Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof

Abstract

To provide a pyrrolobenzodiazepine precursor for treating proliferative diseases such as cancer, to provide a ligand-linker conjugate compound thereof, to provide a composition containing the same, and to provide, in particular, a therapeutic use thereof as an anti-cancer agent.SOLUTION: Provided are a pyrrolobenzodiazepine dimer prodrug, a pharmaceutically acceptable salt or solvate of the pyrrolobenzodiazepine dimer prodrug, and a pyrrolobenzodiazepine dimer prodrug-linker compound (e.g., Compound 28).SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to pyrrolobenzodiazepine dimer prodrugs, their ligand-linker conjugate compounds, compositions containing them, and, in particular, their therapeutic use as anti-cancer drugs.

Background Art

[0002] Pyrrolobenzodiazepine (PBD) is known as a natural product produced by various actinomycetes and exhibits antibiotic activity or antitumor activity. Pyrrolobenzodiazepine is a sequence-selective DNA alkylating anti-cancer drug that covalently binds to the DNA of cells. Pyrrolobenzodiazepine is a DNA cross-linking agent known to exhibit significantly stronger anti-cancer activity than systemic chemotherapeutic drugs and can prevent the division of cancer cells without disrupting the DNA helix.

[0003] Pyrrolobenzodiazepine has the following general structure.

[0004]

Chemical formula

[0005] Pyrrolobenzodiazepine differs in the number, type, and position of substituents on aromatic ring A and pyrrole ring C, as well as the degree of saturation of ring C. In ring B, imine (N-C), carbinolamine (NH-CH(OH)), or carbinolamine methyl ether (NH-CH(OMe)) is present at the N10-C11 position, which is an electrophilic center responsible for the alkylation of DNA.

[0006] Some pyrrolobenzodiazepine dimers are in Phase I clinical trials as SGN-CD123A developed by Seattle Genetics for treating patients with acute myeloid leukemia (AML) and as a dPBD conjugate for the acute myeloid leukemia (AML) disease.

[0007] Kolltan Pharmaceuticals and Genentech / Roche are known to be developing antibody-drug conjugates with pyrrolobenzodiazepines as cytotoxic agents. In addition, Spirogen is developing pyrrolobenzodiazepine-based therapeutic technologies for acute myeloid leukemia.

[0008] In this regard, there are published patents relating to pyrrolobenzodiazepines and their conjugates (MedImmune, LLC, Patent Document 1), published patents relating to asymmetric pyrrolobenzodiazepine dimers for the treatment of proliferative disorders (MedImmune, LLC, Patent Document 2), registered patents relating to pyrrolobenzodiazepines (MedImmune, LLC, Patent Document 3), registered patents relating to pyrrolobenzodiazepines for the treatment of proliferative disorders (MedImmune, LLC, Patent Document 4), published patents relating to pyrrolobenzodiazepines (MedImmune, LLC, Patent Document 5), registered patents relating to pyrrolobenzodiazepines (Spirogen, Patent Document 6), etc. These simply disclose that the structure of pyrrolobenzodiazepine compounds is modified to enhance antitumor activity, or that pyrrolobenzodiazepine compounds having such modified structures can be administered in the form of antibody-drug conjugates to enhance anticancer activity.

[0009] On the other hand, there are technologies relating to antibody-drug conjugates having a form in which a carbamate is linked to a pyrrolobenzodiazepine dimer, papers disclosing that pyrrolobenzodiazepine compounds in monomer form exhibit low cytotoxicity and stability when converted to a prodrug form, and research papers on the preparation and activity of N10-(4-nitrobenzyl)carbamate-protected pyrrolobenzodiazepine prodrugs (see Non-Patent Documents 7, 8, and 9).

[0010] However, these technologies have limitations in that the yield of pyrrolobenzodiazepine synthesis is low, making scale-up difficult, and the issue of insufficient stability of pyrrolobenzodiazepine in the blood after administration remains unresolved. Therefore, there is a need to develop manufacturing methods that can improve the yield of pyrrolobenzodiazepine, and technologies for preparing prodrugs to improve the stability of pyrrolobenzodiazepine in the blood after administration and reduce its toxicity after administration.

[0011] On the other hand, antibody-drug conjugates (ADCs) are a new, targeted technology in which a toxin or drug binds to an antibody that has conjugated an antigen, and then releases the toxic substance inside the cell, causing death in cancer cells and other target cells. This technology allows the drug to be precisely delivered to targeted cancer cells while minimizing the impact on healthy cells, and to be released only under specific conditions. In this way, the drug can demonstrate superior efficacy compared to antibody therapies alone, and the risk of side effects can be significantly reduced compared to conventional anticancer drugs.

[0012] The basic structure of such antibody-drug conjugates consists of "antibody-linker-small molecule drug (toxin)". Here, the linker not only has the functional role of linking the antibody to the drug, but it is also necessary that, when circulating in the body, it stably reaches the target cell, the drug enters the cell, and then detaches through antibody-drug dissociation (for example, as a result of enzymatic hydrolysis), thus producing an effect on the target cancer cells. In other words, the linker plays a very important role in the efficacy and safety, such as systemic toxicity, of antibody-drug conjugates, depending on the stability of the linker (Discovery Medicine 2010, Vol. 10 (No. 53): pp. 329-339).

[0013] The inventors of this invention have developed a linker containing an effective self-destructing group that is more stable in plasma and even when circulating in the body, thereby enabling the drug to be easily released by cancer cells, demonstrating the drug's efficacy, and for which a patent has been obtained (Registered Patent No. 1,628,872 of the Republic of Korea, etc.). [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] Korean Patent Application Publication No. 2013-0040835 (Published April 24, 2013) [Patent Document 2] Korean Patent Application Publication No. 2011-0075542 (Published June 30, 2011) [Patent Document 3] Korean Registered Patent No. 1,700,460 (Registered January 20, 2017) [Patent Document 4] Korean Registered Patent No. 1,687,054 (Registered December 9, 2016) [Patent Document 5] Korean Patent Application Publication No. 2015-0016245 (Published February 11, 2015) [Patent Document 6] Korean Registered Patent No. 1,059,183 (Registered August 18, 2011) [Patent Document 7] No. PCT / US2016 / 063564 [Patent Document 8] PCT / US2016 / 063595 [Patent Document 9] Korean Patent Application Publication No. 2014-0035393 (Published March 21, 2014) [Patent Document 10] WO2017 / 160569 (published on September 21, 2017) [Patent Document 11] U.S. Patent No. 8,697,688 (Registered April 15, 2014) [Patent Document 12] U.S. Patent No. 9,713,647 (Registered July 25, 2017) [Patent Document 13] U.S. Patent Application Publication No. 2015-0283258 (Published October 8, 2015) [Non-patent literature]

[0015] [Non-Patent Document 1] Kemp Gary C et al., Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin, Bioorganic & Medicinal Chemistry Letters Vol. 27 No. 5, 1154 - 1158 (2017) [Non-Patent Document 2] Julia Mantaj et al., From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs), Angewandte Chemie International Edition Vol. 56 No. 2, 462 - 488 (2017) [Non-Patent Document 3] Giddens Anna C. et al., Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates, Bioorganic & Medicinal Chemistry Vol. 24 No. 22, 6075 - 6081 (2016) [Non-Patent Document 4] Hartley, JA, The development of pyrrolobenzodiazepines as antitumour agents, EXPERT OPIN INV DRUG, 20(6) 733 - 744 (2011)

Non-patent Document 5

Non-patent Document 6

Non-patent Document 7

Non-patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

[0016] The present invention aims to provide a pyrrolobenzodiazepine dimer prodrug having a novel structure capable of enhancing the stability of pyrrolobenzodiazepines in the blood, and exhibiting insufficient stability in the blood after administration.

[0017] In this invention, we also intend to provide a drug prodrug-linker-ligand system in which a pyrrolobenzodiazepine dimer prodrug stably reaches target cells, effectively demonstrates drug efficacy, and exhibits significantly reduced toxicity, by combining linker technology containing a self-destructing group that is more stable in plasma and even when circulating in the body, thereby allowing the drug to be easily released to cancer cells and exhibiting maximum drug efficacy. [Means for solving the problem]

[0018] The present invention relates to pyrrolobenzodiazepine dimer prodrugs, or pharmaceutically acceptable salts or solvates thereof.

[0019] More specifically, the present invention provides a pyrrolobenzodiazepine dimer prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein any one selected from the group consisting of -C(O)O*, -S(O)O*, -C(O)*, -C(O)NR*, -S(O)2NR*, -P(O)R'NR*, -S(O)NR* and -PO2NR* is independently bonded to each of the N10 and N'10 positions of the pyrrolobenzodiazepine dimer (wherein * indicates the portion to which the linker is bonded, R and R' are each independently H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, substituted or unsubstituted C 1~8 alkyl, substituted or unsubstituted C 3~8 cycloalkyl, substituted or unsubstituted C 1~8 alkoxy, substituted or unsubstituted C 1~8 alkylthio, substituted or unsubstituted C 3~20 heteroaryl, substituted or unsubstituted C 5~20 aryl, or mono- or di-C 1~8 alkylamino, wherein C 1~8 alkyl, C 3~8 cycloalkyl, C 1~8 alkoxy, C 1~8 alkylthio, C 3~20 heteroaryl and C 5~20 aryl, when substituted, are substituted with substituents selected from the group consisting of H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, halo, C 1~6 alkyl, C 1~6 alkoxy and C 6~12 aryl), and provides a pyrrolobenzodiazepine dimer prodrug or a pharmaceutically acceptable salt or solvate thereof.

[0020] In one aspect of the present invention, a pyrrolobenzodiazepine dimer prodrug is provided. When administered in the form of a prodrug according to the present invention, the pyrrolobenzodiazepine dimer prodrug needs to be converted into an effective drug by further reactions upon exposure to the blood. Therefore, it is advantageous compared to conventional PBD drugs in that it can prevent the occurrence of side effects that may occur when unexpected linker degradation occurs, has reduced toxicity to normal cells, and the drug is more stable.

[0021] In addition, in the preparation of antibody-drug conjugates, those prepared by conventional methods have a high content of impurities, and exposed imine groups are attacked by nucleophiles, thus potentially forming drugs with undesirable structures. However, antibody-drug conjugates prepared by the method according to the present invention have the advantage of being easily separated, as they exhibit higher purity and improved physical properties compared to conventional PBDs or PBD dimers.

[0022] In an embodiment of the present invention, a pyrrolobenzodiazepine dimer prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein the pyrrolobenzodiazepine dimer prodrug has a structure represented by the following chemical formula Ia or Ia'.

[0023] [ka] [In the formula, The dotted line indicates the presence of any double bond between C1 and C2 or between C2 and C3. R1 is H, OH, =O, =CH2, CN, R m , OR m 、=CH-R m' , =C(R m' )2, O-SO2-R m CO2R m COR m Selected from the group consisting of halo and dihalo (In the formula, R m' R mCO2R m COR m Selected from the group consisting of CHO, CO2H, and halo, R m C is either substituted or unsubstituted. 1~12 Alkyl, substituted, or unsubstituted C 2~12 Alkenyl, substituted or unsubstituted C 2~12 Alkinyl, substituted or unsubstituted C 5~20 Aryl, substituted, or unsubstituted C 5~20 Heteroaryl, substituted, or unsubstituted C 3~6 Selected from the group consisting of cycloalkyls, substituted or unsubstituted 3- to 7-membered heterocyclines, substituted or unsubstituted 3- to 7-membered heterocycloalkyls, and substituted or unsubstituted 5- to 7-membered heteroaryls, where, C 1~12 Alkyl, C 1~12 Alkoxy, C 2~12 Alkenil, C 2~12 Alkinyl, C 5~20 Ariel, C 5~20 Heteroaryl, C 3~6 When cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocycloalkyl, or 5-7 membered heteroaryl is substituted, C 1~12 Alkyl, C 1~12 Alkoxy, C 2~12 Alkenil, C 2~12 Alkinyl, C 5~20 Ariel, C 5~20 Heteroaryl, C 3~6 Each hydrogen atom in a cycloalkyl, a 3-7 membered heterocyclyl, a 3-7 membered heterocycloalkyl, or a 5-7 membered heteroaryl is independently C 1~12 Alkyl, C 2~12 Alkenil, C 2~12 Alkinyl, C 5~20 Ariel, C 5~20 Heteroaryl, C 3~6 (Substituted with one or more selected from the group consisting of cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl, and 5- to 7-membered heteroaryl), R2, R3, and R5 are each independently H, Rm 、 OH, OR m 、 SH, SR m 、 NH2, NHR m 、 NR m R m' 、 selected from the group consisting of NO2, Me3Sn and halo (where R m and R m' are as defined above), R4 is H, R m 、 OH, OR m 、 SH, SR m 、 NH2, NHR m 、 NR m R m' 、 NO2, Me3Sn, halo, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 1~6 alkoxy, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~6 cycloalkyl, substituted or unsubstituted 3-7 member heterocycloalkyl, substituted or unsubstituted C 5~12 aryl, substituted or unsubstituted 5-7 member heteroaryl, -CN, -NCO, -OR<00000�5> 、 -OC(O)R n 、 -OC(O)NR n R n' 、 -OS(O)R n [[ID=5३]]、 -OS(O)2R n 、 -SR n 、 -S(O)R n 、 -S(O)2R n 、 -S(O)NR n R n' 、 -S(O)2NR n R n' 、 -OS(O)NR n R n' 、 -OS(O)2NR n R n' 、 -NR n R n' 、 -NR n C(O)R o 、 -NR n C(O)OR o 、 -NR n C(O)NR oR o' , -NR n S(O)R o , -NR n S(O)2R o , -NR n S(O)NR o R o' , -NR n S(O)2NR o R o' , -C(O)R n , -C(O)OR n and -C(O)NR n R n' A group consisting of the following is selected, where, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~12 When aryl and 5- to 7-membered heteroaryls are substituted, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~12 Each hydrogen atom in aryls and 5- to 7-membered heteroaryls is independently C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~12 Aryl, 5-7 member heteroaryl, -OR p -OC(O)R p -OC(O)NR p R p' -OS(O)R p -OS(O)2R p , -SR p ,-S(O)R p -S(O)2R p -S(O)NR p R p' -S(O)2NR pR p' -OS(O)NR p R p' -OS(O)2NR p R p' , -NR p R p' , -NR p C(O)R q , -NR p C(O)OR q , -NR p C(O)NR q R q' , -NR p S(O)R q , -NR p S(O)2R q , -NR p S(O)NR q R q' , -NR p S(O)2NR q R q' , -C(O)R p , -C(O)OR p or -C(O)NR p R p It is also fine if it is replaced with (In the formula, R n , R o , R p and R q These are H and C, respectively, independently. 1~7 Alkyl, C 2~7 Alkenil, C 2~7 Alkinyl, C 3~13 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~10 (Selected from the group consisting of aryls and 5- to 7-membered heteroaryls), Any one selected from the group consisting of -C(O)O*, -S(O)O*, -C(O)*, -C(O)NR*, -S(O)2NR*, -P(O)R'NR*, -S(O)NR*, and -PO2NR* independently combines with X and X' respectively. (In the formula, * indicates the part where the linker connects.) R and R' are, independently, H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, substituted or unsubstituted C. 1~8 Alkyl, substituted, or unsubstituted C3~8 Cycloalkyl, substituted or unsubstituted C 1~8 alkyl, substituted or unsubstituted C 1~8 Alkylthio, substituted or unsubstituted C 3~20 Heteroaryl, substituted, or unsubstituted C 5~20 Aryl, or mono, or diC 1~8 This indicates an alkylamino, where, C 1~8 Alkyl, C 3~8 Cycloalkyl, C 1~8 Alkoxy, C 1~8 Alkylthio, C 3~20 Heteroaryl and C 5~20 When aryl is substituted, it can be H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy and C 6~12 (Substituted with a substituent selected from the group consisting of aryls), Y and Y' are each independently selected from the group consisting of O, S, and N(H). R6 is a saturated or unsaturated C, either substituted or unsubstituted. 3~12 This shows a hydrocarbon chain, where, The chain may be interrupted by one or more heteroatoms, NMe, or substituted or unsubstituted aromatic rings. The chain or aromatic ring has -NH, -NR at the position of one or more hydrogen atoms on the chain or aromatic ring. m ,-NHC(O)R m ,-NHC(O)CH2-[OCH2CH2] n -R or -[CH2CH2O] n -R may be used as a substitution, or it may not be used at all. (In the formula, R m And R are, respectively, R m And R are as defined above, n is an integer from 1 to 12), and R7 is H, substituted or unsubstituted C. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkinyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, -OR r -OC(O)R r -OC(O)NR r R r' -OS(O)R r -OS(O)2R r , -SR r ,-S(O)R r -S(O)2R r -S(O)NR r R r' -S(O)2NR r R r' -OS(O)NR r R r' -OS(O)2NR r R r' , -NR r R r' , -NR r C(O)R s , -NR r C(O)OR s , -NR r C(O)NR s R s' , -NR r S(O)R s , -NR r S(O)2R s , -NR r S(O)NR s R s' , -NR r S(O)2NR s R s , -C(O)R r , -C(O)OR s or -C(O)NR r R r' This shows, and here, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~10 When aryl and 5- to 7-membered heteroaryls are substituted, C1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~10 Each hydrogen atom in aryls and 5- to 7-membered heteroaryls is independently C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 6~10 Aryl, 5-7 member heteroaryl, -OR t -OC(O)R t -OC(O)NR t R t' -OS(O)R t -OS(O)2R t , -SR t ,-S(O)R t -S(O)2R t -S(O)NR t R t' -S(O)2NR t R t' -OS(O)NR t R t' -OS(O)2NR t R t' , -NR t R t' , -NR t C(O)R u , -NR t C(O)OR u , -NR t C(O)NR u R u' , -NR t S(O)R u , -NR t S(O)2R u , -NR t S(O)NR u R u' , -NR t S(O)2NR u R u' , -C(O)R t , -C(O)OR t or -C(O)NR t R t'Replaced by (In the formula, R r , R r' , R s , R s' , R t , R t' , R u and R u' These are H and C, respectively, independently. 1~7 Alkyl, C 2~7 Alkenil, C 2~7 Alkinyl, C 3~13 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~10 (Selected from the group consisting of aryls and 5-7 member heteroaryls),

[0024] [ka] [In the formula, R1, R2, R3, R4, R6, R7 and X are as defined above in chemical formula Ia, R8 is H, halo, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Heteroalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 5~10 Aryl, substituted or unsubstituted 5-7 member heteroaryl, -CN, -NO2, -NCO, -OH, OR m -OC(O)R m -OC(O)NR m R m' -OS(O)R m -OS(O)2R m , -SR m ,-S(O)R m -S(O)2R m -S(O)NR m R m' -S(O)2NR m R m' -OS(O)NR m R m' -OS(O)2NR m R m' , -NR mR m' , -NR m C(O)R m , -NR m C(O)OR n , -NR m C(O)NR n R n' , -NR m S(O)R n , -NR m S(O)2R n , -NR m S(O)NR n R n' , -NR m S(O)2NR n R n' , -C(O)R m , -C(O)OR m and -C(O)NR m R m' A group consisting of the following is selected, where, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Heteroalkyl, 3-7 member heterocycloalkyl, C 5~10 If an aryl or 5- to 7-membered heteroaryl is substituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Heteroalkyl, 3-7 member heterocycloalkyl, C 5~10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is independently C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Heteroalkyl, 3-7 member heterocycloalkyl, C 5~10 Aryl, 5-7 member heteroaryl, -OR m -OC(O)R m -OC(O)NR m R m' -OS(O)R m -OS(O)2R m , -SR m ,-S(O)R m -S(O)2Rm -S(O)NR m R m' -S(O)2NR m R m' -OS(O)NR m R m' -OS(O)2NR m R m' , -NR m R m' , -NR m C(O)R n , -NR m C(O)OR n , -NR m C(O)NR n R n' , -NR m S(O)R n , -NR m S(O)2R n , -NR m S(O)NR n R n' , -NR m S(O)2NR n R n' , -C(O)R m , -C(O)OR m or -C(O)NR m R m' Replaced by (In the formula, R m , R m' , R n and R n' (In chemical formula Ia, as defined above), Z a and Z b Each of these independently represents O, N, or S. R 12a , R 13a and R 14a These are, independently, H, substituted or unsubstituted C. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 5~10Aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, -C(O)R 15a , -C(O)OR 15a or -C(O)NR 15a R 15a' Show (In the formula, R 15a and R 15a' R m (As defined,) C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~10 When aryl and 5- to 7-membered heteroaryls are substituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~10 Each hydrogen atom in aryls and 5- to 7-membered heteroaryls is independently C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocycloalkyl, C 5~10 Aryl, 5-7 member heteroaryl, -OR o -OC(O)R o -OC(O)NR o R o' -OS(O)R o -OS(O)2R o , -SR o ,-S(O)R o -S(O)2R o -S(O)NR o R o' -S(O)2NR o R o' -OS(O)NR o R o' -OS(O)2NR o R o' , -NR o R o' , -NR oC(O)R p , -NR o C(O)OR p , -NR o C(O)NR p R p' , -NR o S(O)R p , -NR o S(O)2R p , -NR o S(O)NR p R p' , -NR o S(O)2NR p R p' , -C(O)R o , -C(O)OR o or -C(O)NR o R o' Replaced with R 13a and R 14a These may bond with the atom to which they are bonded to form a 3-7 member heterocyclyl or 3-7 member heterocycloalkyl, or R 13a and R 14a These may bond with the atom to which they bond to form a 3- to 7-membered heteroaryl, where, Each hydrogen atom present in a 3-7 membered heterocyclyl, 3-7 membered heterocycloalkyl, or 3-7 membered heteroaryl is independently C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~10 Aryl, 5-7 member heteroaryl, -OR o -OC(O)R o -OC(O)NR o R o' -OS(O)R o -OS(O)2R o , -SR o ,-S(O)R o -S(O)2R o -S(O)NR o R o' -S(O)2NR o R o' -OS(O)NR o Ro' -OS(O)2NR o R o' , -NR o R o' , -NR o C(O)R p , -NR o C(O)OR p , -NR o C(O)NR p R p' , -NR o S(O)R p , -NR o S(O)2R p , -NR o S(O)NR p R p' , -NR o S(O)2NR p R p' , -C(O)R o , -C(O)OR o or -C(O)NR o R o' Replaced by (In the formula, R n , R n' , R o , R o' , R p and R p' These are H and C, respectively, independently. 1~7 Alkyl, C 2~7 Alkenil, C 2~7 Alkinyl, C 3~13 Cycloalkyl, 3-7 member heterocycloalkyl, C 5~10 (Selected from the group consisting of aryls and 5- to 7-membered heteroaryls), and R1 ' , R2 ' , R3 ' , R4 ' , R5 ' R7 ' and R8 ' This is as defined for R1, R2, R3, R4, R5, R7, and R8, respectively.

[0025] In this embodiment of the present invention, the dotted line represents the presence of a double bond between C2 and C3.

