Heterocyclic compounds as STING agonists

Abstract

The present disclosure relates to compounds represented by Formula 1, or pharmaceutically acceptable salts thereof, as stimulator of interferon genes (STING) agonists, pharmaceutical compositions containing same, and methods for treating or preventing associated diseases, and uses in the treatment or prevention of associated diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Korean Patent Application No. 10-2022-0147897, filed on November 8, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Stimulator of interferon genes (STING) is a small protein that has recently attracted attention as a target for cancer therapy. STING is an adaptor protein in the cGAS (cyclic GMP-AMP synthase)-STING pathway, a sensing pathway that induces the activation of type I IFN and other inflammatory cytokines, eliciting antiviral and antitumor immune responses (Chen, Q. et al. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 2016, 17, 1142-1149; Woo, SR et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014, 41, 830-842). Furthermore, STING activates signal transducer and activator of transcription 6 (STAT6) and the transcription factor interferon regulatory factor 3 (IRF3) through TANK-binding kinase 1 (TBK1) in antiviral and innate immune responses (Burdette DL, Vance RE, STING and the innate immune response to nucleic acids in the cytosol, 2013, Nature Immunology. 14 (1): 19-26). STING agonists can also induce cytokine expression and trigger T cell-mediated innate immune responses, which inhibit cancer cell growth. However, systemic delivery of STING agonists can cause widespread inflammation.

[0003] Various STING agonists are being tested in preclinical and clinical settings. Various agonists in the form of CDN (cyclic dinucleotide) compounds (e.g., ADU-S100, BI-STING, GSK532, JNJ-4412, SB11285, MK-1454, TAK676), bacterial vectors (e.g., SYNB1891, STACT-TREX-1), acyclic dinucleotide (CDN) compounds (e.g., ALG-031048, JNJ-6196, MK-2118, MSA-1, MSA-2, CRD-5500), nanovaccines (e.g., PC7A NP, cGAMP-NP), and ADCs (e.g., XMT-2056, TAK500) are under development using various strategies.

[0004] The most widely used preclinical compound, DMXAA (a vascular disrupting agent), was used clinically in combination with paclitaxel and carboplatin, but its lack of efficacy was confirmed in Phase 3. Furthermore, ADU-S100, the first STING agonist used clinically, was discontinued in 2020.

[0005] Examples of STING agonists are disclosed, for example, in WO2021 / 014365 (macrocyclic compounds as STING agonists), and US2021 / 0139473 (heterocyclic amide-containing compounds as protein modulators), US 2022 / 0073509 (heterocyclic compounds as STING activators), and KR 2022-0024467 (heterocycle-containing STING agonists), each of which is incorporated by reference herein in its entirety. Summary of the Invention [Problem to be solved by the invention]

[0006] However, existing STING agonists appear to exhibit limited bioavailability and require local administration to tumors or be used in combination with other compounds due to overactivation of cytokine expression. Thus, there remains a need for the development of therapeutically effective STING agonists. [Means for solving the problem]

[0007] overview In some embodiments, the present disclosure provides compounds of structural formula 1:

[0008] [ka] [In the formula, W1 and W2 are each independently selected from alkyl, amino, and amido; each n is independently 0, 1, 2, or 3; Z is selected from a single bond, alkylene, alkenylene, and alkynylene; A and B are each independently a 5-membered heteroaryl; Xa and Xb are each independently selected from CH2, NH, O, and S; Ra is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl; Rb is represented by structural formula 2

[0009] [ka] (In the formula, L1 is alkylene, alkenylene, alkynylene, heteroalkenylene, heteroalkynylene, heteroarylene, Y1-O-Y2 ** , and Y3-NR y -Y4 ** is selected from L2 is NR L selected from C(=NH)NH2, C(=NH)NH2, alkyl, heteroaryl, heterocyclyl, and aryl; Y1 and Y3 are each independently selected from alkylene, alkenylene, and alkynylene; Y2 and Y4 are each independently selected from a single bond, alkylene, alkenylene, and heterocyclylene; * is the connection point to Xb, ** is the connection point to L2, R L is selected from hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl; R y is selected from H, alkyl, or C(=NH)NH is a group represented by or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, for example, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in the prevention or treatment of a disease mediated by stimulator of interferon genes (STING).

[0012] In some embodiments, the present disclosure relates to a method of preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0013] In some embodiments, the present disclosure relates to the use of a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the manufacture of a medicament for treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof.

[0014] In some embodiments, the present disclosure relates to a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 demonstrates tumor volume (mm3) after treatment with various doses of a STING agonist compound (compound 55) in a CT26 syngeneic mouse model. [Figure 2] FIG. 1 demonstrates tumor volume (mm3) after treatment with various doses of a STING agonist compound (compound 55) in a 4T-1 syngeneic mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0016] In some embodiments, the present disclosure provides compounds of structural formula 1:

[0017] [ka] [In the formula, W1 and W2 are each independently selected from alkyl, amino, and amido; each n is independently 0, 1, 2, or 3; Z is selected from a single bond, alkylene, alkenylene, and alkynylene; A and B are each independently a 5-membered heteroaryl; Xa and Xb are each independently selected from CH2, NH, O, and S; Ra is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl; Rb is represented by structural formula 2

[0018] [ka] (In the formula, L1 is alkenylene, alkynylene, heteroalkenylene, heteroalkynylene, heteroarylene, Y1-O-Y2 ** , and Y3-NR y -Y4 ** is selected from L2 is NR L selected from C(=NH)NH2, C(=NH)NH2, amino, alkyl, heteroaryl, heterocyclyl, and aryl; Y1 and Y3 are each independently selected from alkylene, alkenylene, and alkynylene; Y2 and Y4 are each independently selected from a single bond, alkylene, alkenylene, and heterocyclylene; * is the connection point to Xb, ** is the connection point to L2, R L is selected from H, alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl; R y is selected from H, alkyl, or C(=NH)NH is a group represented by or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, when L is substituted or unsubstituted alkylene, L is NR L It is selected from C(=NH)NH2, heteroaryl, substituted heterocyclyl, and aryl.

[0020] In some embodiments, W1 and W2 are each independently selected from the group consisting of C 1~5 alkyl, NH, and C(=O)NH, where each n is 1, 2, or 3. For example, W and W are each independently selected from C 1~3and n is 1. In certain preferred embodiments, W and W are each C(=O)NH. In some embodiments, n is 1.

[0021] In some embodiments, the compound has structural formula 1a:

[0022] [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some preferred embodiments, Z is alkenylene, such as ethenylene. For example, Z is an unsubstituted C 2~6 Alkenylene, e.g., unsubstituted C 2~4 It may be alkenylene. In certain embodiments, Z is selected from CH=CH, CH=CHCH2, CH2CH=CH, CH=CHCH2CH2, CH2CH2CH=CH, and CH2CH=CHCH2, preferably CH=CH.

[0024] In some embodiments, Z is C 1~6 Alkylene, C 2~6 Alkenylene, and C 2~6 alkynylene, C 1~6 Alkylene, C 2~6 Alkenylene, and C 2~6 Each alkynylene independently represents C 1~5 Alkyl, C 1~5 haloalkyl, halogen, OH, —OP(O)(R′R”)2, —OR′, —NR′R″, —OCOR′, —COR′, —SOR′, —SOR′, —SOR′, —CONR′R″, —SORNR′R″, —OCONR′R″, —NR′COR″, —NR′SOR″, —NR′COR″, and —NR′SOR″, where R′ and R″ are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 alkynyl).

[0025] In some embodiments, the compound has structural formula 1b:

[0026] [ka] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, A and B are each independently selected from halogen, OH, CN, NO, amine, amide, amidine, -(CH) p NR'R", C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 Alkynyl (wherein each p is independently selected from 0, 1, 2, or 3; R′ and R″ are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 and alkynyl. For example, A and B may each be independently selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, and isothiazole. In certain preferred embodiments, A and B are each pyrazole.

[0028] In some embodiments, A and B are each independently a substituted or unsubstituted pyrazole. For example, in certain preferred embodiments, A and B each contain two C 1~3 It is an alkyl-substituted pyrazole.

[0029] In some embodiments, the compound has structural formula 1c:

[0030] [ka] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound has structural formula 1d:

[0032] [ka] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound has structural formula 1e:

[0034] [ka] or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound has structural formula 1f:

[0036] [ka] or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the compound has structural formula 1g:

[0038] [ka] or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, Xa is O.

[0040] In some embodiments, Xb is O. In some preferred embodiments, Xa and Xb are each O.

[0041] In some embodiments, Ra is C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6For example, in some embodiments, Ra is selected from C 1~6 Alkyl, preferably C 1~3 In some embodiments, Ra is a C alkyl, a C alkyl, a C alkyl, a C alkyl, a C alkyl, or a C alkyl. For example, Ra is an unsubstituted C 1~3 In some embodiments, Xa is O and Ra is methyl. In some embodiments, Ra is C 2~6 Alkenyl or C 2~6 For example, Ra may be C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, or C6 alkenyl. Alternatively, Ra may be C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl, or C6 alkynyl. In some embodiments, Ra is C 1~5 haloalkyl, halogen, —OR′, —NR′R″, NR′C(═NH)NH, —OCOR′, —COR′, —SOR′, —SOR′, —SOR′, —CONR′R″, —SONR′R″, —OCONR′R″, —NR′COR″, —NR′SOR″, —NR′COR″, and —NR′SOR″, where R′ and R″ are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 C optionally substituted with 1 to 3 independently selected from alkynyl 1~6 For example, Ra is a C substituted with -NR'R" 1~6 It may be an alkyl, preferably a C alkyl substituted with NHCH. In some embodiments, Ra is selected from -(alkylene)carboxylic acid, -(alkylene)guanidine, -(alkylene)NHC(O)CH2guanidine, and -(alkylene)O(alkylene)guanidine.

[0042] In some embodiments, L is C 2~6 Alkenylene or C 2~6 In certain preferred embodiments, L is C2~6 Alkenylene, e.g., C 2~4 Alkenylene, for example, C4 alkenylene. For example, L1 may be unsubstituted C4 alkenylene. In certain preferred embodiments, L1 is C 2~6 Alkynylene, e.g., C 2~4 Alkynylene, for example C4 alkynylene. For example, L1 may be unsubstituted C4 alkynylene.

[0043] In some embodiments, the compound has formula 1h or formula 1i:

[0044] [ka] or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the compound has structural formula 1i:

[0046] [ka] or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the compound has structural formula 1j:

[0048] [ka] or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, L1 is represented by formula 2a, formula 2b, formula 2c, or formula 2d:

[0050] [ka] (In the formula, L 11 , L 12 , L 13 , and L 14are each independently a single bond or C 1~20 is alkylene, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are each independently hydrogen, OH, CN, NO, amine, amide, amidine, carboxylic acid or a salt thereof, ether, ester, sulfone, substituted or unsubstituted C 1~10 Alkyl, substituted or unsubstituted C 2~10 Alkenyl, and substituted or unsubstituted C 2~10 alkynyl) For example, L1 may be a group represented by structural formula 2b. For example, L1 may be a group represented by structural formula 2c. In some preferred embodiments, L1 is a group represented by structural formula 2a or 2d. In some particularly preferred embodiments, L1 is a group represented by structural formula 2a.

[0051] In some embodiments, L is Y-O-Y ** or Y3-NR y -Y4 ** (where ** is the connection point to L2). For example, L1 is Y1-O-Y2 ** Alternatively, L1 may be Y3-NR y -Y4 ** may be.

[0052] In some embodiments, Y is C 2~6 Alkenylene and C 2~6 In some embodiments, Y is selected from C 2~6 Alkenylene, for example, C4 unsubstituted alkenylene.

[0053] In some embodiments, Y is

[0054] [ka] For example, Y1 is selected from

[0055] [ka] In some preferred embodiments, Y may be

[0056] [ka] In some preferred embodiments, Y is

[0057] [ka] is.

[0058] In some embodiments, Y2 is a single bond, C 1~6 Alkylene, C 2~6 It is selected from alkenylene and 4- to 10-membered heterocyclylene. For example, Y2 may be a single bond.

[0059] In some embodiments, Y3 is C 2~6 Alkenylene and C 2~6 In some embodiments, Y is selected from C 2~6 Alkenylene, for example, C4 unsubstituted alkenylene.

[0060] In some embodiments, Y3 is

[0061] [ka] For example, Y3 is selected from

[0062] [ka] In some preferred embodiments, Y3 may be

[0063] [ka] In some preferred embodiments, Y3 is

[0064] [ka] is.

[0065] In some embodiments, Y4 is a single bond, C 1~6 Alkylene, C 2~6 In some embodiments, Y is selected from alkenylene and 4- to 10-membered heterocyclylene. 1~6 Alkylene, e.g., C 2~4 In some preferred embodiments, Y is C alkylene, such as C, C, C, or C alkylene. 1~3 alkylene, preferably C 1~5 Alkyl, C 1~5 haloalkyl, halogen, OH, oxo, —OR′, —NR′R″, —OCOR′, —COR′, —SOR′, —SOR′, —SOR′, —CONR′R″, —SONR′R″, —OCONR′R″, —NR′COR″, —NR′SOR″, —NR′COR″, and —NR′SOR″, where R′ and R″ are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 C optionally substituted with 1 to 3 independently selected from alkynyl 1~3 In some preferred embodiments, Y is an unsubstituted C 1~3 It is alkylene.

[0066] In some embodiments, R y H, unsubstituted C 1~3 alkyl, or C(=NH)NH. In some preferred embodiments, R y is H. Alternatively, R y may be methyl or C(=NH)NH2.

[0067] In some embodiments, L2 is NR L C(=NH)NH2. In some preferred embodiments, R L is hydrogen. Alternatively, R L is C 1~3 It may be alkyl, preferably methyl.

[0068] In some embodiments, L2 is selected from 5-7 membered heteroaryl, 5-7 membered heterocyclyl, and C6 aryl. For example, L2 is C 1~5 Alkyl, C 1~5 haloalkyl, halogen, OH, C(=NH)NH, -OP(O)(R'R"), -OR', -NR'R", -OCOR', -COR', -SOR', -SOR', -SOR', -CONR'R", -SORNR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'COR", and -NR'SOR" (wherein R' and R" are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 In some embodiments, L2 is a 5- to 7-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from C 1~5 Alkyl, halogen, C 1~5 haloalkyl, OH, C(=NH)NH, -OP(O)(R'R"), -OR', -NR'R", -OCOR', -COR', -SOR', -SOR', -SOR', -CONR'R", -SORNR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'COR", and -NR'SOR" (wherein R' and R" are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 In some preferred embodiments, L2 is C6 aryl optionally substituted with 1 to 3 substituents independently selected from C 1~5 Alkyl, C 1~5Haloalkyl, halogen, oxo, OH, C(=NH)NH, -OP(O)(R'R"), -OR', -NR'R", -OCOR', -COR', -SOR', -SOR', -SOR', -CONR'R", -SORNR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'COR", and -NR'SOR" (wherein R' and R" are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 and alkynyl), preferably a 5-7 membered heterocyclyl substituted with substituents selected from oxo, NH, CNNO, OH, and C(=NH)NH. In certain preferred embodiments, L is an unsubstituted 5-7 membered heterocyclyl.

[0069] In some embodiments, L2 is # OC(O)NR 5 -L 4 -NR 6 , # OC(O)-L 4 -NR 6 , or # OC(O)NR 5 -L 4 -(heterocyclylene) (wherein # is L 1 is the connection point to L 4 is alkylene or arylalkylene, and R 5 and R 6 are each independently selected from H, alkyl, and dialkylaminoalkyl.

[0070] In some embodiments, L2 has the following structural formula:

[0071] [ka] TIFF2025538034000026.tif91163. For example, L2 is a moiety represented by one of the following structural formulas:

[0072] [ka] TIFF2025538034000028.tif86163. In some preferred embodiments, L2 may be a moiety represented by one of the following structural formulas:

[0073] [ka] and preferably, L2 is a moiety represented by one of the following structural formulas:

[0074] [ka] One of them, for example,

[0075] [ka] The part represented by

[0076] In some embodiments, L1 is Y3-NR y -Y4 ** and NR y -Y4-L2 has the following structural formula:

[0077] [ka] The part represented by one of the files TIFF2025538034000033.tif81163.

[0078] In some embodiments, L is Y-O-Y ** and O-Y2-L2 has the following structural formula:

[0079] [ka] The part represented by one of the files TIFF2025538034000035.tif57163.

[0080] In some embodiments, A and B each independently represent the following structural formula:

[0081] [ka] [In the formula, R a and R b are each independently hydrogen, C 1~5 Alkyl, C 1~5 haloalkyl, halogen, OH, —OP(O)(R′R”)2, —OR′, —NR′R″, —OCOR′, —COR′, —SOR′, —SOR′, —SOR′, —CONR′R″, —SORNR′R″, —OCONR′R″, —NR′COR″, —NR′SOR″, —NR′COR″, and —NR′SOR″, where R′ and R″ are each independently hydrogen, C 1~10 Alkyl, C 2~10 Alkenyl, and C 2~10 alkynyl) For example, A and B may each independently be represented by one of the following structural formulas:

[0082] [ka] In some preferred embodiments, A and B may each be represented by one of the following structural formulas:

[0083] [ka] is expressed by

[0084] In some embodiments, the compound has structural formula 1k:

[0085] [ka] (In the formula, Ra is CH3 or (CH2)3NCH3, B has the following structural formula:

[0086] [ka] and

[0087] [ka] (the part represented by one of For example, the compound may be represented by structural formula 1k, where L1 is represented by the following structural formula:

[0088] [ka] and preferably, L1 is selected from a moiety represented by one of the following structural formulas:

[0089] [ka] For example, a compound may be represented by structure 1k, and B may be represented by one of the following structures:

[0090] [ka] In some preferred embodiments, the compound may be represented by structural formula 1k, where B is a moiety represented by the following structural formula:

[0091] [ka] In some preferred embodiments, the compound is represented by structural formula 1k, and L2 is a moiety represented by the following structural formula:

[0092] [ka] and preferably, L2 is a moiety represented by one of the following structural formulas:

[0093] [ka] more preferably one of

[0094] [ka] The part represented by

[0095] In some embodiments, the compound has structural formula (Ic*):

[0096] [ka] is expressed by

[0097] In some embodiments, the compound has the structural formula (Id*):

[0098] [ka] is expressed by

[0099] In some embodiments, L 2 comprises one or more moieties selected from a peptide, a sugar, an -OCH2CH2- moiety, and a reactive group, or a combination thereof.

[0100] In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 contains two or more monosaccharides.

[0101] In some embodiments, the sugar has the following structural formula:

[0102] [ka] (In the formula, R 1 is H, alkyl, CH2OR 1A , or CO2R 1B and Each R 2 are independently H or a hydroxyl protecting group; R 1A is H or a hydroxyl protecting group, R 1B is H or a carboxyl protecting group) In some preferred embodiments, the sugar is represented by one of the following structural formulas:

[0103] [ka] is expressed by

[0104] In some embodiments, R 1 is CH2OR 1A or CO2R 1B In some embodiments, R 1A is H. In some embodiments, R 1B is H. In some embodiments, R 2 is H.

[0105] In some embodiments, L 2 In some embodiments, L comprises a peptide. 2 is a peptide. For example, in some embodiments, L 2 For example, in some embodiments, L 2 is a dipeptide.

[0106] In some embodiments, the peptide comprises at least one hydrophilic amino acid. For example, in some embodiments, the peptide comprises an amino acid having a side chain with a charged moiety (e.g., an amine, guanidine, or carboxyl moiety) at neutral pH in aqueous solution. For example, in some embodiments, the peptide comprises an amino acid selected from alanine, aspartic acid, asparagine, glutamic acid, glutamine, glycine, lysine, ornithine, proline, serine, and threonine.

[0107] In some embodiments, L 2 contains 1 to 20 -OCH2CH2- moieties. In some preferred embodiments, L 2 contains 1 to 10 -OCH2CH2- moieties, preferably 2 to 6 -OCH2CH2- moieties.

[0108] In some embodiments, L 2 has structural formula (II*):

[0109] [ka] (In the formula, Y is - # NHC(O)- or - # (CH2) t NHC(O)-, R 3 is -CH2OR 3A or -CO2R 3B and Each R 4 are independently H or a hydroxyl protecting group; R 3A is H or a hydroxyl protecting group, R 3B is H or a carboxyl protecting group, t is 1, 2, or 3, preferably 1; # indicates point of attachment to the phenyl ring) It includes the portion represented by

[0110] In some embodiments, L2 has structural formula (III*):

[0111] [ka] (In the formula, Y is * - # NHC(O)-,- # C(O)NH-, - # (CH2) t NHC(O)- and -COOH, ## is L 1 (indicating the attachment point to It includes the portion represented by

[0112] In some embodiments, Y is - # NHC(O)-. In some embodiments, Y is - # (CH2) t NHC(O)-. In some preferred embodiments, Y is - # C(O)NH-.

[0113] In some embodiments, R 3 Ha-CH2OR 3A In some embodiments, R 3A is H.

[0114] In some embodiments, R 3 HA-COOR 3B In some embodiments, R 3B is H.

[0115] In some embodiments, L 2 has the structural formula (IIa*):

[0116] [ka] (In the formula, L 5 is the linker, RG is a reactive group It includes the portion represented by

[0117] In some embodiments, L 2 is a moiety represented by structural formula (IIa*).

[0118] In some embodiments, L 2 has the structural formula (IIIa*):

[0119] [ka] (In the formula, L 5 is the linker, RG is a reactive group, ## is L 1 (indicating the attachment point to It includes the portion represented by

[0120] In some embodiments, L 2 is a moiety represented by structural formula (IIIa*).

[0121] In some embodiments, L 5 is represented by the structural formula Va, Vb, Vc, Vd, or Ve:

[0122] [ka] (In the formula, L 8 is a single bond or C 1~30 is alkylene, R 11 is H or C 1~10 alkyl) Includes units represented by

[0123] In some embodiments, L 5 comprises units represented by structural formula Va, Vb, or Vc.

[0124] In some embodiments, L 8 is a single bond. Alternatively, in some embodiments, L 8 is C1~30 It is alkylene.

[0125] In some embodiments, R 11 is H. Alternatively, in some embodiments, R 11 is C 1~10 For example, in certain embodiments, R 11 is methyl.

[0126] RG can be any suitable reactive group such that additional moieties having complementary reactive groups can be attached to the compound represented by structural formula (I) through reactions with, e.g., displacement of, RG. In some embodiments, RG is selected from the group consisting of OH, Hal, -NR 12 R 13 , -COOH, -C(O)R 14 , -SO3R 15 , SH, -NHOH, -NH2NH2, -CH(CH2COOH)2, -C(O)C≡CR 16 , N3, -OP(O)(OH)2, alkyl, alkenyl, alkynyl, heterocyclyl, C8-C 10 Cycloalkynyl, sugar, isocyanide, isothiocyanide, 2-pyridyl disulfide, -NHC(O)CH2-Hal, maleimide, tosylate,

[0127] [ka] is selected from Hal is a halogen, R 12 , R 13 , R 14 , R 15 , and R 16 are each independently H or alkyl. For example, in some embodiments, RG is alkyl, e.g., C 1~3 It is alkyl, preferably methyl.

[0128] In some embodiments, RG is OH, NR 12 R 13, —COOH, —C≡CH, N3, —OP(O)(OH)2, —CH(CH2COOH)2, heterocyclyl, and sugar.

[0129] In some embodiments, RG is OH.

[0130] In some embodiments, RG is NR 12 R 13 For example, in certain embodiments, R 12 and R 13 is H. For example, in certain embodiments, R 12 and R 13 is Me.

[0131] In some embodiments, RG is alkyl. In some preferred embodiments, RG is methyl.

[0132] In some embodiments, RG has the following structural formula:

[0133] [ka] is expressed by

[0134] In some embodiments, RG is a sugar. In some embodiments, the sugar is a glucuronide. In some preferred embodiments, the glucuronide is

[0135] [ka] is.

