Heterocyclic compounds as STING agonists

Abstract

The present disclosure relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an interferon gene stimulating factor (STING) agonist, a pharmaceutical composition comprising the same, and related methods and uses for treating or preventing diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Korean Patent Application No. 10-2022-0147897, filed on November 8, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] Stimulator of interferon genes (STING) is a low molecular weight protein that is currently attracting much 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 IFNs and other inflammatory cytokines, triggering 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). In addition, STING activates signal transducer and activator of transcription 6 (STAT6) and 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 trigger the expression of cytokines, causing T cell-mediated innate immune responses, thereby inhibiting cancer cell growth. However, systemic delivery of STING agonists can cause widespread inflammation.

[0004] Various STING agonists have been tested in preclinical and clinical settings. These agonists are being developed through various strategies, including CDN (cyclic dinucleotide) compounds (ADU-S100, BI-STING, GSK532, JNJ-4412, SB11285, MK-1454, TAK676, etc.), bacterial vectors (SYNB1891, STACT-TREX-1), non-cyclic dinucleotide (CDN) compounds (ALG-031048, JNJ-6196, MK-2118, MSA-1, MSA-2, CRD-5500, etc.), nanovaccines (PC7ANP, cGAMP-NP, etc.), and ADCs (XMT-2056, TAK500, etc.).

[0005] The most widely used preclinical compound, DMXAA (a vascular disruptor), was clinically used in combination with paclitaxel and carboplatin, but its efficacy was demonstrated to be lacking in Phase 3. Furthermore, ADU-S100, the first clinically used STING agonist, was discontinued in 2020.

[0006] Examples of STING agonists are disclosed in, for example, WO 2021 / 014365 (macrocyclic compounds as STING agonists), and US 2021 / 0139473 (heterocyclic amide compounds as protein modulators), US 2022 / 0073509 (heterocyclic compounds as STING activators), and KR 2022-0024467 (heterocyclic STING agonists), each of which is incorporated herein by reference in its entirety.

[0007] However, existing STING agonists appear to exhibit only limited bioavailability and require local administration to tumors due to overactivation of cytokine expression, or must be used in combination with other compounds. Therefore, there remains a need to develop therapeutically effective STING agonists. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 Figure 2 shows the tumor volume (mm) after treatment with different doses of STING agonist compound (Compound 55) in the CT26 syngeneic mouse model. 3 ) picture.

[0009] Figure 2 Figure 2 shows the tumor volume (mm) after treatment with different doses of a STING agonist compound (Compound 55) in a 4T-1 syngeneic mouse model. 3 ) picture. Summary of the Invention

[0010] In some embodiments, the present disclosure relates to a compound represented by Structural Formula 1, and pharmaceutically acceptable salts thereof:

[0011] Formula 1

[0012]

[0013] in:

[0014] W1 and W2 are each independently selected from alkyl, amino and amide groups,

[0015] Each n is independently 0, 1, 2 or 3,

[0016] Z is selected from a single bond, an alkylene group, an alkenylene group, and an alkynylene group,

[0017] A and B are each independently a 5-membered heteroaryl group,

[0018] Xa and Xb are each independently selected from CH2, NH, O and S,

[0019] R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl,

[0020] Rb is a group represented by structural formula 2,

[0021] Formula 2

[0022]

[0023] in:

[0024] L1 is selected from alkylene, alkenylene, alkynylene, heteroalkenylene, heteroalkynylene, heteroarylene, Y1-O-Y2 ** and Y3-NR y -Y4 ** ;

[0025] L2 is selected from NR L C(=NH)NH2, C(=NH)NH2, alkyl, heteroaryl, heterocyclyl, and aryl;

[0026] Y1 and Y3 are each independently selected from alkylene, alkenylene and alkynylene,

[0027] Y2 and Y4 are each independently selected from a single bond, an alkylene group, an alkenylene group and a heterocyclylene group,

[0028] * is the connection point with Xb,

[0029] ** is the connection point with L2,

[0030] R Lis selected from hydrogen, alkyl, heterocyclyl, aryl, heteroaryl and cycloalkyl, and

[0031] R y is selected from H, alkyl or C(=NH)NH2.

[0032] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0033] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for preventing or treating diseases mediated by stimulator of interferon genes (STING).

[0034] 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, comprising administering to the subject a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0035] In some embodiments, the present disclosure relates to the use of a compound of the present disclosure, such as 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 stimulator of interferon genes (STING)-mediated disease in a subject in need thereof.

[0036] In some embodiments, the present disclosure relates to a compound of the present disclosure, such as 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. DETAILED DESCRIPTION

[0037] In some embodiments, the present disclosure relates to a compound represented by Structural Formula 1, and pharmaceutically acceptable salts thereof:

[0038] Formula 1

[0039]

[0040] in:

[0041] W1 and W2 are each independently selected from alkyl, amino and amide groups,

[0042] Each n is independently 0, 1, 2 or 3,

[0043] Z is selected from a single bond, an alkylene group, an alkenylene group, and an alkynylene group,

[0044] A and B are each independently a 5-membered heteroaryl group,

[0045] Xa and Xb are each independently selected from CH2, NH, O and S,

[0046] R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl,

[0047] Rb is a group represented by structural formula 2,

[0048] Formula 2

[0049]

[0050] in:

[0051] L1 is selected from alkylene, alkenylene, alkynylene, heteroalkenylene, heteroalkynylene, heteroarylene, Y1-O-Y2 ** and Y3-NR y -Y4 ** ;

[0052] L2 is selected from NR L C(=NH)NH2, C(=NH)NH2, amino, alkyl, heteroaryl, heterocyclyl, and aryl;

[0053] Y1 and Y3 are each independently selected from alkylene, alkenylene and alkynylene,

[0054] Y2 and Y4 are each independently selected from a single bond, an alkylene group, an alkenylene group and a heterocyclylene group,

[0055] * is the connection point with Xb,

[0056] ** is the connection point with L2,

[0057] R L is selected from H, alkyl, heterocyclyl, aryl, heteroaryl and cycloalkyl, and

[0058] R y is selected from H, alkyl or C(=NH)NH2.

[0059] In some embodiments, if L1 is a substituted or unsubstituted alkylene, L2 is selected from NR L C(=NH)NH2, heteroaryl, substituted heterocyclyl, and aryl.

[0060] In some embodiments, W1 and W2 are each independently selected from C 1-5 alkyl, NH2 and C(=O)NH2, and each n is 1, 2 or 3. For example, W1 and W2 can be each independently selected from C 1-3alkyl, NH2 and C(=O)NH2, and n is 1. In certain preferred embodiments, W1 and W2 are each C(=O)NH2. In some embodiments, n is 1.

[0061] In some embodiments, the compound is represented by structural formula 1a, or a pharmaceutically acceptable salt thereof:

[0062] Formula 1a

[0063]

[0064] In some preferred embodiments, Z is an alkenylene group, such as an ethenylene group. For example, Z can be an unsubstituted C 2-6 Alkenylene, such as unsubstituted C 2-4 In certain embodiments, Z is selected from the group consisting of CH=CH, CH=CHCH2, CH2CH=CH, CH=CHCH2CH2, CH2CH2CH=CH, and CH2CH=CHCH2, preferably CH=CH.

[0065] In some embodiments, Z is selected from C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Each of the alkynylene groups is independently substituted by 1 to 3 groups selected from C 1-5 Alkyl, C 1-5 substituted with haloalkyl, halogen, OH, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

[0066] In some embodiments, the compound is represented by structural formula 1b, or a pharmaceutically acceptable salt thereof:

[0067] Formula 1b

[0068]

[0069] In some embodiments, A and B are each independently a 5-membered heteroaryl optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, amine, amide, amidine; -(CH2)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, and R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 For example, A and B can be independently selected from pyrazole, imidazole, oxazole, isoxazole, thiazole and isothiazole. In certain preferred embodiments, A and B are each pyrazole.

[0070] In some embodiments, A and B are each independently substituted or unsubstituted pyrazole. For example, in certain preferred embodiments, A and B are each substituted with 2 C 1-3 Alkyl-substituted pyrazoles.

[0071] In some embodiments, the compound is represented by structural formula 1c, or a pharmaceutically acceptable salt thereof:

[0072] Formula 1c

[0073]

[0074] In some embodiments, the compound is represented by structural formula 1d, or a pharmaceutically acceptable salt thereof:

[0075] Formula 1d

[0076]

[0077] In some embodiments, the compound is represented by structural formula 1e, or a pharmaceutically acceptable salt thereof:

[0078] Formula 1e

[0079]

[0080] In some embodiments, the compound is represented by structural formula 1f, or a pharmaceutically acceptable salt thereof:

[0081] Formula 1f

[0082]

[0083] In some embodiments, the compound is represented by structural formula 1g, or a pharmaceutically acceptable salt thereof:

[0084] Formula 1g

[0085]

[0086] In some embodiments, Xa is O.

[0087] In some embodiments, Xb is O. In some preferred embodiments, Xa and Xb are each O.

[0088] In some embodiments, Ra is selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 For example, in some embodiments, Ra is C 1-6 Alkyl, preferably C 1-3 In some embodiments, Ra is a C1 alkyl, a C2 alkyl, a C3 alkyl, a C4 alkyl, a C5 alkyl, or a C6 alkyl. For example, Ra can be 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 can be C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl or C6 alkenyl. For example, Ra can be C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl or C6 alkynyl. In some embodiments, Ra is C 1-6 Alkyl, which is optionally independently substituted by 1 to 3 groups selected from C 1-5 substituted with haloalkyl, halogen, -OR', -NR'R", NR'C(=NH)NH2, -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 For example, Ra can be C substituted by -NR'R". 1-6 Alkyl, preferably C3 alkyl substituted by NHCH3. In some embodiments, Ra is selected from -(alkylene)carboxylic acid, -(alkylene)guanidine, -(alkylene)NHC(O)CH2guanidine and -(alkylene)O(alkylene)guanidine.

[0089] In some embodiments, L1 is C 2-6 Alkenylene or C 2-6 In certain preferred embodiments, L1 is C 2-6 Alkenylene, such as C 2-4 For example, L1 can be an unsubstituted C4 alkenylene. In certain preferred embodiments, L1 is C 2-6 Alkynylidene, such as C 2-4Alkyne, such as C4 alkynyl. For example, L1 can be an unsubstituted C4 alkynyl.

[0090] In some embodiments, the compound is represented by Structural Formula 1h or Structural Formula 1i, or a pharmaceutically acceptable salt thereof:

[0091] Formula 1h

[0092]

[0093] In some embodiments, the compound is represented by structural formula 1i, or a pharmaceutically acceptable salt thereof:

[0094] Formula 1i

[0095]

[0096] In some embodiments, the compound is represented by structural formula 1j, or a pharmaceutically acceptable salt thereof:

[0097] Formula 1j

[0098]

[0099] In some embodiments, L1 is a group represented by Structure 2a, Structure 2b, Structure 2c, or Structure 2d:

[0100] Formula 2a

[0101]

[0102] Formula 2b

[0103]

[0104] Formula 2c

[0105]

[0106] Formula 2d

[0107]

[0108] in,

[0109] L 11 、L 12 、L 13 and L 14 Each is independently a single bond or C 1-20 Alkylene,

[0110] and

[0111] R 21 、R 22 、R 23、R 24 、R 25 and R 26 Each is independently selected from hydrogen, OH, CN, NO2, amine, amide, amidine, carboxylic acid or its salt, 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 can be a group represented by structural formula 2b. For example, L1 can be a group represented by structural formula 2c. In some preferred embodiments, L1 is a group represented by structural formula 2a or 2b. In some specific preferred embodiments, L1 is a group represented by structural formula 2a.

[0112] In some embodiments, L1 is Y1-O-Y2 ** or Y3-NR y -Y4 ** , where ** is the point of connection to L2. For example, L1 can be Y1-O-Y2 ** Alternatively, L1 can be Y3-NR y -Y4 ** .

[0113] In some embodiments, Y1 is selected from C 2-6 Alkenylene and C 2-6 In some embodiments, Y1 is C 2-6 Alkenylene, for example unsubstituted C4 alkenylene.

[0114] In some embodiments, Y1 is selected from For example, Y1 can be In some preferred embodiments, Y1 is In some preferred embodiments, Y1 is

[0115] In some embodiments, Y2 is selected from a single bond, C 1-6 Alkylene, C 2-6 For example, Y2 can be a single bond.

[0116] In some embodiments, Y3 is selected from C 2-6 Alkenylene and C 2-6 In some embodiments, Y3 is C 2-6 Alkenylene, for example unsubstituted C4 alkenylene.

[0117] In some embodiments, Y3 is selected from For example, Y3 can be In some preferred embodiments, Y3 is In some preferred embodiments, Y3 is

[0118] In some embodiments, Y4 is selected from a single bond, C 1-6 Alkylene, C 2-6 In some embodiments, Y4 is C 1-6 Alkylene, such as C 2-4 In some preferred embodiments, Y4 is C 1-3 Alkylene, preferably C 1-3 Alkylene, which is optionally independently substituted by 1 to 3 groups selected from C 1-5 Alkyl, C 1-5 substituted with haloalkyl, halogen, OH, oxo, -OR', -NR'R", -OCOR', -C02R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 In some preferred embodiments, Y4 is an unsubstituted C 1-3 Alkylene.

[0119] In some embodiments, R y selected from H, unsubstituted C 1-3 In some preferred embodiments, R y It is H. Or, R y It may be methyl or C(=NH)NH2.

[0120] In some embodiments, L2 is NR L C(=NH)NH2. In some preferred embodiments, R L is hydrogen. Alternatively, R L Can be C 1-3 The alkyl group is preferably a methyl group.

[0121] In some embodiments, L2 is selected from 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, and C6 aryl. For example, L2 can be a 5- to 7-membered heteroaryl group, which is optionally independently substituted by 1 to 3 members selected from C 1-5 Alkyl, C 1-5substituted with a substituent selected from the group consisting of haloalkyl, halogen, OH, C(═NH)NH2, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 In some embodiments, L2 is C6 aryl, which is optionally independently substituted by 1 to 3 groups selected from C 1-5 Alkyl, halogen, C 1-5 substituted with a substituent selected from the group consisting of haloalkyl, OH, C(═NH)NH2, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 In some preferred embodiments, L2 is a 5- to 7-membered heterocyclic group, which is optionally independently substituted by 1 to 3 members selected from C 1-5 Alkyl, C 1-5 substituted with a substituent selected from the group consisting of haloalkyl, halogen, oxo, OH, C(=NH)NH2, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl is preferably a 5- to 7-membered heterocyclyl substituted with a substituent selected from oxo, NH2, CNNO2, OH, and C(=NH)NH2. In certain preferred embodiments, L2 is an unsubstituted 5- to 7-membered heterocyclyl.

[0122] In some embodiments, L2 comprises # OC(O)NR 5 -L 4 -NR 6 、 # OC(O)-L 4 -NR 6or # OC(O)NR 5 -L 4 -(heterocyclylene), where # is the same as L 1 The connection point, L 4 is an alkylene group or an arylenealkyl group, and R 5 and R 6 Each is independently selected from H, alkyl and dialkylaminoalkyl.

[0123] In some embodiments, L2 is a moiety represented by one of the following structural formulas:

[0124]

[0125]

[0126] For example, L2 may be a moiety represented by one of the following structural formulas:

[0127] In some preferred embodiments, L2 is a moiety represented by one of the following structural formulas:

[0128] Preferably, L2 is a moiety represented by one of the following structural formulas:

[0129] For example

[0130] In some embodiments, L1 is Y3-NR y -Y4 ** , and NR y -Y4-L2 is a moiety represented by one of the following structural formulas:

[0131]

[0132]

[0133] In some embodiments, L1 is Y1-O-Y2 ** , and O-Y2-L2 is a moiety represented by one of the following structural formulas:

[0134]

[0135]

[0136] In some embodiments, A and B are each independently represented by one of the following structural formulas:

[0137] where R a and R b are each independently selected from hydrogen, C 1-5 Alkyl, C 1-5 haloalkyl, halogen, OH, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 For example, A and B can each independently be represented by one of the following structural formulas:

[0138] In some preferred embodiments, A and B are each represented by the following structural formula:

[0139]

[0140] In some embodiments, the compound is represented by structural formula 1k, or a pharmaceutically acceptable salt thereof:

[0141] Formula 1k

[0142]

[0143] in:

[0144] Ra is CH3 or (CH2)3NCH3, and

[0145] B is a moiety represented by one of the following structural formulas: For example, the compound can be represented by structural formula 1k, and L1 is selected from a moiety represented by one of the following structural formulas: Preferably, L1 is a moiety represented by one of the following structural formulas: For example, the compound is represented by structural formula 1k, and B is a moiety represented by the following structural formula: In some preferred embodiments, the compound can be represented by structural formula 1k, and B is a moiety represented by the following structural formula: In some preferred embodiments, the compound is represented by Structural Formula 1k, and L2 is a moiety represented by one of the following structural formulas:

[0146] Preferably, L2 is a moiety represented by one of the following structural formulas:

[0147] and preferably

[0148] In some embodiments, the compound is represented by structural formula (Ic*):

[0149]

[0150] In some embodiments, the compound is represented by structural formula (Id*):

[0151]

[0152] In some embodiments, L 2 It comprises one or more moieties selected from the group consisting of a peptide, a carbohydrate, an -OCH2CH2- moiety and a reactive group or a combination thereof.

[0153] In some embodiments, L 2 Contains carbohydrates. In some embodiments, L 2 In some embodiments, L 2 Contains two or more monosaccharides.

[0154] In some embodiments, the carbohydrate is represented by one of the following structural formulas:

[0155]

[0156] in

[0157] R 1 H, alkyl, CH2OR 1A or CO2R 1B ;

[0158] Each R 2 are independently H or a hydroxy protecting group;

[0159] R 1A is H or a hydroxy protecting group; and

[0160] R 1B Is H or a carboxyl protecting group. In some preferred embodiments, the carbohydrate is represented by the following structural formula:

[0161]

[0162] In some embodiments, R 1 It 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 It’s H.

[0163] In some embodiments, L 2 In some embodiments, L 2 is a peptide. For example, in some embodiments, L 2 For example, in some embodiments, L 2 It is a dipeptide.

[0164] 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 moiety (e.g., an amine, guanidine, or carboxyl moiety) that is charged in aqueous solution at neutral pH. 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.

[0165] 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.

[0166] In some embodiments, L 2 Contains a moiety represented by structural formula (II*):

[0167]

[0168] in

[0169] Y is - # NHC(O)-or- # (CH2) t NHC(O)-,

[0170] R 3 Yes-CH2OR 3A or -CO2R 3B ;

[0171] Each R 4 are independently H or a hydroxy protecting group;

[0172] R 3A is H or a hydroxyl protecting group;

[0173] R 3B is H or a carboxyl protecting group;

[0174] t is 1, 2 or 3, preferably 1; and

[0175] # indicates the point of attachment to the phenyl ring.

[0176] In some embodiments, L2 Contains a moiety represented by structural formula (III*):

[0177]

[0178] in

[0179] Y is *- # NHC(O)-、- # C(O)NH-、- # (CH2) t NHC(O)- and -COOH, and

[0180] ## indicates that the 1 connection point.

[0181] 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-.

[0182] In some embodiments, R 3 Yes-CH2OR 3A In some embodiments, R 3A It’s H.

[0183] In some embodiments, R 3 Yes-COOR 3B In some embodiments, R 3B It’s H.

[0184] In some embodiments, L 2 Contains a moiety represented by structural formula (IIa*):

[0185]

[0186] in

[0187] L 5 is a connector, and

[0188] RG is a reactive group.

[0189] In some embodiments, L 2 It is a moiety represented by structural formula (IIa*).

[0190] In some embodiments, L 2 Contains a moiety represented by structural formula (IIIa*):

[0191]

[0192] in

[0193] L 5 is a connector, and

[0194] RG is a reactive group, and

[0195] ## indicates that the 1 connection point.