[0026] In an embodiment of the present invention, R1 is a substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 5~7 Aryl and substituted or unsubstituted C 3~6 Selected from the group consisting of heteroaryls.

[0027] In this embodiment of the present invention, R2, R3, and R5 each independently represent H or OH.

[0028] In an embodiment of the present invention, R4 is C 1~6 It represents an alkoxy, and more specifically, R4 represents a methoxy, ethoxy, or butoxy molecule.

[0029] In embodiments of the present invention, X and X' are each independently selected from the group consisting of -C(O)O*, -C(O)*, and -C(O)NR*. (In the formula, R is independently H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, halo, substituted or unsubstituted C) 1~8 Alkyl or substituted or unsubstituted C 1~8 This represents an alkoxy, where C 1~8 Alkyl or C 1~8 Alkoxy compounds, when substituted, are replaced with H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, or halo.

[0030] In this embodiment of the present invention, Y and Y' represent O.

[0031] In embodiments of the present invention, R6 is a substituted or unsubstituted saturated or unsaturated C 3~8 This shows a hydrocarbon chain, where, The chain may be interrupted by one or more heteroatoms or substituted or unsubstituted aromatic rings, where, The heteroatom is O, S, or N(H), and the aromatic ring is benzene, pyridine, imidazole, or pyrazole. The chain or aromatic ring has -NHC(O)CH2-[OCH2CH2] at the position of one or more hydrogen atoms on the chain or aromatic ring. n -R or -[CH2CH2O] n -R can be used as a substitute. (In the formula, R is defined as above for R, n is an integer between 1 and 6.

[0032] In aspects of the present invention, a pyrrolobenzodiazepine dimer prodrug selected from the following, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0033] [ka] [In the formula, R O and R 'O Each of these represents an oxygen protecting group, and they may be the same or different from one another.

[0034] In the present invention, compounds having the following structures are excluded.

[0035] [ka]

[0036] The present invention also provides a conjugate having a structure represented by the following chemical formula IIa, or a pharmaceutically acceptable salt or solvate thereof.

[0037] [chemical IIa] Ligand-(LD) n [In the formula, Ligand indicates the ligand, L indicates the linker. D represents the pyrrolobenzodiazepine dimer prodrug described above, and the linker binds to D at the N10, N10', or N10 and N10' positions of D, or to D via X, X', or X and X' of D. n is an integer between 1 and 20.

[0038] In an embodiment of the present invention, the linker bonds with D at the N10 and N10' positions of D, or with D via the X and X' positions of D.

[0039] In an embodiment of the present invention, n is an integer between 1 and 10.

[0040] The present invention also provides pyrrolobenzodiazepine dimer prodrug-linker compounds having a structure represented by the following chemical formula IIb or IIb', or pharmaceutically acceptable salts or solvates thereof.

[0041] [ka] JPEG2023113699000008.jpg80149[In the formula, Dotted line, R1, R2, R3, R4, R5, R6, R7, X, Y, R1', R2', R3', R4', R5', R7', X', Y', R8, Z a , Z b , R 12a , R 13a , R 14a , R8', Z a ', Z b ', R 12a ', R 13a 'and R 14a ' is defined as follows for the compounds represented by chemical formula Ia and chemical formula Ia', respectively. Xa and Xa' are each independently a combination, substitution, or unsubstituted C. 1~6 This shows alkylene, where C 1~6 Alkylenes, when substituted, have hydrogen and C 1~8 Alkyl or C 3~8 Substituted with cycloalkyl groups, G and G' represent a glucuronide group, a galactoside group, or any derivative of a glucuronide group or a galactoside group. Z is H, C 1~8 Alkyl, Halo, NO2, CN,

[0042] [ka] , and -(CH2) m Selected from the group consisting of -OCH3 (In the formula, R8, R9 and R 10 These are H and C, respectively, independently. 1~8 Alkyl, C 2~6 Alkenyl and C 1~6 Selected from the group consisting of alkoxys, where m is 0-12. n is an integer between 1 and 3, and each Z may be the same or different from one another, provided that n is an integer greater than or equal to 2. W represents -C(O)-, -C(O)NR''-, -C(O)O-, -S(O)2NR''-, -P(O)R'''NR''-, -S(O)NR''-, or -PO2NR'' (wherein R'' and R''' are independently H and C 1~8 Alkyl, C 3~8 Cycloalkyl, C 1~8 Alkoxy, C 1~8 Alkylthio, mono, or diC 1~8 Alkylamino, C 3~20 Heteroaryl or C 6~20 (Indicating an arrow), L represents one or more units selected from the group consisting of branching units, linking units, and joining units, or combinations thereof, where, A connecting unit connects W to a linking unit, W to a branching unit, a branching unit to another branching unit, or a branching unit to a linking unit, and a branching unit connects a connecting unit to W, or a connecting unit to another connecting unit. The branching unit is C 2~100 Alkenyl (where the carbon atoms of the alkenyl may be substituted with one or more heteroatoms selected from the group consisting of N, O, and S, and the alkenyl has one or more C 1~20 (May be further substituted with alkyl), hydrophilic amino acid, -C(O)-, -C(O)NR''''-, -C(O)O-, -(CH2) s -NHC(O)-(CH2) t -,-(CH2) u-C(O)NH-(CH2) v -,-(CH2) s -NHC(O)-(CH2) t -C(O)-, -(CH2) u -C(O)NH-(CH2) v -C(O)-, -S(O)2NR''''-, -P(O)R'''''NR''''-, -S(O)NR''''-, or -PO2NR''''- (wherein R'''' and R''''' are independently H and C 1~8 Alkyl, C 3~8 Cycloalkyl, C 1~8 Alkoxy, C 1~8 Alkylthio, mono, or diC 1~8 Alkylamino, C 3~20 Heteroaryl or C 5~20 (The letters represent an integer, where s, t, u, and v each independently represent an integer between 0 and 10.) The unit of connection is -(CH2) r (V(CH2) p ) q - (wherein r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20, and V indicates a single bond, -O-, or S-), The bonding unit is,

[0043] [ka] (wherein L1 is a single bond or C) 2~30 Showing an alkenyl, R 11 H or C 1~10 It indicates alkyl, and L2 is C 2~30 (showing alkenils), R v C is -NH2, N3, substituted or unsubstituted. 1~12 Alkyl, C 1~12 Alkinyl, C 1~3 alkyl, substituted or unsubstituted C 3~20 Heteroaryl, C 3~20 Heterocyclines or substituted or unsubstituted C 5~20 Here, C 1~12Alkyl, C 3~20 Heteroaryl, C 3~20 Heterocyclyl or C 5~20 If the aryl is substituted, C 3~20 Heteroaryl, C 3~20 Heterocyclyl or C 5~20 One or more hydrogen atoms present in an aryl group can each be independently an OH, =O, halo, or C. 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyloxy, Carboxy, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonyl, formyl, C 3~8 Ariel, C 5~12 Aryloxy, C 5~12 Arylcarbonyl or C 3~6 [Substituted with heteroaryl]

[0044] In embodiments of the present invention, Xa and Xa' are each independently connected or C 1~3 It indicates an alkyl group.

[0045] In an embodiment of the present invention, Z is H,

[0046] [ka] , and -(CH2) m Selected from the group consisting of -OCH3 (In the formula, R8, R9 and R 10 These are H and C, respectively, independently. 1~3 Alkyl and C 1~3 Selected from the group consisting of alkoxys, where m is 1 to 6.

[0047] In embodiments of the present invention, W represents -C(O)-, -C(O)NR'''-, or -C(O)O- (wherein R''' is H or C 1~8 (Indicating alkyl), L represents one or more units selected from the group consisting of branching units, linking units, and joining units, or combinations thereof, where, A connecting unit connects W to a linking unit, W to a branching unit, a branching unit to another branching unit, or a branching unit to a linking unit, and a branching unit connects a connecting unit to W, or a connecting unit to another connecting unit. The branching unit is C 2~8 Alkenyl (where the carbon atoms of the alkenyl may be substituted with one or more heteroatoms selected from the group consisting of N, O, and S, and the alkenyl has one or more C 1~6 (May be further substituted with alkyl), hydrophilic amino acid, -C(O)-, -C(O)NR''''-, -C(O)O-, -(CH2) s -NHC(O)-(CH2) t -,-(CH2) u -C(O)NH-(CH2) v -,-(CH2) s -NHC(O)-(CH2) t -C(O)- or -(CH2) u -C(O)NH-(CH2) v -C(O)- (where R'''' is H, C 1~8 Alkyl, C 3~8 Cycloalkyl, C 1~8 Alkoxy, C 1~8 Alkylthio, mono, or diC 1~8 Alkylamino, C 3~20 Heteroaryl or C 5~20 (The letters represent an integer, where s, t, u, and v each independently represent an integer between 0 and 5.) The unit of connection is -(CH2) r (V(CH2) p ) q - (wherein r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20, and V indicates a single bond or -O-), The bonding unit is,

[0048] [ka] (wherein L1 is a single bond or C) 2~8 Showing an alkenyl, R 11 H or C 1~6 It indicates alkyl, and L2 is C2~8 (showing alkenyls), and The unit of connection is -(CH2) r (V(CH2) p ) q - is (In the formula, r is an integer from 0 to 8, p is an integer from 1 to 12, q is an integer from 1 to 10, and V indicates a single bond or -O-).

[0049] In embodiments of the present invention, G and G' may each independently represent a β-glucuronide group, a galactoside group, or any derivative thereof.

[0050] In aspects of the present invention, a pyrrolobenzodiazepine dimer prodrug-linker compound having a structure represented by the following chemical formula IIc, or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0051] [ka] [In the formula, the dotted line represents the presence of any double bond between C1 and C2 or between C2 and C3.] R1 is selected from the group consisting of methyl, ethyl, methylene, methoxy, and substituted or unsubstituted phenyl, where phenyl is substituted with H, OH, halo, or C. 1~6 Alkyl, C 1~6 Alkoxy and C 6~12 Substituting with substituents selected from the group consisting of aryl compounds, m is an integer from 1 to 10. n is an integer between 1 and 10.

[0052] In aspects of the present invention, R1 in the above chemical formula IIc may represent methyl, methylene, or H, OH, halo, or C 1~6 Alkyl and C 1~6 This may refer to phenyl substituted with substituents selected from the group consisting of alkoxys, or to unsubstituted phenyl.

[0053] In an embodiment of the present invention, m in the above chemical formula IIc may be an integer from 2 to 8, specifically an integer from 3 to 7, and more specifically an integer from 4 to 6.

[0054] In an embodiment of the present invention, n in the above chemical formula IIc may be an integer from 2 to 8, specifically an integer from 3 to 7, and more specifically an integer from 4 to 6.

[0055] The present invention also provides pyrrolobenzodiazepine dimer prodrug-linker compounds having the following chemical structures, or pharmaceutically acceptable salts or solvates thereof. However, the following pyrrolobenzodiazepine dimer prodrug-linker compounds are illustrative, and those skilled in the art can prepare and use a variety of pyrrolobenzodiazepine dimer-linker compounds within the above range.

[0056] [ka] TIFF2023113699000015.tif237160TIFF2023113699000016.tif249133TIFF2023113699000017.tif207128 TIFF2023113699000018.tif215134TIFF2023113699000019.tif223136TIFF2023113699000020.tif109150

[0057] The present invention also provides a pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate having a structure represented by the following chemical formula IIIa or IIIb, or a pharmaceutically acceptable salt or solvate thereof.

[0058] [ka] [In the formula, Dotted line, R1, R2, R3, R4, R5, R6, R7, X, Y, R1', R2', R3', R4', R5', R7', X', Y', R8, Z a , Z b , R12a , R 13a , R 14a , R8', Z a ', Z b ', R 12a ', R 13a 'and R 14a ' is defined as follows for the compounds represented by chemical formula Ia and chemical formula Ia', respectively. Xa, G, Z, W, L, Xa', G', and Z' are defined as follows for each compound represented by chemical formula IIb: Ligand indicates the antigen-binding site.

[0059] In embodiments of the present invention, Ligand is a protein.

[0060] In aspects of the present invention, the protein is a fragment or repeptide of an oligopeptide, polypeptide, antibody, or antigen polypeptide.

[0061] In an embodiment of the present invention, the protein has one or more amino acid motifs that can be recognized by an isoprenoid transferase. In other words, the C-terminus (fragment, analog, or derivative thereof) of the protein may be bound to an amino acid motif that can be recognized by an isoprenoid transferase.

[0062] In an embodiment of the present invention, a spacer unit composed of an amino acid, an oligopeptide, or a polypeptide may be further included between the protein and the amino acid motif.

[0063] In an embodiment of the present invention, the protein is covalently bonded to the linker via an amino acid motif.

[0064] In embodiments of the present invention, the amino acid motif may be covalently bonded to the C-terminus of a protein, or to at least one spacer unit covalently bonded to the C-terminus of a protein. The protein may be directly covalently bonded to the amino acid motif, or it may be linked to the amino acid motif by covalent bonding to a spacer unit. The amino acid spacer unit consists of 1 to 20 amino acids, with glycine units being preferred among these.

[0065] In an embodiment of the present invention, the C-terminus of the protein is that of the light chain or heavy chain of the antibody.

[0066] In an embodiment of the present invention, the protein is a monoclonal antibody.

[0067] In embodiments of the present invention, isoprenoid transferases include FTases (farnesyl protein transferases) and GGTases (geranylgeranyl transferases), each of which is involved in the transfer of farnesyl residues or geranyl-geranyl residues to the C-terminal cysteine ​​of a target protein. GGTases can be classified into GGTase I and GGTase II. FTases and GGTase I can recognize the CAAX motif.

[0068] In embodiments of the present invention, the amino acid motif is CYYX, XXCC, XCXC, or CXX (wherein C represents cysteine, Y represents an aliphatic amino acid, and X represents an amino acid that determines the substrate specificity of the isoprenoid transferase).

[0069] In an embodiment of the present invention, the protein having an amino acid motif is A-HC-(G) Z CVIM, A-HC-(G) z CVLL, A-LC-(G) Z CVIM and A-LC-(G) ZThe group is selected from CVLL (wherein A represents the antibody, HC represents the heavy chain, LC represents the light chain, G represents the glycine unit, and z represents an integer from 0 to 20).

[0070] Isoprenoid transferases can recognize substrates and isosubstrates. Isosubstrates refer to substrate analogs that have modifications to the substrate. Isoprenoid transferases alkylate specific amino acid motifs (e.g., the CAAX motif) at the C-terminus of proteins (see Benjamin P. Duckworth et al., ChemBioChem 2007, Vol. 8, p. 98; Uyen TT Nguyen et al., ChemBioChem 2007, Vol. 8, p. 408; Guillermo R. Labadie et al., J. Org. Chem. 2007, Vol. 72 (No. 24), p. 9291; James W. Wollack et al., ChemBioChem 2009, Vol. 10, p. 2934). Functional proteins can be produced by alkylation at the C-terminus of a protein using isoprenoid transferases and isosubstrates.

[0071] For example, the cysteine ​​residue of the C-terminal CAAX motif can be reacted with an isosubstrate using an isoprenoid transferase. In certain cases, AAX can then be removed by a protease. The resulting cysteine ​​can then be enzymatically methylated at the carboxyl terminus (see Iran M. Bell, J. Med. Chem. 2004, Vol. 47 (No. 8), 1869).

[0072] The proteins of the present invention can be prepared by any molecular biological or cell biological method known in the art. For example, a transient transfection method may be used. A gene sequence encoding a specific amino acid motif recognizable by isoprenoid transferase can be inserted into a known plasmid vector by standard PCR techniques to express a protein (or a fragment thereof) having a C-terminal specific amino acid motif. In this method, a protein having one or more amino acid motifs recognizable by isoprenoid transferase can be expressed.

[0073] In embodiments of the present invention, if the protein is a monoclonal antibody, one or more light chains of the monoclonal antibody, one or more heavy chains of the monoclonal antibody, or both light and heavy chains may contain an amino acid moiety having an amino acid motif that can be recognized by an isoprenoid transferase, and a person skilled in the art can easily select a protein that selectively binds to the target of interest (e.g., the target cell of interest).

[0074] In embodiments of the present invention, the protein may contain an antibody or antigen fragment that specifically binds to a target of interest.

[0075] In embodiments of the present invention, the amino acid motif is CYYX, XXCC, XCXC, or CXX (wherein C represents cysteine, Y represents an aliphatic amino acid, and X represents an amino acid that determines the substrate specificity of the isoprenoid transferase), and it is more preferable that the amino acid motif is CYYX.

[0076] The present invention also provides a pharmaceutical composition for preventing or treating proliferative disorders, comprising the above-mentioned pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate, or a pharmaceutically acceptable salt or solvate thereof.

[0077] The present invention also provides a pharmaceutical composition for preventing or treating proliferative disorders, comprising the above-mentioned pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0078] The present invention also provides a pharmaceutical composition for preventing or treating proliferative disorders, comprising the above-mentioned pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate, or a pharmaceutically acceptable salt or solvate thereof, one or more co-therapeutic agents, and a pharmaceutically acceptable excipient.

[0079] In embodiments of the present invention, the co-therapeutic agent may be, but is not limited to, an agent that exhibits a preventive, ameliorative, or therapeutic effect against proliferative disorders, or an agent that can reduce adverse effects that may occur when a therapeutic agent for proliferative disorders is administered, or an agent that exhibits an immune-enhancing effect. This means that any agent may be applied in combination with pyrrolobenzodiazepine, as long as it exhibits a therapeutically useful effect when applied in the form of a combination drug, and / or further improves the stability of pyrrolobenzodiazepine, and / or reduces side effects that may occur when pyrrolobenzodiazepine is administered, and / or maximizes the therapeutic effect by enhancing immunity.

[0080] In aspects of the present invention, proliferative disorders refer to cell proliferation-related disorders in which undesirable excess or abnormal cells are present in an undesirable and uncontrolled manner, such as neoplasms or hyperplastic proliferation in vitro or in vivo. Proliferative disorders may be selected from the group consisting of neoplasms, tumors, cancers, leukemias, psoriasis, bone diseases, fibrous diseases, and atherosclerosis. Examples of neoplasms and tumors include histiocytoma, glioma, astrocytoma, and osteoma.

[0081] In aspects of the present invention, cancer may be selected from the group consisting of lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, colon 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. However, the present invention can be applied to all cancers in which pyrrolobenzodiazepines exhibit therapeutic effects.

[0082] The present invention also provides a method for treating a proliferative disorder in a subject having a proliferative disorder, comprising administering to the subject a pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate, or a pharmaceutically acceptable salt or solvate thereof, in an amount effective for treating the proliferative disorder.

[0083] In one embodiment of the present invention, a method for treating cancer is provided, comprising administering the above-mentioned pharmaceutical composition to a patient.

[0084] The present invention is suitable for use in providing a PBD compound at a target site. The conjugate according to the present invention releases an active PBD compound that does not have any linker moiety and does not contain anything that could affect the reactivity of the PBD compound.

[0085] [Definition] The following definitions apply herein.

[0086] In this specification, the term “conjugate” refers to a cell-binding agent that covalently binds to one or more molecules of a cytotoxic compound. Here, the “cell-binding agent” is a molecule having affinity for a biological target, and may be, for example, a ligand, a protein, an antibody, specifically a monoclonal antibody, a protein or antibody fragment, a peptide, an oligonucleotide, or an oligosaccharide, and the binding agent functions to induce a biologically active compound against the biological target. In aspects of the present invention, the conjugate may be designed to target tumor cells by a cell surface antigen. The antigen may be a cell surface antigen that is overexpressed or expressed in abnormal cell types. Specifically, the target antigen may be expressed only in proliferating cells (e.g., tumor cells). The target antigen may typically be selected based on different expression between proliferating and normal tissues. In the present invention, the ligand binds to a linker.

[0087] In this specification, the term "antibody" refers to an immunoglobulin molecule that can specifically bind to a target, such as a carbohydrate, polynucleotide, lipid, or polypeptide, by at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” includes not only intact polyclonal or monoclonal antibodies, but also any antigen-binding site of an intact antibody (e.g., “antigen-binding fragment”) or its single chain, antibody-containing fusion proteins, and any other modified sequences of immunoglobulin molecules containing antigen recognition sites, such as, but not limited to, Fab, Fab', F(ab')2Fd fragments, Fv fragments, single-domain antibody (dAb) fragments, isolated complementarity-determining regions (CDRs), single chains (scFv), and single-domain antibodies (e.g., shark and camel antibodies), maxi-bodies, mini-bodies, intra-bodies, dia-bodies, tria-bodies, tetra-bodies, v-NARs, and bis-scFvs (see, for example, Hollinger and Hudson, 2005, Nature Biotechnology, Vol. 23 (No. 9): pp. 1126-1136).

[0088] Examples of antibodies include any class of antibody, such as IgG, IgA, or IgM (or their subclasses), and the antibody does not need to belong to any particular class. Depending on the amino acid sequence in the constant region of the antibody's heavy chain, immunoglobulins may be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further classified into subclasses (isoforms) such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant regions of the heavy chain (HC) corresponding to different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional coordinates of different classes of immunoglobulins are well known. The antibodies of the present invention can be prepared by techniques well known in the relevant art, such as recombinant techniques, phage display techniques, synthesis techniques, or combinations thereof, or by other techniques readily known in the relevant art.

[0089] In this specification, the term “isolated antibody” refers to an antibody that substantially does not contain other antibodies having different antigen specificities, and which may substantially not contain other cellular material and / or chemical substances.

[0090] In this specification, the term “biological target” refers to antigens located on the surface of tumors, cancer cells, and extracellular matrix cells.

[0091] In this specification, the term "linker" refers to a compound that covalently binds a cytotoxic compound to a ligand. In embodiments of the present invention, linkers disclosed in PCT / US2016 / 063564 and PCT / US2016 / 063595 may be used.

[0092] In this specification, the term "therapeutic agent" refers to a drug that exerts cytotoxic, cell proliferation inhibitory, and / or immunomodulatory effects against proliferative disorders, such as cancer cells or activated immune cells. Examples of therapeutic agents include cytotoxic agents, chemotherapeutic agents, cell proliferation inhibitors, and immunomodulators.

[0093] In this specification, the term "chemotherapeutic agent" refers to a chemical compound useful for treating cancer.

[0094] The term “subject” as used herein is intended to include humans and non-human animals, in particular mammals. Examples of subjects may include human subjects, and subjects are concepts that include, for example, human patients with the disorders described herein, more specifically, cancer, or normal subjects. The term “non-human animals” includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, and reptiles), as well as mammals, e.g., non-human primates, animals useful for livestock and / or agriculture (e.g., sheep, dogs, cats, cattle, pigs, etc.) and rodents (e.g., mice, rats, hamsters, guinea pigs, etc.). In certain embodiments, subjects are human patients.

