0398】 Process 3 Crude (3R,5'S)-5-bromo-5'-(hydroxymethyl)spiro[indoline-3,3'-pyrrolidine]-2-one 2,2,2-trifluoroacetate (crude, assumed to be 0.161 mmol) was dissolved in DMF (0.644 mL, 0.25 M), and then iPr2NEt (87 mg, 0.676 mmol, 4.2 equivalents) and N-((benzyloxy)carbonyl)-N-methyl-L-leucine (54 mg, 0.193 mmol, 1.2 equivalents) were added. Once a homogeneous solution was obtained, HATU (73 mg, 0.193 mmol, 1.2 equivalents) was added. After 16 hours, the reaction mixture was diluted with water and subjected to solid-phase extraction in an Oasis HLB (200 mg) extraction cartridge that eluted with water and methanol to obtain benzyl((S)-1-((3R,5'S)-5-bromo-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (94 mg). 【0399】 Process 4 Benzyl((S)-1-((3R,5'S)-5-bromo-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl) carbamate (crude, assumed to be 0.173 mmol) was dissolved in CH2Cl2 (1.5 ml) and cooled to 0°C. Dess-Martin periodinane (110 mg, 0.259 mmol) was then added. The mixture was stirred at 0°C for 2 hours, and then TLC showed consumption of SM (1:1 hexane / ethyl acetate). The reaction mixture was then separated into DCM and saturated Na2S2O3, and the organic phase was washed with saturated NaHCO3 and brine, dried over magnesium sulfate, filtered, and concentrated. The crude residue was used without further purification. 【0400】 Process 5 Benzyl((S)-1-((3R,5'S)-5-bromo-5'-formyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (crude, assumed to be 0.173 mmol) was dissolved in CH2Cl2 (6 mL), and then iPr2NEt (67 mg, 0.519 mmol, 3 equivalents) and hydroxylamine hydrochloride (240 mg, 3.46 mmol) were added. After 4 days, ethyl acetate and water were added. The organic phase was washed with brine, then dried over magnesium sulfate, filtered, and concentrated. The crude residue was used without further purification. 【0401】 Process 6 Benzyl((S)-1-((3R,5'S)-5-bromo-5'-((hydroxyimino)methyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (assuming 0.161 mmol) was dissolved in MeCN (3.22 mL), and copper(II) acetate (9 mg, 0.05 mmol) was added. The mixture was heated at 70°C for 80 minutes. The mixture was then purified by preparative HPLC to obtain benzyl((S)-1-((3R,5'S)-5-bromo-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (1.1 mg, 0.002 mmol, 1% yield over 5 steps). 1H NMR(400 MHz,Methanol-d4)δ 7.40(dd,J=8.3,2.0 Hz,1H),7.35-7.15(m,4H),7.13-7.05(m,2H),6.89(dd,J=8.4,3.3 Hz,1H),5.18(t,J=8.2 Hz,1H),4.99(dd,J=9.1,6.1 Hz,1H),4.95-4.89(m,1H),4.76(d,J=12.3 Hz,1H),4.22(d,J=10.9 Hz,1H),3.87(d,J=10.8 Hz,1H),1.77(ddd,J=14.3,9.0,5.4 Hz,1H),1.65(ddd,J=13.9,8.2,5.9 Hz,1H),1.48(dt,J=13.9,6.8 Hz,1H),0.94(dd,J=15.3,6.5 Hz,6H).[M+Na] m / z 574.82. 【0402】 Example 518 [ka] 【0403】 Process 1 tert-butyl(3R,5'S)-5-bromo-5'-(hydroxymethyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (60 mg, 0.151 mmol), cesium carbonate (148 mg, 0.453 mmol), potassium trifluoro(methyl)borate (36.8 mg, 0.302 mmol), and Pd(dppf)Cl2 (27.6 mg, 0.038 mmol) were heated overnight at 80°C in a sealed vial purged with N2. The mixture was subjected to preparative HPLC to obtain tert-butyl(3R,5'S)-5'-(hydroxymethyl)-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (9 mg, 0.27 mmol, 18%). 【0404】 Process 2 60 mg, 0.151 mmol of tert-butyl(3R,5'S)-5'-(hydroxymethyl)-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate was dissolved in DCM / TFA (1 mL, 1:1 ratio) and stirred at room temperature. After 45 minutes, the mixture was concentrated directly. The residue was redissolved in MeOH and concentrated again. Then the residue was redissolved in ELISA and concentrated again. The resulting residue was used without further purification. 【0405】 Process 3 Crude (3R,5'S)-5'-(hydroxymethyl)-5-methylspiro[indoline-3,3'-pyrrolidine]-2-one (crude, assumed to be 0.045 mmol) was dissolved in DMF (0.563 mL, 0.08 M), and then iPr2NEt (38 mg, 0.293 mmol, 6.5 equivalents) and N-((benzyloxy)carbonyl)-N-methyl-L-leucine (38 mg, 0.135 mmol, 3 equivalents) were added. Once a homogeneous solution was obtained, HATU (51 mg, 0.135 mmol, 3 equivalents) was added. After 16 hours, the reaction mixture was diluted with water and subjected to solid-phase extraction in an Oasis HLB (200 mg) extraction cartridge eluted with water and methanol to obtain benzyl((S)-1-((3R,5'S)-5'-(hydroxymethyl)-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (42 mg). [M+H] m / z 494.387 【0406】 Process 4 Benzyl((S)-1-((3R,5'S)-5'-(hydroxymethyl)-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)carbamate (assuming 42 mg, 0.088 mmol) was dissolved in CH2Cl2 (1.5 ml) and cooled to 0°C. Dess-Martin periodinane (110 mg, 0.259 mmol) was then added. The mixture was stirred at 0°C for 2 hours, and then TLC showed consumption of SM (1:1 hexane / ethyl acetate). The reaction mixture was then separated into DCM and saturated Na2S2O3, and the organic phase was washed with saturated NaHCO3 and brine, dried over magnesium sulfate, filtered, and concentrated. The crude residue was used without further purification. 【0407】 Process 5 Benzyl((S)-1-((3R,5'S)-5'-formyl-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (crude, assumed to be 0.088 mmol) was dissolved in CH2Cl2 (4 mL), and then iPr2NEt (34 mg, 0.264 mmol) and hydroxylamine hydrochloride (153 mg, 2.20 mmol) were added. After 4 days, ethyl acetate and water were added. The organic phase was washed with brine, then dried over magnesium sulfate, filtered, and concentrated. The crude residue was used without further purification. 【0408】 Process 6 Benzyl((S)-1-((3R,5'S)-5'-((hydroxyimino)methyl)-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (crude, assumed to be 0.045 mmol) was dissolved in MeCN (3 mL), and copper(II) acetate (9 mg, 0.05 mmol) was added. The mixture was heated at 70°C for 80 minutes. The mixture was then subjected to preparative HPLC to obtain benzyl((S)-1-((3R,5'S)-5'-cyano-5-methyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)(methyl)carbamate (1.04 mg, 0.002 mmol, 5% yield over 5 steps). 1H NMR(400 MHz,Acetone-d6)δ 9.60(s,1H),7.43-7.17(m,5H),7.15-7.04(m,1H),6.92(d,J=7.8 Hz,1H),6.81(t,J=1.3 Hz,1H),5.22-5.14(m,1H),5.08(dd,J=9.6,5.6 Hz,1H),4.94(d,J=12.6 Hz,1H),4.67(d,J=12.6 Hz,1H),4.35-4.25(m,1H),3.91(dd,J=10.4,4.1 Hz,1H),2.94(s,3H),2.22(s,3H),1.81(ddd,J=14.3,9.6,5.0 Hz,1H),1.64(ddd,J=14.1,8.7,5.7 Hz,1H),1.52(p,J=6.4 Hz,1H),1.04-0.91(m,6H).[M+Na] m / z 511.119. 【0409】 Example 519 [ka] (S)-3-cyclopropyl-2-(4-fluoro-3-methylbenzo[b]thiophene-2-carboxamide)propanoic acid (33 mg, 0.103 mmol) and (3R,5'S)-5-chloro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (27 mg, 0.089 mmol) were dissolved in DMF (0.40 mL). Then, HATU (39 mg, 0.103 mmol) and iPr2NEt (0.041 mL, 0.232 mmol) were added sequentially, and the resulting solution was stirred at room temperature for 20 minutes. Additional HATU (approximately 10 mg) and iPr2NEt (2-3 drops) were added as needed (in this case, after 20 minutes). After 1 hour at room temperature, palladium(II) trifluoroacetate (30 mg, 0.089 mmol), dichloroacetonitrile (0.4 mL), and water (0.4 mL) were added in sequence. The resulting suspension was then heated at 65°C for 1 hour and then cooled to room temperature. The mixture was filtered and subjected to preparative HPLC to obtain N-((S)-1-((3R,5'S)-5-chloro-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-3-cyclopropyl-1-oxopropan-2-yl)-4-fluoro-3-methylbenzo[b]thiophene-2-carboxamide (1.20 mg, 0.0022 mmol, yield 2%).1H NMR(500 MHz,Acetone-d6)δ 9.82(s,1H),7.80-7.70(m,2H),7.48(td,J=8.0,4.8 Hz,1H),7.36-7.25(m,2H),7.16(ddd,J=12.2,8.0,0.8 Hz,1H),7.02(d,J=8.2 Hz,1H),5.29(t,J=8.2 Hz,1H),4.88(q,J=7.0 Hz,1H),4.50-4.44(m,1H),4.13(d,J=10.5 Hz,1H),2.86(ddd,J=13.3,8.5,1.1 Hz,1H),2.80(s,3H),2.73(dd,J=13.3,7.9 Hz,1H),1.85(t,J=7.0 Hz,2H),0.95(dddd,J=15.1,10.2,5.2,2.4 Hz,1H),0.58-0.52(m,2H),0.30(dddd,J=9.4,4.7,2.7,1.4 Hz,1H),0.24(dddd,J=9.0,6.3,2.8,1.2 Hz,1H).[M+H]. + 550.741 【0410】 The following examples were prepared using the same protocol as described above. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] 【0411】 Example 527 [ka] iPr2NEt (35.0 μl, 0.200 mmol) was added to a stirred mixture of 2,5-dioxopyrrolidine-1-yl(((S)-2,2,2-trifluoro-1-phenylethoxy)carbonyl)-L-leucinate (66.3 mg, 0.154 mmol), (3R,5'S)-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (44 mg, 0.154 mmol), and MeCN (0.380 ml). The resulting mixture was stirred at room temperature for 3 hours and then heated to 50°C for 16 hours. After this time, 15 μL of iPr2NEt and 20 μL of 2,5-dioxopyrrolidine-1-yl(((S)-2,2,2-trifluoro-1-phenylethoxy)carbonyl)-L-leucinate were added, and the mixture was further heated to 65°C. After 24 hours, palladium(II) trifluoroacetate (51 mg, 0.154 mmol), dichloroacetonitrile (0.38 mL), and water (0.38 mL) were added, and stirring was continued at 65°C. After 25 minutes, the mixture was cooled to room temperature, filtered, and subjected to preparative HPLC to obtain (S)-2,2,2-trifluoro-1-phenylethyl((S)-1-((3R,5'S)-5'-cyano-5-fluoro-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)carbamate (0.96 mg, 0.0017 mmol, yield 1%).1H NMR(500 MHz,Acetone-d6)δ 9.70(s,1H),7.52(dt,J=6.6,3.8 Hz,2H),7.46(dp,J=4.6,1.7 Hz,3H),7.32(d,J=8.0 Hz,1H),7.07(ddd,J=9.4,8.6,2.6 Hz,1H),7.03-6.95(m,2H),6.09(q,J=7.1 Hz,1H),5.24(t,J=8.2 Hz,1H),4.43(ddd,J=9.7,7.9,4.6 Hz,1H),4.31-4.18(m,1H),4.00(d,J=10.4 Hz,1H),2.82(ddd,J=13.3,8.5,1.0 Hz,2H),2.70(dd,J=13.3,7.9 Hz,1H),1.83-1.59(m,3H),0.95(d,J=6.6 Hz,3H),0.88(d,J=6.5 Hz,3H).[M+H]. + 547.20. 【0412】 Example 528 [ka] 【0413】 Process 1 A 37% aqueous formaldehyde solution (0.312 ml, 4.19 mmol, 1.12 equivalents) was added at room temperature to a solution of (S)-2-amino-3-(4-chloro-1H-indole-3-yl)propanoic acid (892 mg, 3.74 mmol) and 0.5N NaOH (1.1 equivalents of NaOH, 8.22 mL). The resulting mixture was stirred at room temperature for 2 hours, then at 104°C for 24 hours. During this time, additional formaldehyde solution was added to the reaction mixture as needed (in this case, 0.3 mL after 3 hours). The reaction mixture was then cooled to room temperature, and acetic acid (0.449 ml, 7.85 mmol, 2.1 equivalents) was added. The mixture was then filtered and rinsed sequentially with water and THF to obtain crude A-1, which was used without further purification. 【0414】 Process 2 A-1 (assuming 100% yield) was added to a solution of 0.44 M SOCl2 in MeOH (15 mL, 0.25 M relative to the substrate). The resulting mixture was stirred at 40°C for 5 days. After the SM was consumed by LC-MS, the mixture was directly concentrated to obtain crude B-1, which was used without further purification. [M+H] m / z 265.051 【0415】 Process 3 Compound B-1 (assuming 100% yield) was suspended in DCM (14 mL), followed by the addition of Hünig base (1.25 mL, 7.2 mmol), and then a solution of di-tert-butyl dicarbonate (1.2 g, 5.5 mmol) in DCM (2.5 mL). Once TLC (10:1 DCM / MeOH) showed consumption of SM, the reaction mixture was directly concentrated. The residue was subjected to silica gel chromatography eluted with 0-35% siRNA in hexane to obtain C-1 (404 mg, 1.16 mmol, 31% yield over three steps). 【0416】 Process 4 At 0°C, NBS (177 mg, 0.997 mmol, 0.9 equivalents) was added to a vigorously stirred mixture of C-1 (404 mg, 1.107 mmol) in 2-MeTHF / water / acetic acid (ratio 63:28:9, total volume 7.7 mL, 0.114 M). The reaction mixture was stirred at 0°C for 90 minutes, then slowly warmed to room temperature. When TLC showed consumption of SM, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and then extracted with Et2O. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel chromatography eluted with 0-50% siRNA in hexane to obtain D-1 (251 mg, 0.66 mmol, yield 60%). 【0417】 Process 5 D-1 (251 mg, 0.659 mmol) was dissolved in THF (3.30 ml, 0.2 M) and cooled to 0°C. Lithium borohydride (2.0 M in THF, 1.98 mL, 6 equivalents) was then added. Once TLC (hexane / siRNA 1:1) showed complete conversion of SM, the reaction mixture was poured into an ice-cold saturated ammonium chloride aqueous solution. The mixture was extracted with siRNA and diethyl ether, and the pooled organic fraction was then washed with brine, dried over magnesium sulfate, filtered, and concentrated to obtain crude E-1 (228 mg), which was used without further purification. 【0418】 Process 6 Crude E-1 (50 mg, 0.142 mmol) was dissolved in DCM / TFA (4 mL, 1:1 ratio) and stirred at room temperature. After 45 minutes, the mixture was concentrated directly. The residue was redissolved in MeOH and concentrated again. Then, the residue was redissolved in ELISA and concentrated again to obtain F-1, which was used without further purification. 【0419】 Process 7 Compound F-1 was dissolved in DMF (0.947 mL) and iPr2NEt (92 mg, 0.71 mmol), and then (4-fluoro-1H-indole-2-carbonyl)-L-leucine (50 mg, 0.17 mmol) was added. Once the mixture was homogenized, HATU (65 mg, 0.17 mmol) was added. The mixture was stirred at room temperature for 2.5 days, and then diluted with water and DCM. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, then dried over magnesium sulfate, filtered, and concentrated to obtain crude G-1 (assuming 100% yield). [M+H] m / z 526.913 【0420】 Process 8 Crude G-1 was dissolved in CH2Cl2 (1.42 mL) and cooled to 0°C. Dess-Martin periodinane (110 mg) was added, and the mixture was stirred at 0°C. After 1 hour, a further Dess-Martin periodinane (80 mg) was added. After 2 hours, a further Dess-Martin periodinane (200 mg) was added. The reaction mixture was then quenched with saturated Na2S2O3 aqueous solution, and the mixture was extracted with DCM. The organic phase was washed with saturated NaHCO3 aqueous solution and brine, then dried over magnesium sulfate, filtered, and concentrated. The crude residue obtained above was dissolved in DCM (10 mL), and iPr2NEt (92 mg, 0.71 mmol) was added. Next, hydroxylamine hydrochloride (247 mg, 3.55 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added, the phase was separated, and the organic phase was dried on magnesium sulfate and concentrated. The crude residue obtained above was dissolved in MeCN (3 mL), and copper(II) acetate (9 mg, 0.05 mmol) was added. The mixture was heated at 70°C for 1 hour. The mixture was then cooled to room temperature and subjected to preparative HPLC to obtain Example 528 (0.70 mg). 1 H NMR(500 MHz,Acetone-d6)δ 7.42-7.36(m,1H),7.26-7.19(m,1H),6.96(m,1H),6.81(m,1H),5.35(m,1H),5.05(m,1H),4.76(mf,1H),4.69(d,J=11.0 Hz,1H),4.13(d,J=11.0 Hz,1H),3.12(dd,J=14.1,9.7 Hz,1H),2.69(dd,J=14.1,4.5 Hz,1H),1.83(m,2H),1.78-1.68(m,1H),1.06-0.93(m,6H).[M+H] m / z 521.835. 【0421】 The following examples were prepared using the same protocol as described above. [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] 【0422】 Example 535 [ka] 【0423】 Process 1 (3R,5'S)-1'-((S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride (198 mg, 0.48 mmol) was suspended in DCM (4.80 mL), and Et3N (334 μL, 2.40 mmol, 5 equivalents) was added. The mixture was cooled to 0°C, and then acryloyl chloride was added dropwise (42.9 μL, 0.528 mmol). After 45 minutes at 0°C, MeOH (1 mL) was added, and the mixture was concentrated directly. The residue was co-evaporated with RINKAN and used immediately without further purification. 【0424】 Process 2 The crude residue obtained from step 1 (assuming a 100% yield) was suspended in DCM (3.43 mL), and Burgess reagent (0.343 g, 1.440 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated directly. The residue was subjected to silica gel chromatography eluted with 0-80% ELISA in cyclohexane to obtain N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)-N-methylacrylamide (181 mg, 0.439 mmol, 91% yield over two steps). 1H NMR(400 MHz,Acetone-d6)δ 9.67(s,1H),7.22(td,J=7.6,1.5 Hz,1H),7.03-6.91(m,3H),6.48(dd,J=16.7,10.4 Hz,1H),5.85(dd,J=16.7,2.4 Hz,1H),5.70(dd,J=7.5,5.7 Hz,1H),5.49(dd,J=10.4,2.4 Hz,1H),5.16(t,J=8.3 Hz,1H),4.27(dd,J=10.7,1.2 Hz,1H),3.89(d,J=10.7 Hz,1H),2.77-2.58(m,2H),2.36-2.23(m,1H),2.23-2.08(m,1H),1.41-1.35(m,6H).[M+Na] m / z 435.33. 