[0136] In some embodiments, L2 is ## OC(O)NR 5* -L 4* -NR 6* -, ## -OC(O)-L 4* -NR 6* -or ## -OC(O)NR 5* -L 4*-(heterocyclylene) (In the formula, ## is L 1 is the connection point to L 4* is alkylene or arylalkylene, R 5* and R 6* are independently selected from H, alkyl a linker L 2* Further includes:

[0137] In some embodiments, the compound has the following structural formula:

[0138] [ka] TIFF2025538034000062.tif167161TIFF2025538034000063.tif167161TIFF2025538034000064.tif167161TIFF2025538034000065.tif167161TIFF2025538034000066.tif215161TIFF2025538034000067.tif215163TIFF2025538034000068.tif63164, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound is represented by one of the following structural formulas, or a pharmaceutically acceptable salt thereof:

[0140] [ka] TIFF2025538034000070.tif182164TIFF2025538034000071.tif195164TIFF2025538034000072.tif210164 TIFF2025538034000073.tif210165TIFF2025538034000074.tif210165TIFF2025538034000075.tif120165

[0141] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, for example, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0142] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in the prevention or treatment of a disease mediated by stimulator of interferon genes (STING).

[0143] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in the prevention or treatment of a disease mediated by stimulator of interferon genes (STING). In some embodiments, the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease. For example, the STING-mediated disease is cancer or an infectious disease, e.g., cancer. In some embodiments, the disease is cancer selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0144] In some embodiments, the present disclosure relates to a method for preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease. For example, the STING-mediated disease is cancer or an infectious disease, such as cancer. In some embodiments, the disease is a cancer selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0145] In some embodiments, the present disclosure relates to the use of a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the manufacture of a medicament for treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. In some embodiments, the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease. For example, the STING-mediated disease is cancer or an infectious disease, e.g., cancer. In some embodiments, the disease is cancer selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0146] In some embodiments, the present disclosure relates to a compound of the present disclosure, e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. In some embodiments, the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease. For example, the STING-mediated disease is cancer or an infectious disease, e.g., cancer. In some embodiments, the disease is cancer selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0147] Pharmaceutical Composition The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, e.g., comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, e.g., water or physiologically buffered saline, or other solvents or vehicles, e.g., glycols, glycerol, oils, e.g., olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive administration routes (i.e., routes that avoid transport or diffusion through epithelial barriers, e.g., injection or implantation), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions may also be present in transdermal delivery systems, such as skin patches. The compositions may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0148] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that act, for example, to stabilize, increase the solubility, or increase the absorption of compounds such as the compounds of the present disclosure. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, which may, for example, incorporate a compound of the present disclosure therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0149] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0150] The phrase "pharmaceutically acceptable carrier," as used herein, means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solution, and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0151] The pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., as a drench, such as in an aqueous or non-aqueous solution or suspension, a tablet, a capsule (including sprinkle capsules and gelatin capsules), a bolus, a powder, a granule, a paste for application to the tongue), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0152] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0153] Methods of preparing these formulations or compositions include the step of admixing an active compound, such as a compound of the present disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately admixing a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0154] Formulations of the present disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and acacia or tragacanth), lyophilisates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (with an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0155] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as PEG-1000; For example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarders such as paraffin, (6) absorption accelerators such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents such as modified and unmodified cyclodextrins, and (11) coloring agents. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0156] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0157] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various ratios of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water, or some other sterile injectable medium, immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0158] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0159] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0160] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0161] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0162] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0163] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0164] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0165] The phrases "parenteral administration" and "administered parenterally," as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0166] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0167] These compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[0168] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.In this case, the absorption rate of the drug depends on its dissolution rate, which in turn may depend on crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0169] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0170] For use in the methods of the present disclosure, the active compound can be provided per se, or can be provided as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0171] Methods of introduction can also be provided by rechargeable or biodegradable devices. A variety of sustained-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0172] Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0173] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general health, and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0174] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start a dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered together with the compound of the present disclosure. A larger total dose can be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0175] Generally, a suitable daily dose of an active compound used in the compositions and methods of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0176] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six, or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0177] Patients receiving this treatment may be any animal in need thereof, including primates, particularly humans; and other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and pets in general.

[0178] In certain embodiments, the compounds of the present disclosure can be administered alone or together with another type of therapeutic agent.

[0179] The present disclosure includes the use of pharmaceutically acceptable salts of the disclosed compounds in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, Includes salts of gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0180] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0181] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0182] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0183] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the terms used in connection with, and techniques relating to, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0184] The methods and techniques of the present disclosure are generally performed according to conventional methods known in the art, unless otherwise indicated, and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0185] Chemical terms used herein, unless otherwise defined herein, are used in accordance with conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0186] All of the above, and any other publications, patents and published patent applications mentioned in this application, are specifically incorporated herein by reference. In the case of conflict, the present specification, including its specific definitions, will control.

[0187] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biopolymer (e.g., a nucleic acid, an antibody, e.g., a portion thereof, as well as humanized, chimeric, and human antibodies, and monoclonal antibodies, a protein or a portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological material such as a bacterial, plant, fungal, or animal (especially mammalian) cell or tissue. Agents include, for example, agents of known structure and agents of unknown structure.

[0188] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0189] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of the spread of the disease, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0190] The term "preventing," when used in reference to a condition, e.g., local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and well understood in the art, and includes administration of a composition that reduces the frequency of, or delays the onset of, symptoms of the medical condition in a subject compared to subjects not receiving the composition. Thus, preventing cancer includes, for example, reducing, by a statistically and / or clinically significant amount, the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population.

[0191] "Administering" or "administration" of a substance, compound, or agent to a subject can be accomplished using one of a variety of methods known to those of skill in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through the skin's channels). A compound or agent can also be suitably introduced via a rechargeable or biodegradable polymeric device or other device, such as a patch and pump, or formulation that provides extended, sustained, or controlled release of the compound or agent. Administering can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0192] The appropriate method of administering a substance, compound, or agent to a subject also depends, for example, on the age and / or health of the subject, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally to the subject, for example, by ingestion. In some embodiments, the orally administered compound or agent is in an extended- or sustained-release formulation or is administered using such a sustained- or sustained-release device.

[0193] As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic agents, in which a second agent is administered while a previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective in a patient simultaneously, which may involve a synergistic effect of the two agents). For example, the different therapeutic compounds can be administered simultaneously or sequentially, in the same formulation or in separate formulations. Thus, an individual receiving such treatment can benefit from the combined effect of the different therapeutic agents.

[0194] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of drug or agent that has the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur by administration of one dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations. The precise effective amount required for a subject depends, for example, on the subject's size, health, and age, and the nature and extent of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimentation.

[0195] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted alkyl" refers to cases where alkyl can be substituted and cases where alkyl is not substituted.

[0196] It is understood that the substituents and substitution patterns on the compounds of the present disclosure can be selected by those skilled in the art to result in chemically stable compounds that can be easily synthesized from readily available starting materials by techniques known in the art and the methods described below. When a substituent is itself substituted with two or more groups, it is understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure is obtained.

[0197] As used herein, the term "optionally substituted" refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH-O-alkyl, -OP(O)(O-alkyl) or -CH-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to the replacement of one to four hydrogen radicals in a given structure with a substituent as described above. More preferably, one to three hydrogen radicals are replaced by a substituent as described above. It is understood that a substituent may be further substituted.

[0198] As used herein, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can be one to ten carbon atoms (i.e., (C 1~10 ) alkyl) or 1 to 8 carbon atoms (i.e., (C 1~8 ) alkyl) or 1 to 6 carbon atoms (i.e., (C 1~6 ) alkyl) or 1 to 4 carbon atoms (i.e., (C 1~4) alkyl). Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)C H2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2C H(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4- These include, but are not limited to, methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3).

[0199] Additionally, the term "alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C for straight chain). 1~30, C for branched chain 3~30 ), more preferably having 20 or fewer carbon atoms. In certain embodiments, alkyl is unsubstituted unless otherwise specified. However, unless specified, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbon atoms of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0200] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), or 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Examples of alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), 5-hexenyl (-CHCHCHCHCH=CH), and 3-hexenyl (-CHCHCH=CHCHCH). Throughout this specification, one terminal hydrogen of an alkenyl group may be omitted to connect it to the next linking group. In certain embodiments, alkenyl is unsubstituted unless otherwise specified.

[0201] As used herein, the term "alkylene" refers to a group having 1 to 6 (C 1~6 (C) refers to a linear or branched divalent saturated hydrocarbon group having 1 to 4 carbon atoms. 1~4 Alkylenes having 1 to 3 carbon atoms can be used, examples of which include, but are not limited to, methylene, ethylene, trimethylene (propylene), and tetramethylene (n-butylene).

[0202] As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can be an alkynyl group having 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), or 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CHC≡CH), and -CH-C≡C-CH. In certain embodiments, alkynyl is unsubstituted unless otherwise specified.

[0203] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0204] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0205] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0206] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0207] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0208] The term "alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C for straight chain). 1~30 , C for branched chain 3~30 ), more preferably having 20 or fewer carbon atoms.

[0209] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0210] The term “C x~y " or "C x ~C y " when used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, means that the group contains from x to y carbons in the chain. CO alkyl indicates a hydrogen when the group is in a terminal position and a bond when the group is internal. C 1~6 An alkyl group contains, for example, 1 to 6 carbon atoms in the chain.

[0211] The addition of the suffix "-ene" to a base indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0212] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0213] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0214] The term "amide" as used herein refers to the group

[0215] [ka] (In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure) Refers to...

[0216] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, and their salts, e.g.,

[0217] [ka] (In the formula, R 9 , R 10 , and R 10' each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure) It refers to a part that can be represented by

[0218] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0219] As used herein, the term "amidino" or "amidine" refers to the group C(=NR 10 )NR 11 R 12 (In the formula, R 10 , R 11 , and R 12 each independently represents hydrogen or a hydrocarbyl group, or R 11 and R 12 (combined with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure). Non-limiting examples of amidines include C(=NMe)NMe2, C(=NH)NMe2, and C(=NH)NH2.

[0220] As used herein, the term "guanidine" refers to the group -NR 9 C(=NR 10 )NR 11 R 12 (In the formula, R 9 , R 10 , R 11 , and R 12 each independently represents hydrogen or a hydrocarbyl group, or R 11 and R 12 (combined with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure). Non-limiting examples of guanidines include -NMeC(=NMe)NMe2, -NHC(=NMe)NMe2, -NHC(=NH)NMe2, -NMeC(=NH)NH2 and -NHC(=NH)NH2.

[0221] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0222] The term "aryl," as used herein, includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0223] The term "carbamate" is art-recognized and refers to a group

[0224] [ka] (In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group. Refers to...

[0225] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0226] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, three, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In a typical embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Where valences permit, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions that can have a hydrogen atom.

[0227] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0228] The term "carbonate" is art-recognized and refers to the group --OCO.sub.2--.

[0229] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0230] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic ring structures, preferably 4-8 membered rings, more preferably 4-6 membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings, at least one of which is cycloalkyl and contains substituents (e.g., R 100 ) is attached to the cycloalkyl ring; for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline, and the like. Non-limiting examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0231] The term "ester" as used herein refers to the group -C(O)OR 9 (In the formula, R 9 represents a hydrocarbyl group).

[0232] The term "ether," as used herein, refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen atom. Thus, the ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

[0233] The terms "halo" and "halogen," as used herein, mean halogen and include chloro, fluoro, bromo, and iodo.

[0234] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0235] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one non-carbon atom in the ring, which atom may be selected from oxygen, nitrogen, and sulfur, and "heteroaryl" can include multiple fused ring systems having at least one such aromatic ring. Multiple fused ring systems are further described. Thus, "heteroaryl" can include a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms can also be present in oxidized form, provided the ring is aromatic. Examples of heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. In some embodiments, "heteroaryl" includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), and heteroaryl groups defined above can form polycondensed ring systems through fusion with at least one ring selected from heteroaryls (e.g., used to form 1,8-naphthyridinyl), heterocycles (e.g., used to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (e.g., used to form 5,6,7,8-tetrahydroquinolyl), and aryls (e.g., used to form indazolyl). Thus, a heteroaryl (a single aromatic ring or a polycondensed ring system) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. Such polycondensed ring systems can be such that the carbocyclic or heterocyclic portion of the fused ring can be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups. The rings of a multiply fused ring system may be connected to each other through fused, spiro, and bridged bonds, provided that valency requirements are met. The individual rings of a multiply fused ring system may be connected to each other in any order. The point of attachment to a heteroaryl or heteroaryl multiply fused ring system may be at any suitable atom of the heteroaryl or heteroaryl multiply fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Additionally, heteroaryls of a particular atom range (e.g., (C5-C6)) may be used. 10When a heteroaryl is referred to, the atom range is to be understood as being in reference to the total number of ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, C heteroaryl may include thiazolyl, and C 10 Heteroaryl may include quinolinyl. Examples of heteroaryl include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

[0236] As used herein, the term "heterocyclyl" or "heterocycle" refers to a mono-saturated or partially unsaturated non-aromatic compound or non-aromatic polycyclic ring system containing at least one heteroatom in the ring (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has from 5 to about 20 ring atoms, e.g., from 3 to 12 ring atoms, e.g., from 5 to 10 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. Rings in a poly-fused ring system may be connected to each other through fused, spiro, and bridged bonds, provided valency requirements are met. Examples of heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.

[0237] The term "hydrocarbyl," as used herein, refers to a group that is bonded through a carbon atom that has no =0 or =S substituents and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has an =0 substituent on the connecting carbon) and ethoxy (which is connected through an oxygen rather than a carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0238] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0239] The term "lower," when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer atoms, preferably 6 or fewer atoms, in the substituent. "Lower alkyl," for example, refers to alkyl groups containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they appear alone or in combination with other substituents, such as in descriptions of hydroxyalkyl and aralkyl (where, for example, atoms in an aryl group are not counted when counting carbon atoms in an alkyl substituent).

[0240] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0241] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0242] The term "sulfonamide" is art-recognized and can be represented by the general formula

[0243] [ka] (In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl. It refers to a group represented by:

[0244] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0245] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0246] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0247] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" is subject to the permissible valences of the substituted atom and substituent, and also includes the implicit proviso that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0248] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0249] The term "thioester" as used herein refers to the group -C(O)SR 9 or -SC(O)R 9 (In the formula, R 9 represents hydrocarbyl).

[0250] The term "thioether," as used herein, is equivalent to an ether where the oxygen has been replaced with a sulfur.

[0251] The term "urea" is art-recognized and has the general formula

[0252] [ka] (In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl. It can be represented by:

[0253] The term "modulate" as used herein includes inhibiting or suppressing a function or activity (eg, cell proliferation), as well as enhancing a function or activity.

[0254] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0255] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0256] The term "pharmaceutically acceptable acid addition salt," as used herein, refers to any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids which form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids which form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, and sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous form. In general, the acid addition salts of the compounds of formula I are more soluble in water and various hydrophilic organic solvents than their free base forms, and generally have a higher melting point.The selection of suitable salts is known to those skilled in the art.Other pharmaceutically unacceptable salts, such as oxalates, can be used, for example, in the isolation of the compounds of formula I for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0257] The term "pharmaceutically acceptable base addition salt," as used herein, refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any of its intermediates. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or ammonia. The selection of suitable salts is within the skill of the art.

[0258] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may exist in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms (including all possible mixtures of stereoisomers), such as enantiomeric and diastereoisomeric forms of compounds, salts, prodrugs, or mixtures thereof. See, for example, WO 01 / 062726.

[0259] Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers, and in each case, the present disclosure includes both mixtures and the separate individual isomers.

[0260] A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, e.g., hydrolyzed or oxidized, in the host after administration to form a compound of the present disclosure (e.g., a compound of Formula I). ​​Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs that use esters or phosphoramidates as the biologically labile or cleavable (protecting) group are disclosed in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs," Ed. H. Bundgaard, Elsevier, 1985.

[0261] The phrase "pharmaceutically acceptable carrier," as used herein, means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, useful in formulating a drug for pharmaceutical or therapeutic use. In certain embodiments, the present disclosure relates to heterocyclic compounds that have activity as STING agonists.

[0262] In certain embodiments, the pharmaceutical composition further comprises a chemotherapeutic agent, eg, a pharmaceutically effective amount of a chemotherapeutic agent.

[0263] In certain embodiments, the pharmaceutical composition further comprises one or more therapeutic co-agents and one or more pharmaceutically acceptable excipients.

[0264] Therapeutic co-drugs may be, but are not limited to, drugs that exhibit preventive, ameliorative, or therapeutic effects against STING-mediated diseases; drugs that can reduce the occurrence of side effects that occur when administering therapeutic drugs for STING-mediated diseases; or drugs that exhibit immune-enhancing effects. Therapeutic co-drugs can be applied alone or in combination (i.e., a pharmaceutical composition containing a compound of Formula 1 may further contain one or more therapeutic co-drugs). When a STING agonist, which is a compound described herein, is administered together with one or more therapeutic co-drugs, optionally with further combination agents, a therapeutically beneficial effect may be achieved; for example, co-administration of a STING agonist (e.g., a compound disclosed herein, e.g., a compound of Formula 1) with one or more therapeutic co-drugs may further enhance the stability of proteolytic agents, reduce side effects that occur when administering a STING agonist represented by a compound of Formula 1, and / or maximize therapeutic effects through immune enhancement.

[0265] Suitable therapeutic co-agents include, but are not limited to, auristatins, bexarotene, bicalutamide, BMS 184476, bleomycin, cemadotin, chlorambucil, cyclophosphamide, docetaxol, docetaxel, carboplatin, carmustine, cisplatin, cryptophycin, decitabine, dolastatins, doxorubicin, mibobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, nivolumab, onapristone, paclitaxel, procarbazine, tamoxifen, tasonermin, tretinoin, vinblastine, vincristine, PD-1 antagonists, CTLA-4 antagonists, B7 costimulatory molecules, interleukin-2, interleukin-7, and the like.

[0266] In other embodiments, the present disclosure relates to a method of preventing or treating a STING-mediated disease in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein (e.g., a compound of Formula 1) or a pharmaceutically acceptable salt thereof; or administering to the subject a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and optionally further comprising a chemotherapeutic agent. In some embodiments, the STING-mediated disease is cancer, a bacterial infection, a viral infection, a fungal infection, an immune-mediated disorder, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a cerebrovascular disease, a peripheral arterial disease, a cardiovascular disease, an allergic disease, or inflammation. In certain embodiments, the STING-mediated disease is cancer, a bacterial infection, a viral infection, a fungal infection, an immune-mediated disorder, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a cerebrovascular disease, a peripheral arterial disease, a cardiovascular disease, or an allergic disease. In certain embodiments, the STING-mediated disease is cancer or an infectious disease.

[0267] In certain embodiments, the STING-mediated disease is cancer. Cancers suitable for treatment with the compounds and methods disclosed herein include any carcinoma for which a STING agonist (e.g., a compound of Formula 1, or a pharmaceutically acceptable salt thereof) exhibits therapeutic efficacy. Suitable cancers include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. In more specific embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0268] In yet other embodiments, the present disclosure relates to the use of a compound disclosed herein (e.g., a compound of Formula 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for the manufacture of a medicament for treating or preventing a STING-mediated disease in a subject in need thereof. The pharmaceutical composition may further comprise a chemotherapeutic agent. In some embodiments, the STING-mediated disease is cancer, a bacterial infection, a viral infection, a fungal infection, an immune-mediated disorder, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a cerebrovascular disease, a peripheral arterial disease, a cardiovascular disease, an allergic disease, or inflammation. In certain embodiments, the STING-mediated disease is cancer, a bacterial infection, a viral infection, a fungal infection, an immune-mediated disorder, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a cerebrovascular disease, a peripheral arterial disease, a cardiovascular disease, or an allergic disease. In certain embodiments, the STING-mediated disease is cancer or an infectious disease.

[0269] In certain embodiments, the STING-mediated disease is cancer. Cancers suitable for treatment with the compounds and methods disclosed herein include any carcinoma for which a STING agonist (e.g., a compound of Formula 1) exhibits therapeutic efficacy. Suitable cancers include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. In more specific embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0270] Additionally, the compound of Formula 1 (or a pharmaceutically acceptable salt thereof), in any one of its pharmaceutically acceptable salts, can be used as an adjunct for the treatment of other infections, diseases, or disorders, such as cancer. In any of the foregoing methods and uses, the compound of Formula 1 (or a pharmaceutically acceptable salt thereof) may be administered together with another therapeutic agent, such as a chemotherapeutic agent or a toxin. The chemotherapeutic agent or toxin used herein can be an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof. In certain embodiments, the chemotherapeutic agent or toxin is, for example, a CTLA-4 antagonist, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a LAG3 inhibitor, TIM-3, BTLA, B4, B7 costimulatory molecule, an IDO inhibitor, a TDO inhibitor, VISTA, HVEM, TIGIT, PVR, CC-90006, CG-0070, CS-1003, CD160, CGEN-15049, CHK1, CHK2, CEACAM1, OX40, OX40L, GM-CSF, a cyclodextrin, or an anthracycline compound, such as erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethyleneimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylene Thiolethiophosphoramide, trimethylolmelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1,Eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, romosozotocin ... dynemicin, nimustine, ranimustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomycins, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, Chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins mycins), peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, 5-fluorouracil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine,Ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone, propionate, epithiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, eflornithine, elliptinium acetate acetate), etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidamine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziconazole, 2,2',2''-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethane, bile Benzene, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, albumin-engineered nanoparticle formulations of paclitaxel, docetaxel, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, or capecitabine,Not limited to these. [Example]

[0271] Preparation Example 1: Preparation of intermediate compound 2

[0272] [ka]

[0273] Preparation of intermediate compound 1 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (8 g, 51.9 mmol) was dissolved in dichloromethane (50 mL), and then oxalyl chloride (4.97 mL, 57.1 mmol) and N,N-dimethylformamide (0.1 mL) were added at 0° C. The reaction solution was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to give intermediate compound 1.

[0274] Preparation of intermediate compound 2 Intermediate compound 1 (crude) was dissolved in acetone (100 mL), and potassium thiocyanate (6.5 g, 67.5 mmol) was added at 0° C. The reaction solution was stirred at room temperature for 30 minutes, and then hexane (100 mL) was added and the formed solid was filtered. The filtered solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 2 (9.7 g, 95%). 1 EI-MS m / z : [M+H] + 196.00.

[0275] Preparation Example 2: Preparation of intermediate compound 5

[0276] [ka]

[0277] Preparation of intermediate compound 3 Methyl 4-chloro-3-methoxy-5-nitrobenzoate (15 g, 61.1 mmol) was added to aqueous ammonia (28-30% ammonia, 200 mL). The reaction solution was stirred at 50 °C for 6 h, cooled to room temperature, washed with water, filtered, and lyophilized to give intermediate compound 3 (9.51 g, 68%). 1 H-NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 4.01 (s, 3H).

[0278] Preparation of intermediate compound 4 Intermediate compound 3 (300 mg, 1.30 mmol) was added to dichloromethane (9 mL), followed by the addition of aluminum chloride (1.04 g, 7.81 mmol) at 0° C. The reaction solution was stirred at room temperature under nitrogen for 21 hours. The reaction solution was added to ice water, and the resulting solid was then filtered and lyophilized to give intermediate compound 4 (223 mg, 79%). 1 H-NMR (400 MHz, CDCl3), δ 11.73 (s, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H).

[0279] Preparation of intermediate compound 5 Intermediate compound 4 (2 g, 9.23 mmol) and cesium carbonate (3.61 g, 11.08 mmol) were added to N,N-dimethylformamide (15 mL) under nitrogen at 0°C and then stirred for 5 minutes. trans-1,4-Dibromo-2-butene (5.93 g, 27.70 mmol) was added to the reaction solution at room temperature under nitrogen and stirred for 2 hours. The resulting solution was extracted with ethyl acetate (20 mL × 3) and washed with distilled water (15 mL × 2) and brine (15 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. After coagulation using dichloromethane and hexane, it was filtered and dried to give intermediate compound 5 (2.53 g, 78%). 1H-NMR (400 MHz, CDCl3), δ 8.23 ​​(s, 2H), 8.02 (d, J = 1.8 Hz, 2H), 7.84 (d, J = 1.8 Hz, 2H), 7.73 (s, 2H), 6.16-5.98 (m, 4H), 5.70 (s, EI-MS m / z : [M+H] + 350.98.