[0095] In this specification, the terms “treatment” or “to treat” refer to both therapeutic treatments and prophylactic or preventative measures. Subjects requiring treatment include those already suffering from the disease, those susceptible to the disease, or those who should be prevented from the disease. Where used in reference to a disease or subject requiring treatment, the term includes, but is not limited to, inhibiting or slowing the progression of the disease, preventing symptoms, reducing the severity of the disease and / or symptoms, or reducing the duration of the disease compared to an untreated subject.

[0096] In this specification, the term “administer” or “to administer” refers to the supply and / or contact and / or delivery of the compound(s) by any suitable route for achieving the desired effect. Administrations may include, but are not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intra-arterial, intrathecal, intrasternal, intraspinal, intrafocal, or intracranial injection), percutaneous, topical, buccal, rectal, transvaginal, transnasal, ophthalmic and inhalation administrations, and implantation administrations.

[0097] In this specification, the term "unsubstituted or substituted" means a parent group that may be unsubstituted or substituted; the term "substituted" means a parent group having one or more substituents; and the term "substituent" means a chemical moiety that is covalently bonded to or condensed with the parent group.

[0098] In this specification, the term "halo" refers to fluorine, chlorine, bromine, iodine, etc.

[0099] In this specification, the term "alkyl" refers to the monovalent portion obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic saturated or unsaturated (unsaturated, completely unsaturated) hydrocarbon compound. Examples of saturated alkyls include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. Examples of saturated linear alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl(amyl), n-hexyl, and n-heptyl. Examples of saturated branched alkyls include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.

[0100] In this specification, the term "alkoxy" means -OR (wherein R is an alkyl group), and examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0101] In this specification, the term "aryl" means a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.

[0102] In this specification, the term "alkenyl" means an alkyl group having one or more carbon-carbon double bonds, and examples of unsaturated alkenyl groups include ethynyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.

[0103] In this specification, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, and examples of unsaturated alkynyl groups include ethynyl and 2-propynyl.

[0104] In this specification, the term "carboxy" refers to -C(=O)OH.

[0105] In this specification, the term "formyl" refers to -C(=O)H.

[0106] In this specification, the term "aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, "C 5~7 "Aryl" refers to a monovalent part obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, and which has 5 to 7 ring atoms. 5~10 The term "aryl" refers to a monovalent part obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which has 5 to 10 ring atoms. Here, the prefix (C 5~7 , C 5~10 "C" refers to the number of ring atoms or the range of ring atoms, regardless of whether carbon atoms or heteroatoms are present or not. 5~6 "Aryl" refers to an aryl group having 5 to 6 ring atoms. Here, the ring atoms may all be carbon atoms, as in a "carboaryl group." Examples of carboaryl groups, but are not limited to, include those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene, and pyrene. Examples of aryl groups containing a fused ring in which at least one is an aromatic ring include, but are not limited to, groups derived from indan, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acephenanthrene, and aceanthrene. Alternatively, the ring atoms may contain one or more heteroatoms, as in a "heteroaryl group."

[0107] In this specification, the term "heteroaryl" refers to an aryl containing one or more heteroatoms, examples of which may include pyridine, pyrimidine, benzothiophene, furyl, dioxolanil, pyrrolyl, oxazolyl, pyridyl, pyridadinyl, and pyrimidinyl, more specifically, C9 having two fused rings derived from benzofuran, isobenzofuran, indole, isoindole, indidine, indoline, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodioxol, benzofuran, benzotriazole, benzothiofuran, benzothiazole, or benzothiadiazole, and C having two fused rings derived from chromene, isochromene, chroman, isochroman, benzodioxane, quinoline, isoquinoline, quinoridine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, or pteridine. 10 , has two fused rings and is derived from benzodiazepines C 11 , having three condensed rings, and derived from carbazole, dibenzofuran, dibenzothiophene, carboline, pyrimidine, or pyridoindole. 13 , and C having three condensed rings, acridine, xanthene, thioxanthene, oxanthrene, phenoxathiin, phenazine, phenoxazine, phenothiazine, thianthridine, phenanthroline or derived from phenazine 14 These could be cited.

[0108] In this specification, the term "cycloalkyl" means an alkyl group, which is a cyclic group, and refers to the monovalent portion obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups, but not limited to, include those derived from the following: Saturated monocyclic hydrocarbon compounds: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, and methylcyclohexane; Unsaturated monocyclic hydrocarbon compounds: cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene; and Saturated heterocyclic hydrocarbon compounds: norcalane, norpinane, norbornane.

[0109] In this specification, the term "heterocyclyl" refers to the monovalent portion obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.

[0110] In this specification, prefixes (e.g., C 1~12 and C 3~8 ) refers to the number of ring atoms or the range of the number of ring atoms, regardless of whether carbon atoms or heteroatoms are present or not. For example, as used herein, "C 3~6 The term "heterocyclyl" refers to a heterocyclyl group that has 3 to 6 ring atoms.

[0111] Examples of monocyclic heterocyclyl groups, though not limited to those listed below, may include those derived from the following: N1: Aziridines, azetidines, pyrrolidines, pyrrolines, 2H- or 3H-pyrroles, piperidines, dihydropyridines, tetrahydropyridines, and azepines; N2: Imidazolidine, pyrazolidine, imidazoline, pyrazoline, and piperazine; O1: Oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, and oxepin; O2: Dioxolane, dioxane, and dioxepane; O3: Trioxane; N1O1: Tetrahydroxazole, dihydroxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine; S1: Chiiran, Thietan, Thioran, Chian and Thiepan; N1S1: Thiazolin, thiazolidinedione, and thiomorpholine; N2O1: Oxadiazine; O1S1: Oxatiol, oxathian; and N1O1S1: Oxathiazine.

[0112] In this specification, the term "prodrug" refers to a compound that can be converted directly or indirectly to a pyrrolobenzodiazepine drug under physiological conditions in vivo by the action of enzymes and gastric acid (e.g., enzymatic oxidation, reduction, and / or hydrolysis).

[0113] In this specification, "pharmaceutically acceptable salt" can refer to an acid addition salt formed by a pharmaceutically acceptable free acid, and organic or inorganic acids can be used as the free acid.

[0114] Examples of organic acids, though not limited to them, include citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, and aspartic acid. In addition, examples of inorganic acids, though not limited to them, include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

[0115] For example, if a compound is an anion or has a functional group that can be an anion (e.g., -COOH can be -COO-), the salt can be formed using a suitable cation. Examples of suitable inorganic cations include, but are not limited to, Na. + and K + Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth metal cations such as Al3+ Other cations such as the following may be mentioned. Suitable examples of organic cations include, but are not limited to, ammonium ions (i.e., NH4). 4+ ) and substituted ammonium ions (e.g., NH3R + NH2R2 + NHR3 + and NR4 + ) could be cited.

[0116] Some suitable examples of substituted ammonium ions may be derived from: amino acids, e.g., lysine and arginine, as well as ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine. A typical example of a quaternary ammonium ion is N(CH3)4. + That is the case.

[0117] The compound is a cation or has a functional group that can be a cation (for example, -NH2 is -NH3). + If it has (which may be), the salt can be formed using a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrite, phosphoric acid, and phosphorous acid.

[0118] Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphor sulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Suitable polymeric organic anions include, but are not limited to, those derived from polymer acids such as: tannic acid and carboxymethylcellulose.

[0119] In this specification, the term "solvate" refers to a molecular complex between a compound according to the present invention and a solvent molecule. Examples of solvates include, but are not limited to, compounds according to the present invention coupled with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or any mixed solvent thereof.

[0120] It may be convenient or desirable to prepare, purify, and / or manipulate the corresponding solvates of the active compound. The term "solvate" is used herein in its conventional sense to refer to a complex of a solute (e.g., the active compound, a salt of the active compound) and a solvent. When the solvent is water, the solvate may conveniently be referred to as a hydrate, e.g., monohydrate, dihydrate, and trihydrate.

[0121] The pharmaceutical compositions of the present invention may contain pharmaceutically acceptable carriers. Typical pharmaceutically acceptable carriers include gradually metabolized polymers, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, high molecular weight amino acids, amino acid copolymers, and lipid aggregates, which can be appropriately selected and used by those skilled in the art.

[0122] Compositions containing pharmaceutically acceptable carriers may be in various oral or parenteral forms. When preparing formulations, the formulations may be prepared using commonly used diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, or surfactants.

[0123] Examples of solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. Such solid dosage forms are prepared by mixing one or more compounds with at least one or more excipients, such as starch, calcium carbonate, sucrose, or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

[0124] Liquid formulations for oral administration may include suspensions, liquids, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, liquid formulations may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives.

[0125] Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. For suppositories, bases may include vitepsol, macrogol, Tween 61, cocoa butter, lauric butter, and glycerogenous gelatin.

[0126] The pharmaceutical composition may have any one formulation selected from the group consisting of injections, tablets, pills, powders, granules, capsules, suspensions, liquids, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.

[0127] For intravenous, cutaneous, or subcutaneous injection, the active ingredient may be in the form of a pyrogen-free aqueous solution with appropriate pH, isotonicity, and stability, suitable for parenteral administration. Those skilled in the art can prepare a suitable solution using an isotonic medium, such as aqueous sodium chloride solution, Ringer's solution, and lactated Ringer's solution, as well as preservatives, stabilizers, buffers, and antioxidants, or other additives may be included in the solution as needed. A solid form suitable for injection may be prepared as an emulsion or as a polypeptide encapsulated in liposomes.

[0128] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to the amount necessary to achieve the intended therapeutic outcome (in terms of dosage, duration, and means of administration). The effective dose is the minimum amount of the active agent necessary to provide a therapeutic benefit to the subject, and less than the toxic dose. For example, the active agent may be administered in doses ranging from about 100 ng / kg to about 100 mg / kg per patient, more typically in the range of about 1 μg / kg to about 10 mg / kg per patient. If the active compound is a salt, ester, amide, prodrug, etc., the dose is calculated based on the parent compound, and therefore the actual weight used increases proportionally. The pyrrolobenzodiazepine compounds according to the present invention may be formulated to contain 0.1 mg to 3000 mg, 1 mg to 2000 mg, or 10 mg to 1000 mg of the active ingredient per unit dose form, but are not limited to these. The active ingredient may be administered in such a manner that a maximum plasma concentration of the active compound is obtained at approximately 0.05 μM to 100 μM, 1 μM to 50 μM, or 5 μM to 30 μM. For example, the active compound may be administered optionally by intravenous injection of a solution containing the active ingredient in physiological saline at a concentration of 0.1 w / v% to 5 w / v%.

[0129] The concentration of the active compound in the pharmaceutical composition may be determined by the drug's absorption, inactivation, and release rates, as well as other factors known to those skilled in the art. The dosage may be adjusted according to the severity of the symptoms / disease. In addition, the dosage and administration regimen for a particular patient may be adjusted according to the professional judgment of the administration supervisor, taking into account the patient's symptoms / disease severity, needs, age, responsiveness to the drug, etc. The concentration ranges described in this invention are illustrative only and are not intended to limit the embodiments of the composition claimed to be these. In addition, the active ingredient may be administered as a single dose, or a smaller dose may be divided and administered over several doses.

[0130] The prodrug compounds or prodrug-linker compounds and prodrug-linker-ligand conjugate compounds according to the present invention can be used to treat proliferative disorders, particularly cancer. The term “proliferative disorder” refers to undesirable, excessive, or abnormal cell proliferation, such as neoplasms or hyperplastic proliferation, in vitro or in vivo. Examples of proliferative disorders may include neoplasms, tumors, cancers, leukemias, psoriasis, bone diseases, fibrous diseases, and atherosclerosis, and proliferative disorders may include, but are not limited to, the proliferation of benign, precancerous, or malignant cells. Cancers may include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancers, colorectal cancers, colon cancers, breast cancers, ovarian cancers, prostate cancers, testicular cancers, liver cancers, kidney cancers, bladder cancers, pancreatic cancers, brain cancers, sarcomas, osteosarcomas, Kaposi's sarcomas, and melanomas.

[0131] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings generally understood by those skilled in the art.

[0132] In embodiments of the present invention, the pyrrolobenzodiazepine prodrug, pyrrolobenzodiazepine prodrug-linker compound, and pyrrolobenzodiazepine-linker-ligand conjugate according to the present invention can be synthesized by following the procedure described below.

[0133] Synthetic pathway of pyrrolobenzodiazepine prodrugs

[0134] [ka] TIFF2023113699000023.tif140151

[0135] Synthetic pathways for pyrrolobenzodiazepine prodrug-linkers and pyrrolobenzodiazepine prodrug-linker-ligand conjugates The pyrrolobenzodiazepine prodrug-linker compounds and pyrrolobenzodiazepine prodrug-linker-ligand conjugates according to the present invention can be prepared by the techniques presented herein using the knowledge of those skilled in the art.

[0136] For example, linkers may be described in PCT / US2016 / 063564 and PCT / US2016 / 063595, which are incorporated in their entirety herein by reference, but may also be prepared according to references known to those skilled in the art, even if not described herein. [Effects of the Invention]

[0137] The pyrrolobenzodiazepine dimer prodrug, pyrrolobenzodiazepine dimer prodrug-linker, or pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate according to the present invention exhibits excellent stability of the compound itself and its stability in plasma. Because this compound is advantageous in terms of toxicity findings, it is industrially useful in that it can target proliferative diseases such as cancer, perform specific treatments, maximize drug efficacy, and minimize the occurrence of side effects. [Brief explanation of the drawing]

[0138] [Figure 1] This figure shows an example of the synthesis process for compound number 28 according to the present invention. [Modes for carrying out the invention]

[0139] The present invention will be described in more detail below with reference to examples. However, the following examples are intended to aid in understanding the present invention and are not intended to limit the scope of the invention. [Examples]

[0140] [Example 1] Preparation of Compound 4

[0141] [ka]

[0142] Preparation of Compound 2 Oxalyl chloride (3.1 mL, 36.2 mmol) was dissolved in dichloromethane (40 mL), and dimethyl sulfoxide (4.7 mL, 66.4 mmol) was added thereto under a nitrogen atmosphere at -78°C. After 10 minutes, a solution of compound 1 (10 g, 30.2 mmol; compound 1 was prepared by the method described in J. Org. Chem., 2003, Vol. 68, pp. 3923-3931) in dichloromethane (140 mL) was gradually added to the mixture, and the reaction solution was stirred for 1 hour. Then triethylamine (16.7 mL, 120.6 mmol) was added thereto, and the reaction temperature was gradually raised to 0°C over 2 hours. The reaction solution was diluted with dichloromethane (200 mL), and the organic layer was washed with saturated ammonium chloride aqueous solution (200 mL) and brine (200 mL), and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 2 (9.5 g, 95%). 1H-NMR (400 MHz, CDCl3) (rotamer) δ 4.39-4.26 (m, 1H), 4.03-3.80 (m, 2H), 3.69-3.64 (m, 1H), 3.63-3.51 (m, 1H), 2.70-2.60 (m, 1H), 2.43 (d, J = 17.6 Hz), 1.61-1.41 (m, 10H), 0.98-0.67 (m, 6H), 0.08-0.05 (s, 6H).

[0143] Preparation of Compound 3 Methyltriphenylphosphonium bromide (7.6 g, 21.2 mmol) was diluted with tetrahydrofuran (80 mL), and potassium t-butoxide (1 M in THF, 21.2 mL, 21.2 mmol) was added thereto under a nitrogen atmosphere at 0°C. The mixture was stirred for 1 hour, and then a solution of compound 2 (5.0 g, 15.2 mmol) in tetrahydrofuran (10 mL) was gradually added thereto. The mixture was stirred for 4 hours while gradually increasing the reaction temperature to room temperature. A saturated aqueous solution of ammonium chloride (200 mL) was added to the reaction solution, and then the mixture was subjected to extraction using diethyl ether (2 × 200 mL). The combined organic layers were washed with brine (200 mL) and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 3 (4.27 g, 86%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 4.97-4.91 (m, 2H), 4.09-3.93 (m, 2H), 3.84-3.80 (m, 1H), 3.65-3.61 (m, 1H), 3.59-3.34 (m, 1H), 2.64-2.55 (m, 2H), 1.69 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H).

[0144] Preparation of Compound 4 Compound 3 (15.5 g, 47.2 mmol) was dissolved in dichloromethane (120 mL), and then hydrochloric acid (4N 1,4-dioxane solution, 82.6 mL, 330.4 mmol) was added at 0°C. The mixture was stirred under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 4 (6.53 g, 92%) as a white solid. 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 9.79 (br s, 1H), 9.17 (br s, 1H), 5.15 (d, J = 8 Hz, 1H), 4.91 (br s, 1H), 4.10 (m, 5H), 2.76-2.70 (m, 1H), 2.60-2.54 (m, 1H).

[0145] [Example 2] Preparation of Compound 9

[0146] [ka]

[0147] Preparation of compound 6 Compound 5 (10 g, 20.2 mmol; compound 5 was prepared by the method described in J. Med. Chem., 2004, Vol. 47, pp. 1161-1174) was dissolved in dichloromethane (100 mL), and then oxalyl chloride (6.1 mL, 70.8 mmol) and N,N-dimethylformamide (2 drops) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred for 4 hours, then the temperature was raised to room temperature, the reaction solution was stirred for 10 hours, concentrated under reduced pressure, and vacuum dried. The resulting compound was dissolved in dichloromethane (120 mL), and then compound 4 (6.2 g, 41.4 mmol) and triethylamine (9.9 mL, 70.8 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction temperature was raised to room temperature, the mixture was stirred for 3 hours, and saturated ammonium chloride aqueous solution (200 mL) was added to the reaction solution. The mixture was then subjected to extraction using dichloromethane (2 × 200 mL). The combined organic layer was washed with brine (200 mL) and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 6 (12 g, 87%). 1 H-NMR (400 MHz, CDCl3) δ 7.71 (s, 2H), 6.80 (s, 2H), 5.13 (s, 2H), 4.88 (s, 2H), 4.61 (m, 2H), 4.17-4.14 (t, J = 6.2 Hz, 4H), 3.98 (s, 6H), 3.94-3.74 (m, 10H), 2.89-2.83 (m, 2H), 2.52-2.48(m, 2H), 2.04-1.96 (m, 4H), 1.77-1.71 (m, 2H).

[0148] Preparation of Compound 7 Compound 6 (6.4 g, 9.36 mmol) was dissolved in dichloromethane (100 mL), and then imidazole (2.5 g, 37.4 mmol) and t-butyldimethylsilyl chloride (3.5 g, 23.4 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred for 2 hours, and then saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (2 × 100 mL). The combined organic layer was washed with brine (200 mL) and then dried over anhydrous sodium sulfate. The resulting solution was filtered, then concentrated, and purified by column chromatography to obtain compound 7 (6.88 g, 75%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 7.70 (s, 1H), 6.76 (s, 2H), 4.99 (s, 2H), 4.83 (s, 2H), 4.59 (br s, 2H), 4.14, (t, 4H), 3.95 (s, 6H), 3.90 (d, 2H), 3.77-3.69 (m, 4H), 3.57 (q, J = 6.2 Hz, 1H), 3.31-3.29 (m, 1H), 2.82-2.67 (m, 4H), 1.99 (t, J = 7.2 Hz, 4H), 1.75-1.72 (m, 2H), 0.89 (s, 18H), 0.09 (s, 12H).

[0149] Preparation of compound 8 Compound 7 (3.0 g, 3.29 mmol) was dissolved in ethanol (44 mL), and then zinc powder (12.9 g, 197 mmol) and formic acid (5% ethanol solution, 128 mL) were added thereto. The reaction solution was stirred at room temperature for 15 minutes, then filtered through Celite, and ethyl acetate (500 mL) was added thereto. The organic layer was washed with distilled water (200 mL), saturated sodium bicarbonate aqueous solution (200 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated, and purified by column chromatography to obtain compound 8 (2.76 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 6.74 (s, 2H), 6.24 (s, 2H), 4.97 (s, 2H), 4.90 (s, 2H), 4.54 (br s, 2H), 4.33 (br s, 4H), 4.18 (br s, 1H), 4.14 (br s, 2H), 4.14-4.09 (m, 2H), 4.00 (t, J = 8 Hz, 4H), 3.77 (s, 6H), 3.62 (br s. 2H), 2.68 (s, 4H), 1.95-1.88 (m, 4H), 1.66-1.64 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H).

[0150] Preparation of compound 9 Compound 8 (5.0 g, 5.86 mmol) was dissolved in dichloromethane (300 mL), and then pyridine (0.94 mL, 11.7 mmol) and allyl chloroformate (0.62 mL, 5.86 mmol) were added under a nitrogen atmosphere at -78°C. The reaction solution was stirred for 1 hour, then the reaction temperature was raised to room temperature, the reaction solution was concentrated, and then purified by column chromatography to obtain compound 9 (2.23 g, 41%). 1H-NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 6.24 (s, 1H), 5.98-5.92 (m, 1H), 5.37, (dd, J = 17.6 Hz, J = 1.2 Hz, 1H), 5.25 (dd, J = 10.4 Hz, J = 1.2 Hz, 1H), 4.97 (br s, 2H), 4.90 (br s, 2H), 4.63-4.62 (m, 4H), 4.34 (br s, 2H), 4.21-4.18 (m, 2H), 4.10 (t, J = 6.4 Hz, 3H), 3.99 (t, J = 6.4 Hz, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.63 (bs, 1H), 2.68 (br s, 4H), 1.97-1.89 (m, 4H), 1.69-1.61 (m, 2H), 0.87 (s, 18H), 0.02 (br s, 12H).

[0151] [Example 3] Preparation of Compound 12

[0152] [ka]

[0153] Preparation of compound 11 4-hydroxybenzaldehyde (475 mg, 3.89 mmol) and compound 10 (1.7 g, 4.28 mmol; compound 10 was prepared by the method described in Korean Patent No. 1,628,872) were dissolved in acetonitrile (40 mL). Then, a 4 Å molecular sieve (4 g) and silver(I) oxide (3.6 g, 15.6 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water (40 mL), and subjected to extraction using ethyl acetate (2 × 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 11 (1.3 g, 69%). 1H-NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.86 (d, J = 8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 5.38-5.29 (m, 4H), 4.25-4.23 (m, 1H), 3.71 (s, 3H), 2.06 (s, 9H).

[0154] Preparation of compound 12 Compound 11 (1.3 g, 2.96 mmol) was dissolved in chloroform / isopropanol (50 mL / 10 mL), and then silica gel (1.3 g) and sodium borohydride (134 mg, 3.55 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred for 2 hours. Distilled water (40 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 12 (600 mg, 45%). 1 H-NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz 2H), 5.35-5.26 (m, 3H), 5.13 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 4.18-4.16 (m, 1H), 3.73 (s, 3H), 2.06-2.04 (m, 9H), 1.61 (t, J = 5.6 Hz, 1H).