[0196] In some embodiments, L 2 is a moiety represented by the structural formula (IIIa*):

[0197] In some embodiments, L 5 Containing units represented by the structural formula Va, Vb, Vc, Vd or Ve:

[0198]

[0199] in

[0200] L 8 Is a single bond or C 1-30 an alkylene group; and

[0201] R 11 Is H or C 1-10 alkyl.

[0202] In some embodiments, L 5 Contains a unit represented by the structural formula Va, Vb or Vc.

[0203] In some embodiments, L 8 is a single bond. Alternatively, in some embodiments, L 8 It is C 1-30 Alkylene.

[0204] In some embodiments, R 11 is H. Alternatively, in some embodiments, R 11 It is C 1-10 For example, in certain embodiments, R 11 It's methyl.

[0205] RG can be any suitable reactive group such that an additional moiety having a complementary reactive group can be coupled to the compound represented by formula (I) by reacting with RG (e.g., replacing RG). In some embodiments, RG is selected from OH, Hal, -NR 12 R 13 、-COOH、-C(O)R 14 、-SO3R 15 , SH, -NHOH, -NH2NH2, -CH(CH2COOH)2, -C(O)C≡CR16 、N3、-OP(O)(OH)2、alkyl、alkenyl、alkynyl、heterocyclic、C8-C 10 Cycloalkynyl, sugars, isonitrile, isothiocyanate, 2-pyridyl disulfide, -NHC(O)CH2-Hal, maleimide, tosylate in

[0206] Hal is a halogen, and

[0207] R 12 、R 13 、R 14 、R 15 and R 16 Each is independently H or alkyl. For example, in some embodiments, RG is alkyl, such as C 1-3 The alkyl group is preferably a methyl group.

[0208] In some embodiments, RG is selected from OH, NR 12 R 13 , -COOH, -C≡CH, N3, -OP(O)(OH)2, -CH(CH2COOH)2, heterocyclic groups and sugars.

[0209] In some embodiments, RG is OH.

[0210] 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 It's me.

[0211] In some embodiments, RG is alkyl. In some preferred embodiments, RG is methyl.

[0212] In some embodiments, RG is represented by the following structural formula:

[0213]

[0214] In some embodiments, RG is a sugar. In some embodiments, the sugar is a glucuronide. In some preferred embodiments, the glucuronide is

[0215] In some embodiments, L2 further comprises a linker L 2* , the linker comprises ## OC(O)NR 5* -L 4* -NR 6* -、 ##-OC(O)-L 4* -NR 6* -or ## -OC(O)NR 5* -L 4* -(heterocyclylene), wherein:

[0216] ## is with L 1 The connection point,

[0217] L 4* is an alkylene group or an arylenealkyl group, and

[0218] R 5* and R 6* Independently selected from H, alkyl.

[0219] In some embodiments, the compound is represented by one of the following structural formulas:

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the compound is represented by one of the following structural formulae, or a pharmaceutically acceptable salt thereof:

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0236] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for preventing or treating diseases mediated by stimulator of interferon genes (STING).

[0237] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for preventing or treating a disease mediated by the stimulator of interferon genes (STING). In some embodiments, the disease mediated by STING is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disease, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease and allergic disease. For example, the disease mediated by STING 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.

[0238] In some embodiments, the present disclosure relates to a method for preventing or treating a disease mediated by the stimulator of interferon genes (STING) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the disease mediated by STING 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 disease mediated by STING 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.

[0239] In some embodiments, the present disclosure relates to the use of a compound of the present disclosure, such as 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 the stimulator of interferon genes (STING) in a subject in need thereof. In some embodiments, the disease mediated by STING 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 disease mediated by STING 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.

[0240] In some embodiments, the present disclosure relates to compounds of the present disclosure, such as compounds of Formula 1 or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure, for treating or preventing diseases mediated by stimulator of interferon genes (STING) in subjects in need thereof. In some embodiments, the disease mediated by STING is selected from cancer, bacterial infection, viral infection, fungal infection, immune-mediated disease, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease and allergic disease. For example, the disease mediated by STING 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.

[0241] Pharmaceutical composition

[0242] The compositions and methods of the present disclosure can be used to treat individuals in need. 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, it is preferred to administer a composition or compound in the form of a pharmaceutical composition, which comprises, for example, 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, such as water or physiologically buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils (such as olive oil) or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used to administer humans, especially for invasive routes of administration (i.e., avoiding routes of transmission or diffusion through epithelial barriers, such as injection or implantation), the aqueous solution is pyrogen-free, or substantially pyrogen-free. Excipients (e.g.) can be selected to achieve delayed release of the agent or selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules (including spray-on capsules and gelatin capsules), granules, lyophilized products for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be presented in a transdermal delivery system (eg, a skin patch).The composition can also be presented in a solution suitable for topical administration, such as an emulsion, cream, or ointment.

[0243] Pharmaceutically acceptable carriers may contain physiologically acceptable agents, for example, to stabilize compounds such as compounds of the present disclosure, increase their solubility, or increase their absorption. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or polydextrose; antioxidants such as ascorbic acid or glutathione; chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix, into which compounds of the present disclosure may be incorporated. Liposomes (e.g., comprising phospholipids or other lipids) are physiologically acceptable and metabolizable non-toxic carriers that are relatively simple to prepare and administer.

[0244] As used herein, the phrase "pharmaceutically acceptable" refers 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0245] As used herein, the phrase "pharmaceutically acceptable carrier" 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 injurious to the patient. Some examples of substances 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 waxes; (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 glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0246] The pharmaceutical composition (formulation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral administration (e.g., as a bolus solution in the form of an aqueous or non-aqueous solution or suspension, tablets, capsules (including sprinkler capsules and gelatin capsules), boluses, powders, granules, pastes applied to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (e.g., in the form of a patch applied to the skin); and topically (e.g., in the form of a cream, ointment, or spray applied to the skin). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions useful therefor may be found in U.S. Patent 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.

[0247] The formulation is preferably presented in unit dosage form and can be prepared by any method well known in the art of pharmaceutical preparation. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will depend on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with the carrier material to prepare a single dosage form will generally be the amount of compound that produces the therapeutic effect. This amount is generally (in percentage) in the range of about 1% to about 99% active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0248] Methods for preparing these formulations or compositions include the step of bringing into association the active compound (e.g., a compound of the present disclosure) with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining a compound of the present disclosure with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0249] The oral formulations of the present disclosure may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilizates, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or tablets (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or mouthwashes, etc., each containing a predetermined amount of the compound of the present disclosure as the active ingredient. The composition or compound may also be administered in the form of a bolus, a syrup, or a paste.

[0250] To prepare solid dosage forms for oral administration (capsules (including spray-on capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or calcium hydrogen 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, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) humectants, such as propylene glycol. (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (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. In the case of capsules (including spray-on capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also include a buffering agent. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycols.

[0251] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0252] Tablets and other solid dosage forms of pharmaceutical compositions (e.g., dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules) may optionally be scored or prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). They may also be formulated using, for example, hydroxypropylmethylcellulose in varying proportions to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres to provide slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent, in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium prior to use. These compositions may also optionally contain opacifying agents and may be compositions that release the active ingredient only or preferentially in a certain portion of the gastrointestinal tract in an optionally delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be microencapsulated, as appropriate, with one or more of the above-mentioned excipients.

[0253] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilizates for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0254] 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.

[0255] Suspensions, in addition to the active compounds, may contain suspending agents in the form of, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and astragalus, and mixtures thereof.

[0256] 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 any preservatives, buffers, or propellants that may be required.

[0257] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0258] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.

[0259] Transdermal patches have the additional advantage of providing control of the compound of the present disclosure to the delivery of 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 transdermal amount of the compound. The rate of this flow can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0260] As used herein, the phrase "parenteral administration" or "administered parenterally" means modes of administration other than enteral and topical administration, usually injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnical, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous 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.

[0261] 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 (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0262] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be necessary to include isotonic agents, such as sugars, sodium chloride, etc. in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0263] In some cases, in order to prolong the effect of a drug, it is necessary to slow down the absorption of a drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of a drug depends on its dissolution rate, which in turn can be determined by the size of the crystals and the crystalline form. Alternatively, parenteral drug forms can delay absorption by dissolving or suspending the drug in an oily vehicle.

[0264] Injectable depot formulations are made by forming a microencapsulation matrix of the target compound with a biodegradable polymer such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the properties of the specific polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0265] For use in the disclosed methods, the active compound can be administered directly or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) active ingredient and a pharmaceutically acceptable carrier.

[0266] The introduction method can also be provided by refillable or biodegradable devices. In recent years, a variety of slow-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, including biodegradable and non-degradable polymers, can be used to form inserts that continuously release compounds at specific target sites.

[0267] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as 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.

[0268] The selected dosage concentration will depend upon a variety of factors, including the activity of the specific compound or combination of compounds employed, or their esters, salts, or amides; the route of administration; the time of administration; the rate of excretion of the specific compound being employed; other drugs, compounds, and / or materials used in combination with the specific compound employed; the age, sex, weight, condition, general health, and prior medical history of the patient being treated; and like factors well known in the medical arts.

[0269] A physician or veterinarian of ordinary skill can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start administering a 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" means a concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary according to the subject's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's condition, the condition being treated, the stability of the compound, and another type of therapeutic agent administered together with the compound of the present invention, if necessary. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) "Harrison's Principles of Internal Medicine", 13th edition, 1814-1882, incorporated herein by reference).

[0270] In general, a suitable daily dose of the active compound used in the compositions and methods of the present disclosure will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. This effective dose will generally depend on the factors described above.

[0271] If desired, the effective daily dose of the active compound may optionally be administered in unit dosage form as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In certain embodiments of the present disclosure, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound will be administered once daily.

[0272] Patients receiving such treatment are any animal in need thereof, including primates, particularly humans; and other mammals, such as horses, cattle, pigs, sheep, cats, and dogs; and pets in general.

[0273] In certain embodiments, the compounds of the present disclosure may be administered alone or in combination with another type of therapeutic agent.

[0274] The present disclosure includes pharmaceutically acceptable salts of the compounds of the present disclosure for use in the compositions and methods of the present disclosure. In certain embodiments, the contemplated salts of the present disclosure include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, the salts encompassed by the present disclosure include, but are not limited to, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, danol, 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, the contemplated salts of the present disclosure include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In certain embodiments, the salts encompassed by 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, caprylic acid (decanoic acid), caprylic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclohexylaminesulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, hexamethylenetetraminesulfonic acid, octanoic ... Lactobacic acid, gentisic acid, d-glucoheptanoic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, 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 undecylenate.

[0275] Pharmaceutically acceptable acid addition salts may also exist in the form of various solvates, for example, with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. Such solvates may originate from the solvent of crystallization, be inherent in the solvent of preparation or crystallization, or be admixed with such solvent.

[0276] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0277] 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, alpha-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0278] definition

[0279] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with the 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 and their techniques are those well known and commonly used in the art.

[0280] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., 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., W.H. Freeman & Co., New York (2000); Griffiths et al., Introduction to Genetic Analysis, 7th ed., W.H. Freeman & Co., NY (1999); and Gilbert et al., Developmental Biology, 6th ed., Sinauer Associates, Sunderland, MA (1996). Associates, Inc., Sunderland, MA) (2000).

[0281] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art as exemplified by “The McGraw-Hill Dictionary of Chemical Terms,” Parker, S., ed., McGraw-Hill, San Francisco, CA (1985).

[0282] All of the above and any other publications, patents, and published patent applications mentioned in this application are expressly incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0283] The term "pharmaceutical agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., a nucleic acid, an antibody (including portions thereof), and humanized, chimeric, and human antibodies and monoclonal antibodies, a protein or a portion thereof, such as a peptide, lipid, or carbohydrate), or an extract made from a biological material (e.g., a bacterial, plant, fungal, or animal (particularly mammalian) cell or tissue). Pharmaceutical agents include, for example, agents whose structures are known and agents whose structures are unknown.

[0284] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (such as canines, felines, etc.), and rodents (such as mice and rats).

[0285] "Treating" a condition or patient means taking steps to obtain a favorable or desired result, including a clinical result. For the purposes of this disclosure, favorable or desired clinical results include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, reducing the severity of the disease, stabilizing the disease state (i.e., not worsening), preventing the spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0286] The term "prevent" is art-recognized and well understood in the art when used with respect to conditions such as local recurrences (e.g., pain), diseases such as cancer, complex syndromes such as heart failure, or any other medical condition, and includes administering a composition that reduces the frequency of symptoms of a medical condition in a subject or delays its onset relative to a subject not receiving the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a patient population receiving prophylactic treatment relative to an untreated control population; and / or delaying the appearance of detectable cancerous growths in a treated population (e.g., to a statistically and / or clinically significant amount) relative to an untreated control population.

[0287] "Administering" a substance, compound, or agent to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracranially, and transdermally (by absorption, e.g., through a skin duct). The compound or agent can also be suitably introduced via a refillable or biodegradable polymer device or other device, such as a patch and pump or formulation that provides for extended, slowed, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods.

[0288] The appropriate method of administering a substance, compound, or agent to a subject will also depend on, for example, the age and / or physical condition 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 a subject, for example, by ingestion. In some embodiments, the orally administered compound or agent is in the form of an extended-release or slow-release formulation, or is administered using a device for such slow-release or extended-release.

[0289] As used herein, the phrase "administered in combination" refers to any form of administration of two or more different therapeutic agents such that the previously administered therapeutic agent is still effective in the body at the same time as the second agent is administered (e.g., both agents are effective in the patient's body at the same time, which may include a synergistic effect of the two agents). For example, different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, individuals receiving such treatments may benefit from the combined effects of the different therapeutic agents.

[0290] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or pharmaceutical agent is an amount of the drug or pharmaceutical agent that will have the intended therapeutic effect when administered to a subject. The full therapeutic effect may not occur with the administration of a single dose, and may occur only after a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject will depend, 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. One skilled in the art can readily determine the effective amount for a given situation by routine experimentation.

[0291] 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 instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" refers to an alkyl group that can be substituted as well as instances where the alkyl group is unsubstituted.

[0292] It will be understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skill in the art to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and the methods given below. If a substituent is itself substituted with more than one group, it will be understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure results.

[0293] As used herein, the term "optionally substituted" means that one to six hydrogen radicals in a given structure are replaced by a group of a specified substituent, including but not limited to hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen radicals in a given structure are replaced by the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0294] As used herein, the term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group may have 1 to 10 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 suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2C H3), 2-methyl-2-propyl (t-Bu, tert-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 (-CH2CH2CH (CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2 CH3), 4-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), but it is not limited thereto.

[0295] In addition, the term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) group, cycloalkyl substituted by alkyl, and alkyl substituted by cycloalkyl. In preferred embodiments, a straight-chain or branched alkyl group has 30 or fewer carbon atoms in its main chain (e.g., a straight-chain C 1-30 , branched C 3-30), and more preferably 20 or fewer. In certain embodiments, the alkyl group is unsubstituted unless otherwise specified. However, if not specified, the term "alkyl" as used throughout this specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having substituents replacing hydrogens on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0296] As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group may include 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (ie, C 2-6 alkenyl) or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkenyl groups are ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 5-hexenyl (-CH2CH2CH2CH2CH=CH2) and 3-hexenyl (-CH2CH2CH=CHCH2CH2), and are not limited thereto. Throughout this specification, one terminal hydrogen of an alkenyl group is omitted and may be connected to the next linking group. In certain embodiments, an alkenyl group is unsubstituted unless otherwise specified.

[0297] The term "alkylene" as used herein refers to a group having 1 to 6 (C 1-6 ) carbon atoms. For example, a divalent saturated hydrocarbon group having 1 to 4 (C 1-4 ) carbon atoms. Examples include, but are not limited to, methylene, ethylene, trimethylene (propylene), and tetramethylene (n-butylene).

[0298] As used herein, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group may include 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 (ie, C 2-4 Alkynyl). Examples of alkynyl are ethynyl (-C≡CH), propargyl (-CH2C≡CH) and -CH2-C≡C-CH3, but are not limited thereto. In certain embodiments, alkynyl is unsubstituted unless otherwise specified.

[0299] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0300] The term "amido" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0301] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0302] 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.

[0303] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0304] The term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) groups, cycloalkyl substituted by alkyl, and alkyl substituted by cycloalkyl. In preferred embodiments, a straight-chain or branched-chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., a straight-chain C 1-30 , branched chain C 3-30 ), and more preferably 20 or less.

[0305] Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include unsubstituted and substituted alkyl groups, the latter referring 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, and the like.

[0306] The term "C x-y ” or “C x -C y " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing x to y carbons in the chain. C0 alkyl represents hydrogen when the group is in the terminal position and represents a bond when it is internal. For example, C 1-6 Alkyl groups contain one to six carbon atoms in the chain.

[0307] The suffix "-ene" (prefix "-ene") appended to a group 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.

[0308] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0309] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0310] As used herein, the term "amido" refers to a group

[0311]

[0312] where R 9 and R 10 Each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 Together with the nitrogen atom to which it is attached, the heterocycle completes a ring having 4 to 8 atoms in the ring structure.

[0313] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines and salts thereof, such as the moiety represented by

[0314]

[0315] where R 9 、R 10 and R 10' Each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 Together with the nitrogen atom to which it is attached, the heterocycle completes a ring having 4 to 8 atoms in the ring structure.

[0316] The term "aminoalkyl" as used herein refers to an alkyl group substituted with an amino group.

[0317] As used herein, the term "amidino" or "amidine" refers to a group C(=NR 10 )NR 11 R 12 , where R 10 、R 11 and R 12 Each independently represents hydrogen or a hydrocarbon group, or R 11 and R 12 Together with the nitrogen atom to which it is attached, the heterocycle has from 4 to 8 atoms in the ring structure. Non-limiting examples of amidines include C(=NMe)NMe2, C(=NH)NMe2, and C(=NH)NH2.

[0318] As used herein, the term "guanidine" refers to the group -NR 9 C(=NR 10 )NR 11 R 12 , where R 9 、R 10 、R 11 and R 12 Each independently represents hydrogen or a hydrocarbon group, or R11 and R 12 Together with the nitrogen atom to which it is attached, it completes 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.

[0319] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0320] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom in the ring is carbon. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, wherein two or more carbon atoms are shared by two adjacent rings, at least one of which is aromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. Aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0321] The term "carbamate" is art-recognized and refers to a group

[0322]

[0323] where R 9 and R 10 independently represent hydrogen or a hydrocarbon group.

[0324] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl group.

[0325] 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 exemplary embodiments, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle when valence permits. 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 decahydronaphthalene, 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 position or positions capable of having a hydrogen atom.

[0326] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl group.

[0327] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0328] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0329] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one of the rings is a cycloalkyl group and the substituents (e.g., R 100 ) is connected to the cycloalkyl ring, for example other ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radical.Heteroaryl includes for example pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline etc.The limiting examples of monocyclic cycloalkyl is 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.

[0330] As used herein, the term "ester" refers to the group -C(O)OR 9 , where R 9 Represents a hydrocarbon group.

[0331] As used herein, the term "ether" refers to a hydrocarbon group attached to another hydrocarbon group through an oxygen. Thus, an ether substituent of a hydrocarbon group can be hydrocarbon-O-. Ethers can 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 can be represented by the general formula alkyl-O-alkyl.

[0332] As used herein, the terms "halo" and "halogen" mean halogen and include chlorine, fluorine, bromine, and iodine.

[0333] As used herein, the terms "heteroarylalkyl," "hetaralkyl," and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group.

