HETEROCYCLIC COMPOUNDS AS STING AGONISTS Cross-Reference to Related Applications This application claims the benefit of Korean Patent Application No. 10-2022-0147897, filed November 8, 2022, which is incorporated by reference herein in its entirety. Background The stimulator of interferon genes (STING) is a low-molecular-weight protein currently attracting attention as a target for cancer therapies. STING is an adapter protein in the cGAS (cyclic GMP-AMP synthase)-STING pathway, which is a sensing pathway that induces activation of type I IFN 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, S.R. 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 expression of cytokines, giving rise to a T cell-mediated innate immune response which inhibits the growth of cancer cells. However, systemic delivery of STING agonists can cause widespread inflammation. Various STING agonists have been tested in preclinical and clinical environments. A variety of agonists in the form of 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.), nano vaccines (PC7A NP, cGAMP-NP, etc.) and ADCs (XMT- 2056, TAK500, etc.) are under development by various strategies. The most widely used preclinical compound, DMXAA (vascular disrupting agent), was used clinically in combination with paclitaxel and carboplatin, but its lack of efficacy was confirmed in phase 3. Further, ADU-S100, which was first used clinically as the STING agonist, was discontinued from use in 2020. Examples of STING agonists are disclosed, for example, in WO2021/014365 (a macrocyclic compound as STING agonist), and US2021/0139473 (a heterocyclic amide- containing compound as protein modulator), US 2022/0073509 (a heterocyclic compound as STING activator), and KR 2022-0024467 (a heterocycle-containing STING agonist), each of which is incorporated herein by reference in its entirety. However, existing STING agonists appear to exhibit only limited bioavailability and require local administration to tumors due to hyperactivation of cytokine expression, or have to be used in combination with other compounds. Therefore, there remains a demand for development of therapeutically effective STING agonists. Brief Description of the Drawings FIG. 1 is a plot demonstrating tumor volume (mm ³ ) following treatment with STING agonist compound (Compound 55) at various doses in CT26 syngeneic mouse model. FIG. 2 is a plot demonstrating tumor volume (mm ³ ) following treatment with STING agonist compound (Compound 55) at various doses in 4T-1 syngeneic mouse model. Summary In some embodiments, the present disclosure relates to a compound represented by structural Formula 1, or a pharmaceutically acceptable salt thereof: Formula 1 wherein: W ₁ and W ₂ are each independently selected from alkyl, amino, and amido, each n is independently 0, 1, 2 or 3, Z is selected from a single bond, alkylene, alkenylene, and alkynylene, A and B are each independently 5-membered heteroaryl, Xa and Xb are each independently selected from CH ₂ , NH, O, and S, Ra is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and cycloalkylalkyl, Rb is a group represented by structural Formula 2, Formula 2 , wherein: L ₁ is selected from alkylene, alkenylene, alkynylene, heteroalkenylene, heteroalkynylene, heteroarylene, Y ₁ -O-Y ₂ ^** , and Y ₃ -NR ^y -Y ₄ ^** ; L ₂ is selected from NR ^L C(=NH)NH ₂ , C(=NH)NH ₂ , alkyl, heteroaryl, heterocyclyl, and aryl; Y1 and Y3 are each independently selected from alkylene, alkenylene, and alkynylene, Y ₂ and Y ₄ are each independently selected from a single bond, alkylene, alkenylene, and heterocyclylene, * is the point of connection to Xb, ** is the point of connection to L ₂ , R ^L is selected from hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl, and R ^y is selected from H, alkyl, or C(=NH)NH ₂ . In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of the disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in preventing or treating a disease mediated by stimulator of interferon genes (STING). In some embodiments, the present disclosure relates to a method of preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, comprising administering to the subject a compound of the disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. In some embodiments, the present disclosure relates to use of a compound of the disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for the manufacture of a medicament for treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. In some embodiments, the present disclosure relates to a compound of the disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. Detailed Description In some embodiments, the present disclosure relates to a compound represented by structural Formula 1, or a pharmaceutically acceptable salt thereof: Formula 1

wherein: W ₁ and W ₂ are each independently selected from alkyl, amino, and amido, each n is independently 0, 1, 2 or 3, Z is selected from a single bond, alkylene, alkenylene, and alkynylene, A and B are each independently 5-membered heteroaryl, Xa and Xb are each independently selected from CH ₂ , NH, O, and S, Ra is selected 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 , wherein: L ₁ is selected from alkenylene, alkynylene, heteroalkenylene, heteroalkynylene, heteroarylene, Y ₁ -O-Y ₂ ^** , and Y ₃ -NR ^y -Y ₄ ^** ; L ₂ is selected from NR ^L C(=NH)NH ₂ , C(=NH)NH ₂ , amino, alkyl, heteroaryl, heterocyclyl, and aryl; Y ₁ and Y ₃ are each independently selected from alkylene, alkenylene, and alkynylene, Y ₂ and Y ₄ are each independently selected from a single bond, alkylene, alkenylene, and heterocyclylene, * is the point of connection to Xb, ** is the point of connection to L ₂ , R ^L is selected from H, alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl, and R ^y is selected from H, alkyl, or C(=NH)NH ₂ . In some embodiments, if L ₁ is substituted or unsubstituted alkylene, L ₂ is selected from NR ^L C(=NH)NH ₂ , heteroaryl, substituted heterocyclyl, and aryl. In some embodiments, W ₁ and W ₂ are each independently selected from C _1-5 alkyl, NH ₂ , and C(=O)NH ₂ , and each n is 1, 2 or 3. For example, W ₁ and W ₂ may be each independently selected from C _1-3 alkyl, NH ₂ , and C(=O)NH ₂ and n is 1. In certain preferred embodiments, W ₁ and W ₂ are each C(=O)NH ₂ . In some embodiments, n is 1. In some embodiments, the compound is represented by structural formula 1a, or is a pharmaceutically acceptable salt thereof: Formula 1a . In some preferred embodiments, Z is alkenylene, such as ethenylene. For example, Z may be unsubstituted C _2-6 alkenylene, such as unsubstituted C _2-4 alkenylene. In certain embodiments, Z is selected from CH=CH, CH=CHCH ₂ , CH ₂ CH=CH, CH=CHCH ₂ CH ₂ , CH ₂ CH ₂ CH=CH, and CH ₂ CH=CHCH ₂ , preferably CH=CH. In some embodiments, Z is selected from C _1-6 alkylene, C _2-6 alkenylene, and C _2-6 alkynylene, wherein each of C _1-6 alkylene, C _2-6 alkenylene, and C _2-6 alkynylene is independently substituted with 1 to 3 substituents selected from C _1-5 alkyl, C _1-5 haloalkyl, halogen, OH, - OP(O)(R’R”) ₂ , -OR’, -NR’R”, -OCOR’, -CO ₂ R’, -SOR’, -SO ₂ R’, -CONR’R”, -SO ₂ NR’R”, - OCONR’R”, -NR’COR”, -NR’SOR”, -NR’CO ₂ R”, and -NR’SO ₂ R”, and wherein R’ and R" are each independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, and a C _2-10 alkynyl. In some embodiments, the compound is represented by structural formula 1b, or is a pharmaceutically acceptable salt thereof: Formula 1b . In some embodiments, A and B are each independently a 5-membered heteroaryl optionally substituted by 1 to 4 groups independently selected from halogen, OH, CN, NO ₂ , amine, amide, amidine; -(CH ₂ ) _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. For example, A and B may be each independently selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, and isothiazole. In certain preferred embodiments, A and B are each pyrazole. In some embodiments, A and B are each independently substituted or unsubstituted pyrazole. For example, in certain preferred embodiments, A and B are each pyrazole substituted with 2 C _1-3 alkyls. In some embodiments, the compound is represented by structural formula 1c, or is a pharmaceutically acceptable salt thereof: Formula 1c . In some embodiments, the compound is represented by structural formula 1d, or is a pharmaceutically acceptable salt thereof: Formula 1d . In some embodiments, the compound is represented by structural formula 1e, or is a pharmaceutically acceptable salt thereof: Formula 1e . In some embodiments, the compound is represented by structural formula 1f, or is a pharmaceutically acceptable salt thereof: Formula 1f . In some embodiments, the compound is represented by structural formula 1g, or is a pharmaceutically acceptable salt thereof: Formula 1g

. In some embodiments, Xa is O. In some embodiments, Xb is O. In some preferred embodiments, Xa and Xb are each O. In some embodiments, Ra is selected from C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl. For example, in some embodiments, Ra is C1-6 alkyl, preferably C1-3 alkyl. In some embodiments, Ra is C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. For example, Ra may be unsubstituted C _1-3 alkyl, preferably methyl. In some embodiments, Xa is O and Ra is methyl. In some embodiments, Ra is C _2-6 alkenyl or C _2-6 alkynyl. For example, Ra may be C ₂ alkenyl, C ₃ alkenyl, C ₄ alkenyl, C ₅ alkenyl, or C ₆ alkenyl. Alternatively, Ra may be C ₂ alkynyl, C ₃ alkynyl, C ₄ alkynyl, C ₅ alkynyl, or C ₆ alkynyl. In some embodiments, Ra is C _1-6 alkyl optionally independently substituted with 1 to 3 substituents selected from C _1-5 haloalkyl, halogen, -OR’, -NR’R”, NR ^’ C(=NH)NH ₂ , -OCOR’, -CO ₂ R’, -SOR’, -SO ₂ R’, -CONR’R”, -SO ₂ NR’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. For example, Ra may be C _1-6 alkyl substituted with -NR’R”, preferably C ₃ alkyl substituted with NHCH ₃ . In some embodiments, Ra is selected from -(alkylene)carboxylic acid, -(alkylene)guanidine, - (alkylene)NHC(O)CH ₂ guanidine, and -(alkylene)O(alkylene)guanidine. In some embodiments, L ₁ is C _2-6 alkenylene or C _2-6 alkynylene. In certain preferred embodiments, L ₁ is C _2-6 alkenylene, such as C _2-4 alkenylene, such as C ₄ alkenylene. For example, L ₁ may be unsubstituted C ₄ alkenylene. In certain preferred embodiments, L ₁ is C _2-6 alkynylene, such as C _2-4 alkynylene, such as C ₄ alkynylene. For example, L ₁ may be unsubstituted C ₄ alkynylene. In some embodiments, the compound is represented by structural formula 1h or structural formula 1i, or is a pharmaceutically acceptable salt thereof: Formula 1h . In some embodiments, the compound is represented by structural formula structural formula 1i, or is a pharmaceutically acceptable salt thereof: Formula 1i

. In some embodiments, the compound is represented by structural formula 1j, or is a pharmaceutically acceptable salt thereof: . In some embodiments, L ₁ is a group represented by structural formula 2a, structural formula 2b, structural formula 2c, or structural formula 2d: Formula 2a Formula 2d wherein, L ₁₁ , L ₁₂ , L ₁₃ , and L ₁₄ are each independently 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, NO ₂ , amine, amide, amidine, carboxylic acid or a salt thereof, ether, ester, sulfone, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C2-10 alkenyl, and substituted or unsubstituted C _2-10 alkynyl. For example, L ₁ may be a group represented by structural formula 2b. For example, L ₁ may be a group represented by structural formula 2c. In some preferred embodiments, L ₁ is a group represented by structural formula 2a or 2d. In some particularly preferred embodiments, L ₁ is a group represented by structural formula 2a. In some embodiments, L ₁ is Y ₁ -O-Y ₂ ^** or Y ₃ -NR ^y -Y ₄ ^** , wherein ** is the point of connection to L ₂ . For example, L ₁ may be Y ₁ -O-Y ₂ ^** . Alternatively, L ₁ may be Y ₃ -NR ^y -Y ₄ ^** . In some embodiments, Y ₁ is selected from C _2-6 alkenylene, and C _2-6 alkynylene. In some embodiments, Y ₁ is C _2-6 alkenylene, such as C ₄ unsubstituted alkenylene. In some embodiments, Y ₁ is selected from , , and . For example, Y ₁ may be . In some preferred embodiments, Y ₁ is . In some preferred embodiments, Y ₁ is . In some embodiments, Y2 is selected from a single bond, C1-6 alkylene, C2-6 alkenylene and 4- to 10-membered heterocyclylene. For example, Y ₂ may be a single bond. In some embodiments, Y ₃ is selected from C _2-6 alkenylene, and C _2-6 alkynylene. In some embodiments, Y ₃ is C _2-6 alkenylene, such as C ₄ unsubstituted alkenylene. In some embodiments, Y ₃ is selected from , , and . For example, Y ₃ may be . In some preferred embodiments, Y ₃ is . In some preferred embodiments, Y ₃ is . In some embodiments, Y ₄ is selected from a single bond, C _1-6 alkylene, C _2-6 alkenylene and 4- to 10-membered heterocyclylene. In some embodiments, Y4 is C1-6 alkylene, such as C2-4 alkylene, such as C ₁ , C ₂ , C ₃ , or C ₄ alkylene. In some preferred embodiments, Y ₄ is C _1-3 alkylene, preferably a C _1-3 alkylene optionally independently substituted with 1 to 3 substituents selected from C _1-5 alkyl, C _1-5 haloalkyl, halogen, OH, oxo, -OR’, -NR’R”, -OCOR’, -CO ₂ R’, -SOR’, - SO ₂ R’, -CONR’R”, -SO ₂ NR’R”, -OCONR’R”, -NR’COR”, -NR’SOR”, -NR’CO ₂ R”, and - NR’SO ₂ R”, and wherein R’ and R" are each independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl. In some preferred embodiments, Y ₄ is unsubstituted C _1-3 alkylene. In some embodiments, R ^y is selected from H, unsubstituted C _1-3 alkyl, or C(=NH)NH ₂ . In some preferred embodiments, R ^y is H. Alternatively, R ^y may be methyl or C(=NH)NH2. In some embodiments, L ₂ is NR ^L C(=NH)NH ₂ . In some preferred embodiments, R ^L is hydrogen. Alternatively, R ^L may be C _1-3 alkyl, preferably methyl. In some embodiments, L ₂ is selected from 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, and C ₆ aryl. For example, L ₂ may be 5- to 7-membered heteroaryl optionally independently substituted with 1 to 3 substituents selected from C _1-5 alkyl, C _1-5 haloalkyl, halogen, OH, C(=NH)NH ₂ , -OP(O)(R’R”) ₂ , -OR’, -NR’R”, -OCOR’, -CO ₂ R’, -SOR’, -SO ₂ R’, -CONR’R”, -SO ₂ NR’R”, -OCONR’R”, -NR’COR”, -NR’SOR”, -NR’CO ₂ R”, and -NR’SO ₂ R”, and wherein R’ and R" are each independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl. In some embodiments, L ₂ is C ₆ aryl optionally independently substituted with 1 to 3 substituents selected from C _1-5 alkyl, halogen, C _1-5 haloalkyl, OH, C(=NH)NH ₂ , -OP(O)(R’R”) ₂ , -OR’, -NR’R”, -OCOR’, -CO ₂ R’, -SOR’, -SO ₂ R’, -CONR’R”, -SO ₂ NR’R”, -OCONR’R”, -NR’COR”, - NR’SOR”, -NR’CO ₂ R”, and -NR’SO ₂ R”, and wherein R’ and R" are each independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl. In some preferred embodiments, L ₂ is 5- to 7-membered heterocyclyl optionally independently substituted with 1 to 3 substituents selected from C _1-5 alkyl, C _1-5 haloalkyl, halogen, oxo, OH, C(=NH)NH ₂ , -OP(O)(R’R”) ₂ , -OR’, - NR’R”, -OCOR’, -CO ₂ R’, -SOR’, -SO ₂ R’, -CONR’R”, -SO ₂ NR’R”, -OCONR’R”, -NR’COR”, - NR’SOR”, -NR’CO ₂ R”, and -NR’SO ₂ R”, and wherein R’ and R" are each independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, and a C _2-10 alkynyl, preferably a 5- to 7-membered heterocyclyl substituted with a substituent selected from oxo, NH ₂ , CN NO ₂ , OH, and C(=NH)NH ₂ . In certain preferred embodiments, L ₂ is unsubstituted 5- to 7-membered heterocyclyl. In some embodiments, L ₂ 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 the point of connection to L ¹ , L ⁴ is alkylene or arylalkylene, and R ⁵ and R ⁶ are each independently selected from H, alkyl, and dialkylaminoalkyl. In some embodiments, L ₂ is a moiety represented by one of the following structural formulas:

. For example, L ₂ may be a moiety represented by one of the following structural formulas:

, , , and . In some preferred embodiments, L ₂ is a moiety represented by one of the following structural formulas: , , , and , preferably, L ₂ is a moiety represented by one of the following structural formulas: and , such as . In some embodiments, L ₁ is Y ₃ -NR ^y -Y ₄ ^** , and NR ^y -Y ₄ -L ₂ is a moiety represented by one of the following structural formulas: , , , , , and . In some embodiments, L1 is Y1-O-Y2 ^** , and O-Y2-L2 is a moiety represented by one of the following structural formulas: , , , , and

. In some embodiments, A and B are each independently represented by one of the following structural formulas: , , , , and , wherein 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’, - CO ₂ R’, -SOR’, -SO ₂ R’, -CONR’R”, -SO ₂ NR’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. For example, A and B may be each independently represented by one of the following structural formulas: , . In some preferred embodiments, A and B are each represented by the following structural formula: In some embodiments, the compound is represented by structural formula 1k, or is a pharmaceutically acceptable salt thereof: Formula 1k wherein: Ra is CH ₃ or (CH ₂ ) ₃ NCH ₃ , and B is a moiety represented by one of the following structural formulas: and . For example, the compound may be represented by structural formula 1k, and L ₁ is selected from moieties represented by one of the following structural formulas: , , and , , preferably wherein L ₁ is a moiety represented by one of the following structural formulas: and . 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 may be represented by structural formula 1k, and B may be a moiety represented by the following structural formula: . In some preferred embodiments, the compound is represented by structural formula 1k, and L ₂ is a moiety represented by one of the following structural formulas:

, , , and , preferably, L ₂ is a moiety represented by one of the following structural formulas: and , more preferably, . In some embodiments, the compound is represented by structural formula (Ic*): In some embodiments, the compound is represented by structural formula (Id*):

