Novel compounds and their uses

Abstract

This disclosure relates to novel compounds that modulate levels or activity of the Nrf2 protein, and their tautomers, stereoisomers, or pharmaceutically acceptable salts. This disclosure also relates to pharmaceutical compositions comprising one or more of the said compounds and their tautomers, stereoisomers, or pharmaceutically acceptable salts as active ingredients, and to the use of the said compounds and their tautomers, stereoisomers, or pharmaceutically acceptable salts in the treatment of Nrf2-related diseases, disorders, or symptoms, including eye diseases or kidney diseases.

Description

[Technical Field]

[0001] This disclosure provides novel compounds that modulate the level or activity of nuclear factor erythrocyte 2-related factor (Nrf2) protein, and tautomers, stereoisomers, or pharmaceutically acceptable salts thereof. This disclosure also relates to pharmaceutical compositions comprising one or more of the compounds and their tautomers, stereoisomers, or pharmaceutically acceptable salts as active ingredients, and to the use of the compounds and their tautomers, stereoisomers, or pharmaceutically acceptable salts in the treatment of Nrf2-related diseases, disorders, or symptoms, including eye diseases or kidney diseases. [Background technology]

[0002] Nuclear factor erythrocyte 2-related factor (also known as "Nrf2" or "NF-E2-related factor 2") is a member of the cap-n-collar ("CNC") family of transcription factors containing a characteristic basic leucine zipper motif. Under normal conditions, Nrf2 levels are tightly regulated by Kelch-like ECH-related protein 1 (also known as "Keap1"), a cytosolic actin-binding repressor that binds to Nrf2 and targets it for ubiquitination and proteasomal degradation by a Cul3-based E3 ubiquitin ligase complex. Under oxidative stress conditions, modification of reactive cysteine ​​on Keap1 results in conformational changes that alter Nrf2 binding and promote Nrf2 stabilization. Thus, under normal conditions, cytosolic Nrf2 levels are low, but the system is designed to respond immediately to oxidative stress by enhancing Nrf2 activity.

[0003] Oxidative stress is a condition in which the balance between oxidation and antioxidant activity is disrupted, leading to excessive oxidation reactions that negatively impact organisms and cause various diseases. When cells experience oxidative stress, Nrf2 dissociates from Keap1, translocates from the cytoplasm to the nucleus, and binds to transcriptional binding sites called AREs (antioxidant response elements). By binding to AREs located within the promoter regions of specific genes, Nrf2 controls the transcription of approximately 250 genes that together form a multifaceted network integrating cellular activities, including detoxification reactions, maintenance of both redox and protein homeostasis, and energy metabolism (Hayes, JD et al., Trends Biochem. Sci. 2014, 39(4): 199-218). Activation of Nrf2 also leads to the suppression of NF-κB pro-inflammatory signaling. In recent years, therapies based on the activation of Nrf2, which counteracts both oxidative stress and inflammation, have been proposed to be beneficial for chronic diseases (Cuadrado, A. et al., Pharmacol. Rev. 2018, 70, 348-383, Cuadrado, A. et al., Nat. Rev. Drug Discov. 2019, 18(4): 295-317, Lu, MC et al., Med. Res. Rev. 2016, 36(5): 924-963, Zhuang, C. et al., MedChemComm. 2017, 8(2): 286-294). Given its crucial role in regulating cellular defense under stress and hormesis, Nrf2 has been proposed to have great potential as a drug target for the prevention or treatment of a wide range of pathological and chronic conditions associated with increased oxidative stress and inflammation, decreased redox potential, detoxification disorders, and metabolic dysregulation (Calabrese, V. et al., Nat. Rev. Neurosci. 2007, 8(10): 766-775, Trovato Salinaro, A. et al., Immun. Ageing 2018, 15: 8, Calabrese, V. et al., Antioxid. Redox Signaling 2010, 13(11): 1763-1811).

[0004] Additional drugs for treating Nrf2-related diseases, disorders or symptoms including eye diseases or kidney diseases are still being sought. SUMMARY OF THE INVENTION

[0005] In one aspect, the present disclosure provides a compound represented by the following formula (I) [Chemical formula] (wherein,[ W is N or C, L 1 is [Chemical formula] selected from the group consisting of, wherein,[ ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, each optionally substituted independently by one or more R a1 .[ ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, each optionally substituted independently by one or more R a2 .[ [Chemical formula] is a bond by which ring A is fused to ring B, ring E is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, each optionally substituted independently by one or more R a3 .[ L 2 is -C(O)-, -CR 7 R 8 -, -S(O)- and -S(O)2- selected from the group consisting of, L 3 is a bond or is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, each optionally substituted independently by one or more R a4 where W is C and L 1 is [ka] And L 2 If is -C(O)-, then L 3 It is not an aryl or heteroaryl compound, L 4 The group is selected from alkyl, alkylalkoxyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and the alkyl, alkenyl, and alkynyl may be alone or as part of another group, one or more R a5 It is independently and arbitrarily substituted, L 5 is a bond, or alkyl, alkenyl, alkynyl, -alkyl-N(R b Selected from the group consisting of )-, heteroalkyl, heteroalkenyl and heteroalkynyl, and the alkyl, alkenyl, alkynyl and -alkyl-N(R b )- is one or more R, either alone or as part of another base. a6 It is independently and arbitrarily substituted, R 1 , R 2 , R 4 , R 7 and R 8 Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, wherein the alkyl, alkenyl, and alkynyl are individually or as part of another group, one or more R a7 It is independently and arbitrarily substituted, R 3 Hydrogen, halogen, hydroxyl, sulfhydryl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkylalkoxyl, -OR c , and -N(R d ) Selected from the group consisting of 2, the alkyl, alkenyl and alkynyl are one or more R, either alone or as part of another group.a8 It is independently and arbitrarily substituted, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. R b , R c and R d Each of the groups is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and the alkyl, alkenyl, and alkynyl groups are independently and optionally substituted, either alone or as part of another group, with one or more groups independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, and -NO2, or two R groups. b These, together with the nitrogen atom they bond to, form a heterocycline, or two R d These, together with the nitrogen atom that binds to them, form heterocyclines. n is 0, 1, 2 or 3, and (q is 0, 1, 2, or 3) Alternatively, the present invention provides tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.

[0006] In another embodiment, the present disclosure relates to a compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (Ia) or formula (Ib): [ka] [ka] In the formula, R 1 , R 2, R 3 , R 4 , L 1 , L 2 , L 3 and L 4 The present invention provides a compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt, where n and q are as defined above.

[0007] In another embodiment, the present disclosure relates to compounds, their tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein the compounds are represented by the following formulas (II), (III), or (IV): [ka] [ka] [ka] During the ceremony, R 5 and R 6 Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, wherein the alkyl, alkenyl, and alkynyl are individually or as part of another group, one or more R a7 It is independently and arbitrarily substituted, m is 0, 1, 2, or 3. t is 0, 1, 2 or 3, and W,R 1 , R 2 , R 3 , R 4 , L 2 , L 3 , L 4 , L 5 , ring A, ring B, ring E, R a7 The present invention provides a compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt, where n and q are as defined above.

[0008] In another embodiment, the present disclosure relates to compounds, tautomers thereof, stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds are represented by the following formulas (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb): [ka] [ka] [ka] [ka] [ka] [ka] In the formula, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , L 3 , L 4 , L 5 The present invention provides a compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt, wherein each of rings A, B, E, n, m, q, and t is as defined above.

[0009] In another embodiment, the present disclosure relates to a compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (IIa1) or formula (IIa2): [ka] [ka] During the ceremony, L 4 C 3-8 Alkyl or C 3-8It is heteroalkyl, R 1 is hydrogen, halogen or C 1-6 It is alkyl, R 2 is hydrogen, halogen or C 1-6 It is alkyl, R 3 is -OR c And R c is hydrogen or C 1-6 It is alkyl, R 4 is hydrogen, halogen or C 1-6 It is alkyl, R 5 is hydrogen, halogen or C 1-6 It is alkyl, n is either 0 or 1. m is 0 or 1, and The present invention provides a compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt, where q is 1.

[0010] In another embodiment, the present disclosure provides the compounds shown in Tables 1.1 and 1.2, their tautomers, stereoisomers, or pharmaceutically acceptable salts.

[0011] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound described herein, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or pharmaceutically acceptable excipient.

[0012] In another embodiment, the present disclosure provides a method for improving intracellular Nrf2 levels or activity, comprising administering to the cells a compound described herein, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0013] In another embodiment, the Disclosure provides a method for improving the level or activity of Nrf2 in a subject of interest, comprising administering to the subject a therapeutically effective amount of a compound described herein, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0014] In another embodiment, the Disclosure provides a method for preventing, treating or alleviating an Nrf2-related disease, disorder, or symptom of a subject of interest, comprising administering to the subject a therapeutically effective amount of a compound described herein, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. [Modes for carrying out the invention]

[0015] The following examples refer in detail to specific embodiments of the Disclosure as shown in the attached structures and formulas. While the Disclosure is described in relation to the listed embodiments, it should be understood that they are not intended to limit the Disclosure to those embodiments. On the contrary, the Disclosure seeks to cover all variations, modifications, and equivalents that may be included within the scope of the Disclosure as defined in the claims. Those skilled in the art will recognize a number of methods and materials similar or equivalent to those described herein that may be used in the practice of the Disclosure. The Disclosure is not limited to the methods and materials described herein. If one or more of the incorporated references and similar materials, not limited to defined terms, usage of terms, or the techniques described herein, differ from or conflict with this application, the Disclosure shall prevail. All references, patents, and patent applications cited herein are incorporated herein by reference as a whole.

[0016] For clarity, certain features of the Disclosure described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, various features of the Disclosure described in the context of a single embodiment for brevity may be provided separately or in any preferred subcombination. definition

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. As used herein, the following terms are intended to have the following meanings:

[0018] As used in the specification and the attached claims, singular forms such as "a, an" and "the" include plural forms unless otherwise clearly indicated by the context. Therefore, for example, a reference to "a compound" includes both a single compound and multiple different compounds.

[0019] As used herein, the terms “approximately” or “about” are intended to indicate that the cited value should not be taken as absolute, and that measurement errors, batch-to-batch variability and / or inter-device variability should also be taken into account. In certain embodiments, the terms “approximately” or “about” refer to a range of values ​​within the range of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the cited value, unless otherwise specified or made clear from the context (except when the numerical value in question exceeds 100% of a possible value).

[0020] As used herein and in the following claims, the terms “comprise,” “comprising,” and “include,” “including,” “includes” are intended to identify the presence of a specified feature, integer, component, or step, but do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0021] The "compounds" of the present disclosure can exist in solvated and non-solvated forms, such as hydrated forms, solid forms, etc., and it is understood that the present disclosure is intended to encompass all such solvated and non-solvated forms. Further, it is understood that the "compounds" of the present disclosure can exist in the form of pharmaceutically acceptable salts. In some embodiments, the "compounds" of the present disclosure are ionizable lipids. In some embodiments, the "compounds" of the present disclosure can exist as cationic lipids at physiological pH.

[0022] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of the present disclosure, chemical elements are specified according to the CAS version of the Periodic Table of the Elements, inside the front and back covers of the 75th Edition of the Handbook of Chemistry and Physics, and specific functional groups are defined generally as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, 2 nd Edition, University Science Books, Sausalito, 2006, Smith and March March’s Advanced Organic Chemistry, 6 th Edition, John Wiley & Sons, Inc., New York, 2007, Larock, Comprehensive Organic Transformations, 3 rd Edition, VCH Publishers, Inc., New York, 2018, Carruthers, Some Modern Methods of Organic Synthesis, 4 th Edition, Cambridge University Press, Cambridge, 2004.

[0023] Linking substituents are described at various places in the present disclosure. When the structure clearly requires a linking group, the Markush variables listed for that group are understood to be the linking group. For example, when the structure requires a linking group and "alkyl" is listed in the definition of the Markush group of that variable, "alkyl" is understood to represent a linking alkylene group.

[0024] When the attachment to a substituent is shown to cross a bond connecting two atoms within a ring, such a substituent can be attached to any atom within that ring. When a substituent is listed without indicating through which atom it is attached to the remainder of a compound of a given formula, such a substituent can be attached to any atom in that formula. Combinations of substituents and / or variables can be tolerated as long as stable compounds are formed.

[0025] If any constituent of a compound or any variable (e.g., R i ) appears more than once, its definition is independent for each appearance. Thus, for example, if a group is shown to be substituted with from 0 to 2 R i moieties, the group can optionally be substituted with up to 2 R i moieties, and each R i is independently selected from the definition of R i . Also, combinations of substituents and / or variables can be tolerated as long as stable compounds are formed.

[0026] As used herein, the term "C i-j " indicates a range of the number of carbon atoms, where i and j are integers, the range of the number of carbon atoms includes the endpoints (i.e., i and j), and each integer point therebetween, and where j is greater than i. For example, C 1-6 indicates a range of from 1 to 6 carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C 1-12 " indicates from 1 to 12, particularly from 1 to 10, particularly from 1 to 8, particularly from 1 to 6, particularly from 1 to 5, particularly from 1 to 4, particularly from 1 to 3, or particularly from 1 to 2 carbon atoms.

[0027] As used herein, the term “alkyl” means a linear or branched hydrocarbon radical, whether used as part of another term or independently, which may optionally be independently substituted with one or more substituents as described below. i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0028] Alkyl groups may be further substituted with substituents that independently replace one or more hydrogen atoms on one or more carbon atoms of the alkyl group. Examples of such substituents include acyl, alkyl, alkenyl, alkynyl, oxo, halogen, hydroxyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino(alkylamino, dial The following may, but are not limited to, substituted alkenyl groups, arylamino groups, diarylamino groups and alkylarylamino groups, acylamino groups (including alkylcarbonylamino groups, arylcarbonylamino groups, carbamoyl groups and ureido groups), amidino groups, imino groups, sulfhydryl groups, alkylthio groups, arylthio groups, thiocarboxylates, sulfates, alkylsulfinyl groups, sulfonates, sulfamoyl groups, sulfonamides, nitro groups, trifluoromethyl groups, cyano groups, nitro groups, azides, heterocyclyl groups, alkylaryl groups, or aromatic or heteroaromatic moieties. The alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups described below may also be substituted in the same manner.

[0029] As used herein, the term “alkenyl,” whether used as part of another term or independently, means a linear or branched hydrocarbon radical having at least one carbon-carbon double bond, which may optionally be independently substituted with one or more substituents as described herein, and includes radicals having “cis” and “trans” orientations, or “E” and “Z” orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. In some embodiments, the alkenyl group contains one or more “Z” carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, etylene (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, and 5-hexenyl. In some embodiments, the alkenyl group has at least one carbon-carbon double bond. In some embodiments, the alkenyl group has at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten carbon-carbon double bonds. In some embodiments, two or more carbon-carbon double bonds in the alkenyl group are conjugated. In some embodiments, two or more carbon-carbon double bonds in the alkenyl group are not conjugated. In some embodiments, two or more carbon-carbon double bonds in the alkenyl group are isolated, aggregated, or conjugated.

[0030] As used herein, the term “alkynyl,” whether used as part of another term or independently, refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may optionally be independently substituted with one or more substituents as described herein. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, and 2-propynyl. In some embodiments, the alkynyl group has at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten carbon-carbon triple bonds. In some embodiments, two or more carbon-carbon triple bonds in the alkynyl group are conjugated. In some embodiments, two or more carbon-carbon triple bonds in the alkynyl group are not conjugated.

[0031] As used herein, the term “alkoxyl” refers to an alkyl group bonded to a parent molecule via an oxygen atom, as previously defined, whether used as part of another term or independently. i-j"Alkoxyl" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 11 carbon atoms. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. 1~6 Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentoxy, and n-hexoxy.

[0032] As used herein, the term “alkylalkoxyl” refers to an alkyl moiety substituted with one or more alkoxyl moieties, whether used as part of another term or independently. “Alkylalkoxyl” can be bonded to the parent molecule structure via an alkyl group or an alkoxyl group.

[0033] As used herein, the term “alkylcycloalkyl” refers to an alkyl moiety substituted with one or more cycloalkyl moieties, whether used as part of another term or independently. “Alkylcycloalkyl” can be bonded to the parent molecule structure via an alkyl group or cycloalkyl group.

[0034] As used herein, the term "amino" refers to -NH2. In some embodiments, the amino can be substituted with any possible substituent on the nitrogen.

[0035] As used herein, the term “aryl,” whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 12 ring members. Examples of “aryl” include, but are not limited to, phenyl, biphenyl, naphthyl, and anthrasyl, which may have one or more substituents. The scope of the term “aryl” also includes groups in which an aromatic ring is fused to one or more additional rings, as used herein. In the case of polycyclic ring systems, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), but all rings may be aromatic (e.g., quinoline). The second ring may also be a fused ring, a bridging ring, or a spiro-ring. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl. The aryl group may be substituted with the above substituents at one or more ring positions.

[0036] As used herein, the term “cycloalkyl,” whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and which contain at least three ring-forming carbon atoms. In some embodiments, cycloalkyls may contain 3 to 12 ring-forming carbon atoms, 3 to 11 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 3 to 4 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 11 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, and 4 to 5 ring-forming carbon atoms. Cycloalkyls may be saturated or partially unsaturated. Cycloalkyls may be substituted. In some embodiments, cycloalkyls may be saturated cyclic alkyl groups. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group containing at least one double or triple bond within the ring system.

[0037] In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopento-1-enyl, 1-cyclopento-2-enyl, 1-cyclopento-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0038] In some embodiments, the cycloalkyl group may be a saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic system, which may be arranged as a fused ring, spiro-ring, or bridging ring system. As used herein, the term “fused ring” refers to a ring system having two rings sharing two adjacent atoms, the term “spiro-ring” refers to a ring system having two rings connected via a single common atom, and the term “bridging ring” refers to a ring system having two rings sharing three or more atoms. Examples of fused carbocyclils include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, and fluorenyl. Examples of spirocarbocyclils include, but are not limited to, spiro[5.5]undecanyl, spiropentadienyl, and spiro[3.6]-decanyl. Examples of cross-linked carbocyclils include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, and bicyclo[3.3.3]undecanyl.

[0039] As used herein, the term "cyano" refers to -CN.

[0040] As used herein, the term “halogen” refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iod).

[0041] As used herein, the term “haloalkyl” refers to an alkyl group having one or more halogen substituents, whether used as part of another term or independently. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl (-CF3), pentafluoroethyl (-C2F5), difluoromethyl (-CHF2), trichloromethyl (-CCl3), dichloromethyl (-CHCl2), and pentachloroethyl (-C2Cl5).

[0042] As used herein, the term “haloalkoxyl” refers to an alkoxyl group having one or more halogen substituents, whether used as part of another term or independently. Consequently, the term “halo C i-j The term "alkoxyl" refers to a C molecule having one or more halogen substituents, whether used as part of another term or independently. i-j This refers to an alkoxyl group. Examples of haloalkoxyls include, but are not limited to, -O-CF3, -O-C2F5, -O-CHF2, -O-CCl3, -O-CHCl2, and -O-C2Cl5.

[0043] As used herein, the term “heteroatom” means nitrogen (N), oxygen (O), sulfur (S), and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen (including N-oxides).

[0044] As used herein, the terms “heteroalkyl,” “heteroalkenyl,” or “heteroalkynyl” refer to an alkyl, alkenyl, or alkynyl group containing one or more heteroatoms, whether used as part of another term or independently. Consequently, the term “hetero-C” i-j "Alkyl", "Hetero-C" i-j Alkenyl, Hetero-C i-j Alkinyl, C i-j "heteroalkyl", "C i-j "Heteroalkenyl" or "C i-j "Heteroalkynyl" refers to a C molecule containing one or more heteroatoms, whether used as part of another term or independently. i-j Alkyl, C i-j Alkenyl, or C i-j This refers to alkynyl. For example, the term "hetero-C" 1-6 "Alkyl" or "C 1-6 "Hyperalkyl" refers to a C molecule containing one or more heteroatoms, whether used as part of another term or independently. 1-6This refers to alkyl groups. In some embodiments, a heteroalkyl group, heteroalkenyl group, or heteroalkynyl group contains at least one heteroatom. In some embodiments, a heteroalkyl group, heteroalkenyl group, or heteroalkynyl group contains at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten heteroatoms. In some embodiments, two or more heteroatoms in a heteroalkyl group, heteroalkenyl group, or heteroalkynyl group are the same. In some embodiments, two or more heteroatoms in a heteroalkyl group, heteroalkenyl group, or heteroalkynyl group are different. In some embodiments, two or more heteroatoms in a heteroalkyl group, heteroalkenyl group, or heteroalkynyl group are directly bonded. In some embodiments, two or more heteroatoms in a heteroalkyl group, heteroalkenyl group, or heteroalkynyl group are not directly bonded.

[0045] As used herein, the term “heteroaryl,” whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to a carbon atom. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthylidinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which a heteroaromatic ring is fused to one or more aryl rings, heteroaryl rings, alicyclic rings, or heterocyclyl rings, where the radical or bond site is on the heteroaromatic ring or other rings. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranil, benzo[1,3]dioxolyl, dibenzofuranil, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0046] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are carbon, where one or more ring atoms may be independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in the ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of basic nitrogen. The heterocyclyl radical may be carbon-bonded or nitrogen-bonded, where possible. In some embodiments, the heterocycle is carbon-bonded. In some embodiments, the heterocycle is nitrogen-bonded. For example, a group derived from pyrrole may be pyrrole-1-yl (nitrogen-bonded) or pyrrole-3-yl (carbon-bonded). Furthermore, the imidazole-derived group may be imidazole-1-yl (nitrogen-bonded type) or imidazole-3-yl (carbon-bonded type).

[0047] Heterocyclyl groups can be monocyclic. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, azetidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, and triazinonyl.

[0048] Heterocyclyl groups can be polycyclic and include fused ring systems, spiro-ring systems, and bridging ring systems. Fused heterocyclyl groups include radicals in which a heterocyclyl radical is fused with a saturated, partially unsaturated, or completely unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Examples of condensed heterocyclyls include, but are not limited to, phenyl condensed rings or pyridinyl condensed rings such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindridinyl, pteridinyl, clomenyl, isoclomenyl, indolyl, isoindolyl, indazolyl, prinyl, benzofuranil, isobenzofuranil, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenadinyl, phenothiazinyl, phenantridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, and [1,2,3]triazolo[4,3-a]pyridinyl groups. Examples of spiroheterocyclils include, but are not limited to, spiropyranil, spirooxazinil, 5-aza-spiro[2.4]heptanil, 6-aza-spiro[2.5]octanil, 6-aza-spiro[3.4]octanil, 2-oxa-6-aza-spiro[3.3]heptanil, 2-oxa-6-aza-spiro[3.4]octanil, 6-aza-spiro[3.5]nonanil, 7-aza-spiro[3.5]nonanil, and 1-oxa-7-aza-spiro[3.5]nonanil. Examples of cross-linked heterocyclils include, but are not limited to, 3-azabicyclo[3.1.0]hexanil, 8-azabicyclo[3.2.1]octanil, 1-azabicyclo[2.2.2]octanil, 2-azabicyclo[2.2.1]heptanil, and 1,4-diazabicyclo[2.2.2]octanil.

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

[0050] As used herein, the term "sulfhydryl" refers to -SH.

[0051] As used herein, the term "sulfonyl" refers to -SO2R', where R' is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0052] As used herein, the term "-Boc" refers to t-butoxylcarbonyl.

[0053] As used herein, the term “partially unsaturated” refers to a radical containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moieties, but not to include aromatic (i.e., fully unsaturated) moieties.

[0054] As used herein, the term “substituted” means that one or more hydrogens of a specified moiety are replaced with a preferred substituent, whether or not it is preceded by the term “optionally.” “Substituted,” “substituted by,” or “substituted with” is understood to imply the implicit condition that the substitution is subject to the permissible valence of the substituted atom and that the substitution results in a stable or chemically feasible compound that does not undergo spontaneous transformations such as rearrangement, cyclization, or elimination. Unless otherwise specified, an “optionally substituted” group may have preferred substituents at each substituted position of the group, and the substituents may be the same or different at each position if multiple positions in a given structure can be substituted with substituents selected from a particular group. Those skilled in the art will understand that substituents may be substituted themselves where appropriate. Unless otherwise specified as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, references to an “aryl” group or moiety implicitly include both substituted and unsubstituted variants. compound

[0055] This disclosure provides novel compounds or their tautomers, stereoisomers, or pharmaceutically acceptable salts, methods for synthesizing the compounds, pharmaceutical compositions containing these, and various uses of the disclosed compounds.

[0056] In one embodiment, the present disclosure relates to a compound represented by the following formula (I). [ka] (In the formula, W is either N or C. L 1 teeth, [ka] A group consisting of the following is selected, where, Ring A consists of one or more R a1 Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, Ring B consists of one or more R a2 Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, [ka] This is a bond in which ring A is condensed with ring B, Ring E is composed of one or more R a3 Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, L 2 -C(O)-, -CR 7 R 8 Selected from the group consisting of -, -S(O)- and -S(O)2-, L 3 This is either a combination or each is one or more R a4 Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl, where W is C and L 1 but [ka] And L 2 If is -C(O)-, then L 3 It is not an aryl or heteroaryl compound, L 4 The group is selected from alkyl, alkylalkoxyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and the alkyl, alkenyl, and alkynyl may be alone or as part of another group, one or more R a5 It is independently and arbitrarily substituted, L 5 is a bond, or alkyl, alkenyl, alkynyl, -alkyl-N(R b Selected from the group consisting of )-, heteroalkyl, heteroalkenyl and heteroalkynyl, and the alkyl, alkenyl, alkynyl and -alkyl-N(R b )- is one or more R, either alone or as part of another base. a6 It is independently and arbitrarily substituted, R 1 , R 2 , R 4 , R 7 and R 8 Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, wherein the alkyl, alkenyl, and alkynyl are individually or as part of another group, one or more R a7 It is independently and arbitrarily substituted, R 3 Hydrogen, halogen, hydroxyl, sulfhydryl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkylalkoxyl, -OR c , -NHR d and -N(R d) Selected from the group consisting of 2, the alkyl, alkenyl and alkynyl are one or more R, either alone or as part of another group. a8 It is independently and arbitrarily substituted, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. R b , R c and R d Each of the groups is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and the alkyl, alkenyl, and alkynyl groups are independently and optionally substituted, either alone or as part of another group, with one or more groups independently selected from the group consisting of hydrogen, halogen, hydroxyl sulfhydryl, cyano, -NH2, and -NO2, or two R groups. b These, together with the nitrogen atom they bond to, form a heterocycline, or two R d These, together with the nitrogen atom that binds to them, form heterocyclines. n is 0, 1, 2 or 3, and (q is 0, 1, 2, or 3) Alternatively, the present invention provides tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.

[0057] In some embodiments, the compound is represented by the following formula (Ia) or formula (Ib), [ka] [ka] In the formula, R1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 and L 4 n and q are as defined above.

[0058] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] And # is L 2 It is connected to.

[0059] In some embodiments, ring A is one or more R a1 This is an aryl that has been arbitrarily substituted with, where each R a1 The group is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. For example, ring A may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a1 It is an aryl that is optionally substituted with R. In some embodiments, ring A is one or more R a1 These are 3-12 member aryls, 3-11 member aryls, 3-10 member aryls, 3-9 member aryls, 3-8 member aryls, 3-7 member aryls, 3-6 member aryls, 3-5 member aryls, or 3-4 member aryls, where each R a1 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0060] In some embodiments, ring A is one or more R a1 It is a monocyclic aryl compound with arbitrary substitutions. For example, ring A may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Rs. a1 It is a monocyclic aryl with optional substitutions. In some embodiments, ring A is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a1 The ring A is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic aryl ring, optionally substituted with R. In some embodiments, ring A is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a1 A phenyl compound optionally substituted with R, where each R a1 The ring A is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. In some embodiments, ring A is an unsubstituted phenyl. In some embodiments, ring A is a halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, C 1-6 Alkoxyl, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Heteroalkyl, C 1-6 Heteralkenyl, C 1-6 Heteroalkynyl and Halo C 1-6 It is a phenyl compound substituted with a group selected from the group consisting of alkyl groups. In some embodiments, ring A is C 1-6 It is a phenyl substituted with an alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In some embodiments, ring A is a phenyl substituted with methyl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] And here [ka] This is a bond in which ring A is condensed with ring B.

[0061] In some embodiments, ring A is one or more R a1 A heterocycline in which R is arbitrarily substituted, where each R a1 The group is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. For example, ring A may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a1 It is a heterocyclyl optionally substituted with R. In some embodiments, ring A is one or more R a1 These are 3-12 member heterocyclines, 3-11 member heterocyclines, 3-10 member heterocyclines, 3-9 member heterocyclines, 3-8 member heterocyclines, 3-7 member heterocyclines, 3-6 member heterocyclines, 3-5 member heterocyclines, or 3-4 member heterocyclines, where each R a1 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0062] In some embodiments, ring A is one or more R a1 It is a monocyclic heterocycline in which R is arbitrarily substituted. For example, ring A has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a1It is a monocyclic heterocycline optionally substituted with R. In some embodiments, ring A is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a1 The ring A is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic heterocyclil optionally substituted with R. In some embodiments, ring A is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic heterocyclil containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a1 They are optionally substituted with. In some embodiments, ring A is a 3-12 member (e.g., 3-11 member, 3-10 member, 3-9 member, 3-8 member, 3-7 member, 3-6 member, 3-5 member, or 3-4 member) monocyclic heterocyclil containing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a1 It is optionally substituted with. In some embodiments, ring A is a 3-12 member (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) monocyclic heterocyclil containing one or two nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a1 It is arbitrarily replaced.

[0063] In some embodiments, ring A is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a1 It is a saturated monocyclic heterocycline optionally substituted with R. In some embodiments, ring A is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a1The ring A is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) saturated monocyclic heterocyclil optionally substituted with R. In some embodiments, ring A is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) saturated monocyclic heterocyclil containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a1 They are optionally substituted with. In some embodiments, ring A is a 3-12 member (e.g., 3-11 member, 3-10 member, 3-9 member, 3-8 member, 3-7 member, 3-6 member, 3-5 member, or 3-4 member) saturated monocyclic heterocyclyl containing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a1 It is optionally substituted with. In some embodiments, ring A is a 3-12 member (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) saturated monocyclic heterocyclyl containing one or two nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a1 It is optionally substituted with R. In some embodiments, ring A is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a1 It is a piperidinyl that is optionally substituted with. In some embodiments, ring A is an unsubstituted piperidinyl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] And here [ka] This is a bond in which ring A is condensed with ring B.

[0064] In some embodiments, ring B is each one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a2 The rings are independently and arbitrarily substituted heterocyclyl or aryl rings. In some embodiments, rings A and B cannot be heterocyclyl or aryl rings at the same time. For example, if ring A is a heterocyclyl, ring B is an aryl ring, and if ring A is an aryl ring, ring B is a heterocyclyl ring.

[0065] In some embodiments, ring B is one or more R a2 A heterocycline in which R is arbitrarily substituted, where each R a2 R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. For example, ring B may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a2 It is a heterocyclyl optionally substituted with R. In some embodiments, ring B is one or more R a2 These are 3-12 member heterocyclines, 3-11 member heterocyclines, 3-10 member heterocyclines, 3-9 member heterocyclines, 3-8 member heterocyclines, 3-7 member heterocyclines, 3-6 member heterocyclines, 3-5 member heterocyclines, or 3-4 member heterocyclines, where each R a2 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0066] In some embodiments, ring B is one or more R a2It is a monocyclic heterocycline in which R is arbitrarily substituted. For example, ring B has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a2 It is a monocyclic heterocycline optionally substituted with R. In some embodiments, ring B is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a2 The ring B is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic heterocyclil optionally substituted with R. In some embodiments, ring B is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic heterocyclil containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a2 It is optionally substituted with. In some embodiments, ring B is a 3-12 member (e.g., 3-11 member, 3-10 member, 3-9 member, 3-8 member, 3-7 member, 3-6 member, 3-5 member, or 3-4 member) monocyclic heterocyclil containing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a2 It is optionally substituted with. In some embodiments, ring B is a 3-12 member (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) monocyclic heterocyclil containing one or two nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a2 It is arbitrarily replaced.