[0334] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one non-carbon atom in the ring, wherein the atom may be selected from oxygen, nitrogen, and sulfur, and "heteroaryl" may include multiple condensed ring systems having at least one such aromatic ring. Multiple condensed ring systems are described further. Thus, "heteroaryl" may include a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. Examples of heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. In some embodiments, "heteroaryl" includes a polycondensed ring system (e.g., a ring system comprising 2, 3, or 4 rings), and the heteroaryl defined above can be formed by condensing with at least one ring selected from the following: heteroaryl (for example, 1,8-naphthyridinyl), heterocycle (for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (for example, indazolyl). Thus, the heteroaryl group (single aromatic ring or polycondensed ring system) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. The polycondensed ring system can be such that the carbocyclic or heterocyclic portion of the condensed ring can be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups. The rings of the polycondensed ring system can be connected to each other by fusion, spirocyclic, and cross-linking bonds, as long as the valence requirements are met. The individual rings in the polycondensed ring system can be connected to each other in any order. The point of attachment of the heteroaryl or heteroaryl polycondensed ring system can be any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). In addition, when referring to a specific atomic range member heteroaryl (e.g., (C5-C 10 ) heteroaryl), the atom range is understood to be relative to the total number of ring atoms of the heteroaryl and is understood to include carbon atoms and heteroatoms. For example, C5 heteroaryl may include thiazolyl and C 10Heteroaryl groups may include quinolyl. Examples of heteroaryl groups include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolylbenzofuranyl, benzimidazolyl, thiazolyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole, and are not limited thereto.

[0335] In addition, the term "heterocyclyl" or "heterocycle" as used herein refers to a monosaturated or partially unsaturated non-aromatic compound or a non-aromatic polycyclic ring system, wherein the ring includes at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 5 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 5 to 10 ring atoms. Thus, the term includes a monosaturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. The rings of the polycondensed ring system can be connected to each other by fusion, spiro, and cross-linking bonds, as long as the valence requirements are met. Examples of heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.

[0336] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom, having no =O or =S substituents and typically having at least one carbon-hydrogen bond and a primarily carbon backbone, but optionally including heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl groups, but substituents such as acetyl (which has a =O substituent on the attached carbon) and ethoxy (which is attached through oxygen rather than carbon) are not hydrocarbyl groups. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0337] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0338] The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups having ten or less, preferably six or less atoms in the substituent. "Lower alkyl" for example refers to an alkyl group containing ten or less, preferably six or less, 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 group, respectively, whether occurring alone or in combination with other substituents, such as in hydroxyalkyl and aralkyl groups (in such cases, for example, the atoms in the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0339] The terms "polycyclic" and "polycycle" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic) in which two or more atoms are shared by two adjacent rings, e.g., the rings are "fused rings". Each ring in the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring in the polycyclic ring contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0340] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0341] The term "sulfonamido" is art-recognized and refers to a group represented by the formula

[0342]

[0343] where R 9 and R 10 independently represents hydrogen or a hydrocarbon group.

[0344] The term "sulfoxide" is art-recognized and refers to the group -S(O)-.

[0345] The term "sulfonate" is art-recognized and refers to the group -SO3H, or a pharmaceutically acceptable salt thereof.

[0346] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0347] The term "substituted" refers to a substituent group that partially has a hydrogen on one or more carbons that replace the main chain. It should be understood that "replacement" or "substituted" includes implicit restrictions, that is, this type of substitution is consistent with the allowed valence of the substituted atom and the substituent group, and the substitution produces a stable compound, such as it will not spontaneously be transformed, for example, by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, permissible substituents can be one or more and the same or different. For the purposes of this disclosure, for example, the heteroatom of nitrogen can have a hydrogen substituent and / or any permitted substituent group of an organic compound that satisfies the heteroatom valence as described herein. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moiety substituted on the hydrocarbon chain may itself be substituted where appropriate.

[0348] As used herein, the term "sulfanyl" refers to an alkyl group substituted with a thiol group.

[0349] As used herein, the term "thioester" refers to the group -C(O)SR 9 or –SC(O)R 9 ,

[0350] where R 9 Represents a hydrocarbon group.

[0351] As used herein, the term "thioether" is equivalent to an ether in which the oxygen is replaced by sulfur.

[0352] The term "urea" is art-recognized and can be represented by the following general formula

[0353]

[0354] where R 9 and R 10 independently represents hydrogen or a hydrocarbon group.

[0355] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation) as well as enhancing a function or activity.

[0356] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0357] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to acid addition salts or base addition salts that are suitable for use in treating a patient or are compatible with such treatment.

[0358] As used herein, the term "pharmaceutically acceptable acid addition salt" means any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that 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 that form suitable salts include monocarboxylic acids, dicarboxylic acids 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, as well as sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or di-acid salts can be formed, and such salts can be hydrated, dissolved or substantially anhydrous. In general, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The selection of suitable salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be useful, for example, in isolating compounds of Formula I for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0359] As used herein, the term "pharmaceutically acceptable base addition salt" means any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any of its intermediates. Illustrative inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Illustrative 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 known to those skilled in the art.

[0360] Many compounds suitable for use in the methods and compositions of the present disclosure have at least one stereogenic center in their structure. This stereogenic center can exist in an R or S configuration, with the R and S symbols being used in accordance with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure encompasses all stereoisomeric forms, such as enantiomeric and diastereomeric forms (including all possible mixtures of stereoisomers) of compounds, salts, prodrugs, or mixtures thereof. See, for example, WO 01 / 062726.

[0361] Additionally, certain compounds containing alkenyl groups may exist as either Z (ipsilateral) or E (heterolateral) isomers. In each case, the disclosure includes both the mixture and the individual individual isomers.

[0362] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized in the host after administration, such as hydrolyzed or oxidized to form a compound of the present disclosure (e.g., a compound of formula I). Typical examples of prodrugs include compounds having biologically unstable or cleavable (protecting) groups on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminized, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce an active compound. Examples of prodrugs using esters or phosphoramidates as biologically unstable or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. Prodrugs of the present disclosure are metabolized to produce compounds of formula I. The present disclosure includes prodrugs of the compounds described herein within its scope. General procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0363] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, suitable for formulating a medicament for medical or therapeutic use. In certain embodiments, the present disclosure relates to heterocyclic compounds having activity as STING agonists.

[0364] In certain embodiments, the pharmaceutical composition further contains a chemotherapeutic agent, such as a pharmaceutically effective amount of a chemotherapeutic agent.

[0365] In certain embodiments, the pharmaceutical compositions further comprise one or more therapeutic adjuvants and one or more pharmaceutically acceptable excipients.

[0366] The therapeutic adjuvant may be, but is not limited to, an agent that exhibits a preventive, ameliorating, or therapeutic effect on a STING-mediated disease; or an agent that can reduce the expression of side effects that may occur when a therapeutic agent is administered for a STING-mediated disease; or an agent that exhibits an immunopotentiating effect. The therapeutic adjuvant may be administered alone or in combination (i.e., a pharmaceutical composition comprising a compound of Formula 1 may also comprise one or more therapeutic adjuvants). When a STING agonist, which is a compound described herein, is administered together with one or more therapeutic adjuvants, optionally also with a compounding agent, a therapeutically useful 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) and one or more therapeutic adjuvants may further enhance the stability of the proteolytic agent, reduce side effects that occur when administering the STING agonist represented by the compound of Formula 1, and / or exhibit an effect of maximizing the therapeutic effect by enhancing immunity.

[0367] Suitable therapeutic adjuvants include, but are not limited to, auristatin, bexarotene, bicalutamide, BMS184476, bleomycin, semadotin, chlorambucil, cyclophosphamide, docetaxel, docetaxel, carboplatin, carmustine, cisplatin, cryptophycin, decitabine, dolastatin, doxorubicin, mibobulin, isethionate, and the like. (isethionate), rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, nivolumab, onapristone, paclitaxel, procarbazine, tamoxifen, tasonermin, tretinoin, vinblastine, vincristine, PD-1 antagonist, CTLA-4 antagonist, B7 costimulatory molecule, interleukin-2, interleukin-7, etc.

[0368] In other embodiments, the present disclosure relates to a method for preventing or treating a disease mediated by STING in a subject in need thereof, 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, 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.

[0369] In a specific embodiment, the STING-mediated disease is cancer. Cancers suitable for treatment with the compounds and methods disclosed herein include any cancer for which a STING agonist (e.g., a compound of Formula 1 or a pharmaceutically acceptable salt thereof) exhibits a therapeutic effect. 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 a more specific embodiment, 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.

[0370] In 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 the use of a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the preparation of a medicament for treating or preventing a disease mediated by STING 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.

[0371] In a specific embodiment, the STING-mediated disease is cancer. Cancers suitable for treatment with the compounds and methods disclosed herein include any cancer for which a STING agonist (e.g., a compound of Formula 1) exhibits a therapeutic effect. 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 a more specific embodiment, 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.

[0372] In addition, the compound of Formula 1 (or its pharmaceutically acceptable salt) can be used as an adjuvant in any of its pharmaceutically acceptable salts for the treatment of other infectious diseases, diseases or conditions, including cancer. In any of the aforementioned methods and uses, the compound of Formula 1 (or its pharmaceutically acceptable salt) can be administered in combination with another therapeutic agent (e.g., a chemotherapeutic agent or 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 can be, 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, a 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-based compound, such as erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, or a combination thereof.mesylate), PTK787 / ZK222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone one), meturedopa, uredopa, ethyleneimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylmelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 88), dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracilmustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin AA), clodronate, esperamicin, neocarzinostatin chromophore, aclacinomycins, actinomycin, antrmycin, azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycin mycins), dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, N-morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acidacid), nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, 5-fluorouracil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, Thiamiprine, thiguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acidacid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate acetate), etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-K, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid acid), triaziquone, 2,2',2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridinA), anguidine, carbamate, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, gemcitabine, 6-thioguanine; mercaptopurine ine), cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS2000, difluoromethylornithine, retinoic acid, or capecitabine, but are not limited thereto.

[0373] Examples

[0374] <Preparation Example 1> Preparation of Intermediate Compound 2

[0375]

[0376] Preparation of intermediate compound 1

[0377] After dissolving 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (8 g, 51.9 mmol) in dichloromethane (50 mL), oxalyl chloride (4.97 mL, 57.1 mmol) and N,N-dimethylformamide (0.1 mL) were added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain Intermediate Compound 1.

[0378] Preparation of intermediate compound 2

[0379] After intermediate compound 1 (crude material) was dissolved in acetone (100 mL), potassium thiocyanate (6.5 g, 67.5 mmol) was added at 0°C. After the reaction solution was stirred at room temperature for 30 minutes, 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 obtain intermediate compound 2 (9.7 g, 95%).

[0380] 1 H-NMR (400MHz, CDCl3), δ7.78(d,1H),7.41(s,1H),7.38(d,1H),3.88(s,3H),2.57(s,3H). EI-MSm / z:[M+H] + 196.00.

[0381] <Preparation Example 2> Preparation of Intermediate Compound 5

[0382]

[0383] Preparation of intermediate compound 3

[0384] To methyl 4-chloro-3-methoxy-5-nitrobenzoate (15 g, 61.1 mmol) was added aqueous ammonia solution (28% to 30% ammonia, 200 mL). The reaction solution was stirred at 50° C. for 6 hours, cooled to room temperature, and then washed with water, filtered and lyophilized to give intermediate compound 3 (9.51 g, 68%).

[0385] 1 H-NMR (400MHz, CDCl3) δ8.29(s,1H),8.04(d,1H),7.87(d,1H),7.78(s,1H),4.01(s,3H).

[0386] Preparation of intermediate compound 4

[0387] Intermediate compound 3 (300 mg, 1.30 mmol) was added to dichloromethane (9 mL), and then aluminum chloride (1.04 g, 7.81 mmol) was added at 0° C. Under nitrogen, the reaction solution was stirred at room temperature for 21 hours. The reaction solution was added to ice water, and then the resulting solid was filtered and lyophilized to obtain intermediate compound 4 (223 mg, 79%).

[0388] 1 H-NMR (400MHz, CDCl3), δ11.73(s,1H),8.21(s,1H),7.92(s,1H),7.80(s,1H),7.66(s,1H).

[0389] Preparation of intermediate compound 5

[0390] Under nitrogen, intermediate compound 4 (2g, 9.23mmol) and cesium carbonate (3.61g, 11.08mmol) are added to N, N- dimethylformamide (15mL) at 0 DEG C, and then stirred for 5 minutes. Under nitrogen, trans-1,4- dibromo-2-butene (5.93g, 27.70mmol) is added to the reaction solution at room temperature, and stirred for 2 hours. The resulting solution is extracted with ethyl acetate (20mL×3) and washed with distilled water (15mL×2) and brine (15mL). The combined organic layer is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated. After solidifying with dichloromethane and hexane, it is filtered and dried to obtain intermediate compound 5 (2.53g, 78%).

[0391] 1 H-NMR (400MHz, CDCl3), δ8.23(s,2H),8.02(d,J=1.8Hz,2H),7.84(d,J=1.8Hz,2H),7.73(s,2H), 6.16-5.98(m,4H),5.70(s,1H),4.83(d,J=3.5Hz,4H),4.25(d,J=5.4Hz,1H),4.20-4.14(m,3H). EI-MSm / z:[M+H] + 350.98.

[0392] <Preparation Example 3> Preparation of Intermediate Compound 9

[0393]

[0394] Preparation of intermediate compound 6

[0395] After dissolving 4-chloro-3-methoxy-5-nitro-benzamide (11.4 g, 61.57 mmol) in ethanol (100 mL), intermediate compound 3 (10 g, 43.4 mmol) and N,N-diisopropylethylamine (14.9 mL, 86.7 mmol) were added and stirred at 120° C. for 12 hours. The reaction solution was concentrated and diluted with diethyl ether (40 mL), and the resulting solid was then filtered and dried to give intermediate compound 6 (12.6 g, 76%).

[0396] 1 H-NMR(400MHz,DMSO-d6),δ8.18(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).

[0397] Preparation of intermediate compound 7

[0398] After dissolving Intermediate Compound 6 (10 g, 26.28 mmol) in methanol (90 mL), aqueous ammonia solution (28% to 30% ammonia, 90 mL) and sodium bisulfite (Na2S2O4, 45 g, 262.8 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Methanol (100 mL) was added to the reaction solution, and the resulting solid was filtered. The filtered solution was concentrated and then diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain Intermediate Compound 7 (6.9 g, 75%).

[0399] 1 H-NMR(400MHz,DMSO-d6),δ7.62(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).

[0400] Preparation of intermediate compound 8

[0401] After dissolving Intermediate Compound 7 (6.9 g, 19.7 mmol) in N,N-dimethylformamide (50 mL), 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. After concentrating the reaction solution, it was diluted with diethyl ether (20 mL), and the resulting solid was filtered to obtain Intermediate Compound 8 (7.7 g, 76%).

[0402] 1 H-NMR(400MHz,DMSO-d6),δ12.86(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).

[0403] Preparation of intermediate compound 9

[0404] After dissolving intermediate compound 8 (7.7 g, 15.05 mmol) in dichloromethane (25 mL) and methanol (25 mL), hydrochloric acid (4M 1,4-dioxane solution, 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 obtain intermediate compound 9 (5.6 g, 76%).

[0405] 1 H-NMR(400MHz,DMSO-d6)δ8.02(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-MSm / z:[M+H] + 823.0.

[0406] <Example 1> Preparation of Compound 13

[0407]

[0408] Preparation of intermediate compound 10

[0409] After intermediate compound 5 (580 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (5 mL), morpholine (0.13 mL, 1.01 mmol) and cesium carbonate (590 mg, 1.81 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 obtain intermediate compound 10 (504 mg, 70%).

[0410] 1 H-NMR (400MHz, CDCl3), δ7.73–7.66(m,1H),6.03–5.84(m,1H),4.75(dd,J=5.0,1 .2Hz, 1H), 3.75-3.68 (m, 2H), 3.06 (dd, J = 6.0, 1.1Hz, 1H), 2.46 (t, J = 4.7Hz, 2H). EI-MSm / z:[M+H] + 356.09.

[0411] Preparation of intermediate compound 11

[0412] After intermediate compound 9 (818 mg, 1.68 mmol) and intermediate compound 10 (300 mg, 0.84 mmol) were dissolved in n-butanol (13 mL), N,N-diisopropylethylamine (0.74 mL, 4.21 mmol) was added at room temperature, heated to 120 ° C, and stirred for 24 hours. After 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 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-MSm / z: [M + H] + 731.03.

[0413] Preparation of intermediate compound 12

[0414] After intermediate compound 11 (129 mg, 0.17 mmol) was dissolved in methanol (2 mL) and distilled water (0.1 mL), aqueous ammonia solution (28% to 30% ammonia, 0.17 mL) and sodium bisulfite (Na2S2O4, 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, and the resulting solid was filtered and concentrated to the filtered solution, and 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 obtain intermediate compound 12 (126 mg, crude material). EI-MSm / z: [M+H] + 701.08.

[0415] Preparation of compound 13

[0416] After intermediate compound 12 (126 mg, 0.18 mmol, crude material) was dissolved in N, N-dimethylformamide (2 mL), 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 obtain compound 13 (5.6 mg, 4%). EI-MSm / z: [M+H] + 862.03.

[0417] <Example 2> Preparation of Compound 18

[0418]

[0419] Preparation of intermediate compound 14

[0420] After dissolving intermediate compound 5 (265 mg, 0.76 mmol) in N,N-dimethylformamide (4 mL), piperidine-4-tert-butylcarbamate (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-MSm / z: [M+H] + 469.06.

[0421] Preparation of intermediate compound 15

[0422] After intermediate compound 9 (628 mg, 1.3 mmol) and compound 14 (304 mg, 0.65 mmol) were dissolved in n-butanol (5 mL), diisopropylethylamine (0.56 mL, 3.24 mmol) was added at room temperature, heated to 120 ° C, and stirred for 24 hours. After 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 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 obtain intermediate compound 15 (124 mg, 23%). EI-MSm / z: [M + H] + 844.02.

[0423] Preparation of intermediate compound 16

[0424] After intermediate compound 15 (124 mg, 0.15 mmol) was dissolved in methanol (4 mL) and distilled water (0.5 mL), aqueous ammonia solution (28% to 30% ammonia, 0.4 mL) and sodium bisulfite (Na2S2O4, 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 obtain intermediate compound 16 (119 mg, crude material). EI-MSm / z: [M+H] + 814.81.

[0425] Preparation of intermediate compound 17

[0426] After intermediate compound 16 (119 mg, 0.15 mmol, crude material) was dissolved in N, N-dimethylformamide (1 mL), 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 obtain intermediate compound 17 (36 mg, 25%). EI-MSm / z: [M+H] + 975.15.

[0427] Preparation of compound 18

[0428] After dissolving intermediate compound 17 (36 mg) in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to obtain compound 18 (15.2 mg, 47%). EI-MS m / z: [M+H] + 875.06.

[0429] <Example 3> Preparation of Compound 23

[0430]

[0431] Preparation of intermediate compound 19

[0432] After intermediate compound 5 (500 mg, 1.43 mmol) was dissolved in N,N-dimethylformamide (5 mL), tert-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 obtain intermediate compound 19 (472 mg, 72%).

[0433] 1 H-NMR(400MHz,DMSO-d6),δ8.26(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-MSm / z:[M+H] + 455.11.

[0434] Preparation of intermediate compound 20

[0435] After intermediate compound 9 (495 mg, 1.02 mmol) and intermediate compound 19 (310 mg, 0.68 mmol) were dissolved in n-butanol (7 mL), diisopropylethylamine (0.59 mL, 3.41 mmol) was added at room temperature, 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-MSm / z: [M + H] + 830.01.

[0436] Preparation of intermediate compound 21

[0437] After intermediate compound 20 (336 mg, 0.31 mmol) was dissolved in methanol (10 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30% ammonia, 0.33 mL) and sodium bisulfite (Na2S2O4, 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 obtain intermediate compound 21 (153 mg, 60%, crude material). EI-MSm / z: [M+H] + 800.09.

[0438] Preparation of intermediate compound 22

[0439] After intermediate compound 21 (153 mg, 0.19 mmol, crude material) was dissolved in N, N- dimethylformamide (2 mL), 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 obtain intermediate compound 22 (116 mg, 63%). EI-MSm / z: [M+H] + 961.07.

[0440] Preparation of compound 23

[0441] After intermediate compound 22 (41 mg) was dissolved in dichloromethane (5 mL), 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 obtain compound 23 (26 mg, 46%).