[0155] [Example 4] Preparation of Compound 15

[0156] [ka]

[0157] Preparation of compound 13 5-Formylsalicylic acid (5.0 g, 30.1 mmol) was dissolved in methanol (50 mL), and concentrated sulfuric acid (2 mL) was added thereto. The reaction solution was heated under reflux for 24 hours, then concentrated under reduced pressure, and diluted with ethyl acetate (100 mL). The organic layer was washed with distilled water (100 mL), saturated sodium bicarbonate aqueous solution (200 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated, and vacuum-dried to obtain compound 13 (4.62 g, 85%) as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 9.88 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H).

[0158] Preparation of compound 14 Compound 13 (1.7 g, 9.38 mmol) and Compound 10 (4.1 g, 10.3 mmol) were dissolved in acetonitrile (50 mL), and then a 4 Å molecular sieve (4 g) and silver(I) oxide (8.7 g, 37.5 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water (50 mL), and then extracted using ethyl acetate (2 × 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 14 (2.85 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.29 (d, J = 2 Hz, 1H), 8.01 (dd, J = 8.4 Hz, J = 2 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 5.42-5.30 (m, 4H), 4.27 (d, J = 9.2 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H).

[0159] Preparation of compound 15 Compound 14 (2.85 g, 5.74 mmol) was dissolved in chloroform:isopropanol (50 mL / 10 mL), and then silica gel (2.8 g) and sodium borohydride (434 mg, 11.5 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred for 2 hours. Distilled water (40 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (2 × 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 15 (1.42 g, 49%).

[0160] [Example 5] Preparation of Compound 20

[0161] [ka]

[0162] Preparation of compound 16 5-formylsalicylic acid (10.0 g, 60.1 mmol) was diluted with tetrahydrofuran (30 mL), and then N,N-diisopropylethylamine (29.8 mL, 180 mmol) and benzyl bromide (7.15 mL, 60.1 mmol) were added at room temperature. The reaction solution was heated under reflux for 18 hours, then the temperature was lowered to room temperature, and 100 mL of 2N aqueous hydrochloric acid was added. The mixture was subjected to extraction using ethyl acetate (2 × 100 mL), and the combined organic layer was dried over anhydrous sodium sulfate. The resulting solution was filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain compound 16 (12.9 g, 83%). 1 H-NMR (400 MHz, CDCl3) δ 11.38 (s, 1H), 9.86 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.44 (m, 5H), 7.12 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H).

[0163] Preparation of compound 17 Compound 16 (5.0 g, 19.5 mmol) and Compound 10 (8.5 g, 21.4 mmol) were dissolved in acetonitrile (100 mL), and a 4 Å molecular sieve (10 g) and silver(I) oxide (18.0 g, 78.0 mmol) were added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water (100 mL), and subjected to extraction using ethyl acetate (2 × 100 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 17 (8.63 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.46-7.28 (m, 6H), 5.41-5.32 (m, 6H), 4.27 (d, J = 9.2 Hz, 1H), 3.71 (s, 3H), 2.06-2.04 (m, 9H).

[0164] Preparation of compound 18 Compound 17 (3.10 g, 5.41 mmol) was dissolved in chloroform / isopropanol (45 mL / 9 mL), and then silica gel (3 g) and sodium borohydride (0.41 g, 10.8 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred for 2 hours. Distilled water (100 mL) was added to the reaction solution, and then the mixture was subjected to extraction using ethyl acetate (200 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 18 (2.73 g, 87%) as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.48-7.34 (m, 6H), 7.16 (d, J = 8.8 Hz, 1H), 5.35-5.26 (m, 5H), 5.16-5.14 (m, 1H), 4.17-4.15 (m, 1H), 3.73 (s, 3H), 2.04 (s, 9H), 1.73 (t, J = 7.2 Hz, 1H).

[0165] Preparation of compound 19 Compound 18 (2.40 g, 4.17 mmol) was dissolved in ethanol (150 mL), and then Raney nickel (240 mg) was added thereto. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 10 minutes. The reaction solution was filtered through Celite and concentrated to obtain compound 19 (2.10 g) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.06 (s, 1H) 7.61 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.0 Hz 1H), 5.43-5.29 (m, 5H), 4.17 (s, 2H), 4.32 (d, J = 8.4 Hz, 1H) 3.69 (s, 3H), 2.11-2.08 (m, 9H), 1.24 (t, 1H).

[0166] Preparation of compound 20 Compound 19 (7.0 g, 14.5 mmol) and 2-methoxyethylamine (1.38 mL, 1.59 mmol) were dissolved in N,N-dimethylformamide (14 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (6.57 g, 17.3 mmol) and N,N-diisopropylethylamine (5 mL, 28.9 mmol) were added to the mixture under a nitrogen atmosphere at 0°C. The reaction solution was stirred at room temperature for 2 hours, and then saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution. The mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine (200 mL) and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 20 (7.53 g, 96%). 1 H-NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2 Hz, 1H), 7.49 (br s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.42-5.28 (m, 4H), 4.66 (s, 1H), 4.19 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H), 2.05 (s, 9H).

[0167] [Example 6] Preparation of Compound 22

[0168] [ka]

[0169] Compound 19 (1.0 g, 2.06 mmol) and Compound 21 (1.49 g, 2.80 mmol; Compound 21 was prepared by the method described in PCT / US2016 / 063564) were dissolved in N,N-dimethylformamide (10 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (1.56 g, 4.12 mmol) and N,N-diisopropylethylamine (1.07 mL, 6.18 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred at room temperature for 12 hours, and then saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 22 (1.6 g, 80%). 1 H-NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.41 (br s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.93-5.25 (m, 4H), 4.67 (d, J = 5.2 Hz, 2H), 4.20 (d, J = 9.6 Hz, 1H), 4.08 (t, J = 4.8 Hz, 2H), 3.74 (s, 6H), 3.72-3.49 (m, 22H), 2.06 (s, 9H), 1.53 (s, 18H).

[0170] [Example 7] Preparation of Compound 25

[0171] [ka]

[0172] Preparation of compound 23 Compound 9 (2.2 g, 2.34 mmol) was dissolved in toluene (65 mL), and triphosgene (250 mg, 0.84 mmol) and triethylamine (0.44 mL, 3.16 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 20 (1.39 g, 2.58 mmol) was dissolved in dry tetrahydrofuran (65 mL), and triethylamine (0.44 mL, 3.16 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (50 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 23 (2.5 g, 72%). EI-MS m / z : [M+H] + 1504.7, 1 / 2[M+H] + 753.5.

[0173] Preparation of compound 24 Compound 23 (2.0 g, 1.33 mmol) was dissolved in dichloromethane (15 mL), and then pyrrolidine (0.13 mL, 1.59 mmol) and tetrakis(triphenylphosphine)palladium (0) (76 mg, 0.066 mmol) were added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 24 (1.7 g, 90%). EI-MS m / z : [M+H] + 1420.6, 1 / 2[M+H] + 711.2.

[0174] Preparation of compound 25 Compound 24 (1.2 g, 0.84 mmol) was dissolved in toluene (24 mL), triphosgene (90 mg, 0.30 mmol) and pyridine (0.33 mL, 4.22 mmol) were added at -10°C, and the mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 22 (974 mg, 1.01 mmol) was dissolved in dry tetrahydrofuran (24 mL), and N,N-diisopropylethylamine (0.21 mL, 1.26 mmol) was added thereto, and this solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. The obtained solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 25 (800 mg, 40%). EI-MS m / z : [M+H] + 2409.9, 1 / 2[M+Na] + 1214.3.

[0175] [Example 8] Preparation of Compound 28

[0176] [ka]

[0177] Preparation of compound 26 Compound 25 (800 mg, 0.33 mmol) was dissolved in tetrahydrofuran / distilled water (4 mL / 4 mL), acetic acid (8 mL) was added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 26 (660 mg, 90%). EI-MS m / z : [M+H] + 2181.6, 1 / 2[M-Boc+H] + 1041.5.

[0178] Preparation of compound 27 Compound 26 (660 mg, 0.15 mmol) was dissolved in dichloromethane (15 mL), and then dess-martinperiodinane (141 mg, 0.33 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 3.5 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 27 (477 mg, 70%). EI-MS m / z : [M+H] + 2177.6, 1 / 2[M+H] + 1089.5.

[0179] Preparation of compound 28 Compound 27 (150 mg, 0.068 mmol) was dissolved in methanol / tetrahydrofuran (3 mL / 3 mL), and then a solution of lithium hydroxide (26 mg, 0.62 mmol) in distilled water (3 mL) was gradually added thereto at -40°C. The mixture was stirred for 2 hours while gradually raising the reaction temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and vacuum dried. The resulting solid was diluted with dichloromethane (5 mL), then trifluoroacetic acid (1.2 mL) was added thereto at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 28 (20 mg, 16%) as a white solid. EI-MS m / z : [M+H] + 1697.5, 1 / 2[M+H] + 849.3.

[0180] [Example 9] Preparation of Compound 29

[0181] [ka] Compound 29 was prepared from Compound 9 and Compound 12 by the same method as that used for the synthesis of Compound 28. EI-MS m / z: [M+H] + 1596.9, 1 / 2[M+H] + 799.3.

[0182] [Example 10] Preparation of Compound 30

[0183] [ka] Compound 30 was prepared from compounds 9 and 15 by the same method as that used for the synthesis of compound 28. EI-MS m / z: [M+H] + 1655.3, 1 / 2[M+H] + 828.1.

[0184] [Example 11] Preparation of Compound 32

[0185] [ka] Compound 32 was prepared from Compound 19 and Compound 31 (Compound 31 was prepared by the method described in PCT / US2016 / 063564) by the same method as the method for the synthesis of Compound 22. 1 H-NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.41 (bs, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.72 (s, 1H), 5.42-5.27 (m, 4H), 4.66 (d, J = 5.2 Hz, 2H), 4.25 (d, J = 9.6 Hz, 1H), 3.97 (t, J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.74-3.64 (m, 10H), 2.04 (s, 9H), 1.53 (s, 9H). EI-MS m / z: [M+H] + 731.5.

[0186] [Example 12] Preparation of Compound 34

[0187] [ka] Compound 34 was prepared from compound 24 and compound 32 by the same method as the method for synthesizing compound 28. EI-MS m / z : [M+H] + 1565.5, 1 / 2[M+H] + 783.4.

[0188] [Example 13] Preparation of Compound 39

[0189] [ka] Compounds 35 and 36 were prepared by the method described in PCT / US2016 / 063564.

[0190] [ka]

[0191] Preparation of compound 37 Compound 24 (400 mg, 0.28 mmol) was dissolved in toluene (10 mL), and triphosgene (30 mg, 0.10 mmol) and triethylamine (0.053 mL, 0.38 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 35 (177 mg, 0.33 mmol) was dissolved in dry tetrahydrofuran (10 mL), and triethylamine (0.053 mL, 0.38 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 37 (192 mg, 34%). EI-MS m / z : [M+H] + 1971.8, 1 / 2 [M+H] + 986.6.

[0192] Preparation of compound 38 Compound 37 (192 mg, 0.097 mmol) was dissolved in dichloromethane (5 mL), and then pyrrolidine (0.012 mL, 0.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (11.2 mg, 0.096 mmol) were added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 38 (180 mg, 96%). EI-MS m / z : [M+H] + 1932.8, 1 / 2 [M+H] + 966.5

[0193] Preparation of compound 39 Compound 38 (180 mg, 0.093 mmol) and Compound 36 (112 mg, 0.116 mmol) were dissolved in N,N-dimethylformamide (2 mL), and then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU, 46 mg, 0.121 mmol) and N,N-diisopropylethylamine (0.032 mL, 0.186 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred at room temperature for 36 hours, and then distilled water (20 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL) and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 39 (133 mg, 50%). EI-MS m / z : [M+H] + 2876.4, 1 / 2[M+H] + 1438.6.

[0194] [Example 14] Preparation of Compound 42

[0195] [ka]

[0196] Preparation of compound 40 Compound 39 (133 mg, 0.046 mmol) was dissolved in tetrahydrofuran / distilled water (1 mL / 1 mL), acetic acid (2 mL) was added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 40 (67.4 mg, 55%). EI-MS m / z : [M+H] + 2647.4, 1 / 2[M+H] + 1324.5.

[0197] Preparation of compound 41 Compound 40 (67.4 mg, 0.025 mmol) was dissolved in dichloromethane (2 mL), and then dess-martinperiodinane (23.7 mg, 0.056 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 3.5 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 41 (43 mg, 65%). EI-MS m / z : [M+H] + 2643.1, 1 / 2[M+H] + 1322.5.

[0198] Preparation of compound 42 Compound 41 (43 mg, 0.016 mmol) was dissolved in methanol / tetrahydrofuran (0.5 mL / 0.5 mL), and then a solution of lithium hydroxide (6.8 mg, 0.16 mmol) in distilled water (0.5 mL) was gradually added thereto at -40°C. The mixture was stirred for 2 hours while gradually increasing the reaction temperature to -10°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and vacuum dried. The resulting solid was diluted with dichloromethane (1 mL), then trifluoroacetic acid (0.2 mL) was added thereto at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and freeze-dried to obtain compound 42 as a white solid (7.0 mg). EI-MS m / z : [M+H] + 2263.4, 1 / 2[M+H] +1132.3.

[0199] [Example 15] Preparation of Compound 48

[0200] [ka]

[0201] Preparation of compound 44 Compound 43 (37 g, 40.2 mmol; compound 43 was prepared by the method described in J. Med. Chem., 2004, Vol. 47, pp. 1161-1174) was dissolved in dichloromethane (400 mL), and then trichloroisocyanuric acid (14.9 g, 64.3 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy (1.3 g, 8.0 mmol) were added at 0°C, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The reaction solution was diluted by adding dichloromethane (400 mL), washed in the order of saturated sodium bicarbonate aqueous solution (400 mL), sodium thiosulfate (0.2 M, 400 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain compound 44 (35 g, 83%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 7.72 (s, 2H), 6.73 (s, 2H), 4.97 (d, 2H), 4.31 (d, 2H), 4.12 (t, 4H), 3.95-3.96 (m, 6H), 3.71 (d, 2H), 3.64 (d, 2H), 3.45 (d, 2H), 2.82-2.75 (m, 2H), 2.55 (d, 2H), 1.99 (m, 4H), 1.72 (m, 2H), 0.85 (s, 18H), 0.08 (d, 12H).

[0202] Preparation of compound 45 Compound 44 (5 g, 5.45 mmol) was dissolved in dichloromethane (90 mL), and then 2,6-lutidine (5.1 mL, 43.8 mmol) and trifluic anhydride (5.5 mL, 39.0 mmol) were added at -40°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. The reaction solution was diluted by adding dichloromethane (90 mL), washed with saturated sodium bicarbonate aqueous solution (90 mL), distilled water (90 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 45 (4.0 g, 62%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 7.71 (s, 2H), 6.77 (s, 2H), 6.08 (s, 2H), 4.79-4.78 (m, 2H), 4.18-4.09 (m, 6H), 4.02-3.92 (m, 8H), 3.22-3.14 (m, 2H), 3.01-2.97 (m, 2H), 2.02-1.97 (m, 4H), 0.91 (s, 18H), 0.11 (s, 12H).

[0203] Preparation of compound 46 Compound 45 (3.1 g, 2.6 mmol) was dissolved in toluene (45 mL), and then methylboronic acid (1.1 g, 18.2 mmol), silver(I) oxide (4.8 g, 20.9 mmol), potassium phosphate (6.6 g, 31.5 mmol), triphenylarsine (642 mg, 2.1 mmol), and bis(triphenylphosphine)palladium(II) dichloride (184 mg, 0.3 mmol) were added under an argon atmosphere. The mixture was heated and stirred at 80°C for 3 hours. The reaction solution was filtered through Celite, then concentrated and purified by column chromatography to obtain compound 46 (955 mg, 40%). 1H-NMR (400 MHz, CDCl3) (rotamer) δ 7.68 (s, 2H), 6.77 (s, 2H), 5.52 (s, 2H), 4.66-4.64 (m, 2H), 4.14-4.07 (m, 6H), 3.94-3.92 (m, 8H), 2.75-2.73 (m, 2H), 2.55-2.51 (m, 2H), 1.99-1.93 (m, 4H), 1.72-1.68 (m, 2H), 1.60 (s, 6H), 0.88 (s, 18H), 0.09 (s, 12H).

[0204] Preparation of compound 47 Compound 46 (2.9 g, 3.17 mmol) was dissolved in ethanol (44 mL), and then zinc powder (12.9 g, 197 mmol) and formic acid (5% ethanol solution, 128 mL) were added thereto. The reaction solution was stirred at room temperature for 15 minutes, then filtered through Celite, and ethyl acetate (500 mL) was added thereto. The organic layer was washed in the order of distilled water (200 mL), saturated sodium bicarbonate aqueous solution (200 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated, and purified by column chromatography to obtain compound 47 (3.0 g, 82%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 6.74 (s, 2H), 6.23 (s, 2H), 6.18 (bs, 2H), 4.64 (bs, 2H), 4.34 (s, 3H), 4.07-3.93 (m, 6H), 3.80-3.76 (m, 7H), 2.74-2.68 (m, 2H), 2.53 (d, 2H), 1.91 (m, 4H), 1.67-1.62 (m, 8H), 0.88 (s, 18H), 0.05 (d, 12H).

[0205] Preparation of compound 48 Compound 47 (3.0 g, 3.51 mmol) was dissolved in dichloromethane (175 mL), and then pyridine (0.57 mL, 7.03 mmol) and allyl chloroformate (0.34 mL, 3.16 mmol) were added under a nitrogen atmosphere at -78°C. The reaction solution was stirred for 1 hour, then the reaction temperature was raised to room temperature, the reaction solution was concentrated, and then purified by column chromatography to obtain compound 48 (1.33 g, 44%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 8.80 (br s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.23 (s, 1H), 6.19 (br s, 2H), 5.99-5.90 (m, 1H), 5.34 (d, 1H), 5.23 (d, 1H), 4.63 (m, 4H), 4.35 (br s, 2H), 4.10 (t, 2H), 3.99 (t, 3H), 3.99 (m, 2H), 3.80 (s, 5H), 3.76 (s, 4H), 2.73 (m, 2H), 2.55 (m, 2H), 1.95-1.90 (m, 4H), 1.68-1.63 (m, 8H), 0.88 (s, 18H), 0.05 (d, 12H).

[0206] [Example 16] Preparation of Compound 49

[0207] [ka] Compound 19 (3.7 g, 7.56 mmol) and propargylamine (0.43 mL, 7.07 mmol) were dissolved in N,N-dimethylformamide (50 mL), and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.32 g, 12.1 mmol) and 1-hydroxybenzotriazole (2.04 g, 15.1 mmol) were added thereto. The reaction solution was stirred at room temperature for 12 hours, and then distilled water (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine (200 mL) and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated, and purified by column chromatography to obtain compound 49 (3.4 g, 86%). 1 H-NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.57 (t, 1H), 7.49 (dd, 1H), 7.02 (d, 1H), 5.42-5.38 (m, 1H), 5.36-5.28 (m, 2H), 4.67 (d, 2H), 4.31-4.13 (m, 3H), 2.23 (t, 1H), 2.07-2.06 (m, 9H), 1.88 (t, 1H).

[0208] [Example 17] Preparation of Compound 53

[0209] [ka]

[0210] Preparation of compound 51 Compound 50 (4.5 g, 25.68 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (1.23 g, 30.82 mmol) was added thereto under a nitrogen atmosphere at 0°C. The mixture was stirred for 30 minutes, and then propargyl bromide (up to 80% toluene solution, 4.96 mL, 33.4 mmol) was added thereto. The mixture was then stirred at room temperature for 3 hours. Distilled water (40 mL) was added to the reaction solution, and the mixture was then subjected to extraction using ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (100 mL) and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 51 (4.35 g, 79%). 1 H-NMR (400 MHz, CDCl3) δ 4.21 (d, J = 2.4 Hz, 2H), 3.70-3.38 (m, 10 H), 3.39 (t, J = 5.2 Hz, 2H), 2.43 (t, J = 2.4 Hz, 1H).

[0211] Preparation of compound 52 Compound 51 (1.55 g, 7.03 mmol) was dissolved in dry tetrahydrofuran (30 mL) / distilled water (2.53 mL), and then triphenylphosphine (2.21 g, 8.44 mmol) was added thereto. The mixture was stirred at room temperature for 24 hours. The resulting mixture was concentrated and purified by column chromatography to obtain compound 52 (1.3 g, 99%). 1 EI-MS m / z : [M+H] + 188.2.

[0212] Preparation of compound 53 Compound 52 (2.0 g, 10.68 mmol) and Compound 19 (4.7 g, 9.71 mmol) were dissolved in N,N-dimethylformamide (50 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (3.71 g, 11.6 mmol) and N,N-diisopropylethylamine (3.38 mL, 19.4 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred at room temperature for 24 hours, and then distilled water (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine (200 mL) and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain Compound 53 (4.78 g, 75%). 1 H-NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41-7.37 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.41-5.25 (m, 4H), 4.65 (d, J = 4.4 Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 4.17 (s, 2H), 3.74 (s, 3H), 3.68 (s, 11H), 3.56-3.50 (m, 1H), 2.05 (s, 9H).

[0213] [Example 18] Preparation of Compound 55

[0214] [ka]

[0215] Preparation of compound 55 Compound 19 (3.68 g, 7.60 mmol) and Compound 54 (1.46 g, 8.40 mmol; Compound 54 was prepared by the method described in PCT / US2016 / 063564) were dissolved in N,N-dimethylformamide (10 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (4.53 g, 11.40 mmol) and N,N-diisopropylethylamine (3.97 mL, 22.80 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of ammonium chloride (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The extract was then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 55 (3.31 g, 68%). 1 H-NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 5.42-5.25 (m, 4H), 4.68 (d, J = 5.6 Hz, 2H), 4.20 (d, J = 9.2 Hz, 1H), 3.78-3.68 (m, 11H), 3.58-3.52 (m, 1H), 3.39-3.36 (m, 2H), 2.06 (s, 9H), 1.89-1.86 (m, 1H).

[0216] [Example 19] Preparation of Compound 58

[0217] [ka]

[0218] Preparation of compound 56 Compound 48 (1.33 g, 1.41 mmol) was dissolved in toluene (40 mL), and triphosgene (151 mg, 0.51 mmol) and triethylamine (0.26 mL, 1.91 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 20 (845 mg, 1.56 mmol) was dissolved in dry tetrahydrofuran (40 mL), and triethylamine (0.26 mL, 1.91 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 56 (1.15 mg, 54%). EI-MS m / z : [M+H] + 1504.7, 1 / 2[M+H] + 753.5.

[0219] Preparation of Compound 57 Compound 56 (1.15 g, 0.79 mmol) was dissolved in dichloromethane (10 mL), and then pyrrolidine (0.08 mL, 1.35 mmol) and tetrakis(triphenylphosphine)palladium (0) (45 mg, 0.057 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 57 (820 mg, 72%). EI-MS m / z : [M+H] + 1420.6, 1 / 2[M+H] + 711.2.