[0280] Preparation Example 3: Preparation of intermediate compound 9

[0281] [ka]

[0282] Preparation of intermediate compound 6 4-Chloro-3-methoxy-5-nitro-benzamide (11.4 g, 61.57 mmol) was dissolved in ethanol (100 mL), and then intermediate compound 3 (10 g, 43.4 mmol) and N,N-diisopropylethylamine (14.9 mL, 86.7 mmol) were added and stirred for 12 hours at 120° C. The reaction solution was concentrated and diluted with diethyl ether (40 mL), and the resulting solid was filtered and dried to give intermediate compound 6 (12.6 g, 76%). 1 H-NMR (400 MHz, DMSO-d6), δ 8.18 (d, 1H), 8.01(s, 1H), 7.73 (t, 1H), 7.55 (d, 1H), 7.31 (s, 1H), 6.92 (s, 1H), 5.53 (s, 2H), 4.08 (s, 2H), 3.47 (s, 2H), 1.35 (m, 9H).

[0283] Preparation of intermediate compound 7 Intermediate compound 6 (10 g, 26.28 mmol) was dissolved in methanol (90 mL), and then aqueous ammonia (28-30% ammonia, 90 mL) and sodium hydrosulfite (NaSO, 45 g, 262.8 mmol) were added successively at 0 °C. The mixture was stirred at room temperature for 1 hour and 30 minutes. After adding methanol (100 mL) to the reaction solution, the resulting solid was filtered. The filtered solution was concentrated, then diluted with dichloromethane (100 mL), washed with distilled water (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to give intermediate compound 7 (6.9 g, 75%). 1 H-NMR(400 MHz, DMSO-d6), δ 7.62 (br s, 1H), 6.98 (br s, 1H), 6.92 (t, 1H), 6.87 (d, 1H), 6.79 (d, 1H), 5.57 (q, 2H), 4.67 (br s, 2H), 3.82 (br s, 1H), 3.76 (s, 3H), 3.51 (dd, 4H), 1.37 (s, 9H).

[0284] Preparation of intermediate compound 8 Intermediate compound 7 (6.9 g, 19.7 mmol) was dissolved in N,N-dimethylformamide (50 mL), and then intermediate compound 2 (4.9 g, 25.59 mmol) was added at 0° C. and stirred at room temperature for 30 minutes. Triethylamine (5.4 mL, 39.38 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (4.2 g, 27.56 mmol) were added at 0° C., and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated, then diluted with diethyl ether (20 mL), and the resulting solid was filtered to give intermediate compound 8 (7.7 g, 76%). 1H-NMR (400 MHz, DMSO-d6), δ 12.86 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.40 (m, 2H), 6.93 (m, 1H), 6.65 (s, 1H), 5.67 (m, 2H), 4.93 (d, 2H), 4.61 (q, 2H), 3.98 (s, 3H), 3.51 (m, 2H), 2.55 (m, 2H), 2.18 (s, 3H), 1.35 (t, 3H), 1.32 (s, 9H).

[0285] Preparation of intermediate compound 9 Intermediate compound 8 (7.7 g, 15.05 mmol) was dissolved in dichloromethane (25 mL) and methanol (25 mL), and then hydrochloric acid (4 M in 1,4-dioxane, 27 mL) was added and stirred for 2 hours and 30 minutes. The reaction solution was concentrated and diluted with diethyl ether (20 mL), and the resulting solid was filtered to give intermediate compound 9 (5.6 g, 76%). 1 H-NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 8.67(d, 1H), 7.41 (d, 1H), 7.37 (s, 1H), 6.66 (s, 1H), 6.01 (m, 1H), 5.65 (m, 1H), 4.97 (d, 2H), 4.60 (q, 2H), 3.98 (s, 3H), 2.66 (m, 5H), 2.33 (m, 3H), 1.35 (m, 3H). EI-MS m / z : [M+H] + 823.0.

[0286] Example 1 Preparation of Compound 13

[0287] [ka]

[0288] Preparation of intermediate compound 10 Intermediate compound 5 (580 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of morpholine (0.13 mL, 1.01 mmol) and cesium carbonate (590 mg, 1.81 mmol) under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to give intermediate compound 10 (504 mg, 70%). 1 H-NMR (400 MHz, CDCl3), δ 7.73-7.66 (m,1H), 6.03-5.84 (m,1H), 4.75 (dd, J = 5.0, 1.2 Hz, 1H), 3.75-3.68 (m, 2H), 3.06 (dd, J = 6.0, 1.1 Hz, 1H), 2.46 (t, J = 4.7 Hz, 2H). EI-MS m / z : [M+H] + 356.09.

[0289] Preparation of intermediate compound 11 Intermediate compound 9 (818 mg, 1.68 mmol) and intermediate compound 10 (300 mg, 0.84 mmol) were dissolved in n-butyl alcohol (13 mL), and then N,N-diisopropylethylamine (0.74 mL, 4.21 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. After cooling to room temperature, the reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. After dilution with diethyl ether, the resulting solid was filtered and dried to give intermediate compound 11 (129 mg, 21%). EI-MS m / z: [M+H] + 731.03.

[0290] Preparation of intermediate compound 12 Intermediate compound 11 (129 mg, 0.17 mmol) was dissolved in methyl alcohol (2 mL) and distilled water (0.1 mL), and then aqueous ammonia (28-30% ammonia, 0.17 mL) and sodium hydrosulfite (NaSO, 321 mg, 1.84 mmol) were added to the reaction solution under nitrogen. After stirring at room temperature for 1 hour, methanol (50 mL) was added to the reaction solution, the resulting solid was filtered, the filtered solution was concentrated, then diluted with dichloromethane (100 mL), washed with distilled water (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to give intermediate compound 12 (126 mg, crude). EI-MS m / z: [M+H] + 701.08.

[0291] Preparation of Compound 13 Intermediate compound 12 (126 mg, 0.18 mmol, crude) was dissolved in N,N-dimethylformamide (2 mL), and then intermediate compound 2 (39 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.27 mmol) were added and stirred at room temperature for 16 hours. The resulting material was concentrated under reduced pressure and purified by HPLC to give compound 13 (5.6 mg, 4%). EI-MS m / z: [M+H] + 862.03.

[0292] Example 2 Preparation of Compound 18

[0293] [ka]

[0294] Preparation of intermediate compound 14 Intermediate compound 5 (265 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then t-butyl piperidin-4-ylcarbamate (167 mg, 0.83 mmol) and cesium carbonate (296 mg, 0.91 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to give intermediate compound 14 (248 mg, 70%). EI-MS m / z: [M+H] + 469.06.

[0295] Preparation of intermediate compound 15 Intermediate compound 9 (628 mg, 1.3 mmol) and compound 14 (304 mg, 0.65 mmol) were dissolved in n-butyl alcohol (5 mL), and diisopropylethylamine (0.56 mL, 3.24 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. After cooling to room temperature, the reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The reaction solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to give intermediate compound 15 (124 mg, 23%). EI-MS m / z: [M+H] + 844.02.

[0296] Preparation of intermediate compound 16 Intermediate compound 15 (124 mg, 0.15 mmol) was dissolved in methanol (4 mL) and distilled water (0.5 mL), and then aqueous ammonia (28-30% ammonia, 0.4 mL) and sodium hydrosulfite (NaSO, 218 mg, 2.94 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL), and filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 16 (119 mg, crude). EI-MS m / z: [M+H] + 814.81.

[0297] Preparation of intermediate compound 17 Intermediate compound 16 (119 mg, 0.15 mmol, crude) was dissolved in N,N-dimethylformamide (1 mL), and then intermediate compound 2 (32 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and triethylamine (0.06 mL, 0.44 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 17 (36 mg, 25%). EI-MS m / z: [M+H] + 975.15.

[0298] Preparation of Compound 18 Intermediate compound 17 (36 mg) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (1 mL) was added under nitrogen at 0° C. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to give compound 18 (15.2 mg, 47%). EI-MS m / z: [M+H] + 875.06.

[0299] Example 3 Preparation of Compound 23

[0300] [ka]

[0301] Preparation of intermediate compound 19 Intermediate compound 5 (500 mg, 1.43 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then t-butyl piperazine-1-carboxylate (320 mg, 1.71 mmol) and cesium carbonate (512 mg, 1.57 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to give intermediate compound 19 (472 mg, 72%). 1 H-NMR (400 MHz, DMSO-d6), δ 8.26 (s, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 5.91-5.83 (m, 2H), 4.84 (d, 1H), 3.29-3.27 (m, 4H), 2.98 (d, 2H), 2.73 (t, 4H), 1.39 (s, 9H). EI-MS m / z : [M+H] + 455.11.

[0302] Preparation of intermediate compound 20 Intermediate compound 9 (495 mg, 1.02 mmol) and intermediate compound 19 (310 mg, 0.68 mmol) were dissolved in n-butyl alcohol (7 mL), and then diisopropylethylamine (0.59 mL, 3.41 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 20 (336 mg, 46%). EI-MS m / z: [M+H] + 830.01.

[0303] Preparation of intermediate compound 21 Intermediate compound 20 (336 mg, 0.31 mmol) was dissolved in methanol (10 mL) and distilled water (1 mL), and then aqueous ammonia (28-30% ammonia, 0.33 mL) and sodium hydrosulfite (NaSO, 549 mg, 3.16 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL), and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give intermediate compound 21 (153 mg, 60%, crude). EI-MS m / z: [M+H] + 800.09.

[0304] Preparation of intermediate compound 22 Intermediate compound 21 (153 mg, 0.19 mmol, crude) was dissolved in N,N-dimethylformamide (2 mL), and then intermediate compound 2 (45 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (192 mg, 0.28 mmol) and triethylamine (0.1 mL, 0.76 mmol) were added and stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 22 (116 mg, 63%). EI-MS m / z: [M+H] + 961.07.

[0305] Preparation of Compound 23 Intermediate compound 22 (41 mg) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added under nitrogen at 0° C. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to give compound 23 (26 mg, 46%). 1 H-NMR (400 MHz, DMSO-d6), δ 8.66 (br s, 1H), 7.96 (d, 2H), 7.65 (s, 2H), 7.37 (br s, 2H), 7.30 (d, 2H), 6.53 (d, 2H), 5.86-5.63 (m, EI-MS m / z : [M+H] + 861.21.

[0306] Example 4 Preparation of Compound 28

[0307] [ka]

[0308] Preparation of intermediate compound 24 t-Butyl 3-oxopiperazine-1-carboxylate (300 mg, 0.86 mmol) was dissolved in tetrahydrofuran (4 mL), and potassium hydroxide (57.7 mg, 1.02 mmol) and TBAB (tetrabutylammonium bromide, 55.3 mg, 0.17 mmol) were added successively, followed by stirring at room temperature for 30 minutes. Intermediate compound 5 (300 mg, 0.858 mmol) was dissolved in THF (2 mL), then slowly added to the reaction solution, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (30 mL), and then dried over anhydrous magnesium sulfate. The reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography to give intermediate compound 24 (213 mg, 52.9%). 1 H-NMR (400 MHz, CDCl3), δ 8.26 (br s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 5.90-5.80 (m, 2H), 4.84 (d, J = 4.4 Hz, 1H), 4.00 (d, J = 4.8 Hz, 2H), 3.92 (s, 2H), 3.53-3.51 (m, 2H), 3.27-3.24 (m, 2H), 1.41 (s, 9H). EI-MS m / z : [M+H] + 469.07.

[0309] Preparation of intermediate compound 25 Intermediate compound 9 (440 mg, 0.91 mmol) and intermediate compound 24 (213 mg, 0.45 mmol) were dissolved in n-butyl alcohol (4.5 mL), and diisopropylethylamine (0.43 mL, 2.49 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 25 (213 mg, 55.5%). EI-MS m / z: [M+H]+ 844.04.

[0310] Preparation of intermediate compound 26 Intermediate compound 25 (210 mg, 0.25 mmol) was dissolved in methanol (6 mL) and distilled water (1 mL), and then aqueous ammonia (28-30%, 0.44 mL) and sodium hydrosulfite (NaSO, 433 mg, 2.48 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour and 45 minutes, diluted with methanol (50 mL), and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 26 (crude). EI-MS m / z: [M+H] + 814.14.

[0311] Preparation of intermediate compound 27 Intermediate compound 26 (0.24 mmol, crude) was dissolved in N,N-dimethylformamide (2.5 mL), and then intermediate compound 2 (50.9 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (68.1 mg, 0.35 mmol) and triethylamine (0.1 mL, 0.71 mmol) were added, and the mixture was stirred at room temperature for 18 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 27 (48 mg, 20%). EI-MS m / z: [M+H] + 975.19.

[0312] Preparation of Compound 28 Intermediate compound 27 (48 mg) was dissolved in dichloromethane (3.2 mL), and then trifluoroacetic acid (0.8 mL) was added under nitrogen at 0° C. The reaction solution was stirred at 0° C. for 40 minutes, concentrated, and then purified by HPLC to give compound 28 (10.2 mg, 17%). 1H-NMR (400 MHz, DMSO-d6), δ 1.28 (br s, 2H), 9.13 (br s, 1H), 7.96 (d, J = 14.7 Hz, 2H), 7.65 (s, 2H), 7.37 (br s, 2H), 7.30 (s, 2H), 6.53 (d, J = 6.3 Hz, 2H), 5.86-5.63 (m, 4H), 4.92-4.89 (m, 4H), 4.56-4.50 (m, 4H), 3.31 (s, 5H), 2.11 (d, J = 4.9 Hz, 6H) 1.29-1.25 (m, 6H). EI-MS m / z : [M+H] + 875.11.

[0313] Example 5 Preparation of Compound 33

[0314] [ka]

[0315] Preparation of intermediate compound 29 Intermediate compound 4 (1.5 g, 6.93 mmol) and cesium carbonate (2.5 g, 7.62 mmol) were dissolved in N,N-dimethylformamide (6 mL) under nitrogen at 0°C and stirred for 5 minutes. cis-1,4-Dibromo-2-butene (3.7 g, 17.32 mmol) was added to the reaction solution at room temperature under nitrogen and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (20 mL x 2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The solid obtained by diluting with dichloromethane and hexane was filtered and dried to give intermediate compound 29 (1.64 g, 67%). EI-MS m / z: [M+H] + 351.23.

[0316] Preparation of intermediate compound 30 Intermediate compound 29 (450 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then morpholine (0.1 mL, 1.17 mmol) and cesium carbonate (417 mg, 1.28 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and then dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and hexane was filtered and dried to give intermediate compound 30 (298 mg, 71%). EI-MS m / z: [M+H] + 356.11.

[0317] Preparation of intermediate compound 31 Intermediate compound 9 (592 mg, 1.22 mmol) and intermediate compound 30 (290 mg, 0.82 mmol) were dissolved in n-butyl alcohol (6 mL), and then diisopropylethylamine (0.71 mL, 4.08 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The reaction solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 31 (174 mg, 29%). EI-MS m / z: [M+H] + 731.05.

[0318] Preparation of intermediate compound 32 Intermediate compound 31 (173 mg, 0.24 mmol) was dissolved in methanol (2 mL) and distilled water (0.1 mL), and then aqueous ammonia (28-30%, 0.34 mL, 4.76 mmol) and sodium hydrosulfite (NaSO, 412 mg, 2.37 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL), and filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give intermediate compound 32 (48 mg, crude, 29%). EI-MS m / z: [M+H] + 701.22.

[0319] Preparation of Compound 33 Intermediate compound 32 (48 mg, 0.07 mmol, crude) was dissolved in N,N-dimethylformamide (1 mL), and then intermediate compound 2 (16 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (16 mg, 0.09 mmol) and triethylamine (0.03 mL, 0.2 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to give compound 33 (17.5 mg, 30%). EI-MS m / z: [M+H] + 862.08.

[0320] Example 6 Preparation of Compound 38

[0321] [ka]

[0322] Preparation of intermediate compound 34 Intermediate compound 29 (649 mg, 1.86 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of t-butyl piperidin-4-ylcarbamate (338 mg, 1.69 mmol) and cesium carbonate (660 mg, 2.03 mmol) under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and then dried over anhydrous sodium sulfate. The resulting material was filtered and concentrated under reduced pressure. The solid obtained by dilution with dichloromethane and hexane was filtered and dried to give intermediate compound 34 (628 mg, 79%). 1 H-NMR (400 MHz, DMSO), δ 8.21 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 6.16 - 6.01 (m, 2H), 4.82 (d, J = 3.5 Hz, 2H), 4.17 (d, J = 5.5 Hz, 2H). EI-MS m / z : [M+H] + 469.49.

[0323] Preparation of intermediate compound 35 Intermediate compound 9 (413 mg, 0.85 mmol) and intermediate compound 34 (600 mg, 1.28 mmol) were dissolved in n-butyl alcohol (8 mL), and then diisopropylethylamine (0.74 mL, 4.27 mmol) was added at room temperature. The mixture was heated to 120° C. and stirred for 24 hours. The reaction solution was cooled to room temperature, then diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 35 (147 mg, 20%). EI-MS m / z: [M+H] + 844.13.

[0324] Preparation of intermediate compound 36 Intermediate compound 35 (147 mg, 0.17 mmol) was dissolved in methanol (3 mL) and distilled water (0.1 mL), and then aqueous ammonia (28-30%, 0.25 mL) and sodium hydrosulfite (NaSO, 303 mg, 1.74 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL), and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give intermediate compound 36 (141 mg, crude). EI-MS m / z: [M+H] + 814.81.

[0325] Preparation of intermediate compound 37 Intermediate compound 36 (141 mg, 0.17 mmol, crude) was dissolved in N,N-dimethylformamide (1 mL), and then compound 2 (37 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50 mg, 0.09 mmol) and triethylamine (0.03 mL, 0.22 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 37 (48 mg, 28%). EI-MS m / z: [M+H] + 975.16.

[0326] Preparation of Compound 38 Intermediate compound 37 (48 mg) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (1 mL) was added under nitrogen at 0° C. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to give compound 38 (6.4 mg, 14%). EI-MS m / z: [M+H] + 875.17.

[0327] Example 7 Preparation of Compound 43

[0328] [ka]

[0329] Preparation of intermediate compound 39 t-Butyl 3-oxopiperazine-1-carboxylate (210 mg, 1.05 mmol) was dissolved in N,N-dimethylformamide (6 mL), potassium hydroxide (66.2 mg, 1.02 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Intermediate compound 29 (350 mg, 1.20 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then slowly added to the reaction solution. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (30 mL), and then dried over anhydrous magnesium sulfate. The dried material was filtered, concentrated under reduced pressure, and purified by column chromatography to give intermediate compound 39 (432 mg, 92.0%). 1 H-NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.87 (s, 1H), 7.62 (s, 1H), 5.82-5.81 (m, 2H), 4.76, (d, 1H), 4.10-4.05 (m, 4H), 3.65 (t, 2H), 3.34 (t, 2H), 1.47 (s, 9H). EI-MS m / z : [M+H] + 469.10.

[0330] Preparation of intermediate compound 40 Intermediate compound 9 (542 mg, 1.11 mmol) and intermediate compound 39 (350 mg, 0.746 mmol) were dissolved in n-butyl alcohol (4.5 mL), and diisopropylethylamine (0.65 mL, 3.73 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 40 (135 mg, 21.4%). EI-MS m / z: [M+H] + 844.12.

[0331] Preparation of intermediate compound 41 Intermediate compound 40 (135 mg, 0.16 mmol) was dissolved in methanol (6 mL) and distilled water (1 mL), and then aqueous ammonia (28-30%, 0.3 mL) and sodium hydrosulfite (NaSO, 278 mg, 1.59 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 2 hours, diluted with methanol (50 mL), and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give intermediate compound 41 (91 mg, 69.8%). EI-MS m / z: [M+H] + 814.12.

[0332] Preparation of intermediate compound 42 Intermediate compound 41 (91 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (2.5 mL), and then intermediate compound 2 (32.7 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (34 mg, 0.22 mmol) and triethylamine (0.03 mL, 0.24 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give intermediate compound 42 (125 mg, crude). EI-MS m / z: [M+H] + 975.17.

[0333] Preparation of Compound 43 Intermediate compound 42 (125 mg, crude) was dissolved in dichloromethane (3.2 mL), and then trifluoroacetic acid (0.8 mL) was added under nitrogen at 0° C. The reaction solution was stirred at 0° C. for 40 minutes, concentrated, and then purified by HPLC to give compound 43 (34 mg, 25%). 1 H-NMR (400 MHz, DMSO-d6), δ 12.84 (bs, 2H), 9.16 (bs, 2H), 7.97 (d, 2H), 7.65 (s, 2H), 7.36 (s, 2H), 7.30 (s, 2H), 6.53 (d, 2H), 5.79 (s, 2H), 5.73-5.60 (m, 2H), 4.90 (bs, 4H), 4.55-4.50 (m, 6H), 3.84 (d, 2H), 3.73 (s, 2H), 3.69 (s, 4H), 2.11 (d, 6H), 1.29-1.24 (m, 6H). EI-MS m / z : [M+H] + 875.13.

[0334] Example 8 Preparation of Compound 48

[0335] [ka]

[0336] Preparation of intermediate compound 44 Intermediate compound 4 (2.0 g, 9.23 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 1,4-dibromo-2-butyne (5.8 g, 27.70 mmol) and cesium carbonate (3.6 g, 11.08 mmol) under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (100 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The dried material was filtered and concentrated under reduced pressure. The solid obtained by dilution with dichloromethane and hexane was filtered and dried to give intermediate compound 44 (2.0 g, 62%). 1 EI-MS m / z : [M+H] + 348.99.

[0337] Preparation of intermediate compound 45 Intermediate compound 44 (300 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of morpholine (0.09 mL, 1.03 mmol) and cesium carbonate (309 mg, 0.95 mmol) under nitrogen. The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The dried material was filtered, concentrated under reduced pressure, and purified by column chromatography to give intermediate compound 45 (230 mg, 75%). 1 H-NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 5.17 (s, 2H), 3.52 (t, J = 11.5 Hz, 4H), 3.29 (s, 2H), 2.36 (t, J = 11.0 EI-MS m / z : [M+H] +354.13.

[0338] Preparation of intermediate compound 46 Intermediate compound 9 (500 mg, 1.03 mmol) and intermediate compound 45 (215 mg, 0.60 mmol) were dissolved in n-butyl alcohol (4 mL), and diisopropylethylamine (0.53 mL, 3.03 mmol) was added at room temperature. The mixture was heated to 120°C and stirred for 24 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 46 (303 mg, 68%). EI-MS m / z: [M+H] + 729.11.

[0339] Preparation of intermediate compound 47 Intermediate compound 46 (303 mg, 0.41 mmol) was dissolved in methanol (10 mL) and distilled water (1 mL), and then aqueous ammonia (28-30% ammonia, 0.45 mL) and sodium hydrosulfite (NaSO, 724 mg, 4.16 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL), and filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give intermediate compound 47 (97 mg, 33%, crude). EI-MS m / z: [M+H] + 699.07.

[0340] Preparation of compound 48 Intermediate compound 47 (97 mg, 0.14 mmol, crude) was dissolved in N,N-dimethylformamide (1.5 mL), and then intermediate compound 2 (32 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (0.5 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and triethylamine (0.06 mL, 0.42 mmol) were added and stirred at room temperature for 13 hours. The reaction solution was concentrated under pressure and purified by HPLC to give compound 48 (38 mg, 32%). 1 H-NMR (400 MHz, MeOD-d4), δ 7.60 (d, J = 1.3 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 6.60 (d, J = 0.6 Hz, 1H), 6.58 (d, J = 0.6 Hz, 1H), 5.89-5.86 (m, 4H), 5.04-5.01 (m, 4H), 4.61-4.55 (m, 4H), 4.07(s, 2H), 3.71 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 1.37-1.30 (m, 6H). EI-MS m / z : [M+H] + 860.08.

[0341] Example 9 Preparation of Compound 55

[0342] [ka]

[0343] Preparation of intermediate compound 49 To a solution of 4-nitropyrazole (1 g, 6.13 mmol) in methanol (20 mL) was added ammonia solution (28-30% ammonia, 2.2 mL) and sodium hydrosulfite (7.7 g). After stirring at room temperature for 1 h, the reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. Methanol (15 mL) was added to the concentrated filtrate, followed by the addition of di-t-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) at room temperature. The reaction solution was stirred at room temperature for 16 h, then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 49 (0.7 g, 43%). 1 H-NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H).