[0442] 1 H-NMR(400MHz,DMSO-d6),δ8.66(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,4H),4.93-4.89(m,4H),4.56-4.50(m,6H),3.71(s,3H),2.11(d,6H)1.30-1.25(m,6H). EI-MSm / z:[M+H] + 861.21.

[0443] <Example 4> Preparation of Compound 28

[0444]

[0445] Preparation of intermediate compound 24

[0446] tert-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 in sequence, and then stirred at room temperature for 30 minutes. Intermediate compound 5 (300 mg, 0.858 mmol) was dissolved in THF (2 mL), and then slowly added to the reaction solution, and 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 reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compound 24 (213 mg, 52.9%).

[0447] 1 H-NMR(400MHz, CDCl3), δ8.26(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=4.4Hz,1H) ,4.00(d,J=4.8Hz,2H),3.92(s,2H),3.53-3.51(m,2H),3.27-3.24(m,2H),1.41(s,9H). EI-MSm / z:[M+H]+ 469.07.

[0448] Preparation of intermediate compound 25

[0449] After intermediate compound 9 (440 mg, 0.91 mmol) and intermediate compound 24 (213 mg, 0.45 mmol) were dissolved in n-butanol (4.5 mL), diisopropylethylamine (0.43 mL, 2.49 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then 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-MSm / z: [M + H] + 844.04.

[0450] Preparation of intermediate compound 26

[0451] After intermediate compound 25 (210 mg, 0.25 mmol) was dissolved in methanol (6 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30%, 0.44 mL) and sodium bisulfite (Na2S2O4, 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 obtain intermediate compound 26 (crude material). EI-MSm / z: [M+H] + 814.14.

[0452] Preparation of intermediate compound 27

[0453] After intermediate compound 26 (0.24mmol, crude material) was dissolved in N,N-dimethylformamide (2.5mL), intermediate compound 2 (50.9mg, 0.26mmol) was dissolved in N,N-dimethylformamide (1mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (68.1mg, 0.35mmol) and triethylamine (0.1mL, 0.71mmol) were added and stirred at room temperature for 18 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 27 (48mg, 20%). EI-MS m / z: [M+H]+ 975.19.

[0454] Preparation of compound 28

[0455] After dissolving Intermediate Compound 27 (48 mg) in dichloromethane (3.2 mL), 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 obtain Compound 28 (10.2 mg, 17%).

[0456] 1 H-NMR (400MHz, DMSO-d6), δ1.28 (br s, 2H), 9.13 (br s, 1H), 7.96 (d, J = 14.7Hz, 2H), 7.65 (s, 2H), 7.37 (br s,2H),7.30(s,2H),6.53(d,J=6.3Hz,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 = 4.9Hz, 6H) 1.29-1.25 (m, 6H). EI-MSm / z:[M+H] + 875.11.

[0457] <Example 5> Preparation of Compound 33

[0458]

[0459] Preparation of intermediate compound 29

[0460] Under nitrogen, 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) at 0 ° C and then stirred for 5 minutes. Under nitrogen, cis-1,4-dibromo-2-butene (3.7 g, 17.32 mmol) was added to the reaction solution at room temperature and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (20 mL×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-MSm / z: [M+H] + 351.23.

[0461] Preparation of intermediate compound 30

[0462] After intermediate compound 29 (450 mg, 1.29 mmol) was dissolved in N, N-dimethylformamide (5 mL), 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, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to give intermediate compound 30 (298 mg, 71%). EI-MSm / z: [M + H] + 356.11.

[0463] Preparation of intermediate compound 31

[0464] After intermediate compound 9 (592 mg, 1.22 mmol) and intermediate compound 30 (290 mg, 0.82 mmol) were dissolved in n-butanol (6 mL), diisopropylethylamine (0.71 mL, 4.08 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then 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 then 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-MSm / z: [M+H] + 731.05.

[0465] Preparation of intermediate compound 32

[0466] After intermediate compound 31 (173 mg, 0.24 mmol) was dissolved in methanol (2 mL) and distilled water (0.1 mL), aqueous ammonia solution (28% to 30%, 0.34 mL, 4.76 mmol) and sodium bisulfite (Na2S2O4, 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 material, 29%). EI-MSm / z: [M+H] + 701.22.

[0467] Preparation of compound 33

[0468] After intermediate compound 32 (48 mg, 0.07 mmol, crude material) was dissolved in N, N-dimethylformamide (1 mL), 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 obtain compound 33 (17.5 mg, 30%). EI-MSm / z: [M+H] + 862.08.

[0469] <Example 6> Preparation of Compound 38

[0470]

[0471] Preparation of intermediate compound 34

[0472] After intermediate compound 29 (649 mg, 1.86 mmol) was dissolved in N, N-dimethylformamide (6 mL), piperidine-4-tert-butylcarbamate (338 mg, 1.69 mmol) and cesium carbonate (660 mg, 2.03 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 obtained material was filtered and concentrated under reduced pressure, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to obtain intermediate compound 34 (628 mg, 79%).

[0473] 1 H-NMR (400MHz, DMSO), δ8.21 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 6.16–6.01 (m, 2H), 4.82 (d, J = 3.5Hz, 2H), 4.17 (d, J = 5.5Hz, 2H). EI-MSm / z:[M+H] + 469.49.

[0474] Preparation of intermediate compound 35

[0475] After intermediate compound 9 (413 mg, 0.85 mmol) and intermediate compound 34 (600 mg, 1.28 mmol) were dissolved in n-butanol (8 mL), diisopropylethylamine (0.74 mL, 4.27 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and 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-MSm / z: [M + H] + 844.13.

[0476] Preparation of intermediate compound 36

[0477] After intermediate compound 35 (147 mg, 0.17 mmol) was dissolved in methanol (3 mL) and distilled water (0.1 mL), aqueous ammonia solution (28% to 30%, 0.25 mL) and sodium bisulfite (Na2S2O4, 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 material). EI-MSm / z: [M+H] + 814.81.

[0478] Preparation of intermediate compound 37

[0479] After intermediate compound 36 (141 mg, 0.17 mmol, crude material) was dissolved in N,N-dimethylformamide (1 mL), 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 obtain intermediate compound 37 (48 mg, 28%). EI-MS m / z: [M+H] + 975.16.

[0480] Preparation of compound 38

[0481] After dissolving intermediate compound 37 (48 mg) in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to obtain compound 38 (6.4 mg, 14%). EI-MS m / z: [M+H] + 875.17.

[0482] <Example 7> Preparation of Compound 43

[0483]

[0484] Preparation of intermediate compound 39

[0485] 3-Oxopiperazine-1-carboxylic acid tert-butyl ester (210mg, 1.05mmol) was dissolved in N, N-dimethylformamide (6mL), potassium hydroxide (66.2mg, 1.02mmol) was added and then stirred at room temperature for 30 minutes. After intermediate compound 29 (350mg, 1.20mmol) was dissolved in N, N-dimethylformamide (4mL), it was slowly added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50mL), washed with distilled water (30mL), and then dried over anhydrous magnesium sulfate. The dried material was filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compound 39 (432mg, 92.0%).

[0486] 1 H-NMR(400MHz, CDCl3)δ7.80(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-MSm / z:[M+H] + 469.10.

[0487] Preparation of intermediate compound 40

[0488] After intermediate compound 9 (542 mg, 1.11 mmol) and intermediate compound 39 (350 mg, 0.746 mmol) were dissolved in n-butanol (4.5 mL), diisopropylethylamine (0.65 mL, 3.73 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then 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 40 (135 mg, 21.4%). EI-MSm / z: [M + H] + 844.12.

[0489] Preparation of intermediate compound 41

[0490] After intermediate compound 40 (135 mg, 0.16 mmol) was dissolved in methanol (6 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30%, 0.3 mL) and sodium bisulfite (Na2S2O4, 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 obtain intermediate compound 41 (91 mg, 69.8%). EI-MSm / z: [M+H] + 814.12.

[0491] Preparation of intermediate compound 42

[0492] After intermediate compound 41 (91 mg, 0.11 mmol) was dissolved in N, N- dimethylformamide (2.5 mL), 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 stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate compound 42 (125 mg, crude material). EI-MSm / z: [M+H] + 975.17.

[0493] Preparation of compound 43

[0494] After dissolving intermediate compound 42 (125 mg, crude material) in dichloromethane (3.2 mL), 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 obtain compound 43 (34 mg, 25%).

[0495] 1 H-NMR(400MHz,DMSO-d6),δ12.84(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-MSm / z: [M+H] + 875.13.

[0496] <Example 8> Preparation of Compound 48

[0497]

[0498] Preparation of intermediate compound 44

[0499] After intermediate compound 4 (2.0 g, 9.23 mmol) was dissolved in N, N-dimethylformamide (10 mL), 1,4-dibromo-2-butyne (5.8 g, 27.70 mmol) and cesium carbonate (3.6 g, 11.08 mmol) were added 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, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to obtain intermediate compound 44 (2.0 g, 62%).

[0500] 1 H-NMR (400MHz, DMSO-d6), δ8.25(s,1H),8.12(s,1H),7.95(s,1H),7.80(s,1H),5.22(s,2H),4.34(t,J=5.5Hz,2H). EI-MSm / z:[M+H] + 348.99.

[0501] Preparation of intermediate compound 45

[0502] After intermediate compound 44 (300 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (3 mL), morpholine (0.09 mL, 1.03 mmol) and cesium carbonate (309 mg, 0.95 mmol) were added 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 obtain intermediate compound 45 (230 mg, 75%).

[0503] 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=11.5Hz,4H),3.29(s,2H),2.36(t,J=11.0Hz,4H). EI-MSm / z:[M+H] + 354.13.

[0504] Preparation of intermediate compound 46

[0505] After intermediate compound 9 (500 mg, 1.03 mmol) and intermediate compound 45 (215 mg, 0.60 mmol) were dissolved in n-butanol (4 mL), diisopropylethylamine (0.53 mL, 3.03 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then 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-MSm / z: [M + H] + 729.11.

[0506] Preparation of intermediate compound 47

[0507] After intermediate compound 46 (303 mg, 0.41 mmol) was dissolved in methanol (10 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30% ammonia, 0.45 mL) and sodium bisulfite (Na2S2O4, 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 material). EI-MSm / z: [M+H] + 699.07.

[0508] Preparation of compound 48

[0509] After intermediate compound 47 (97 mg, 0.14 mmol, crude material) was dissolved in N,N-dimethylformamide (1.5 mL), 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 reduced pressure and purified by HPLC to obtain compound 48 (38 mg, 32%).

[0510] 1 H-NMR (400MHz, MeOD-d4), δ7.60(d,J=1.3Hz,1H),7.58(d,J=1.3Hz,1H),7.44(d,J=1.4Hz,1H),7.31(d,J=1.4Hz,1H),6.60(d,J=0.6Hz,1H),6.58 (d,J=0.6Hz,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-MSm / z:[M+H] + 860.08.

[0511] <Example 9> Preparation of Compound 55

[0512]

[0513] Preparation of intermediate compound 49

[0514] To a solution of 4-nitropyrazole (1g, 6.13mmol) in methanol (20mL) is added ammonia solution (28% to 30% ammonia, 2.2mL) and sodium bisulfite (7.7g). After stirring at room temperature for 1 hour, the reaction solution is filtered with diatomaceous earth, and the filtrate is evaporated under reduced pressure. Methanol (15mL) is added to the concentrated filtrate, and then di-tert-butyl dicarbonate (2.24mL, 9.73mmol) and triethylamine (1.86mL, 13.27mmol) are added at room temperature. The reaction solution is stirred at room temperature for 16 hours, and then diluted with ethyl acetate (50mL) and washed with distilled water (50mL×2). The organic layer is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to obtain intermediate compound 49 (0.7g, 43%).

[0515] 1 H-NMR (400MHz, DMSO-d6) δ9.05(s,1H),7.44(s,1H),1.42(s,9H).

[0516] Preparation of intermediate compound 50

[0517] 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 obtain intermediate compound 50 (867 mg, 71%).

[0518] 1 H-NMR(400MHz, CDCl3)δ7.66(s,1H),7.33(s,1H),6.24(s,1H),6.00–5.90(m,1H),5. 87(td,J=13.2,5.9Hz,1H), 4.69(d,J=5.6Hz,2H), 3.94(d,J=6.9Hz,2H), 1.50(s,9H). EI-MSm / z: [M+H]+317.26.

[0519] Preparation of intermediate compound 51

[0520] To a solution of intermediate compound 4 (540 mg, 2.5 mmol) in N, N-dimethylformamide (15 mL) was 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 obtain intermediate compound 51 (830 mg, 73%).

[0521] 1 H-NMR(400MHz,DMSO-d6)δ9.12(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=15.4Hz,1H),5.86(d,J=15.8Hz,1H),4.82(d,J=5.4Hz,2H),4.74(d,J=5.9Hz,2H),1.44(d,J=2.3Hz,9H). EI-MSm / z:[M+H] + 452.31.

[0522] Preparation of intermediate compound 52

[0523] 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, 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 obtain intermediate compound 52 (420 mg, 28%). EI-MS m / z: [M + H] + 827.39.

[0524] Preparation of intermediate compound 53

[0525] To a solution of intermediate compound 52 (420 mg, 0.51 mmol) in methanol (5 mL) was added aqueous ammonia solution (28% to 30% ammonia, 1.8 mL, 12.66 mmol) and sodium bisulfite (882 mg, 5.06 mmol). After stirring at room temperature for 2.5 hours, 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.

[0526] Preparation of intermediate compound 54

[0527] To a solution of intermediate compound 53 (400 mg, 0.51 mmol) in N,N-dimethylformamide (1.5 mL) was added compound 2 (109 mg, 0.55 mmol) in N,N-dimethylformamide (1 mL) at 0°C. After 30 minutes, 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 hours, the reaction solution was concentrated under reduced pressure and purified by reverse phase chromatography to give intermediate compound 54 (97 mg, 20%).

[0528] Preparation of compound 55

[0529] 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%).

[0530] 1 H-NMR (400MHz, CD3OD) δ7.80 (s, 1H), 7.57 (d, J = 11.4Hz, 3H), 7.29 (s, 1H), 7.23 ( s,1H),6.62(d,J=1.7Hz,1H),6.56(s,1H),5.85(d,J=18.0Hz,3H),5.70(d,J=15. 6Hz,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=12.3Hz,6H),1.34(dt,J=21.7,6.9Hz,6H). EI-MS m / z: [M+H] + 858.54.

[0531] <Example 10> Preparation of Compound 65

[0532]

[0533] Preparation of intermediate compound 56

[0534] Under nitrogen, cesium carbonate (11.2 g, 34.62 mmol) was added to a solution of intermediate compound 4 (5 g, 23.08 mmol) in N, N-dimethylformamide (30 mL) 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 solidification with dichloromethane and hexane, the obtained solid was filtered and dried to give intermediate compound 56 (4.7 g, 61%), which was used without further purification.

[0535] 1 H-NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 4.25 (m, 2H), 4.09-4.04 (q, J = 7.2Hz, 2H), 1.19-1.15 (t, J = 7.2Hz, 3H). EI-MSm / z:[M+H] + 331.20.

[0536] Preparation of intermediate compound 57

[0537] To a solution of intermediate compound 56 (4.5 g, 13.60 mmol) in ethanol (30 mL) was added tert-butyl (E)-(4-aminobut-2-ene-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 obtain intermediate compound 57 (4.5 g, 68%).

[0538] 1 H-NMR(400MHz,DMSO-d6)δ8.10(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-MSm / z:[M+H] + 481.28.

[0539] Preparation of intermediate compound 58

[0540] To a solution of intermediate compound 57 (4.4 g, 9.156 mmol) in methanol (20 mL) was added aqueous ammonia solution (28% to 30% ammonia, 10 mL) and sodium bisulfite (Na2S2O4, 15 g, 91.6 mmol) at 0°C. After stirring at room temperature for 1.5 hours, the reaction solution was filtered through celite and methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 58 (4 g, 96%). EI-MS m / z: [M+H] + 451.31.

[0541] Preparation of intermediate compound 59

[0542] 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. Then, the reaction solution was concentrated, and the resulting residue was purified by column chromatography to obtain intermediate compound 59 (3.8 g, 71%).

[0543] 1 H-NMR (400MHz, DMSO-d6) δ12.86(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=16Hz, 1H),5.58-5.54(d,J=16Hz,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-MSm / z:[M+H] + 612.31.

[0544] Preparation of intermediate compound 60

[0545] To a solution of intermediate compound 59 (3.8 g, 6.21 mmol) in dichloromethane (50 mL) was added hydrochloric acid (4 M 1,4-dioxane solution, 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 obtain intermediate compound 60 (3.9 g, quantitative).

[0546] 1 H-NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.88(m,2H),7.68(s,1H),7.39(s,2H),6.67(s,1H),6.08-6.04(d,J=16Hz,1H),5.59- 5.55(d,J=16Hz,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-MSm / z:[M+H] + 512.31.

[0547] Preparation of intermediate compound 61

[0548] 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 obtain intermediate compound 61 (1.6 g, 38%). EI-MSm / z: [M + H] + 926.98.

[0549] Preparation of intermediate compound 62

[0550] To a solution of intermediate compound 61 (1.6 g, 1.83 mmol) in methanol (8 mL) was added ammonia solution (28% to 30% ammonia, 3.2 mL) and sodium bisulfite (Na2S2O4, 3.1 g, 18.3 mmol) under nitrogen. The reaction solution was stirred at room temperature for 1 hour and then methanol (50 mL) was added, and the resulting solid was filtered out. The filtrate was concentrated and 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-MSm / z: [M+H] + 897.05.

[0551] Preparation of intermediate compound 63

[0552] To a solution of intermediate compound 62 (1.35 g, 1.51 mmol) in N,N-dimethylformamide (10 mL) was added compound 2 (324 mg, 1.66 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. 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.

[0553] Preparation of intermediate compound 64

[0554] Under nitrogen, lithium hydroxide monohydrate (13.8 mg, 0.28 mmol) in distilled water (1 mL) was added to a solution of intermediate compound 63 (100 mg, 0.094 mmol) in methanol (2 mL) at -50°C. After stirring at 0°C for 2 hours, the reaction solution was acidified to pH 4 to 5 with acetic acid, and then concentrated and lyophilized to give intermediate compound 64 (100 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 1029.95.

[0555] Preparation of compound 65

[0556] To a solution of intermediate compound 64 (100 mg, 0.097 mmol, crude) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) under nitrogen at 0° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated and purified by HPLC to give compound 65 (42 mg, 34%).

[0557] 1 H-NMR(400MHz,DMSO-d6)δ12.80(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,6 H),3.92(m,3H),2.24(s,2H),2.11(m,6H),1.74(m,2H),1.26(m,6H). EI-MSm / z:[M+H] + 929.98.

[0558] <Example 11> Preparation of Compound 69

[0559]

[0560] Preparation of intermediate compound 67

[0561] 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. WO2022 / 155518A1) 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.

[0562] Preparation of intermediate compound 68

[0563] To a solution of intermediate compound 67 (280 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) was 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 obtain intermediate compound 68 (158 mg, 62%). EI-MS m / z: [M+H] + 945.00.

[0564] Preparation of compound 69

[0565] To a solution of intermediate compound 68 (50 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) under nitrogen 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).

[0566] 1H-NMR (400MHz, CD3OD) δ7.82(d,J=0.8Hz,1H),7.58(d,J=0.8Hz,1H),7.53(d,J=1.3Hz,1H),7.4 2(d,J=1.5Hz,1H),7.24(d,J=1.4Hz,1H),7.17(d,J=1.4Hz,1H),6.61(d,J=0.7Hz,1H),6.49(d, J=0.7Hz,1H),5.95–5.80(m,3H),5.78–5.67(m,1H),5.04(dd,J=17.4,3.9Hz,4H),4.67–4.57(m ,4H),4.57–4.46(m,4H),2.20(s,3H),2.16(s,3H),1.36(t,J=7.1Hz,3H),1.28(t,J=7.1Hz,3H). EI-MSm / z:[M+H] + 845.07.