[0067] In some embodiments, ring B is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a2 It is a saturated monocyclic heterocycline optionally substituted with R. In some embodiments, ring B is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) Ra2 The ring B is a 3- to 12-membered (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) saturated monocyclic heterocyclil optionally substituted with R. In some embodiments, ring B is a 3- to 12-membered (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) saturated monocyclic heterocyclil containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a2 It is optionally substituted with. In some embodiments, ring B is a 3-12 member (e.g., 3-11 member, 3-10 member, 3-9 member, 3-8 member, 3-7 member, 3-6 member, 3-5 member, or 3-4 member) saturated monocyclic heterocyclyl containing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a2 It is optionally substituted with. In some embodiments, ring B is a 3-12 member (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) saturated monocyclic heterocyclyl containing one or two nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a2 It is optionally substituted with R. In some embodiments, ring B is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a2 It is a piperidinyl optionally substituted with. In some embodiments, ring B is an unsubstituted piperidinyl. In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] And here [ka] This is a bond in which ring B is condensed with ring A.

[0068] In some embodiments, ring B is one or more R a2 These are aryls arbitrarily substituted with each R a2 R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. For example, ring B may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a2 It is an aryl that is optionally substituted with R. In some embodiments, ring B is one or more R a2 These are 3-12 member aryls, 3-11 member aryls, 3-10 member aryls, 3-9 member aryls, 3-8 member aryls, 3-7 member aryls, 3-6 member aryls, 3-5 member aryls, or 3-4 member aryls, where each R a2 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0069] In some embodiments, ring B is one or more R a2 It is a monocyclic aryl compound in which R is arbitrarily substituted. For example, ring B may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a2 It is a monocyclic aryl with optional substitutions. In some embodiments, ring B is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a2 The ring B is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic aryl ring, which is optionally substituted with R. In some embodiments, ring B is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) Ra2 A phenyl compound optionally substituted with R, where each R a2 The ring B is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. In some embodiments, ring B is an unsubstituted phenyl. In some embodiments, ring B is a halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, C 1-6 Alkoxyl, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, C 1-6 Heteroalkyl, C 1-6 Heteralkenyl, C 1-6 Heteroalkynyl and Halo C 1-6 It is a phenyl compound substituted with a group selected from the group consisting of alkyl groups. In some embodiments, ring B is C 1-6 It is a phenyl substituted with an alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In some embodiments, ring B is a phenyl substituted with methyl. In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] And here [ka] This is a bond in which ring B is condensed with ring A.

[0070] In some embodiments, ring A is one or more R a1 A phenyl molecule optionally substituted with R, where ring B is one or more R a2 It is a piperidinyl optionally substituted with C. In some embodiments, ring A is C1-6 Ring A is an alkyl (e.g., methyl) substituted phenyl ring, and ring B is an unsubstituted piperidinyl ring. In some embodiments, ring A is an unsubstituted phenyl ring, and ring B is an unsubstituted piperidinyl ring.

[0071] In some embodiments, ring A is one or more R a1 It is a piperidinyl optionally substituted with, and ring B is one or more R a2 It is a phenyl that is optionally substituted with C. In some embodiments, ring A is an unsubstituted piperidinyl and ring B is C 1-6 It is an alkyl (e.g., methyl) substituted phenyl. In some embodiments, ring A is an unsubstituted piperidinyl and ring B is an unsubstituted phenyl.

[0072] In some embodiments, ring A is one or more R a1 A phenyl molecule optionally substituted with R, where ring B is one or more R a2 It is a phenyl compound that is optionally substituted. In some embodiments, both ring A and ring B are unsubstituted phenyl compounds.

[0073] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] And # is L 2 It is connected to L. In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] And # is L 2 It is connected to L. In some embodiments, L 1 teeth, [ka] And # is L 2 It is connected to L. In some embodiments, L 1 teeth, [ka] That is the case.

[0074] In some embodiments, ring E is one or more R a3 This is an aryl that has been arbitrarily substituted with, where each R a3 R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. For example, ring E may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a3 It is an aryl that is optionally substituted with R. In some embodiments, the ring E is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a3 These are 3-12 member aryls, 3-11 member aryls, 3-10 member aryls, 3-9 member aryls, 3-8 member aryls, 3-7 member aryls, 3-6 member aryls, 3-5 member aryls, or 3-4 member aryls, where each R a3 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0075] In some embodiments, ring E is one or more R a3It is a monocyclic aryl compound in which R is arbitrarily substituted. For example, ring E has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a3 It is a monocyclic aryl with optional substitutions. In some embodiments, the ring E is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a3 The ring E is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic aryl ring, optionally substituted with R. In some embodiments, the ring E is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a3 A phenyl compound optionally substituted with R, where each R a3 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0076] In some embodiments, ring E is one or more R a3 A heteroaryl with arbitrary substitutions, where each R a3 R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. For example, ring E may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more R a3 It is a heteroaryl with optional substitutions. In some embodiments, ring E is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a3 These are 3-12 member heteroaryls, 3-11 member heteroaryls, 3-10 member heteroaryls, 3-9 member heteroaryls, 3-8 member heteroaryls, 3-7 member heteroaryls, 3-6 member heteroaryls, 3-5 member heteroaryls, and 3-4 member heteroaryls, where each R a3The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0077] In some embodiments, ring E is one or more R a3 It is a monocyclic heteroaryl with arbitrary substitutions of R. For example, ring E may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Rs. a3 It is a monocyclic heteroaryl with optional substitutions. In some embodiments, ring E is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a3 The ring E is a monocyclic heteroaryl with 3 to 12 members (e.g., 3 to 11 members, 3 to 10 members, 3 to 9 members, 3 to 8 members, 3 to 7 members, 3 to 6 members, 3 to 5 members, or 3 to 4 members) optionally substituted with R. In some embodiments, ring E is a monocyclic heteroaryl containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S) and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a3 They are optionally substituted with. In some embodiments, ring E is a monocyclic heteroaryl containing one or more (e.g., 1, 2, 3, 4 or more) nitrogen atoms and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a3 It is optionally substituted with. In some embodiments, ring E is a 3-12 member (e.g., 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, or 3-4 member) monocyclic heteroaryl containing one or two nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a3 It is optionally substituted with R. In some embodiments, ring E is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a3 It is a pyridinyl compound that has been arbitrarily substituted.

[0078] In some embodiments, L 1 teeth, [ka] And each of X is C, CR a3 CH, N, NR a3 It is independently selected from the group consisting of , and NH.

[0079] In some embodiments, L 1 teeth, [ka] And each of X is C, CR a3 CH, N, NR a3 Independently selected from the group consisting of , and NH, # is L 2 It is connected to.

[0080] In some embodiments, L 5 R is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) a6 A heteroalkyl group optionally substituted with R, where each R a6 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. In some embodiments, L 5 is a heteroalkyl compound containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a6 It is optionally replaced by L. In some embodiments, L 5 is a heteroalkyl group containing at least one (e.g., 1, 2, 3, 4, 5 or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a6It is optionally replaced by L. In some embodiments, L 5 It is a heteroalkyl group containing 1 to 6 carbon atoms and at least one (e.g., 1, 2, 3, 4, 5 or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a6 It is optionally replaced by L. In some embodiments, L 5 is -CH2-N(R a6 )-,-(CH2)2-N(R a6 )-,-(CH2)3-N(R a6 )-,-(CH2)4-N(R a6 )-,-(CH2)5-N(R a6 )- and -(CH2)6-N(R a6 Selected from the group consisting of )-. In some embodiments, R a6 is alkyl. In some embodiments, R a6 C 1-6 Alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In some embodiments, R a6 It is methyl.

[0081] In some embodiments, L 1 teeth, [ka] That is the case.

[0082] In some embodiments, L 2 It is -C(O)- or -S(O)2-.

[0083] In some embodiments, L 3 L is a bond. In some embodiments, L 3 is a cycloalkyl. In some embodiments, L 3 C 3-12 It is a cycloalkyl (for example, a cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms). In some embodiments, L3 C 3-11 Cycloalkyl, C 3-10 Cycloalkyl, C 3-9 Cycloalkyl, C 3-8 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl or C 3-4 It is cycloalkyl. In some embodiments, L 3 is unsubstituted C 3-12 It is a cycloalkyl (for example, a cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms). In some embodiments, L 3 C is a C substituted with a group selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. 3-12 It is a cycloalkyl (for example, a cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms). In some embodiments, L 3 L is cyclohexyl. In some embodiments, L 3 teeth, [ka] That is the case.

[0084] In some embodiments, L 3 L is a heterocycline. In some embodiments, L 3 L is a 3-12 member heterocycline, a 3-11 member heterocycline, a 3-10 member heterocycline, a 3-9 member heterocycline, a 3-8 member heterocycline, a 3-7 member heterocycline, a 3-6 member heterocycline, a 3-5 member heterocycline, or a 3-4 member heterocycline. In some embodiments, L 3L is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) heterocyclyl containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S). In some embodiments, L 3 The heterocyclil is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) heterocyclil containing one or more (e.g., 1, 2, 3, 4 or more) nitrogen atoms. In some embodiments, the heterocyclil is unsubstituted or substituted with groups consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0085] In some embodiments, L 3 It is a monocyclic heterocycline. In some embodiments, L 3 L is a 3-12 member (e.g., 3-11 member, 3-10 member, 3-9 member, 3-8 member, 3-7 member, 3-6 member, 3-5 member, or 3-4 member) monocyclic heterocyclil. In some embodiments, L 3 L is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic heterocycline containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S). In some embodiments, L 3This is a 3- to 12-membered (e.g., 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 3- to 4-membered) monocyclic heterocyclyl containing one or more (e.g., 1, 2, 3, 4 or more) nitrogen atoms. In some embodiments, the monocyclic heterocyclyl is unsubstituted or substituted with groups consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. In some embodiments, L 3 is piperidinyl or piperazinyl. In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] And * is L 2 It is connected to.

[0086] In some embodiments, L 3 L is an aryl. In some embodiments, L 3 The aryl group is a 3-12 membered aryl, a 3-11 membered aryl, a 3-10 membered aryl, a 3-9 membered aryl, a 3-8 membered aryl, a 3-7 membered aryl, a 3-6 membered aryl, a 3-5 membered aryl, or a 3-4 membered aryl. In some embodiments, the aryl is unsubstituted or substituted with a group selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0087] In some embodiments, L 3 It is a monoring aryl. In some embodiments, L 3This is a 3- to 12-member (e.g., 3- to 11-member, 3- to 10-member, 3- to 9-member, 3- to 8-member, 3- to 7-member, 3- to 6-member, 3- to 5-member, or 3- to 4-member) monocyclic aryl. In some embodiments, L 3 L is phenyl. In some embodiments, the monocyclic aryl or phenyl is unsubstituted or substituted with a group selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl. In some embodiments, L 3 teeth, [ka] That is the case.

[0088] In some embodiments, L 4 R is selected from the group consisting of alkyl, alkenyl, heteroalkyl or heteroalkenyl, and the alkyl, alkenyl, heteroalkyl and heteroalkenyl are one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a5 Each R is independently and arbitrarily substituted, a5 The element is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0089] In some embodiments, L 4 C 1-12 Alkyl (for example, an alkyl containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms) or C 2-12 Alkenyl (e.g., alkenyl containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a5It is optionally replaced by L. In some embodiments, L 4 C 3-10 Alkyl, C 3-9 Alkyl, C 3-8 Alkyl, C 3-7 Alkyl, C 3-6 Alkyl, C 3-5 Alkyl, or C 3-4 It is alkyl. In some embodiments, L 4 teeth, [ka] That is the case.

[0090] In some embodiments, L 4 is a heteroalkyl compound containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a5 It is optionally replaced by L. In some embodiments, L 4 is a heteroalkyl group containing one or more (e.g., 1, 2, 3, 4 or more) oxygen or nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a5 It is optionally replaced by L. In some embodiments, L 4 This is a heteroalkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms and at least one (e.g., 1, 2, 3, 4, 5, or more) oxygen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a5 It is optionally replaced by L. In some embodiments, L 4 C contains one or two oxygen atoms. 3-12 A heteroalkyl (for example, a heteroalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms), where the oxygen atom is C 3-12 It is inserted into the main chain of the heteroalkyl group. In some embodiments, L 4teeth, [ka] That is the case.

[0091] In some embodiments, L 4 This is a heteroalkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms and at least one (e.g., 1, 2, 3, 4, 5, or more) nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) R a5 It is optionally replaced by L. In some embodiments, L 4 C contains one nitrogen atom. 3-12 It is a heteroalkyl (for example, a heteroalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms), and the nitrogen atom is C 3-12 It is inserted into the main chain of the heteroalkyl group. In some embodiments, L 4 teeth, [ka] That is the case.

[0092] In some embodiments, L 4 is a heteroalkenyl containing one or more (e.g., 1, 2, 3, 4 or more) heteroatoms (e.g., O, N, S), and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a5 It is optionally replaced by L. In some embodiments, L 4 is a heteroalkenyl containing one or more (e.g., 1, 2, 3, 4 or more) oxygen or nitrogen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a5 It is optionally replaced by L. In some embodiments, L 4This is a heteroalkenyl containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms and at least one (e.g., 1, 2, 3, 4, 5 or more) oxygen atoms, and one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) R a5 It is optionally replaced by L. In some embodiments, L 4 C contains one or two oxygen atoms. 2-12 A heteroalkenyl (for example, a heteroalkenyl containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms), where the oxygen atom is C 2-12 It is inserted into the main chain of the heteroalkenyl. In some embodiments, L 4 teeth, [ka] That is the case.

[0093] In some embodiments, R a5 is alkyl. In some embodiments, R a5 C 1-6 Alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl). In some embodiments, R a5 It is methyl.

[0094] In some embodiments, R 1 is hydrogen or C 1-6 It is alkyl. In some embodiments, R 1 C 1-6 Alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 1 C 1-6It is an alkyl group and is optionally substituted with one or more groups independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0095] In some embodiments, R 2 is hydrogen or C 1-6 It is alkyl. In some embodiments, R 2 C 1-6 Alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 2 C 1-6 It is an alkyl group and is optionally substituted with one or more groups independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0096] In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 1.

[0097] In some embodiments, R 3 is -OR c In some embodiments, R c is hydrogen or C 1-6 It is alkyl. In some embodiments, R c is hydrogen. In some embodiments, R c C 1-6The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl, and is optionally substituted with one or more groups independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl.

[0098] In some embodiments, n is 0 or 1. In some embodiments, n is 1.

[0099] In some embodiments, R 4 is alkyl. In some embodiments, R 4 C 1-6 Alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is a halogen (e.g., F, Cl, Br, I). In some embodiments, R 4 It is Cl.

[0100] In some embodiments, the compounds provided herein are represented by the following formulas (II), (III), or (IV): [ka] [ka] [ka] During the ceremony, R 5 and R 6Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH2, -NO2, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, wherein the alkyl, alkenyl, and alkynyl are individually or as part of another group, one or more R a7 It is independently and arbitrarily substituted, m is 0, 1, 2, or 3. t is 0, 1, 2 or 3, and W,R 1 , R 2 , R 3 , R 4 , L 2 , L 3 , L 4 , L 5 , ring A, ring B, ring E, R a7 n and q are as defined above.

[0101] In some embodiments, the compounds provided herein are represented by the following formulas (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb): [ka] [ka] [ka] [ka] [ka] [ka] In the formula, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L2 , L 3 , L 4 , L 5 Rings A, B, E, n, m, q, and t are as defined above.

[0102] In some embodiments, the compounds provided herein are represented by the following formula (IIa1) or formula (IIa2), [ka] [ka] During the ceremony, L 4 C 3-8 Alkyl or C 3-8 It is heteroalkyl, R 1 is hydrogen, halogen or C 1-6 It is alkyl, R 2 is hydrogen, halogen or C 1-6 It is alkyl, R 3 is -OR c And R c is hydrogen or C 1-6 It is alkyl, R 4 is hydrogen, halogen or C 1-6 It is alkyl, R 5 is hydrogen, halogen or C 1-6 It is alkyl, n is either 0 or 1. m is 0 or 1, and q is 1.

[0103] In some embodiments, the compounds provided herein are represented by formula (IIa1) or formula (IIa2), where L 4 C 3-8 Alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl), R 1 is hydrogen, and R 2is hydrogen, and R 3 is -OH, and R 4 is hydrogen, halogen or C 1-6 Alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl), R 5 is hydrogen, halogen or C 1-6 The element is alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl), where n is 0 or 1, m is 0 or 1, and q is 1.

[0104] In some embodiments, the compounds provided herein are represented by formula (IIa1) or formula (IIa2), where L 4 C 3-8 Alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl), R 1 is hydrogen, and R 2 is hydrogen, and R 3 is -OH, n is 0, m is 0, and q is 1.

[0105] In some embodiments, the present disclosure provides novel compounds shown in Table 1.1 or Table 1.2 below. [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 2-1] [Table 2-2] [Table 2-3]

[0106] The compounds provided herein will be described with reference to both general formulas and specific compounds. In addition, the compounds of this disclosure may exist in a variety of forms or derivatives, not limited to stereoisomers, racemic mixtures, positional isomers, tautomers, salts, prodrugs, soft drugs, active metabolic derivatives (active metabolites), solvated forms, different crystalline forms or polymorphs, all of which are within the scope of this disclosure.

[0107] Because the compounds of this disclosure may contain one or more chiral centers, they can exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. Thus, the compounds and compositions thereof of this disclosure may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of mixtures of stereoisomers. In certain embodiments, the compounds of this disclosure are enantiomerically pure compounds. In certain embodiments, mixtures of enantiomers or diastereomers are provided.

[0108] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

[0109] Furthermore, certain compounds described herein may have one or more double bonds that can exist as Z or E isomers unless otherwise specified. The disclosure additionally includes compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers, for example, as a racemic mixture of enantiomers. In addition to the compounds themselves described above, the disclosure also includes compositions comprising one or more compounds.

[0110] As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomer” includes cis-isomers and trans-isomers, E-isomers and Z-isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, which are within the scope of the present invention. For example, stereoisomers may, in some embodiments, be provided such that they substantially do not contain one or more corresponding stereoisomers, and may also be called “stereochemically concentrated.”

[0111] Where a particular enantiomer is preferred, in some embodiments it may be provided substantially free of the opposite enantiomer, and may also be called “optically concentrated.” “Optically concentrated” means, as used herein, that the compound is configured such that the proportion of one enantiomer is significantly higher. In certain embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound consists of at least about 95% by weight, 98% by weight, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from the racemic mixture by any method known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC) and chiral salt formation and crystallization, or it may be prepared by asymmetric synthesis. For example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen, SH, et al., Tetrahedron 33:2725 (1977), Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0112] The compounds of this disclosure may also exist in different tautomer forms, all of which are included within the scope of this disclosure. The term “tautomer” or “tautomer form” refers to structural isomers of different energies that are interconvertible across a low-energy barrier. The presence and concentration of isomer forms may depend on the environment in which the compound exists, for example, whether the compound is a solid, an organic solution, or an aqueous solution. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enols, amide-imido acids, lactam-lactimes, and imine-enamine isomerizations, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system. Valence tautomers include interconversions by rearrangement of some of the bonding electrons. Tautomers can be brought to equilibrium by appropriate substitution or sterically fixed into a single form. Compounds of this disclosure identified by name or structure as a specific tautomer are intended to include other tautomer forms unless otherwise specified.

[0113] As used herein, the term “prodrug” refers to a compound or a pharmaceutically acceptable salt thereof that, when metabolized or converted by solvolysis under physiological conditions, produces a desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of active compounds. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of active compounds, and during metabolism, the ester group is cleaved to obtain the active drug. Also, some prodrugs are enzymatically activated to produce the active compound, or a compound that produces the active compound through further chemical reactions. Prodrugs may progress from the prodrug form to the active form in a single step, or they may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs are discussed in their entirety in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, Vol. 14 of the ACS Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, and in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, both of which are incorporated herein by reference.

[0114] As used herein, the term “soft drug” refers to a compound that exerts pharmacological effects but has a limited duration of activity due to its breakdown into inactive metabolites. For example, see “Soft drugs: Principles and methods for the design of safe drugs”, Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449–469, 1984, which is incorporated herein by reference in its entirety.

[0115] As used herein, the term “metabolite,” for example, “active metabolite,” overlaps with the term “prodrug” as described above. Thus, such metabolites are pharmacologically active compounds, or compounds that are further metabolized into pharmacologically active compounds that are derivatives resulting from metabolic processes within the subject body. For example, such metabolites may arise from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, and enzymatic degradation of the administered compound or salt or prodrug. Among these, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, the prodrug compound is generally inactive or less active than the metabolite. In the case of active metabolites, the parent compound may be an active compound or an inactive prodrug.

[0116] Prodrugs and active metabolites can be identified using commonly known techniques in this field. See, for example, Bertolini et al., 1997, J Med Chem 40:2011-2016, Shan et al., J Pharm Sci 86:756-757, and Bagshawe, 1995, Drug Dev Res 34:220-230.

[0117] As used herein, the term “active intermediate” refers to an intermediate compound in a synthetic process that exhibits the same or essentially the same biological activity as the final synthesized compound.

[0118] The compounds of this disclosure can be formulated as pharmaceutically acceptable salts or in this form. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0119] As used herein, the term “pharmaceutically acceptable” means that a substance or composition is chemically and / or toxicologically compatible with other components that constitute and / or treat the subject of the preparation.

[0120] As used herein, the term “pharmaceutically acceptable salt” includes, unless otherwise specified, salts that retain the biological effects of the free acids and bases of a particular compound and are not biologically or otherwise undesirable. Forms of pharmaceutically acceptable salts considered include, but are not limited to, mono, bis, tris, and tetrakis. Pharmaceutically acceptable salts are nontoxic at the doses and concentrations administered. The preparation of such salts can facilitate the pharmacological use of a compound by altering its physical properties without interfering with the exertion of its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0121] Pharmacopoecitable salts include acid addition salts containing sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, sulfamates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates. Pharmacopoecitable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0122] Pharmaceutically acceptable salts also include base addition salts containing acidic functional groups such as carboxylic acids or phenols, such as benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. For example, Remington's Pharmaceutical Sciences, 19 th See ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995, and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using appropriate corresponding bases.

[0123] Pharmacopoeiatically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be isolated by dissolving it in a suitable solvent such as an aqueous solution containing a suitable acid or a water-alcohol solution, and then evaporating the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, or salicylic acid, or a pyranosidylic acid such as glucuronic acid or galacturonic acid, or an α-hydroxy acid such as citric acid or tartaric acid, or an amino acid such as aspartic acid or glutamic acid, or an aromatic acid such as benzoic acid or cinnamic acid, or a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid.

[0124] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, such as treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide. Examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0125] The compounds of this disclosure can exist in non-solvated, solvated (e.g., hydrated), and solid (e.g., crystalline or polymorphic) forms, and it is understood that this disclosure aims to encompass all such forms.

[0126] As used herein, the term “solvate” or “solvated form” refers to a solvated form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates because they capture solvent molecules in a constant molar ratio in their crystalline solid state. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more water molecules and one molecule of a substance that holds water in the H2O state. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0127] As used herein, the terms “crystal form,” “crystal shape,” “polymorph,” and “polymorph” are interchangeable and refer to crystalline structures in which a compound (or its salt or solvate) can crystallize in different crystal packing configurations, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. A particular crystalline form may become dominant due to the recrystallization solvent, crystallization rate, storage temperature, and other factors. Crystallographic polymorphs of a compound can be prepared by crystallization under different conditions.

[0128] This disclosure is also intended to include all isotopes of atoms in a compound. An isotope of an atom includes atoms with the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide, or iodine in the compounds of this disclosure are, for example, 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 It is intended to include those isotopes, not limited to I. In some embodiments, hydrogen includes protium, deutherium, and tritium. In some embodiments, carbon is 12 C and 13 Includes C. Compound synthesis

[0129] The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is shown in the synthesis schemes in the Examples. Since the compounds provided herein can be prepared by any known organic synthesis technique and can be synthesized according to any of numerous possible synthetic routes, these schemes are illustrative only and are not intended to limit other possible methods that may be used to prepare the compounds provided herein. In addition, the steps in the schemes are for illustrative purposes only and may be modified as necessary. The embodiments of the compounds in the Examples were synthesized for research and potentially for submission to regulatory authorities.

[0130] The reactions for preparing the compounds of this disclosure can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be those that are substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, for example, in the range from the freezing temperature to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of several solvents. Those skilled in the art can select a solvent suitable for a particular reaction step, depending on that step.

[0131] When carrying out a hydrolysis reaction at each step, an acid or base may be used as a reagent. In addition, when carrying out an acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane, etc. may be added to reductively capture the by-produced tert-butyl cation.

[0132] When esterification, amidation, or ureation reactions are carried out in each step, examples of reagents used include, but are not limited to, acid halides such as acid chlorides and acid bromides, and activated carboxylic acids in the form of acid anhydrides, activated esters, or sulfate esters. Examples of carboxylic acid activators include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD), triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMT-MM), carbonate ester condensing agents such as 1,1-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), and benzotriazole-1-yloxy-trisdimethylami This includes, but is not limited to, nophosphonium salts (BOP reagent), 2-chloro-1-methylpyridinium iodide (Mukoyama reagent), thionyl chloride, lower alkyl halomates such as ethyl chloroformate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxidetetrafluoroborate (TBTU), sulfuric acid, and combinations thereof. When using carbodiimide coupling agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction.

[0133] When carrying out the alkylation reaction in each step, the reagents may include electrophiles such as alkyl halides or optionally substituted sulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), nucleophiles (e.g., amines, alcohols, active methylene compounds adjacent to electron-withdrawing groups, etc.), and bases (e.g., organic bases, metal alkoxides, inorganic bases, etc.). In addition, the alkylation may be carried out in the presence of an acid such as a silyl enol ether and 1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide after converting the alcohol to an active ester. Alternatively, the alkylation may be carried out in the presence of an alcohol, a silyl enol ether, and a Lewis acid.

[0134] The preparation of the compounds of this disclosure may involve the protection and deprotection of various chemical groups. Those skilled in the art will readily be able to determine the need for protection and deprotection, and the selection of appropriate protecting groups. For the chemistry of protecting groups, see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference as a whole.

[0135] When carrying out a coupling reaction in each step, examples of metal catalysts that can be used include, but are not limited to, palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(O) and 1,1'-bis(diphenylphosphineno)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(O); rhodium compounds such as chloro(1,5-cyclooctadiene)rhodium(I) (dimer) and tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. In addition, phosphine ligands may be added to the reaction, and examples of such phosphines include triphenylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, and tri-o-tolylphosphine. Furthermore, bases may be added to the reaction, and examples of such bases include organic bases and inorganic bases.

[0136] When carrying out the borylation reaction step by step, examples of metal catalysts to be used include, but are not limited to, palladium compounds such as tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O), and 1,1'-bis(diphenylphosphine)ferrocenepalladium(II) chloride. Furthermore, a base may be added to the reaction, and examples of such bases include organic bases and inorganic bases. In addition, an example of a boron starting material is pinacol diborane. Moreover, the borate ester group can be converted to a borate group using ammonium acetate and sodium periodate as reagents.

[0137] When carrying out the cyanation reaction in each step, examples of metal catalysts to be used include, but are not limited to, palladium compounds such as palladium acetate, tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O), and 1,1'-bis(diphenylphosphine)ferrocenepalladium(II) chloride, as well as cyanides such as sodium cyanide, zinc cyanide, and copper cyanide. In addition, phosphine ligands such as 1,1'-bis(diphenylphosphine)ferrocene or zinc powder may be added to the reaction.

[0138] When carrying out the Mitsunobu reaction step by step, azodicarboxylic acid esters (e.g., diethyl azodicarboxylic acid (DEAD), diisopropyl azodicarboxylic acid (DIAD), etc.) and triphenylphosphine may be used as reagents.

[0139] When carrying out a ring-closing metathesis (RCM) reaction in each step, ruthenium compounds such as the first-generation Grubbs catalyst (Grubbs I, benzylidene-bis-(tricyclohexylphosphine)dichlororuthenium), the second-generation Grubbs catalyst (Grubbs II, (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium), and the second-generation Hoveyda-Grubbs catalyst (Hoveyda-Grubbs II, [1,3-bis(2,4,6-trimethylphenyl)imidazolidinylidene]-2-ylidene]-dichloro-[(2-propane-2-yloxyphenyl)methylidene]ruthenium) may be used as metal catalysts.

[0140] The compound and / or intermediate may be in salt form, but are not particularly limited as long as the reaction is achieved.

[0141] The reaction can be monitored according to any suitable method known in the field. For example, nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C) Product formation can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometer (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Those skilled in the art can purify the compound by various methods, including high-performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, incorporated herein by reference as a whole), and normal-phase silica chromatography.

[0142] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is 10 -6 It is expressed in units of (ppm). 1 ¹H-NMR spectra are recorded using a Bruker instrument (400 MHz or 500 MHz) in CDCl3, CD3OD, or DMSO-d6 solution, with tetramethylsilane (TMS) as the reference standard (0.0 ppm) (reported in ppm).

[0143] Unless otherwise specified, the reactions described herein are typically carried out under positive pressure of nitrogen or argon or in a dry tube in anhydrous solvent, and the reaction flasks are typically fitted with rubber diaphragms for introducing substrates and reagents via syringe. Glassware is oven-dried and / or heat-dried. Pharmaceutical composition

[0144] This disclosure provides pharmaceutical compositions comprising one or more compounds of the Disclosure or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises one or more compounds of the Disclosure or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0145] A "pharmaceutical composition" is a formulation containing the compound of this disclosure in a form suitable for administration to a subject, as used herein. In some embodiments, the pharmaceutical composition is a bulk or unit dosage form. A unit dosage form is any of the various forms, such as tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories. The amount of the active ingredient (e.g., a formulation of the compound of this disclosure or a salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is a therapeutically effective dose and will vary depending on the specific treatment in question. Those skilled in the art will understand that it may be necessary to adjust the dosage on a daily basis depending on the patient's age and symptoms. The dosage also depends on the route of administration. Various routes of administration are possible, including oral, pulmonary, rectal, extraintestinal, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, and intranasal. Dosage forms for topical or percutaneous administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In some embodiments, the compounds of the present disclosure are mixed under sterile conditions with pharmaceutically acceptable excipients and any necessary preservatives, buffers, or sprays.

[0146] As used herein, the term “pharmaceutically acceptable excipient” means an excipient useful for preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for veterinary and human pharmaceutically acceptable use. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and more such excipients.

[0147] As used herein, the term “therapeutic effective dose” refers to a drug that treats, improves or prevents an identified disease or symptom, or exhibits a detectable therapeutic or inhibitory effect. Such effect can be detected by any assay method known in the art. The exact effective dose for a subject depends on the subject’s weight, size, and health status, the nature and severity of the symptom, and the chosen therapeutic agent or combination of therapeutic agents. A therapeutic effective dose for a given situation can be determined by routine experimentation, within the scope of the clinician’s skill and judgment.