In some embodiments, L ² comprises one or more moieties selected from a peptide, a saccharide, a -OCH ₂ CH ₂ - moiety, and a reactive group, or a combination thereof. In some embodiments, L ² comprises a saccharide. In some embodiments, L ² comprises a monosaccharide. In some embodiments, L ² comprises two or more monosaccharides. In some embodiments, the saccharide is represented by one of the following structural formulas: , , , wherein R ¹ is H, alkyl, CH ₂ OR ^1A , or CO ₂ R ^1B ; each R ² is independently H or a hydroxyl protecting group; R ^1A is H or a hydroxyl protecting group; and R ^1B is H or a carboxyl protecting group. In some preferred embodiments, the saccharide is represented by the following structural formula: , In some embodiments, R ¹ is CH ₂ OR ^1A or CO ₂ R ^1B . In some embodiments, R ^1A is H. In some embodiments, R ^1B is H. In some embodiments, R ² is H. In some embodiments, L ² comprises a peptide. In some embodiments, L ² is a peptide. For example, in some embodiments, L ² comprises a dipeptide. For example, in some embodiments, L ² is a dipeptide. 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 having a moiety that bears a charge at neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety). For example, in some embodiments, the peptide comprises an amino acid selected from alanine, aspartate, asparagine, glutamate, glutamine, glycine, lysine, ornithine, proline, serine, and threonine. In some embodiments, L ² comprises from 1 to 20 -OCH ₂ CH ₂ - moieties. In some preferred embodiments, L ² comprises from 1 to 10 -OCH ₂ CH ₂ - moieties, preferably 2 to 6 - OCH ₂ CH ₂ - moieties. In some embodiments, L ² comprises a moiety represented by structural formula (II*): wherein Y is - ^# NHC(O)- or - ^# (CH ₂ ) _t NHC(O)-, R ³ is -CH ₂ OR ^3A , or -CO ₂ R ^3B ; each R ⁴ is independently H or a hydroxyl protecting group; R ^3A is H or a hydroxyl protecting group; R ^3B is H or a carboxyl protecting group; t is 1, 2, or 3, preferably 1; and # indicates the point of attachment to the phenyl ring. In some embodiments, L ² comprises a moiety represented by structural formula (III*): wherein Y is * - ^# NHC(O)-, - ^# C(O)NH-, - ^# (CH ₂ ) _t NHC(O)-, and -COOH, and ## indicates the point of attachment to L ¹ . In some embodiments, Y is - ^# NHC(O)-. In some embodiments, Y is - ^# (CH ₂ ) _t NHC(O)-. In some preferred embodiments, Y is - ^# C(O)NH-. In some embodiments, R ³ is -CH ₂ OR ^3A . In some embodiments, R ^3A is H. In some embodiments, R ³ is -COOR ^3B . In some embodiments, R ^3B is H. In some embodiments, L ² comprises a moiety represented by structural formula (IIa*): wherein L ⁵ is a linker, and RG is a reactive group. In some embodiments, L ² is a moiety represented by structural formula (IIa*). In some embodiments, L ² comprises a moiety represented by structural formula (IIIa*): wherein L ⁵ is a linker, and RG is a reactive group, and ## indicates the point of attachment to L ¹ . In some embodiments, L ² is a moiety represented by structural formula (IIIa*). In some embodiments, L ⁵ comprises a unit represented by structural formula Va, Vb, Vc, Vd, or Ve: wherein L ⁸ is a single bond or C _1-30 alkylene; and R ¹¹ is H or C _1-10 alkyl. In some embodiments, L ⁵ comprises a unit represented by structural formula Va, Vb, or Vc. In some embodiments, L ⁸ is a single bond. Alternatively, in some embodiments, L ⁸ is C _{1- 30} alkylene. In some embodiments, R ¹¹ is H. Alternatively, in some embodiments, R ¹¹ is C _1-10 alkyl. For example, in certain embodiments, R ¹¹ is methyl. RG can be any suitable reactive group, such that an additional moiety with a complementary reactive group may be coupled to the compound represented by structural formula (I) through reaction with RG, e.g. a reaction that displaces RG. In some embodiments, RG is selected from OH, Hal, -NR ¹² R ¹³ , -COOH, -C(O)R ¹⁴ , -SO ₃ R ¹⁵ , SH, -NHOH, -NH ₂ NH ₂ , - CH(CH ₂ COOH) ₂ ^^^&^2^&Ł&5 ¹⁶ , N ₃ , -OP(O)(OH) ₂ , alkyl, alkenyl, alkynyl, heterocyclyl, C ₈ -C ₁₀ cycloalkynyl, saccharide, isocyanide, isothiocyanide, 2-pyridyl disulfide, -NHC(O)CH ₂ -Hal, maleimide, tosylate, wherein Hal is halogen, and R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , and R ¹⁶ are each independently H or alkyl. For example, in some embodiments, RG is alkyl, such as C _1-3 alkyl, preferably methyl. In some embodiments, RG is selected from OH, NR ¹² R ¹³ ^^^&22+^^^&Ł&+^^1 ₃ , - OP(O)(OH) ₂ , -CH(CH ₂ COOH) ₂ , heterocyclyl, and saccharide. In some embodiments, RG is OH. In some embodiments, RG is NR ¹² R ¹³ . For example, in certain embodiments, R ¹² and R ¹³ are H. For example, in certain embodiments, R ¹² and R ¹³ are Me. In some embodiments, RG is alkyl. In some preferred embodiments, RG is methyl. In some embodiments, RG is represented by the following structural formula: In some embodiments, RG is a saccharide. In some embodiments, the saccharide is a glucuronide. In some preferred embodiments, the glucuronide is In some embodiments, L2 further comprises a linker L ^2* , comprising ^## OC(O)NR ^5* -L ^4* - NR ^6* -, ^## -OC(O)-L ^4* -NR ^6* -, or ^## -OC(O)NR ^5* -L ^4* -(heterocyclylene), wherein ## is the point of connection to L ¹ , L ^4* is alkylene or arylalkylene, and R ^5* and R ^6* are independently selected from H, alkyl. In some embodiments, the compound is represented by one of the following structural formulas: ,

, ,

, ,

, ,

, ,

, , ,

, , and

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

In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a compound of the disclosure, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a compound of the disclosure, such as a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in preventing or treating a disease mediated by stimulator of interferon genes (STING). In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a compound of the disclosure, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in preventing or treating a disease mediated by 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 disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, cerebrovascular disease, peripheral arterial disease, cardiovascular disease, and allergic disease. For example, a 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 sarcoma, and melanoma. In some embodiments, the present disclosure relates to a method of preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, the method comprising administering to the subject a compound of the disclosure, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the 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, a 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 sarcoma, and melanoma. In some embodiments, the present disclosure relates to use of a compound of the disclosure, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for the manufacture of a medicament for treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. In some embodiments, the 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, a 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, sarcoma and melanoma. In some embodiments, the present disclosure relates to a compound of the disclosure, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof. In some embodiments, the 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, a 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 sarcoma, and melanoma. Pharmaceutical Compositions The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the 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 preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment. A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the disclosure. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the disclosure. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which 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 carboxymethyl cellulose, ethyl cellulose 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 glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste. To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients. Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 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. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. For use in the methods of this disclosure, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. 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. The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) 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. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference). In general, a suitable daily dose of an active compound used in the compositions and methods of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily. The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general. In certain embodiments, compounds of the disclosure may be used alone or conjointly administered with another type of therapeutic agent. The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)- camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acid salts. The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. 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. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, 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 this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (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., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000). Chemistry terms used herein, unless otherwise defined 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, C.A. (1985). All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount. “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the 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, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents. A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted. It is understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH ₂ -O-alkyl, - OP(O)(O-alkyl) ₂ or –CH ₂ -OP(O)(O-alkyl) ₂ . Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted. The term “alkyl” used herein refers to a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group may have 1 to 10 carbon atoms (that is, (C _1-10 )alkyl) or 1 to 8 carbon atoms (that is, (C _1-8 )alkyl) or 1 to 6 carbon atoms (that is, ( C _1-6 alkyl) or 1 to 4 carbon atoms (that is, (C _1-4 )alkyl). Examples of the alkyl group include methyl (Me, -CH ₃ ), ethyl (Et, - CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s- Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl- 2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (- CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (- CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (- CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (- CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (- C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (- C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ , and octyl (-(CH ₂ ) ₇ CH ₃ ), but are not limited thereto. Furthermore, the term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C _1-30 for straight chains, C _3-30 for branched chains), and more preferably 20 or fewer. In certain embodiments, alkyl is unsubstituted, except as otherwise specified. However, if not specified, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. The term "alkenyl" used herein refers to a linear 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 (that is, C _2-8 alkenyl), or 2 to 6 carbon atoms (that is, C _2-6 alkenyl), or 2 to 4 carbon atoms (that is, C _2-4 alkenyl). Examples of the alkenyl group are ethylene or vinyl (- CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH=CH ₂ ), and 3-hexenyl (- CH ₂ CH ₂ CH ₌ CHCH ₂ CH ₂ ), and are not limited thereto. Throughout the present specification, one terminal hydrogen of the alkenyl group is omitted and may be connected with the next linking group. In certain embodiments, alkenyl is unsubstituted, except as otherwise specified. The term "alkylene" used herein refers to a linear or branched divalent saturated hydrocarbon group having 1 to 6 (C _1-6 ) carbon atoms. For example, an alkylene having 1 to 4 (C _{1- 4} ) carbon atoms may be used. Examples thereof include, but are not limited to, methylene, ethylene, trimethylene (propylene), and tetramethylene (n-butylene). The term “alkynyl” used herein refers to a linear 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 (that is, C _2-8 alkynyl), or 2 to 6 carbon atoms (that is, C _2-6 alkynyl), or 2 to 4 carbon atoms (that is, C _2-4 alkynyl). Examples of alkynyl groups are acetylenyl (-CŁCH), propargyl (-CH ₂ CŁCH), and -CH ₂ -CŁC-CH ₃ , but are not limited thereto. In certain embodiments, alkynyl is unsubstituted, except as otherwise specified. The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. 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. The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C _1-30 for straight chains, C _3-30 for branched chains), and more preferably 20 or fewer. Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. 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 meant to include groups that contain from x to y carbons in the chain. C ₀ alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C _1-6 alkyl group, for example, contains from one to six carbon atoms in the chain. Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-. The term “amido”, as used herein, refers to a group , wherein R ⁹ and R ¹⁰ each independently represent a hydrogen or hydrocarbyl group, or R ⁹ and R ¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein R ⁹ , R ¹⁰ , and R ¹⁰ ’ each independently represent a hydrogen or a hydrocarbyl group, or R ⁹ and R ¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. As used herein, the term “amidino” or “amidine” refers to a group C(=NR ¹⁰ )NR ¹¹ R ¹² , wherein R ¹⁰ , R ¹¹ , and R ¹² each independently represent a hydrogen or a hydrocarbyl group, or R ¹¹ and R ¹² taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. Non-limiting examples of amidines include C (=NMe)NMe ₂ , C(=NH)NMe ₂ , and C(=NH)NH ₂ . As used herein, the term “guanidine” refers to a group –NR ⁹ C(=NR ¹⁰ )NR ¹¹ R ¹² , wherein R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² each independently represent a hydrogen or a hydrocarbyl group, or R ¹¹ and R ¹² taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. Non-limiting examples of guanidines include - ^{NMeC(=NMe)NMe} ₂ ^{, -NHC(=NMe)NMe} ₂ ^{, -NHC(=NH)NMe} ₂ ^{, -NMeC(=NH)NH} ₂ ^{and -} NHC(=NH)NH ₂ . The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbamate” is art-recognized and refers to a group , wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl group. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbonate” is art-recognized and refers to a group -OCO ₂ -. The term “carboxy”, as used herein, refers to a group represented by the formula -CO ₂ H. The term “cycloalkyl” includes substituted or unsubstituted non-aromatic single ring 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 cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R ¹⁰⁰ ) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like. Non- limiting examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1 -cyclohex-1-enyl, 1- cyclohex-2-enyl, and 1-cyclohex-3-enyl. The term “ester”, as used herein, refers to a group -C(O)OR ⁹ wherein R ⁹ represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl. The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo. The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group. The term “heteroaryl” used herein 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 a multiple condensed ring system having at least one such aromatic ring. The multiple condensed ring systems will be further described. Thus, the “heteroaryl” may include a single aromatic ring having about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from oxygen, nitrogen and sulfur. Sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. An example of the heteroaryl ring systems includes, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. In some embodiments, “heteroaryl” includes a multiple condensed ring system (for example, a ring system including 2, 3 or 4 rings), and the heteroaryl group as defined above may form a multiple condensed ring system through condensation with at least one ring selected fromheteroaryl (used to form, for example, 1,8-naphthyridinyl), heterocycle (used to form, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (used to form, for example, 5,6,7,8-tetrahydroquinolyl), and aryl (used to form, for example, indazolyl). Thus, a heteroaryl (a single aromatic ring or a multiple condensed ring system) may have about 1-20 carbon atoms and about 1-6 heteroatoms in the heteroaryl ring. Such multiple condensed ring systems may be such that the carbocycle or heterocycle portion of the condensed ring may be substituted with one or more (for example, 1, 2, 3, or 4) oxo groups. The rings of a multiple condensed ring system may be linked to one another through fusion, spiro and cross-linking bonds as long as valency requirements are satisfied. The individual rings of the multiple condensed ring system may be linked to one another in any order. The point of attachment for the heteroaryl or the heteroaryl multiple condensed ring system may be any suitable atom of the heteroaryl or the heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (for example, nitrogen). Also, when a particular atom-range member heteroaryl (for example, (C ₅ -C ₁₀ ) heteroaryl) is referred to, the atomic range is to be understood as being relative to the total number of ring atoms of the heteroaryl and as including a carbon atom and a heteroatom. For example, a C ₅ heteroaryl may include a thiazolyl and a C ₁₀ heteroaryl may include a quinolinyl. Examples of heteroaryls include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b, 4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazole, and are not limited thereto. The term “heterocyclyl” or “heterocycle” used herein refers to a monosaturated or partially unsaturated non-aromatic compound or non-aromatic multi-ring system in which at least one heteroatom (that is, at least one cyclic heteroatom selected from oxygen, nitrogen and sulfur) is included in the ring. Unless otherwise specified, heterocyclyl groups have 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 single saturated or partially unsaturated ring (for example, 3, 4, 5, 6 or 7-membered rings), having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen and sulfur, in the ring. The rings of a multiple condensed ring system may be linked to one another through fusion, spiro and cross-linking bonds as long as valency requirements are satisfied. Examples of heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N- chloropiperidine, and the like. The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof. The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group. The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term “sulfate” is art-recognized and refers to the group –OSO ₃ H, or a pharmaceutically acceptable salt thereof. The term “sulfonamido” is art-recognized and refers to the group represented by the general formulae , wherein R ⁹ and R ¹⁰ independently represents hydrogen or hydrocarbyl. The term “sulfoxide” is art-recognized and refers to the group–S(O)-. The term “sulfonate” is art-recognized and refers to the group SO ₃ H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group –S(O) ₂ -. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group -C(O)SR ⁹ or –SC(O)R ⁹ wherein R ⁹ represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. The term “urea” is art-recognized and may be represented by the general formula _, wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl. The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity. The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients. The term “pharmaceutically acceptable acid addition salt” as used herein means any non- toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. The term “pharmaceutically acceptable basic addition salt” as used herein means any non- toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726. Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers. “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile 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. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use. In certain embodiments, the disclosure relates to heterocyclic compounds with activity as STING agonists. In certain embodiments, the pharmaceutical composition additionally contains a chemotherapeutic agent, such as a pharmaceutically effective amount of a chemotherapeutic agent. In certain embodiments, the pharmaceutical composition additionally includes one or more therapeutic co-agents, and one or more pharmaceutically acceptable excipients. The therapeutic co-agent may be, but is not limited to, an agent that exhibits preventive, ameliorative, or therapeutic effects on STING mediated diseases; or an agent that can reduce the expression of side effects that appear when administering a treatment for STING mediated diseases; or an agent that exhibits an immune enhancing effect. The therapeutic co-agents can be applied alone or in combination (i.e., the pharmaceutical composition comprising a compound of Formula 1 may further comprise one or more therapeutic co-agents). A therapeutically useful effect may be achieved when a STING agonist that is a compound described herein is administered along with one or more therapeutic co-agents, optionally also with a compounding agent; for example, co-administration of a STING agonist (e.g., a compound disclosed herein, such as a compound of Formula 1) and one or more therapeutic co-agents, may further enhance the stability of proteolytic agents, reduce side effects occurring when administering a STING agonist represented by the compound of Formula 1, and/or show the effect of maximizing the therapeutic effect through the enhancement of immunity. Suitable therapeutic co-agents include, but are not limited to, auristatin, bexarotene, bicalutamide, BMS 184476, bleomycin, semadotin, chlorambucil, cyclophosphamide, docetaxol, docetaxel, carboplatin, carmustine, cisplatin, cryptophycin, decitabine, dolastatin, doxorubicin, mibobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, nivolumab, onapristone, paclitaxel, procarbazine, tamoxifen, tasonermin, tretinoin, vinblastine, vincristine, PD-1 antagonists, CTLA-4 antagonists, B7 co-stimulatory molecules, interleukin-2, interleukin-7, and the like. In other embodiments, the disclosure relates to a method for preventing or treating a STING-mediated disease 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 the compound disclosed herein (e.g., a compound of Formula 1) or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, optionally further comprising a chemotherapeutic agent. In some embodiments, the STING-mediated disease is a 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, allergic disease or inflammation. In certain embodiments, the STING-mediated disease is a 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 or allergic disease. In certain embodiments, the STING mediated disease is a cancer or an infectious disease. In particular embodiments, the STING-mediated disease is cancer. Cancers suitable for treatment with the compounds and methods disclosed herein include any carcinoma in which the STING agonist (e.g., the compound of Formula 1, or 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 more particular embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma. In still other embodiments, the disclosure relates to use of a compound disclosed herein (e.g., a compound of Formula 1) or pharmaceutically acceptable salt thereof, or use of a pharmaceutical composition comprising the compound disclosed herein or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for the manufacture 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 a 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, allergic disease or inflammation. In certain embodiments, the STING- mediated disease is a 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 or allergic disease. In certain embodiments, the STING mediated disease is a cancer or an infectious disease. In particular embodiments, the STING-mediated disease is cancer. Cancers suitable for treatment with the compounds and methods disclosed herein include any carcinoma in which the STING agonist (e.g., the 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 more particular embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma. In addition, the compound of Formula 1 (or pharmaceutically acceptable salt thereof) can be used as an adjuvant for the treatment of other infectious diseases, diseases, or disorders, including cancer, in any one of pharmaceutically usable salts. In any of the foregoing methods and uses, the compound of Formula 1 (or pharmaceutically acceptable salt thereof) may be conjointly administered with another therapeutic agent, such as a chemotherapeutic agent or toxin. The chemotherapeutic agent or toxin used herein may 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 may be, for example, CTLA-4 antagonist, PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, LAG3 inhibitor, TIM-3, BTLA, B4, B7 costimulatory molecule, IDO inhibitor, TDO inhibitor, VISTA, HVEM, TIGIT, PVR, CC-90006, CG-0070, CS-1003, CD160, CGEN-15049, CHK1, CHK2, CEACAM1, OX40, OX40L, GM-CSF, cyclodextrin, or anthracycline-based compounds, such as erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin, 5-fluorouracil,leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrmycin, azaserine, bleomycins, cactinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, 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 acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium 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, triaziquone, 2,2',2''-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, gemcitabine, 6-thioguanine; mercaptopurine,cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine, retinoic acid, or capecitabine, but is not limited thereto. Examples <Preparation Example 1> Preparation of Intermediate Compound 2 Preparation of Intermediate Compound 1 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 ºC ,andthereactionsolutionwasstirredatroomtemperaturefor2hours. The reaction solution was concentrated under reduced pressure to afford Intermediate Compound 1. Preparation of Intermediate Compound 2 After dissolving Intermediate Compound 1 (crude) in acetone (100 mL), potassium thiocyanate( 6.5g, 67.5mmol)was adde d at 0 ºC. After stirring the reaction solution 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 afford Intermediate Compound 2 (9.7 g, 95%). (s, 3H). EI-MS m/z : [M+H] ⁺ 196.00.