[0567] <Example 12> Preparation of Compound 79

[0568]

[0569] Preparation of intermediate compound 70

[0570] Under nitrogen, sodium acetate (2.0 g, 24.4 mmol) was added to a solution of trans-1,4-dibromo-2-butene (10.4 g, 48.7 mmol) in N,N-dimethylformamide (30 mL) at 0 ° C. The reaction solution was stirred at room temperature for 17 hours, and 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 filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 70 (2.98 g, 63%).

[0571] 1 H-NMR (400MHz, CDCl3) δ6.02-5.82 (m, 2H), 4.59 (d, J = 5.6Hz, 2H), 3.95 (d, J = 7.2Hz, 2H), 2.08 (s, 3H).

[0572] Preparation of intermediate compound 71

[0573] 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 tert-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%).

[0574] 1 H-NMR (400MHz, CDCl3) δ5.87-5.71(m,2H),4.99(s,1H),4.58-4.52(m,2H),3.26(d,J=5.7Hz,2H),3.2 3-3.18(m,2H),2.70-2.65(m,2H),2.07(d,J=2.7Hz,3H),1.68(d,J=6.6Hz,2H),1.45(d,J=2.6Hz,9H).

[0575] Preparation of intermediate compound 72

[0576] To a solution of intermediate compound 71 (790 mg, 2.76 mmol) in dichloromethane (10 mL) was added fluorenylmethoxycarbonyl 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 filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 72 (1.4 g, 98%). EI-MSm / z: [M+H] + 509.19.

[0577] Preparation of intermediate compound 73

[0578] Potassium carbonate (1.96 g, 14.15 mmol) was added to a solution of intermediate compound 72 (790 mg, 2.76 mmol) in methanol (20 mL) 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 filtering and concentrating 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.

[0579] Preparation of intermediate compound 74

[0580] 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 methanesulfonyl 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. It was filtered and concentrated under reduced pressure to give intermediate compound 74 (380 mg, crude material), which was used without further purification. EI-MS m / z: [M + H] + 467.17.

[0581] Preparation of intermediate compound 76

[0582] 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. WO2022 / 155518A1) 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 filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 76 (468 mg, 68%). EI-MSm / z: [M+H] + 1093.72.

[0583] Preparation of intermediate compound 77

[0584] 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.

[0585] Preparation of intermediate compound 78

[0586] To a solution of intermediate compound 77 (256 mg, 0.27 mmol) in N,N-dimethylformamide (3 mL) was added N,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboximidamide (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 obtain intermediate compound 78 (103 mg, 32%). EI-MS m / z: [M + H] + 1192.17.

[0587] Preparation of compound 79

[0588] 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%).

[0589] 1 H-NMR (400MHz, CD3OD) δ7.29(d,J=1.4Hz,1H),7.26(d,J=1.4Hz,1H),6.59(d,J=0.6H z,1H),6.56(d,J=0.6Hz,1H),5.88–5.77(m,2H),5.75–5.69(m,2H),5.02(d,J=3.3Hz ,4H),4.64–4.50(m,6H),3.94(d,J=4.2Hz,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=7.8Hz,2H),1.34(dt,J=14.6,7.1Hz,6H). EI-MSm / z:[M+H] + 891.09.

[0590] <Example 13> Preparation of Compound 89

[0591]

[0592] Preparation of intermediate compound 80

[0593] To a solution of 4-piperidineethanol (5 g, 38.7 mmol) in dichloromethane (200 mL) was added triethylamine (8.1 mL, 58.05 mmol) and di-tert-butyl dicarbonate (9.78 mL, 42.57 mmol) under nitrogen. The reaction solution was stirred at room temperature for 3 hours, and 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 filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 80 (7.25 g, 81.6%).

[0594] 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 = 8.0Hz, 2H), 3.64 (t, J = 8.0Hz, 2H), 4.03-4.08 (m, 2H). EI-MSm / z:[M+Na] + 252.26.

[0595] Preparation of intermediate compound 81

[0596] Under nitrogen, oxalyl chloride (0.34 mL, 3.93 mmol) was slowly added to a solution of dimethyl sulfoxide (0.93 mL, 13.08 mmol) in dichloromethane (20 mL) at -78 ° C. 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, 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 filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 81 (990 mg, 99%).

[0597] 1 H-NMR (300MHz, 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-MSm / z:[M+H] + 228.23.

[0598] Preparation of intermediate compound 82

[0599] Under nitrogen, to a solution of lithium chloride (17.2g, 40.65mmol) in acetonitrile (40mL) at room temperature, triethyl phosphonoacetate (7.33mL, 50.81mmol) was added. After stirring for 5 minutes, triethylamine (5.67mL, 40.65mmol) was added to the reaction solution at room temperature and kept for 10 minutes. Compound 81 (7.7g, 33.88mmol) in acetonitrile (60mL) was added to the reaction solution. After stirring at room temperature for 17 hours, the reaction solution was diluted with ethyl acetate (150mL) and washed with distilled water (150mL). The organic layer was dried over anhydrous magnesium sulfate. After filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 82 (5.59g, 58.2%).

[0600] 1H-NMR (400MHz, 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,2H),1.67(s,2H),1.59-1.55(m,1H),1.54(s,9H),1.18-1.11(m,2H). EI-MSm / z:[M+H] + 284.01.

[0601] Preparation of intermediate compound 83

[0602] Under nitrogen, diisobutylaluminum hydride (1.0 M cyclohexane solution, 19 mL, 19.00 mmol) was added to a solution of intermediate compound 82 (2.5 g, 8.82 mmol) in dichloromethane (30 mL) at -78 ° C. After stirring for 3 hours at -78 ° C, 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%).

[0603] 1 H-NMR (400MHz, CDCI3): δ = 5.70-5.65 (m, 2H), 4.18-4.01 (m, 4H), 2.69 (t, 2H, J = 12.6Hz), 2.02 (t, 2H, J = 5.6Hz), 1.72-1.62 (m, 3H), 1.47 (s, 9H), 1.1 1(qd,2H,J=12.2Hz,3.9Hz). EI-MSm / z:[M+H] + 256.06.

[0604] Preparation of intermediate compound 84

[0605] 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 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. After filtration, the filtrate was removed under reduced pressure and used without purification to obtain intermediate compound 84 (2.59 g, crude material).

[0606] Preparation of intermediate compound 85

[0607] To a solution of intermediate compound 5 (1 g, 4.62 mmol) in N, N-dimethylformamide (15 mL) was 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 obtain intermediate compound 85 (1.18 g, 56.3%).

[0608] 1 H-NMR (400MHz, 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-MSm / z:[M+H] + 454.17.

[0609] Preparation of intermediate compound 86

[0610] 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 and 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 obtain intermediate compound 86 (157 mg, 15.6%). EI-MS m / z: [M + H] + 829.22.

[0611] Preparation of intermediate compound 87

[0612] To a solution of intermediate compound 86 (157 mg, 0.19 mmol) in methanol (3 mL) was added ammonia solution (28% to 30% ammonia, 0.5 mL, 4.74 mmol) and sodium bisulfite (Na2S2O4, 330 mg, 1.89 mmol). After stirring at room temperature for 1 hour, the reaction solution was filtered through celite and washed with methanol. After filtration, the filtrate was removed under reduced pressure and used without purification to give intermediate compound 87 (151 mg, crude material), which was used without further purification.

[0613] Preparation of intermediate compound 88

[0614] 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 obtain intermediate compound 88 (100 mg, 54%). EI-MS m / z: [M+H] + 961.13.

[0615] Preparation of compound 89

[0616] 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.

[0617] <Example 14> Preparation of Compound 95

[0618]

[0619] Preparation of intermediate compound 90

[0620] To a solution of 3-aminophenol (1 g, 9.16 mmol) in tetrahydrofuran (10 mL) was added di-tert-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%).

[0621] 1 H-NMR (400MHz, CDCl3) δ9.24(s,1H),9.18(s,1H),6.88(m,2H),6.83(m,1H),6.35(m,1H),1.46(s,9H). EI-MSm / z:[M+H] + 209.10.

[0622] Preparation of intermediate compound 91

[0623] Under nitrogen, cesium carbonate (560 mg, 1.72 mmol) and intermediate compound 5 (551 mg, 1.57 mmol) were added to a solution of intermediate compound 90 (300 mg, 1.43 mmol) in N, N-dimethylformamide (5 mL) 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 adding dichloromethane and diethyl ether, then filtered and dried to give intermediate compound 91 (474 mg, 69%), which was used without further purification.

[0624] 1 H-NMR(400MHz, CDCl3)δ9.29(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,1H),6.14(m,2H),4.87(d,J=3.6Hz,2H),4.57(d,J=3.2Hz,2H),1.46(s,9H). EI-MSm / z:[M+H] + 478.00.

[0625] Preparation of intermediate compound 92

[0626] 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.

[0627] Preparation of intermediate compound 93

[0628] To a solution of intermediate compound 92 (100 mg, 0.11 mmol) in methanol (5 mL) was added ammonia solution (28% to 30% ammonia, 0.209 mL) and sodium bisulfite (Na2S2O4, 204 mg, 1.172 mmol) under nitrogen. After stirring at room temperature for 1 hour, 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 material), which was used without further purification. EI-MSm / z: [M+H] + 823.36.

[0629] Preparation of intermediate compound 94

[0630] Under nitrogen, to a solution of intermediate compound 93 (100 mg, 0.12 mmol, crude material) 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. 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 by dichloromethane and diethyl ether, then filtered and dried to give intermediate compound 94 (54 mg, 53%). EI-MSm / z: [M+H] + 984.84.

[0631] Preparation of Compound 95

[0632] 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.

[0633] <Example 15> Preparation of Compound 104

[0634]

[0635] Preparation of intermediate compound 96

[0636] 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 while stirring for 17 hours, the reaction solution was filtered through celite and concentrated under reduced pressure to give intermediate compound 96 (2.7 g, crude material) without purification.

[0637] 1 H-NMR (400MHz, DMSO-d6): δ7.48(d,J=15.8Hz,1H),7.06(t,J=7.8Hz,1H),6.85-6 .79(m,2H),6.65-6.61(m,1H),6.41(d,J=15.8Hz,1H),5.19(s,2H),3.71(s,3H).

[0638] Preparation of intermediate compound 97

[0639] To the solution of intermediate compound 96 (2.7g, 15.24mmol) dissolved in 1,4-dioxane (10mL), di-tert-butyl dicarbonate (3.85mL, 16.76mmol) and saturated sodium bicarbonate aqueous solution (3.2g, 38.09mmol) dissolved in water (50mL) were added. After stirring at room temperature for 21 hours, the reaction mixture was diluted with ethyl acetate (50mL) and washed with distilled water (50mL×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 obtain intermediate compound 97 (3g, 71%).

[0640] 1 H-NMR (CD3OD, 400MHz) δ7.65 (s, 1H), 7.62 (d, 1H, J = 16.1Hz), 7.43 (d, 1H, J = 7.6Hz), 7.28 ( t,1H,J=7.6Hz),7.20(d,1H,J=7.6Hz),6.47(d,1H,J=16.1Hz),3.76(s,3H),1.51(s,9H).

[0641] Preparation of intermediate compound 98

[0642] Under nitrogen, diisobutylaluminum hydride (1.0 M in cyclohexane, 19 mL, 18.75 mmol) was added to a solution of intermediate compound 97 (1.3 g, 4.69 mmol) in dichloromethane (20 mL) 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.

[0643] Preparation of intermediate compound 99

[0644] 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.

[0645] Preparation of intermediate compound 100

[0646] To a solution of intermediate compound 4 (762 mg, 3.52 mmol) in N,N-dimethylformamide (15 mL) was 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.

[0647] Preparation of intermediate compound 101

[0648] 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 obtain intermediate compound 101 (316 mg, 34%). EI-MSm / z: [M + H]+ 823.42.

[0649] Preparation of intermediate compound 102

[0650] To a solution of intermediate compound 101 (316 mg, 0.38 mmol) in methanol (6 mL) was added aqueous ammonia solution (28% to 30% ammonia, 0.7 mL, 9.6 mmol) and sodium bisulfite (Na2S2O4, 668 mg, 3.84 mmol). After stirring at room temperature for 1 hour, 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 material), which was used without further purification. EI-MS m / z: [M+H] + 793.51.

[0651] Preparation of intermediate compound 103

[0652] 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 and maintained for 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 103 (12 mg, 3%). EI-MSm / z: [M+H] + 954.47.

[0653] Preparation of Compound 104

[0654] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 103 (12 mg, 0.001 mmol) in dichloromethane (1 mL) at 0°C. After stirring at room temperature for 0.5 hours, 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.

[0655] <Example 16> Preparation of Compound 110

[0656]

[0657] Preparation of intermediate compound 105

[0658] To a solution of tert-butyl propane-2-en-1-ylcarbamate (1.0 g, 6.44 mmol) in N,N-dimethylformamide (9 mL) and methanol (1 mL) was 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) and washed with saturated aqueous ammonium chloride solution (50 mL × 2) and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 105 (373 mg, 29%).

[0659] 1 H-NMR (400MHz, CDCl3) δ7.65 (s, 1H), 5.09 (s, 1H), 4.43 (d, J = 6.0Hz, 2H), 1.46 (s, 9H).

[0660] Preparation of intermediate compound 106

[0661] Under nitrogen, potassium carbonate (102 mg, 0.74 mmol) was added 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) at room temperature. 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 filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 106 (146 mg, 50%).

[0662] 1 H-NMR (400MHz, DMSO) δ8.27(s,1H),8.06(s,1H),7.86(d,J=8.3Hz,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=6.0Hz,2H),4.84(d,J=5.2Hz,2H),4.16(d,J=5.9Hz,2H),1.38(s,9H).

[0663] Preparation of intermediate compound 107

[0664] 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 and 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 obtain intermediate compound 107 (352 mg, 73%). EI-MSm / z: [M + H] + 842.42.

[0665] Preparation of intermediate compound 108

[0666] To a solution of intermediate compound 107 (352 mg, 0.42 mmol) in methanol (10 mL) and distilled water (2 mL) was added ammonia solution (28% to 30% ammonia, 0.6 mL) and sodium bisulfite (Na2S2O4, 728 mg, 4.2 mmol) under nitrogen. After stirring at room temperature for 2 hours, 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.

[0667] Preparation of intermediate compound 109

[0668] 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 at room temperature and kept for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 109 (80 mg, 66%). EI-MSm / z: [M+H] + 973.54.

[0669] Preparation of Compound 110

[0670] Under nitrogen, trifluoroacetic acid (1 mL) was added to a solution of intermediate compound 109 (80 mg, 0.08 mmol) in dichloromethane (3 mL) at -78°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 intermediate compound 110 (25 mg, 35%).

[0671] 1 H-NMR (400MHz, DMSO) δ12.84(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=2.6Hz,2H),5.9 6–5.79(m,3H),4.95–4.87(m,6H),4.58–4.48(m,6H),4.10(q,J=5.7Hz,2H),3.70(s,3H),2.10(d,J=6.5Hz,6H),1.26(q,J=7.1Hz,6H). EI-MSm / z:[M+H] + 873.55.

[0672] <Example 17> Preparation of Compound 120

[0673]

[0674] Preparation of intermediate compound 111

[0675] To a solution of (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (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 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL) and 0.1N 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 obtain intermediate compound 111 (1.65 g, 75%).

[0676] 1 H-NMR (400MHz, CDCl3) δ9.60–9.44(m,1H),4.13(d,J=61.6Hz,1H),3.62–3.40(m,2H),2.23–1.82(m,4H),1.46(d,J=19.7Hz,9H).

[0677] Preparation of intermediate compound 112

[0678] 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 filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 112 (1.43 g, 67%).

[0679] 1 H-NMR (400MHz, CDCl3) δ6.14(t,J=10.0Hz,1H),5.74(d,J=11.4Hz,1H),5.32–5.22(m,1H),3.71(s,3H),3.59–3.34(m, 2H), 2.31 (d, J = 12.9Hz, 1H), 1.84 (ddt, J = 12.5, 8.4, 6.0Hz, 2H), 1.67 (dt, J = 13.2, 6.6Hz, 1H), 1.42 (d, J = 22.5Hz, 9H).

[0680] Preparation of intermediate compound 113

[0681] 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 1N 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.

[0682] 1 H-NMR (400MHz, CDCl3) δ6.91(d,J=13.0Hz,1H),5.84(d,J=15.6Hz,1H),4.46(d,J =56.8Hz,1H),3.45(s,2H),2.10(s,1H),1.87(q,J=6.6Hz,5H),1.49–1.40(m,9H).

[0683] Preparation of intermediate compound 114

[0684] Isobutyl chloroformate (0.37 mL, 2.87 mmol) and triethylamine (0.46 mL, 3.28 mmol) were added to a solution of intermediate compound 113 (660 mg, 2.74 mmol) in tetrahydrofuran (10 mL) 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 and filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate compound 114 (494 mg, 79%).

[0685] 1 H-NMR (400MHz, CDCl3) δ5.66(s,1H),4.31(d,J=39.6Hz,1H),4.14(d,J=5.0Hz,2H),3.39(s,1 H), 2.01 (s, 1H), 1.94–1.76 (m, 3H), 1.71 (ddd, J = 11.0, 6.7, 3.1Hz, 4H), 1.45 (d, J = 6.8Hz, 9H).

[0686] Preparation of intermediate compound 115

[0687] 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 methanesulfonyl 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.

[0688] 1 H-NMR (400MHz, CDCl3) δ5.82(s,1H),5.67(s,1H),4.72(d,J=6.5Hz,2H),4.32(d,J=39.2Hz,1H),4.17 –4.09(m,1H),3.40(s,1H),3.02(s,3H),2.05(s,1H),1.84(p,J=6.4Hz,2H),1.58(s,2H),1.44(s,9H).

[0689] Preparation of intermediate compound 116

[0690] Under nitrogen, potassium carbonate (314 mg, 2.27 mmol) was added 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) at room temperature. 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 obtain intermediate compound 116 (563 mg, 63%).

[0691] 1 H-NMR (400MHz, DMSO) δ8.25(s,1H),8.04(d,J=1.9Hz,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 = 5.9Hz, 2H), 4.21 (s, 1H), 3.29–3.19 (m, 2H), 1.77 (q, J = 6.7Hz, 2H), 1.65 (s, 1H), 1.33 (d, J = 27.7Hz, 9H).

[0692] Preparation of intermediate compound 117

[0693] 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 obtain intermediate compound 117 (263 mg, 46%). EI-MSm / z: [M + H] + 801.41.

[0694] Preparation of intermediate compound 118

[0695] To a solution of intermediate compound 117 (263 mg, 0.32 mmol) in methanol (10 mL) and distilled water (2 mL) was added ammonia solution (28% to 30% ammonia, 0.5 mL) and sodium bisulfite (Na2S2O4, 572 mg, 3.28 mmol) under nitrogen. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The reaction mixture was filtered with diatomaceous earth and washed with methanol. The filtrate was concentrated and 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 obtain intermediate compound 118 (223 mg, 88%) without purification. EI-MSm / z: [M+H] + 771.43.

[0696] Preparation of intermediate compound 119

[0697] To a solution of intermediate compound 118 (223 mg, 0.29 mmol) in N,N-dimethylformamide (2 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.07 mL, 0.43 mmol) and triethylamine (0.12 mL, 0.87 mmol) under nitrogen. 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 obtain intermediate compound 119 (99 mg, 36%). EI-MSm / z: [M+H] + 932.48.

[0698] Preparation of Compound 120

[0699] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 119 (99 mg, 0.11 mmol) in dichloromethane (1.6 mL) 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 intermediate compound 120 (56 mg, 64%).