[0220] Preparation of compound 58 Compound 57 (730 mg, 0.51 mmol) was dissolved in toluene (20 mL), and triphosgene (54 mg, 0.36 mmol) and pyridine (0.2 mL, 2.56 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 49 (321 mg, 0.61 mmol) was dissolved in dry tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (0.14 mL, 0.77 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 58 (650 mg, 64%). EI-MS m / z : [M+H] + 1969.2, 1 / 2 [M+H] + 985.2.

[0221] [Example 20] Preparation of Compound 61

[0222] [ka]

[0223] Preparation of compound 59 Compound 58 (650 mg, 0.33 mmol) was dissolved in tetrahydrofuran / distilled water (3.5 mL / 3.5 mL), acetic acid (7 mL) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 59 (440 mg, 78%). EI-MS m / z : [M+H] + 1740.0, [M+Na] + 1762.0, 1 / 2[M+H] + 871.0.

[0224] Preparation of compound 60 Compound 59 (440 mg, 0.25 mmol) was dissolved in dichloromethane (25 mL), and then dess-martinperiodinane (236 mg, 0.55 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 60 (365 mg, 84%). EI-MS m / z : [M+H] + 1736.0, 1 / 2[M+H] + 869.5.

[0225] Preparation of compound 61 Compound 60 (365 mg, 0.21 mmol) was dissolved in methanol / tetrahydrofuran (9 mL / 2 mL), and then a solution of lithium hydroxide (58 mg, 1.4 mmol) in distilled water (9 mL) was gradually added thereto at -40°C. The mixture was stirred for 2 hours while gradually raising the reaction temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 61 (100 mg, 32%) as a white solid. EI-MS m / z : [M+H] + 1456.8, 1 / 2[M+H] + 729.5.

[0226] [Example 21] Preparation of Compound 62

[0227] [ka] Compound 62 was prepared from compounds 53 and 57 by the same method as that used for the synthesis of compound 61. EI-MS m / z : [M+H] + 1588.7, 1 / 2[M+H] + 795.3.

[0228] [Example 22] Preparation of Compound 63

[0229] [ka] Compound 63 was prepared from compounds 55 and 57 by the same method as that used for the synthesis of compound 61. EI-MS m / z : [M+H] + 1575.8, 1 / 2[M+H] + 788.7.

[0230] [Example 23] Preparation of Compound 65

[0231] [ka]

[0232] Preparation of compound 65 Compound 61 (100 mg, 0.068 mmol) was dissolved in dimethyl sulfoxide (1.6 mL), and then compound 64 (136 mg, 0.302 mmol; compound 64 was prepared by the method described in PCT / US2016 / 063564) was added under a nitrogen atmosphere. Then, a solution of copper(II) sulfate pentahydrate (7.4 mg, 0.03 mmol) and sodium ascorbate (28 mg, 0.15 mmol) in distilled water (0.4 mL) was added to the reaction solution. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 65 (15.2 mg, 13%) as a white solid. EI-MS m / z : [M+H] + 1645.8, 1 / 2[M+H] + 823.9.

[0233] [Example 24] Preparation of Compound 70

[0234] [ka]

[0235] Preparation of compound 66 3-amino-1-propanol (3.0 g, 66.57 mmol) was dissolved in dichloromethane (150 mL), and then di-t-butyl dicarbonate (16 g, 73.2 mmol) was added under a nitrogen atmosphere at 0°C. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 66 (6.4 g, 92%). 1 H-NMR (400 MHz, CDCl3) δ 4.78 (s, 1H), 3.65 (m, 2H), 3.30 (m, 2H), 2.90 (s, 1H), 1.68 (m, 2H), 1.48 (s, 9H).

[0236] Preparation of compound 67 Compound 66 (6.04 g, 34.47 mmol) and triethylamine (14.4 mL, 103.4 mmol) were dissolved in tetrahydrofuran (100 mL), and then methanesulfonic anhydride (7.21 g, 41.36 mmol) was gradually added thereto under a nitrogen atmosphere at 0°C. The temperature was gradually increased to room temperature, and then the mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 67 (9.01 g, 98%). 1 H-NMR (400 MHz, CDCl3) δ 4.73 (s, 1H), 4.30 (t, J = 5.9 Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J = 6.1 Hz, 2H), 1.44 (s, 9H).

[0237] Preparation of compound 68 Compound 67 (3.0 g, 11.84 mol) was dissolved in N,N-dimethylformamide (40 mL), and sodium azide (924 mg, 14.21 mmol) was added thereto under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 60 °C for 12 hours. Distilled water (50 mL) and 1 N aqueous hydrochloric acid solution (5 mL) were added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (100 mL). The extract was then dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 68 (2.3 g, 99%). 1 H-NMR (600 MHz, CDCl3) δ 4.63 (s, 1H), 3.36 (t ,J = 6.6 Hz, 2H), 3.24-3.18 (m, 2H), 1.80-1.75 (m, 2H), 1.45 (s, 9H).

[0238] Preparation of compound 69 Compound 68 (3.8 g, 18.98 mmol) was dissolved in dichloromethane (10 mL), and hydrochloric acid (10 mL of 4 M 1,4-dioxane solution) was gradually added under a nitrogen atmosphere at 0°C. The reaction mixture was stirred for 12 hours and then concentrated under reduced pressure to obtain compound 69 (2.5 g, 99%). 1 H-NMR (600 MHz, DMSO-d6) δ 8.06 (s, 3H), 3.47 (t, J = 6.6 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 1.84-1.79 (m, 2H).

[0239] Preparation of compound 70 Compound 19 (4.1 g, 8.46 mmol) and Compound 69 (1.1 g, 11.0 mmol) were dissolved in N,N-dimethylformamide (20 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (4.39 g, 11.0 mmol) and N,N-diisopropylethylamine (2.96 mL, 16.92 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of ammonium chloride (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The extract was then dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain Compound 70 (5.48 g, 88%). 1 H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.50-7.46 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.45-5.30 (m, 4H), 4.69 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.67-3.60 (m, 1H), 3.47-3.41 (m, 3H), 2.80 (s, 2H), 2.07-2.05 (m, 9H), 1.98-1.91 (m, 2H), 1.80-1.77 (m, 1H).

[0240] [Example 25] Preparation of Compound 72

[0241] [ka]

[0242] Preparation of compound 72 Compound 19 (3.6 g, 7.42 mmol) and Compound 71 (1.0 g, 8.16 mmol; Compound 71 was prepared by the same method as for the synthesis of Compound 69) were dissolved in N,N-dimethylformamide (15 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (4.2 g, 11.2 mmol) and N,N-diisopropylethylamine (3.2 mL, 18.6 mmol) were added to the mixture under a nitrogen atmosphere at 0°C. The reaction solution was stirred at room temperature for 14 hours, and then saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution. The mixture was subjected to extraction using ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain compound 72 (3.9 g, 95%). EI-MS m / z : [M+H] + 553.3, [M+Na] + 575.4.

[0243] [Example 26] Preparation of Compound 73

[0244] [ka] Compound 73 was prepared from compounds 24 and 55 by the same method as that used for the synthesis of compound 63. EI-MS m / z : [M+H] + 1575.7, 1 / 2[M+H] + 788.8.

[0245] [Example 27] Preparation of Compound 74

[0246] [ka] Compound 74 was prepared from compound 24 and compound 70 by the same method as that used for the synthesis of compound 63. EI-MS m / z : [M+H] + 1500.9, 1 / 2[M+H] + 751.2.

[0247] [Example 28] Preparation of Compound 75

[0248] [ka] Compound 75 was prepared from Compound 24 and Compound 72 by the same method as the method used for the synthesis of Compound 63. EI-MS m / z : [M+H] + 1486.42, [M+Na] + 1509.31.

[0249] [Example 29] Preparation of Compound 80

[0250] [ka]

[0251] Preparation of Compound 77 Compound 76 (7.30 g, 28.5 mmol; compound 76 was prepared by the method described in Angew. Chem. Int. Ed., 2016, Vol. 55, pp. 12338-12342) and compound 16 (14.0 g, 29.4 mmol) were dissolved in acetonitrile (145 mL). Then, a 4 Å molecular sieve (14.6 g) and silver(I) oxide (27.0 g, 116.4 mmol) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction solution was filtered through Celite, concentrated, and then purified by column chromatography to obtain compound 77 (15.3 g, 92%). 1H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.27 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.46-7.29 (m, 6H), 5.64-5.59 (m, 1H), 5.49-5.48 (m, 1H), 5.36 (s, 2H), 5.18 (d, J = 8.0 Hz, 1H), 5.19-5.11 (m, 1H), 4.27-4.10 (m, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H).

[0252] Preparation of compound 78 Compound 77 (15.30 g, 26.10 mmol) was dissolved in chloroform / isopropanol (200 mL / 40 mL), and then silica gel (16 g) and sodium borohydride (1.53 g, 40.50 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred for 30 minutes. Distilled water (200 mL) was added to the reaction solution, and then the mixture was subjected to extraction using ethyl acetate (400 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 78 (14.0 g, 91%). 1 H-NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.47-7.31 (m, 6H), 7.19 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 9.2 Hz, 1H), 5.46 (d, J = 3.2 Hz, 1H), 5.36-5.28 (m, 2H), 5.12-5.04 (m, 2H), 4.66 (d, J = 6.0 Hz, 2H), 4.26-4.04 (m, 3H), 2.18 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.67 (t, J = 5.6 Hz, 1H).

[0253] Preparation of compound 79 Compound 78 (14.0 g, 23.8 mmol) was dissolved in ethanol (550 mL), and then Raney nickel (14.0 g) was added thereto. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through Celite and concentrated to obtain compound 79 (11.4 g, 96%). 1 H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H) 7.58 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz 1H), 5.57 (t, J = 9.2 Hz, 1H), 5.49 (d, J = 3.2 Hz, 1H), 5.22 (d, J = 8.0 Hz, 1H), 5.17-5.14 (m, 1H), 4.71 (s, 2H), 4.25-4.10 (m, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H).

[0254] Preparation of compound 80 Compound 79 (3.00 g, 6.00 mmol) and 2-methoxyethylamine (0.57 mL, 6.6 mmol) were dissolved in N,N-dimethylformamide (15 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (2.86 g, 7.20 mmol) and N,N-diisopropylethylamine (2.10 mL, 12.0 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of ammonium chloride (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The extract was then dried over anhydrous magnesium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 80 (2.3 g, 68%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.48-7.44 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 5.55 (t, J = 9.2 Hz, 1H), 5.49 (d, J = 2.8 Hz, 1H), 5.20-5.14 (m, 2H), 4.69 (d, J = 5.2 Hz, 2H), 4.25-4.09 (m, 3H), 3.78-3.74 (m, 1H), 3.62-3.51 (m, 3H), 3.40 (s, 3H), 2.21 (s, 3H), 2.07 (m, 6H), 2.02 (s, 3H), 1.71 (t, J = 6.0 Hz, 1H).

[0255] [Example 30] Preparation of Compound 81

[0256] [ka]

[0257] Preparation of compound 81 Compound 79 (2.19 g, 4.38 mmol) and Compound 31 (1.50 g, 5.70 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (2.26 g, 5.7 mmol) and N,N-diisopropylethylamine (1.53 mL, 8.76 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of ammonium chloride (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The extract was then dried over anhydrous magnesium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain Compound 81 (2.73 g, 84%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.68 (s, 1H), 7.46-7.44 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 5.56-5.49 (m, 2H), 5.18-5.14 (m, 2H), 4.68 (d, J = 4.8 Hz, 2H), 4.27-4.10 (m, 3H), 3.97-3.95 (m, 2H), 3.83-3.78 (m, 1H), 3.71-3.67 (m, 7H), 3.57-3.52 (m, 1H), 2.22 (s, 3H), 2.07 (m, 6H), 2.03 (s, 3H), 1.47 (s, 9H).

[0258] [Example 31] Preparation of Compound 82

[0259] [ka] Compound 82 was prepared from Compound 9, Compound 80, and Compound 81 by the same method as the method for synthesizing Compound 28. EI-MS m / z : [M+H] + 1537.7, 1 / 2[M+H] + 769.7.

[0260] [Example 32] Preparation of Compound 83

[0261] [ka] Compound 83 was prepared from Compound 9, Compound 80, and Compound 32 by the same method as the method for synthesizing Compound 28. EI-MS m / z : [M+H] + 1551.6, 1 / 2[M+H] + 776.7.

[0262] [Example 33] Preparation of Compound 85

[0263] [ka] Compound 85 was prepared from Compound 9, Compound 84 (Compound 84 was prepared by the method described in WO2011 / 130598A1), and Compound 32 by the same method as the method for the synthesis of Compound 28. EI-MS m / z : [M+H] + 1587.8, 1 / 2[M+H] + 794.7.

[0264] [Comparative Example 1] Preparation of Compound 86, Compound 87, and Compound 88

[0265] [ka] Compounds 86, 87, and 88 were prepared by the method described in PCT / US2016 / 063564.

[0266] [Example 34] Preparation of Compound 94

[0267] [ka]

[0268] Preparation of compound 90 Compound 89 (4.5 g, 4.88 mmol; compound 89 was prepared by the method described in J. Med. Chem., 2004, Vol. 47, pp. 1161-1174) was dissolved in dichloromethane (100 mL), and then 2,2,6,6-tetramethyl-1-piperidinyloxy (153 mg, 0.98 mmol) and (diacetoxyiodo)benzene (7.0 g, 21.7 mmol) were added thereto under a nitrogen atmosphere at room temperature. The reaction solution was stirred for 24 hours, and then distilled water (200 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (2 × 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 90 (4.25 g, 95%). 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 6.73 (s, 2H), 4.97 (d, J = 8.8 Hz, 1H), 4.39-4.27 (m, 8H), 3.96 (s, 6H), 3.80-3.70 (m, 2H), 3.58-3.52 (m, 2H), 3.42-2.79 (m, 2H), 2.74-2.56 (m, 2H), 2.52-2.44 (m, 2H), 2.08 (s, 2H), 0.85 (s, 18H), 0.97 (s, 12H).

[0269] Preparation of compound 91 Compound 90 (10.0 g, 10.9 mmol) was dissolved in dichloromethane (450 mL), and then 2,6-lutidine (10.0 mL, 87.2 mmol) and trifluic anhydride (11.0 mL, 65.4 mmol) were added thereto under a nitrogen atmosphere at -40°C. The reaction solution was stirred for 2 hours, and then saturated sodium bicarbonate aqueous solution (500 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (2 × 500 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 91 (10.6 g, 47%).

[0270] Preparation of compound 92 Compound 91 (1.7 g, 1.44 mmol) was dissolved in ethanol / toluene / distilled water (12 mL / 24 mL / 12 mL), and then 4-methylphenylboronic acid (568 mg, 3.74 mmol), sodium carbonate (793 mg, 7.48 mmol), and tetrakis(triphenylphosphine)palladium (0) (133 mg, 0.115 mmol) were added thereto under a nitrogen atmosphere at room temperature. The reaction solution was stirred for 2 hours, then diluted with ethyl acetate (100 mL), and the organic layer was washed with brine (100 mL) and distilled water (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 92 (1.25 g, 79%). 1 H-NMR (400 MHz, CDCl3) δ 7.80 (s, 2H), 7.13 (d, J = 8.8 Hz, 4H), 6.90 (s, 2H), 6.79 (d, J = 8.0 Hz, 4H), 6.14 (s, 2H), 4.80-4.50 (m, 2H), 4.39-4.36 (m, 4H), 3.98 (s, 6H), 3.79 (s, 6H), 3.17 (bs, 2H), 3.02-2.98 (m, 2H), 2.50-2.47 (m, 2H), 0.88 (s, 18H), 0.11 (s, 12 H). EI-MS m / z : [M+H] + 1069.8, 1 / 2[M+H] + 535.6.

[0271] Preparation of compound 93 Compound 92 (8.0 g, 7.48 mmol) was dissolved in ethanol (300 mL), and then zinc powder (29 g, 28.1 mmol) and formic acid (5% in EtOH, 320 mL) were added thereto. The reaction solution was stirred at room temperature for 20 minutes, then filtered through Celite, and ethyl acetate (1 L) was added thereto. The organic layer was washed in the order of distilled water (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), and brine (500 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated, and purified by column chromatography to obtain compound 93 (4.85 g, 64%). 1H-NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 4H), 6.78 (d, J = 6.4 Hz, 8H), 6.30 (s, 2H), 4.71-4.41 (m, 2H), 4.25 (br s, 4H), 4.19-4.17 (m, 4H), 4.10-4.05 (m, 2H), 3.95-3.81 (m, 2H), 3.73 (s, 6H), 3.72 (s, 6H), 3.64-3.10 (m, 2H), 3.03-2.93 (m, 2H), 2.36-2.34 (m, 2H), 0.81 (s, 18H), 0.11 (s, 12 H). EI-MS m / z : [M+H] + 1010.4, 1 / 2[M+H] + 505.7.

[0272] Preparation of compound 94 Compound 93 (4.6 g, 4.56 mmol) was dissolved in dichloromethane (300 mL), and then pyridine (0.74 mL, 9.11 mmol) and allyl chloroformate (0.48 mL, 4.56 mmol) were added under a nitrogen atmosphere at -78°C. The reaction solution was stirred for 1 hour, then the reaction temperature was raised to room temperature, the reaction solution was concentrated, and then purified by column chromatography to obtain compound 94 (1.46 g, 29%). EI-MS m / z : [M+H] + 1093.6.

[0273] [Example 35] Preparation of Compound 97

[0274] [ka]

[0275] Preparation of compound 95 Compound 94 (200 mg, 0.18 mmol) was dissolved in toluene (7.5 mL), and triphosgene (19 mg, 0.067 mmol) and triethylamine (0.035 mL, 0.25 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 20 was dissolved in dry tetrahydrofuran (7.5 mL), and triethylamine (0.035 mL, 0.25 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 95 (130 mg, 43%). EI-MS m / z : [M+H] + 1661.6, 1 / 2[M+H] + 831.4.

[0276] Preparation of compound 96 Compound 95 (380 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), and then pyrrolidine (0.023 mL, 0.27 mmol), tetrakis(triphenylphosphine)palladium (0) (13 mg, 0.011 mmol), and triphenylphosphine (15 mg, 0.057 mmol) were added in that order. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 96 (260 mg, 72%). EI-MS m / z : [M+H] + 1577.6, 1 / 2[M+H] + 789.4.

[0277] Preparation of compound 97 Compound 96 (260 mg, 0.16 mmol) was dissolved in toluene (5 mL), and triphosgene (17.6 mg, 0.06 mmol) and diisopropylethylamine (0.053 mL, 0.30 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 22 was dissolved in dry tetrahydrofuran (5 mL), and pyridine (0.066 mL, 0.80 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 97 (168 mg, 41%). EI-MS m / z : [M+H] + 2567.1, 1 / 2[M+H] + 1283.8.

[0278] [Example 36] Preparation of Compound 100

[0279] [ka]

[0280] Preparation of compound 98 Compound 97 (168 mg, 0.065 mmol) was dissolved in tetrahydrofuran / distilled water (1 mL / 1 mL), acetic acid (2 mL) was added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 98 (130 mg, 85%). EI-MS m / z : [M+H] + 2337.8, 1 / 2[M+H] + 1169.5.

[0281] Preparation of compound 99 Compound 98 (130 mg, 0.055 mmol) was dissolved in dichloromethane (5 mL), and then dess-martinperiodinane (57 mg, 0.13 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 3.5 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 99 (96 mg, 82%). EI-MS m / z : [M+H] + 2333.7, 1 / 2[M+H] + 1167.5.

[0282] Preparation of compound 100 Compound 99 (96 mg, 0.041 mmol) was dissolved in methanol / tetrahydrofuran (1 mL / 1 mL), and then a solution of lithium hydroxide (16 mg, 0.41 mmol) in distilled water (1 mL) was gradually added thereto at -40°C. The mixture was stirred for 2 hours while gradually raising the reaction temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and vacuum dried. The resulting solid was diluted with dichloromethane (2 mL), then trifluoroacetic acid (0.5 mL) was added thereto at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and freeze-dried to obtain compound 100 (2.4 mg) as a pale yellow solid. EI-MS m / z : [M+H] + 1853.8, 1 / 2[M+H] + 927.4.

[0283] [Example 37] Preparation of Compound 102

[0284] [ka]

[0285] Preparation of compound 101 1,3-diaminopropane (0.93 mL, 11.1 mmol) was dissolved in dichloromethane (30 mL), and di-t-butyl dicarbonate (0.84 mL, 3.7 mmol) was added thereto under a nitrogen atmosphere at 0°C. After stirring the reaction solution at room temperature for 3 hours, brine (50 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL), and the extract was then dried over anhydrous sodium sulfate. After filtration, the reaction solution was filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain compound 101 (658 mg, 100% based on Boc2O). 1 H-NMR (400 MHz, CDCl3) δ 4.88 (br s, 1H), 3.26-3.14 (m, 2H), 2.77 (t, J = 6.8 Hz, 2H), 1.66-1.57 (m, 2H), 1.44 (s, 9H), 1.32 (br, 2H).

[0286] Preparation of compound 102 Compound 19 (1.50 g, 3.10 mmol) and Compound 101 (0.65 g, 3.73 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (1.60 g, 4.03 mmol) and N,N-diisopropylethylamine (1.08 mL, 6.20 mmol) were added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of ammonium chloride (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 100 mL). The extract was then dried over anhydrous magnesium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain Compound 102 (1.67 g, 84%). 1H-NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.49-7.47 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 5.42-5.30 (m, 4H), 4.69 (d, J = 6.0 Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 3.74 (s, 3H), 3.63-3.58 (m, 1H), 3.44-3.39 (m, 1H), 322-3.13 (m, 2H), 2.06-2.05 (m, 9H), 1.79-1.74 (m, 2H), 1.45 (s, 9H).

[0287] [Example 38] Preparation of Compound 103

[0288] [ka] Compound 103 was prepared from compound 24 and compound 102 by the same method as the method for synthesizing compound 28. EI-MS m / z : [M+H] + 1475.8, 1 / 2[M+H] + 738.3.

[0289] [Example 39] Preparation of Compound 104

[0290] [ka] Compound 103 (35 mg, 0.024 mmol) and maleimide acetate N-hydroxysuccinimide (9 mg, 0.035 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and then N,N-diisopropylethylamine (0.021 mL, 0.23 mmol) was added thereto under a nitrogen atmosphere at 0°C. The reaction temperature was gradually increased to room temperature, and then the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 104 (15.1 mg, 37%) as a white solid. EI-MS m / z : [M+H] +1612.6, 1 / 2[M+H] + 807.2.

[0291] [Example 40] Preparation of Compound 110

[0292] [ka]

[0293] Preparation of compound 105 L-asparagine (3.0 g, 22.7 mmol) was dissolved in 30 mL of 1 N aqueous sodium carbonate solution, and then benzyl chloroformate (6.3 mL, 45.4 mmol) was added at 0°C. The mixture was stirred under a nitrogen atmosphere for 12 hours. Distilled water (50 mL) was added to the reaction solution, and then the reaction solution was acidified with 1 N aqueous hydrochloric acid solution (pH 2). This mixture was subjected to extraction using ethyl acetate (3 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The resulting mixture was filtered and then concentrated under reduced pressure to obtain compound 105 (3.5 g, 58%). 1 H-NMR (400 MHz, DMSO-d6) δ 7.51-7.40 (d, J = 8.0 Hz, 1H), 7.35 (s, 6H), 6.92 (s, 1H), 5.02 (s, 2 H), 2.61-2.35 (m, 2H).