【0425】 The following examples were prepared using the same protocol as described above. [Table 26-1] [Table 26-2] 【0426】 Example 539 [ka] Triethylamine (47 μL, 7 equivalents) was added to a solution of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)-N-methylacrylamide (20 mg, 0.048 mmol) and dimethylamine hydrochloride (59 mg, 0.727 mmol) in MeOH (0.485 mL). When LC-MS showed product formation, the reaction mixture was subjected to preparative HPLC to obtain N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-fluoro-4-methyl-1-oxopentan-2-yl)-3-(dimethylamino)-N-methylpropanamide (1.95 mg, 0.0043 mmol, yield 9%). 1H NMR(400 MHz,Acetone-d6)δ 7.32(td,J=7.7,1.2 Hz,1H),7.12(td,J=7.5,1.1 Hz,1H),7.04(d,J=7.7 Hz,1H),6.97(dt,J=7.4,1.0 Hz,1H),5.68(dd,J=7.2,6.0 Hz,1H),5.19(t,J=8.4 Hz,1H),4.28(dd,J=10.8,1.3 Hz,1H),3.86(d,J=10.7 Hz,1H),3.01(s,3H),2.79-2.62(m,3H),2.62-2.44(m,2H),2.44-2.24(m,4H),2.16-2.10(m,1H),1.37(m,6H).[M+H] m / z 458.488. 【0427】 The following examples were prepared using the same protocol as described above. [Table 27-1] [Table 27-2] [Table 27-3] 【0428】 Example 548 [ka] 【0429】 Process 1 Boc DAP OH (2 g, 9.79 mmol) was suspended in a mixture of THF (70.0 ml) and iPr2EtN (3.42 ml, 19.59 mmol), and then cooled to 0°C. 4-chlorobutanoyl chloride (1.096 ml, 9.79 mmol) was then added dropwise (10:25 am). After stirring at room temperature for 40 minutes, the reaction mixture was cooled to 0°C. KOtBu (4.40 g, 39.2 mmol) was then added gradually over 2 minutes, starting at 11:15 am. After 10 minutes, the reaction mixture was titrated to pH 1 with 1 N HCl and then extracted with ELISA. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was subjected to silica chromatography eluted with 30-100% ethyl acetate in cyclohexane to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(2-oxopyrrolidine-1-yl)propanoic acid (1.42 g, 2.87 mmol, yield 29%). 1H NMR(400 MHz,DMSO-d6)δ 12.73(s,1H),7.09(d,J=8.5 Hz,1H),4.15(td,J=8.5,5.4 Hz,1H),3.59(dd,J=13.7,5.4 Hz,1H),3.40-3.28(m,4H),2.24-2.11(m,2H),1.91-1.80(m,2H),1.37(s,9H).[M+Na] m / z 295.326. 【0430】 Process 2 (S)-2-((tert-butoxycarbonyl)amino)-3-(2-oxopyrrolidine-1-yl)propanoic acid (389 mg, 1.43 mmol) was added at room temperature to a stirred solution of 4N HCl in dioxane (4.3 mL, 12 equivalents of HCl). After 30 minutes at room temperature, the resulting white suspension was directly concentrated to obtain (S)-2-amino-3-(2-oxopyrrolidine-1-yl)propano hydrochloride (408 mg, crude). The crude white solid was used without further purification. 1H NMR(400 MHz,Deuterium Oxide)δ 4.17(dd,J=6.4,4.2 Hz,1H),3.89(dd,J=15.1,4.2 Hz,1H),3.79(d,J=6.4 Hz,1H),3.54(td,J=7.3,1.6 Hz,2H),2.45(dd,J=9.1,7.6 Hz,2H),2.08(qd,J=8.2,6.9 Hz,2H). 【0431】 Process 3 (S)-2-amino-3-(2-oxopyrrolidine-1-yl)propanoate (20 mg, crude) was dissolved in a mixture of THF (0.48 mL) and water (0.48 mL), and then solid NaHCO3 (40 mg, 0.48 mmol) was added. The mixture was cooled to 0°C, and then CbzCl (15 μL, 0.105 mmol) was added. The mixture was stirred at room temperature for 3 days, and then separated between RINKAN and 1 N HCl. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated to obtain crude (S)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxopyrrolidine-1-yl)propanoic acid, which was used without further purification (assuming 100% yield). [M+H] m / z 307.322 【0432】 Process 4 HATU (35 mg, 0.092 mmol) and iPr2NEt (74 μL, 0.424 mmol) were sequentially added at -10°C to a stirred mixture of compound 1-4 (29.5 mg, 0.11 mmol) and (S)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxopyrrolidine-1-yl)propanoic acid (crude, assumed to be 0.085 mmol) in DMF (0.42 mL). The mixture was then warmed to room temperature. The reaction was separated into  and HCl and water, and the organic phase was sequentially washed with saturated NaHCO3 aqueous solution and brine, then dried over magnesium sulfate, filtered, and concentrated. The crude residue (assuming 100% yield) was used without further purification. [M+H] m / z 520.468 【0433】 Process 5 At room temperature, a stirred mixture of benzyl((S)-1-((3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(2-oxopyrrolidine-1-yl)propan-2-yl)carbamate (assumed to be 0.085 mmol) was mixed with Burgess reagent (122 mg, 0.51 mmol). After 45 minutes, MeOH was added, and the mixture was subjected to preparative HPLC purification to obtain benzyl((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-1-oxo-3-(2-oxopyrrolidine-1-yl)propan-2-yl)carbamate (1.28 mg). 1H NMR(400 MHz,Acetone-d6)δ 9.69(s,1H),7.37-7.29(m,5H),7.26(td,J=7.7,1.2 Hz,1H),7.18(d,J=7.4 Hz,1H),7.00(t,J=7.8 Hz,2H),6.82(d,J=8.1 Hz,1H),5.16(dd,J=8.7,7.0 Hz,1H),5.03(d,J=12.6 Hz,1H),4.95(d,J=12.6 Hz,1H),4.77(td,J=7.9,4.9 Hz,1H),4.16(q,J=10.6 Hz,2H),3.68(dd,J=14.1,7.8 Hz,1H),3.60-3.40(m,4H),2.78(dd,J=13.4,8.8 Hz,1H),2.66(dd,J=13.3,7.1 Hz,1H),2.20(td,J=8.2,2.1 Hz,2H),2.09-2.00(m,4H),2.00-1.87(m,2H).[M+H] m / z 502.481. 【0434】 Example 549 [ka] 【0435】 Process 1 (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid (3 g, 14.62 mmol) and a magnetic stirring bar were placed in a 500 mL round-bottom flask. Methanol (50 mL) was added to produce a white suspension. The flask was blown out with N2, sealed with a rubber septum, and cooled to 0°C. While stirring the flask in an ice bath, thionyl chloride (3.20 ml, 43.9 mmol) was slowly added to positive N2 pressure. The resulting pale yellow solution was stirred for 10 minutes while warming to near room temperature, and then heated under reflux for 2 hours. The reaction solution was evaporated to obtain a white solid, which was removed without further purification. 【0436】 Process 2 To a 500 mL round-bottom flask containing crude 7-aza-tryptophan methyl ester, a magnetic stirring bar was used, followed by the addition of pyridine (37 mL). A white gas was generated, and mild exothermic reaction was observed. The mixture was then sonicated to obtain a pale golden solution. Next, formaldehyde (1.197 mL, 16.08 mmol, 1.10 equivalents, 37% w / w aqueous solution containing 10% methanol) was added. The reaction vessel was equipped with a condenser, heated under reflux, and stirred for 1 hour. At this point, the reaction was determined to be complete by LC-MS. The reaction vessel was placed in an ice bath for 20 minutes to obtain a thick off-white slurry. This slurry was then filtered through a frit funnel, and the filtration cake was washed with pre-cooled pyridine (2 × 20 mL), followed by DCM (10 mL). The solid was then dried overnight under a nitrogen stream to obtain beta-carbolin 549-1 as a white solid, which was accepted without further purification. 【0437】 Process 3 In a 250 mL round-bottom flask containing crude beta-carbolin 549-1 (3.38 g, 14.62 mmol) and a magnetic stirring bar, water (7.5 mL) and THF (30 mL) were added to obtain a turbid solution. The reaction vessel was then cooled to 0°C, and triethylamine (6.11 ml, 43.9 mmol), followed by di-tert-butyl dicarbonate (8.49 ml, 36.6 mmol), was added. The reaction vessel was blown out with nitrogen and placed under positive nitrogen pressure. After stirring for 2 days, the reaction mixture was separated into toluene and water, and the layers were separated. The aqueous phase was then extracted with toluene (3 × 20 mL), and the combined organic phase was dried over Na₂SO₄, filtered, and concentrated to obtain a yellowish residue. Purification by flash chromatography of silica gel eluted with ethyl acetate in cyclohexane yielded 549-2 as a colorless residue (1.61 g, 33% across three steps). 1 H NMR(400 MHz,DMSO-d6), mixture of rotamers:δ 11.40(app.d,J=24.6 Hz,1H),8.13(dd,J=4.8,1.5 Hz,1H),7.85(dd,J=7.8,1.6 Hz,1H),7.02(dd,J=7.8,4.7 Hz,1H),5.31-5.13(m,1H),4.75(t,J=16.9 Hz,1H),4.49-4.27(m,1H),3.57(d,J=8.0 Hz,3H),3.27(m,1H),3.00(dd,J=15.5,7.1 Hz,1H),1.46(app.d,J=17.6 Hz,9H). 