[0344] Preparation of intermediate compound 50 To a solution of intermediate compound 49 (0.7 g, 3.82 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (3.7 g, 11.46 mmol) and trans-1,4-dibromo-2-butene (2.45 g, 11.46 mmol). After stirring at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (50 mL) and then washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 50 (867 mg, 71%). 1H-NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.33 (s, 1H), 6.24 (s, 1H), 6.00 - 5.90 (m, 1H), 5.87 (td, J = 13.2, 5.9 Hz, 1H), 4.69 (d, J = EI-MS m / z : [M+H]+ 317.26.

[0345] Preparation of intermediate compound 51 To a solution of intermediate compound 4 (540 mg, 2.5 mmol) in N,N-dimethylformamide (15 mL) were added cesium carbonate (894 mg, 2.75 mmol) and compound 50 (867 mg, 2.75 mmol). After stirring at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 51 (830 mg, 73%). 1 H-NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.30 (s, 1H), 6.08 (d, J = 15.4 Hz, 1H), 5.86 (d, J = 15.8 Hz, 1H), 4.82 (d, J = 5.4 Hz, 2H), 4.74 (d, J = 5.9 Hz, 2H), 1.44 (d, J = 2.3 Hz, 9H). [M+H] + 452.31.

[0346] Preparation of intermediate compound 52 To a solution of intermediate compound 51 (830 mg, 1.83 mmol) and compound 9 (1.13 g, 2.76 mmol) in n-butanol (11 mL) was added N,N-diisopropylethylamine (1.6 mL, 9.18 mmol). The reaction solution was stirred at 0° C. for 5 minutes and then heated to 120° C. for 24 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 52 (420 mg, 28%). EI-MS m / z: [M+H] + 827.39.

[0347] Preparation of intermediate compound 53 To a solution of intermediate compound 52 (420 mg, 0.51 mmol) in methanol (5 mL) was added aqueous ammonia (28-30% ammonia, 1.8 mL, 12.66 mmol) and sodium hydrosulfite (882 mg, 5.06 mmol). After stirring at room temperature for 2.5 h, the reaction solution was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure and purified by reverse-phase column chromatography to give intermediate compound 53 (400 mg). EI-MS m / z: [M+H] + 797.48.

[0348] Preparation of intermediate compound 54 To a solution of intermediate compound 53 (400 mg, 0.51 mmol) in N,N-dimethylformamide (1.5 mL) at 0 °C, compound 2 (109 mg, 0.55 mmol) in N,N-dimethylformamide (1 mL) was added. After 30 min, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.1 mL, 0.61 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added to the reaction solution. After stirring at room temperature for 15 h, the reaction solution was concentrated under reduced pressure and purified by reverse-phase chromatography to give intermediate compound 54 (97 mg, 20%).

[0349] Preparation of Compound 55 To a solution of intermediate compound 54 (30 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated and purified by HPLC to give compound 55 (10 mg, 27%). 1 H-NMR (400 MHz, CD3OD) δ 7.80 (s, 1H), 7.57 (d, J = 11.4 Hz, 3H), 7.29 (s, 1H), 7.23 (s, 1H), 6.62 (d, J = 1.7 Hz, 1H), 6.56 (s, 1H), 5.85 (d, J = 18.0 Hz, 3H), 5.70 (d, J = 15.6 Hz, 1H), 5.01 (s, 4H), 4.63 (s, 3H), 4.61 - 4.52 (m, 2H), 4.45 (s, 2H), 3.74 (s, 2H), 3.31 (m, 3H), 2.65 (s, 1H), 2.20 (d, J = 12.3 Hz, 6H), 1.34 (dt, J = 21.7, 6.9 Hz, 6H). EI-MS m / z : [M+H] + 858.54.

[0350] Example 10 Preparation of Compound 65

[0351] [ka]

[0352] Preparation of intermediate compound 56 To a solution of intermediate compound 4 (5 g, 23.08 mmol) in N,N-dimethylformamide (30 mL) was added cesium carbonate (11.2 g, 34.62 mmol) under nitrogen at 0 °C. After 5 minutes, ethyl 4-bromobutyrate (5.4 g, 27.70 mmol) was added to the reaction solution at room temperature under nitrogen. After stirring for 2 hours, the reaction solution was diluted with ethyl acetate (60 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. After coagulation with dichloromethane and hexane, the resulting solid was filtered and dried to give intermediate compound 56 (4.7 g, 61%), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 8.28 (s,1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 4.25 (m, 2H), 4.09-4.04 (q, J = 7.2 Hz, 2H), 1.19-1.15 (t, J = 7.2 Hz, 3H). EI-MS m / z : [M+H] + 331.20.

[0353] Preparation of intermediate compound 57 To a solution of intermediate compound 56 (4.5 g, 13.60 mmol) in ethanol (30 mL) was added t-butyl (E)-(4-aminobut-2-en-1-yl)carbamate (2.5 g, 13.60 mmol) and N,N-diisopropylethylamine (2.37 mL, 27.21 mmol). After stirring at 120 °C for 12 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to give intermediate compound 57 (4.5 g, 68%). 1H-NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 8.01(s, 1H), 7.68 (t, 1H), 7.58 (s, 1H), 7.30 (s, 1H), 6.90 (s, 1H), 5.54 (s, 2H), 4.10 (m, 6H), 3.48 (s, 3H), 2.07 (m, 2H) 1.35 (m, 9H) 1.17 (m, 4H). EI-MS m / z : [M+H] + 481.28.

[0354] Preparation of intermediate compound 58 To a solution of intermediate compound 57 (4.4 g, 9.156 mmol) in methanol (20 mL) was added aqueous ammonia (28-30% ammonia, 10 mL) and sodium hydrosulfite (NaSO, 15 g, 91.6 mmol) at 0 °C. After stirring at room temperature for 1.5 h, the reaction solution was filtered through Celite with the aid of methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 58 (4 g, 96%). EI-MS m / z: [M+H] + 451.31.

[0355] Preparation of intermediate compound 59 To a solution of intermediate compound 58 (4.0 g, 8.87 mmol) in N,N-dimethylformamide (30 mL) was added compound 2 (1.9 g, 9.76 mmol) at 0 °C. After stirring at room temperature for 30 minutes, triethylamine (3.7 mL, 26.63 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (2.7 g, 17.75 mmol) were added to the reaction solution at 0 °C. The resulting reaction solution was stirred at room temperature for 17 hours. The reaction solution was then concentrated, and the resulting residue was purified by column chromatography to give intermediate compound 59 (3.8 g, 71%). 1H-NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.37-7.35 (m, 2H), 6.89 (m, 1H), 6.63 (s, 1H), 5.79-5.72 (d, J = 16 Hz, 1H), 5.58-5.54 (d, J = 16 Hz, 1H) 4.94 (s, 2H), 4.62 (m, 2H), 4.22 (s, 3H), 4.20 (m, 6H), 2.31 (m, 3H), 2.11 (s, 2H), 1.36 (m, 9H), 1.17 (m, 4H). EI-MS m / z: [M+H] + 612.31.

[0356] Preparation of intermediate compound 60 To a solution of intermediate compound 59 (3.8 g, 6.21 mmol) in dichloromethane (50 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 11.5 mL). After stirring for 2 hours, the reaction solution was concentrated and diluted with diethyl ether (20 mL). The resulting solid was filtered to give intermediate compound 60 (3.9 g, quantitative yield). 1 H-NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.88 (m, 2H), 7.68 (s, 1H), 7.39 (s, 2H), 6.67 (s, 1H), 6.08-6.04 (d, J = 16 Hz, 1H), 5.59-5.55 (d, J = 16 Hz, 1H), 5.00 (s, 2H), 4.61 (m, 2H), 4.22 (m, 2H), 4.10 (m, 2H), 2.19 (s, 3H), 2.11 (m, 2H), 1.37 (m, 3H), 1.19 (m, 3H). EI-MS m / z : [M+H] + 512.31.

[0357] Preparation of intermediate compound 61 To a solution of intermediate compound 60 (3.8 g, 6.63 mmol) and intermediate compound 51 (2 g, 4.42 mmol) in n-butanol (13 mL) was added N,N-diisopropylethylamine (3.85 mL, 22.13 mmol) at room temperature. After stirring at 100° C. for 21 hours, the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 61 (1.6 g, 38%). EI-MS m / z: [M+H] + 926.98.

[0358] Preparation of intermediate compound 62 To a solution of intermediate compound 61 (1.6 g, 1.83 mmol) in methanol (8 mL) under nitrogen, ammonia solution (28-30% ammonia, 3.2 mL) and sodium hydrosulfite (NaSO, 3.1 g, 18.3 mmol) were added. The reaction solution was stirred at room temperature for 1 hour, then methanol (50 mL) was added and the resulting solid was removed by filtration. The filtrate was concentrated, diluted with dichloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate compound 62 (1.4 g, 85%). EI-MS m / z: [M+H] + 897.05.

[0359] Preparation of intermediate compound 63 To a solution of intermediate compound 62 (1.35 g, 1.51 mmol) in N,N-dimethylformamide (10 mL) under nitrogen, compound 2 (324 mg, 1.66 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour, and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (465 mg, 3.02 mmol) and triethylamine (0.63 mL, 4.53 mmol) were added. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 63 (560 mg, 35%). EI-MS m / z: [M+H] + 1057.96.

[0360] Preparation of intermediate compound 64 To a solution of intermediate compound 63 (100 mg, 0.094 mmol) in methanol (2 mL) under nitrogen at -50 °C was added lithium hydroxide monohydrate (13.8 mg, 0.28 mmol) in distilled water (1 mL). After stirring at 0 °C for 2 h, the reaction solution was acidified with acetic acid to pH 4-5, then concentrated and lyophilized to give intermediate compound 64 (100 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 1029.95.

[0361] Preparation of Compound 65 To a solution of intermediate compound 64 (100 mg, 0.097 mmol, crude) in dichloromethane (5 mL) under nitrogen was added trifluoroacetic acid (1 mL) at 0° C. After stirring at room temperature for 2 h, the reaction solution was concentrated and purified by HPLC to give compound 65 (42 mg, 34%). 1H-NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.77 (s, 2H), 7.96 (s, 1H), 7.87 (m, 2H), 7.65 (s, 2H), 7.53 (s, 1H), 7.34 (s, 2H), 7.28 (s, 2H), 6.53 (s, 2H), 5.79 (m, 3H), 5.65 (m, 1H), 4.90 (s, 4H), 4.62 (m, 2H), 4.50 (m, 6H), 3.92 (m, 3H), 2.24 (s, 2H), 2.11 (m, 6H), 1.74 (m, 2H), 1.26 (m, 6H). EI-MS m / z: [M+H] + 929.98.

[0362] Example 11 Preparation of Compound 69

[0363] [ka]

[0364] Preparation of intermediate compound 67 To a solution of intermediate compound 66 (300 mg, 0.32 mmol, intermediate compound 66 was prepared by the method described in International Patent Publication No. WO 2022 / 155518 A1) in dichloroethane (30 mL) was added boron tribromide (1.0 M in dichloromethane, 3.2 mL, 3.16 mmol). After stirring at reflux for 17 hours, the reaction solution was concentrated under reduced pressure and diluted with dichloromethane / diethyl ether (50 mL / 50 mL). The resulting solid was filtered to give intermediate compound 67 (280 mg, 84%). EI-MS m / z: [M+H] + 709.15.

[0365] Preparation of intermediate compound 68 To a solution of intermediate compound 67 (280 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) were added cesium carbonate (607 mg, 1.87 mmol) and intermediate compound 50 (101 mg, 0.32 mmol). After stirring at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure and purified by reverse-phase column chromatography to give intermediate compound 68 (158 mg, 62%). EI-MS m / z: [M+H] + 945.00.

[0366] Preparation of Compound 69 To a solution of intermediate compound 68 (50 mg) in dichloromethane (1.5 mL) under nitrogen was added trifluoroacetic acid (0.5 mL) at 0° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated and the resulting residue was purified by HPLC to give compound 69 (8 mg). 1 H-NMR (400 MHz, CD3OD) δ 7.82 (d, J = 0.8 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 7.17 (d, J = 1.4 Hz, 1H), 6.61 (d, J = 0.7 Hz, 1H), 6.49 (d, J = 0.7 Hz, 1H), 5.95 - 5.80 (m, 3H), 5.78 - 5.67 (m, 1H), 5.04 (dd, J = 17.4, 3.9 Hz, EI-MS m / z : [M+H] + 845.07.

[0367] Example 12 Preparation of Compound 79

[0368] [ka]

[0369] Preparation of intermediate compound 70 To a solution of trans-1,4-dibromo-2-butene (10.4 g, 48.7 mmol) in N,N-dimethylformamide (30 mL) was added sodium acetate (2.0 g, 24.4 mmol) at 0 °C under nitrogen. The reaction solution was stirred at room temperature for 17 hours, then diluted with ethyl acetate (100 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 70 (2.98 g, 63%). 1 H-NMR (400 MHz, CDCl3) δ 6.02-5.82 (m, 2H), 4.59 (d, J = 5.6 Hz, 2H), 3.95 (d, J = 7.2 Hz, 2H), 2.08 (s, 3H).

[0370] Preparation of intermediate compound 71 To a solution of intermediate compound 70 (838 mg, 4.34 mmol) in dichloromethane (60 mL) was added triethylamine (1.83 mL, 13.02 mmol) and t-butyl(3-aminopropyl)carbamate (2.27 g, 13.02 mmol) in dichloromethane (40 mL) at 0 °C. The reaction solution was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 71 (380 mg, 30%). 1 H-NMR (400 MHz, CDCl3) δ 5.87-5.71 (m, 2H), 4.99 (s, 1H), 4.58-4.52 (m, 2H), 3.26 (d, J = 5.7 Hz, 2H), 3.23-3.18 (m, 2H), 2.70-2.65 (m, 2H), 2.07 (d, J = 2.7 Hz, 3H), 1.68 (d, J = 6.6 Hz, 2H), 1.45 (d, J = 2.6 Hz, 9H).

[0371] Preparation of intermediate compound 72 To a solution of intermediate compound 71 (790 mg, 2.76 mmol) in dichloromethane (10 mL) were added fluorenylmethyloxycarbonyl chloride (Fmoc-Cl, 856 mg, 3.31 mmol) and N,N-diisopropylethylamine (0.78 mL, 5.52 mmol). After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 72 (1.4 g, 98%). EI-MS m / z: [M+H] + 509.19.

[0372] Preparation of intermediate compound 73 To a solution of intermediate compound 72 (790 mg, 2.76 mmol) in methanol (20 mL) was added potassium carbonate (1.96 g, 14.15 mmol) at 0 °C. After stirring at room temperature for 30 minutes, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (10 mL), and then 4-nitrophenyl(2-(trimethylsilyl)ethyl)carbonate (Teoc-PNP, 962 mg, 3.39 mmol) and N,N-diisopropylethylamine (0.80 mL, 5.66 mmol) were added, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 73 (596 mg, 54%). EI-MS m / z: [M+H] + 389.28.

[0373] Preparation of intermediate compound 74 To a solution of intermediate compound 73 (300 mg, 0.77 mmol) in dichloromethane (5 mL) was added triethylamine (0.33 mL, 2.31 mmol) and methanesulfonic anhydride (175 mg, 1.00 mmol) at 0° C. After stirring at room temperature for 1 hour, the reaction solution was diluted with dichloromethane (50 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave intermediate compound 74 (380 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 467.17.

[0374] Preparation of intermediate compound 76 To a solution of intermediate compound 75 (450 mg, 0.62 mmol; intermediate compound 75 was prepared according to the method described in International Patent Publication No. WO 2022 / 155518 A1) in N,N-dimethylformamide (5 mL) was added cesium carbonate (811 mg, 2.49 mmol) and intermediate compound 74 (349 mg, 0.75 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL) and methanol (10 mL), and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 76 (468 mg, 68%). EI-MS m / z: [M+H] + 1093.72.

[0375] Preparation of intermediate compound 77 To a solution of intermediate compound 76 (468 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.1 mL, 2.14 mmol). After stirring under reflux for 5 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography to give intermediate compound 77 (256 mg, 63%). EI-MS m / z: [M+H] + 950.12.

[0376] Preparation of intermediate compound 78 To a solution of intermediate compound 77 (256 mg, 0.27 mmol) in N,N-dimethylformamide (3 mL) was added N,N-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (126 mg, 0.40 mmol) and triethylamine (0.11 mL, 0.81 mmol). After stirring at 60° C. for 17 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 78 (103 mg, 32%). EI-MS m / z: [M+H] + 1192.17.

[0377] Preparation of Compound 79 To a solution of intermediate compound 78 (103 mg, 0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) under nitrogen at 0° C. The reaction solution was stirred at room temperature for 2 hours. After concentration, the resulting residue was purified by HPLC to give intermediate compound 79 (48 mg, 45%). 1 H-NMR (400 MHz, CD3OD) δ 7.29 (d, J = 1.4 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 6.59 (d, J = 0.6 Hz, 1H), 6.56 (d, J = 0.6 Hz, 1H), 5.88 - 5.77 (m, 2H), 5.75 - 5.69 (m, 2H), 5.02 (d, J = 3.3 Hz, 4H), 4.64 - 4.50 (m, 6H), 3.94 (d, J = 4.2 Hz, 2H), 3.75 (s, 3H), 3.42 - 3.32 (m, 4H), 3.01 - 2.93 (m, 2H), 2.24 - 2.17 (m, 6H), 1.97 (p, J = 7.8 Hz, 2H), 1.34 (dt, J = 14.6, 7.1 Hz, 6H). EI-MS m / z : [M+H] + 891.09.

[0378] Example 13 Preparation of Compound 89

[0379] [ka]

[0380] Preparation of intermediate compound 80 To a solution of 4-piperidineethanol (5 g, 38.7 mmol) in dichloromethane (200 mL) under nitrogen, triethylamine (8.1 mL, 58.05 mmol) and di-t-butyl dicarbonate (9.78 mL, 42.57 mmol) were added. The reaction solution was stirred at room temperature for 3 hours, then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 80 (7.25 g, 81.6%). 1 H-NMR (CDCl3) δ: 1.04-1.10 (m, 2H), 1.48 (s, 9H), 1.49-1.55 (m, 3H), 1.60-1.66 (m, 2H), 2.27 (s, 1H), 2.64 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 4.03-4.08 (m, 2H). EI-MS m / z : [M+Na] + 252.26.

[0381] Preparation of intermediate compound 81 To a solution of dimethyl sulfoxide (0.93 mL, 13.08 mmol) in dichloromethane (20 mL) was slowly added oxalyl chloride (0.34 mL, 3.93 mmol) at −78° C. under nitrogen. After stirring for 30 minutes, intermediate compound 80 (1 g, 4.36 mmol) in dichloromethane (5 mL) was added to the reaction solution. The reaction solution was stirred at −50° C. for 2 hours. Triethylamine (1.8 mL, 13.1 mmol) was added to the reaction solution. After warming to 0° C. and stirring for 30 minutes, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 81 (990 mg, 99%). 1 H-NMR (300 MHz, CDCl3), δ (ppm): 9.78 (br s, 1H), 4.08 (br d, 2H), 2.74 (br t, 2H), 2.39 (d, 2H), 2.12-1.89 (m, 1H), 1.79-1.64 (m, 2H), 1.45 (s, 9H), 1.26-1.10 (m, 2H). EI-MS m / z : [M+H] + 228.23.

[0382] Preparation of intermediate compound 82 To a solution of lithium chloride (17.2 g, 40.65 mmol) in acetonitrile (40 mL) was added triethyl phosphonoacetate (7.33 mL, 50.81 mmol) at room temperature under nitrogen. After stirring for 5 minutes, triethylamine (5.67 mL, 40.65 mmol) was added to the reaction solution over 10 minutes at room temperature. Compound 81 (7.7 g, 33.88 mmol) in acetonitrile (60 mL) was added to the reaction solution. After stirring for 17 hours at room temperature, the reaction solution was diluted with ethyl acetate (150 mL) and washed with distilled water (150 mL). The organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 82 (5.59 g, 58.2%). 1H-NMR (400 MHz, CDCl3), δ (ppm): 6.96-6.88 (m,1H), 5.85-5.811 (m, 1H), 4.08(s,2H), 3.73(s,3H), 2.07-2.64 (m, 2H), 2.17-2.13 (m, EI-MS m / z : [M+H] + 284.01.

[0383] Preparation of intermediate compound 83 To a solution of intermediate compound 82 (2.5 g, 8.82 mmol) in dichloromethane (30 mL) was added diisobutylaluminum hydride (1.0 M in cyclohexane, 19 mL, 19.00 mmol) under nitrogen at −78° C. After stirring at −78° C. for 3 hours, methanol (100 mL) was added to the reaction solution. The reaction solution was filtered through Celite and washed with methanol. The filtrate was removed under reduced pressure and used without purification to give intermediate compound 83 (1.91 g, 84.8%). 1 H-NMR (400 MHz, CDCI3): δ = 5.70-5.65 (m, 2H), 4.18-4.01 (m, 4H), 2.69 (t, 2H, J = 12.6 Hz), 2.02 (t, 2H, J = 5.6 Hz), 1 .72-1 .62 (m, EI-MS m / z : [M+H] + 256.06.

[0384] Preparation of intermediate compound 84 To a solution of intermediate compound 83 (1.91 g, 7.48 mmol) in dichloromethane (20 mL) was added triethylamine (1.6 mL, 11.2 mmol) and methanesulfonyl chloride (0.87 mL, 11.2 mmol) at 0 °C. After stirring at room temperature for 3 h, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was removed under reduced pressure to give intermediate compound 84 (2.59 g, crude), which was used without purification.

[0385] Preparation of intermediate compound 85 To a solution of intermediate compound 5 (1 g, 4.62 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (766 mg, 5.54 mmol) and compound 84 (2.3 g, 6.94 mmol). After stirring at room temperature for 14 hours, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 85 (1.18 g, 56.3%). 1 H-NMR (400 MHz, CDCI3): δ = 7.82-7.72, 5.83-5.69 (m, 2H), 4.80-4.71 (m, 2H), 4.04-4.03 (m, 2H), 2.65 (s, 2H), 2.05-1.93 (m, 1H), 1.07-1.04 (m, 2H). EI-MS m / z : [M+H] + 454.17.

[0386] Preparation of intermediate compound 86 To a solution of intermediate compound 85 (550 mg, 1.21 mmol) in n-butanol (5 mL) was added intermediate compound 9 (1.17 g, 2.42 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.06 mmol). After stirring at 0° C. for 5 minutes, the reaction solution was heated to 120° C., stirred for 24 hours, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The concentrated reaction product was purified by column chromatography to give intermediate compound 86 (157 mg, 15.6%). EI-MS m / z: [M+H] + 829.22.

[0387] Preparation of intermediate compound 87 To a solution of intermediate compound 86 (157 mg, 0.19 mmol) in methanol (3 mL) was added ammonia solution (28-30% ammonia, 0.5 mL, 4.74 mmol) and sodium hydrosulfite (NaSO, 330 mg, 1.89 mmol). After stirring at room temperature for 1 h, the reaction solution was passed through a Celite filter and washed with methanol. After filtration, the filtrate was removed under reduced pressure and used without further purification to give intermediate compound 87 (151 mg, crude), which was used without further purification.

[0388] Preparation of intermediate compound 88 To a solution of intermediate compound 87 (151 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added compound 2 (40 mg, 0.21 mmol) at 0° C. The reaction solution was stirred for 30 minutes, and then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.04 mL, 0.24 mmol) and triethylamine (0.11 mL, 0.76 mmol) were added, and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 88 (100 mg, 54%). EI-MS m / z: [M+H] + 961.13.

[0389] Preparation of Compound 89 To a solution of intermediate compound 88 (20 mg, 0.02 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at 0° C. The reaction solution was stirred at room temperature for 0.5 hours. After concentration, the resulting residue was purified by HPLC to give intermediate compound 89 (4.8 mg, 27%). EI-MS m / z: [M+H] + 861.30.

[0390] Example 14 Preparation of Compound 95

[0391] [ka]

[0392] Preparation of intermediate compound 90 To a solution of 3-aminophenol (1 g, 9.16 mmol) in tetrahydrofuran (10 mL) was added di-t-butyl dicarbonate (2.52 mL, 10.99 mmol). After stirring at room temperature for 16 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The reaction solution was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure and used without purification to give compound 90 (1.8 g, 93%). 1 EI-MS m / z : [M+H] + 209.10.