Preparation Example 2> Preparation of Intermediate Compound 5

3 4 5

Preparation of Intermediate Compound 3

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

¹ H-NMR (400 MHz, CDCh) δ 8.29 (s, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 4.01 (s, 3H).

Preparation of Intermediate Compound 4

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. The reaction solution was stirred for 21 hours at room temperature under nitrogen. The reaction solution was added to ice water, and then the resulting solid was filtered and lyophilized to afford Intermediate Compound 4 (223 mg, 79%).

¹ H-NMR (400 MHz, CDCh), δ 11.73 (s, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H).

Preparation of Intermediate Compound 5

Intermediate Compound 4 (2 g, 9.23 mmol) and cesium carbonate (3.61 g, 11.08 mmol) were added to N,N-dimethylformamide (15 mL) at 0 °C under nitrogen and then stirred for 5 minutes. Trans- 1 ,4-dibromo-2-butene (5.93 g, 27.70 mmol) was added to the reaction solution at room temperature under nitrogen and stirred for 2 hours. The resulting solution was extracted with ethyl acetate (20 mL x 3) and washed with distilled water (15 mL x 2) and brine (15 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. After solidification using dichloromethane and hexane, it was filtered and dried to afford Intermediate Compound 5 (2.53 g, 78%). ¹ H-NMR (400 MHz, CDCh), δ 8.23 (s, 2H), 8.02 (d, J = 1.8 Hz, 2H), 7.84 (d, J = 1.8 Hz, 2H), 7.73 (s, 2H), 6.16-5.98 (m, 4H), 5.70 (s, 1H), 4.83 (d, J= 3.5 Hz, 4H), 4.25 (d, J = 5.4 Hz, 1H), 4.20-4.14 (m, 3H). EI-MS m/z : [M+H] ⁺ 350.98.

Preparation Example 3> Preparation of Intermediate Compound 9

Preparation of Intermediate Compound 6

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 then the resulting solid was filtered and dried to afford Intermediate Compound 6 (12.6 g, 76%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 8.18 (d, 1H), 8.01(s, 1H), 7.73 (t, 1H), 7.55 (d, 1H), 7.31 (s, 1H), 6.92 (s, 1H), 5.53 (s, 2H), 4.08 (s, 2H), 3.47 (s, 2H), 1.35 (m, 9H).

Preparation of Intermediate Compound 7

After dissolving Intermediate Compound 6 (10 g, 26.28 mmol) in methanol (90 mL), ammonia aqueous solution (28-30% ammonia, 90 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 45 g, 262.8 mmol) were sequentially added at 0 °C, and the mixture was stirred at room temperature for 1 hour and 30 minutes. After adding methanol (100 mL) to the reaction solution, the resulting solid was filtered, the filtered solution was concentrated, and then diluted with di chloromethane (100 mL) and 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 afford Intermediate Compound 7 (6.9 g, 75%).

¹ H-NMR(400 MHz, DMSO -d ₆ ), δ 7.62 (hr s, 1H), 6.98 (hr s, 1H), 6.92 (t, 1H), 6.87 (d, 1H), 6.79 (d, 1H), 5.57 (q, 2H), 4.67 (hr s, 2H), 3.82 (hr s, 1H), 3.76 (s, 3H), 3.51 (dd, 4H), 1.37 (s, 9H).

Preparation of Intermediate Compound 8

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 afford Intermediate Compound 8 (7.7 g, 76%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 12.86 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.40 (m, 2H), 6.93 (m, 1H), 6.65 (s, 1H), 5.67 (m, 2H), 4.93 (d, 2H), 4.61 (q, 2H), 3.98 (s, 3H), 3.51 (m, 2H), 2.55 (m, 2H), 2.18 (s, 3H), 1.35 (t, 3H), 1.32 (s, 9H).

Preparation of Intermediate Compound 9

After dissolving Intermediate Compound 8 (7.7 g, 15.05 mmol) in di chloromethane (25 mL) and methanol (25 mL), hydrochloric acid (4 M 1,4-dioxane solution, 27 mL) was added and stirred for 2 hours and 30 minutes. The reaction solution was concentrated, diluted with diethyl ether (20 mL), and then the resulting solid was filtered to afford Intermediate Compound 9 (5.6 g, 76%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (s, 1H), 8.67(d, 1H), 7.41 (d, 1H), 7.37 (s, 1H), 6.66 (s, 1H), 6.01 (m, 1H), 5.65 (m, 1H), 4.97 (d, 2H), 4.60 (q, 2H), 3.98 (s, 3H), 2.66 (m, 5H), 2.33 (m, 3H), 1.35 (m, 3H). EI-MS m/z : [M+H] ⁺ 823.0.

<Example 1> Preparation of Compound 13

Preparation of Intermediate Compound 10

After dissolving Intermediate Compound 5 (580 mg, 1.66 mmol) 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 x 2), and dried with 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 afford Intermediate Compound 10 (504 mg, 70%).

¹ H-NMR (400 MHz, CDCh), δ 7.73-7.66 (m,lH), 6.03-5.84 (m,lH), 4.75 (dd, J = 5.0, 1.2 Hz, 1H), 3.75-3.68 (m, 2H), 3.06 (dd, J = 6.0, 1.1 Hz, 1H), 2.46 (t, J = 4.7 Hz, 2H). EI-MS m/z : [M+H] ⁺ 356.09.

Preparation of Intermediate Compound 11

After dissolving Intermediate Compound 9 (818 mg, 1.68 mmol) and Intermediate Compound 10 (300 mg, 0.84 mmol) in normal butyl alcohol (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 cooling the reaction solution 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 afford Intermediate Compound 11 (129 mg, 21%). EI-MS m/z : [M+H] ⁺ 731.03. Preparation of Intermediate Compound 12 After dissolving Intermediate Compound 11 (129 mg, 0.17 mmol) in methyl alcohol (2 mL) and distilled water (0.1 mL), aqueous ammonia solution (28-30% ammonia, 0.17 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 the filtered solution was concentrated, and then diluted with dichloromethane (100 mL), washed with distilled water (50 mL), and then the organic layer was dried with anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to afford Intermediate Compound 12 (126 mg, crude). EI-MS m/z : [M+H] ⁺ 701.08. Preparation of Compound 13 After dissolving Intermediate Compound 12 (126 mg, 0.18 mmol, crude) 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 afford Compound 13 (5.6 mg, 4%). EI-MS m/z : [M+H] ⁺ 862.03. <Example 2> Preparation of Compound 18

Preparation of Intermediate Compound 14

After dissolving Intermediate Compound 5 (265 mg, 0.76 mmol) in N,N- dimethylformamide (4 mL), t-butyl piperidm-4-ylcarbamate (167 mg, 0.83 mmol) and cesium carbonate (296 mg, 0.91 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL x 2), and dried with 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 afford Intermediate Compound 14 (248 mg, 70%). EI-MS m/z : [M+H] ⁺ 469.06.

Preparation of Intermediate Compound 15

After dissolving Intermediate Compound 9 (628 mg, 1.3 mmol) and Compound 14 (304 mg, 0.65 mmol) in normal butyl alcohol (5 mL), diisopropylethylamine (0.56 mL, 3.24 mmol) was added at room temperature, heated to 120 °C and stirred for 24 hours. After cooling the reaction solution 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 with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to afford Intermediate Compound 15 (124 mg, 23%). EI-MS m/z : [M+H] ⁺ 844.02.

Preparation of Intermediate Compound 16

After dissolving Intermediate Compound 15 (124 mg, 0.15 mmol) in methanol (4 mL) and distilled water (0.5 mL), an aqueous ammonia solution (28-30% ammonia, 0.4 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 di chloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The washed material was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford Intermediate Compound 16 (119 mg, crude). EI-MS m/z : [M+H] ⁺ 814.81.

Preparation of Intermediate Compound 17

After dissolving Intermediate Compound 16 (119 mg, 0.15 mmol, crude) 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 afford Intermediate Compound 17 (36 mg, 25%). EI-MS m/z : [M+H] ⁺ 975.15.

Preparation of Compound 18

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 afford Compound 18 (15.2 mg, 47%). EI-MS m/z : [M+H] ⁺ 875.06.

<Example 3> Preparation of Compound 23

Preparation of Intermediate Compound 19

After dissolving Intermediate Compound 5 (500 mg, 1.43 mmol) in N,N- dimethylformamide (5 mL), /-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 x 2), and dried with 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 afford Intermediate Compound 19 (472 mg, 72%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 8.26 (s, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 5.91-5.83 (m, 2H), 4.84 (d, 1H), 3.29-3.27 (m, 4H), 2.98 (d, 2H), 2.73 (t, 4H), 1.39 (s, 9H). EI-MS m/z : [M+H] ⁺ 455.11.

Preparation of Intermediate Compound 20

After dissolving Intermediate Compound 9 (495 mg, 1.02 mmol) and Intermediate Compound 19 (310 mg, 0.68 mmol) in normal butyl alcohol (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 di chloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried with 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 afford Intermediate Compound 20 (336 mg, 46%). EI-MS m/z : [M+H] ⁺ 830.01.

Preparation of Intermediate Compound 21

After dissolving Intermediate Compound 20 (336 mg, 0.31 mmol) in methanol (10 mL) and distilled water (1 mL), an aqueous ammonia solution (28-30% ammonia, 0.33 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford Intermediate Compound 21 (153 mg, 60%, crude). EI-MS m/z : [M+H] ⁺ 800.09.

Preparation of Intermediate Compound 22

After dissolving Intermediate Compound 21 (153 mg, 0.19 mmol, crude) 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 afford an Intermediate Compound 22 (116 mg, 63%). EI-MS m/z : [M+H] ⁺ 961.07.

Preparation of Compound 23

After dissolving Intermediate Compound 22 (41 mg) in di chloromethane (5 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 afford Compound 23 (26 mg, 46%). ¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 8.66 (br s, 1H), 7.96 (d, 2H), 7.65 (s, 2H), 7.37 (br s, 2H), 7.30 (d, 2H), 6.53 (d, 2H), 5.86-5.63 (m, 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-MS m/z : [M+H] ⁺ 861.21.

<Example 4> Preparation of Compound 28

Preparation of Intermediate Compound 24

LButyl 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 sequentially added, 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 with anhydrous magnesium sulfate. The reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography to afford an Intermediate Compound 24 (213 mg, 52.9%).

¹ H-NMR (400 MHz, CDCh), δ 8.26 (br s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 5.90-5.80 (m, 2H), 4.84 (d, J= 4.4 Hz, 1H), 4.00 (d, J= 4.8 Hz, 2H), 3.92 (s, 2H), 3.53-3.51 (m, 2H), 3.27-3.24 (m, 2H), 1.41 (s, 9H). EI-MS m/z : [M+H] ⁺ 469.07.

Preparation of Intermediate Compound 25

After dissolving Intermediate Compound 9 (440 mg, 0.91 mmol) and Intermediate Compound 24 (213 mg, 0.45 mmol) in normal butyl alcohol (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 with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to afford Intermediate Compound 25 (213 mg, 55.5%). EI-MS m/z : [M+H] ⁺ 844.04.

Preparation of Intermediate Compound 26

After dissolving Intermediate Compound 25 (210 mg, 0.25 mmol) in methanol (6 mL) and distilled water (1 mL), an aqueous ammonia solution (28-30%, 0.44 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford Intermediate Compound 26 (crude). EI-MS m/z : [M+H] ⁺ 814.14.

Preparation of Intermediate Compound 27

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

Preparation of Compound 28

After dissolving Intermediate Compound 27 (48 mg) in di chloromethane (3.2 mL), trifluoroacetic acid (0.8 mL) was added at 0 °C under nitrogen. The reaction solution was stirred at 0 °C for 40 minutes, concentrated, and then purified by HPLC to afford Compound 28 (10.2 mg, 17%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 1.28 (br s, 2H), 9.13 (br s, 1H), 7.96 (d, J= 14.7 Hz, 2H), 7.65 (s, 2H), 7.37 (br s, 2H), 7.30 (s, 2H), 6.53 (d, J= 6.3 Hz, 2H), 5.86-5.63 (m, 4H), 4.92- 4.89 (m, 4H), 4.56-4.50 (m, 4H), 3.31 (s, 5H), 2.11 (d, J= 4.9 Hz, 6H) 1.29-1.25 (m, 6H). EI-MS m/z : [M+H] ⁺ 875.11.

<Example 5> Preparation of Compound 33

Preparation of Intermediate Compound 29

Intermediate Compound 4 (1.5 g, 6.93 mmol) and cesium carbonate (2.5 g, 7.62 mmol) were dissolved in N,N-dimethylformamide (6 mL) at 0 °C under nitrogen, and then stirred for 5 minutes. Cis-l,4-dibromo-2-butene (3.7 g, 17.32 mmol) was added to the reaction solution at room temperature under nitrogen and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (20 mL x 2) and brine (20 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The solid obtained by diluting with di chloromethane and hexane was filtered and dried to afford Intermediate Compound 29 (1.64 g, 67%). EI-MS m/z : [M+H] ⁺ 351.23. Preparation of Intermediate Compound 30

After dissolving Intermediate Compound 29 (450 mg, 1.29 mmol) 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 x 2), and then dried with 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 afford Intermediate Compound 30 (298 mg, 71%). EI-MS m/z : [M+H] ⁺ 356.11.

Preparation of Intermediate Compound 31

After dissolving Intermediate Compound 9 (592 mg, 1.22 mmol) and Intermediate Compound 30 (290 mg, 0.82 mmol) in normal butyl alcohol (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 di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The reaction solution was dried with 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 afford Intermediate Compound 31 (174 mg, 29%). EI-MS m/z : [M+H] ⁺ 731.05.

Preparation of Intermediate Compound 32

After dissolving Intermediate Compound 31 (173 mg, 0.24 mmol) in methanol (2 mL) and distilled water (0.1 mL), an aqueous ammonia solution (28-30%, 0.34 mL, 4.76 mmol) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 di chloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford Intermediate Compound 32 (48 mg, crude, 29%). EI-MS m/z : [M+H] ⁺ 701.22.

Preparation of Compound 33

After dissolving Intermediate Compound 32 (48 mg, 0.07 mmol, crude) 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 afford Compound 33 (17.5 mg, 30%). EI-MS m/z : [M+H] ⁺ 862.08.

<Example 6> Preparation of Compound 38

Preparation of Intermediate Compound 34

After dissolving Intermediate Compound 29 (649 mg, 1.86 mmol) in N,N- dimethylformamide (6 mL), t-butyl piperidin-4-ylcarbamate (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 x 2), and then dried with 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 afford Intermediate Compound 34 (628 mg, 79%).

¹ H-NMR (400 MHz, DMSO), δ 8.21 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 6.16 - 6.01 (m, 2H), 4.82 (d, J= 3.5 Hz, 2H), 4.17 (d, J= 5.5 Hz, 2H). EI-MS m/z : [M+H] ⁺ 469.49. Preparation of Intermediate Compound 35

After dissolving Intermediate Compound 9 (413 mg, 0.85 mmol) and Intermediate Compound 34 (600 mg, 1.28 mmol) in normal butyl alcohol (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 di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The washed material was dried with 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 afford Intermediate Compound 35 (147 mg, 20%). EI-MS m/z : [M+H] ⁺ 844.13.

Preparation of Intermediate Compound 36

After dissolving Intermediate Compound 35 (147 mg, 0.17 mmol) in methanol (3 mL) and distilled water (0.1 mL), an aqueous ammonia solution (28-30%, 0.25 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 di chloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford Intermediate Compound 36 (141 mg, crude). EI-MS m/z : [M+H] ⁺ 814.81.

Preparation of Intermediate Compound 37

After dissolving Intermediate Compound 36 (141 mg, 0.17 mmol, crude) 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 afford Intermediate Compound 37 (48 mg, 28%). EI-MS m/z : [M+H] ⁺ 975.16.

Preparation of Compound 38

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 afford Compound 38 (6.4 mg, 14%). EI-MS m/z : [M+H] ⁺ 875.17.

<Example 7> Preparation of Compound 43

Preparation of Intermediate Compound 39

LButyl 3 -oxopiperazine- 1 -carboxylate (210 mg, 1.05 mmol) was dissolved in N,N- dimethylformamide (6 mL), and potassium hydroxide (66.2 mg, 1.02 mmol) was added and then stirred at room temperature for 30 minutes. After dissolving Intermediate Compound 29 (350 mg, 1.20 mmol) in N,N-dimethylformamide (4 mL), it was 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 with anhydrous magnesium sulfate. The dried material was filtered, then concentrated under reduced pressure, and purified by column chromatography to afford Intermediate Compound 39 (432 mg, 92.0%).

¹ H-NMR (400 MHz, CDCh) δ 7.80 (s, 1H), 7.87 (s, 1H), 7.62 (s, 1H), 5.82-5.81 (m, 2H), 4.76, (d, 1H), 4.10-4.05 (m, 4H), 3.65 (t, 2H), 3.34 (t, 2H), 1.47 (s, 9H). EI-MS m/z : [M+H] ⁺ 469.10.

Preparation of Intermediate Compound 40 After dissolving Intermediate Compound 9 (542 mg, 1.11 mmol) and Intermediate Compound 39 (350 mg, 0.746 mmol) in normal butyl alcohol (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 with 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 afford Intermediate Compound 40 (135 mg, 21.4%). EI-MS m/z : [M+H] ⁺ 844.12.

Preparation of Intermediate Compound 41

After dissolving Intermediate Compound 40 (135 mg, 0.16 mmol) in methanol (6 mL) and distilled water (1 mL), an aqueous ammonia solution (28-30%, 0.3 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford Intermediate Compound 41 (91 mg, 69.8%). EI-MS m/z : [M+H] ⁺ 814.12.

Preparation of Intermediate Compound 42

After dissolving Intermediate Compound 41 (91 mg, 0.11 mmol) 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 tri ethylamine (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 afford Intermediate Compound 42 (125 mg, crude). EI-MS m/z : [M+H] ⁺ 975.17.