[0294] Preparation of compound 106 Compound 105 (3.5 g, 13.1 mmol) was dissolved in ethyl acetate / acetonitrile / distilled water (30 mL / 30 mL / 15 mL), and then (diacetoxyiodo)benzene (5.1 g, 15.7 mmol) was added thereto. The mixture was stirred under a nitrogen atmosphere for 10 hours. The resulting solid was filtered and concentrated under reduced pressure to obtain compound 106 (2.8 g, 89%). 1H-NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.96 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.37 (s, 5H), 5.07 (s, 2H), 4.29 (s, 1H), 3.23 (br, 1H), 3.02 (br, 1H).

[0295] Preparation of compound 107 Compound 106 (2.8 g, 11.7 mmol) was dissolved in 1,4-dioxane / distilled water (25 mL - 46 mL), and then sodium hydroxide (0.5 g, 11.7 mmol) and di-t-butyl dicarbonate (3.0 mL, 12.9 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 8 hours. Distilled water (50 mL) was added to the reaction solution, and then the mixture was washed with ethyl acetate (2 × 50 mL). The aqueous layer was acidified by the addition of citric acid and subjected to extraction using ethyl acetate (3 × 50 mL), and then the extract was dried over anhydrous sodium sulfate. The obtained product was filtered and concentrated under reduced pressure to obtain compound 107 (2.7 g, 68%). 1 H-NMR (400 MHz, CDCl3) δ 7.31 (s, 5H), 5.15-5.01 (m, 2H), 4.82-4.02 (m, 1H), 3.68-3.43 (m, 2H), 1.39 (s, 9H).

[0296] Preparation of compound 108 Compound 107 (2.7 g, 7.9 mmol) was dissolved in methanol (40 mL), and then palladium / carbon (10%) (Pd / C, 0.5 g) was added thereto. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through Celite and concentrated to obtain compound 108 (1.2 g, 75%). 1 H-NMR (400 MHz, D2O) δ 3.70-3.65 (m, 1H), 3.55-3.25 (m, 2H), 1.28 (s, 9H).

[0297] Preparation of compound 109 Compound 108 (0.40 g, 1.96 mmol) and maleic anhydride (192 mg, 1.96 mmol) were dissolved in acetic acid (1.6 mL), and the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (10 mL) was added thereto, and the resulting solid was filtered and then vacuum-dried. This dried solid was diluted with toluene (15 mL), and then triethylamine (1.2 mL, 8.6 mmol) and N,N-dimethylacetamide (0.75 mL) were added thereto, and the mixture was heated under reflux. After 16 hours of reaction, the reaction solution was concentrated under reduced pressure, purified by HPLC, and then freeze-dried to obtain compound 109 (287 mg, 52%). 1 H-NMR (400 MHz, CDCl3) δ 6.66 (s, 2H), 5.17 (br, 1H), 4.61 (br, 1H), 3.68 (br, 1H),1.35 (s, 9H).

[0298] Preparation of compound 110 Compound 109 (0.15 g, 0.52 mmol) was dissolved in N,N-diisopropylethylamine (3 mL), and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.15 g, 0.79 mmol) and N-hydroxysuccinimide (0.09 g, 0.79 mmol) were added thereto. The reaction solution was stirred at room temperature for 12 hours. Distilled water (30 mL) was added to the reaction solution, and then the mixture was subjected to extraction using ethyl acetate (30 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 110 (0.08 g, 40%). EI-MS m / z : [M+Na] + 404.3.

[0299] [Example 41] Preparation of Compound 112

[0300] [ka]

[0301] Preparation of compound 111 Compound 103 (57 mg, 0.04 mmol) and Compound 110 (0.016 g, 0.04 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then N,N-diisopropylethylamine (0.02 mL, 0.12 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain Compound 111 (37 mg, 58%). EI-MS m / z : [M+H] + 1741.7, 1 / 2[M+H] + 871.7.

[0302] Preparation of compound 112 Compound 111 (0.035 g, 0.02 mmol) was diluted with dichloromethane (3 mL), and then trifluoroacetic acid (0.3 mL) was added at 0°C. The mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 112 (6.5 mg, 20%) as a white solid. EI-MS m / z : [M+H] + 1641.9, 1 / 2[M+H] + 821.8.

[0303] [Example 42] Preparation of Compound 115

[0304] [ka]

[0305] Preparation of compound 114 10 mL of dichloromethane was dissolved in 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]acetic acid (1.1 g, 4.71 mmol). Then, 0.75 g of 1-hydroxybenzotriazole (5.60 mmol) and 1.15 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6.03 mmol) were added in that order under a nitrogen atmosphere at 0°C, and the mixture was stirred for 30 minutes. A solution of compound 113 (1.5 g, 4.31 mmol, compound 113 was prepared by the method described in WO2017 / 160569A1) and triethylamine (1.08 mL, 7.76 mmol) in dichloromethane (10 mL) was added to the mixture under a nitrogen atmosphere. The reaction temperature was raised to room temperature, the mixture was stirred for 12 hours, then diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 114 (2.1 g, 87%). 1 H-NMR (400 MHz, CDCl3) δ 6.83 (d, 1H), 4.15-4.11 (m, 1H), 3.96 (s, 2H), 3.72-3.62 (m, 14H), 3.39-3.37 (m, 2H) 1.81-1.60 (m, 4H), 0.88 (s, 18H) 0.42 (s, 12H).

[0306] Preparation of compound 115 Compound 114 (2.1 g, 3.73 mmol) was dissolved in methanol (30 mL), and concentrated hydrochloric acid (0.5 mL) was then added under a nitrogen atmosphere at 0°C. The mixture was then stirred at room temperature for 2 hours. The reaction solution was neutralized with triethylamine, then concentrated, and purified by column chromatography to obtain compound 115 (1.2 mg, 98%). 1H-NMR (400 MHz, CDCl3) δ7.54 (br s,1H), 4.31-4.28 (m, 1H), 4.02 (s, 2H), 3.68-3.65 (m, 14H), 3.43-3.40 (m, 2H), 3.21 (br s, 2H), 1.93-1.85 (m, 2H), 1.64-1.57 (m, 2H).

[0307] [Example 43] Preparation of Compound 118

[0308] [ka]

[0309] Preparation of compound 117 Compound 116 (1.32 g, 4.73 mmol; compound 116 was prepared by the method described in PCT / US2016 / 063564) was dissolved in dichloromethane (20 mL), and then 1-hydroxybenzotriazole (0.86 g, 5.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added thereto under a nitrogen atmosphere at 0°C. A solution of compound 113 (1.5 g, 4.31 mmol) and triethylamine (1.08 mL, 7.74 mmol) in dichloromethane (5 mL) was added to the mixture under a nitrogen atmosphere at 0°C. The reaction temperature was raised to room temperature, and the mixture was stirred for 12 hours, then diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 117 (2.05 g, 79%). 1H-NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.15-4.10 (m, 1H), 4.05-4.03 (m, 2H), 3.97 (s, 1H), 3.73-3.66 (m, 10H), 1.84-1.72 (m, 4H), 1.48 (s, 9H), 0.89 (m, 18H), 0.05 (s, 12H).

[0310] Preparation of compound 118 Compound 117 (2.05 g, 3.37 mmol) was dissolved in methanol (10 mL), and camphor sulfonic acid (158 mg, 0.68 mmol) was added thereto under a nitrogen atmosphere at 0°C. The mixture was then stirred at 0°C for 4 hours. The reaction solution was neutralized with triethylamine (1 mL), then concentrated, and purified by column chromatography to obtain compound 118 (1.28 g, 99%). 1 H-NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 4.32-4.29 (m, 1H), 4.05-4.03 (m, 4H), 3.75-3.69 (m, 10H), 3.48 (br s, 2H), 1.94-1.85 (m, 2H), 1.68-1.61 (m, 4H), 1.48 (s, 9H).

[0311] [Example 44] Preparation of Compound 124

[0312] [ka]

[0313] Preparation of compound 119 3,5-pyrazoledicarboxylic acid hydrate (5 g, 28.71 mmol) was dissolved in methanol (50 mL), and then thionyl chloride (6.28 mL, 86.15 mmol) was added thereto under a nitrogen atmosphere at 0°C. The mixture was then heated to 80°C. The reaction solution was stirred for 4 hours and then concentrated to obtain compound 119 (7.1 g, 99%). 1 H-NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 3.96 (s, 6H).

[0314] Preparation of compound 120 Compound 119 (3.8 g, 20.63 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium aluminum hydride (1 M tetrahydrofuran solution, 41.2 mL, 41.26 mmol) was added thereto under a nitrogen atmosphere at 0°C. The mixture was then heated under reflux and stirred for 12 hours. The reaction mixture was cooled to 0°C, and distilled water (50 mL) was gradually added thereto. The mixture was then concentrated and diluted with methanol (200 mL), and then heated again to 80°C. The thermal reaction product was filtered, and the filtrate was concentrated. The filtrate was diluted with ethanol (10 mL), and hydrochloric acid (4 N 1,4-dioxane solution, 82.6 mL, 22.7 mmol) was added thereto, and the mixture was stirred for 20 minutes. Diethyl ether (200 mL) was added to the reaction solution, and the resulting solid was filtered and dried to obtain compound 120 (2.6 g, 78%). 1 H-NMR (400 MHz, DMSO-d6) δ 6.32 (s, 1H), 4.52 (s, 4H).

[0315] Preparation of compound 121 Compound 120 (2.59 g, 15.73 mmol) was dissolved in N,N-dimethylformamide (75 mL), and then imidazole (5.35 g, 78.68 mmol) and t-butyldimethylsilyl chloride (5.69 g, 37.8 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred for 4 hours, then diluted with ethyl acetate (100 mL), washed in the order of saturated ammonium chloride aqueous solution (100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, then concentrated, and purified by column chromatography to obtain compound 121 (4.56 g, 81%). 1 H-NMR (400 MHz, CDCl3) δ 6.09 (s, 1H), 4.74 (s, 4H), 0.88 (s, 18H), 0.09 (s, 12H).

[0316] Preparation of compound 122 Compound 121 (1.6 g, 4.48 mmol) was dissolved in N,N-dimethylformamide (25 mL), and then cesium carbonate (3.2 g, 9.8 mmol) and triethylene glycol ditosylate (4.05 g, 8.97 mmol) were added under a nitrogen atmosphere at 0°C. The mixture was then heated to 50°C. The reaction solution was stirred for 4 hours, then diluted with ethyl acetate (100 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 122 (1.69 g, 60%). 1H-NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 6.10 (s, 1H), 4.67 (d, J = 5.2 Hz, 4H), 4.25-4.22 (m, 2H), 4.13-4.11 (m, 2H), 3.79-3.76 (m, 2H), 3.62-3.60 (m, 2H), 3.49-3.48 (m, 2H), 3.46-3.45 (m, 2H), 0.89 (d, J = 18 Hz, 18H), 0.06 (d, J = 5.6 Hz, 12H).

[0317] Preparation of compound 123 Compound 122 (1.69 g, 2.62 mmol) was dissolved in acetonitrile (25 mL), and then t-butyl N-hydroxycarbamate (1.35 g, 5.51 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.8 mL, 5.38 mmol) were added thereto under a nitrogen atmosphere at 0°C, and the mixture was then heated to 50°C. The reaction solution was stirred for 12 hours, then diluted with ethyl acetate (100 mL), then washed with brine (100 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, then concentrated, and purified by column chromatography to obtain compound 123 (1.5 g, 60%). 1 H-NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 4.70 (d, J = 8 Hz, 4H), 4.29-4.26 (m, 2H), 3.83-3.74 (m, 4H), 3.63-3.62 (m, 2H), 3.55-3.53 (m, 2H), 1.49 (s, 9H), 0.92 (d, J = 18 Hz, 18H), 0.09 (d, J = 0.8 Hz, 12H).

[0318] Preparation of compound 124 Compound 123 (1.5 g, 2.13 mmol) was dissolved in tetrahydrofuran (20 mL), and then tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 8.18 mL, 8.18 mmol) was added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred for 12 hours, then diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL), and then dried over anhydrous sodium sulfate. The resulting solution was filtered, then concentrated, and purified by column chromatography to obtain compound 124 (660 mg, 66%). 1 H-NMR (400 MHz, CDCl3) δ 6.22 (s, 1H), 4.65 (d, J = 4.8 Hz, 2H), 4.57 (d, J = 6 Hz, 2H), 4.34-4.31 (m, 2H), 3.38-3.38 (m, 2H), 3.66-3.54 (m, 8H), 1.52 (s, 9H).

[0319] [Example 45] Preparation of Compound 131

[0320] [ka]

[0321] Preparation of compound 126 Compound 125 (1.12 g, 5.67 mmol; compound 125 was prepared by the method described in WO2016 / 148674Al) was dissolved in dichloromethane (30 mL), and then pyridine (0.67 mL, 8.51 mmol) and allyl chloroformate (0.66 mL, 6.24 mmol) were added thereto under a nitrogen atmosphere at 0°C, and the mixture was stirred for 1 hour. The reaction solution was concentrated and then purified by column chromatography to obtain compound 126 (1.17 g, 73%). 1H-NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.06 (s, 1H), 7.44 (s, 1H), 6.07 (s, 1H), 6.02-5.92 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.66 (d, J = 5.2, 2H), 3.89 (s, 6H).

[0322] Preparation of compound 127 Compound 115 (920 mg, 2.75 mmol), Compound 126 (1.7 g, 6.05 mmol), and triphenylphosphine (2.52 g, 9.35 mmol) were dissolved in dry tetrahydrofuran. Then, diisopropyl azodicarboxylate (1.66 mL, 8.52 mmol) was added thereto under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated and purified by column chromatography to obtain Compound 127 (1.54 g, 65%). 1 H-NMR (400 MHz, CDCl3) δ 10.54 (s, 2H), 8.07 (s, 2H), 7.41 (s, 2H), 6.00-5.93 (m, 2H), 5.36 (d, J = 17.2 Hz, 2H), 5.25 (d, J = 10.0 Hz, 2H), 4.64-4.63 (m, 4H), 4.44 (bs, 1H), 4.23-4.20 (m, 4H), 3.99 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.66-3.60 (m, 11H), 3.35-3.34 (m, 2H), 2.25-2.13 (m, 4H).

[0323] Preparation of compound 128 Compound 127 (1.54 g, 1.78 mmol) was dissolved in methanol / tetrahydrofuran / distilled water (15 mL / 15 mL / 15 mL), then sodium hydroxide (0.28 g, 7.15 mmol) was added, and the mixture was stirred at 40°C for 5 hours. The reaction solution was diluted with ethyl acetate (100 mL) and subjected to extraction using distilled water (100 mL). The combined aqueous layer was acidified with 1 N hydrochloric acid aqueous solution, then subjected to extraction using ethyl acetate (100 mL), and the extract was dried over anhydrous sodium sulfate. The obtained product was filtered and then concentrated to obtain compound 128 (1.48 g). 1 H-NMR (400 MHz, DMSO-d6) δ 10.84 (s, 2H), 7.94 (s, 2H), 7.40 (s, 2H), 6.00-5.95 (m, 2H), 5.34 (d, J = 17.2 Hz, 2H), 5.24 (d, J = 10.0 Hz, 2H), 4.64-4.63 (m, 4H), 4.18 (br s, 1H), 4.04-4.01 (m, 4H), 3.88 (s, 2H), 3.74 (s, 6H), 3.55-3.51 (m, 12H), 2.05-1.98 (m, 4H).

[0324] Preparation of compound 129 Compound 128 (1.63 g, 1.95 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (2.22 g, 5.87 mmol) was added thereto under a nitrogen atmosphere at 0°C, and the mixture was stirred for 30 minutes. A solution of Compound 4 (0.64 g, 4.3 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.78 mmol) in N,N-dimethylformamide (5 mL) was added to the mixture under a nitrogen atmosphere. The reaction temperature was raised to room temperature, and the mixture was stirred for 12 hours, then diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (200 mL), and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 129 (1.2 g). 1 H-NMR (400 MHz, CDCl3) δ 8.65 (br s, 2H), 7.34 (br s, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.75 (s, 2H), 6.00-5.90 (m, 2H), 5.35 (d, J = 16.8 Hz, 2H), 5.23 (d, J = 10.4 Hz, 2H), 5.00-4.92 (m, 4H), 4.68-4.57 (m, 6H), 4.48-4.40 (m, 1H), 4.20-4.08 (m, 8H), 3.97 (s, 2H), 3.79 (s, 6H), 3.67-3.63 (m, 14H), 3.39-3.37 (m, 2H), 2.80-2.72 (m, 2H), 2.48-2.44 (m, 2H), 2.22-2.17 (m, 2H), 2.10-2.04 (m, 2H).

[0325] Preparation of compound 130 Compound 129 (1.2 g, 1.17 mmol) was dissolved in dichloromethane (10 mL), and then imidazole (0.4 g, 5.86 mmol) and t-butyldimethylsilyl chloride (0.53 g, 3.5 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred for 12 hours, then brine (50 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (2 × 100 mL), and then the extract was dried over anhydrous sodium sulfate. The obtained product was filtered, then concentrated, and purified by column chromatography to obtain compound 130 (0.98 g, 40% in 3 steps). 1 H-NMR (400 MHz, CDCl3) δ 8.81 (br s, 2H), 7.77 (s, 2H), 7.12 (d, J = 8 Hz, 1H), 6.80 (s, 2H), 5.99-5.89 (m, 2H), 5.34 (d, J = 17.2 Hz, 2H) 5.23 (d, J = 10.4 Hz, 2H), 4.98-4.91 (m, 4H), 4.65-4.56 (m, 6H), 4.54-4.44 (m, 1H), 4.19-4.14 (m, 8H) 4.01 (s, 2H), 3.80 (s, 6H), 3.66-3.61 (m, 14H), 3.39-3.36 (m, 2H), 2.69 (s, 4H), 2.28-2.19 (m, 2H), 2.15-2.05 (m, 2H), 0.87 (s, 18H), 0.03 (s, 12H).

[0326] Preparation of compound 131 Compound 130 (0.98 g, 0.78 mmol) was dissolved in dichloromethane (5 mL), and then pyrrolidine (0.16 mL, 1.95 mmol) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.015 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. Distilled water (50 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (50 mL). The extract was then dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 131 (0.59 g, 70%). 1 H-NMR (400 MHz, CDCl3) δ 7.12. (d, J = 9.2 Hz, 1H), 6.73 (s, 2H), 6.26 (s, 2H), 4.96-4.90 (m, 4H), 4.52 (bs, 1H), 4.38-4.35 (m, 4H), 4.21-4.17 (m, 2H), 4.11-4.03 (m, 6H), 4.00 (s, 2H), 3.75 (s, 6H), 3.66-3.61 m, 12H), 3.37-3.34 (m, 2H), 2.7-2.68 (m, 4H) 2.21-2.18 (m, 2H), 2.12-2.05 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H).

[0327] [Example 46] Preparation of Compound 135

[0328] [ka]

[0329] Preparation of compound 132 Compound 131 (590 mg, 0.54 mmol) was dissolved in dry tetrahydrofuran (5 mL), and triphosgene (116 mg, 0.39 mmol) and triethylamine (0.2 mL, 1.47 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 20 (707 mg, 1.30 mmol) was dissolved in dry tetrahydrofuran (5 mL), and triethylamine (0.2 mL, 1.47 mmol) was added thereto. This solution was gradually added to the reaction solution. After 1 hour, the reaction solution was heated under reflux and stirred for 12 hours. The reaction solution was diluted with ethyl acetate (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The obtained solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 132 (1.0 g, 83%). EI-MS m / z : [M+H] + 2219.10, 1 / 2[M+H] + 1110.30

[0330] Preparation of compound 133 Compound 132 (1 g, 0.45 mmol) was dissolved in tetrahydrofuran / distilled water (5 mL / 5 mL), acetic acid (15 mL) was added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (50 mL), and then dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 133 (720 mg, 80%). EI-MS m / z : [M+H] + 1990.95, 1 / 2 [M+H] + 996.06.

[0331] Preparation of compound 134 Compound 133 (370 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), and then dess-martinperiodinane (181 mg, 0.42 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate aqueous solution (20 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 134 (350 mg, 90%). EI-MS m / z : [M+H] + 1986.61, 1 / 2 [M+H] + 994.11.

[0332] Preparation of compound 135 Compound 134 (350 mg, 0.17 mmol) was dissolved in methanol / tetrahydrofuran (7.5 mL / 7.5 mL), and then lithium hydroxide (66 mg, 1.58 mmol) dissolved in distilled water (7.5 mL) was gradually added at -40°C. The reaction temperature was gradually raised to 0°C, and the mixture was stirred for 2 hours. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 135 (150 mg, 50%) as a white solid. EI-MS m / z : [M+H] + 1706.20, 1 / 2[M+H] + 854.00.

[0333] [Example 47] Preparation of Compound 137

[0334] [ka]

[0335] Preparation of compound 136 Compound 136 was prepared from compounds 126 and 118 by the same method as that used for the synthesis of compound 134. EI-MS m / z : [M+H] +2032.98, 1 / 2[M+H] + 1017.03.

[0336] Preparation of compound 137 Compound 136 (205 mg, 0.10 mmol) was dissolved in methanol / tetrahydrofuran (4 mL / 6 mL), and then a solution of lithium hydroxide (38 mg, 0.91 mmol) in distilled water (4 mL) was gradually added thereto at -40°C. The mixture was stirred for 4 hours while gradually raising the reaction temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and freeze-dried. The resulting solid was diluted with dichloromethane (5 mL), then trifluoroacetic acid (1.5 mL) was added thereto at 0°C, and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and freeze-dried to obtain compound 137 (29 mg, 17%) as a white solid. EI-MS m / z : [M+H] + 1653.01, 1 / 2[M+H] + 826.89.

[0337] [Example 48] Preparation of Compound 138

[0338] [ka] Compound 138 was prepared from compounds 126 and 124 by the same method as that used for the synthesis of compound 137. EI-MS m / z : [M+H] + 1647.60, 1 / 2[M+H] + 824.31.