[0393] Preparation of intermediate compound 91 To a solution of intermediate compound 90 (300 mg, 1.43 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (560 mg, 1.72 mmol) and intermediate compound 5 (551 mg, 1.57 mmol) under nitrogen at 0° C. After stirring for 2 hours, the reaction solution was diluted with ethyl acetate (30 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was solidified by the addition of dichloromethane and diethyl ether, then filtered and dried to give intermediate compound 91 (474 ​​mg, 69%), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.12 (m, 2H), 7.10 (d, 1H), 6.56 (m, EI-MS m / z : [M+H] + 478.00.

[0394] Preparation of intermediate compound 92 To a solution of intermediate compound 9 (607 mg, 1.47 mmol) and intermediate compound 91 (470 mg, 0.98 mmol) in n-butanol (5 mL) was added diisopropylethylamine (0.68 mL, 3.93 mmol) at room temperature. After heating to 120° C. for 24 hours, the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate compound 92 (100 mg, 12%), which was used without further purification. EI-MS m / z: [M+H] + 853.30.

[0395] Preparation of intermediate compound 93 To a solution of intermediate compound 92 (100 mg, 0.11 mmol) in methanol (5 mL) under nitrogen, ammonia solution (28-30% ammonia, 0.209 mL) and sodium hydrosulfite (NaSO, 204 mg, 1.172 mmol) were added. After stirring at room temperature for 1 h, the reaction solution was diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate compound 93 (100 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 823.36.

[0396] Preparation of intermediate compound 94 To a solution of intermediate compound 93 (100 mg, 0.12 mmol, crude) in N,N-dimethylformamide (2 mL) was added intermediate compound 2 (26 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) at 0° C. under nitrogen. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.18 mmol) and triethylamine (0.05 mL, 0.36 mmol) were added to the reaction mixture. After stirring at room temperature for 13 hours, the reaction solution was concentrated under reduced pressure, solidified with dichloromethane and diethyl ether, filtered, and dried to give intermediate compound 94 (54 mg, 53%). EI-MS m / z: [M+H] + 984.84.

[0397] Preparation of Compound 95 To a solution of intermediate compound 94 (50 mg, 0.061 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at 0° C. After stirring at room temperature for 40 minutes, the reaction solution was concentrated and purified by HPLC to give compound 95 (1.7 mg, 3%). EI-MS m / z: [M+H] + 884.37.

[0398] Example 15 Preparation of Compound 104

[0399] [ka]

[0400] Preparation of intermediate compound 96 To a solution of methyl 3-nitrocinnamate (3.5 g, 16.89 mmol) in methanol (20 mL) and distilled water (5 mL) was added concentrated hydrochloric acid (0.25 mL) and iron powder (9 g, 161.15 mmol). After heating to reflux with stirring for 17 h, the reaction solution was filtered through Celite and concentrated under reduced pressure to give intermediate compound 96 (2.7 g, crude) without further purification. 1 H-NMR (400 MHz, DMSO-d6): δ 7.48 (d, J= 15.8 Hz, 1H), 7.06 (t, J= 7.8 Hz, 1H), 6.85-6.79 (m, 2H), 6.65-6.61 (m, 1H), 6.41 (d, J= 15.8 Hz, 1H), 5.19 (s, 2H), 3.71 (s, 3H).

[0401] Preparation of intermediate compound 97 To a solution of intermediate compound 96 (2.7 g, 15.24 mmol) dissolved in 1,4-dioxane (10 mL) was added di-t-butyl dicarbonate (3.85 mL, 16.76 mmol) and saturated aqueous sodium bicarbonate (3.2 g, 38.09 mmol) dissolved in water (50 mL). After stirring at room temperature for 21 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The reaction solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 97 (3 g, 71%). 1H-NMR (CD3OD, 400 MHz) δ 7.65 (s, 1H), 7.62 (d, 1H, J = 16.1 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.28 (t, 1H, J = 7.6 Hz), 7.20 (d, 1H, J = 7.6 Hz), 6.47 (d, 1H, J = 16.1 Hz), 3.76 (s, 3H), 1.51 (s, 9H).

[0402] Preparation of intermediate compound 98 To a solution of intermediate compound 97 (1.3 g, 4.69 mmol) in dichloromethane (20 mL) was added diisobutylaluminum hydride (1.0 M in cyclohexane, 19 mL, 18.75 mmol) under nitrogen at −78° C. After stirring at −78° C. for 3 hours, methanol (100 mL) was added to the reaction solution at room temperature. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 98 (815 mg, 70%). EI-MS m / z: [M+Na] + 272.05.

[0403] Preparation of intermediate compound 99 To a solution of intermediate compound 98 (800 mg, 3.21 mmol) in dichloromethane (16 mL) was added triethylamine (0.7 mL, 4.81 mmol) and methanesulfonyl chloride (0.3 mL, 3.53 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction solution was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 99 (1 g, 95%), which was used without further purification.

[0404] Preparation of Intermediate Compound 100 To a solution of intermediate compound 4 (762 mg, 3.52 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (663 mg, 4.8 mmol) and compound 99 (1.05 g, 3.2 mmol). After stirring at 50° C. for 15 hours, the reaction solution was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 100 (815 mg, 57%), which was used without further purification. EI-MS m / z: [M+H] + 448.25.

[0405] Preparation of intermediate compound 101 To a solution of intermediate compound 100 (500 mg, 1.12 mmol) in n-butanol (6 mL) was added compound 9 (811 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.8 mL, 4.47 mmol). After stirring at 0° C. for 5 minutes, the reaction mixture was heated to 120° C. and stirred for 23 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 101 (316 mg, 34%). EI-MS m / z: [M+H] + 823.42.

[0406] Preparation of intermediate compound 102 To a solution of intermediate compound 101 (316 mg, 0.38 mmol) in methanol (6 mL) was added aqueous ammonia (28-30% ammonia, 0.7 mL, 9.6 mmol) and sodium hydrosulfite (NaSO, 668 mg, 3.84 mmol). After stirring at room temperature for 1 h, the precipitate was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 102 (304 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 793.51.

[0407] Preparation of intermediate compound 103 To a solution of intermediate compound 102 (304 mg, 0.38 mmol) in N,N-dimethylformamide (2 mL) was added compound 2 (82 mg, 0.42 mmol) at 0° C. After stirring for 30 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.08 mL, 0.48 mmol) and triethylamine (0.21 mL, 1.54 mmol) were added to the reaction solution at room temperature over 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 103 (12 mg, 3%). EI-MS m / z: [M+H] + 954.47.

[0408] Preparation of Compound 104 To a solution of intermediate compound 103 (12 mg, 0.001 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at 0° C. After stirring at room temperature for 0.5 h, the reaction solution was concentrated. The resulting residue was purified by HPLC to give compound 104 (4.3 mg, 40%). EI-MS m / z: [M+H] + 855.46.

[0409] Example 16 Preparation of Compound 110

[0410] [ka]

[0411] Preparation of intermediate compound 105 To a solution of t-butyl prop-2-en-1-ylcarbamate (1.0 g, 6.44 mmol) in N,N-dimethylformamide (9 mL) and methanol (1 mL) were added trimethylsilyl azide (1.27 mL, 9.66 mmol) and copper(I) iodide (613 mg, 3.22 mmol). After stirring at 90 °C for 18 hours, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride solution (50 mL × 2), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 105 (373 mg, 29%). 1 H-NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 5.09 (s, 1H), 4.43 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H).

[0412] Preparation of intermediate compound 106 To a solution of intermediate compound 105 (122 mg, 0.62 mmol) and compound 5 (315 mg, 0.68 mmol) in N,N-dimethylformamide (55 mL) was added potassium carbonate (102 mg, 0.74 mmol) at room temperature under nitrogen. After stirring for 16 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with distilled water (150 mL × 2) and brine (150 mL). The reaction solution was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 106 (146 mg, 50%). 1 H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.30 (s, 1H), 6.17 - 6.07 (m, 1H), 5.97 - 5.93 (m, 1H), 5.07 (d, J = 6.0 Hz, 2H), 4.84 (d, J = 5.2 Hz, 2H), 4.16 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H).

[0413] Preparation of intermediate compound 107 To a solution of intermediate compound 106 (265 mg, 0.57 mmol) and intermediate compound 9 (412 mg, 0.85 mmol) in n-butanol (3 mL) was added N,N-diisopropylethylamine (0.49 mL, 2.84 mmol) at room temperature. After heating to 100°C and stirring for 21 hours, the reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 107 (352 mg, 73%). EI-MS m / z: [M+H] + 842.42.

[0414] Preparation of intermediate compound 108 To a solution of intermediate compound 107 (352 mg, 0.42 mmol) in methanol (10 mL) and distilled water (2 mL) under nitrogen, ammonia solution (28-30% ammonia, 0.6 mL) and sodium hydrosulfite (NaSO, 728 mg, 4.2 mmol) were added. After stirring at room temperature for 2 h, the reaction solution was diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate compound 108 (100 mg, 29%), which was used without further purification. EI-MS m / z: [M+H] 812.47.

[0415] Preparation of intermediate compound 109 To a solution of intermediate compound 108 (100 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) was added compound 2 (29 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.03 mL, 0.17 mmol) and triethylamine (0.05 mL, 0.05 mmol) were added to the reaction solution over a period of 16 hours at room temperature. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 109 (80 mg, 66%). EI-MS m / z: [M+H] + 973.54.

[0416] Preparation of Compound 110 To a solution of intermediate compound 109 (80 mg, 0.08 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at −78° C. under nitrogen. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 110 (25 mg, 35%). 1 H-NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 8.19 (s, 2H), 8.04 - 7.91 (m, 3H), 7.65 (s, 2H), 7.37 (s, 2H), 7.30 (s, 2H), 6.52 (d, J = 2.6 Hz, 2H), 5.96 - 5.79 (m, 3H), 4.95 - 4.87 (m, 6H), 4.58 - 4.48 (m, 6H), 4.10 (q, J = 5.7 Hz, 2H), 3.70 (s, 3H), 2.10 (d, J = 6.5 Hz, 6H), 1.26 (q, J = 7.1 Hz, 6H). EI-MS m / z: [M+H] + 873.55.

[0417] Example 17 Preparation of Compound 120

[0418] [ka]

[0419] Preparation of intermediate compound 111 To a solution of I t-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.2 g, 10.93 mmol) in dichloromethane (20 mL) was added dimethyl sulfoxide (5 mL), triethylamine (9.2 mL, 65.6 mmol), and sulfur trioxide pyridine complex (4.3 g, 27.33 mmol) at 0 °C. After stirring at room temperature for 17 h, the reaction solution was diluted with dichloromethane (100 mL), washed with distilled water (50 mL) and 0.1 N hydrochloric acid solution (50 mL), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the product was purified by column chromatography to give intermediate compound 111 (1.65 g, 75%). 1 H-NMR (400 MHz, CDCl3) δ 9.60 - 9.44 (m, 1H), 4.13 (d, J = 61.6 Hz, 1H), 3.62 - 3.40 (m, 2H), 2.23 - 1.82 (m, 4H), 1.46 (d, J = 19.7 Hz, 9H).

[0420] Preparation of intermediate compound 112 To a solution of lithium chloride (421 mg, 9.94 mmol) and trimethyl phosphonoacetate (2.2 g, 12.42 mmol) in acetonitrile (8 mL) was added triethylamine (1.4 mL, mmol) at 0 °C. The reaction solution was stirred at room temperature for 10 minutes. To the reaction solution was added intermediate compound 111 (1.6 g, 8.28 mmol) in acetonitrile (12 mL). After stirring at room temperature for 17 hours, the reaction solution was diluted with diethyl ether (100 mL) and washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 112 (1.43 g, 67%). 1H-NMR (400 MHz, CDCl3) δ 6.14 (t, J = 10.0 Hz, 1H), 5.74 (d, J = 11.4 Hz, 1H), 5.32 - 5.22 (m, 1H), 3.71 (s, 3H), 3.59 - 3.34 (m, 2H), 2.31 (d, J = 12.9 Hz, 1H), 1.84 (ddt, J = 12.5, 8.4, 6.0 Hz, 2H), 1.67 (dt, J = 13.2, 6.6 Hz, 1H), 1.42 (d, J = 22.5 Hz, 9H).

[0421] Preparation of intermediate compound 113 To a solution of intermediate compound 112 (700 mg, 2.74 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (219 mg, 5.48 mmol) in distilled water (10 mL) at 0 °C. After stirring at room temperature for 17 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with 1 N hydrochloric acid solution (100 mL). The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give intermediate compound 113 (660 mg, 99%), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 6.91 (d, J = 13.0 Hz, 1H), 5.84 (d, J = 15.6 Hz, 1H), 4.46 (d, J = 56.8 Hz, 1H), 3.45 (s, 2H), 2.10 (s, 1H), 1.87 (q, J = 6.6 Hz, 5H), 1.49 - 1.40 (m, 9H).

[0422] Preparation of intermediate compound 114 To a solution of intermediate compound 113 (660 mg, 2.74 mmol) in tetrahydrofuran (10 mL) was added isobutyl chloroformate (0.37 mL, 2.87 mmol) and triethylamine (0.46 mL, 3.28 mmol) at −78° C. After stirring at room temperature for 1 hour, methanol (5 mL) and sodium borohydride (310 mg, 8.21 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 114 (494 mg, 79%). 1 H-NMR (400 MHz, CDCl3) δ 5.66 (s, 1H), 4.31 (d, J = 39.6 Hz, 1H), 4.14 (d, J = 5.0 Hz, 2H), 3.39 (s, 1H), 2.01 (s, 1H), 1.94 - 1.76 (m, 3H), 1.71 (ddd, J = 11.0, 6.7, 3.1 Hz, 4H), 1.45 (d, J = 6.8 Hz, 9H).

[0423] Preparation of intermediate compound 115 To a solution of intermediate compound 114 (494 mg, 2.17 mmol) in dichloromethane (20 mL) was added N-methylmorpholine (0.48 mL, 4.34 mmol) and methanesulfonic anhydride (416 mg, 2.39 mmol) at −78° C. After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate compound 115 (632 mg, 95%), which was used without further purification. 1H-NMR (400 MHz, CDCl3) δ 5.82 (s, 1H), 5.67 (s, 1H), 4.72 (d, J = 6.5 Hz, 2H), 4.32 (d, J = 39.2 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.40 (s, 1H), 3.02 (s, 3H), 2.05 (s, 1H), 1.84 (p, J = 6.4 Hz, 2H), 1.58 (s, 2H), 1.44 (s, 9H).

[0424] Preparation of intermediate compound 116 To a solution of intermediate compound 115 (632 mg, 2.07 mmol) and compound 5 (448 mg, 2.07 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (314 mg, 2.27 mmol) at room temperature under nitrogen. After stirring for 16 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with distilled water (100 mL × 2) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 116 (563 mg, 63%). 1 H-NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 5.92 - 5.82 (m, 1H), 5.69 - 5.62 (m, 1H), 4.83 (d, J = 5.9 Hz, 2H), 4.21 (s, 1H), 3.29 - 3.19 (m, 2H), 1.77 (q, J = 6.7 Hz, 2H), 1.65 (s, 1H), 1.33 (d, J = 27.7 Hz, 9H).

[0425] Preparation of intermediate compound 117 To a solution of intermediate compound 116 (300 mg, 0.70 mmol) and intermediate compound 9 (511 mg, 0.98 mmol) in n-butanol (4 mL) was added N,N-diisopropylethylamine (0.61 mL, 3.52 mmol) at room temperature. After heating to 120 °C and stirring for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 117 (263 mg, 46%). EI-MS m / z: [M+H] + 801.41.

[0426] Preparation of intermediate compound 118 To a solution of intermediate compound 117 (263 mg, 0.32 mmol) in methanol (10 mL) and distilled water (2 mL) under nitrogen, ammonia solution (28-30% ammonia, 0.5 mL) and sodium hydrosulfite (NaSO, 572 mg, 3.28 mmol) were added. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated, diluted with dichloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 118 (223 mg, 88%) without further purification. EI-MS m / z: [M+H] + 771.43.

[0427] Preparation of intermediate compound 119 To a solution of intermediate compound 118 (223 mg, 0.29 mmol) in N,N-dimethylformamide (2 mL) under nitrogen, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.07 mL, 0.43 mmol) and triethylamine (0.12 mL, 0.87 mmol) were added. After stirring at room temperature for 1 hour, intermediate compound 2 (47 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) was added to the reaction solution. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 119 (99 mg, 36%). EI-MS m / z: [M+H] + 932.48.

[0428] Preparation of Compound 120 To a solution of intermediate compound 119 (99 mg, 0.11 mmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at −78° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 120 (56 mg, 64%).

[0429] Example 18 Preparation of Compound 127

[0430] [ka]

[0431] Preparation of intermediate compound 121 To a solution of 5-nitroindole (1 g, 6.13 mmol) in methanol (15 mL) was added palladium on charcoal (85 mg). After stirring at room temperature for 3 hours under a hydrogen balloon, the reaction solution was passed through Celite. The filtrate was concentrated under reduced pressure. The concentrated filtrate was dissolved in N,N-dimethylformamide (15 mL) at room temperature, and then di-t-butyl dicarbonate (1.3 g, 6.13 mmol) and diisopropylethylamine (0.79 g, 6.13 mmol) were added. After stirring at room temperature for 5 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous ammonium chloride (50 mL × 2), and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure to give intermediate compound 121 (1.15 g, 80%), which was used without further purification. 1 H-NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.25 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 1.48 (s, 9H).

[0432] Preparation of intermediate compound 122 To a solution of intermediate compound 121 (1 g, 4.28 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (711 mg, 5.14 mmol) and trans-1,4-dibromo-2-butene (2.75 g, 12.86 mmol) at room temperature. After stirring at 60 °C for 18 hours, the reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 122 (372 mg, 23%). 1H-NMR (400 MHz, DMSO) δ 9.21 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.14 (dd, J = 15.1, 7.1 Hz, 1H), 5.88 (q, J = 7.5 Hz, 1H), 5.05 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 6.8 Hz, 1H), 4.16 (d, J = 7.3 Hz, 2H), 1.48 (s, 9H).

[0433] Preparation of intermediate compound 123 To a solution of intermediate compound 122 (369 mg, 1.0 mmol) in N,N-dimethylformamide (4 mL) under nitrogen, 4-chloro-3-hydroxy-5-nitrobenzamide (182 mg, 0.84 mmol) and potassium carbonate (174 mg, 1.26 mmol) were added. After stirring at 50 °C for 5 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 123 (312 mg, 74%). 1 H-NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.24 (d, J = 17.5 Hz, 2H), 8.06 (s, 1H), 7.87 (d, J = 13.6 Hz, 2H), 7.78 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 6.21 (dt, J = 15.8, 6.2 Hz, 1H), 6.01 - 5.90 (m, 1H), 5.10 (d, J = 6.1 Hz, 2H), 4.86 (d, J = 5.3 Hz, 2H), 1.48 (s, 9H).EI-MS m / z: [M+H] + 502.31.

[0434] Preparation of intermediate compound 124 To a solution of intermediate compound 123 (310 mg, 0.62 mmol) and intermediate compound 9 (406 mg, 0.98 mmol) in n-butanol (6 mL) was added diisopropylethylamine (0.21 mL, 1.24 mmol) at room temperature. After heating to 120° C. and stirring for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. After dilution with dichloromethane and diethyl ether, the resulting solid was filtered. The solid was dried to give 124 (crude), which was used without further purification. EI-MS m / z: [M+H] + 877.59.

[0435] Preparation of intermediate compound 125 To a solution of intermediate compound 124 (0.20 mmol, crude) in methanol (7 mL) and distilled water (1 mL) was added ammonia solution (28-30% ammonia, 0.2 mL) and sodium hydrosulfite (NaSO, 355 mg, 2.04 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated and diluted with acetonitrile (10 mL), and the resulting solid was filtered. The solid was dried to give compound 125 (crude), which was used without further purification. EI-MS m / z: [M+H] + 847.58.

[0436] Preparation of intermediate compound 126 To a solution of intermediate compound 125 (0.20 mmol, crude) in N,N-dimethylformamide (4 mL) was added intermediate compound 2 (47 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (47 mg, 0.30 mmol) and triethylamine (0.72 mL, 0.61 mmol) were added to the reaction solution over 16 hours at room temperature. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 126 (83 mg, 40%). EI-MS m / z: [M+H] + 1008.64.

[0437] Preparation of Compound 127 To a solution of intermediate compound 126 (33 mg, 0.03 mmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.4 mL) at −78° C. under nitrogen. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 127 (11 mg, 27%). 1 H-NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.68 - 7.60 (m, 3H), 7.45 (s, 1H), 7.37 - 7.28 (m, 3H), 7.06 (d, J = 9.2 Hz, 1H), 6.52 (s, 2H), 6.02 (dt, J = 14.1, 6.5 Hz, 1H), 5.79 (s, 2H), 4.90 (dd, J = 20.3, 7.7 Hz, 5H), 4.52 (dq, J = 14.1, 6.3 Hz, 5H), 3.69 (s, 3H), 2.10 (d, J = 10.6 Hz, 6H), 1.25 (q, J = 7.9 Hz, 6H). EI-MS m / z : [M+H] + 908.54.

[0438] Example 19 Preparation of Compound 133

[0439] [ka]

[0440] Preparation of intermediate compound 128 To a solution of t-butyl carbazate (5 g, 37.83 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60%, 3.8 g, 94.6 mmol) at 0 °C. After stirring at 0 °C for 0.5 h, 1,3-dibromopropane (3.8 mL, 37.8 mmol) was added to the reaction solution at room temperature over 3 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with distilled water (150 mL × 2). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to give intermediate compound 128 (3.9 g, 57%). 1 H-NMR (400 MHz, CDCl3) δ 3.86 (s, 1H), 3.49 - 3.41 (m, 2H), 3.07 - 2.99 (m, 2H), 2.03 (p, J = 6.8 Hz, 2H), 1.52 - 1.44 (m, 9H).

[0441] Preparation of intermediate compound 129 To a solution of intermediate compound 128 (1.2 g, 6.86 mmol) and intermediate compound 5 (2.0 g, 5.72 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.1 g, 8.58 mmol) at room temperature under nitrogen. After stirring for 18 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with distilled water (100 mL × 2). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to give intermediate compound 129 (2.0 g, 80%). 1H-NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 6.02 - 5.83 (m, 2H), 4.81 (d, J = 5.1 Hz, 2H), 3.26 (d, J = 6.0 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.00 (t, J = 7.3 Hz, 2H), 1.37 (s, 9H).

[0442] Preparation of intermediate compound 130 To a solution of intermediate compound 129 (2 g, 4.54 mmol) and intermediate compound 9 (4.7 g, 9.07 mmol) in n-butanol (35 mL) was added N,N-diisopropylethylamine (5.5 mL, 31.8 mmol) at room temperature and heated to 100° C. After stirring for 21 hours, the reaction mixture was cooled to room temperature and diluted with dichloromethane and diethyl ether. The resulting solid was filtered and washed with ether. The filtered solid was purified by column chromatography to give intermediate compound 130 (1.0 g, 28%). EI-MS m / z: [M+H] + 816.52.

[0443] Preparation of intermediate compound 131 To a solution of intermediate compound 130 (1.0 g, 1.29 mmol) in methanol (20 mL) and water (4 mL) under nitrogen, ammonia solution (28-30% ammonia, 1.4 mL) and sodium hydrosulfite (NaSO, 2.2 g, 12.87 mmol) were added. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated, diluted with dichloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to give intermediate compound 131 (1.0 g, crude). EI-MS m / z: [M+H] + 786.58.

[0444] Preparation of intermediate compound 132 To a solution of intermediate compound 131 (1.0 g, 1.29 mmol) in N,N-dimethylformamide (6 mL) was added compound 2 (301 mg, 1.54 mmol) in N,N-dimethylformamide (3 mL) at room temperature under nitrogen. After stirring for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.34 mL, 1.93 mmol) and triethylamine (0.36 mL, 2.57 mmol) were added to the reaction mixture at room temperature over 17 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 132 (545 mg, 44%). EI-MS m / z: [M+H] + 947.62.