Preparation of Compound 43

After dissolving Intermediate Compound 42 (125 mg, crude) in di chloromethane (3.2 mL), trifluoroacetic acid (0.8 mL) was added at 0 °C under nitrogen. The reaction solution was stirred at 0 °C for 40 minutes, concentrated, and then purified by HPLC to afford Compound 43 (34 mg, 25%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 12.84 (bs, 2H), 9.16 (bs, 2H), 7.97 (d, 2H), 7.65 (s, 2H), 7.36 (s, 2H), 7.30 (s, 2H), 6.53 (d, 2H), 5.79 (s, 2H), 5.73-5.60 (m, 2H), 4.90 (bs, 4H), 4.55- 4.50 (m, 6H), 3.84 (d, 2H), 3.73 (s, 2H), 3.69 (s, 4H), 2.11 (d, 6H), 1.29-1.24 (m, 6H). EI-MS m/z : [M+H] ⁺ 875.13.

<Example 8> Preparation of Compound 48

Preparation of Intermediate Compound 44

After dissolving Intermediate Compound 4 (2.0 g, 9.23 mmol) 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 x 2), and dried with 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 afford Intermediate Compound 44 (2.0 g, 62%).

¹ H-NMR (400 MHz, DMSO-d ₆ ), δ 8.25 (s, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 5.22 (s, 2H), 4.34 (t, J= 5.5 Hz, 2H). EI-MS m/z : [M+H] ⁺ 348.99. Preparation of Intermediate Compound 45

After dissolving Intermediate Compound 44 (300 mg, 0.86 mmol) 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 x 2), and dried with anhydrous sodium sulfate. The dried material was filtered, concentrated under reduced pressure, and purified by column chromatography to afford Intermediate Compound 45 (230 mg, 75%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 5.17 (s, 2H), 3.52 (t, J= 11.5 Hz, 4H), 3.29 (s, 2H), 2.36 (t, J= 11.0 Hz, 4H). EI-MS m/z : [M+H] ⁺ 354.13.

Preparation of Intermediate Compound 46

After dissolving Intermediate Compound 9 (500 mg, 1.03 mmol) and Intermediate Compound 45 (215 mg, 0.60 mmol) in normal butyl alcohol (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 di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried with 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 afford Intermediate Compound 46 (303 mg, 68%). EI-MS m/z : [M+H] ⁺ 729.11.

Preparation of Intermediate Compound 47

After dissolving Intermediate Compound 46 (303 mg, 0.41 mmol) in methanol (10 mL) and distilled water (1 mL), an aqueous ammonia solution (28-30% ammonia, 0.45 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford Intermediate Compound 47 (97 mg, 33%, crude). EI-MS m/z : [M+H] ⁺ 699.07.

Preparation of Compound 48

After dissolving Intermediate Compound 47 (97 mg, 0.14 mmol, crude) 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 tri ethylamine (0.06 mL, 0.42 mmol) were added and stirred at room temperature for 13 hours. The reaction solution was concentrated under pressure and purified by HPLC to afford Compound 48 (38 mg, 32%).

¹ H-NMR (400 MHz, MeOD-d ₄ ), δ 7.60 (d, J= 1.3 Hz, 1H), 7.58 (d, J= 1.3 Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 6.60 (d, J = 0.6 Hz, 1H), 6.58 (d, J= 0.6 Hz, 1H), 5.89-5.86 (m, 4H), 5.04-5.01 (m, 4H), 4.61-4.55 (m, 4H), 4.07(s, 2H), 3.71 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 1.37-1.30 (m, 6H). EI-MS m/z : [M+H] ⁺ 860.08.

<Example 9> Preparation of Compound 55

Preparation of Intermediate Compound 49 To a solution of 4-nitropyrazole (1 g, 6.13 mmol) in methanol (20 mL) were added ammonia solution (28-30% ammonia, 2.2 mL) and sodium hydrosulfite (7.7 g). After stirred at room temperature for 1 hour, the reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. Methanol (15 mL) was added to the concentrated filtrate and then di-t-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 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 and filtered. The filtrate was concentrated under reduced pressure. The reduced was purified by column chromatography to afford Intermediate compound 49 (0.7 g, 43%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H).

Preparation of Intermediate Compound 50

To a solution of Intermediate compound 49 (0.7 g, 3.82 mmol) in A, N-dimethylformamide (15 mL) were added cesium carbonate (3.7 g, 11.46 mmol) and trans- 1 ,4-dibromo-2-butene (2.45 g, 11.46 mmol). After stirred 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 x x 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 afford Intermediate compound 50 (867 mg, 71%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.33 (s, 1H), 6.24 (s, 1H), 6.00 - 5.90 (m, 1H), 5.87 (td, J = 13.2, 5.9 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 3.94 (d, J = 6.9 Hz, 2H), 1.50 (s, 9H). EI-MS m/z : [M+H]+ 317.26.

Preparation of Intermediate Compound 51

To a solution of Intermediate compound 4 (540 mg, 2.5 mmol) in A, N-dimethylformamide (15 mL) were added cesium carbonate (894 mg, 2.75 mmol) and compound 50 (867 mg, 2.75 mmol). After stirred 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 x 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 afford Intermediate compound 51 (830 mg, 73%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.30 (s, 1H), 6.08 (d, J = 15.4 Hz, 1H), 5.86 (d, J= 15.8 Hz, 1H), 4.82 (d, J= 5.4 Hz, 2H), 4.74 (d, J= 5.9 Hz, 2H), 1.44 (d, J = 2.3 Hz, 9H). EI-MS m/z : [M+H] ⁺ 452.31.

Preparation of Intermediate Compound 52

To a solution of Intermediate compound 51 (830 mg, 1.83 mmol) and compound 9 (1.13 g, 2.76 mmol) in n-butanol (11 mL) were added A, 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 cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 52 (420 mg, 28%). EI-MS m/z : [M+H] ⁺ 827.39.

Preparation of Intermediate Compound 53

To a solution of Intermediate compound 52 (420 mg, 0.51 mmol) in methanol (5 mL) were added aqueous ammonia solution (28 ~ 30% ammonia, 1.8 mL, 12.66 mmol) and sodium hydrosulfite (882 mg, 5.06 mmol). After stirred 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 reversed phase column chromatography to afford Intermediate compound 53 (400 mg). EI-MS m/z : [M+H] ⁺ 797.48.

Preparation of Intermediate Compound 54

To a solution of Intermediate compound 53 (400 mg, 0.51 mmol) in N,N - dimethylformamide (1.5 mL) at 0 °C was added compound 2 (109 mg, 0.55 mmol) in N,N- dimethylformamide (1 mL). After 30 minutes, N-(3-dimethylaminopropyl)-N -ethyl carbodiimide (0.1 mL, 0.61 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added to the reaction solution. After stirred at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure and purified by reverse phase chromatography to afford Intermediate compound 54 (97 mg, 20%).

Preparation of Compound 55

To a solution of Intermediate compound 54 (30 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at 0 °C. After stirred at room temperature for 30 minutes, the reaction mixture was concentrated and purified by HPLC to afford Compound 55 (10 mg, 27%).

¹ H-NMR (400 MHz, CD ₃ OD) δ 7.80 (s, 1H), 7.57 (d, J= 11.4 Hz, 3H), 7.29 (s, 1H), 7.23 (s, 1H), 6.62 (d, J= 1.7 Hz, 1H), 6.56 (s, 1H), 5.85 (d, J= 18.0 Hz, 3 H), 5.70 (d, J= 15.6 Hz, 1H), 5.01 (s, 4H), 4.63 (s, 3H), 4.61 - 4.52 (m, 2H), 4.45 (s, 2H), 3.74 (s, 2H), 3.31 (m, 3H), 2.65 (s, 1H), 2.20 (d, J= 12.3 Hz, 6H), 1.34 (dt, J= 21.7, 6.9 Hz, 6H). EI-MS m/z : [M+H] ⁺ 858.54.

<Example 10> Preparation of Compound 65

65

Preparation of Intermediate Compound 56

To a solution of Intermediate compound 4 (5 g, 23.08 mmol) in A, N-dimethylformamide (30 mL) was added cesium carbonate (11.2 g, 34.62 mmol) at 0 °C under nitrogen. After 5 minutes, ethyl 4-bromobutyrate (5.4 g, 27.70 mmol) was added to the reaction solution at room temperature under nitrogen. After stirred for 2 hours, the reaction solution was diluted with ethyl acetate (60 mL) and washed with distilled water (15 mL x 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. After solidification used dichloromethane and hexane, the resulting solid was filtered and dried to afford Intermediate compound 56 (4.7 g, 61%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 8.28 (s,lH), 8.04 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 4.25 (m, 2H), 4.09-4.04 (q, J= 7.2 Hz, 2H), 1.19-1.15 (t, J= 12 Hz, 3H). EI-MS m/z : [M+H] ⁺ 331.20.

Preparation of Intermediate Compound 57

To a solution of Intermediate compound 56 (4.5 g, 13.60 mmol) in ethanol (30 mL) were added t-butyl (E)-(4-aminobut-2-en-l -yl)carbamate (2.5 g, 13.60 mmol) and N,N- diisopropylethylamine (2.37 mL, 27.21 mmol). After stirred at 120 °C for 12 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted ethyl acetate (60 mL) and washed with distilled water (15 mL x 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 afford Intermediate compound 57 (4.5 g, 68%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 8.01(s, 1H), 7.68 (t, 1H), 7.58 (s, 1H), 7.30 (s, 1H), 6.90 (s, 1H), 5.54 (s, 2H), 4.10 (m, 6H), 3.48 (s, 3H), 2.07 (m, 2H) 1.35 (m, 9H) 1.17 (m, 4H). EI-MS m/z : [M+H] ⁺ 481.28.

Preparation of Intermediate Compound 58

To a solution of Intermediate compound 57 (4.4 g, 9.156 mmol) in methanol (20 mL) were added aqueous ammonia solution (28 ~ 30% ammonia, 10 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 15 g, 91.6 mmol) at 0 °C. After stirred at room temperature for 1.5 hours, the reaction solution was filtered through Celite with methanol. The filtrate was concentrated under reduced pressure to afford Intermediate compound 58 (4 g, 96%). EI-MS m/z : [M+H] ⁺ 451.31.

Preparation of Intermediate Compound 59

To a solution of Intermediate compound 58 (4.0 g, 8.87 mmol) in N, N-dimethylformamide (30 mL) was added compound 2 (1.9 g, 9.76 mmol) at 0 °C. After stirred at room temperature for 30 min, triethylamine (3.7 mL, 26.63 mmol) and N-(3-dimethylaminopropyl)-N- ethyl carbodiimide (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 afford Intermediate compound 59 (3.8 g, 71%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.37-7.35 (m, 2H), 6.89 (m, 1H), 6.63 (s, 1H), 5.79-5.72 (d, J = 16 Hz, 1H), 5.58-5.54 (d, J= 16 Hz, 1H) 4.94 (s, 2H), 4.62 (m, 2H), 4.22 (s, 3H), 4.20 (m, 6H), 2.31 (m, 3H), 2.11 (s, 2H), 1.36 (m, 9H), 1.17 (m, 4H). EI-MS m/z : [M+H] ⁺ 612.31.

Preparation of Intermediate Compound 60

To a solution of Intermediate compound 59 (3.8 g, 6.21 mmol) in dichloromethane (50 mL) was added hydrochloric acid (4 M 1,4-dioxane solution, 11.5 mL). After stirred for 2 hours, the reaction solution was concentrated, and diluted with diethyl ether (20 mL). The resulting solid was filtered to afford Intermediate compound 60 (3.9 g, quant.).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (s, 1H), 7.88 (m, 2H), 7.68 (s, 1H), 7.39 (s, 2H), 6.67 (s, 1H), 6.08-6.04 (d, J= 16 Hz, 1H), 5.59-5.55 (d, J = 16 Hz, 1H), 5.00 (s, 2H), 4.61 (m, 2H), 4.22 (m, 2H), 4.10 (m, 2H), 2.19 (s, 3H), 2.11 (m, 2H), 1.37 (m, 3H), 1.19 (m, 3H). EI-MS m/z : [M+H] ⁺ 512.31.

Preparation of Intermediate Compound 61

To a solution of Intermediate compound 60 (3.8 g, 6.63 mmol) and Intermediate compound 51 (2 g, 4.42 mmol) in n-butanol (13 mL) was added N, N-diisopropylethylamine (3.85 mL, 22.13 mmol) at room temperature. After stirred 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 layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to afford Intermediate compound 61 (1.6 g, 38%). EI-MS m/z : [M+H] ⁺ 926.98.

Preparation of Intermediate Compound 62

To a solution of Intermediate compound 61 (1.6 g, 1.83 mmol) in methanol (8 mL) were added ammonia solution (28-30% ammonia, 3.2 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 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 afford Intermediate compound 62 (1.4 g, 85%). EI-MS m/z : [M+H] ⁺ 897.05.

Preparation of Intermediate Compound 63

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 tri ethylamine (0.63 mL, 4.53 mmol) were added. After stirred at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography to afford Intermediate compound 63 (560 mg, 35%). EI-MS m/z : [M+H] ⁺ 1057.96.

Preparation of Intermediate Compound 64

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

Preparation of Compound 65

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

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.80 (s, 1H), 9.77 (s, 2H), 7.96 (s, 1H), 7.87 (m, 2H), 7.65 (s, 2H), 7.53 (s, 1H), 7.34 (s, 2H), 7.28 (s, 2H), 6.53 (s, 2H), 5.79 (m, 3H), 5.65 (m, 1H), 4.90 (s, 4H), 4.62 (m, 2H), 4.50 (m, 6H), 3.92 (m, 3H), 2.24 (s, 2H), 2.11 (m, 6H), 1.74 (m, 2H), 1.26 (m, 6H). EI-MS m/z : [M+H] ⁺ 929.98.

<Example 11> Preparation of Compound 69

Preparation of Intermediate Compound 67 To a solution of Intermediate compound 66 (300 mg, 0.32 mmol, Intermediate compound 66 was prepared by the method described in the International patent publication No. WO 2022/155518 A1) in dichloroethane (30 mL) was added boron tribromide (1.0 M in dichloromethane, 3.2 mL, 3.16 mmol). After stirred under 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 afford Intermediate compound 67 (280 mg, 84 %). EI-MS m/z : [M+H] ⁺ 709.15. Preparation of Intermediate Compound 68 To a solution of Intermediate compound 67 (280 mg, 0.27 mmol) in N,N- dimethylformamide (2 mL) were added cesium carbonate (607 mg, 1.87 mmol) and Intermediate compound 50 (101 mg, 0.32 mmol). After stirred at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure and purified by reversed phase column chromatography to afford Intermediate compound 68 (158 mg, 62%). EI-MS m/z : [M+H] ⁺ 945.00. Preparation of Compound 69 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 stirred at room temperature for 1 hour, the reaction solution was concentrated and the resulting residue was purified by HPLC to afford Compound 69 (8 mg).

¹ H-NMR (400 MHz, CD ₃ OD) δ 7.82 (d, J = 0.8 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 7.17 (d, J= 1.4 Hz, 1H), 6.61 (d, J = 0.7 Hz, 1H), 6.49 (d, J = 0.7 Hz, 1H), 5.95 - 5.80 (m, 3H), 5.78 - 5.67 (m, 1H), 5.04 (dd, J = 17.4, 3.9 Hz, 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= 7.1 Hz, 3H), 1.28 (t, J= 7.1 Hz, 3H). EI-MS m/z : [M+H] ⁺ 845.07.

<Example 12> Preparation of Compound 79

Preparation of Intermediate Compound 70

To a solution of trans- 1 ,4-dibromo-2-butene (10.4 g, 48.7 mmol) in N,N- dimethylformamide (30 mL) was added sodium acetate (2.0 g, 24.4 mmol) at 0 °C under nitrogen. The reaction solution was stirred at room temperature for 17 hours and then diluted with ethyl acetate (100 mL) and washed with distilled water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 70 (2.98 g, 63%).

¹ H-NMR (400 MHz, CDCh) δ 6.02-5.82 (m, 2H), 4.59 (d, J = 5.6 Hz, 2H), 3.95 (d, J 7.2 Hz, 2H), 2.08 (s, 3H).

Preparation of Intermediate Compound 71

To a solution of Intermediate compound 70 (838 mg, 4.34 mmol) in di chloromethane (60 mL) were added tri ethylamine (1.83 mL, 13.02 mmol) and t-buty 1(3 -aminopropyl) carbamate (2.27 g, 13.02 mmol) in di chloromethane (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 afford Intermediate compound 71 (380 mg, 30%).

¹ H-NMR (400 MHz, CDCh) δ 5.87-5.71 (m, 2H), 4.99 (s, 1H), 4.58-4.52 (m, 2H), 3.26 (d, J = 5.7 Hz, 2H), 3.23-3.18 (m, 2H), 2.70-2.65 (m, 2H), 2.07 (d, J = 2.7 Hz, 3H), 1.68 (d, J = 6.6 Hz, 2H), 1.45 (d, J= 2.6 Hz, 9H).

Preparation of Intermediate Compound 72

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

Preparation of Intermediate Compound 73

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

Preparation of Intermediate Compound 74

To a solution of Intermediate compound 73 (300 mg, 0.77 mmol) in dichloromethane (5 mL) were added tri ethylamine (0.33 mL, 2.31 mmol) and methanesulfonyl anhydride (175 mg, 1.00 mmol) at 0 °C. After stirred 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. Liltration and concentration under reduced pressure gave Intermediate compound 74 (380 mg, crude) which was used without further purification. EI-MS m/z : [M+H] ⁺ 467.17.

Preparation of Intermediate Compound 76

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

Preparation of Intermediate Compound 77

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

Preparation of Intermediate Compound 78

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

Preparation of Compound 79

To a solution of Intermediate compound 78 (103 mg, 0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 °C under nitrogen. The reaction solution was stirred at room temperature for 2 hours. After concentration, the resulting residue was purified by HPLC to afford Intermediate compound 79 (48 mg, 45%)

¹ H-NMR (400 MHz, CD ₃ OD) δ 7.29 (d, J = 1.4 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 6.59 (d, J= 0.6 Hz, 1H), 6.56 (d, J= 0.6 Hz, 1H), 5.88 - 5.77 (m, 2H), 5.75 - 5.69 (m, 2H), 5.02 (d, J = 3.3 Hz, 4H), 4.64 - 4.50 (m, 6H), 3.94 (d, J = 4.2 Hz, 2H), 3.75 (s, 3H), 3.42 - 3.32 (m, 4H), 3.01 - 2.93 (m, 2H), 2.24 - 2.17 (m, 6H), 1.97 (p, J = 7.8 Hz, 2H), 1.34 (dt, J= 14.6, 7.1 Hz, 6H). EI-MS m/z : [M+H] ⁺ 891.09.