[0339] [Example 49] Preparation of Compound 142

[0340] [ka]

[0341] Preparation of compound 139 Dimethyl sulfoxide (3.53 mL, 3.88 mmol) was dissolved in dichloromethane (30 mL), and then oxalyl chloride (2.0 M dichloromethane solution, 13 mL, 23.9 mmol) was added thereto under a nitrogen atmosphere at -78°C. Compound 6 (6.8 g, 9.94 mmol) was dissolved in dichloromethane (20 mL), and then this solution was gradually added to the mixture under a nitrogen atmosphere at -78°C. The reaction solution was stirred for 10 minutes, then the temperature was raised to 0°C, and triethylamine (13.85 mL, 4.41 mmol) was gradually added thereto, and then the mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution (200 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and then dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 139 (5.76 g, 85%). 1 H-NMR (400 MHz, CDCl3) δ 9.80 (s, 2H), 7.72 (s, 2H), 6.85 (s, 2H), 5.07 (s, 2H), 4.93 (s, 2H), 4.22-4.10 (m, 6H), 4.00 (s, 6H), EI-MS m / z : [M+H] + 681.6.

[0342] Preparation of compound 140 Compound 139 (1.84 g, 2.71 mmol) was dissolved in benzene and N,N-dimethylformamide (v / v=10:1, 30 mL), and then ethylene glycol (1.5 mL, 27.11 mmol) and camphor sulfonic acid (251 mg, 0.81 mmol) were successively added under a nitrogen atmosphere at room temperature. The reaction solution was stirred for 5 minutes, and then heated under reflux and stirred for 2 hours using a Dean-Stark apparatus. The reaction solution was concentrated and diluted with ethyl acetate (100 mL), and then saturated sodium bicarbonate aqueous solution (100 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and then dried over anhydrous sodium sulfate. The obtained product was filtered, concentrated, and purified by column chromatography to obtain compound 140 (1.53 g, 72%). 1 H-NMR (400 MHz, CDCl3) δ 7.70 (s, 2H), 6.78 (s, 2H), 5.07 (s, 2H), 4.81 (s, 2H), 4.69 (s, 2H), 4.20-4.02 (m, 6H), 4.00-3.90 (m, EI-MS m / z : [M+H] + 769.8.

[0343] Preparation of compound 141 Compound 140 (1.11 g, 1.45 mmol) was dissolved in ethanol (22 mL), and then zinc powder (2.84 g, 43.39 mmol) and formic acid (5% ethanol solution, 1.96 mL) were added thereto. The reaction solution was stirred at room temperature for 3 hours, then filtered through celite, and ethyl acetate (300 mL) was added thereto. The organic layer was washed in the order of distilled water (2 × 100 mL), saturated aqueous sodium hydrogen carbonate solution (2 × 200 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. The obtained product was filtered, then concentrated, and purified by column chromatography to obtain Compound 141 (800 mg, 78%). 1 H-NMR (400 MHz, CDCl3) δ 6.78 (s, 2H), 6.23 (s, 2H), 5.12 (s, 2H), 4.97 (s, 2H), 4.91 (s, 2H), 4.78 (br s, 2H), 4.54 (br s, 2H), 4.33 - 4.21 (m, 2H), 4.10 - 3.91 (m, 12H), 3.90 - 3.82 (m, 4H), 3.78 (s, 6H), 2.72 - 2.58 (m, 4H), 1.98 - 1.84 (m, 4H), 1.74 - 1.58 (m, 2H), 0.87 (s, 18H), 0.02 (s, 12H). EI-MS m / z : [M+H] + 709.8.

[0344] Preparation of Compound 142 Compound 141 (640 mg, 0.90 mmol) was dissolved in dichloromethane (45 mL), and then pyridine (0.15 mL, 1.80 mmol) and allyl chloroformate (86 μL, 0.81 mmol) were added thereto at -78 °C under a nitrogen atmosphere. After the reaction solution was stirred for 1 hour, the reaction temperature was raised to room temperature, the reaction solution was concentrated, and then purified by column chromatography to obtain Compound 142 (320 mg, 43%). 1H-NMR (400 MHz, CDCl3) δ 8.75 (br, 1H), 7.83 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.23 (s, 1H), 5.97-5.91 (m, 1H), 5.34,(d, J = 17.2 Hz, 1H), 5.23 (d, J = 10.0 Hz, 1H), 5.08 (br s, 1H), 5.02-4.88 (m, 6H), 4.80 (br s, 1H), 4.68-4.56 (m, 2H), 4.44 (br s, 2H), 4.30-4.18 (m, 2H), 4.16-4.06 (m, 3H), 3.92-3.84 (m, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 2.74-2.56 (m, 4H), 1.99-1.86 (m, 4H), 1.72-1.60 (m, 2H).

[0345] [Example 50] Preparation of Compound 146

[0346] [ka]

[0347] Preparation of compound 143 Compound 142 (260 mg, 0.35 mmol) was dissolved in tetrahydrofuran (4 mL), and triphosgene (40 mg, 0.13 mmol) and triethylamine (0.078 mL, 0.56 mmol) were added at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 20 (208 mg, 0.39 mmol) and triethylamine (0.087 mL, 0.62 mmol) were dissolved in dry tetrahydrofuran (3 mL), and this solution was gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 3 hours. The reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (2 × 20 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 143 (340 mg, 71%). 1 H-NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.95 (d, J = 12.2 Hz, 1H), 7.83 (br s, 1H), 7.52-7.41 (m, 2H), 7.27 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.00-5.88 (m, 1H), 5.42-5.23, (m, 10H), 5.20-5.08 (m, 4H), 5.06-4.82 (m, 8H), 4.67 (s, 1H), 4.28-4.18 (m, 6H), 4.16-4.06 (m, 8H), 4.05-3.86 (m, 6H), 3.86 (s, 3H), 3.76 (s, 3H), 3.52-3.62 (m, 3H), 3.41 (s, 3H), 2.78-2.58 (m, 2H), 2.12-2.06 (m, 2H), 2.05 (s, 9H), 1.86-2.01 (m, 4H), 1.72-1.60 (m, 2H), 1.27 (t, J = 7.2 Hz, 2H). EI-MS m / z : [M+H] + 1361.5, 1 / 2[M+H] + 681.6.

[0348] Preparation of compound 144 Compound 143 (330 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), and then pyrrolidine (0.026 mL, 0.365 mmol) and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.012 mmol) were added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 144 (290 mg, 90%). 1H-NMR (400 MHz, CDCl3) δ 8.82 (broad singlet, 1H), 8.05 (singlet, 1H), 7.52 - 7.42 (multiplet, 2H), 7.04 (doublet, J = 8.2 Hz, 1H), 6.82 (singlet, 1H), 6.78 (singlet, 1H), 6.24 (singlet, 1H), 5.44 - 5.26, (multiplet, 4H), 5.16 - 5.04 (multiplet, 4H), 5.02 - 4.86 (multiplet, 5H), 4.52 - 4.38 (multiplet, 2H), 4.30 - 4.10 (multiplet, 6H), 4.16 - 4.07 (multiplet, 5H), 4.04 - 3.92 (multiplet, 6H), 3.91 - 3.84 (multiplet, 6H), 3.83 (singlet, 3H), 3.78 (singlet, 3H), 3.72 (singlet, 3H), 3.60 - 3.52 (multiplet, 3H), 3.41 (singlet, 3H), 2.71 - 2.58 (multiplet, 4H), 2.05 (singlet, 9H), 1.97 - 1.85 (multiplet, 4H), 1.72 - 1.58 (multiplet, 4H), 1.25 (triplet, J = 7.2 Hz, 2H). EI-MS m / z : [M+H] + 1277.2, 1 / 2[M+H] + 639.4.

[0349] Preparation of Compound 145 Compound 144 (340 mg, 0.29 mmol) was dissolved in dry tetrahydrofuran (3 mL), then triphosgene (25 mg, 0.09 mmol) and triethylamine (0.060 mL, 0.43 mmol) were added thereto at -10 °C, and the mixture was stirred for 1 hour under a nitrogen atmosphere. Compound 32 (229 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (3 mL), triethylamine (0.060 mL, 0.43 mmol) was added thereto, and then this solution was gradually added to the reaction solution. After 30 minutes, the reaction solution was heated to reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), then washed with brine (2 × 50 mL) and dried over anhydrous sodium sulfate. The resulting product was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 145 (250 mg, 43%). EI-MS m / z : [M+Na] + 2056.4, 1 / 2[M+H] + 967.7.

[0350] Preparation of compound 146 Compound 145 (230 mg, 0.113 mmol) was dissolved in methanol / tetrahydrofuran (3 mL / 3 mL), and then a solution of lithium hydroxide (48 mg, 1.13 mmol) in distilled water (6 mL) was gradually added thereto at -40°C. The mixture was stirred for 2 hours while gradually raising the reaction temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and vacuum dried. The resulting solid was diluted with dichloromethane (10 mL), then trifluoroacetic acid (2 mL) was added thereto at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 146 (15.6 mg) as a white solid. EI-MS m / z : [M+H] + 1653.7, 1 / 2[M+H] + 827.6.

[0351] [Example 51] Preparation of Compound 148

[0352] [ka]

[0353] Preparation of compound 147 Compound 144 (266 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran (3 mL), and triphosgene (16 mg, 0.06 mmol) and triethylamine (0.044 mL, 0.31 mmol) were added thereto at -10°C. The mixture was stirred under a nitrogen atmosphere for 1 hour. Compound 55 (147 mg, 0.23 mmol) was dissolved in dry tetrahydrofuran (3 mL), and triethylamine (0.044 mL, 0.31 mmol) was added thereto. This solution was then gradually added to the reaction solution. After 30 minutes, the reaction solution was heated under reflux and stirred for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 × 50 mL), and dried over anhydrous sodium sulfate. The obtained solution was filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 147 (170 mg, 42%). EI-MS m / z : [M+Na] + 1944.6, 1 / 2 [M+H] + 972.8.

[0354] Preparation of compound 148 Compound 147 (120 mg, 0.087 mmol) was dissolved in methanol / tetrahydrofuran (3 mL / 3 mL), and then a solution of lithium hydroxide (37 mg, 0.87 mmol) in distilled water (6 mL) was gradually added thereto at -40°C. The mixture was stirred for 2 hours while gradually raising the reaction temperature to 0°C. The reaction solution was neutralized with acetic acid, then concentrated under reduced pressure, and vacuum dried. The resulting solid was diluted with dichloromethane (8 mL), then trifluoroacetic acid (2 mL) was added thereto at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and freeze-dried to obtain compound 148 (31 mg) as a white solid. EI-MS m / z : [M+H] + 1663.4, 1 / 2[M+H] + 832.7.

[0355] [Example 52] Preparation of Compound 155

[0356] [ka] JPEG2023113699000078.jpg54167

[0357] Preparation of compound 149 Compound 4 (13.8 g, 92.5 mmol) was dissolved in dichloromethane (400 mL), and then imidazole (18.8 g, 277.5 mmol) and t-butyldimethylsilyl chloride (15.3 g, 101.7 mmol), dissolved in dichloromethane (100 mL), were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred at room temperature for 2 hours, then brine (30 mL) was added to the reaction solution, and the mixture was subjected to extraction using dichloromethane (2 × 300 mL), and the extract was dried over anhydrous sodium sulfate. The obtained solution was filtered, then concentrated, and purified by column chromatography to obtain compound 149 (17 g, 80%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 4.91, (d, J = 14.4 Hz, 2H), 3.66-3.47 (m, 4H), 3.27-3.24 (m, 1H), 2.47-2.42 (m, 1H), 2.24-2.18 (m, 1H), 0.91 (s, 9H), 0.05 (s, 6H).

[0358] Preparation of compound 151 Compound 150 (17.3 g, 46.8 mmol; compound 150 was prepared by the method described in ACS Med. Chem. Lett. 2016, Vol. 7, p. 983) was dissolved in N,N-dimethylformamide (100 mL), and then 1-hydroxybenzotriazole (6.8 g, 50.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.4 g, 54.6 mmol) were added in that order under a nitrogen atmosphere at 0°C, and the mixture was then stirred for 30 minutes. A solution of compound 149 (8.8 g, 39.0 mmol) and triethylamine (9.78 mL, 70.2 mmol) in dichloromethane (50 mL) was added to the mixture under a nitrogen atmosphere. The reaction temperature was raised to room temperature, the mixture was stirred for 12 hours, then diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate aqueous solution (100 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 151 (19.9 g, 89%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 7.69 (s, 1H), 6.72 (s, 1H), 4.97 (s, 1H), 4.82 (s, 1H), 4.57-4.54 (m, 1H) 3.89 (s, 4H), 3.74-3.71 (m, 2H) 3.30-3.27 (m, 1H), 2.76-2.52 (m, 2H), 1.31-1.23 (m, 3H), 1.08 (s, 18H), 0.89 (s, 9H), 0.08 (s, 3H).

[0359] Preparation of compound 152 Compound 151 (29.5 g, 50.9 mmol) was dissolved in ethanol (720 mL), and then zinc powder (66.6 g, 1019.1 mmol) and formic acid (38 mL, 1019.1 mmol) were added thereto. The reaction solution was stirred at room temperature for 40 minutes, then filtered through Celite, and ethyl acetate (500 mL) was added thereto. The organic layer was washed in the order of distilled water (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), and brine (500 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated, and purified by column chromatography to obtain compound 152 (27.9 g, 99%). 1 H-NMR (400MHz, CDCl3) (rotamer) δ 6.71 (s, 1H), 6.25 (s, 1H), 4.96-4.89 (m, 2H), 4.53 (br s, 1H), 4.21-4.09 (m, 4H), 3.74 (br s, 1H), 3.71 (s, 3H), 3.62 (br s, 1H), 2.73-2.63 (m, 2H), 1.29-1.21 (m, 3H), 1.05 (s, 18H), 0.87 (s, 9H), 0.02 (s, 6H).

[0360] Preparation of compound 153 Compound 152 (27.9 g, 50.8 mmol) was dissolved in dichloromethane (300 mL), and then pyridine (9 mL, 111.8 mmol) and allyl chloroformate (5.9 mL, 55.9 mmol) were added under a nitrogen atmosphere at -78°C. After stirring the reaction solution for 1 hour, the reaction temperature was raised to room temperature, the reaction solution was concentrated, and then purified by column chromatography to obtain compound 153 (31.8 g, 99%). 1H-NMR (400MHz, CDCl3) (rotamer) δ 8.67 (br s, 1H), 7.75 (s, 1H), 6.78 (s, 1H), 5.99-5.89 (m, 1H), 5.33, (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.98-4.90 (m, 2H), 4.66-4.57 (m, 3H), 4.19-4.11 (m, 1H), 4.01 (br s, 1H), 3.86 (br s, 1H), 3.76 (s, 3H), 3.65 (br s, 1H), 2.68 (s, 2H), 1.33-1.24 (m, 3H), 1.05 (s, 18), 0.87 (s, 9H), 0.03 (s, 6H).

[0361] Preparation of compound 154 Compound 153 (31.8 g, 50.2 mmol) was dissolved in N,N-dimethylformamide (300 mL) and distilled water (6 mL). Then, sodium acetate (5 g, 60.2 mmol) was added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (300 mL), washed with distilled water (300 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 154 (17.7 g, 74%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 8.75 (br s, 1H), 7.75 (s, 1H), 6.78 (s, 1H), 6.14 (s, 1H), 5.94-5.90 (m, 1H), 5.32, (d, J = 17.2 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.97-4.90 (m, 2H), 4.65-4.56 (m, 3H), 4.18-4.15 (m, 1H), 4.01 (br s, 1H), 3.85 (s, 4H), 3.65 (br s, 1H), 2.68 (s, 2H), 0.87 (s, 9H), 0.02 (s, 6H).

[0362] Preparation of compound 155 Compound 154 (18.6 g, 39.0 mmol) was dissolved in acetone (200 mL), and then 1,5-diiodopentane (11.6 mL, 156 mmol) and potassium carbonate (5.9 g, 42.9 mmol) were added in that order under a nitrogen atmosphere. The mixture was then stirred at 60°C for 12 hours. The reaction solution was concentrated and purified by column chromatography to obtain compound 155 (23 g, 87%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 8.88 (br s, 1H), 7.83 (s, 1H), 6.81 (s, 1H), 5.98-5.90 (m, 1H), 5.34, (d, J = 17.2 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.98-4.90 (m, 2H), 4.67-4.58 (m, 3H), 4.21-4.12 (m, 1H), 4.10-4.06 (m, 3H) 3.82 (s, 4H), 3.64 (br s, 1H), 3.23-3.19 (m, 2H), 2.69 (s, 2H), 1.94-1.84 (m, 4H), 1.62-1.55 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H).

[0363] [Example 53] Preparation of Compound 162

[0364] [ka]

[0365] Preparation of compound 156 Compound 151 (9.3 g, 16.0 mmol) was dissolved in N,N-dimethylformamide (100 mL) and distilled water (2 mL). Then, sodium acetate (1.6 g, 19.2 mmol) was added under a nitrogen atmosphere at 0°C, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (100 mL), washed with distilled water (100 mL), and dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and purified by column chromatography to obtain compound 156 (5.4 g, 80%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 7.75 (s, 1H), 6.76 (s, 1H), 6.07 (s, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.58-4.54 (m, 1H), 3.99 (s, 3H), 3.89-3.87 (m, 1H), 3.77-3.70 (m, 2H), 3.33-3.29 (m, 1H), 2.81-2.53 (m, 2H), 0.89 (s, 9H), 0.09 (s, 6H).

[0366] Preparation of compound 157 Compound 156 (3.0 g, 7.1 mmol) was dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (1.1 g, 7.8 mmol) and benzyl bromide (0.9 mL, 7.8 mmol) were added thereto under a nitrogen atmosphere at 0°C. The reaction solution was stirred for 3 hours, and then saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was subjected to extraction using ethyl acetate (2 × 50 mL). The combined organic layers were washed with distilled water (2 × 100 mL) and brine (100 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 157 (3.6 g, 97%). 1H-NMR (400 MHz, CDCl3) (rotamer) δ 7.77 (d, J = 4.8 Hz, 1H), 7.46-7.33 (m, 5H), 6.79 (d, J = 18.8 Hz, 1H), 5.22 (d, J = 5.2 Hz, 2H), 5.09 (d, J = 7.6 Hz, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.58 (br s, 1H), 3.96 (s, 3H), 3.87 (br s, 1H), 3.77-3.69 (m, 2H), 3.30-3.28 (m, 1H), 2.81-2.53 (m, 2H), 0.89 (s, 9H), 0.09 (s, 6H).

[0367] Preparation of compound 158 Compound 157 (3.6 mg, 6.9 mmol) was dissolved in tetrahydrofuran / distilled water (15 mL / 15 mL), acetic acid (30 mL) was added thereto, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography to obtain compound 158 (2.8 g, 99%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ7.77 (s, 1H), 7.47-7.35 (m, 5H), 6.81 (s, H), 5.22 (s, 2H), 5.02 (s, 1H), 4.87 (s, 1H), 4.60 (br s, 1H), 3.99 (s, 3H), 3.88 (br s, 1H), 3.83-3.72 (m, 3H), 3.54 (br s, 1H), 2.88-2.82 (m,1H), 2.52-2.48 (m,1H).

[0368] Preparation of compound 159 Oxalyl chloride (2.1 mL, 14.1 mmol) was dissolved in dichloromethane (20 mL), and then dimethyl sulfoxide (1.5 mL, 21.1 mmol) was added thereto under a nitrogen atmosphere at -78°C. After 1 hour, a solution of compound 158 (2.7 g, 6.9 mmol) in dichloromethane (50 mL) was gradually added to the mixture. The reaction solution was stirred for 2 hours, and then triethylamine (3.4 mL, 42.3 mmol) diluted with dichloromethane (30 mL) was gradually added thereto. The reaction temperature was gradually raised to 0°C over 2 hours. The reaction solution was diluted with dichloromethane (100 mL), and the organic layer was washed with saturated ammonium chloride aqueous solution (200 mL) and brine (200 mL), and then dried over anhydrous sodium sulfate. The resulting mixture was filtered, concentrated, and purified by column chromatography to obtain compound 159 (2.7 g, 96%). 1 H-NMR (400 MHz, CDCl3) (rotamer) δ 9.79 (s, 1H), 7.79 (s, 1H), 7.46-7.26 (m, 5H), 6.87 (s, 1H), 5.22 (s, 2H), 5.06-4.96 (m, 1H), 4.93-4.90 (m, 1H), 4.78 (br s,1H), 4.62-4.56 (m, 1H), 3.99 (s, 3H), 3.93 (s, 1H), 3.85 (s, 1H), 2.91-2.62 (m, 2H).

[0369] Preparation of compound 160 Compound 159 (2.7 g, 6.8 mmol) was dissolved in tetrahydrofuran / distilled water (60 mL / 40 mL), and then sodium dithionite (Na2S2O4, 11.2 g, 64.4 mmol) was added thereto. The mixture was stirred under a nitrogen atmosphere for 20 hours. The reaction solution was diluted by adding methanol (60 ml), acidified (pH 2) by adding 6 N hydrochloric acid aqueous solution, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to remove methanol. The reaction solution was acidified (pH 2) by adding 6 N hydrochloric acid aqueous solution and subjected to extraction using ethyl acetate (5 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. The resulting mixture was filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain compound 160 (1.8 g, 77%). EI-MS m / z : [M+H] + 349.3, [M+H2O] + 367.3.

[0370] Preparation of compound 161 Compound 160 (1.8 g, 5.3 mmol) was dissolved in dichloromethane / N,N-dimethylformamide (20 mL / 8 mL), and then sodium triacetoxyborate (1.2 g, 5.8 mmol) was added under a nitrogen atmosphere at 0°C, and the mixture was stirred for 2 hours. Distilled water (40 mL) was added to the reaction solution, and then the mixture was subjected to extraction using dichloromethane (2 × 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 161 (1.2 g, 64%). 1H-NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.41-7.30 (m, 5H), 6.05 (s, 1H), 5.12 (s, 2H), 5.06 (s, 1H), 5.02 (s, 1H), 4.38 (d, J = 18 Hz, 1H), 4.27 (d, J = 16.4 Hz, 1H), 4.04-3.96 (m, 1H), 3.86 (s, 3H), 3.49 (d, J = 11 Hz, 1H), 3.29 (dd, J = 9.2 Hz, 1H), 2.91-2.85 (m, 1H), 2.40 (dd, J = 10 Hz, 1H).

[0371] Preparation of compound 162 Compound 161 (1.3 g, 3.7 mmol) was dissolved in dichloromethane (70 mL), and then methanesulfonic acid (25 mL) was added. The mixture was stirred under a nitrogen atmosphere for 2 hours. Distilled water (20 mL) was added to the reaction solution, and then the reaction solution was neutralized by the addition of sodium carbonate. The reaction solution was diluted by the addition of water (200 mL) and subjected to extraction using dichloromethane (3 × 50 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 162 (620 mg, 64%). 1 H-NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 6.17 (s, 1H), 5.88 (br s, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 4.41 (d, J = 16.4 Hz, 1H), 4.31 (d, J = 16.4 Hz, 1H), 4.08-3.99 (m, 1H), 3.88 (s, 3H), 3.54 (d, J = 12.4 Hz, 1H), 3.49 (d, J = 11 Hz, 1H), 3.34 (dd, J = 9.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.43 (dd, J = 6.4 Hz, 1H).