【0438】 Process 4 Compound 549-2 (1.60 g, 4.83 mmol) was added to THF (22.80 ml) and dissolved, and the mixture was placed in a 1000 mL round-bottom flask containing a magnetic stirring bar. Water (2.85 ml) was added, and the resulting colorless magnetically stirred solution was then cooled to 0°C. N-bromosuccinimide (0.859 g, 4.83 mmol) was added gradually over several minutes to obtain a yellow solution. The flask was then capped with a rubber septum, and glacial acetic acid (1.935 ml, 33.8 mmol) was added. The color of the reaction mixture became significantly darker to a deep orange-yellow, and stirring was continued for 30 minutes. Potassium carbonate (3.34 g, 24.14 mmol) and water were then added, and the reaction mixture was allowed to come to room temperature. The layers were separated, and the aqueous phase was extracted with phenylethylamine. The combined organic matter was dried over Na₂SO₄, decanted, and concentrated under reduced pressure to obtain a yellowish-brown gum or foam. Purification by flash chromatography of silica gel eluted with ethyl acetate in cyclohexane yielded a pure product 549-3 (220 mg) as a single diastereomer, as well as an impure product (1.44 g, approximately 3:1 dr desirable / undesirable) as a mixture of diastereomers. 【0439】 Process 5 100 mL of rbf containing 549-3 (220 mg, 0.633 mmol) and a magnetic stirring bar was mixed with methanolic ammonia (4.52 mL of 7 M solution, 31.7 mmol). The flask was sealed with a plastic septum punctured with a needle, and the yellow reaction solution was heated to 55°C and stirred for 6 days. The reaction mixture was then evaporated, revealing a yellowish-brown solid, 549-4. 【0440】 Process 6 Crude amide 549-4 was suspended in a HCl dioxane solution (3 mL of 4.0 M solution, 12 mmol). The suspension was vigorously stirred overnight at room temperature and then evaporated, revealing amine hydrochloride 549-5 as an off-white solid (95 mg, 49% across three steps). 1H NMR(400 MHz,deuterium oxide)δ 8.19(dd,J=5.7,1.4 Hz,1H),8.01(ddd,J=7.5,1.5,0.6 Hz,1H),7.30(dd,J=7.7,5.9 Hz,1H),4.94(t,J=8.5 Hz,1H),3.94(t,J=13.2 Hz,1H),3.81(d,J=12.9 Hz,1H),2.92(dd,J=14.1,9.1 Hz,1H),2.73(dd,J=14.1,7.9 Hz,1H). 【0441】 Process 7 Compound 549-5 (181 mg, 0.593 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-leucine (198 mg, 0.807 mmol), and a magnetic stirring bar were combined in a 40 mL glass reaction vial. DCM (3 ml) and DMF (0.750 ml) were added to obtain a white suspension. The mixture was cooled to 0°C, and N-methylmorpholine (0.261 ml, 2.373 mmol), followed by HATU (226 mg, 0.593 mmol), was added. The container was blown out with nitrogen, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then evaporated on Celite, and the crude mixture was purified by flash chromatography of silica gel (4 g) eluted with DCM / MeOH to obtain an intermediate purity product, which was subsequently purified by reverse-phase HPLC, revealing product 549-6 as a colorless solid. 【0442】 Process 8 The 549-6 obtained above was placed in a glass scintillation chamber containing a magnetic stirring bar and treated with HCl in dioxane (2 mL of 4.0 M solution, 8.00 mmol). The resulting heterogeneous suspension was stirred for 11 hours. Then, volatile substances were removed under reduced pressure to obtain the white solid 549-7. 【0443】 Process 9 Compound 549-7 obtained above was dissolved in DCM (0.8 ml) and DMF (0.200 ml) to obtain a white suspension. N-methylmorpholine (0.0717 ml, 0.652 mmol) was added. The mixture immediately clarified, and a colorless solution was obtained. HATU (62.0 mg, 0.163 mmol) was added under a stream of nitrogen, followed by 4,6-difluoro-1H-indole-2-carboxylic acid (32.1 mg, 0.163 mmol). The vial was blown out again with nitrogen, capped, and the reaction mixture was stirred for 3 hours, at which point the reaction was quenched by segregation between a 1 / 4 saturated NaHCO3 aqueous solution and toluene. The layers were separated, and the aqueous phase was extracted with toluene (3 × 10 mL). The combined organic matter was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to reveal an off-white residue 549-8. 【0444】 Step 10 To a 40 mL glass reaction vial containing crude amide product 549-8 and a magnetic stirring bar, DCM (1.25 ml) was added. The vial was blown out with nitrogen and cooled to 0°C, and triethylamine (0.1555 ml, 1.116 mmol) was added. Then, trifluoroacetic anhydride (0.0787 ml, 0.557 mmol) was added dropwise to obtain a yellowish reaction mixture, which was heated to room temperature and stirred for 1.25 hours, at which point LC-MS showed consumption of the starting materials. The reaction mixture was quenched with saturated NaHCO3 aqueous solution. The layers were then separated, the organic matter was dried over brine, and then concentrated under reduced pressure to reveal a yellow gum. The crude product was purified by reverse-phase HPLC to obtain a colorless film, which was freeze-dried to obtain Example 549 as a free-flowing white powder (34 mg, 11% yield over four steps). 1H NMR(400 MHz,Acetone-d6)δ 10.87(s,1H),10.26(s,1H),7.93(s,1H),7.36(d,J=7.3 Hz,1H),7.12-7.00(m,2H),6.81-6.67(m,2H),5.55(dd,J=9.7,5.4 Hz,1H),5.21(t,J=8.3 Hz,1H),4.43(d,J=10.8 Hz,1H),4.03(d,J=10.8 Hz,1H),3.47(s,3H),2.83(ddd,J=13.4,8.6,1.2 Hz,1H),2.72(dd,J=13.4,8.0 Hz,1H),1.96(ddd,J=14.4,9.7,4.9 Hz,1H),1.76(ddd,J=14.2,8.8,5.4 Hz,1H),1.62(dtd,J=8.9,6.6,4.9 Hz,1H),1.00(d,J=6.7 Hz,3H),0.94(d,J=6.5 Hz,3H).LCMS [M+H] + 521.0. 【0445】 The following examples were prepared using the same protocol as described above. [Table 28-1] [Table 28-2] 【0446】 biological activity SARS-CoV-2 3C-like (3CL) protease fluorescence assay (FRET): Recombinant SARS-CoV-2 3CL protease was expressed and purified. The TAMRA-SITSAVLQSGFRKMK-Dabcyl-OH peptide 3CLpro substrate was synthesized. A black, small-volume, round-bottom, 384-well microplate was used. In a typical assay, 0.85 μL of the test compound was dissolved in DMSO and then incubated with SARS-CoV-2 3CL-protease (10 nM) in 10 μL of assay buffer (50 mM HEPES [pH 7.5], 1 mM DTT, 0.01% BSA, 0.01% Triton-X 100) at room temperature for 30 minutes. Next, 10 μL of 3CL protease substrate (40 μM) was added to the assay buffer, and the assay was monitored continuously for 1 hour using an Envision multimode plate reader operating in fluorescence dynamics mode, excited at 540 nm and emitted at 580 nm at room temperature. Conventionally, a compound-free (DMSO only) and enzyme-free control was included in each plate. All experiments were repeated. 【0447】 Data Analysis: SARS-CoV-2 3CL-protease enzyme activity was measured as the initial rate of linear phase (RFU / s), normalized against the control sample DMSO (100% activity) and no enzyme (0% activity), and the residual activity percentage at various concentrations of the test compound (0-10 μM) was determined. The data were fitted to a normalized activity (variable slope) versus concentration fit in GraphPad Prism 7 to determine IC. 50 We decided to repeat all experiments and achieve IC. 50 The ranges are reported as follows: A < 0.1 μM; B 0.1 ~ 1 μM; C > 1 μM. Table 1. Overview of Activity [Table 29-1] [Table 29-2] [Table 29-3] [Table 29-4] [Table 29-5] [Table 29-6] [Table 29-7] 【0448】 229E Assay Protocol Virus stock preparation: MRC-5 cells (a diploid cell culture line composed of fibroblasts, originally developed from lung tissue of a 14-week-old Caucasian male fetus that was miscarried) were used to culture 229E human coronavirus (hCoV). hCoV-229E was inoculated into flasks, and the virus stock was collected when the cytopathic effect (CPE) exceeded 70%. The virus stock in growth medium (EMEM, Penn / Strep 1%, non-essential amino acids 1%, heat-inactivated FBS 10%) with 5% glycerol was rapidly frozen using liquid nitrogen and stored at -80°C. The virus stock titer was recorded using the TCID as described elsewhere. 50 (50% median tissue culture infectious dose) was quantified by assay. 