[0445] Preparation of Compound 133 A solution of intermediate compound 132 (63 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL) was added under nitrogen at −0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 133 (42 mg, 53%). EI-MS m / z: [M+H]+ 847.55.

[0446] Example 20: Preparation of Compound 139

[0447] [ka]

[0448] Preparation of intermediate compound 134 To a solution of intermediate compound 5 (300 mg, 0.86 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (84 mg, 1.29 mmol) at 0° C. After stirring at 0° C. for 2 hours, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with distilled water (150 mL×2). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and diluted with dichloromethane and hexane. The resulting solid was filtered and dried to give intermediate compound 134 (225 mg, 84%), which was used without further purification. 1 H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 8.07 (d, J = 1.7 Hz, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 6.11 - 5.94 (m, 2H), 4.88 (d, J = 4.7 Hz, 2H), 3.97 (d, J = 5.5 Hz, 2H).

[0449] Preparation of intermediate compound 135 To a solution of intermediate compound 134 (225 mg, 0.72 mmol) in ethanol (3 mL), dichloromethane (2 mL), and water (3 mL) was added t-butyl prop-2-ynylcarbamate (145 mg, 0.94 mmol), copper(II) sulfate pentahydrate (36 mg, 0.14 mmol), and sodium L-ascorbate (57 mg, 0.29 mmol) at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (100 mL) and methanol (10 mL) and washed with saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and then diluted with dichloromethane and hexane. The resulting solid was filtered and dried to give intermediate compound 135 (283 mg, 84%), which was used without further purification. 1H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.30 (s, 1H), 6.17 - 6.07 (m, 1H), 5.97 - 5.93 (m, 1H), 5.07 (d, J = 6.0 Hz, 2H), 4.84 (d, J = 5.2 Hz, 2H), 4.16 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H).

[0450] Preparation of intermediate compound 136 To a solution of intermediate compound 135 (243 mg, 0.52 mmol) and intermediate compound 9 (428 mg, 1.04 mmol) in n-butanol (3 mL) was added N,N-diisopropylethylamine (0.45 mL, 2.60 mmol) at room temperature. After heating to 100° C. and stirring for 21 hours, the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to give intermediate compound 136 (241 mg, 55%). EI-MS m / z: [M+H] + 842.54.

[0451] Preparation of intermediate compound 137 To a solution of intermediate compound 136 (241 mg, 0.29 mmol) in methanol (10 mL) and water (2 mL) under nitrogen, ammonia solution (28-30% ammonia, 0.4 mL) and sodium hydrosulfite (NaSO, 498 mg, 2.86 mmol) were added. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated, diluted with dichloromethane (100 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give intermediate compound 137 (168 mg, crude), which was used without further purification. EI-MS m / z: [M+H]+ 812.54.

[0452] Preparation of intermediate compound 138 To a solution of intermediate compound 137 (168 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL) was added compound 2 (48 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) at room temperature under nitrogen. After stirring for 1 hour, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) and triethylamine (0.09 mL, 0.62 mmol) were added to the reaction solution at room temperature over 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 138 (175 mg, 87%). EI-MS m / z: [M+H] + 973.60.

[0453] Preparation of Compound 139 To a solution of intermediate compound 138 (72 mg, 0.07 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) at −0° C. under nitrogen. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 139 (51 mg, 56%). EI-MS m / z: [M+H] + 873.52.

[0454] Example 21 Preparation of Compound 147

[0455] [ka]

[0456] Preparation of intermediate compound 140 To a solution of di-t-butyl-iminodiacetate (684 mg, 3.15 mmol) in N,N-dimethylformamide (7 mL) was added cesium carbonate (1.12 mg, 3.43 mmol). After stirring at room temperature for 10 minutes, intermediate compound 5 (1 g, 2.86 mmol) was added to the reaction solution over 17 hours at room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 140 (1.05 g, 71%). 1 H-NMR (400 MHz, CDCl3) δ 7.79 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 6.62 (s, 1H), 5.95 (dt, J = 16.0, 5.2 Hz, 1H), 5.81 (dt, J = 15.7, 5.6 Hz, 1H), 4.74 (d, J = 5.4 Hz, 2H), 4.24 (d, J = 5.1 Hz, 2H), 1.48 (s, 18H).

[0457] Preparation of intermediate compound 141 To a solution of intermediate compound 140 (423 mg, 0.87 mmol) in methanol (4 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (105 mg, 2.61 mmol) in water (0.5 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 141 (223 mg, 69%). 1H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 5.95 - 5.72 (m, 2H), 4.80 (d, J = 5.5 Hz, 2H), 3.60 (d, J = 6.0 Hz, 2H), 1.37 (s, 9H).

[0458] Preparation of intermediate compound 142 To a solution of intermediate compound 141 (650 mg, 1.68 mmol) and compound 9 (831 mg, 2.02 mmol) in n-butanol (8 mL) was added N,N-diisopropylethylamine (1.2 mL, 8.42 mmol) at −0° C. After stirring for 5 minutes, the reaction mixture was heated to 120° C. for 20 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 142 (297 mg, 23%). EI-MS m / z: [M+H] + 761.45.

[0459] Preparation of intermediate compound 143 To a solution of intermediate compound 142 (294 mg, 0.39 mmol) in methanol (6 mL) was added ammonia solution (28-30% ammonia, 0.7 mL, 9.5 mmol) and sodium hydrosulfite (NaSO, 672 mg, 3.86 mmol). After stirring at room temperature for 1 h, the resulting solid was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 143 (202 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 731.5.

[0460] Preparation of intermediate compound 144 To a solution of intermediate compound 143 (202 mg, 0.28 mmol) in N,N-dimethylformamide (1 mL) was added compound 149 (30 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL). After stirring at 0° C. for 30 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43.7 mg, 0.28 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 144 (122 mg, 49%). EI-MS m / z: [M+H] + 892.5.

[0461] Preparation of intermediate compound 145 To a solution of intermediate compound 144 (50 mg, 0.05 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at −0° C. The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 1 h. After that, the reaction mixture was concentrated under reduced pressure to give intermediate compound 145 (63 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 792.53.

[0462] Preparation of intermediate compound 146 To a solution of intermediate compound 145 (35.4 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.22 mmol), carbonyldiimidazole (22 mg, 0.13 mmol), and 1-(t-butoxycarbonyl)piperazine (25 mg, 0.13 mmol). After stirring at room temperature for 20 hours, the reaction solution was concentrated under reduced pressure to give intermediate compound 146 (45 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 1004.59.

[0463] Preparation of Compound 147 To a solution of intermediate compound 146 (45 mg, 0.04 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at −0° C. After stirring at room temperature under nitrogen for 1 hour, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 147 (5.4 mg, 9.5%).

[0464] Example 22 Preparation of Compound 151

[0465] [ka]

[0466] Preparation of intermediate compound 148 To a solution of 4-ethyl-2-methyl-oxazole-5-carboxylic acid (100 mg, 0.64 mmol, prepared according to the method described in Chinese Patent Publication No. CN 111471056 A) in tetrahydrofuran (1 mL) was added oxalyl chloride (0.82 mL, 0.96 mmol) and N,N-dimethylformamide (0.1 mL) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 148 (crude), which was used without further purification.

[0467] Preparation of intermediate compound 149 To a solution of intermediate compound 148 (crude) in acetone (1 mL) was added potassium thiocyanate (125 mg, 1.28 mmol) at 0° C. After stirring at room temperature for 30 minutes, hexane (10 mL) was added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 149 (64 mg, 50%). 1 H-NMR (400 MHz, CDCl3), δ 2.90 (q, J = 7.6 Hz, 2H), 2.54 (s, 3H), 2.72 (t, J = 7.6 Hz, 3H). EI-MS m / z: [M+H] + 197.21.

[0468] Preparation of intermediate compound 150 To a solution of intermediate compound 53 (112 mg, 0.14 mmol) in N,N-dimethylformamide (1.5 mL) was added compound 149 (30 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL). After stirring at 0° C. for 30 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43.7 mg, 0.28 mmol) and triethylamine (0.06 mL, 0.42 mmol) were added to the reaction solution, which was then stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 150 (25 mg, 19%). EI-MS m / z: [M+H] + 959.24.

[0469] Preparation of Compound 151 To a solution of intermediate compound 150 (25 mg, 0.03 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at −0° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated. The resulting residue was purified by HPLC to give compound 151 (9.3 mg, 42%). 1 H-NMR (400 MHz, DMSO-d6) δ 8.00 - 7.83 (m, 2H), 7.65 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 6.51 (s, 1H), 5.91 (d, J = 15.0 Hz, 1H), 5.76 (d, J = 14.3 Hz, 2H), 4.89 (s, 3H), 4.66 (d, J = 5.9 Hz, 1H), 4.51 (d, J = 7.3 Hz, 2H), 3.71 (s, 2H), 2.82 (q, J = 7.9Hz, 1H), 2.40 (s, 2H), 2.10 (s, 2H), 1.25 (t, J = 7.2 Hz, 2H), 1.02 (t, J = 7.7 Hz, 2H). EI-MS m / z: [M+H] + 859.27.

[0470] Example 23 Preparation of Compound 155

[0471] [ka]

[0472] Preparation of intermediate compound 152 To a solution of 4-ethyl-2-methylthiazole-5-carboxylic acid (100 mg, 0.58 mmol) in tetrahydrofuran (1 mL) was added oxalyl chloride (0.75 mL, 0.87 mmol) and N,N-dimethylformamide (0.1 mL) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 152 (crude), which was used without further purification.

[0473] Preparation of intermediate compound 153 To a solution of intermediate compound 152 (crude) in acetone (1 mL) was added potassium thiocyanate (113 mg, 1.16 mmol) at 0° C. After stirring at room temperature for 30 minutes, hexane (10 mL) was added to the reaction mixture. The resulting solid was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 153 (21 mg, 16%). EI-MS m / z: [M+H] + 213.20.

[0474] Preparation of intermediate compound 154 To a solution of intermediate compound 53 (166 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was added intermediate compound 153 (35 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (1 mL) at 0 °C. After stirring for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (46 mg, 0.29 mmol) and triethylamine (0.06 mL, 0.44 mmol) were added to the reaction solution at room temperature over 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 154 (30 mg, 21%). EI-MS m / z: [M+H]+ 975.26.

[0475] Preparation of Compound 155 To a solution of intermediate compound 154 (30 mg, 0.03 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at −0° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 155 (18 mg, 68%). 1 H-NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 14.1 Hz, 1H), 7.82 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.47 (s, 0H), 7.30-7.21 (m, 2H), 6.45 (s, 1H), 5.77 (dq, 2H), 4.81 (d, J = 17.4 Hz, 2H), 4.60 (d, J = 6.0 Hz, 1H), 4.51 (s, 1H), 4.44 (d, J = 7.7 Hz, 1H), 3.64 (s, 2H), 3.03 (q, J = 7.9 Hz, 2H), 2.66 (s, EI-MS m / z : [M+H] + 875.24.

[0476] Example 24 Preparation of Compound 160

[0477] [ka]

[0478] Preparation of intermediate compound 156 To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (285 mg, 0.88 mmol) and trans-1,4-dibromo-2-butene (625 mg, 2.92 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 156 (592 mg, 94%), which was used without further purification.

[0479] Preparation of intermediate compound 157 To a solution of intermediate compound 156 (592 mg, 1.55 mmol) in methanol (10 mL) was added hydrazine monohydrate (0.2 mL, 4.64 mmol). After stirring at room temperature for 1 hour, dichloromethane and diethyl ether were added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 157 (352 mg, 90%).

[0480] Preparation of intermediate compound 158 To a solution of intermediate compound 157 (350 mg, 1.39 mmol) in dichloromethane (20 mL) was added N,N'-diisopropylethylamine (1.2 mL, 6.93 mmol) and bis(pentafluorophenyl)carbonate (1.6 g, 4.16 mmol) at -0 °C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. Dichloromethane and hexane were added to the reaction mixture. The resulting solid was filtered and dried to give intermediate compound 158 (310 mg, 24%), which was used without further purification.

[0481] Preparation of intermediate compound 159 To a solution of intermediate compound 158 (97 mg, 0.11 mmol) in N,N-dimethylformamide (2 mL) was added intermediate compound 75 (50 mg, 0.05 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.26 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane and hexane were added to the reaction mixture. The resulting solid was filtered and dried to give intermediate compound 159 (59 mg, crude), which was used without further purification.

[0482] Preparation of Compound 160 To a solution of intermediate compound 159 (59 mg, crude) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at −0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 160 (30 mg, 45%).

[0483] Example 25 Preparation of Compound 164

[0484] [ka]

[0485] Preparation of intermediate compound 161 To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (285 mg, 0.88 mmol) and trans-1,4-dibromo-2-butene (625 mg, 2.92 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 161 (111 mg, 62%). EI-MS m / z: [M+H] + 304.11.

[0486] Preparation of intermediate compound 162 To a solution of intermediate compound 66 (50 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added cesium carbonate (34 mg, 0.1 mmol) and intermediate compound 161 (23 mg, 0.08 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 162 (16 mg, 24%). EI-MS m / z: [M+H] + 946.27.

[0487] Preparation of intermediate compound 163 To a solution of intermediate compound 162 (67 mg, 0.07 mmol) in acetic acid (1 mL) was added zinc powder (46 mg). After stirring at room temperature for 2 hours, the reaction mixture was filtered through Celite and then washed with methanol. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 163 (3.2 mg, 3.6%). EI-MS m / z: [M+H] + 916.03.

[0488] Preparation of Compound 164 To a solution of intermediate compound 163 (43 mg, 0.05 mmol) in methanol (1.5 mL) was added lithium hydroxide monohydrate (24 mg, 0.14 mmol) dissolved in water (0.5 mL) at -50 °C. After stirring at 0 °C for 20 h, the reaction mixture was adjusted to pH 4-5 with acetic acid. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 164 (1 mg, 1.7%). EI-MS m / z: [M+H] + 902.00.

[0489] Example 26 Preparation of Compound 166

[0490] [ka]

[0491] Preparation of intermediate compound 165 To a solution of intermediate compound 145 (40 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine (0.10 mL, 0.745 mmol) and N,N-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (17 mg, 0.06 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 165 (37 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 1035.01.

[0492] Preparation of Compound 166 To a solution of intermediate compound 165 (45 mg, 0.04 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) at −0° C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 166 (23.8 mg, 46%). EI-MS m / z: [M+H] + 835.09.

[0493] Example 27 Preparation of Compound 168

[0494] [ka]

[0495] Preparation of intermediate compound 167 To a solution of intermediate compound 67 (2.0 g, 2.07 mmol; intermediate compound 67 was prepared according to the method described in International Patent Publication No. WO 2022 / 155518 A1) in N,N-dimethylformamide (20 mL) was added cesium carbonate (5.4 g, 16.54 mmol) and intermediate compound 50 (654 mg, 2.07 mmol) in N,N-dimethylformamide (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and chloroform (100 mL) and methanol (20 mL) were added, followed by washing with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give intermediate compound 167 (958 mg, 38%). EI-MS m / z: [M+H] + 1179.46.

[0496] Preparation of Compound 168 To a solution of intermediate compound 167 (40 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at −0° C. After stirring at room temperature under nitrogen for 1.5 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 168 (17 mg, 29%). EI-MS m / z: [M+H] + 979.29.

[0497] Example 28 Preparation of Compound 175

[0498] [ka]

[0499] Preparation of intermediate compound 169 To a solution of 4-aminopyrazole (5.89 g, 70.8 mmol) in tetrahydrofuran (200 mL) was added triethylamine (15 mL, 106.13 mmol) and di-t-butyl dicarbonate (48.8 mL, 212.26 mmol) under nitrogen. After stirring at room temperature for 20 hours, ethyl acetate (50 mL) was added to the reaction mixture and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 169 (5.9 g, 29%). 1 H-NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.63 (s, 1H), 6.34 (s, 1H), 1.64 (d, J = 3.9 Hz, 9H), 1.52 (s, 9H).

[0500] Preparation of intermediate compound 170 To a solution of intermediate compound 169 (1.1 g, 3.88 mmol) in acetonitrile (30 mL) were added potassium carbonate (590 mg, 4.27 mmol), 18-crown-6 (513 mg, 1.94 mmol), and methyl acrylate (367 mg, 4.27 mmol). After stirring at room temperature for 30 minutes, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 170 (1.38 g, 96%). 1 H-NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.27 (d, J = 3.1 Hz, 1H), 3.92 (dt, J = 9.4, 5.8 Hz, 2H), 3.71 - 3.65 (m, 3H), 2.68 - 2.59 (m, 2H), 1.65 (q, J = 2.4 Hz, 9H), 1.54 - 1.48 (m, 9H). EI-MS m / z : [M+H] + 370.32.

[0501] Preparation of intermediate compound 171 To a solution of intermediate compound 170 (1.38 g, 3.73 mmol) in methanol (20 mL) was added potassium carbonate (770 mg, 5.6 mmol) at −0° C. After stirring at room temperature for 30 minutes, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 171 (950 mg, 94%). 1 H-NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.53 (s, 1H), 3.96 - 3.87 (m, 2H), 3.67 (s, 3H), 2.64 (p, J = 5.0 Hz, 2H), 1.50 (s, 9H).

[0502] Preparation of intermediate compound 172 To a solution of intermediate compound 171 (167 mg, 0.62 mmol) in N,N-dimethylformamide (30 mL) were added cesium carbonate (303 mg, 0.93 mmol) and trans-1,4-dibromo-2-butene (397 mg, 1.86 mmol). After stirring at room temperature for 3 hours, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 172 (177 mg, 71%). EI-MS m / z: [M+H] + 402.24.

[0503] Preparation of intermediate compound 173 To a solution of intermediate compound 66 (264 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) were added cesium carbonate (179 mg, 0.43 mmol) and compound 172 (177 mg, 0.44 mmol). After stirring at room temperature for 12 hours, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 173 (133 mg, 34%). EI-MS m / z: [M+H] + 1045.34.

[0504] Preparation of intermediate compound 174 To a solution of intermediate compound 173 (150 mg, 0.14 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.25 mL) at −0° C. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give intermediate compound 174 (135 mg, crude), which was used without further purification.

[0505] Preparation of Compound 175 To a solution of intermediate compound 174 (135 mg, crude) in methanol (1 mL) was added lithium hydroxide monohydrate (11.7 mg, 0.28 mmol) in water (1 mL) at −45° C. After stirring at −0° C. for 2 h, the reaction mixture was adjusted to pH 4-5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 175 (34 mg, 42%). EI-MS m / z: [M+H] + 902.

[0506] Example 29 Preparation of Compound 178

[0507] [ka]

[0508] Preparation of intermediate compound 176 To a solution of intermediate compound 49 (300 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (693 mg, 2.13 mmol) and 1,4-dibromo-2-butene (1.04 g, 4.91 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 176 (320 mg, 62%).

[0509] Preparation of intermediate compound 177 To a solution of intermediate compound 66 (400 mg, 0.42 mmol, intermediate compound 66 was prepared according to the method described in International Patent Publication No. WO 2022 / 155518 A1) in N,N-dimethylformamide (5 mL) was added cesium carbonate (548 mg, 1.68 mmol) and intermediate compound 176 (158 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane (50 mL) and methanol (10 mL) were added to the reaction mixture and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 177 (246 mg, 61%). EI-MS m / z: [M+H] + 956.52.

[0510] Preparation of Compound 178 To a solution of intermediate compound 177 (246 mg, 0.26 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at −0° C. After stirring at room temperature under nitrogen for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 178 (92 mg, 30%). EI-MS m / z: [M+H] + 856.48.

[0511] Example 30: Preparation of Compound 187

[0512] [ka]

[0513] Preparation of intermediate compound 179 To a solution of 3-bromopropanol (2.0 g, 14.39 mmol) in acetone (30 mL) under nitrogen at −0° C. was added potassium thiocyanate (1.8 g, 15.83 mmol). After stirring at room temperature for 17 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 179 (1.26 g, 65%). 1 H-NMR (400 MHz, CDCl3) δ 3.65 (q, J = 5.6 Hz, 2H), 3.01 (dq, J = 9.3, 3.3 Hz, 2H), 2.39 - 2.30 (m, 3H), 2.04 (t, J = 5.8 Hz, 1H), 1.83 (q, J = 6.0 Hz, 2H).

[0514] Preparation of intermediate compound 180 To a solution of intermediate compound 179 (1.26 g, 9.39 mmol) in dichloromethane (30 mL) was added imidazole (958 mg, 14.08 mmol) and triisopropylsilyl chloride (2.0 g, 10.33 mmol) at −0° C. After stirring at room temperature for 4 hours, the reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride (70 mL) and distilled water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 180 (2.7 g, 99%). 1 H-NMR (400 MHz, CDCl3) δ 3.74 (q, J = 5.4 Hz, 2H), 2.99 (q, J = 6.3 Hz, 2H), 2.35 - 2.30 (m, 3H), 1.81 (q, J = 6.2 Hz, 2H), 1.06 (s, 21H).

[0515] Preparation of intermediate compound 181 To a solution of intermediate compound 180 (2.7 g, 9.29 mmol) in methanol (30 mL) was added methyl iodide (0.69 mL, 10.2 mmol) and potassium carbonate (4.1 g, 30.25 mmol) at −0° C. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with dichloromethane (100 mL) and washed with distilled water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 181 (1.73 g, 65%). 1 H-NMR (400 MHz, CDCl3) δ 3.86 - 3.73 (m, 2H), 2.60 (tt, J = 7.0, 2.5 Hz, 2H), 2.11 (q, J = 2.3 Hz, 3H), 1.82 (q, J = 6.2 Hz, 2H), 1.15 - 1.02 (m, 21H).

[0516] Preparation of intermediate compound 182 To a solution of intermediate compound 181 (1.2 g, 4.57 mmol) in methanol (20 mL) was added iodobenzene diacetate (3.7 g, 11.43 mmol) and ammonium carbonate (1.3 g, 13.71 mmol) at −0° C. After stirring and refluxing for 2 h, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 182 (1.5 g, crude). 1 H-NMR (400 MHz, CDCl3) δ 3.84 (q, J = 5.4 Hz, 2H), 3.28 - 3.21 (m, 2H), 3.03 - 2.97 (m, 3H), 2.11 - 2.03 (m, 2H), 1.06 (d, J = 4.4 Hz, 21H).

[0517] Preparation of intermediate compound 183 To a solution of intermediate compound 182 (1.5 g, crude) in dichloromethane (20 mL) was added pyridine (0.71 mL, 8.86 mmol) and ethyl chloroformate (0.51 mL, 5.31 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was diluted with dichloromethane (100 mL) and washed with 0.5 N hydrochloric acid solution (70 mL) and distilled water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 183 (1.47 g, 91%). 1 H-NMR (400 MHz, CDCl3) δ 4.15 (s, 2H), 3.83 (t, J = 5.2 Hz, 2H), 3.51 (d, J = 10.0 Hz, 2H), 3.25 (s, 3H), 2.10 (s, 2H), 1.29 (t, J = 5.8 Hz, 3H), 1.06 (d, J = 4.3 Hz, 21H).

[0518] Preparation of intermediate compound 184 To a solution of intermediate compound 183 (1.5 g, 4.02 mmol) in dichloromethane (30 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 12 mL) at 0° C. After stirring for 2.5 hours, the reaction mixture was concentrated. Ethyl acetate (100 mL) and distilled water (70 mL) were added to the reaction mixture. The resulting aqueous layer was concentrated. To the reaction mixture were added dichloromethane (50 mL) and methanol (5 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 184 (752 mg, 89%). 1 H-NMR (400 MHz, CDCl3) δ 4.14 (tt, J = 8.5, 4.5 Hz, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.67 - 3.42 (m, 2H), 3.31 - 3.25 (m, 3H), 2.16 (q, J = 6.1 Hz, 2H), 1.29 (dt, J = 8.7, 4.8 Hz, 3H).

[0519] Preparation of intermediate compound 185 To a solution of intermediate compound 184 (50 mg, 0.24 mmol) in dichloromethane (3 mL) was added triethylamine (0.07 mL, 0.48 mmol) and methanesulfonic anhydride (50 mg, 0.29 mmol) at −0° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (50 mL) and washed with distilled water (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give intermediate compound 185 (50 mg, 73%), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 4.41 (d, J = 5.9 Hz, 2H), 4.15 (dq, J = 10.5, 3.7 Hz, 2H), 3.51 (d, J = 53.9 Hz, 2H), 3.30 (q, J = 2.4 Hz, 3H), 3.06 (q, J = 2.4 Hz, 3H), 2.40 (d, J = 8.7 Hz, 2H), 1.35 - 1.25 (m, 3H).