[0700] <Example 18> Preparation of Compound 127

[0701]

[0702] Preparation of intermediate compound 121

[0703] To a solution of 5-nitroindole (1g, 6.13mmol) in methanol (15mL) was added palladium / charcoal (85mg). After stirring at room temperature for 3 hours under a hydrogen balloon, the reaction solution was passed through diatomaceous earth. The filtrate was concentrated under reduced pressure. The concentrated filtrate was dissolved in N,N-dimethylformamide (15mL) at room temperature, and then di-tert-butyl dicarbonate (1.3g, 6.13mmol) and diisopropylethylamine (0.79g, 6.13mmol) were added. After stirring at room temperature for 5 hours, the reaction mixture was diluted with ethyl acetate (50mL) and washed with saturated aqueous ammonium chloride solution (50mL×2) and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure to give intermediate compound 121 (1.15g, 80%), which was used without further purification.

[0704] 1 H-NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.25(s,1H),7.96(s,1H),7.87(s,1H),7.42(d,J=8.4Hz,1H),7.35(d,J=8.8Hz,1H),1.48(s,9H).

[0705] Preparation of intermediate compound 122

[0706] At room temperature, potassium carbonate (711 mg, 5.14 mmol) and trans-1,4-dibromo-2-butene (2.75 g, 12.86 mmol) were added to a solution of intermediate compound 121 (1 g, 4.28 mmol) in N, N-dimethylformamide (40 mL). Stirred at 60 ° C for 18 hours for 6 hours. The reaction solution was diluted with ethyl acetate (50 mL) and 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 obtain intermediate compound 122 (372 mg, 23%).

[0707] 1 H-NMR (400MHz, DMSO) δ9.21(s,1H),8.19(s,1H),7.85(s,1H),7.49(d,J=8.9Hz,1H),7.21(d,J=8.5Hz,1H),6.14(dd,J=1 5.1, 7.1Hz, 1H), 5.88 (q, J = 7.5Hz, 1H), 5.05 (d, J = 6.0Hz, 2H), 4.23 (d, J = 6.8Hz, 1H), 4.16 (d, J = 7.3Hz, 2H), 1.48 (s, 9H).

[0708] Preparation of intermediate compound 123

[0709] To a solution of intermediate compound 122 (369 mg, 1.0 mmol) in N, N-dimethylformamide (4 mL) was added 4-chloro-3-hydroxy-5-nitrobenzamide (182 mg, 0.84 mmol) and potassium carbonate (174 mg, 1.26 mmol) under nitrogen. 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 obtain intermediate compound 123 (312 mg, 74%).

[0710] 1 H-NMR (400MHz, DMSO-d6) δ9.23(s,1H),8.24(d,J=17.5Hz,2H),8.06(s,1H),7.87(d,J=13.6Hz,2H),7.78(s,1H),7.50(d,J=9.2Hz,1 H), 7.22 (d, J = 9.2Hz, 1H), 6.21 (dt, J = 15.8, 6.2Hz, 1H), 6.01–5.90 (m, 1H), 5.10 (d, J = 6.1Hz, 2H), 4.86 (d, J = 5.3Hz, 2H), 1.48 (s, 9H). EI-MSm / z:[M+H] + 502.31.

[0711] Preparation of intermediate compound 124

[0712] 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 obtain 124 (crude material), which was used without further purification. EI-MSm / z: [M+H] + 877.59.

[0713] Preparation of intermediate compound 125

[0714] To a solution of intermediate compound 124 (0.20 mmol, crude material) in methanol (7 mL) and distilled water (1 mL) was added ammonia solution (28% to 30% ammonia, 0.2 mL) and sodium bisulfite (Na2S2O4, 355 mg, 2.04 mmol). After stirring at room temperature for 1 hour, 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 material), which was used without further purification. EI-MS m / z: [M+H] + 847.58.

[0715] Preparation of intermediate compound 126

[0716] To a solution of intermediate compound 125 (0.20 mmol, crude material) 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 at room temperature and maintained for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 126 (83 mg, 40%). EI-MSm / z: [M+H] + 1008.64.

[0717] Preparation of Compound 127

[0718] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 126 (33 mg, 0.03 mmol) in dichloromethane (1.6 mL) 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 intermediate compound 127 (11 mg, 27%).

[0719] 1H-NMR(400MHz,DMSO-d6)δ12.84(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=9.2Hz,1H),6.52(s,2H ),6.02(dt,J=14.1,6.5Hz,1H),5.79(s,2H),4.90(dd,J=20.3,7.7Hz,5H),4.52(d q,J=14.1,6.3Hz,5H),3.69(s,3H),2.10(d,J=10.6Hz,6H),1.25(q,J=7.9Hz,6H). EI-MS m / z:[M+H] + 908.54.

[0720] <Example 19> Preparation of Compound 133

[0721]

[0722] Preparation of intermediate compound 128

[0723] To a solution of tert-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 hours, 1,3-dibromopropane (3.8 mL, 37.8 mmol) was added to the reaction solution at room temperature and maintained for 3 hours. 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 obtain intermediate compound 128 (3.9 g, 57%).

[0724] 1 H-NMR (400MHz, CDCl3) δ3.86 (s, 1H), 3.49–3.41 (m, 2H), 3.07–2.99 (m, 2H), 2.03 (p, J = 6.8Hz, 2H), 1.52–1.44 (m, 9H).

[0725] Preparation of intermediate compound 129

[0726] Under nitrogen, potassium carbonate (1.1 g, 8.58 mmol) was added 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) at room temperature. 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 obtain intermediate compound 129 (2.0 g, 80%).

[0727] 1 H-NMR (400MHz, DMSO) δ8.28 (s, 1H), 8.05 (d, J = 2.1Hz, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 6.02–5.83 (m, 2H), 4.81 (d, J = 5.1Hz, 2H), 3.26 (d, J = 6.0Hz, 2H), 2.84 (t, J = 6.8Hz, 2H), 2.00 (t, J = 7.3Hz, 2H), 1.37 (s, 9H).

[0728] Preparation of intermediate compound 130

[0729] 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 obtained solid was filtered and washed with ether. The filtered solid was purified by column chromatography to obtain intermediate compound 130 (1.0 g, 28%). EI-MSm / z: [M+H] + 816.52.

[0730] Preparation of intermediate compound 131

[0731] To a solution of intermediate compound 130 (1.0 g, 1.29 mmol) in methanol (20 mL) and water (4 mL) was added ammonia solution (28% to 30% ammonia, 1.4 mL) and sodium bisulfite (Na2S2O4, 2.2 g, 12.87 mmol) under nitrogen. 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 and 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 obtain intermediate compound 131 (1.0 g, crude material). EI-MSm / z: [M+H]+ 786.58.

[0732] Preparation of intermediate compound 132

[0733] Under nitrogen, 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. 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 and kept for 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-MSm / z: [M+H] + 947.62.

[0734] Preparation of compound 133

[0735] 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 at -0 ° C under nitrogen. 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.

[0736] <Example 20> Preparation of Compound 139

[0737]

[0738] Preparation of intermediate compound 134

[0739] 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.

[0740] 1H-NMR (400MHz, DMSO) δ8.27(s,1H),8.07(d,J=1.7Hz,1H),7.90(s,1H),7.78(s,1H),6.11–5.94(m,2H),4.88(d,J=4.7Hz,2H),3.97(d,J=5.5Hz,2H).

[0741] Preparation of intermediate compound 135

[0742] 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 tert-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.

[0743] 1 H-NMR (400MHz, DMSO) δ8.27(s,1H),8.06(s,1H),7.86(d,J=8.3Hz,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=6.0Hz,2H),4.84(d,J=5.2Hz,2H),4.16(d,J=5.9Hz,2H),1.38(s,9H).

[0744] Preparation of intermediate compound 136

[0745] 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 obtain intermediate compound 136 (241 mg, 55%). EI-MSm / z: [M + H]+ 842.54.

[0746] Preparation of intermediate compound 137

[0747] To a solution of intermediate compound 136 (241 mg, 0.29 mmol) in methanol (10 mL) and water (2 mL) was added ammonia solution (28% to 30% ammonia, 0.4 mL) under nitrogen, and sodium bisulfite (Na2S2O4, 498 mg, 2.86 mmol) was added to the reaction mixture. 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 and 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 material), which was used without further purification. EI-MSm / z: [M+H] + 812.54.

[0748] Preparation of intermediate compound 138

[0749] Under nitrogen, to a solution of intermediate compound 137 (168 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL) at room temperature, compound 2 (48 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was added to the reaction mixture. 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 and kept for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 138 (175 mg, 87%). EI-MSm / z: [M+H] + 973.60.

[0750] Preparation of Compound 139

[0751] Under nitrogen, trifluoroacetic acid (0.5 mL) was added to a solution of intermediate compound 138 (72 mg, 0.07 mmol) in dichloromethane (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 intermediate compound 139 (51 mg, 56%). EI-MS m / z: [M+H] + 873.52.

[0752] <Example 21> Preparation of Compound 147

[0753]

[0754] Preparation of intermediate compound 140

[0755] To a solution of di-tert-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 at room temperature and kept for 17 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 magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 140 (1.05 g, 71%).

[0756] 1 H-NMR (400MHz, CDCl3) δ7.79(d,J=1.9Hz,1H),7.63(d,J=1.9Hz,1H),6.62(s,1H),5.95(dt,J=16.0, 5.2Hz, 1H), 5.81 (dt, J = 15.7, 5.6Hz, 1H), 4.74 (d, J = 5.4Hz, 2H), 4.24 (d, J = 5.1Hz, 2H), 1.48 (s, 18H).

[0757] Preparation of intermediate compound 141

[0758] 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 obtain intermediate compound 141 (223 mg, 69%).

[0759] 1 H-NMR (400MHz, DMSO) δ8.24 (s, 1H), 8.04 (d, J = 2.2Hz, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7. 04(s,1H),5.95–5.72(m,2H),4.80(d,J=5.5Hz,2H),3.60(d,J=6.0Hz,2H),1.37(s,9H).

[0760] Preparation of intermediate compound 142

[0761] 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 and maintained for 20 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 142 (297 mg, 23%). EI-MS m / z: [M + H] + 761.45.

[0762] Preparation of intermediate compound 143

[0763] To a solution of intermediate compound 142 (294 mg, 0.39 mmol) in methanol (6 mL) was added ammonia solution (28% to 30% ammonia, 0.7 mL, 9.5 mmol) and sodium bisulfite (Na2S2O4, 672 mg, 3.86 mmol). After stirring at room temperature for 1 hour, 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 material), which was used without further purification. EI-MS m / z: [M+H] + 731.5.

[0764] Preparation of intermediate compound 144

[0765] 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 obtain intermediate compound 144 (122 mg, 49%). EI-MSm / z: [M+H] + 892.5.

[0766] Preparation of intermediate compound 145

[0767] 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 warmed to room temperature and stirred under nitrogen for 1 hour, then concentrated under reduced pressure to give intermediate compound 145 (63 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] +792.53.

[0768] Preparation of intermediate compound 146

[0769] 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-(tert-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 material), which was used without further purification. EI-MS m / z: [M+H] + 1004.59.

[0770] Preparation of Compound 147

[0771] 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%).

[0772] <Example 22> Preparation of Compound 151

[0773]

[0774] Preparation of intermediate compound 148

[0775] 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 111471056A) 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 material), which was used without further purification.

[0776] Preparation of intermediate compound 149

[0777] To a solution of intermediate compound 148 (crude material) 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%).

[0778] 1 H-NMR (400MHz, CDCl3), δ2.90 (q, J=7.6Hz, 2H), 2.54 (s, 3H), 2.72 (t, J=7.6Hz, 3H). EI-MSm / z:[M+H] + 197.21.

[0779] Preparation of intermediate compound 150

[0780] 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 and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 150 (25 mg, 19%). EI-MSm / z: [M+H] + 959.24.

[0781] Preparation of Compound 151

[0782] 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%).

[0783] 1 H-NMR(400MHz,DMSO-d6)δ8.00–7.83(m,2H),7.65(s,1H),7.54(s,1H),7.36(s,1 H),7.31(s,1H),6.51(s,1H),5.91(d,J=15.0Hz,1H),5.76(d,J=14.3Hz,2H),4.8 9(s,3H),4.66(d,J=5.9Hz,1H),4.51(d,J=7.3Hz,2H),3.71(s,2H),2.82(q,J=7. 9Hz, 1H), 2.40 (s, 2H), 2.10 (s, 2H), 1.25 (t, J = 7.2Hz, 2H), 1.02 (t, J = 7.7Hz, 2H). EI-MS m / z: [M+H] + 859.27.

[0784] <Example 23> Preparation of Compound 155

[0785]

[0786] Preparation of intermediate compound 152

[0787] To a solution of 4-ethyl-2-methylthiazole-5-carboxylic acid (100 mg, 0.58 mmol) in tetrahydrofuran (1 mL) were 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 material), which was used without further purification.

[0788] Preparation of intermediate compound 153

[0789] To a solution of intermediate compound 152 (crude material) 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. 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.

[0790] Preparation of intermediate compound 154

[0791] 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 and kept for 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 154 (30 mg, 21%). EI-MSm / z: [M+H] + 975.26.

[0792] Preparation of compound 155

[0793] 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%).

[0794] 1 H-NMR (400MHz, DMSO-d6) δ7.88(d,J=14.1Hz,1H),7.82(s,1H),7.56(d,J=8.4Hz,1H ),7.47(s,0H),7.30-7.21(m,2H),6.45(s,1H),5.77(dq,2H),4.81(d,J=17.4Hz,2H ),4.60(d,J=6.0Hz,1H),4.51(s,1H),4.44(d,J=7.7Hz,1H),3.64(s,2H),3.03(q,J =7.9Hz,2H),2.66(s,2H),2.02(s,2H),1.19(t,J=7.4Hz,2H),1.07(t,J=7.7Hz,2H). EI-MSm / z:[M+H] + 875.24.

[0795] <Example 24> Preparation of Compound 160

[0796]

[0797] Preparation of intermediate compound 156

[0798] 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.

[0799] Preparation of intermediate compound 157

[0800] 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 obtain intermediate compound 157 (352 mg, 90%).

[0801] Preparation of intermediate compound 158

[0802] 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.

[0803] Preparation of intermediate compound 159

[0804] 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 material), which was used without further purification.

[0805] Preparation of Compound 160

[0806] To a solution of intermediate compound 159 (59 mg, crude material) 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%).

[0807] <Example 25> Preparation of Compound 164

[0808]

[0809] Preparation of intermediate compound 161

[0810] 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-MSm / z: [M+H] +304.11.

[0811] Preparation of intermediate compound 162

[0812] To a solution of intermediate compound 66 (50 mg, 0.07 mmol) in N, N-dimethylformamide (2 mL) was 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 obtain intermediate compound 162 (16 mg, 24%). EI-MSm / z: [M+H] + 946.27.

[0813] Preparation of intermediate compound 163

[0814] 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.

[0815] Preparation of Compound 164

[0816] 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 hours, the reaction mixture was adjusted to pH 4 to 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.

[0817] <Example 26> Preparation of Compound 166

[0818]

[0819] Preparation of intermediate compound 165

[0820] 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(tert-butoxycarbonyl)-1H-pyrazole-1-carboximidamide (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 material), which was used without further purification. EI-MS m / z: [M+H] + 1035.01.

[0821] Preparation of Compound 166

[0822] 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.

[0823] <Example 27> Preparation of Compound 168

[0824]

[0825] Preparation of intermediate compound 167

[0826] 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 / 155518A1) 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 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 reverse phase column chromatography to give intermediate compound 167 (958 mg, 38%). EI-MS m / z: [M+H] + 1179.46.

[0827] Preparation of Compound 168

[0828] 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.

[0829] <Example 28> Preparation of Compound 175

[0830]

[0831] Preparation of intermediate compound 169

[0832] 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-tert-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 obtain intermediate compound 169 (5.9 g, 29%).

[0833] 1 H-NMR (400MHz, CDCl3) δ8.19 (s, 1H), 7.63 (s, 1H), 6.34 (s, 1H), 1.64 (d, J = 3.9Hz, 9H), 1.52 (s, 9H).

[0834] Preparation of intermediate compound 170

[0835] To a solution of intermediate compound 169 (1.1 g, 3.88 mmol) in acetonitrile (30 mL) was added potassium carbonate (590 mg, 4.27 mmol), 18-crown-6 (513 mg, 1.94 mmol) and methyl acrylate (367 mg, 4.27). 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 obtain intermediate compound 170 (1.38 g, 96%).

[0836] 1H-NMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.27 (d, J = 3.1Hz, 1H), 3.92 (dt, J = 9.4, 5.8Hz, 2H), 3.71–3.65 (m, 3H), 2.68–2.59 (m, 2H), 1.65 (q, J = 2.4Hz, 9H), 1.54–1.48 (m, 9H). EI-MSm / z:[M+H] + 370.32.

[0837] Preparation of intermediate compound 171

[0838] 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 obtain intermediate compound 171 (950 mg, 94%).

[0839] 1 H-NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.53 (s, 1H), 3.96–3.87 (m, 2H), 3.67 (s, 3H), 2.64 (p, J = 5.0Hz, 2H), 1.50 (s, 9H).

[0840] Preparation of intermediate compound 172

[0841] To a solution of intermediate compound 171 (167 mg, 0.62 mmol) in N,N-dimethylformamide (30 mL) was 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 obtain intermediate compound 172 (177 mg, 71%). EI-MSm / z: [M+H] + 402.24.

[0842] Preparation of intermediate compound 173

[0843] To a solution of intermediate compound 66 (264 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was 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 obtain intermediate compound 173 (133 mg, 34%). EI-MSm / z: [M + H] + 1045.34.

[0844] Preparation of intermediate compound 174

[0845] 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 hour, the reaction mixture was concentrated under reduced pressure to give intermediate compound 174 (135 mg, crude material), which was used without further purification.

[0846] Preparation of compound 175

[0847] To a solution of intermediate compound 174 (135 mg, crude material) in methanol (1 mL) was added lithium hydroxide monohydrate (11.7 mg, 0.28 mmol) dissolved in water (1 mL) at -45 ° C. After stirring at -0 ° C for 2 hours, the reaction mixture was adjusted to pH 4 to 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.

[0848] <Example 29> Preparation of Compound 178

[0849]

[0850] Preparation of intermediate compound 176

[0851] 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 obtain intermediate compound 176 (320 mg, 62%).

[0852] Preparation of intermediate compound 177

[0853] 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. WO2022 / 155518A1) 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-MSm / z: [M+H] + 956.52.

[0854] Preparation of Compound 178

[0855] 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.

[0856] <Example 30> Preparation of Compound 187

[0857]

[0858] Preparation of intermediate compound 179

[0859] To a solution of 3-bromopropanol (2.0 g, 14.39 mmol) in acetone (30 mL) was added potassium thiocyanate (1.8 g, 15.83 mmol) under nitrogen at -0°C. 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 afford Intermediate Compound 179 (1.26 g, 65%).

[0860] 1 H-NMR (400MHz, CDCl3) δ3.65(q,J=5.6Hz,2H),3.01(dq,J=9.3,3.3Hz,2H),2.39–2.30(m,3H),2.04(t,J=5.8Hz,1H),1.83(q,J=6.0Hz,2H).

[0861] Preparation of intermediate compound 180

[0862] 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 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 obtain intermediate compound 180 (2.7 g, 99%).

[0863] 1 H-NMR (400MHz, CDCl3) δ3.74 (q, J = 5.4Hz, 2H), 2.99 (q, J = 6.3Hz, 2H), 2.35–2.30 (m, 3H), 1.81 (q, J = 6.2Hz, 2H), 1.06 (s, 21H).

[0864] Preparation of intermediate compound 181

[0865] To a solution of intermediate compound 180 (2.7 g, 9.29 mmol) in methanol (30 mL) was added iodomethane (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 obtain intermediate compound 181 (1.73 g, 65%).

[0866] 1H-NMR (400MHz, CDCl3) δ3.86–3.73(m,2H),2.60(tt,J=7.0,2.5Hz,2H),2.11(q,J=2.3Hz,3H),1.82(q,J=6.2Hz,2H),1.15–1.02(m,21H).

[0867] Preparation of intermediate compound 182

[0868] 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 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 182 (1.5 g, crude material).