【0449】 229E Live Virus Assay: A 384-well black cell culture-treated clear-bottom plastic plate is used for this assay. Using an ECHO liquid dispenser, 3-fold serial dilutions of the control and test compounds suspended in DMSO are added to the plate wells in double rows at a total volume of 125 nL per well. MRC-5 cells less than 17 passages are seeded at a rate of 1,500 cells per well in 12.5 μL of growth medium in the inner 240 wells of the 384-well plate. The virus stock is then added to the wells at a volume of 12.5 μL per well with a MOI of 0.05, bringing the total volume of each well to approximately 25 μL. Each plate has a 20-well control column containing cells to which DMSO and virus are added but the compound is not (positive control, maximum CPE, minimum ATPlite signal), a column containing cells to which DMSO is added but the compound or virus is not added (negative control, minimum CPE, maximum ATPlite signal), and a column containing no cells, virus or compound (background plate / reagent control). Control wells containing cells but no virus are given an additional 12.5 μL of growth medium containing the same amount of glycerol as the well receiving the virus stock, in order to maintain constant medium and volume conditions. The outer two rows / tiers of wells are filled with 30 μL of moat media (DMEM, 1% Penn / Strep) to act as a heat and evaporation barrier around the test wells. After adding all components, gently tap the sides of the plate with your hand to promote uniform cell distribution throughout the wells. Once cell distribution is confirmed, incubate the plate in a CO2 humidity-controlled incubator at 34°C for 6 days. After the 6-day incubation period, read the plate using ATPlite (add 12.5 μL per well) to quantify the amount of ATP (measure of cell health) present in each well. Read the assay plate using an Envision luminometer. Use these data to calculate the cell health percentage per well relative to the negative control well and the EC of each compound. 50 This is calculated using ExcelFit software and 4-parameter logistic curve fitting analysis. 【0450】 All experiments were repeated, EC 50 The ranges are reported as follows: A < 0.1 μM; B 0.1 ~ 1 μM; C > 1 μM. Table 2. Overview of Activity [Table 30-1] [Table 30-2] [Table 30-3] [Table 30-4] [Table 30-5] [Table 30-6] [Table 30-7] 【0451】 Although the present invention has been specifically shown and described with reference to its preferred embodiments, it will be understood by those skilled in the art that various modifications in form and detail can be made without departing from the scope of the invention as encompassed by the appended claims. Although this may overlap with other descriptions, the various aspects of the present invention are shown below. However, the present invention is not limited to the following. [1] It is expressed by equation (Ia): [C1] TIFF0007875859000323.tif33166 During the ceremony, A is 1)-R11 ; 2)-OR 12 and 3)-NR 13 R 14 Selected from B is an optionally substituted aryl or optionally substituted heteroaryl, X is 1)-CN; 2)-C(O)R 15 ; 3)-CH(OH)SO 3 R 16 4)-C(O)NR 13 R 14 and 5)-C(O)C(O)NR 13 R 14 Selected from, R 1 、R 2 and R 3 Each of them operates independently. 1) Hydrogen; 2) Even if it is substituted -C 1 -C 8 alkyl; 3) Even if not substituted -C 2 -C 8 Alkenil; 4) -C may be substituted. 2 -C 8 Alkinnil; 5) -C may be substituted. 3 -C 8 Cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Aryls that may be substituted; 8) Arylalkyls which may be substituted; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl which may be substituted Select from, Alternatively, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form a substituted or substituted 3- to 8-membered carboncyclic ring or a substituted or substituted 3- to 8-membered heterocyclic ring. R 3 -C may be hydrogen or substituted. 1 -C 6 It is alkyl, R 4 -C may be hydrogen, or substituted. 1 -C 4 Alkyl, may be substituted-C 2 -C 4 Alkenyl, or possibly substituted -C 3 -C 6 It is a cycloalkyl, R 11 and R 12 Each of them operates independently. 1) Even if it is substituted -C 1 -C 8 alkyl; 2) Even if it is substituted -C 2 -C 8 Alkenil; 3) Even if not substituted -C 2 -C 8 Alkinnil; 4) -C may be substituted. 3 -C 8 Cycloalkyl; 5) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 6) Aryls that may be substituted; 7) Arylalkyls which may be substituted; 8) heteroaryls which may be substituted; and 9) Optionally substituted heteroarylalkyl groups Selected from, R 13 and R 14 Each of them operates independently. 1) Hydrogen 2) Even if it is substituted -C 1 -C 8 alkyl; 3) Even if not substituted -C 2 -C 8 Alkenil; 4) -C may be substituted. 2 -C 8 Alkinnil; 5) -C may be substituted. 3 -C 8 Cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Aryls that may be substituted; 8) Arylalkyls which may be substituted; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl which may be substituted Select from, Alternatively, R 13 and R 14 These, together with the nitrogen atoms to which they are bonded, form a substituted, possibly substituted, 3- to 8-membered heterocyclic ring. R 15 is hydrogen, hydroxyl, or may be substituted with -C 1 -C 8 It is alkyl, R 16 is hydrogen or Na + That is, A compound or a pharmaceutically acceptable salt thereof. [2] The compound described in [1], wherein A may be derived from and substituted from one of the following: [Case 2] TIFF0007875859000324.tif127166 [3] X is -CN, -C(O)R 5 Or -C(O)C(O)NR 3 R 4 And R 3 、R 4 and R 5 The compound according to [1], wherein the compound is as defined in claim 1. [4] It is expressed by one of the equations (Ia-2), [C3] TIFF0007875859000325.tif30166 In the formula, A, B, R 1 、R 3 、R 4 , and X is as defined in claim 1, the compound or a pharmaceutically acceptable salt thereof according to [1]. [5] It can be expressed by one of equations (IIa): [C4] TIFF0007875859000326.tif35166 In the formula, n is 0, 1, 2, 3, or 4, and each R 9 However, independently, halogen;-CN;-OR11 ;-SR 11 ;-NR 13 R 14 ;-OC(O)NR 13 R 14 ; may be replaced -C 1 -C 6 Alkyl; may be substituted -C 3 -C 8 Selected from cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl, A, R 1 、R 2 、R 3 、R 4 、R 11 、R 13 、R 14 , and X is as defined in claim 1, the compound or a pharmaceutically acceptable salt thereof according to [1]. [6] It can be expressed by one of the equations (VIII-1a) to (VIII-5a): [5] TIFF0007875859000327.tif71166 In the formula, R 9 However, independently, halogen;-CN;-OR 11 ;-SR 11 ;-NR 13 R 14 ;-OC(O)NR 13 R 14 ; may be replaced -C 1 -C 6 Alkyl; may be substituted -C 3 -C 8 Selected from cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl, R 11 、R 13 、R 14 , A, R 1 , and R 3 However, the compounds described in [1] or their pharmaceutically acceptable salts, as defined in [1]. [7] It is expressed by one of the equations (XIII-1) to (XIII-6): [6] TIFF0007875859000328.tif79166 In the formula, n is 0, 1, 2, 3, or 4, m is 0, 1, 2, 3, 4, or 5, v is 0, 1, or 2, R 9 However, independently, halogen;-CN;-OR 11 ;-SR 11 ;-NR 13 R 14 ;-OC(O)NR 13 R 14 ; may be replaced -C 1 -C 6 Alkyl; may be substituted -C 3 -C 8 Selected from cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl, R 10 However, it may be substituted -C 1 -C 4 Alkyl or possibly substituted-C 3 -C 6 It is cycloalkyl, R 4 、R 11 、R 13 , and R 14 However, the compounds described in [1] or their pharmaceutically acceptable salts, as defined in [1]. [8] In certain embodiments, the compound of formula (Ia) is represented by one of formulas (XVIII-1) or (XVIII-2): [7] TIFF0007875859000329.tif39166 In the formula, n is 0, 1, 2, 3, or 4, and R 9 However, independently, halogen;-CN;-OR 11 ;-SR 11 ;-NR 13 R 14 ;-OC(O)NR 13 R 14 ; may be replaced -C 1 -C 6 Alkyl; may be substituted -C 3 -C 8 Selected from cycloalkyls; optionally substituted 3- to 8-membered heterocycloalkyls; optionally substituted aryls; and optionally substituted heteroaryls, where one U is N or NR 13 And another U is N, NR 13 , or CR 13 And another U is N, NR 13 , or CR 13 And the fourth U is O, S, N, NR 13 , or CR 13 And each V independently, CR 13 or N, R 1 、R 3 、R 4 、R 9、R 13 、R 14 And X is as defined in [1]. [9] It is expressed by equation (XI-3), [8] TIFF0007875859000330.tif37166 During the ceremony, Each n is 0, 1, 2, 3, or 4. v is 0, R 3 is hydrogen, methyl or CD 3 And, R 1 C 1 -C 8 - Alkyl or arylalkyl, R 4 That is hydrogen, Each R 9 is halogen or C 1 -C 8 - The compound described in [1] is an alkoxy.