<Example 13> Preparation of Compound 89

o

Preparation of Intermediate Compound 80

To a solution of 4-Piperidinethanol (5 g, 38.7 mmol) in di chloromethane (200 mL) were added triethylamine (8.1 mL, 58.05 mmol) and di-t-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 x 2). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 80 (7.25 g, 81.6%).

¹ H-NMR (CDCh) δ: 1.04-1.10 (m, 2H), 1.48 (s, 9H), 1.49-1.55 (m, 3H), 1.60-1.66 (m, 2H), 2.27 (s, 1H), 2.64 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 4.03-4.08 (m, 2H). EI-MS m/z : [M+Na] ⁺ 252.26.

Preparation of Intermediate Compound 81

To a solution of Dimethyl sulfoxide (0.93 mL, 13.08 mmol) in dichloromethane (20 mL) was slowly added oxalyl chloride (0.34 mL, 3.93 mmol) at -78°C under nitrogen. After stirred for 30 minutes, the reaction solution was added Intermediate Compound 80 (1 g, 4.36 mmol) in dichloromethane (5 mL). The reaction solution was stirred at -50°C for 2 hours. The reaction solution was added triethylamine (1.8 mL, 13.1 mmol). After raised to 0°C stirred for 30 minutes, the reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 81 (990 mg, 99%).

¹ H-NMR (300 MHz, CDCh), δ (ppm): 9.78 (hr s, 1H), 4.08 (hr d, 2H), 2.74 (hr t, 2H), 2.39 (d, 2H), 2.12-1.89 (m, 1H), 1.79-1.64 (m, 2H), 1.45 (s, 9H), 1.26-1.10 (m, 2H). EI-MS m/z : [M+H] ⁺ 228.23.

Preparation of Intermediate Compound 82

To a solution of lithium chloride (17.2 g, 40.65 mmol) in acetonitrile (40 mL) was added triethylphosphonoacetate (7.33 mL, 50.81 mmol) at room temperature under nitrogen. After stirred for 5 minutes, the reaction solution was added Triethylamine (5.67 mL 40.65 mmol) at room temperature for 10 minutes. Compound 81 (7.7 g, 33.88 mmol) in acetonitrile (60 mL) was added to the reaction solution. After stirred at room temperature for 17 hours, the reaction solution was diluted with ethyl acetate (150 mL), washed with distilled water (150 mL). The organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 82 (5.59 g, 58.2%).

¹ H-NMR (400 MHz, CDCh), δ (ppm): 6.96-6.88 (m,lH), 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-MS m/z : [M+H] ⁺ 284.01.

Preparation of Intermediate Compound 83

To a solution of Intermediate compound 82 (2.5 g, 8.82 mmol) in dichloromethane (30 mL) was added diisobutylaluminium hydride (1.0 M cyclohexane solution, 19 mL, 19.00 mmol) at -78 °C under nitrogen. After stirred at -78 °C for 3 hours, the reaction solution was added methanol (100 mL). The reaction solution was filtered through Celite and washed with methanol. The filtrate was removed under reduced pressure and used without purification to afford Intermediate compound 83 (1.91 g, 84.8%).

¹ H-NMR (400 MHz, CDCI ₃ ): 6 = 5.70-5.65 (m, 2H), 4.18-4.01 (m, 4H), 2.69 (t, 2H, J = 12.6 Hz), 2.02 (t, 2H, J = 5.6 Hz), 1 .72-1 .62 (m, 3H), 1 .47 (s, 9H), 1 .1 1 (qd, 2H, J = 12.2 Hz, 3.9 Hz). EI-MS m/z : [M+H] ⁺ 256.06.

Preparation of Intermediate Compound 84

To a solution of Intermediate compound 83 (1.91 g, 7.48 mmol) in dichloromethane (20 mL) were added triethylamine (1.6 mL, 11.2 mmol) and methanesulfonyl chloride (0.87 mL, 11.2 mmol) at 0 °C. After stirred at room temperature for 3 hours, the reaction mixture 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 afford Intermediate compound 84 (2.59 g, crude).

Preparation of Intermediate Compound 85

To a solution of Intermediate compound 5 (1 g, 4.62 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (766 mg, 5.54 mmol) and compound 84 (2.3 g, 6.94 mmol). After stirred at room temperature for 14 hours, the reaction mixture 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 afford Intermediate compound 85 (1.18 g, 56.3%).

¹ H-NMR (400 MHz, CDCI3): 6 = 7.82-7.72, 5.83-5.69 (m, 2H), 4.80-4.71 (m, 2H), 4.04- 4.03 (m, 2H), 2.65 (s, 2H), 2.05-1.93 (m, 1H), 1.07-1.04 (m, 2H). EI-MS m/z : [M+H] ⁺ 454.17.

Preparation of Intermediate Compound 86

To a solution of Intermediate compound 85 (550 mg, 1.21 mmol) in n-butanol (5 mL) were added Intermediate compound 9 (1.17 g, 2.42 mmol) and A, N-diisopropylethylamine (1.05 mL, 6.06 mmol). After stirred 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 afford Intermediate compound 86 (157 mg, 15.6%). EI-MS m/z : [M+H] ⁺ 829.22.

Preparation of Intermediate Compound 87

To a solution of Intermediate compound 86 (157 mg, 0.19 mmol) in methanol (3 mL) were added ammonia solution (28-30% ammonia, 0.5 mL, 4.74 mmol) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 330 mg, 1.89 mmol). After stirred at room temperature for 1 hour, the reaction solution was passed through Celite filter and washed with methanol. After filtration, the filtrate was removed under reduced pressure and used without purification to afford Intermediate compound

87 (151 mg, crude), which was used without further purification.

Preparation of Intermediate Compound 88

To a solution of Intermediate compound 87 (151 mg, 0.19 mmol) in N,N- dimethylformamide (2 mL) was added compound 2 (40 mg, 0.21 mmol) at 0 °C. The reaction solution was stirred for 30 minutes and then N-(3-dimethylaminopropyl)-N’ -ethylcarbodiimide (0.04 mL, 0.24 mmol) and triethylamine (0.11 mL, 0.76 mmol) were added and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to afford Intermediate compound

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

Preparation of Compound 89

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

<Example 14> Preparation of Compound 95

Preparation of Intermediate Compound 90

To a solution of 3-Aminophenol (1 g, 9.16 mmol) in tetrahydrofuran (10 mL) was added di-t-butyl dicarbonate (2.52 mL, 10.99 mmol). After stirred for 16 hours at room temperature, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 x 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 afford compound 90 (1.8 g, 93%).

¹ H-NMR (400 MHz, CDCh) δ 9.24 (s, 1H), 9.18 (s, 1H), 6.88(m, 2H), 6.83 (m, 1H), 6.35 (m, 1H), 1.46 (s, 9H). EI-MS m/z : [M+H] ⁺ 209.10.

Preparation of Intermediate Compound 91

To a solution of Intermediate compound 90 (300 mg, 1.43 mmol) in N,N- dimethylformamide (5 mL) were added cesium carbonate (560 mg, 1.72 mmol) and Intermediate compound 5 (551 mg, 1.57 mmol) at 0 °C under nitrogen. After stirred for 2 hours, the reaction solution was diluted with ethyl acetate (30 mL) and washed with distilled water (15 mL x 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and filtered and concentrated. The concentrate was solidified by added dichloromethane and diethyl ether, then filtered and dried to afford Intermediate compound 91 (474 mg, 69%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 9.29 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.12 (m, 2H), 7.10 (d, 1H), 6.56 (m, 1H), 6.14 (m, 2H), 4.87 (d, J= 3.6 Hz, 2H), 4.57 (d, J= 3.2 Hz, 2H), 1.46 (s, 9H). EI-MS m/z : [M+H] ⁺ 478.00.

Preparation of Intermediate Compound 92

To a solution of Intermediate compound 9 (607 mg, 1.47 mmol) and Intermediate compound 91 (470 mg, 0.98 mmol) in n-butanol (5 mL) were added diisopropylethylamine (0.68 mL, 3.93 mmol) at room temperature. After heated 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 and filtered and concentrated to afford Intermediate compound 92 (100 mg, 12%), which was used without further purification. EI-MS m/z : [M+H] ⁺ 853.30.

Preparation of Intermediate Compound 93

To a solution of Intermediate compound 92 (100 mg, 0.11 mmol) in methanol (5 mL) were added ammonia solution (28-30% ammonia, 0.209 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 204 mg, 1.172 mmol) under nitrogen. After stirred 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 and filtered and concentrated to afford Intermediate compound 93 (100 mg, crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 823.36.

Preparation of Intermediate Compound 94

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

Preparation of Compound 95

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

<Example 15> Preparation of Compound 104

Preparation of Intermediate Compound 96

To a solution of methyl 3 -nitrocinnamate (3.5 g, 16.89 mmol) in methanol (20 mL) and distilled water (5 mL) were added cone, hydrochloric acid (0.25 mL) and iron powder (9 g, 161.15 mmol). After heated to reflux with stirring for 17 hours, the reaction solution was filtered through Celite and concentrated under reduced pressure to afford Intermediate compound 96 (2.7 g, crude) without purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 67.48 (d, J= 15.8 Hz, 1H), 7.06 (t, J= 7.8 Hz, 1H), 6.85- 6.79 (m, 2H), 6.65-6.61 (m, 1H), 6.41 (d, J= 15.8 Hz, 1H), 5.19 (s, 2H), 3.71 (s, 3H).

Preparation of Intermediate Compound 97

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

¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.65 (s, 1H), 7.62 (d, 1H, J= 16.1 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.28 (t, 1H, J= 7.6 Hz), 7.20 (d, 1H, J= 7.6 Hz), 6.47 (d, 1H, J= 16.1 Hz), 3.76 (s, 3H), 1.51 (s, 9H).

Preparation of Intermediate Compound 98

To a solution of Intermediate compound 97 (1.3 g, 4.69 mmol) in dichloromethane (20 mL) were added diisobutylaluminum hydride (1.0M in cyclohexane, 19 mL, 18.75 mmol) at -78°C under nitrogen. After stirred at -78 °C for 3 hours, the reaction solution was added methanol (100 mL) 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 afford Intermediate compound 98 (815 mg, 70%). EI-MS m/z : [M+Na] ⁺ 272.05.

Preparation of Intermediate Compound 99

To a solution of Intermediate Compound 98 (800 mg, 3.21 mmol) in dichloromethane (16 mL) were added tri ethylamine (0.7 mL, 4.81 mmol) and methanesulfonyl chloride (0.3 mL, 3.53 mmol) at 0 °C. After stirred at room temperature for 3 hours, the reaction solution 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 afford Intermediate compound 99 (1 g, 95 %), which was used without further purification. Preparation of Intermediate Compound 100

To a solution of Intermediate compound 4 (762 mg, 3.52 mmol) in N,N- dimethylformamide (15 mL) were added potassium carbonate (663 mg, 4.8 mmol) and compound 99 (1.05 g, 3.2 mmol). After stirred at 50 °C for 15 hours, the reaction solution 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 afford Intermediate compound 100 (815 mg, 57%), which was used without further purification. EI-MS m/z : [M+H] ⁺ 448.25.

Preparation of Intermediate Compound 101

To a solution of Intermediate compound 100 (500 mg, 1.12 mmol) in n-butanol (6 mL) were added compound 9 (811 mg, 1.68 mmol) and N^/V-diisopropylethylamine (0.8 mL, 4.47 mmol). After stirred 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 afford Intermediate compound 101(316 mg, 34%). EI-MS m/z : [M+H] ⁺ 823.42.

Preparation of Intermediate Compound 102

To a solution of Intermediate compound 101 (316 mg, 0.38 mmol) in methanol (6 mL) were added aqueous ammonia solution (28-30% ammonia, 0.7 mL, 9.6 mmol) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 668 mg, 3.84 mmol). After stirred at room temperature for 1 hour, the precipitate was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure and obtained Intermediate compound 102 (304 mg, crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 793.51.

Preparation of Intermediate Compound 103

To a solution of Intermediate compound 102 (304 mg, 0.38 mmol) in N,N- dimethylformamide (2 mL) was added compound 2 (82 mg, 0.42 mmol) at 0 °C. After stirred for 30 minutes, the reaction solution was added N-(3-dimethylaminopropyl)-A’-ethylcarbodiimide (0.08 mL, 0.48 mmol) and triethylamine (0.21 mL, 1.54 mmol) at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 103 (12 mg, 3%). EI-MS m/z : [M+H] ⁺ 954.47. Preparation of Compound 104

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

<Example 16> Preparation of Compound 110

Preparation of Intermediate Compound 105

To a solution of t-butyl prop-2-en-l-ylcarbamate (1.0 g, 6.44 mmol) in N,N- dimethylformamide (9 mL) and methanol (1 mL) were added trimethylsilylazide (1.27 mL, 9.66 mmol) and copper(I) iodide (613 mg, 3.22 mmol). After stirred 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 x 2) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 105 (373 mg, 29%).

¹ H-NMR (400 MHz, CDCh) δ 7.65 (s, 1H), 5.09 (s, 1H), 4.43 (d, J= 6.0 Hz, 2H), 1.46 (s,

9H).

Preparation of Intermediate Compound 106

To a solution of Intermediate compound 105 (122 mg, 0.62 mmol) and compound 5 (315 mg, 0.68 mmol) in N, N-dimethylformamide (55 mL) was added potassium carbonate (102 mg, 0.74 mmol) at room temperature under nitrogen. After stirred for 16 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with distilled water (150 mLx2) and brine (150 mL). The reaction solution was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 106 (146 mg, 50%).

¹ H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 8.06 (s, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.78 (s, 1H), 7.30 (s, 1H), 6.17 - 6.07 (m, 1H), 5.97 - 5.93 (m, 1H), 5.07 (d, J= 6.0 Hz, 2H), 4.84 (d, J = 5.2 Hz, 2H), 4.16 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H).

Preparation of Intermediate Compound 107

To a solution of Intermediate compound 106 (265 mg, 0.57 mmol) and Intermediate compound 9 (412 mg, 0.85 mmol) in n-butanol (3 mL) was added N,N-diisopropylethylamine (0.49 mL, 2.84 mmol) at room temperature. After heated to 100 °C and stirred 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 afford Intermediate compound 107 (352 mg, 73%). EI-MS m/z : [M+H] ⁺ 842.42.

Preparation of Intermediate Compound 108

To a solution of Intermediate compound 107 (352 mg, 0.42 mmol) in methanol (10 mL) and distilled water (2 mL) were added ammonia solution (28-30% ammonia, 0.6 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 728 mg, 4.2 mmol) under nitrogen. After stirred 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 di chloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered and concentrated to afford Intermediate compound 108 (100 mg, 29%), which was used without further purification. EI-MS m/z : [M+H]+ 812.47.

Preparation of Intermediate Compound 109

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

Preparation of Compound 110

To a solution of Intermediate compound 109 (80 mg, 0.08 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at -78 °C under nitrogen. After stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford the compound 110 (25 mg, 35%).

¹ H-NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 8.19 (s, 2H), 8.04 - 7.91 (m, 3H), 7.65 (s, 2H), 7.37 (s, 2H), 7.30 (s, 2H), 6.52 (d, J= 2.6 Hz, 2H), 5.96 - 5.79 (m, 3H), 4.95 - 4.87 (m, 6H), 4.58 - 4.48 (m, 6H), 4.10 (q, J= 5.7 Hz, 2H), 3.70 (s, 3H), 2.10 (d, J= 6.5 Hz, 6H), 1.26 (q, J = 7.1 Hz, 6H). EI-MS m/z : [M+H] ⁺ 873.55.

<Example 17> Preparation of Compound 120

OMe OH

119 120

Preparation of Intermediate Compound 111

To a solution of I t-butyl (S)-2-(hydroxymethyl)pyrrolidine-l -carboxylate (2.2 g, 10.93 mmol) in dichloromethane (20 mL) were 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 stirred at room temperature for 17 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL) and 0.1 N hydrochloric acid solution (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the product was purified by column chromatography to afford Intermediate compound 111 (1.65 g, 75%).

¹ H-NMR (400 MHz, CDCh) δ 9.60 - 9.44 (m, 1H), 4.13 (d, J= 61.6 Hz, 1H), 3.62 - 3.40 (m, 2H), 2.23 - 1.82 (m, 4H), 1.46 (d, J= 19.7 Hz, 9H).

Preparation of Intermediate Compound 112

To a solution of Lithium chloride (421 mg, 9.94 mmol) and trimethyl phosphonoacetate (2.2 g, 12.42 mmol) in acetonitrile (8 mL) was added triethylamine (1.4 mL, mmol) at 0 °C. The reaction solution was stirred at room temperature for 10 minutes. The reaction solution was added Intermediate compound 111 (1.6 g, 8.28 mmol) in acetonitrile (12 mL) After stirred at room temperature for 17 hours, the reaction solution was diluted with diethyl ether (100 mL) and washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to afford Intermediate compound 112 (1.43 g, 67%).

¹ H-NMR (400 MHz, CDCh) δ 6.14 (t, J = 10.0 Hz, 1H), 5.74 (d, J= 11.4 Hz, 1H), 5.32 - 5.22 (m, 1H), 3.71 (s, 3H), 3.59 - 3.34 (m, 2H), 2.31 (d, J= 12.9 Hz, 1H), 1.84 (ddt, J= 12.5, 8.4, 6.0 Hz, 2H), 1.67 (dt, J= 13.2, 6.6 Hz, 1H), 1.42 (d, J= 22.5 Hz, 9H).

Preparation of Intermediate Compound 113

To a solution of Intermediate compound 112 (700 mg, 2.74 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (219 mg, 5.48 mmol) in distilled water (10 mL) at 0 °C After stirred at room temperature for 17 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with 1 N hydrochloric acid solution (100 mL). The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to afford Intermediate compound 113 (660 mg, 99%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 6.91 (d, J= 13.0 Hz, 1H), 5.84 (d, J= 15.6 Hz, 1H), 4.46 (d, J= 56.8 Hz, 1H), 3.45 (s, 2H), 2.10 (s, 1H), 1.87 (q, J= 6.6 Hz, 5H), 1.49 - 1.40 (m, 9H).

Preparation of Intermediate Compound 114

To a solution of Intermediate compound 113 (660 mg, 2.74 mmol) in tetrahydrofuran (10 mL) were added isobutyl chloroformate (0.37 mL, 2.87 mmol) and triethylamine (0.46 mL, 3.28 mmol) at -78 °C. After stirred at room temperature for 1 hour, the reaction solution was added methanol (5 mL) and sodium borohydride (310 mg, 8.21 mmol). The reaction solution was stirred at room temperature for 2 hours and 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 resulting residue was purified by column chromatography to afford the Intermediate compound 114 (494 mg, 79%).