[0869] 1 H-NMR (400MHz, CDCl3) δ3.84 (q, J = 5.4Hz, 2H), 3.28–3.21 (m, 2H), 3.03–2.97 (m, 3H), 2.11–2.03 (m, 2H), 1.06 (d, J = 4.4Hz, 21H).

[0870] Preparation of intermediate compound 183

[0871] To a solution of intermediate compound 182 (1.5 g, crude material) 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 hours, 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 obtain intermediate compound 183 (1.47 g, 91%).

[0872] 1 H-NMR (400MHz, CDCl3) δ4.15 (s, 2H), 3.83 (t, J = 5.2Hz, 2H), 3.51 (d, J = 10.0Hz ,2H),3.25(s,3H),2.10(s,2H),1.29(t,J=5.8Hz,3H),1.06(d,J=4.3Hz,21H).

[0873] Preparation of intermediate compound 184

[0874] To a solution of intermediate compound 183 (1.5 g, 4.02 mmol) in dichloromethane (30 mL) was added hydrochloric acid (4 M 1,4-dioxane solution, 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 obtained aqueous layer was concentrated. Dichloromethane (50 mL) and methanol (5 mL) were added to the reaction mixture. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 184 (752 mg, 89%).

[0875] 1 H-NMR (400MHz, CDCl3) δ4.14(tt,J=8.5,4.5Hz,2H),3.81(t,J=5.4Hz,2H),3.67–3 .42(m,2H),3.31–3.25(m,3H),2.16(q,J=6.1Hz,2H),1.29(dt,J=8.7,4.8Hz,3H).

[0876] Preparation of intermediate compound 185

[0877] 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 methanesulfonyl 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.

[0878] 1 H-NMR (400MHz, CDCl3) δ4.41 (d, J=5.9Hz, 2H), 4.15 (dq, J=10.5, 3.7Hz, 2H), 3.51 (d, J=53.9H z, 2H), 3.30 (q, J = 2.4Hz, 3H), 3.06 (q, J = 2.4Hz, 3H), 2.40 (d, J = 8.7Hz, 2H), 1.35–1.25 (m, 3H).

[0879] Preparation of intermediate compound 186

[0880] 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. WO2022 / 155518A1) 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-MSm / z: [M+H] + 914.41.

[0881] Preparation of Compound 187

[0882] 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.

[0883] <Example 31> Preparation of Compound 197

[0884]

[0885] Preparation of intermediate compound 188

[0886] To a solution of intermediate compound 4 (400 mg, 1.85 mmol) in N, N-dimethylformamide (5 mL) was 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 obtain intermediate compound 188 (600 mg, 80%).

[0887] 1H-NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.73 (d, J = 4.3Hz, 1H), 4.38 (q, J = 6.0Hz, 2H), 4.13 (q, J = 6.5Hz, 2H) ,3.81–3.65(m,1H),3.54(d,J=14.8Hz,1H),3.37–3.25(m,3H),2.56–2.48(m,2H),1.29(q,J=6.6Hz,3H).

[0888] Preparation of intermediate compound 189

[0889] To a solution of intermediate compound 188 (600 mg, 1.47 mmol) in ethanol (10 mL) was added tert-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.

[0890] Preparation of intermediate compound 190

[0891] 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% to 30% ammonia, 1 mL) and sodium bisulfite (Na2S2O4, 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-MSm / z: [M+H] + 528.39.

[0892] Preparation of intermediate compound 191

[0893] 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 mmol, 0.84 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to the reaction solution at room temperature and maintained for 17 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 191 (390 mg, 88%). EI-MSm / z: [M+H] + 689.37.

[0894] Preparation of intermediate compound 192

[0895] 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 1,4-dioxane solution, 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.

[0896] Preparation of intermediate compound 193

[0897] 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 obtain intermediate compound 193 (127 mg, 34%). EI-MS m / z: [M + H] + 1004.40.

[0898] Preparation of intermediate compound 194

[0899] 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% to 30% ammonia, 0.2 mL) and sodium bisulfite (220 mg, 1.26 mmol) at -0 ° C. After stirring at room temperature for 2.5 hours, 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.

[0900] Preparation of intermediate compound 195

[0901] 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 mmol, 0.10 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to the reaction mixture at room temperature and kept for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 195 (42 mg, 49%). EI-MSm / z: [M+H] + 1135.55.

[0902] Preparation of intermediate compound 196

[0903] 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 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 196 (50 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 1063.53.

[0904] Preparation of Compound 197

[0905] To a solution of intermediate compound 196 (50 mg, crude material) 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%).

[0906] 1 H-NMR (400MHz, DMSO) δ7.96 (d, J = 20.3Hz, 2H), 7.86 (d, J = 0.8Hz, 1H), 7.67 (dd, J = 14.8 ,1.2Hz,2H),7.41–7.36(m,2H),7.28(dd,J=7.1,1.4Hz,2H),6.53(s,2H),5.87–5.54( m,5H),4.95–4.85(m,4H),4.54(dq,J=20.2,6.5Hz,6H),4.47–4.41(m,2H),4.01(t,J= 6.1Hz, 3H), 2.12 (d, J = 7.1Hz, 6H), 2.00 (q, J = 7.1Hz, 2H), 1.27 (dt, J = 9.3, 7.1Hz, 6H). EI-MSm / z:[M+H] + 963.53.

[0907] <Example 32> Preparation of Compound 199

[0908]

[0909] Preparation of intermediate compound 198

[0910] To a solution of intermediate compound 64 (90 mg, 0.08 mmol) in N,N-dimethylformamide (10 mL) was added 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) under nitrogen. 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.

[0911] Preparation of Compound 199

[0912] Under nitrogen, trifluoroacetic acid (1 mL) was added to a solution of intermediate compound 198 (32 mg, 0.02 mmol) in dichloromethane (3 mL) at 0°C. After stirring at room temperature for 0.5 hours, 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.

[0913] <Example 33> Preparation of Compound 212

[0914]

[0915] Preparation of intermediate compound 200

[0916] Under nitrogen, 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. 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 solution (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 obtain intermediate compound 200 (2.72 mg, 63%).

[0917] 1 H-NMR (400MHz, CDCl3) δ7.62(d,J=16.0Hz,1H),7.34-7.27(m,5H),5.22(d,J=16.0Hz,1H),4.57 (t, J=4.0Hz, 2H), 4.01 (t, J=4.0Hz, 2H), 3.77 (d, J=4.0Hz, 2H), 3.70-7.69 (m, 5H), 3.64 (s, 2H). EI-MSm / z:[M+Na] + 303.27.

[0918] Preparation of intermediate compound 201

[0919] To a solution of intermediate compound 200 (2.7 g, 9.63 mmol) in methanol (10 mL) was added palladium / charcoal (540 mg). After stirring at room temperature under a hydrogen balloon for 4 hours, 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.

[0920] 1 H-NMR (400MHz, CDCl3) δ3.80-3.60 (m, 13H), 2.60 (dd, J=8.0, 4.0Hz, 2H). EI-MSm / z:[M+Na] + 215.23, [M+H] + 193.30.

[0921] Preparation of intermediate compound 202

[0922] Under nitrogen, trimethylamine (0.87 mL, 6.24 mmol) and methanesulfonyl anhydride (870 mg, 4.99 mmol) were added to a solution of intermediate compound 201 (480 mg, 2.49 mmol) in dichloromethane (20 mL) 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 material), which was used without further purification. EI-MS m / z: [M + Na] + 293.27, [M+H] + 271.26.

[0923] Preparation of intermediate compound 203

[0924] Under nitrogen, a methylamine solution (1.0 M in tetrahydrofuran, 12 mL) was added to a solution of intermediate compound 202 (680 mg, crude material) in tetrahydrofuran (2 mL) at 0°C. After stirring at 60°C for 16 hours, the reaction solution was concentrated under reduced pressure to give intermediate compound 203 (512 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 206.27.

[0925] Preparation of intermediate compound 204

[0926] Under nitrogen, trimethylamine (1.05mL, 7.49mmol) and di-tert-butyl dicarbonate (0.63mL, 2.74mmol) were added to a solution of intermediate compound 203 (512mg, 2.49mmol) in dichloromethane (4mL) at 0°C. After stirring at room temperature for 12 hours, the reaction solution was diluted with ethyl acetate (50mL) and washed with distilled water (50mL). 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 obtain intermediate compound 204 (450mg, 59%).

[0927] 1 H-NMR (400MHz, CDCl3) δ3.76 (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 = 4.0Hz, 3H), 1.45 (s, 9H). EI-MSm / z:[M+Na] + 328.37.

[0928] Preparation of intermediate compound 205

[0929] 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 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid and concentrated under reduced pressure to give intermediate compound 205 (310 mg, 72%), which was used without further purification.

[0930] 1 H-NMR (400MHz, CDCl3) δ3.77(t,J=6.1Hz,2H),3.67-3.54(m,6H),3.40(s,2H),2.91(s,3H),2.62(t,J=6.1Hz,2H),1.46(s,9H). EI-MSm / z:[M+Na] + 314.37.

[0931] Preparation of intermediate compound 206

[0932] To a solution of methyl 1-O-(4-(tert-butyldimethylsilyloxy)methyl-2-aminophenyl)-2,3,4-tri-O-acetyl-β-d-glucuronide (327 mg, 01.12 mmol, prepared by the method described in International Patent Publication No. WO 2019 / 236954A1) 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) at 0° C. under nitrogen. After stirring at room temperature for 15 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution (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 obtain intermediate compound 206 (290 mg, 61%).

[0933] 1H-NMR (400MHz, DMSO) δ8.67(s,1H),7.89(s,1H),7.03(s,2H),5.56(d,J=7.9Hz,1H),5.49(t,J=9.6Hz,1H),5.21-5.12(m,2H),5.06(t,J=9.8Hz, 1H),4.71(d,J=10.0Hz,1H),3.69(t,J=6.4Hz,2H),3.64(s,3H),3.53(s, 4H), 3.48 (t, J = 5.8Hz, 2H), 2.77 (s, 3H), 2.06-1.95 (m, 9H), 1.37 (s, 9H). EI-MSm / z:[M+H] + 843.50.

[0934] Preparation of intermediate compound 207

[0935] 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 afford Intermediate Compound 207 (200 mg, 90%). EI-MS m / z: [M+H] + 729.40.

[0936] Preparation of intermediate compound 208

[0937] Under nitrogen, bis(pentafluorophenyl) carbonate (59 mg, 0.15 mmol) and N,N'-diisopropylethylamine (0.07 mL, 0.45 mmol) were added to a solution of intermediate compound 207 (110 mg, 0.15 mmol) in dichloromethane (3 mL) 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 × 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-MSm / z: [M+H] + 820.32.

[0938] Preparation of intermediate compound 209

[0939] Under nitrogen, N,N'-diisopropylethylamine (0.10 mL, 0.58 mmol) was added 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) at 0 ° C. 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 obtain intermediate compound 209 (180 mg, 95%). EI-MS m / z: [M / 2 + H] + 807.23.

[0940] Preparation of intermediate compound 210

[0941] 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 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain intermediate compound 210 (130 mg, 79%). EI-MS m / z: [M / 2 + H] + 737.23.

[0942] Preparation of intermediate compound 211

[0943] Under nitrogen, trifluoroacetic acid (0.45 mL) was added to a solution of intermediate compound 210 (130 mg, 0.088 mmol) in dichloromethane (3 mL) 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%).

[0944] 1H-NMR (400MHz, DMSO) δ12.82(s,2H),9.47(s,1H),9.10(s,1H),8.31(s,2H),8.18(s,1H),7.94(d,J=15.0Hz,2H),7.70- 7.58(m,2H),7.40-7.21(m,4H),7.15-6.96(m,2H),6.51(d,J=2.9Hz,2H),5.94-5.85(m,1H),5.79(s,2H),5.68(d,J=15. 6Hz,1H),4.99(s,2H),4.87(dd,J=14.7,8.8Hz,4H),4.52(t,J=13.5Hz,6H),3.89(d,J=9.6Hz,1H),3.70(d,J=6.6Hz,4H) ,3.61(t,J=5.1Hz,2H),3.05(d,J=6.3Hz,2H),2.63(q,J=6.2Hz,3H),2.09(d,J=3.1Hz,5H),1.25(td,J=7.1,5.3Hz,5H). EI-MSm / z:[M / 2+H] + 687.16.

[0945] Preparation of Compound 212

[0946] 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 hour, the reaction mixture was adjusted to pH 6 with 1N aqueous sodium hydroxide solution and then concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain compound 212 (33 mg, 50%).

[0947] 1H-NMR (400MHz, DMSO) δ12.82(s,2H),9.47(s,1H),9.20(s,1H),9.09(s,1H),8.18(s,1H),7.94(d,J=15.6Hz,2H),7.63(d,J=10.1Hz ,2H),7.34(s,1H),7.30(d,J=5.4Hz,2H),7.12-7.01(m,2H),6.51(d,J=3.0Hz,1H),5.90(d,J=15.6Hz,2H),5.79(s,2H),5.68(d,J=1 5.7Hz,1H),4.99(s,2H),4.88(t,J=10.2Hz,4H),4.54(d,J=17.8Hz,6H),3.90(d,J=9.6Hz,1H),3.68(d,J=9.4Hz,5H),3.57(s,4H), 2.72(d,J=4.2Hz,4H), 2.67(p,J=1.8Hz,3H), 2.33(p,J=1.9Hz,4H), 2.09(d,J=3.1Hz,5H), 1.91(s,1H), 1.25(td,J=7.1,5.3Hz,5H). EI-MSm / z:[M / 2+H] + 694.17.

[0948] <Example 34> Preparation of Compound 214

[0949]

[0950] Preparation of Compound 214

[0951] To a solution of compound 55 (50 mg, 0.04 mmol) and intermediate compound 213 (36 mg, 0.05 mmol, intermediate compound 448 prepared by the method described in Korean Patent Application No. 10-2023-0099038) in N,N-dimethylformamide (2 mL) was added N,N'-diisopropylethylamine (0.036 mL, 0.2 mmol) at 0°C under nitrogen. After stirring at room temperature for 20 hours, 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.

[0952] <Example 35> Preparation of Compound 221

[0953]

[0954] Preparation of intermediate compound 215

[0955] Under nitrogen, trimethylamine (2.2 mL, 15.92 mmol) and tert-butyldimethylsilyl chloride (1.0 g, 7.96 mmol) were added to a solution of trans-2-butene-1,4-diol (1.5 g, 11.94 mmol) in dichloromethane (100 mL) 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 solution (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 obtain intermediate compound 215 (1.2 g, 74%).

[0956] 1 H-NMR (400MHz, MeOD) δ5.88–5.71(m,2H),4.19(dt,J=4.3,1.4Hz,2H),4.09–4.02(m,2H),0.92(s,9H).

[0957] Preparation of intermediate compound 216

[0958] Under nitrogen, trimethylamine (1.04mL, 7.41mmol), pyridine (0.60mL, 7.41mmol) and 4-nitrophenyl chloroformate (747mg, 3.70mmol) were added to a solution of intermediate compound 215 (500mg, 2.47mmol) in dichloromethane (10mL) at 0°C. After stirring at room temperature for 20 hours, the reaction solution was diluted with dichloromethane (100mL) and washed with saturated sodium bicarbonate aqueous solution (50mL) and 2% sodium hydroxide aqueous solution (50mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate compound 216 (729mg, 80%).

[0959] 1 H-NMR(400MHz, CDCl3)δ8.32–8.24(m,2H),7.42–7.34(m,2H),6.04–5.84(m,2H),4 .78(dq,J=5.9,1.1Hz,2H),4.23(dq,J=4.2,1.4Hz,2H),0.92(s,9H),0.08(s,6H).

[0960] Preparation of intermediate compound 217

[0961] Under nitrogen, trimethylamine (0.56 mL, 3.97 mmol) and tert-butyl methyl (2- (methylamino) ethyl) carbamate (485 mg, 2.58 mmol) were added to a solution of intermediate compound 216 (729 mg, 1.98 mmol) in dichloromethane (10 mL) at 0 ° C. After stirring at room temperature for 3 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate aqueous solution (50 mL) and 2% sodium hydroxide aqueous 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 obtain intermediate compound 217 (825 mg, 99%).

[0962] 1 H-NMR (400MHz, CDCl3) δ5.85–5.78 (m, 2H), 4.58 (s, 2H), 4.18 (d, J = 2.6Hz, 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).

[0963] Preparation of intermediate compound 218

[0964] Under nitrogen, tetrabutylammonium fluoride solution (1.0M in tetrahydrofuran, 3mL, 2.97mmol) was added to a solution of intermediate compound 217 (825mg, 0.43mmol) in tetrahydrofuran (10mL) at 0°C. After stirring at room temperature for 17 hours, the reaction solution was diluted with dichloromethane (100mL) and washed with saturated sodium bicarbonate aqueous solution (50mL) and saturated ammonium chloride aqueous solution (50mL). 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 obtain intermediate compound 218 (514mg, 86%).

[0965] 1 H-NMR (400MHz, CDCl3) δ5.96–5.73(m,2H),4.58(d,J=5.9Hz,2H),4.15(d,J=12.5Hz ,2H),3.45–3.27(m,4H),2.94(d,J=5.0Hz,3H),2.87(d,J=11.5Hz,3H),1.45(s,9H).

[0966] Preparation of intermediate compound 219

[0967] Under nitrogen, trimethylamine (0.14 mL, 0.99 mmol) and methanesulfonyl anhydride (103 mg, 0.59 mmol) were added to a solution of intermediate compound 218 (150 mg, 0.50 mmol) in dichloromethane (5 mL) 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 material), which was used without further purification.

[0968] 1 H-NMR (400MHz, CDCl3) δ6.06–5.77 (m, 2H), 4.73 (dt, J = 6.2, 1.1Hz, 2H), 4.63 (s, 2H), 3.38 (s, 4H), 3.03 (s, 3H), 2.95 (s, 3H), 2.87 (d, J = 7.8Hz, 3H), 1.45 (s, 9H).

[0969] Preparation of intermediate compound 220

[0970] Under nitrogen, to a solution of intermediate compound 66 (350 mg, 0.37 mmol, intermediate compound 66 was prepared according to 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. 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-MSm / z: [M+H] + 1007.74.

[0971] Preparation of Compound 221

[0972] Under nitrogen, trifluoroacetic acid (0.2 mL) was added to a solution of intermediate compound 220 (75 mg, 0.12 mmol) in dichloromethane (1 mL) 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 material), which was used without further purification. EI-MS m / z: [M+H] + 908.38.

[0973] <Example 36> Preparation of Compounds 222 to 245

[0974] As shown in Table A below, compounds 222 to 245 were prepared according to procedures analogous to those outlined in the above Examples using appropriate starting materials as described in the above Examples or obtained from commercial sources.

[0975] Table A

[0976]

[0977]

[0978]

[0979] <Example 37> Preparation of Comparative Compound #1

[0980] The compound of comparative compound 1 has the following structure and was purchased from ChemScene (#CS-0077291) and used.

[0981]

[0982] <Example 38> Preparation of Comparative Compound #2

[0983] The compound of Comparative Compound #2 has the following structure and was prepared by the method described in US Patent Publication No. 2021-0032269A1.

[0984]

[0985] <Experimental Example 1> Evaluation of STING agonist activity

[0986] To evaluate the activity of STING agonists, reporter cells from Invivogen were used. The cell line used in the experiment was THP1Dual expressing the endogenous STING variant HAQ. TM (InvivoGen#thpd-nfis) and THP1 Dual into which the STING R232 or H232 variant gene was injected after the STING HAQ gene was deleted. TM KI-hSTING–R232 (InvivoGen #thpd-r232 / h232) This cell line has a luciferase reporter gene inserted under the IFN regulatory factor (IRF) promoter, and thus the activity of the IFN regulatory factor (IRF) machinery can be assessed by luciferase expression.