[10] formula [9] TIFF0007875859000331.tif33166 It is expressed as, in the formula, X is CN, R 3 is hydrogen, methyl or CD 3 And, R 1 C 1 -C 8 -alkyl, arylalkyl or C 3 -C 6 -Cyclopropyl-C 1 -C 4 -It is alkyl, R 4 That is hydrogen, R 9 C 1 -C 6 -alkyl, or halogen, C 1 -C 6 -Alkyl and C 1 -C 6 -The compound described in [1], which is a phenyl compound that may be substituted with 1 to 3 substituents independently selected from a haloalkyl group.

[11] A compound described in [1] or a pharmaceutically acceptable salt thereof, selected from the compounds listed below: [Table 1-1] TIFF0007875859000332.tif234166 [Table 1-2] TIFF0007875859000333.tif210166 [Table 1-3] TIFF0007875859000334.tif205166 [Table 1-4] TIFF0007875859000335.tif218166 [Table 1-5] TIFF0007875859000336.tif222166 [Table 1-6] TIFF0007875859000337.tif231166 [Table 1-7] TIFF0007875859000338.tif229166 [Table 1-8] TIFF0007875859000339.tif209166 [Table 1-9] TIFF0007875859000340.tif228166 [Table 1-10] TIFF0007875859000341.tif213166 [Table 1-11] TIFF0007875859000342.tif208166 [Table 1-12] TIFF0007875859000343.tif216166 [Table 1-13] TIFF0007875859000344.tif211166 [Table 1-14] TIFF0007875859000345.tif231166 [Table 1-15] TIFF0007875859000346.tif232166 [Table 1-16] TIFF0007875859000347.tif232166 [Table 1-17] TIFF0007875859000348.tif235166 [Table 1-18] TIFF0007875859000349.tif231166 [Table 1-19] TIFF0007875859000350.tif230166 [Table 1-20] TIFF0007875859000351.tif231166 [Table 1-21] TIFF0007875859000352.tif234166 [Table 1-22] TIFF0007875859000353.tif232166 [Table 1-23] TIFF0007875859000354.tif231166 [Table 1-24] TIFF0007875859000355.tif204166 [Table 1-25] TIFF0007875859000356.tif217166 [Table 1-26] TIFF0007875859000357.tif231166 [Table 1-27] TIFF0007875859000358.tif208166 [Table 1-28] TIFF0007875859000359.tif231166 [Table 1-29] TIFF0007875859000360.tif208166 [Table 1-30] TIFF0007875859000361.tif208166 [Table 1-31] TIFF0007875859000362.tif214166 [Table 1-32] TIFF0007875859000363.tif203166 [Table 1-33] TIFF0007875859000364.tif219166 [Table 1-34] TIFF0007875859000365.tif225166 [Table 1-35] TIFF0007875859000366.tif231166 [Table 1-36] TIFF0007875859000367.tif226166 [Table 1-37] TIFF0007875859000368.tif192166 [Table 1-38] TIFF0007875859000369.tif56166