[0148] In some embodiments, the pharmaceutical composition may be formulated to administer a dose of the compound of the Disclosure or a pharmaceutically acceptable salt thereof in doses of 0.01 to 500 mg / kg body weight / day, for example, 0.05 to 500 mg / kg body weight / day, 0.1 to 500 mg / kg body weight / day, 0.1 to 400 mg / kg body weight / day, 0.1 to 300 mg / kg body weight / day, 0.1 to 200 mg / kg body weight / day, 0.1 to 100 mg / kg body weight / day, 0.1 to 80 mg / kg body weight / day, 1 to 100 mg / kg body weight / day, or 1 to 80 mg / kg body weight / day.

[0149] In some embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient, and further comprises a second active ingredient. The second active ingredient may be any agent known in the art, for example, a chemotherapeutic agent or an immunotherapeutic agent. In some embodiments, the second active ingredient is selected from the group consisting of chemotherapeutic agents, antitumor agents, radiotherapeutic agents, immunotherapeutic agents, anti-angiogenic agents, targeted therapy agents, cell therapy agents, gene therapy agents, hormone therapy agents, antiviral agents, antibiotics, analgesics, antioxidants, metal chelators, and cytokines. In some embodiments, the second active ingredient is a Keap1 inhibitor.

[0150] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent. In some embodiments, there is one additional therapeutic agent. In some embodiments, there are two additional therapeutic agents. In some embodiments, there are three or more additional therapeutic agents.

[0151] In some embodiments, the amount of additional therapeutic agent present in the pharmaceutical composition of the Disclosure may be less than or equal to the amount typically administered in a pharmaceutical composition containing that therapeutic agent as the sole active agent. In certain embodiments, the amount of additional therapeutic agent in the pharmaceutical composition of the Disclosure is in the range of about 50% to 100% of the amount typically present in a pharmaceutical composition containing that therapeutic agent as the sole therapeutic active agent.

[0152] Accordingly, in another embodiment, the Specified Provision provides compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) in combination with one or more therapeutic agents listed above, or tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.

[0153] As used herein, the term “combination” refers to simultaneous administration, individual administration, or sequential administration. In some embodiments, “combination” refers to simultaneous administration. In some embodiments, “combination” refers to individual administration. In some embodiments, “combination” refers to sequential administration. In the case of sequential or individual administration, the delay in administering the second component should not cause loss of the beneficial effect of the combination.

[0154] In a further embodiment, the Specified Provision provides pharmaceutical compositions comprising a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) in combination with one or more therapeutic agents listed above, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0155] In a further embodiment, the Specified Provision provides a kit comprising a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, in combination with one or more therapeutic agents listed above.

[0156] In a further manner, this specification states a) Compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) of the first unit dosage form, or their tautomers, stereoisomers, or pharmaceutically acceptable salts, b) A therapeutic agent selected from the above-listed second unit dosage forms, c) A kit is provided, comprising a container for housing the first and second dosage forms. Use of compounds

[0157] In one embodiment, the present disclosure provides compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) exhibiting Nrf2 modulating (e.g., activating) activity, or pharmaceutically acceptable salts thereof.

[0158] As used herein, the term “Nrf2 activating activity” means an improvement in the level or activity of Nrf2 as a direct or indirect response to the presence of a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or a pharmaceutically acceptable salt thereof, compared to the level or activity of Nrf2 in the absence of a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or a pharmaceutically acceptable salt thereof. Such improvements in level or activity are due to direct interactions between Nrf2 and compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or pharmaceutically acceptable salts thereof, or to interactions between compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or pharmaceutically acceptable salts thereof, and one or more other factors that further affect Nrf2 level or activity. For example, compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or pharmaceutically acceptable salts thereof, may increase Nrf2 by directly binding to the Nrf2 protein, by (directly or indirectly) enhancing Nrf2 activity by another factor, or by (directly or indirectly) increasing the amount of Nrf2 protein present in cells or organisms.

[0159] In some embodiments, the compounds of the Disclosure are converted to active metabolites (parent drugs) in vivo. In some embodiments, the compounds of the Disclosure are partially converted to active metabolites in vivo. In some embodiments, the compounds of the Disclosure are completely converted to active metabolites in vivo.

[0160] While we do not wish to be bound to any particular theory, the compounds disclosed herein can exhibit Nrf2 activating activity by directly inhibiting the Keap1-Nrf2 protein-protein interaction (PPI), which is emerging as a promising strategy for activating Nrf2. The compounds disclosed herein have the advantage of being able to tightly bind to the Nrf2 binding pocket on Keap1 and / or activating Nrf2 with higher target selectivity than covalent Keap1 inhibitors (or Nrf2 activators), thereby reducing potential safety risks due to off-target activity.

[0161] In some embodiments, the compounds of the present disclosure have an IC50 of less than 10 μM when tested in the assay according to the examples described below. 50 It exhibits Nrf2 activation activity having the following characteristics: 50 These are less than 2000 nM, less than 1000 nM, less than 500 nM, less than 200 nM, less than 100 nM, or less than 50 nM.

[0162] As a result of their Nrf2 activating activity, formulas (I), (Ia), (Ib), (II), (IIa), (IIa1), (IIa2), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), or (IVb), or their pharmaceutically acceptable salts thereof, are useful for a method of activating intracellular Nrf2, a method comprising contacting cells with an effective amount of the compound or pharmaceutical composition described herein to activate intracellular Nrf2. In certain embodiments, the method comprises administering an effective amount of the compound or pharmaceutical composition described herein to a target subject requiring it.

[0163] In some embodiments, the compounds of the present disclosure have an EC of less than 100 μM when tested in the assay according to the examples described below. 50 It exhibits Nrf2 activation activity having the following characteristics: 50 This is less than 50 μM, less than 40 μM, less than 30 μM, less than 20 μM, less than 10 μM, or less than 5 μM.

[0164] In some embodiments, compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or pharmaceutically acceptable salts thereof, are useful for therapies, such as the treatment of diseases or disorders associated with oxidative stress. Diseases or disorders associated with oxidative stress include liver diseases (e.g., hepatitis (e.g., non-alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, hepatitis B, hepatitis C, hepatic veno-occlusive disease)), cirrhosis, bile duct diseases (e.g., primary sclerosing cholangitis (PSC)), cardiovascular diseases (e.g., heart failure, pulmonary hypertension, myocardial infarction, arteriosclerosis, angina pectoris, cerebral infarction, cerebral hemorrhage, aortic aneurysm, aortic dissection, nephrosclerosis (e.g., hypertensive nephrosclerosis), peripheral artery disease (PAD), obstructive arteriosclerosis, arrhythmias) Lung diseases (e.g., chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis, asthma, pneumonia, aspiration pneumonia, interstitial pneumonia, respiratory infections, acute lung injury, acute respiratory distress syndrome (ARDS), α1 antitrypsin deficiency), kidney diseases (e.g., chronic kidney disease (CKD), diabetic nephropathy (DKD), acute kidney injury (AKI), glomerulonephritis, pyelonephritis, interstitial nephritis, glomerulosclerosis, nephrotic syndrome, lupus nephritis, Alport syndrome, IgA nephropathy, polycystic kidney disease) Central nervous system disorders (e.g., Parkinson's disease, Alzheimer's disease, dementia, stroke, amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), polyglutamine diseases, prion diseases, Huntington's disease, traumatic brain injury, epilepsy, autism, depression, adrenoleukodystrophy), mitochondrial diseases (e.g., Friedreich's ataxia, mitochondrial myopathy), inflammatory diseases (e.g., multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome) , scleroderma, autoimmune hepatitis, type 1 diabetes, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), spondyloarthritis, hay fever, collagen disease), lifestyle-related diseases (e.g., diabetes, hyperlipidemia, obesity, hypertension, hypercholesterolemia) and their complications (e.g., diabetic retinopathy, DKD, diabetic neuropathy), sickle cell disease, thalassemia, anemia (e.g., aplastic anemia, hemolytic anemia), cancer (e.g., liver cancer, lung cancer, kidney cancer, colon cancer, melanoma, medulloblastoma, neuroblastoma, leukemia), cachexia,Digestive disorders (e.g., gastrointestinal motility disorders, gastric ulcers, reflux esophagitis, pancreatitis), endocrine disorders (e.g., Cushing's syndrome, Hashimoto's disease), eye disorders (e.g., age-related macular degeneration, corneal endothelial disorders, Fuchs endothelial-corneal dystrophy (FECD), ocular inflammation, eye pain, retinopathy of prematurity, cataracts, dry eye), skin disorders (e.g., psoriasis, dermatitis, radiation-induced skin damage, epidermolysis bullosa, atopic dermatitis, stomatitis), wound healing failure, bone disorders (e.g., osteoporosis, skeletal disorders, fractures), viral infections (e.g., HIV virus, cytomegalovirus, respiratory syncytial virus, influenza virus), heavy metal poisoning (e.g., lead poisoning, waterborne illness). This includes, but is not limited to, silver poisoning, pesticide poisoning (e.g., paraquat poisoning, organophosphate poisoning), drug-induced injuries (e.g., drug-induced nephropathy, drug-induced hepatopathy (e.g., acetaminophen-induced hepatopathy), drug-induced lung injury), orthopedic diseases (e.g., lower back pain, sciatica, herniated disc, neck pain, stiff shoulders), pain (e.g., fibromyalgia, neuropathic pain), ischemia-reperfusion injury and shock during organ transplantation and surgery, aging, progeria, decreased motor function (e.g., sarcopenia), urinary tract diseases (e.g., urinary dysfunction), dental diseases (e.g., periodontal disease), otolaryngological diseases (e.g., hearing loss), altitude sickness, chronic fatigue syndrome, and hair loss. In addition, the compounds of this disclosure can enhance cancer treatment efficacy and survival rate improvement when used in combination with immune system anticancer agents (e.g., immune checkpoint inhibitor antibodies). Furthermore, they can exhibit regenerative activity (e.g., liver regeneration promoter after hepatectomy).

[0165] In some embodiments, diseases or disorders associated with oxidative stress include liver diseases (e.g., non-alcoholic steatohepatitis (NASH)), biliary tract diseases (e.g., primary sclerosing cholangitis (PSC)), cardiovascular diseases (e.g., heart failure or pulmonary arterial hypertension), lung diseases (e.g., chronic obstructive pulmonary disease (COPD)), kidney diseases (e.g., chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system diseases (e.g., Parkinson's disease, Alzheimer's disease, stroke), mitochondrial diseases (e.g., Friedreich's ataxia, mitochondrial myopathy), inflammatory diseases (e.g., multiple sclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease, cancer, and the like.

[0166] As used herein, the term “therapy” is intended to have its usual meaning of addressing a disease in order to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying condition. Unless otherwise specified, the term “therapy” also includes “prevention.” The terms “therapeutic” and “therapeutically” should be interpreted in their corresponding ways.

[0167] As used herein, the term “prevention” is intended to have its ordinary meaning and includes primary prevention, which prevents the onset of a disease, and secondary prevention, which protects the patient temporarily or permanently from exacerbation or worsening of the disease or the onset of new symptoms associated with the disease, once the disease has already occurred.

[0168] The term “treatment” (treatment, treat, or treating) is used as a synonym for “therapy.” Similarly, the term “treat” may be considered as “to apply therapy,” where “therapy” is as defined herein.

[0169] Accordingly, in one embodiment, the Specified Provision provides compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) for use in therapy, or pharmaceutically acceptable salts thereof.

[0170] In some embodiments, this specification provides compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or pharmaceutically acceptable salts thereof, for use in the treatment of Nrf2-related diseases, disorders, or symptoms.

[0171] In some embodiments, Nrf2-related diseases, disorders, or symptoms are associated with decreased levels or activity of the Nrf2 protein. In some embodiments, Nrf2-related diseases, disorders, or symptoms are associated with increased oxidative stress, inflammation, decreased redox potential, detoxification disorders, or metabolic dysregulation. In some embodiments, diseases, disorders, or symptoms are selected from the group consisting of eye diseases, hepatobiliary diseases, cardiovascular diseases, lung diseases, kidney diseases, neurodegenerative diseases, neuropsychiatric disorders, cancer, sickle cell disease, mitochondrial diseases, inflammatory diseases, respiratory diseases, aging, autoimmune diseases, brain diseases, diabetes (e.g., type 1 diabetes, type 2 diabetes, maternal diabetes), metabolic syndrome, and diabetic complications.

[0172] In some embodiments, this specification provides compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) for use as pharmaceuticals, or pharmaceutically acceptable salts thereof.

[0173] In some embodiments, this specification provides the use of compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the prevention, treatment, or mitigation of Nrf2-related diseases, disorders, or symptoms. In some embodiments, the disease, disorder, or symptom is related to a decrease in Nrf2 protein levels or activity. In some embodiments, the disease, disorder, or symptom is related to increased oxidative stress, inflammation, decreased redox potential, detoxification impairment, or metabolic dysregulation. In some embodiments, the disease, disorder, or symptom is selected from the group consisting of eye diseases, hepatobiliary diseases, cardiovascular diseases, lung diseases, kidney diseases, neurodegenerative diseases, neuropsychiatric disorders, cancer, sickle cell disease, mitochondrial diseases, inflammatory diseases, respiratory diseases, aging, autoimmune diseases, brain diseases, diabetes (e.g., type 1 diabetes, type 2 diabetes, maternal diabetes), metabolic syndrome, and diabetic complications. Treatment method

[0174] In a further embodiment, the Disclosure provides a method for preventing, treating or alleviating an Nrf2-related disease, disorder or symptom of a subject of interest, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) of the Disclosure, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, by the Nrf-2 activating activity of the compounds of the Disclosure.

[0175] In some embodiments, Nrf2-related diseases, disorders, or symptoms are associated with increased oxidative stress, inflammation, decreased redox potential, detoxification disorders, or metabolic dysregulation. In some embodiments, Nrf2-related diseases, disorders, or symptoms are selected from the group consisting of eye diseases, hepatobiliary diseases, cardiovascular diseases, lung diseases, kidney diseases, neurodegenerative diseases, neuropsychiatric disorders, cancer, sickle cell disease, mitochondrial diseases, inflammatory diseases, respiratory diseases, aging, autoimmune diseases, brain diseases, diabetes (e.g., type 1 diabetes, type 2 diabetes, maternal diabetes), metabolic syndrome, and diabetic complications.

[0176] In some embodiments, eye diseases include age-related macular degeneration (AMD), retinitis pigmentosa (RP), geographic atrophy (GA), macular edema, macular edema associated with retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), central retinal vein occlusion, corneal neovascularization (CNV), ocular neovascularization (intraocular neovascularization affecting the choroid, cornea, or retinal tissue), retinopathy of prematurity (ROP), pathological myopia, glaucoma (e.g., vascular glaucoma), retinoblastoma, retinal vein occlusion, uveitis, ocular trauma, Fuchs corneal endothelial dystrophy (FECD), cataract, ophthalmic neurodegenerative diseases, optic neuropathy, and neuromyelitis optica.

[0177] In some embodiments, kidney diseases include autosomal dominant polycystic kidney disease (ADPKD), acute kidney injury (AKI), diabetic nephropathy, IgA nephropathy (IgAN), chronic kidney disease (CKD), Alstrom syndrome and Alport syndrome, renal fibrosis, focal segmental glomerulosclerosis, contrast-induced nephropathy, sepsis-induced acute kidney injury, and kidney diseases or renal failures that occur during kidney transplantation.

[0178] In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive decline, amyloidosis, amyotrophic lateral sclerosis, and multiple sclerosis.

[0179] In some embodiments, the neuropsychiatric disorder is selected from the group consisting of schizophrenia, bipolar disorder, depression, anxiety disorder, Friedreich's ataxia, autism, and attention deficit hyperactivity disorder.

[0180] In some embodiments, diabetic complications are selected from the group consisting of diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and diabetic wound healing.

[0181] In some embodiments, hepatobiliary diseases are selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, toxin-induced liver disease (e.g., acetaminophen-induced liver disease), alcoholic liver disease (ALD), cholestasis, primary sclerosing cholangitis (PSC), viral hepatitis, cirrhosis, primary biliary cholangitis (PBC), end-stage liver disease, and hepatic fibrosis.

[0182] In some embodiments, the lung disease is selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, acute lung injury, lung infection, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension, environmental lung disease, chronic and acute asthma, and acute respiratory distress syndrome.

[0183] In some embodiments, cardiovascular diseases are selected from the group consisting of atherosclerosis, hypertension, heart failure, stroke, cardiomyopathy, coronary heart disease, vascular endothelial dysfunction, blood-brain barrier dysfunction, reperfusion injury (brain, heart, kidney, liver, retina), and myocardial ischemia.

[0184] In some embodiments, the inflammatory disease is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, arthritis, osteoarthritis, dermatitis (e.g., radiation dermatitis, allergic contact dermatitis), reflux esophagitis, and lupus nephritis.

[0185] In some embodiments, the autoimmune disease is selected from the group consisting of psoriasis, Sjögren's syndrome, lupus, pemphigus, vitiligo, and alopecia areata.

[0186] In some embodiments, the brain disease is selected from the group consisting of traumatic brain injury, cerebral edema, cerebral ischemia, encephalopathy (e.g., hepatic encephalopathy), and cerebral infarction.

[0187] In some embodiments, Nrf2-related diseases, disorders, or symptoms are selected from the group consisting of nerve injury, epilepsy, spinal cord injury, radiation-induced immunosuppression, pre-eclampsia, altitude sickness, wound healing, mitochondrial myopathy, malaria, ferroptosis / iron overload, alcoholism, anemia, Asperger's syndrome, eczema, chronic fatigue syndrome, Duchenne muscular dystrophy, edema, encephalitis, male / female fertility, fracture healing, gastroesophageal reflux disease, hearing loss, influenza infection, intestinal barrier dysfunction, osteoporosis, radiation injury, seizures, skin ulcers, and Down syndrome.

[0188] In some embodiments, the cancer is selected from the group consisting of colon cancer, lung cancer, esophageal cancer, breast cancer, bladder cancer, liver cancer, prostate cancer, and colorectal cancer.

[0189] As used herein, the term “required subjects” refers to subjects having Nrf2-related diseases, disorders, or symptoms, or subjects at increased risk of developing Nrf2-related diseases, disorders, or symptoms compared to the general population. In the case of cancer, required subjects may have precancerous conditions. “Subjects” includes warm-blooded animals. In some embodiments, warm-blooded animals are mammals, such as humans.

[0190] In this context, the term “therapeutic dose” means the amount of a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, that is effective in providing “therapy” in a subject or in “treating” an Nrf2-related disease, disorder, or symptom in a subject. In the case of cancer, the therapeutic dose is the amount that can induce any observable or measurable change in the subject, as defined above in the definitions of “therapy,” “treatment,” and “prevention.” For example, an effective dose may reduce the number of cancer cells or tumor cells, decrease the overall tumor size, inhibit or halt the invasion of tumor cells into peripheral organs such as soft tissues and bone, inhibit or halt tumor metastasis, inhibit or halt tumor growth, alleviate one or more cancer-related symptoms to some extent, reduce morbidity and mortality, improve quality of life, or achieve a combination of such effects. An effective dose may be sufficient to alleviate the symptoms of a disease that responds to Nrf2 activation. As those skilled in the art will recognize, the effective dose may vary depending on the route of administration, the use of excipients, and concomitant use with other drugs. For example, when using combination therapy, the amounts of compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb) described herein, or their tautomers, stereoisomers, or pharmaceutically acceptable salts, and the amounts of other pharmaceutically active agents, when combined, are jointly effective in damaging the target of the animal patient. In this context, the combined amount is a “therapeutic effective amount” if, when combined, it is sufficient to alleviate the pathological symptoms of the disease in response to Nrf2 activation as described above.

[0191] Generally, a “therapeutic dose” can be determined by those skilled in the art, for example, by starting with the dosage ranges described herein for the compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or their tautomers, stereoisomers, or pharmaceutically acceptable salts, and by beginning with the approved or published dosage ranges for other pharmaceutically active compounds.

[0192] The use of Nrf2 activators and / or the same is incorporated herein by reference in all its contents, including but not limited to the prior art, such as Hayes, JD et al., Trends Biochem. Sci. 2014, 39, 199-218, Cuadrado, A. et al., Pharmacol. Rev. 2018, 70, 348-383, Cuadrado, A. et al., Nat. Rev. Drug Discovery 2019, 18, 295-317, Lu, MC et al., Med. Res. Rev. 2016, 36, 924-963, Zhuang, C. et al., MedChemComm 2017, 8, 286-294, and Montes Diaz, G. et al., Autoimmun. Rev. 2018, 17. 1240-1250, Doss, JF et al., PLoS One 2016, 11, No. e0152895, Wang, YY et al., Drug Des., Dev. Ther. 2014, 8, 2075-2088, Zhuang, C. et al., MedChemComm 2017, 8, 286-294, Pallesen, JS et al., J. Med. Chem. 2018, 61, 8088-8103, Jiang, ZY et al., J. Med. Chem. 2016, 59, 10837-10858, Satoh, T. et al., F1000Research 2017, 6, 2138, Liu, P. et al., Cell. Chem. Biol. 2019, 26, 1427-1435, Cuadrado, A. et al., Nat. Rev. Drug Discovery 2019, 18, 295-317, Calabrese, V. et al., Nat. Rev. Neurosci. 2007, 8, 766-775, Trovato Salinaro, A. et al., Immun. Ageing 2018, 15,8, Calabrese, V. et al., Antioxid.This is also described in Redox Signaling 2010, 13, 1763-1811.

[0193] The methods for preventing, treating, or alleviating Nrf2-related diseases, disorders, or symptoms described herein may be used as monotherapy. As used herein, the term “monotherapy” means administering a single active or therapeutic compound to a subject in need. In some embodiments, monotherapy involves administering a therapeutically effective amount of one of the compounds of this disclosure, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

[0194] Depending on the specific disease or symptom being treated, the methods for treating Nrf2-related diseases, disorders, or symptoms described herein may include, in addition to the administration of the compounds disclosed herein, one or more additional therapies, such as conventional surgery, radiotherapy, chemotherapy, immunotherapy, or a combination of such additional therapies. As used herein, the term “combination therapy” refers to the administration of a combination of multiple active compounds.

[0195] Additional therapies, such as additional antitumor agents, may be administered separately from the compounds of this disclosure as part of a multi-dose regimen. Alternatively, these additional therapies may be part of a single dosage form mixed with the compounds of this disclosure in a single composition.

[0196] In some embodiments, the compounds of the present disclosure may be administered concurrently with, sequentially with, or separately from, conventional surgical, radiotherapy, chemotherapy, or immunotherapy treatments.

[0197] Accordingly, in one embodiment, the present disclosure provides a method for preventing, treating or alleviating a target Nrf2-related disease, disorder, or symptom of interest, wherein a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIa1), formula (IIa2), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), or formula (IVb), or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered simultaneously with, separately from, or sequentially with a second therapy.

[0198] In some embodiments, the second therapy is chemotherapy or immunotherapy. In some embodiments, the second therapy is selected from the group consisting of chemotherapeutic agents, antitumor agents, radiotherapy agents, immunotherapy agents, anti-angiogenic agents, targeted therapy agents, cell therapy agents, gene therapy agents, hormone therapy agents, antiviral agents, antibiotics, analgesics, antioxidants, metal chelating agents, and cytokines. In some embodiments, the second therapy is a Keap1 inhibitor. Examples

[0199] For illustrative purposes, the following examples are included. However, it will be understood that these examples are not intended to limit the invention and are intended only to suggest ways of carrying out the disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many other compounds of the disclosure, and that alternative methods for preparing the compounds of the disclosure will be considered within the scope of the disclosure. For example, the synthesis of compounds not illustrated in the disclosure can be successfully carried out by modifications obvious to those skilled in the art, such as appropriately protecting interfering groups, using other suitable reagents known in the art other than those described, and / or conventionally modifying the reaction conditions. Alternatively, it will be recognized that other reactions disclosed herein or known in the art are applicable to preparing other compounds of the disclosure.

[0200] The following abbreviations have the following definitions. [Table 3] Example 1 Compound Preparation Example 1.1 Synthesis of Compound 1

[0201] tert-butyl2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-6,9-dioxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacycloundecafan-2-yl)acetic acid (compound 1) [ka]

[0202] tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1-2)

[0203] Pd(dppf)Cl2 (2.6g, 3.2mol) was added at room temperature to a solution of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.0g, 32.0 mmol), B2Pin2 (9.0g, 35.3 mmol), and KOAc (9.4g, 96.1 mmol) in dioxane (150 mL). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (500 mL) and then extracted with ethyl acetate (80 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:20~1:10) to obtain the desired products 1-2 (9.2g, 80.0%).

[0204] 1-Bromo-4-fluoro-2-methyl-3-nitrobenzene(1-4)

[0205] NBS (120.5 g, 676.9 mmol) was added at 0°C to a solution of 1-fluoro-3-methyl-2-nitrobenzene (100.0 g, 644.6 mmol) in TFA (500 mL) and H2SO4 (250 mL concentrated). The resulting mixture was stirred at 30°C under a nitrogen atmosphere for 19 hours. The mixture was then slowly poured into ice water (3 L). The precipitate was filtered and washed with cold water (1 L x 3). The filtered cake was then vacuum-dried to obtain the desired products 1-4 (145.6 g, 96.5%).

[0206] 1 H NMR (400 MHz, DMSO-d6) δ 8.00-7.96 (m, 1H), 7.49 (t, J = 9.3 Hz, 1H), 2.37 (s, 3H).

[0207] 2-(2-((4-bromo-3-methyl-2-nitrophenyl)amino)ethoxy)ethane-1-ol(1-5)

[0208] To a solution of 1-4 (10.0 g, 42.7 mmol) and 2-(2-aminoethoxy)ethane-1-ol (5.8 g, 55.5 mmol) in DMF (100 mL), K2CO3 (11.8 g, 85.4 mmol) was added at 20 °C. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (1 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to obtain crude product 1-5 (6.9 g, 50.8%).

[0209] C 11 H 15 The MS(ESI) calculated value for BrN2O4 was 319.2, and the measured value was 320.2.

[0210] 2-(2-((2-amino-4-bromo-3-methylphenyl)amino)ethoxy)ethane-1-ol(1-6)

[0211] To a solution of 1-5 (6.9 g, 21.7 mmol) and NH4Cl (10.9 g, 203.6 mmol) in EtOH (50 mL) and H2O (16 mL), Fe powder (11.4 g, 203.6 mmol) was added at 20 °C. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours. After cooling to 40 °C, the mixture was filtered through a Celite pad. The filtrate was concentrated to dryness to obtain crude product 1-6 (5.9 g, 94.4%).

[0212] C 11 H 17 The MS(ESI) calculated value for BrN2O2 was 289.2, and the measured value was 290.2.

[0213] 2-(2-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethane-1-ol(1-7)

[0214] To a solution of 1-6 (5.4 g, 18.7 mmol) in HCl (6 M in H2O, 60 mL), NaNO2 (2.6 g, 37.4 mmol) in H2O (60 mL) was added at 0°C. The resulting mixture was stirred at 25°C for 2.5 hours. Subsequently, the reaction mixture was neutralized with 4N NaOH at 0°C and extracted with ethyl acetate (150 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:1) to obtain the desired product 1-7 (5.5 g, 97.9%).

[0215] C 11 H 14 The MS(ESI) calculated value for BrN3O2 was 299.0, and the measured value was 300.1.

[0216] Ethyl(E)-3-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acrylate(1-8)

[0217] Pd(OAc)2 (438.0 mg, 2.0 mmol) and P(p-tol)3 (1.2 g, 3.9 mmol) were added at 20°C to a solution of 1-7 (3.9 g, 13.0 mmol), ethyl acrylate (7.8 g, 78.0 mmol), and DIEA (3.4 g, 26.0 mmol) in DMF (40 mL). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (200 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:2 to 1:1) to obtain the desired product 1-8 (3.5 g, 84.3%).

[0218] tert-butyl7-(3-ethoxy-1-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1-9)

[0219] [Rh(1,5-cod)Cl]2 (231.7 mg, 0.5 mmol) was added at room temperature to a mixture of CPME (40 mL) and water (20 mL) containing 1-8 (1.5 g, 4.7 mmol), sodium dodecyl sulfate (6.8 g, 23.5 mmol), TEA (1.4 g, 14.1 mmol), and compound 1-2 (3.4 g, 9.4 mmol). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain the desired product 1-9 (1.0 g, 38.5%).

[0220] Ethyl 3-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(1-10)

[0221] To a solution of 1-9 (1.0 mg, 1.8 mmol) in MeOH (10 mL), HCl (4 M in dioxane, 5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, and then concentrated to dryness to obtain the desired product 1-10 (820.0 mg, 98.5%).

[0222] Ethyl 3-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-(2-((4-hydroxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(1-11)

[0223] Pyridine (1.3 g, 15.9 mmol) was added at 0°C to a solution of 1-10 (720.0 mg, 1.6 mmol) and 4-hydroxybenzenesulfonyl chloride (367.5 mg, 1.9 mmol) in MeOH (7 mL). The resulting mixture was stirred at 25°C for 6 hours. After cooling to room temperature, the mixture was poured into ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 1-11 (90.0 mg, 9.3%).

[0224] Ethyl 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6,9-Dioxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacycloundecafan-2-yl)acetate(1,12)

[0225] DEAD (100.1 mg, 0.6 mmol) and PPh3 (150.8 mg, 0.6 mmol) were added at 0°C to a solution of 1-11 (70.0 mg, 0.1 mmol) in DCM (2 mL) and THF (2 mL). The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 4 hours. The mixture was then poured into ice water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 1-12 (50.0 mg, 73.6%).

[0226] C 31 H 34 The calculated MS(ESI) value for N4O6S was 590.2, and the measured value was 591.2.

[0227] tert-butyl2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6,9-Dioxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacycloundecafan-2-yl)acetic acid (compound 1) [ka]

[0228] NaOH (10 mg, 0.2 mmol) was added to a solution of 1-12 (50.0 mg, 85.0 μmol) in THF (2 mL), MeOH (2 mL), and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was neutralized with 1N HCl at 0°C and then extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 1 (6.0 mg, 12.5%).

[0229] C 29 H 30 The calculated MS(ESI) value for N4O6S was 562.2, and the measured value was 563.2.

[0230] 1 H NMR (400 MHz, DMSO-d6) δ 7.72 - 7.66 (m, 2H), 7.65 - 7.60 (m, 1H), 7.33 - 7.28 (m, 1H), 7.03 - 6.97 (m, 1H), 6.86 - 6.81 (m, 1H), 6.76 - 6.70 (m, 3H), 4.88 - 4.76 (m, 3H), 4.70 - 4.61 (m, 1H), 4.50 - 4.42 (m, 1H), 3.98 - 3.81 (m, 4H), 3.64 - 3.51 (m, 4H), 3.08 - 2.92 (m, 2H), 2.92 - 2.87 (m, 3H), 2.70 - 2.59 (m, 2H). Example 1.2 Synthesis of Compound 2

[0231] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(4,1)-piperidine-1-iumacyclodecafane-5 1- Procedure for Ium Chloride (Compound 2) [ka]

[0232] tert-butyl7-(1-(1-(5-(4-(tert-butoxycarbonyl)piperidine-1-yl)pentyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(2-2)

[0233] To a mixture of tert-butyl 7-(3-ethoxy-1-(4-methyl-1-(5-((methylsulfonyl)oxy)pentyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (380.0 mg, 0.6 mmol) in ACN (10 mL), K2CO3 (163.0 mg, 1.2 mmol) and tert-butylpiperidine-4-carboxylate (138.8 mg, 0.8 mmol) were added at 0°C. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and then extracted with ethyl acetate (15 mL x 2). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (elution at DCM:MeOH = 10:1) to obtain the desired product 2-2 (266.0 mg, yield 61.3%).

[0234] C 41 H 59 The calculated MS(ESI) value for N5O6 was 717.5, and the measured value was 718.5.