[0520] Preparation of intermediate compound 186 To a solution of intermediate compound 66 (100 mg, 0.11 mmol; intermediate compound 66 was prepared according to the method described in International Patent Publication No. WO 2022 / 155518 A1) in N,N-dimethylformamide (2 mL) was added cesium carbonate (113 mg, 0.35 mmol) and intermediate compound 185 (36 mg, 0.13 mmol) dissolved in N,N-dimethylformamide (1 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane (50 mL) and methanol (10 mL) were added to the reaction mixture and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 186 (48 mg, 50%). EI-MS m / z: [M+H] + 914.41.

[0521] Preparation of Compound 187 To a solution of intermediate compound 186 (48 mg, 0.05 mmol) in ethanol (20 mL) was added sodium ethoxide (21% w / w ethanol, 0.24 mL, 0.64 mmol). After stirring and refluxing for 14 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 187 (25 mg, 55%). EI-MS m / z: [M+H] + 842.39.

[0522] Example 31 Preparation of Compound 197

[0523] [ka]

[0524] Preparation of intermediate compound 188 To a solution of intermediate compound 4 (400 mg, 1.85 mmol) in N,N-dimethylformamide (5 mL) were added cesium carbonate (782 mg, 2.40 mmol) and compound 185 (584 mg, 2.03 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 188 (600 mg, 80%). 1 H-NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.73 (d, J = 4.3 Hz, 1H), 4.38 (q, J = 6.0 Hz, 2H), 4.13 (q, J = 6.5 Hz, 2H), 3.81 - 3.65 (m, 1H), 3.54 (d, J = 14.8 Hz, 1H), 3.37 - 3.25 (m, 3H), 2.56 - 2.48 (m, 2H), 1.29 (q, J = 6.6 Hz, 3H).

[0525] Preparation of intermediate compound 189 To a solution of intermediate compound 188 (600 mg, 1.47 mmol) in ethanol (10 mL) was added t-butyl (E)-(4-aminobut-2-en-1-yl)carbamate (548 mg, 2.94 mmol) and triethylamine (0.62 mL, 4.41 mmol). After stirring at 120° C. for 20 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 189 (550 mg, 67%). EI-MS m / z: [M+H] + 558.31.

[0526] Preparation of intermediate compound 190 To a solution of intermediate compound 189 (550 mg, 0.99 mmol) in methanol (5 mL) and distilled water (1 mL) was added ammonia solution (28-30% ammonia, 1 mL) and sodium hydrosulfite (NaSO, 1.7 g, 9.86 mmol) at -0 °C. After stirring at room temperature for 1.5 hours, methanol (10 mL) was added to the reaction solution. The resulting solid was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The reaction mixture was added and washed with distilled water (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 190 (339 mg, 65%), which was used without further purification. EI-MS m / z: [M+H] + 528.39.

[0527] Preparation of intermediate compound 191 To a solution of intermediate compound 190 (339 mg, 0.64 mmol) in N,N-dimethylformamide (3 mL) was added intermediate compound 2 (150 mg, 0.77 mmol) at −0° C. After stirring at room temperature for 30 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (160 mg, 0.84 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to the reaction solution over 17 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 191 (390 mg, 88%). EI-MS m / z: [M+H] +689.37.

[0528] Preparation of intermediate compound 192 To a solution of intermediate compound 191 (390 mg, 0.57 mmol) in dichloromethane (5 mL) and methanol (1 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 1.5 mL). After stirring for 2 hours, the reaction mixture was concentrated. Diethyl ether (20 mL) was added to the reaction mixture. The resulting solid was filtered and dried to give intermediate compound 192 (360 mg, 96%). EI-MS m / z: [M+H] + 589.38.

[0529] Preparation of intermediate compound 193 To a solution of intermediate compound 192 (360 mg, 0.54 mmol) in n-butanol (3 mL) was added compound 51 (170 mg, 0.38 mmol) and triethylamine (0.26 mL, 1.88 mmol) at −0° C. After stirring at 120° C. for 24 hours, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 193 (127 mg, 34%). EI-MS m / z: [M+H] + 1004.40.

[0530] Preparation of intermediate compound 194 To a solution of intermediate compound 193 (127 mg, 0.13 mmol) in methanol (5 mL) and distilled water (1 mL) was added ammonia solution (28-30% ammonia, 0.2 mL) and sodium hydrosulfite (220 mg, 1.26 mmol) at -0 °C. After stirring at room temperature for 2.5 h, methanol (10 mL) was added to the reaction mixture. The resulting solid was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. Dichloromethane (60 mL) was added to the reaction mixture and washed with distilled water (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give intermediate compound 194 (74 mg, 60%), which was used without further purification. EI-MS m / z: [M+H] + 974.47.

[0531] Preparation of intermediate compound 195 To a solution of intermediate compound 194 (74 mg, 0.08 mmol) in N,N-dimethylformamide (1 mL) was added compound 2 (18 mg, 0.09 mmol) at −0° C. After stirring at room temperature for 15 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.10 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to the reaction mixture over a period of 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 195 (42 mg, 49%). EI-MS m / z: [M+H] + 1135.55.

[0532] Preparation of intermediate compound 196 To a solution of intermediate compound 195 (42 mg, 0.04 mmol) in ethanol (2 mL) was added sodium ethoxide (21% w / w ethanol, 0.14 mL, 0.37 mmol). After stirring at reflux for 7 h, the reaction mixture was concentrated under reduced pressure to give intermediate compound 196 (50 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 1063.53.

[0533] Preparation of Compound 197 To a solution of intermediate compound 196 (50 mg, crude) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) under nitrogen at −0° C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 197 (23 mg, 49%). 1H-NMR (400 MHz, DMSO) δ 7.96 (d, J = 20.3 Hz, 2H), 7.86 (d, J = 0.8 Hz, 1H), 7.67 (dd, J = 14.8, 1.2 Hz, 2H), 7.41 - 7.36 (m, 2H), 7.28 (dd, J = 7.1, 1.4 Hz, 2H), 6.53 (s, 2H), 5.87 - 5.54 (m, 5H), 4.95 - 4.85 (m, 4H), 4.54 (dq, J = 20.2, 6.5 Hz, 6H), 4.47 - 4.41 (m, 2H), 4.01 (t, J = 6.1 Hz, 3H), 2.12 (d, J = 7.1 Hz, 6H), 2.00 (q, J = 7.1 Hz, 2H), 1.27 (dt, J = 9.3, 7.1 Hz, 6H) EI-MS m / z : [M+H] + 963.53.

[0534] Example 32 Preparation of Compound 199

[0535] [ka]

[0536] Preparation of intermediate compound 198 To a solution of intermediate compound 64 (90 mg, 0.08 mmol) in N,N-dimethylformamide (10 mL) under nitrogen, alendronic acid (80 mg, 0.32 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 91 mg, 0.24 mmol), and triethylamine (0.04 mL, 0.32 mmol) were added. After stirring at room temperature for 3 days, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 198 (32 mg, 31%). EI-MS m / z: [M+H] + 1262.42.

[0537] Preparation of Compound 199 To a solution of intermediate compound 198 (32 mg, 0.02 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0° C. under nitrogen. After stirring at room temperature for 0.5 h, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 199 (14 mg, 47%). EI-MS m / z: [M+H] + 1162.53.

[0538] Example 33 Preparation of Compound 212

[0539] [ka]

[0540] Preparation of intermediate compound 200 To a solution of 2-(2-(benzyloxy)ethoxy)ethanol (3 g, 15.2 mmol) in acetonitrile (20 mL) was added methyl propiolate (2.72 mL, 30.5 mmol) and N-methylmorpholine (0.33 mL, 3.05 mmol) at 0° C. under nitrogen. After stirring at room temperature for 16 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 200 (2.72 mg, 63%). 1 H-NMR (400 MHz, CDCl3) δ 7.62 (d, J = 16.0 Hz, 1H), 7.34-7.27 (m, 5H), 5.22(d, J = 16.0 Hz, 1H), 4.57 (t, J = 4.0 Hz, 2H), 4.01 (t, J = 4.0 Hz, 2H), 3.77 (d, J = 4.0 Hz, 2H), 3.70-7.69 (m, 5H), 3.64(s, 2H). EI-MS m / z : [M+Na] + 303.27

[0541] Preparation of intermediate compound 201 To a solution of intermediate compound 200 (2.7 g, 9.63 mmol) in methanol (10 mL) was added palladium on charcoal (540 mg). After stirring at room temperature for 4 hours under a hydrogen balloon, the reaction solution was filtered through Celite and washed with dichloromethane (200 mL). The filtrate was concentrated under reduced pressure to give intermediate compound 201 (1.7 g, 91%), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 3.80-3.60 (m, 13H), 2.60 (dd, J = 8.0, 4.0 Hz, 2H). EI-MS m / z : [M+Na] + 215.23, [M+H] + 193.30.

[0542] Preparation of intermediate compound 202 To a solution of intermediate compound 201 (480 mg, 2.49 mmol) in dichloromethane (20 mL) was added trimethylamine (0.87 mL, 6.24 mmol) and methanesulfonic anhydride (870 mg, 4.99 mmol) under nitrogen at 0° C. After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (50 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 202 (680 mg, crude), which was used without further purification. EI-MS m / z: [M+Na] + 293.27, [M+H] + 271.26.

[0543] Preparation of intermediate compound 203 To a solution of intermediate compound 202 (680 mg, crude) in tetrahydrofuran (2 mL) was added methylamine solution (1.0 M in tetrahydrofuran, 12 mL) at 0° C. under nitrogen. After stirring at 60° C. for 16 hours under a sealed condition, the reaction solution was concentrated under reduced pressure to give intermediate compound 203 (512 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 206.27.

[0544] Preparation of intermediate compound 204 To a solution of intermediate compound 203 (512 mg, 2.49 mmol) in dichloromethane (4 mL) was added trimethylamine (1.05 mL, 7.49 mmol) and di-tert-butyl dicarbonate (0.63 mL, 2.74 mmol) under nitrogen at 0° C. After stirring at room temperature for 12 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 204 (450 mg, 59%). 1 H-NMR (400 MHz, CDCl3) δ 3.76 (t, J = 8.0 Hz, 2H), 3.69 (s, 3H), 3.61-3.58 (m,6H), 3.42(m, 2H), 2.91 (s, 3H), 2.61 (t, J = 4.0 Hz, 3H), 1.45 (s, 9H). EI-MS m / z : [M+Na] + 328.37.

[0545] Preparation of intermediate compound 205 To a solution of intermediate compound 204 (450 mg, 1.47 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added lithium hydroxide monohydrate (68 mg, 1.62 mmol) in distilled water (4 mL) at −50° C. After stirring at 0° C. for 2 h, the reaction mixture was adjusted to pH 4-5 with acetic acid and concentrated under reduced pressure to give intermediate compound 205 (310 mg, 72%), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 3.77 (t, J = 6.1 Hz, 2H), 3.67-3.54 (m, 6H), 3.40 (s, 2H), 2.91 (s, 3H), 2.62 (t, J = 6.1 Hz, 2H), 1.46 (s, 9H). EI-MS m / z : [M+Na] + 314.37.

[0546] Preparation of intermediate compound 206 To a solution of methyl-1-O-(4-(tert-butyldimethylsilyloxy)methyl-2-aminophenyl)-2,3,4-tri-o-acetyl-β-d-glucuronate (327 mg, 0.12 mmol, prepared by the method described in International Patent Publication No. WO 2019 / 236954 A1) and intermediate compound 205 (320 mg, 0.56 mmol) in N,N-dimethylformamide (5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 448 mg, 1.17 mmol) and N,N'-diisopropylethylamine (0.48 mL, 2.8 mmol) under nitrogen at 0°C. After stirring at room temperature for 15 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 206 (290 mg, 61%). 1 H-NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.89 (s, 1H), 7.03 (s, 2H), 5.56 (d, J = 7.9 Hz, 1H), 5.49 (t, J = 9.6 Hz, 1H), 5.21-5.12 (m, 2H), 5.06 (t, J = 9.8 Hz, 1H), 4.71 (d, J = 10.0 Hz, 1H), 3.69 (t, J = 6.4 Hz, 2H), 3.64 (s, 3H), 3.53 (s, 4H), 3.48 (t, J = 5.8 Hz, 2H), 2.77 (s, 3H), 2.06-1.95 (m, 9H), 1.37 (s, 9H). EI-MS m / z : [M+H] + 843.50.

[0547] Preparation of intermediate compound 207 To a solution of intermediate compound 206 (280 mg, 0.33 mmol) in methanol (1 mL) was added (1S)-(+)-10-camphorsulfonic acid (15 mg, 0.066 mmol) under nitrogen at 0° C. After stirring at 0° C. for 2 hours, the reaction solution was neutralized with triethylamine. After concentration under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 207 (200 mg, 90%). EI-MS m / z: [M+H] + 729.40

[0548] Preparation of intermediate compound 208 To a solution of intermediate compound 207 (110 mg, 0.15 mmol) in dichloromethane (3 mL) was added bis(pentafluorophenyl)carbonate (59 mg, 0.15 mmol) and N,N'-diisopropylethylamine (0.07 mL, 0.45 mmol) under nitrogen at 0°C. After stirring at room temperature for 14 hours, the reaction solution was diluted with dichloromethane (15 mL) and washed with distilled water (15 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 208 (130 mg, 91%). EI-MS m / z: [M+H] + 820.32.

[0549] Preparation of intermediate compound 209 To a solution of intermediate compound 55 (140 mg, 0.12 mmol) and intermediate compound 208 (131 mg, 0.14 mmol) in N,N-dimethylformamide (2 mL) was added N,N'-diisopropylethylamine (0.10 mL, 0.58 mmol) at 0°C under nitrogen. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 209 (180 mg, 95%). EI-MS m / z: [M / 2+H] + 807.23.

[0550] Preparation of intermediate compound 210 To a solution of intermediate compound 209 (180 mg, 0.11 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added lithium hydroxide monohydrate (21 mg, 0.50 mmol) in distilled water (2 mL) at -50 °C. After stirring at 0 °C for 3 h, the reaction mixture was adjusted to pH 4-5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 210 (130 mg, 79%). EI-MS m / z: [M / 2+H] + 737.23.

[0551] Preparation of intermediate compound 211 To a solution of intermediate compound 210 (130 mg, 0.088 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.45 mL) under nitrogen at 0° C. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give intermediate compound 211 (90 mg, 74%). 1H-NMR (400 MHz, DMSO) δ 12.82 (s, 2H), 9.47 (s, 1H), 9.10 (s, 1H), 8.31 (s, 2H), 8.18 (s, 1H), 7.94 (d, J = 15.0 Hz, 2H), 7.70-7.58 (m, 2H), 7.40-7.21 (m, 4H), 7.15-6.96 (m, 2H), 6.51 (d, J = 2.9 Hz, 2H), 5.94-5.85 (m, 1H), 5.79 (s, 2H), 5.68 (d, J = 15.6 Hz, 1H), 4.99 (s, 2H), 4.87 (dd, J = 14.7, 8.8 Hz, 4H), 4.52 (t, J = 13.5 Hz, 6H), 3.89 (d, J = 9.6 Hz, 1H), 3.70 (d, J = 6.6 Hz, 4H), 3.61 (t, J = 5.1 Hz, 2H), 3.05 (d, J = EI-MS m / z : [M / 2+H] + 687.16.

[0552] Preparation of Compound 212 To a solution of compound 211 (65 mg, 0.047 mmol) in methanol (1 mL) was added trimethylamine (0.033 mL), formaldehyde solution (37 wt. in water, 0.035 mL, 0.09 mmol), sodium cyanoborohydride (3.5 mg, 0.056 mmol), and acetic acid (0.027 mL, 0.047 mmol) at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was adjusted to pH 6 with 1 N aqueous sodium hydroxide and then concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 212 (33 mg, 50%). 1H-NMR (400 MHz, DMSO) δ 12.82 (s, 2H), 9.47 (s, 1H), 9.20 (s, 1H), 9.09 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 15.6 Hz, 2H), 7.63 (d, J = 10.1 Hz, 2H), 7.34 (s, 1H), 7.30 (d, J = 5.4 Hz, 2H), 7.12-7.01 (m, 2H), 6.51 (d, J = 3.0 Hz, 1H), 5.90 (d, J = 15.6 Hz, 2H), 5.79 (s, 2H), 5.68 (d, J = 15.7 Hz, 1H), 4.99 (s, 2H), 4.88 (t, J = 10.2 Hz, 4H), 4.54 (d, J = 17.8 Hz, 6H), 3.90 (d, J = 9.6 Hz, 1H), 3.68 (d, J = 9.4 Hz, 5H), 3.57 (s, 4H), 2.72 (d, J = 4.2 Hz, 4H), 2.67 (p, J = 1.8 Hz, 3H), 2.33 (p, J = 1.9 Hz, 4H), 2.09 (d, J = 3.1 Hz, 5H), 1.91 (s, 1H), 1.25 (td, J = 7.1, 5.3 Hz, 5H). EI-MS m / z: [M / 2+H] + 694.17.

[0553] <Example 34> Preparation of compound 214

[0554]

change

[0555] Modulation of compound 214 To a solution of compound 55 (50 mg, 0.04 mmol) and intermediate compound 213 (36 mg, 0.05 mmol; intermediate compound 448 was prepared by the method described in Korean Patent Application No. 10-2023-0099038) in N,N-dimethylformamide (2 mL), N,N'-diisopropylethylamine (0.036 mL, 0.2 mmol) was added at 0 °C under nitrogen. After stirring at room temperature for 20 h, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 214 (12 mg). EI-MS m / z: [M+H]+ 1393.72.

[0556] Example 35 Preparation of Compound 221

[0557] [ka]

[0558] Preparation of intermediate compound 215 To a solution of trans-2-butene-1,4-diol (1.5 g, 11.94 mmol) in dichloromethane (100 mL) was added trimethylamine (2.2 mL, 15.92 mmol) and t-butyldimethylsilyl chloride (1.0 g, 7.96 mmol) under nitrogen at 0 °C. After stirring at room temperature for 4 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride (50 mL) and distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 215 (1.2 g, 74%). 1 H-NMR (400 MHz, MeOD) δ 5.88 - 5.71 (m, 2H), 4.19 (dt, J = 4.3, 1.4 Hz, 2H), 4.09 - 4.02 (m, 2H), 0.92 (s, 9H).

[0559] Preparation of intermediate compound 216 To a solution of intermediate compound 215 (500 mg, 2.47 mmol) in dichloromethane (10 mL) was added trimethylamine (1.04 mL, 7.41 mmol), pyridine (0.60 mL, 7.41 mmol), and 4-nitrophenyl chloroformate (747 mg, 3.70 mmol) under nitrogen at 0° C. After stirring at room temperature for 20 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and 2% aqueous sodium hydroxide (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 216 (729 mg, 80%). 1 H-NMR (400 MHz, CDCl3) δ 8.32 - 8.24 (m, 2H), 7.42 - 7.34 (m, 2H), 6.04 - 5.84 (m, 2H), 4.78 (dq, J = 5.9, 1.1 Hz, 2H), 4.23 (dq, J = 4.2, 1.4 Hz, 2H), 0.92 (s, 9H), 0.08 (s, 6H).

[0560] Preparation of intermediate compound 217 To a solution of intermediate compound 216 (729 mg, 1.98 mmol) in dichloromethane (10 mL) was added trimethylamine (0.56 mL, 3.97 mmol) and tert-butylmethyl(2-(methylamino)ethyl)carbamate (485 mg, 2.58 mmol) under nitrogen at 0° C. After stirring at room temperature for 3 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and 2% aqueous sodium hydroxide (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 217 (825 mg, 99%). 1H-NMR (400 MHz, CDCl3) δ 5.85 - 5.78 (m, 2H), 4.58 (s, 2H), 4.18 (d, J = 2.6 Hz, 2H), 3.37 (s, 4H), 2.94 (s, 3H), 2.88 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H).

[0561] Preparation of intermediate compound 218 To a solution of intermediate compound 217 (825 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 3 mL, 2.97 mmol) under nitrogen at 0° C. After stirring at room temperature for 17 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 218 (514 mg, 86%). 1 H-NMR (400 MHz, CDCl3) δ 5.96 - 5.73 (m, 2H), 4.58 (d, J = 5.9 Hz, 2H), 4.15 (d, J = 12.5 Hz, 2H), 3.45 - 3.27 (m, 4H), 2.94 (d, J = 5.0 Hz, 3H), 2.87 (d, J = 11.5 Hz, 3H), 1.45 (s, 9H).

[0562] Preparation of intermediate compound 219 To a solution of intermediate compound 218 (150 mg, 0.50 mmol) in dichloromethane (5 mL) was added trimethylamine (0.14 mL, 0.99 mmol) and methanesulfonic anhydride (103 mg, 0.59 mmol) under nitrogen at 0° C. After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (50 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 219 (164 mg, crude), which was used without further purification. 1 H-NMR (400 MHz, CDCl3) δ 6.06 - 5.77 (m, 2H), 4.73 (dt, J = 6.2, 1.1 Hz, 2H), 4.63 (s, 2H), 3.38 (s, 4H), 3.03 (s, 3H), 2.95 (s, 3H), 2.87 (d, J = 7.8 Hz, 3H), 1.45 (s, 9H).

[0563] Preparation of intermediate compound 220 To a solution of intermediate compound 66 (350 mg, 0.37 mmol; intermediate compound 66 was prepared by the method described in International Patent Publication No. WO 2022 / 155518 A1) and intermediate compound 219 (154 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (600 mg, 1.84 mmol) at 0°C under nitrogen. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL) and methanol (10 mL), and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 220 (207 mg, 56%). EI-MS m / z: [M+H] + 1007.74.

[0564] Preparation of Compound 221 To a solution of intermediate compound 220 (75 mg, 0.12 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) under nitrogen at 0° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure to give compound 221 (93 mg, crude), which was used without further purification. EI-MS m / z: [M+H] + 908.38.

[0565] Example 36 Preparation of Compounds 222 to 245 Compounds 222-245 shown in Table A below were prepared following procedures similar to those outlined in the above examples using the appropriate starting materials described in the above examples or obtained from commercial sources.

[0566] [ka] TIFF2025538034000120.tif173162TIFF2025538034000121.tif165162TIFF2025538034000122.tif153162

[0567] Example 37: Preparation of Comparative Compound #1 The compound of comparative compound 1 has the following structure and was purchased from ChemScene (#CS-0077291) and used.

[0568] [ka]

[0569] Example 38: Preparation of Comparative Compound #2 The compound of Comparative Compound #2 has the following structure and was prepared by the method described in U.S. Patent Publication No. 2021-0032269 A1.

[0570] [ka]

[0571] <Experimental Example 1> Evaluation of STING agonist activity To evaluate the activity of STING agonists, we used reporter cells from Invivogen. The cell lines used in the experiments were THP1 Dual™ (InvivoGen #thpd-nfis), which expresses the endogenous STING variant HAQ, and THP1 Dual™ KI-hSTING-R232 (InvivoGen #thpd-r232 / h232), in which the STING HAQ gene was deleted and then the STING R232 or H232 variant gene was introduced. The cell lines contained a luciferase reporter gene inserted under the IFN regulatory factor (IRF) promoter, allowing us to evaluate the activity of the IFN regulatory factor (IRF) machinery through luciferase expression.

[0572] 9.0 × 10 cells were cultured per well in a 96-well plate using RPMI 1640 medium (Gibco, #22400097) supplemented with 10% heat-inactivated FBS and 1× antibiotic-antimycotic (Gibco, #15240062), 10 pg / mL blasticidin (Gibco, #A1113902), and 100 pg / mL zeocin (Gibco, #R25005). 4 Reporter cells were seeded at 100 μL / 100 μL of cells. The seeded cells were cultured at 37°C and 5% CO2 for 24 hours, then treated with 100 μL of serially diluted compounds in each well, and then cultured at 37°C and 5% CO2 for 24 hours. After culture, 20 μL of cell culture medium was transferred to a 96-well white plate, and QUANTI-Luc™ (InvivoGen#rep-qlcl) was added at 50 μL / well. Using a microplate reader (Perkin Elmer), the increased luminescence signal in the drug-treated experimental group was calculated compared to the drug-untreated control group. GraphPad Prism was used to calculate the EC depending on the compound concentration. 50 Table 1 below shows the results of evaluating the activity of STING agonists using THP1 reporter cells.