[12] A pharmaceutical composition comprising a compound described in any of [1] to

[11] and a pharmaceutically acceptable carrier or excipient.

[13] A method for treating or preventing a viral infection, including viral infection from RNA-based viruses, coronaviruses, rhinoviruses, and noroviruses, in a subject susceptible to or suffering from such viral infection, comprising administering a 3C protease enzyme inhibitor to the subject, wherein the inhibitor is a compound or pharmaceutically acceptable salt described in any of [1] to

[11] .

[14] A method for treating or preventing coronavirus infection in a subject requiring treatment or prevention of coronavirus infection, comprising administering to the subject a therapeutically effective amount of any compound or combination of compounds described in [1] to

[11] , or a pharmaceutically acceptable salt thereof.

[15] The method described in

[13] , wherein the virus is a coronavirus selected from 229E, NL63, OC43, HKU1, SARS-CoV, or MERS coronaviruses.

[16] A method for treating or preventing a viral infection in a subject who is susceptible to or has a viral infection, comprising administering a 3C protease enzyme inhibitor to the subject, wherein the inhibitor comprises a compound described in any of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[17] A method for inhibiting viral 3C protease or viral 3CL protease in a mammal, comprising administering an effective amount of any of the compounds described in [1] to

[11] or a pharmaceutically acceptable salt thereof to the subject.

[18] The method according to

[17] , wherein the subject is a human.

[19] A method for treating a respiratory disease in a subject requiring treatment, including acute asthma, lung disease secondary to environmental exposure, acute lung infection, and chronic lung infection, comprising administering a compound described in any of [1] to

[11] to the subject.

[20] The method according to

[19] , wherein the compound or pharmaceutical composition is administered orally, subcutaneously, intravenously, or by inhalation.