[0235] 1-(5-(5-(3-ethoxy-3-oxo-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)propyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)pentyl)piperidine-4-carboxylic acid(2-3)

[0236] Compound 2-2 (260.0 mg, 2.1 mmol) was dissolved in dioxane (10 mL) and HCl (4N in dioxane, 3 mL) was added at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 19 hours, and then concentrated to obtain the crude desired product 2-3 (270.4 mg, crude).

[0237] C 32 H 43 The calculated MS(ESI) value for N5O4 was 561.3, and the measured value was 561.4.

[0238] Ethyl 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(4,1)-piperidinacyclodecafan-2-yl)acetate(2-4)

[0239] HATU (274.0 mg, 0.7 mmol) was added at 0°C to a mixture of compound 2-3 (270.0 mg, 0.5 mmol) and DIPEA (620.2 mg, 4.8 mmol) in DMF (5 mL). The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:1 to 99:1) to obtain the desired product 2-4 (85.5 mg, 79.5%).

[0240] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(4,1)-piperidine-1-iumacyclodecafane-5 1- Ium chloride (compound 2) [ka]

[0241] NaOH (150.0 mg, 3.8 mmol) was added at room temperature to a solution of 2-4 (85.0 mg, 156.5 μmol) in THF (2 mL), MeOH (3 mL), and water (2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The reaction mixture was then neutralized with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 2 (21.0 mg, 24.7%).

[0242] C 30 H 37 The calculated MS(ESI) value for N5O3 was 515.3, and the measured value was 516.5.

[0243] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (brs, 1H), 7.64-7.60 (m, 1H), 7.53-7.50 (m, 1H), 7.32 - 6.91 (m, 3H), 4.83-4.79 (m, 1H), 4.67-4.50 (m, 4H), 3.68-3.60 (m, 4H), 3.06 - 2.72 (m, 12H), 1.96 - 1.64 (m, 8H), 1.28-1.19 (m, 2H). Example 1.3 Synthesis of Compound 3

[0244] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1H-8-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(4,1)-Piperidine-1-Iumacyclodecafane-5 1 - Procedure for Ium Chloride (Compound 3) [ka]

[0245] Ethyl(E)-3-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acrylate(3-2)

[0246] 2-(2-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethane-1-ol (5.0 g, 16.8 mmol), ethyl acrylate (10.1 g, 100.6 mmol), and DIEA (6.5 g, 50.3 mmol) were mixed in DMF (50 mL) and Pd(OAc)2 (376.5 mg, 1.7 mmol) and (p-tol)3P (1.0 g, 3.4 mmol) were added at 20 °C. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 3-2 (4.5 g, 80.8%).

[0247] C 16 H 21 The calculated MS(ESI) value for N3O4 was 319.2, and the measured value was 320.2.

[0248] tert-butyl7-(3-ethoxy-1-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(3-3)

[0249] [Rh(1,5-cod)Cl]2 (150.3 mg, 0.3 mmol) was added at room temperature to a mixture of CPME (20 mL) and water (4 mL) containing 3-2 (1.0 g, 3.1 mmol), sodium dodecyl sulfate (350.0 mg, 1.5 mmol), Et3N (1.1 g, 9.0 mmol), and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.3 g, 9.3 mmol). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 3-3 (800.1 mg, 58.2%).

[0250] tert-butyl7-(3-ethoxy-1-(4-methyl-1-(2-(2-((methylsulfonyl)oxy)ethoxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(3-4)

[0251] MsCl (230.0 mg, 2.0 mmol) was added dropwise to a mixture of 3-3 (0.8 g, 1.3 mmol) and DIEA (0.5 mL, 0.75 mmol) in DCM (5 mL). The mixture was stirred overnight at 25°C and then concentrated under reduced pressure. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 3-4 (560.1 mg, 61.2%).

[0252] tert-butyl7-(1-(1-(2-(2-(4-(tert-butoxycarbonyl)piperidine-1-yl)ethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(3-5)

[0253] To a solution of 3-4 (560.1 mg, 0.8 mmol) in ACN (30 mL), K2CO3 (216.0 mg, 1.6 mmol) and tert-butylpiperidine-4-carboxylate (120.0 mg, 1.1 mmol) were added. The mixture was stirred overnight at 80°C. TLC indicated that the reaction was complete. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10~1:2) to obtain the desired product 3-5 (400.0 mg, 48.5%).

[0254] 1-(2-(2-(5-(3-ethoxy-3-oxo-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)propyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethyl)piperidine-4-carboxylic acid(3-6)

[0255] To a solution of 3-5 (0.4 g, 0.7 mmol) in MeOH (5 mL), HCl (4 M in dioxane, 5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then concentrated to dryness to obtain the desired product 3-6 (400.0 mg, crude).

[0256] Ethyl 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1H-8-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(4,1)-Piperidinacyclodecafan-2-yl)acetate(3-7)

[0257] HATU (420.0 mg, 1.1 mmol) was added to a mixture of 3-6 (400.0 mg, crude) and DIEA (0.5 mL, 6.9 mmol) in DMF (5 mL). The resulting mixture was stirred overnight at 25°C. The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5 to 50:1) to obtain the desired product 3-7 (200.0 mg, 38.2%).

[0258] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-8-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(4,1)-Piperidine-1-Iumacyclodecafane-5 1 - Ium chloride (compound 3) [ka]

[0259] A mixture of 3-7 (200.0 mg, 0.4 mmol), LiOH·H2O (80 mg, 2.0 mmol), MeOH (5.0 mL), and water (2 mL) was stirred at 25°C for 2 hours. The reaction mixture was then neutralized with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 3 (70.1 mg, 35.8%).

[0260] C 29 H 35 The calculated MS(ESI) value for N5O4 was 517.2, and the measured value was 518.2.

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 7.62-7.57 (m, 1H), 7.51-7.47 (m, 1H), 7.17 - 6.99 (m, 3H), 4.80-4.70 (m, 3H), 4.59 - 4.50 (m, 2H), 3.90-3.75 (m, 3H), 3.58 - 3.40 (m, 8H), 3.12-2.99 (m, 2H), 2.89 - 2.62 (m, 6H), 2.32 - 2.27 (m, 2H), 1.91-1.88 (m, 1H), 1.51-1.35 (m, 3H). Example 1.4 Synthesis of Compound 4

[0262] 2-(1 4 ,3 5 -dimethyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-7-oxa-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacyclodecafan-2-yl)acetic acid (compound 4) [ka]

[0263] tert-butyl7-(1-(1-(3-((4-(tert-butoxycarbonyl)benzyl)oxy)propyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-5-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(4-2)

[0264] [Rh(1,5-cod)Cl]2 (51.5 mg, 0.1 mmol) was added at room temperature to a mixture of 4-1 (0.5 g, 1.0 mmol), sodium dodecyl sulfate (150.3 mg, 0.5 mmol), Et3N (316.1 mg, 3.0 mmol), and tert-butyl 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (779.0 mg, 2.0 mmol) in CPME (4 mL) and water (2 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 4-2 (355.0 mg, 46.8%).

[0265] C 42 H 54 The calculated MS(ESI) value for N4O7 was 726.4, and the measured value was 727.1.

[0266] 4-((3-(5-(3-ethoxy-1-(5-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-3-oxopropyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)benzoic acid (4-3)

[0267] To a solution of 4-2 (355.0 mg, 0.5 mmol) of dioxane (2.5 mL), HCl (4.0 M in dioxane, 2.5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours. The mixture was then concentrated to dryness to obtain the desired product 4-3 (420.0 mg, crude).

[0268] C 33 H 38 The calculated MS(ESI) value for N4O5 was 570.3, and the measured value was 571.1.

[0269] Ethyl 2-(1 4 ,35 -dimethyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-7-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Benzenacyclodecafan-2-yl)acetate(4-4)

[0270] DIPEA (102.0 mg, 0.8 mmol) and HATU (150.2 mg, 0.4 mmol) were added to a solution of 4-3 (150.0 mg, 263.1 μmol) in DMF (2 mL) at 20°C. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The mixture was then poured into ice water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting at MeOH:DCM = 1:50~1:10) to obtain the desired product 4-4 (113.0 mg, 77.9%).

[0271] C 33 H 36 The calculated MS(ESI) value for N4O4 was 552.3, and the measured value was 553.4.

[0272] 2-(1 4 ,3 5 -dimethyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-7-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Benzenacyclodecafan-2-yl)acetic acid (Compound 4) [ka]

[0273] NaOH (85.0 mg, 2.0 mmol) was added to a solution of 4-4 (113.0 mg, 204.7 μmol) in THF (5 mL), MeOH (2 mL), and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was then neutralized with 1N HCl at 0°C. The aqueous layer was extracted with ethyl acetate (5 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 4 (8.0 mg, 7.5%).

[0274] C 31 H 32 The calculated MS(ESI) value for N4O4 was 524.2, and the measured value was 525.3.

[0275] 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.7 Hz, 1H), 7.26-7.22 (m, 2H), 6.90-6.88 (m, 2H), 6.80-6.78 (m, 2H), 5.90 (s, 1H), 4.90 (t, J = 7.8 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.75 - 4.69 (m, 1H), 4.54-4.51 (m, 1H), 4.24-4.20 (m, 1H), 4.17 - 4.11 (m, 1H), 4.03 (s, 2H), 3.89 - 3.82 (m, 1H), 3.46-3.43 (m, 1H), 3.41 - 3.34 (m, 1H), 3.30-3.26 (m, 1H), 3.11 - 3.03 (m, 1H), 2.88-2.84 (m, 2H), 2.73 (s, 3H), 2.57 - 2.50 (m, 1H), 2.44 (s, 1H), 2.31 (s, 3H). Example 1.5 Synthesis of Compound 5

[0276] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,34 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(4,1)-piperazine-1-iumacyclodecafane-5 1 - Procedure for Ium Chloride (Compound 5) [ka]

[0277] 5-((4-bromo-3-methyl-2-nitrophenyl)amino)pentan-1-ol(5-1)

[0278] To a solution of 1-4 (75.0 g, 320.5 mmol) and 5-aminopentan-1-ol (39.7 g, 384.6 mmol) in DMF (500 mL), K2CO3 (66.4 g, 480.7 mmol) was added at 20 °C. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (2 L) and then extracted with ethyl acetate (300 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to obtain crude product 5-1 (90.7 g, 89.2%).

[0279] C 12 H 17 The MS(ESI) calculated value for BrN2O3 was 316.0, and the measured values ​​were 317.1 and 319.1.

[0280] 5-((2-amino-4-bromo-3-methylphenyl)amino)pentan-1-ol(5-2)

[0281] To a solution of 5-1 (90.0 g, 283.8 mmol) and NH4Cl (45.5 g, 851.2 mmol) in EtOH (5 L) and H2O (0.6 L), Fe powder (110.9 g, 2.0 mol) was added at 20°C. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 4.5 hours. After cooling to 40°C, the mixture was filtered through a Celite pad. The filtrate was concentrated to dryness to obtain crude product 5-2 (70.9 g, 87.0%), which was used directly in the next reaction.

[0282] C 12 H 19 The MS(ESI) calculated value for BrN2O was 286.1, and the measured values ​​were 287.1 and 289.1.

[0283] 5-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)pentan-1-ol(5-3)

[0284] To a solution of 5-2 (70.0 g, 243.7 mmol) in HCl (6 M in H2O, 1.5 L), NaNO2 (33.6 g, 487.5 mmol) in H2O (200 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 2.5 hours, and then neutralized with 4N NaOH at 0°C. The resulting mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain the desired product 5-3 (50.2 g, 69.1%).

[0285] C 12 H 16 The MS(ESI) values ​​for BrN3O were calculated at 297.1, measured at 298.1 and 300.1, respectively.

[0286] 5-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)pentan-1-ol(5-4)

[0287] Pd(OAc)2 (376.5 mg, 1.7 mmol) and P(o-tol)3 (1.0 g, 3.4 mmol) were added at 20°C to a solution of 5-3 (5.0 g, 16.8 mmol), ethyl acrylate (10.1 g, 100.6 mmol), and DIEA (6.5 g, 50.3 mmol) in DMF (50 mL). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (500 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:2) to obtain the desired product 5-4 (5.1 g, 95.8%).

[0288] tert-butyl7-(3-ethoxy-1-(1-(5-hydroxypentyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(5-5)

[0289] [Rh(1,5-cod)Cl]2 (49.3 mg, 0.1 mmol) was added at room temperature to a mixture of 5-4 (318.0 mg, 1.0 mmol), sodium dodecyl sulfate (145.0 mg, 0.5 mmol), Et3N (303.1 mg, 3.0 mmol), and 1-2 (1.1 g, 3.0 mmol) in CPME (20 mL) and water (4 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:2) to obtain the desired product 5-5 (320.1 mg, 58.2%).

[0290] tert-butyl7-(1-(1-(5-(4-((benzyloxy)carbonyl)piperazine-1-yl)pentyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(5-6)

[0291] MsCl (62.4 mg, 544.8 μmol) was added at 0°C to a 10 mL solution of 5-5 (200.0 mg, 363.2 μmol) and Et3N (73.5 mg, 726.4 μmol) in DCM. The resulting mixture was stirred at 20°C for 2.5 hours. The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:1 to 2:1) to obtain the desired product 5-6 (190.0 mg, 83.2%).

[0292] tert-butyl7-(1-(1-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)pentyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(5-7)

[0293] K2CO3 (62.6 mg, 0.5 mmol) was added at 0°C to a solution of 5-6 (190.0 mg, 0.3 mmol) and benzylpiperazine-1-carboxylate (79.9 mg, 0.4 mmol) in acetonitrile (10 mL). The resulting mixture was then stirred at 80°C for 6.5 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 5-7 (120.0 mg, 53.3%).

[0294] tert-butyl7-(3-ethoxy-1-(4-methyl-1-(5-(piperazin-1-yl)pentyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(5-8)

[0295] Pd(OH)2 (20.2 mg) was added to a solution of 5-7 (120.0 mg, 0.2 mmol) in MeOH (10 mL). The resulting mixture was stirred at 20°C under an H2 atmosphere for 6.5 hours. The catalyst was then removed by filtration, and the filtrate was concentrated to obtain the desired product 5-8 (90.0 mg, 93.8%).

[0296] C 35 H 50 The calculated MS(ESI) value for N6O4 was 618.4, and the measured value was 619.5.

[0297] tert-butyl7-(3-ethoxy-1-(4-methyl-1-(5-(4-((4-nitrophenoxy)carbonyl)piperazine-1-yl)pentyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(5-9)

[0298] 4-nitrophenyl chloroformate (27.3 mg, 0.2 mmol) was added at 0°C to a solution of 5-8 (90.0 mg, 0.1 mmol) and K2CO3 (30.1 mg, 0.2 mmol) in acetonitrile (10 mL). The resulting mixture was stirred at 20°C for 19 hours. The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 5-9 (50.0 mg, 44.0%).

[0299] Ethyl 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,33 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperadinacyclodecafan-2-yl)acetate(5-10)

[0300] To a solution of 5-9 (40.0 mg, 0.1 mmol) in MeOH (5 mL), HCl (4 M in dioxane, 2.5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then concentrated to dryness to obtain the desired amine (30.0 mg) as a colorless oil, which was redissolved in DMF (5 mL). K2CO3 (12.1 mg, 0.1 mmol) was added to the above solution. The resulting mixture was placed in a sealed tube and heated in a microwave reactor at 130°C for 3 hours. After cooling to room temperature, the mixture was concentrated and purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 5-10 (20.0 mg, 72% in 2 steps).

[0301] C 31 H 40 The calculated MS(ESI) value for N6O3 was 544.3, and the measured value was 545.3.

[0302] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(4,1)-piperazine-1-iumacyclodecafane-5 1 - Ium chloride (compound 5) [ka]

[0303] NaOH (8.8 mg, 0.2 mmol) was added to a solution of 5-10 (24.0 mg, 44.1 μmol) in THF (5 mL), MeOH (2 mL), and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was then neutralized with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 5 (1.8 mg, 7.4%).

[0304] C 29 H 36 The calculated MS(ESI) value for N6O3 was 516.2, and the measured value was 517.3.

[0305] 1 H NMR (400 MHz, MeOH-d4) δ 7.69 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 6.75 (s, 1H), 4.95 (t, J = 7.8 Hz, 1H), 4.78 - 4.67 (m, 2H), 4.25 (s, 2H), 3.76-3.71 (m, 1H), 3.66 - 3.52 (m, 1H), 3.20 - 2.80 (m, 12H), 2.72 (s, 3H), 2.68-2.64 (m, 2H), 2.35 - 2.20 (m, 1H), 2.19-2.10 (m, 1H), 1.42-1.19 (m, 4H). Example 1.6 Synthesis of Compound 6

[0306] 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1Procedure for H-6-oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 6) [ka]

[0307] tert-butyl 4-(allyloxy)piperidine-1-carboxylate(6-2)

[0308] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g, 8.3 mmol) in DMF (30 mL), NaH (60% in mineral oil, 1.0 g, 25.0 mmol) was added at 0°C. The resulting mixture was stirred for approximately 30 minutes. 3-bromopropa-1-ene was added to the mixture, and the resulting mixture was stirred for a further 12 hours. The mixture was then poured into ice water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:5) to obtain the desired product 6-2 (2.1 g, yield 80%).

[0309] 1 H NMR (400 MHz, CDCl3) δ 6.03 - 5.82 (m, 1H), 5.31-5.30 (m, 1H), 5.17 (m, 1H), 4.03-4.01 (m, 2H), 3.86 - 3.68 (m, 2H), 3.55 - 3.41 (m, 1H), 3.08 (m, 2H), 1.82 (m, 2H), 1.58 - 1.47 (m, 2H), 1.45 (s, 9H).

[0310] 4-(allyloxy)piperidine(6-3)

[0311] To a stirred solution of 6-2 (1.0 g, 4.2 mmol) in DCM (20 mL), HCl (4N, 10 mL) from dioxane was added at room temperature. The resulting mixture was stirred for approximately 2 hours, and then concentrated under reduced pressure to obtain the desired product 6-3 (1.0 g, crude).

[0312] 4-(allyloxy)piperidine-1-sulfonyl chloride (6-4)

[0313] SO2Cl2 (0.3g, 2.5 mmol) was added dropwise to a mixture of 6-3 (0.3g, 2.1 mmol) and DIEA (0.5 mL, 0.75 mmol) in ACN (10 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 4.5 hours. The mixture was then concentrated under reduced pressure to obtain the desired product 6-4 (0.3g, crude). This was used in the next step without further purification.

[0314] (E)-5-bromo-1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole(6-6)

[0315] (E)-4-bromo-N1-(buta-2-en-1-yl)-3-methylbenzene-1,2-diamine (2.3 g, 9.1 mmol) was dissolved in THF (30 mL) and HCl (6N aqueous solution, 60 mL) and NaNO2 (1.9 g, 27.3 mmol) were added sequentially at 0°C. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 3 hours. The mixture was then poured into ice water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10) to obtain the desired product 6-6 (2.1 g, 85.7%).

[0316] C 11 H 12 The MS(ESI) values ​​for BrN3 were calculated at 265.0, measured at 266.1 and 268.1.

[0317] Ethyl (E)-3-(1-((E)-buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acrylate (6-7)

[0318] DIPEA (6.5g, 50.3 mmol) was added to a DMF solution of 6-6 (2.1g, 7.9 mmol), ethylpropane-2-enoate (4.7g, 47.3 mmol), tri-p-tolylphosphan (0.2g, 0.7 mmol), and Pd(OAc)2 (0.2g, 0.8 mmol). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10~1:3) to obtain the desired product 6-7 (1.6g, yield 71.1%).

[0319] C 16 H 19 The calculated MS(ESI) value for N3O2 was 285.0, and the measured value was 286.5.

[0320] tert-butyl(E)-7-(1-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(6-8)

[0321] [Rh(1,5-cod)Cl]2 (120.0 mg, 0.3 mmol) was added at room temperature to a mixture of 6-7 (1.6 g, 3.5 mmol), sodium dodecyl sulfate (0.5 g, 1.8 mmol), Et3N (303.1 mg, 3.0 mmol), and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.0 g, 6.0 mmol) in CPME (30 mL) and water (3 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 4.5 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 6-8 (1.2 g, 59.6%).

[0322] Ethyl(E)-3-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(6-9)

[0323] A mixture of 6-8 (0.2 g, 0.5 mmol) and dioxane (5 mL) was mixed with HCl (4 M in dioxane, 5 mL) at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours, then concentrated to dryness to obtain the desired product 6-9 (150.0 mg, crude). This was used in the next step without further purification.

[0324] Ethyl(E)-3-(2-((4-(allyloxy)piperidine-1-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-3-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)propanoate(6-10)

[0325] 6-4 (171.8 mg, crude) was slowly added to a mixture of 6-9 (150.0 mg, crude) and DIEA (0.1 g, 1.1 mmol) in DMF (5 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 19 hours. The mixture was then poured into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 6-10 (120.0 mg, 55.0%).

[0326] Ethyl(E)-2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6-Oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-8-en-2-yl)acetate(6-11)

[0327] A mixture of 6-10 (120.0 mg, 0.2 mmol) in DCM (30.0 mL) was mixed with Grubbs catalyst (40.0 mg, 0.1 mmol) at room temperature. The resulting mixture was stirred at 40°C under a nitrogen atmosphere for 19 hours. The mixture was then concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 6-11 (100.0 mg, 89.4%).

[0328] Ethyl 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 -Tetrahydro-11H-6-oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetate(6-12)

[0329] A mixture of 6-11 (100.0 mg, 0.2 mmol) and Pd / C (20.0 mg) in MeOH (20 mL) was stirred at room temperature under an H2 atmosphere for 2 hours. The mixture was then filtered through a Celite filter. The filtrate was concentrated under vacuum to obtain the desired product 6-12 (100.0 mg, 99%).

[0330] 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6-Oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 6) [ka]

[0331] A mixture of 6-12 (100.0 mg, crude) and LiOH·H2O (50 mg) in MeOH (5.0 mL) and water (2.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was then neutralized with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 6 (5.1 mg, 5.8%).

[0332] C 29 H 36 The calculated MS(ESI) value for N6O3 was 553.7, and the measured value was 554.2.

[0333] 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.86-4.82 (m, 1H), 4.77 - 4.66 (m, 2H), 4.18 (d, J = 16.0 Hz, 1H), 4.10 (d, J = 16.0 Hz, 1H), 3.20 - 3.11 (m, 4H), 2.90-2.80 (m, 1H), 2.80-2.75 (m, 4H), 2.75-2.70 (m, 3H), 2.70 - 2.62 (m, 1H), 2.37 (m, 2H), 2.02-1.90 (m, 1H), 1.82 - 1.70 (m, 1H), 1.31-1.25 (m, 2H), 1.21 - 1.12 (m, 2H), 0.98 (m, 2H), 0.85-0.72 (m, 1H). Example 1.7 Synthesis of Compound 7

[0334] Synthesis of 2-(14,5-dimethyl-6-oxo-11H-9-oxa-5-aza-1(5,1)-benzo[d][1,2,3]triazola-3(1,3),7(1,4)-dibenzenacyclododecafan-2-yl)acetic acid (compound 7) [ka]

[0335] tert-butyl(3-bromobenzyl)(methyl)carbamate(7-2)

[0336] (Boc)2O (39.1 g, 188.0 mmol) was added dropwise to a solution of 1-(3-bromophenyl)-N-methylmethaneamine (25.0 g, 125.0 mmol) and TEA (52.6 mL, 375.0 mmol) in DCM (300 mL). The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10~1:5) to obtain the desired product 7-2 (37.0 g, 80.0%).

[0337] tert-butyl 4-(allyloxy)piperidine-1-carboxylate (7-3)

[0338] Pd(dppf)Cl2 (0.5g, 6.7mmol) was added at 20°C to a solution of 7-2 (37.0g, 123.3mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (34.0g, 135.6mmol), and AcOK (4.5g, 369.9mmol) in DMF (300mL). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (500mL) and then extracted with ethyl acetate (100mL*3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10~1:2) to obtain the desired product 7-3 (20.1g, 45.8%).

[0339] 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.60 (m, 2H), 7.45 - 7.29 (m, 2H), 4.42 (s, 2H), 2.81 (s, 3H), 1.49 (s, 9H), 1.34 (s, 12H).

[0340] tert-butyl4-((3-(5-(1-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)-3-ethoxy-3-oxopropyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)benzoate(7-5)

[0341] [Rh(1,5-cod)Cl]2 (30.0 mg, 0.1 mmol) was added at room temperature to a mixture of 7-4 (0.3 g, 0.7 mmol), sodium dodecyl sulfate (250.0 mg, 0.4 mmol), Et3N (0.2 g, 2.1 mmol), and 7-3 (0.5 g, 1.4 mmol) in CPME (10 mL) and water (3 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:5 to 1:2) to obtain the desired product 7-5 (230.0 mg, 68.2%).

[0342] 4-((3-(5-(3-ethoxy-1-(3-((methylamino)methyl)phenyl)-3-oxopropyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)benzoic acid (7-6)

[0343] To a stirred mixture of 7-5 (230.0 mg, 0.3 mmol) in MeOH (10 mL), HCl (4 M, 10 mL) from dioxane was added. The resulting mixture was stirred at 20°C for 2 hours. TLC showed that the starting material had been consumed. The mixture was concentrated under reduced pressure to obtain the desired product 7-6 (0.2 g, crude).

[0344] Ethyl 2-(1 4 ,5-dimethyl-6-oxo-1 1 H-9-Oxa-5-aza-1(5,1)-benzo[d][1,2,3]triazola-3(1,3),7(1,4)-dibenzenacyclododecafan-2-yl)acetate(7-7)

[0345] HATU (200.0 mg, 0.5 mmol) was added at 0°C to a solution of 7-6 (200.0 mg, crude) and DIEA (0.5 mL, 6.9 mmol) in DMF (5 mL). The resulting mixture was stirred overnight at 25°C. TLC indicated that the reaction was complete. The mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5~2:1) to obtain the desired product 7-7 (120.0 mg, 58.2%).

[0346] 2-(1 4 ,5-dimethyl-6-oxo-1 1 H-9-Oxa-5-aza-1(5,1)-benzo[d][1,2,3]triazola-3(1,3),7(1,4)-dibenzenacyclododecafan-2-yl)acetic acid (compound 7) [ka]

[0347] A mixture of 7-7 (120.0 mg, 0.2 ml), LiOH·H2O (45.0 mg, 1.0 mmol) in MeOH (5.0 mL) and water (2.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was then neutralized with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 7 (16.1 mg, 15.0%).

[0348] C 29 H 30 The calculated MS(ESI) value for N4O4 was 498.2, and the measured value was 499.2.

[0349] 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.60 (m, 1H), 7.51-7.40 (m, 1H), 7.40-7.33 (m, 1H), 7.30-7.20 (m, 1H), 7.15-7.10 (m, 1H), 7.00-6.66 (m, 4H), 6.53 (s, 1H), 4.90 - 4.77 (m, 2H), 4.71-4.48 (m, 3H), 4.30-4.20 (m, 3H), 3.39-3.30 (m, 1H), 3.17 - 3.02 (m, 3H), 2.97-2.82 (m, 2H), 2.70-2.61 (m, 3H), 2.43-2.29 (m, 2H). Example 1.8 Synthesis of Compound 8

[0350] 2-(1 4 -methyl-4-oxo-1 1 Procedure for H-8-oxa-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperadina-3(2,7)-naphthalenacyclodecafan-2-yl)acetic acid (compound 8) [ka]

[0351] 7-Bromo-2-naphthoic acid (8-2)

[0352] 2,7-Dibromonaphthalene (10.0 g, 35.0 mmol) was mixed with THF (140 mL) and n-butyllithium (1.6 M in hexane, 23 mL, 36.8 mmol). The resulting mixture was stirred at -76°C for 15 minutes, and then CO2 (gas) was blown into the reaction solution. The resulting mixture was stirred at -76°C under a CO2 atmosphere for 0.5 hours, and then warmed to room temperature. The solution was then stirred at 25°C under a CO2 atmosphere for 16 hours, and then acidified with 1N HCl at 0°C. The resulting mixture was then poured into ice water (500 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:5) to obtain the desired product 8-2 (8.2 g, 93.4%).

[0353] 1 H NMR (400 MHz, DMSO-d6) δ 13.20(s, 1H), 8.59 (s, 1H), 8.45-8.40 (m, 1H), 7.93-8.11(m, 3H), 7.80-7.75 (m, 1H).

[0354] 7-Brom-2-Naphthoate Methyl (8-3)

[0355] Sulfuric acid (1.2 mL, 22.9 mmol) was added at room temperature to a mixture of 8-2 (8.2 g, 32.7 mmol) in MeOH (10 mL). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to obtain the crude desired product 8-3 (8.5 g, crude).

[0356] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-methyl naphthoate (8-4)

[0357] Pd(dppf)Cl2 (2.6g, 3.2mmol) was added to a 100mL solution of 8-3 (8.5g, 32.0mmol), B2Pin2 (9.0g, 35.3mmol), and KOAc (9.4g, 96.1mmol) in dioxane. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (300mL) and then extracted with ethyl acetate (80mL*3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:20~1:10) to obtain the desired product 8-4 (8.9g, 88.6%).

[0358] tert-butyl(E)-3-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)acrylate(8-6)

[0359] 2-(2-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethane-1-ol (1.0 g, 3.3 mmol), tert-butyl acrylate (2.6 g, 20.0 mmol), and DIEA (863.0 mg, 6.6 mmol) were dissolved in DMF (10 mL) to which Pd(OAc)2 (112.0 mg, 0.5 mmol) and P(o-tol)3 (305 mg, 1.0 mmol) were added at 20 °C. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:3) to obtain the desired product 8-6 (850.3 mg, 81.8%).

[0360] C 18 H 25 The calculated MS(ESI) value for N3O4 was 347.2, and the measured value was 348.5.

[0361] 7-(3-(tert-butoxy)-1-(1-(2-(2-hydroxyethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropyl)-2-methyl naphthoate(8-7)

[0362] [Rh(1,5-cod)Cl]2 (106.6 mg, 0.22 mmol) was added at room temperature to a mixture of 8-6 (750.0 mg, 2.2 mmol), sodium dodecyl sulfate (311.2 mg, 1.1 mmol), Et3N (654.9 mg, 6.6 mmol), and 3 (1.3 g, 4.4 mmol) in CPME (5 mL) and water (2.5 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain the desired product 8-7 (560.0 mg, 48.5%).

[0363] C 30 H 35 The calculated MS(ESI) value for N3O6 was 533.3, and the measured value was 534.5.

[0364] 7-(3-(tert-butoxy)-1-(4-methyl-1-(2-(2-((methylsulfonyl)oxy)ethoxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-2-methyl naphthoate(8-8)

[0365] MsCl (145.0 mg, 1.3 mmol) was added at 0°C to a solution of 8-7 (560.0 mg, 1.1 mmol) and Et3N (318.3 mg, 3.3 mmol) in DCM (5 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The mixture was then poured into water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to obtain the crude product 8-8 (580.2 mg, 90.3%).

[0366] Benzyl 4-(2-(2-(5-(3-(tert-butoxy)-1-(7-(methoxycarbonyl)naphthalene-2-yl)-3-oxopropyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethyl)piperazine-1-carboxylate(8-9)

[0367] K2CO3 (271.0 mg, 2.1 mmol) was added at 0°C to a solution of 8-8 (0.4 g, 0.7 mmol) and benzylpiperazine-1-carboxylate (173.0 mg, 0.8 mmol) in ACN (4 mL). The resulting mixture was stirred at 80°C for 6.5 hours. After cooling to room temperature, the mixture was poured into ice water (15 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 8-9 (232.0 mg, 48.2%).