¹ H-NMR (400 MHz, CDCh) δ 5.66 (s, 1H), 4.31 (d, J= 39.6 Hz, 1H), 4.14 (d, J= 5.0 Hz, 2H), 3.39 (s, 1H), 2.01 (s, 1H), 1.94 - 1.76 (m, 3H), 1.71 (ddd, J= 11.0, 6.7, 3.1 Hz, 4H), 1.45 (d, J= 6.8 Hz, 9H).

Preparation of Intermediate Compound 115

To a solution of Intermediate compound 114 (494 mg, 2.17 mmol) in di chloromethane (20 mL) were added N-methylmorpholine (0.48 mL, 4.34 mmol) and methanesulfonyl anhydride (416 mg, 2.39 mmol) at -78 °C. After stirred 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 and filtered and concentrated under reduced pressure to afford the Intermediate compound 115 (632 mg, 95%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 5.82 (s, 1H), 5.67 (s, 1H), 4.72 (d, J = 6.5 Hz, 2H), 4.32 (d, J= 39.2 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.40 (s, 1H), 3.02 (s, 3H), 2.05 (s, 1H), 1.84 (p, J= 6.4 Hz, 2H), 1.58 (s, 2H), 1.44 (s, 9H).

Preparation of Intermediate Compound 116

To a solution of Intermediate compound 115 (632 mg, 2.07 mmol) and compound 5 (448 mg, 2.07 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (314 mg, 2.27 mmol) at room temperature under nitrogen. After stirred for 16 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with distilled water (100 mL x 2) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 116 (563 mg, 63%).

¹ H-NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.04 (d, J= 1.9 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 5.92 - 5.82 (m, 1H), 5.69 - 5.62 (m, 1H), 4.83 (d, J = 5.9 Hz, 2H), 4.21 (s, 1H), 3.29 - 3.19 (m, 2H), 1.77 (q, J= 6.7 Hz, 2H), 1.65 (s, 1H), 1.33 (d, 27.7 Hz, 9H). Preparation of Intermediate Compound 117

To a solution of Intermediate compound 116 (300 mg, 0.70 mmol) and Intermediate compound 9 (511 mg, 0.98 mmol) in n-butanol (4 mL) was added N,N-diisopropylethylamine (0.61 mL, 3.52 mmol) was added at room temperature. After heated to 120 °C and stirred for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture 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 and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the Intermediate compound 117 (263 mg, 46%). EI-MS m/z : [M+H] ⁺ 801.41.

Preparation of Intermediate Compound 118

To a solution of Intermediate compound 117 (263 mg, 0.32 mmol) in methanol (10 mL) and distilled water (2 mL) were added ammonia solution (28-30% ammonia, 0.5 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 572 mg, 3.28 mmol) under nitrogen. After stirred at room temperature for 2 hours, the reaction solution was added methanol (50 mL). The reaction mixture was filtered through Celite 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 afford the Intermediate compound 118 (223 mg, 88%) without purification. EI-MS m/z : [M+H] ⁺ 771.43.

Preparation of Intermediate Compound 119

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

Preparation of Compound 120

To a solution of Intermediate compound 119 (99 mg, 0.11 mmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.4 mL) at -78 °C under nitrogen. After stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford the compound 120 (56 mg, 64%).

<Example 18> Preparation of Compound 127

Preparation of Intermediate Compound 121

To a solution of 5-nitroindole (1 g, 6.13 mmol) in methanol (15 mL) was added palladium/ charcoal (85 mg). After stirred at room temperature under hydrogen balloon for 3 hours, the reaction solution was passed through Celite. The filtrate was concentrated under reduced pressure. The concentrated filtrate was dissolved in N,N-dimethylformamide (15 mL) at room temperature and then di-t-butyl dicarbonate (1.3 g, 6.13 mmol) and diisopropylethylamine (0.79 g, 6.13 mmol) were added. After stirred at room temperature for 5 hours, the reaction mixture diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 mL x 2) and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure to afford Intermediate compound 121 (1.15 g, 80%), which was used without further purification. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 9.25 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 1.48 (s, 9H).

Preparation of Intermediate Compound 122

To a solution of Intermediate compound 121 (1 g, 4.28 mmol) in A, N-dimethylformamide (40 mL) were added potassium carbonate (711 mg, 5.14 mmol) and trans- 1 ,4-dibromo-2-butene (2.75 g, 12.86 mmol) at room temperature. After 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 x 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 afford the Intermediate compound 122 (372 mg, 23%).

¹ H-NMR (400 MHz, DMSO) δ 9.21 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.14 (dd, J = 15.1, 7.1 Hz, 1H), 5.88 (q, J = 7.5 Hz, 1H), 5.05 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 6.8 Hz, 1H), 4.16 (d, J = 7.3 Hz, 2H), 1.48 (s, 9H).

Preparation of Intermediate Compound 123

To a solution of Intermediate compound 122 (369 mg, 1.0 mmol) in N,N- dimethylformamide (4 mL) were added 4-chloro-3-hydroxy-5-nitrobenzamide (182 mg, 0.84 mmol) and potassium carbonate (174 mg, 1.26 mmol) under nitrogen. After stirred at 50 °C for 5 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL x 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 afford the Intermediate compound 123 (312 mg, 74%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.24 (d, J = 17.5 Hz, 2H), 8.06 (s, 1H), 7.87 (d, J= 13.6 Hz, 2H), 7.78 (s, 1H), 7.50 (d, J= 9.2 Hz, 1H), 7.22 (d, J= 9.2 Hz, 1H), 6.21 (dt, J= 15.8, 6.2 Hz, 1H), 6.01 - 5.90 (m, 1H), 5.10 (d, J= 6.1 Hz, 2H), 4.86 (d, J= 5.3 Hz, 2H), 1.48 (s, 9H). EI-MS m/z : [M+H] ⁺ 502.31.

Preparation of Intermediate Compound 124

To a solution of Intermediate compound 123 (310 mg, 0.62 mmol) and Intermediate compound 9 (406 mg, 0.98 mmol) in n-butanol (6 mL) was added diisopropylethylamine (0.21 mL, 1.24 mmol) at room temperature. After heated to 120 °C and stirred for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture 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 obtained solid was filtered. The solid was dried to afford 124 (crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 877.59.

Preparation of Intermediate Compound 125

To a solution of Intermediate compound 124 (0.20 mmol, crude) in methanol (7 mL) and distilled water (1 mL) were added ammonia solution (28-30% ammonia, 0.2 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 355 mg, 2.04 mmol). After stirred 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 obtained solid was filtered. The solid was dried to afford Compound 125 (crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 847.58.

Preparation of Intermediate Compound 126

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

Preparation of Compound 127

To a solution of Intermediate compound 126 (33 mg, 0.03mmol ) in dichloromethane (1.6mL) was added trifluoroacetic acid (0.4mL) at -78 °C under nitrogen. After stirred at room temperature fori hour, the reaction solution concentrated under reduced pressure. The resulting residue was purified by HPLC to afford the compound 127 (11 mg, 27%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.68 - 7.60 (m, 3H), 7.45 (s, 1H), 7.37 - 7.28 (m, 3H), 7.06 (d, J= 9.2 Hz, 1H), 6.52 (s, 2H), 6.02 (dt, J= 14.1, 6.5 Hz, 1H), 5.79 (s, 2H), 4.90 (dd, J= 20.3, 7.7 Hz, 5H), 4.52 (dq, J= 14.1, 6.3 Hz, 5H), 3.69 (s, 3H), 2.10 (d, J= 10.6 Hz, 6H), 1.25 (q, J= 7.9 Hz, 6H). EI-MS m/z : [M+H] ⁺ 908.54.

<Example 19> Preparation of Compound 133

Preparation of Intermediate Compound 128

To a solution of t-butyl carbazate (5 g, 37.83 mmol) in N, N-dimethylformamide (30 mL) was added sodium hydride (60%, 3.8 g, 94.6 mmol) at 0 °C. After stirred at 0°C for 0.5 hours, the reaction solution was added 1,3-dibromopropane (3.8 mL, 37.8 mmol) at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with distilled water (150 mL x 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 afford Intermediate compound 128 (3.9 g, 57%).

¹ H-NMR (400 MHz, CDCh) δ 3.86 (s, 1H), 3.49 3.41 (m, 2H), 3.07 - 2.99 (m, 2H), 2.03 (p, J= 6.8 Hz, 2H), 1.52 - 1.44 (m, 9H).

Preparation of Intermediate Compound 129

To a solution of Intermediate compound 128 (1.2 g, 6.86 mmol) and Intermediate compound 5 (2.0 g, 5.72 mmol) in N, N-dimethylformamide (15 mL) was added potassium carbonate (1.1 g, 8.58 mmol) at room temperature under nitrogen. After stirred for 18 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with distilled water (100 mLx2). 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 afford Intermediate compound 129 (2.0 g, 80%).

¹ H-NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 6.02 - 5.83 (m, 2H), 4.81 (d, J = 5.1 Hz, 2H), 3.26 (d, J = 6.0 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.00 (t, J= 13 Hz, 2H), 1.37 (s, 9H).

Preparation of Intermediate Compound 130

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

Preparation of Intermediate Compound 131

To a solution of Intermediate compound 130 (1.0 g, 1.29 mmol) in methanol (20 mL) and water (4 mL) were added ammonia solution (28-30% ammonia, 1.4 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 2.2 g, 12.87 mmol) under nitrogen. After stirred at room temperature for 2 hours, the reaction solution was added methanol (50 mL). 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 afford Intermediate compound 131 (1.0 g, crude). EI-MS m/z : [M+H] ⁺ 786.58.

Preparation of Intermediate Compound 132

To a solution of Intermediate compound 131 (1.0 g, 1.29 mmol) in N,N- dimethylformamide (6 mL) was added compound 2 (301 mg, 1.54 mmol) in N,N- dimethylformamide (3 mL) under nitrogen at room temperature. After stirred for 1 hour, the reaction mixture were added N-(3 -di methy lam i nopropyl)-N'-ethylcarbodiimide hydrochloride (0.34 mL, 1.93 mmol) and triethylamine (0.36 mL, 2.57 mmol) 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 132 (545 mg, 44%). EI-MS m/z : [M+H] ⁺ 947.62.

Preparation of Compound 133

To 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 stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 133 (42 mg, 53%). EI- MS m/z : [M+H]+847.55.

<Example 20> Preparation of Compound 139 Preparation of Intermediate Compound 134

To a solution of Intermediate compound 5 (300 mg, 0.86 mmol) in N,N- dimethylformamide (5 mL) was added sodium azide (84 mg, 1.29 mmol) at 0 °C. After stirred at 0 °C for 2 hours, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with distilled water (150 mL x 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 afford Intermediate compound 134 (225 mg, 84%), which was used without further purification.

¹ H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 8.07 (d, J= 1.7 Hz, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 6.11 - 5.94 (m, 2H), 4.88 (d, J = 4.7 Hz, 2H), 3.97 (d, J = 5.5 Hz, 2H).

Preparation of Intermediate Compound 135

To a solution of Intermediate compound 134 (225 mg, 0.72 mmol) in ethanol (3 mL), dichloromethane (2 mL) and water (3 mL) were added t-butyl propa-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 stirred at room temperature for 2 hours, the reaction mixture was diluted with di chloromethane (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 then diluted with dichloromethane and hexane. The resulting solid was filtered and dried to afford Intermediate compound 135 (283 mg, 84%), which was used without further purification.

¹ H-NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 8.06 (s, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.78 (s, 1H), 7.30 (s, 1H), 6.17 - 6.07 (m, 1H), 5.97 - 5.93 (m, 1H), 5.07 (d, J= 6.0 Hz, 2H), 4.84 (d, J = 5.2 Hz, 2H), 4.16 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H).

Preparation of Intermediate Compound 136

To a solution of Intermediate compound 135 (243 mg, 0.52 mmol) and Intermediate compound 9 (428 mg, 1.04 mmol) in n-butanol (3 mL) were added N, N-di isopropyl ethyl amine (0.45 mL, 2.60 mmol) at room temperature. After heated to 100 °C and stirred for 21 hours, the reaction solution was to room temperature. The reaction solution was diluted with dichloromethane (100 mL), 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 afford Intermediate compound 136(241 mg, 55%). EI-MS m/z : [M+H] ⁺ 842.54.

Preparation of Intermediate Compound 137

To a solution of Intermediate compound 136 (241 mg, 0.29 mmol) in methanol (10 mL) and water (2 mL) were added ammonia solution (28-30% ammonia, 0.4 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 498 mg, 2.86 mmol) to the reaction mixture under nitrogen. After stirred at room temperature for 2 hours, the reaction solution was added methanol (50 mL). 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 afford Intermediate compound 137 (168 mg, crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 812.54.

Preparation of Intermediate Compound 138

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

Preparation of Compound 139

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

<Example 21> Preparation of Compound 147

Preparation of Intermediate Compound 140 To a solution of di-t-butyl-iminodiacetate (684 mg, 3.15 mmol) in N,N- dimethylformamide (7 mL) was added cesium carbonate (1.12 mg, 3.43 mmol). After stirred at room temperature for 10 minutes, the reaction solution was added Intermediate compound 5 (1 g, 2.86 mmol) at room temperature 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 afford Intermediate compound 140 (1.05 g, 71%).

¹ H-NMR (400 MHz, CDCh) δ 7.79 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 6.62 (s, 1H), 5.95 (dt, J= 16.0, 5.2 Hz, 1H), 5.81 (dt, J= 15.7, 5.6 Hz, 1H), 4.74 (d, J= 5.4 Hz, 2H), 4.24 (d, J= 5.1 Hz, 2H), 1.48 (s, 18H).

Preparation of Intermediate Compound 141

To a solution of Intermediate compound 140 (423 mg, 0.87 mmol) in methanol (4 mL) and tetrahydrofuran (10 mL) were added sodium hydroxide (105 mg, 2.61 mmol) in water (0.5 mL). After stirred 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 afford Intermediate compound 141 (223 mg, 69%).

¹ H-NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 8.04 (d, J= 2.2 Hz, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 5.95 - 5.72 (m, 2H), 4.80 (d, J= 5.5 Hz, 2H), 3.60 (d, J= 6.0 Hz, 2H), 1.37 (s, 9H).

Preparation of Intermediate Compound 142

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

Preparation of Intermediate Compound 143

To a solution of Intermediate compound 142 (294 mg, 0.39 mmol) in methanol (6 mL) were added ammonia solution (28-30% ammonia, 0.7 mL, 9.5 mmol) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 672 mg, 3.86 mmol). After stirred at room temperature for 1 hours, the resulting solid was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to afford Intermediate compound 143 (202 mg, crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 731.5.

Preparation of Intermediate Compound 144 To a solution of Intermediate compound 143 (202 mg, 0.28 mmol) in N,N- dimethylformamide (1 mL) was added compound 149 (30 mg, 0.15 mmol) in N,N- dimethylformamide (1 mL). After stirring at 0°C for 30 minutes, the reaction solution was added N-(3-dimethylaminopropyl)-N -ethylcarbodiimide (43.7 mg, 0.28 mmol). 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 afford Intermediate compound 144 (122 mg, 49%). EI-MS m/z : [M+H] ⁺ 892.5.

Preparation of Intermediate Compound 145

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

Preparation of Intermediate Compound 146

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

Preparation of Compound 147

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

<Example 22> Preparation of Compound 151

Preparation of Intermediate Compound 148

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

Preparation of Intermediate Compound 149

To a solution of Intermediate compound 148 (crude) in acetone (1 mL) was added potassium thiocyanate (125 mg, 1.28 mmol) at 0 °C. After stirred at room temperature for 30 minutes, the reaction solution was added hexane (10 mL). The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 149 (64 mg, 50%).

¹ H-NMR (400 MHz, CDCh), δ 2.90 (q, J= 7.6 Hz, 2H), 2.54 (s, 3H), 2.72 (t, J= 7.6 Hz, 3H). EI-MS m/z: [M+H] ⁺ 197.21.

Preparation of Intermediate Compound 150

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

Preparation of Compound 151

To a solution of Intermediate compound 150 (25 mg, 0.03 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at -0 °C. After stirred at room temperature for 2 hours. The reaction solution was concentrated. The resulting residue was purified by HPLC to afford Compound 151 (9.3 mg, 42%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.00 - 7.83 (m, 2H), 7.65 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 6.51 (s, 1H), 5.91 (d, J= 15.0 Hz, 1H), 5.76 (d, J= 14.3 Hz, 2H), 4.89 (s, 3H), 4.66 (d, J= 5.9 Hz, 1H), 4.51 (d, J= 7.3 Hz, 2H), 3.71 (s, 2H), 2.82 (q, J= 7.9 Hz, 1H), 2.40 (s, 2H), 2.10 (s, 2H), 1.25 (t, J= 7.2 Hz, 2H), 1.02 (t, J= 7.7 Hz, 2H). EI-MS m/z: [M+H] ⁺ 859.27.

<Example 23> Preparation of Compound 155

Preparation of Intermediate Compound 152

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

Preparation of Intermediate Compound 153

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

Preparation of Intermediate Compound 154

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

Preparation of Compound 155

To a solution of Intermediate compound 154 (30 mg, 0.03 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at -0 °C. After stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 155 (18mg, 68%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J= 14.1 Hz, 1H), 7.82 (s, 1H), 7.56 (d, J= 8.4 Hz, 1H), 7.47 (s, OH), 7.30-7.21 (m, 2H), 6.45 (s, 1H), 5.77 (dq, 2H), 4.81 (d, J= 17.4 Hz, 2H), 4.60 (d, J= 6.0 Hz, 1H), 4.51 (s, 1H), 4.44 (d, J= 7.7 Hz, 1H), 3.64 (s, 2H), 3.03 (q, J = 7.9 Hz, 2H), 2.66 (s, 2H), 2.02 (s, 2H), 1.19 (t, J = 7.4 Hz, 2H), 1.07 (t, J = 7.7 Hz, 2H). EI-MS m/z : [M+H] ⁺ 875.24.

<Example 24> Preparation of Compound 160

Preparation of Intermediate Compound 156 To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.54 mmol) in N,N- dimethylformamide (3 mL) were added cesium carbonate (285 mg, 0.88 mmol) and trans-1,4- dibromo-2-butene (625 mg, 2.92 mmol). After stirred at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL), 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 afford Intermediate compound 156 (592 mg, 94%), which was used without further purification. Preparation of Intermediate Compound 157 To a solution of Intermediate compound 156 (592 mg, 1.55 mmol) in methanol (10 mL) was added hydrazine monohydrate (0.2 mL, 4.64 mmol). After stirred at room temperature for 1 hour, the reaction solution was added Dichloromethane and diethyl ether. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 157 (352 mg, 90%). Preparation of Intermediate Compound 158 To a solution of Intermediate compound 157 (350 mg, 1.39 mmol) in dichloromethane (20 mL) were added N,N’-diisopropylethylamine (1.2 mL, 6.93 mmol) and bis(pentafluorophenyl)carbonate (1.6 g, 4.16 mmol) at -0 °C. After stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The reaction mixture was added dichloromethane and hexane. The resulting solid was filtered and dried to afford Intermediate compound 158 (310 mg, 24%), which was used without further purification.