[0987] The reporter cells were cultured at 9.0 × 10 cells / mL using RPMI1640 medium (Gibco, #22400097) supplemented with 10% heat-inactivated FBS, 1× antibiotic-antimycotic (Gibco, #15240062), 10 pg / mL blasticidin (Gibco, #A1113902), and 100 pg / mL Zeocin (Gibco, #R25005). 4 Cells / 100 μL / well were seeded in a 96-well culture plate. The seeded cells were cultured at 37°C, 5% CO2 for 24 hours, and then treated with 100 μL of serially diluted compounds in each well, and then cultured at 37°C, 5% CO2 for 24 hours. After the culture, 20 μL of cell culture medium was transferred to a 96-well white culture plate, and 50 μL / well of QUANTI-Luc was added. TM (InvivoGen #rep-qlcl). Using a microplate reader (Perkin Elmer), the value of the increased luminescence signal in the experimental group treated with drugs was calculated compared with the control group not treated with drugs. EC was derived based on the concentration of the compound using GraphPad Prism. 50 Table 1 below shows the results of evaluating the activity of STING agonists using THP1 reporter cells.

[0988] [Table 1] STING activity using hSTING-R232 cells

[0989]

[0990]

[0991] [Table 2] STING activity using hSTING-HAQ or H232 cells

[0992]

[0993] In addition, to analyze the direct binding potency of the STING agonist compounds described herein to human STING, a human STING WT binding kit (Cisbio, #64BDSTGPEG) was used according to the manufacturer's instructions. The STING agonist compounds were confirmed to bind directly to the human STING protein in vitro, and the resulting data are summarized as EC 50 Presented in Table 3.

[0994] [Table 3] Binding efficacy

[0995] Compound number <![CDATA[EC 50 (nM)]]> Comparison #1 0.52 55 0.22 65 0.43 133 0.43 151 0.13 155 0.40 160 0.47

[0996] <Experimental Example 2> Pharmacokinetic Evaluation

[0997] To evaluate the STING agonist compounds described herein in vivo in naive Balb / C mice, a single dose of 1.5 mg / kg of the STING agonist compounds was administered intravenously to 6- to 8-week-old female BALB / c mice (Orientbio, South Korea). Pharmacokinetics of the STING agonist compounds were studied following injection into the Balb / C mice. Plasma samples were obtained at various time points and stored frozen for analysis. Plasma concentrations of the STING agonist compounds at the indicated time points were measured using LC-MS / MS analysis.

[0998] Briefly, 250 μL of acetonitrile (ACN) solution was added to 50 μL of sample and 50 μL of plasma containing 10 nM dextromethorphan (internal standard), and the solution was vigorously mixed for 5 minutes using a vortex mixer. The sample was then rapidly centrifuged at 14,000 rpm for 5 minutes at 4°C. 100 μL of the supernatant was combined with 100 μL of mobile phase A (0.1% formic acid / water containing 5% ACN) and mixed thoroughly. STING agonist compounds in the sample were measured using LC-MS / MS (Nexera LC40 (SHIMADZU) and QTRAP4500 (SCIEX)).

[0999] The PK profiles of Compounds 55, 65, 133, Comparison #1 and #2 are summarized in Tables 4 to 8. Compared to Comparison #1 and 2, the STING agonist compounds showed remarkably stable pharmacokinetic profiles in mice.

[1000] [Table 4] Compound 55

[1001]

[1002] [Table 5] Compound 65

[1003]

[1004] [Table 6] Compound 133

[1005]

[1006] [Table 7] Comparison #1

[1007]

[1008] [Table 8] Comparison #2

[1009]

[1010] <Experimental Example 3> In vitro evaluation of cytotoxicity of normal cells

[1011] PBMCs were also purchased from STEMCELL TM (#700025.2). Cells (8.0×10 4 Cells were plated in RPMI 1640 medium (Gibco, #22400097) with 10% heat-inactivated FBS and 1× antibiotic-antimycotic (Gibco, #15240062) in flat-bottom 96-well culture plates and incubated at 37°C for 24 hours. Cells 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.

[1012] To verify the role of STING agonist compounds in the cytotoxicity of normal cells, PBMCs were treated with STING agonist compounds for 3 days and the percentage of cell death was measured. 50 ) values show that all STING agonist compounds have higher CC compared to comparison #1 50 value, which means lower cytotoxicity to normal immune cells.

[1013] [Table 9] Cytotoxicity of PBMC cells in vitro

[1014] Compound number <![CDATA[CC 50 (nM)]]> Comparison #1 3.3 28 12.7 55 4.0 65 18.5

[1015] CD34 + Hematopoietic stem cells (HSC) were purchased from STEMCELL TM (#70002.3). Cells (2×10 4 cells / well) in a flask supplemented with StemSpan TM StemSpan CD34+ Expansion Supplement (#02691) TM The cells were cultured in SFEMII medium in 6-well culture plates 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 × 10 4 cells / well) were seeded in a 96-well white culture dish and allowed to stand for 24 hours under the same conditions.

[1016] To validate the effects of the STING agonist compounds described herein on cytotoxicity in 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) was as shown in Table 10. 50 ) values show that all STING agonist compounds have higher CC compared to comparison #1 50 value, which means lower cytotoxicity to HSCs.

[1017] [Table 10] In vitro CD34 + Cytotoxicity of HSC cells

[1018] Compound number <![CDATA[CC 50 (nM)]]> Comparison #1 2.1 28 24.9 55 7.9 65 3.9

[1019] <Experimental Example 4> In vivo efficacy in a syngeneic mouse model

[1020] All studies were performed using 6-week-old female BALB / c mice (KOTECH, South Korea) and were approved by the Legochembio Science's Institutional Animal Care and Use Committee (IACUC). CT26 or 4T-1 cells (American Type Culture Collection (ATCC), #CRL-2638, #CRL-2539) were maintained in RPMI 1640 medium (Gibco, #22400097) supplemented with 10% heat-inactivated FBS and 1× antibiotic-antimycotic (Gibco, #15240062) at 37°C and 5% CO2. All experiments used Mycoplasma negative cells and were routinely tested using e-Myco. TM Mycoplasma detection was performed using the VALiD Mycoplasma PCR Detection Kit (iNtRON biotechnology, #25239). CT26 cells (2×10 5 cells / mouse) or 4T-1 cells (5×10 5 The tumor volume was measured twice a week and the volume was calculated according to the formula 0.5×(length)×(width)2 Calculate tumor volume.

[1021] To determine the in vivo efficacy of a STING agonist compound (Compound 55) in a syngeneic CT26 mouse model, the tumors were 50 to 100 mm in size. 3 To determine the in vivo efficacy of the STING agonist compound (Compound 55) in the 4T-1 syngeneic mouse model, 1.5 mg / kg of compound was administered on days 0, 4, and 7. 3 When the cells were treated with 1.5 mg / kg of compound, the compounds were administered on days 0, 4, and 7.

[1022] In both CT26 and 4T-1 syngeneic models, STING agonist compounds significantly inhibited tumor growth ( Figure 1 and Figure 2 ).

[1023] Consistent with the in vitro potency, the STING agonist compounds described herein exhibited excellent in vivo efficacy in different syngeneic mouse models.

[1024] In summary, the STING agonist compounds described herein possess a strong competitive profile with high anti-tumor activity but low toxicity.

[1025] Incorporated by reference

[1026] All publications and patents cited herein are incorporated by reference to the same extent as if each individual publication or patent had been specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[1027] Equivalent

[1028] While specific embodiments of the present disclosure have been discussed, the foregoing description is illustrative and not restrictive. Numerous 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 and their equivalents, as well as the specification, and such variations.

Claims

1. A compound represented by structural formula 1 or a pharmaceutically acceptable salt thereof: Formula 1 in: W1 and W2 are each independently selected from an alkyl group, an amino group and an amide group, Each n is independently 0, 1, 2 or 3, Z is selected from a single bond, an alkylene group, an alkenylene group, and an alkynylene group, A and B are each independently a 5-membered heteroaryl group, Xa and Xb are each independently selected from CH2, NH, O and S, R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl, Rb is a group represented by structural formula 2, Formula 2 in: L1 is selected from alkylene, heteroalkenylene, alkenylene, alkynylene, cycloalkylene, heteroalkenylene, heteroalkynylene, arylene, heteroarylene, *Y1-O-Y2 ** and *Y3-NR y -Y4 ** , L2 is selected from NR L C(=NH)NH2, C(=NH)NH2, alkyl, amino, 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, an alkylene group, an alkenylene group, and a heterocyclylene group, * is the point of connection with Xb, ** is the point of connection with L2, R L is selected from H, alkyl, heterocyclyl, aryl, heteroaryl and cycloalkyl, and R y is selected from H, alkyl or C(=NH)NH2.

2. The compound according to claim 1, wherein if L1 is a substituted or unsubstituted alkylene, and L2 is selected from NR L C(=NH)NH2, heteroaryl, substituted heterocyclyl and aryl.

3. The compound according to claim 1, wherein L 2 Include # OC(O)NR 5 -L 4 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 4 -(heterocyclylene), wherein # is with L 1 The connection point, L 4 is an alkylene group or an arylenealkyl group, and R 5 and R 6 Each is independently selected from H, alkyl and dialkylaminoalkyl.

4. The compound according to any one of claims 1 to 3, wherein: W1 and W2 are each independently selected from C 1-5 alkyl, NH2 and C(=O)NH2, and Each n is 1, 2, or 3.

5. The compound according to claim 4, wherein: W1 and W2 are each independently selected from C 1-3 alkyl, NH2 and C(=O)NH2, and n is 1. The compound according to claim 5 , wherein W 1 and W 2 are each C(═O)NH 2 .

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, such as vinylene.

9. The compound according to any one of claims 1 to 8, wherein A and B are each independently a 5-membered heteroaryl group optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, OH, CN, NO2, amine, amide, amidine; -(CH2) 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, and R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

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

11. The compound according to claim 10, wherein A and B are each independently 1-3 Alkyl-substituted pyrazoles.

12. The compound according to any one of claims 1 to 11, wherein the compound is represented by structural formula 1f, or a pharmaceutically acceptable salt thereof: Formula 1f 13. The compound according to any one of claims 1 to 12, wherein the compound is represented by structural formula 1g, or a pharmaceutically acceptable salt thereof: Formula 1g 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. The compound according to any one of claims 1 to 15, wherein Ra is selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

17. The compound according to claim 16, wherein Ra is C 1-6 alkyl.

18. The compound according to claim 17, wherein Ra is unsubstituted C 1-3 alkyl.

19. The compound according to claim 18, wherein Ra is methyl.

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

21. The compound according to claim 20, wherein Ra is C substituted by NR'R" 1-6 Alkyl, wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

22. The compound according to any one of claims 1 to 21, wherein L1 is C 2-6 Alkenylene or C 2-6 Alkynylidene.

23. The compound according to claim 22, wherein L1 is C 2-6 Alkenylene.

24. The compound of claim 23, wherein L1 is unsubstituted C4 alkenylene.

25. The compound according to any one of claims 1 to 24, wherein the compound is represented by structural formula 1h, or a pharmaceutically acceptable salt thereof: Formula 1h 26. The compound according to any one of claims 1 to 24, wherein the compound is represented by structural formula 1i, or a pharmaceutically acceptable salt thereof: Formula 1i 27. The compound according to any one of claims 1 to 22, wherein L1 is C 2-6 Alkynylidene.

28. The compound according to claim 27, wherein the compound is represented by structural formula 1j, or a pharmaceutically acceptable salt thereof: Formula 1j 29. The compound according to any one of claims 1 to 21, wherein L1 is a group represented by Structural Formula 2a, Structural Formula 2b, Structural Formula 2c or Structural Formula 2d: Formula 2a Formula 2b Formula 2c Formula 2d in, L 11 、L 12 、L 13 and L 14 Each is independently a single bond or C 1-20 alkylene, and R 21 、R 22 、R 23 、R 24 、R 25 and R 26 are each independently selected from hydrogen, OH, CN, NO2, amine, amide, amidine, carboxylic acid or its salt, 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.

30. The compound according to any one of claims 1 to 21, wherein L1 is Y1-O-Y2 ** or Y3-NR y -Y4 ** .

31. The compound of claim 30, wherein L1 is Y1-O-Y2 ** .

32. The compound according to claim 31, wherein Y1 is C 2-6 Alkenylene.

33. The compound of claim 32, wherein Y1 is unsubstituted C4 alkenylene.

34. The compound according to claim 31, wherein Y1 is selected from 35. The compound of any one of claims 30 to 34, wherein Y2 is a single bond.

36. The compound of claim 30, wherein L1 is Y3-NR y -Y4 ** .

37. The compound according to claim 36, wherein Y3 is C 2-6 Alkenylene.

38. The compound of claim 37, wherein Y3 is unsubstituted C4 alkenylene.

39. The compound according to claim 36, wherein Y3 is selected from 40. The compound according to any one of claims 36 to 39, wherein Y4 is C 1-6 Alkylene.

41. The compound according to claim 40, wherein Y4 is C 1-3 Alkylene, optionally substituted with 1 to 3 substituents selected from the group consisting of: C 1-5 Alkyl, C 1-5 haloalkyl, halogen, OH, oxo, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

42. The compound according to claim 40, wherein Y4 is unsubstituted C 1-3 Alkylene.

43. The compound according to any one of claims 36 to 42, wherein R y selected from H, unsubstituted C 1-3 Alkyl, or C(=NH)NH2.

44. The compound according to claim 43, wherein R y It’s H.

45. The compound according to claim 43, wherein R y It is methyl or C(=NH)NH2.

46. The compound according to any one of claims 1 to 45, wherein L2 is selected from NR L C(=NH)NH2, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclic group, and C 6-12 Aryl.

47. The compound of claim 46, wherein L2 is NR L C(=NH)NH2.

48. The compound according to claim 47, wherein R L It’s H.

49. The compound of claim 46, wherein L2 is selected from 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, and C6 aryl.

50. The compound of claim 49, wherein L2 is a 5- to 7-membered heteroaryl group, optionally substituted independently with 1 to 3 substituents selected from the group consisting of: C 1-5 Alkyl, C 1-5 haloalkyl, halogen, OH, C(=NH)NH2, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

51. The compound of claim 49, wherein L2 is an unsubstituted 5- to 7-membered heterocyclyl.

52. The compound of any one of claims 1 to 46, wherein L2 is a moiety represented by one of the following structural formulas:

53. The compound of any one of claims 1 to 30 and 36 to 46, wherein L1 is Y3-NR y -Y4 ** , and where NR y -Y4-L2 is a moiety represented by one of the following structural formulas:

54. The compound according to any one of claims 1 to 35, wherein L1 is Y1-O-Y2 ** , and wherein O-Y2-L2 is a moiety represented by one of the following structural formulas:

55. The compound of any one of claims 1 to 54, wherein A and B are each independently represented by one of the following structural formulas: in R a and R b are each independently selected from hydrogen, C 1-5 Alkyl, C 1-5 haloalkyl, halogen, OH, -OP(O)(R'R")2, -OR', -NR'R", -OCOR', -CO2R', -SOR', -SO2R', -CONR'R", -SO2NR'R", -OCONR'R", -NR'COR", -NR'SOR", -NR'CO2R", and -NR'SO2R", and wherein R' and R" are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

56. The compound of claim 1, wherein the compound is represented by structural formula (Ic*):

57. The compound of claim 1, wherein the compound is represented by structural formula (Id*):

58. The compound of any one of claims 1 to 45, 56 and 57, wherein L 2 It comprises one or more moieties selected from the group consisting of a peptide, a carbohydrate, an -OCH2CH2- moiety and a reactive group, or a combination thereof.

59. The compound according to claim 58, wherein L 2 Contains sugars.

60. The compound of claim 59, wherein the carbohydrate is represented by one of the following structural formulas: in R 1 H, alkyl, CH2OR 1A or CO2R 1B ; Each R 2 are independently H or a hydroxy protecting group; R 1A is H or a hydroxy protecting group; and R 1B is H or a carboxyl protecting group.

61. The compound according to claim 58, wherein L 2 Contains peptides.

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

63. The compound of claim 61 or 62, wherein the peptide comprises amino acids with side chains having moieties (e.g., amine, guanidine, or carboxyl moieties) that are charged at neutral pH in aqueous solution.

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

65. The compound of any one of claims 1 to 45 and 56 to 64, wherein L 2 Contains 1 to 20 -OCH2CH2- moieties.

66. The compound according to claim 65, wherein L 2 Contains 2 to 6 -OCH2CH2- moieties.

67. The compound of any one of claims 1 to 45 and 56 to 66, wherein L 2 Contains a moiety represented by structural formula (II*): in Y is - # NHC(O)-or- # (CH2) t NHC(O)-, R 3 Yes-CH2OR 3A or -CO2R 3B ; Each R 4 are independently H or a hydroxy 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; and # indicates the point of attachment to the phenyl ring.

68. The compound of any one of claims 1 to 45 and 56 to 66, wherein L 2 Contains a moiety represented by structural formula (III*): in Y is selected from - # NHC(O)-、- # C(O)NH-、- # (CH2) t NHC(O)- and -COOH, and ## indicates that the 1 connection point.

69. The compound according to claim 67, wherein L 2 Contains a moiety represented by structural formula (IIa): in L 5 is a connector, and RG is a reactive group.

70. The compound according to claim 68, wherein L 2 Contains a moiety represented by structural formula (IIIa): in L 5 is a connector, and RG is a reactive group, and ## indicates that the 1 connection point.

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

72. The compound of any one of claims 68 or 70, wherein Y is - # C(O)NH-.

73. The compound of any one of claims 67 to 72, wherein L 5 Contains 3 to 5 -OCH2CH2- moieties.

74. The compound of any one of claims 67 to 73, wherein L 5 Containing units represented by the structural formula Va, Vb, Vc, Vd or Ve: in L 8 Is a single bond or C 1-30 an alkylene group; and R 11 Is H or C 1-10 alkyl.

75. The compound according to any one of claims 69 to 74, wherein RG is selected from a single bond, 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、heterocyclic、C8-C 10 Cycloalkynyl, sugars, isonitrile, isothiocyanate, 2-pyridyl disulfide, -NHC(O)CH2-Hal, maleimide, tosylate, in Hal is a halogen, and R 12 、R 13 、R 14 、R 15 and R 16 Each is independently H or alkyl.

76. The compound of claim 75, wherein RG is represented by the following structural formula:

77. The compound of claim 75, wherein RG is represented by the following structural formula:

78. The compound of any one of claims 1 to 45 and 56 to 77, wherein L 2 Also includes connector L 2* , the connector comprises # OC(O)NR 5* -L 4* -NR 6* -、 ## -OC(O)-L 4* -NR 6* -or ## -OC(O)NR 5* -L 4* -(heterocyclylene), wherein ## is with L 1 The connection point, L 4* is an alkylene group or an arylenealkyl group, and R 5* and R 6* Independently selected from H, alkyl.

79. The compound of claim 1, wherein the compound is represented by one of the following structural formulas: or a pharmaceutically acceptable salt thereof.

80. The compound of claim 1, wherein the compound is represented by one of the following structural formulas: or a pharmaceutically acceptable salt thereof.

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

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

83. The pharmaceutical composition for use according to claim 82, wherein the disease mediated by STING 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. The pharmaceutical composition of claim 82, wherein the disease is a cancer selected from the group consisting of 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 sarcoma, and melanoma.

85. 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 according to any one of claims 1 to 80 or a pharmaceutical composition according to claim 81.

86. The method of claim 85, wherein the disease mediated by STING is selected from the group consisting of 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. The method of claim 85, wherein the disease mediated by STING is cancer or an infectious disease.

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

89. The method of claim 88, wherein the cancer is selected from the group consisting of 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. 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 method of claim 90, wherein the disease mediated by STING is selected from the group consisting of 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 according to claim 90, wherein the disease mediated by STING is cancer or an infectious disease.

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

94. The use according to 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 treating a disease mediated by stimulator of interferon genes (STING).

96. The compound of claim 95, wherein the disease mediated by STING is selected from the group consisting of 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 disease mediated by STING is cancer or an infectious disease.

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

99. The compound of claim 98, wherein the cancer is selected from the group consisting of 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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