[0368] C 42 H 49 The calculated MS(ESI) value for N5O7 was 735.4, and the measured value was 736.5.

[0369] 7-(1-(1-(2-(2-(4-((benzyloxy)carbonyl)piperazine-1-yl)ethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-(tert-butoxy)-3-oxopropyl)-2-naphthoic acid (8-10)

[0370] NaOH (60.0 mg, 1.5 mmol) was added to a solution of 8-9 (232.0 mg, 0.3 mmol) in THF (2 mL), MeOH (1 mL), and H2O (0.5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was then neutralized with 1N HCl at 0°C. The aqueous layer was extracted with ethyl acetate (5 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude desired product 8-10 (235.5 mg, crude).

[0371] 7-(3-(tert-butoxy)-1-(4-methyl-1-(2-(2-(piperazin-1-yl)ethoxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-2-naphthoic acid (8-11)

[0372] Pd(OH)2 (24.0 mg) was added to a solution of 8-10 (235.0 mg, crude) in MeOH (2 mL). The resulting mixture was stirred at 20°C under an H2 atmosphere for 6.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired product 8-11 (180.5 mg, 94.1%).

[0373] C 33 H 41 The calculated MS(ESI) value for N5O5 was 587.3, and the measured value was 588.5.

[0374] tert-butyl2-(1 4 -methyl-4-oxo-1 1 H-8-Oxa-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperazina-3(2,7)-naphthalenacyclodecafan-2-yl)acetate(8-12)

[0375] HATU (76.0 mg, 0.2 mmol) was added at 25°C to a solution of 8-11 (85.0 mg, 0.1 mmol) and DIEA (51.6 mg, 0.4 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The mixture was then poured into water (8 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (methyl alcohol:dichloromethane = 1:30~1:15) to obtain the desired product 8-12 (16.0 mg, 19.5%).

[0376] C 33 H 39 The calculated MS(ESI) value for N5O4 was 569.3, and the measured value was 570.5.

[0377] 2-(1 4 -methyl-4-oxo-1 1 H-8-Oxa-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperadina-3(2,7)-naphthalenacyclodecafan-2-yl)acetic acid (compound 8) [ka]

[0378] To a solution of 8-12 (16.0 mg, 28.1 μmol) in MeOH (0.5 mL), HCl (4.0 M in dioxane, 0.5 mL) was added at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours, and then concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 8 (1.3 mg, 9.0%).

[0379] C 29 H 31 The calculated MS(ESI) value for N5O4 was 513.2, and the measured value was 514.5.

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.03 - 7.76 (m, 4H), 7.69 - 7.40 (m, 4H), 5.04-5.00 (m, 1H), 4.90-4.85 (m, 2H), 3.93-3.89 (m, 4H), 3.80 - 3.73 (m, 4H), 3.20-3.15 (m, 6H), 2.79-2.75 (m, 3H), 2.71-2.66 (m, 2H). Example 1.9 Synthesis of Compound 9

[0381] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1H-6,9-Dioxa-3(2,7)-Isoquinoline-2-Iuma-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Piperidinacycloundecafane-3 2 - Procedure for Ium Chloride (Compound 9) [ka]

[0382] 2-(tert-butyl)7-methyl3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate(9-1)

[0383] Pd(OAc)2 (0.3g, 1.6 mmol) was added at 20°C to a DMA (50 mL) solution of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 16.0 mmol), TEA (4.4 g, 43.9 mmol), and MeOH (30 mL). The resulting mixture was stirred at 120°C under a CO atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:1) to obtain the desired compound 9-1 (3.1 g, 66.5%).

[0384] C 16 H 21 The calculated MS(ESI) value for NO4 was 291.2, and the measured value was 292.2.

[0385] 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (9-2)

[0386] NaOH (2.1g, 53.2mol) was added at 0°C to a THF:MeOH:H2O (18mL:6mL:6mL) solution of 9-1 (3.1g, 10.6 mmol). The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 4 hours, then concentrated to dryness to obtain the desired product 9-2 (3.0g, crude), which was used directly in the next reaction.

[0387] 7-Benzyl 2-(tert-butyl)3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate(9-3)

[0388] BnOH (2.9g, 27.3 mmol) was added at 0°C to a 10 mL solution of 9-2 (2.5 g, 9.08 mmol), HOBt (2.5 g, 18.2 mmol), EDCI (3.5 g, 18.2 mmol), and TEA (2.8 g, 27.3 mmol) in DMF (10 mL). The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 19 hours. The mixture was poured into ice water (200 mL) and then extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5 to 1:3) to obtain the desired product 9-3 (3.0 g, 89.6%).

[0389] Benzyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate(9-4)

[0390] To a solution of 9-3 (3.6 g, 13.4 mmol) in MeOH (30 mL), HCl (4 M in dioxane, 30 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours and then concentrated to dryness. The residue was then dissolved in NaHCO3 (aqueous solution, 150 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the desired product 9-4 (1.5 g, 41.9%), which was used directly in the next reaction.

[0391] C 17 H 17 The calculated MS(ESI) value for NO2 was 267.1, and the measured value was 268.2.

[0392] 1-(2-(2-((1-((benzyloxy)carbonyl)piperidine-4-yl)oxy)ethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-carboxylic acid(9-6)

[0393] Et3SiH (1.1g, 9.7mmol) was added at 20°C to a 10mL solution of 9-5 (0.5g, 1.0mmol), Na2CO3 (0.2g, 1.9mmol), xanthophos (111.8mg, 0.2mmol), and Pd(OAc)2 (21.7mg, 0.1mmol) in DMF (10mL). The resulting mixture was stirred at 120°C under a CO atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (70mL) and extracted with ethyl acetate (20mL*3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:5~2:1) to obtain the desired product 9-6 (350.0mg, 73.0%).

[0394] C 25 H 30 The calculated MS(ESI) value for N4O6 was 482.2, and the measured value was 483.2.

[0395] Benzyl 4-(2-(2-(5-(hydroxymethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethoxy)piperidine-1-carboxylate(9-7)

[0396] Borane-tetrahydrofuran complex (1M, 5mL) was added to a solution of 9-6 (350.0 mg, 0.7 mmol) in THF (5 mL) at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The reaction was then quenched with MeOH (10 mL), and the resulting mixture was concentrated to dryness to obtain the desired product 9-7 (0.3 g, 87.7%).

[0397] C 25 H 32The calculated MS(ESI) value for N4O5 was 468.2, and the measured value was 469.2.

[0398] Benzyl 4-(2-(2-(5-formyl-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethoxy)piperidine-1-carboxylate(9-8)

[0399] Dess Martin periodinane (212.8 mg, 0.5 mmol) was added at 0°C to a 10 mL solution of 9-7 (0.2 g, 0.4 mmol) in DCM. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then poured into 50 mL of ice water and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5 to 3:1) to obtain the desired product 9-8 (179.2 mg, 88.4%).

[0400] C 25 H 32 The calculated MS(ESI) value for N4O5 was 468.2, and the measured value was 469.2.

[0401] Benzyl 2-(1-(1-(2-(2-((1-((benzyloxy)carbonyl)piperidine-4-yl)oxy)ethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-methoxy-3-oxopropyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate(9-9)

[0402] B(OMe)3 (133.6 mg, 1.3 mmol) was added to a DMSO (3 mL) solution of 9-4 (343.8 mg, 1.3 mmol) at 20°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Next, a DMSO (1 mL) solution of 9-8 (0.2 g, 0.4 mmol) was added to the above mixture. Subsequently, the resulting mixture was stirred at room temperature for a further 1 hour. Then, tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (242.2 mg, 1.3 mmol) was added. Subsequently, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for a further 19 hours. After that, the mixture was poured into ice water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:2 to 3:1) to obtain the desired product 9-9 (60.0 mg, 23.6%).

[0403] C 45 H 51 The calculated MS(ESI) value for N5O8 was 789.4, and the measured value was 790.4.

[0404] 2-(3-Methoxy-1-(4-methyl-1-(2-(2-(piperidine-4-yloxy)ethoxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid(9-10)

[0405] Pd(OH)2 (15 mg) was added to a 10 mL solution of 9-9 (60.0 mg, 76.0 μmol) in MeOH at 20°C. The resulting mixture was stirred at room temperature under an H2 atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired product 9-10 (40.0 mg, 93.1%).

[0406] C 30 H 39 The calculated MS(ESI) value for N5O6 was 565.3, and the measured value was 565.4.

[0407] Methyl 2-(1 4-methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6,9-Dioxa-3(2,7)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Piperidinacycloundecafan-2-yl)acetate(9-11)

[0408] DIPEA (18.3 mg, 140 μmol) and HATU (53.8 mg, 140 μmol) were added to a solution of 9-10 (40.0 mg, 70.7 μmol) in DMF (2 mL) at 20°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then poured into ice water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting at MeOH:DCM = 1:50~1:10) to obtain the desired product 9-11 (35.0 mg, 90.4%).

[0409] C 30 H 37 The calculated MS(ESI) value for N5O5 was 547.3, and the measured value was 548.3.

[0410] 2-(carboxymethyl)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6,9-Dioxa-3(2,7)-Isoquinoline-2-Iuma-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Piperidinacycloundecafane-3 2 - Ium chloride (compound 9) [ka]

[0411] NaOH (12.8 mg, 0.3 mmol) was added to a solution of 9-11 (35.0 mg, 63.9 μmol) in THF (5 mL), MeOH (2 mL), and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was neutralized with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 9 (3.0 mg, 8.8%).

[0412] C 29 H 35 The calculated MS(ESI) value for N5O5 was 533.3, and the measured value was 534.3.

[0413] 1 H NMR (400 MHz, MeOH-d4) δ 7.93-7.82 (m, 2H), 7.57-7.49 (m, 2H), 6.54 (s, 1H), 5.24-5.20 (m, 1H), 5.03 - 4.91 (m, 2H), 4.54-4.48 (m, 1H), 4.27 - 3.47 (m, 14H), 3.02-2.68 (m, 4H), 1.94 (s, 3H), 1.48 - 1.16 (m, 2H), 0.82-0.66 (m, 2H). Example 1.10 Synthesis of Compound 10

[0414] 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-6-oxa-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 10) [ka]

[0415] 4-(allyloxy)piperidine-1-carbonyl chloride (10-2)

[0416] Triphosgene (594.0 mg, 2.0 mmol) was added at 0°C to a mixture of 4-(allyloxy)piperidine (200.0 mg, 1.3 mmol) and TEA (0.5 mL, 4.0 mmol) in DCM (5 mL). The resulting mixture was stirred overnight under a nitrogen atmosphere at 25°C, and then concentrated under reduced pressure to obtain the desired product 10-2 (800.0 mg, crude).

[0417] Ethyl(E)-3-(2-(4-(allyloxy)piperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-3-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)propanoate(10-3)

[0418] A mixture of 6-9 (100.0 mg, crude) and TEA (0.5 mL, 6.9 mmol) in DMF (5 mL) was added to a solution of 10-2 (80.0 mg, crude) in DMF (5 mL) at 0°C. The resulting mixture was stirred overnight at 25°C. TLC indicated that the reaction was complete. The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5 to 1:2) to obtain the desired product 10-3 (120.0 mg, 52.2%).

[0419] Ethyl(Z)-2-(14-methyl-4-oxo-3) 1 ,3 2 ,3 3 ,3 4 -Tetrahydro-11H-6-oxa-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafane-8-en-2-yl)acetate(10-4)

[0420] Grubbs catalyst (40.0 mg, 0.1 mmol) was added to a solution of 10-3 (120.0 mg, 0.2 mmol) in DCM (30.0 mL). The resulting mixture was stirred at 40°C under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 10-4 (180.0 mg, crude).

[0421] Ethyl 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 -Tetrahydro-11H-6-oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetate(10-5)

[0422] A mixture of 10-4 (100.0 mg, crude) and Pd / C (20.0 mg) in MeOH (20.0 mL) was stirred at 20°C under an H2 atmosphere for 2 hours. The catalyst was then removed by filtration, and the filtrate was concentrated to obtain the desired product 10-5 (90.0 mg, crude).

[0423] 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Piperidinacyclodecafan-2-yl)acetic acid (Compound 10) [ka]

[0424] LiOH·H2O (36.1 mg, 859.5 μmol) was added at room temperature to a mixture of 10⁻⁵ (90.0 mg, 0.2 mmol) of MeOH (5 mL) and water (2 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours, and then acidified with HCl (1 M). The resulting mixture was concentrated to dryness, and the residue was purified by Prep-HPLC (CH₃CN / H2O, 0.1% HCl) to obtain the desired product, compound 10 (2.1 mg, 2.6%).

[0425] C 29 H 35 The calculated MS(ESI) value for N5O4 was 517.2, and the measured value was 518.2.

[0426] 1 H NMR (400 MHz, MeOH-d4) δ 7.59 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.99-4.90 (m, 1H), 4.78 - 4.73 (m, 2H), 4.18-4.08 (m, 2H), 3.69-3.61 (m, 1H), 3.56 - 3.42 (m, 2H), 3.42 - 3.35 (m, 1H), 3.26 - 3.18 (m, 1H), 3.16 - 3.01 (m, 4H), 2.90-2.82 (m, 2H), 2.80-2.72 (m, 1H), 2.67 (s, 3H), 2.63 - 2.54 (m, 1H), 2.40-2.22 (m, 1H), 2.20 - 2.10 (m, 1H), 2.00 - 1.91 (m, 1H), 1.64-1.60 (m, 1H), 1.57 - 1.49 (m, 1H), 1.45-1.39 (m, 1H), 1.18 - 1.08 (m, 1H), 0.90-0.80 (m, 1H), 0.60-0.51 (m, 1H). Example 1.11 Synthesis of Compound 11

[0427] (Z)-2-(1 4-methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-6-oxa-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafane-8-en-2-yl)acetic acid (compound 11) [ka]

[0428] A mixture of 10⁻⁴ (80.0 mg, crude) and LiOH·H₂O (30 mg) in MeOH (5.0 mL) and water (2 mL) was stirred at 20°C for 2 hours. The reaction mixture was then acidified with 1 M HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH₃CN / H₂O, 0.1% HCl) to obtain the desired product, compound 11 (1.9 mg, 2.2%).

[0429] C 29 H 33 The calculated MS(ESI) value for N5O4 was 515.2, and the measured value was 516.3.

[0430] 1H NMR (400 MHz, MeOH-d4) δ 7.49 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 6.7 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 6.02 - 5.84 (m, 1H), 5.54 - 5.36 (m, 2H), 5.23-5.17 (m, 1H), 4.99 (t, J = 7.5 Hz, 1H), 4.18 - 3.94 (m, 4H), 3.69-3.62 (m, 1H), 3.56 - 3.40 (m, 1H), 3.25 - 3.11 (m, 2H), 3.11-3.01 (m, 1H), 3.01 - 2.88 (m, 2H), 2.88 - 2.76 (m, 5H), 2.60 - 2.41 (m, 2H), 1.67 - 1.46 (m, 2H), 1.46 - 1.30 (m, 2H), 1.21 - 0.91 (m, 3H). Example 1.12 Synthesis of Compound 12

[0431] 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-7-oxa-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 12) [ka]

[0432] 3-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propylmethanesulfonate (12-2)

[0433] 3-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propan-1-ol (2 g, 7.4 mmol) and TEA (752.0 mg, 14.8 mmol) were dissolved in DCM (10 mL) and MsCl (1.3 g, 11.2 mmol) was added at 0°C. The resulting mixture was stirred at 20°C for 2.5 hours. The mixture was then poured into ice water (50 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:1 to 2:1) to obtain the desired product 12-2 (2.2 g, 85.3%).

[0434] C 11 H 14 MS(ESI) calculation value for BrN3O3S: 348.2, measured values: 349.3, 351.4

[0435] tert-butyl 4-((3-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)piperidine-1-carboxylate(12-3)

[0436] To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.6 g, 7.56 mmol) in DMF (10 mL), NaH (60% in mineral oil, 68.9 mg, 18.9 mmol) was added at 0°C. After 0.5 hours, 12-2 (2.2 g, 6.3 mmol) and TBAI (233.4 mg, 0.6 mmol) were added. The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (80 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 12-3 (1.1 g, 37.4%).

[0437] 5-Bromo-4-methyl-1-(3-(piperidine-4-ylmethoxy)propyl)-1H-benzo[d][1,2,3]triazole(12-4)

[0438] To a solution of 12-3 (1.7 g, 3.6 mmol), HCl (4 M in dioxane, 20 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then concentrated to dryness to obtain the desired product 12-4 (1.5 g, wet).

[0439] Benzyl 4-((3-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)piperidine-1-carboxylate(12-5)

[0440] To a solution of 12-4 (1.5 g, 4.1 mmol) in ACN:H2O (20 mL:20 mL), NaHCO3 (857.7 mg, 10.2 mmol) and Cbz-Cl (1.1 g, 6.1 mmol) were added at 0°C. The resulting mixture was stirred at 80°C for 6.5 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:1 to 3:1) to obtain the desired product 12-5 (0.9 g, 43.8%).

[0441] C 24 H 29 MS(ESI) calculation value for BrN4O3: 501.4, measured values: 502.5, 504.4

[0442] Benzyl(E)-4-((3-(5-(3-ethoxy-3-oxopropa-1-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)piperidine-1-carboxylate(12-6)

[0443] Pd(OAc)2 (60.4 mg, 0.3 mmol) and (p-tol)3P (163.7 mg, 0.6 mmol) were added at 20°C to a solution of 12-5 (0.9 g, 1.9 mmol), ethyl acrylate (718.8 mg, 7.2 mmol), and DIEA (463.1 mg, 3.6 mmol) in DMF (20 mL). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:2) to obtain the desired product 12-6 (950.0 mg, 96.0%).

[0444] C 29 H 36 N4O5 MS(ESI) calculated value: 520.6, measured value: 521.7

[0445] tert-butyl(S)-7-(1-(1-(3-((1-((benzyloxy)carbonyl)piperidine-4-yl)methoxy)propyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(12-7)

[0446] [Rh(1,5-cod)Cl]2 (89.9 mg, 0.2 mmol) was added at room temperature to a mixture of CPME (6 mL) and water (3 mL) containing 12-6 (950.0 mg, 1.8 mmol), sodium dodecyl sulfate (262.8 mg, 0.9 mmol), TEA (552.9 mg, 5.5 mmol), and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.0 g, 5.4 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4.5 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 12-7 (550.0 mg, 40.5%).

[0447] C 45 H 55 The calculated MS(ESI) value for N5O7 was 753.94, and the measured value was 754.9.

[0448] tert-butyl(S)-7-(3-ethoxy-1-(4-methyl-1-(3-(piperidine-4-ylmethoxy)propyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(12-8)

[0449] Pd(OH)2 (91.6 mg) was added to a solution of 12-7 (550.0 mg, 0.7 mmol) in MeOH (10 mL). The resulting mixture was stirred at 20°C under an H2 atmosphere for 6.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired product 12-8 (330.0 mg, 76.1%).

[0450] C 35 H 49 The calculated MS(ESI) value for N5O5 is 619.8, and the measured value is 700.1.

[0451] tert-butyl(S)-7-(3-ethoxy-1-(4-methyl-1-(3-((1-(((perfluorophenoxy)carbonyl)piperidine-4-yl)methoxy)propyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(12-9)

[0452] DIEA (42.0 mg, 0.4 mmol) was added at 0°C to a solution of 12-8 (0.1 g, 0.2 mmol) and bis(perfluorophenyl) carbonate (70.0 mg, 220.0 μmol) in DMF (5 mL). The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 4 hours. The mixture was then poured into ice water (80 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:2) to obtain the desired product 12-9 (0.1 g, 60.3%).

[0453] Perfluorophenyl(S)-4-((3-(5-(3-ethoxy-3-oxo-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)propyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)piperidine-1-carboxylate(12-10)

[0454] To a solution of 12-9 (0.1 g, 0.1 mmol) in MeOH (5 mL), HCl (4 M in dioxane, 2.5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then concentrated to dryness to obtain the desired product 12-10 (30.0 mg, 41.1%).

[0455] Ethyl 2-((2S)-1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1H-7-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Piperidinacyclodecafan-2-yl)acetate(12-11)

[0456] K2CO3 (12.1 mg, 276.6 μmol) was added to a solution of 12-10 (90.0 mg, 123.3 μmol) in DMF (5 mL). The resulting mixture was heated in a microwave reactor at 120 °C for 3 hours in a sealed state. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 12-11 (14 mg, 20.9%).

[0457] 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-7-Oxa-3(7,2)-Isoquinolina-1(5,1)-Benzo[d][1,2,3]Triazola-5(1,4)-Piperidinacyclodecafan-2-yl)acetic acid (Compound 12) [ka]

[0458] NaOH (4.8 mg, 0.1 mmol) was added to a solution of 12-11 (14.0 mg, 25.7 μmol) in THF (9 mL), MeOH (3 mL), and H2O (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Subsequently, the reaction mixture was acidified with 1N HCl at 0°C and then extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 12 (1.8 mg, 7.4%).

[0459] C 29 H 35 The calculated MS(ESI) value for N5O4 was 517.6, and the measured value was 518.8.

[0460] 1 H NMR (400 MHz, MeOH-d4) δ 7.55-7.45 (m, 1H), 7.44-7.34 (m, 1H), 7.33-7.26 (m, 1H), 7.24-7.13 (m, 1H), 6.55 (s, 1H), 4.97-4.92 (m, 1H), 4.81 - 4.71 (m, 1H), 4.64-4.56 (m, 1H), 4.08 (s, 2H), 3.71-3.66 (m, 1H), 3.58 - 3.46 (m, 2H), 3.24 - 2.85 (m, 8H), 2.68 (s, 3H), 2.30 (m, 3H), 1.46 - 1.23 (m, 4H), 0.78 - 0.45 (m, 3H). Example 1.13 Synthesis of Compound 13

[0461] 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-6-oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacyclodecafan-2-yl)acetic acid (compound 13) [ka]

[0462] Ethyl(E)-3-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-(2-((4-hydroxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(13-1)

[0463] TEA (1.6 g, 15.6 mmol) was added at 0°C to a 20 mL solution of 6-9 (1.6 g, 3.9 mmol) and 4-hydroxybenzenesulfonyl chloride (0.9 g, 4.7 mmol) in DCM. The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 6 hours. The mixture was then poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:1) to obtain the desired product 13-1 (1.6 g, 71.6%).

[0464] C 31 H 34 The calculated MS(ESI) value for N4O5S was 574.2, and the measured value was 575.2.

[0465] Ethyl(E)-3-(2-((4-(allyloxy)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-3-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)propanoate(13-2)

[0466] K2CO3 (0.7g, 5.2 mmol) was added to a solution of 13-1 (1.5g, 2.6 mmol) and 3-bromopropa-1-ene (632.3 mg, 5.2 mmol) in DMF (15 mL). The resulting mixture was stirred at 50°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:1) to obtain the desired product 13-2 (530 mg, 33.0%).

[0467] C 34 H 38 The calculated MS(ESI) value for N4O5S was 614.3, and the measured value was 615.4.

[0468] Ethyl(E)-2-(14 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6-Oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacyclodecafane-8-en-2-yl)acetate(13-3)

[0469] Grubbs II catalyst (210.2 mg, 0.2 mmol) was added to a solution of 13-2 (0.5 g, 0.8 mmol) in DCM (20 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:2 to 1:1) to obtain the desired product 13-3 (60.1 mg, 12.9%).

[0470] C 31 H 32 The calculated MS(ESI) value for N4O5S was 572.2, and the measured value was 573.2.

[0471] Ethyl 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6-Oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacyclodecafan-2-yl)acetate(13-4)

[0472] Pd / C (30 mg) was added to a solution of 13-3 (60.1 mg, 105.0 μmol) in THF (6 mL). The resulting mixture was stirred at 25 °C under a hydrogen atmosphere for 19 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired product 13-4 (60.0 mg, 99.4%).

[0473] C 31 H 34 The calculated MS(ESI) value for N4O5S was 574.2, and the measured value was 575.2.

[0474] 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-6-Oxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-benzenacyclodecafan-2-yl)acetic acid (compound 13) [ka]

[0475] NaOH (8.8 mg, 0.2 mmol) was added to a solution of 13-4 (60.0 mg, 104.0 μmol) in THF (2 mL), MeOH (1 mL), and H2O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was acidified with 1N HCl at 0°C and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 13 (4.0 mg, 7.0%).

[0476] C 29 H 30 The calculated MS(ESI) value for N4O5S was 546.2, and the measured value was 547.2.

[0477] 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.22 (d, J = 8.9 Hz, 2H), 4.86 - 4.67 (m, 3H), 4.52-4.34 (m, 2H), 3.45-3.27 (m, 3H), 3.10 (d, J = 8.0 Hz, 2H), 2.94 (s, 3H), 2.79-2.74 (m, 1H), 2.63 (t, J = 6.3 Hz, 2H), 2.13 - 1.95 (m, 2H), 1.80 - 1.58 (m, 1H), 1.55 - 1.34 (m, 1H). Example 1.14 Synthesis of Compound 14

[0478] 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 14) [ka]

[0479] tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate(14-2)

[0480] Dess Martin's reagent (9.0 g, 24.0 mmol) was added at 0°C to a stirred mixture of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (5.0 g, 21.8 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then injected into saturated NaHCO3 (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:20~1:10) to obtain the desired product 14-2 (4.8 g, yield 96%).

[0481] 1 H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 4.22-3.94 (m, 2H), 2.69-2.49 (m, 2H), 2.52-2.41 (m, 2H), 1.72-1.55 (m, 4H), 1.47-1.38 (m, 10H), 1.10-1.01 (m, 2H).

[0482] tert-butyl 4-(buta-3-en-1-yl)piperidine-1-carboxylate(14-3)

[0483] n-butyllithium (2.5 mL, 6.0 mmol) was added to a solution of (bromomethyl)triphenylphosphonium bromide (11.2 g, 4.0 mmol) in THF (150 mL) at -78°C. The resulting mixture was stirred under a nitrogen atmosphere at -78°C for approximately 2 hours. The above solution was added dropwise to a solution of 14-2 (4.8 g, 2.0 mmol) in THF (25 mL). The resulting mixture was stirred further under a nitrogen atmosphere at room temperature for 19 hours. TLC showed that the starting material had been consumed. The mixture was then concentrated under reduced pressure. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:20~1:10) to obtain the desired product 14-3 (650.0 mg, yield 13.0%).

[0484] 1H NMR (400 MHz, CDCl3) δ 5.80 (m, 1H), 5.06 - 4.90 (m, 2H), 4.15 - 3.98 (m, 2H), 2.67 (t, J = 12.3 Hz, 2H), 2.14 - 2.05 (m, 2H), 1.69-1.55 (m, 2H), 1.45 (s, 9H), 1.37 - 1.31 (m, 3H), 1.15 - 1.01 (m, 2H).

[0485] 4-(buta-3-en-1-yl)piperidine(14-4)

[0486] To a solution of 14-3 (650.0 mg, 2.7 mmol) in MeOH (5 mL), HCl (4 M in dioxane, 2.5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours. The mixture was then concentrated to dryness to obtain the desired product 14-4 (720.0 mg, crude), which was used directly in the next reaction.

[0487] 4-(buta-3-en-1-yl)piperidine-1-carbonyl chloride (14-5)

[0488] To a solution of 14-4 (720.0 mg, crude) in DCM (30 mL), TEA (6 mL, 8.1 mmol) and triphosgene (1.5 g, 5.4 mmol) were added at 0°C. The resulting mixture was stirred at 20°C for 4 hours. The mixture was then concentrated to dryness to obtain the desired product 14-5 (1.0 g, crude), which was used directly in the next reaction.

[0489] Ethyl(E)-3-(1-(buta-2-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-(2-(4-(buta-3-en-1-yl)piperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(14-6)

[0490] 14-5 (1.0 g, crude) was added at 0°C to a 30 mL solution of 6-9 (0.7 g, 1.6 mmol) and TEA (810.0 mg, 8.0 mmol) in DCM. The reaction was stirred overnight at 25°C. The mixture was then concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 14-6 (0.5 g, yield 45.2%).

[0491] C 35 H 45 The calculated MS(ESI) value for N5O3 was 583.4, and the measured value was 584.8.

[0492] Ethyl(Z)-2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafane-8-en-2-yl)acetate(14-7)

[0493] Grubbs II catalyst (15.0 mg, 0.2 mmol) was added to a solution of 14-6 (0.5 g, 0.9 mmol) in DCM (30 mL) at 25 °C. The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 19 hours. Subsequently, the mixture was concentrated under vacuum to obtain the desired product 14-7 (560.0 mg, crude), which was used directly in the next reaction.

[0494] Ethyl 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetate(14-8)

[0495] Pd / C (60.0 mg) was added to a solution of 14-7 (560.0 mg, crude) in MeOH (10 mL). The resulting mixture was stirred at room temperature under an H2 atmosphere for 19 hours. The catalyst was then removed by filtration, and the filtrate was concentrated to obtain the desired product 14-8 (550.0 mg, crude).

[0496] 2-(1 4 -methyl-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 14) [ka]

[0497] LiOH·H2O (0.2 g) was added to a solution of 14-8 (550.0 mg, crude) in MeOH (10.0 mL) and water (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then acidified with 1N HCl at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, compound 14 (15.0 mg, 9.6%).

[0498] 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 4.77 (t, J = 7.8 Hz, 1H), 4.73-4.65 (m, 2H), 4.06-3.95 (m, 2H), 3.42 - 3.36 (m, 2H), 3.14-2.60 (m, 4H), 2.80-2.70 (m, 2H), 2.60 (s, 3H), 2.49-2.10 (m, 1H), 2.15-2.10 (m, 2H), 2.00-1.95 (m, 1H), 1.29-1.15 (m, 3H), 1.06-1.04 (m, 2H), 1.00-0.98 (m, 2H), 0.81 - 0.60 (m, 3H), 0.50 - 0.36 (m, 1H).

[0499] C 30 H 37 The calculated MS(ESI) value for N5O3 was 515.3, and the measured value was 516.3. Example 1.15 Synthesis of Compound 15

[0500] 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-6,9-dioxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacycloundecafan-2-yl)acetic acid (compound 15) [ka]

[0501] Benzyl-4-(2-(2-(5-(3-ethoxy-3-oxopropa-1-en-1-yl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethoxy)piperidine-1-carboxylate(15-1)

[0502] Benzyl 4-(2-(2-(5-bromo-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)ethoxy)ethoxy)piperidine-1-carboxylate (1.5 g, 2.9 mmol), ethyl acrylate (1.74 g, 17.4 mmol), and DIEA (3.3 g, 25.2 mmol) were dissolved in DMF (30 mL) and Pd(OAc)2 (37.7 mg, 0.2 mmol) and (p-tol)3P (0.1 g, 0.3 mmol) were added at 20 °C. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (150 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 15-1 (1.2 g, 77.1%).

[0503] C 29 H 36 The calculated MS(ESI) value for N4O6 was 536.3, and the measured value was 537.3.

[0504] tert-butyl7-(1-(1-(2-(2-((1-((benzyloxy)carbonyl)piperidine-4-yl)oxy)ethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-yl)-3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(15-2)

[0505] [Rh(1,5-cod)Cl]2 (113.1 mg, 0.2 mmol) was added at room temperature to a mixture of CPME (100 mL) containing 15-1 (1.2 g, 2.2 mmol), sodium dodecyl sulfate (0.3 g, 1.1 mmol), TEA (0.7 g, 0.7 mmol), and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.4 g, 6.7 mmol) and water (20 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain the desired product 15-2 (0.9 g, 52.3%).