Claims

[Claim 1] It is expressed by equation (Ia): 【Chemistry 1】 During the ceremony, A is, 1)-R １１ ; 2) -OR １２ ; and 3)-NR １３ R １４ Selected from B is an optionally substituted aryl or optionally substituted heteroaryl, X is, 1) -CN; 2)-C(O)R １５ ; 3)-CH(OH)SO ３ R １６ 4) -C(O)NR １３ R １４ ; and 5)-C(O)C(O)NR １３ R １４ Selected from, R1 and R2 are independent of each other. 1) Hydrogen; 2) Substitutions may occur - C １ -C ８ Alkyl; 3) Substitution may occur - C ２ -C ８ Alkenil; 4) Substitution may occur - C ２ -C ８ Alkinyl; 5) Substitution may occur - C ３ -C ８ Cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Arials that may be substituted; 8) Optionally substituted arylalkyls; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl group which may be substituted. Select from, Alternatively, R １ and R ２ These, together with the carbon atoms to which they are bonded, form a substituted or substituted 3- to 8-membered carboncyclic ring or a substituted or substituted 3- to 8-membered heterocyclic ring. R ３ C may be hydrogen or substituted. １ -C ６ It is alkyl, R ４ C is hydrogen, which may be substituted. １ -C ４ Alkyl, may be substituted -C ２ -C ４ Alkenyl, or possibly substituted-C ３ -C ６ It is a cycloalkyl, R １１ and R １２ Each of them operates independently. 1) Substitution may occur - C １ -C ８ Alkyl; 2) Substitutions may occur - C ２ -C ８ Alkenil; 3) Substitution may occur - C ２ -C ８ Alkinyl; 4) Substitution may occur - C ３ -C ８ Cycloalkyl; 5) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 6) Aryls that may be substituted; 7) Arylalkyls which may be substituted; 8) Optionally substituted heteroaryls; and 9) A heteroarylalkyl group which may be substituted. Selected from, R １３ and R １４ Each of them operates independently. 1) Hydrogen 2) Substitutions may occur - C １ -C ８ Alkyl; 3) Substitution may occur - C ２ -C ８ Alkenil; 4) Substitution may occur - C ２ -C ８ Alkinyl; 5) Substitution may occur - C ３ -C ８ Cycloalkyl; 6) 3- to 8-membered heterocycloalkyl groups, which may be substituted; 7) Arials that may be substituted; 8) Optionally substituted arylalkyls; 9) Optionally substituted heteroaryls; and 10) A heteroarylalkyl group which may be substituted. Select from, Alternatively, R １３ and R １４ These, together with the nitrogen atoms to which they are bonded, form a substituted, or possibly substituted, 3- to 8-membered heterocyclic ring. R １５ is hydrogen, hydroxyl, or possibly substituted -C １ -C ８ It is alkyl, R １６ is hydrogen or Na ＋ That is, A compound or a pharmaceutically acceptable salt thereof. [Claim 2] The compound according to claim 1, wherein A may be selected from the following group and substituted accordingly. 【Chemistry 2】 [Claim 3] The compound according to claim 1, wherein X is -CN, -C(O)R 15 or -C(O)C(O)NR 13 R 14, and R 13, R 14 and R 15 are as defined in claim 1. [Claim 4] It is expressed by equation (Ia-2), 【Transformation 3】 In the formula, A, B, R １ , R ３ , R ４ , and a pharmaceutically acceptable salt thereof of the compound or, and the compound or the compound, and the [Claim 5] It is expressed by equation (IIa): 【Chemistry 4】 In the formula, n is 0, 1, 2, 3, or 4, and each R ９ However, independently, halogen; -CN; -OR １１ ;-SR １１ ;-NR １３ R １４ ;-OC(O)NR １３ R １４ ; May be substituted - C １ -C ６ Alkyl; may be substituted -C ３ -C ８ Selected from cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl, A, R １ , R ２ , R ３ , R ４ , R １１ , R １３ , R １４ , and a pharmaceutically acceptable salt thereof of the compound or, and the compound or the compound, and the [Claim 6] It is expressed by one of the equations (VIII-1a) to (VIII-5a): 【Transformation 5】 wherein R ９ is independently halogen; -CN; -OR １１ ; -SR １１ ; -NR １３ R １４ ; -OC(O)NR １３ R １４ ; optionally substituted -C １ -C ６ alkyl; optionally substituted -C ３ -C ８ cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl, and R １１ , R １３ , R １４ , A, R １ , and R ３ are as defined in claim 1, a compound according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 7] It is expressed by one of the equations (XIII-1) to (XIII-6): 【Transformation 6】 where n is 0, 1, 2, 3, or 4, m is 0, 1, 2, 3, 4 or 5, v is 0, 1 or 2, and R ９ is, independently, halogen; -CN; -OR １１ ; -SR １１ ; -NR １３ R １４ ; -OC(O)NR １３ R １４ ; optionally substituted -C １ -C ６ alkyl; optionally substituted -C ３ -C ８ cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl, and R １０ is optionally substituted -C １ -C ４ alkyl or optionally substituted -C ３ -C ６ cycloalkyl, and R ４ , R １１ , R １３ , and R １４ are as defined in claim 1, a compound according to claim 1 or a pharmaceutically acceptable salt thereof. [Claim 8] It is expressed by either equation (XVIII-1) or equation (XVIII-2): 【Transformation 7】 In the formula, n is 0, 1, 2, 3, or 4, and R ９ However, independently, halogen; -CN; -OR １１ ;-SR １１ ;-NR １３ R １４ ;-OC(O)NR １３ R １４ ; May be substituted - C １ -C ６ Alkyl; may be substituted -C ３ -C ８ Selected from cycloalkyls; optionally substituted 3- to 8-membered heterocycloalkyls; optionally substituted aryls; and optionally substituted heteroaryls, where one U is N or NR １３ And another U is N, NR １３ , or CR １３ And another U is N, NR １３ , or CR １３ And the fourth U is O, S, N, NR １３ , or CR １３ And each V independently, CR １３ or N, R １ , R ３ , R ４ , R ９ , R １３ , R １４ The compound according to claim 1, wherein X is as defined in claim 1. [Claim 9] It is expressed by equation (XI-3), 【Transformation 8】 During the ceremony, Each n is 0, 1, 2, 3, or 4. v is 0, R ３ is hydrogen, methyl or CD ３ And, R １ C １ -C ８ - Alkyl or arylalkyl, R ４ That is hydrogen, Each R ９ is halogen or C １ -C ８ - The compound according to claim 1, wherein it is an alkoxy. [Claim 10] formula 【Chemistry 9】 It is expressed as, in the formula, X is CN, R ３ is hydrogen, methyl or CD ３ And, R １ C １ -C ８ - Alkyl, arylalkyl or C ３ -C ６ -Cyclopropyl-C １ -C ４ -It is alkyl, R ４ That is hydrogen, R ９ C １ -C ６ - Alkyl or halogen, C １ -C ６ - Alkyl and C １ -C ６ - The compound according to claim 1, which is a phenyl that may be substituted with one to three substituents independently selected from a haloalkyl group. [Claim 11] A compound according to claim 1, selected from the compounds listed below, or a pharmaceutically acceptable salt thereof: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 [Claim 12] The compound is 【Chemistry 10】 The compound according to claim 11. [Claim 13] The compound is 【Chemistry 11】 The compound according to claim 11. [Claim 14] The compound is 【Chemistry 12】 The compound according to claim 11. [Claim 15] The compound is 【Chemistry 13】 The compound according to claim 11. [Claim 16] The compound is 【Chemistry 14】 The compound according to claim 11. [Claim 17] The compound is 【Chemistry 15】 The compound according to claim 11. [Claim 18] A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier or excipient. [Claim 19] The pharmaceutical composition according to claim 18 for use in the treatment or prevention of coronavirus infection. [Claim 20] The pharmaceutical composition according to claim 19, wherein the coronavirus is SARS-CoV-2.

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