Preparation of Intermediate Compound 159

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

Preparation of Compound 160

To a solution of Intermediate compound 159 (59 mg, crude) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at -0 °C. After stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Intermediate compound 160 (30 mg, 45%).

<Example 25> Preparation of Compound 164

Preparation of Intermediate Compound 161 To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.54 mmol) in N,N- dimethylformamide (3 mL) were added cesium carbonate (285 mg, 0.88 mmol) and trans-1,4- dibromo-2-butene (625 mg, 2.92 mmol) After stirred 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 afford Intermediate compound 161 (111 mg, 62%). EI-MS m/z : [M+H] ⁺ 304.11. Preparation of Intermediate Compound 162 To a solution of Intermediate compound 66 (50 mg, 0.07 mmol) in N,N- dimethylformamide (2 mL) were added cesium carbonate (34 mg, 0.1 mmol) and Intermediate compound 161 (23 mg, 0.08 mmol). After stirred 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 afford Intermediate compound 162 (16 mg, 24%). EI-MS m/z : [M+H] ⁺ 946.27.

Preparation of Intermediate Compound 163

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

Preparation of Compound 164

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

<Example 26> Preparation of Compound 166

Preparation of Intermediate Compound 165

To a solution of Intermediate compound 145 (40 mg, 0.04 mmol) in N,N- dimethylformamide (1 mL) were added triethylamine (0.10 mL, 0.745 mmol) and N,N-bis(t- butoxycarbonyl)- l/7-pyrazole- l -carboxamidine (17 mg, 0.06 mmol) After stirred at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to afford Intermediate compound 165 (37 mg, crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 1035.01.

Preparation of Compound 166

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

<Example 27> Preparation of Compound 168

Preparation of Intermediate Compound 167

To a solution of Intermediate compound 67 (2.0 g, 2.07 mmol, Intermediate compound 67 was prepared according to the method described in the International patent publication No. WO 2022/155518 Al) in N,N-dimethylformamide (20 mL) were added cesium carbonate (5.4 g, 16.54 mmol) and Intermediate compound 50 (654 mg, 2.07 mmol) in A/N-dimethylformamide (5 mL). After stirred 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 reversed-phase column chromatography to afford Intermediate compound 167 (958 mg, 38%). EI-MS m/z : [M+H] ⁺ 1179.46.

Preparation of Compound 168

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

<Example 28> Preparation of Compound 175

173 174 175

Preparation of Intermediate Compound 169

To a solution of 4-aminopyrazole (5.89 g, 70.8 mmol) was in tetrahydrofuran (200 mL) were added triethylamine (15 mL, 106.13 mmol) and di-t-butyl dicarbonate (48.8 mL, 212.26 mmol) under nitrogen. After stirred at room temperature for 20 hours, the reaction mixture was added ethyl acetate (50 mL) and washed with distilled water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 169 (5.9 g, 29 %).

¹ H-NMR (400 MHz, CDC13) δ 8.19 (s, 1H), 7.63 (s, 1H), 6.34 (s, 1H), 1.64 (d, J = 3.9 Hz, 9H), 1.52 (s, 9H).

Preparation of Intermediate Compound 170

To a solution of Intermediate Compound 169 (1.1 g, 3.88 mmol) in acetonitrile (30 mL) were added potassium carbonate (590 mg, 4.27 mmol), 18-crow«-6 (513 mg, 1.94 mmol) and methyl acrylate (367 mg, 4.27). After stirred at room temperature for 30 minutes, the reaction solution was added Ethyl acetate (50 mL) and washed with distilled water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 170. (1.38 g, 96 %).

¹ H-NMR (400 MHz, CDC13) δ 7.77 (s, 1H), 7.27 (d, 1 = 3.1 Hz, 1H), 3.92 (dt, J = 9.4, 5.8 Hz, 2H), 3.71 - 3.65 (m, 3H), 2.68 - 2.59 (m, 2H), 1.65 (q, J = 2.4 Hz, 9H), 1.54 - 1.48 (m, 9H). EI-MS m/z : [M+H] ⁺ 370.32.

Preparation of Intermediate Compound 171

To a solution of Intermediate compound 170 (1.38 g, 3.73 mmol) in methanol (20 mL) was added potassium carbonate (770 mg, 5.6 mmol) at -0°C. After stirred at room temperature for 30 minutes, the reaction solution was added Ethyl acetate (50 mL) was added and washed with distilled water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 171. (950 mg, 94 %).

¹ H-NMR (400 MHz, CDC13) δ 7.66 (s, 1H), 7.53 (s, 1H), 3.96 - 3.87 (m, 2H), 3.67 (s, 3H), 2.64 (p, J = 5.0 Hz, 2H), 1.50 (s, 9H).

Preparation of Intermediate Compound 172

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

Preparation of Intermediate Compound 173

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

Preparation of Intermediate Compound 174

To a solution of Intermediate compound 173 (150 mg, 0.14 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.25 mL) at -0 °C. After stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to afford Intermediate compound 174 (135 mg, crude), which was used without further purification.

Preparation of Compound 175

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

<Example 29> Preparation of Compound 178

177 178

Preparation of Intermediate Compound 176

To a solution of Intermediate compound 49 (300 mg, 1.64 mmol) in N,N- dimethylformamide (10 mL) were added cesium carbonate (693 mg, 2.13 mmol) and 1 ,4-dibromo- 2-butene (1.04 g, 4.91 mmol). After stirred at room temperature for 1 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous ammonium chloride solution (2 x 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 afford Intermediate compound 176 (320 mg, 62 %).

Preparation of Intermediate Compound 177

To a solution of Intermediate compound 66 (400 mg, 0.42 mmol, Intermediate compound 66 was prepared according to the method described in the International patent publication No. WO 2022/155518 Al) in A/N-dimethylformamide (5 mL) were added cesium carbonate (548 mg, 1.68 mmol) and Intermediate compound 176 (158 mg, 0.50 mmol) in A/N-dimethylformamide (2 mL). After stirred at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The reaction mixture was added 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 afford Intermediate compound 177 (246 mg, 61%). EI-MS m/z : [M+H] ⁺ 956.52.

Preparation of Compound 178

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

<Example 30> Preparation of Compound 187

186 187

Preparation of Intermediate Compound 179

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) at -0 °C under nitrogen. After stirred 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%).

¹ H-NMR (400 MHz, CDCh) δ 3.65 (q, J = 5.6 Hz, 2H), 3.01 (dq, J 9.3, 3.3 Hz, 2H), 2.39 - 2.30 (m, 3H), 2.04 (t, J= 5.8 Hz, 1H), 1.83 (q, J = 6.0 Hz, 2H).

Preparation of Intermediate Compound 180

To a solution of Intermediate Compound 179 (1.26 g, 9.39 mmol) in dichloromethane (30 mL) were added imidazole (958 mg, 14.08 mmol) and triisopropylsilyl chloride (2.0 g, 10.33 mmol) at -0 °C. After stirred at room temperature for 4 hours, the reaction mixture was diluted with dichloromethane (100 mL), 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 afford Intermediate Compound 180 (2.7 g, 99%).

¹ H-NMR (400 MHz, CDCh) δ 3.74 (q, J= 5.4 Hz, 2H), 2.99 (q, J= 6.3 Hz, 2H), 2.35 - 2.30 (m, 3H), 1.81 (q, J= 6.2 Hz, 2H), 1.06 (s, 21H).

Preparation of Intermediate Compound 181

To a solution of Intermediate Compound 180 (2.7 g, 9.29 mmol) in methanol (30 mL) were added methyl iodide (0.69 mL, 10.2 mmol) and potassium carbonate (4.1 g, 30.25 mmol) at -0 °C. After stirred 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 afford Intermediate Compound 181 (1.73 g, 65%).

¹ H-NMR (400 MHz, CDCh) δ 3.86 - 3.73 (m, 2H), 2.60 (tt, J = 7.0, 2.5 Hz, 2H), 2.11 (q, J= 2.3 Hz, 3H), 1.82 (q, J = 6.2 Hz, 2H), 1.15 - 1.02 (m, 21H).

Preparation of Intermediate Compound 182

To a solution of Intermediate Compound 181 (1.2 g, 4.57 mmol) in methanol (20 mL) were added iodobenzene diacetate (3.7 g, 11.43 mmol) and ammonium carbonate (1.3 g, 13.71 mmol) at -0 °C. After stirred and reflux for 2 hours, the reaction mixture was concentrated. The resulting residue was purified by purified by HPLC to afford Compound 182 (1.5 g, crude).

¹ H-NMR (400 MHz, CDCh) δ 3.84 (q, J= 5.4 Hz, 2H), 3.28 - 3.21 (m, 2H), 3.03 - 2.97 (m, 3H), 2.11 - 2.03 (m, 2H), 1.06 (d, J = 4.4 Hz, 21H).

Preparation of Intermediate Compound 183

To a solution of Intermediate Compound 182 (1.5 g, crude) in di chloromethane (20 mL) were added pyridine (0.71 mL, 8.86 mmol) and ethyl chloroformate (0.51 mL, 5.31 mmol) at 0 °C. After stirred at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (100 mL), 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 afford Intermediate Compound 183 (1.47 g, 91%). ¹ H-NMR (400 MHz, CDCh) δ 4.15 (s, 2H), 3.83 (t, J= 5.2 Hz, 2H), 3.51 (d, J= 10.0 Hz, 2H), 3.25 (s, 3H), 2.10 (s, 2H), 1.29 (t, J= 5.8 Hz, 3H), 1.06 (d, J= 4.3 Hz, 21H).

Preparation of Intermediate Compound 184

To a solution of Intermediate Compound 183 (1.5 g, 4.02 mmol) in dichloromethane (30 mL) was added hydrochloric acid (4 M 1,4-di oxane solution, 12 mL) at 0 °C. After stirred for 2.5 hours, the reaction mixture was concentrated. The reaction mixture was added ethyl acetate (100 mL) and distilled water (70 mL). The obtained aqueous layer was concentrated. The reaction mixture was added dichloromethane (50 mL), methanol (5 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford Intermediate Compound 184 (752 mg, 89%).

¹ H-NMR (400 MHz, CDCh) δ 4.14 (tt, J= 8.5, 4.5 Hz, 2H), 3.81 (t, J= 5.4 Hz, 2H), 3.67 - 3.42 (m, 2H), 3.31 - 3.25 (m, 3H), 2.16 (q, J = 6.1 Hz, 2H), 1.29 (dt, J = 8.7, 4.8 Hz, 3H).

Preparation of Intermediate Compound 185

To a solution of Intermediate Compound 184 (50 mg, 0.24 mmol) in dichloromethane (3 mL) were added triethylamine (0.07 mL, 0.48 mmol) and methanesulfonyl anhydride (50 mg, 0.29 mmol) at -0 °C. After stirred 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 afford Intermediate Compound 185 (50 mg, 73%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 4.41 (d, J= 5.9 Hz, 2H), 4.15 (dq, J= 10.5, 3.7 Hz, 2H), 3.51 (d, J= 53.9 Hz, 2H), 3.30 (q, J= 2.4 Hz, 3H), 3.06 (q, J= 2.4 Hz, 3H), 2.40 (d, J= 8.7 Hz, 2H), 1.35 - 1.25 (m, 3H).

Preparation of Intermediate Compound 186

To a solution of Intermediate Compound 66 (100 mg, 0.11 mmol, Intermediate Compound 66 was prepared according to the method described in the International patent publication No. WO 2022/155518 Al) in /V,/V-dimethylformamide (2 mL) were added cesium carbonate (113 mg, 0.35 mmol) and Intermediate Compound 185 (36 mg, 0.13 mmol) dissolved in /V,/V-dimethylformamide (1 mL). After stirred at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The reaction mixture was added 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 afford Intermediate Compound 186 (48 mg, 50%). EI- MS m/z : [M+H] ⁺ 914.41. Preparation of Compound 187 To a solution of Intermediate Compound 186 (48 mg,0.05 mmol) in ethanol (20 mL) was added sodium ethoxide (21% w/w ethanol, 0.24 mL, 0.64 mmol). After stirred and reflux for 14 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to afford Compound 187 (25 mg, 55%). EI-MS m/z : [M+H] ⁺ 842.39. <Example 31> Preparation of Compound 197 Preparation of Intermediate Compound 188 To a solution of Intermediate compound 4 (400 mg, 1.85 mmol) in N,N- dimethylformamide (5 mL) were added cesium carbonate (782 mg, 2.40 mmol) and compound 185 (584 mg, 2.03 mmol). After stirred 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 afford Intermediate compound 188 (600 mg, 80 %).

¹ H-NMR (400 MHz, CDCh) δ 7.85 (s, 1H), 7.73 (d, J= 4.3 Hz, 1H), 4.38 (q, J = 6.0 Hz, 2H), 4.13 (q, J= 6.5 Hz, 2H), 3.81 - 3.65 (m, 1H), 3.54 (d, J= 14.8 Hz, 1H), 3.37 - 3.25 (m, 3H), 2.56 - 2.48 (m, 2H), 1.29 (q, J= 6.6 Hz, 3H).

Preparation of Intermediate Compound 189

To a solution of Intermediate compound 188 (600 mg, 1.47 mmol) in ethanol (10 mL) were added t-butyl (E)-(4-aminobut-2-en- l -yl)carbamate (548 mg, 2.94 mmol) and triethylamine (0.62 mL, 4.41 mmol). After stirred at 120 °C for 20 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compoundl89 (550 mg, 67 %). EI-MS m/z : [M+H] ⁺ 558.31.

Preparation of Intermediate Compound 190

To a solution of Intermediate compound 189 (550 mg, 0.99 mmol) in methanol (5 mL) and distilled water (1 mL) were added ammonia solution (28-30% ammonia, 1 mL) and sodium hydrosulfite (Na ₂ S ₂ O ₄ , 1.7 g, 9.86 mmol) at -0 °C. After stirred at room temperature for 1.5 hour, the reaction solution was added methanol (10 mL). 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 afford Intermediate compound 190 (339 mg, 65%), which was used without further purification. EI-MS m/z : [M+H] ⁺ 528.39.

Preparation of Intermediate Compound 191

To a solution of Intermediate compound 190 (339 mg, 0.64 mmol) in N,N- dimethylformamide (3 mL) was added Intermediate compound 2 (150 mg, 0.77 mmol) at -0 °C. After stirred at room temperature for 30 minutes, the reaction solution were added N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (160 mg, 0.84 mmol) and tri ethylamine (0.05 mL, 0.38 mmol) 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 191 (390 mg, 88%). EI-MS m/z : [M+H] ⁺ 689.37. Preparation of Intermediate Compound 192

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

Preparation of Intermediate Compound 193

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

Preparation of Intermediate Compound 194

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

Preparation of Intermediate Compound 195

To a solution of Intermediate compound 194 (74 mg, 0.08 mmol) in N,N- dimethylformamide (1 mL) was added compound 2 (18 mg, 0.09 mmol) at -0 °C. After stirred at room temperature for 15 minutes, the reaction mixture was added N-(3 -di methy lam i nopropyl)-N'- ethylcarbodiimide hydrochloride (19 mg, 0.10 mmol) and triethylamine (0.05 mL, 0.38 mmol) at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate compound 195 (42 mg, 49%). EI-MS m/z : [M+H] ⁺ 1135.55.

Preparation of Intermediate Compound 196

To a solution of Intermediate compound 195 (42 mg, 0.04 mmol) in ethanol (2 mL) was added sodium ethoxide (21% w/w ethanol, 0.14 mL, 0.37 mmol). After stirred at reflux for 7 hours, the reaction mixture was concentrated under reduced pressure to afford Intermediate compound

196 (50 mg, crude), which was used without further purification. EI-MS m/z : [M+H] ⁺ 1063.53.

Preparation of Compound 197

To a solution of Intermediate compound 196 (50 mg, crude) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at -0 °C under nitrogen. After stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 197 (23 mg, 49%).

¹ H-NMR (400 MHz, DMSO) δ 7.96 (d, J = 20.3 Hz, 2H), 7.86 (d, J = 0.8 Hz, 1H), 7.67 (dd, J= 14.8, 1.2 Hz, 2H), 7.41 - 7.36 (m, 2H), 7.28 (dd, J= 7.1, 1.4 Hz, 2H), 6.53 (s, 2H), 5.87 - 5.54 (m, 5H), 4.95 - 4.85 (m, 4H), 4.54 (dq, J= 20.2, 6.5 Hz, 6H), 4.47 - 4.41 (m, 2H), 4.01 (t, J= 6.1 Hz, 3H), 2.12 (d, J= 7.1 Hz, 6H), 2.00 (q, J= 7.1 Hz, 2H), 1.27 (dt, J= 9.3, 7.1 Hz, 6H) EI-MS m/z : [M+H] ⁺ 963.53.

<Example 32> Preparation of Compound 199

Preparation of Intermediate Compound 198

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

Preparation of Compound 199

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

<Example 33> Preparation of Compound 212

212

Preparation of Intermediate Compound 200

To a solution of 2-(2-(benzyloxy)ethoxy)ethanol (3 g, 15.2 mmol) in acetonitrile (20 mL) were methyl propiolate (2.72 mL, 30.5 mmol) and N-methylmorpholine (0.33 mL, 3.05 mmol) were added at 0 °C under nitrogen. After stirred 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 afford Intermediate Compound 200 (2.72 mg, 63%).

¹ H-NMR (400 MHz, CDCh) δ 7.62 (d, J= 16.0 Hz, 1H), 7.34-7.27 (m, 5H), 5.22(d, J = 16.0 Hz, 1H), 4.57 (t, J= 4.0 Hz, 2H), 4.01 (t, J= 4.0 Hz, 2H), 3.77 (d, J= 4.0 Hz, 2H), 3.70-7.69 (m, 5H), 3.64(s, 2H). EI-MS m/z : [M+Na] ⁺ 303.27

Preparation of Intermediate Compound 201

To a solution of Intermediate Compound 200 (2.7 g, 9.63 mmol) in methanol (10 mL) was added palladium/ charcoal (540 mg). After stirred at room temperature under 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 afford Intermediate Compound 201 (1.7 g, 91%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 3.80-3.60 (m, 13H), 2.60 (dd, J= 8.0, 4.0 Hz, 2H). EI-MS m/z : [M+Na] ⁺ 215.23, [M+H] ⁺ 193.30.

Preparation of Intermediate Compound 202

To a solution of Intermediate Compound 201 (480 mg, 2.49 mmol) in dichloromethane (20 mL) were added trimethylamine (0.87 mL, 6.24 mmol) and methanesulfonyl anhydride (870 mg, 4.99 mmol) at 0 °C under nitrogen. After stirred 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 afford Intermediate Compound 202 (680 mg, crude), which was used without further purification. EI-MS m/z : [M+Na] ⁺ 293.27, [M+H] ⁺ 271.26.