[0506] tert-butyl7-(3-ethoxy-1-(4-methyl-1-(2-(2-(piperidine-4-yloxy)ethoxy)ethyl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(15-3)

[0507] Pd(OH)2 (20.2 mg) was added at room temperature to a solution of 15-2 (0.9 g, 0.2 mmol) in MeOH (30 mL). The resulting mixture was stirred at 20 °C under an H2 atmosphere for 6.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired product 15-3 (450.0 mg, 60.6%), which was used directly in the next reaction.

[0508] C 35 H 49 The calculated MS(ESI) value for N5O6 was 635.4, and the measured value was 636.5.

[0509] Ethyl 3-(1-(2-(2-((1-(chlorosulfonyl)piperidin-4-yl)oxy)ethoxy)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanoate (15-4)

[0510] To a solution of 15-3 (250.0 mg, 0.4 mmol) and pyridine (155.5 mg, 2.0 mmol) in DCM (20 mL) was added SO2Cl2 (106.1 mg, 0.8 mmol) in DCM (20 mL) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. TFA (357.2 mg, 3.2 mmol) was added to the above mixture at 0 °C. The resulting mixture was further stirred at room temperature under a nitrogen atmosphere for 2 hours. Then, the mixture was concentrated to dryness to obtain the crude desired product 15-4 (460.2 mg, impure), which was used directly in the next reaction.

[0511] C 30 H 40 The calculated value of MS(ESI) for ClN5O6S is 633.2, and the measured value is 634.3.

[0512] Ethyl 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 1 H-6,9-dioxa-4-thia-3(7,2)-isoquinolino[1,5,1]benzotriazolo[5,1,4]piperidinacycloundecaphane-2-yl)acetate (15-5)

[0513] TEA (0.5 g, 3.9 mmol) and DMAP (4.8 mg, 39.4 μmol) were added to a solution of 15-4 (crude, 460.0 mg, up to 0.4 mmol) in DMF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 h. Then, the mixture was poured into ice water (60 mL) and then extracted with ethyl acetate (20 mL * 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product 15-5 (100.4 mg, 48.2%).

[0514] C 30 H 39 The calculated value of MS (ESI) for N5O6S is 597.3, and the measured value is 598.3.

[0515] 2-(1 4 -methyl-4,4-dioxide-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 1 H-6,9-dioxa-4-thia-3(7,2)-isoquinolina-1(5,1)-benzod][1,2,3]triazola-5(1,4)-piperidinacycloundecaphane-2-yl)acetic acid (Compound 15)

Chemical Structure

[0516] NaOH (3.3 mg, 0.1 mmol) was added to a solution of 15-5 (90.0 mg, 0.2 mmol) in THF (5 mL), MeOH (2 mL) and H2O (2 mL) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 h. Then, the reaction mixture was acidified with 1N HCl at 0 °C and then extracted with ethyl acetate (15 mL * 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired product, Compound 15 (25.0 mg, 29.1%).

[0517] C 28 H 35 The calculated MS(ESI) value for N5O6S was 569.2, and the measured value was 570.2.

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.7 Hz, 1H), 7.37 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.25-7.21 (m, 1H), 7.08 (d, J = 7.9 Hz, 1H), 4.91 - 4.66 (m, 3H), 4.36-4.20 (m, 2H), 3.90-3.82 (m, 1H), 3.75-3.69 (m 1H), 3.63-3.57 (m, 1H), 3.50-3.45 (m, 2H), 3.36 - 3.30 (m, 1H), 3.25 - 3.18 (m, 1H), 3.16-2.99 (m, 5H), 2.90 (s, 3H), 2.82-2.77 (m, 2H), 2.67 - 2.56 (m, 1H), 2.42-2.33 (m, 2H), 1.25-1.15 (m, 2H), 0.92 - 0.67 (m, 2H). Example 1.16 Synthesis of Compound 16 and Compound 17

[0519] 2-(1 4 ,3 4 ,5-trimethyl-6-oxo-1 1 Procedure for H-9-oxa-5-aza-1(5,1)-benzo[d][1,2,3]triazola-3(1,3),7(1,4)-dibenzenacyclododecafan-2-yl)acetic acid (compounds 16 and 17) [ka]

[0520] 5-Bromo-N,2-dimethylbenzamide(16-2)

[0521] To a solution of 5-bromo-2-methylbenzoic acid (10.0 g, 46.5 mmol) in DMF (100 mL), MeNH2·HCl (6.3 g, 93.0 mmol), DIPEA (24.0 g, 186.0 mmol), and HATU (26.5 g, 69.8 mmol) were added at 0°C. The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to obtain the desired product 16-2 (12.8 g, crude).

[0522] C9H 10 BrNO's MS(ESI) calculated value: 226.9, measured values: 228.1, 230.5

[0523] 1-(5-bromo-2-methylphenyl)-N-methylmethanamine(16-3)

[0524] Borane-tetrahydrofuran complex (1M, 150mL) was added to a solution of 16-2 (12.8g, 56.1 mmol) in THF (50mL) at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. Subsequently, the reaction was quenched by adding MeOH (300mL), and the resulting mixture was concentrated to dryness to obtain the desired product 16-3 (9.5g, 79.1%).

[0525] C9H 12 BrN's MS(ESI) calculated value was 213.0, measured values ​​were 214.3 and 216.2.

[0526] tert-butyl(5-bromo-2-methylbenzyl)(methyl)carbamate(16-4)

[0527] (Boc)2O (11.6g, 53.4 mmol) was added to a solution of 16-3 (9.5g, 44.4 mmol) in THF (100 mL) and water (10 mL) at 25°C. The resulting mixture was stirred at room temperature for 19 hours. The mixture was then poured into ice water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain the desired product 16-4 (9.0g, 94.7%).

[0528] C 14 H 20 BrNO2 MS(ESI) calculated value: 313.1, measured values: 314.3, 316.2

[0529] tert-butylmethyl(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate(16-5)

[0530] Pd(dppf)Cl in a 60 mL solution of dioxane containing 16-4 (5.0 g, 16.0 mmol), B2Pin2 (4.5 g, 17.6 mmol), and AcOK (3.1 g, 31.6 mmol). 2( 1.2 g (1.6 mmol) was added. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (100 mL) and then extracted with ethyl acetate (80 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain the desired product 16-5 (2.7 g, 14.3%).

[0531] C 20 H 32 BNO4 MS(ESI) calculated value: 361.2, measured value: 362.3

[0532] tert-butyl4-((3-(5-(1-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-methylphenyl)-3-ethoxy-3-oxopropyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)benzoate(16-6)

[0533] TEA (375.2 mg, 0.5 mmol) and [Rh(1,5-cod)Cl]2 (73.0 mg, 0.2 mmol) were added to a solution of 16-5 (1.3 g, 4.5 mmol), 7-4 (0.7 g, 1.5 mmol), and sodium dodecyl sulfate (210.0 mg, 0.8 mmol) in CPME (20 mL) and water (5 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (80 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:2 to 1:1) to obtain the desired compound 16-6 (280.0 mg, 26.1%).

[0534] C 41 H 54 N4O7 MS(ESI) calculated value: 714.4, measured value: 715.2

[0535] 4-((3-(5-(3-ethoxy-1-(4-methyl-3-((methylamino)methyl)phenyl)-3-oxopropyl)-4-methyl-1H-benzo[d][1,2,3]triazole-1-yl)propoxy)methyl)benzoic acid (16-7)

[0536] To a solution of 16-6 (280.0 mg, 0.4 mmol) in MeOH (5 mL), HCl (4 M in dioxane, 5 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then concentrated to dryness to obtain the desired product 16-7 (260.0 mg, crude).

[0537] C 32 H 38The calculated MS(ESI) value for N4O5 was 558.2, and the measured value was 559.7.

[0538] Ethyl 2-(1 4 ,3 4 ,5-trimethyl-6-oxo-1 1 H-9-Oxa-5-aza-1(5,1)-benzo[d][1,2,3]triazola-3(1,3),7(1,4)-dibenzenacyclododecafan-2-yl)acetate(16-8)

[0539] HATU (0.3g, 0.7 mmol) was added at 0°C to a solution of 16-7 (260.0 mg, crude) and DIEA (0.3 g, 2.3 mmol) in DMF (10 mL). The resulting mixture was stirred at 20°C for 2 hours. The mixture was then poured into ice water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:2 to 2:1) to obtain the desired product 16-8 (240.0 mg, 95.2%).

[0540] C 32 H 36 The calculated MS(ESI) value for N4O4 was 540.3, and the measured value was 541.2.

[0541] 2-(1 4 ,3 4 ,5-trimethyl-6-oxo-1 1 H-9-Oxa-5-aza-1(5,1)-benzo[d][1,2,3]triazola-3(1,3),7(1,4)-dibenzenacyclododecafan-2-yl)acetic acid (compounds 16 and 17) [ka]

[0542] NaOH (50 mg) was added at 0°C to a solution of 16-8 (120 mg, 221.8 μmol) in MeOH (2 mL), water (2 mL), and THF (4 mL). The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 19 hours. Subsequently, the reaction mixture was acidified with 1N HCl at 0°C and then extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by Prep-HPLC (CH3CN / H2O, 0.1% HCl) to obtain the desired products, compound 16 and compound 17 (3.9 mg, 3.4%).

[0543] C 30 H 32 The calculated MS(ESI) value for N4O4 was 512.2, and the measured value was 513.4.

[0544] 1 H NMR (400 MHz, DMSO-d6): δ 13.04 - 11.15 (m, 1H), 8.29 - 6.03 (m, 9H), 5.10 - 3.86 (m, 7H), 3.15 - 2.66 (m, 7H), 2.45 - 1.90 (m, 6H), 1.27-1.20 (m, 2H).

[0545] Compounds 16 and 17 were separated by prep-HPLC using a BP-C18 column, 10 μm, 21.2*250 mm (Pntulips). Isomer 1 (i.e., compound 16) (retention time = 5.728 min) and isomer 2 (i.e., compound 17) (retention time = 6.655 min) were obtained. Example 1.17 Synthesis of Compounds 28 and 29

[0546] Procedure for the preparation of compound 28 and compound 29 [ka]

[0547] Column: DAIEL CHIRALPAK AD (250 mm*30 mm, 10 μm), mobile phase: [0.1% NH3·H2O MEOH], B%: 45%~45%, 360 mg of compound 14 was separated by SFC for 45 min. Isomer 1 of compound 14 (i.e., compound 28) (138 mg, retention time = 3.037 min) and isomer 2 of compound 14 (i.e., compound 29) (141 mg, retention time = 3.249 min) were obtained.

[0548] Isomer 1 of compound 14 (i.e., compound 28) 1 HNMR: (400 MHz, DMSO-d6) δ ppm 7.58 (d, J = 8.7 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.05 (d, J = 7.9Hz, 1H), 6.43 (s, 1H), 4.81 (br t, J = 7.4 Hz, 1H),4.71 - 4.59 (m, 2H), 4.04 - 3.90 (m, 2H), 3.56 -3.44 (m, 2H), 3.11 (br d, J = 12.6 Hz, 1H), 2.80(br d, J = 13.3 Hz, 1H), 2.74 (br t, J = 6.5 Hz, 2H), 2.69 - 2.59 (m, 2H), 2.58 - 2.54 (m, 3H),2.34 - 2.21 (m, 1H), 2.18 - 2.03 (m, 2H), 2.02 -1.89 (m, 1H), 1.30 - 1.13 (m, 2H), 1.09 - 0.92 (m,5H), 0.80 - 0.58 (m, 3H), 0.50 - 0.36 (m, 1H) LCMS: [M+H] + = 516.3, retention time = 0.834min HPLC: retention time = 3.853min, purity 94.150%.

[0549] Isomer 2 of compound 14 (i.e., compound 29) 1HNMR: (400 MHz, DMSO-d6) δ ppm 7.65 (d, J = 8.7 Hz, 1H),7.42 (d, J = 8.7 Hz, 1H), 7.33(br d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.52 (s, 1H), 4.81- 4.73 (m, 1H), 4.70 - 4.63 (m,2H), 4.05 - 3.93 (m, 2H), 3.40(br s, 2H), 3.05 (br s, 3H), 2.80 -2.73 (m, 3H), 2.59 (s, 3H), 2.33- 2.25 (m, 1H), 2.15 - 2.06 (m,2H), 1.97 (br dd, J = 5.4, 11.8Hz, 1H), 1.27 - 1.15 (m, 2H),1.09 - 0.93 (m, 5H), 0.78 - 0.59(m, 3H), 0.50 - 0.36 (m, 1H) LCMS: [M+H] + = 516.2, retention time = 0.834min HPLC: retention time = 3.848min, purity 94.231%. Example 1.18 Synthesis of Compound 30

[0550] 2-(1 4 -Chloro-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 Procedure for H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafan-2-yl)acetic acid (compound 30) [ka]

[0551] 4-Vinylpiperidine(30-2)

[0552] To a solution of tert-butyl-4-vinylpiperidine-1-carboxylate (1.0 g, 4.7 mmol) in dioxane (10 mL), HCl (4 M in dioxane, 10 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then concentrated to dryness to obtain the desired product 30-2 (660.0 mg, wet).

[0553] 4-Vinylpiperidine-1-carbonyl chloride (30-3)

[0554] Bis(trichloromethyl) carbonate (881.2 mg, 3.0 mmol) was added at 0°C to a solution of 30-2 (660 mg, 5.9 mmol) and DIEA (2.3 g, 17.8 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to obtain crude product 30-3 (1.0 g, 97.0%).

[0555] 4-Bromo-3-chloro-2-nitroaniline(30-5)

[0556] 3-chloro-2-nitroaniline (25 g, 144.8 mmol) was dissolved in AcOH (250 mL) and NBS (28.4 g, 159.3 mol) was added at 20 °C. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the reaction mixture was poured into ice water. The resulting precipitate was filtered and dried under high vacuum to obtain crude product 30-5 (35.0 g, 96%).

[0557] 4-Bromo-3-chloro-2-nitro-N-(penta-4-en-1-yl)aniline(30-6)

[0558] NaH (3.8 g, 95.4 mmol) was added at 0°C to a solution of 30-5 (20.0 g, 79.5 mmol) in DMF (200 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hours. A solution of 5-bromopenta-1-ene (17.8 g, 119.3 mmol) in THF (10 mL) was added to the above mixture. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (1 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:10~1:5) to obtain the desired product 30-6 (11.3 g, 44.5%).

[0559] 4-Bromo-3-chloro-N 1 -(penta-4-en-1-yl)benzene-1,2-diamine(30-7)

[0560] Fe powder (19.8 g, 353.6 mol) was added at 20°C to a solution of 30-6 (11.3 g, 35.4 mmol) and NH4Cl (18.9 g, 353.6 mmol) in EtOH (120 mL) and H2O (40 mL). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 4 hours. After cooling to 40°C, the mixture was filtered through a Celite pad. The filtrate was concentrated to dryness to obtain the crude product 30-7 (6.3 g, 61.5%).

[0561] 5-bromo-4-chloro-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole(30-8)

[0562] To a solution of 30-7 (6.3 g, 21.8 mmol) in HCl (6 M in H2O, 70 mL), NaNO2 (3.0 g, 43.5 mmol) in H2O (20 mL) was added at 0°C. The resulting mixture was stirred at 25°C for 4 hours. The reaction mixture was then neutralized with 4N NaOH at 0°C. The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:5 to 1:3) to obtain the desired product 30-8 (2.8 g, 42.4%).

[0563] Benzyl(E)-3-(4-chloro-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)acrylate(30-9)

[0564] Pd(OAc)2 (310.0 mg, 1.4 mmol) and P(o-tol)3 (840 mg, 2.8 mmol) were added at 20°C to a solution of 30-8 (2.8 g, 9.2 mmol), benzyl acrylate (9.0 g, 55.3 mmol), and DIEA (2.4 g, 26.0 mmol) in DMF (30 mL). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was poured into ice water (150 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:1) to obtain the desired product 30-9 (2.3 g, 65.4%).

[0565] C 21 H 20 The MS(ESI) calculated value for ClN3O2 was 381.1, and the measured value was 382.1.

[0566] tert-butyl7-(3-(benzyloxy)-1-(4-chloro-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(30-10)

[0567] [Rh(1,5-cod)Cl]2 (183.0 mg, 0.4 mmol) was added at room temperature to a mixture of CPME (20 mL) containing 30-9 (1.4 g, 3.7 mmol), sodium dodecyl sulfate (534 mg, 1.9 mmol), Et3N (1.1 g, 11.1 mmol), and tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (4.0 g, 11.1 mmol) and water (10 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the mixture was poured into ice water (50 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:3 to 1:1) to obtain the desired product 30-10 (1.2 g, 53.8%).

[0568] C 35 H 39 The MS(ESI) values ​​for ClN4O4 were calculated at 614.3, measured at 559.3 and 515.3, respectively.

[0569] Benzyl 3-(4-chloro-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(30-11)

[0570] To a solution of 30-10 (1.2 g, 2.0 mmol) in dioxane (20 mL), HCl (4 M in dioxane, 20 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours. The mixture was then concentrated to dryness to obtain the desired product 30-11 (1.1 g, wet).

[0571] C 30 H 31 The MS(ESI) calculated value for ClN4O2 was 514.2, and the measured value was 515.2.

[0572] Benzyl 3-(4-chloro-1-(penta-4-en-1-yl)-1H-benzo[d][1,2,3]triazole-5-yl)-3-(2-(4-vinylpiperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)propanoate(30-12)

[0573] DIEA (375.3 mg, 2.9 mmol) was added at 0°C to a 10 mL solution of 30-11 (500.0 mg, 1.0 mmol) and 30-3 (252.6 mg, 1.5 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The mixture was then poured into ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting ethyl acetate:petroleum ether = 1:2 to 1:1) to obtain the desired product 30-12 (550.0 mg, 86.7%).

[0574] C 38 H 42 The calculated MS(ESI) value for ClN5O3 was 651.3, and the measured value was 652.2.

[0575] Benzyl(E)-2-(1 4 -Chloro-4-oxo-3 1 ,3 2 ,3 3 ,3 4 - Tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodecafane-6-en-2-yl)acetate(30-13)

[0576] To a solution of 30-12 (550 mg, 0.8 mmol) in DCM (15 mL) was added Grubbs II catalyst (215 mg, 0.3 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 19 h. Then, the mixture was poured into ice water (20 mL) and extracted with DCM (20 mL * 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with ethyl acetate:petroleum ether = 1:2 - 1:1) to give the desired product 30-13 (70 mg, 13.3%).

[0577] C 36 H 38 The calculated value of MS (ESI) for ClN5O3 is 623.3, and the measured value is 624.3.

[0578] 2-(1 4 -chloro-4-oxo-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 1 H-3(7,2)-isoquinolina-1(5,1)-benzo[d][1,2,3]triazola-5(1,4)-piperidinacyclodeca-fan-2-yl)acetic acid (Compound 30)

Chemical Structure

[0582] Procedure for the preparation of compounds 34, 35, 47, 48, 49, and 50 [ka]

[0583] Procedure for the preparation of compound 34-2

[0584] 500 mL of AcOH solution containing 34-1 (50.0 g, 328 mmol, 1.00 equivalent) was mixed with NBS (58.4 g, 328 mmol, 1.00 equivalent). The mixture was stirred at 110°C for 1 hour. The reaction mixture was quenched by adding 20.0 L of ice water at 25°C, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to the next step without purification. 34-2 (71.0 g, 291 mmol, yield 88.8%, purity 95.0%) was obtained. LCMS:[M+H] + =230.9, retention time=0.723min

[0585] Procedure for the preparation of compound 34-3

[0586] To a DMA (200 mL) solution of 34-2 (50.0 g, 216 mmol, 1.00 equivalent), 5-bromopenta-1-ene (38.7 g, 259 mmol, 1.20 equivalent) and K2CO3 (179 g, 1.30 mol, 6.00 equivalent) were added. The mixture was stirred at 100°C for 72 hours. The reaction mixture was partitioned into EA (200 mL) and H2O (200 mL). The organic phase was separated, washed with H2O (300 mL), washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, eluate of a 0-10% ethyl acetate / petroleum ether gradient at 100 mL / min). 34-3 (29.7g, 99.2 mmol, yield 45.8%) was obtained.

[0587] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.52 (d, J = 9.05 Hz, 1 H) 6.71 (d, J = 9.17 Hz, 1 H) 5.80 (m, 1 H) 5.02 (m, 1 H) 4.95 (m, 1 H) 3.12 (m, 2 H) 2.24 (s, 3 H) 2.05 (m, 2 H) 1.60 (m, 2 H) LCMS: [M+H] + = 299.0, holding time=0.867min

[0588] Procedure for the preparation of compound 34-4

[0589] To a solution of 34-3 (29.7 g, 99.2 mmol, 1.00 equivalent) in EtOH (300 mL) and H2O (100 mL), Fe (38.8 g, 694 mmol, 7.00 equivalent) and NH4Cl (15.9 g, 297 mmol, 3.00 equivalent) were added. The mixture was stirred at 90°C for 2 hours. The reaction mixture was partitioned into EA (200 mL) and H2O (200 mL). The organic phase was separated, washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Compound 34-4 (25.0 g, 90.0 mmol, yield 90.7%, purity 97.0%) was obtained.

[0590] Procedure for the preparation of compounds 34-5

[0591] Solution 1: HBF4 (40.7 g, 185 mmol, 28.9 mL, 40.0% purity, 2.00 equivalents) and tert-butyl nitrite (14.3 g, 139 mmol, 16.5 mL, 1.50 equivalents) were dissolved in 300 mL of acetonitrile and cooled to 0°C. Solution 2: Solution of 34-4 (25.0 g, 92.8 mmol, 1.00 equivalent) dissolved in MeCN (250 mL). Solution 1 was slowly added dropwise to Solution 2 while maintaining the internal temperature below 5°C. The reaction mixture was stirred at 25°C for 2 hours. 500 mL of aqueous H2O was added dropwise to the reaction mixture, the combined organic layer was washed with aqueous NaCl (500 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, eluate with a 0-30% ethyl acetate / petroleum ether gradient at 100 mL / min). 34-5 (19.0 g, 67.8 mmol, yield 73.0%) was obtained.

[0592] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.67 (m, 1 H) 7.67 (d, J=1.10 Hz, 1 H) 5.79 (ddt, J=16.97, 10.43, 6.22, 6.22 Hz, 1 H) 4.97 (m, 2 H) 4.68 (m, 2H) 2.69 (s, 3H) 1.99 (m, 4H) LCMS: [M+H] + = 281.9, holding time=0.782min

[0593] Procedure for the preparation of compound 34-6

[0594] To a solution of 34-5 (19.0 g, 67.8 mmol, 1.00 equivalent) and ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (15.3 g, 67.8 mmol, 1.00 equivalent) in dioxane (200 mL) and H2O (50 mL), Cs2CO3 (44.1 g, 135 mmol, 2.00 equivalent) and di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (2.21 g, 3.39 mmol, 0.05 equivalent) were added. The mixture was stirred at 100 °C under N2 for 2 hours. An aqueous H2O solution (500 mL) was added dropwise to the reaction mixture, the combined organic layer was washed with an aqueous NaCl solution (500 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, eluate with a 0-30% ethyl acetate / petroleum ether gradient at 100 mL / min). 34-6 (13.3 g, 44.4 mmol, yield 65.5%) was obtained.

[0595] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.98 (m, 2 H) 7.71 (m, 1 H) 6.64 (d, J=15.76 Hz, 1 H) 5.37 (m, 2 H) 4.71 (m, 2 H) 4.21 (q, J=7.09 Hz, 2 H) 2.80 (s, 3 H) 2.59 (m, 2 H) 1.49 (d, J=4.75 Hz, 2 H) 1.28 (t, J=7.13 Hz, 3 H)

[0596] Procedure for the preparation of compound 34-7

[0597] A mixture of 34-6 (16.0 g, 53.4 mmol, 1.00 equivalent), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (30.7 g, 85.5 mmol, 1.60 equivalent), sodium dodecyl sulfate (7.71 g, 26.7 mmol, 7.63 mL, 0.50 equivalent), and chlororhodium (1Z,5Z)-cycloocta-1,5-diene (2.64 g, 5.34 mmol, 0.10 equivalent) was degassed with H2O (50 mL) and methoxycyclopentane (100 mL), purged three times with N2, and then stirred at 90°C under an N2 atmosphere for 4 hours. A 500 mL aqueous solution of H2O was added dropwise to the reaction mixture, the combined organic layer was washed with a 500 mL aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, eluate from a 0-40% ethyl acetate / petroleum ether gradient at 100 mL / min). 34-7 (26.0 g, 48.8 mmol, yield 91.3%) was obtained.

[0598] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.60 (d, J = 8.58 Hz, 1 H) 7.50 (m, 1 H) 7.12 (br d, J = 8.36 Hz, 2 H) 7.04 (m, 1 H) 5.36 (m, 1 H) 4.81 (br t, J = 7.81 Hz, 1 H) 4.64 (br t, J = 6.82 Hz, 2 H) 4.42 (br s, 2 H) 3.92 (q, J = 6.97 Hz, 2 H) 3.49 (br t, J = 5.61 Hz, 2 H) 3.15 (br d, J = 7.92 Hz, 2 H) 2.76 (m, 3 H) 2.68 (br t, J = 5.61 Hz, 2 H) 2.55 (br d, J = 6.16 Hz, 2 H) 1.49 (m, 2 H) 1.40 (s, 9 H) 0.99 (t, J = 7.15 Hz, 3 H) 0.84 (m, 2 H)

[0599] Procedure for the preparation of compound 34-8

[0600] HCl / dioxane (4.00 M, 100 mL, 10.6 equivalents) was added to a 100 mL solution of dioxane 34-7 at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain 34-8 (19.4 g, 35.1 mmol, yield 93.6%, purity 85.0%, HCl salt), which was used directly in the next step.

[0601] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.62 (m, 1 H) 7.61 (m, 1 H) 7.48 (m, 1 H) 7.24 (brd, J = 8.13 Hz, 1 H) 7.19 (s, 1 H) 7.19 (m, 1 H) 7.12 (d, J = 8.00 Hz, 1 H) 7.12 (m, 1 H) 5.37 (m, 1 H) 4.83 (t, J = 7.88 Hz, 1 H) 4.65 (m, 2 H) 4.31 (br s, 1 H) 4.17 (br s, 2 H) 3.93 (q, J = 7.05 Hz, 2 H) 3.56 (s, 1 H) 3.31 (br d, J = 4.63 Hz, 2 H) 3.16 (br d, J = 8.00 Hz, 2 H) 2.92 (br t, J = 6.07 Hz, 2 H) 2.77 (m, 3 H) 1.50 (d, J = 3.88 Hz, 2 H) 1.07 (s, 3 H) 1.00 (t, J = 7.07 Hz, 3 H)

[0602] Procedure for the preparation of compound 34-9

[0603] To a solution of 34-8 (10.0 g, 21.3 mmol, 1.00 equivalent, HCl), 4-vinylcyclohexanecarboxylic acid (3.95 g, 25.5 mmol, 1.20 equivalents), anhydrous 1-hydroxybenzotriazole (5.76 g, 42.6 mmol, 2.00 equivalents), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine hydrochloride (8.17 g, 42.6 mmol, 2.00 equivalents) in DMF (100 mL), TEA (8.63 g, 85.2 mmol, 11.8 mL, 4.00 equivalents) was added, and the reaction mixture was stirred at 25 °C under N2 for 15 hours. The mixture was diluted with H2O (500 mL) and extracted with EA (500 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, eluate with a 0-30% ethyl acetate / petroleum ether gradient at 100 mL / min). 34-9 (10.0 g, 17.5 mmol, yield 82.4%) was obtained.

[0604] 1H NMR: (400 MHz, DMSO-d6)δ ppm 7.59 (m, 1 H) 7.49 (m, 1 H) 7.13 (m, 2 H) 7.05 (m, 1 H) 5.36 (m, 1 H) 4.99 (m, 1 H) 4.91 (m, 1 H) 4.82 (br d, J = 6.00 Hz, 1 H) 4.63 (br d, J = 6.38 Hz, 2 H) 4.52 (br s, 1 H) 3.92 (q, J = 7.09 Hz, 2 H) 3.83 (br d, J = 6.13 Hz, 1 H) 3.64 (m, 2 H) 3.30 (s, 1 H) 3.15 (br d, J = 8.13 Hz, 2 H) 2.76 (br d, J = 5.00 Hz, 4 H) 2.65 (m, 1 H) 2.55 (br d, J = 6.00 Hz, 1 H) 1.94 (m, 3 H) 1.69 (m, 4 H) 1.59 (br d, J = 7.38 Hz, 1 H) 1.49 (br d, J = 4.00 Hz, 2 H) 1.36 (m, 3 H) 1.16 (m, 2 H) 1.06 (s, 1 H) 0.98 (t, J = 7.07 Hz, 3 H) LCMS: [M+H] + = 569.2, Holding time = 0.844 min

[0605] The preparation method of compound 34-10 and compound 35-1

[0606] To a solution of 34-9 (10.0 g, 17.6 mmol, 1.00 equivalent) in DCE (200 mL), [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (440 mg, 703 μmol, 0.20 equivalents) was added under N2 conditions. The mixture was stirred at 50°C for 18 hours. The mixture was concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluate from a 0-50% ethyl acetate / petroleum ether gradient at 60 mL / min). A mixture of 34-10 and 35-1 (1.40 g, 2.38 mmol, yield 14.0%, purity 92.0%) was obtained.

[0607] Procedure for the preparation of compounds 34-11 and 35-2

[0608] A mixed solution of 34-10 and 35-1 (1.34 g, 2.48 mmol, 1.00 equivalent) in MeOH (15.0 mL) was mixed with wet Pd / C (1.00 g, purity 10.0%) under H2 (15.0 psi). The mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered and concentrated. The residue was subjected to the next step without purification. A mixture of 34-11 and 35-2 (1.30 g, 2.16 mmol, yield 86.9%, purity 90.0%) was obtained. LCMS:[M+H] + =529, holding time=0.760min, [M+H] + =543, holding time=0.780min

[0609] Procedure for the preparation of compounds 34 and 35

[0610] To a solution of 34-11 and 35-2 (mixture, 1.30 g, 2.40 mmol, 1.00 equivalent) in MeOH (50.0 mL) and H2O (2.00 mL), NaOH (2.00 M, 5.39 mL, 4.50 equivalents) was added at 0°C. The resulting mixture was stirred at 25°C for 18 hours. Subsequently, the reaction mixture was acidified with 1.00 M HCl equivalent at 0°C and extracted with ethyl acetate (50 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30 mm*3 μm, mobile phase: [water (FA)-ACN], B%: 23%~63%, 9 min) to obtain compounds 34 and 35.

[0611] Procedure for the preparation of compounds 47, 48, 49, and 50 [ka]

[0612] Compounds 34 and 35 were further separated by SFC (column: Boston Prime C18 150*30mm*5um, mobile phase: [water (ammonia hydroxide v / v)-ACN], B%: 33%~53%, 9 min) and SFC (column: DAIEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: [0.1%NH3H2O ​​ETOH], B%: 60%~60%, min). Isomer 1 of compound 34 (i.e., compound 47) (246.5 mg, 491 μmol, yield 20.5%, retention time = 4.060 min), isomer 2 of compound 34 (i.e., compound 48) (261.6 mg, 521 μmol, yield 21.7%, retention time = 6.821 min), isomer 1 of compound 35 (i.e., compound 49) (18.5 mg, 35.9 μmol, yield 1.50%, retention time = 4.229 min), and isomer 2 of compound 35 (i.e., compound 50) (23.5 mg, 45.6 μmol, yield 1.91%, retention time = 6.076 min) were obtained.