[0573] [Table 1] TIFF2025538034000126.tif61159

[0574] [Table 2]

[0575] Furthermore, to analyze the direct binding ability of the STING agonist compounds described herein to human STING, the HUMAN STING WT BINDING KIT (Cisbio, #64BDSTGPEG) was used according to the manufacturer's instructions. The STING agonist compounds were confirmed to directly bind to human STING protein in vitro, and the resulting data are summarized in Table 3. 50 It was presented as.

[0576] [Table 3]

[0577] Experimental Example 2: Evaluation of pharmacokinetics For in vivo evaluation of the STING agonist compounds described herein in naive Balb / c mice, a single dose of the STING agonist compound was administered intravenously at 1.5 mg / kg to 6-8 week-old female BALB / c mice (Orientbio, Korea). After injection of the STING agonist compound into Balb / c mice, pharmacokinetics was studied. Plasma samples were collected at various time points and frozen for analysis. Plasma concentrations of the STING agonist compound at the indicated time points were measured using LC-MS / MS analysis.

[0578] Briefly, 250 μL of acetonitrile (ACN) solution was added to both 50 μL of sample containing 10 nM dextromethorphan (internal standard) and 50 μL of plasma, and the solution was vigorously mixed using a vortex mixer for 5 minutes. The sample was then spun down at 14,000 rpm at 4 °C for 5 minutes. 100 μL of the supernatant was combined with 100 μL of mobile phase A (0.1% formic acid in water with 5% ACN) and mixed thoroughly. The sample was measured for STING agonist compounds using LC-MS / MS (Nexera LC40 (SHIMADZU) and QTRAP4500 (SCIEX)).

[0579] The PK profiles of compounds 55, 65, 133, Comparative #1, and #2 are summarized in Tables 4 to 8. Compared to Comparative #1 and #2, the STING agonist compounds exhibited significantly more stable pharmacokinetic profiles in mice.

[0580] [Table 4]

[0581] [Table 5] TIFF2025538034000131.tif29160

[0582] [Table 6]

[0583] [Table 7]

[0584] [Table 8] TIFF2025538034000135.tif24160

[0585] <Experimental Example 3> In vitro evaluation of cytotoxicity in normal cells PBMCs were also purchased from STEMCELL™ (# 700025.2). Cells (8.0 x 10 per well) 4 Cells (number of cells) were seeded into flat-bottom 96-well plates in RPMI 1640 medium (Gibco, #22400097) with 10% heat-inactivated FBS and 1x antibiotic-antimycotic (Gibco, #15240062) and incubated at 37°C for 24 hours. Cells were treated with serial dilutions of STING agonist compounds described herein (compounds 28, 55, 65, and comparative #1). After 72 hours, cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, #G7573) according to the manufacturer's instructions. Signals were detected using an EnVision Xcite multilabel reader, and data were analyzed using GraphPad Prism 8 software.

[0586] To confirm the effect of STING agonist compounds on cytotoxicity in normal cells, PBMCs were treated with STING agonist compounds for 3 days and the percentage of cell death was measured. The 50% cytotoxic concentration (CC) in Table 9 was used. 50 As shown in the CC values, all STING agonist compounds exhibited higher CC values ​​compared to control #1. 50 value, which indicated lower cytotoxicity in normal immune cells.

[0587] [Table 9]

[0588] CD34 + Hematopoietic stem cells (HSCs) were purchased from STEMCELL™ (# 70002.3). Cells (2 x 10 per well) 4Cells (4 x 10 per well) were cultured in StemSpan™ SFEM II medium supplemented with StemSpan™ CD34+ Expansion Supplement (#02691) in 6-well plates at 37°C for 7 days. On day 3 or 4, an equal volume of fresh complete medium was added to the cell culture. On day 7, cells (4 x 10 per well) were cultured in StemSpan™ SFEM II medium supplemented with StemSpan™ CD34+ Expansion Supplement (#02691) at 37°C for 7 days. On day 3 or 4, an equal volume of fresh complete medium was added to the cell culture. 4 The cells were seeded onto a 96-well white plate and left to stand under the same conditions for 24 hours.

[0589] To confirm the effect of the STING agonist compounds described herein on the cytotoxicity of normal cells, HSCs were treated with serial dilutions of the STING agonist compounds described herein (compounds 28, 55, 65, and comparative #1). After 72 hours, cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, # G7573) according to the manufacturer's instructions. Signals were detected using an EnVision Xcite multilabel reader, and data were analyzed using GraphPad Prism 8 software. The 50% cytotoxic concentration (CC) in Table 10 was used. 50 As shown in the CC values, all STING agonist compounds exhibited higher CC values ​​compared to control #1. 50 values, which indicated lower cytotoxicity in HSCs.

[0590] [Table 10]

[0591] Experimental Example 4: In vivo efficacy in a syngeneic mouse model Six-week-old female BALB / c mice (KOTECH, Korea) were used for all studies completed under the approval of the Institutional Animal Care and Use Committee (IACUC) of Legochembio Science. CT26 or 4T-1 cells (American Type Culture Collection (ATCC), #CRL-2638, #CRL-2539) were maintained at 37°C and 5% CO2 in RPMI 1640 medium (Gibco, #22400097) supplemented with 10% heat-inactivated FBS and 1x antibiotic-antimycotic (Gibco, #15240062). Mycoplasma-negative cells were used for all experiments, and mycoplasma testing was performed regularly using the e-Myco™ VALiD Mycoplasma PCR Detection Kit (iNtRON biotechnology, #25239). CT26 cells (2x10) in PBS were cultured at 37°C and 5% CO2. 5 cells / mouse) or 4T-1 cells (5 × 10 5 Cells (cells / mouse) were implanted subcutaneously into the shaved right flank. Tumor volume was measured twice weekly and calculated using the formula 0.5 × (length) × (width). 2 was calculated according to

[0592] A syngeneic system was used to evaluate the ability of STING agonist compounds to induce immune responses and promote antitumor immune responses. To determine the in vivo efficacy of a STING agonist compound (compound 55) in the CT26 syngeneic mouse model, tumors with tumor volumes between 50 and 100 mm were cultured. 3 The compound was administered at 1.5 mg / kg on days 0, 4, and 7. To determine the in vivo efficacy of the STING agonist compound (compound 55) in the 4T-1 syngeneic mouse model, tumors with tumor volumes between 50 and 100 mm were treated. 3 The compound was administered at 1.5 mg / kg on days 0, 4, and 7.

[0593] In both the CT26 and 4T-1 syngeneic models, STING agonist compounds significantly controlled tumor growth (Figures 1 and 2).

[0594] Consistent with their in vitro efficacy, the STING agonist compounds described herein demonstrated excellent in vivo efficacy in various syngeneic mouse models.

[0595] Taken together, the STING agonist compounds described herein possess a highly competitive profile of high antitumor activity and low toxicity.

[0596] Incorporation by Reference All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0597] equivalent While specific embodiments of the present disclosure have been discussed, the foregoing specification is illustrative and not limiting. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and by reference to the specification, along with such variations.

Claims

1. Structural formula 1: 【Chemistry 1】 [In the formula, W 1 and W 2 are each independently selected from alkyl, amino, and amido; each n is independently 0, 1, 2, or 3; Z is selected from a single bond, alkylene, alkenylene, and alkynylene; A and B are each independently a 5-membered heteroaryl; Xa and Xb each independently represent CH 2 , NH, O, and S; Ra is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl; Rb is represented by structural formula 2 【Chemistry 2】 (In the formula, L 1 is heteroalkenylene, alkenylene, alkynylene, cycloalkylene, heteroalkenylene, heteroalkynylene, arylene, heteroarylene, *Y 1 -OY 2 ** , and *Y 3 -NR y -Y 4 ** is selected from L 2 is NR L C(=NH)NH 2 , C(=NH)NH 2 , alkyl, amino, heteroaryl, heterocyclyl, and aryl; Y 1 and Y 3 are each independently selected from alkylene, alkenylene, and alkynylene; Y 2 and Y 4 are each independently selected from a single bond, alkylene, alkenylene, and heterocyclylene; * is the point of attachment to Xb; ** is L 2 is the connection point to R L is selected from H, alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl; R y is H, alkyl, or C(=NH)NH 2 (selected from is a group represented by or a pharmaceutically acceptable salt thereof.

2. L 1 When L is substituted or unsubstituted alkylene, 2 But NR L C(=NH)NH 2 , heteroaryl, substituted heterocyclyl, and aryl.

3. L 2 but, # OC(O)NR 5 -L 4 -NR 6 , # OC(O)-L 4 -NR 6 , or # OC(O)NR 5 -L 4 -(heterocyclylene) (In the formula, # is L 1 is the connection point to L 4 is alkylene or arylalkylene, R 5 and R 6 are each independently selected from H, alkyl, and dialkylaminoalkyl.

2. The compound of claim 1, comprising:

4. W 1 and W 2 However, independently, C 1～5 Alkyl, NH 2 , and C(=O)NH 2 is selected from The compound of any one of claims 1 to 3, wherein each n is 1, 2, or 3.

5. W 1 and W 2 However, independently, C 1～3 Alkyl, NH 2 , and C(=O)NH 2 5. The compound of claim 4, wherein n is selected from the group consisting of:

6. W 1 and W 2 are C(=O)NH 2 6. The compound of claim 5, wherein:

7. The compound according to any one of claims 1 to 4, wherein n is 1.

8. A compound according to any one of claims 1 to 7, wherein Z is alkenylene, for example ethenylene.

9. A and B are each independently a halogen, OH, CN, NO 2 , amines, amides, amidines, -(CH 2 ) p NR'R", C 1～10 Alkyl, C 2～10 Alkenyl, and C 2～10 Alkynyl (In the formula, each p is independently selected from 0, 1, 2, or 3; R' and R" are each independently hydrogen, C 1～10 Alkyl, C 2～10 Alkenyl, and C 2～10 alkynyl) 9. The compound of any one of claims 1 to 8, which is a 5-membered heteroaryl optionally substituted with 1 to 4 groups independently selected from:

10. The compound of any one of claims 1 to 9, wherein A and B are each independently a substituted or unsubstituted pyrazole.

11. A and B are each independently two C 1～3 11. The compound of claim 10, which is an alkyl-substituted pyrazole.

12. 1. The compound of formula 1f: 【Transformation 3】 12. The compound of any one of claims 1 to 11, which is represented by: or a pharmaceutically acceptable salt thereof.

13. The compound has the structural formula 1g: 【Chemistry 4】 13. The compound of any one of claims 1 to 12, which is represented by: or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 13, wherein Xa is O.

15. The compound according to any one of claims 1 to 14, wherein Xb is O.

16. Ra is C 1～6 Alkyl, C 2～6 Alkenyl, and C 2～6 The compound of any one of claims 1 to 15, selected from alkynyl.

17. Ra is C 1～6 17. The compound of claim 16, wherein the compound is alkyl.

18. Ra is unsubstituted C 1～3 18. The compound of claim 17, wherein the compound is alkyl.

19. 19. The compound of claim 18, wherein Ra is methyl.

20. 20. The compound of claim 19, wherein Xa is O and Ra is methyl.

21. Ra is NR'R" (wherein R' and R" are each independently hydrogen, C 1～10 Alkyl, C 2～10 Alkenyl, and C 2～10 C substituted with 1～6 21. The compound of claim 20, wherein the compound is alkyl.

22. L 1 But C 2～6 Alkenylene or C 2～6 The compound of any one of claims 1 to 21, which is an alkynylene.

23. L 1 C 2～6 23. The compound of claim 22 which is alkenylene.

24. L 1 is unsubstituted C 4 24. The compound of claim 23 which is alkenylene.

25. 1. The compound of formula 1h: 【Transformation 5】 25. The compound of any one of claims 1 to 24, which is represented by: or a pharmaceutically acceptable salt thereof.

26. 1. The compound of formula 1i: 【Transformation 6】 25. The compound of any one of claims 1 to 24, which is represented by: or a pharmaceutically acceptable salt thereof.

27. L 1 C 2～6 The compound of any one of claims 1 to 22, which is an alkynylene.

28. 1. The compound of formula 1j: 【Transformation 7】 28. The compound of claim 27, which is represented by: or a pharmaceutically acceptable salt thereof.

29. L 1 が、Construction 2a、Construction 2b、Construction 2c、Also はConstruction 2d: 【Transformation 8】 (In the formula, L 11 , L 12 , L 13 , and L 14 are each independently a single bond or C 1～20 is alkylene, R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are each independently hydrogen, OH, CN, NO 2 , amines, amides, amidines, carboxylic acids or their salts, ethers, esters, sulfones, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 2～10 Alkenyl, and substituted or unsubstituted C 2～10 alkynyl) The compound according to any one of claims 1 to 21, wherein the compound is a group represented by

30. L 1 But, Y 1 -OY 2 ** or Y 3 -NR y -Y 4 ** The compound according to any one of claims 1 to 21,

31. L 1 Y 1 -OY 2 ** 31. The compound of claim 30, wherein:

32. Y 1 C 2～6 32. The compound of claim 31 which is alkenylene.

33. Y 1 C 4 33. The compound of claim 32 which is an unsubstituted alkenylene.

34. Y 1 but, 【Chemistry 9】 32. The compound of claim 31 , selected from:

35. Y 2 The compound according to any one of claims 30 to 34, wherein is a single bond.

36. L 1 Y 3 -NR y -Y 4 ** 31. The compound of claim 30, wherein:

37. Y 3 C 2～6 37. The compound of claim 36 which is alkenylene.

38. Y 3 C 4 38. The compound of claim 37 which is an unsubstituted alkenylene.

39. Y 3 but, 【Chemistry 10】 37. The compound of claim 36, selected from:

40. Y 4 C 1～6 40. The compound of any one of claims 36 to 39, which is alkylene.

41. Y 4 But C 1～5 Alkyl, C 1～5 Haloalkyl, halogen, OH, oxo, -OR', -NR'R", -OCOR', -CO 2 R', -SOR', -SO 2 R', -CONR'R", -SO 2 NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO 2 R", and -NR'SO 2 R" (In the formula, R' and R" are each independently hydrogen, C 1～10 Alkyl, C 2～10 Alkenyl, and C 2～10 alkynyl) C optionally substituted with 1 to 3 substituents selected from 1～3 41. The compound of claim 40, which is alkylene.

42. Y 4 is unsubstituted C 1～3 41. The compound of claim 40, which is alkylene.

43. R y H, unsubstituted C 1～3 Alkyl, or C(=NH)NH 2 43. The compound according to any one of claims 36 to 42, selected from:

44. R y 44. The compound of claim 43, wherein is H.

45. R y is methyl or C(=NH)NH 2 44. The compound of claim 43, wherein:

46. L 2 But NR L C(=NH)NH 2 , 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl, and C 6～12 46. ​​The compound of any one of claims 1 to 45, wherein the compound is selected from aryl.

47. L 2 NR L C(=NH)NH 2 47. The compound of claim 46, wherein:

48. R L 48. The compound of claim 47, wherein is H.

49. L 2 is 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, and C 6 47. The compound of claim 46, wherein the aryl is selected from:

50. L 2 But C 1～5 Alkyl, C 1～5 Haloalkyl, halogen, OH, C(=NH)NH 2 , -OP(O)(R'R") 2 , -OR', -NR'R", -OCOR', -CO 2 R', -SOR', -SO 2 R', -CONR'R", -SO 2 NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO 2 R", and -NR'SO 2 R" (In the formula, R' and R" are each independently hydrogen, C 1～10 Alkyl, C 2～10 Alkenyl, and C 2～10 alkynyl) 50. The compound of claim 49, which is a 5- to 7-membered heteroaryl optionally substituted independently with 1 to 3 substituents selected from:

51. L 2 50. The compound of claim 49, wherein is unsubstituted 5-7 membered heterocyclyl.

52. L 2 has the following structural formula: 【Chemistry 11】 【change】 47. The compound of any one of claims 1 to 46, which is a moiety represented by one of:

53. L 1 But, Y 3 -NR y -Y 4 ** and NR y -Y 4 -L 2 has the following structural formula: 【Chemistry 12】 【change】 47. The compound of any one of claims 1 to 30 and 36 to 46, which is a moiety represented by one of:

54. L 1 But, Y 1 -OY 2 ** and OY 2 -L 2 has the following structural formula: 【Chemistry 13】 36. The compound of any one of claims 1 to 35, which is a moiety represented by one of:

55. A and B each independently represent the following structural formula: 【Chemistry 14】 【change】 [In the formula, R a and R b are each independently hydrogen, C 1～5 Alkyl, C 1～5 Haloalkyl, halogen, OH, -OP(O)(R'R") 2 , -OR', -NR'R", -OCOR', -CO 2 R', -SOR', -SO 2 R', -CONR'R", -SO 2 NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO 2 R", and -NR'SO 2 R" (In the formula, R' and R" are each independently hydrogen, C 1～10 Alkyl, C 2～10 Alkenyl, and C 2～10 alkynyl) Select from 55. The compound of any one of claims 1 to 54, represented by one of:

56. The compound has the structural formula (Ic*): 【Chemistry 15】 2. The compound of claim 1, represented by:

57. The compound has the structural formula (Id*): 【Chemistry 16】 2. The compound of claim 1, represented by:

58. L 2 However, peptides, sugars, -OCH 2 CH 2 60. The compound of any one of claims 1 to 45, 56, and 57, comprising one or more moieties selected from a - moiety, and a reactive group, or a combination thereof.

59. L 2 59. The compound of claim 58, wherein comprises a sugar.

60. The sugar has the following structural formula: 【Chemistry 17】 (In the formula, R 1 is H, alkyl, CH 2 OR 1A , or CO 2 R 1B and Each R 2 are independently H or a hydroxyl protecting group; R 1A is H or a hydroxyl protecting group, R 1B is H or a carboxyl protecting group) 60. The compound of claim 59, represented by one of:

61. L 2 59. The compound of claim 58, wherein comprises a peptide.

62. 62. The compound of claim 61, wherein the peptide comprises at least one hydrophilic amino acid.

63. 63. The compound of claim 61 or 62, wherein the peptide comprises an amino acid having a side chain with a moiety (e.g., an amine, guanidine, or carboxyl moiety) that carries a charge at neutral pH in aqueous solution.

64. 64. The compound of any one of claims 61 to 63, wherein the peptide comprises amino acids selected from alanine, aspartic acid, asparagine, glutamic acid, glutamine, glycine, lysine, ornithine, proline, serine, and threonine.

65. L 2 However, 1 to 20 -OCH 2 CH 2 65. The compound of any one of claims 1 to 45 and 56 to 64, comprising a - moiety.

66. L 2 However, 2 to 6 -OCH 2 CH 2 66. The compound of claim 65, comprising a - moiety.

67. L 2 has structural formula (II*): [Chemistry 18] (In the formula, Y is - # NHC(O)- or- # (CH 2 ) t NHC(O)-, R 3 is -CH 2 OR 3A or -CO 2 R 3B and Each R 4 are independently H or a hydroxyl protecting group; R 3A is H or a hydroxyl protecting group, R 3B is H or a carboxyl protecting group, t is 1, 2, or 3, preferably 1; # indicates point of attachment to the phenyl ring) 67. The compound of any one of claims 1 to 45 and 56 to 66, comprising a moiety represented by:

68. L 2 However, the structural formula (III*): 【Chemistry 19】 (In the formula, Y is - # NHC(O)-,- # C(O)NH-, - # (CH 2 ) t NHC(O)—, and —COOH; ## is L 1 (indicating the attachment point to 67. The compound of any one of claims 1 to 45 and 56 to 66, comprising a moiety represented by:

69. L 2 has structural formula (IIa): 【Chemistry 20】 (In the formula, L 5 is the linker, RG is a reactive group 68. The compound of claim 67, comprising a moiety represented by:

70. L 2 has structural formula (IIIa): 【Chemistry 21】 (In the formula, L 5 is the linker, RG is a reactive group, ## is L 1 (indicating the attachment point to 69. The compound of claim 68, comprising a moiety represented by:

71. Y is- # The compound according to any one of claims 67 to 70, which is NHC(O)-.

72. Y is- # 71. The compound of claim 68 or 70, which is C(O)NH—.

73. L 5 But 3 to 5 -OCH 2 CH 2 73. The compound of any one of claims 67 to 72, comprising a - moiety.

74. L 5 has the structural formula Va, Vb, Vc, Vd, or Ve: 【Chemistry 22】 (In the formula, L 8 is a single bond or C 1～30 is alkylene, R 11 is H or C 1～10 alkyl) 74. The compound of any one of claims 67 to 73, comprising a unit represented by:

75. RG is a single bond, OH, Hal, or -NR 12 R 13 , -COOH, -C(O)R 14 , -SO 3 R 15 , SH, -NHOH, -NH 2 NH 2 , -CH(CH 2 COOH) 2 , -C(O)C≡CR 16 , N 3 , -OP(O)(OH) 2 , alkyl, alkenyl, alkynyl, heterocyclyl, C 8 ~C 10 Cycloalkynyl, sugar, isocyanide, isothiocyanide, 2-pyridyl disulfide, -NHC(O)CH 2 -Hal, maleimide, tosylate, 【Chemistry 23】 is selected from Hal is a halogen; R 12 , R 13 , R 14 , R 15 , and R 16 is each independently H or alkyl.

76. RG has the following structural formula: 【Chemistry 24】 76. The compound of claim 75, represented by:

77. RG has the following structural formula: 【Chemistry 25】 76. The compound of claim 75, represented by:

78. L 2 but, ## OC(O)NR 5* -L 4* -NR 6* -, ## -OC(O)-L 4* -NR 6* -or ## -OC(O)NR 5* -L 4* -(heterocyclylene) (In the formula, ## is L 1 is the connection point to L 4* is alkylene or arylalkylene, R 5* and R 6* are independently selected from H, alkyl a linker L 2* The compound of any one of claims 1 to 45 and 56 to 77, further comprising:

79. The compound has the following structural formula: 【Chemistry 26】 【change】 【change】 【change】 【change】 【change】 【change】 10. The compound of claim 1, wherein the compound is represented by one of:

80. The compound has the following structural formula: 【Chemistry 27】 【change】 【change】 【change】 【change】 【change】 【change】 10. The compound of claim 1, wherein the compound is represented by one of:

81. A pharmaceutical composition comprising a compound according to any one of claims 1 to 80 and a pharmaceutically acceptable excipient.

82. 81. A pharmaceutical composition comprising a compound according to any one of claims 1 to 80 and a pharmaceutically acceptable excipient for use in the prevention or treatment of a disease mediated by the stimulator of interferon genes (STING).

83. 83. The pharmaceutical composition for use according to claim 82, wherein the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease.

84. 83. The pharmaceutical composition of claim 82, wherein the disease is a cancer selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

85. 82. A method for preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 80 or a pharmaceutical composition of claim 81.

86. 86. The method of claim 85, wherein the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease.

87. 86. The method of claim 85, wherein the STING-mediated disease is cancer or an infectious disease.

88. 86. The method of claim 85, wherein the STING-mediated disease is cancer.

89. 89. The method of claim 88, wherein the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

90. 82. Use of a compound according to any one of claims 1 to 80 or a pharmaceutical composition according to claim 81 for the manufacture of a medicament for treating or preventing a disease mediated by Stimulator of Interferon Genes (STING) in a subject in need thereof.

91. The use of claim 90, wherein the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease.

92. The use of claim 90, wherein the STING-mediated disease is cancer or an infectious disease.

93. The use of claim 90, wherein the STING-mediated disease is cancer.

94. 94. The use of claim 93, wherein the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

95. A compound according to any one of claims 1 to 80 or a pharmaceutical composition according to claim 81 for use in the treatment of a disease mediated by the stimulator of interferon genes (STING).

96. The compound of claim 95, wherein the STING-mediated disease is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease.

97. The compound of claim 95, wherein the STING-mediated disease is cancer or an infectious disease.

98. 96. The compound of claim 95, wherein the STING-mediated disease is cancer.

99. 99. The compound of claim 98, wherein the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

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