Preparation of Intermediate Compound 203

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

Preparation of Intermediate Compound 204

To a solution of Intermediate Compound 203 (512 mg, 2.49 mmol) in dichloromethane (4 mL) were added trimethylamine (1.05 mL, 7.49 mmol) and di-tert-butyl dicarbonate (0.63 mL, 2.74 mmol) at 0 °C under nitrogen. After stirred at room temperature for 12 hours, the reaction solution was diluted with ethylacetate (50 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate Compound 204 (450 mg, 59%).

¹ H-NMR (400 MHz, CDCh) δ 3.76 (t, J = 8.0 Hz, 2H), 3.69 (s, 3H), 3.61-3.58 (m,6H), 3.42(m, 2H), 2.91 (s, 3H), 2.61 (t, J= 4.0 Hz, 3H), 1.45 (s, 9H). EI-MS m/z : [M+Na] ⁺ 328.37.

Preparation of Intermediate Compound 205

To a solution of Intermediate Compound 204 (450 mg, 1.47 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added lithium hydroxide monohydrate (68 mg, 1.62 mmol) in distilled water (4 mL) at -50 °C. After stirred for 2 hours at 0 °C, the reaction mixture was adjusted to pH 4-5 with acetic acid and concentrated under reduced pressure to afford Intermediate Compound 205 (310 mg, 72%), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 3.77 (t, J= 6.1 Hz, 2H), 3.67-3.54 (m, 6H), 3.40 (s, 2H), 2.91 (s, 3H), 2.62 (t, J= 6.1 Hz, 2H), 1.46 (s, 9H). EI-MS m/z : [M+Na] ⁺ 314.37.

Preparation of Intermediate Compound 206

To a solution of methyl- 1-O-(4-(tert- butyldimethylsilyloxy)methyL2-aminopheny 1)- 2,3,4-tri-o-acetyLP-d-glucuronate (327 mg, 01.12 mmol, this compound was prepared by the method described in the International patent publication No. WO 2019/236954 Al) and Intermediate Compound 205 (320 mg, 0.56 mmol) in N, N-dimethylformamide (5 mL) were added 1 - [Bis(dimethy lamino)methylene] - 1 H- 1 ,2,3 -triazolo [4, 5 -b] py ridi mum 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 stirred at room temperature for 15 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 afford Intermediate Compound 206 (290 mg, 61%).

¹ H-NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.89 (s, 1H), 7.03 (s, 2H), 5.56 (d, J = 7.9 Hz, 1H), 5.49 (t, J= 9.6 Hz, 1H), 5.21-5.12 (m, 2H), 5.06 (t, J= 9.8 Hz, 1H), 4.71 (d, J= 10.0 Hz, 1H), 3.69 (t, J= 6.4 Hz, 2H), 3.64 (s, 3H), 3.53 (s, 4H), 3.48 (t, J= 5.8 Hz, 2H), 2.77 (s, 3H), 2.06- 1.95 (m, 9H), 1.37 (s, 9H). EI-MS m/z : [M+H] ⁺ 843.50.

Preparation of Intermediate Compound 207

To a solution of Intermediate Compound 206 (280 mg, 0.33 mmol) in methanol (1 mL) was added (lS)-(+)-10-camphorsulfonic acid (15 mg, 0.066 mmol) at 0 °C under nitrogen. After stirred for 2 hours at 0 °C, the reaction solution was neutralized with triethylamine. After concentration 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

Preparation of Intermediate Compound 208

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

Preparation of Intermediate Compound 209

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

Preparation of Intermediate Compound 210

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

Preparation of Intermediate Compound 211

To a solution of Intermediate Compound 210 (130 mg, 0.088 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.45 mL) at 0 °C under nitrogen. After stirred 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 afford Intermediate Compound 211 (90 mg, 74%).

¹ H-NMR (400 MHz, DMSO) δ 12.82 (s, 2H), 9.47 (s, 1H), 9.10 (s, 1H), 8.31 (s, 2H), 8.18 (s, 1H), 7.94 (d, J= 15.0 Hz, 2H), 7.70-7.58 (m, 2H), 7.40-7.21 (m, 4H), 7.15-6.96 (m, 2H), 6.51 (d, J = 2.9 Hz, 2H), 5.94-5.85 (m, 1H), 5.79 (s, 2H), 5.68 (d, J= 15.6 Hz, 1H), 4.99 (s, 2H), 4.87 (dd, J= 14.7, 8.8 Hz, 4H), 4.52 (t, J= 13.5 Hz, 6H), 3.89 (d, J= 9.6 Hz, 1H), 3.70 (d, J= 6.6 Hz, 4H), 3.61 (t, J = 5.1 Hz, 2H), 3.05 (d, J = 6.3 Hz, 2H), 2.63 (q, J = 6.2 Hz, 3H), 2.09 (d, J = 3.1 Hz, 5H), 1.25 (td, J = 7.1, 5.3 Hz, 5H). EI-MS m/z : [M/2+H] ⁺ 687.16.

Preparation of Compound 212

To a solution of compound 211 (65 mg, 0.047 mmol) in methanol (1 mL) were 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 stirred for 1 hours at room temperature, the reaction mixture was adjusted to pH 6 with IN sodium hydroxide aqueous solution and then concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 212 (33 mg, 50%).

¹ H-NMR (400 MHz, DMSO) δ 12.82 (s, 2H), 9.47 (s, 1H), 9.20 (s, 1H), 9.09 (s, 1H), 8.18 (s, 1H), 7.94 (d, J= 15.6 Hz, 2H), 7.63 (d, J= 10.1 Hz, 2H), 7.34 (s, 1H), 7.30 (d, J= 5.4 Hz, 2H), 7.12-7.01 (m, 2H), 6.51 (d, J= 3.0 Hz, 1H), 5.90 (d, J= 15.6 Hz, 2H), 5.79 (s, 2H), 5.68 (d, J = 15.7 Hz, 1H), 4.99 (s, 2H), 4.88 (t, J = 10.2 Hz, 4H), 4.54 (d, J = 17.8 Hz, 6H), 3.90 (d, J = 9.6 Hz, 1H), 3.68 (d, J= 9.4 Hz, 5H), 3.57 (s, 4H), 2.72 (d, J = 4.2 Hz, 4H), 2.67 (p, J= 1.8 Hz, 3H), 2.33 (p, J= 1.9 Hz, 4H), 2.09 (d, J= 3.1 Hz, 5H), 1.91 (s, 1H), 1.25 (td, J= 7.1, 5.3 Hz, 5H). EI- MS m/z : [M/2+H] ⁺ 694.17.

<Example 34> Preparation of Compound 214

Preparation of Compound 214

To a solution of Compound 55 (50 mg, 0.04 mmol) and Intermediate compound 213 (36 mg, 0.05 mmol, Intermediate compound 448 was prepared by the method described in the 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 stirred at room temperature for 20 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford Compound 214 (12 mg). EI-MS m/z : [M+H]+ 1393.72.

<Example 35> Preparation of Compound 221

Preparation of Intermediate Compound 215

To a solution of trans-2-butene-l,4-diol (1.5 g, 11.94 mmol) in dichloromethane (100 mL) were added trimethylamine (2.2 mL, 15.92 mmol) and t-butyldimethylsilyl chloride (1.0 g, 7.96 mmol) at 0 °C under nitrogen. After stirred at room temperature for 4 hours, the reaction solution was diluted with di chloromethane (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 afford Intermediate Compound 215 (1.2 g, 74%).

¹ H-NMR (400 MHz, MeOD) δ 5.88 - 5.71 (m, 2H), 4.19 (dt, J= 4.3, 1.4 Hz, 2H), 4.09 - 4.02 (m, 2H), 0.92 (s, 9H).

Preparation of Intermediate Compound 216

To a solution of Intermediate Compound 215 (500 mg, 2.47 mmol) in dichloromethane (10 mL) were added trimethylamine (1.04 mL, 7.41 mmol), pyridine (0.60 mL, 7.41 mmol) and 4-nitrophenyl chloroformate (747 mg, 3.70 mmol) at 0 °C under nitrogen. After stirred at room temperature for 20 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate 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 afford Intermediate Compound 216 (729 mg, 80%).

¹ H-NMR (400 MHz, CDCh) δ 8.32 - 8.24 (m, 2H), 7.42 - 7.34 (m, 2H), 6.04 - 5.84 (m, 2H), 4.78 (dq, J = 5.9, 1.1 Hz, 2H), 4.23 (dq, J= 4.2, 1.4 Hz, 2H), 0.92 (s, 9H), 0.08 (s, 6H).

Preparation of Intermediate Compound 217

To a solution of Intermediate Compound 216 (729 mg, 1.98 mmol) in di chloromethane (10 mL) were added trimethylamine (0.56 mL, 3.97 mmol) and tert-butyl methyl(2- (methylamino)ethyl)carbamate (485 mg, 2.58 mmol) at 0 °C under nitrogen. After stirred at room temperature for 3 hours, the reaction solution was diluted with di chloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate 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 afford Intermediate Compound 217 (825 mg, 99%).

¹ H-NMR (400 MHz, CDCh) δ 5.85 - 5.78 (m, 2H), 4.58 (s, 2H), 4.18 (d, J= 2.6 Hz, 2H), 3.37 (s, 4H), 2.94 (s, 3H), 2.88 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H).

Preparation of Intermediate Compound 218

To a solution of Intermediate Compound 217 (825 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 3 mL, 2.97 mmol) at 0 °C under nitrogen. After stirred at room temperature for 17 hours, the reaction solution was diluted with di chloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate Compound 218 (514 mg, 86%).

¹ H-NMR (400 MHz, CDCh) δ 5.96 - 5.73 (m, 2H), 4.58 (d, J = 5.9 Hz, 2H), 4.15 (d, J = 12.5 Hz, 2H), 3.45 - 3.27 (m, 4H), 2.94 (d, J= 5.0 Hz, 3H), 2.87 (d, J= 11.5 Hz, 3H), 1.45 (s, 9H).

Preparation of Intermediate Compound 219

To a solution of Intermediate Compound 218 (150 mg, 0.50 mmol) in dichloromethane (5 mL) were added trimethylamine (0.14 mL, 0.99 mmol) and methanesulfonyl anhydride (103 mg, 0.59 mmol) at 0 °C under nitrogen. After stirred 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 concentrated under reduced pressure to afford Intermediate Compound 219 (164 mg, crude), which was used without further purification.

¹ H-NMR (400 MHz, CDCh) δ 6.06 - 5.77 (m, 2H), 4.73 (dt, J= 6.2, 1.1 Hz, 2H), 4.63 (s, 2H), 3.38 (s, 4H), 3.03 (s, 3H), 2.95 (s, 3H), 2.87 (d, J= 7.8 Hz, 3H), 1.45 (s, 9H).

Preparation of Intermediate Compound 220

To a solution of Intermediate Compound 66 (350 mg, 0.37 mmol, Intermediate Compound 66 was prepared by the method described in the International patent publication No. WO 2022/155518 Al) and Intermediate Compound 219 (154 mg, 0.40 mmol) in N,N- dimethylformamide (2 mL) was added cesium carbonate (600 mg, 1.84 mmol) were added at 0 °C under nitrogen. After stirred at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure and 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 afford Intermediate Compound 220 (207 mg, 56%). EI-MS m/z : [M+H] ⁺ 1007.74.

Preparation of Compound 221

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

<Example 36> Preparation of Compounds 222 to 245

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

<Example 37> Preparation of Comparative Compound #1 The compound of Comparative Compound 1 has the following structure and was purchased from ChemScene (#CS-0077291) and used.

Example 38> Preparation of Comparative Compound #2

The compound of Comparative Compound #2 has the following structure and was prepared by the method described in the United States patent publication No. 2021-0032269 Al.

Experimental Example 1> Evaluation of activity of STING agonist

In order to evaluate the activity of the STING agonist, reporter cells from Invivogen were used. The cell lines used in the experiment were THP1 Dual™(InvivoGen#thpd-nfis) expressing the endogenous STING variant HAQ and THP1 Dual™KI-hSTING-R232 (InvivoGen#thpd- r232/h232) into which the STING R232 or H232 variant gene was injected after removing the STING HAQ gene. The cell lines have a luciferase reporter gene inserted below the IFN regulatory factor (IRF) promoter, and thus the activity of the IFN regulatory factor (IRF) mechanism can be evaluated through luciferase expression.

The reporter cells were plated at 9.0 x 10 ⁴ cells/100 μL per well in a 96- well plate using RPMI 1640 medium (Gibco, #22400097) supplemented with 10% heat-inactivated FBS and 1 x Antibiotic- Antimycotic (Gibco, #15240062), 10 pg/mL blasticidin (Gibco, #A1113902), and 100 pg/mL Zeocin (Gibco, #R25005). The plated cells were cultured at 37 °C, 5 % CO2 for 24 hours, and then treated with 100 μL of the serially diluted compound in each well, and then cultured at 37 °C, 5 % CO2 for 24 hours. After culturing, 20 μL of the cell culture medium was transferred to a 96 well white plate, and QU ANTI-Luc™ (InvivoGen#rep-qlcl) was added at 50 μL/well. Using a microplate reader (Perkin Elmer), the value of the luminescence signal increased in the experimental group treated with the drug compared to the control group not treated with the drug was calculated. EC50 values were derived according to the concentration of the compound using GraphPad Prism. Table 1 below shows the results of evaluating the activity of the STING agonist using THP1 reporter cells.

[Table 1] STING activity using hSTING-R232 cells

168

[Table 2] STING activity using hSTING-HAQ or H232 cells Additionally, for analysis of direct binding potency of STING agonist compounds described herein to human STING, HUMAN STING WT BINDING KIT (Cisbio, #64BDSTGPEG) was used according to the manufacturer's instruction. It was confirmed that the STING agonist compounds directly bind to human STING protein in vitro, and summary result data were presented as EC ₅₀ in Table 3. [Table 3] Binding potency <Experimental Example 2> Assessment of pharmacokinetics For in vivo evaluation of STING agonist compounds described herein in naïve Balb/C mouse, single doses of STING agonist compounds were given at 1.5 mg/kg intravenously into female BALB/c mice (Orientbio, South Korea) at 6-8 weeks of age. Pharmacokinetics were studied following injection of the STING agonist compounds into Balb/C mice. Plasma samples were taken at various time points and stored frozen for analysis. The plasma concentrations of the STING agonist compounds at the indicated time points were measured using a LC-MS/MS analysis method.

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

The PK profiles of Compound 55, 65, 133, Comparative #1 and #2 were summarized in Tables 4 to 8. Compared to the Comparative #1 and 2, the STING agonist compounds showed significantly stable pharmacokinetic profiles in mice.

[Table 4] Compound 55

[Table 5] Compound 65

170 [Table 6] Compound 133 [Table 7] Comparative #1 [Table 8] Comparative #2

Experimental Example 3> in vitro Assessment of normal cell cytotoxicity

PBMCs were also purchased from STEMCEI-L™ (# 700025.2). The cells (8.0 x IQ ⁴ cells per well) were seeded in a flat-bottomed 96-well plate in RPMI 1640 medium (Gibco, #22400097) with 10% heat-inactivated FBS and 1 x Antibiotic- Antimycotic (Gibco, #15240062) and rested for 24 hours at 37°C. The cells were treated with the STING agonist compounds described herein (Compound 28, 55, 65, and Comparative #1) in a serial dilution. After 72 hours, the cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay (Promega, #G7573) according to the manufacture’s instruction. The signal was detected using an EnVision Xcite multilabel reader and data were analyzed using GraphPad Prism 8 software.

To verify the effect of the STING agonist compounds in normal cell cytotoxicity, the PBMCs were treated with the STING agonist compounds for 3 days and measured the percentage of cell death. As shown in 50% cytotoxic concentration (CC ₅₀ ) values in Table 9, compared to the Comparative #1, all STING agonist compounds had higher CC ₅₀ values, implying lower cytotoxicity in normal immune cells.

[Table 9] In vitro cell cytotoxicity in PBMCs

The CD34 ⁺ hematopoietic stem cells (HSCs) were purchased from STEMCEI-L™ (# 70002.3). The cells (2 x 10 ⁴ cells per well) were cultured in StemSpan™ SEEM II medium supplemented with StemSpan™ CD34+ Expansion Supplement (#02691) in a 6- well plate at 37°C for 7 days. On day 3 or 4, an equal volume of fresh complete medium was added into the cell culture. On day 7, the cells (4 x 10 ⁴ cells per well) were seeded in a 96- well white plate and rested for 24 hours in the same condition.

To verify the effect of STING agonist compounds described herein in normal cell cytotoxicity, the HSCs were treated with STING agonist compounds described herein (Compound 28, 55, 65, and Comparative #1) in a serial dilution. After 72 hours, the cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay (Promega, # G7573) according to the manufacture’s instruction. The signal was detected using an EnVision Xcite multilabel reader and data were analyzed using GraphPad Prism 8 software. As shown in 50% cytotoxic concentration (CC ₅₀ ) values in Table 10, compared to the Comparative #1, all STING agonist compounds had higher CC ₅₀ values, implying lower cytotoxicity in HSCs. [Table 10] In vitro cell cytotoxicity in CD34 ⁺ HSC <Experimental Example 4> In vivo efficacy in syngeneic mouse models Female BALB/c mice (KOTECH, South Korea) with 6 weeks of age, were used for all studies that were completed under the approval of 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) DW^ ^^^^ ZLWK^ ^^^ &2 _2. The mycoplasma-negative cells were used for all experiments and mycoplasma test was done regularly using e-Myco^ VALiD Mycoplasma PCR Detection Kit (iNtRON biotechnology, #25239). CT26 cells (2×10 ⁵ cells/mouse) or 4T-1 cells (5×10 ⁵ cells/mouse) in PBS were implanted subcutaneously into the shaved right flank. Tumor volumes were measured twice a week, and they were calculated according to the formula 0.5 × (length) × (width) ² . A syngeneic system was used to assess the ability of the STING agonist compounds to induce immune responses and drive an anti-tumor immune response. To determine in vivo efficacy of STING agonist compound (Compound 55) in CT26 syngeneic mouse model, when tumor volume^50 to 100 mm ³ , the compound was given at 1.5 mg/kg on days 0, 4, and 7. To determine in vivo efficacy of STING agonist compound (Compound 55) in 4T-1 syngeneic mouse model, when tumor volume^50 to 100 mm ³ , the compound was given at 1.5 mg/kg on days 0, 4, and 7. In both CT26 and 4T-1 syngeneic models, the STING agonist compounds remarkably controlled tumor growth (FIGS.1 and 2). Consistent with in vitro effectiveness, the STING agonist compounds described herein showed the superior in vivo efficacy in different syngeneic mouse models. Taken together, the STING agonist compounds described herein have strongly competitive profiles of high anti-tumor activity, but low toxicity. Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents While specific embodiments of the disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.