[0613] Isomer 1 of compound 34 (i.e., compound 47) 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=8.56 Hz, 1 H) 7.50 (br d, J=8.68 Hz, 1 H) 7.43 (br d, J=7.70 Hz, 1 H) 7.18 (d, J=7.70 Hz, 1 H) 6.80 (s, 1 H) 4.99 (br t, J=7.95 Hz, 1 H) 4.75 (m, 3 H) 4.38 (m, 2 H) 3.73 (m, 2 H) 3.19 (m, 2 H) 2.91 (br t, J=6.85 Hz, 2 H) 2.78 (s, 3 H) 2.27 (br t, J=11.74 Hz, 1 H) 1.96 (m, 2 H) 1.31 (br d, J=13.69 Hz, 2 H) 1.22 (m, 2 H) 1.03 (br d, J=7.46 Hz, 2 H) 0.94 (br s, 2 H) 0.72 (br s, 2 H) 0.56 (br s, 1 H) 0.45 (br d, J=11.86 Hz, 1 H) 0.34 (br d, J=11.00 Hz, 1 H) LCMS: [M+H] + = 501.2, Holding time = 0.878 min

[0614] Compound 34's opposite body 2 (i.e., Compound 48) 11H NMR: (400 MHz, DMSO-d6) δ ppm 7.57 (broad d, J = 8.68 Hz, 1 H) 7.48 (broad s, 1 H) 7.39 (broad d, J = 6.97 Hz, 1 H) 7.14 (d, J = 7.70 Hz, 1 H) 6.75 (s, 1 H) 4.95 (multiplet, 1 H) 4.71 (multiplet, 3 H) 4.34 (multiplet, 2 H) 3.67 (multiplet, 2 H) 3.13 (multiplet, 2 H) 2.87 (broad t, J = 6.79 Hz, 2 H) 2.74 (s, 3 H) 2.23 (broad t, J = 11.55 Hz, 1 H) 1.92 (multiplet, 2 H) 1.27 (broad d, J = 13.20 Hz, 3 H) 1.15 (multiplet, 2 H) 0.98 (broad d, J = 7.83 Hz, 2 H) 0.90 (broad s, 2 H) 0.67 (broad s, 2 H) 0.51 (broad s, 1 H) 0.43 (broad s, 1 H) 0.30 (broad d, J = 11.25 Hz, 1 H) LCMS: [M+H] + = 501.2, retention time = 0.870 min

[0615] Isomer 1 of Compound 35 (i.e., Compound 49) 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.57 (multiplet, 1 H) 7.50 (multiplet, 1 H) 7.41 (broad d, J = 7.95 Hz, 1 H) 7.16 (d, J = 7.82 Hz, 1 H) 6.85 (s, 1 H) 4.92 (multiplet, 3 H) 4.68 (multiplet, 2 H) 4.41 (multiplet, 2 H) 3.70 (t, J = 6.72 Hz, 2 H) 3.12 (multiplet, 2 H) 2.87 (broad t, J = 6.60 Hz, 2 H) 2.73 (s, 3 H) 2.38 (broad t, J = 11.49 Hz, 1 H) 2.10 (broad doublet of doublets, J = 12.65, 7.40 Hz, 2 H) 1.28 (broad d, J = 7.09 Hz, 4 H) 1.06 (multiplet, 5 H)+ = 515.2, holding time=0.902min

[0616] Isomer 2 of compound 35 (i.e., compound 50) 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.57 (m, 1 H) 7.50 (m, 1 H) 7.41 (br d, J=7.70 Hz, 1 H) 7.16 (d, J=7.70 Hz, 1 H) 6.85 (s, 1 H) 4.68 (br t, J=3.79 Hz, 2 H) 4.55 (br s, 3 H) 4.41 (m, 2 H) 3.70 (t, J=6.72 Hz, 2 H) 3.12 (m, 2 H) 2.87 (br t, J=6.54 Hz, 2 H) 2.73 (s, 3 H) 2.38 (br t, J=11.55Hz, 1H) 2.11 (m, 2 H) 1.28 (br d, J=6.36 Hz, 4 H) 1.04 (m, 5 H) 0.87 (br d, J=12.96 Hz, 2 H) 0.74 (m, 1 H) 0.52 (m, 2 H) LCMS: [M+H] + = 515.2, holding time=0.900min Example 1.20 Synthesis of Compound 40

[0617] Procedure for the preparation of compound 40 [ka]

[0618] Procedure for the preparation of compound 40-2

[0619] To a 100 mL solution of TFA containing 40-1 (23 g, 148 mmol, 1 equivalent), H2SO4 (40 mL) was slowly added at 0°C, followed by the gradual addition of NBS (29.0 g, 163 mmol, 1.1 equivalents). The mixture was stirred at 0-25°C for 16 hours. The resulting mixture was poured onto ice, and the precipitated solid was collected by filtration. After washing with water and vacuum drying, compound 40-2 (29 g, 124 mmol, yield 83.6%) was obtained.

[0620] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.96 (dd, J = 9.0, 5.0 Hz, 1 H) 7.47 (t, J = 9.3 Hz, 1 H) 2.35 (s, 3 H)

[0621] Procedure for the preparation of compound 40-3

[0622] A mixture of 40-2 (15g, 64.10 mmol, 1 equivalent), ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (14.5g, 64.1 mmol, 1 equivalent), di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (2.09g, 3.20 mmol, 0.05 equivalents), and cesium carbonate (41.8g, 128 mmol, 2 equivalents) in dioxane (160mL) and H2O (40mL) was degassed, purged three times with N2, and then stirred at 100°C under an N2 atmosphere for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (100mL) and extracted with SiO2 (100mL x 3). The combined organic layer was washed with brine (300 mL x 2), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluate of a 0-15% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain compound 40-3 (13.2 g, 52.1 mmol, yield 81.3%).

[0623] 1H NMR: (400 MHz, DMSO-d6) δ ppm 8.05 (dd, J = 8.9, 5.6 Hz, 1 H) 7.79 (d, J = 15.8 Hz, 1 H) 7.52 (t, J = 9.3 Hz, 1 H) 6.63 (d, J = 15.8 Hz, 1 H) 4.21 (q, J = 7.0 Hz, 2 H) 2.35 (s, 3 H) 1.27 (t, J = 7.0 Hz, 3 H)

[0624] Procedure for the preparation of compound 40-4

[0625] A mixture of 40-3 (2.5 g, 9.87 mmol, 1 equivalent), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (5.32 g, 14.8 mmol, 1.5 equivalents), sodium dodecyl sulfate (1.42 g, 4.94 mmol, 1.41 mL, 0.5 equivalents), chlororhodium, (1Z,5Z)-cycloocta-1,5-diene (487 mg, 987 μmol, 0.1 equivalents) TEA (6 mL), methoxycyclopentane (60 mL), and H2O (30 mL) was degassed, purged three times with N2, and then stirred at 90°C under an N2 atmosphere for 4 hours. The reaction mixture was partitioned into H2O (30 mL) and siRNA (100 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluate with a 0-18% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain compound 40-4 (3.9 g, 8.02 mmol, yield 81.2%).

[0626] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.70 (dd, J=8.9, 5.6 Hz, 1 H) 7.43 (t, J=9.2 Hz, 1 H) 7.01 - 7.17 (m, 3 H) 4.65 (t, J=7.9 Hz, 1 H) 4.43 (br s, 2 H) 3.97 (q, J=7.2 Hz, 2 H) 3.51 (br t, J=5.5 Hz, 2 H) 3.08 - 3.23 (m, 2 H) 2.70 (br t, J=5.9 Hz, 2 H) 2.29 (s, 3 H) 1.41 (s, 9 H) 1.05 (t, J=7.0Hz, 3H)

[0627] Procedure for the preparation of compound 40-5

[0628] A mixture of 40-4 (2g, 4.11 mmol, 1 equivalent), tert-butyl N-(8-aminooctyl)carbamate (2.01g, 8.22 mmol, 2 equivalents), and Na2CO3 (1.31g, 12.33 mmol, 3 equivalents) in DMSO (20 mL) was degassed, purged three times with N2, and then stirred at 140°C under an N2 atmosphere for 5 hours. The residue was diluted with H2O (15 mL) and extracted with SiO2 (20 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate (0 / 1~4 / 1) to obtain compound 40-5 (2.5g, 3.52 mmol, yield 85.5%).

[0629] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.33 (d, J = 8.8 Hz, 1 H) 6.99 - 7.10 (m, 3 H) 6.65 - 6.79 (m, 2 H) 5.67 (t, J = 5.5 Hz, 1 H) 4.47 - 4.56 (m, 1 H) 4.43 (br s, 2 H) 3.88 - 4.10 (m, 1 H) 3.88 - 4.10 (m, 2 H) 3.50 (br s, 2 H) 2.97 (br d, J = 7.8 Hz, 1 H) 2.94 - 3.15 (m, 3 H) 2.87 (q, J = 6.5Hz, 2H) 2.69 (br t, J = 5.9 Hz, 2 H) 2.14 (s, 3 H) 1.99 (s, 1 H) 1.41 (s, 8 H) 1.38 - 1.45 (m, 1 H) 1.36 (s, 9 H) 1.13 - 1.29 (m, 10 H) 1.05 (t, J = 7.2Hz, 3H)

[0630] Procedure for the preparation of compound 40-6

[0631] To a solution of 40-5 (1 g, 1.41 mmol, 1 equivalent) in EtOH (9 mL) and H2O (3 mL), Fe (550 mg, 9.85 mmol, 7 equivalents) and NH4Cl (150 mg, 2.81 mmol, 2 equivalents) were added. The mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluate from a 0-25% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain compound 40-6 (0.86 g, 1.26 mmol, yield 89.8%). LCMS:[M+H] + =667, holding time = 1.002 min

[0632] Procedure for the preparation of compound 40-7

[0633] To a solution of 40-6 (860 mg, 1.26 mmol, 1 equivalent) in AcOH (15 mL), NaNO2 (104 mg, 1.52 mmol, 1.2 equivalents) in H2O (3 mL) was added dropwise at 25°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the AcOH. The residue was diluted with H2O (30 mL) and extracted with siRNA (50 mL x 2). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 40-7 (820 mg, 1.19 mmol, yield 93.8%).

[0634] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.56 - 7.62 (m, 1 H) 7.49 (d, J = 8.8 Hz, 1 H) 7.08 - 7.16 (m, 2 H) 7.02 - 7.06 (m, 1 H) 6.71 (br s, 1 H) 4.81 (t, J = 7.9 Hz, 1 H) 4.61 (br t, J = 6.9 Hz, 2 H) 4.42 (br s, 2 H) 3.92 (q, J = 7.1 Hz, 2 H) 3.49 (br t, J = 5.8 Hz, 2 H) 3.13 - 3.18 (m, 2 H) 2.84 (q, J = 6.6 Hz, 2 H) 2.76 (s, 3 H) 2.68 (br t, J = 5.6 Hz, 2 H) 1.79 - 1.89 (m, 2 H) 1.40 (s, 9 H) 1.34 (s, 9 H) 1.12 - 1.27 (m, 10 H) 0.98 (t, J = 7.2 Hz, 3H)

[0635] Procedure for the preparation of compound 40-8

[0636] A mixture of 40-7 (0.2 g, 289 μmol, 1 equivalent) in HCl / dioxane (4 M, 10 mL) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without further purification. Compound 40-8 (140 mg, 284 μmol, 98.5% yield) was obtained.

[0637] Procedure for the preparation of compound 40-9

[0638] To a solution of 40-8 (0.26 g, 528 μmol, 1 equivalent) in DMF (26 mL), CDI (85.7 mg, 528 μmol, 1 equivalent) and TEA (321 mg, 3.17 mmol, 441 μL, 6 equivalents) were added at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with RINKAN (50 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 8 g SepaFlash® silica flash column, eluate from a 0-70% ethyl acetate / petroleum ether gradient at 50 mL / min) to obtain compound 40-9 (30 mg, 57.9 μmol, yield 10.9%).

[0639] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.59 (d, J = 8.8 Hz, 1 H) 7.25 - 7.38 (m, 2 H) 7.08 (d, J = 7.8 Hz, 1 H) 6.52 (s, 1 H) 6.17 (br t, J = 4.9 Hz, 1 H) 4.84 (br t, J = 7.9 Hz, 1 H) 4.57 - 4.77 (m, 2 H) 4.08 - 4.27 (m, 2 H) 3.96 (q, J = 7.0 Hz, 2 H) 2.97 - 3.19 (m, 2 H) 2.77 (s, 3 H) 2.66 (br s, 2 H) 1.91 (br d, J = 6.3 Hz, 2 H) 1.18 - 1.27 (m, 3 H) 0.72 - 1.17 (m, 14 H)

[0640] Procedure for the preparation of compound 40-10

[0641] To a 10 mL solution of 40-9 (40 mg, 77.2 μmol, 1 equivalent) in DMF, NaH (30.91 mg, 772 μmol, 60% purity, 10 equivalents) and MeI (10.9 mg, 77.3 μmol, 4.81 μL, 1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding saturated NH4Cl (20 mL) and extracted with HCl (20 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product 40-10 (32 mg, 60.2 μmol, 77.9% yield) was used in the next step without further purification. LCMS:[M+H] + =518.3, retention time=1.789min

[0642] Procedure for the preparation of compound 40

[0643] NaOH (1M, 300μL, 5 equivalents) was added to a solution of 40-10 (32 mg, 60.2 μmol, 1 equivalent) in MeOH (2 mL). The mixture was stirred at 25°C for 4 hours. Subsequently, the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the MeOH. The residue was purified by prep-HPLC (FA conditions) to obtain compound 40 (11 mg, 21.2 μmol, yield 35.3%, purity 97.272%).

[0644] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.66 (d, J = 8.8 Hz, 1 H) 7.49 (d, J = 8.5 Hz, 1 H) 7.32 (br d, J = 7.5 Hz, 1 H) 7.08 (d, J = 7.8 Hz, 1 H) 6.54 (s, 1 H) 4.75 - 4.82 (m, 1 H) 4.61 - 4.75 (m, 2 H) 4.00 - 4.17 (m, 2 H) 3.22 - 3.44 (m, 2 H) 3.08 (tt, J = 16.0, 8.1 Hz, 2 H) 2.76 - 2.89 (m, 2 H) 2.71 (br t, LCMS: [M+H] + =504.3, retention time=0.675min HPLC: retention time=3.813, purity 97.272% Example 1.21 Synthesis of Compound 41

[0645] Procedure for the preparation of compound 41 [ka]

[0646] Procedure for the preparation of compound 41-1

[0647] A mixture of 40-4 (1 g, 2.06 mmol, 1 equivalent), 10-aminodecanoic acid (1.25 g, 6.67 mmol, 3.25 equivalents), and Na2CO3 (653.54 mg, 6.17 mmol, 3 equivalents) in DMSO (3 mL) was degassed, purged three times with N2, and then stirred at 140°C under an N2 atmosphere for 5 hours. The residue was diluted with 15 mL of H2O and extracted with 60 mL of siRNA (20 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel chromatography eluted with petroleum ether:ethyl acetate (0 / 1 to 4 / 1) to obtain compound 41-1 (0.994 g, 1.52 mmol, yield 73.9%).

[0648] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 11.95 (br s, 1 H) 7.33 (d, J = 8.8 Hz, 1 H) 6.96 - 7.12 (m, 3 H) 6.70 (d, J = 9.0 Hz, 1 H) 5.66 (t, J = 5.4 Hz, 1 H) 4.51 (t, J = 7.9 Hz, 1 H) 4.43 (br s, 2 H) 4.09 (q, J = 5.0 Hz, 2 H) 3.96 (q, J = 7.2 Hz, 2 H) 3.50 (br s, 2 H) 3.17 (d, J = 4.8 Hz, 4 H) 2.98 - 3.10 (m, 4 H) 2.69 (br t, J = 5.8 Hz, 2 H) 2.17 (t, J = 7.3 Hz, 2 H) 2.14 (s, 3 H) 1.41 (s, 9 H) 1.24 (br s, 16 H) 1.05 (t, J = 7.2 Hz, 3 H)

[0649] Procedure for the preparation of compound 41-2

[0650] To a solution of 41-1 (0.9 g, 1.38 mmol, 1 equivalent) in EtOH (9 mL) and H2O (3 mL), Fe (538 mg, 9.64 mmol, 7 equivalents) and NH4Cl (147 mg, 2.75 mmol, 2 equivalents) were added. The mixture was stirred at 90°C for 2 hours. The reaction mixture was diluted with 50 mL of H2O and extracted with siRNA (50 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluate from a 0-60% ethyl acetate / petroleum ether gradient at 60 mL / min) to obtain compound 41-2 (460 mg, 737 μmol, yield 53.6%).

[0651] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 6.89 - 7.03 (m, 3 H) 6.49 (d, J = 8.3 Hz, 1 H) 6.30 (d, J = 8.3 Hz, 1 H) 4.50 (br t, J = 7.8 Hz, 1 H) 4.40 (br s, 2 H) 3.94 (q, J = 7.0 Hz, 2 H) 3.44 - 3.57 (m, 2 H) 2.84 - 3.00 (m, 4 H) 2.68 (br t, J = 5.5 Hz, 2 H) 2.13 - 2.22 (m, 2 H) 1.96 (s, 3 H) 1.53 - 1.60 (m, 2H) 1.41 (s, 12 H) 1.20 - 1.31 (m, 12 H) 1.06 (t, J = 7.2 Hz, 3 H) 0.81 - 0.92 (m, 1 H)

[0652] Procedure for the preparation of compound 41-3

[0653] To a solution of 41-2 (450 mg, 721 μmol, 1 equivalent) in AcOH (20 mL), NaNO2 (59.7 mg, 865 μmol, 1.2 equivalents) in H2O (4 mL) was added dropwise at 25°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with HCl (10 mL x 3). The combined organic layer was washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluate with a 0-40% HCl / petroleum ether gradient at 50 mL / min) to obtain compound 41-3 (170 mg, 268 μmol, yield 37.1%).

[0654] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1 H) 7.57 - 7.63 (m, 1 H) 7.50 (d, J = 8.8 Hz, 1 H) 7.09 - 7.17 (m, 2 H) 7.01 - 7.08 (m, 1 H) 4.82 (t, J = 7.9 Hz, 1 H) 4.61 (br t, J = 6.9 Hz, 2 H) 4.42 (br s, 2 H) 3.92 (q, J = 7.0 Hz, 2 H) 3.49 (br t, J = 5.6 Hz, 2 H) 3.12 - 3.19 (m, 2 H) 2.77 (s, 3H) 2.68 (br t, J = 5.6 Hz, 2 H) 2.15 (t, J = 7.4 Hz, 2 H) 1.79 - 1.90 (m, 2 H) 1.40 (s, 9 H) 1.13 - 1.28 (m, 12 H) 0.99 (t, J = 7.2 Hz, 3 H)

[0655] Procedure for the preparation of compound 41-4

[0656] The HCl / dioxane (4M, 10 mL) mixture 41-3 (150 mg, 236 μmol, 1 equivalent) was degassed, purged three times with N2, and then the mixture was stirred at 25°C under an N2 atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 41-4 (101 mg, 176 μmol, yield 74.8%, HCl salt). LCMS:[M+H] + =549.4, retention time=0.687min

[0657] Procedure for the preparation of compounds 41-5

[0658] To a solution of 41-4 (101 mg, 189 μmol, 1 equivalent) in MeCN (3 mL), 1-methylimidazole (155 mg, 1.89 mmol, 150 μL, 10 equivalents) and [chloro(dimethylamino)methylene]-dimethylammonium hexafluorophosphate (58.3 mg, 207 μmol, 1.1 equivalents) in ACN (3 mL) were added dropwise. The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove ACN. The residue was diluted with H2O (20 mL) and extracted with RINKAN (20 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude compound 41-5 (163 mg, 110 μmol, yield 58.4%, purity 35%). LCMS: [M+H] + =517.3, retention time=1.856min

[0659] Procedure for the preparation of compound 41

[0660] To a solution of 41-5 (190 mg, 128 μmol, 35% purity, 1 equivalent) in MeOH (5 mL), NaOH (1 M, 643 μL, 5 equivalents) was added. The mixture was stirred at 70°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (FA conditions) to obtain compound 41 (16 mg, 31.5 μmol, 24.5% yield, 96.2% purity).

[0661] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.57 (br s, 1 H) 7.41 - 7.51 (m, 1 H) 7.00 - 7.24 (m, 3 H) 4.79 (br s, 1 H) 4.43 - 4.64 (m, 4 H) 3.04 (br s, 2 LCMS: [M+H] + =489.6, retention time=0.769min Example 1.22 Synthesis of Compound 44

[0662] Synthesis of 2-(14,6-dimethyl-7-oxo-11H-6-aza-1(5,1)-benzo[d][1,2,3]triazola-8(1,4)-piperidina-3(1,4)benzenacyclotridekafan-2-yl)acetic acid (compound 44) [ka]

[0663] Procedure for the preparation of compound 44-1

[0664] A mixture of 44-1 (420 mg, 583 μmol, 1 equivalent) and HCl / dioxane (10 mL) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product 44-2 (325 mg, 548 μmol, yield 94.00%, 2HCl) was used in the next step without further purification. Compound 44-2 (325 mg, 548 μmol, yield 94.00%, 2HCl) was obtained. LCMS:[M+H] + =520.3, holding time=1.380min

[0665] Procedure for the preparation of compound 44-3

[0666] To a 5 mL solution of 44-2 (400 mg, 769 μmol, 1 equivalent) in DCM, bis(trichloromethyl) carbonate (91.3 mg, 307 μmol, 0.4 equivalents) and DIPEA (994 mg, 7.70 mmol, 1.34 mL, 10 equivalents) were added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. Crude product 44-3 (100 mg, 183 μmol, yield 23.8%) was used in the next step without further purification. Compound 44-3 (100 mg, 183 μmol, yield 23.8%) was obtained. LCMS:[M+H] + =546.3, retention time=0.981min

[0667] Procedure for the preparation of 2-(14,6-dimethyl-7-oxo-11H-6-aza-1(5,1)-benzo[d][1,2,3]triazola-8(1,4)-piperidina-3(1,4)-benzenacyclotridekafan-2-yl)acetic acid (compound 44) [ka]

[0668] To a solution of 44-3 (100 mg, 183 μmol, 1 equivalent) in MeOH (5 mL), NaOH (1 M, 916 μL, 5 equivalents) was added. The mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (TFA conditions). Compound 44 (5 mg, 9.44 μmol, yield 5.15%, purity 97.6%) was obtained.

[0669] 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.59 - 7.66 (m, 1 H) 7.52 (d, J=8.6 Hz, 1 H) 7.24 (d, J=8.1 Hz, 2 H) 7.03 (d, J=8.0 Hz, 2 H) 4.77 (t, J=7.9 Hz, 1 H) 4.66 (br t, J=5.6 Hz, 2 H) 3.03 (br d, J=7.9 Hz, 2 H) 2.86 (br d, J=13.3 Hz, 1 H) 2.64 - 2.78 (m, 6 H) 2.60 (s, 3 H) 2.25 - 2.33 (m, 1 H) 1.83 - 1.97 (m, 3 H) 1.44 (br t, J=11.6 Hz, 1 H) 1.05 - 1.14 (m, 1 H) 0.99 (br d, J=11.3 Hz, 1 H) 0.80 - 0.93 (m, 2 H) 0.73 (br dd, J=12.9, 6.2 Hz, 1 H) 0.53 - 0.66 (m, 1 H) 0.33 - 0.52 (m, 4 H) -0.02 - 0.08 (m, 1 H) -0.06 - 0.10 (m, 1 H) LCMS: [M+H] + =518.3, retention time=0.872min Example 1.23 Synthesis of Compounds 55 and 56

[0670] Procedure for the preparation of 2-(4-oxo-31,32,33,34-tetrahydro-13H-3(7,2)-isoquinolina-1(6,3)-[1,2,3]triazolo[4,5-b]pyridina-5(1,4)-cyclohexanacyclodecafan-2-yl)acetic acid (compound 55) and 2-(4-oxo-31,32,33,34-tetrahydro-13H-3(7,2)-isoquinolina-1(6,3)-[1,2,3]triazolo[4,5-b]pyridina-5(1,4)-cyclohexanacyclonononaphane-2-yl)acetic acid (compound 56) [ka]

[0671] Procedure for the preparation of compound 55-2

[0672] To a DMA (300 mL) solution of 55-1 (20 g, 91.7 mmol, 1 equivalent), K2CO3 (76.1 g, 550 mmol, 6 equivalents) and 5-bromopenta-1-ene (27.3 g, 183 mmol, 21.7 mL, 2 equivalents) were added. The mixture was stirred at 90°C for 18 hours. The reaction mixture was diluted with H2O (500 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was washed with aqueous brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SepaFlash® silica flash column, eluate of 0-10% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain compound 55-2 (24 g, 83.9 mmol, yield 91.4%).

[0673] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 8.49 - 8.56 (m, 2 H) 8.47 (d, J=2.2 Hz, 1 H) 5.64 - 5.96 (m, 1 H) 4.82 - 5.12 (m, 2 H) 3.46 - 3.59 (m, 2 H) 2.06 (q, J=7.0 Hz, 2 H) 1.67 (quin, J=7.3 Hz, 2 H)

[0674] Procedure for the preparation of compound 55-3

[0675] A mixture of 55-2 (22 g, 76.9 mmol, 1 equivalent), NH4Cl (8.23 g, 154 mmol, 2 equivalents), and Fe (30.1 g, 538 mmol, 7 equivalents) in EtOH (180 mL) and H2O (60 mL) was stirred at 90 °C under an N2 atmosphere for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (100 mL) and extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 55-3 (19.5 g, 76.1 mmol, yield 99.0%).

[0676] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.36 (d, J=2.0 Hz, 1 H) 6.78 (d, J=2.0 Hz, 1 H) 5.75 - 5.81 (m, 1 H) 4.85 - 5.14 (m, 5 H) 3.21 - 3.32 (m, 2 H) 2.04 - 2.11 (m, 2 H) 1.60 - 1.68 (m, 2 H)

[0677] Procedure for the preparation of compound 55-4

[0678] To a 200 mL solution of 55-3 (20 g, 78.1 mmol, 1 equivalent) of ACN, trifluoroborane hydrofluoride (13.7 g, 156 mmol, 9.73 mL, 2 equivalents) and tert-butyl nitrite (12.1 g, 117 mmol, 13.9 mL, 1.5 equivalents) were added at 0°C. The mixture was stirred at 0-25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the ACN. The residue was diluted with H₂O (50 mL) and extracted with siRNA (50 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330g SepaFlash® silica flash column, eluate with a 0-20% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain compound 55-4 (11.8 g, 44.2 mmol, yield 56.6%).

[0679] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 8.93 (d, J=2.0 Hz, 1 H) 8.84 (d, J=2.0 Hz, 1 H) 5.78 (ddt, J=17.0, 10.4, 6.3, 6.3 Hz, 1 H) 4.90 - 5.06 (m, 2 H) 4.64 - 4.77 (m, 2 H) 2.05 (br d, J=3.3 Hz, 4 H)

[0680] Procedure for the preparation of compound 55-5

[0681] A mixture of dioxane (200 mL) and H2O (50 mL) containing 55-4 (11.9 g, 44.7 mmol, 1 equivalent), ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (12.2 g, 53.6 mmol, 1.2 equivalents), di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (1.17 g, 1.79 mmol, 0.04 equivalents), and Cs2CO3 (29.1 g, 89.4 mmol, 2 equivalents) was degassed, purged three times with N2, and then stirred at 100°C under an N2 atmosphere for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the dioxane (200 mL). The residue was diluted with H2O (50 mL) and extracted with SiO2 (100 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluate of a 0-20% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain compound 55-5 (11.5 g, 40.1 mmol, yield 89.6%).

[0682] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 9.14 (d, J=1.8 Hz, 1 H) 8.98 (d, J=1.8 Hz, 1 H) 7.89 (d, J=16.3 Hz, 1 H) 6.95 (d, J=16.1 Hz, 1 H) 5.66 - 5.97 (m, 1 H) 4.92 - 5.06 (m, 2 H) 4.72 (t, J=6.6 Hz, 2 H) 4.22 (q, J=7.0 Hz, 2 H) 1.99 - 2.12 (m, 4 H) 1.28 (t, J=7.2 Hz, 3 H)

[0683] Procedure for the preparation of compounds 55-6

[0684] A mixture of 55-5 (11.4 g, 39.7 mmol, 1 equivalent), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (21.4 g, 59.6 mmol, 1.5 equivalents), chlororhodium (1Z,5Z)-cycloocta-1,5-diene (1.96 g, 3.97 mmol, 0.1 equivalents), sodium dodecyl sulfate (5.73 g, 19.9 mmol, 5.67 mL, 0.5 equivalents) TEA (20 mL), methoxycyclopentane (200 mL), and H2O (100 mL) was degassed, purged three times with N2, and then the mixture was stirred at 90°C under an N2 atmosphere for 4 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, eluate from a 0-20% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain compound 55-6 (16.6 g, 31.9 mmol, yield 80.1%).

[0685] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 8.79 (d, J=1.8 Hz, 1 H) 8.58 (d, J=1.8 Hz, 1 H) 7.17 - 7.33 (m, 2 H) 7.06 (d, J=7.8 Hz, 1 H) 5.67 - 5.90 (m, 1 H) 4.89 - 5.05 (m, 2 H) 4.62 - 4.73 (m, 3 H) 4.44 (br s, 2 H) 3.93 - 3.96 (m, 2 H) 3.49 (br t, J=5.5 Hz, 2 H) 2.68 (br t, J=5.8 Hz, 2 H) 2.36 - 2.56 (m, 2 H) 1.99 - 2.06 (m, 4 H) 1.40 (s, 9 H) 1.02 (t, J=7.0 Hz, 3 H)

[0686] Procedure for the preparation of compound 55-7

[0687] A mixture of 55-6 (4 g, 7.70 mmol, 1 equivalent) in HCl / siRNA (15 mL) was degassed, purged three times with N2, and then the mixture was stirred at 25°C under an N2 atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 55-7 (3.5 g, 7.68 mmol, 99.7% yield, HCl salt). LCMS:[M+H] + =420.5, retention time=0.817min

[0688] Procedure for the preparation of compound 55-8

[0689] A mixture of 1-hydroxybenzotriazole (1.48 g, 10.97 mmol, 2 equivalents), TEA (2.22 g, 21.9 mmol, 3.05 mL, 4 equivalents), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine hydrochloride (2.10 g, 10.97 mmol, 2 equivalents) in DMF (15 mL) was degassed, purged three times with N2, and 4-vinylcyclohexanecarboxylic acid (1.01 g, 6.58 mmol, 1.2 equivalents) was added at 25°C. After stirring for 0.5 hours, 55-7 (2.5 g, 5.48 mmol, 1 equivalent, HCl salt) from DMF (25 mL) was added dropwise, and the mixture was stirred at 25°C under an N2 atmosphere for 18 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with SiO (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, eluate from a 0-60% ethyl acetate / petroleum ether gradient at 100 mL / min). Compound 55-8 (2 g, 3.60 mmol, yield 65.6%) was obtained.