[0372] [Example 54] Preparation of Compound 164

[0373] [ka]

[0374] Preparation of compound 163 Compound 162 (374 mg, 1.4 mmol) and Compound 155 (1.0 g, 1.5 mmol) were dissolved in acetone / N,N-dimethylformamide (20 mL / 20 mL), and potassium carbonate (258 mg, 1.8 mmol) was added thereto under a nitrogen atmosphere. The mixture was heated and stirred at 80°C for 12 hours. The reaction solution was filtered, then concentrated under reduced pressure, and distilled water (200 mL) was added to the reaction solution. The mixture was then subjected to extraction using ethyl acetate (3 × 30 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain Compound 163 (620 mg, 53%). 1H-NMR (400 MHz, CDCl3) (rotamer) δ 8.86 (br s, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 6.82 (s, 1H), 6.06 (s, 1H), 6.01-5.91 (m, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 5.08 (s, 1H), 5.05 (s, 1H), 5.00 (s, 1H), 4.92 (br s, 1H), 4.63 (d, J = 4.8 Hz, 2H), 4.41 (d, J = 16.4 Hz, 1H), 4.30 (d, J = 16.4 Hz, 1H), 4.20 (d J = 14 Hz, 1H), 4.13-4.10 (m, 3H), 4.05-3.98 (m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.66 (bs, 1H), 3.55 (d, J = 12.8 Hz, 1H), 3.32 (dd, J = 9.2 Hz, 1H), 2.91 (dd, J = 8.8 Hz, 1H), 2.70 (br s, 2H), 2.43 (dd, J = 7.2 Hz, 1H), 1.97-1.91 (m, 4H), 1.69-1.64 (m, 2H), 0.89 (s, 9H), 0.04 (br s, 6H).

[0375] Preparation of compound 164 Compound 164 was prepared from compound 163 by the same method as that used for the synthesis of compound 28. EI-MS m / z : [M+H] + 1548, 1 / 2[M+H] + 775.

[0376] [Example 55] Preparation of Compound 167

[0377] [ka]

[0378] Preparation of compound 165 L-histidine (5.0 g, 32.22 mmol) was dissolved in dichloromethane (45 mL), and then dichlorodimethylsilane (3.9 mL, 32.22 mmol) and triethylamine (9.0 mL, 64.44 mmol) were added at room temperature. The reaction solution was heated under a nitrogen atmosphere and refluxed for 4 hours. Trityl chloride (8.9 g, 32.22 mmol) and triethylamine (4.5 mL, 32.22 mmol) were added, and the mixture was stirred under a nitrogen atmosphere for 2 hours. Methanol (50 mL) was added to the reaction solution, and then the mixture was concentrated under reduced pressure. Distilled water (50 mL) and triethylamine were added to adjust the pH to approximately 8-8.5. The insoluble slurry was filtered off therefrom, and the filtered product was washed with chloroform (50 mL), diethyl ether (50 mL), and distilled water (50 mL) in that order. The resulting white solid compound was dried to obtain compound 165 (triethylamine salt, 12.4 g, 95%). 1 H-NMR (400 MHz, CD3OD) δ 7.45-7.32 (m, 10H), 7.21-7.15 (m, 5H), 3.75-3.77 (m, 1H), 3.20 (q, 2H), 3.00-2.97 (m,1H), 1.32 (t, 3H).

[0379] Preparation of compound 166 Compound 165 (1.0 g, 2.52 mmol) and N-methoxycarbonylmaleimide (429 mg, 2.77 mmol) were dissolved in 1,4-dioxane / distilled water (5 mL / 2.5 mL), and sodium carbonate (267 mg, 2.52 mmol) was added thereto. The mixture was heated under a nitrogen atmosphere under reflux for 12 hours. The reaction solution was concentrated under reduced pressure and dissolved in N,N-dimethylformamide (3 mL). Triethylamine (0.16 mL, 1.12 mmol) was then added to the reaction solution, and the mixture was stirred under a nitrogen atmosphere for 10 hours. Distilled water (5 mL) was added to the reaction solution, and the reaction solution was then acidified (pH 4) by adding 0.5 N hydrochloric acid aqueous solution. The solution was then subjected to extraction using dichloromethane (3 × 10 mL), and the extract was dried over anhydrous sodium sulfate. The obtained compound was filtered and concentrated under reduced pressure to obtain compound 166 (504 mg, 32%). EI-MS m / z : [M+H] + 478.4, [M+Na] + 500.4.

[0380] Preparation of compound 167 Compound 166 (252 mg, 0.53 mmol) was dissolved in N,N-diisopropylethylamine (4 mL), and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (132 mg, 0.69 mmol) and N-hydroxysuccinimide (85 mg, 0.74 mmol) were added thereto. The reaction solution was stirred at room temperature for 12 hours. Distilled water (30 mL) was added to the reaction solution, and then the mixture was subjected to extraction using ethyl acetate (2 × 30 mL). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 167 (274 mg, 90%). EI-MS m / z : [M+H] + 575.3.

[0381] [Example 56] Preparation of Compound 169

[0382] [ka]

[0383] Preparation of compound 168 Compound 103 (50 mg, 0.03 mmol) and Compound 167 (27.4 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (1 mL), and then N,N-diisopropylethylamine (0.01 mL, 0.05 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain Compound 168 (11 mg, 18%). EI-MS m / z : [M+H] + 1934.8, 1 / 2 [M+H] + 968.0.

[0384] Preparation of compound 169 Compound 168 (11 mg, 6 μmol) and anisole (6 μL, 60 μmol) were diluted with dichloromethane (0.75 mL), and then trifluoroacetic acid (0.25 mL) was added at 0°C. The mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 169 (2 mg, 21%) as a white solid. EI-MS m / z : [M+H] + 1692.7, 1 / 2[M+H] + 846.9.

[0385] [Example 57] Preparation of Compound 171

[0386] [ka]

[0387] Preparation of compound 170 DBCO-PEG4 acid (50 mg, 91 μmol) was dissolved in dichloromethane (1 mL), and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (19 mg, 99 mol) and N-hydroxysuccinimide (11 mg, 99 μmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 170 (59 mg). EI-MS m / z : [M+H] + 650.7.

[0388] Preparation of compound 171 Compound 103 (47 mg, 32 μmol) and compound 170 (24 mg, 38 μmol) were dissolved in N,N-dimethylformamide / dichloromethane (1 mL / 0.25 mL), and then N,N-diisopropylethylamine (51 μL, 38 μmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and lyophilized to obtain compound 171 (8.1 mg, 14%). EI-MS m / z : [M+H] + 2010.1, 1 / 2 [M+H] + 1005.6.

[0389] Preparation of compounds 172-178 Pyrrolobenzodiazepine dimer compounds 172-178, having the structures shown in Table 1 below, were prepared with reference to the references.

[0390] [Table 1]

[0391] [Example 58] ADC preparation ADC was prepared in two steps, and LCB14-0511, LCB14-0512, and LCB14-0606, which are commonly used, were prepared by the method described in Korean Patent Application Publication No. 10-2014-0035393. The structural formulas of LCB14-0606, LCB14-0511, and LCB14-0512 are as follows.

[0392] [ka]

[0393] Step 1: Preparation of prenylated antibodies Antibody prenylation reaction mixture was prepared and reacted at 30°C for 16 hours. The reaction mixture consisted of 24 μM antibody, 200 nM FTase (Calbiochem #344145), and a buffer containing 0.144 mM LCB14-0511, LCB14-0512, or LCB14-0606 (50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 10 μM ZnCl2, 0.5 mM DTT). After the reaction was complete, the prenylated antibody was desalted using a G25 Sepharose column (AKTA Purifier, GE Healthcare) equilibrated with PBS buffer.

[0394] Step 2: Drug-conjugation method [Conjugation by oxime bond formation] The reaction mixture for oxime bond formation between prenylated antibody and linker-drug was prepared by mixing 100 mM sodium acetate buffer (pH 4.5), 10% DMSO, 24 μM antibody, and 240 μM linker-drug (homemade, compounds listed in Table 1, which were the final products of Examples 8-10 and Comparative Example 1), and gently stirring at 30°C. After 24 hours of reaction, the excess low molecular weight compounds used were removed by FPLC (AKTA purifier, GE Healthcare), and the protein fraction was collected and concentrated.

[0395] [Conjugation triggered by clicks] The click reaction between the prenylated antibody and the linker-drug was prepared by mixing 10% DMSO, 24 μM antibody, 240 μM linker-drug (homemade, compounds from Table 1 which were the final products of Examples 20, 21, 22, 26, 27, 28, and 46), 1 mM copper(II) sulfate pentahydrate, 2 mM (BimC4A)3 (Sigma-Aldrich 696854), 10 mM sodium ascorbate, and 10 mM aminoguanidine hydrochloride, reacting at 25°C for 3 hours, and then treating with 2.0 mM EDTA and reacting for 30 minutes. After the reaction was complete, the excess low molecular weight compounds used were removed by FPLC (AKTA purifier, GE Healthcare), and the protein fraction was collected and concentrated.

[0396] [Table 2]

[0397] [Experimental Example 1] Evaluation of cytotoxicity in vitro The inhibitory activity of the drugs and ADCs listed in Table 2 below against cancer cell lines was measured. Commercially available human breast cancer cell lines, MCF-7 (HER2-negative to normal), SK-BR3 (HER2-positive), and JIMT-1 (HER2-positive), were used as cancer cell lines. MMAF-OMe was used as the drug, and the ADCs listed in Table 1 were used. Each cancer cell line was seeded in 96-well plates at 5,000-13,000 cells per well for the 72-hour treatment group, and 1,500-3,000 cells per well for the 168-hour treatment group. After incubation for 24 hours, the cells were treated with antibodies and ADCs at concentrations of 0.0051-33.33 nM or 0.0015-10.0 nM (3-fold serial dilution), and with drugs at concentrations of 0.023-50 nM (3-fold serial dilution). After 72 / 168 hours, the number of viable cells was quantified using SRB (sulfolodamine B) dye.

[0398] [Table 3]

[0399] Among antibody-drug conjugates, samples of ADC1, 2, and 3, which were introduced with prodrug linkers-drugs 28, 29, and 30 having carbamate structures at the N10 position of both pyrrolobenzodiazepines, showed superior cytotoxicity in the SK-BR3 and JIMT-1 breast cancer cell lines compared to samples of ADC22, 23, and 24.

[0400] When administered in the form of a prodrug according to the present invention, this compound needs to be converted into an effective drug through further reactions upon exposure to the blood. Therefore, it is advantageous compared to conventional PBD drugs in that it can prevent the occurrence of side effects that may occur during unexpected linker degradation, resulting in reduced toxicity to normal cells and greater drug stability.

[0401] In addition, in the preparation of antibody-drug conjugates, the content of impurities is high, and the exposed imine group is attacked by a nucleophile. In the case of antibody-drug conjugates prepared by conventional methods, this can lead to the formation of drugs with undesirable structures. However, antibody-drug conjugates prepared by the method according to the present invention have the advantage that the imine group of the PBD dimer is in the form of a prodrug, thus protecting it from attack by nucleophiles, and that they have higher purity and improved physical properties compared to conventional PBD or PBD dimers, making them easy to separate. [Industrial applicability]

[0402] The pyrrolobenzodiazepine dimer prodrug, pyrrolobenzodiazepine dimer prodrug-linker, or pyrrolobenzodiazepine dimer prodrug-linker-ligand conjugate according to the present invention can be used in the targeting and specific treatment of proliferative diseases such as cancer.

Claims

Claim 1 A compound having a structure represented by the following formula I or a pharmaceutically acceptable salt thereof. 【Chemical 1】 [In the formula, R 1 and R 1 ' are each independently H, OH, =O, =CH 2 , CN, R m , OR m , =CH-R m' , =C(R m' ) 2 , O-SO 2 -R m , CO 2 R m , COR m and are selected from halo and dihalo, R m' is R m CO 2 R m COR m CHO, CO 2 selected from H and halo, R m is selected from substituted or unsubstituted C 1～12 alkyl, substituted or unsubstituted C 2～12 alkenyl, substituted or unsubstituted C 2～12 alkynyl, substituted or unsubstituted C 5～20 aryl, substituted or unsubstituted C 3～6 heteroaryl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and substituted or unsubstituted 5- to 7-membered heteroaryl, wherein when C 1～12 alkyl, C 2～12 alkenyl, C 2～12 alkynyl, C 5～20 aryl, C 5～20 heteroaryl, C 3～6 cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl or 5- to 7-membered heteroaryl is substituted, the C 1～12 alkyl, C 2～12 alkenyl, C 2～12 alkynyl, C 5～20 aryl, C 5～20 heteroaryl, C 3～6 cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl or 5- to 7-membered heteroaryl, each hydrogen atom in is independently selected from methoxy, C 1～12 alkyl, C 2～12 alkenyl, C 2～12 alkynyl, C 5～20 aryl, C 5～20 heteroaryl, C 3～6 cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl and 5- to 7-membered heteroaryl, and is substituted with any one or more selected from them, R 2 、R 3 、R 5 、R 2 ', R 3 ' and R 5 ' are each independently selected from H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m' , NO 2 , Me 3 , Sn and halo, R 4 and R 4 ' are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m' , NO 2 , Me 3 , Sn, halo, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy, substituted or unsubstituted C 2～6 alkenyl, substituted or unsubstituted C 2～6 alkynyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 5～12 aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, -CN, -NCO, -OR n , -OC(O)R n , -OC(O)NR n R n' , -OS(O)R n , -OS(O) 2 R n , -SR n , -S(O)R n , -S(O) 2 R n , -S(O)NR n R n' , -S(O) 2 NR n R n' , -OS(O)NR n R n' , -OS(O) 2 NR n R n' , -NR n R n' , -NR n C(O)R o , -NR n C(O)OR o , -NR n C(O)NR o R o' , -NR n S(O)R o , -NR n S(O) 2 R o 、 -NR n S(O)NR o R o' 、 -NR n S(O) 2 NR o R o' 、 -C(O)R n 、 -C(O)OR n and -C(O)NR n R n' selected from, where C 1～6 alkyl, C 1～6 alkoxy, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3 - to 7 - membered heterocycloalkyl, C 5～12 aryl and 5 - to 7 - membered heteroaryl are substituted, C 1～6 alkyl, C 1～6 alkoxy, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3 - to 7 - membered heterocycloalkyl, C 5～12 the hydrogen atoms in aryl and 5 - to 7 - membered heteroaryl are each independently C 1～6 alkyl, C 1～6 alkoxy, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3 - to 7 - membered heterocycloalkyl, C 5～12 aryl, 5 - to 7 - membered heteroaryl, -OR p 、 -OC(O)R p 、 -OC(O)NR p R p' 、 -OS(O)R p 、 -OS(O) 2 R p 、 -SR p 、 -S(O)R p 、 -S(O) 2 R p 、 -S(O)NR p R p' 、 -S(O) 2 NR p R p' 、 -OS(O)NR p R p' 、 -OS(O) 2 NR p R p' 、 -NR p R p' 、 -NR p C(O)R q 、 -NR p C(O)OR q 、 -NR p C(O)NR q H、 -NR p S(O)R q 、 -NR p S(O) 2 R q 、 -NR p S(O)NR q H、 -NR p S(O) 2 NR q H、 -C(O)R p 、 -C(O)OR p or -C(O)NR p R p may be substituted with R n 、R n' 、R o 、R o' 、R p 、R p' and R q are each independently selected from H, C 1～7 alkyl, C 2～7 alkenyl, C 2～7 alkynyl, C 3～13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 7-membered heteroaryl, X' is selected from -C(O)O-, -S(O)O-, -C(O)-, -C(O)NR-, -S(O) 2 NR-, -P(O)R'NR-, -S(O)NR- and -PO 2 NR- Xa' is a bonded or substituted or unsubstituted C 1～6 alkylene, where C 1～6 alkylene, when substituted, is substituted with C 1～8 alkyl or C 3～8 cycloalkyl, and R and R' are each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, substituted or unsubstituted C 1～8 alkyl, substituted or unsubstituted C 3～8 cycloalkyl, substituted or unsubstituted C 1～8 alkoxy, substituted or unsubstituted C 1～8 alkylthio, substituted or unsubstituted C 3～20 heteroaryl, substituted or unsubstituted C 5～20 aryl, or mono- or di-C 1～8 alkylamino, where C 1～8 alkyl, C 3～8 cycloalkyl, C 1～8 alkoxy, C 1～8 alkylthio, C 3～20 heteroaryl and C 5～20 aryl, when substituted, is substituted with a substituent selected from OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1～6 alkyl, C 1～6 alkoxy and C 6～12 aryl, and is substituted with a substituent selected from Y and Y' are each independently selected from O, S, and N(H), R 6 is a substituted or unsubstituted, saturated or unsaturated C 3～12 hydrocarbon chain, wherein the chain may be interrupted by one or more heteroatoms, NMe or a substituted or unsubstituted aromatic ring, and the chain or aromatic ring is at the position of any one or more hydrogen atoms on the chain or aromatic ring, -NH, -NR m , -NHC(O)R m , -NHC(O)CH 2 -[OCH 2 CH 2 n -R or -[CH 2 CH 2 O] n -R and may be substituted or unsubstituted (wherein R m and R are each as defined above for R m and R, and n is an integer from 1 to 12), and​ R 7 and R 7 ' are each independently H, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 2～6 alkenyl, substituted or unsubstituted C 2～6 alkynyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 6～10 aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, -OR r , -OC(O)R r , -OC(O)NR r R r' , -OS(O)R r , -OS(O) 2 R r , -SR r , -S(O)R r , -S(O) 2 R r , -S(O)NR r R r' , -S(O) 2 NR r R r' , -OS(O)NR r R r' , -OS(O) 2 NR r R r' , -NR r R r' , -NR r C(O)R s , -NR r C(O)OR s , -NR r C(O)NR s R s' , -NR r S(O)R s , -NR r S(O) 2 R s , -NR r S(O)NR s R s' , -NR r S(O) 2 NR s R s , -C(O)R r , -C(O)OR s or -C(O)NR r R r' wherein, C 1～6 alkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 7-membered heteroaryl are each independently substituted, C 1～6 alkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 the hydrogen atoms in aryl and 5- to 7-membered heteroaryl are each independently C 1～6 alkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl, 5- to 7-membered heteroaryl, -OR t , -OC(O)R t , -OC(O)NR t R t' , -OS(O)R t , -OS(O) 2 R t , -SR t , -S(O)R t , -S(O) 2 R t , -S(O)NR t R t' , -S(O) 2 NR t R t' , -OS(O)NR t R t' , -OS(O) 2 NR t R t' , -NR t R t' , -NR t C(O)R u , -NR t C(O)OR u , -NR t C(O)NR u R u' , -NR t S(O)R u 、 -NR t S(O) 2 R u 、 -NR t S(O)NR u R u' 、 -NR t S(O) 2 NR u R u' 、 -C(O)R t 、 -C(O)OR t or -C(O)NR t R t' and is substituted by R r 、R r' 、R s 、R s' 、R t 、R t' 、R u and R u' are each independently selected from H, C 1～7 alkyl, C 2～7 alkenyl, C 2～7 alkynyl, C 3～13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 5～10 aryl and 5- to 7-membered heteroaryl, G' represents a glucuronide group or a galactoside group, Z' is, independently of each other, H, C 1～8 alkyl, halo, NO 2 , CN, 【Chemical 2】 selected from R 9 、R 10 and R 16 are each independently selected from H, C 1～8 alkyl, C 2～6 alkenyl, C 1～6 alkoxy and methyloxyethyl, n is an integer from 1 to 3, W represents -C(O)-, -C(O)NR'', -C(O)O-, -S(O) 2 NR'', -P(O)R'''NR'', -S(O)NR'' or -PO 2 NR'' and R'' and R''' are each independently H, C 1～8 alkyl, C 3～8 cycloalkyl, C 1～8 alkoxy, C 1～8 alkylthio, mono- or di-C 1～8 alkylamino, C 3～20 heteroaryl or C 6～20 aryl] Claim 2 The compound according to claim 1, having a structure represented by the following formulas Ia and Ib, or a pharmaceutically acceptable salt thereof. [Chemical Formula 3] Claim 3 R 1 ' is C 3～6 The compound according to claim 2, wherein ' is cycloalkyl. Claim 4 R 1 The compound according to claim 2, wherein 'is phenyl which may be substituted or unsubstituted. Claim 5 R 1 The compound according to claim 2, wherein ' is a 5- to 7-membered heteroaryl. Claim 6 R 1 ' is C 1～12 The compound according to claim 2, wherein 'is alkyl. Claim 7 R 1 ' is C 1～12 The compound according to claim 2, wherein ' is alkenyl. Claim 8 R 1 The compound according to claim 2, wherein R is substituted or unsubstituted phenyl. Claim 9 R 1 The compound according to claim 2, wherein R is OH. Claim 10 R 1 is C 1～12 The compound according to claim 2, wherein is alkenyl. Claim 11 R 1 is C 1～12 alkyl, the compound according to claim 2. Claim 12 R 2 and R 2 ' are each H, the compound according to claim 2. Claim 13 R 3 and R 3 ' are each H, the compound according to claim 2. Claim 14 R 4 and R 4 ' are each H, the compound according to claim 2. Claim 15 R 5 and R 5 ' are each H, the compound according to claim 2. Claim 16 R 6 is an unsubstituted saturated C 3～12 hydrocarbon chain, the compound according to claim 2. Claim 17 R 7 and R 7 ' are each H, the compound according to claim 2. Claim 18 The compound according to claim 2, wherein X' is -C(O)O-. Claim 19 Xa' is unsubstituted C 1～6 The compound according to claim 2, wherein Xa' is alkylene. Claim 20 The compound according to claim 2, wherein G' is a glucuronide group. Claim 21 The compound according to claim 2, wherein G' is a galactoside group. Claim 22 Z' is 【Chemical Formula 4】 The compound according to claim 2. Claim 23 R 9 The compound according to claim 22, wherein R is H. Claim 24 R 16 The compound according to claim 22, wherein R is methyloxyethyl. Claim 25 The compound according to claim 22, wherein n is 1. Claim 26 R 1 ' is C 3～6 cycloalkyl, substituted or unsubstituted phenyl, 5- to 7-membered heteroaryl, C 1～12 alkyl, or C 1～12 alkenyl, and R 1 is a substituted or unsubstituted phenyl, OH, C 1～12 alkenyl, or C 1～12 alkyl, and R 2 、 R 2 ', R 3 、 R 3 ', R 4 、 R 4 ', R 5 、 R 5 ', R 7 、 R 7 ', and R 9 are each H, R 6 is an unsubstituted saturated C 3～12 hydrocarbon chain, and X' is -C(O)O-, Xa' is unsubstituted C 1～6 alkylene, and Z' is 【Chemical Formula 5】 and R 16 is methyloxyethyl, and n is 1, The compound according to claim 2.

27. 【Chemical Formula 6】 [Chemical] 【Chem.】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Claim 28 A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient. Claim 29 A pharmaceutical composition for treating cancer, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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