[0690] 1H NMR: (400 MHz, DMSO-d6) δ ppm 8.78 (br s, 1 H) 8.52 - 8.62 (m, 1 H) 7.95 (s, 1 H) 7.20 - 7.35 (m, 2 H) 7.07 (d, J=8.0 Hz, 1 H) 5.69 - 5.83 (m, 2 H) 4.93 - 5.04 (m, 3 H) 4.89 (br d, J=10.5 Hz, 1 H) 4.61 - 4.72 (m, 3 H) 4.54 (s, 1 H) 3.89 - 4.00 (m, 2 H) 3.55 - 3.73 (m, 2 H) 2.89 (s, 4H) 2.73 (s, 4 H) 1.95 - 2.08 (m, 4 H) 1.70 (br t, J=12.5 Hz, 4 H) 1.31 - 1.48 (m, 2 H) 1.02 (t, J=7.2 Hz, 3 H)

[0691] Procedure for the preparation of compounds 55-9 and 56-1

[0692] [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (226 mg, 360 μmol, 0.2 equivalents) was added to a solution of 55-8 (1 g, 1.80 mmol, 1 equivalent) in DCE (300 mL). The mixture was stirred at 50 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluate from a 0-40% ethyl acetate / petroleum ether gradient at 80 mL / min) to obtain a mixture of 55-9 and 56-1 (180 mg, 341 μmol, yield 18.9%). LCMS: [M+H] + =513.8, [M+H] + =528.0, retention time=3.451min

[0693] Procedure for the preparation of compounds 55-10 and 56-2

[0694] Pd / C (100 mg, 10% purity) was added to a 30 mL MeOH solution of 55-9 and 56-1 (216 mg, mixture, 409 μmol, 1 equivalent) under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25°C for 18 hours under H2 (15 Psi). The reaction mixture was filtered and concentrated to obtain a mixture of 55-10 and 56-2 (160 mg, 302 μmol, yield 73.8%). LCMS:[M+H] + =516.3, retention time=0.908min, [M+H] + =530.3, retention time=0.944min

[0695] Procedure for the preparation of 2-(4-oxo-31,32,33,34-tetrahydro-13H-3(7,2)-isoquinolina-1(6,3)-[1,2,3]triazolo[4,5-b]pyridina-5(1,4)-cyclohexanacyclodecafan-2-yl)acetic acid (compound 55) and 2-(4-oxo-31,32,33,34-tetrahydro-13H-3(7,2)-isoquinolina-1(6,3)-[1,2,3]triazolo[4,5-b]pyridina-5(1,4)-cyclohexanacyclonononaphane-2-yl)acetic acid (compound 56) [ka]

[0696] NaOH (1M, 1.81 mL, 6 equivalents) was added to a solution of 55-10 and 56-2 (160 mg, 302 μmol, 1 equivalent) in MeOH (5 mL). The mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (TFA conditions) to obtain the desired compounds. Compound 55 (5.2 mg, 10.2 μmol, yield 3.39%, purity 98.8%) was obtained. Compound 56 (5.9 mg, 12.1 μmol, yield 4.01%, purity 100%) was obtained.

[0697] Compound 55 11H NMR: (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=1.8 Hz, 1 H) 8.24 (d, J=1.7 Hz, 1 H) 7.46 (br d, J=6.4 Hz, 1 H) 7.21 (d, J=7.8 Hz, 1 H) 6.91 (s, 1 H) 4.67 - 4.73 (m, 2 H) 4.37 - 4.51 (m, 2 H) 3.65 - 3.88 (m, 2 H) 3.21 (br d, J=7.9 Hz, 2 H) 2.88 (t, J=6.8 Hz, 2 H) 2.40 (br t, J=11.6 Hz, 1 H) 2.07 - 2.26 (m, 2 H) 1.21 (br d, J=11.2 Hz, 4 H) 0.99 - 1.11 (m, 4 H) 0.64 - 0.96 (m, 4 H) 0.35 - 0.58 (m, 2 H) LCMS: [M+H] + = 502.3, retention time = 0.841 min

[0698] of Compound 56 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 8.66 (s, 1 H) 8.37 (s, 1 H) 7.42 (br d, J=6.2 Hz, 1 H) 7.15 (d, J=7.7 Hz, 1 H) 6.87 (s, 1 H) 4.75 - 4.80 (m, 4 H) 4.31 - 4.50 (m, 2 H) 3.89 (br s, 1 H) 3.51 - 3.75 (m, 1 H) 3.17 - 3.25 (m, 2 H) 2.86 (t, J=6.8 Hz, 2 H) 2.23 (br t, J=11.5 Hz, 1 H) 2.04 (br d, J=3.8 Hz, 2 H) 0.67 - 1.17 (m, 11 H) 0.35 (br s, 1 H) 0.02 - 0.20 (m, 1 H) 0.00 - 0.00 (m, 1 H) LCMS: [M+H] + = 488.2, retention time = 0.806 min

[0699] The following compounds were synthesized by the same method as described above, except that the conditions were changed and the starting materials were different. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] Example 2: Biological testing of the compound Example 2.1 Keap1-Nrf2 binding inhibitory activity assay

[0700] Materials and equipment PerkinElmer EnVision 2105 Multi-Label Reader PerkinElmer FITC FP Dual Emission Label 2100-8060 LABCYTE Echo 650 Corning 384-well microplate #4514 Keap1_FL, Sino Biological, Catalog 11981-H20B FITC-Nrf2 peptide, GL Biochem, Lot number: p210427-XQ892761

[0701] method:

[0702] a) Reference titration

[0703] 1. Keap1-Nrf2 assay buffer was prepared: 10 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 mM EDTA, 0.05% Tween20, 0.1 mg / ml BSA (freshly added before use).

[0704] 2. A 2.04X tracer working solution was prepared: 2.04 nM FITC-Nrf2 peptide in assay buffer from 1 μM DMSO stock.

[0705] 3. A 2X protein working solution was prepared: 25 nM Keap1-FL in assay buffer.

[0706] 4. A 100X compound working solution containing DMSO was prepared. Starting at 100 μM, it was serially diluted 3-fold (10 points) by Echo on a 384-well LDV microplate, and then 200 nL of the compound was transferred from the duplicate wells to a Corning 4514 plate.

[0707] 5. The tracer working solution was added to the Corning 4514 plate at a rate of 9.8 μL / well.

[0708] 6. Protein working solution was added to Corning 4514 plates at 10 μL / well, except for the first two rows to which dilution buffer was added to act as a "positive control".

[0709] 7. The plates were incubated at room temperature for 60 minutes.

[0710] b) Data was read using EnVision with the following settings: excitation light (%): 84, measurement height: 9.4, G-coefficient: 1, detector gain 1: 220, detector gain 2: 220, and number of flashes: 50.

[0711] Keap1-Nrf2 binding inhibitory activity assay of the test compound (IC) 50 The results are shown in Table 2 below. All test compounds were considered to have Keap1-Nrf2 binding inhibitory activity. For each test compound, "+" indicates an IC of 0.1 μM or less greater than 0. 50 The symbol "++" represents an IC that is greater than 0.1 μM and less than or equal to 1 μM. 50 "+++" represents ICs that are greater than 1 μM and less than or equal to 10 μM. 50 It represents. [Table 5]

[0712] As shown in Table 2 above, the compounds of this disclosure are effective in strategies for activating Nrf2 by inhibiting the Keap1-Nrf2 protein-protein interaction (PPI). This approach, which uses non-reactive molecules that tightly bind to the Nrf2 binding pocket on Keap1, has the advantage of activating Nrf2 with higher target selectivity than covalent Keap1 inhibitors (or Nrf2 activators), and is therefore thought to reduce potential safety risks due to off-target activity. Example 2.2 Nrf2 cell assay

[0713] Procedure for Nrf2 cell assay

[0714] Day 1: Plasmid preparation

[0715] 1. The pGL4.37[luc2P / ARE / Hygro] vector was diluted to 25 ng / μL using Opti-MEM.

[0716] 2. Lipofectamine 3000 was added to a 2:1 lipid:DNA mixture. The mixture was mixed by pipetting and incubated at room temperature for 15 minutes.

[0717] 3. HepG2 cells were cultured in complete medium (DMEM + 10% FBS).

[0718] 4. Trypsin is added to the cells after filtering them through a cell strainer to remove cell clusters, then the cells are quantified and stored in complete medium at a concentration of 2 × 10⁻⁶. 5 Diluted to cells / ml.

[0719] 5. The cells and plasmid were mixed and seeded into a 384-well plate at 50 μL / well (50 ng of DNA / well), and incubated at 37°C in a 5% CO2 incubator for 24 hours.

[0720] Day 2: Change of transfection medium

[0721] 1. The culture medium was removed from the cells and replaced with 36 μL of DMEM + 10% FBS per well.

[0722] 2. The samples were incubated overnight in a 37°C, 5% CO2 incubator.

[0723] Day 3: Compound treatment

[0724] 1. The test compound was serially diluted with DMSO and then further diluted to 10x the final concentration with DMEM (containing 10% FBS).

[0725] 2. 4 μL of 10x compound was added to each well, the plate was shaken for 10 seconds in a plate shaker, and incubated at 37°C in a 5% CO2 incubator for 6 hours.

[0726] Day 3: Luciferase measurement

[0727] 1. Remove the plate from the 37°C, 5% CO2 incubator and allow it to cool to room temperature for approximately 15 minutes.

[0728] 2. 40 μL of Glo Luciferase Assay System detection reagent was added, the plate was shaken for 3 minutes, and the luminescence was measured.

[0729] Nrf2 cell assay of test compound (EC 50 The results are shown in Table 3 below. For each test compound, "*" indicates an EC greater than 0 and less than or equal to 10 μM. 50 The symbol "**" represents an EC of greater than 10 μM and less than or equal to 30 μM. 50 This represents an EC of over 30 μM, where "***" indicates an EC of over 30 μM. 50 I...

Claims

1. Compound represented by the following formula (I) 【Chemistry 1】 (In the formula, W is either N or C, L １ teeth, 【Chemistry 1-1】 A group consisting of the following is selected, where, Ring A each contains one or more R ａ１ Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, Ring B consists of one or more R ａ２ Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, 【Chemistry 1-2】 This is a bond in which ring A is condensed with ring B, Ring E is composed of one or more R ａ３ Selected from the group consisting of independently and arbitrarily substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, L ２ -C(O)-, -CR ７ R ８ -, -S(O)- and -S(O) ２ - Selected from the group consisting of, L ３ is a bond or each is cycloalkyl, heterocyclyl, aryl or heteroaryl independently optionally substituted with one or more R ａ４ selected from the group consisting of, provided that W is C and L １ is [Chemistry 1-3] And L ２ If is -C(O)-, then L ３ It is not an aryl or heteroaryl, L ４ The group is selected from alkyl, alkylalkoxyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and the alkyl, alkenyl, and alkynyl may be alone or as part of another group, one or more R ａ５ It is independently and arbitrarily substituted, L ５ is a bond, or alkyl, alkenyl, alkynyl, -alkyl-N(R) ｂ ) - Selected from the group consisting of heteroalkyl, heteroalkenyl and heteroalkynyl, the alkyl, alkenyl, alkynyl and -alkyl-N(R ｂ ) - is one or more R, either alone or as part of another group. ａ６ It is independently and arbitrarily substituted, R １ , R ２ , R ４ , R ７ and R ８ Each of these is hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH ２ , -NO ２ A group independently selected from the group consisting of alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, wherein the alkyl, alkenyl, and alkynyl are individually or as part of another group, one or more R ａ７ It is independently and arbitrarily substituted, R ３ This includes hydrogen, halogen, hydroxyl, sulfhydryl, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkylalkoxyl, -OR ｃ , - NHR ｄ and -N(R ｄ ) ２ Selected from the group consisting of, the alkyl, alkenyl and alkynyl are used individually or as part of another group, one or more R ａ８ It is independently and arbitrarily substituted, R ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａ５ , R ａ６ , R ａ７ and R ａ８ Each of these is hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH ２ , -NO ２ Independently selected from the group consisting of alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, R ｂ , R ｃ and R ｄ Each of these is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, and alkynyl are, alone or as part of another group, hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH ２ and -NO ２ It is independently and arbitrarily substituted with one or more groups independently selected from the group consisting of, or two R ｂ These, together with the nitrogen atom they bond to, form a heterocycline, or two R ｄ Together with the nitrogen atoms that bind to them, they form heterocyclines. n is 0, 1, 2 or 3, and (q is 0, 1, 2, or 3) or its tautomers, stereoisomers, or pharmaceutically acceptable salts.

2. The compound is represented by the following formula (Ia) or formula (Ib), 【Chemistry 2】 【Transformation 3】 In the formula, R １ , R ２ , R ３ , R ４ , L １ , L ２ , L ３ and L ４ The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein each of n and q is as defined in claim 1.

3. L １ teeth, 【Chemistry 3-1】 And # is L ２ A compound according to claim 1 or 2, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, linked to a compound according to claim 1 or 2.

4. Ring A is one or more R ａ１ A compound according to any one of claims 1 to 3, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the aryl is optionally substituted with aryl.

5. Ring A is one or more R ａ１ The compound according to claim 4, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a 3- to 12-membered aryl optionally substituted with the compound.

6. Ring A is one or more R ａ１ The compound according to claim 4 or 5, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a monocyclic aryl optionally substituted with .

7. Ring A is one or more R ａ１ The compound according to claim 6, a phenyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein ring A is an unsubstituted phenyl compound.

9. Ring A consists of halogen, hydroxyl, sulfhydryl, cyano, and -NH. ２ , -NO ２ , C １－６ Alkoxyl, C １－６ Alkyl, C １－６ Alkenil, C １－６ Alkinyl, C １－６ Heteroalkyl, C １－６ Heteralkenyl, C １－６ Heteroalkynyl and Halo C １－６ The compound according to claim 7, a phenyl substituted with a group selected from the group consisting of alkyl groups, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

10. Ring A is C １－６ The compound according to claim 9, wherein the phenyl is alkyl-substituted, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein ring A is a methyl-substituted phenyl compound.

12. Ring A is, 【Chemistry 3-2】 And, 【Chemistry 3-3】 The compound according to claim 11, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the bond is such that ring A is condensed with ring B.

13. Ring A is one or more R ａ１ A compound according to any one of claims 1 to 3, which is a heterocyclyl optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

14. Ring A is one or more R ａ１ The compound according to claim 13, which is a 3- to 12-membered heterocycline optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

15. Ring A is one or more R ａ１ The compound according to claim 13 or 14, which is a monocyclic heterocycline optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

16. Ring A is one or more R ａ１ The compound according to claim 15, which is a 3- to 12-membered monocyclic heterocycline optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

17. Ring A is a 3- to 12-membered monocyclic heterocycline containing one or two nitrogen atoms, and one or more R ａ１ The compound according to claim 16, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is optionally substituted with.

18. Ring A is one or more R ａ１ The compound according to claim 17, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein piperidinyl is optionally substituted with.

19. Ring A is, [Chemistry 3-4] And, [Transformation 3-5] The compound according to claim 18, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the bond is such that ring A is condensed with ring B.

20. Ring B consists of one or more R ａ２ A compound according to any one of claims 1 to 19, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a heterocyclyl or aryl independently and optionally substituted.

21. The compound according to claim 20, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein ring A and ring B are not simultaneously heterocyclyl or aryl.

22. Ring B is one or more R ａ２ The compound according to claim 20, a heterocyclyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

23. Ring B is one or more R ａ２ The compound according to claim 22, which is a 3- to 12-membered heterocycline optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

24. Ring B is one or more R ａ２ The compound according to claim 22 or 23, which is a monocyclic heterocycline optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

25. Ring B is one or more R ａ２ The compound according to claim 24, which is a 3- to 12-membered monocyclic heterocycline optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

26. Ring B is a 3- to 12-membered monocyclic heterocycline containing one or two nitrogen atoms, and one or more R ａ２ The compound according to claim 25, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is optionally substituted with.

27. Ring B is one or more R ａ２ The compound according to claim 26, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein piperidinyl is optionally substituted with.

28. Ring B is, [Chemistry 3-6] And, 【Chemistry 3-7】 The compound according to claim 27, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the bond is such that ring B is condensed with ring A.

29. Ring B is one or more R ａ２ A compound according to any one of claims 1 to 21, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the aryl is optionally substituted with aryl.

30. Ring B is a 3- to 12-membered aryl optionally substituted by one or more Rs ａ２ The compound according to claim 29, its tautomer, stereoisomer, or pharmaceutically acceptable salt, which is a 3- to 12-membered aryl optionally substituted by ａ２ .

31. Ring B is one or more R ａ２ The compound according to claim 29 or 30, a monocyclic aryl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

32. Ring B is one or more R ａ２ The compound according to claim 31, a 3- to 12-membered monocyclic aryl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

33. Ring B is one or more R ａ２ The compound according to claim 32, a phenyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

34. The compound according to claim 33, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein ring B is an unsubstituted phenyl compound.

35. L １ teeth, 【Transformation 3-8】 A compound according to any one of claims 1 to 34, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

36. L １ teeth, 【Chemistry 3-9】 And # is L ２ A compound according to claim 35, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, linked to the compound.

37. L １ is 【Chemistry 3-10】 The compound according to claim 35, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

38. L １ teeth, 【Chemistry 3-11】 And # is L ２ A compound according to claim 37, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, linked to the compound.

39. L １ teeth, 【Chemistry 3-12】 And # is L ２ A compound according to claim 37, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, linked to the compound.

40. L １ teeth, 【Chemistry 3-13】 The compound according to claim 1 or 2, its tautomer, stereoisomer, or pharmaceutically acceptable salt.

41. Ring E is one or more R ａ３ The compound according to claim 40, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the aryl is optionally substituted with aryl.

42. Ring E is one or more R ａ３ The compound according to claim 41, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a 3- to 12-membered aryl optionally substituted with the compound.

43. Ring E is one or more R ａ３ The compound according to claim 41 or 42, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a monocyclic aryl optionally substituted with .

44. Ring E is one or more R ａ３ The compound according to claim 43, a 3- to 12-membered monocyclic aryl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

45. Ring E is one or more R ａ３ The compound according to claim 44, a phenyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

46. Ring E is one or more R ａ３ The compound according to claim 40, a heteroaryl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

47. Ring E is one or more R ａ３ The compound according to claim 46, a 3- to 12-membered heteroaryl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

48. Ring E is one or more R ａ３ The compound according to claim 46 or 47, a monocyclic heteroaryl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

49. Ring E is one or more R ａ３ The compound according to claim 48, which is a 3- to 12-membered monocyclic heteroaryl optionally substituted with , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

50. Ring E is a monocyclic heteroaryl containing one or two nitrogen atoms, and one or more R ａ３ The compound according to claim 49, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is optionally substituted with.

51. Ring E is one or more R ａ３ The compound according to claim 50, a pyridinyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

52. L １ teeth, 【Chemistry 3-14】 And each of X is C, CR ａ３ CH, N, NR ａ３ A compound according to claim 40, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, independently selected from the group consisting of , and NH.

53. L １ teeth, 【Chemistry 3-15】 And each of X is C, CR ａ３ CH, N, NR ａ３ Independently selected from the group consisting of , and NH, # is L ２ A compound according to claim 52, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, linked to the compound.

54. L ５ is one or more R ａ６ A compound according to any one of claims 40 to 53, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a heteroalkyl optionally substituted with .

55. L ５ This contains one or more R atoms, each containing at least one nitrogen atom. ａ６ The compound according to claim 54, a heteroalkyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

56. L ５ It contains one to six carbon atoms and one nitrogen atom, and one or more R ａ６ The compound according to claim 55, a heteroalkyl optionally substituted with, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

57. L ５ is, -CH ２ -N(R) ａ６ )-,-(CH ２ ) ２ -N(R) ａ６ )-,-(CH ２ ) ３ -N(R) ａ６ )-,-(CH ２ ) ４ -N(R) ａ６ )-,-(CH ２ ) ５ -N(R) ａ６ ) - and - (CH ２ ) ６ -N(R) ａ６ A compound according to claim 55, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of ) -

58. R ａ６ C １－６ A compound according to any one of claims 54 to 57, which is alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

59. R ａ６ The compound according to claim 58, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein is methyl.

60. L １ teeth, 【Chemistry 3-16】 A compound according to any one of claims 40 to 59, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

61. L ２ is -C(O)- or -S(O) ２ - A compound according to any one of claims 1 to 60, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

62. L ３ The compound according to any one of claims 1 to 61, its tautomer, stereoisomer, or pharmaceutically acceptable salt, wherein the compound is a bond.

63. L ３ The compound according to any one of claims 1 to 61, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a cycloalkyl compound.

64. L ３ C ３－１２ A compound according to claim 63, which is a cycloalkyl compound, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

65. L ３ The compound according to claim 64, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is cyclohexyl.

66. L ３ teeth, 【Chemistry 3-17】 The compound according to claim 65, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

67. L ３ The compound according to any one of claims 1 to 61, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a heterocycline.

68. L ３ The compound according to claim 67, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a 3- to 12-membered heterocycline.

69. L ３ The compound according to claim 68, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is a 3- to 12-membered heterocycline containing one or two nitrogen atoms.

70. L ３ The compound according to claim 69, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is piperidinyl or piperazinyl.

71. L ３ teeth, 【Chemistry 3-18】 The compound according to claim 70, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

72. L ３ teeth, 【Chemistry 3-19】 And * is L ２ A compound according to claim 71, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, linked to the compound.

73. L ３ The compound according to any one of claims 1 to 61, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is an aryl compound.

74. L ３ The compound according to claim 73, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is a 3- to 12-membered aryl compound.

75. L ３ The compound according to claim 73 or 74, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound is a monocyclic aryl compound.

76. L ３ The compound according to claim 75, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is a 3- to 12-membered monocyclic aryl.

77. L ３ The compound according to claim 76, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein is phenyl.

78. L ３ teeth, 【Chemistry 3-20】 The compound according to claim 77, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

79. L ４ R is selected from the group consisting of alkyl, alkenyl, heteroalkyl or heteroalkenyl, and the alkyl, alkenyl, heteroalkyl and heteroalkenyl is one or more R ａ５ A compound according to any one of claims 1 to 78, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is independently and arbitrarily substituted by.

80. L ４ is one or more R ａ５ C arbitrarily replaced by １－１２ Alkyl or C ２－１２ The compound according to claim 79, which is an alkenyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

81. L ４ C ３－１０ A compound according to claim 80, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is alkyl.

82. L ４ teeth, 【Chemistry 3-21】 The compound according to claim 81, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

83. L ４ The compound according to claim 79, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is a heteroalkyl compound containing one or more oxygen or nitrogen atoms.

84. L ４ C contains one or two oxygen atoms. １－１２ A compound according to claim 83, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a heteroalkyl compound.

85. L ４ C contains one or two oxygen atoms. ３－１２ It is a heteroalkyl group, and the oxygen atom is C ３－１２ A compound according to claim 84, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, inserted into a heteroalkyl main chain.

86. L ４ teeth, 【Chemistry 3-22】 The compound according to claim 85, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

87. L ４ C contains one or two nitrogen atoms. １－１２ A compound according to claim 83, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a heteroalkyl compound.

88. L ４ C contains one nitrogen atom. ３－１２ It is a heteroalkyl group, and the nitrogen atom is the C ３－１２ A compound according to claim 87, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, inserted into a heteroalkyl main chain.

89. L ４ teeth, 【Chemistry 3-23】 The compound according to claim 88, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

90. L ４ The compound according to claim 83, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is a heteroalkenyl containing one or more oxygen atoms.

91. L ４ C contains one oxygen atom. ２－１２ A compound according to claim 90, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is a heteroalkenyl.

92. L ４ C contains one oxygen atom. ２－１２ It is a heteroalkenyl, and the oxygen atom is the C ２－１２ A compound according to claim 91, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, inserted into the main chain of a heteroalkenyl.

93. L ４ teeth, 【Chemistry 3-24】 The compound according to claim 92, its tautomers, stereoisomers, or pharmaceutically acceptable salts.

94. R ａ５ The compound according to any one of claims 79 to 93, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is alkyl.

95. R ａ５ C １－６ A compound according to claim 94, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is alkyl.

96. R ａ５ The compound according to claim 95, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein is methyl.

97. R １ is hydrogen or C １－６ A compound according to any one of claims 1 to 96, which is alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

98. R ２ is hydrogen or C １－６ A compound according to any one of claims 1 to 97, which is alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

99. A compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 98, wherein q is 1.

100. R ３ is, -OR ｃ A compound according to any one of claims 1 to 99, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

101. R ｃ is hydrogen or C １－６ A compound according to claim 100, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is alkyl.

102. R ｃ The compound according to claim 101, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein is hydrogen.

103. The compound according to claim 102, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein n is 0 or 1.

104. R ４ The compound according to any one of claims 1 to 103, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein is alkyl.

105. R ４ C １－６ A compound according to claim 104, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which is alkyl.

106. R ４ The compound according to claim 105, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein is methyl.

107. The compound is represented by the following formulas (II), (III), or (IV): 【Chemistry 4】 【Transformation 5】 【Transformation 6】 During the ceremony, R ５ and R ６ Each of these is hydrogen, halogen, hydroxyl, sulfhydryl, cyano, -NH ２ , -NO ２ A group independently selected from the group consisting of alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, and alkylalkoxyl, wherein the alkyl, alkenyl, and alkynyl are individually or as part of another group, one or more R ａ７ It is independently and arbitrarily substituted, m is 0, 1, 2, or 3. t is 0, 1, 2 or 3, and W, R １ , R ２ , R ３ , R ４ , L ２ , L ３ , L ４ , L ５ , ring A, ring B, ring E, R ａ７ A compound according to claim 1 or 2, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each of n and q is as defined in claim 1.

108. The aforementioned compound is represented by the following formulas (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb), 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 In the formula, W, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , L ２ , L ３ , L ４ , L ５ The compound according to claim 107, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each of rings A, B, E, n, m, q, and t is as defined in claim 107.

109. The compound is represented by the following formula (IIa1) or formula (IIa2), 【Chemistry 13】 【Chemistry 14】 During the ceremony, L ４ C ３－８ Alkyl or C ３－８ It is heteroalkyl, R １ is hydrogen, halogen or C １－６ It is alkyl, R ２ is hydrogen, halogen or C １－６ It is alkyl, R ３ is, -OR ｃ And R ｃ is hydrogen or C １－６ It is alkyl, R ４ is hydrogen, halogen or C １－６ It is alkyl, R ５ is hydrogen, halogen or C １－６ It is alkyl, n is either 0 or 1, m is 0 or 1, and The compound according to claim 108, its tautomers, stereoisomers, or pharmaceutically acceptable salts, wherein q is 1. 【Request Item 110】 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 Compounds selected from the group consisting of the following, their tautomers, stereoisomers, or pharmaceutically acceptable salts.

111. A pharmaceutical composition comprising a compound according to any one of claims 1 to 110, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

112. A method for improving the level or activity of Nrf2 in cells, comprising exposing the cells to a compound according to any one of claims 1 to 110, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 111.

113. A method for improving the level or activity of Nrf2 in a target subject, comprising administering to the target a therapeutically effective amount of a compound according to any one of claims 1 to 110, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 111.

114. A method for preventing, treating or alleviating an Nrf2-related disease, disorder, or symptom of a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 110, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 111.

115. The method according to claim 114, wherein the Nrf2-related disease, disorder, or symptom is related to a decrease in the level or activity of the Nrf2 protein.

116. The method according to claim 114 or 115, wherein the Nrf2-related disease, disorder, or symptom is associated with increased oxidative stress, inflammation, decreased redox potential, detoxification impairment, or metabolic dysregulation.

117. The method according to claim 114 or 115, wherein the disease, disorder, or symptom is selected from the group consisting of eye diseases, hepatobiliary diseases, cardiovascular diseases, lung diseases, kidney diseases, neurodegenerative diseases, neuropsychiatric disorders, cancer, sickle cell anemia, mitochondrial diseases, inflammatory diseases, respiratory diseases, aging, autoimmune diseases, brain diseases, diabetes (e.g., type 1 diabetes, type 2 diabetes, maternal diabetes), metabolic syndrome, and diabetic complications.

118. The method according to claim 117, wherein the eye disease is age-related macular degeneration (AMD), retinitis pigmentosa (RP), geographic atrophy (GA), macular edema, macular edema associated with retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), central retinal vein occlusion, corneal neovascularization (CNV), ocular neovascularization (intraocular neovascularization affecting the choroid, cornea, or retinal tissue), retinopathy of prematurity (ROP), pathological myopia, glaucoma (e.g., vascular glaucoma), retinoblastoma, retinal vein occlusion, uveitis, ocular trauma, Fuchs corneal endothelial dystrophy (FECD), cataract, ophthalmic neurodegenerative disease, optic neuropathy, and neuromyelitis optica.

119. The method according to claim 117, wherein the kidney disease is autosomal dominant polycystic kidney disease (ADPKD), acute kidney injury (AKI), diabetic nephropathy, IgA nephropathy (IgAN), chronic kidney disease (CKD), Alstrom syndrome and Alport syndrome, renal fibrosis, focal segmental glomerulosclerosis, contrast-induced nephropathy, sepsis-induced acute kidney injury, and kidney disease or renal dysfunction occurring during kidney transplantation.

120. The method according to claim 117, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive decline, amyloidosis, amyotrophic lateral sclerosis, and multiple sclerosis.

121. The method according to claim 117, wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, bipolar disorder, depression, anxiety disorder, Friedreich's ataxia, autism, and attention deficit hyperactivity disorder.

122. The method according to claim 117, wherein the aforementioned diabetic complication is selected from the group consisting of diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and diabetic wound healing.

123. The method according to claim 117, wherein the hepatobiliary disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, toxin-induced liver disease (e.g., acetaminophen-induced liver disease), alcoholic liver disease (ALD), cholestasis, primary sclerosing cholangitis (PSC), viral hepatitis, cirrhosis, primary biliary cholangitis (PBC), end-stage liver disease, and hepatic fibrosis.

124. The method according to claim 117, wherein the lung disease is selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, acute lung injury, lung infection, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension, environmental lung disease, chronic asthma and acute asthma, and acute respiratory distress syndrome.

125. The method according to claim 117, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, hypertension, heart failure, stroke, cardiomyopathy, coronary heart disease, vascular endothelial dysfunction, blood-brain barrier dysfunction, reperfusion injury (brain, heart, kidney, liver, retina), and myocardial ischemia.

126. The method according to claim 117, wherein the inflammatory disease is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, arthritis, osteoarthritis, dermatitis (e.g., radiation dermatitis, allergic contact dermatitis), reflux esophagitis, and lupus nephritis.

127. The method according to claim 117, wherein the autoimmune disease is selected from the group consisting of psoriasis, Sjögren's syndrome, lupus, pemphigus, vitiligo, and alopecia areata.

128. The method according to claim 117, wherein the brain disease is selected from the group consisting of traumatic brain injury, cerebral edema, cerebral ischemia, encephalopathy (e.g., hepatic encephalopathy), and cerebral infarction.

129. The method according to claim 117, wherein the Nrf2-related disease, disorder, or symptom is selected from the group consisting of nerve injury, epilepsy, spinal cord injury, radiation-induced immunosuppression, pre-eclampsia, altitude sickness, wound healing, mitochondrial myopathy, malaria, ferroptosis / iron overload, alcoholism, anemia, Asperger's syndrome, eczema, chronic fatigue syndrome, Duchenne muscular dystrophy, edema, encephalitis, male / female fertility, fracture healing, gastroesophageal reflux disease, hearing loss, influenza infection, intestinal barrier dysfunction, osteoporosis, radiation injury, seizures, skin ulcers, and Down syndrome.

130. The method according to claim 117, wherein the cancer is selected from the group consisting of colon cancer, lung cancer, esophageal cancer, breast cancer, bladder cancer, liver cancer, prostate cancer, and colorectal cancer.

131. The method according to any one of claims 114 to 130, wherein a compound according to any one of claims 1 to 110, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 111 is administered simultaneously with, separately from, or sequentially with the second therapy.

132. The method according to claim 131, wherein the second therapy is chemotherapy or immunotherapy.

133. The method according to claim 132, wherein the second therapy is selected from the group consisting of chemotherapeutic agents, antitumor agents, radiotherapy agents, immunotherapy agents, anti-angiogenic agents, targeted therapy agents, cell therapy agents, gene therapy agents, hormone therapy agents, antiviral agents, antibiotics, analgesics, antioxidants, metal chelating agents, and cytokines.

134. The method according to claim 131, wherein the second therapy is a Keep1 inhibitor.

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